Electrolyte Abnormalities in Critically Ill Patients

Sodium
Standard serum sodium concentrations are 135–145 mEq/L. Sodium is the predominant
extracellular cation and helps regulate ECF volume and water distribution. Sodium
abnormalities are independent risk factors for in-hospital mortality in ICU patients. Both
hyponatremia and hypernatremia occur due to either an increase or decrease of water in
relation to serum sodium; thus, to adequately diagnose and treat sodium abnormalities,
volume status must be evaluated.

1-Hyponatremia
Hyponatremia (< 135 mEq/L) occurs in up to 30% of ICU patients and is associated with
increased mortality and length of stay. Mild to moderate signs and symptoms of
hyponatremia include nausea, confusion, headache, weakness, and gait instability. Severe
hyponatremia can manifest as seizures, respiratory failure, and coma. Signs and symptoms of
hyponatremia may be more pronounced with serum < 125 mEq/L or with acute
hyponatremia. Serum osmolality should be measured as osmotic pressure, and serum
osmolality regulate water distribution between fluid compartments. Water moves from areas
of lower osmolality to areas of higher osmolality until equilibrium occurs. Normal serum
osmolality is generally 280–295 mOsm/kg. Urine sodium may indicate whether renal sodium
losses are occurring.

Hyponatraemia symptoms: This depends upon severity and is dictated not only by the
absolute serum sodium level but also by the rate of fall.

1-Hyponatraemia is often asymptomatic if it is mild to moderate and also chronic (lasting

more than 48 hours).
2-Chronic mild hyponatraemia may be asymptomatic whilst a sudden fall to only 125
mmol/L from normal values can result in convulsions (usually from inappropriate
intravenous fluids).

3-The clinical picture can be confusing, because mild hyponatraemia can cause significant
symptoms if the drop in sodium level is sudden, whereas severe chronic hyponatraemia can
cause no symptoms, due to cerebral adaption .

However, the following symptoms may occur:

• Mild - anorexia, headache, nausea, vomiting, lethargy.

• Moderate - personality change, muscle cramps and weakness, confusion, ataxia.
• Severe - drowsiness.
Signs: These are again highly variable and depend on the level and rate of fall of the serum
sodium. They may include:

Neurological signs:
o Decreased level of consciousness.
o Cognitive impairment (eg, short-term memory loss, disorientation, confusion, depression).
o Focal or generalised seizures.
o Brainstem herniation - seen in severe acute hyponatraemia; signs include coma; fixed,
unilateral, dilated pupil; decorticate or decerebrate posturing; respiratory arrest.
Signs of hypovolaemia - dry mucous membranes, tachycardia, diminished skin turgor.
Signs of hypervolaemia - pulmonary rales, S3 gallop (third heart sound), jugular venous
distention, peripheral oedema, ascites.

Causes of hyponatraemia:

Dehydrated Euvolaemic Fluid Overloaded

GI losses and rehydration with free Increased ADH secretion (SIADH): Excess IV fluid
water: administration
• Pulmonary: pneumonia, Nephrotic syndrome
• Gastroenteritis bronchiolitis, mechanical Cirrhosis
ventilation Heart Failure
• Secretory/osmotic diarrhoea
 Skin losses (CF / burns) • CNS: infections, injury, tumour Acute/Chronic Renal Failure
Abdominal 3rd spacing Obstructive uropathy
• Post-operative, trauma, pain
Hyperglycaemia
Renal Losses: • Endocrine: Hypothyroid, low
cortisol
• Thiazide Diuretic Administration of enteral
• Cerebral salt wasting hypotonic fluids (including dilute
formula, Oral Rehydration
Primary renal tubular disorders Solutions, excessive water intake)
Hypoaldosteronism Psychogenic Polydipsia
Metabolic alkalosis Medications:

• Chemotherapy
(cyclophosphamide, vincristine,
platinum-based agents)
• Antiepileptics (valproate,
carbamazepine, oxcarbazepine)
• Vasopressin

Pathophysiology: Thirst stimulation, antidiuretic hormone (ADH) secretion, and

handling of filtered sodium by kidneys maintain serum sodium and osmolality.
Normal plasma osmolality is around 275 mOsm/kg to 290 mOsm/kg. To maintain normal
osmolality, water intake should be equal to water excretion. The imbalance of water intake
and excretion causes hyponatremia or hypernatremia. Water intake is regulated by the
thirst mechanism, where osmoreceptors in the hypothalamus trigger thirst when body
osmolality reaches 295 mOsm/kg.
Water excretion is tightly regulated by antidiuretic hormone (ADH), synthesized in the
hypothalamus, and stored in the posterior pituitary gland. Changes in tonicity lead to either
enhancement or suppression of ADH secretion. Increased ADH secretion causes
reabsorption of water in the kidney, and suppression causes the opposite effect.
Baroreceptors in the carotid sinus can also stimulate ADH secretion, but it is less sensitive
than the osmoreceptors. Baroreceptors trigger ADH secretion due to decreased effective
circulating volume, nausea, pain, stress, and drugs.
1-Hypertonic Hyponatremia (Serum osmolality of greater than 290 mOsm/kg)
• Hyperglycemia
• Mannitol
2-Isotonic Hyponatremia (Serum osmolality between 275 mOsm/kg and 290 mOsm/kg)
•Pseudo-hyponatremia is a laboratory artifact. It is usually caused by hypertriglyceridemia,
cholestasis (lipoprotein X), and hyperproteinemia (monoclonal gammopathy, intravenous
immunoglobulin [IVIG]). Two-thirds of clinical labs in use still use indirect ion-selective
electrode technology, and therefore this problem is still present.
•Nonconductive irrigant solutions: these solutions contain mannitol, glycine, or sorbitol
and are used in urological and gynecological procedures such as transurethral resection of
the prostate (TURP).
3-Hypotonic Hyponatremia (Serum osmolality of less than 275 mOsm/kg)
Hypotonic hyponatremia represents an excess of free water. This excess free water can be
caused by two mechanisms:
•Increased free water intake: The patient drinks a large volume of free water (greater than
18 L/day or greater than 750 mL/h) that overwhelms the kidney's capacity to excrete free
water. Examples of this are psychogenic polydipsia, marathon runners, water drinking
competitions, and ecstasy.
•Decreased free water excretion: Patients drink a normal volume of free water, but the
kidneys cannot excrete the water for some reason.
There are three mechanisms involved in the inability of kidneys to excrete water:
1. High ADH activity: Three different mechanisms can cause high ADH:
•Decreased effective arterial blood volume (EABV): antidiuretic hormone (ADH) is released
when there is a reduction of 15% or more of the EABV. This occurs with hypovolemia (e.g.,
vomiting, diarrhea), decreased cardiac output (e.g., heart failure), or vasodilation (e.g.,
cirrhosis).
•SIADH: ADH is secreted autonomously. Four general causes of this are brain disorders,
lung disorders, drugs (e.g., SSRI), and miscellanea (e.g., nausea and pain).
•Cortisol deficiency: Cortisol exerts an inhibitory effect on ADH release. When cortisol is
decreased, ADH is released in large amounts. Adrenal insufficiency is the cause of this
mechanism.
2. Low glomerular filtration rate (GFR): a low glomerular filtration rate would impair the
kidney's ability to get rid of water. Typical examples are acute kidney injury (AKI), chronic
kidney disease (CKD), and end-stage renal disease (ESRD).
3. Low solute intake: Patients on a regular diet consume 600 mOsm to 900 mOsm of solute
per day. Solutes are defined as substances that are freely filtered by the glomeruli but have
relative or absolute difficulty in being reabsorbed by the tubules in relationship to water.
The main solutes are urea (which comes from the metabolism of proteins) and electrolytes
(e.g., salt). Carbohydrates do not contribute to solute load. In steady-state conditions,
solute intake is equal to urine solute load. Therefore, it is expected that these patients also
excrete 600 mOsm to 900 mOsm of solute in the urine. Urine volume, and hence water
excretion, is dependent on the urine solute load. The more solute one needs to excrete, the
larger the urine volume one needs to produce. The less solute one needs to excrete, the
smaller the urine volume one needs to produce. Patients who eat a low amount of solute
per day (eg., 200 mOsm/day) on steady-state conditions will also excrete a low amount of
solute in the urine, and therefore they will do it in a smaller volume of urine. This decreased
urine volume will limit the capacity of the kidneys to excrete water. Typical examples of this
are beer potomania and the tea-and-toast diet.
Algorithm for the evaluation of hyponatremia

Hyponatremia can be further categorized by volume status. Hypertonic

hyponatremia occurs when an osmotically active substance besides sodium in the ECF pulls
fluid from the intracellular fluid (ICF) into the ECF, resulting in dilutional hyponatremia.
Diabetic ketoacidosis is a common cause and for every 100 mg/dL blood glucose > 100 mg/dL,
the serum sodium is 1.6–2.4 mEq/L higher than reported. The underlying cause should be
corrected, and no treatment is required. Isotonic hyponatremia is a laboratory artifact from
a now infrequently used assay, resulting from elevated concentrations of lipids or proteins in
the nonaqueous portion of plasma, causing serum sodium to appear low.

Investigations: 1-Clinical examination should be focused on fluid status, including blood

pressure (BP), postural deficit, heart rate, peripheral oedema and central venous filling, as
well as chest and heart examination.

2-Clinical assessment should identify potential causes, establish the severity of

hyponatraemia and determine if the patient is hypovolaemic, euvolaemic, or
hypervolaemic.

3-Serum sodium. Before embarking on other investigations for hyponatraemia, consider

whether the sample suffered from dilution by being taken near the site of an infusion, or
whether there is any chance of laboratory error. If necessary, repeat the test.
4-Serum potassium. If raised, consider Addison's disease.
 5-SIADH needs to be confirmed by results of paired serum and urine samples: serum hypo-
osmolality is <275 mOsm/kg, and urine osmolality >100 mOsm/kg and sodium ≥30 mmol/L,
in the absence of hypovolaemia, hypervolaemia, adrenal or thyroid dysfunction and use of
diuretics.
6-Urine sodium level. If this is >20 mmol/L, a renal cause should be sought.
7-Serum thyroid-stimulating hormone and free thyroxine level. These should be checked
to exclude hypothyroidism.
8-Random serum cortisol levels or adrenocorticotropic hormone (ACTH) stimulation test.
Either of these should be considered in patients with suspected adrenal suppression (eg,
patients who have recently taken oral steroids).
9-Imaging. This may be contributory in some clinical situations. For example, a CXR may be
required in suspected congestive cardiac failure, or a CT brain scan in patients with
confusion or altered consciousness.
Treatment of hyponatremia depends upon the degree of hyponatremia, duration of
hyponatremia, severity of symptoms, and volume status.

Acute Symptomatic Hyponatremia: 1-Severely symptomatic hyponatremia: Administer 3%

sodium chloride; 100 mL intravenous (IV) bolus (repeat up to twice if symptoms persist).

2-Mild to moderately symptomatic hyponatremia: 3% Sodium chloride, slow infusion (use

sodium deficit formula to calculate the rate of infusion but recalculate rate with frequent
sodium monitoring).
Chronic Asymptomatic Hyponatremia
1-Hypovolemic hyponatremia: Isotonic fluids administration and holding of any diuretics.
2-Hypervolemic hyponatremia: Treat underlying condition, restrict salt and fluids, and
administer loop diuretics.
3-Euvolemic hyponatremia: Fluid restriction to less than 1 liter per day.

Hypotonic hypovolemic hyponatremia is characterized by the loss of both total body

sodium and total body water (TBW), but the decrease in total body sodium is greater. Signs
and symptoms of hypovolemia occur, including hypotension and hemodynamic instability,
tachycardia, dry mucous membranes, and decreased skin turgor.

Hypotonic euvolemic hyponatremia involves normal salt handling in the setting of

increased TBW, with a small portion of excess water in the ECF. Physical symptoms of
hypovolemia or volume overload are not present. The syndrome of inappropriate antidiuretic
hormone secretion (SIADH) is a common cause of euvolemic hyponatremia, where
antidiuretic hormone (vasopressin) is secreted inappropriately, resulting in water retention
and dilutional hyponatremia.. In some cases, SIADH can be treated with vasopressin-2
receptor antagonists, such as conivaptan or tolvaptan, which cause water loss with no effect
on sodium excretion.
Treatment of Severe Symptomatic Hyponatremia

Hypotonic hypervolemic hyponatremia occurs when total body sodium is increased,

but TBW is increased to a larger degree, causing serum sodium to appear low. Physical signs
of volume overload (e.g., edema, pulmonary congestion) are present. Management involves
sodium and water restriction. IV fluids should be discontinued, enteral nutrition (EN) solutions
should be concentrated, and parenteral nutrition (PN) solutions should restrict both sodium
and fluid. Medications with higher sodium content (e.g., piperacillin-tazobactam, ampicillin-
sulbactam, nafcillin) should be evaluated, though alteration of regimens may not always be
possible. Loop diuretics and vasopressin antagonists may be required to treat refractory
cases.

Hypertonic saline should be reserved for patients with severe and/or symptomatic
hyponatremia. There are many dosing strategies and concentrations of hypertonic saline,
though few studies have specifically evaluated its use in ICU patients and some dosing
strategies are extrapolated from data in exercise-associated hyponatremia. In general,
sodium levels should not be corrected by more than 10–12 mEq/L/day in acute hyponatremia
or 6–8 mEq/L in chronic hyponatremia. Overcorrection can lead to rapid fluid shifts and
osmotic demyelination syndrome (ODS), which results in neurologic symptoms, including
seizures, quadriparesis, movement disorders, and “locked in” syndrome. If overcorrection
occurs, sodium replacement therapy should be discontinued. Although there is no robust
evidence, hypotonic fluids and desmopressin may be utilized in some instances to counteract
overcorrection. Historically it has been recommended to infuse hypertonic saline only
through central IV access devices due to concerns for extravasation and phlebitis. More
contemporary data indicate hypertonic saline may be safely infused via peripheral access
devices, which allows additional flexibility, particularly in emergent situations where rapid
administration of hypertonic saline is indicated.

Complications of hyponatraemia : If left untreated or inadequately treated,

patients with hyponatremia can develop rhabdomyolysis, altered mental status, seizures,
and even coma. Rapid correction of chronic hyponatremia (greater than 10 mEq/L to 12
mEq/L of sodium in 24 hrs) can lead to osmotic demyelination syndrome.

Osmotic demyelination syndrome, formerly known as central pontine myelinolysis, is a

complication of rapid correction of sodium in patients with chronic hyponatremia. In
patients with hyponatremia, the brain adapts to a fall in serum sodium level, without
developing cerebral edema, in about 48 hours. As a result, patients with chronic
hyponatremia are mostly asymptomatic. Once the brain adapts to low serum sodium, the
rapid correction of sodium leads to osmotic demyelination syndrome. Clinical
manifestations are typically delayed by a few days and comprise several irreversible
neurological symptoms, including seizures, disorientation, and even coma. "Locked-in"
syndrome occurs in severely affected patients. These patients are awake but unable to move
or can communicate with the help of their eyes only

2-Hypernatremia
Hypernatremia (> 145 mEq/L) is a hypertonic state that results from a decrease in TBW
relative to total body sodium. The presence of hypernatremia is an independent risk factor
for mortality in ICU patients. Mild to moderate symptoms are nonspecific and include
increased thirst, hypotension, and nausea/vomiting. Severe symptoms, including seizures and
coma, may not be present until serum sodium concentrations are significantly elevated
(> 160–180 mEq/L) and are associated with higher mortality.

Table 1. Subcategories of causes of hypernatraemia

Water Deficiency
Impaired Access to fluids
Impaired thirst mechanism
Immobility
Reduced level of consciousness
Reduced Intake Dysphagia
Pyrexia
Central DI
Increased Output Nephrogenic DI
Excessive Water Loss
Loop diuretics
Sensible Losses Urinary Osmotic diuresis
 Vomiting
Diarrhoea
Gastrointestinal Bleeding
Gastrointestinal Artificial feeding
Burns
Insensible Losses Desquamative Dermatological condition
Excess sodium administration
Salt tablets
Salt ingestion Increased dietary salt in setting of very low water intake
Administration of fluids Intravenous 0.9% Saline/Sodium Bicarbonate
Other iatrogenic causes Peritoneal dialysis prescriptions
Redistribution
Increased intracellular solute Seizures
Rhabdomyolysis

Table 2. Principal causes and the underlying mechanisms of drug-induced hypernatraemia

Mechanism Examples of Drugs
Renal Water Losses
Acquired Drug induced
nephrogenic hypokalaemia Diuretics, cisplatin, aminoglycosides, amphotericin, penicillin
Diabetes Drug induced
Insipidus hypercalcaemia Lithium, vitamin A or D excess
Other drugs Lithium, colchicine, vasopressin & vinblastine
Central Diabetes Insipidus Lithium, phenytoin & ethanol
Loop diuretics, osmotic diuresis, mannitol, nutritional supplements,
urea, medications that increase urea production e.g., high-protein
Others supplements, corticosteroids & urea products
Gastrointestinal Water Losses
Lactulose
Osmotic agents Sorbitol
Hypertonic Sodium Gain
Sodium Bicarbonate
Hypertonic infusions Sodium Chloride
Parenteral Feed
Hypertonic Dialysis
Iatrogenic hypertonic preparations Hypertonic Saline enemas
Procedural administration Hypertonic Saline Irrigation of hydatid cysts
Intrauterine injection of hypertonic saline
N-acetylcysteine
Hypernatremia can also be categorized by volume status.

Hypovolemic hypernatremia involves both water and sodium losses, but the loss of TBW is
greater. Signs and symptoms may include hypotension, tachycardia, and decreased skin
turgor. If hemodynamic instability is present, isotonic fluids should be used to increase blood
pressure. Once the hemodynamic status has normalized, IV or enteral hypotonic fluids should
be utilized to replace the water deficit. The water deficit can be calculated as

Water deficit (L) = TBW × [(serum Na/140) – 1]. The water deficit does not reflect ongoing
losses and requires reevaluation. No more than 50% of the water deficit should be corrected
in the first 24 h and the remaining 50% can be corrected over the next 24–48 h.

Water and sodium content can be increased in parenteral PN formulations (up to stability
limits) and less concentrated EN formulas should be utilized with increased water flushes if
possible. Euvolemic hypernatremia involves a loss of TBW with normal total sodium. Patients
will be clinically euvolemic though water loss is occurring from the ICF and the ECF. Treatment
is directed at the etiology of the hypernatremia and can include discontinuation of
medications that may cause diabetes insipidus (DI), desmopressin for treatment of central DI,
and water replacement. Other management includes hypotonic fluids to replace the
water deficit.

Hypervolemic hypernatremia occurs due to an increase in total body sodium with

normal TBW. Treatment involves discontinuing the offending agent and sodium removal.
Loop diuretics with hypotonic fluids may be required. Sodium should also be decreased or
removed from PN solutions. It is generally recommended to limit hypernatremia correction
to 8–10 mEq/day due to the risk of seizures and cerebral edema. This has been observed more
in pediatric patients and there is little data regarding correction rates in adult ICU patients.
Acute hypernatremia can be corrected at a rate of 2 mEq/L/hr until serum sodium reaches
145 mEq/L. Serum sodium should be measured at least twice daily in asymptomatic patients
and at least every 4 h in symptomatic patients.

Sodium Concentration of Intravenous Fluids

Treatment / Management: Proper management of hypernatremia involves identifying
the underlying condition and correcting the hypertonicity. The goal of therapy is to correct
both the serum sodium and the intravascular volume. Fluids should be administered orally
or via a feeding tube whenever possible. In patients with severe dehydration or shock, the
initial step is fluid resuscitation with isotonic fluids before free water correction.
Hypernatremia is corrected by calculating the free water deficit using one of the following
formulas.
• Total Body Water[0.6 in men and 0.5 in women x body weight(kg)] x [(plasma
sodium/140) -1]
• 4ml x bodyweight x (desired change in serum sodium meq/L)
It is important to remember that rapid correction of hypernatremia can lead to cerebral
edema because water moves from the serum into the brain cells. The goal is to decrease
serum sodium by not more than 12 meq in 24 hours. Close serial monitoring of serum
sodium every 2 to 4 hours is essential during the acute phase of correction. Seizures
occurring during the correction of hypernatremia are a sign of cerebral edema due to rapid
shifts in osmolality, and the administration of hypotonic fluids should be halted. The
estimated free water deficit should be corrected over 48 to 72 hours with a decrease in
serum sodium not exceeding 0.5 meq per hour. Patients should be carefully monitored for
the rate of correction, urine output, and ongoing losses. In cases of sodium intoxication, the
free water requirement may be too large and cause volume overload, requiring the use of
loop diuretics and, at times, peritoneal dialysis to remove excess sodium. There are no
published reports of seizures or cerebral edema complicating rapid correction of
hypernatremia in adults. Older children and adults with central DI may need desmopressin,
which is available in intranasal and oral forms. Water intoxication and hyponatremia are
adverse effects seen with the use of desmopressin.

Isotonic saline is unsuitable for correcting hypernatremia. The sole indication for
administering isotonic saline to a patient with hypernatremia is a depletion of extracellular-
fluid volume that is sufficient to cause substantial hemodynamic compromise. Even in this
case, after a limited amount of isotonic saline has been administered to stabilize the
 patient's circulatory status, a hypotonic fluid (i.e., 0.2 percent or 0.45 percent sodium
chloride) should be substituted in order to restore normal hemodynamic values while
correcting the hypernatremia. If a hypotonic fluid is not substituted for isotonic saline, the
extracellular-fluid volume may become seriously overloaded.

Extreme care must be taken to avoid excessively rapid correction or overcorrection of

hypernatremia, which increases the risk of iatrogenic cerebral edema, with possibly
catastrophic consequences.

Potassium
Potassium is the most abundant cation in the human body, with total body potassium stores
of 50–75 mEq/kg body weight. A primarily intracellular electrolyte, 98% of total potassium
stores are located in the cells which generate a concentration gradient critical to cellular
excitability and function. To maintain this gradient, serum potassium levels are carefully
regulated between 3.5 and 5 mEq/L. Although serum levels may not necessarily correlate with
total body stores, small changes in levels can drastically alter the cellular gradient and lead to
dangerous deficiencies in cellular function . Approximately 90% of potassium excretion occurs
via the kidney and the remaining 10% via theGI tract. Other than renal function, factors that
play a critical role in regulating potassium distribution include catecholamines, insulin,
aldosterone, and acid–base balance.

1- Hypokalemia
Hypokalemia is defined as a serum potassium level less than 3.5 mEq/L, with severe
hypokalemia typically defined as a level less than 2.5 mEq/L. Mild hypokalemia is often
asymptomatic. Moderate or severe hypokalemia can cause muscle weakness and fatigue
that can lead to muscle paralysis, slowed GI transit and ileus, metabolic acidosis, and polyuria.
Life-threatening complications of severe hypokalemia include cardiac arrhythmias such
as TdP and ventricular fibrillation. Patients with ischemic heart disease or heart failure, or on
digoxin therapy, are at an increased risk of arrhythmias from hypokalemia.

Based on serum potassium, hypokalemia can be classified into:

1-Mild Hypokalemia: - Serum Potassium 3-3.4 mEq/L (mmol/L)

2-Moderate Hypokalemia: - Serum Potassium 2.5-2.9 mEq/L (mmol/L)

3-Severe Hypokalemia: - Serum Potassium <2.5 mEq/L (mmol/L)

Clinical features usually occur when serum potassium<2.5 mEq/L (mmol/L) and includes
muscle pain, cramps, weakness, fatigue, constipation, syncope and palpitations

In critically ill patients, hypokalemia may be caused by excess renal or extrarenal losses or
transcellular shifting of potassium. Measurement of urine potassium levels and the urine
potassium-to-creatinine ratio may help to differentiate between renal and non-renal causes
of hypokalemia. The optimal dosing and rate of potassium replacement depend on several
factors, including kidney function, body weight, IV access, and the presence of symptoms,
especially EKG changes. As previously discussed, low intracellular magnesium levels can result
in hypokalemia that is refractory to treatment; therefore, hypomagnesemia must be
corrected to prevent further potassium wasting. Intravenous potassium is generally provided
as potassium chloride and must be diluted prior to infusion. Solutions containing
10 mEq/100 mL may be administered via a peripheral line, while solutions with
20 mEq/100 mL should be given via a central line.

Oral potassium is available in tablet, capsule, and liquid formulations and is generally
preferred over intravenous administration due to its high bioavailability and the potent
vesicant potential of intravenous potassium. Although oral potassium is associated with GI
effects, including nausea, vomiting, diarrhea, abdominal discomfort, and small bowel
ulcerations, most patients can tolerate enteral replacement at doses of 40 mEq or less. In
patients with feeding tubes, liquid formulations or powder packets can be utilized but should
be diluted to prevent osmotic diarrhea . Occasionally, potassium sparing diuretics can be
used to prevent or treat hypokalemia in patients with volume overload and normal renal
function that have an indication for these agents.

Symptoms and signs of hypokalemia.

Mild to moderate hypokalemia Asymptomatic or with mild symptomatology, especially in elderly
Severe hypokalemia people or in people suffering from heart or kidney disease
Renal system
• Metabolic acidosis
• Rhabdomyolysis
• Hypokalemic kidney disease (tubular interstitial nephritis,
nephrogenic diabetes insipidus)
Nervous system
• Leg cramps
• Weakness and paresis
• Ascending paralysis
Gastrointestinal system
• Constipation or intestinal paralysis
Respiratory system
• Respiratory failure
Cardiovascular system
• ECG changes (U waves, T wave flattening, ST-segment changes)
• Cardiac arrhythmias
• Heart failure
Causes of hypokalemia.
Gastrointestinal • Chronic diarrhea, including chronic laxative abuse and bowel diversion
tract losses • Clay (bentonite) ingestion, which binds potassium and greatly decreases
absorption
• Villous adenoma of the colon, which causes massive potassium secretion
(rarely)
Intracellular shift • Glycogenesis during total parenteral nutrition or enteral hyperalimentation
(stimulating insulin release)
• Insulin administration
• Stimulation of the sympathetic nervous system, particularly with beta 2-
agonists (albuterol, terbutaline)
• Thyrotoxicosis (occasionally) due to excessive beta-sympathetic stimulation
(hypokalemic thyrotoxic periodic paralysis)
• Familial periodic paralysis
Renal potassium • Adrenal steroid excess (Cushing’s syndrome)
losses • Primary hyperaldosteronism
• Rare renin-secreting tumors
• Glucocorticoid-remediable congenital adrenal hyperplasia.
• Ingestion of substances such as glycyrrhizin
• Bartter syndromeGitelman syndrome Liddle syndrome
• Renal tubular acidosis Fanconi syndrome
• Hypomagnesemia
Drugs • Thiazides
• Loop diuretics
• Osmotic diuretics
• Laxatives
• Amphotericin B
• Antipseudomonal penicillins (carbenicillin)
• Penicillin in high doses
• Theophylline (both acute and chronic intoxication)

Hypokalemic Periodic Paralysis (hypoPP)

1-Hypokalemic periodic paralysis (hypoPP) is a rare channelopathy caused by skeletal

muscle ion channel mutations, mainly affecting calcium or sodium channels. Patients with hypoPP
experience a sudden onset of generalized or focal flaccid paralysis associated with low blood
potassium levels (or hypokalemia), which can last for several hours before resolving spontaneously.
Most cases of hypoPP are hereditary or familial. The evaluation for hypoPP includes excluding
secondary causes such as hyperthyroidism through thyroid function tests and monitoring for
electrocardiogram abnormalities such as prolonged QT interval. The most common familial form,
type 1 hypoPP, is characterized by a mutation in the dihydropyridine-sensitive skeletal muscle
calcium channel gene, CACNA1S. On the other hand, the type 2 familial form of hypoPP is associated
with mutations in the voltage-sensitive skeletal muscle sodium channel gene, SCN4A. In addition,
disease-causing mutations in the genes KCNJ2 and KCNJ18, which code for the inward rectifier
potassium (Kir) channel, have also been identified as contributors to hypoPP
2-Although the genetic abnormality remains throughout the life span of an affected individual, the
mean age of presentation of attacks is the first or second decade of life, commonly during late
childhood or teenage years. The frequency of these attacks tends to decrease as individuals age.
However, in cases of thyrotoxic hypoPP, onset usually occurs after the age of 20. HypoPP is
characterized by sporadic attacks rather than regular occurrences, with episodes occurring
suddenly and episodically. The most consistent triggers are rest following strenuous exercise and
consumption of carbohydrate-rich diets.
3-These triggering factors lead to an increase in plasma epinephrine or insulin levels, causing an
intracellular shift of potassium and subsequently lowering serum potassium levels, thus initiating
episodes of weakness. Other identified but less consistent triggers include excitement, stress, fear,
cold temperatures, high salt intake, glucocorticoid use, alcohol consumption, or undergoing
anesthesia procedures. Patients typically experience sudden and severe attacks of generalized
muscle weakness, with more pronounced involvement of proximal muscles than distal muscles and
a significant decrease in serum potassium levels (below 2.5 mmol/L). Usually, patients go to bed in
a normal state of health and wake up in the middle of the night or the morning, experiencing an
attack of muscle weakness.
4-Many patients also report experiencing prodromal symptoms such as fatigue, paresthesias, and
behavioral changes a day before a muscle weakness attack. However, when attacks are incomplete,
they typically affect the lower limbs more than the upper limbs. Bulbar, ocular, and respiratory
muscles are usually unaffected, although respiratory muscle involvement can be life-threatening in
severe cases. The pattern of muscle weakness is similar in both familial and thyrotoxic hypoPP, and
signs of hyperthyroidism are often evident in most cases of thyrotoxic hypoPP, although they may
not always be present. Muscle weakness attacks occur during periods of hyperthyroidism and never
during normal thyroid function. The frequency of attacks varies widely, with some patients
experiencing attacks only once in their lifetime, while others may have them several times a
week. Women tend to have fewer attacks than men. The duration of each attack varies as well,
ranging from minutes to days, with some attacks lasting several hours before resolving
spontaneously.

5-During a muscle weakness attack, neurological examination typically reveals generalized

muscle weakness, with proximal muscles more affected than distal ones. In incomplete attacks, the
legs are often more involved than the arms. Hyporeflexia or areflexia is a common finding.
Neurological examination findings are typically normal between attacks. Myotonia is uncommon in
hypoPP, unlike hyperkalemic periodic paralysis, where myotonia is a common feature. Some
individuals with hypoPP may experience a milder form of muscle weakness between attacks that
fluctuates and improves with mild exercise.[
6-The primary goals of treating hypoPP are to alleviate acute attack symptoms, prevent and
manage immediate complications, and prevent both late complications and future attacks.

7-Acute Treatment : The primary goal is to normalize serum potassium levels by administering
oral potassium chloride, which is more readily absorbed than other oral potassium solutions and
helps alleviate muscle weakness symptoms. Treatment typically begins with incremental doses of
oral potassium chloride, starting at 0.5 to 1 mEq/kg (equivalent to 60-120 mEq for a 60 kg
individual). If there is no response to the initial dose, a repeat dose of 30% (0.3 mEq/kg) can be
administered every 30 minutes. Some clinicians suggest administration at a slower rate (10 mEq/h)
to minimize rebound hyperkalemia.
If a patient requires more than 100 mEq of oral potassium, close monitoring of serum potassium
levels is essential, and the total oral potassium dose should not exceed 200 mEq within 24 hours of
initiating treatment. The initial dose of oral potassium may vary based on the severity of
hypokalemia. Patients should be monitored with ECG, and muscle strength should be assessed
regularly. Serum potassium levels should be monitored for 24 hours after treatment, as the post-
treatment rise in serum potassium levels can have adverse effects on patients.
Intravenous (IV) potassium is not typically the first choice of treatment and is reserved for specific
situations such as arrhythmias due to hypokalemia, swallowing difficulties, or respiratory muscle
paralysis. When IV potassium is necessary, it is preferably administered with mannitol rather than
dextrose or saline. This preference is due to the potential of carbohydrates and salt to trigger
muscle paralysis, which may exacerbate weakness. IV potassium therapy necessitates inpatient
care with continuous ECG monitoring. A common protocol involves infusing 40 mEq/L of IV
potassium in a 5% mannitol solution at a rate not exceeding 20 mEq/h, with a total dosage not
exceeding 200 mEq in 24 hours.
Individuals experiencing milder attacks can also benefit from low-level exercises. These exercises
can help improve muscle function and reduce the severity of symptoms during attacks.
7-Preventive Treatment : Both pharmacological and nonpharmacological interventions can be used
to prevent recurrent future attacks. Nonpharmacological interventions include educating patients
about trigger factors and implementing lifestyle modifications to avoid these triggers, as discussed
later. Pharmacological interventions include medications such as chronic potassium
supplementation, carbonic anhydrase inhibitors, and potassium-sparing diuretics when lifestyle
modifications alone are insufficient in reducing attack rates. The preferred approach involves
combining one diuretic with chronic potassium supplementation, with the initial choice of diuretic
being the carbonic anhydrase inhibitor acetazolamide.
Carbonic anhydrase inhibitors have shown efficacy in decreasing future attacks of muscle weakness
in hypoPP, although the exact mechanism in hypoPP remains unclear. These inhibitors work by
promoting urinary potassium loss and inducing non-anion gap metabolic acidosis, thereby reducing
the patient's susceptibility to muscle paralysis. Additionally, carbonic anhydrase inhibitors may
enhance the opening of calcium-activated potassium channels. They also help reduce intracellular
sodium accumulation, mitigating cellular toxicity and preventing muscle degeneration, which can
effectively treat permanent weakness. A dosage of 250 mg of acetazolamide taken twice daily has
been found to effectively reduce the frequency of attacks in hypoPP patients.
The genetic variation in response to acetazolamide treatment among hypoPP patients. Patients
with SCN4A mutations tend to show a weaker response compared to those with CACNA1S
mutations. A study involving 74 identified cases of hypoPP revealed that 56% (31 out of 55) of
patients with CACNA1S mutations responded positively to acetazolamide therapy, while only 16%
(3 out of 19) of patients with SCN4A mutations showed a response. In fact, some patients with
SCN4A mutations reported worsened symptoms with acetazolamide therapy. Despite this
variability, approximately half of hypoPP patients benefit from acetazolamide treatment.
The U.S. Food and Drug Administration (FDA) recently approved dichlorphenamide for the
treatment of hypoPP. A dosage of 50 mg twice daily has been shown to be more effective than a
placebo in reducing the frequency, severity, and duration of future attacks. Dichlorphenamide is
considered the first-line treatment or an alternative for patients who do not adequately respond to
or are refractory to acetazolamide.
Some patients have also experienced benefits from the addition of a potassium-sparing diuretic
such as spironolactone (100 mg daily) or triamterene (150 mg daily) either in combination with
carbonic anhydrase inhibitors or as monotherapy. Regular electrolyte monitoring is essential for
patients on diuretic therapy. Although there is no definitive therapy established for late-onset
myopathy associated with hypoPP, reducing the frequency of muscle weakness attacks can help
mitigate the resulting myopathy. The results of a study also reported the improvement in severity
and frequency of attacks with topiramate therapy in 11-year-old twins with hypoPP, necessitating
further study regarding the efficacy of topiramate in hypoPP.

EKG changes associated

with hypokalemia are:

1-Decreased T wave
amplitude

2-ST-segment depression

3-Presence of U wave (giant

U waves may be mistaken for
peaked T waves)

4-Other findings include QT

prolongation, ventricular
extrasystoles, ventricular
arrythmias.

Treatment
1-Goals of treatment are to reduce
further potassium loss, replenish
potassium stores, evaluate potential
toxicities and treatment of the
underlying cause.

2-Due to the intracellular nature of

potassium deficit means that
intravascular potassium must be
administered slowly, and time is
required for potassium to enter the
cells. Rapid administration may cause
serum levels to be elevated even
though there is a total body deficit
leading to serum hyperkalemia.

3-When treating hypokalemia, the goal

potassium is >3.5 mEq/L (mmol/L).
Traditionally, potassium goal >4
(mmol/L) was used to reduce the risk of
arrythmias however larger studies have
shown that the safest potassium level in
myocardial ischemia is 3.5-4.5 (mmol/L) with evidence of higher/lower levels correlate with
worse outcomes. In the specific case of DKA, with the absence of renal dysfunction, target
potassium is >5.3 mEq/L (mmol/L).

4-Enteral potassium repletion is preferred compared to IV route. Enteral potassium is

cheaper, safer and does not irritate veins.

5-Potassium chloride is the most commonly used formulation and are especially useful with
metabolic alkalosis (increases serum chloride). Slow release formulations are suboptimal if
immediate effect is desired however better tolerated. Another formulation is potassium
citrate which may be useful in non-anion gap metabolic acidosis (the citrate will be converted
into bicarbonate, thereby improving the acidosis).

6-IV potassium can be used when there is lack of gut access/function, severe hypokalemia in
need of emergent treatment or profound shock with severe hypokalemia. The rate of
administration is 10 mEq/hour through a peripheral line or 20 mEq/hour through a central
line. When IV repletion is >20 mEq/hour then continuous cardiac monitoring is suggested.

7-Magnesium should be repleted as well because failure to treat this will make it difficult to
fix hypokalemia. In patients with ongoing gastric losses, initiation of proton pump inhibitor
may minimize electrolyte derangements.

Treatment of hypokalemia.
Hypokalemia Treatment Comments
Mild (3.0– Potassium tablets • Usually asymptomatic
3.4 mEq/L) (72 mmol/day) or i.v. • Monitor potassium levels daily and adjust
potassium infusion 25 mL treatment accordingly
(75 mmol/day) • Consider i.v. potassium if patient cannot
tolerate oral potassium
Moderate (2.5– Potassium tablets • No or minor symptoms
2.9 mEq/L) (96 mmol/day) or i.v. • Monitor potassium levels daily and adjust
potassium infusion 25 mL treatment accordingly
(100 mmol/day) • Consider i.v. potassium if patient cannot
tolerate oral potassium
Severe (<2.5 mEq/L Intravenous replacement • Standard infusion rate: 10 mmol/h
or symptomatic) 40 mmol KCl in 1 L 0.9% • Maximum infusion rate: 20 mmol/h
NaCl (glucose 5% may be • Check magnesium levels (reported automatically
used) if K < 2.8 mEq/L)
• If patient hypomagnesemic: initially give 4 mL
MgSO4 50% (8 mmol) diluted in 10 mL of NaCl
0.9% over 20 min, then start first 40 mmol KCl
infusion, followed by magnesium replacement

2- Hyperkalemia
Hyperkalemia is defined as a serum potassium level greater than 5 mEq/L, although patient-
specific factors such as cardiac morphology, physiologic adaptation, acute illness, and
medications affect the threshold at which toxicity will manifest. Rapid increases in serum
potassium lower cardiac resting membrane potential that may be accompanied by sequential
EKG changes: peaked T-waves, prolonged PR interval, flattened or absent P-waves, QRS
prolongation, sinus wave pattern, ventricular fibrillation, asystole, and pulseless electrical
activity. In a prospective study, only 46% of patients with serum potassium levels greater than
6 mEq/L had corresponding EKG changes. Physical symptoms (e.g., paresthesia, weakness,
depressed tendon reflexes, and flaccid paralysis) are often overshadowed by the clinical
illness causing hyperkalemia and may not be apparent in sedated or obtunded patients.

The most common cause of hyperkalemia is pseudohyperkalemia, which is not reflective of

the true serum potassium levels. Pseudohyperkalemia is most commonly due to hemolysis of
the sample, causing intracellular potassium to be measured in the serum. Hemolysis is more
common when a syringe is used than a vacuum device. Using tourniquets and excessive fist-
pumping during the blood draw also increase the risk. Specimens drawn from patients with
leukocytosis or thrombocytosis are also frequently associated with falsely elevated potassium
concentrations.

Causea and pathogenesis of hyperkalemia:

1-Increased Potassium Intake: Increased potassium intake from food is a very uncommon
cause of hyperkalemia in adult patients with normal renal function but can be an important
cause in those with kidney disease. Foods with high potassium content include dried fruits,
seaweed, nuts, molasses, avocados, and Lima beans. Many vegetables that are also high in
potassium include spinach, potatoes, tomatoes, broccoli, beets, carrots, and squash. High-
potassium-containing fruits include kiwis, mangoes, oranges, bananas, and cantaloupe. Red
meats are also rich in potassium. While generally safe to consume even in large quantities by
patients with normal potassium homeostasis, these foods should be avoided in patients with
severe renal disease or other underlying conditions or medications predisposing them to
hyperkalemia. Intravenous intake through high potassium-containing fluids, particularly total
parenteral nutrition, medications with high potassium content, and massive blood
transfusions can significantly elevate serum potassium levels.
2-Intracellular Potassium Shifts: Cellular injury can release large quantities of intracellular
potassium into the extracellular space. This can be due to rhabdomyolysis from a crush injury,
excessive exercise, or other hemolytic processes. Metabolic acidosis may cause intracellular
potassium to shift into the extracellular space without red cell injury. Metabolic acidosis is
most frequently caused by decreased, effective circulating arterial blood volume. Sepsis or
dehydration may lead to hypotension and decreased tissue perfusion leading to metabolic
acidosis with subsequent potassium elevation.
Insulin deficiency and diabetic ketoacidosis may cause dramatic extracellular shifts causing
measured serum potassium to be elevated in the setting of whole-body potassium depletion.
Certain medications, such as succinylcholine, may cause severe, acute potassium elevations
in patients with up-regulation of receptors, particularly in subacute neuromuscular disease.
Tumor lysis syndrome, particularly in patients receiving chemotherapy for hematogenous
malignancy, may cause acute hyperkalemia due to massive cancer cell death. Hyperkalemic
periodic paralysis is a rare, autosomal dominant condition that causes potassium to shift into
the extracellular space due to impaired sodium channel function in skeletal muscle.
3-Impaired Potassium Excretion: Acute or chronic kidney disease is a common cause of
hyperkalemia. Hyperkalemia is usually not seen until the glomerular filtration rate falls below
30 ml/min. This is commonly due to primary renal dysfunction but may be due to acute
volume depletion from dehydration or bleeding or decreased circulating blood volume due
to congestive heart failure or cirrhosis. Tubular dysfunction due to aldosterone deficiency or
insensitivity can also cause hyperkalemia.
4- Drugs inducing hyperkalemia
Drugs inducing hyperkalemia
Drug Mechanisms
Amiloride Blocking sodium channels of luminal membrane of principal
cells
Spironolactone Mineralocorticoid receptor antagonist (competing with
aldosterone)
Inhibition of adrenal aldosterone biosynthesis
Cyclosporine, Tacrolimus Inhibition of adrenal aldosterone biosynthesis
Induction of chloride channel shunt
Increasing potassium efflux from cells
Trimetoprim, Pentamidine Blocking of sodium channels in the luminal membrane of
principal cells
NSAIDs Induction of hyporeninemic hypoaldosteronism through
inhibiting renal prostaglandin synthesis
ACE inhibitors, Angiotensin-II Reduction in adrenal aldosterone biosynthesis through
receptor antagonists interrupting renin-aldosterone axis
Reduction in effective glomerular filtration rate
Beta blockers Inhibiting renin secretion
Decrease in cellular potassium uptake
Calcium channels blockers Inhibition of adrenal aldosterone biosynthesis
(Nifedipine, Amlodipine)
Reduction in aldosterone secretion
Succinylcholine Leakage of potassium out of cells through depolarization of
cell membranes
Digoxin Inhibition of Na+/K+-ATPase
Heparin Inhibition of adrenal aldosterone biosynthesis
Decreasing number and affinity of angiotensin-II receptors
Mannitol “Solvent drag phenomena” whereby potassium shifts out of cells
due to the body’s attempt to maintain isotonicity while undergoing a
hypertonic infusion
Clinical presentation: 1-Hyperkalemia can manifest with neuromuscular weakness,
bradycardia and ventricular tachycardia/fibrillation. In practice however, most patients are
asymptomatic. As the myocardium is highly sensitive to any changes in potassium ion
concentration, the imbalance of the potassium concentration gradient in hyperkalemia can
cause a progression of EKG changes such as increased T wave amplitude (peaked T waves),
prolongation of the PR interval and QRS duration, loss of P waves, AV conduction delay,
culminating in the merging of the QRS complex with the T wave producing a sine wave
pattern, and asystole. Clinically, patients can present with palpatations, syncope, and sudden
cardiac death. Furthermore, hyperkalemia causes sustained spontaneous depolarization of
skeletal muscles that leads to inactivation of sodium channels of the muscle membrane. These
changes can produce the symptoms of muscle weakness and in extreme cases, paralysis

2-Hyperkalemia is usually caused by increased potassium intake, decreased renal excretion

and transcellular shift in potassium. The various pathologies that could lead to hyperkalemia
can be divided based on underlying mechanism of cause:

3-Pseudo-hyperkalemia refers to artificially elevated potassium which is seen in hemolysis,

severe polycythemia and prolonged tourniquet application.

Hyperkalemic Periodic Paralysis

1-Periodic paralysis is a group of inherited diseases that present as episodic muscle weakness and
paralysis. Hyperkalemic periodic paralysis (HYPP, HyperKPP) is a rare condition that begins in
childhood and can continue until middle adulthood or may even last into late adulthood. It presents
as muscle weakness, ranging from mild weakness to paralysis. During these episodes, it is common
to have higher than normal blood levels of potassium.
2-The condition is caused by a mutation in the SCN4A gene that codes for voltage-gated sodium
channel Na1.4. Several diagnostic modalities exist in assisting diagnosis, such as genetic testing,
although they are not always definitive. Treatment for HYPP is both proactive and reactive, with
avoidance of triggers being the mainstay of therapy. It is important to diagnose this condition
quickly and accurately as long-term complications, including weakness and fatigue, can lead to a
decrease in the quality of life.
Hyperkalemic periodic paralysis is caused by a point mutation in the SCN4A gene. This gene enco
This gene encodes proteins responsible for sodium transport in skeletal muscles
Patients typically present in the first or second decade of life with intermittent bouts of weakness
or paralysis in the hips, shoulders, and back triggered by diet, stress, or exercise. Attacks are
generally intermittent and last 15 minutes to 1 hour. Affected individuals may also present with
paramyotonia (muscle stiffness or inability to relax muscles). Approximately 50% of affected
individuals will present with weakness or paralysis before age 10. The attacks initially are
uncommon; however, they increase in intensity and frequency until the fifth decade of life, at which
point there is a steep decline. Common triggers are potassium-rich foods, a cold environment, and
rest after physical activity. Attacks may last from 15 minutes to 1 hour. Individuals over 40 years of
age commonly report permanent muscle weakness, with a third of individuals developing chronic
progressive myopathy.
The Different Categories of Periodic Paralyses (PP) with Membrane Excitability Disorder and
Associated Findings
TPP ATS
Thyrotoxic Andersen-
HypoPP NormoPP HyperPP
Periodic Tawil
paralysis syndrome

Episodic,
Weakness periodic
Weakness Weakness
episodes Identical to paralysis,
episodes episodes
lasting mins to that of the ventricular
Main clinical lasting hrs to lasting hrs to
hrs paralytic arrhythmias,
features days days
w/concomitant episodes of prolonged
w/concomitant w/concomitant
normo- or hypoPP QT interval,
hypokalemia normokalemia
hyperkalemia characteristic
anomalies 2

Late in 1st
Variable, decade or in
Late in 1st Late in 1st
Age at first dependent on 2nd decade
decade or in decade or in 1st years of life
attacks onset of (usually after
2nd decade 2nd decade
thyrotoxicosis cardial
events)

Cold, rest after

exercise,
Rest after Rest after stress, fatigue,
exercise, exercise, alcohol, Prolonged
carbohydrate carbohydrate hunger, rest, rest
Main triggers Thyrotoxicosis
rich meal, salt rich meal, salt changes in after
intake, stress, intake, stress, activity level, exertion
cold cold potassium in
food, specific
foods

EMG:
myotonic No Some Some No No
discharges
 Variable
(CMAP
Late Late
Initial CMAP increase +
decrement decrement
EMG tests Pattern IV, V increase + decline,
w/LET w/LET
decline normal
(Pattern IV, V) (Pattern IV, V)
CMAP +
decline etc)

Possible
Cardiac
Extramuscular manifestations
None None None arrhythmia;
expression of
Dysmorphy
thyrotoxicosis

Prevention of Normal
paralysis ACZ, DCP ACZ, DCP ACZ, DCP thyroid ACZ, DCP
attacks function

Treatment of
Curative
None None None thyroid None
treatment
disorder

Known causal
or CACNA1S;
SCN4A SCN4A KCNJ18 KCNJ2
susceptibility SCN4A
gene(s)

Cav 1.1;
Defective ion
Nav 1.4; Nav 1.4 Nav 1.4 Kir 6.2 Kir 2.1
channel(s)
Kir 6.2
ACZ = acetazolamide; CMAP = compound muscle action potential; DCP = dichlorphenamide; LET = long exercise test; SET = short
exercise test

Clinical presentation of PPPs

Feature HypoPP HyperPP Andersen-Tawil syndrome
Ictal K + level Low High/normal Variable
Age at onset Age 5–35 y Before age 20 y Age 2–18 y
Mean duration of >2 h <2 h 1 to 36 h
episodes
Muscle stiffness Absent Moderate Absent
Episodic weakness Yes Yes Yes
Maximum weakness Severe Mild to severe Moderate
Characteristic facies Absent Absent Present
Arrhythmias Absent Absent Long QT arrhythmia
Diagnosis is initially guided by the clinical presentation of the affected individual. This
includes intermittent paralysis and/or paramyotonia after certain triggers. Diagnosis is based
primarily on several criteria, which include a history of transient episodes of weakness, ictal serum
potassium levels, electromyography, and exclusion of secondary causes. The proposed diagnostic
criteria are as follows: 2 or more attacks of weakness with serum potassium greater than 4.5
mEq/L or 1 attack in the patient with a relative with 1 attack with serum potassium greater than 4.5
mEq/L.
In addition, 3 of the 6 following clinical or laboratory features can also assist in making a diagnosis:
symptom onset before age 30; attacks must last less than 2 hours; identifiable triggers, myotonia;
family history; confirmed genetic testing for sodium channel mutation in the SCN4A, or positive
McManis short exercise test. Additionally, other causes must be excluded.

Treatment / Management: The treatment approach should include both the management
of acute attacks and the prevention of attacks. Treatments include behavioral interventions
directed at avoiding triggers and modifying potassium levels through diet, diuretics, and carbonic
anhydrase inhibitors. Attacks may be treated at the onset of weakness with mild physical activity,
oral intake of carbohydrate-rich foods, salbutamol inhalation, or intravenous calcium gluconate.
Individuals may prevent attacks by consuming frequent carbohydrate-rich meals, a thiazide
diuretic, or a carbonic anhydrase inhibitor. Individuals should avoid potassium-rich medications and
foods, fasting, strenuous work, and exposure to cold to prevent attacks. Surveillance methods
include scheduled evaluation of neurologic status. Individuals who develop permanent muscle
weakness may require lifelong thiazide diuretics and interval MRI of the proximal leg muscle every
1 to 3 years.
Prophylactic treatment necessitates serum potassium levels twice yearly to avoid diuretic
complications and annual evaluation of thyroid function. It is imperative to avoid factors that may
precipitate an episode. These include ingesting potassium-rich food or medications, prolonged
fasting, intense physical activity, a cold environment, and depolarizing anesthetic agents that may
be used during general anesthesia.
:

Hyperkalemia ECG
Hyperkalemia can cause life-threatening arrhythmia, and thus recognizing related patterns on the
ECG is crucial.
The ECG findings of hyperkalemia change as the potassium level increases, from slightly high
levels to very high levels. The ECG findings include:
1-Peaked T waves best seen in the precordial leads, shortened QT interval and, at times, ST
segment depression

2-Widening of the QRS complex (usually potassium level ≥ 6.5 mEq/L). This frequently appears
as “non-specific intraventricular conduction delay,” characterized by a widened QRS complex of
greater than 120 milliseconds that does not meet the criteria for a left or right bundle branch block.
Frequently, an IVCD will look like a LBBB in lead V1 with a rS complex or monomorphic S wave, and
it appears like a RBBB in leads I and V6 with a broad, slurred S wave.
CLINICAL PEARL: If you see an intraventricular conduction delay IVCD, think of hyperkalemia.
3-Decreased amplitude of the P waves, an increase in the PR interval and bradycardia in the form
of atrioventricular blocks occur as the potassium level exceeds 7.0 mEq/L
CLINICAL PEARL: Supportive measurements like fluids, pacing and pressors do not work in the
setting of hyperkalemia. You must treat the hyperkalemia first.

4-Absence of the P waves and eventually a “sine wave” pattern, as seen below, which is frequently
a fatal rhythm

Hyperkalemia with Sine Wave Pattern

Severe hyperkalemia: Absence of P wave, widened QRS complex with sine-wave morphology.

-Hypokalaemia creates the illusion that the T wave is “pushed down”, with resultant T-wave flattening/inversion, ST depression, and prominent U
waves
-In hyperkalaemia, the T wave is “pulled upwards”, creating tall “tented” T waves, and stretching the remainder of the ECG to cause P wave flattening,
PR prolongation, and QRS widening

CLINICAL PEARL: Giving intravenous calcium is “cardioprotective” in the setting of hyperkalemia.

Frequently, instant reversal of all hyperkalemic ECG changes within seconds of administration is
experienced. Calcium does not decrease the potassium levels; therefore, other therapy such
bicarbonate or insulin is needed to do this. Calcium administration can be fatal when digoxin
toxicity is causing hyperkalemia and should be avoided.
Acute management of hyperkalemia:
1-IV calcium gluconate is preferred over calcium chloride because calcium chloride causes skin
irritation and extravasation which can lead to skin necrosis or thrombophlebitis. Peripherally, 3 g IV
calcium gluconate can be given over 10 min. For central access, 1 g over 10 min or slow IV push can
be done. Calcium lasts for 30-60 mins so it may need to be repeated.

2-Regular insulin 10-20 units IV can be given with dextrose 25 g (when blood glucose <250 mg/dl).
In patients with renal insufficiency, short acting insulin can be used. Insulin lasts for a few hours
therefore may need to be re-dosed.

3-Beta-adrenergic agonists (salbutamol, reproterol) stimulate potassium to shift from extra to

intracellular space via Na+/K+-ATPase as described above. Salbutamol can be applied via nebulizer
or given intravenously. If given iv, the lowering effect of salbutamol is quite predictable with a mean
decrease of 1.6-1.7 mmol/l after 2 h . It can cause tachycardia. Salbutamol has been shown to be
safe and even superior to rectal cation-exchange resin in nonoliguric preterms with hyperkalemia
 iv: 4-5 μg/kg in 15 ml of 5% dextrose/water, short infusion over 15 min Tachycardia
Nebulized: 2.5 mg if <25 kg and 5 mg if >25 kg

4-Ultimately, patients will require elimination of excess potassium from the body.

5-Diuresis with furosemide is suggested in hypervolemic/euvolemic patients able to produce urine.

Furosemide increases urinary excretion of potassium which can be used in both acute and chronic
management.

6-Dialysis should be considered in patients who fail medical management, severe AKI/ESRD or
persistent EKG changes.

7-Sodium bicarbonate increases the extracellular concentration of H+ which in turn increases

intracellular Na+ via Na+ –H+ antiporter resulting in an intracellular shift of sodium that activates
the Na+ K+ ATPase to exchange intracellular sodium for potassium. There is little evidence for the
use of sodium bicarbonate monotherapy in hyperkalemia; several studies suggest a lack of or
delayed efficacy. There may be a role for administration in patients with metabolic acidosis. The
BICAR-ICU trial, which evaluated the impact of sodium bicarbonate 4.2% administration on mortality
and organ dysfunction in critically ill patients with acidemia, is one of the only studies demonstrating
a statistically significant reduction in serum potassium levels (p = 0.0341); however, this was a safety
endpoint that requires further evaluation. In the absence of metabolic acidosis, sodium bicarbonate
should not be used for routine management of hyperkalemia, given the availability of more effective
treatment options without the risk of fluid overload.
 8-Chronic Management of hyperkalemia includes maintaining serum potassium after acute
treatment.

A-Treatment options include reviewing medication that can cause hyperkalemia, reduction in
dietary potassium intake and start medication that can increase potassium excretion.

B-Sodium zirconium cyclosilicate (Lokelma) should not be used for the acute management of
hyperkalemia due to delayed onset of action. Onset of action is 1-6 hours with duration possibly 4-
12 hours. Sodium polystyrene sulfonate (Kayexalate) has a high sodium load, and its time of onset
is variable making it a poor choice for acute management.

Magnesium
Magnesium is the fourth most abundant mineral in the body and the second most prevalent
intracellular cation. The standard serum magnesium concentration ranges from 1.5 to
2.4 mg/dL. It plays an abundance of critical roles in the human body, including, but not limited
to, acting as a cofactor for reactions powered by adenosine triphosphate (ATP), involvement
in the active transport of calcium and potassium ions across cell membranes, economization
of cardiac pump function, and utilization of certain vitamins (e.g., vitamin D and B vitamins).
The kidneys, intestines, and bones are all involved in magnesium homeostasis. Table 1 lists
etiologies for hypomagnesemia and other common electrolyte abnormalities in the ICU.

1- Hypomagnesemia
Hypomagnesemia (< 1.5 mg/dL) has been associated with increased mortality, longer
mechanical ventilation, and increased ICU length of stay. The consequences of
hypomagnesemia leading to poor outcomes include increased muscle weakness, respiratory
failure, development of cardiovascular disease, dysrhythmias, and more.The earliest
manifestations of magnesium deficiency are usually neuromuscular and neuropsychiatric
disturbances. The most common clinical manifestations are hyperexcitability, including
positive Chvostek's and Trousseau's signs, tremor, fasciculations and tetany. Frank tetany in
magnesium deficiency is usually associated with hypocalcaemia. There may be several
mechanisms contributing to the wide variety of neuromuscular problems in magnesium
deficiency. Magnesium is required for stabilisation of the axon.

Causes of hypomagnesemia.
Decreased Intake
Decreased Dietary consumption
Alcohol Dependence
Parenteral Nutrition

Redistribution from Extracellular to Intracellular Compartment:

Refeeding Syndrome
Hungry Bone Syndrome
 Treatment of Diabetic Ketoacidosis
Acute Pancreatitis

Gastrointestinal Losses:
Diarrhea
Vomiting
Nasogastric suction
Fistulas
Malabsorption
Small bowel bypass surgery
Proton Pump Inhibitors

Renal Losses:
Familial:
Bartter syndrome, Gitelman syndrome, Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
(FHHNC)
Acquired:
Medications: Thiazide Diuretic, Aminoglycoside Antibiotics, Amphotericin B, Cisplatin, Pentamidine,
Tacrolimus, Cyclosporine
Alcohol Dependence, Hypercalcemia

Clinical Features of Hypomagnesaemia and magnesium deficiency

Neuromuscular and central nervous Cardiovascular
system
Atrial tachycardias, fibrillation
Carpopedal spasm
Supraventricular arrhythmias
Convulsations
Ventricular arrhythmias
Muscle cramps
Torsade de pointes
Muscle weakness, fasciculations,
Digoxin sensitivity
tremors
Complications of magnesium deficiency
Vertigo
Altered glucose homeostasis
Nystagmus
Atherosclerotic vascular disease
Depression, psychosis
Hypertension
Athetoid movements & choreform
movements Myocardial infarction
Osteoporosis
Electrolyte disturbance Miscellaneous
Hypokalaemia Migraine
Hypocalcaemia Asthma
 Chronic fatigue syndrome
Impaired athletic performance

Magnesium deficiency can affect cardiac electrical activity, myocardial contractility and
vascular tone. It also potentiates digoxin toxicity. Although cardiac arrhythmias are well
known to be associated with hypomagnesaemia, the contribution of hypomagnesaemia to its
pathogenesis is not fully known due to coexisting hypokalaemia and other electrolyte
disturbances. The relationship between magnesium deficiency and arrhythmias associated
with acute myocardial infarction seems to be complex.

The frequency of cardiac arrhythmias occurring after myocardial infarction is higher in

hypomagnesaemic patients and is reduced by magnesium administration.

ECG changes are non-specific and include a slight prolongation of conduction and the
depression of the ST segment. Magnesium depletion increases susceptibility to
arrhythmogenic effects of drugs such as isoproterenol and cardiac glycosides. The spectrum
includes supraventricular and ventricular arrhythmias. Torsade de pointes, a repetitive
polymorphous ventricular tachycardia with prolongation of QT interval, has been reported in
cases of hypomagnesaemia, and this and other arrhythmias have been successfully treated
with magnesium. However, this may be a pharmacological effect, independent of underlying
magnesium deficiency. Hypomagnesaemia is present in <10% of patients with mild to
moderate heart failure but is more common in severe congestive heart failure. The effects of
hypomagnesaemia are complicated by concomitant abnormalities in potassium.
Hypomagnesaemia has been shown to increase the frequency of arrhythmias in heart failure,
but is not associated with increased mortality.

Consideration of potassium must occur in patients with hypomagnesemia. Depletion of

intracellular magnesium allows potassium to be freely secreted through luminal potassium
channels (the renal outer medullary potassium channel, or ROMK). Therefore, magnesium
replacement is often necessary before hypokalemia can be corrected . Both hypomagnesemia
and hypokalemia are predisposing risk factors for the development of Torsades de Pointes
(TdP). Hypocalcemia may also manifest from hypomagnesemia from inhibition of the release
of parathyroid hormone (PTH). Consequently, hypocalcemia may predispose patients to
cardiac manifestations of hypomagnesemia.
 Biochemical Manifestations :hypomagnesemia may presented by:

A)Hypokalaemia: Magnesium and potassium homeostases are closely

related. Hypokalaemia is a frequent finding in patients with hypomagnesaemia, and
hypokalaemia predicts the presence of hypomagnesaemia. Potassium depletion cannot be
corrected until magnesium depletion is corrected. The exact mechanism for the
development of hypokalaemia in magnesium deficiency is not clear, but may be related to
the dependence of Na+,K+-ATPase, Na,K-Cl co-transport, potassium channels and other
transport processes on magnesium. Hypokalaemia of magnesium deficiency contributes to
the cardiac manifestations of hypomagnesaemia, but may delay the onset of tetany.

B) Hypocalcaemia: Hypocalcaemia is a common manifestation in hypomagnesaemia. Up to

one third of patients with hypomagnesaemia in intensive care units may have
hypocalcaemia. Symptomatic hypocalcaemia is usually seen in moderate to severe
magnesium deficiency and there is a positive correlation between serum magnesium and
calcium concentrations. Even mild degrees of magnesium depletion can cause a significant
decrease in serum calcium concentration. Hypocalcaemia of magnesium deficiency cannot
be corrected by treatment with calcium, vitamin D or both. Magnesium therapy alone will
restore serum calcium concentration to normal. Several factors contribute to the
hypocalcaemia of magnesium deficiency. One of the important factors is impaired
secretion of PTH. Although the acute effect of extracellular magnesium on PTH secretion is
similar to that of calcium, in magnesium deficiency there is impaired PTH release. In
addition to impaired PTH secretion there is evidence for an increase in metabolism of PTH
and end-organ resistance for PTH. End-organ resistance is suggested by the presence of
normal or elevated serum concentration of PTH in the face of hypocalcaemia, and
decreased osteocalcin concentration. Administration of exogenous PTH to patients with
hypocalcaemic hypomagnesaemia has little effect on serum calcium concentrations or on
urinary excretion of cyclic AMP and phosphate. In magnesium deficiency, vitamin D
metabolism is altered with a decrease in serum 1,25 dihydroxyvitamin D due to impairment
in conversion of 25 hydroxyvitamin D to 1,25 dihydroxyvitamin D. There is also evidence for
increased clearance of 1,25 dihydroxyvitamin D and end- organ resistance.
Hypomagnesemia can influence myocardial excitability. The consequences of
hypomagnesemia have been correlated to an increased risk of abnormal rhythms, including
atrial and ventricular arrhythmias. Concurrent electrocardiography (EKG) findings with
hypomagnesemia include flattened T-waves, U-waves, prolonged QT interval, and widened
QRS complexes.

Hypomagnesemia induced EKG changes include:

1-Flattened T wave and U waves

2-Prolonged QT interval and widened QRS complex

3-Prolonged QT interval
Hypomagnesaemia with QTC prolonged at 510ms

The following ECGs were taken from a 76-year-old man presenting with
palpitations. He was found to have a serum Magnesium level of 0.28 mmol/L.

Comment: 1-There are runs of nonsustained ventricular tachycardia (NSVT), as well as ventricular ectopics
2-QTC during normal rhythm is 465ms
Magnesium repletion is generally safe except for myasthenia gravis (due to increased
risk of muscle weakness) and renal failure.

1-For patients with mild hypomagnesemia (1.5-2 mg/dl), oral magnesium can be used. Oral
formulations are magnesium oxide 400 mg twice a day or magnesium hydroxide milk of
magnesia) 15 ml once daily. If unable to take PO medication, 2 g of IV magnesium sulphate
can be given.

2-For moderate hypomagnesemia (1.2-1.5 mg/dl), intermittent infusions of 2-4 g magnesium

sulphate IV can be given. To improve intracellular absorption, the dose can be infused for a
longer period of time.

3-For severe hypomagnesemia (<1.2 mg/dl), multiple doses of IV magnesium can be given or
a continuous infusion of IV magnesium (4-8 g IV magnesium sulphate over 24 hours).

4-1 g magnesium sulphate is equivalent to 100 mg of elemental magnesium.

5-In Torsade de Pointes or seizures secondary to hypomagnesemia, patients can be loaded

with 2 g magnesium sulphate over 5-15 min followed by 2 g additionally over 30-60 min.
These are followed by a continuous infusion of magnesium sulphate 1 g/hour. If the
magnesium level is 5-7 mg/dl, the infusion should be reduced by 50%. If magnesium is
>7 mg/dl then the infusion should be stopped.

2-Hypermagnesemia
Magnesium >2.6 mg/dl is defined as hypermagnesemia. Patients with serum
magnesium<4.8 mg/dl are usually asymptomatic, deep tendon reflexes may be diminished
with serum magnesium>6.1 mg/dl and absent when >12 mg/dl. Patients can present with
lethargy, confusion, nausea, vomiting, bradycardia. In severe cases, muscle weakness,
respiratory distress, apnea, heart block, severe bradycardia, delirium and coma.

Causes of hypermagnesemia.
Category Sub-Category Causes Mechanisms
Reduced Kidney Disease Acute kidney injury Reduced ability of the kidneys to
Renal Chronic kidney disease excrete Mg
Excretion
Endocrinological Hyperparathyroidism Abnormalities in calcium metabolism
Conditions Adrenal insufficiency or renal blood flow/filtration rate
Hypothyroidism
Certain Drugs Lithium, angiotensin- Alteration of renal endothelial
converting enzyme vessels and angiotensin system
inhibitors, non-steroidal
anti-inflammatory drugs
Increased Bowel Conditions Elderly patients with Enhanced absorption or reduced gut
Intake of bowel conditions motility
Mg
Medications Anticholinergics, Increased intake or absorption of Mg
laxatives, and
medications containing
Mg
Other Causes Milk alkali syndrome, Various mechanisms
increased dialysate Mg,
post-urethral irrigation
with hemiacidrin,
excessive infusion of Mg
sulfate
Mg Leak to Hemolysis Tumor lysis syndrome Movement of Mg from intracellular
Extracellular to extracellular space
Fluid
Metabolic Acidosis Diabetic ketoacidosis Movement of Mg from intracellular
to extracellular space
Other Causes Chronic low-grade Various mechanisms
metabolic acidosis

Clinical Manifestations of Hypermagnesaemia

Neuromuscular
Confusion
Lethargy
Respiratory depression
Absent tendon reflexes
Paralytic ileus
Bladder paralysis
Muscle weakness/paralysis
Cardiovascular
Hypotension
Bradycardia
Inhibition of AV and inteventricular conduction
Heart block
Cardiac arrest
Others
Nausea, vomiting
EKG will show widened QRS complex with peaked T waves. Heart block can also be seen.

Renal failure is required in addition to another source of magnesium to cause persistent

hypermagnesemia. Concomitant causes of hypermagnesemia are:

1-Exogenous magnesium:- Magnesium infusion for pre-eclampsia, magnesium containing

antacids and magnesium containing laxatives/enema

2-Endogenous magnesium from cellular lysis:- Rhabdomyolysis, hemolysis, tumor lysis

syndrome and crush injury, severe burns.

Clinical points in hypermagnesemia:

1-Magnesium is also cardiotoxic. At serum magnesium concentrations greater than 3
mmol/L, prolonged PR intervals, increased QRS duration and prolonged QT intervals are
seen. Mild bradycardia is observed at concentrations greater than 7 mmol/L, and complete
heart block as well as cardiac arrest may occur at concentrations greater than 7 mmol/L.
Electrocardiographic changes in hypermagnesaemia are not specific and cannot be relied
upon for the diagnosis of magnesium intoxication.

2-Hypocalcaemia: Magnesium intoxication causes a reduction in serum calcium

concentration. This has most commonly been reported in patients receiving magnesium
therapy for pregnancy-induced hypertension. Serum parathyroid hormone concentration
falls rapidly in response to magnesium infusion showing that hypocalcaemia may be partly
due to the suppressive effects of acute hypermagnesaemia on PTH secretion.

3-Hypermagnesaemia may cause smooth muscle paralysis resulting in paralytic ileus. Other
non-specific manifestations of magnesium intoxication include nausea, vomiting and
cutaneous flushing. Hypermagnesaemia may also interfere with blood clotting due to
interference with platelet adhesiveness, thrombin generation time and clotting time.

In most cases of hypermagnesemia, discontinuing magnesium containing drugs or

supplements or volume replacement can sufficiently treat it.

In patients with moderate hypermagnesemia (3.6-10 mg/dl or no cardiac/respiratory

symptoms), the underlying cause should be treated. Furosemide can be used to enhance
magnesium excretion.

In patients with severe hypermagnesemia (causing cardiac/respiratory symptoms), IV

calcium is required to stabilize the myocardium (2 g of calcium gluconate IV over 5-10 min
followed by a continuous infusion in severe cases). In patients who are non-oliguric,
furosemide with IV fluids can be used for elimination of magnesium. In patients who are
oliguric, emergent dialysis is required.
 Calcium
Normal total serum ranges 8.6–10.2 mg/dL or ionized serum calcium ranges 1.12–
1.30 mmol/L. Nearly 99% of total body calcium resides in the bones, and the remaining 1% in
the extracellular fluid (ECF). About half of circulating calcium is bound to albumin, and the
remaining is ionized calcium, which is biologically active and maintains physiologic functions.
Calcium homeostasis depends on the regulation of calcium fluxes in relation to the intestinal
tract, bone, and kidneys. Calcium is regulated predominantly by PTH and calcitriol (1,25-
dihydroxy vitamin D3 (1,25(OH)2D3). Hypoalbuminemia decreases total calcium with
minimal effect on the ionized calcium. Conversely, acidemia reduces protein binding but
increases ionized calcium. Correction formulas are proposed for adjusting for low albumin
and pH, but studies have demonstrated a poor correlation between corrected calcium and
ionized calcium. To guide calcium correction, ionized calcium should be used whenever
possible.

1- Hypocalcemia
Hypocalcemia is defined as total serum calcium concentration of < 8.6 mg/dL or ionized
calcium concentration of < 1.1 mmol/L. Hypocalcemia is multifactorial, reported in up to 90%
of inpatients, with hypocalcemia measured by ionized calcium reported in 20% of ICU
patients. Symptoms of hypocalcemia usually correlate with the severity and rapidity of serum
calcium decrease. The hallmark manifestation of severe acute hypocalcemia is tetany. Other
manifestations include seizures and cardiac rhythm disturbances due to prolonged QT
interval.

The flexed wrist and metacarpophalangeal joint, and the extended distal and proximal interphalangeal joint are
characteristic of Trousseau sign of latent tetany

Hypocalcaemia Overview
• Normal serum corrected calcium = 2.2 – 2.6 mmol/L.
• Mild-moderate hypocalcaemia = 1.9 – 2.2 mmol/L.
• Severe hypocalcaemia = < 1.9 mmol/L.
Causes of Hypocalcaemia
• Hypoparathyroidism
• Vitamin D deficiency
• Acute pancreatitis
• Hyperphosphataemia
• Hypomagnesaemia
• Diuretics (frusemide)
• Pseudohypoparathyroidism
• Congenital disorders (e.g. DiGeorge syndrome)
• Critical illness (e.g. sepsis)
• Factitious (e.g. EDTA blood tube contamination)
Symptoms of Hypocalcaemia
• Neuromuscular excitability
• Carpopedal spasm
• Tetany
• Chvostek sign
• Trousseau sign
• Seizures

Hypocalcaemia: QTc 500ms in a patient with hypoparathyroidism (post thyroidectomy) and serum corrected
calcium of 1.40 mmol/L
 Hypocalcaemia: QT prolongation in a patient with DiGeorge’s syndrome and serum
calcium of 1.32 mmol/L

Hypocalcaemia causing a long QTc (510ms)

Symptoms attributable to low calcium

are not well described in the critically ill.
Despite a paucity of data on the benefits
of calcium measurement and correction,
calcium correction is a common practice
aimed at normalizing serum levels
instead of being guided by response to
therapy or relief of symptoms. Notably, a
few studies suggest correction may be
harmful . Collage et al. reported a
retrospective study of 526 ICU patients
with low ionized calcium where 18%
received IV calcium. After adjusting for
the severity of illness and demographic
covariates, mortality was higher in
patients that received calcium. Despite
uncertainty on the benefits of correcting
ionized calcium, calcium should be corrected in cases with concurrent hypomagnesemia,
nutritional deficits, medication-induced hypocalcemia, blood transfusions, and
extracorporeal devices.

Signs of HYPOcalcemia: Remember, calcium acts like a sedative, so when there's not
enough, everything with speed up! This can result in assessment findings such as
hyperactive bowel sounds, diarrhea, irritability, and even seizures.

Two important signs of hypocalcemia:

▪️ Chvostek's sign: hyperexcitability of the facial nerves - to elicit this response, tap at the
angle of the jaw via the masseter muscle and the facial muscles on the same side of the
face will contract momentarily (the lips or nose will twitch)
 ▪️ Trousseau's sign: place a blood pressure cuff and around the upper arm and inflate it to a
pressure greater than the systolic blood pressure and hold it in place for 3 minutes. A
positive result is when the hand of the arm where the blood pressure is being taken
contracts involuntarily.

EKG changes that are seen in hypocalcemia are

1-QT segment prolongation or ST segment lengthening

2-AV conduction block

3-Acute anteroseptal injury without myocardial infarction

4-Abnormal T waves

5- Dysrhythmias are uncommon, although atrial fibrillation has been reported Torsades de
pointes may occur, but is much less common than with hypokalaemia or hypomagnesaemia

The ECG hallmark of hypocalcemia remains the prolongation of the QTcinterval because of
lengthening of the ST segment, which isdirectly proportional to the degree of hypocalcemia
or, as otherwisestated, inversely proportional to the serum calcium level.

Treatment for hypocalcemia depends on severity and etiology. Symptomatic and severe
hypocalcemia warrants IV calcium. Intravenous calcium gluconate is preferred for correcting
symptomatic moderate (total serum calcium concentration 7.5–8.0 mg/dL) or severe
hypocalcemia (total serum calcium concentration < 7.5 mg/dL or ionized calcium
concentration < 0.9 mmol/L). Calcium chloride can be administered via peripheral line in
emergent situations (e.g., cardiac arrest) but a central line is preferred when available. In
select cases such as massive blood transfusion, plasmapheresis, or citrate anticoagulation, a
continuous infusion of calcium may be required, and serum calcium level should be monitored
every 6 h.

2- Hypercalcemia
Hypercalcemia (> 10.2 mg/dL) occurs in approximately 15% of patients. It is categorized as
mild to moderate (total serum calcium concentration of 10.5–11.9 mg/dL) or severe (total
calcium of ≥ 12 mg/dL). Hypercalcemia of malignancy secondary to PTH-related increased
bone resorption is the most common etiology of hypercalcemia. Patients with severe
hypercalcemia are often volume depleted and symptomatic. Neurologic manifestations of
hypercalcemia include anorexia, confusion, and obtundation. Cardiac manifestations include
arrhythmias and EKG changes (shortened QT).
Causes of Hypercalcemia
Parathyroid hormone-related

Primary hyperparathyroidism*

Sporadic, familial, associated with multiple endocrine neoplasia I or II

Tertiary hyperparathyroidism

Associated with chronic renal failure or vitamin D deficiency

Vitamin D-related

Vitamin D intoxication

Usually 25-hydroxyvitamin D2 in over-the-counter supplements

Granulomatous disease sarcoidosis, berylliosis, tuberculosis

Hodgkin's lymphoma

Malignancy

Humoral hypercalcemia of malignancy* (mediated by PTHrP)

Solid tumors, especially lung, head, and neck squamous cancers, renal cell tumors

Local osteolysis* (mediated by cytokines) multiple myeloma, breast cancer

Medications

Thiazide diuretics (usually mild)*

Lithium

Milk-alkali syndrome (from calcium antacids)

Vitamin A intoxication (including analogs used to treat acne)

Other endocrine disorders

Hyperthyroidism

Adrenal insufficiency

Acromegaly

Pheochromocytoma

Genetic disorders

Familial hypocalciuric hypercalcemia: mutated calcium-sensing receptor

Other

Immobilization, with high bone turnover (e.g., Paget's disease, bedridden child)

Recovery phase of rhabdomyolysis

Hypercalcemia can be classified based on severity:

1-Mild Hypercalcemia:- Total calcium 10.5-12 mg/dl or ionized calcium 5.6-8 mg/dl

2-Moderate Hypercalcemia:- Total calcium 12-14 mg/dl or ionized calcium 8-10 mg/dl

3-Hypercalcemic Crises:- Total calcium >14 mg/dl or ionized calcium >10 mg/dl.

Clinical features: 1-Mild hypercalcemia may be asymptomatic however rapid increases are
more likely is be associated with symptoms than chronic hypercalcemia.

2-This can present as bone pain, delirium (which could progress to stupor/coma),
paresthesia, muscle weakness, GI symptoms (abdominal pain, pancreatitis, constipation,
ileus, nausea/vomiting).

3-Hypercalcemia does not commonly affect EKG or cardiac function however short QT
interval may be a common finding.

Clinical Manifestations of Hypercalcemia

Renal “stones”

Nephrolithiasis

Nephrogenic diabetes insipidus

Dehydration

Nephrocalcinosis

Skeleton “bones”

Bone pain

Arthritis

Osteoporosis

Osteitis fibrosa cystica in hyperparathyroidism (subperiosteal resorption, bone cysts)

Gastrointestinal “abdominal moans”

Nausea, vomiting

Anorexia, weight loss

Constipation

Abdominal pain

Pancreatitis

Peptic ulcer disease

Neuromuscular “psychic groans”

Impaired concentration and memory

 Confusion, stupor, coma

Lethargy and fatigue

Muscle weakness

Corneal calcification (band keratopathy)

Cardiovascular

Hypertension

Shortened QT interval on electrocardiogram

Cardiac arrhythmias

Vascular calcification

Other

Itching

Keratitis, conjunctivitis

Treatment: 1-Overall, almost 90% of hypercalcemia is due to primary

hyperparathyroidism or malignancy.

2-Factitious Hypercalcemia may also occur when total calcium is elevated but ionized calcium
is normal. This occurs when serum albumin or protein levels are elevated.

3-Initial volume resuscitation is essential since hypercalcemia typically causes volume

depletion due to enhanced fluid excretion by the kidneys and reduced oral intake. Plasmalyte
is a good choice since it is a balanced crystalloid which does not contain calcium. Lactated
ringer contains calcium and normal saline can cause acidosis (possibly increasing risk of renal
injury) therefore both are suboptimal compared to plasmalyte.

4-Mild to moderate hypercalcemia without symptoms does not require aggressive treatment.
The underlying disease should be treated, and potentially contributing medication
discontinued. Immobility may exacerbate hypercalcemia therefore patients should be
mobilized.

5-In patients with severe hypercalcemia, IV fluid hydration (at least 2-4 L/day for 1-3 days)
should be given in association with bisphosphonates and calcitonin to reduce serum calcium
levels.

6-Bisphosphonates block calcium release from bones causing unidirectional uptake by the
bones. These take days to work and should be started early. Bisphosphonates should be
avoided in patients with increased calcium intake (milk-alkali syndrome. The main side effect
is renal failure however the most common is flu-like syndrome which can be treated
symptomatically. Various options are pamidronate 60-90 mg IV or zoledronic acid 4 mg IV.

7-Calcitonin is an excellent agent to control severe symptomatic hypocalcemia while waiting

for bisphosphonates to take effect. These work by reducing bone calcium reabsorption and
cause a temporary reduction in calcium. Calcitonin can cause nausea, vomiting and flushing.
For adults, calcitonin 4 U/kg subcutaneously every 12 hours for 24 hours; effect of calcitonin
is short lived, and tolerance typically develops within 2 days.

8-In patients who bisphosphonates and calcitonin are ineffective, denosumab (monoclonal
antibody that inhibits osteoclast formation and bone resorption) can be considered.

9-Loop diuretics can be used once volume status normalizes to enhance calcium excretion
and to avoid volume overload. They may have to be started earlier if patient has a history of
congestive heart failure or kidney disease. Glucocorticoids can be given in patients with
granulomatous disease, Vit D overdose or malignancy to inhibit conversion of Vit D to
calcitriol.

10-In renal failure, dialysis with low calcium bath is an option.

Phosphorous
Phosphorous, an intracellular anion, is essential in cellular function and other processes.
Normal serum phosphate ranges from 2.5 to 4.5 mg/dL (0.8–1.45 mmol/L) .Levels depend on
an intricate combination of dietary intake, intra to extracellular transfer, kidney function, and
tubular phosphate reabsorption. Occurring in only 5% of all inpatients, up to 50% of ICU
patients experience hypophosphatemia, particularly in the first week of admission, and risk
factors for hypophosphatemia exist in almost all ICU patients. Serum phosphate
concentrations have a circadian pattern and should preferentially be collected in the morning.
Phosphate homeostasis depends on numerous transporters, hormones, and other
mechanisms affected by a variety of factors. Additionally, critically ill patients experience
shifts in phosphate faster than seen with chronic hypophosphatemia.

1-Hypophosphatemia
Mild to moderate hypophosphatemia may not be problematic in most patients; it may be
asymptomatic, transient, or reversible by correcting the underlying cause. In contrast, severe
hypophosphatemia (< 2 mg/dL) can cause many complications, including arrhythmias, muscle
weakness, and respiratory failure. In the ICU, hypophosphatemia has been associated with
increases in illness severity, longer mechanical ventilation, longer ICU and hospital stays, and
higher mortality up to six months after hospitalization. Like other electrolyte abnormalities,
hypophosphatemia can be caused by medications and physiologic conditions; it may also
occur subsequent to the use of other management strategies in critical illness, most notably
CRRT which is known to remove phosphorus .

Symptoms of Hypophosphatemia
Neurologic

• Seizures, paresthesias, tremor.

• Confusion, dysarthria, stupor, coma.
• May promote the development of central pontine myelinolysis.

Cardiac

• Impaired contractility, heart failure.

• Arrhythmia (supraventricular and ventricular tachycardia).

Muscular

• Rhabdomyolysis.
• Rare; May mask diagnosis of hypophosphatemia by release of phosphate from muscle!
• Muscle weakness, including diaphragm:
• May sometimes contribute to difficult weaning.

Other rare manifestations

• Insulin resistance.
• Hemolysis, thrombocytopenia.

Causes of hypophosphatemia are:

1-Shifting phosphate into cells: Diabetic ketoacidosis, refeeding syndrome, respiratory
alkalosis, hungry bone syndrome

2-Reduced GI uptake: Inadequate oral intake, chronic diarrhea, drugs(chronic use of

antacids containing calcium, magnesium or aluminum).

3-Increased Renal losses: Diuretics (loop diuretics, acetazolamide, thiazides), osmotic

diuresis, auto-diuresis (post-ATN, iatrogenic volume overload), CRRT, hyperparathyroidism,
other medications (aminoglycosides, IV iron, tenofovir, chemotherapeutic agents).

4-Multifactorial: Alcoholism, Vitamin D deficiency, critical illness (sepsis, trauma, major

surgery, burns).

5-Potential causes of pseudo-hypophosphatemia are hyperbilirubinemia, mannitol,

paraprotei

When should phosphate be checked ?

1-When initiating nutrition in patients at-risk for refeeding syndrome.

2-Patients with diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome

(HHNS).

3-Patients on continuous renal replacement therapy (CRRT).

 4-Possibly once, upon admission for all patients entering the ICU?

5-If there is clinical concern of symptoms due to hypophosphatemia.

6-In patients with difficulty weaning from ventilation (some evidence shows that
hypophosphatemia may be a contributory factor by causing diaphragmatic weakness).

spurious hypophosphatemia (pseudohypophosphatemia) Uncommon Potential causes:

hyperbilirubinemia, mannitol, paraproteins, acute leukemia

IV phosphate can be given for severe hypophosphatemia, symptomatic, or in patients

with lack of enteral access or malabsorption. These should be infused slowly since rapid
infusion can lead to transient hyperphosphatemia (leading to hypocalcemia). Either
potassium or sodium phosphate can be used.

Oral phosphate can be given however tends to cause diarrhea. It is available as Phos-NAK
packets (which contains 8 mM phosphate, 7 mEq potassium and 7 mEq sodium), oral sodium
phosphate liquid and oral potassium phosphate liquid.

Phosphate ≤1.5 mg/dl:- Orally, 16 mM phosphate every 6 hours. Intravenously, initial dose
can be 30 mM infused over 4 hours

Phosphate >1.5 mg/dl:- Orally, 8 mM phosphate every 8 hours. Intravenously, initial dose of
15 mM phosphate can be infused over 2 hours.

Cautions: Significant hypophosphatemia (e.g. phosphate <2 mg/dL or <0.65 mM) should
generally be repleted, with the following potential exceptions:

(1) Renal insufficiency: Phosphate should be given only if truly necessary, since these
patients tend to develop hyperphosphatemia over time.

(2) Hypercalcemia: Increasing phosphate may risk precipitation of calcium-phosphate in

tissues (calciphylaxis). Try to keep the calcium-phosphate product <70 (calcium multiplied
by phosphate, both in mg/dL).
 (3) Hypocalcemia: Rapid infusion of IV phosphate may reduce calcium level. If hypotension
occurs during infusion of IV phosphate, consider possibility of hypocalcemia.

Patients with active refeeding syndrome and morbid obesity, can consider using higher doses
than indicated based on phosphate levels.

2-Hyperphosphatemia
Hyperphosphatemia is defined as serum phosphate >4.5 mg/dl in adults.

Phosphate level 2.5-5 mg/dL = normal phosphate. Pseudohyperphosphatemia (false

elevation) may result from:Hyperlipidemia. Hyperbilirubinemia. Hyperglobulinemia (e.g.
multiple myeloma). Hemolyzed specimen. Liposomal amphotericin B.

Calcium-phosphate product: More important than the phosphate level alone, as this predicts
the risk of calciphylaxis (precipitation of calcium phosphate in tissues). Defined as calcium
level multiplied by phosphate level (with both measured in mg/dL). Calcium-phosphate
product above 70 mg*mg/dL*dL causes a risk of calciphylaxis.

Hyperphosphatemia is itself, asymptomatic however can indirectly cause symptoms by

causing symptomatic hypocalcemia (by binding to calcium) or calciphylaxis (precipitation of
calcium phosphate in tissues which can manifest as skin ulceration).

Sustained hyperphosphatemia generally occurs in renal failure since normally the kidneys
are efficient in phosphate excretion. Possible inciting events are

1-Tissue necrosis: Tumor lysis syndrome, rhabdomyolysis, hemolysis, fulminant hepatitis,

severe hyperthermia

2-Endocrinopathy: Hypoparathyroidism,hypothyroidism/hyperthyroidism, adrenal

insufficiency, acromegaly

3-Medications: Exogenous phosphate intake (phosphate containing laxatives/enemas, TPN),

Vit D toxicity, bisphosphonates, fosphenytoin

False elevation of phosphate can be seen in hyperlipidemia, hyperbilirubinemia,

hyperglobulinemia (multiple myeloma) or a hemolyzed specimen.

Calcium phosphate product can predict the risk of calciphylaxis

and is more important than the phosphate level alone.
Calcium-phosphate product>70 causes an increased risk of
calciphylaxis

Hyperphosphatemia itself is generally asymptomatic. However, hyperphosphatemia may

indirectly cause symptoms in two ways.
More common of hyperphosphatemia is: symptomatic hypocalcemia

Phosphate binds calcium, which can lead to hypocalcemia.

Hypocalcemia may cause symptoms, for example:

1-Paresthesias (tingling around mouth, hands).

2-Muscle cramping, weakness, laryngospasm.

3-Anxiety, confusion, seizure.

4-Hypotension, ventricular arrhythmias.

5-Rare: calciphylaxis Elevation of phosphate may promote calciphylaxis (the precipitation of

calcium phosphate in tissues). This may manifest with necrotizing skin ulceration:

Calcium Phosphate Product= Serum Calcium x Serum Phosphate

Acute treatment of hyperphosphatemia includes treating inciting event, phosphate
restricted diet, fluid resuscitation and forced diuresis (acetazolamide+ − furosemide) or
dialysis. If patient has persistent renal failure, can start oral phosphate binder. Calcium
acetate can be useful in patients with concomitant hypocalcemia and should be avoided in
patients with hypercalcemia, Vitamin D toxicity and Ca-Phos product> 66. Sevelamer is a
nonabsorbable resin that is preferred for patients on dialysis

Chapter 45: Refeeding Syndrome

Refeeding syndrome (RFS) is a potentially fatal condition commonly characterised by
rapid changes in fluid and electrolyte balance leading to problems of cardiac arrthymias,
cardiac and respiratory failure. Other manifestations include acute fatty liver, endocrine and
haematological abnormalities, acute thiamine deficiency and neurological syndromes such as
delirium and centropontine myelinolysis. Hidden sepsis, a separate dangerous problem, can
also occur in malnourished individuals and sometimes is mistaken for a manifestation of RFS.

Refeeding problems have been recognised since the the liberation of starved communities
under siege. The main clinical problems may relate to hypophosphataemia,
hypomagnesaemia and hypokalaemia with a risk of sudden death; thiamine deficiency with
the risk of Wernike’s encephalopathy/Korsakoff psychosis and sodium/water retention. The
problems are greatest with oral/enteral feeding and especially with carbohydrate due to it
increasing plasma insulin and thus glucose entry into cells. It is difficult to predict patients at
risk of refeeding problems so there must be a high clinical suspicion on refeeding any
malnourished patient (including any who have had no or very little nutrition for over 5 days).
Generous vitamin and electrolyte supplementation may be given while monitoring closely and
increasing the calorie intake reasonably rapidly from 10 to 20 kcal/kg/24 hours. Often patients
in this category are not hungry, but over the course of a few days, the restoration of their
appetite is an indication that the risks of refeeding have been managed and it is now safe to
increase the feed aiming for repletion. If problems do occur, the feed should be slowed to the
previous day’s amount, reduced further or rarely stopped while fluid and electrolyte issues
are corrected.

Key points. 1-Refeeding syndrome describes the adverse clinical and biochemical
problems that may result from feeding malnourished patients via any route, be it oral,
enteral or parenteral.

2-Clinicians need to be aware of it and assume most malnourished patients are at risk.

3-Hypophosphataemia is the most commonly used marker for refeeding problems and it
commonly occurs when artificial nutritional support is started (especially with carbohydrate)
and can rarely cause death.

4-Hypophosphataemia is more common with oral/enteral feeding than parenteral nutrition.

5-Hypomagnesaemia, hypokalaemia, hypoglycaemia (occasionally hyper) and thiamine

deficiency may occur.

6-Sodium retention (causing oedema) is common, especially after glucose (and sodium) are
given.

7-Non-protein energy is given as 50/50 carbohydrate (CHO)/lipid and initially at <50%

requirements.

Patients at high risk of refeeding syndrome

• Patients with anorexia nervosa
• Patients with chronic alcoholism
• Oncology patients
• Postoperative patients
• Elderly patients (comorbidities, decreased physiological reserve)
• Patients with uncontrolled diabetes mellitus (electrolyte depletion, diuresis)
• Patients with chronic malnutrition as:
• -Marasmus
• -Prolonged fasting or low energy diet
• -Morbid obesity with profound weight loss
• - High stress patient unfed for >7 days
• -Malabsorptive syndrome (such as inflammatory bowel disease, chronic pancreatitis,
cystic fibrosis, short bowel syndrome)
• Long term users of antacids (magnesium and aluminium salts bind phosphate)
• Long term users of diuretics (loss of electrolytes)
Criteria from the guidelines of the National Institute for Health and Clinical Excellence
for identifying patients at high risk of refeeding problems (level D recommendations*)
• Either the patient has one or more of the following:
• Body mass index (kg/m2) <16
• Unintentional weight loss >15% in the past three to six months
 • Little or no nutritional intake for >10 days
• Low levels of potassium, phosphate, or magnesium before feeding
Or the patient has two or more of the following:
• Body mass index <18.5
• Unintentional weight loss >10% in the past three to six months
• Little or no nutritional intake for >5 days
• History of alcohol misuse or drugs, including insulin, chemotherapy, antacids, or diuretics

The clinical symptoms associated with refeeding syndrome are highly varied.
Symptoms reflect electrolyte changes compromise
biochemical changes as cell membrane potentials and cellular
functions. Consequently, patients present with multisystem
complaints ranging from nausea to hypotension. Clinically, it
has been observed that a patient's first described feeling of
nausea can be interpreted as a precursor to hypotension.
Reported cardiovascular changes include arrhythmias,
hypotension, cardiomyopathy, shock, bradycardia,
tachycardia, and cardiac arrest. Renal changes such as acute
tubular necrosis, renal failure, and metabolic acidosis have
been reported due to sodium and phosphate alterations.
Respiratory manifestations in refeeding syndrome include
respiratory failure, pulmonary edema, and hypoventilation. Several musculoskeletal
manifestations have also been reported, including rhabdomyolysis, myalgias, fatigue, muscle
twitching, and diaphragm weakness.

Gastrointestinal symptoms have been linked to hypokalemia and hypomagnesemia in

refeeding syndrome and include diarrhea and constipation, nausea and vomiting, and
paralytic ileus. Of note, many refeeding syndrome patients have comorbidities such as
electrolyte and vitamin deficiencies that may be exacerbated in the setting of alcohol use
disorder.
Neurological: Wernicke encephalopathy (ocular abnormalities , ataxia, delirium). Delirium,
coma. Seizure. Weakness (including respiratory muscle weakness).
Important symptoms and clinical sequelae of RFS
System Symptoms

Tachycardia
Arrhythmias
Hypotension
Cardiovascular Congestive heart failure
Shock
Edemas
Sudden death

Maldigestion and malabsorption

Vomiting
Gastrointestinal
Constipation
Abdominal pain
 Weakness
Myalgia
Musculoskeletal
Rhabdomyolysis
Osteomalacia

Tachypnea
Dyspnea
Respiratory Respiratory failure
Ventilator dependency
Diaphragm muscle weakness

Anorexia
Paresthesia
Tremor
Wernicke encephalopathy
Korsakoff syndrome
Neurologic
Ataxia
Tetany
Delirium
Seizures
Coma

Hyperglycemia
Metabolic alkalosis
Metabolic Metabolic acidosis
Respiratory alkalosis
Insulin resistance

Thrombocytopenia
Hemolysis
Hematologic Anemia
Leukocyte dysfunction
Decreased 2,3-DPG

Renal Acute tubular necrosis

Hepatological Acute liver failure

DR.Khalil TIPS: 1-Hypophosphataemia is the hallmark characteristic of this syndrome. It may also
feature hypokalaemia, hypomagnesaemia and thiamine deficiency, due to underlying malnutrition
and consumption of reserves during the carbohydrate metabolism, that begins with refeeding. This
results in multiple system disorders, including cardiovascular (myocardial contractility impairment
and arrhythmias), respiratory (diaphragm contractility impairment and ventilatory failure),
gastrointestinal (liver cytolysis), muscular (muscle weakness and rhabdomyolysis) and neurological
manifestations (tremors, delirium, seizures or Wernicke's encephalopathy due to thiamine deficit,
even in the absence of alcoholism).

2- Sodium retention (causing oedema) is common, especially after glucose (and sodium) are
given.

3- Considering the high prevalence of hospital malnutrition (approximately 30%), it is essential

to be aware of this condition, which is preventable and remains relatively unknown in the medical
community. The aggressive refeeding of this malnourished woman, highly stimulating anabolism,
resulted in severe metabolic changes that led to multi-organ failure with cardiogenic shock,
ventilatory failure and Wernicke's encephalopathy.
The following criteria seem reasonable:
[1] Cessation of nutrition (usually >5 days) followed by refeeding.

[2] Hypophosphatemia that occurs within three days of refeeding. The optimal cutoff is
unclear, possibly an absolute serum phosphate level below ~1.5 mg/dL (0.5 mM).

[3] Absence of another obvious cause of hypophosphatemia that is felt to account for the
hypophosphatemia

[4] A decrease in phosphate, potassium, and/or magnesium levels by >10-20% (mild

refeeding syndrome) and/or organ dysfunction due to a decrease in any of these and/or due
to thiamine deficiency.

[5] Occurring within five days of reinitiating or substantially increasing energy provision.

Clinical conditions at particular risk of developing RFS.

Clinical Conditions
- Malnourished, catabolic patients - Chronic wasting disease
- Geriatric patients - Chronic pancreatitis
- Oncologic patients - Chronic infectious disease
- Trauma patients - Inflammatory bowel syndrome
- Critically ill patients - Liver cirrhosis
- Hunger strikers or prolonged fasting - Patients with dysphagia
- Short -bowel syndrome - Patients with hemodialysis
- Bariatric surgery - Patients with chemotherapy
- Anorexia nervosa - Patients with chronic alcoholism
- Cystic fibrosis - Drug dependent patients

Pathophysiology and clinical manifestations: The pathophysiology of

the RFS is probably related to the shift from the catabolic to the anabolic metabolic pathways
occurring after the re-start of feeding in undernourished subjects. During early starvation,
blood glucose and insulin levels decline while glucagon concentrations increase by stimulating
glycogenolysis in the liver. When glycogen reserves become depleted, gluconeogenesis is
stimulated in the liver, using amino acids derived from muscle breakdown.
During prolonged fasting, the body switches to use fats as the main sources of energy with a
decrease in basal metabolic rate of 20–25%. Increased lipolysis in fat reserves leads to the
production of ketones that are used by the brain as preferred fuel during starvation. During
prolonged fasting, several intracellular minerals become severely depleted, particularly
phosphate, potassium, and magnesium. However, the concentrations of these minerals may
remain within the normal range in the serum because there is a reduction in their renal
excretion and because of the phosphate outflow from the cells into the blood, leading to
normal blood phosphate levels despite depleted storages. Symptoms generally appear within
2–5 days of re-feeding and may range from absent/mild to a severe and life-threating clinical
syndrome, depending on the pre-existing degree of malnutrition and comorbidity. All the
body organs may be involved, leading to cardiac, respiratory, hematologic, gastrointestinal,
neurologic, and musculoskeletal manifestations, until death

1-Insulin and carbohydrate metabolism: Rapid refeeding in a starved patient causes

the metabolic and hormonal changes underlying the syndrome. The provision of nutrients,
above all carbohydrates, increases insulin secretion and promotes a sudden shift from fat to
carbohydrates metabolism. Insulin stimulates the sodium potassium ATPase symporter, with
magnesium as co-factor, which transports glucose and potassium into the cells and moves
out sodium. Moreover, insulin release stimulates anabolic processes that require minerals
(promoting cellular uptake of phosphate, potassium, and magnesium) and coenzymes, such
as thiamine. The electrolyte shift, along with the depletion of the mineral pool, could lead to
profound hypophosphatemia and low extracellular magnesium and potassium
concentrations, but not necessarily to the depletion of all together. Furthermore, insulin has
an anti-natriuretic effect on renal tubules causing a decrease in urinary sodium and water
excretion. This determines a rapid fluid overload that can lead to congestive cardiac failure,
arrhythmia, and pulmonary edema.
2-Hypophosphatemia: The phosphate is predominantly an intracellular mineral that plays
a key role in energy production and transfer (as a component of adenosine triphosphate
(ATP)and it is necessary for many enzymatic processes of cellular metabolic pathways. During
refeeding, the increased phosphate consumption due to enhanced production of
phosphorylated intermediates results in reduced generation of ATP and 2,3-
diphosphoglycerate with impaired cardiac and respiratory functions, and decreased oxygen
release to the tissues (Table 4).
Effects of hypophosphataemia
Muscular Weakness (diaphragm), respiratory failure
Rhabdomyolysis
Cardiac Biventricular failure, low blood pressure
Arrhythmias, sudden death
Haematological Low and dysfunctional white blood cells, red blood cells, platelets
Haemolysis
Neurological Weakness, lower motor neurone-type paralysis (loss of reflexes)
Cranial nerve palsies
Confusion, ataxia, tremors, fits, coma
Hepatic Dysfunction (especially alcohol excess)

Table 4. Physiopathology and main clinical features of the RFS

Pathophysiological mechanisms Clinical manifestations

1-Hypophosphatemia
Increased phosphate consumption Impaired cardiac and respiratory functions (i.e.,
due to enhanced production of tachycardia and tachypnea)
phosphorylated intermediates for
Neurologic symptoms (i.e., confusion, somnolence,
glycolysis, the Krebs cycle, and the
lethargy, coma, paresthesia, seizures)
electron transport chain to produce
adenosine triphosphate and 2,3- Hematologic disorders (i.e., hemolysis, dysfunction of
diphosphoglycerate platelets and leukocytes, thrombocytopenia)
Hypoxia (due to impaired oxygen release from 2,3-
diphosphoglycerate)
Muscular disorders (i.e., weakness, rhabdomyolysis,
decreased cardiac contractility, myalgia)

2-Hypokalemia
Intracellular shift of potassium by Cardiac arrhythmias
insulin stimulation of the
Na + /K + ATPase
Impairment of potassium reuptake Neurologic symptoms (i.e., weakness, hyporeflexia,
in the nephron (role of respiratory depression, and paralysis) due to impaired
hypomagnesemia) transmission of electrical impulses
 3-Hypomagnesemia
Not completely clear Increased renal losses of potassium
Cardiac arrhythmias (i.e., torsade de pointes, atrial
Intracellular shift of magnesium fibrillation, ventricular arrhythmias)
after carbohydrate feeding Electrocardiograph changes (i.e., prolonged QT and PR,
widened QRS)
Abdominal discomfort (i.e., anorexia, diarrhea, nausea,
vomiting)
Neuromuscular symptoms (i.e., tremor, paraesthesia,
tetany, seizures, irritability, confusion, weakness, ataxia)

4-Thiamine deficiency
Increased consumption of thiamine Neurologic disorders or dry beriberi, Wernicke
by glucose metabolism enzymes encephalopathy and Korsakoff’s syndrome (i.e., ataxia,
disturbance of consciousness, oculomotor abnormalities,
symptoms of acute peripheral neuropathy, coma)
Cardiovascular disorders or wet beriberi (i.e., peripheral
edema, heart failure)
Metabolic acidosis (due to glucose conversion to lactate)

5-Sodium and fluid retention

Renal sodium and fluid retention Peripheral edema
due to insulin antinatriuretic
Pulmonary edema and heart failure (due to increased
properties (after carbohydrate
vasoconstriction and peripheral resistance by sodium
feeding)
stimulation of noradrenaline and angiotensin II)

6-Hyperglycemia
Increased tissue resistance to Metabolic acidosis
endogenous glucose
Hypercapnia, respiratory failure, and risk of fatty liver due
to lipogenesis (stimulated by insulin)
ATP adenosine triphosphate

3-Hypokalemia: Potassium is an intracellular mineral and it is crucial for the

maintenance of the sodium–potassium membrane gradient; hypokalemia causes imbalance
in the electrochemical membrane potential and impaired transmission of electrical impulses
resulting in arrhythmias, cardiac arrest, and neurologic symptoms.
4-Hypomagnesemia: Magnesium plays a role as a cofactor for the phosphorylation of
ATP and it is important for the maintenance of neuromuscular and enzymatic functions. Its
depletion results in increased renal losses of potassium, aggravating hypokalemia with
arrhythmias and ECG abnormalities, and in abdominal discomfort and neuromuscular
symptoms.
5-Thiamine deficit: Thiamine is another cofactor in ATP production. Its increased
consumption during refeeding by the enhanced activity of enzymes implicated in the
carbohydrate metabolism may lead to neurologic disorders (dry beriberi, Wernicke
encephalopathy and Korsakoff’s syndrome), cardiovascular disorders, and metabolic acidosis
(due to the conversion of glucose into lactate).

6-Moderate abnormalities of liver function: Liver enzyme abnormalities are

commonly found both in periods of starvation as well as during the refeeding phase. Excess
glucose administered in the early phase of refeeding, particularly after prolonged periods of
starvation leads to lipogenesis, again as a result of insulin stimulation. Deposition of fatty
acids and triglycerides in the liver can lead to an acute fatty liver often being detected through
raised liver transaminases. Moderate abnormalities of liver function (eg, alanine
transaminase up to 10 times the upper limit of the normal range) should not delay feeding.
7-Other metabolic /clinical abnormalities: Both hyperglycaemia or hypoglycaemia
can occur and need to be managed carefully. Glucose intake after a period starvation, can
suppress gluconeogenesis through the release of insulin. Excessive administration of glucose
can therefore lead to hyperglycaemia and its sequelae including osmotic diuresis,
dehydration, metabolic acidosis and ketoacidosis. Conversely, hypoglycaemia can also occur,
particularly in the presence of sepsis. This may relate to depleted glycogen stores, impaired
gluconeogenesis and increased peripheral glucose utilisation. Hypoglycaemia must be
detected and corrected quickly as if prolonged can lead to permanent cerebral damage.
8-Infection: Hypothermia and low blood glucose are often an indication of sepsis and these
must be urgently treated. In a case series of 14 patients, 2 patients developed occult sepsis
that proved fatal in one case despite intensive therapy unit (ITU) treatment.18 While infection
and sepsis are not classical presentations of RFS, it is important to monitor for these during
the initial period of refeeding as patients with significant malnutrition are at higher risk of
developing severe infections. These patients often do not develop the usual signs of sepsis
(eg, fever, neutrophilia or increased C reactive protein). The combination of low BMI,
hypoglycaemia and hypothermia is often termed the deadly triad and is a marker for severe
infection and should always trigger consideration of antibacterial treatment.

Clinical manifestations of electrolyte abnormalities associated with

refeeding syndrome.
 Clinical Manifestation
Phosphate Hypophosphataemia (normal range 0.8–1.45 mmol/l) presents as
(PO4 2−)
Cardiovascular: heart failure, arrhythmia, hypotension, cardiomyopathy shock,
death
Renal: acute tubular necrosis, metabolic acidosis
Skeleton: rhabdomyolysis, weakness, myalgia, diaphragm weakness
Neurology: delirium, coma, seizures, tetany
Endocrine: hyperglycemia, insulin resistance, osteomalacia
Haematology: haemolysis, thrombocytopenia, leukocyte dysfunction

Potassium Hypokalemia (normal range 3.5–5.1 mmol/l) presents as

(K+)
Cardiovascular: hypotension, ventricular arrhythmias, cardiac arrest, bradycardia
or tachycardia
Respiratory: hypoventilation, respiratory distress, respiratory failure
Skeleton: weakness, fatigue, muscle twitching
Gastrointestinal: diarrhoea, nausea, vomiting, anorexia, paralytic ileus,
constipation
Metabolic: metabolic alkalosis

Magnesium Hypomagnesaemia (normal range 0.77–1.33 mmol/l) presents as

(Mg2+)
Cardiovascular: paroxysmal atrial or ventricular arrhythmias, repolarisation
alternans
Respiratory: hypoventilation, respiratory distress, respiratory failure
Neuromuscular: weakness, fatigue, muscle cramps (Trousseau and Chvostek)
weakness, ataxia, vertigo, paresthesia, hallucinations, depression, convulsions
Gastrointestinal: abdominal pain, diarrhoea, vomiting, loss of appetite, and
constipation
Other: anaemia, hypocalcemia
NB: many cases of hypomagnesaemia do not manifest clinically till very late

Sodium Hyponatremia (normal range 136–145 mmol/l) ensues during RFS due to
(Na+) hyperglycaemia and presents as:
Cardiovascular: heart failure and arrhythmia
Respiratory: respiratory failure, pulmonary oedema.
Renal: renal failure
Skeleton: muscle cramps, fatigue, fluid retention and swelling (oedema)
 Vitamins Deficiency of thiamine (especially in alcoholism) presents as
Neurology: Wernicke-Korsakoff syndrome, Karsakoff's psychosis,
Cardiovascular: congestive heart failure and lactic acidosis, beriberi, disease
Skeleton: muscle weakness

Prevention and treatment: The identification of patients at risk for RFS is the
first step to prevent the onset of the syndrome, and to avoid an excessive nutritional
replenishment in those individuals. Risk factors should be carefully investigated before
starting either oral, enteral, or parenteral nutrition, because every route of calorie
administration is implicated in the occurrence of the RFS.
Prevention & monitoring for at-risk patients
[1] Electrolyte monitoring & repletion

Follow lytes (including Ca/Mg/Phos) for 3 days:

A-Any hypophosphatemia should be aggressively treated (e.g., <2.5 mg/dL or <1.6 mM).
B-If phosphate falls below <1.5 mg/dL (<0.5 mM) this indicates refeeding syndrome.
C-Aggressive repletion of K and Mg (target K>4 mM and Mg >2 mg/dL).
D-Consider early enteral phosphate in very high-risk patients:
Criteria for prophylactic phosphate supplementation:
[1] Very high risk of refeeding syndrome.
[2] GFR >>30 ml/min.
[3] Phosphate is low or low-normal (below ~3.5 mg/dL).
[4] Absence of hypercalcemia (which could increase risk of Ca-Phos precipitation). A reasonable
dose might be 8 mM PO TID for three days.
[2] Micronutrients: Thiamine 100 mg IV daily. It's unclear whether IV thiamine is absolutely
required here, or whether oral thiamine would be adequate. Some studies have demonstrated that
the bioavailability of oral thiamine is substantial. However, sufficient thiamine might not be
absorbed rapidly enough for patients at the highest risk of refeeding syndrome. Thus, the choice of
IV versus PO may depend on clinical factors (e.g. individual risk of refeeding syndrome and
functionality of the gastrointestinal tract). Vitamin B12, 1000 mcg PO daily. Daily multivitamin.

[3] For the highest risk patients: gradual initiation of nutrition ….Ideal composition?

Carbohydrate intake should probably be limited, because this stimulates an endogenous insulin
surge which contributes to electrolyte depletion.

Perhaps carbohydrates should initially be limited to <40% of the total energy intake.

Ideal rate? Many sources recommend starting conservatively (e.g., 50% energy requirement), with
gradual advancement. For patients with the highest risk of refeeding syndrome, starting with 5
kcal/kg/day might even be considered (e.g., for a patient with BMI <14 kg/m2 and no nutritional
intake for two weeks).
 [4] Permissive glycemic control: Insulin appears to play a central role in the generation of refeeding
syndrome. It seems logical to avoid aggressive insulin administration (e.g., allowing glucose to rise
to ~250 mg/dL).

Well-trained medical staff and specialized nutritional support teams, consisting of physicians,
dieticians, nurses, and pharmacists, positively impact on the patient outcomes. However, a
multidisciplinary team is not available in all hospital settings, and often the evaluation of the
risk for RFS is left to the clinician's critical sense at the time of starting nutritional support.
After defining the degree of RFS risk, the rate of fluid and nutrition administration, the
correction of electrolyte imbalances, and the supplementation of vitamins and micronutrients
(zinc, iron, selenium) can be determined. If a prolonged nutritional support is required,
adjustments over time in accordance with the patient clinical conditions might be necessary.
Diagnostic criteria for RFS severity
Severity of RFS Mild Moderate Severe
Serum electrolytes* 10–20% less 20–30% less > 30% less and/or organ dysfunction**
Timing From hours up to 5 days after increasing the energy provision in an individual at risk
*Decrease in any (one or more) of electrolyte serum levels, among phosphate, potassium, and/or
magnesium

**Resulting from the decrease in any electrolyte and/or from thiamine deficiency

Cancer: Up to 50–80% of patients with advanced cancer are at high risk of developing RFS, in
particular individuals with head and neck cancer. Cancer cachexia cannot be arrested or reversed by
any known form of nutritional, hormonal, or pharmacological treatment. There are no specific
guidelines on how to re-feed cancer patients at risk for RFS, being NICE recommendations the most
frequently used. In patients eating little or nothing for more than 5 days, refeeding should be started
with no more than 50% of the caloric requirements, with ≤ 10 kcal/kg/day in high-risk patients
and ≤ 5 kcal/kg/day in very high-risk patients (BMI < 14 kg/m2 or negligible intake for 2 weeks or
more. Owing to the potential benefit of protein intake on muscle anabolism, cancer patients should
receive a protein intake of 1 g/kg/day up to 1.5 g/kg/day. When oral refeeding is possible, the use
of oral nutritional supplements can be useful in reaching nutritional goals; if oral feeding is either
impossible or insufficient, enteral, or parenteral nutrition should be considered, with slow
progressive caloric increase to reach the full needs within 4–7 days. In the case of cancer cachexia,
a very cautious refeeding should begin by initially supplying about 25% of the estimated calorie
requirement, with a very gradual caloric increase over several days, and a careful monitoring of
phosphate and electrolytes serum levels.
For patients at high risk of developing refeeding syndrome, nutritional
repletion of energy should be started slowly (maximum 0.042 MJ/kg/24 hours) and should be
tailored to each patient. It can then be increased to meet or exceed full needs over four to
seven days. In patients who are very malnourished (body mass index ≤14 or a negligible intake
for two weeks or more), the NICE guidelines recommend that refeeding should start at a
maximum of 0.021 MJ/kg/24 hours, with cardiac monitoring owing to the risk of cardiac
arrhythmias (level D recommendation). This explicit specification of the rate of refeeding in
severely malnourished patients should help avoid complications arising from rapid refeeding
and is an improvement on previous guidelines. The NICE guidelines also state that correcting
electrolyte and fluid imbalances before feeding is not necessary and that this should be done
along with feeding. This is a change from previous guidelines4 and potentially avoids
prolongation of malnourishment and its effects on patients.

All guidelines recommend that vitamin supplementation should be started

immediately, before and for the first 10 days of refeeding. Circulatory volume should also be
restored. Oral, enteral, or intravenous supplements of the potassium, phosphate, calcium,
and magnesium should be given unless blood levels are high before refeeding. Good quality
studies on the exact levels of supplementation are lacking, however, and so the required
levels of these supplements cited by NICE (figure) are only level D recommendations.

Electrolyte levels should be measured once daily for one week, and at least three times in the
following week. Urinary electrolytes could also be checked to help assess body losses and to
guide replacement.

How can refeeding syndrome be detected and treated? Treatment of

patients at risk of refeeding problems:

1-Once detected these patients should be carefully observed/monitored while their

circulatory volume (dehydration) is restored (generally using little/no sodium-containing
solutions) and their fluid balance/daily weight is monitored. Hypothermia and sepsis if
present must be treated. Cardiac monitoring is recommended for inpatients with cardiac
manifestations and/or ECG changes secondary to hypokalaemia, patients with a QTc >450 ns
or where intravenous correction of potassium at a rate of >10 mmol/hour is deemed
necessary. These severely at-risk patients should ideally be managed by the hospital nutrition
support team.

2-Energy: When the UK NICE guidelines were published there were no good quality trials
to enable evidence-based management protocols to be developed so reliance was on expert
opinion. It suggested that people who had eaten little or nothing for >5 days should have
nutrition support introduced at no more than 50% of requirements for the first 2 days; that
the prescription for people at high risk of developing refeeding problems could be given
nutritional support at a maximum of 10 kcal/kg/day, increasing slowly to meet or exceed full
needs by 4–7 days. However, prolonged administration of very low energy feed risks the
problem of underfeeding which may exacerbate problems associated with malnutrition. A
survey in 2008 showed 39% felt the guidance was appropriate and 36% felt it was too
cautious.

A reasonable strategy to avoid the risks of both refeeding problems as well as underfeeding
would be to start feeding cautiously in patients at high risk of refeeding problems at 10–20
kcal/kg/day, while simultaneously correcting electrolyte deficiencies, but then increasing the
feeding rate at least daily aiming to achieve feeding to match their metabolic demands over
a period of 5–7 days , while keeping a careful watch on clinical and biochemical
parameters. Feeding to full requirements should be achieved within 5–7 days. Specialist
dietitians or nutrition support teams are invaluable in providing expert advice on this aspect
of care. The non-protein energy should be given as approximately 50% carbohydrate and 50%
lipid mix. If signs of refeeding problems or adverse clinical markers ensue, the feed may need
to be temporally slowed, reduced or stopped.

3-Phosphate replacement:A low threshold for starting intravenous correction

should be employed and most advocate intravenous replacement for patients at high risk of
RFS at PO4 levels of <0.6 mmol. Intravenous phosphate supplements could be in the form of
monobasic potassium phosphate or the more widely used phosphate infusion, Polyfusor.
Electrolytes need to be closely monitored as the latter contains significant amounts of sodium
and potassium. One litre of Polyfusor contains 100 mmol of PO₄³ˉ, 162 mmol of sodium and
19 mmol of potassium. Excessive doses should also be avoided as they can result in
hypocalcaemia and metastatic calcification. Small infusions of 10–20 mmol phosphate, that
is, 100–200 mL of Polyfusor are advocated and repeated if necessary to reduce the risk of
metastatic calcification. Phosphate must be administered concurrently with low rate feeding,
to avoid the risk of desirable electrolytes simply being excreted in the urine, rather than being
transported into the cells.

4-Thiamine, other vitamins and trace elements: It is crucial that thiamine

supplementation is started prior to and continued during nutrition support and glucose
administration. Oral thiamine can be given at a dose of 200–300 mg/day. One to two tablets
of vitamin B co strong can be given three times a day. A daily intravenous vitamin B
preparation such as Pabrinex can be given intravenously (usually for 3–5 days) in addition to
an oral multivitamin supplement. A balanced multivitamin/trace element supplement once
daily for 10 days is recommended in UK NICE guidelines. If signs of Wernicke’s
encephalopathy are present the B vitamins need to be given intravenously.

5-Electrolytes (potassium and magnesium): A drop of serum potassium by 1 mmol/L

is equivalent to a total deficit of approximately 200–400 mmol. Mild asymptomatic
hypokalaemia is ideally corrected orally with potassium chloride used to provide up to
50 mmol/day. Intravenous potassium can be used to treat significant hypokalaemia with
potassium levels <3.0 mmol/L. Intravenous infusion with potassium chloride concentration of
40 mmol/L is used when using peripheral veins. This can be administered at a rate of 10–
20 mmol/hour. Higher concentrations of intravenous potassium delivered into a central vein
can be used with close cardiac monitoring after specialist advice. The UK NICE guideline
recommends providing oral, enteral or intravenous supplements of potassium with the likely
requirements being 2–4 mmol/kg/day. About 80% of plasma magnesium is filtered through
glomeruli. Intravenous infusion of magnesium will result in a transient increase in magnesium
levels and consequently renal wasting of a substantial proportion of that magnesium. So, in
more severe hypomagnesaemia where higher magnesium supplements are required, these
should be administered over longer hours to avoid sudden increases in magnesium levels. In
hypomagnesaemia, 20–40 mmol of magnesium sulfate can be given over 1–2 hours. The UK
NICE guideline recommends providing oral, enteral or intravenous supplements of
magnesium with the likely requirements being 0.2 mmol/kg/day intravenously,
0.4 mmol/kg/day orally.
Cautious use of insulin: Exogenous insulin will exacerbate the electrolyte
abnormalities involved in refeeding syndrome (e.g., hypophosphatemia, hypokalemia).

[A] Uncontrolled hypokalemia or hypophosphatemia are contraindications to insulin. Hold

insulin until electrolytes can be repleted appropriately.

[B] Avoid aggressive insulin administration (e.g., allowing glucose to rise to ~250 mg/dL).

6-Fluid: Should problems with fluid overload occur, an ‘ABC’ approach to resuscitation
should be taken and transfer to intensive care unit (ICU) should be considered. If absolutely
necessary, diuretics may be required but may have the effect of lowering circulating
electrolytes further. If this occurs, central access should be sought and administration of
concentrated electrolytes in ICU may be appropriate. The feed should be slowed further while
these issues are being managed.
Refeeding regime for patients at risk of RFS
Day Calorie intake (All feeding routes) Supplements

Day 1 10 kcal/kg/day Prophylactic supplement

For extreme cases PO4 2−: 0.5–0.8 mmol/kg/day
(BMI < 14 kg/m2 or no food >15 days) K+: 1–3 mmol/kg/day
5 kcal/kg/day Mg2+: 0.3-0.4 mmmol/kg/day
Carbohydrate: 50–60% Na+: <1 mmol/kg/day (restricted)
Fat: 30–40% IV fluids-Restricted, maintain “zero”
Protein: 15–20% balance
IV Thiamine + vitamin B complex 30
minutes prior to feeding

Day 2–4 Increase by 5 kcal/kg/day Check all biochemistry and correct any
If low or no tolerance stop or keep abnormality
minimal feeding regime Thiamine + vitamin B complex orally or IV
till day 3
Monitoring as required

Day 5–7 20–30 kcal/kg/day Check electrolytes, renal and liver functions
and minerals
Fluid: maintain zero balance
Consider iron supplement from day 7

Day 8–10 30 kcal/kg/day or increase to full requirement Monitor as required

Suggested supplementation regimen

Potassium Magnesium Phosphate

Mild 3.1–3.5 mmol/L 0.5–0.7 mmol/L 0.61–0.8 mmol/L

deficiency Oral replacement with Oral replacement with Oral replacement with 0.3
 20 mmol (as KCl or 10–15 mmol MgCl2 or mmol/kg/day PO4 (divided
other salts) Mg-citrate or Mg-L- doses to minimize diarrhea)
OR aspartate OR
i.v. replacement with Oral Mg should be i.v. replacement with 0.3
20 mmol KCl over 4 to given in divided doses mmol/kg/day PO4 (as
8 h. Check levels the to minimize diarrhea K3PO4 or Na3PO4) over 8–12
next day. (absorption process is h. Check levels the next day.
saturated at about 5–
10 mmol Mg) 0.32–0.6 mmol/L
2.5–3.0 mmol/L
i.v. replacement with 0.6
i.v. replacement with
mmol/kg/day PO4 (as
20–40 mmol KCl over
Moderate K3PO4 or Na3PO4) over 8–12
4–8 h. Check levels
deficiency h. Check levels after 8–12 h
after 8 h; if not normal,
and repeat infusion if
give an additional 20
necessary (max. of 50 mmol
mmol KCl.
PO4 in 24 h).

<2.5 mmol/L
<0.5 mmol/L
i.v. replacement with
i.v. replacement with
40 mmol KCl over 4–8 <0.32 mmol/L
Severe 20–24 mmol
h. Check levels after 8 Same replacement therapy
deficiency MgSO4 (4–6 g) over 4–
h; if not normal, give as for moderate deficiency.
8 h. Reassess every 8
an additional 40 mmol
to 12 h.
KCl.
Fluid repletion should be carefully controlled to avoid fluid overload as described earlier. Sodium
administration should be limited to the replacement of losses. In patients at high risk of cardiac
decompensation, central venous pressure and cardiac rhythm monitoring should be considered.
 Chapter 48: Interesting Cases To Study
Case 1: A 29-year-old woman has been admitted to the hospital. She complains of severe
shortness of breath. Her room air arterial blood gas values are as follows: PaO2 = 65 mm Hg PaCO2 =
30 mm Hg pH = 7.45 HCO3 − = 20 mEq/L FIO2 = 0.21 PB = 760 mm Hg How much oxygen is needed to
achieve a PaO2 of 90 mm Hg?

What FIO2 should be used?

Discussion: The equation used to calculate a FIO2 required for a desired PaO2 is as follows:

This equation is a rearrangement of the alveolar air equation.

The following shows the alveolar air equation solved for FIO2:

PAO2 = FIO2 (PB − 47) − PaCO2 × 1.2 (1)

FIO2 (PB − 47) = PAO2 + PaCO2 × 1.2 (2)

FIO2 =(PAO2 + PaCO2 × 1.2)/(PB – 47) (3)

Equation 3 is similar to the “FIO2 required” equation. In fact, equation 3 can be used to calculate the
FIO2 required. The PAO2 in the numerator of equation 3 is the PAO2 needed to produce the desired
PaO2. This needed PAO2 can be calculated as follows if the original PaO2/PAO2 ratio is known:

Needed PAO2 = Desired PaO2 / (PaO2 / PAO2) The term “desired PaO2/(PaO2/PAO2)” in the
numerator of the “FIO2 required” equation is merely a way to calculate the PAO2 needed to achieve
the PaO2 desired. The PaO2/PAO2 ratio can be calculated from the current measured PaO2, and the
PAO2 can be calculated from the current FIO2.

First, the patient’s PaO2/PAO2 ratio is calculated from current data. This ratio indicates the fraction
of the PAO2 that entered the arterial blood. Dividing the desired PaO2 by this fraction provides the
PAO2 that must exist in the alveoli to produce the desired PaO2 in the arterial blood. Using the patient’s
current data, you can determine the following:

Current PAO2 = 0.21(760− 47)− (30 × 1.2) = 113.73 mm Hg Current PaO2 = 65 mm Hg PaO2/PAO2
=65/113.73 = 0.57

This means 0.57, or 57%, of the PAO2 enters the blood. Therefore, the desired PaO2 of 90 mm Hg
must be 0.57 of the needed PAO2, as the following shows:

90 mm Hg =0.57 × needed PAO2

90 mm Hg/0.57= 157.9 mm Hg = needed PAO2 to achieve PaO2 of 90 mm Hg Referring to the “FI O2

required” equation at the beginning, the appropriate numbers are inserted to arrive at the following
solution:
FIO2 = 157.8 + (30 × 1.2) /(760 − 47)

FIO2 = 193.8 /713

FIO2 = 0.27

An FIO2 of 0.27 should produce a PaO2 of about 90 mm.

Case 2: You are asked to assess a breathless patient in the emergency department. He has
a history of anxiety and depression and says he feels like he is having a panic attack. He has a raised
respiratory rate but saturations are with target range 94–98% on air. He has an arterial blood gas taken
on air, which shows:

• pH 7.52 • Pao2 12.3 kPa • Paco2 2.7 kPa • HCO3 21 mmol/L What is the single most likely explanation
for these findings?

A Hyperventilation syndrome

B Pulmonary embolus

C Salicylate overdose

D St John’s Wort poisoning

E Viral pneumonitis

Answer (B) Pulmonary Embolism… The Pao2 is within ‘normal range’ but is not normal when the
Paco2 is also considered. If the Paco2 is normal the Pao2 for different Fio2 can be estimated as: Pao2
(kPa) = Fio2 (%) × 0.75. If the patient is breathing air, the sum of the Pao2 and Paco2 should be around
17 kPa if the lungs are normal. This is a useful rule of thumb that does not require complex calculations.
Therefore this cannot be hyperventilation alone [A] since a Pao2 of 15.75 kPa would be expected
breathing air (21% O2), and the sum of Pao2 and Paco2 in this case is 15 kPa, not 17 kPa as expected.
Pulmonary embolus explains the findings completely [B]. In salicylate overdose [C], a respiratory
alkalosis is common, and in severe cases a metabolic acidosis is also present giving a mixed picture. St
John’s Wort poisoning leads to hyperventilation and a respiratory alkalosis but no decrease in Pao2
[D]. A viral pneumonitis [E] could result in these results on arterial blood gas but considering the history
it is less likely than PE.

Case 3: You are called to the accident and emergency (A&E) department to review a 19-year-
old female non-smoker with pleuritic chest pain. A CXR does not demonstrate any obvious
abnormality. An arterial blood gas has been performed on room air:

• pH 7.44 • po2 85 mmHg • pco2 26 mmHg • HCO3 22 mmol/L •Lactate 1.1

What is the single most accurate statement regarding these results?

A- A CTPA is indicated

B- A left to right cardiac shunt requires exclusion

C- The blood gas needs repeating

D- The normal po2 excludes pulmonary embolism.

E- This value is not possible in this age group

Answer is (A) A CTPA is indicated Despite the seemingly ‘normal’ po2 the pco2 is low indicating
hyperventilation.

Normal PaO2 +PCO2 = 17 Kpa about 130 mmHg .. so if PCO2 26 mmHg PaO2 should be 130- 26 = 104
mmHg but here only 85 so there is relative hypoxia to agiven CO2.

A-a gradient at sea level

PAO2 = 150-1.25 X PaCo2 = 150- 32.5= 117.5 mmHg

A-a gradient = 117.5- 85= 32.5 mmHg….So there is hypoxia with increase alveo-arterial gradient.

Hypoxia with increase alveo-arterial gradient may suggest pulmonary embolism supported by normal
x ray and clinical picture.

The A-a gradient has been calculated as 32.5 mmHg, indicating a V/Q mismatch, i.e. the po2 is
inappropriately low for this level of hyperventilation and therefore a PE [A] should be excluded. A right
to left cardiac shunt is another cause of a raised A-a gradient and therefore [B] is incorrect. A normal
A-a gradient in this age group is 1–2 kPa. Measurement of the A-a gradient allows you to calculate the
difference between what the arterial po2 (pao2) is, and what it should be, based on the alveolar po2
(pAo2). This is calculated from the alveolar gas equation. You would not be expected to calculate A-a
gradient yourself in the examination but you should be aware of the range of possible values. There
are many apps and online tools available to aid calculation of A-a gradient in daily practice. The normal
A-a gradient increases from 1 to 3 kPa with age.

Case 4: A mechanical ventilator is delivering 10 breaths per minute to your patient. The VT is 700
mL, and the patient’s estimated VD anat is 160 mL. Arterial blood gas results reveal a PaCO2 of 40 mm
Hg. What happens to V˙ A and PaCO2 if the respiratory rate is increased to 16 breaths per minute but
the V˙E remains constant?

Discussion

Initial V˙E and V˙ A are calculated as follows:

V˙E =700 × 10 =7000 mL/min

V˙A =(700 − 160) × 10 = 5400 mL/min

With a V˙A of 5400 mL/min, PaCO2 is normal at 40 mm Hg.

If V˙E stays the same while you increase the respiratory rate to 16 breaths per minute, VT must
decrease (i.e., the ventilatory pattern is changed to a rapid, shallow pattern).

This is shown as follows: 7000 = VT × 16

VT = 7000 / 16 = 437.5 mL

Because VD anat remains the same at 160 mL, V˙A must decrease. This is shown as follows:

V˙A = (437.5 − 160) × 16 = 4440 mL/min After the change in respiratory rate, arterial blood gases reveal
a PaCO2 increase from 40 mm Hg to 49 mm Hg. CO2 production remained the same, and the reduced
V˙A resulted in a decreased removal of CO2 from the body, creating a state of hypoventilation.
Case 5: The lungs of a patient in the intensive care unit are mechanically ventilated with the
following settings:

f= 12/min VT = 500 mL You also have the following information about your patient:

VD = 150 mL PaCO2 =40 mm Hg Approximately 1 hour later, the patient seems to be agitated and is
triggering the ventilator at a rate of 24/min (VT is still 500 mL). Estimate the patient’s new PaCO2.

Discussion: To solve this problem, you first must determine the V˙ A for both situations. This is done
as follows:

Initial V˙A
V˙A = V˙ E − VD

V˙A = (500 mL × 12)− (150 mL × 12)

V˙A = 6000 mL/min − 1800 mL/min

V˙A = 4200 mL/min

New V˙A
V˙A = (500 × 24)− (150 × 24)

V˙A = 12, 000 mL/min − 3600 mL/min

V˙A = 8400 mL/min Solve for PaCO2 using the following equation:

PaCO2 × V˙A = K This is equivalent to the following:

Initial (PaCO2 × V˙A) =new (PaCO2 × V˙A) Solve for the new PaCO2.

This is done as follows:

PaCO2 (initial) × V˙ A (initial) = PaCO2 (new) × V˙A (new)

40 × (40 × 4200)/ 8400 = PaCO2 (new)

168, 000 /8400 = 20 mm Hg

The inverse relationship between PaCO2 and V˙ A is shown. In this situation, V˙A was doubled, reducing
PaCO2 by one half. Thus, the PaCO2 of a patient whose lungs are mechanically ventilated changes if
the ventilator’s delivered V˙ E is changed (i.e., by changing VT, respiratory rate, or both).

Case 6: A patient with acute respiratory distress syndrome whose lungs are
mechanically ventilated is in the intensive care unit. Current arterial blood gas values are as follows:
pH = 7.34 PaCO2 = 50 mm Hg HCO− 3 = 26 mEq/L The patient’s lungs have such low compliance that
dangerously high pressures are required to maintain normal tidal volumes and alveolar ventilation (V˙
A).

The respiratory therapist and attending physician decide to decrease the tidal volume delivered by the
ventilator to prevent structural damage to lung tissue. In this way, alveolar pressures and the risk of
alveolar rupture can be decreased. However, the decrease in tidal volume will cause the PaCO2, which
is already above normal, to increase further, decreasing the arterial pH even more.
Nevertheless, some degree of hypercapnia and acidemia is acceptable if the detrimental effect of
pressure-induced alveolar trauma (barotrauma) is avoidable. The respiratory therapist and physician
decide they will not allow the pH to decrease below 7.25.

The patient’s lungs are being ventilated with a tidal volume of 700 mL at a frequency of 10 breaths per
minute for a V˙E of 7 L per minute. How high can the PaCO2 be allowed to increase without decreasing
the arterial pH below 7.25, and how much should the tidal volume be decreased to accomplish this?

Discussion
First, the PaCO2 that will produce a pH of 7.25 needs to be calculated as follows, using known values:

A PaCO2 of 62 mm Hg will produce a pH of about 7.25.* Next, V˙E required to produce a PaCO2 of 62
mm Hg must be calculated. Chapter 9 indicated that V˙E is inversely proportional to PaCO2, as the
following equation shows:

(V˙E)1 × (PaCO2)1 = (V˙E)2 × (PaCO2)2

In this equation, subscripts 1 and 2 represent current and future values.

The solution for (V˙E)2 is as follows:

7 L/min × 50 mm Hg = (V˙E)2 × 62 mm Hg

(7 × 50)/62= (V˙E)2 5.65 L/min = (V˙E)2

Decreasing V˙ E from the current value of 7 L per minute to 5.65 L per minute produces a PaCO2 of
approximately 62 mm Hg and a pH of 7.25.

The newly calculated V˙ E of 5.65 L per minute is divided by the respiratory frequency (10 breaths per
minute) to calculate the new tidal volume (VT = 5.65 L/ min ÷ 10 = 0.565 L or 565 mL).

A tidal volume of 565 mL at a respiratory rate of 10 breaths per minute should produce a pH of about
7.25 in the patient. This example is more theoretical than it is practical; in the clinical setting, the
patient’s minute ventilation would be gradually reduced over time to allow the kidneys to compensate
(retain HCO− 3 ions) and keep the pH closer to the normal range.

Case 7: A 40-year-old woman came to the hospital for an elective upper endoscopy. Her throat
was sprayed with benzocaine prior to the case. She tolerated the procedure well but shortly after the
case she complained of shortness of breath. She was noted to be cyanotic. The RT placed her on a
pulse oximeter and treated her with 100% O2 via a mask. Her O2 saturation was 85% unresponsive to
O2. Blood was drawn for an ABG. The blood was noted to be chocolate brown in color. Running the
blood sample through a calibrated ABG analyzer without a hemoximeter produced the following
results:

pH = 7.30 PaO2 = 104 mm Hg PaCO2 = 17 mm Hg SaO2 = 98% What other information is needed to
diagnose the patients’ problem?
Solution The patient shows signs of methemoglobinemia. The O2 saturation levels measured with
pulse oximetry are substantially lower than ABG O2 saturation levels. This saturation gap should alert
the practitioner that an alternative, nonfunctional species of hemoglobin is present. A sample of blood
should be run through a hemoximeter to check the metHb level to confirm the diagnosis.

Case 8: A patient with ARDS has deteriorating oxygenation associated with a new infiltrate
on chest x-ray. Gram-negative bacterial ventilator-associated pneumonia is strongly suspected, and FB
is deemed necessary before adjusting antibiotic therapy because the suspected pathogen is likely to
be multidrug resistant. The patient has a high minute ventilation demand of 13 L/min to maintain a pH
of 7.40 and PaCO2 of 40 mm Hg. The patient has sepsis and currently requires norepinephrine at 12
mcg/min to maintain a mean arterial pressure of 65 mm Hg. The physician decides that during FB, a
pH of 7.24 would be tolerable for the estimated procedure time of 10 minutes.

The RT is asked if there is a clinical formula to estimate what rise in PaCO2 would likely produce the
target minimum pH. In addition, the RT is asked to estimate the minimum minute ventilation needed
during FB that would likely maintain pH at 7.24.

Discussion In patients without chronic hypercapnia, an acute rise in PaCO2 of 10 mm Hg

produces a decrease in pH of 0.008.89 Because tidal volume can be greatly reduced during FB, the RT
can reasonably begin with an estimated PaCO2 increase of 20 mm Hg. This would yield an estimated
drop in pH of 0.16 units (20 × 0.008) and a pH of 7.24 (7.40 − 0.16). The clinical formula for corrected
minute ventilation then can be used to estimate the minimum acceptable minute ventilation.

Patients with high minute ventilation demands who require vasopressor support to maintain adequate
perfusion may be particularly sensitive to sudden respiratory acidosis. The fact that this patient already
requires the highest recommended dose of norepinephrine to maintain an adequate blood pressure
is cause for concern about the safety of performing FB. The steps described previously are only
estimates for guiding management during FB and assessing the risk-to-benefit ratio.

Case 9: Apatient presents with: pH 7.45, PCOZ 65, [HC03-] 44, AG 14. Short of breath for 3 days.

Step 1: Both the PCO2 and the [HC03-] are very high. The pH is normal. Let's call this a metabolic
alkalosis because the pH is a little on the high side.

Step 2: What should the PCO2 be? For a metabolic alkalosis, the PCO2 should be 40 + .7 X (44 - 24) =
54. The patient's PCO2 of 65 is 11 mm Hg too high. Therefore: respiratory acidosis.

Step 3: The anion gap is normal. Answer: Respiratory acidosis and metabolic alkalosis. Note that the
pH is normal, while the PCO2 and the [HC03-] are both severely abnormal. This tells us immediately
that there is a mixed disorder, because a patient cannot compensate all the way to a normal pH except
in the case of a chronic respiratory alkalosis.
This is an example of two disorders offsetting each other; that is, the disorders tend to cancel each
other by pushing the pH in opposite directions. If you just eyeball the chemistries you might think that
this patient has a simple respiratory acidosis with metabolic compensation: The data look as if there is
only one disorder. Step 2 tells us that this is not just a simple respiratory acidosis with metabolic
compensation. This patient has two distinct disorder

Case 10: A previously well patient presents with 30 minutes of respiratory distress and pH 7.26,
PC02 60, [HC03-] 26, AG 14.

Step 1 : The PCO~ is up. The pH is down. Respiratory acidosis. The history says acute.

Step 2: For respiratory disorders we ask: What should the [HC03-] be? Remember that the calculations
for metabolic compensation are in terms of changes of 10 in Pcoz. The PCOZ is up by 20 which is 2 X
10.

For an acute respiratory acidosis, the [HC03-] should change by 1 mEqL for every 10 mm Hg increase
in the PCOZ. Therefore, the [HC03-] should change by 2 X 1 mEqL = 2 mEqL. Using 24 as normal, the
[HC03-] should become: 24 + 2 = 26. Therefore, the compensation is appropriate, and there is no
metabolic disorder. Step 3: The AG is normal. We are finished. Answer Acute respiratory acidosis.

Case 11: Anxious. Can't seem to get enough air for last 4 days. pH 7.42, PCO2 30, [HC03-] 19, AG 16.
Step 1: PCO2 down. pH up. Respiratory alkalosis. The history indicates chronic respiratory alkalosis.

Step 2: What should the [HC03-] be? Remember that the calculations for metabolic compensation are
in terms of changes of 10 in PCOZ. The PCO~ is down by 10 which is 1 X 10. For a chronic respiratory
alkalosis, the [HC03-] should be down by 5 for every 10 mm Hg decrease in Pco2. For this chronic
respiratory alkalosis, the [HC03-] should be down by 1 X 5. The [HC03-] should be 24 - 5 = 24 - 5 = 19.

Therefore, the compensation is appropriate, and there is no metabolic disorder.

Step 3: The AG is normal. We are finished. Answer: Chronic respiratory alkalosis. It is of interest that
chronic respiratory alkalosis is the only simple disorder in which compensation can bring the pH back
into the normal range (7.42 in this case).

Case 12: A patient presents with: pH 7.08, [HC03-] 10, PCO2 35, anion gap 14 mEq/L.

Step 1: The [HC03-] is 10, and the pH is 7.08. There is a severe metabolic acidosis.

Step 2: What should the PCOZ be? The PCO~ should be:

The PCOZ of 35 mm Hg is much higher than we would expect! Therefore, there is something pushing
the PCO2 up. It is a coexisting respiratory acidosis. There is a respiratory acidosis present as well as a
metabolic acidosis.

Step 3: The anion gap is 14 (normal). We are finished.

Answer: Normal anion gap metabolic acidosis plus respiratory acidosis.

The patient's Pco2 is 35. This is much higher than predicted by the formula. Therefore, the patient has
a respiratory acidosis which might represent "tiring out" of the patient's respiration and impairment
of his ability to compensate for the metabolic acidosis. It could also be a clue to a coincident pulmonary
process. The rising PCO2 is a dangerous sign in metabolic acidosis, because further increase in the
PCO2 could lead to a precipitous fall in pH.

An important clinical note about the maximum compensation possible for a metabolic acidosis: In a
young person, the maximum respiratory compensation (the lowest attainable Pco~) is around 10-15
mm Hg. The value is about 20 mm Hg in an older person, indicating less ability to compensate by
increasing ventilation.

Therefore, there is a limit to the magnitude of respiratory compensation possible for a metabolic
acidosis. A patient with a [HC03-] of 3 and maximal respiratory compensation will have a PCO2 of
roughly 1.5 X 3 + 8 = 12.5 mm Hg. This is approximate because the compensation curve is not entirely
linear at extremely low levels of HC03. The pH with this HC03- concentration and P02 will be 7.00.

To keep the PCO2 at 12.5 mm Hg takes a big effort. How long can the patient keep breathing deep and
fast enough to hold the PCO2 at 12.5 mm Hg before tiring out? Suppose the patient begins to develop
respiratory muscle fatigue, and the PCO2 creeps up to 20 mm Hg. The pH will plummet to 6.80! The
clinical point is that a young patient with severe metabolic acidosis and a Pco2 of 10-15 mm Hg or an
older patient with a PCO2 of 20 mm Hg is "on the edge" of compensation; any further increase in PCO~
or further decrease in [HCO3-] can mean disaster!

Case 13: A 40-year-old man is admitted with the following chemistries: sodium I 140 mEq/L,
chloride 86 mEq/L, bicarbonate 40 mEq/L, potassium 3.0 mEq/L, glucose 120 mg/dl, BUN 32 mg/dl, Cr
1.4 mg/dl. Arterial blood gas: pH 7.52, P02 5 1 mrn Hg, HCO3- 40 mEq/L. What is your general approach
to this patient? Answer: The diagnosis of acid-base disorders requires a systematic approach to identify
all the disorders present in a given patient

Step 1: Identify a single disorder. The pH is high and the bicarbonate is also high. Therefore, metabolic
alkalosis is present.

Step 2: See if the compensation is correct. If the compensatory change in PCO2 in response to the
metabolic alkalosis is not as predicted by the formula, then a respiratory disorder is present. For a
metabolic alkalosis, the PCO2 should be PCO2 = 40 + .7 X ([HC03- (measured)] - [HC03- (normal)])

= 40 + .7 (40-24) = 51.2 mm Hg.

This assumes a normal [HC03-] of 24 mEq/L.

The measured PCO2 of 51 mm Hg is equal to that predicted by the formula.

Therefore, compensation is appropriate, and no respiratory disorder is present. Remember to use

values for both the PC02 and the [HC03-] from the arterial blood gas for Step 2.

Step 3: Calculate the anion gap using serum values:

AG = [Na+] - ([Cl-] + [HC03-]) = 140 - (86 + 40) = 14 The anion gap is normal. We are finished. This
analysis tells us that the only acid-base disorder present is a metabolic alkalosis.

Now, we must turn our attention to finding and correcting the cause for the abnormal renal retention
of bicarbonate. We perform a careful history and physical, which includes checking for ECFV depletion
due to vomiting, nasogastric suction, chronic diarrhea , laxative use, and diuretics, as well as signs of
secondary hyperaldosteronism (congestive heart failure and cirrhosis). Hypertension suggests
renovascular disease, primary hyperaldosteronism, or Cushing's syndrome, although primary
hypertension may occur without any of these disorders. Remember that profound potassium
depletion alone may cause renal retention of bicarbonate. The urine chloride is helpful in diagnosing
metabolic alkalosis caused by ECFV depletion. It is generally low (less than 10 mEq/L) in cases of
metabolic alkalosis maintained by ECFV depletion. The urine sodium, which is also generally low in
cases of volume depletion, is less helpful in cases of metabolic alkalosis caused by ECFV depletion. The
reason is that excess bicarbonate that is not reabsorbed by the proximal tubule acts as a non-
reabsorbable anion, bringing sodium to the collecting tubule. This results in more sodium in the urine,
and consequently, a higher urine sodium. Therefore, the urine chloride is a better test than the urine
sodium for extracellular volume depletion when metabolic alkalosis is present.

Case 14: You are called to see a 40-year-old 60 kg woman who has had a generalized tonic-clonic
seizure 36 hours after undergoing resection of a tubo-ovarian abscess. She is poorly arousable, but
without focal neurological findings. She has the following laboratory data:

Na 112 mEq/L, K 5.0 mEq/L, C174 mEq/L, [HC03-] 16 mEqn, OSM(,) 252 mOsm/L, pH 7.32, PCO~ 32.
You check the preoperative lab results:

Na 124 mEq/L, K 5.0 mEqn, C1 90 mEq/L, [HC03-I24 mEqL. OSM 270 mOsm/L.

What is your diagnosis and what would you do?

Answer: Acute severly symptomatic hyponatremia with hypotonicity. There has been a large, rapid
drop in the sodium concentration. You check what postop IV fluids the patient received: 6 liters of D5
0.45% saline over the last 36 hours. You stop the IV fluids immediately. This patient had significant
hyponatremia on admission: Preoperatively, the sodium concentration was 124 mEq/L. …Unexplained
hyponatremia of this degree should be carefully evaluated preoperatively if possible. The evaluation
does not take a long time in most cases, and should not delay the surgery needlessly. The cause of the
hyponatremia could be as simple as a thiazide diuretic or one of the medications. The low preoperative
serum sodium concentration and low measured osmolality indicate preexisting hyponatremia with
hypotonicity.

A patient with hyponatremia and hypotonicity should not receive hypotonic fluids under any
circumstances. In general, hypotonic fluids should not be given to any patient postoperatively, either.
Therefore, two serious errors contributed to this patient's cerebral edema. Determination of the
underlying cause of the hyponatremia will have to wait for the time being, because we need to start
emergency treatment.

Remember that the rate of fall of the serum sodium concentration is critical in determining
whether there is severe brain edema and therefore whether there are symptoms or not. This patient
has had a marked drop (12 mEq/L) in serum sodium over a period of only 36 hours, indicating that the
patient's symptoms are due to cerebral edema secondary to acute hyponatremia. This patient may die
if appropriate management is not begun immediately. If you cannot remember how to do the
calculations for 3% saline infusion, you may temporarily begin with 3% saline at 50-100 mVhr for a
brief period until you can calculate a more precise rate.

Carefully review the safety guidelines for rapid correction of acute, severely symptomatic
hyponatremia with 3% saline. Using the safety parameters and the values of serum sodium in this
patient, calculate the amount of sodium to be given as 3% saline over 4 hours. At 4 hours what would
you like the serum sodium to be? Looking at the safety guidelines for rapid correction of hyponatremia
we would like the sodium to be approximately 116 mEq/L. Now use the equation:
Na (mEq) = ([Na+(desired)] - [Na+measured)]) X Estimated Total Body Water Na+(mEq) = (116
- 112) X (.5 X 60kg) Na+ (mEq) = 120 mEq
So 120 mEq of sodium is to be given as 3% saline over the next 4 hours. Because 3% saline has 513
mEq sodiud, the volume of 3% would be: 120/513 = .234 L = 234 ml over 4 hours (about 60 mVhr). The
serum sodium concentration should be rechecked every 1-2 hours to monitor therapy.

Acid-base disorder. Step 1: [HC03-] down, pH down.

Metabolic acidosis-most likely lactic acidosis.

Step 2: What should the PCO2 be? 1.5 X 16 + 8 = 32. No coexisting respiratory disorder.

Step 3: The anion gap of 11 2 - (1 2 + 74) = 22 indicates that an anion gap acidosis is probably present.
Comparing the anion gap with the previous day is very helpful here. The anion gap was 10
preoperatively.

The increase of 12 in the anion gap indicates an AG acidosis. The expected decrease in the [HC03-] is
1211.5 = 8, which exactly matches the decrease in our patient. Therefore, there is no "hidden"
metabolic disorder. The AG acidosis is consistent with a lactic acidosis (urine ketones are negative).
Answer: Anion gap metabolic acidosis, probably a lactic acidosis due to the seizure. If this is the case,
it should clear in 1-2 hours with no specific therapy

Case 15: A 79-year-old man (60 kg body weight) with a history of multi-infarct
dementia is bedridden and requires enteral tube feedings. He is found to be tachypneic and poorly
arousable, and the nurse tells you that he has been having profuse diarrhea.The following data are
obtained: sodium 173 mEq/L, potassium 2.8 mEqL, bicarbonate 18 rnEq/L, chloride 137 mEq/L. The
arterial blood gas: pH 7.22, PC02 45, bicarbonate 18 mEq/L. The urine volume is .6 L/24 hours with an
osmolality of 670 mOsmlL and sodium of 8 mEq./L

What is causing the hypernatremia?

Answer: Tube feedings can cause diarrhea, which leads to hypernatremia from loss of water in stool,
hypokalemia from loss of potassium in stool, and metabolic acidosis from loss of bicarbonate in stool.
The free water deficit is approximately:

H20 deficit = TBW x ([Na+(measured)] - [Na+ normal)/[Na+normal)

where TBW is total body water, [Na+measured)] is the measured serum sodium concentration, and
[Na+(normal)] is the normal serum sodium concentration.

H20 deficit = TBW x ([Na+(measured)] - [Na+ ~normall)/[Na+normall

= .6 X 60 X (173-140)/140 = 8.5 L or,
using TBW = .5 X weight (kg) because this is an elderly patient:
= .5 X 60 X (173-140)/140 = 7.1 L

So the total water deficit is probably somewhere between 7.1 Land 8.5 L.

This formula can also give the amount of water to be given in order to reduce the sodium concentration
to a desired value. Suppose we wanted to correct him to a sodium concentration of 163 rnEq/L in the
first 12 hours, and assuming 0.5 L urine volume and 0.5 L insensible loss (the patient is tachypneic) in
this 12 hour period: Hz0 to bring sodium to 163 mEq/L =

TBW X ([Na+(measured)l - [Na+ (desired)l)/[Na+(desired)

= .5 X 60 X (173-163)/160 = 1.8 L
Now, add 0.5 L for insensible losses. The volume of water (which could be given as D5W) over the
next 12 hours would be about 2.3 L.

Remember to keep an eye on continued losses: If the patient continues to lose water in stool, then
the amount of water needed to correct the patient to 163 mEq/L will be greater.

The sodium concentration should be checked every 2-3 hours during treatment to avoid overly rapid
correction, or inadequate correction. The formula will give only an approximation of the actual water
requirement.

What about the hypokalemia?

Answer: The potassium deficit in this patient is very severe, in view of the pH 7.22. Remember that
metabolic acidosis shifts potassium out of cells leading to the misleadingly high concentration of 2.8
mEq/L in this case. This tells us that a severe potassium deficit is present. Severe hypokalemia in the
setting of significant metabolic acidosis is a medical emergency. This man should be given potassium
replacement in a closely monitored setting.

I would not treat this man with bicarbonate initially, even though he is acidemic. The resultant increase
in pH could worsen the hypokalemia and precipitate cardiac arrhythmias. After potassium replacement
is well underway, I could reevaluate the need for bicarbonate. The other reason I would not give
bicarbonate initially is that part of the drop in pH is explained by a respiratory acidosis in addition to
the moderate metabolic acidosis caused by the diarrhea

Case 16: A 50-year-old woman was admitted to the hospital with protracted nausea, vomiting,
and abdominal pain.

Abdominal X-rays revealed an ileus, which

resolved with nasogastric suction and IV fluids
(0.9% saline with 30 mEiqL KC1). She says that
her abdominal pain, which had initially
improved with nasogastric suction and IV
fluids, has now returned. She now has a
temperature of 101.6 and her blood pressure
has fallen from 130 /86 to 86 /52. The
abdomen is very tender, and no bowel sounds
are present.

Her laboratory studies: Na 140 mEqL, K 4.5

mEiqL, C180 mEqL, HC03- 25 mEiqL, pH 7.40,
PO2 100, PCO2 40, HCO3- 25 mEqL. What is
your diagnosis? Complex acid-base disorder.
Step 1 : On inspection of the laboratory studies, there is no obvious acid-base disorder present. The
pH, PCO2, and [HC03-] are all normal.

Step 2: Because there is no apparent acid-base disorder present, appropriateness of compensation is

not an issue.

Step 3: The anion gap is 140 - (25 + 80) = 35! Therefore, a severe (most likely lactic) anion gap metabolic
acidosis is present. This acidosis is probably the result of bowel ischemia. Why is the [HC03-] normal?

Because there is an equally profound metabolic alkalosis present, which is "masking" the metabolic
acidosis. We calculate the change in anion gap and compare it to the change in the HC03.

The change in anion gap is 35 - 12 = 23. Therefore, in this lactic acidosis, the [HC03-] should be around
25 – 23/1.5 = 25 - 15.3 = 9.7!

There is an opposing metabolic alkalosis pushing up the [HC03-] by around 15.3 in this case, and
therefore the normal [HCO3-] disguises two severe acid-base disorders:

Anion gap acidosis from ischemic bowel. Metabolic alkalosis from vomiting and nasogastric suction. It
is important to follow the 3 steps for every single set of acid-base chemistries that you evaluate, even
if everything looks normal at first glance. Calculating the anion gap was central to solving this case.

Case 17: A 27-year-old male with a history of type 1 DM presents to the emergency
department with complaints of intractable vomiting, generalized weakness, and abdominal pain for
the last 10 hours. He was diagnosed with type 1 DM about 10 years ago with the last hemoglobin A1C
of 9.5 (3 weeks before admission). He was prescribed insulin Lantus 30 units once a day along with
insulin aspart 8 units along with three meals. The patient noticed non-adherence to insulin dosages
during the current illness and states that diabetes and vomiting have been a real problem because of
frequent admissions to the hospital.

Initial vital signs: Afebrile, blood pressure 97/54 mm Hg, respiratory rate 26/min, pulse 115/min,
oxygen saturation 99% in room air, body mass index (BMI) 23.2.

• ECG: Normal sinus rhythm with a rate of 110/min.

• On admission, he was lethargic, with rapid and deep breathing (kussmaul respiration), and severe
epigastric abdominal pain.
• Point-of-care ultrasound: Small IVC with >50% collapsibility and hyperkinetic heart.
• Initial lab investigations revealed: blood glucose 418 mg/dL, serum sodium 138 meq/dL, chloride 94
meq/L, potassium 3.5 meq/L, and moderate amounts of urinary ketones. The corrected anion gap
was 24.3 meq/L.
o Arterial blood gas analysis showed pH 7.56, PCO2 27 mm Hg, and bicarbonate 21 mmol/L. Other
labs are mentioned in the table below.

Biochemical profile On admission After IV fluid resuscitation

Arterial blood gas pH 7.56 7.24

PCO2 (mm Hg) 27 33

 Bicarbonate (mmol/L) 21 14

Sodium (meq/L) 138 133

Potassium (meq/L) 3.5 3.4

Chloride (meq/L) 94 100

Albumin (G/L) 3.2 3.5

Glucose (mg/dL) 418 285

Blood urea nitrogen (mg/dL) 24 24

Creatinine (mg/dL) 0.7 0.6

Lactic acid 2.1 1.7

Urinary ketones Moderate –

Corrected anion gap 24.3 20.5

Delta-delta ratio ~4 0.85

Moderate amounts of urine ketones and a high anion gap in the context of hyperglycemia suggest
diabetic ketoacidosis. however, a pH of 7.56 does not fulfill the diagnostic triad of DKA. In this case,
a delta-delta ratio of four unmasks the presence of mixed acid-base disorder ”high anion gap
metabolic acidosis” plus “metabolic alkalosis”.

Treatment with intravenous (IV) saline, potassium replenishment, and IV insulin was started
immediately. After receiving 3 liters of IV saline, the patient was awake and alert. Repeating the
metabolic panel revealed the above values after initial fluid resuscitation.

Discussion: Diabetic ketoacidosis (DKA) is due to absolute or relative insulin deficiency (more
on the pathophysiology of DKA). The diagnosis of DKA is based on the triad of hyperglycemia, ketosis,
and metabolic acidosis. Although different professional societies have agreement on the main
diagnostic feature of DKA which is the elevation in circulating total blood ketone level, the other
diagnostic criteria, such as serum glucose and bicarbonate levels, differ .

“Pure” DKA is defined as pH ≤ 7.3, bicarbonate ≤15, and an anion gap (AG) >12 with positive serum
and/or urine ketones. Blood glucose is usually ≥250 mg/dL but can be lower, especially with the use
of SGLT2 inhibitors .
Diagnosis is more challenging in the presence of mixed acid-base disorders (e.g. associated vomiting,
which will raise the bicarbonate level) . Ketoalkalosis (aka. “masked DKA” or “alkaline ketoacidosis”)
Refers to cases of ketoacidosis in which the acidosis is masquerade by a coexisting alkalosis. Causes of
alkalemia in DKA patients:

1-Recurrent vomiting: This will cause metabolic alkalosis due to hydrogen ion loss from the
gastrointestinal tract and contraction alkalosis due to volume depletion. Patients with DKA commonly
present with profuse vomiting. There is also evidence that patients having autonomic neuropathy such
as gastroparesis due to poorly controlled diabetes, usually present with recurrent vomiting.

2-Alkali ingestion.

3-Hypercortisolism

4-Contraction alkalosis due to dehydration and/or diuretic use.

Clinical presentation: Clinical presentation of DKA includes symptoms and signs of:

Hyperglycemia: Polyuria, polydipsia, weakness, signs of circulatory volume depletion such as

tachycardia, decreased skin turgor, and capillary refill *.

Acidosis: Nausea, vomiting, abdominal pain, altered sensorium, air hunger, and kussmaul
respiration.

Precipitating illness (e.g. infection, myocardial infarction, stroke).

Diagnostic evaluation

Lab investigations for diagnosis of DKA include:

o Blood glucose.
▪ Note that blood glucose could be normal in euglycemic DKA.
o Serum and/or urinary ketone
o Chemistry panel
▪ Calculating the anion gap and delta-delta ratio helps to reveal the mixed acid-base disorders *.
• Evaluate for other causes of elevated anion gap e.g. lactic acidosis by sepsis, salicylate overdose, uremia,
or toxic alcohol ingestion *.
• Evaluate for the precipitating causes of DKA (if it is unclear):
o Complete blood count with a differential, ECG, urinalysis, +/- urine & blood culture.
Is blood gas analysis helpful in the diagnosis of DKA?

1-Although current guidelines widely recommend obtaining blood gases, neither VBG nor ABG is
usually helpful in diagnosing DKA.

2-Blood gas provides information only regarding the respiratory component of pH (i.e. PCO2).

3-If the chemistry panel is evaluated and a comprehensive history and physicals are performed,
blood gas analysis (i.e. pH, PCO2) usually will not have a major effect on the diagnosis and
management of the patients *.
4-The diagnosis of diabetic ketoacidosis should be based on an analysis of
the metabolic derangements in the acid-base status (e.g. anion gap, beta-hydroxybutyrate level).

5-As explored above, pH could be normal or even alkalotic in patients with underlying DKA.

Diagnosis of masked DKA (aka. “ketoalkalosis”, or “alkaline ketoacidosis”)

1-Diagnosis of DKA should be suspected whenever patients have significant hyperglycemia,

especially if they are ill or highly symptomatic.

2-Suspecting DKA, the clinician should calculate for the mixed acid-base disorder by calculating
the anion gap and the delta–delta ratio.

3-Patients with masked DKA often present with hyperglycemia >250 mg/dL, normal or alkalotic
pH, and bicarbonate >20 meq/L (which does not meet the criteria for DKA).

4-An elevated AG in this context is suggestive of ketoacidosis (however other causes of high AG
need to be eliminated e.g. lactate, toxic alcohols, salicylates).

5-A delta–delta ratio > ~1.6 will support the presence of metabolic alkalosis *.

6-Following the administration of IV fluid and replacement of electrolytes, diagnosis of DKA

becomes evident on laboratory analysis.

7-Treatment of diabetic ketoalkalosis

A-Treatment of diabetic ketoalkalosis does not differ from the conventional management of DKA.
These patients should be treated with

B-Aggressive IV fluids

C-Electrolyte supplementation (especially potassium)

D-Insulin IV infusion.

E-Administration of IV fluids with timely replenishment of electrolytes remains of utmost priority.

Learning Points:1- The absence of low serum bicarbonate or low pH does not rule out DKA, as there
may be a mixed acid-base disorder.

2-Calculating the anion gap and the delta–delta ratio will detect the underlying mixed acid-base
disorder.

3-Treatment of diabetic ketoalkalosis follows the conventional treatment of DKA with IV fluid, insulin
infusion, and electrolyte replacement (especially potassium).
Case 18: A 54 year-old lady is a known case of anxiety/depression for many years. For last
6 months she is also taking Acetazolamide for her eye condition. She comes to the Hospital for
extreme weakness and feeling of breathlessness. Her ABG report is as follows, pH = 7.40 PCaO2 =
4 kPa, (30 mm of Hg) PaO2 = 15 kPa (105 mm of Hg), on room air Standard HCO3 − = 12 mmol/L or
mEq/L What is your interpretation of the results?

Answer: The pH is normal. The PaCO2 and bicarbonate are decreased pointing towards respiratory
alkalosis. In chronic respiratory alkalosis there is fall of approximately 5 mmol of HCO3 − for each
10 mm of Hg fall in PaCO2 . In this case there is a fall of PaCO2 by 10 mm of Hg. (40 – 30) (when 40 mm
of Hg, is considered to be normal level of PaCO2 .)

In chronic respiratory alkalosis (if this patient has one) the fall in PaCO2 by 10 mm of Hg, the expected
fall in the HCO3 − is by 5 mmol/L. The expected HCO3 − level should be (24 – 5) = 19 mmol/L.)
However, in this patient the HCO3 − is at 15 mmol/L. This is lower than the expected lever of the HCO3
−. The fall in HCO3 − is disproportionately low. Sure there has to be some more cause of low HCO3 –
(so co existing metabolic acidosis).

Case 19: A 79-year-old 60 kg man from a nursing home is admitted with fever, obtundation,
and a urinalysis revealing pyuria and many bacteria. His temperature is 101.6 degrees, his blood
pressure is 148/194, and his pulse 104. His mouth is dry, and he has poor skin turgor. His serum sodium
is 184 rnEq/L. The urine volume is .6 L/ 24 hours with urine osmolality 640 mOsrn/L. What is the cause
of the hypematremia, and what should be done? Answer: The hypernatremia is most likely due to
extrarenal losses accompanied by impaired thirst, causing inadequate water replacement. Infection is
a common setting for hypematremia in elderly debilitated patients. The total water deficit is:

Total H20 deficit = .5 X 60 X (184-140)1140 = 9.4 L

Because of the age of this patient, I have arbitrarily used the rough approximation TBW = 0.5 X body
weight to avoid an overestimation of the total body water (.6 may be too high a fraction for body water
in an elderly man). On the other hand, if

TBW = .6 X body weight is used, the total water deficit is:

Total H20 deficit = .6 X 60 X (1 84-140)/140 = 11.3 L
The actual TBW may be somewhere in between .5 and .6 X body weight, and therefore, the total water
deficit may be somewhere in between 9.4 and 11.3 L. We do not want to correct the sodium
concentration too rapidly, but rather to correct it carefully to avoid cerebral edema. A good rate would
be to correct the serum sodium concentration from 184 to 174 in the first 10 hours (1 mEqn per hour
correction of serum sodium).

H20 deficit = 0.5 X 60 X (184-174)1174 = 1.7 L

We need to keep an eye on all ongoing water losses. Ongoing losses need to be calculated into the
final fluid volume of D5W to be given over the 10- hour period. Basal insensible loss over this 10-hour
period will be perhaps 0.25 L. The amount of water replacement will be increased because of fever in
this patient.

The amount of D5W to be given to replace loss due to fever in addition to basal insensible loss would
be (101.6-98.6) X 80 = 3 X 80 = 240 cc.
Therefore, the amount of D5W to be given over the next 10 hours should be about 1.7 L + .25 L (basal
insensible loss) + .24 L (insensible loss from fever) = 2.19 L.

(I would round this to 2.2 L). The sodium concentration should be rechecked at 2 to 4-hour intervals
to monitor therapy. Ignoring ongoing losses of water may lead to inadequate water replacement and
prolongation of brain dehydration. Conversely,

overly rapid correction may lead to cerebral edema. The serum sodium concentration should therefore
be checked at frequent intervals to monitor therapy. As for any patient receiving IV fluids, this patient
should be weighed daily if possible, and have daily measurements of electrolytes, BUN and Cr.

Case 20: A 25-year-old 50 kg man with a history of post traumatic encephalopathy from a
motor vehicle accident is admitted from a nursing home with fever, obtundation, and a urinalysis that
reveals pyuria and 4+ bacteria. His serum sodium is 185 mEq/L. The urine volume is 0.7 Ll24 hours with
a urine osmolality of 710 mOsm/L. He is treated initially with 1 L per hour then 500 ml per hour of
D5W. After 4 hours of therapy, he becomes more arousable, but after 12 hours, he has again become
poorly responsive. His sodium concentration is 150 mEqlL.

What has happened? Answer: Cerebral edema secondary to overly rapid correction of the
hypernatremia. The brain adapts to a hypertonic ECFV by accumulating electrolytes, amino acids, and
other osmoles that serve to increase the solute of the brain in order to "hold" water and prevent brain
shrinkage as hypernatremia develops. The consequence of rapidly administering water is that water
will rapidly enter brain cells, causing cerebral edema. It is generally agreed that a safe rate of correction
of hypernatremia is about a 0.5-1 mEq/L per hour decrease in the serum sodium concentration initially,
and that complete correction should not be achieved for at least 36-72 hours.

IV Fluids used in the treatment of hypernatremia

One approach would have been to correct the sodium from 185 to 175 mEq/L in 10 hours and then
make further adjustments at a slower rate. The formula used to calculate the water deficit is:

This formula gives the amount of water to be given in order to reduce the sodium concentration to the
desired value. For our patient: H20 deficit = .6 X 50 X (185-175)/175 = 1.7 L This would be in addition
to insensible losses of roughly .25 L (assuming no fever or hyperventilation) for a total of 1.7 + 0.25 =
1.95 L over the next 10 hours.

Case 21: A 79-year-old man (60 kg body weight) with a history of multi-infarct dementia is
bedridden and requires enteral tube feedings. He is found poorly arousable and has a respiratory rate
of 26lminute. The following data are obtained: sodium 173 mEq/L, potassium 3.1 mEq/L, bicarbonate
18 mEq/L, chloride 137 mEq/L. The urine volume is < 400 mu24 hours and the low urine sodium are
against osmotic diuresis. Diarrhea leads to hypernatremia from loss of water in stool, hypokalemia
from loss of potassium in stool, and metabolic acidosis from loss of bicarbonate in stool. The treatment
is replacement of water, potassium, and (sometimes) bicarbonate. In this patient, the total free water
deficit is approximately:

Total H20 deficit = TBW x ([Na+(rneasured)] - [Na+ (desired)] )/[Na+(desired)]

= .5 X 60 X (173-140)/140 = 7.1 L
Because of the patient's age, .5 X body weight is used instead of .6 X body weight, although this is a
rough approximation.

The water deficit using .6 X body weight is 8.5 L. The actual water deficit may be in between .5 and .6
X body weight and therefore, between 7.1 and 8.5 L. It is important to get an idea of the general range
of the water deficit in a patient such as this one: the calculations give only rough approximations of
water deficit. Suppose we wanted to correct him to a sodium concentration of 160 mEqL in the first 14
hours, assuming 1 Ll24 hours insensible loss because of the rapid respirations and therefore roughly
0.5 L in this 14-hour period: H20 to bring sodium to 160 mEq/L =

TBW X ([Na+(measured)] - [Na+ (desired)]) 1 [Na+(desired)l

= .5 X 60 X (173-160)/160 = 2.4 L
Now add roughly 0.5 L for insensible loss because the patient is tachypneic. The volume of water,
which could be given as D5W over the next 14 hours, would be about 2.4 + 0.5 = 2.9 L

One of the keys to successful correction of the patient's hypernatremia is close observation for ongoing
water loss in the stool. If he continues to have diarrhea, the patient will most likely need to have
increased water replacement to account for the stool losses. Therapy must be monitored closely with
frequent serum sodium determinations

Case 22: A 50-year-old man is admitted with rapid respiration, tachycardia, and a blood
pressure of 90/60. His chemistries are: sodium 142 mEq, potassium 3.6 mEqn, chloride 100 mEqL,
bicarbonate 12 mEqn, glucose 180 mgldl, BUN 28 mg/dl.

Arterial blood gas: pH 7.28, Pco2 26, HC03- 12.

Urinalysis: calcium oxalate crystals. What is your differential diagnosis, and what do you do to make
a diagnosis?

Answer: High anion gap acidosis. A measured osmolality is 360 mOs& and there are calcium oxalate
crystals in the urine. The calculated osmolality is:

Calculated osmolality = 2 X [sodium concentration] + [glucose concentration]/l8 + [Blood Urea

Nitrogenl/2.8 =
 2 X 142 + 180/1 8 + 28/2.8 = 304 mOsm/L

The osmolal gap is:

= 360 - 304 = 56 mOs& The osmolal gap is markedly increased. The combination of high AG and high
osmolal gap suggests either ethylene glycol or methanol poisoning

although a high osmolal gap can occur in ketoacidosis. The calcium oxalate crystals in the urine suggest
ethylene glycol.

Case 23: A 45-year-old 80 kg man presents with sodium 140 mEqL, potassium 3.8 mEqL, chloride
110 mEqn, bicarbonate 8 mEqL, glucose 180 mgl dl, BUN 28 mg/dl. Arterial blood gas: pH 7.10, Pcoz
20, HC03- 6. The patient is developing respiratory fatigue.

Calculate the amount of bicarbonate required to bring the bicarbonate from 6 mEqL to 10 mEqL..

Answer: The amount of bicarbonate required to bring the bicarbonate from 6 mEq/L to 10 mEqL:
HCO3- deficit = .5 x Body weight(kg) X ([HC03-(desired)]- [HC03-(measured)I)

= .5 X 80 X (10 - 6)= 160mEq

If the decision is made to replace HC03-, give this calculated amount slowly and remeasure pH, HC03-
and pC02 to assess the effect of therapy on the acid-base status.

Case 24: A 40-year-old man is admitted with the following chemistries: sodium I 140 mEq/L, chloride 86 mEq/L,
bicarbonate 40 mEq/L, potassium 3.0 mEq/L, glucose 120 mg/dl, BUN 32 mg/dl, Cr 1.4 mg/dl. Arterial blood gas:
pH 7.52, P~02 5 1 mrn Hg, HCO3- 40 mEq/L. What is your general approach to this patient? Answer: The diagnosis
of acid-base disorders requires a systematic approach to identify all the disorders present in a given patient.
Chapter 9 describes a simple, three-step method to use for every single acid-base problem. Do not worry if you
do not understand all three steps right now. Just follow along.

Step 1: Identify a single disorder. The pH is high and the bicarbonate is also high. Therefore, metabolic alkalosis
is present.

Step 2: See if the compensation is correct. If the compensatory change in PCO~ in response to the metabolic
alkalosis is not as predicted by the formula, then a respiratory disorder is present. For a metabolic alkalosis, the
PCO2 should be

PCO2 = 40 + .7 X ([HC03- (measured)] - [HC03- (normal)])

= 40 + .7 (40-24) = 51.2 mm Hg. This assumes a normal [HC03-] of 24 mEq/L. The measured PCO2 of 51 mm Hg
is equal to that predicted by the formula. Therefore, compensation is appropriate, and no respiratory disorder is
present. Remember to use values for both the PC02 and the [HC03-] from the arterial blood gas for Step 2.

Step 3: Calculate the anion gap using serum values: AG = [Na+] - ([Cl-] + [HC03-]) = 140 - (86 + 40) = 14
The anion gap is normal. We are finished. This analysis tells us that the only acid-base disorder present is a
metabolic alkalosis. Now, we must turn our attention to finding and correcting cause for the abnormal renal
retention of bicarbonate. We perform a careful history and physical, which includes checking for ECFV depletion
due to vomiting, nasogastric suction, chronic diarrheal laxative use, and diuretics, as well as signs of secondary
hyperaldosteronism (congestive heart failure and cirrhosis). Hypertension suggests renovascular disease,
primary hyperaldosteronism, or Cushing's syndrome, although primary hypertension may occur without any of
these disorders. Remember that profound potassium depletion alone may cause renal retention of bicarbonate.
The urine chloride is helpful in diagnosing metabolic alkalosis caused

by ECFV depletion. It is generally low (<10 mEq/L) in cases of metabolic alkalosis maintained by ECFV depletion.
The urine sodium, which is also generally low in cases of volume depletion, is less helpful in cases of metabolic
alkalosis caused by ECFV depletion. The reason is that excess bicarbonate that is not reabsorbed by the proximal
tubule acts as a non-reabsorbable anion, bringing sodium to the collecting tubule. This results in more sodium
in the urine, and consequently, a higher urine sodium. Therefore, the urine chloride is a better test than the urine
sodium for extracellular volume depletion when metabolic alkalosis is present

Case 25: A 20-year-old woman is admitted with the following serum chemistries: sodium 140
mEq/L, chloride 90 mEq/L, bicarbonate 34 mEq/L, potassium 3.0 mEq/L, glucose 120 mgldl, BUN 30
mgldl. Arterial blood gas: pH 7.48, PCO~ 47 mm Hg, HCO3- 34 mEq/L. She tells you that she thinks she
might have "Gitelman's syndrome." She consistently denies vomiting, laxatives, or diuretics. What do
you do? Answer: First, see what disorders you have.

Step 1 : Identify the most apparent disorder. The pH is high and the bicarbonate is also high. Therefore,
metabolic alkalosis is present.

Step 2: See if the compensation is correct (if the compensation of the PCO~ for the metabolic alkalosis
is not what is predicted from the formula, then a respiratory disorder is present). For a metabolic
alkalosis, the Pc02 should be PCO~ = 40 + .7 X (measured)] - [HCO3- (normal)]) = 40 + .7 X (34-24) = 47
mm Hg. This assumes a normal [HC03-] of 24 mEq/L. The measured PCO~ of 47 mm Hg is equal to that
predicted by the formula. Therefore, compensation is appropriate, so no respiratory disorder is
present.

Step 3: Calculate the anion gap: AG = [Na+] - ([Cl-] + [HC03-I) = 140 - (90 + 34) = 16

The AG is normal. Metabolic alkalosis is the only disorder present. We begin our clinical evaluation.
There is a drop in blood pressure and increase in heart rate with standing, indicating ECFV depletion.
The presence of ECFV depletion suggests vomiting, diuretics, chronic diarrhea and laxative abuse. The
spot urine sodium is 40 mEq/L, and the chloride 5 mEq/L. The urine potassium is 10 mEq/ gm
creatinine.

Now what? Answer: These studies suggest that ECFV depletion is present, either from surreptitious
vomiting, diuretic abuse, or from chronic laxative abuse. The urine concentrations of chloride and
potassium are low, consistent with renal conservation of these ions. The urine sodium is higher than
we might normally expect for ECFV depletion, but during metabolic alkalosis HC03- "carries" sodium
with it, elevating the urine sodium concentration. The urine chloride is a more reliable indicator of
ECFV depletion in states of metabolic alkalosis. Several repeated urine tests for diuretics and a stool
sample for laxatives could be helpful. Gitelman's syndrome is associated with normotension and high
urine chloride, sodium, and potassium concentrations because these ions are being lost in the urine.
Gitelman's syndrome is also rare, so always suspect the more common causes of metabolic alkalosis first.

Case 26: A patient presents to the emergency room in septic shock with the following: an anion
gap that has increased from 12 to 30 (change in AG is 18) and a serum [HC03-] that has decreased from
26 to 4 (change in [HC03-] is 22).

ABG: The PCO~ has fallen from 40 to 15, the [HC03-] has fallen to 4, and the pH has fallen from 7.40
to 7.05. What is your diagnosis? Answer:
Step 1: The pH has fallen and the [HC03-] has fallen: metabolic acidosis.
Step 2: What should the PCO2 be? PC02 = (1.5 X 4) + 8 = 14. The measured PCO~ matches the
predicted Pco~. Therefore, there is no respiratory disorder present.

Step 3: A high anion gap acidosis in the setting of septic shock is most likely a lactic acidosis. The
change in the AG is 18. We would expect the [HCO3-] to fall by about 18/1.5 = 12 mEq/L. This would
lead to a [HC03-] of 26 - 12 = 14 mEq/L. But the [HC03-] has fallen to 4. The [HC03-] is much less than
predicted by a high anion gap acidosis alone. Something is pushing down the-[HC03-] by an additional
10 rnEq/L. The decrease in [HC03-] is explained by a coexisting normal anion gap metabolic acidosis.

These examples have pointed out how using the anion gap can identify additional "hidden" metabolic
disorders in cases of lactic acidosis and ketoacidosis. In actuality, using the change in the anion gap to
predict the change in bicarbonate is only an approximate method. Nevertheless, a significant deviation
from this approximation suggests that an additional metabolic disorder may be present. That is: If the
measured bicarbonate concentration is significantly higher than predicted by the increase in the AG, a
"hidden" metabolic alkalosis may be present. If the measured bicarbonate concentration is
significantly less than predicted by the increase in the AG, then a "hidden" normal anion gap metabolic
acidosis may be present.

Exercises: Putting the Three Steps Together For the sake of the following exercises assume that all the
patients have the same baseline lab values: pH 7.40, PCO~ 40, [HC03-] 24, AG 12. All the changes and
calculations for solving the cases should be based upon these baseline values.

Case 27: A patient presents with: pH 7.15, calculated [HC03-] 6 mEq/L, PCOZ 18 mm Hg, sodium
135 mEq/L, chloride 114 mEq/L,, potassium 4.5 mEqL, serum [HC03-] 6 mEq/L.

Step 1 : This patient has a very severe metabolic acidosis.

Step 2: For a metabolic acidosis, what should the PCO2 be? We want to know whether this is a simple
metabolic acidosis or if there is also a respiratory disorder present. The question we ask is: What should
the PCO2 be after compensation?

We answer this question with the formula for expected respiratory compensation for metabolic
acidosis: The patient's PCO2 of 18 is close to the 17 we would expect for the appropriate respiratory
compensation for a simple metabolic acidosis. Therefore, we conclude that there is no respiratory
disorder present.

Step 3: The anion gap is AG = 135 - (6 + 114) = 15 mEq/L (normal). We are finished. There are no
further steps if the AG does not suggest a high AG acidosis. Answer: Simple normal anion gap metabolic
acidosis.

Case 28: A patient presents with: pH 7.08, [HC03-] 10, PCOZ 35, anion gap 14 mEq/L.

Step 1: The [HC03-] is 10, and the pH is 7.08. There is a severe metabolic acidosis.
Step 2: What should the PCOZ be? The PCO~ should be: The PCO2 of 35 mm Hg is much higher than
we would expect! Therefore, there is something pushing the PCO2 up. It is a coexisting respiratory
acidosis. There is a respiratory acidosis present as well as a metabolic acidosis.

Step 3: The anion gap is 14 (normal). We are finished. Answer: Normal anion gap metabolic acidosis
plus respiratory acidosis. The patient's Pco2 is 35. This is much higher than predicted by the formula.
Therefore, the patient has a respiratory acidosis which might represent "tiring out" of the patient's
respiration and impairment of his ability to compensate for the metabolic acidosis. It could also be a
clue to a coincident pulmonary process. The rising PCO2 is a dangerous sign in metabolic acidosis,
because further increase in the PCO2 could lead to a precipitous fall in pH.

An important clinical note about the maximum compensation possible for a metabolic acidosis: In
a young person, the maximum respiratory compensation (the lowest attainable Pco2) is around 10-15
mm Hg. The value is about 20 mm Hg in an older person, indicating less ability to compensate by
increasing ventilation. Therefore, there is a limit to the magnitude of respiratory compensation
possible for a metabolic acidosis.

A patient with a [HC03-] of 3 and maximal respiratory compensation will have a PCO2 of roughly 1.5
X 3 + 8 = 12.5 mm Hg. This is approximate because the compensation curve is not entirely linear at
extremely low levels of HC03-. The pH with this HC03- concentration and P02 will be 7.00. To keep the
PCO2 at 12.5 mm Hg takes a big effort. How long can the patient keep breathing deep and fast enough
to hold the PCO2 at 12.5 mm Hg before tiring out? Suppose the patient begins to develop respiratory
muscle fatigue, and the PCO2 creeps up to 20 mm Hg. The pH will plummet to 6.80! The clinical point
is that a young patient with severe metabolic acidosis and a Pco2 of 10-15 mm Hg or an older patient
with a PCO2 of 20 mm Hg is "on the edge" of compensation; any further increase in PCO~ or further
decrease in HCO3 can mean disaster!

Case 29: A patient presents with: pH 7.49, [HC03-1 35, PCO2 48, AG 16.
Step 1: The [HC03-] is increased and so is the pH: Metabolic alkalosis.
Step 2: What should the PCO~ be? We want to know if there is a respiratory disorder in addition to
the metabolic alkalosis. Assuming a normal [HC03-] of 24 and a normal PCO~ of 40, the answer is:

PCO2 = 40 + .7 X (35 - 24) = 47.7. The patient's PCO~ is 48 mm Hg, which is what it should be for
respiratory compensation for a simple metabolic alkalosis. Therefore, there is no coexisting respiratory
disorder. Step 3: The anion gap is 16 (normal). Answer: Simple metabolic alkalosis.

Case 30: A patient presents with: pH 7.68, HC03 140, PCO2 35, AG 14.
Step 1: [HC03-] is up. pH is up. Metabolic alkalosis.
Step 2: What should the PCO~ be? The answer is: PCO~ = 40 + .7 X (40 - 24) = 5 1.2 mm Hg. The
patient's PCO~ is much less than predicted by the formula, even giving the PCO2 5 mm Hg to
account for variation in respiratory response to a metabolic alkalosis. Therefore, there is a coexisting
respiratory alkalosis in addition to the metabolic alkalosis.

Step 3: The anion gap is 14 (normal). We are finished.

Answer: Metabolic alkalosis plus respiratory alkalosis.

Case 31:A previously well patient presents with 30 minutes of respiratory distress and pH 7.26, PC02
60, [HC03-] 26, AG 14. Step 1 : The PCO~ is up. The pH is down. Respiratory acidosis. The history says
acute. Step 2: For respiratory disorders we ask: What should the [HC03-] be? Remember that the
calculations for metabolic compensation are in terms of changes of 10 in Pco2. The PCO2 is up by 20
which is 2 X 10. For an acute respiratory acidosis, the [HC03-] should change by 1 mEqL for every 10
mm Hg increase in the PCO2. Therefore, the [HC03-] should change by 2 X 1 mEqL = 2 mEqL. Using 24
as normal, the [HC03-] should become: 24 + 2 = 26. Therefore, the compensation is appropriate, and
there is no metabolic disorder. Step 3: The AG is normal. We are finished. Answer Acute respiratory
acidosis.

Case 32: Anxious. Can't seem to get enough air for last 4 days. pH 7.42, PCO~ 30, [HC03-] 19, AG 16.
Step 1: PCOZ down. pH up. Respiratory alkalosis. The history indicates chronic respiratory alkalosis.

Step 2: What should the [HC03-] be? Remember that the calculations for metabolic compensation are
in terms of changes of 10 in PCOZ. The PCO~ is down by 10 which is 1 X 10. For a chronic respiratory
alkalosis, the [HC03-] should be down by 5 for every 10 mrn Hg decrease in Pco2. For this chronic
respiratory alkalosis, the [HC03-] should be down by 1 X 5. The [HC03-] should be 24 - 5 = 24 - 5 = 19.
Therefore, the compensation is appropriate, and there is no metabolic disorder. Step 3: The AG is
normal. We are finished.

Answer: Chronic respiratory alkalosis. It is of interest that chronic respiratory alkalosis is the only
simple disorder in which compensation can bring the pH back into the normal range (7.42 in this case).

Case 33 Short of breath. Two weeks. pH 7.38, PCO~ 70, [HC03-] 40, AG 16.
Step 1: PCO2 up. Respiratory acidosis. By history: chronic.
Step 2: What should the [HC03-] be? The PCO2 is up by 30 which is 3 X 10. For this chronic respiratory
acidosis, the [HCOs-] should increase by 3 X 3.5 = 10.5. Using 24 as normal, the [HC03-] should become:
24 + 10.5 = 35.5. In short: For this chronic respiratory acidosis the [HC03-] should be 24 + (3 X 3.5) =
35.5. The patient's [HC03-] is higher than it should be. Therefore, there is a modest metabolic alkalosis
present as well. The high [HC03-] is not just compensation for the respiratory acidosis but is caused by
a separate acid-base disorder: metabolic alkalosis.

Step 3: The AG is normal Answer: Chronic respiratory acidosis plus metabolic alkalosis. There are two
distinct acid-base disorders present in this patient. Both disorders are pathologic - one is not
compensation for the other, even though the pH may be close to normal. In other words, this patient
has two processes going on at the same time that tend to offset each other: A metabolic alkalosis that
is secondary to one of the causes listed in Fig. 8-1 plus a respiratory acidosis. Causes for each of the
two disorders should be considered separately.

Case 34 Try approaching case 7 the other way, starting with metabolic alkalosis. Step 1 : The [HC03-
] is high: metabolic alkalosis. Step 2: For a metabolic alkalosis, what should the PCO2 be? It should be
40 + .7 X (40 - 24) = 5 1. The PCO2 is much higher than this. Something is pushing it up: a respiratory
acidosis. (Also, remember that for compensation for a metabolic alkalosis the Pco2 should not be
higher than 55 mm Hg: It is higher than 55 mm Hg, indicating that a respiratory acidosis is present.)

Step 3: The AG is normal. Answer: Metabolic alkalosis plus respiratory acidosis. The pH is often close
to normal when offsetting disorders are present. Each disorder is pushing the pH in the opposite
direction.

If given the choice of a metabolic or a respiratory disorder of equal severity being present at the same
time, I will generally start my analysis of the data 1 from the standpoint of the metabolic disorder first,
because it will avoid the question of acute versus chronic and which formula to apply. The 3-step
method will work either way, however, whether you begin with the metabolic disorder or the
respiratory disorder. I just find that beginning with the metabolic disorder is sometimes less
cumbersome.
Case 35 A patient presents with: pH 7.68, PCO2 35, [HC03-] 40, AG 18.
Step 1 : The pH is up and the [HC03-] is up: metabolic alkalosis.
Step 2: What should the PCO2 be? Apply the formula for metabolic alkalosis: Pco2 = 40 + .7 X ( [HC03-
(,,&)] - [HC03- (norm*)]) = 40 + .7 X (40 - 24) = 40 + 11.2 = 51.2. The patient's PCO2 of 35 mrn Hg is
significantly lower than predicted. Therefore, it is being pushed down by a respiratory alkalosis.

Step 3: The AG is 18. This AG is abnormal but it is less than 20 and we cannot make assertions about
the presence of an AG acidosis. We are finished. Answer: Metabolic alkalosis plus respiratory alkalosis.
The pH is often severely abnormal when disorders are synergistic, each pushing the pH in the same
direction

Case 36 Apatient presents with: pH 7.45, PCOZ 65, [HC03-] 44, AG 14. Short of breath for 3 days.
Step 1: Both the PCOZ and the [HC03-] are very high. The pH is normal. Let's call this a metabolic
alkalosis because the pH is a little on the high side.

Step 2: What should the PCOZ be? For a metabolic alkalosis, the PCOZ should be 40 + .7 X (44 - 24) =
54. The patient's PCO2 of 65 is 11 mm Hg too high. Therefore: respiratory acidosis.

Step 3: The anion gap is normal.

Answer: Respiratory acidosis and metabolic alkalosis. Note that the pH is normal, while the PCO2 and
the [HC03-] are both severely abnormal. This tells us immediately that there is a mixed disorder,
because a patient cannot compensate all the way to a normal pH except in the case of a chronic
respiratory alkalosis. This is an example of two disorders offsetting each other; that is, the disorders
tend to cancel each other by pushing the pH in opposite directions. If you just eyeball the chemistries
you might think that this patient has a simple respiratory acidosis with metabolic compensation: The
data look as if there is only one disorder. Step 2 tells us that this is not just a simple respiratory acidosis
with metabolic compensation. This patient has two distinct disorders.

Case 37 Same as Case 10, but start from the respiratory disorder: pH 7.45, PCOZ 65, [HC03-] 44, AG
14. Short of breath for 3 days.

Step 1 : Both the PCOZ and the [HC03-] are abnormal. The pH is normal. Let's call this a respiratory
acidosis-chronic because the history suggests that this has been going on for 3 days.

Step 2: What should the [HC03-] be? For a chronic respiratory acidosis, the HC03 should be 24 + (2.5
X 3.5) = 24 + 8.75 = 32.75. The [HC03-] of 44 mEq is too high. Therefore: metabolic alkalosis.

Step 3: The anion gap is normal. Answer: Respiratory acidosis and metabolic alkalosis

Case 38 Apatient presents with: pH 7.65, PCOZ 30, [HC03-] 32, AG 30. The patient has a temperature
of 102 degrees and a blood pressure 80150. He is diaphoretic. The urinalysis shows numerous white
blood cells and many bacteria. Aurine dipstick test for ketones is negative.

Step 1: pH is up. [HCO3-] is up (metabolic alkalosis), and PCOZ is down (respiratory alkalosis). Let's
start with the metabolic alkalosis though it would work out either way.

Step 2: For metabolic alkalosis what should the PCO2 be?

PCO2 = 40 + .7 X (32 - 24) = 45.6. The patient's PCOZ of 30 is much lower than 45.6. Therefore,
respiratory alkalosis is also present.

Step 3: The anion gap is 30! Therefore, a high anion gap acidosis is present. We are up to three
disorders. Captain, I don't think our engines can stand the heat! The most likely cause of high anion
gap acidosis in this patient is lactic acidosis. The change in the anion gap is 30 - 12 = 18. We compare
this to the change in HCOs. The expected decrease in [HC03-] is roughly: Change in AG 11.5 = 18/1.5 =
12. The [HC03-] did not decrease, but is up by 8 mEq/L. It should be down by roughly 12 mEqL.

Therefore, the [HC03-] is about 20 mEqL higher than we would expect. This means that there is a
severe metabolic alkalosis acting to push the [HC03-] up by roughly 20 mEqL in addition to a very
severe high anion gap acidosis acting to push the [HC03-] down by roughly 12 mEqL. The metabolic
alkalosis and the metabolic acidosis tend to cancel each other, but they are both quite severe.

Answer: Metabolic alkalosis (severe), AG metabolic acidosis (severe), and respiratory alkalosis
(moderate to severe). Note that the [HC03-] of 32 mEqL does not look too bad at first glance.
Calculating the AG and then comparing the increase in the AG to the decrease in [HC03-] was helpful
in this case.

Case 39 A patient presents with diabetic ketoacidosis: pH 6.95, PCO2 28, [HC03-] 6, AG 32.
Step 1: The metabolic acidosis is so severe that this patient is in danger of cardiovascular collapse.

Step 2: What should the PCO~ be? PCO2 = (1.5 X 6) + 8 = 17. The patient's PCO2 is much higher than
expected for this metabolic acidosis. The higher than expected PCO2 indicates a respiratory acidosis,
possibly secondary to respiratory muscle fatigue. Some might call this "inadequate compensation"
instead of respiratory acidosis because the value of the PCO2 is low, not high. They would be partially
correct, but let's just stick to our original terminology so as not to gum things up. This is a severe
metabolic acidosis in which the patient's respiratory compensation is beginning to "tire out."

Remember that patients cannot keep their PCO~ in the 10-20 range indefinitely without eventually
tiring out. Therefore, this patient has a metabolic acidosis and a respiratory acidosis secondary to
respiratory muscle fatigue.

Step 3: The anion gap is 32. Therefore an anion gap acidosis is present. The increase in the anion gap
is 20 mEq/L, supporting the diagnosis of AG acidosis. The predicted fall in the [HC03-] is roughly 20
mEq/L. The fall in the [HC03-] is 18, which is very close to 20. Therefore, the [HC03-] is close to what it
should be for a ketoacidosis alone, and there is no "hidden" metabolic disorder. Answer: AG acidosis
secondary to diabetic ketoacidosis; respiratory acidosis due to respiratory muscle fatigue.

Case 40 A patient with recurrent episodes of small bowel obstruction presents with severe
abdominal pain and vomiting: pH 7.33, PCO2 35, [HC03-] 18, AG 33. Urine dipstick negative for ketones.
The blood pressure is 82/54 and the heart rate 116.

Step 1: [HC03-] down, pH down. Metabolic acidosis. Most likely a lactic acidosis. Looks pretty mild at
first glance.

Step 2: What should the PCO2 be? (1.5 X 18) + 8 = 35. No respiratory disorder.
Step 3: The anion gap of 33 indicates that an anion gap acidosis is present. The increase in anion gap
is 21. The decrease in the [HC03-] should be somewhere around 21/1.5 = 14 for a lactic acidosis, but
is only 6. Therefore, there is probably a "hidden" metabolic alkalosis acting to "push" the bicarbonate
to a higher level.

Answer: Severe (18 mEq/L) anion gap metabolic acidosis plus metabolic alkalosis.

Case 41 A 21-year-old diabetic patient presents with vomiting and pH 7.75, PCO2 24, [HC03-] 32, AG
30. The urine is strongly positive for ketones and serum ketones are strongly positive.

Step 1: The pH is way up. [HC03-] is up. PCO2 is down. Both of these are pushing the pH up. This is an
example of a synergistic disorder in which the pH gets pushed the same way by both the PCO2 and the
[HC03-. This patient has life-threatening alkalemia. You could start with either the PCO~ or the [HC03-
] in this case. I prefer to start with the metabolic alkalosis.

Step 2: What should the PCO2 be? 40 + .7 X (32-24) = 45.6 mm Hg. The patient's PCO2 of 24 mm Hg is
much lower than predicted. Severe respiratory alkalosis is present in addition to the metabolic alkalosis

Step 3: The AG is 30. AG acidosis is present. The increase in the AG is 18. Accordingly, the [HC03-]
should have fallen by roughly 18 mEqL to the range of 6 mEqL. But it is increased to 32. The [HC03-]
went up, not down! There is something pushing up the [HC03-] from the range of 6 mEqL to 32 mEqL!
! Therefore: severe metabolic alkalosis. The initial eyeballing of the [HC03-] suggested that the
metabolic alkalosis was "mild," but we can now see that it is very severe.

Answer: Respiratory alkalosis (severe), AG acidosis (severe), metabolic alkalosis (severe).

Case 42: This is a totally optional question: Reread the comment about maximum respiratory
compensation for a metabolic acidosis that follows Case 2. How did I know that the pH of 7.00 in a
patient with a [HC03-] of 3 and PCO~ 12.5 would plummet to 6.80 if the PCO~ increased to 20 mm Hg?

Answer: I used the Henderson-Hasselbalch equation pH = 6.1 + log ( [HC03-11.03 X Pco2] ) and simply
plugged in the values [HC03-] = 3 and PCO~ = 20. pH = 6.1 + log ( 3/(.03 X 20 )) pH = 6.1 + log ( 3 1.6 )
= 6.1 + log (5) = 6.1 + .70 = 6.80 This equation is also useful to see if the pH, [HC03-1, and PCO~ are
consistent with each other or if there has been a lab error in measuring one of these variables. This
formula is included because it is sometimes useful to have a way of verifying that the pH, [HC03-1, and
Pc02results are correct, and to predict what would happen to the pH given a change in [HC03-] or Pco~.
There are approximate methods available that don't involve using logarithms, but the Henderson-
Hasselbalch equation is the easiest for me. I just bite the bullet and pull out my calculator. This formula
is included because you might find it useful someday, but it is not important to working any of the
exercises in this boo

Case 43: A 50-year-old 70 kg alcoholic man presents with 4 days of nausea, vomiting, and mild
abdominal pain following a week-long drinking binge. He is unable to take anything by mouth. His
mucous membranes are dry, and his vital signs reveal an orthostatic blood pressure drop with a rise in
pulse. The following laboratory data are obtained: Na 134 mEqn, K 3.1 mEq/L, [HC03-] 20 mEq/L, C1
80 mEq/L, glucose 86 mg/dl, BUN 52 mg/dl, Cr 1.4 mg/dl, amylase pending, serum ketones: high
positive reading. ABG: pH 7.32, PCO2 40 mm Hg, [HC03-] 20 mEq/L. Urine sodium 7 mEqL (low). Urine
ketones: high reading. What is your diagnosis, and what do you do?

Answer: The history and laboratory studies suggest alcoholic ketoacidosis with hyponatremia
secondary to volume depletion (vomiting) and hypokalemia secondary to vomiting and ketoacidosis.
There may also be pancreatitis. There is a complex acid-base disorder, although the pH is only mildly
depressed.
Complex acid-base disorder.
Step 1 : pH is slightly decreased. [HC03-] is slightly down: metabolic acidosis. PCO2 is "normal".
Step 2: For metabolic acidosis what should the PCO~ be? PCO~ = (1.5 X 20) + 8 = 38. The measured
PCO~ of 40 mm Hg is very close to this value, so no respiratory disorder is present.

Step 3: The anion gap is 134 - (20 + 80) = 34! Therefore an anion gap acidosis is present. Now compare
the change in the anion gap (34 - 12 = 22) to the change in the [HC03-] ( = 4). The expected decrease
in [HC03-] based upon a ketoacidosis is in the range of 22 mEq/L. The [HC03-] only decreased by 4
instead of 22 mEqn. Therefore, there is a metabolic alkalosis acting to push the HC03 up and a severe
anion gap acidosis acting to push the [HC03-] down. They tend to cancel each other, but they are both
severe. The solution to the acid-base disorder is: Anion gap metabolic acidosis due to alcoholic
ketoacidosis

Metabolic alkalosis due to vomiting.

Primary to remember to consider ethylene glycol and methanol in an alcoholic patient with a high AG
acidosis.

Hyponatremia: The patient has a history of vomiting and clinical evidence of ECFV depletion. The
urine sodium is low.

Hypokalemia: The hypokalemia is probably secondary to vomiting and ketoacidosis. A spot urine
potassium to creatinine ratio > 20 mEq1gm would support urinary potassium loss (remember that
hypokalemia is due to urine potassium loss in both vomiting and ketoacidosis). The serum potassium
concentration of 3.1 mEqL suggests a large deficit of as much as 400 mEq. The potassium
concentration may fall with glucose administration, so potassium replacement should be started as
soon as you know the patient is not anuric, and the potassium concentration rechecked in 2-3 hours.
If the potassium concentration falls, then replacement should be increased (if the potassium
concentration falls rapidly, then the glucose-containing saline solution could be held temporarily and
0.9% saline without glucose could be used if necessary). It is also important to measure a magnesium
concentration in such a patient.

Remember that potassium deficits cannot be replaced until the magnesium deficiency is corrected.

Orders: Patients with alcoholic ketoacidosis require glucose supplementation along with isotonic
saline to reverse ketosis. Also, multivitamins, thiamine, and folate should be replaced in such a patient.
IV glucose could precipitate an acute Wernicke's encephalopathy in this patient if thiamine (100 mg
IM) is not given first. So, in an alcoholic, first give the thiamine; then start the fluids. The IV orders
might look like: 100 mg thiamine IM stat and every day for three days

Liter #1: D5 0.9% saline with 30 mEqn KC1 5 mg folate 1 Amp Multivitamins at 250 cc/hr.

Liter #2: D5 0.9% saline with 30 mEqL KC1 5 mg folate 1 Amp Multivitamins at 175 cch.

Liter #3: D5 0.9% saline with 30 mEqn KCl at 175 cch. An IV order is not complete until the monitoring
orders are written: Daily weight in the morning. Glucose, sodium, potassium, chloride, bicarbonate,
blood urea nitrogen (BUN), and creatinine (Cr) in 3 hours, 6 hours, 9 hours, and in the morning. If the
potassium concentration falls, then replacement should be increased.
Case 44: A 50-year-old woman was admitted to the hospital with protracted nausea, vomiting,
and abdominal pain. Abdominal X-rays revealed an ileus, which resolved with nasogastric suction and
IV fluids (0.9% saline with 30 mEq/L KC1). She says that her abdominal pain, which had initially
improved with nasogastric suction and IV fluids, has now returned. She now has a temperature of
101.6 and her blood pressure has fallen from 130/86 to 86/52. The abdomen is very tender, and no
bowel sounds are present. Her laboratory studies: Na 140 mEqL, K= 4.5 mEqL, C1 80 mEqL, HC03- 25
MeqL, pH 7.40, Po2 100, PCO2 40, HCO3- 25 mEqL. What is your diagnosis? Complex acid-base
disorder.

Step 1 : On inspection of the laboratory studies, there is no obvious acid-base disorder present. The
pH, PCO2, and [HC03-] are all normal.

Step 2: Because there is no apparent acid-base disorder present, appropriateness of compensation is

not an issue.

Step 3: The anion gap is 140 - (25 + 80) = 35! Therefore, a severe (most likely lactic) anion gap
metabolic acidosis is present. This acidosis is probably the result of bowel ischemia. Why is the [HC03-
] normal? Because there is an equally profound metabolic alkalosis present, which is "masking" the
metabolic acidosis. We calculate the change in anion gap and compare it to the change in the HC03.
The change in anion gap is 35 - 12 = 23. Therefore, in this lactic acidosis, the [HC03-] should be around
25 – 23/1.5 = 25 - 15.3 = 9.7! There is an opposing metabolic alkalosis pushing up the [HC03-] by around
15.3 in this case, and therefore the normal [HCO3-] disguises two severe acid-base disorders: Anion
gap acidosis from ischemic bowel. Metabolic alkalosis from vomiting and nasogastric suction. It is
important to follow the 3 steps for every single set of acid-base chemistries that you evaluate, even if
everything looks normal at first glance. Calculating the anion gap was central to solving this case

Case 45: A 75-year-old man is admitted with septic shock. Shortly after admission, blood tests
reveal the following:

Identify the acid-base disturbance. ○ Metabolic acidosis

● Check whether the patient has compensation/additional disturbance.

○ Choose the formula PaCO2 = 1.5 x HCO3 + 8 ± 2

○ Substitute the values PaCO2 = 1.5 x 7 + 8 ± 2 PaCO2 = 18.5 ± 2 PaCO2 = (16.5 - 20.5)

○ Interpret the result The patient’s value is 16 Which almost falls within the range, that means that
the metabolic acidosis is being compensated properly with respiratory alkalosis.

○ Calculate the anion gap AG = Na - (Cl +HCO3) AG = 138 - (95+7) = 36 (high)

● Indicate what is causing the acid base disturbance?

○ Lactic acidosis (associated with shock ) shock > shifting to anaerobic metabolism > high lactate >
low PH (metabolic acidosis)

Case 46: A 68-year-old woman is being treated for congestive heart failure in the coronary
care unit. After several days of treatment, the following results are returned
 Identify the acid-base disturbance. Metabolic
alkalosis

● Check whether the patient has

compensation/additional disturbance.

○ Choose the formula ↑PaCO2 = 0.7 x ∆HCO3 ○

Substitute the values ↑PaCO2 = 0.7 x (39-24)
↑PaCO2 = 10.5

○ Add to the normal range ↑PaCO2 = 40 + 10.5 =

50.5 ± 2 ↑PaCO2 = (48.5-52.5) ○ Interpret the
result the metabolic alkalosis is compensated
properly by respiratory acidosis.

● Indicate what is causing the acid base

disturbance? use of Diuretics (diuretics decrease
blood volume so as a response to that, the kidneys increase reabsorption of sodium bicarbonate)

Case 47: A 70-year-old man with chronic obstructive pulmonary disease (COPD) is admitted with
increasing confusion. Shortly after admission, blood tests reveal the following:

Identify the acid-base disturbance.

Respiratory acidosis (+ metabolic acidosis )

● Check whether the patient has

compensation/additional disturbance.

○ Choose the formula Ask yourself, is it Acute or

chronic? COPD = Chronic

↑HCO3 = 0.35 x ∆PaCO2

○ Substitute the values ↑HCO3 = 0.35 x (83-40)

↑HCO3 = 15

○ Add to the normal range ↑HCO3 = 24 + 15 = 39 ± 2

↑HCO3 = (37-41) BUT in our patient only 34mmol/L

○ Interpret the result there is an additional metabolic

acidosis on top of the respiratory acidosis

● Calculate the anion gap AG = Na - (Cl +HCO3 ) AG =

140 - (94+34) = 12 (normal)

● Indicate what is causing the acid base disturbance? CO2 retention caused by COPD (CO2
accumulation may itself lead to drowsiness That further depresses respiratory drive)
Case 48: A 40-year-old man developed profuse diarrhea following antibiotic treatment of a chest
infection. He is thirsty, and light headed. Shortly after admission, blood tests reveal the following:

Identify the acid-base disturbance. Metabolic acidosis

● Check whether the patient has

compensation/additional disturbance. ○ Choose the
formula PaCO2 = 1.5 x HCO3 + 8 ± 2

○ Substitute the values PaCO2 = 1.5 x 17 + 8 ± 2 PaCO2 =

33.5 ± 2 PaCO2 = (31.5-35.5)

○ Interpret the result the metabolic acidosis is

compensated properly by respiratory alkalosis.

● Calculate the anion gap AG = Na - (Cl +HCO3) AG = 134

- (104+17) = 13 (normal)

● Indicate what is causing the acid base disturbance?

Diarrhea

Case 49: Patient comes with diabetic ketoacidosis at 0 hours at presentation. pH 7.06, CO2 = 10.3,
HCO3 − = 6.1, Na+/Cl− 142/106 • pH acidemia, primary condition metabolic with pH and HCO3 − both
decreased

• AG = 142 – (106 + 6.1) = 30↑↑ = HAGMA

• Compensation for metabolic acidosis: Winter’s formula: Expected CO2 = (1.5 × 6) + 8 = 17, but actual
value 10 < 17, indicating respiratory alkalosis (hyperventilation)

• Delta ratio = AG-12/HCO3 − -24 = 18/18 = 1, no non-AG acidosis ( Cl− normal) Thus, patient has
HAGMA with respiratory alkalosis. Same patient after 6 hours of treatment with insulin and saline, pH
7.22, CO2 = 24, HCO3 − = 10.2, Na+/Cl− 140/120

• pH = acidemia, primary condition metabolic with pH and HCO3 − both decreased

• AG = 140–130 = 10, now normal indicating NAGMA

• Metabolic acidosis compensation: Expected CO2 = (1.5 × 10) + 8 = 23 matches the measured CO2
(Winter’s formula). Thus, compensation is adequate.

• Delta AG = (AG – 12) + measured HCO3 − = 2 + 10 = 12 < 24, indicating hidden NAGMA (Cl− 120).
Delta ratio which is the ratio of difference in AG and bicarbonates = (AG - 12)/(HCO3 −–24) = 2/14 < 1.
With saline, hyperchloremic acidosis sets in. Thus, the patient now has NAGMA owing to the
treatment. Ketoacids are being cleared (AG ↓), thus indicating a good response. Only HCO3 − will not
indicate adequacy of response.

Treatment of metabolic acidosis includes treating underlying cause, HCO3 − therapy as per the formula
0.5 × weight (kg) × HCO3 − deficit (mEq/L). The objective is to raise the pH to >7.2 and HCO3 − > 10
mEq/L..
Case 50: A 70 year old man was admitted with severe congestive cardiac failure. He has been
unwell for about a week and has been vomiting for the previous 5 days. He was on no
medication. He was hyperventilating and was very distressed. Admission biochemistry is listed
below. He was on high concentration oxygen by mask.
Biochemistry results: Na+ 127, K+ 5.2, Cl- 79, HCO3- 20, urea 50.5, creatinine 0.38 & glucose 9.5
mmols/l. Anion gap 33 mmols/l

Arterial Blood Gases

pH 7.58
pCO2 21 mmHg
pO2 154 mmHg
HCO3 19 mmol/l

Assessment

Initial Clinical Assessment

The history suggests the following possibilities:

• Respiratory alkalosis in response to the dyspnoea associate with the congestive heart failure
• A lactic acidosis is possible if cardiac output is low and tissue perfusion is poor
• Vomiting suggests metabolic alkalosis

The renal failure could be associated with a high anion gap acidosis

Acid-base Diagnosis

1-pH: pH is greater than 7.44 so an alkalaemia is present. The cause is an alkalosis

2-Pattern: pCO2 & bicarbonate are both low suggesting either a metabolic acidosis or a respiratory
alkalosis. As we already know an alkalosis is present then the primary disorder is a respiratory
alkalosis.

3-Clues: The anion gap is noted to be very high so there must be a high-anion gap metabolic
acidosis present as well. To briefly explore the 4 causes of a HAGMA:

Ketoacidosis: The normal glucose makes ketoacidosis unlikely. Urinalysis for ketones and glucose
should be carried out.

Renal failure: The creatinine is high enough to indicate a GFR low enough (<20 mls/min) to cause
hyperkalaemia (due impaired potassium excretion) and metabolic acidosis (due to renal retention
of acid anions)

Toxic acidosis: There is no evidence presented of toxic ingestions and no suggestive history (eg
neurological symptoms)
Lactic acidosis: No lactate results are reported so this cannot be excluded.

4-Compensation: Asessing the compensation for a respiratory alkalosis (using rule 4 - "the 5 for
10" rule): The expected HCO3 is (24 - 10) = 14. The actual HCO3 is higher (19) which indicates the
presence of a metabolic alkalosis.

5-Formulation: Triple acid-base disorder (respiratory alkalosis, high anion gap metabolic acidosis
& a metabolic alkalosis).

6-Confirmation: A lactate level should be checked to exclude a lactic acidosis. A urine test for
ketones and glucose should be done and should be routine.

Clinical Diagnosis
Congestive cardiac failure with:

• respiratory distress causing respiratory alkalosis

• renal failure possibly of pre-renal cause causing a high anion gap metabolic acidosis, and
• vomiting (causing a metabolic alkalosis) resulting in a complicated acid-base picture.

Interestingly, all of these possibilities were suggested by the history.

A co-existing lactic acidosis is not excluded.

Case 51: A 69 year old patient had a cardiac arrest soon after return to the ward following
an operation. Resuscitation was commenced and included intubation and ventilation. Femoral
arterial blood gases were collected about five minutes after the arrest. Other results: Anion gap
24, Lactate 12 mmol/l.

Arterial Blood Gases

pH 6.85
pCO2 82 mmHg
pO2 214 mmHg
HCO3 14 mmol/l
Assessment: Firstly: Initial clinical assessment The expected result here would be a mixed disorder
with respiratory acidosis (due inadequate ventilation) and a lactic acidosis (related to poor
perfusion).
Secondly: The acid-base diagnosis

1-pH: The pH is extremely low (severe acidaemia) so a severe acidosis is present

2-Pattern: The combination of a high pCO2 and a low bicarbonate means that a mixed disorder is
present: there must be 2 or more primary acid-base disorders present. This pattern is found with
a combined acidosis: metabolic acidosis (low bicarbonate) and a respiratory acidosis (high pCO2).

3-Clues: The anion gap result confirms a high anion gap acidosis and the high lactate level confirms
this as a severe lactic acidosis.
4-Compensation: Consider the expected pCO2 for the metabolic acidosis: By the one & a half plus
8 rule (rule 5): Expected pCO2 = (1.5 x 14 + 8 ) = 29mmHg. The actual pCO2 of 82 mmHg is very
much higher which confirms the presence of a co-existent respiratory acidosis. The pCO2 level of
82 mmHg is so high that a respiratory acidosis must be present. (In exceptional cases of severe
metabolic alkalosis a pCO2 of 86mmHg has been recorded).

5-Formulation: A severe mixed acidosis due to lactic acidosis and respiratory acidosis.

6-Confirmation: Nil else is required. There should be clinical evidence to support the conclusion of
poor peripheral perfusion. If not, then an ischaemic gut cause should be considered but there is
no evidence of this here. Compared to standard normal values, the anion gap has increased by 12
& the bicarbonate level has decreased by 10 so the delta ratio is 12/10 = 1.2 - this is consistent
with a high anion gap acidosis.

Finally: The Clinical Diagnosis: Cardiac arrest with low cardiac output and tissue hypoperfusion
causing a severe lactic acidosis. Ventilation is depressed causing a respiratory acidosis.

Comments The pCO2 of 82mmHg is too high to have developed from a level of 40 mmHg in 5 minutes. An
elevated pCO2 must have been present before the arrest. Inadequate ventilation in this pre-arrest phase
may have been related to several factors, in particular inadequate reversal of neuromuscular paralysis,
airway obstruction in a supine sedated patient or acute pulmonary oedema. The hypercapnia would have
been associated with hypoxaemia and this would have contributed to the arrest. The high pO2 level on the
gases is due to the high inspired oxygen fraction as such a level is not possible when breathing room air.
 Paraoxygenation (Apneic Oxygenation)
Para oxygenation is the technique of providing uninterrupted oxygen supply to the patient
after the onset of apnoea in order to prolong the safe apnoea time especially in patients
with difficult airways to provide adequate time to the anaesthesiologist for uninterrupted
execution of the attempts to secure the airway. Paraoxygenation is also known as apnoeic
oxygenation. Figure 1: Apneic Oxygenation Post-preoxygenation O2: oxygen, -ve: negative pressure

Physiologic basis of para oxygenation:

Aventilatory mass flow /diffusion
respiratio /apnoeic diffusion of oxygen:
The oxygen consumption of a health
adult is 250 ml/min while the carbon
dioxide production is 200 ml/min.
Inapnoeic patients the extraction of
oxygen from the alveoli continues at the
rate of 250 ml/min while carbon dioxide
delivery to the alveoli is 21 ml/min
thereby causing the alveolar pressure to
become sub atmospheric leading to a
generation of pressure gradient which
enables the movement of additional
administered oxygen provided the
airway is patent. Preoxygenation
facilitates the process of apnoeic
oxygenation by denitrogenating the
alveoli. In the absence of adequate preoxygenation, the persistence of nitrogen in the lungs
along with the accumulating carbon dioxide will diminish the pressure gradient available
for the mass flow of oxygen into the alveoli thereby hastening the onset of hypoxemia. The
persistent delivery of 100 percent oxygen prevents the renitrogenation of the alveoli during
the apnoea. The sub atmospheric pressure also promotes carbon dioxide transfer from
blood to the alveoli. The degree of oxygen extraction from the alveoli exceeds the degree
of carbon dioxide return to the alveoli since carbon dioxide is buffered in the body but with
time the alveolar accumulation of carbon dioxide reaches a critical level beyond which the
pressure gradient is reduced thereby reducing the aventilatory mass flow of oxygen.

In the apnoeic patient, extraction of oxygen from the alveolus into the blood causes
alveolar pressure to become subatmospheric, generating a pressure gradient which
enables the movement of additional administered oxygen into the alveolus .

This helps to maintain oxygenation and prevent the onset of hypoxemia, which can occur
rapidly if the preoxygenation is inadequate. If preoxygenation is not sufficient, the presence
of nitrogen in the lungs, along with accumulating carbon dioxide, reduces the pressure
gradient available for oxygen transfer to the alveoli. This diminishes the effectiveness of
apneic oxygenation and hastens the onset of hypoxemia (Figure 2). Figure 2: Apneic Oxygenation
Without Preoxygenation
This is termed ‘aventilatory mass flow’, formerly referred to as ‘diffusion respiration’ or ‘apnoeic
diffusion of oxygenation’. Apnoeic oxygenation is facilitated by ‘denitrogenation’ of the patient's
lungs, by breathing O2 for a suitable duration, before the onset of apnoea. Otherwise, the
persistence of nitrogen in the lung, combined with accumulating carbon dioxide, diminishes the
pressure gradient available for oxygen
transfer to the alveolus and hastens the
onset of hypoxaemia. Re-nitrogenation is
prevented by the delivery of a fraction of
inspired oxygen of 1.0 during the apnoeic
period. In this theory, the
subatmospheric alveolar pressure also
promotes carbon dioxide transfer from
the blood to the alveolus.

The pressure gradient is not

immediately obliterated as the degree
of oxygen extraction from the alveolus
exceeds the degree of carbon dioxide
return to the alveolus, given the
capacitance of the body to buffer and
store carbon dioxide, for example,
bicarbonate formation by carbonic anhydrase. With time, alveolar accumulation of carbon
dioxide diminishes the pressure gradient for oxygen transfer to the alveolus and limits the
duration of success of aventilatory mass flow. ‘Hypoventilatory mass flow’ has been
proposed as an alternative term to ‘aventilatory mass flow’ because, whenever carbon
dioxide is being cleared from the alveolus, this implies ‘ventilation’ and is therefore not a
true aventilatory state. Additionally, the term acknowledges that carbon dioxide removal
from the alveolus leads to a decline in alveolar pressure that can facilitate mass flow of
oxygen into the alveolus or accommodate the transfer of further carbon dioxide from the
blood.
The theory above also accommodates a possible role for cardiogenic oscillations, which are
airflow alterations caused by contractions of the heart and may assist with gas exchange
during apnoe. The change in heart volume during the cardiac cycle is believed to promote
gas movement by altering intrathoracic
pressure.

Additional contributions to pulsatile gas flow

may arise from direct compression and
expansion of the lung parenchyma adjacent
to the heart and from pulsatile flow in the
pulmonary vasculature. Gas mixing
secondary to cardiogenic oscillations is
believed to occur predominantly in the
conducting airways, but can also arise in the
acini. The magnitude of its contribution to
overall gas exchange in the apnoeic state
remains unknown; oscillations may be
enhanced by the apnoea-associated
respiratory acidosis, which stimulates a
tachycardia. The proposed mechanisms of
apnoeic oxygenation are illustrated in Fig. 1.

Figure 1 Apnoeic oxygenation involves the mass flow of a high fraction of

inspired oxygen, aided by flushing of dead space, generation of positive
airway pressure and cardiogenic oscillations. Higher flow rates can enable
clearance of carbon dioxide.

Carbon dioxide clearance: The

elimination of carbon dioxide from the body is limited during apnoeic oxygenation, such
that hypercarbia and acidaemia ensue over time. During normal spontaneous ventilation,
partial pressure of carbon dioxide (PCO2) is highest in mixed venous blood (PvCO2), then in
the alveolus (PACO2), then in arterial blood (PaCO2). During the initial period of apnoeic
oxygenation, venous, alveolar and arterial partial pressures of carbon dioxide transiently
reach equilibrium. Thereafter, the arteriovenous carbon dioxide gradient described above
becomes reversed, with arterial PCO2 exceeding venous PCO2. The reversal is attributed to
retention of carbon dioxide within the pulmonary circulation due to impaired gas exchange,
and is compounded by the Haldane effect, wherein oxygenation of arterial blood displaces
carbon dioxide from haemoglobin.

The degree of carbon dioxide accumulation that occurs in the blood during the first minute
of apnoea is greater than in any subsequent minute. Stock demonstrated a mean PaCO2 rise
of 1.6 kPa during the first minute, followed by a rise of 0.45 kPa with each subsequent
minute during complete airway obstruction in elective surgical patients, simulated by
clamping the tracheal tube. Similar blood gas alterations have been observed during
apnoea testing for brainstem death.

It is notable that some carbon dioxide clearance can occur, depending on the flow rate of
administered gases and the proximity of their site of administration to the alveoli. Higher
flow rates are believed to extend the region of turbulent gas flow more distally in the
airways, resulting in improved gas exchange, sufficient to maintain a normocarbic state
during apnoeic oxygenation in animals. This degree of gas exchange has seldom been
attained in human studies despite use of endobronchial catheter flow rates in excess of 0.5
l.kg.min−1 . High-flow nasal oxygen attenuates the rise of carbon dioxide in the blood, with
mean elevations of 0.21 kPa.min−1 and 0.24 kPa.min−1 in two case series. Preceding apnoeic
oxygenation with a period of hyperventilation does not exert a prolonged effect on
lowering PaCO2.

The gradient between PaCO2 and end-tidal carbon dioxide (ETCO2) increases with apnoea
duration (where the latter is measured at the first postapnoeic breath). Bohr hypothesised
that this divergence was caused by atelectasis and ventilation–perfusion mismatch. As a
consequence, ETCO2 measurements progressively underestimate the hypercarbic burden.

Patient factors that can affect efficacy and efficiency of preoxygenation

Effect on preoxygenation
Patient factor
Efficacy* Efficiency¶

Obesity: ↓ ↓
▪ Reduced FRC

▪ Atelectasis

▪ Tidal volume may fall within

closing capacity

Pregnancy: ↓ ↓
 ▪ Reduced FRC

▪ Atelectasis

▪ Increased oxygen consumption

Very young age: Faster preoxygenation ↓↓ Δ

▪ Reduced FRC

▪ Increased oxygen consumption

Older adults: Slower, less effective ↓

▪ Reduced oxygen consumption preoxygenation

▪ Reduced lung function

Critically ill; varies: Slower, less effective ↓↓

▪ Increased oxygen consumption preoxygenation

▪ Anemia

▪ Acidemia

▪ Cardiopulmonary disease
FRC: functional residual capacity.* Efficacy refers to achieving end tidal oxygen >90%.
¶ Efficiency refers to prolongation of safe apnea time (ie, time during apnea until oxygen saturation falls to 90%).Δ Children
desaturate faster than adults during apnea; the younger the child the more rapidly he/she desaturates.

The steps of apneic oxygenation: The technique of apneic oxygenation involves

specific steps to ensure effective oxygenation during periods of apnea:

1. Preoxygenation: Before the induction of anesthesia, ensure that the patient is pre-
oxygenated. This can be done using a non-rebreather oxygen mask at a flow rate of 15 liters
per minute or by connecting the patient to an anesthesia machine ventilatory circuit.
Preoxygenation helps denitrogenate the lungs and maximize the oxygen reservoir.

2. Induction of Anesthesia: Once preoxygenation is complete, administer the chosen

induction agent to induce anesthesia and initiate apnea.

3. Maintain the Nasal Cannula Flow Rate: During the apneic period, it is important to
maintain the flow rate of oxygen via a nasal cannula. This ensures a continuous supply of
oxygen to the upper airway.

If the patient is already on HFNO, continue using it with a flow rate of 50-60 L/min and
increase the fraction of FiO2 to 100%. If the patient is not on HFNO, consider using a nasal
cannula at a flow rate of five liters per minute or adjust the oxygen flow rate accordingly

4. Maintain a Patent Airway: It is crucial to keep the patient's airway open and patent until
the time of intubation. This can be achieved using techniques such as jaw thrust, and/or
nasopharyngeal airway. These maneuvers help prevent airway obstruction and ensure the
passive movement of oxygen from the upper airway to the trachea.

5. Continue Oxygenation During Intubation: Even during the process of intubation, it is

important to continue delivering oxygen via the nasal cannula (NC) or high-flow nasal
oxygen (HFNO). This ensures that oxygenation is maintained throughout the procedure.

Pitfalls to avoid during apneic oxygenation

1. Failing to Maintain Airway Patency: If the airway is not kept open, the passive movement
of oxygen from the nasal cannula to the trachea may be compromised, affecting the
effectiveness of apneic oxygenation.

2. Inadequate Preoxygenation: Insufficient preoxygenation can diminish the efficacy of the

passive flow of oxygen from the upper airway to the alveoli, as described in the
physiological mechanism earlier.

3. Relying on an Ambu Bag: An Ambu bag or manual resuscitator with a one-way valve
should not be used as the sole method of apneic oxygenation. The one-way valve prevents
the passive flow of oxygen to the mask, and attempting to provide active breaths during
intubation poses risks such as gastric distension and aspiration.

Figure 3: Different Components of Ambu Bag …Figure 4: A Closer Look at the One-Way Valve

Prerequisite for para oxygenation

1-Patent upper airway: A patent airway is an absolute prerequisite for successful
paraoxygenation. This allows the oxygen to be delivered to the hypopharynx and be
entrained into the trachea Patient should be positioned to maximise upper airway patency
using ear to sternal notch positioning. During the apnoeic period, upper airway obstruction
should be prevented by using the airway manoeuvres like head tilt, chin lift, jaw thrust or
by using the oropharyngeal airway/nasopharyngeal airway.

2-Adequate preoxygenation: The benefit of apnoeic diffusion oxygenation is dependent on

achieving maximal preoxygenation before apnoea.
3-Placement of a device to deliver oxygen: Para oxygenation can be achieved by using any
device that administers oxygen into the respiratory tract including, nasal cannula,
nasopharyngeal catheter, rigid bronchoscope, catheter placed in trachea, endobronchial
catheters, front of neck catheter, channels located in direct and video laryngoscopes.

4-Oxygen source: Auxiliary port in the anaesthesia machine or an oxygen cylinder in case
of intubations done in out of operating room settings can be used for the oxygen
denitrogenating supply.

Techniques: Various techniques for administration of paraoxygenation have been

described. Oxygen can be delivered at different locations in the upper and lower airway
during apnoea: Devices can be placed at following sites: Nares, nasopharynx, oropharynx,
oral cavity, trachea, Primarybronchi (Figure 4).

1-NODESAT: Nasal oxygenation during efforts securing a tube

2-Direct pharyngeal insufflation

3-THRIVE: Trans nasal humidified rapid insufflation ventilatory exchange

4-Other techniques: Apnoeic oxygenation with nasopharyngeal catheters, intratracheal

catheters, Bilateral or unilateral endobronchial catheters, buccal oxygen delivery with
modified RAE tube, channels located in direct and videolaryngoscopes,

Figure 4. Techniques of paraoxygenation.

1-NODESAT: Nasal oxygenation during efforts securing a tube.

NODESAT was first described by Levitan, as a method to extend the safe apnea time during
rapid sequence anaesthesia in the emergency department. Inappropriately sized nasal
cannula is used to administer the standard unwarmed and dry oxygen at the rate of 15
litres/min while attempts for intubating the trachea by conventional laryngoscopy or video
laryngoscopy or flexible fibreoptic bronchoscope are being made. Unlike other techniques,
this technique does not require any special equipment and can be easily done in the
operating theatre with nasal prongs and auxiliary oxygen port. However, they can impair
the face mask seal during bag mask ventilation. The administration of dry, cold oxygen at
high flows can lead to mucosal injury and mucociliary dysfunction (Figure 5).

Figure 5. (a) NODESAT during preoxygenation; (b) NODESAT during intubation.

2- Direct pharyngeal oxygen insufflation:

Para oxygenation can be achieved by using any device that administers oxygen
to the pharynx (Figure 6).

Figure 6. Naso-Flo.
Nasopharyngeal catheter: A nasopharyngeal catheter advanced into the nasopharynx can
be used to deliver oxygen during apnoea. The distance from the nares to the tragus of the
ear is measured as taken as depth of the catheter insertion. Achar et al found
nasopharyngeal catheters to be more effective than nasal prongs in delivering oxygen
during apnoea. The Naso-Flo®(Medis medical CO Ltd) is soft silicone nasopharyngeal airway
device that allows for direct oxygen delivery into the pharynx, while humidification vents
positioned towards the distal tip facilitate heat and moisture transfer.
Fig. 1. Design of the nasopharyngeal apnoeic oxygenation device. The design brief was to simulate a resource constrained
environment, using components found in the theatre supply of a LMIC hospital. It was composed of a nasopharyngeal airway

Buccal oxygen delivery: An inexpensive, readily available method of apneic oxygenation

was described by Andrew Heard et al.. A 3.5 mm south facing Ring Adair and Elwin (RAE)
tube was cut above the murphy’s eye. Standard oxygen tubing was connected from the cut
end to the auxiliary oxygen outlet on the anaesthesia machine. The blunt proximal end was
placed in the buccal space with the tube angle opposed to the left side of the mouth. The
tube was fixed to the external cheek to maintained the position. This method of buccal
oxygen delivery provided a viable alternative to the nasal route (Figure 7).
Figure 7. Buccal oxygen delivery device. As described by Andrew Heard et al.(a) RAE tube (b) RAE tube cut
above murphy’s eye (c) Standard oxygen tubing connected from the cut end to the oxygen source. The Blunt
proximal end (connector detached) is placed in the buccal space with the tube angle apposed to the side of
the mouth.

3-THRIVE: Trans nasal humidified rapid insufflation ventilatory exchange:

Patel and Nourae, introduced the delivery of warm and humidified high flow nasal oxygen
using OPTIFLOW™ system . Not only the apnea time were prolonged but the rate of rise of
carbon dixoide was found to be one third of what was expected. This suggested a
physiology supplementing classic apneic oxygenation. The clearance of carbon dioxide can
be explained by the interaction of cardiogenic oscillations and turbulent primary
supraglottic vortex.

Primary supraglottic vortex: High-flow nasal oxygen enters the nose at 70-90 L/min, loops
around the soft palate, and exits through the mouth. This creates a highly turbulent
‘primary supraglottic vortex” which has the following effects:

It replenishes the pharynx with oxygen and prevents entrainment of room air. It effectively
bypasses the upper airways which ordinarily account for approximately 50% of the
resistance of the entire respiratory system to airflow. By effectively breathing ‘directly from
the glottis’, work of breathing is reduced by approximately 50%. It also generates a positive
airway pressure which in turn reduces upper airway collapsibility and distal airway
atelectasis. The primary vortex does not, however, extend deep into the trachea and
cannot by itself account for the observed level of gaseous exchange.

Cardiogenic oscillations: The compression and expansion of the small airways is brought
about by the blood leaving and entering the thoracic cavity with each heartbeat. The typical
amplitude of a ‘cardiogenic breath’ is around 7-15 ml per heartbeat. Ordinarily, cardiogenic
oscillations result in small-volume mass movement of gases within the trachea.

During THRIVE, this small volume is flushed into the supraglottic vortex during cardiogenic
‘expiration’, is removed, and replaced by 100% oxygen. Cardiogenic ‘inspiration’ moves this
oxygen towards the distal airways and also entrains turbulence, which enhances
intratracheal mixing. e.g.

1-Volume of a ‘cardiogenic breath’ to be 12 ml per heartbeat,

2-Heart rate:70 beats per minute.

840 ml of gas which contains CO2 is removed, and is replaced with 100% oxygen. This is not
enough to achieve full CO2 clearance. That is why carbondioxide still accumulates during
THRIVE, but at a slower rate than with classical apnoeic oxygenation.

THRIVE is administered through a standard commercially available high flow oxygen

delivery system e.g. Optiflow (Fischer and Paykel health care), Airvo, Airvo2 (Fischer and
Paykel health care). It consists of a flowmeter, humidifier, heating system, heated non
condensing circuit, and an oxygen connector for gas supply. Some of the ventilators. e.g
Bellavista ventilators, IMT medical, Switzerland available in the market have an inbuilt
system that provides the high flow oxygen therapy as well as invasive ventilation modes
(Figures 8–10).

Figure 8. Nasal prongs for high flow nasal oxygenation.

Figure 9.Equipment for high flow nasal oxygenation AIRVO2. Figure 10. Bellavista ventilator.

High-flow nasal oxygen represents a recent breakthrough in the area of apnoeic

oxygenation, enhancing both oxygenation and carbon dioxide clearance as compared with
low-flow nasal oxygen . Proposed mechanisms include reduced dilution of administered
oxygen by nitrogen, enhanced dead space flushing, positive airway pressure
generation and benefits derived from gas heating and humidification. High-flow nasal
oxygen promotes washout of gases from anatomical dead space, including more distal
conducting airways, as demonstrated by scintigraphy studies in breath-holding subjects.
Sampling of inspired gases from tracheostomised patients has demonstrated a flow-
dependent increase in inspired tracheal oxygen concentration and reduced rebreathing .
Intraoperative setting of
HFNO suspension
laryngoscopy, A position of
the nasal prongs (Opti
Flow©) during
preoxygenation, B insertion
of the suspension
laryngoscope with
persisting nasal prongs

HFNO Nasal Cannula

Can provide pre-oxygenation Cheap and available
Freehand Can provide BMV if needed
Advantages
Might be more effective in
Sample ETO2
laryngeal pathologies
Relatively expensive
Can’t provide pre-oxygenation
Not widely available
Disadvantages
Can’t provide BMV
Might not be as effective as HFNO in laryngeal pathologies
Can’t sample ETO2
Table 1: Comparison between HFNO and NC

Positive airway pressure generation by high-flow nasal oxygen increases end-expiratory

lung impedance in spontaneously breathing patients, which is consistent with an increase
in end-expiratory lung volume and functional residual capacity . It also assists with upper
airway patency, as observed in patients with obstructive sleep apnoea, who have less
inspiratory flow limitation with nasal insufflation . A linear relationship exists between high-
flow nasal oxygen flow rate and positive airway pressure generation in the nasopharynx of
awake patients. Each 10-l increase in flow rate achieves an additional positive airway
pressure of 0.5 cmH20 with an open mouth and 1 cmH20 with a closed mouth, albeit with
significant inter-patient variability . Furthermore, the heating and humidification of
administered oxygen improves airway function through enhanced gas flow and pulmonary
compliance , maintenance of ciliary function and avoidance of the bronchoconstrictor
response that arises with cold, dry gases.

4- Others
A-Endobronchial catheters: Endobronchial catheters are placed in the main stem
bronchi. The catheter placedeither in right or left main stem bronchi or in both
the bronchi can be used for apnoeic oxygenation. Babinski et al. used two
polyethylene catheters (2.5 mm OD) with angulation of 20 degree for the right
side and 30 degree for the left were placed in the bronchi under fibreoptic
guidance for endobronchial apnoeic oxygenation. Humidified oxygen was
delivered at 0.6 to0.7 L/min. The authors found the adequate oxygenation was
maintained till 30 minutes with a mean co2 rise at rate 0.6mmhg/min (Figure
11).

Figure 11. ShileyEndobronchial suction catheters with color coded connectors.

B-Dual use laryngoscopes: Dual use laryngoscopes are specifically designed to

allow for the insufflation of oxygen during laryngoscopy. The miller port
American profile conventional blade is commercially available laryngoscope that
has an integrated tube that permits the delivery of oxygen and other gas mixtures
during laryngoscopy (Figure 12).
Figure 12. Miller port American profile blade.

C-Tracheal tube introducer: An Eschmann tracheal tube introducer was used by Millar
et al. for administering apnoeic oxygenation. Two holes were drilled at both the end of the
Eschmann gum elastic bougie and apnoeic oxygenation was tested on an anaesthetic
simulator model. The modified bougie was positioned 2–3 cm beyond the vocal cords with
8 l/min of oxygen flowing through it. The time taken for the oxygen saturation to fall was
significantly prolonged when modified gum elastic bougie was used for apnoeic
oxygenation. COOKS airway exchange catheter (AEC) has a blunt tip which is a traumatic to
internal structures. The lumen and distal side ports are designed to deliver oxygen. The
removable Rapi-Fit Adapter permits oxygen delivery during an airway exchange procedure.
Although cook’s airway is intended for tracheal tube exchange, it can also be used to
paraoxygenate the airways (Figure 13a–c).

Figure 13. Cooks airway exchange catheter (cook medical). (a) Cook’s Airway exchange catheter; (b) Distal end of Cook’s AEC Designed
to deliver oxygen; and (c) distal lumen of the cooks airway exchange catheter.

C-Intratracheal catheters: A retrospective study was conducted by Rudlof and

Hohenhorst analysing 47 patients who underwent apnoeic oxygenation at 0.5 l/min using
a catheter inserted into the trachea. The median Spo2 at the end of the apnoeic period was
found to be 100 percent. The mean apnoea time was found to be 24.7 min with no adverse
effects.

Technique Device used Advantages Disadvantages

1.No special equipment
required Dry and cold oxygen delivery
NODESAT Nasal prongs
2.Easily done in emergency leading to mucosal injury
and elective settings
1.Humidified oxygen
Commercially delivery
Costly equipment
THRIVE available devices 2.Higher flow than
Not readily available
(OPTIFLOW) NODESAT upto 60 L/min
3. Carbon dioxide clearance
1.Nasopharyngeal 1.More effective than nasal
DIRECT
catheter prongs Dry and cold oxygen delivery
PHARYNGEAL
2.Buccal oxygen 2.Buccal delivery is an leading to mucosal injury
INSUFFLATION
delivery alternative to nasal route
1.Endobronchial
1.Endobronchial
OTHER catheters Dry and cold oxygen delivery
oxygenation
TECHNIQUES 2.Dual use leading to mucosal injury
During the laryngoscopy
laryngoscope
Table 1. Summary of techniques of paraoxygenation.

(A) Humidified high flow nasal

cannula.
(B) Humidified high flow nasal
cannula in place during direct
laryngoscopy.
(C) Continuous insufflation via
modified nasal airway.
(D) Laryngoscope blade with
auxiliary oxygen supply
attached to side port.
(E) Close view of laryngoscope
oxygen side port.
(F) Continuous insufflation via
endotracheal tube in the side
channel of a video
laryngoscope.
(G) Nasal airway modified
with 15 mm adaptor from an endotracheal tube.
 Apneic preoxygenation without nasal prongs: the
“Hungarian Air Ambulance method”
Nasopharyngeal and nasal oxygenation during apnea has been shown to prolong the onset
of desaturation in normal and obese patients anaesthetized and paralyzed for elective
surgery. Oxygen supplementation through a nasal cannula during laryngoscopy, also known
as apneic preoxygenation, has recently been suggested by Weingart and Levitan to prevent
desaturation during rapid sequence intubation (RSI). The method was associated with
decreased desaturation rates during RSI
There is several pitfalls with the nasal cannula method
1) First, it can be challenging to apply and keep the nasal prongs in place if nasopharyngeal
airways (NPAs) are chosen to maximise preoxygenation, such as in patients with reduced
level of consciousness.
2) Second, once applied any manipulation to the face and neck, such as chin lift or manual
in-line stabilization, can easily dislodge the prongs from the nostrils or from the NPAs.
3) Third, the presence of blood, sometimes found in head or maxillofacial trauma, can easily
obstruct the passage of oxygen. In severe cases continuous nasal suctioning is needed even
during the laryngoscopy, however this is impossible without removing the nasal cannula.
4) Fourth, if only one oxygen source and one competent assistant is available, a situation
common prehospitally, the assistant needs to ensure the tubing is swapped not just after
the intubation (ie. to start supplementing the bag-valve), but after the induction as well (ie.
to start apneic preoxygenation). As the tubing and cylinder are usually out of sight during
the intubation, it is easy to forget about the second swap, thus making the patient prone
to desaturation.
We have developed a new method that eliminates the problems mentioned above and at
the same time is easier and quicker to perform. It is applicable to every patient who has at
least one appropriately sized, flinged nasopharyngeal airway inserted at the time of
laryngoscopy. Preoxygenation is carried out in the standard way with a non-rebreathing
mask (NRBM) set at 15 lpm (Fig. 1a).

After the onset of apnea the intubator cuts the tubing of the NRBM (Fig. 1b), removes the
mask and inserts the free end of the tubing approximately 3–5 cm deep into the
nasopharyngeal airway (Fig. 1c) with the flow kept at 15 lpm. The laryngoscopy is
performed with the “tube in the tube” (Fig. 1d). An additional movie file shows this in more
detail [see Additional file 1].
Fig. 1 Apneic oxygenation without nasal prongs - the “Hungarian Air Ambulance method”.

a The intubator preoxygenates the patient with a non-rebreathing mask (15 lpm). Upper airway
patency is maximized by two naso- and one oropharyngeal airway.
b The intubator cuts the tubing of the mask after the onset of apnea.
c The intubator removes the mask and inserts the free end of the tubing approximately 3–5 cm
deep into the nasopharyngeal airway.
d The laryngoscopy is performed with the “tube in the tube”

Once the correct endotracheal position is confirmed, the assistant swaps the oxygen
source, removes the tube from the NPA and the procedure is continued as usual. If the
team has an extra cylinder the swap can be eliminated, and in case of a failed laryngoscopy
with desaturation, the reoxygenation can be augmented by double oxygenation (ie.
reservoir-bag-valve-mask plus nasal supplementation).
In our experience the wall of the tube is rigid enough not to kink beneath the facemask.
Should the patient have pharyngeal bleeding, continuous suctioning can be applied through
the opposite NPA. This will most probably reduce the oxygen concentration within the
pharynx, although it seems logical that it is still better than suctioning without oxygen
supplementation. One concern with nasopharyngeal oxygen insufflation is the risk of
iatrogenic gastric rupture.
Possible mechanisms for stomach rupture included direct oesophageal insufflation (i.e.
catheter placed or migrated to or below the level of the cricopharyngeus) or oxygen stream
induced deglutition reflex resulting in persistent aerophagia. Air swallowing might have also
been coupled by the suctioning effect of negative intrathoracic pressure from spontaneous
breathing, exacerbated by the decreased tone of the oesophageal sphincter (direct drug
effect) and/or the partial airway obstruction subsequent to the reduced level of
consciousness. Given the fact that this method is:
1) Applied only for a short period of time (usually less than a minute)

2) The patient has no spontaneous breathing while applied and

3) There is no risk of catheter misplacement (i.e. the tubing needs to be introduced only a
couple of centimetres in order to sit firm in the NPA), we believe the risk of iatrogenic
gastric rupture is extremely small even with high flow and is undoubtedly outweighed by
the benefit of preventing desaturation.
There are two limitations we have identified so far.
1) First, the method requires a NPA. We do not recommend passing the oxygen tube
directly in the nasal passage, as it can provoke bleeding. In contrast to the soft and pliable
NPA, oxygen tubing can penetrate the cranium through a basal skull fracture.
2) Second, the oxygen tube can not be inserted into pediatric NPAs due to its diameter,
although this is not relevant in infants and small children where bag-mask ventilation is
mandatory during the onset of muscle relaxation (‘modified RSI’).
Apart from these limitations we believe this simple “Hungarian Air Ambulance method”
could be useful for those clinicians, that intubate patients requiring NPAs due to reduced
level of consciousness and/or maxillofacial bleeding or any patient in whom NPAs can be
inserted before or right after the induction of anesthesia.
Clinical applications of paraoxygenation/apnoeic oxygenation

Figure 14.Clinical applications of paraoxygenation.

1- Routine elective endotracheal intubation: Para oxygenation through nasal or

nasopharyngeal catheter prolongs the safe apnoea time and also decreases the degree of
desaturation during induction of anaesthesia and endotracheal intubation in adult ASA 1–
2 patients undergoing anaesthesia for elective surgery. Apnoeic oxygenation has been
shown to be associated with increased per intubation oxygen saturation, decreased rate of
hypoxemia and first pass intubation success. During one lung ventilation, apneic
oxygenation of the deflated lung through a suction catheter can reduces the likelihood of
hypoxemia and need for resumption of double lung ventilation .

2-Difficult airway management: Awake intubation: Awake fibreoptic intubation is

indicated in cases with anticipated difficult airways. Even though the procedure can be
done with local anaesthesia, sedation is often required to improve the patient tolerance
and cooperation. Sedative induced apnea, can lead to hypoventilation, and upper airway
obstruction during awake fibreoptic intubation in difficult airway resulting in critical oxygen
desaturation. Paraoxyygention can be used as an effective tool to ensure adequate
oxygenation while the airway is being navigated by the scope. Schroeder et alevaluated a
special oropharyngeal oxygenation device (OOD), allowing a continuous laryngeal oxygen
insufflation during and parallel with bronchoscopy . Apnoeic laryngeal oxygenation in a
preoxygenated manikin with both oxygen insufflation via the OOD and the bronchoscope
kept oxygen saturation in the test lung at 95% over 20 min. Oxygen insufflation via OOD or
bronchoscope was found to be more effective than nasal oxygen insufflation.

3-Physiologically difficult airway: Peri intubation hypoxia is more common in

physiologically difficult airways e.g., paediatric, obstetric and obese patient population.
Obesity leads to decreased in function residual capacity, increases atelectasis and shunting
in the dependent region of the lung. Resting metabolic rate, work of breathing and minute
oxygen demand however are increased. This combination of the factors makes the obese
patient prone to hypoxemia during the induction of the induction of anaesthesia. Oxygen
insufflation at 15 l/min through nasopharyngeal airway and standard nasal cannula can
significantly increase the safe apnea time during induction of anaesthesia in obese patients.

Although apnoeic oxygenation is extensively studied in the adult population, very few
studies have been conducted on the paediatric population, there is evidence that apnoeic
oxygenation is a simple easy to apply intervention that can decrease hypoxemia during
paediatric endotracheal intubation. Not only it increases the time until desaturation but
also reduced the overall incidence of hypoxia during laryngoscopy in paediatric population.

AIDA Are commends the universal use of 15 L/min oxygen insufflation via nasal cannula for
obstetric general anaesthesia they recommend the use of nasal prongs to insufflate oxygen
during the apnoeic period in patients with difficult airway.

5-Bronchoscopy: Apnoeic oxygenation can be done in patient undergoing rigid

bronchoscopy with passive oxygen insufflation through the side port of the bronchoscope
or a tracheal catheter. High flow administration of oxygen via side sport of bronchoscope
risk barotrauma if the path for gas egress becomes obstructed even for brief period.

6-Critical care: Recent guidelines for the management of airway in critical care
patients have recommended that nasal oxygen should be applied throughout the airway
management. If the standard nasal cannula is used it should be applied during
preoxygenation with a flow of 5 L/min while awake and increased to 15 L/min when the
patient loses conscious. A high flow nasal cannula can also be used if already in place.

7-Obesity: Obese patients experience a more rapid onset of hypoxaemia during apnoea,
which can be delayed by apnoeic oxygenation. Baraka et al. assessed the impact of pre-
oxygenation alone compared with pre-oxygenation followed by oxygen insufflation via a
nasopharyngeal catheter on the time to desaturation of morbidly obese patients at
induction of anaesthesia. The insufflation group demonstrated a longer time to
desaturation over a 4-min study period. Ramachandran et al. measured the effects of
apnoeic oxygenation via nasal cannulae at 5 l.min−1 on obese patients at induction of
anaesthesia while simulating a Cormack and Lehane grade-4 view during laryngoscopy.
Those patients who received nasal oxygen were more likely to maintain SpO2 ≥ 95% over a
6-min study period. Published studies utilising high-flow nasal oxygen have contained few
obese patients and the magnitude of benefit this population can derive from this
intervention remains uncertain.

8-Obstetrics: Guidelines issued by the Difficult Airway Society and Obstetric

Anaesthetists’ Association for the management of difficult tracheal intubation in obstetric
patients mention the potential role for apnoeic oxygenation via tight-fitting facemask,
nasopharyngeal catheter or nasal cannulae, based on evidence from non-obstetric settings.
The All India Difficult Airway Association recommends the universal use of 15
l.min−1 oxygen insufflation via nasal cannulae for obstetric general anaesthesia.

Pillai et al. undertook computational modelling of apnoeic oxygenation with high-flow nasal
oxygen in ‘virtual parturients’: high-flow nasal oxygen increased the time to desaturation
to 40% (an unusually low end-point) from 4.5 to 58 min. The clinical relevance of this
modelling has been questioned and this magnitude of benefit has not yet been observed in
clinical practice. An ongoing trial aims to characterise the efficacy and safety of high-flow
nasal oxygen as an isolated pre-oxygenation or apnoeic oxygenation technique in the
obstetric population and is due for completion in 2019.

9-Paediatrics: Randomised controlled trials have shown a delayed time to oxygen

desaturation with use of pharyngeal oxygen insufflation during elective traxcheal
intubation . In one study, apnoeic oxygenation with high-flow nasal oxygen at 1–2
l.kg.min−1 reduced the incidence of desaturation during intubation when compared with a
control arm that did not receive any supplemental oxygen during apnoea . Another trial
compared use of low-flow nasal oxygen at 0.2 l.kg.min−1 (FIO2 1.0), high-flow nasal oxygen
at 2 l.kg.min−1(FIO2 1.0), and high-flow nasal oxygen 2 l.kg.min−1(FIO2 0.3) at induction of
anaesthesia . Oxygen desaturation was the cause of study termination for all patients in
this last group. However, for 35 of all 38 patients receiving an FIO2 of 1.0, the study was
terminated due to attainment of a transcutaneous PCO2 of 8.7 kPa or an apnoea duration
of 10 min, before oxygen desaturation occurred. Therefore, this study was unable to
determine whether administration of 100% oxygen via high-flow nasal cannulae delays
time to oxygen desaturation when compared with low-flow nasal cannulae. Both
aforementioned high-flow nasal oxygen studies did not demonstrate clearance of carbon
dioxide when compared with control arms, questioning whether this is attainable in a
paediatric population despite high-flow insufflation.

10-Tubeless anaesthesia: Managing the shared

airway in the glottic and subglottic pathologies presents a
challenge to the anaesthesiologist as well as the surgeon.
Tubeless anaesthesia with apnoeic oxygenation allows a
good access and visualisation of the glottis without oxygen
desaturation. Figure 3 Apnoeic oxygenation provided via high-flow nasal cannulae
(visible just under the eye mask worn by the patient) while a surgeon performs
microlaryngeal surgery via a suspension laryngoscope.

Apneic oxygenation enables tubeless anaesthesia for

extended period of time. Vocalcordbiopsy, balloon dilation of
subglottic stenosis has been done using this technique.
Apnoeic oxygenation with nasal cannula and THRIVE has
been found to be safe and feasible for the endoscopic management of subglottic stenosis
in short glottic surgical procedures. Recently, apnoeic oxygenation with high-flow nasal
oxygen has enabled tubeless anaesthesia for extended periods, in excess of that which is
achievable with low-flow nasal oxygen and buccal oxygen administration (Fig. 3) . A
summary of relevant case series is included in the Supporting Information. Procedures have
included vocal cord biopsy, injection thyroplasty and balloon dilatation of subglottic
stenosis. One variation of the technique, undertaken by the authors of this article, involves
pre-oxygenation with high-flow nasal oxygen followed by total intravenous anaesthesia
with propofol and remifentanil infusions and administration of a neuromuscular blocking
drug. Airway patency is maintained with jaw thrust or laryngoscopy while apnoeic
oxygenation is undertaken with high-flow nasal oxygen (FIO2 1.0) at flow rates of 80
l.min−1. Intra-operative monitoring includes venous blood gas analysis at 15-min intervals.
Techniques to manage oxygen desaturation include: jet ventilation; temporary tracheal
intubation using a microlaryngoscopy tube via the suspension laryngoscope or removal of
the suspension laryngoscope; followed by conventional airway management, such as bag-
mask ventilation or supraglottic airway device insertion.

Randomised controlled trials comparing the risks and benefits of tubeless anaesthesia with
high-flow nasal oxygen vs. more traditional airway management have not yet been
undertaken. Optimal FIO2 and flow rate settings for this technique are also unknown.
Compression and absorption atelectasis leading to ventilation–perfusion mismatch are
hypothesised as reasons for the limited duration of successful oxygenation in the
unobstructed apnoeic patient . There is an ongoing trial aiming to quantify changes in lung
volume by electrical impedance tomography during use of high-flow nasal oxygen for
tubeless anaesthesia.

The absence of a tracheal tube precludes intra-operative end-tidal carbon dioxide

measurement. Some clinicians undertake arterial or venous blood gas analysis during the
apnoeic period , whereas others await ETCO2 measurement on completion of surgery .
Clinicians must exert caution in interpreting ETCO2 measurements as they underestimate
the rate of carbon dioxide accumulation, and consequently, underestimate the degree of
acidaemia. Transcutaneous PCO2 measurement has also been used

Apnoeic oxygenation can be undertaken for rigid bronchoscopy with passive oxygen
insufflation through the side port of the bronchoscope or a tracheal catheter . When low-
flow insufflation is used, leak around the rigid bronchoscope can be prevented by packing
the oropharynx with gauze. Alternatively, high-flow nasal oxygen can exploit an incomplete
seal around the bronchoscope in order to deliver oxygen to the lungs in an apnoeic state.
High-flow administration of oxygen via the side port of a bronchoscope risks barotrauma if
the path for gas egress becomes obstructed even for a brief period and is not
recommended. Cases of tracheostomy formation under apnoeic oxygenation have also
been described.

11-Apnoeic oxygenation for the avoidance of lung movement:

Apnoeic oxygenation of the deflated lung during one-lung ventilation reduces the likelihood
of hypoxaemia and the need for resumption of double-lung ventilation. This can be
achieved via an endobronchial suction catheter or, during bronchial anastomosis
formation, via a surgically-placed catheter distal to the anastomosis. Oxygen insufflation
via a tracheal tube or endobronchial catheter has been used instead of conventional
mechanical ventilation to improve surgical access during internal mammary artery harvest
for coronary artery bypass grafting. Apnoeic oxygenation can enhance the quality of
medical imaging by abolishing respiratory motion artefact, such as during computed
tomography (CT) pulmonary angiography. Apnoeic oxygenation can also prolong breath-
holding in awake patients in order to maintain a static thorax for improved dose
homogeneity during intensity-modulated radiotherapy.

12-Diagnosis of brain death: In the diagnosis of brain death, the absence of

respiratory effort despite hypercapnia is consistent with absent brainstem respiratory
reflexes and brainstem death. Apnoea test done in diagnosis of brain death involves the
temporary suspension of mechanical ventilation. During this time oxygen is insufflate
through the tracheal tube via a catheter to prevent hypoxemia. The apnoea test involves
temporary suspension of mechanical ventilation, leading to hypercarbia and acidaemia,
and is typically terminated when a pre-determined PaCO2 is attained. Hypoxaemia is
prevented by oxygen delivered through the tracheal tube via a catheter, T-piece or self-
inflating bag system. Failure to attain an adequate PaCO2 rise for successful testing can be
due to enhanced carbon dioxide clearance from an excessively high flow of oxygen .

13-Cardiac arrest: The potential utility of apnoeic oxygenation combined with

continuous chest compressions during cardiopulmonary resuscitation is recognised in
guidelines of the American Heart Association (AHA) and European Resuscitation Council
but is not routinely recommended. The AHA highlights witnessed out-of-hospital cardiac
arrest with a shockable rhythm as a circumstance where positive pressure ventilation can
be delayed in order to deliver three cycles of continuous chest compressions.

The ability of passive decompression of the thorax to generate a negative intrathoracic

pressure, aiding alveolar ventilation and venous return, is contested. Continuous oxygen
insufflation in lieu of positive pressure ventilation via a modified tracheal tube
demonstrated comparable outcomes in a small randomised controlled trial in humans. A
retrospective analysis demonstrated more neurologically favourable survival with passive
oxygen delivery via an oral airway compared with bag-mask ventilation after witnessed out-
of-hospital cardiac arrest with a shockable rhythm. More recently, a case of apnoeic
oxygenation with high-flow nasal oxygen during a brief intra-operative maternal cardiac
arrest has been reported.

14-Extracorporeal carbon dioxide removal: Combined use of apnoeic oxygenation

and extracorporeal carbon dioxide removal (ECCO2R) has been achieved in patients with
acute respiratory distress syndrome (ARDS). ‘Resting the lung’ using extracorporeal
assistance for gas exchange reduces systemic and pulmonary inflammatory mediators in
experimental acute respiratory distress syndrome when compared with a conventional
lung-protective ventilation strategy , and has been proposed as a mechanism of limiting
ventilator-induced lung injury. Continued improvements in ECCO2R technologies, chiefly in
the form of smaller dual lumen catheters for veno-venous ECCO2R and reduced
requirements for anticoagulation, may lead to greater use of ‘ultra-protective’ lung
ventilation in the management of ARDS. The results of multiple clinical trials are awaited.

15- Emergency intubation: Patients requiring emergency airway management are

at a greater risk of hypoxemia due to underlying lung pathology, high metabolic
requirements, high respiratory drive or inability to protect the airway. Rapid sequence
intubation in critically ill patients is associated with episodes of hypoxia. Apneic
oxygenation has been shown to reduce the incidence of desaturation in patient undergoing
rapid sequence intubation in emergency. A systematic review to investigate the effect of
apnoeic oxygenation on incidence of clinically significant hypoxemia during emergency
endotracheal intubation concluded that paraoxygentaion reduces the incidence of
hypoxemia in emergency endotracheal intubation and supported the inclusion of apnoeic
oxygenation in everyday practice.

Complications of Paraoxygenation
1-Hypercarbia: During Para oxygenation carbon dioxide cannot be vented out. Co2 levels
continue to rise leading to an increase in PH and development of respiratory acidosis .
Paco2 levels increase with a speed of 1.1–3.4 mmHg. Mean CO2 levels can reach as high as
160 mmHg. However, with THRIVE the rate of carbon dioxide accumulation is less than that
seen in classic apnoeic-oxygenation. The effects of hypercarbia are versatile ranging from
tachycardia, increased cardiac output, increased cerebral blood flow. Prolonged apnoeic
oxygenation should be avoided in patients with contraindication to hypercapnia e.g.,
cardiac arrythmia, hemodynamic instability, raised intracranial pressure. Para oxygenation
interrupts the early detection of rise of carbon dioxide. Since the end-tidal carbon dioxide
monitoring cannot be done during apnea, transcutaneous carbon dioxide measurements
may help in minimizing the risk and optimal utilization of Para oxygenation.

2-Acidosis: Gradual increase in the carbon dioxide levels leads to respiratory acidosis
however, during testing for brain death in addition to respiratory acidosis, a mild metabolic
acidosis of unknown cause also develops during apnoeic oxygenation. Figure 15. Complications
of paraoxygenation.

3-Oxygenation can be maintained for

prolonged periods with apneic oxygenation,
however without ventilation there is no
removal of CO2. Respiratory acidosis
develops, and accumulation of
alveolar CO2 dilutes the alveolar oxygen
concentration. The arterial partial pressure of
carbon dioxide (PaCO2) rises approximately 8
to 16 mmHg per minute during the first minute
of apnea, with a subsequent rise of
approximately 3 mmHg per minute during
continued apnea, ultimately causing
hypercarbia and acidosis. The rise
in CO2 during apnea was demonstrated in a
study of healthy surgical patients who were intubated, paralyzed, and provided apneic
oxygenation through the endotracheal tube attached to 100 percent oxygen via the
anesthesia circuit . The longest duration of apnea was 53 minutes, with apnea terminated
for acidemia, with a pH of 6.72 and partial pressure of carbon dioxide of 250 mmHg. At that
time oxygen saturation was still 98 percent.
4-Gastric insufflation – Use of positive airway pressure techniques during
preoxygenation could theoretically insufflate air into the stomach and increase the risk of
regurgitation and aspiration. There is no evidence that this occurs when using continuous
positive airway pressure (CPAP) or high flow nasal oxygen (HFNO) for preoxygenation.
HFNO during anesthetic induction may lead to a small increase in gastric volume and may
be exacerbated by airway obstruction. The increase in gastric volume associated with HFNO
may be less than that produced by facemask positive pressure ventilation at 15 cm H2O.
There are no reports of gastric aspiration or cardiovascular compromise associated with
use of HFNO during anesthetic induction.

5-Oxygen toxicity – Oxygen toxicity can occur after administration of supplemental

oxygen; there is not a well-defined FiO2 or duration of exposure below which oxygen
toxicity does not occur. Nonetheless, the risk of oxygen toxicity is likely very small given the
short duration of administration of 100 percent oxygen for preoxygenation.

6-Absorption atelectasis – When breathing room air, alveoli contain high

concentration of nitrogen, which is poorly soluble in blood and remains largely in the
alveoli, helping to stent them open. Once the nitrogen has been replaced with oxygen, if
apnea or hypoventilation occurs, oxygen in the alveoli may be absorbed faster than it is
delivered, causing alveoli to collapse. This is referred to as absorption atelectasis. Using a
fraction of inspired oxygen (FiO2) lower than 1.0 for preoxygenation and apneic
oxygenation may reduce the incidence of absorption atelectasis but would also reduce the
time to desaturation during intubation. Atelectasis can be prevented or reversed with use
of positive end expiratory pressure (PEEP) or recruitment maneuvers after intubation.

7-Accidental awareness: Apnoeic oxygenation does not deliver volatile agents to the
lung. Hence adequate anaesthesia during the airway management should be ensured to
avoid accidental awareness. Total intravenous anaesthesia {TIVA} can be used during
paraoxygenation to avoid the accidental awareness during this procedure. Tubeless
anaesthesia with apnoeic oxygenation for the short glottic procedures also requires the
administration of intravenous anaesthesia to ensure adequate depth during the procedure.

8-NODESAT, (Nasal oxygenation during efforts securing a tube) ….direct pharyngeal

insufflation delivers dry and cold oxygen to the respiratory tree. Administration of dry and
cold gases can induce bronchoconstriction in patients with asthma. Airway resistance is
increased to reduce the airflow in the upper and trachea to protect the lungs from the
challenge of dry and cold gases. Dry gases cause excessive water loss by the nasal mucosa.
This may reduce the nasal mucociliary clearance rate due to the changes in the rheological
properties or adhesiveness of the nasal mucus and slowing of ciliary pulses. High flow dry
gases result in inspissated secretions that can cause life threatening airway obstruction.

9-Barotrauma: Apnoeic oxygenation is a widely accepted method for apnea testing in

brain death. During the apnea testing, ventilator assistance is discontinued and oxygen is
delivered into the trachea via an oxygen catheter placed at the level of carina while waiting
for the spontaneous respiratory movements. Apnea testing related pneumothorax was first
reported by Bar joseph et al.. In order to avoid pneumothorax authors proposed that the
oxygen flow rates should not exceed 6 l/min, oxygen catheter diameter should be narrower
than the diameter of the endotracheal tube and the tip of the oxygen catheter should not
exceed the tip of the endotracheal tube to avoid wedge position in the trachea. A case of
pneumothorax and pneumomediatinum was reported by saposnik et al. during apnea
testing. Vivien et al. Aproposed that a 12 french catheter should be advanced only 5 cm
into the endotracheal tube and oxygen flow rates should not exceed 8 l/min to avoid
pneumothorax during apnea testing. Barotraumacan occur if there is no clear route for
egress of gases during apnoeic-oxygenation. AT- piece or a self-inflating bag valve system
can be used as an alternative technique to conduct apnoea test. Serious air leak syndromes
have been reported with the use of high flow especially in paediatric age group. HFNC is
being used as a respiratory support for preterm infants. HFNC is being used as an
alternative to nasal continuous positive airway pressure (CPAP) and in particular to prevent
postextubation failures. A case of tension pneumocephalus in a preterm infant was
reported by Iglesias et al. as a complication during HFNC ventilation. Significant
neurological impairment was detected and support was eventually withdrawn. Clinicians
need to be aware of this rare but possible complication during HFNC therapy, as timely
diagnosis and treatment caAn prevent neurological sequelae. Paying close attention to flow
rate, nasal cannula size and insertion, regularly checking insertion depth can help to avoid
these complications. Cases of pneumo-orbitus, epistaxis, subcutaneous emphysema,
oesophageal rupture, gastric rupture have all been reported with use of apneic
oxygenation.

Why should we Maintain of a patent airway during preoxygenation? There is a dynamical

balance between O2 and CO2 during breathing. The volume of CO2 passing from the pulmonary
circulation to the alveolar space is 80% of the oxygen volume moving in the reverse direction. This
changes radically at the onset of apnea. During apnea, the rate of oxygen extraction from the alveoli
remains at 250 mL/min without being affected. The amount of CO2 entering the alveoli is very low.
The reason is that CO2 is more water soluble than oxygen. For this reason, only 10% of the
CO2 produced per minute (about 20 mL) reaches the alveolar space. The remaining 90% remain
molten in the textures. Therefore, the volume of gas in the lungs decreases rapidly during apnea,
and if the airway becomes clogged, intrathoracic pressure decreases due to oxygen consumption
and thoracic compliance. The closed airway apex begins with an intrathoracic pressure equal to or
slightly greater than the ambient pressure. Oxygen uptake causes by an almost subatmospheric
intrathoracic pressure. During long-standing apnea, the intrathoracic pressure may be much lower
than the environmental pressure, and the alveolar partial pressure of oxygen is significantly
dangerously reduced. An open airway will allow oxygen to spread to the apneic lung. Providing an
open airway and exposing 100% oxygen creates “apneic mass movement oxygenation,” which has
been shown to provide oxygen saturation for up to 100 minutes in animal and simulated human
studies. If the denitrogenesis of the alveolar space is as complete as possible and a tight compliance
mask is used, this passive diffusion of oxygen is more effective. It is important to provide a very high
oxygen fraction FiO2 in order to extend the safety time of the apnea; increasing the oxygen fraction
applied to the respiratory tract from 90 to 100% doubles critical hypoxia time with open air.
Increasing the FiO2 applied to the airway from 21 to 90% has a much greater effect on the critical
hypoxia time. In a patient with an apnea, 100% oxygen administration to the patent airway will
delay the onset of critical hypoxia, but this approach will not reverse the hypoxemia that is currently
developing. Moreover, after a while, it does not prevent continuous development of hypercapnia,
which is life threatening and acidosis related to hypercapnia.

Reoxygenation: When airway obstruction is relieved during apnea, there is a flow of gas
through the pressureless thorax. Securing a high FiO2 during this one passive inhalation
saves time to save the airway. Securing a high FiO2 during this one-time passive inhalation
may lead to a significant prolongation of the duration of the apnea. If airway obstruction is
relieved with 100% oxygen, the patient is likely to have a temporary improvement in
hemoglobin oxygen desaturation, even though the tidal volume is not maintained and
inspired oxygen volume is small.

End points to preoxygenation: Completion of effective pre oxygenation is

typically determined one of the following criteria:

1-End-Tidal Oxygen Concentration: ideally oxygen analysers capable of measuring end-

tidal oxygen concentrations should be available in all settings in which advanced airway
management takes place as this represents the most reliable way of assessing the adequacy
of preoxygenation. Generally an end-tidal O2 (ETO2) concentration > 80% can be
considered to represent full preoxygenation – but the highest achievable ETO2 should
always be aimed for. While ETO2 monitoring is standard in an operating theatre
environment it may not be available routinely in other settings such as PACU, ED or ICU.

2-Time: where end-tidal O2 analysis is not available, preoxygenation is usually considered

to be complete after 3 minutes (assuming normal tidal ventilation and a good seal) as
described above.

3-Number of Breaths: as described above, 8 vital capacity breaths will usually achieve full
PreO2 when gas analysis is not available.

“a static saturation reading is in fact irrelevant to determining whether a patient is adequately

preoxygenated”

Note that oxygen saturations are not included amongst the list of criteria to assess the
adequacy of preoxygenation. A static saturation reading is in fact irrelevant to determining
whether a patient is adequately preoxgenated. Since most healthy individuals have an SpO2
close to 100% when breathing 21% oxygen, a high SpO2 cannot be used to infer that the
FRC contains gas with an oxygen concentration approaching 100%. Similarly, very unwell
patients may have poor gas exchange and thus poor oxygen saturations despite full
preoxygenation.

Only a dynamic SpO2 reading is relevant to determining whether the patient is adequately
preoxygenated: if the SpO2 is continuing to rise during PreO2, then the oxygen content of
the blood is rising and it is reasonable to assume that the alveolar oxygen concentration is
also still rising, and to continue preoxygenation until the SaO2 plateaus, even if the 3
minute time period for PreO2 has already elapsed.
 Hypothermia
Hypothermia can be defined as an unintentional fall in core body temperature below 35°C. It
can be classified as mild (core body temperature 32.2-35°C), moderate (< 32.2-28°C), or
severe (< 28°C).

What conditions predispose to hypothermia?

1-Old age—Compared with younger adults, elderly people have a lower basal metabolic
rate, an impaired vasoconstrictor response to cold, and reduced ability to recognise lower
ambient temperature.

2-Malnutrition, self neglect, and chronic debilitating conditions (such as Parkinson's disease
or stroke)—These patients are less likely to be able to generate heat by mobilisation.
Furthermore, reduced muscle mass depresses the size of the shivering response to cold.
Malnourished patients have a low basal metabolic rate, as a consequence of a reduction in
muscle and fat reserves.

3-Dementia—The behavioural response to cold is impaired in people with dementia, and

they may not seek shelter or dress in warm clothes in cold weather.

4-Hypothyroidism, hypopituitarism, and hypoadrenalism— These patients have a reduced

metabolic rate.

5-Septicaemia, pneumonia, urinary tract infection, and cellulitis—Sepsis may cause

peripheral vasodilation and subsequently promote cutaneous heat loss. Release of cytokines
may impair thermoregulation.

6-Alcohol consumption, acute intoxication, and chronic misuse—Alcohol compromises

gluconeogenesis, thereby heat production. Chronic alcohol use predisposes to malnutrition.

7-Substance misuse (such as cannabis and narcotics)— These drugs may reduce the person's
awareness of a cold environment.

8-Neuroleptic drugs (such as chlorpromazine)—These drugs interfere with hypothalamic

function, thereby compromising thermoregulation.

9-Burns, exfoliate dermatitis, and severe psoriasis— Dermal adaptive mechanisms such as
vasoconstriction of cutaneous arterioles are disturbed. Heat is lost through evaporation of
fluid from weeping skin.

10-Poverty, poor quality accommodation, and social isolation—Living in poor quality and
insufficiently heated accommodation may lead to heat loss by conduction to the
surrounding air and by radiation to cooler objects in the vicinity. Failure to draughtproof a
house may cause heat loss by air currents.

11-Drowning or immersion—Water has greater conductivity for heat compared with air.
 Conditions associated with secondary hypothermia,
Impaired Thermoregulation Decreased Heat Increased Heat Loss
Production
Central nervous system Endocrine failure Dermatologic lllness
failure
Anorexia nervosa Alcoholic or Burns
diabetic
ketoacidosis
Stroke Hypoadrenalism Induced vasodilation
Traumatic brain injury Hypopituitarism Medications and toxins
Hypothalamic dysfunction Lactic acidosis
Metabolic failure Iatrogenic
Neoplasm Insufficient fuel Emergency childbirth (possibly
without prevention of hypothermia)
Parkinson’s disease Extreme physical Cold infusions
exertion
Pharmacologic effects Hypoglycaemia Heat-stroke treatment
(anaesthetic drugs)
Stroke, haemorrhagic or Malnutrition
ischaemic
Toxins Other associated clinical states
Neuromuscular Carcinomatosis
compromise
Peripheral failure Extremes of age Cardiopulmonary disesae
Acute spinal cord transection Impaired shivering Major infections
Peipheral neuropathy Inactivity Multiple trauma
Shock

From Pathophysiology to Clinical Manifestations: Any situation

that results in significant sudden heat loss can result in hypothermia because the mechanisms
that cause heat build-up are slower than the ones responsible for heat dispersion (60% of
heat is lost through radiation, 10–15% through conduction and convection and 25–30%
through evaporation and respiratory expiration. As already mentioned above, thermal
homeostasis is performed by the regulatory center in the preoptic area of the hypothalamus
and integrated by effectors of autonomous mechanisms and by behavioral attitudes.
Resistance to hypothermia therefore improves both the correctness of the behavioral
adaptation and the integrity of the complex regulatory center.
Clinical manifestations of accidental hypothermia
Mild Moderate Severe

Neurologic Confusion, Lethargy, hallucinations, Loss of

slurred speech, loss of pupillary reflexes, cerebrovascular
impaired EEG abnormalities regulation, decline in
judgment, EEG activity, coma,
amnesia loss of ocular reflexes

Cardiovascular Tachycardia, Progressive bradycardia Decline in BP and

increased (unresponsive to cardiac output,
cardiac output atropine); decreased ventricular fibrillation
and systemic cardiac output and BP; (<28°C; 82.4°F) and
vascular atrial and ventricular asystole (<20°C; 68°F)
resistance arrhythmias, J (Osborn)
wave on ECG

Respiratory Tachypnea, Hypoventilation, Pulmonary edema,

bronchorrhea decreased oxygen apnea
consumption and CO2
production, loss of
cough reflex

Renal Bladder atony, Cold diuresis Decreased renal

cold diuresis perfusion, oliguria

Musculoskeletal Increased Decreased shivering Patient may appear

shivering (<32°C; 89.6°F) muscle dead ("pseudo-rigor
rigidity mortis")

Metabolic Increased Decreased metabolic

metabolic rate, rate, hyper- or
hyperglycemia hypoglycemia

Hematologic Increase in
hematocrit,
decreased
platelet count
and white
blood cell
 count,
bleeding
diathesis, DIC

Gastrointestinal Ileus,
pancreatitis,
gastric stress
ulcers, hepatic
dysfunction

BP: blood pressure; CO2: carbon dioxide; DIC: disseminated intravascular coagulation; ECG: electrocardiogram; EEG:
electroencephalogram.
The main physiological responses to cold stress occur at the level of several systems
and are hereby described in detail.

1-Cardiovascular System: In cases of mild hyperthermia, the thermoregulatory center

can determine increased secretion of catecholamines following the activation of the
sympathetic nervous system. The result is an increase in mean arterial pressure and cardiac
output by means of tachycardia and increased peripheral resistance. On the other hand, when
moderate hypothermia occurs, cardiovascular function gradually deteriorates.Cardiac
conduction is also affected by hypothermia through decreased pacemaker cell activity,
resulting in bradycardia. This bradycardia is typically refractory to atropine, because it is not
vaguely mediated. If cold stress causes severe hypothermia, there is a risk of developing atrial
and ventricular arrhythmias due to a reduction in transmembrane resting potentials. In
young, healthy adults, hypothermia-induced cardiac arrest may occur below 30 °C. In elderly
patients and those with comorbidities, the myocardium may become more irritable and
hypothermia-induced cardiac arrest may be triggered below 32 °C. Vital signs may still be
present in patients with core temperatures below 24 °C. Hypothermic cardiac arrest is
fundamentally different than normothermic cardiac arrest. Treatment and outcomes differ
substantially.

Cardiocirculatory collapse during extrication or transfer of hypothermic patients is

referred to as rescue collapse. This can manifest as a witnessed cardiac arrest. The underlying
mechanism is not well understood and may be multifactorial. In hypothermic patients, rescue
collapse may be coincidental during rescue, but is more likely to be caused by hypovolemia,
cardiac dysrhythmias triggered by interventions, such as central venous catheterisation,
biochemical changes, or, most frequently, by mechanical stimuli such as sudden movement.
In hypothermic patients, cardiac arrest may also be caused by afterdrop (further cooling, even
after rewarming has started). The main cause of afterdrop is reperfusion of cold body parts
during rewarming, but conductive heat transfer between colder and warmer body regions
may also play a role.

Rewarming out of hospital can be difficult. Attempts to rewarm should not delay transport.
Hypothermic patients are at risk of cardiac arrest (CA). They should receive adequate
oxygenation and be placed on a cardiac monitor. Defibrillation pads should be applied instead
of monitor leads, as they decrease electrocardiographic artifact from shivering allowing rapid
detection and treatment of shockable rhythms. While peripheral venous access is desirable,
it may be difficult to obtain because of hypothermia-induced peripheral vasoconstriction. If
intravenous (IV) access cannot be established, the intraosseous (IO) approach should be used.
When intravenous or intraosseous fluids are required, they should be warmed to 38–42 °C
and should be given in boluses guided by vital signs. Use of heated fluids helps to limit
secondary cooling and may protect lines from freezing but has little direct effect on
rewarming.

In moderate or severe hypothermia, bradycardia and low blood pressure do not require
specific treatment other than rewarming as they are responses to the global decrease in
cellular metabolism. Supraventricular arrhythmias, including atrial fibrillation, usually resolve
spontaneously with rewarming. Endotracheal intubation is difficult in cold conditions. IV lines
can freeze. Most drugs are ineffective in hypothermia., Endotracheal tubes become less
pliable. Endotracheal intubation should usually be deferred until the patient is in a warm
environment. Once in a warm environment, rapid-sequence endotracheal intubation should
be used. The risk of causing a malignant arrhythmia is minimal compared to the advantages
of optimal oxygenation and airway protection. Rigidity, and trismus in severely hypothermic
patients can make intubation difficult. End-tidal carbon dioxide (ETCO2) is not reliable in
severe hypothermia. Patients should be ventilated using standard weight-based settings
without relying on ETCO2. Hyperventilation is less detrimental than hypoventilation. Patients
should be transported gently and horizontally to avoid triggering hypothermic CA (rescue
collapse).
2. Central and Peripheral Nervous Systems Hypothermia causes a linear decrease in
central nervous system metabolism as the internal body temperature decreases; more
specifically, there is a decrease in oxygen consumption of about 6% for each reduction of 1
°C after the first loss. This is reflected in a brain syndrome characterized by behavioral
changes, amnesia, disorientation, dysarthria and ataxia. Consciousness is progressively
impaired with the progression of hypothermia.

3. Respiratory System: Hypothermia can affect pulmonary functions via different

mechanisms: pulmonary vascular resistance is increased with increased cutaneous
vasoconstriction. As the exposure to cold progresses and hypothermia becomes more severe,
there is a progressive decrease in tidal volume and respiratory rate, a decrease in thoracic
compliance and an increase in dead space. In the case of severe hypothermia, the control of
respiration is depressed until a picture of respiratory acidosis is formed, due to tissue
accumulation of CO2.

4. Fluid Shifts, Electrolyte Balance and Kidney Function: Cold stress causes
peripheral vasoconstriction with sequestration of the plasma volume and an increase in
hematocrit. This phenomenon, in conjunction with the loss of distal tubular water and the
reabsorption of electrolytes, would determine the suppression of the release of the
antidiuretic hormone, causing so-called “cold diuresis”.Cold stress is also responsible for a
reduction in renal oxygen consumption, compromising tubular function. In cases of severe
hypoxia, the kidney is no longer able to guarantee serum levels of electrolytes, and a
reduction in the tubular secretion of hydrogen ions is observed. In these cases of impaired
renal function, intense muscle contraction following shivering can lead to rhabdomyolysis.
Electrolytes: The hypothermia induced diuresis, along with tubular dysfunction and
intracellular ion shifts, resulting in a decreased serum concentration of several electrolytes,
including magnesium, potassium, and phosphate. Regular measurement and correction (if
necessary) should be performed.
Hypomagnesaemia may cause cerebral and coronary vasoconstriction and can exacerbate
reperfusion injury. Hypokalemia and hypophosphatemia may cause life-threatening
tachyarrhythmias and respiratory muscle weakness that can increase the risk of respiratory
infections and wean from mechanical ventilation. Regular measurement of serum electrolytes
and correction (if necessary) are crucial preventative measures that must be taken in these
patients. It is also important to remember that high dose electrolyte supplementation is often
necessary to correct these abnormalities.
The rewarming phase may also be associated with electrolyte disturbances. Hyperkalemia
often occurs in this phase due to the release of intracellular potassium and may result in
cardiac arrhythmias. Rewarming the patient at a slow and controlled rate can prevent this
complication by giving the kidneys more time to excrete the excess potassium.

5. Blood and Coagulation Parameters: Hypothermia can be responsible for an

increased risk of thrombosis through several mechanisms. Blood viscosity increases due to
the previously discussed hematological concentration and increase in hematocrit.
Hypothermia also causes an alteration in the homeostatic enzymatic activity of coagulation
factors, leading to coagulation disorders. An increase in spontaneous platelet activation is
observed at temperatures below 37 degrees Celsius, and hypothermia also causes bleeding
due to thrombocytopenia following hepatic sequestration. With moderate hypothermia, a
reduction in fibrinogen synthesis is also observed, with a consequent increased risk of
bleeding.

6. Endocrine and Metabolic Responses: The release of catecholamines stimulates

thermogenesis when the core temperature is greater than 32 °C Catecholamine-induced
glycogenolysis also induces hyperglycemia, with a decrease in insulin release, the inhibition
of insulin transport (that becomes inactive at core temperatures < 31 °C), a decrease in liver
enzyme function, and a decrease in the renal clearance of glucose that promotes
hyperglycemia. However, glycemic levels during hypothermia have been reported to be both
high and low , thus indicating that glycemic control is primarily dependent on the metabolic
state of the patient . Interestingly, pancreatitis is a common finding in autopsies of
hypothermic patients.On a side note, acute cold exposure causes an increase in metabolic
heat production.

7. Gastrointestinal Tract: Intestinal motility decreases below about 34.8 °C, resulting in
an ileus when the temperature falls below 28.8 °C; therefore, a nasogastric tube should be
placed to reduce the chance of aspiration in hypothermic patients. The absorption of
medication given orally or via a nasogastric tube will also be impaired in this situation, and
this administration route should therefore be avoided. Punctate hemorrhages may occur
throughout the gastrointestinal tract. Hepatic impairment can develop, probably as a
consequence of reduced cardiac output, and the decreased metabolic clearance of lactic acid
contributes to acidosis. Pancreatitis frequently occurs as a consequence of hypothermia,
being found at autopsy in 20–30% of cases, and mildly elevated serum amylase without
clinical evidence of pancreatitis is even more common, being present in 50% of patients in
one series.

8-Immune System: Hypothermia induces several immune function changes, many of

which are thought to contribute to the protective effects of hypothermia against brain injury.
However, they may also increase the risk of infectious complications. Hypothermia inhibits
various inflammatory responses. It impairs the secretion of pro-inflammatory cytokines and
suppresses leukocyte migration and phagocytosis. Hyperglycemia and peripheral
vasoconstriction that often occurs with hypothermia also contribute to the increased risk of
infections. The risk of infectious complications increases with prolonged hypothermia. A
meta-analysis of randomized trials of therapeutic hypothermia which reported infectious
complications found that the prevalence of all infections was not increased (rate ratio, 1.21
[95% confidence interval 0.95-1.54]), but the risk of pneumonia and sepsis was (risk ratio for
pneumonia, 1.44 [95% CI, 1.10-1.90]; risk ratio for sepsis, 1.80 [95% CI, 1.04-3.10]). Most of
the studies included in this trial lacked clear definitions of infectious complications and
reported them with insufficient details. Nevertheless, a high level of vigilance should be
maintained, and certain measures should be taken in all therapeutic hypothermia patients for
the prevention and early detection of infections. These include regular microbiological
surveillance, timely catheter replacement, examining wounds and catheter insertion sites,
and avoiding hyperglycemia.

9-Metabolic: Hypothermia causes a linear decrease in the metabolic rate by 5% to 7%

per 1 degree Celsius decrease in core body temperature. A left shift in the oxygen hemoglobin
dissociation curve reduces tissue oxygen availability and may contribute to the development
of metabolic acidosis .Oxygen consumption and CO2 production are equally decreased. If
ventilator settings are not properly adjusted, decreased CO2 production may promote
respiratory alkalosis and hypocapnia. This results in cerebral vasoconstriction increased
cerebral vascular resistance and decreased cerebral blood flow. Pharmacokinetic and
pharmacodynamic alterations in drug metabolism can occur in patients receiving therapeutic
hypothermia. These patients receive multiple drugs during their treatment course, including
paralytics, anticonvulsants, sedatives, and cardiovascular drugs.
Unanticipated drug toxicity may occur due to changes in metabolism, especially since many
of these drugs have a narrow therapeutic window. The mechanisms involved in these
changes are drug-specific and can occur in one or more of the different phases of drug
metabolism, response, or elimination. Clinical studies evaluating the effect of hypothermia
on the metabolism of specific drugs found that for many commonly used drugs such as
propofol, vecuronium, rocuronium, midazolam, and phenytoin, there was an increase in
serum concentration, decrease in clearance rate, and increase in the duration of
action. Metabolism gradually returned to baseline during the rewarming phase. This suggests
that doses should be lowered to prevent toxicity. TH may be associated with decreased insulin
sensitivity and decreased insulin secretion by pancreatic islet cells. It has been shown that
hyperglycemia is associated with poor neurological outcomes and increased
mortality. However, it is unclear whether the hyperglycemia is due to hypothermia or due to
the initial stress of cardiac arrest and the resultant organ hypoperfusion. Some studies show
that therapeutic hypothermia does not have an independent effect on glucose homeostasis,
and when compared with normothermic patients, blood glucose levels only differs between
the period of cardiac arrest and the initiation of hypothermia treatment. These conflicting
results raise the question of whether hyperglycemia affects neurological outcome and
survival directly, or simply that the glucose level is proportional to the severity of initial
neurological damage, which would be associated with a less favorable outcome.

Clinical Diagnosis: The diagnosis of accidental hypothermia includes (i) a history or

evidence of exposure to cold stress and (ii) an internal temperature < 35 °C. For a correct
diagnosis, it is necessary to use the correct instrument (thermometer). A low-reading
thermometer (capable of measuring temperatures up to 25 °C) is preferred, and it should be
used via the rectal, esophageal (more suitable) or bladder route. Bladder and rectal
temperatures should not be used in critically ill patients during rewarming

Tympanic temperature measurement may also represent a practical, non-invasive approach

to core temperature monitoring in an emergency setting. It has indeed been demonstrated
that tympanic temperature is a good index of core temperature and it accurately reflects both
esophageal and bladder temperatures with a very small discrepancy. The signs and symptoms
that can guide us to a diagnosis depend on the severity of hypothermia. The various
physiological alterations that occur in hypothermia can be grouped summarily according to
the degree of severity of the hypothermia itself.

In mild hypothermia, the patient is conscious and presents vigorous shivering, increased
cardiac output due to increased peripheral resistance, and tachycardia; they also present
tachypnoea, and in cases of the persistence of the cold stress, neurological signs such as
dysarthria, ataxia and motor impediment are observed. Cold diuresis occurs secondary to
peripheral vasoconstriction, which is also responsible for cold extremities and pallor. At the
gastrointestinal level, cold stress can lead to the formation of gastric ulcers and pancreatitis.
For what concerns the blood system, the risk of thrombosis due to hemoconcentration and
the risk of bleeding due to the inactivation of coagulation factors are already seen in the early
stages of hypothermia.

Moderate hypothermia is characterized by decreased cardiac output and blood pressure,

hypoventilation and hyporeflexia. The loss of the shivering mechanism is also observed. The
resulting picture ranges from an impairment of mental function up to a loss of consciousness.
The gross impairment of motor control, cessation of shivering, cyanosis, muscle rigidity,
mydriasis, atrial or ventricular cardiac dysrhythmias and bradycardia also occur. In this phase,
the behavioral defenses are compromised in some subjects, who paradoxically undress.If the
cold stress perdures, or if the regulatory mechanisms are so compromised as to progress to a
state of severe hypothermia, the patient may present in a state of shock or pre-shock with
hypotension, pulmonary congestion, edema, muscle rigidity, areflexia, oliguria and coma.
Tissues have decreased oxygen consumption at lower temperatures; at 28 °C, oxygen
consumption is reduced by about 50%, and at 22 °C by about 75%.

More severe pictures include spontaneous ventricular fibrillation and cardiac

arrest.Severe cases can mimic death. At 18 °C, the brain can tolerate ten times longer periods
of cardiac arrest than at 37 °C. When faced with a patient in cardiac arrest who is hypothermic,
it is important to remember that they should not be declared dead until they have been
rewarmed …When the core temperature cannot readily be measured, the Swiss staging
system, which distinguishes among five levels of hypothermia based on clinical appearance,
can be a useful tool to determine the severity of hypothermia:

Classical staging of accidental hypothermia based on clinical signs.

Stage Clinical Findings Estimated Core Temperature (
°C)
Hypothermia I (mild) Conscious, shivering * 35–32 °C
Hypothermia II Impaired consciousness *; may <32–28 °C
(moderate) or may not be shivering
 Hypothermia III Unconscious *; vital signs <28 °C
(severe) present
Hypothermia IV Apparent death; vital signs Classically < 24 °C **
(severe) absent

Laboratory Studies: What investigations should I perform and why?

1-Urea and electrolytes—Hypothermia may cause oliguric renal failure. This may be a
consequence of low cardiac output or rhabdomyolysis. Hyperkalaemia may be severe.

2-Full blood count—Thrombocytopenia may be a consequence of hepatosplenic

sequestration. The packed cell volume increases slightly as core body temperature falls.

3-Glucose—This is an important investigation for any patient with a reduced level of

consciousness. All patients should have a blood glucose test on admission.

4-Coagulation—Hypothermia may cause coagulopathy, but this is difficult to detect in clinical

practice. This is because the laboratory assay is performed at 37°C, and at this temperature
the coagulopathy resolves.

5-Arterial blood gases—Metabolic acidosis is a feature of severe hypothermia and may be a

consequence of lactic acid generation due to poor tissue perfusion. You may also identify type
I or type II respiratory failure. Interpreting arterial blood gases is difficult in people with
hypothermia. In simple terms, the pH of neutrality increases on cooling. Blood gas analysers
heat samples to 37°C before analysis and may calculate corrected values according to the core
temperature of the patient. However, some authorities currently support the use of
uncorrected arterial blood gas measurements to guide treatment.

6-Thyroid function tests—Hypothyroidism is a known precipitant of hypothermia and should

be recognised and treated.

7-Electrocardiography—This may detect the classic J wave. More commonly, arrhythmias

such as atrial fibrillation may be recognised. The ECG may show an enlargement of the QRS
complex or a J wave (Osborn’s wave) plus a prolonged QT interval and T wave inversion. These
signs are not pathognomonic, but are needed both to suspect and to understand the severity
of the cold stress to which the organism has been subjected . In advanced stages, a reduction
in cardiac output may also occur due to both an increase in afterload and a decrease in heart
rate.
Hypothermia ECG Review: The ECG findings of hypothermia include:
1-An "Osborne wave" characterized by a notch in the downward portion of the R wave in
the QRS complex.
2-Low voltage.

3-Bradycardia: This can be sinus bradycardia, junctional bradycardia, atrial fibrillation with
a slow ventricular response or higher grade AV blocks.

4-Baseline artifact from shivering

5-Prolonged PR, QRS and QT intervals

6-Ventricular ectopics

7-Cardiac arrest due to VT, VF or asystole

FIGURE 1 On 12-lead electrocardiography, elevation of the J point (Osborn wave; arrows) is typically seen in precordial leads V3 to
V6 and is a marker for hypothermia. The amplitude of Osborn waves is directly proportional to the degree of hypothermia.
J point in a) normal; b) J point elevation; c) with Osborn wave (J wave); d) J point depression
 Note: The letter J on the ECG defines 2 totally
different and unrelated events. The J point is a
point in time marking the end of the QRS and
the onset of the ST segment present on all
ECGs. The J wave is a much less common, slow
deflection of uncertain origin originally
described in relation to hypothermia.

7-Imaging should be dictated by clinical scenarios; a chest X-ray is not uncommon for severely
hypothermic patients in order to detect signs of pulmonary edema

8-An EEG could be necessary based on clinical circumstances. An electroencephalogram (EEG)

is abnormal at a core temperature < 33.5 °C, suppressed at 22 °C, and becomes silent between
19 and 20 °C.

Therapeutic hypothermia: Post–Cardiac Arrest Brain Injury: During

cardiac arrest, there is a total lack of perfusion to the brain, which initiates a complex
cascade of events. A key aspect of these events is that they are all temperature dependent.
There are two main components of post–cardiac arrest brain injury: ischemia and
reperfusion. Due to the lack of blood flow during cardiac arrest, there is a loss of adenosine
triphosphate (ATP) production in the brain causing the release of glutamate, which is
responsible for neuronal injury. An influx of intracellular calcium causes an increase of cell
permeability that contributes to brain cell death. After return of spontaneous circulation,
reperfusion injury can occur from free radicals and mitochondrial injury.There are multiple
proposed mechanisms by which therapeutic hypothermia protects against neurologic
injury. Hypothermia decreases neuronal metabolism, glucose and oxygen consumption,
glutamate release, and blood-brain barrier breakdown. Overall, the neurologic cell death is
decreased with hypothermia
There are 4 stages of TH: initiation, maintenance, rewarming, and return to
normothermia. TH should be initiated as soon as possible after the ROSC with a target
temperature of 32°C to 34°C.

There is a 20% increase in mortality for every hour of delay in the initiation of TH.11 There
are multiple methods to induce and maintain TH. Ice bags and cooling blankets are simple
and effective but difficult to titrate to a target temperature. Temperature-regulated surface
and endovascular devices that circulate cold water allow easier temperature control during
the maintenance phase and prevent rapid temperature changes during rewarming.
Several liters of cooled intravenous saline will promptly decrease temperatures by 1°C
within 30 minutes, will help prevent postresuscitation hypotension, and can be delivered
by first responders or emergency department personnel.
We use a combination of ice packs and standard cooling blankets for rapid initiation of TH
with a transition to a temperature-regulated surface cooling device to maintain target
temperatures through maintenance and rewarming. During the maintenance phase,
temperature fluctuations should be minimized to <0.5°C.

Figure 2. Phases of hypothermia. BP indicates blood pressure; K+, serum potassium concentrations; O2 sat, oxygen
saturation; and SBP, systolic blood pressure.

Physiological Consequence and Complications of TH

Shivering: All patients receiving TH should receive low-dose, continuous infusions of both a
sedative and an analgesic agent to prevent any potentially painful sensation or discomfort
and to suppress shivering. Preference should be given to agents with short half-lives (eg,
propofol or midazolam for sedatives and fentanyl or hydromorphone for analgesia) because
hypothermia reduces the clearance of most sedatives, analgesics, and neuromuscular
blockade agents (NMBAs). This strategy will facilitate neurological assessments after return
to normothermia.

Shivering, a natural reaction to cooling, occurs in most patients receiving TH. Shivering
should be recognized early and treated aggressively because it increases the metabolic rate
and prevents or delays achieving target temperature. Shivering typically occurs during
changes in temperature, between 35°C and 37°C. Once a patient achieves the target
temperature of 32°C to 34°C, shivering is less common. Nonpharmacological techniques
that raise cutaneous temperatures such as wrapping the face, hands, and feet with warm
blankets or even placing a warming blanket over the torso are effective at preventing
shivering. Magnesium sulfate may raise the shivering threshold, so we give an initial 4-g
bolus to all patients receiving TH. If shivering persists, rapid uptitration of anesthetics with
analgesic boluses is effective, although some patients require NMBAs to completely
suppress shivering. We have found that selective use of NMBA boluses (3 doses of
cisatracurium 0.15 mg/kg IV every 10 minutes) is often effective and allows patients to
achieve target temperature without a continuous NMBA infusion. Some centers use
continuous NMBAs in all patients during the entire TH process; others limit NMBA infusion
to just the initiation period.

Hemodynamics: Hypothermia affects hemodynamics in several ways. At the initiation of

TH, tachycardia and hypertension may occur as a result of cutaneous vasoconstriction and
shivering as the patient attempts to conserve heat. Once patients begin to cool, bradycardia
is the most common arrhythmia, together with PR prolongation, sinus bradycardia, and
even junctional or ventricular escape rhythms. Bradycardia should be treated only if it is
associated with hypotension. Hypothermia also prolongs the QT interval, although there
are no data to suggest that it increases the risk of torsade de pointes.

Blood pressure depends on many factors. TH triggers peripheral vasoconstriction and

increased systemic vascular resistance. However, more frequently, patients after ROSC are
hypotensive as a result of vasodilatation from a postresuscitation inflammatory release and
direct cardiac dysfunction from ischemia (either global or regional). Hypotension should be
aggressively reversed to avoid cerebral hypotension and recurrent hypoperfusion.16 On the
basis of data from patients with intracranial hemorrhage, a mean arterial pressure should
be maintained higher than typically required in order to reduce vasoconstriction and to
improve cerebral perfusions, with mean arterial pressure goals of 80 to 100 mm Hg.
Hypotension occurs frequently during rewarming. When required, the decision to initiate
and the choice of pressors should be based on the individual hemodynamic requirements
of the patient.
Patients who have ROSC and any degree of vasoplegia are effectively intravascularly
depleted and usually require a significant volume of resuscitation with several liters of
saline. Targeting a goal central venous pressure of at least 10 to 12 mm Hg often prevents
hypotension and reduces vasopressor requirements.
If significant dysrhythmias or hemodynamic instability develops, patients should be treated
with standard medical procedures. If the instability persists and TH is thought either to be
the cause of the instability (eg, profound bradycardia) or to potentially be worsening the
instability (eg, bleeding), the target goal temperature can be increased to 34°C to 35°C (93°F
to 95°F) at a rate of 0.25°C (0.5°F) per hour. The full TH protocol often can be completed at
a slightly higher target temperature.

Oxygenation/Ventilation: All patients receiving TH require mechanical ventilation with a

goal arterial oxygen saturation of 94% to 96%. FiO2 should be reduced as soon as possible
to avoid prolonged oxygen saturations of 100%, which may further exacerbate reactive
oxygen production and neurological damage. The ventilatory goal is to maintain
normocarbia and to avoid both hyperventilation and hypoventilation.

Glucose Control: Hyperglycemia is common during TH as lower temperatures decrease

insulin secretion and increase insulin resistance. Blood glucose should be measured at least
hourly during TH to avoid hypoglycemia, especially in patients receiving intravenous insulin,
 and during rewarming, when glucose levels can fall precipitously. Given these concerns,
hyperglycemia typically does not require treatment until glucose levels exceed 200 mg/mL.
It is prudent to stop intravenous insulin as soon as glucose levels fall below 200 mg/mL
unless the patient has type I diabetes mellitus.

Potassium: Hypothermia will lower serum potassium levels, primarily by promoting inward
cellular potassium flux, although hypothermia also induces a mild diuresis with concurrent
electrolyte wasting. Serum electrolytes should be measured at regular intervals (every 4–6
hours). Potassium should be repleted to maintain levels above 3.5 mEq/L. Rewarming
reverses the potassium flux and increases serum levels, so repletion should be held 4 hours
before rewarming begins. In our experience, clinically significant hyperkalemia is unusual in
patients with preserved renal function.

Infection: Infections are common in patients who have a CA and particularly in those
receiving TH, which suppresses cellular and antibody immunity. Overall, more than two
thirds of patients who have ROSC after CA and are treated with TH experience some
infectious complication. Pulmonary infections, most likely related to cardiopulmonary
resuscitation, emergent intubation, and mechanical ventilation, are most common,
followed by bloodstream and catheters infections. Fortunately, despite a higher risk of
infection in TH, infection does not appear to increase mortality. Patients who receive TH
should have surveillance cultures, and if an infection is suspected, prompt, broad-spectrum
antibiotics that cover community- and hospital-acquired pathogens should be initiated.

Rewarming: Rewarming begins 12 to 24 hours after the initiation of cooling. In our

institution, we begin after 24 hours, although other institutions begin 24 hours after the
target temperature is achieved. The greatest risks during rewarming are hypotension,
hyperkalemia, and hypoglycemia. Rewarming should be slow, with a target rate of 0.25°C
(0.5°F) every hour until the patient returns to normothermia (37°C [98.6°F]). It will take ≈12
to 16 hours to rewarm. After normothermia is achieved, the goal of therapy is to maintain
a temperature of 37°C and to avoid hyperthermia. Post-CA fevers are particularly harmful
and associated with worse neurological outcomes. We use the same surface cooling pads
to maintain normothermia for an additional 48 hours.

Treatment / Management:

General Resuscitative Measures

1-Airway: Intubate if necessary. However, if possible, it's preferable to avoid or delay
intubation (to allow for stabilization and warming prior to the hemodynamic stress of
intubation).

2-Access: If central access is needed, make sure not to stimulate the ventricle with the
guidewire (cold hearts are very susceptible to VT/VF). A femoral line might be the preferred
site. The alternative is placing an upper extremity line, with careful attention to keep the
guidewire relatively shallow.
-Ensure blood glucose is checked immediately
-Assess fluid status—this is vital because patients with hypothermia are often hypovolaemic
due to dehydration and sepsis
-If dehydrated, give warm, intravenous fluids
-Insert a urinary catheter, if necessary, to monitor urine output
-Insert a central venous line if necessary to guide fluid replacement therapy and prevent the
complications of fluid overload.

3-Cardiovascular: Hypothermia itself causes bradycardia. Trying to speed up the heart with
medications or pacing is generally a mistake, as this may precipitate ventricular tachycardia.

A-The key therapy for bradycardia is re-warming.

B-Hypotension: Mild/moderate hypotension is common and should resolve with rewarming.

Be cautious with vasopressors, given the risk of inducing arrhythmias.

C-Vasodilation can occur with rewarming, so if blood pressures fall with rewarming this
could be a better indication for vasopressors.

D-Intubation and mechanical ventilation may be necessary if the patient is not maintaining
an airway or has respiratory failure. Discuss management with a critical care team if
necessary

4-Fluid & electrolyte

A-Volume management: Crystalloid should be administered only if the patient is felt to be

clinically hypovolemic.

B-Hypothermia often stimulates diuresis (“cold diuresis”), so patients are often volume
depleted.Additional factors (clinical history, echocardiography) may help determine
whether crystalloid is needed.If crystalloid is given, it should ideally be warmed. Warming
the fluid prevents dropping the patient's temperature further. However, giving warmed fluid
is not an effective strategy for increasing the patient's temperature (figure below).

Method of rewarming: This is ideally done using an in-line warming device (e.g. Level-I
infuser, Belmont). If no rewarmer is available, fluids can be warmed by placing each liter in a
microwave oven on high for ~2 minutes. Shake before administration to equilibrate the
temperature. Fluid bags should feel comfortably, mildly warm.
5-Rebound hyperkalemia: Hypothermia tends to cause hypokalemia. With re-
warming, the potassium will tend to rise.Be conservative in the administration of potassium
while the patient is still hypothermic (this may promote rebound hyperkalemia).Patients with
prolonged cardiac arrest may eventually develop hyperkalemia. Thus, an admission
potassium above >12 mM is an extremely poor prognostic sign (in a pulseless patient this may
indicate futility of further resuscitation).

6-Rebound hypoglycemia: Glucose may initially be elevated, due to catecholamine

release and insulin resistance (both resulting from hypothermia).Avoid giving lots of insulin
while the patient is still hypothermic (insulin may accumulate and cause rebound
hypoglycemia once the temperature improves).

7-Rhabdomyolysis & DIC: Hypothermia may cause rhabdomyolysis.Hypothermia causes

a clinical tendency to bleed despite normal levels of clotting factors. Usually, the measured
levels of clotting factors will be normal (the lab measures these after warming blood to
37C).The only way to reverse this coagulopathy is re-warming. For active hemorrhage in the
hypothermic patient, desmopressin might improve platelet function. Less commonly,
hypothermia may also cause disseminated intravascular coagulation (DIC). In this case,
measured levels of coagulation labs will be low.Subcutaneous heparin for DVT prophylaxis is
contraindicated in severe hypothermia, due to poor skin absorption.

Other strategy to treat hypothermia:

1-Hypothermia management focuses on quick rewarming and preventing further heat loss,
ensuring that the airway, breathing, and circulation are adequately and promptly addressed.
Wet clothing should be immediately removed and replaced with dry clothing or insulation.
Once emergencies have been ruled out, a more detailed examination must be made, noting
the complete history, mental status, physical exam, and core temperature.
2-Patients presenting with symptoms of moderate or severe hypothermia must be moved
gently, as movements may increase cardiac irritability and precipitate fatal arrhythmia.
Comorbid medical conditions and trauma must also be investigated and addressed.
Individuals who have documented hypoglycemia may be supplied oral glucose.
3-Rewarming of hypothermic patients involves passive external rewarming, active external
rewarming, active internal rewarming, or a combination of these techniques. The treatment
of choice for mild hypothermia is passive external rewarming at a rate of 0.5 to 2 °C per hour.
After removing wet clothing, additional insulating layers are placed on the patient's body to
prevent heat loss and promote heat retention.
4-Shivering allows the body to produce up to a 5-fold heat increase from baseline
spontaneously. However, this method requires adequate glucose stores. Additionally,
vigorous shivering can be problematic in people with limited cardiopulmonary reserves as it
increases oxygen consumption.
5-Active external rewarming is necessary for moderate to severe hypothermia and mild
hypothermia refractory to standard measures. A heated air unit can decrease heat loss and
transfer heat through convection. Placing a heated pack on the patient's body can also help
facilitate rewarming. Heat must be applied to the axillae, chest, and back for efficiency.
6-Water immersion is an alternative but more cumbersome and challenging to monitor.
Immersing the extremities in warm water (44-45 °C) requires great care and attention. Rapid
rewarming can cause peripheral vasodilation, forcing cold venous blood to return to
circulation and increase cardiac load abruptly. Some patients may require more invasive
methods besides active external rewarming. Methods range from airway rewarming with
humidified air to full cardiopulmonary bypass. Humidified air and warm intravenous fluids at
40 to 42 °C can be used safely. Warm saline lavage of various body cavities such as the
stomach, bladder, colon, peritoneal, and pleura may also be considered. Pleural and
peritoneal lavages are preferable due to the larger mucosal surface areas.
9-Arteriovenous (AV) rewarming entails warming femoral arterial blood and allowing it to
flow to the contralateral femoral vein. This method raises the temperature by 4.5 °C per hour.
Both hemodialysis and AV rewarming require the patient to have adequate blood pressure.
Cardiopulmonary bypass surgery and venoarterial ECMO are the most effective but highly
invasive rewarming methods. These procedures are reserved for patients in cardiac arrest,
hemodynamically unstable individuals, and people unresponsive to less invasive rewarming
techniques. Cardiopulmonary bypass and ECMO can raise the core temperature by 7 to 10 °C
per hour and simultaneously improve oxygenation and circulatory support. However, not all
facilities can offer these procedures. Cardiopulmonary bypass and ECMO also require
systemic anticoagulation, predisposing patients to spontaneous bleeding.

Rewarming a patient with pulses

The following measures may be considered for patients with moderate or severe
hypothermia (or mild hypothermia with failure to rewarm with less aggressive measures).
(1) External warming: Two general options exist, depending on available resources
and the patient's level of acuity:

(i) Warming blankets (e.g. heated-air systems such as the “Bair Hugger”).

(ii) External adaptive temperature control device using a circulating water bath (e.g. Arctic
Sun). Direct contact with the skin may increase thermal conductivity between the device and
the patient, thereby accelerating effective warming.May be used for patients not responding
to warming blankets.Should be used for patients with cardiac arrest or severe neurologic
injury, because this device will prevent over-shoot hyperthermia. Once these patients are
successfully resuscitated, they may be maintained at 36C using a targeted temperature
management approach.

(2) Warming via the lungs: The alveoli have the combined surface area of a tennis
court. They are usually a source of heat loss from the body. Providing heated, humidified gas
reverses this: instead of losing heat from the lungs, patients gain heat.

For non-intubated patients, this may be accomplished as follows:

i) High-flow nasal cannula (at maximal temperature setting). This may be preferred for
patients with altered mental status and risk of emesis.

ii) CPAP or BiPAP using in-line heated humidification. This may be done using either a BIPAP
device or a formal mechanical ventilator (if the usual BiPAP device lacks the ability to heat
and humidify gas).

For intubated patients, this may be performed by heating and humidifying the ventilator
circuit (work with the respiratory therapist to make sure this is adjusted to the warmest
setting possible).

(3) Thoracic lavage ;This can achieve 3-6C warming per hour.Traditional
strategy involves two chest tubes.You may place one anterior chest tube and one lateral chest
tube, if you're comfortable with anterior chest tubes (making sure to avoid vascular structures,
e.g. the internal mammary artery). Alternatively, two chest tubes may be placed in the lateral
chest, with one directed more anteriorly and one directed more posteriorly.Using the left
pleura may be superior for directly warming the myocardium. If possible, it may be most
effective to perform this simultaneously on both sides of the chest (with a total of four chest
tubes).

Infuse warmed crystalloid (temperature of 42C or 107F) into the more anterior chest
tube. The ideal approach is to attach the chest tube to a Level-I or Belmont fluid
warmer/infuser. If this isn't available, there are reports of using warm tap water.
Drain fluid from the chest by attaching the posterior chest tube to a drainage system.
The volume of fluid administered may rapidly fill a standard chest tube drainage system
(Pleurovac). For intubated patients, the chest tube may be attached to any sterile receptacle
(positive intrathoracic pressure should promote fluid drainage out of the chest, without the
need for external suction).Carefully monitor fluid drainage (if the lower chest tube kinks or
becomes dysfunctional, ongoing instillation of warmed fluid may generate a tension
hydrothorax). Alternative strategy involves placement of only one chest tube. Place one large-
bore chest tube in the lateral chest, directed posteriorly.

Instill 300-500 ml of warmed fluid, clamp the chest tube for 15 minutes, then drain fluid and
repeat. Carefully monitor for pneumothorax. If there is laceration of the lung (e.g. due to CPR
or chest tube insertion), a tension pneumothorax could develop while the chest tube is
clamped. Thus, this strategy is only viable in the absence of lung laceration (in the presence
of a pre-existing pneumothorax or lung laceration, a two-tube strategy described above must
be used).

Bladder lavage: Less effective than thoracic lavage, but it may be considered if it won't
detract from other therapies.Two ways to achieve this:

i) Use a dedicated 3-way Foley catheter with continuous irrigation of warmed fluid (~42C).

ii) Instill 300 ml of warmed fluid, clamp the Foley for 15 minutes, then drain the bladder and
repeat.

4-Extracorporeal rewarming techniques allow for even faster rewarming. The

methods include hemodialysis, continuous arteriovenous rewarming, cardiopulmonary
bypass, and extracorporeal membrane oxygenation (ECMO) if available. Hemodialysis is the
most accessible and can raise the core temperature by 2 to 3 °C per hour.
 Rewarming strategies
1-Passive rewarming: For most patients that are admitted with mild hypothermia,
rewarming may be effectively achieved by covering the head and body with warm blankets.
2-Active rewarming: Consider active rewarming for patients with moderate to severe
hypothermia. The following techniques are available.
Forced air rewarming (Bair Hugger) blanket: This system consists of a warming device and
single use, disposable, laminate blankets that allow warm air to flow directly onto the
patient's skin.
Possible disadvantages of forced air rewarming include:
1-Hypotension may occur during rewarming, probably a consequence of peripheral
vasodilation
2-Afterdrop—This refers to a drop in core body temperature during rewarming. Afterdrop
is thought to occur as a consequence of peripheral vasodilation and release of cold
peripheral blood to the body core. One randomised controlled trial reported that the rate
of rewarming was greater with use of a Bair Hugger blanket compared with passive
rewarming. Furthermore, evidence suggests that afterdrop and hypotension are probably
clinically insignificant.
3-Warm intravenous fluids: Many emergency departments have facilities to warm bags of
intravenous fluids. A microwave or “blood warmer” may be used. The temperature of fluids
should be 42-44°C. An observational study has shown that giving warm intravenous fluids
is a safe and effective form of treatment, but there are no randomised controlled trials
supporting the use of warm intravenous fluids for patients with moderate to severe
hypothermia.
Other techniques
If available, consider using the following techniques:
• Warm humidified oxygen or air1
• Peritoneal dialysis or pleural cavity lavage with warm fluids1
• Cardiopulmonary bypass for severely hypothermic patients with cardiac arrest
• An observational study supported the use of cardiopulmonary bypass for patients with
cardiacarrest and severe hypothermia. All patients recruited to this study were younger
than 35 years.
Other important management considerations

1-Thiamine deficiency—Patients who are malnourished or have a history of alcohol abuse

are potentially deficient in thiamine. There is a risk of developing Wernicke's encephalopathy
during rewarming if thiamine deficiency remains uncorrected. Therefore, these patients
should receive immediate intravenous thiamine.

2-Myxoedema coma—This is a serious condition with a high mortality. If you suspect

myxoedema you should consider immediate administration of intravenous triiodothyronine.
Treating myxoedema coma with thyroid hormone may precipitate an adrenal crisis if adrenal
insufficiency coexists; it is therefore prudent to give parenteral corticosteroids.

3-Intravenous corticosteroids—These are not required routinely for patients with

hypothermia unless you suspect hypoadrenalism.

4-Sepsis—Sepsis is common in patients with hypothermia, but it can be difficult to detect

because the classic features may not be present. Broad spectrum antibiotics may be indicated
if you suspect sepsis, even if it is not clinically obvious.

5-Resuscitation—In patients who have had a cardiac arrest, remember that hypothermia
may exert protective effects on the brain. You may reliably certify death only once core body
temperature reaches 35°C. Remember the dictum: “You're not dead until you're warm and
dead.” You may, however, use your discretion to decide when resuscitation should be
stopped according to the individual circumstances.21 Guidelines state that the patient's
doctors may make the decision to end resuscitation if it is clinically indicated.

6-Defibrillation—Cardiac defibrillation is usually ineffective in severely hypothermic

patients. If core body temperature is below 30°C and the patient develops ventricular
tachycardia or fibrillation, then DC cardioversion should be attempted. Guidelines
recommend that if this is unsuccessful, then there should be no further attempts until core
body temperature has surpassed 30°C.

7-Vasoactive drugs—Drugs such as adrenaline and lignocaine are not recommended until
core temperature reaches 30°C. This is because these drugs are usually ineffective and may
accumulate in the venous circulation of a hypothermic patient. During rewarming the drug
may then be released in toxic quantities. Once core body temperature has exceeded 30°C
vasoactive drugs may be used, but the interval between doses should be increased.

8-Treating underlying issues: sepsis, adrenal insufficiency, myxedema: For

patients without an obvious cause of hypothermia, consideration should be given to all
possible causes. Many of these are listed above, but three are most important regarding
immediate management.

A-Sepsis: Hypothermia commonly occurs due to sepsis (particularly if no other cause is

evident).If infection is suspected, consider starting empiric antibiotics. A reasonable approach
is often to start a single broad-spectrum agent (e.g. piperacillin-tazobactam). This should be
stopped within 48 hours unless there is further evidence to support infection (e.g. positive
procalcitonin or positive blood culture results).

B-Consider empiric therapy for myxedema coma or adrenal insufficiency: Hypothyroidism

and adrenal insufficiency can both cause hypothermia and must always be considered.In very
ill patients, it may be appropriate to start therapy immediately (even before confirming the
diagnosis).

Myxedema coma: Empiric therapy may be considered (depending on the index of suspicion
and the turn-around time for thyroid function labs). This may consist of a single dose of 250
mcg IV levothyroxine. Make sure a full thyroid panel of labs is drawn before this is
administered. Stress-dose steroid is generally administered simultaneously with thyroid
replacement (to prevent precipitation of adrenal crisis, in case there is dysfunction of both
glands).

Adrenal insufficiency : Treating this empirically is extremely reasonable for hypothermic,

shocky patients.

C-Start dexamethasone (4-6 mg of IV) while awaiting the serum cortisol level.
Dexamethasone is used because it doesn't interfere with the cortisol test. Further
management depends on the cortisol level: If cortisol levels are low (<20 ug/dL), then an ACTH
stimulation test should be performed immediately to clarify whether the patient truly has
adrenal insufficiency. If cortisol levels are adequate (>20 ug/dL), then adrenal insufficiency is
excluded.

Inpatient treatment of moderate-to-severe hypothermia.

Type of Rewarming

Passive External Active External Active Internal (Core)

When Mild hypothermia, Can be used for It can be used alone or combined with
to in which moderate-to-severe active external rewarming in patients with
adopt thermoregulation hypothermia and for severe hypothermia (<28 °C) or patients
mechanisms are patients with mild with moderate hypothermia who fail to
still functional. hypothermia who are respond to less aggressive measures
unstable, lack
physiologic reserve, or
fail to respond to
passive external
rewarming
What After wet clothing Relies on the delivery IV administration of warmed crystalloid (40
to do is removed, the of heat to the surface to 42 °C) or extracorporeal blood
patient is covered of the body (some rewarming
with blankets or combination of warm
other types of blankets, heating
insulation. pads, radiant heat,
warm baths or forced
warm air, is applied
directly to the
patient’s skin).
Rewarming techniques in patients with accidental hypothermia
Rewarming Technique Rewarming Rate Notes & Controversies Rewarming
Complications

Passive Rewarming

Passive rewarming 0.5–4 °C /h Protects from further heat Negligible in isolated

(dependends on loss and allows patient to mild hypothermia. For
patient’s self-rewarm. colder patients and
thermoregulatory those with secondary
function and hypothermia or
metabolic comorbidities, passive
reserves) rewarming alone is not
adequate.

Passive rewarming 1–5 °C /h Exercise immediately after Increased afterdrop

with active movement rescue increases afterdrop could cause rescue
collapse.

Active External Rewarming

Active rewarming 0.5–4 °C /h Protects from further heat Similar to passive

including forced-air loss, delivers external heat. rewarming
surface rewarmin, Warmed IV fluids are not
heating pads, e.g. effective if used as the sole
Arctic Sun®],warmed method of rewarming.
IV fluids (40 °C).

Active Internal Rewarming

Bladder lavage Variable. Adds < Not recommended Negligible unless

0.5 °C /h Rewarming is intermittent difficult catheterisation
and slow because of small
surface area. Poor control
of infusate temperature

Gastric lavage May add ~0.5–1 Not recommended. Potential for

°C /h Unacceptably high risk to aspiration, fluid and
benefit ratio electrolyte shifts

Intravascular catheter Device specific Uncertain indications for Potential for

rewarming, e.g., (adds ~0.5–2.5 °C use. Potential beneficial for haemorrhage or
CoolGuard® /h) colder patients, especially thrombosis, potentially
Quattro® worsening arterial
Cool Line® those with comorbidites, hypotension in
Innercool® with stable circulation unstable patients

Thoracic Variable, May be useful in unstable Potential for

or peritoneal lavage depending on patients when ECLS haemorrhage, lung or
tempearture and rewarming is not available. bowel trauma, fluid
flow rate of Very invasive. and electrolyte shifts.
paricardial Thoracic lavage may
irrigation. interfere with CPR
CRRT (including Adds ~1.5–3 °C Not recommended unless Problems rare. Local
CVVHF, CVVHD, /h ECLS rewarming not vascular complications.
CVVHDF) available. Require adequate Air embolism. Arterial
blood pressure. hypotension
Heparinisation, citrate
anticoagulation, or
prostacyclin required
Haemodialysis Adds ~2–3 °C /h Patient must be able to Potential for arterial
increase cardiac output to hypotension,
perfuse the external circuit. haemorrhage,
Heparinisation required thrombosis,
haemolysis, etc.
Veno-venous ~4–10 °C /h Provides no circulatory or Potential for arterial
rewarming (usually ventilatory support in case hypotension,
with ECMO) of cardiac arrest. Patient haemorrhage,
must be able to increase thrombosis,
cardiac output to perfuse haemolysis, etc.
the external circuit
Extra-corporeal life ~4–10 °C /h Preferred rewarming Potential for
support (ECLS; VA- method for patients in haemorrhage and
ECMO, CPB including cardiac arrest. ECMO arterial hypotension,
minimally invasive preferred over CPB. ECMO thrombosis,
extracorporeal can use femoral route haemolysis, etc., as
circulation (MiECC)) avoiding need for with all intravascular
sternotomy. Can be used to de
treat post-rewarming
pulmonary complications,
such as ARDS.
 Chapter 43: Post Cardiac Arrest Syndrome
If a person has a return of spontaneous circulation (ROSC), start post-resuscitation care
immediately. Post-resuscitation care is meant to optimize ventilation and circulation,
preserve organ/tissue function, and maintain recommended blood glucose levels.

Pathophysiology of post cardiac arrest syndrome: Regardless of the cause

of cardiac arrest, the hypoxia, ischaemia and reperfusion that occur during and after the
resuscitation phase result in damage to multiple organ systems. This condition, called post-
cardiac arrest syndrome, comprises four major components:

(a) Persistent precipitating pathology: the precipitating aetiology that leads to cardiac arrest
needs to be rapidly identified and addressed. The most common pathology is coronary
thrombus, which causes myocardial infarction. Other non-coronary causes that can lead to
cardiac arrest include hypoxia, pulmonary embolism (PE) and sepsis.

(b) Anoxic brain injury: the reperfusion that occurs after a period of cerebral hypoxia results
in the formation of free radicals and activation of cell-death signalling pathways causing
disturbance of cerebral microvascular homeostasis. This injury can continue for hours to days
and is aggravated by additional insults such as fever, poor glucose control and hyperoxia. The
symptoms of anoxic brain injury include coma, seizures, myoclonus, various degrees of
neurocognitive dysfunction and brain death.

(c) Post-cardiac arrest myocardial dysfunction: there is hypokinesia of the cardiac muscles
associated with a significant drop in left ventricular ejection fraction, especially during the
first 24–48 hours after ROSC. It occurs despite preserved coronary blood flow. This manifests
as tachycardia, hypotension, poor cardiac output and elevated left ventricular end-diastolic
pressure.

(d) Systemic ischaemia/reperfusion response: whole-body hypoxia/ischaemia followed by

post-ROSC reperfusion results in systemic inflammation, endothelial activation, and
activation of the immunologic and coagulation pathways. This resembles the pathophysiology
occurring during severe sepsis and increases the risk of multiple organ dysfunction syndrome.
Clinical manifestations include fever and altered oxygen consumption, as well as increased
susceptibility to infection.

Table 1. Post Cardiac Arrest Syndrome: Pathophysiology and Potential Treatment

Strategies
Post Cardiac Anoxic Brain Arrest-Related Systemic Persistent
Arrest Injury Myocardial Ischemic/Reperfusio Precipitating
Syndrome Dysfunction n Response Pathology
Pathophysiolog Disrupted Stunning Intra-arrest global ACS plaque
y calcium phenomenon tissue hypotension rupture/thrombus
homeostasis Free Global Reperfusion injury formation Chronic
 radical formation hypokinesis Endothelial activation ischemic
Cell death Elevated LVEDP Systemic myocardial scar
signaling Preserved inflammation Pulmonary
pathways coronary blood Activation of clotting embolism
Reperfusion flow (excluding cascades Cardiomyopathies
injury No reflow patients with Intravascular volume : dilated,
Additional insults: ACS) depletion Disturbed restrictive,
pyrexia, vasoregulation Risk of hypertrophic,
hyperglycemia, infection genetic,
hyperoxygenatio channelopathy,
n congenital
Potential Therapeutic Systems of care Goal-directed therapy Address disease
therapeutic hypothermia Revascularizatio Intravenous fluids specific origin
approaches Early n Intravenous Vasopressors Glucose
hemodynamic fluid Inotropes control
optimization IABP ECMO Hemofiltration
Ventilation and LVAD Antimicrobials
airway protection
Seizure control
Controlled
oxygenation
Post-resuscitation care is an evolving science that requires a well-coordinated
multidisciplinary effort with participation of physicians from the disciplines of emergency
medicine, critical and intensive care, nursing, cardiology and anaesthesiology, at the very
least. There is a need to identify approaches and optimise workflow for the integration of
post-ROSC care as a standard of care in treating cardiac arrest patients who attain ROSC. This
can be achieved by determining how the various interventions needed in post-resuscitation
care can be bundled into a care regimen and implemented in most clinical care areas. In this
article, the National Resuscitation Council, Singapore, has evaluated the current research in
this field and produced the guidelines that can be further adopted in our clinical practice and
updated with research in our local setting and environment.

Systemic consequences of cardiac arrest

Pathophysiology Clinical consequences

Ischemia - √ Free radical formation √ Multiorgan failure

reperfusion injury √ Apoptosis, necrosis √ Infection/sepsis
√ “Sterile inflammation” √ Microbiome disturbances
√ Impaired resistance to infection √ Tissue hypoxia/ischemia
√ Endothelial damage √ Hyperglycemia
√ Impaired vasoregulation √ Increase of intra-abdominal
√ Adrenal suppression pressure
√ Electrolytes disturbances √ Development of abdominal
√ Acidosis, hypoxia, catabolism compartment syndrome
 Brain injury/global √ Calcium homeostasis disruption √ Damage of blood-brain barrier
cerebral ischemia √ No reflow (BBB) (endothelial dysfunction
(GCI) √ Pyrexia and capillary permeability)
√ Hyperglycemia √ Coma
√ Hyperoxygenation √ Seizures
√ Impaired cerebrovascular √ Cognitive dysfunction
autoregulation √ Stroke
√ Impairment of hypothalamic- √ Brain death
pituitary-adrenal axis √ Pulmonary complications
√ Raised corticotropin releasing factor following cerebral ischemia
(CRF)-blood flow changes (neurogenic pulmonary edema,
acute distress respiratory
syndrome, pneumonia)

Myocardial √ Global hypokinesis √ Acute myocardial infarction

dysfunction √ Preserved coronary blood flow (AMI)
√ Elevated systemic and pulmonary √ Arrhythmias
vascular resistance √ Cardiomyopathies: dilated,
√ Impaired ventricular function restrictive, hypertrophic
√ Decreased venous return, cardiac √ Cardiovascular collapse
compliance, and cardiac output.
√ Decreased contractility

Arrest related lung √ Reperfusion injury √ Pneumonia

injury √ Endothelial damage √ Acute respiratory distress
√ Systemic inflammation syndrome
√ Activation of clotting cascades √ Pulmonary thromboembolism
√ Ventilation-perfusion mismatch
(ventilatory pressure)
√ Basal atelectasis

Arrest related liver √ Reperfusion injury √ Hypoxic hepatitis/acute liver

and kidney injury √ Reduced blood flow failure
√ Reduced urine output √ Acute kidney injury

Scope of Post ROSC Care

Cardiac arrest is multifactorial and can severely affect multiple organ systems regardless
of cause, hypoxaemia, ischaemic injuries and reperfusion injuries. Post-resuscitation care
must be tailored to the needs of the individual patient. The following areas need to be
addressed to improve outcomes: (a) identification and treatment of the cause of cardiac
arrest; (b) airway and ventilation management; (c) haemodynamic management; (d) targeted
temperature management (TTM) or therapeutic hypothermia (TH); (e) glycaemic control; and
(f) seizure management and neuroprognostication.
Multiple System Approach to Post–Cardiac Arrest Care
Ventilation Hemodynamics Cardiovascular Neurological Metabolic
•Capnography •Frequent Blood •Continuous •Serial •Serial Lactate
◦Rationale: Pressure Cardiac Neurological Exam ◦Rationale:
Confirm secure Monitoring/Arterial- Monitoring ◦Rationale: Serial Confirm
airway and line ◦Rationale: Detect examinations adequate
titrate ◦Rationale: Maintain recurrent define coma, brain perfusion
ventilation perfusion and arrhythmia injury, and
◦Endotracheal prevent recurrent ◦No prophylactic prognosis
tube when hypotension antiarrhythmics ◦Response to
possible for ◦Mean arterial ◦Treat arrhythmias verbal commands
comatose pressure ≥65 mm Hg as required or physical
patients or systolic blood ◦Remove stimulation
◦PETCO2∼35–40 pressure ≥90 mm Hg reversible causes ◦Pupillary light and
mm Hg corneal reflex,
◦Paco2∼40–45 spontaneous eye
mm Hg movement
◦Gag, cough,
spontaneous
breaths
•Chest X-ray •Treat Hypotension •12-lead •EEG Monitoring If •Serum
◦Rationale: ◦Rationale: Maintain ECG/Troponin Comatose Potassium
Confirm secure perfusion ◦Rationale: Detect ◦Rationale: Exclude ◦Rationale:
airway and ◦Fluid bolus if Acute Coronary seizures Avoid
detect causes or tolerated Syndrome/ST- ◦Anticonvulsants if hypokalemia
complications of ◦Dopamine 5–10 Elevation seizing which
arrest: mcg/kg per min Myocardial promotes
pneumonitis, ◦Norepinephrine Infarction; Assess arrhythmias
pneumonia, 0.1–0.5 mcg/kg per QT interval ◦
pulmonary min Replace to
edema ◦Epinephrine 0.1–0.5 maintain K
mcg/kg per min >3.5 mEq/L
•Pulse … •Treat Acute •Core •Urine Output,
Oximetry/ABG Coronary Temperature Serum
◦Rationale: Syndrome Measurement If Creatinine
Maintain ◦Aspirin/heparin Comatose ◦Rationale:
adequate ◦Transfer to acute ◦Rationale: Detect acute
oxygenation and coronary Minimize brain kidney injury
minimize FIO2 treatment center injury and improve ◦Maintain
◦SpO2 ≥94% ◦Consider outcome euvolemia
◦ emergent PCI or ◦Prevent ◦Renal
PaO2∼100 mm fibrinolysis hyperpyrexia replacement
Hg >37.7°C therapy if
◦Reduce FIO2 as ◦Induce indicated
tolerated therapeutic
◦Pao2/FIO2 ratio hypothermia if no
to follow acute contraindications
lung injury ◦Cold IV fluid bolus
30 mL/kg if no
contraindication
 ◦Surface or
endovascular
cooling for 32°C–
34°C×24 hours
◦After 24 hours,
slow rewarming
0.25°C/hr
•Mechanical … •Echocardiogram •Consider Non- •Serum
Ventilation ◦Rationale: Detect enhanced CT Scan Glucose
◦Rationale: global stunning, ◦Rationale: Exclude ◦Rationale:
Minimize acute wall-motion primary Detect
lung injury, abnormalities, intracranial hyperglycemia
potential oxygen structural process and
toxicity problems or hypoglycemia
◦Tidal Volume 6– cardiomyopathy ◦Treat
8 mL/kg hypoglycemia
◦Titrate minute (<80 mg/dL)
ventilation to with dextrose
PETCO2∼35–40 ◦Treat
mm Hg hyperglycemia
Paco2∼40–45 to target
mm Hg glucose 144–
◦Reduce Fio2 as 180 mg/dL
tolerated to keep ◦Local insulin
Spo2 or protocols
Sao2 ≥94%
… •Treat Myocardial •Sedation/Muscle •Avoid
Stunning Relaxation Hypotonic
◦Fluids to optimize ◦Rationale: To Fluids
volume status control shivering, ◦Rationale:
(requires clinical agitation, or May increase
judgment) ventilator edema,
◦Dobutamine 5–10 desynchrony as including
mcg/kg per min needed cerebral
◦Mechanical edema
augmentation (IABP)

Identification of the cause of cardiac arrest: Once ROSC has been achieved, the
factors that contributed to cardiac arrest should be identified early for appropriate
intervention to treat the cause. A good history of the events leading to the collapse, careful
physical examination and basic investigation would help to rapidly determine the cause. Some
of these causes might become apparent during resuscitation of the patient, especially while
evaluating the 5Hs and 5Ts of cardiac arrest. Some common known causes are listed below.

1-Coronary artery disease: As soon as possible following ROSC, 12-lead

electrocardiography (ECG) should be performed to diagnose ST-segment elevation
myocardial infarction (STEMI), and an immediate coronary angiography arranged. In a series
of patients who underwent urgent coronary angiography following cardiac arrest, a coronary
artery lesion was found in 96% of the patients with STEMI and in 58% of the patients without
ST elevation on ECG. Myocardial and neurological functions can improve after percutaneous
coronary intervention following cardiac arrest.
Diagnosis of acute coronary syndrome: Acute coronary syndrome accounts for ~65% of out-
of-hospital cardiac arrests with a shockable rhythm. Acute coronary syndrome may be
suggested by:

• History of chest pain or angina symptoms prior to arrest.

• Shockable rhythm.
• Serial ECG suggestive of ischemia.
• Elevated troponin levels.
• Echocardiography revealing a focal wall motion abnormality.
• Cardiac CT angiography to evaluate coronary arteries.

Timing of coronary angiography: Indications for emergent PCI:

[1] ECG indicative of OMI (occlusive myocardial infarction).

[2] Cardiogenic shock (note however that post-ROSC distributive shock due to a systemic
inflammatory response syndrome is common and doesn't mandate PCI).

[3] Recurrent arrhythmias.

For patients with NOMI (nonocclusive MI), there is no clear delineation of the optimal timing
of cardiac catheterization.

Medical management for type-1 MI: Medical therapies may be indicated for patients with
probable/definite type-1 NOMI who are awaiting cardiac catheterization. This often involves:
Aspirin. Heparin infusion for patients pending coronary angiography.

Multiple studies have demonstrated improved survival to hospital discharge, as well as

improved neurologically favourable outcomes associated with emergency coronary
angiography in patients with ST elevation after cardiac arrest. Some patients are hypotensive
despite revascularisation and may need mechanical augmentation via intra-aortic balloon
pump or extracorporeal membrane oxygenation. Thus, immediate coronary angiography
should be performed on out-of-hospital cardiac arrest patients with suspected cardiac
aetiology and STEMI on ECG following ROSC (Class I). It is also reasonable to perform
emergency coronary angiography following ROSC in unstable patients with suspected cardiac
aetiology but no ST elevation on ECG (Class IIa). All patients should undergo continuous
cardiac monitoring for arrhythmias in the period following cardiac arrest. Arrhythmias should
be managed appropriately as per resuscitation guidelines.

2-Acute pulmonary embolism: Cardiac arrest due to PE is often not obvious and
accounts for about 2%–10% of cases. Indicators of this cause include poor arterial oxygen
saturation following ROSC with appropriate ECG changes. Current guidelines do not support
the routine use of fibrinolytics during cardiac arrest. Following ROSC, it is preferable to
confirm the diagnosis of PE on imaging before fibrinolysis is initiated. When direct imaging is
unavailable or unsafe because of the patient’s unstable condition, fibrinolytics may be used
in post-cardiac arrest patients who are suspected to have collapsed from severe PE, i.e.
patients with sustained hypotension (systolic blood pressure < 90 mm Hg for at least 15
minutes or requiring inotropic support, not clearly due to a cause other than PE), a high clinical
pretest probability of PE and right ventricular dysfunction on bedside transthoracic
echocardiography.

3-Cardiotoxic agents: Drugs such as tricyclic antidepressants, cardiac glycosides and

recreational drugs are the main pharmacologic agents that result in cardiac arrest. However,
identifying the drug involved is usually a major challenge. Since most cardiotoxic drugs are
water-soluble and may be excreted by the kidney, forced alkaline diuresis may be employed.
This is a slow process owing to the mechanisms of excretion of the drugs. The use of intralipids
to enhance the elimination of cardiotoxic drugs may be considered once ROSC is achieved. If
started before collapse, prolonged cardiopulmonary resuscitation may be required to allow
time for these agents to exert their effects. These agents must be continued for at least 24
hours following ROSC. If the cardiotoxic agent is known, available antidotes may be
administered. Frequently, massive drug overdoses resulting in cardiovascular collapse require
rapid removal via haemodialysis. However, this may only be considered if the patient has
attained ROSC and supportive care is in progress.

4-Metabolic disturbances: A number of metabolic disorders such as hyperkalaemia,

hypokalaemia and hypercalcaemia can cause cardiac arrest. ECG following ROSC may be the
only initial clue to this diagnosis. Treatment to correct this metabolic disorder, initiated during
resuscitation or following ROSC, must proceed in tandem with other supportive care
measures. For instance, hyperkalaemic patients would require calcium gluconate and glucose
plus insulin, in addition to haemodialysis, to remove the excessive potassium load, while
hypokalaemic patients would need replacement therapy.

5-Sepsis: Sepsis is one of the common causes of cardiovascular collapse. Once suspected,
blood cultures should be obtained and the appropriate intravenous antibiotics administered,
in addition to identifying the source of infection and appropriate management. Protocolised
resuscitation of patients using sepsis-care bundles has been shown to decrease mortality in
this group of patients.
Findings that may indicate CA etiology.
Organ System Clinical Findings Potential Etiology
Pulmonary Diminished or abolished Unilateral: Pneumothorax, right mainstem
breath sounds intubation (left side less common)
Bilateral: Pulmonary edema
Cardiovascular New murmur Papillary rupture, valve abnormality
Unequal pulses or blood Aortic dissection
pressure
 Bradycardia Toxidrome, hypoxia, hypo/hyperkalemia,
hypo/hypercalcaemia, hypothermia,
exogenous intoxication, acid-basic
disturbances
Tachycardia Tachyarrhythmias, thyrotoxic storm
Abdomen Distention/rigidity Hemorrhage/inflammatory process
Pulsatile mass Aortic aneurism rupture
Extremity Unilateral Pulmonary embolism, septic shock
swelling/erythema
Hemodialysis fistula Hyperkalemia
Skin Cyanosis Hypoxia, methemoglobinemia
sulfhemoglobinemia
Mottling, slow capillary Septic shock, hemorrhagic shock
refill
IV injection sites Drug overdose
Open wounds/cellulitis Septic shock
Diffuse urticaria Anaphylactic shock
Neurologic Focal motor deficits Stroke
Global motor deficits Toxidrome, hypoxic/anoxic brain injury

Most important etiologies of cardiac arrest.

Organ System Etiology
Cardiovascular Acute coronary syndrome
Arrhythmia
Structural heart disease
Cardiac tamponade
Aortic dissection
Respiratory Venous thromboembolism
Upper airway obstruction
Drowning
Pneumothorax
Hypoxia
Metabolic Acidosis
Hypo/Hyperkalemia
 Hypomagnesemia
Neurologic Subarachnoid hemorrhage
Status epilepticus
Stroke
Others Trauma
Hypothermia
Intoxication
Non-traumatic exsanguination

Treatable conditions associated with cardiac arrest

Condition Common associated clinical settings

Acidosis Diabetes, diarrhea, drug overdose, renal dysfunction, sepsis, shock

Anemia Gastrointestinal bleeding, nutritional deficiencies, recent trauma

Cardiac Post-cardiac surgery, malignancy, post-myocardial infarction, pericarditis, trauma

tamponade

Hyperkalemia Drug overdose, renal dysfunction, hemolysis, excessive potassium intake,

rhabdomyolysis, major soft tissue injury, tumor lysis syndrome

Hypokalemia* Alcohol abuse, diabetes mellitus, diuretics, drug overdose, profound gastrointestinal
losses

Hypothermia Alcohol intoxication, significant burns, drowning, drug overdose, elder patient,
endocrine disease, environmental exposure, spinal cord disease, trauma

Hypovolemia Significant burns, diabetes, gastrointestinal losses, hemorrhage, malignancy, sepsis,

trauma

Hypoxia Upper airway obstruction, hypoventilation (CNS dysfunction, neuromuscular

disease), pulmonary disease

Myocardial Cardiac arrest

infarction

Poisoning History of alcohol or drug abuse, altered mental status, classic toxidrome (eg,
sympathomimetic), occupational exposure, psychiatric disease

Pulmonary Immobilized patient, recent surgical procedure (eg, orthopedic), peripartum, risk
embolism factors for thromboembolic disease, recent trauma, presentation consistent with
acute pulmonary embolism

Tension Central venous catheter, mechanical ventilation, pulmonary disease (eg, asthma,
pneumothorax chronic obstructive pulmonary disease), thoracentesis, thoracic trauma
Adult Cardiac Arrest Algorithm
Adult post-cardiac arrest care algorithm

Post Resuscitation Care:

A – Airway: Patients who only have a brief period of cardiac arrest and respond
immediately to resuscitation may achieve a return of normal cerebral function and may not
require intubation if they are able to maintain their airway. However, if there is any doubt
about the ability to protect airway such as a depressed conscious level, tracheal intubation
and mechanical ventilation should be instituted. It is reasonable to consider using a tracheal
tube with subglottic secretion drainage to reduce ventilator-associated pneumonia, which
has a higher incidence during TTM.
Normocapnia Goals:
1-Most current guidelines recommend targeting normocapnia (35-45 mm Hg or 4.5-6 kPa).

2-Hypocapnia is probably the most dangerous, as this will cause cerebral vasoconstriction
and reduced brain perfusion.

3-Hypercapnia causes cerebral vasodilation. This might be good (increased perfusion) or it

might be harmful (increased brain edema, elevated intracranial pressure). The TAME trial
found that targeting mild hypercapnia (50-55 mm) didn't improve neurologic outcomes.

Strategy: 1-Immediately after intubation, adjust the minute ventilation to achieve an end-
tidal CO2 of 30-35 mm. Since pCO2 is always above the end-tidal CO2, this will generally put
the pCO2 into a safe range.

2-Only after the end tidal CO2 is optimized, obtain an ABG/VBG to verify that the pCO2 is
within the target range (35-45 mm Hg or 4.5-6 kPa). Adjust the ventilator as needed, and
continue to carefully follow the end tidal CO2.

3-Patients with chronic hypercapnia are an exception to this paradigm; they may benefit
from being maintained at their chronic, baseline pCO2.

Normoxia : 1-Both extremes are likely harmful (hypoxemia and hyperoxia).

2-The BOX trial demonstrated that targeting a PaO2 of 68-72 mm was equivalent to
targeting a PaO2 of 98-105 mm. This suggests that a relatively broad range of PaO2 is safe
(e.g., at least 68-105 mm).

3-In practice, usual oxygen targets may be used (similarly to any other critically ill patient).
The AHA/NCC guidelines recommend targeting an oxygen saturation between 92-98%.

4-The most common mistake here is leaving the ventilation set to 100% FiO2 for hours. The
FiO2 will always be 100% immediately after intubation, but this should be down-titrated as
rapidly as possible.

The following guidelines are important for initial mechanical ventilation in the post-
cardiac arrest patient:

A●Target a carbon dioxide tension (PaCO2) of 40 to 50 mmHg or end-tidal

carbon dioxide (EtCO2) of approximately 35 to 45 mmHg.

Hyperventilation and the resulting hypocapnia lead to cerebral vasoconstriction that may
worsen brain injury after cardiac arrest. In a randomized trial, mild therapeutic hypercapnia
(PaCO2 50 to 55 mmHg) resulted in lower concentrations of biomarkers of brain injury than
 targeted normocapnia (PaCO2 35 to 45 mmHg). In observational studies, PaCO2 in a normal
to mildly elevated range (PaCO2 35 to 55 mmHg) is associated with better outcomes than a
lower PaCO2. Significant hypercarbia may worsen acidosis.

The Mild hypercapnia or normocapnia after out-of-hospital cardiac arrest (TAME) trial
randomized 1700 patients to targeted mild therapeutic hypercapnia (PaCo2 50-55mmHg)
or targeted normocapnia (PaCO2 35-45mmHg) and found no difference in functionally
favorable survival using the Glasgow Outcome Scale, adverse events, or key secondary
outcomes. TAME corrected sample temperature to 37°C before analysis (alpha-stat
method). This adjustment is made because the actual PaCO2 may be lower than what
is measured in the laboratory at 37°C; however, the approach has been associated with
decreased cerebral blood flow after cardiac arrest in some studies.

No available data support hypocapnia as a therapeutic approach after cardiac arrest, and it
remains controversial whether to correct blood gas results for low temperatures while
patients are hypothermic during targeted temperature management (TTM). For these
reasons, the authors think that a PaCO2 of 40 to 50 mmHg is a safer target than 35 mmHg
at all patient temperatures.
B●Maintain oxygen saturation (SpO2) >94 percent.
Hypoxia must be avoided in the post-cardiac arrest patient, but hyperoxia (arterial oxygen
tension [PaO2] >300 mmHg) has also been associated with worse outcomes. We suggest
titrating the fraction of inspired oxygen (FiO2) to the lowest value necessary to maintain
SpO2 >94 percent, or the PaO2 to around 100 mmHg. If the patient's core temperature is
maintained at 33°C, the PaO2 reported by the laboratory may be higher than the patient's
actual PaO2. Thus, in this clinical setting, maintaining a PaO2 of 100 to 120 mmHg is
reasonable.

Awake patients who are able to maintain their airway and have spontaneous respiratory
effort can be monitored without intubation. Supplemental oxygen is recommended to
maintain blood oxygen saturation (SpO2) of 94%–98%. Following ROSC, comatose patients
should have a definitive airway established and mechanical ventilation commenced. Previous
guidelines recommend appropriate titration of supplemental oxygenation to prevent hypoxia
and avoid prolonged periods of hyperoxia. There is increasing evidence to suggest that
excessive oxidative stress during hyperoxia may harm various organs, causing neuronal
damage as well as irreversible changes within the alveolar space. Severe hyperoxia was
independently associated with decreased survival to hospital discharge. Following ROSC,
hyperoxaemia during the reperfusion phase with 100% oxygen leads to increased brain lipid
peroxidation, greater metabolic dysfunction and neurological degeneration. These concerns
and their impact on short-term functional outcome have resulted in calls to ventilate with
room air or fraction of inspired oxygen (FiO2) titrated to maintain a pulse oximetry reading of
94%–98%. In the phase following ROSC, it is reasonable to commence mechanical ventilation
using the highest oxygen concentration (FiO2 100%) to avoid hypoxia. Once reliable SpO2 can
be measured or arterial blood gas is obtained to measure oxygenation, it is important to
titrate FiO2 to maintain the oxyhaemoglobin saturation at 94%–98% on pulse oximetry.

Hypocapnia is associated with worse neurological outcomes. It is suggested that the initial
ventilator settings should begin with tidal volumes of 6–8 mL/kg body weight and ventilatory
rates of 10–12 breaths/minute. The aim of optimal ventilation should be to maintain
normocarbia (end-tidal carbon dioxide 30–40 mmHg or partial pressure of arterial carbon
dioxide 35–45 mmHg). Hyperventilation is not recommended, as it decreases the partial
pressure of carbon dioxide, which in turn decreases cerebral blood flow, causing cerebral
vasoconstriction and aggravating anoxic brain damage. Minute ventilation should thus be
titrated, guided by serial arterial blood gas measurements.

Aspiration Pneumonia & Antibiotic Prophylaxis

Why aspiration pneumonia is potentially problematic: Many patients aspirate
during cardiac arrest. Patients are intubated and mechanically ventilated, usually with poor
mental status – conditions which do not promote secretion clearance. Early diagnosis of
pneumonia is impossible for many reasons (inability to measure a fever due to therapeutic
temperature monitoring, inability to report symptoms due to intubated/sedated status,
masking of mild hypoxemia because patients are on mechanical ventilation already).

One very small, single-center study found benefit from a three-day prophylactic course of
ampicillin-sulbactam.

Bottom line? Use of prophylactic antibiotics following cardiac arrest remains

controversial. Overall, it appears safe and is supported by available evidence. If prophylactic
antibiotics are used:

(a) Reasonably narrow agents should be used (e.g., ampicillin/sulbactam or ceftriaxone

monotherapy).

(b) The course should be limited to 48 hours.

If prophylactic antibiotics aren't used, then there should be a low threshold to initiate
antibiotics if the patient shows any signs of pneumonia. Cardiac arrest may cause elevation
of procalcitonin and CRP levels. An elevation of these levels within following cardiac arrest is
nonspecific and doesn't necessarily indicate infection.

B – BREATHING

1-Oxygenation: Hypoxaemia (PaO2 < 60 mmHg or PaO2/fraction of inspired oxygen

[FiO2] ratio < 300) increases the likelihood of further cardiac arrest and contributes to
secondary brain injury. Conversely, hyperoxaemia (PaO2 ≥ 300 mmHg) has the potential to
cause oxidative stress, worsening neurological injury and increasing mortality. The
recommendation, therefore, is to target blood oxygen saturation (SpO2) of 94%–98%. We
should also avoid using a high level of positive end expiratory pressure (PEEP; e.g. > 10
cmH2O), as high intra-thoracic pressures may reduce cerebral venous drainage, increasing
cerebral blood volume and intracranial pressure (ICP). Thereafter, FiO2 should be titrated to
achieve oxygenation targets.

2-Ventilation: Hypocapnia causes cerebral vasoconstriction and reduces cerebral blood

flow, contributing to poorer neurological outcomes. Conversely, pilot studies have shown that
mild hypercapnia is associated with better neurological prognosis in post-cardiac arrest
patients. Until definitive studies supporting mild hypercapnia are reported, the current
recommendation is to aim for normocapnia, i.e. target PaCO2 35–45 mmHg. It may be
reasonable to consider targeted therapeutic mild hypercapnia, i.e. PaCO2 50–55 mmHg, if
there is evidence of low cerebral oxygenation and no contraindications to mild hypercapnia
such as raised ICP or severe metabolic acidosis. Although the in vivo PaCO2 decreases by 2
mmHg for each degree Celsius below 37°C, there is currently no recommendation for
temperature correction of CO2. The use of end tidal carbon dioxide (ETCO2) for continuous
monitoring is invaluable and the PaCO2-PETCO2 gradient should be determined daily. Both
hypothermia and the use of neuromuscular blocking agents can reduce CO 2 production and
increase the risk of hypocapnia. Routine lung protective ventilation strategies, i.e. tidal
volume 6–8 mL/kg, predicted body weight and maintaining plateau pressure ≤ 30 cmH 2O,
should be employed to reduce the incidence of ventilator-induced lung injury. Chest
radiography should be performed to confirm the positions of tracheal tube, gastric tube and
central venous catheter, and to detect pulmonary oedema, pneumonia and complications
arising from resuscitation (e.g. rib fractures).
Pulmonary Statements
1-Lung-protective ventilation is a standard of care for most critically ill patients who are at
risk for developing ARDS, including those who remain comatose after CA.
2-Once a reliable arterial oxygen saturation is available after ROSC, titrate FiO2 to achieve an
oxygen saturation (SpO2) of 92% to 98% (91.3%, 21/23).
3-Do not titrate down FiO2 until reliable measurements of the oxygen saturation (SpO2) are
available.
4-Generally, adjust ventilation to target normal PaCO2 (35–45 mm Hg) after ROSC. There may
be specific patients for whom higher or lower CO2 may be appropriate. A higher PaCO2 may
be appropriate as long as pH can be maintained (>7.2). Alternatively, a slightly lower
PaCO2 within the normal range may be used to maintain a safe pH (>7.2) in patients with
metabolic acidosis until acidosis can be otherwise treated
C – Circulation:
1-Coronary angiography: Acute coronary syndrome is a frequent cause of OHCA, and 59%–
71% of patients with OHCA without an obvious non-cardiac cause have an acute coronary
lesion found on coronary angiography. As such, urgent coronary angiography should be
performed in patients after ROSC if the electrocardiogram (ECG) shows ST-segment
elevation (Class I recommendation by both American Heart Association [AHA] and European
Society of Cardiology [ESC]). For patients with no ST-segment elevation, it is reasonable to
consider emergent coronary angiography if they have a high probability of a coronary cause
for the arrest and/or have ongoing electrical or haemodynamic instability (Class IIa
recommendation by AHA and ESC).

2-Intravenous fluids and inotropic drugs should be titrated to optimise blood

pressure, cardiac output and urine output, and administered judiciously. The aim is to
optimise cardiac output, tissue perfusion and oxygen delivery to achieve an ScvO2 ≥ 70%.
Although there is no gold standard, pharmaceutical agents that may be used to support
circulation include adrenaline, noradrenaline, dopamine and dobutamine. Dosages must be
adjusted based on the parameters monitored. Echocardiography should usually be performed
at 24–48 hours following ROSC to monitor ejection fraction and rule out regional wall motion
abnormalities.

3-Haemodynamic monitoring: Treatment should be guided by blood pressure (BP), cardiac

output, central venous oxygen saturation (ScvO2), urine output and lactate clearance. An
arterial cannula should be inserted for continuous BP monitoring. As cardiac function is often
impaired after cardiac arrest, it is also reasonable to consider continuous cardiac output and
continuous ScvO2 monitoring. Serial focused ultrasonography for fluid responsiveness and
echo-Doppler techniques to monitor stroke volume may also be performed.

4-Vasopressors: Vasoactive drugs may be administered after ROSC to support cardiac

output, especially blood flow to the heart and brain. Drugs may be selected to improve heart
rate (chronotropic effects), myocardial contractility (inotropic effects), or arterial pressure
(vasoconstrictive effects), or to reduce afterload (vasodilator effects). Unfortunately many
adrenergic drugs are not selective and may increase or decrease heart rate and afterload,
increase cardiac arrhythmias, and increase myocardial ischemia by creating a mismatch
between myocardial oxygen demand and delivery. Myocardial ischemia, in turn, may further
decrease heart function. Some agents may also have metabolic effects that increase blood
glucose, lactate, and metabolic rate. There is a paucity of data about which vasoactive drug
to select first, although providers should become familiar with the differing adverse effects
associated with these drugs, which might make a particular agent more or less appropriate
for a specific patient.

Haemodynamic support: Post-resuscitation myocardial dysfunction causes haemodynamic

instability, manifesting as hypotension, low cardiac output and arrhythmias. Myocardial
dysfunction often requires inotropic support, with dobutamine having the most evidence for
use. However, the systemic inflammatory response syndrome (SIRS) that occurs in PCAS also
causes vasodilation and, sometimes, vasoplegia. If vasoplegia predominates, it is
recommended to start noradrenaline first to achieve haemodynamic targets and also because
it is less arrhythmogenic. However, if up-titration of noradrenaline reduces stroke volume or
ScvO2 (suggesting an excessive increase in left ventricular afterload causing a drop in cardiac
output), it may be useful to add on a low-dose inotrope (e.g. dobutamine 3–5 mcg/kg/min).
Noradrenaline, with or without an inotrope, is usually the most effective therapeutic regime.
 Common Vasoactive Drugs
Drug Typical Starting Dose (Then Titrate to Effect)
Epinephrine 0.1–0.5 mcg/kg/min (In 70-kg adult, 7–35 mcg/min)
•Useful for symptomatic bradycardia if atropine and transcutaneous
pacing fail or if pacing is not available
•Used to treat severe hypotension (eg, systolic blood pressure <70 mm
Hg)
•Useful for anaphylaxis associated with hemodynamic instability or
respiratory distress
Norepinephrine 0.1–0.5 mcg/kg/min (In 70-kg adult, 7–35 mcg/min)
•Used to treat severe hypotension (eg, systolic blood pressure <70 mm
Hg) and a low total peripheral resistance
•Relatively contraindicated in patients with hypovolemia. It may
increase myocardial oxygen requirements, mandating cautious use in
patients with ischemic heart disease
•Usually induces renal and mesenteric vasoconstriction; in sepsis,
however, norepinephrine improves renal blood flow and urine output
Phenylephrine 0.5–2.0 mcg/kg/min (In 70-kg adult, 35–140 mcg/min)
•Used to treat severe hypotension (eg, systolic blood pressure <70 mm
Hg) and a low total peripheral resistance
Dopamine 5–10 mcg/kg/min
•Used to treat hypotension, especially if it is associated with
symptomatic bradycardia
•Although low-dose dopamine infusion has frequently been
recommended to maintain renal blood flow or improve renal function,
more recent data have failed to show a beneficial effect from such
therapy
Dobutamine 5–10 mcg/kg/min
•The (+) isomer is a potent beta-adrenergic agonist, whereas the (–)
isomer is a potent alpha-1-agonist163
•The vasodilating beta2-adrenergic effects of the (+) isomer
counterbalance the vasoconstricting alpha-adrenergic effects, often
leading to little change or a reduction in systemic vascular resistance
Milrinone Load 50 mcg/kg over 10 minutes then infuse at 0.375 mcg/kg/min
•Used to treat low cardiac output
•May cause less tachycardia than dobutamine
In general, adrenergic drugs should not be mixed with sodium bicarbonate or other alkaline solutions in the IV line because there is
evidence that adrenergic agents are inactivated in alkaline solutions. Norepinephrine (levarterenol) and other catecholamines that
activate α-adrenergic receptors may produce tissue necrosis if extravasation occurs. Therefore, administration through a central line is
preferred whenever possible. If extravasation develops, infiltrate 5 to 10 mg of phentolamine diluted in 10 to 15 mL of saline into the site
of extravasation as soon as possible to prevent tissue death and sloughing.
5-Haemodynamic targets: Although the optimal target for mean arterial pressure (MAP)
remains debatable, it is recommended to consider the patient’s baseline BP and any evidence
of raised ICP or acute kidney injury. In the absence of invasive ICP monitoring, an
ultrasonography assessment of the optic nerve sheath diameter (ONSD) > 5 mm correlates
well with an ICP > 20 cmH2O. During PCAS, cerebral autoregulation is impaired and cerebral
blood flow varies directly with cerebral perfusion pressure. The recommended MAP target is
at least 65 mmHg, and a higher MAP target (e.g. 80–85 mmHg) may be reasonable if the
patient has chronic hypertension, or evidence of raised ICP or end-organ hypoperfusion.

6-Bradycardia: Bradycardia is common during induced mild hypothermia. It usually does

not result in haemodynamic compromise and may be associated with better neurological
outcomes. Therefore, there is no need to intervene if the patient develops sinus bradycardia
with a heart rate of 30–40/min, if the BP, ScvO2 and lactate clearance are adequate. However,
if there is advanced atrioventricular block, the target temperature can be increased slightly,
up to 36°C.

D – Disability (NEUROLOGY) : Indications for computed tomography: In the

absence of preceding cardiac symptoms and ischaemic ECG changes, and/or in the presence
of symptoms or signs suggestive of a neurological cause (headache, seizures, focal
neurological deficits) for the cardiac arrest, computed tomography (CT) of the head should be
considered. Similarly, if a respiratory cause (dyspnoea, hypoxia in patients with known
respiratory disease) is suspected, CT of the thorax should be considered.

1-Cerebral monitoring: Seizures are common after anoxic brain injury and occur in
approximately one-third of patients who remain comatose after ROSC. Therefore, patients
should be on continuous electroencephalography (cEEG) monitoring. If cEEG is not available,
limited evidence suggests that sedation monitors may be helpful, as they provide four
channels of continuous frontal EEG monitoring. A spot EEG should be obtained whenever
there is clinical suspicion of seizures if patient is not already on EEG monitoring. In addition,
cerebral blood flow and cerebral tissue oxygenation may be indirectly monitored using near-
infrared spectroscopy to measure cerebral regional oxygen saturation (rSO2). The use of
cerebral rSO2 is useful to guide management. For example, up-titration of noradrenaline to
achieve a particular MAP target may result in decreased cerebral blood flow from cerebral
vasoconstriction and/or a drop in stroke volume from increased left ventricular afterload. The
decrease in cerebral blood flow will manifest as a drop in cerebral rSO 2. A drop in rSO2 can
also be an early warning of hypocapnia from hyperventilation to reduce ICP or after the start
of neuromuscular blocking agent for shivering during induction of hypothermia.

2-Sedation: Adequate sedation reduces oxygen consumption and improves the balance
between oxygen supply and demand. Sedation also helps to reduce the incidence of shivering
during induced hypothermia. It is also important to start sedation if neuromuscular blocking
agents are used, to prevent awareness during paralysis. Although there is no data to support
whether the choice of agents affects outcome, it is recommended to use short-acting drugs
(e.g. remifentanil and propofol), as they allow more reliable and earlier neurological
assessment. This is especially important, as the metabolism of sedatives and neuromuscular
blocking agents is reduced with hypothermia.

Either dexmedetomidine or propofol may be used for sedation. Both have the following
properties:

1) Don't interfere with neurologic examination (e.g. propofol may be held for exams).

2) Decrease shivering.

3) Will not accumulate or delay extubation.

Some patients will have difficulty tolerating these agents due to hypotension. This
can generally be managed by co-administration of a vasopressor or inotrope to balance out
hemodynamic effects of the propofol or dexmedetomidine.

1-Propofol causes vasodilation, which may be counterbalanced with a phenylephrine or

norepinephrine infusion.

2-Dexmedetomidine causes bradycardia, which may be counterbalanced with a low-dose

epinephrine or dobutamine infusion.

3-The best strategy here might be a combination of dexmedetomidine and pain-dose

ketamine infusions (“KetaDex”):

A-Ketamine and dexmedetomidine have synergistic analgesic and anti-shivering effects.

B-Both ketamine and dexmedetomidine tend to prevent delirium and facilitate extubation.
Longer acting drugs should ideally be avoided (even fentanyl), as this may impair
neuroprognostication.

Sedation and Analgesia Statements

1-The goals of analgesia and sedation during temperature control after CA are to provide
comfort, to reduce shivering, and to prevent recall during NMB
2-Short-acting sedative and analgesic agents are preferred for patients in post-CA coma
undergoing temperature control to reduce the duration of mechanical ventilation, time to
awakening, and confounding of delayed prognostication
3-Propofol, remifentanil, and fentanyl are favored over midazolam and morphine infusions
4-Use NMB as needed during temperature control rather than as a continuous infusion. In
addition, it is important to note that NMB may mask seizures in unmonitored patients
3-EEG monitoring: Video EEG monitoring plays two important roles: neuroprognostication
and detection of seizure. Unless the patient is following commands, video EEG monitoring
should be initiated (if available).

Patients with coma or respiratory dysfunction after ROSC are routinely intubated and
maintained on mechanical ventilation for a period of time, which results in discomfort, pain,
and anxiety. Intermittent or continuous sedation and/or analgesia can be used to achieve
specific goals. Patients with post–cardiac arrest cognitive dysfunction may display agitation
or frank delirium with purposeless movement and are at risk of self-injury. Opioids,
anxiolytics, and sedative-hypnotic agents can be used in various combinations to improve
patient-ventilator interaction and blunt the stress-related surge of endogenous
catecholamines. Other agents with sedative and antipsychotic-tranquilizer properties, such
as α2-adrenergic agonists, and butyrophenones are also used based on individual clinical
circumstances.
If patient agitation is life-threatening, neuromuscular blocking agents can be used for short
intervals with adequate sedation. Caution should be used in patients at high risk of seizures
unless continuous electroencephalographic (EEG) monitoring is available. In general sedative
agents should be administered cautiously with daily interruptions and titrated to the desired
effect. A number of sedation scales and motor activity scale were developed to titrate these
pharmacological interventions to a clinical goal.
Shorter-acting medications that can be used as a single bolus or continuous infusion are
usually preferred. There is little evidence to guide sedation/analgesia therapy immediately
after ROSC. One observational study found an association between use of sedation and
development of pneumonia in intubated patients during the first 48 hours of therapy.
However, the study was not designed to investigate sedation as a risk factor for either
pneumonia or death in patients with cardiac arrest.
Although minimizing sedation allows a better clinical estimate of neurological status,
sedation, analgesia, and occasionally neuromuscular relaxation are routinely used to facilitate
induced hypothermia and to control shivering. The duration of neuromuscular blocker use
should be minimized and the depth of neuromuscular blockade should be monitored with a
nerve twitch stimulator.
It is reasonable to consider the titrated use of sedation and analgesia in critically ill patients
who require mechanical ventilation or shivering suppression during induced hypothermia
after cardiac arrest. Duration of neuromuscular blocking agents should be kept to a minimum
or avoided altogether.

4-Paralysis: Limited data suggests that continuous infusion of neuromuscular blocking

agents is associated with decreased mortality in PCAS. However, the use of neuromuscular
blocking agents interferes with clinical examination and masks seizures. Therefore, cEEG or a
sedation monitor with continuous frontal EEG monitoring should be utilised whenever
patients are on paralytics.

5-Seizures: Levetiracetam or valproic acid are reasonable first-line anti-seizure medications.

Myoclonus is the most common seizure and occurs in 18%–25% of patients, the remainder
being focal or generalised tonic-clonic seizures. Seizures increase the cerebral metabolic rate
of oxygen (CMRO2) and can potentially result in secondary brain injury. They should be
treated aggressively, and the recommended options are levetiracetam and sodium valproate,
as they have less adverse cardiac effects. The prevalence of seizures in post-cardiac arrest
patients is about 12%–20%. As seizure is detrimental to brain function, it should be treated
promptly with benzodiazepines and other anticonvulsant medication. There is no role for the
prophylactic administration of anticonvulsant drugs. Electroencephalogram should be
performed without delay, and readings should be monitored frequently or continuously in
comatose patients following ROSC.

6-General approach to shivering management

Tier #1 therapies (preventative therapy for all patients undergoing TTM)

• Acetaminophen, usually 1,000 mg PO q6hr scheduled.

• Buspirone 30 mg per tube q8hr. (29278601)
• Contraindicated by recent intake of MAO inhibitor.
• IV magnesium repletion to target a normal level (e.g., >2 mg/dL or >0.8 mM)

Tier #2 therapies (use as needed, PRN shivering)

• Increase the temperature target: Increase the target temperature to 37.5C (the TTM2 trial
found that targeting 37.5C was safe).
• Warming hands & feet (tricks body into feeling warm).
• Dexmedetomidine and/or propofol infusions.
• Dexmedetomidine appears to be more effective than propofol.
• Ketamine infusion at ~0.2-0.3 mg/kg/hour.
• Boluses of 0.5-0.75 mg/kg ketamine may also be utilized PRN.
• IV magnesium targeting a slightly elevated level (~3-4 mg/dL or ~1.2-1.6 mM).

Tier #3 therapies (use if necessary but ideally avoid; may interfere with prognostication
/extubation)

• Fentanyl boluses PRN (safer than meperidine).

• Paralysis is the treatment of last resort.

Risks of shivering: Shivering can be extremely detrimental, posing a risk to numerous

organs. Consequences of shivering may include: (Lactic acidosis. Elevated intracranial
pressure. Rhabdomyolysis. Discomfort. Impairment of monitoring devices (e.g., pulse
oximeter, EEG).

E – Electrolyte: Regarding serum electrolytes, aim for normal sodium level (e.g. 140–
145 mmol/L), but if ICP is raised, the target can be increased (e.g. to 150–155 mmol/L). Mild
hypokalaemia during hypothermia is common because of cold diuresis and transcellular shift.
Accept mild hypokalaemia (e.g. 3.0–3.5 mmol/L) if there are no significant arrhythmias, and
avoid aggressive replacement to prevent rebound hyperkalaemia during subsequent
rewarming.

F – Fluid: Choice of fluids: Cerebral oedema may occur transiently after ROSC, but it is
rarely associated with a clinically relevant increase in ICP. Nonetheless, it is important to avoid
hypotonic solutions, which may worsen brain swelling. Balanced electrolyte solutions such as
lactated Ringer’s Solution and Plasma-Lyte A are recommended. These potassium-containing
fluids may also help to reduce the hypokalaemia commonly encountered during hypothermia.

G – Gastrointestinal feeding and glucose: Early enteral feeding is recommended as per

standard ICU practice to reduce infectious complications. However, feeding should be started
at low rates (trophic feeding), as hypothermia may lead to gastroparesis and prolonged
intestinal transit time. There could be high gastric residual volume requiring the use of
prokinetic agents. A combination of metoclopramide and erythromycin has been shown to
have synergistic effects in reducing gastric residual volume. Monitor for QT interval
prolongation if the patient is on both erythromycin and hypothermia therapy.
Digestive System Statements
1-Initiate EN as soon as possible after ICU admission.
2-In patients with enteral intolerance or shock, start with trophic EN (rates of 10–20 mL/h)
and adjust according to tolerance.
3-Start parenteral nutrition when enteral feeding is not tolerated or is contraindicated after
5 to 7 days after CA.
4-Give proton pump inhibitor or H2 blockers for stress ulcer prophylaxis per standard
indications in the critically ill patient.
5-In patients receiving EN, stress ulcer prophylaxis may not be necessary.

Both low and high blood glucose levels have adverse effects on the neurological prognosis.
Hypothermia is associated with both hyperglycaemia (because of reduced insulin sensitivity)
and increased blood glucose variability, both of which are associated with increased mortality
and unfavourable neurological outcomes after cardiac arrest. Based on the available data, the
recommendation is to target normoglycaemia (e.g. blood glucose 6–10 mmol/L). Use
intravenous insulin infusion, rather than subcutaneous insulin, to control blood glucose levels
when the patient is on vasopressors and/or hypothermia therapy, as subcutaneous
absorption may be erratic.

H – Hypothermia: TTM includes both targeted hypothermia (targeting core body

temperature 32°C–34°C) and targeted normothermia (targeting core body temperature
35°C–37°C). Guidelines advocate TTM for all adult patients with OHCA and in-hospital cardiac
arrest (IHCA) who remain comatose after ROSC regardless of initial cardiac rhythm. A target
temperature of 32°C–36°C should be selected, achieved and maintained consistently for at
least 24 hours. Data indicates that mild hypothermia is neuroprotective and improves
outcomes after ROSC. Cooling suppresses pathways that lead to apoptosis, decreases
CMRO2 by 6% with every degree Celsius reduction in core body temperature, and reduces the
release of excitatory amino acids and free radicals. Conversely, several studies have
documented an association between post-cardiac arrest pyrexia and poor neurological
outcomes. Therefore, it is reasonable to treat hyperthermia occurring after cardiac arrest with
antipyretics and consider the use of active cooling.
Targeted temperature management: TTM Trial randomised 950 patients with OHCA to
TTM at 33°C vs. 36°C, and the results showed no difference in all-cause mortality or
neurological outcomes at the 180-day follow-up. Unfortunately, this led to some centres
misinterpreting the trial results and abandoning TTM use altogether. It is important to note
that the TTM Trial had two active treatment arms (i.e. TTM at 33°C vs. TTM at 36°C). It was
not a trial of TTM versus no TTM. Active temperature management was also advocated for
patients randomised to the 36°C arm.

Centres that have changed their target

temperature from 33°C to 36°C have
shown that maintenance of target
temperature at 36°C is technically more
challenging compared to 33°C (time in
target temperature 50% vs. 87%), as is
the avoidance of pyrexia (incidence of
fever 19% vs. 0%), with a trend towards
increased mortality. Therefore, it is
important for ICUs adopting a strategy of
TTM at 36°C to be aware that patients on
targeted normothermia still require
active temperature management,
including the use of sedatives,
neuromuscular blocking agents and
cooling devices, to minimise fluctuations
in temperature and prevent fever.

In line with international guidelines, the

Singapore National TTM Workgroup
recommends TTM for all adult patients
with ROSC after OHCA or IHCA who are
unable to obey commands (Glasgow
motor score < 6), regardless of initial
cardiac rhythm (i.e. VF, ventricular
tachycardia, pulseless electrical activity
or asystole).

Exclusion criteria for TTM: (a) patients

deemed unsuitable for further
resuscitation; and/or (b) patients with
baseline Cerebral Performance Category
3 or 4. (Note that bleeding diathesis, sepsis, bradycardia and prolonged QT interval are not
contraindications to TTM. Cardiac arrest patients with these conditions will still benefit from
TTM, but a higher target temperature may be selected, up to 36°C.)
We recommend targeting a temperature of 33°C for PCAS (range 32°C–34°C). However, for
patients who are intolerant of 33°C (e.g. those with bleeding diathesis, significant bradycardia
or marked QT interval prolongation), it is reasonable to aim for a higher target temperature
of up to 36°C. A cooling method with effective temperature monitoring that minimises
temperature fluctuations is preferred. This is best achieved with internal or external cooling
devices that have continuous temperature feedback to achieve a set target temperature,
using thermistors placed in the oesophagus or urinary bladder to monitor the core body
temperature. Temperature should be monitored continuously and recorded at least hourly in
the clinical charts. Endovascular cooling catheters and gel-coated adhesive cooling pads
provide more rapid hypothermia induction and more effective temperature maintenance
with minimal fluctuations compared to water-circulating cooling blankets.

Induction phase
A) If target temperature is 33°C and the patient’s temperature is below 33°C, allow passive
(not active) rewarming to 33°C, and then start endovascular or surface cooling to maintain
the temperature at 33°C.

B) If target temperature is 33°C and the patient’s temperature is above 33°C, start
endovascular or surface cooling to reach the target temperature of 33°C. Avoid rapid infusion
of large volumes of cold fluids, which have been shown to cause pulmonary oedema and
recurrent cardiac arrest.

C) If target temperature is 36°C and the patient’s temperature is below 36°C, allow passive
(not active) rewarming to 36°C, and then start endovascular or surface cooling to maintain
the temperature at 36°C.

D) If target temperature is 36°C and the patient’s temperature is above 36°C, start
endovascular or surface cooling to reach the target temperature of 36°C.

Maintenance phase: Maintain the patient at the target temperature for at least 24
hours after reaching the target temperature. It may be reasonable to consider maintaining a
longer duration at the target temperature for patients who have a longer duration of no flow
and/or low flow time. Shivering increases metabolic rate and causes heat production. The
occurrence of shivering in patients who undergo mild hypothermia is associated with better
neurological outcomes as it is a sign of normal physiological response. Management of
shivering includes: (a) skin counter-warming; (b) intravenous magnesium; (c) increasing
sedation; and (d) starting paralytics (put on cEEG or sedation monitoring, as seizures will be
masked).

Rewarming phase: Rewarm the patient very gradually (e.g. at 0.1°C–0.25°C per hour)
until the temperature reaches 37°C, and maintain the temperature at 37°C (controlled
normothermia) for another 24 hours. The development of hyperthermia after induced mild
hypothermia (i.e. rebound hyperthermia) is associated with increased mortality and worse
neurological outcomes. Therefore, slow, controlled rewarming at 0.1°C–0.25°C per hour is
recommended. Other effects during rewarming include: (a) increased oxygen consumption;
(b) increased CO2 production from increased metabolic activities (may need to increase
minute volume to maintain normocapnia); (c) hypotension from vasodilation (do not wean
off noradrenaline too early); (d) tachyarrhythmias, which may cause myocardial ischaemia;
(e) cerebral desaturation from increased CMRO2 (continue to monitor cerebral rSO2); (f)
seizures from lowering in seizure threshold (continue to monitor EEG); (g) rebound
hyperkalaemia from transcellular shift (keep potassium low-normal before rewarming); and
(h) hypoglycaemia from increased insulin sensitivity (may need to reduce insulin infusion).

Potential adverse effects of mild hypothermia include the following:

●Mild coagulopathy ● Increased risk of infection, especially pneumonia ● Increased risk of

bradyarrhythmia ● Hyperglycemia ● Hypokalemia ● Cold diuresis ● Slowed metabolism and
excretion of medications
At temperatures below 35°C, clotting enzymes operate more slowly, and platelets function
less effectively. As a result, minor bleeding is seen in up to 20 percent of patients treated with
hypothermia, although transfusion is rarely required. In the event of significant bleeding (eg,
hemodynamic instability, intracranial hemorrhage, noncompressible site), the target
temperature is 36°C. Patients colder than this should be rewarmed to 36°C to correct cold-
induced coagulopathy.
Hypothermia impairs leukocyte function. The incidence of significant infection is likely to
increase if hypothermia is maintained longer than 24 hours. While an increase in infection
rates has been noted in several cohorts treated with 24 hours of hypothermic temperature
control, these infections were not associated with increased mortality.
Hypothermia slows cardiac conduction and can provoke arrhythmias, including bradycardia
and QT interval prolongation. Mild asymptomatic bradycardia (eg, heart rate in 40s) is
common at 33°C and does not require intervention if the blood pressure is acceptable. If
intervention is needed for VF or pulseless VT, animal studies report similar or improved first-
shock success with defibrillation in specimens with mild hypothermia compared with those
with normothermia. Temperature control to 33°C is not associated with an increased need
for vasopressor support compared with targeted normothermia or historical controls.
Hyperglycemia due to insulin resistance has been noted during hypothermia. Higher doses of
insulin may be needed in hyperglycemic, hypothermic patients.
Hypothermia leads to a "cold diuresis," which can contribute to hypovolemia, hypokalemia,
hypomagnesaemia, and hypophosphatemia. In addition, temperature fluctuations during the
induction of hypothermic temperature control and rewarming cause potassium to move
between the extracellular and intracellular compartments. Therefore, careful monitoring of
volume status and measurement of basic electrolytes approximately every three to four hours
during hypothermia is prudent. Hypokalemia is more frequently encountered in patients
maintained at 33°C.

Hypothermia slows the metabolism and excretion of many drugs, and thus, their duration of
effect may be prolonged

I – Haematology: Hypothermia results in mild coagulopathy. However, there is usually

no clinically significant bleeding and, therefore, the use of antiplatelets and anticoagulants is
not contraindicated. However, if there is bleeding, a higher target temperature may be
selected, up to 36°C. Intermittent pneumatic compression device should be applied for deep
venous thrombosis prophylaxis.

Hematologic Management Statements

1-As for other critically ill patients, initiate Red Blood Cell Transfusion RBCT when
hemoglobin is <7 g/dL; however, higher transfusion thresholds (ie, <9 g/dL) may be
indicated in patients with acute coronary disease
2-Individualize RBCTs to the clinical situation
3-Initiate DVT prophylaxis within 48 hours after admission unless there is contraindication
4-Low-molecular-weight heparin is the first choice for DVT prophylaxis
5-Low-dose heparin, dalteparin, or reduced doses of other low-molecular-weight heparins
can be used in patients with kidney dysfunction. Monitoring of anti-Xa activity may be
considered when low-molecular-weight heparin is used in this setting
J – Infectious disease: There is a higher incidence of lower respiratory tract infections
with hypothermia therapy because of mild immune paresis. However, there is no current
recommendation for prophylactic antibiotics. The SIRS response in PCAS should resolve in the
first 24–48 hours after cardiac arrest. If systemic vascular resistance remains persistently low,
screen for sepsis and check infective markers, as the patient will not mount a fever response
during TTM.
Infectious Disease Statements
1-Empirical antibiotics may be used in patients who are treated with temperature
management to a hypothermic target after CA to reduce the incidence of pneumonia.
2-Do not use C-reactive protein and procalcitonin to guide antibiotic initiation or duration of
therapy.

K-Endocrine: steroid: Cardiac arrest of any cause may cause cytokine release and a
sepsis-like clinical syndrome. Features may include vasopressor dependent shock and
transient reduction in systolic heart function (similar to septic cardiomyopathy; this often
improves over time with supportive care). Management this is similar to the treatment of
septic shock (e.g., judicious fluid resuscitation, vasopressor support tailored to
hemodynamics and bedside echocardiography).

Glycaemic control: Hyperglycaemia following ROSC has been associated with increased
mortality and worse neurological outcomes Similarly, hypoglycaemia is also associated with
poor outcomes in critically ill patients; the optimal range of blood sugar in these patients
remains unknown. Strict blood sugar control with intensive insulin therapy increases the risk
of hypoglycaemia, which has been associated with increased mortality.) A study comparing
strict versus moderate glucose control did not show any mortality benefit with strict
monitoring in post-cardiac arrest patients. Thus, blood sugar levels should be maintained at
6–10 mmol/L through regular blood glucose monitoring and insulin therapy.

If there is any possibility of infection (e.g. chest infiltrates), empiric antibiotic is

reasonable while awaiting culture results.
Benefits of steroid may include: 1-Improved hemodynamic stability, prevention of post-arrest
multi-organ failure. 2-Antipyretic effect helps prevent shivering and rebound fever.

Should steroid be given? Routine administration of steroid post-cardiac arrest is

recommended by the ESICM/SCCM guidelines, but not the ERC/ESICM guidelines. The
AHA/NCC guidelines don't recommend steroid for all patients, but state that steroid may be
useful to treat persistent shock in patients with suspected or proven adrenal suppression.

if steroids are used, what is a reasonable dose? Intra-arrest: methylprednisolone (e.g., 60-125
mg) may be given intra-arrest.

Post-arrest: a stress dose steroid may be considered (e.g., 50 mg hydrocortisone IV q6hr, or

simply prednisone 40-50 mg daily). One retrospective study suggested that high doses of
steroid is undesirable (defined as >50 mg/day prednisone).

1-Do not use sodium bicarbonate routinely in patients after CA who have metabolic acidosis.
Sodium bicarbonate may be considered in patients with severe metabolic acidosis (pH <7.2,
bicarbonate <20) and AKI stage 2 or 3

2-Consider renal replacement therapy RRT after CA for when life-threatening changes in fluid,
electrolytes, and/or acid-base balance exist and for conditions that can potentially be modified with
RRT.

3-Do not administer empirical corticosteroids to all patients after CA, although supplemental
corticosteroids may be useful to treat persistent shock in patients with proven or suspected adrenal
suppression 4-Consider treatment of hyperglycemia with glucose targets of 81 to 180 mg/dL
 Post-Resuscitation Shock
A post-resuscitation shock occurs in 50–70% of patients who had a cardiac arrest. It is an
early and transient complication of the post-resuscitation phase, which frequently leads to
multiple-organ failure and high mortality and most often results from multiple-organ
failure, including (1) myocardial dysfunction in up to two third of patients (2) acute renal
failure in 10–80% of patients according to the definition used with a pooled incidence of
37% requiring renal replacement therapy in one third of patients and associated with long-
term occurrence of chronic kidney disease, (3) hypoxic hepatitis in almost 15% of patients
and (4) metabolic acidosis in up to 90% of patients. All these organ failures were shown to
be associated with poor outcome in this setting.

Outcome of cardiac arrest (CA) remains very poor. Over 60% of patients with out-of-hospital
cardiac arrest (OHCA) will die without sustainable return of spontaneous circulation (ROSC).
Among patients with sustainable ROSC, intensive care unit (ICU) mortality remains high,
ranging from 60% to 80%of patients. In-hospital mortality after OHCA mainly results from
different causes including recurrent CA, irreversible anoxic brain damage (including brain
death), as well as comorbid withdrawal of care

Pathophysiology of post-resuscitation shock: The pathophysiology of

post-resuscitation shock is both due to the cause of CA and to the ischemia–reperfusion
syndrome, which results in a complex and multifactorial puzzle of organ dysfunctions.
Whatever the aetiology of CA, the post-resuscitation shock is mainly a combination of
myocardial dysfunction, vasoplegia and hypovolemia.

A-Myocardial dysfunction: In a pivotal study combining angiographic data and

pulmonary artery catheter monitoring, Laurent and colleagues prospectively described the
hemodynamic profile of consecutive patients after CA from cardiac origin before ICU
admission at the time of initial left ventricular angiography and within the first 72 h of ICU
stay . When left ventricular angiography was performed, the ejection fraction was reduced in
all patients, whereas filling pressure was increased in patients with hemodynamic instability
but low to normal in patients without hemodynamic instability. Few hours after ICU
admission, the cardiac index was found to be decreased with low or normal filling pressure in
all patients, suggesting hypovolemia. Thereafter, the cardiac index gradually improved with a
return to normal values within 24 h, whereas filling pressure remained unchanged over time.
Despite improvement of cardiac index, all patients required large amount of fluid
administration and high doses of vasopressors within the first 72 h to maintain acceptable
mean arterial pressure (MAP) level. On the whole, these observations were suggestive of an
early and severe myocardial dysfunction, usually regressive within 48 h, associated with a
vasoplegia.

Using echocardiography, it has been shown that this post-resuscitation myocardial

dysfunction is very common, concerning up to 70% of the patients. The most common pattern
is an early and transient systolic and diastolic left ventricular dysfunction, which can be
considered as a model of myocardial stunning following the ischemia–reperfusion syndrome.
Of course, this myocardial dysfunction is very common when CA results from a coronary
occlusion. However, this myocardial dysfunction may be worsened by repeated defibrillations
(especially when using a monophasic and high-energy current), and may also be partly
considered as an “adrenergic cardiopathy”, as illustrated by the independent association
between the epinephrine dose administered during cardiopulmonary resuscitation and the
severity of the cardiac dysfunction.

B-Vasoplegia: Regarding the vasoplegia that is commonly observed as a consequence of

the ischemia–reperfusion syndrome, two mechanisms are mainly suspected on the basis on
prospective human studies. First, neutrophils accumulation, neutrophil-endothelial
interaction and neutrophils activation in microvessels following global ischemia and
reperfusion lead to endothelial cell dysfunction. The latter increases the transduction of
inducible NO-synthase, which in turn induces a relaxation of vascular smooth muscle cells and
promotes the activation of the coagulation cascade. Second, the reactive oxygen species
generated by the ischemia–reperfusion syndrome activate the innate immune cells. It leads
to an increase in inflammatory cytokines release and inducible NO-synthase expression, both
worsening the endothelial dysfunction and thus vasoplegia. Since these two mechanisms are
very similar to those involved in the pathophysiology of sepsis, the post-resuscitation shock
is frequently considered as “a sepsis-like syndrome”. In addition, an authentic sepsis may also
contribute to this hemodynamic profile as infectious complications are very common at this
stage.
C-Hypovolemia: Hypovolemia after CA is common but often undertreated, because of the
fear of fluid overload in these patients with potential myocardial dysfunction. It results from
vasoplegia (relative hypovolemia due to the mismatch between contents and container),
from the capillary-leak syndrome in the most severe patients with prolonged resuscitation
before ROSC and/or under extracorporeal life support (ECLS) and in a later phase, from the
third compartment syndrome related to ileus and intestinal injury.

D-Splanchnic dysfunction and endotoxemia: Some human and prospective studies

have suggested that gut injury could also contribute to the vasoplegia observed in the post-
resuscitation shock through its ability to provoke or worsen a systemic inflammatory
response. Indeed, in post-CA patients, markers of intestinal injury are increased and
endotoxemia is frequent, this latter being associated with the severity of vasoplegia.
However, its incidence is still unknown and the relationship between post-resuscitation shock
and gut injury is complex, as the two are closely intertwined.

E-Hormonal dysfunction: A relative adrenal insufficiency could also participate to the

vasoplegia observed during the post-resuscitation shock. Pène and colleagues prospectively
performed corticotropin-stimulation test in consecutive post-CA patients admitted in ICU and
they observed that 52% of these patients had a relative adrenal insufficiency that was
associated with shock-related mortality. These findings were confirmed by other teams,
highlighting the concept of both relative adrenal insufficiency and adrenal reserve exhaustion
(as observed in patients with septic shock). In addition, the hypothalamic release of arginine-
vasopressin seems to be impaired in patients after CA, also contributing to vasoplegia.
Importantly, there is an interindividual variability in the respective weight of the different
mechanisms described above in the pathophysiology of post-resuscitation shock.
Nevertheless, all are closely interplayed and result in a vicious circle that self-perpetuates it
(Fig. 1).

Fig. 1. Vicious circle perpetuating post-resuscitation shock

Management of post-resuscitation shock
Symptomatic treatments

1-Early-goal directed therapy: Similarities between septic and post-resuscitation shock

led some authors to advocate for post-resuscitation shock an early-goal directed therapy
strategy including hemodynamic resuscitation and therapeutic hypothermia. The
hemodynamic resuscitation that is proposed is based on an aggressive step-by-step strategy
including fluids, vasopressors, inotropes and blood transfusion, in order to target predefined
MAP level and to normalize the central venous oxygen saturation, used as a surrogate of
oxygen delivery within the first hours of therapy. Preliminary results from an exploratory
study including 20 patients without systematic assessment of cardiac function suggested that
this early-goal directed therapy did not improve mortality after comparison with matched
historic controls. A recent multicentre and randomized study confirmed that such an early-
goal directed therapy strategy was neither shown to improve mortality nor to limit the extent
of anoxic brain damage or neurological outcome despite an improvement in cerebral
oxygenation. Nevertheless, it might be reasonable to use such a strategy in post-resuscitation
shock in order to maintain an adequate organ perfusion (Fig. 2).

Fig. 2. Proposal for management of post-resuscitation shock. ECLS extracorporeal life support
2-Vasopressors and inotropic drugs: Besides fluid administration, the hemodynamic
management of post-resuscitation shock is mostly based on vasopressors because of the
severe vasoplegia and vasodilation, in combination with inotropes when post-resuscitation
myocardial dysfunction is present (Fig. 2).

Norepinephrine should be considered as the first-line vasopressor, in order to avoid

arrhythmogenic effects of other catecholamines. Regarding inotropes, dobutamine is the
most established treatment in this situation. These two animal studies showed that
dobutamine successfully overcome the global systolic and diastolic left ventricular
dysfunction resulting from prolonged CA. In addition, the most effective dose would be
5 µg/kg/min: a lower dose would be inefficient and a higher dose would increase in a too large
extent the myocardial oxygen consumption. Importantly, this threshold value of 5 µg/kg/min
could not necessarily be transposed in humans and the potential detrimental effects of higher
dose of dobutamine deserve further studies.

Levosimandan could also be an interesting alternative to dobutamine in this setting, as

suggested by an animal study, as well as phosphodiesterase inhibitor such as milrinone.
Nevertheless, nothing was done in this field since nearly one decade and both treatments still
require further clinical validation and are not recommended for the management of post-
resuscitation shock so far.
Management of shock after return of sustained circulation

3-Target for mean arterial pressure level: Because arterial hypotension is

associated with poor neurological outcomes in patients after CA and because the
autoregulation of cerebral blood flow may be impaired after ROSC, the MAP level is an
important therapeutic goal in patients with post-resuscitation shock. In this regard, several
observational studies have suggested that maintenance of higher MAP levels was associated
with a better brain tissue oxygenation an improvement in survival and a better neurological
outcome. In a recent multicenter and randomized study (COMACARE study), it has been
shown in 120 comatose patients after OHCA that, targeting a low-normal (65–75 mmHg) or a
high-normal (80–100 mmHg) MAP level for the first 36 h after ICU admission neither affect
the neuron-specific enolase (NSE) serum level nor mortality or neurological outcomes .
However, targeting a high-normal MAP level was recently shown to decrease troponin release
as a marker of myocardial injury. Thus, although it is currently recommended that
hemodynamic treatments should be guided by arterial pressure, the optimal MAP level still
remains unknown and may probably vary according to patients.

4-Ventilatory management: A vast majority of post-CA patients are mechanically

ventilated, according to current guidelines. Regarding protective lung ventilation strategies,
it has been shown in a retrospective study that lower tidal volumes (≤ 6 mL/kg) were
independently associated with favorable neurocognitive outcome, more ventilator-free days
and more shock-free days. Regarding the positive end-expiratory pressure (PEEP) level, a
secondary analysis of three international prospective, observational and multicenter studies
including 812 patients mechanically ventilated after CA, showed that the PEEP level increased
from 3.5 ± 3 to 6.5 ± 3 cmH2O between 1998 and 2010 and that lower PEEP levels were
independently associated with the occurrence of ICU-acquired pneumonia. Thus, although no
study has specifically investigated this issue, a PEEP level between 4 and 8 cmH20 or higher
in patients with acute respiratory distress syndrome, seems to be rationale. To summarize, it
seems to be reasonable to consider protective lung ventilation in such patients who are
exposed to a marked inflammatory response.

Hypoxemia and hypercapnia should be strictly controlled, since both may contribute to
secondary brain injury, even in patients receiving ECLS. However, the role of oxygenation
remains still debated: the results of an exploratory post-hoc substudy of the Target
Temperature Management (TTM) trial suggested that hyperoxemia and hypoxemia were not
associated with poor neurological outcome and increase in biomarker of brain injury, whereas
some retrospective and/or meta-analysis of experimental and clinical studies found that
hyperoxia could be linked to poor neurological outcome through oxidative stress and
potential direct pulmonary and cardiovascular toxicity of oxygen. Finally, preliminary
experimental and human studies might suggest a potential interest of hyperbaric oxygenation
as a curative treatment of reperfusion injury, with a decrease in neuronal death and an
improvement of neurological outcomes or cognitive functions after CA not related to carbon
monoxide poisoning or gas embolism. In the multicenter and randomized COMACARE study,
targeting a low-normal or a normal-high range in partial pressure of arterial carbon dioxide
(PaCO2) and oxygen (PaO2) during the first 36 h after ICU admission did not affect NSE serum
level. However, high-normal PaCO2 (5.8–6.0 kPa) and moderate hyperoxia (PaO2: 20–25 kPa)
resulted in better cerebral oxygenation. Another large multicenter and randomized trial
comparing normocapnia and mild hypercapnia in patients after OHCA is still ongoing. At that
time, current guidelines recommend to target normoxia and normocapnia during the first
72 h.

5-Targeted temperature management: Targeted temperature management

(TTM) is currently recommended in patients after OHCA with initial shockable rhythm who
remain comatose after ROSC and is suggested in patients after OHCA with non-shockable
rhythm or after in-hospital CA with any initial rhythm who remain comatose after ROSC, for
at least 24 h. TTM should be started immediately at ICU admission. However, the optimal
target temperature, the optimal duration of TTM as well as the cooling procedures are still
matter of debate. Beyond neuroprotective effects, TTM might also have cardioprotective
effects, especially in patients experiencing post-resuscitation myocardial dysfunction.
Currently, there is no sufficient data to contraindicate TTM in patients with post-resuscitation
shock. However, when TTM is used, there are some arguments that suggest avoiding lowest
temperature targets. In a sub-study of the TTM trial, TTM at 33 °C was associated with more
frequent hemodynamic alterations (decreased heart rate, elevated levels of lactate, and need
for increased vasopressor support) compared with TTM at 36 °C.

6-Steroids: The use of steroids in patients with post-resuscitation shock is still debated
despite the evidence for the hormonal dysfunction. Although beneficial effects of
glucocorticoids administration during cardiopulmonary resuscitation have been suggested by
retrospective or pilot studies , only a few studies have focused on the impact of
corticosteroids administration in successfully resuscitated patients. In a randomized
controlled trial by Mentzelopoulos and colleagues comparing a strategy combining
vasopressin, methylprednisolone and epinephrine versus epinephrine alone, patients who
were successfully resuscitated received either a stress-dose of hydrocortisone (300 mg daily
for 7 days) or saline. Interestingly, the administration of hydrocortisone (at least one dose)
improved survival to hospital discharge with favorable neurological status, suggesting a
potential benefit of steroids. Nevertheless, because multiple interventions were
concomitantly used, it is difficult to affirm the effect of hydrocortisone itself on outcome.

7-Specific treatments

A-Coronary reperfusion: There is a large consensus for considering acute coronary

disease as a frequent cause of CA in adult patients. By analogy with the management of other
acute coronary syndromes, the most common strategy is to perform a coronary angiogram
(CAG) as soon as possible, since many observational studies reported a significant association
between early percutaneous coronary intervention and improved outcome after OHCA.
Current guidelines argue for a large use of early CAG in these patients. Once the interest of
percutaneous coronary intervention in CA of ischemic cause is universally acknowledged,
there are several unsolved issues. Among these issues, selection of the best candidates and
optimal timing for CAG are the most debated. Regarding the indication, the decision for early
CAG should be based on a panel of arguments encompassing previous medical history,
warning symptoms before arrest, initial cardiac rhythm, electrocardiographic pattern after
ROSC, and biomarkers if available. In addition, recent retrospective data highlight the interest
of focusing coronary interventions for patients with preserved neurological status.

Regarding the timing, there is a consensus for early CAG (i.e., as soon as possible after hospital
arrival) in ST-elevation myocardial infarction (STEMI) patients with preserved neurological
prognosis, since this “scoop and run” strategy offers the benefit of both immediate diagnosis
and treatment and may avoid secondary cardio-circulatory deterioration related to untreated
coronary occlusion. By contrast, a “wait and see” strategy (delayed CAG) may be proposed in
patients without evidence of STEMI. Thus, Lemkes and colleagues showed in a multicenter
and randomized controlled trial that the survival of patients who had CA without signs of
STEMI was similar regardless the timing of CAG. In addition, a delayed strategy avoided a
significant number of useless CAG. These two strategies (early versus delayed CAG in non-
STEMI patients) are currently evaluated in several ongoing studies which should be helpful
for establishing future guidelines.

B-Extracorporeal life support: Mechanical circulatory support can be necessary in

the most severe forms of post-resuscitation shock, when the neurological prognosis is
assumed to be favourable. Several technics have been proposed, such as Impella, or intra-
aortic balloon pump. However, the post-resuscitation myocardial dysfunction can be very
severe and global with unpredictable severity, up to refractory cardiogenic shock. For these
reasons, veno-arterial extra-corporeal membrane oxygenation is the most commonly
employed ECLS technic in the post-resuscitation shock. The main issue is to identify the most
suitable patients with post-resuscitation shock eligible for ECLS. Bascom and colleagues have
proposed to use the “CREST score” (Table 1) for early identification of patients carrying the
highest risk of circulatory-related death after CA, who could, therefore, be elective candidates
for ECLS. It has also been shown that in patients with post-resuscitation shock treated by ECLS,
admission SOFA score < 14, initial shockable rhythm and international normalized ratio < 2.4
as well as initial arterial pH (odds ratio = 1.7 per 0.1 increase) and implantation of ECLS later
than 24 h after ROSC were associated with survival and thus could be useful triage tools in
such patients . Interestingly, 25–28% of these ECLS patients survived to hospital discharge
with favourable neurological and long-term outcome, supporting the use of ECLS in carefully
selected patients with post-resuscitation shock.
Table 1. Summarize of the different scores that can be used to select eligible patients with post-
resuscitation shock to extracorporeal life support
Scores Points
Assessment of risk of circulatory-related death
CREST score
History of coronary artery disease 1
Non-shockable rhythm 1
LVEF at time of admission < 30% 1
Shock at presentation 1
Ischemic time > 25 min 1
Assessment of neurological prognosis
CAHP score
Age 1.1 × (age − 10)
Setting 0 if public setting and 24 if
home
Initial Rhythm 0 if shockable and 27 if non-
shockable
Collapse-BLS duration (min) 2.8 × duration
BLS-ROSC duration (min) 0.8 × duration
pH 585–77 × pH
Epinephrine dose during ressuscitation (total) 0 if 0 mg and 27 if 1 or 2 mg
 OHCA score
Ventricular fibrillation or tachycardia − 13 if the initial recorded
rhythm is VF or ventricular
No-flow interval (min)
tachycardia
Low-flow interval (min)
Serum creatinine (µmol/L) + 6 × ln (no-flow interval)
Lactate (mmol/L)
+ 9 × ln (low-flow interval)

− 1434/serum creatinine

+ 10 × ln (arterial lactate)
CAST score
0 1 2 3
Initial rhythm Shockable Non-shockable – –
Witness/ROSC time (min) < 20 min ≥ 20 min No –
witness
pH ≥ 7.31 7.16–7.30 7.01– ≤ 7.00
7.15
Lactate (mmol/L) ≤ 5.0 5.1–10.0 10.1– ≥ 14.1
14.0
Motor component of Glasgow coma scale ≥2 1 – –
Gray matter attenuation to white matter ≥ 1.201 1.151–1.200 ≤ 1.150 –
attenuation ratio
Albumin (g/dL) ≥ 3.6 3.1–3.5 ≤ 3.0 –
Hemoglobin (g/dL) ≥ 13.1 11.1–13.0 ≤ 11.0
For the CREST score, ischemic time was defined as estimated time from cardiac arrest to return of spontaneous circulation
LVEF left ventricular ejection fraction, BLS basic life support, Ln natural logarithm, ROSC return of spontaneous circulation
Beyond hemodynamic severity, the neurological prognosis should be also considered before the decision of
ECLS in patients with post-resuscitation shock. Several scores have been proposed to assess neurological
prognosis after OHCA and could be useful to guide the therapeutic strategy in patients experiencing CA.

Favorable factors for VA-ECMO for refractory cardiac arrest CA

Initial shockable rhythm

Duration of CPR before ECPR <66 min

Arterial pH ≥ 7.03 on arrival

Serum lactate ≤11.81 mmol/L on arrival

Age <70 years

Received bystander CPR

PaO₂ ≥134 mmHg on arrival

PaCO₂ ≤58.5 mmHg on arrival

Sustained VF or pVT before ECPR

List of complications related to ECPR

Complications Description Management/Preventive Frequency Outcomes
Measures
Hypoxic- · Result of global · Early reversal of hypoxia · 23% · No data
ischemic brain cerebral ischemia and ischemia reported
injury caused by reduced · Targeted temperature
cerebral blood flow management
· Occurs prior to · Neurological monitoring
cannulation · Management of
neurologic sequelae such as
seizures and cerebral
edema
Ischemic · Commonly occurs · Adequate systemic · 6% · 76%
stroke from anticoagulation mortality(5)
thromboembolism · Routine surveillance of
· Usually occurs later ECMO circuit and
during ECMO course intracardiac thrombus(
· Risk factors: renal
replacement
therapy, ECMO
circuit mechanical
failure
Intracranial · Usually occurs · Temporary suspension of · 4% · 90%
hemorrhage early during the anticoagulation mortality(
ECMO course
· Risk factors: low
platelet count,
female, central
cannulation
Seizures · Often secondary to · Antiepileptic agents · 6% · No data
ICH, stroke, or HIBI · Hypnotic agents (i.e. reported
propofol)
· Close monitoring with
continuous EEG
Differential · Unique to · Increasing ECMO blood · 9% · No data
hypoxemia peripheral ECMO flow reported
· Affects coronary, · Adjusting ventilator
cerebral, upper limb settings
· Occurs in patients · Convert to V-AV ECMO by
with recovered placing an additional right IJ
native cardiac cannula
function but
persistent
pulmonary
insufficiency
Pulmonary · Risk due to the · Prevention of DVT · 30% after · No data
embolism formation of · Consider routine screening decannulation reported
thrombus on the with Doppler ultrasound
venous cannula and after decannulation
DVT · Consider therapeutic
· Risk persists after anticoagulation for 90 days
decannulation
Pulmonary · Occurs due to poor · Decrease LV pressures · 20-30%( · 2.5-fold
congestion LV ejection and using inotropes and/or increase
increased LV unloading devices mortality
diastolic pressure
Pulmonary · Occurs due to · Increase ECMO blood flow · No data · No data
malperfusion decreased to maintain partial reported reported
transpulmonary pulmonary perfusion
blood flow · Convert to V-AV ECMO
· Can lead to lung
ischemia
Access site · Includes posterior · Can be managed · 20% · Discharge
complications vessel wall conservatively while some rate of 18%
perforation, may require open or with
dissection, endovascular repair vascular
pseudoaneurysm, · Avoid excess vessel complication
and thrombosis dilatation and manipulation vs 49%
· Can lead to large during cannulation those
hematoma due to without
systemic
anticoagulation,
coagulopathy,
thrombocytopenia
Limb ischemia · Occurs at the · Place distal perfusion · 3-15% · Higher
ipsilateral side to cannula within 4 hours of bleeding
the return cannula ECMO cannulation rate
· Occurs due to · Monitor calf issue O2 · 3-fold
thromboembolism saturation with NIRS and/or increase in
or vessel occlusion Doppler ultrasound mortality
from the cannula · 79% in-
hospital
mortality,
92% 6-
month
mortality
Bleeding · Most common · Cautious anticoagulation · 8-70% · Associated
complication management balancing with higher
· Related to systemic hemorrhagic or thrombotic in-hospital
anticoagulation but complications mortality)
multifactorial · Can consider withholding
· Can occur in anticoagulation for 4-6
cannulation site, hours, up to 12 hours in
 brain, oropharynx, cases of significant
thorax, bleeding(2)
gastrointestinal, and
retroperitoneum
Acute renal · Contributing · CRRT can be initiated · 60% · 51.6% in-
failure factors: refractory using ECMO circuit · 46% requiring hospital
hypotension prior to · Strategies to ensure CRRT mortality)
cannulation, adequate end-organ
hemolysis resulting perfusion
in hemoglobinuria,
micro-emboli to
renal vasculature,
and renin
angiotensin
aldosterone system
dysfunction(2)
Infection · High infection risk · Avoid maintaining ECPR · 8-22% · 30%
due to emergent for longer than necessary survival
cannulation during · Use percutaneous rate(
simultaneous CPR cannulation
· Risk factors: older · Consider early extubation
age, prolonged when appropriate
duration of ECPR, · Regularly monitor for the
underlying cannula site infection
autoimmune · Obtain cultures when
disorder, higher clinically indicated
severity of illness · Enforce sterile access to
prior to cannulation, the circuit
immunocompromise · Ensure therapeutic levels
status, central of antimicrobial medication
cannulation, surgical
cannulation
HIBI (Hypoxic-Ischemic Brain Injury), ICH (Intracranial Hemorrhage), ECMO (Extracorporeal Membrane Oxygenation), IJ
(Internal Jugular), DVT (Deep Vein Thrombosis), LV (Left Ventricle), EEG (Electroencephalogram), V-AV ECMO (Veno-
Arteriovenous Extracorporeal Membrane Oxygenation), NIRS (Near-Infrared Spectroscopy), CRRT (Continuous Renal
Replacement Therapy), CPR (Cardiopulmonary Resuscitation), ECPR (Extracorporeal Cardiopulmonary Resuscitation).