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DKA & HYPERGLYCEMIC HYPEROSMOLAR STATE (HHS

)
D. Franzon, MD

Pathogenesis: Physiology
Diabetic ketoacidosis (DKA) is probably the most commonly encountered
metabolic disorder in the PICU. The incidence of DKA is 4.6-8.0 per 1000
person-years among patients with diabetes and it is a significant cause of
morbidity and mortality with a mortality rate between 4 and 10% although in
pediatrics, the mortality rate is 1-2%. 
Essential Pathophysiology of DKA:
• Absolute or relative deficiency of insulin
• Resultant excess of counter-regulatory hormones
• Increased hepatic glucose production and diminished glucose uptake by
peripheral tissues cause the hyperglycemia in DKA leading to glycosuria,
osmotic diuresis and dehydration 
Insulin
• Insulin has both stimulatory and inhibitory effects.
o Stimulatory effects (+): anabolism – glycogen storage; protein and
fat storage in muscle, liver, and adipose tissue; enhances cellular
uptake of ketone bodies.
o Inhibitory effect (-): prevent catabolism – glycogenolysis,
gluconeogenesis, proteolysis, lipolysis, and ketogenesis.
• Insulin deficiency states, such as diabetes, effect end organ metabolic
responses, which in turn increases serum glucose levels.
o Liver: uninhibited hepatic ketogenesis and gluconeogenesis and
glycogenolysis occur.
o Muscle: anabolic functions are impaired and glucose fails to enter
cells, glycogen is depleted, and catabolism takes place.
o Fat tissue: lipolysis continues while fat absorption and triglyceride
synthesis are blocked. 
Counter-Regulatory Hormones are elevated when insulin is deficient
• Glucagon stimulates beta-oxidation of fatty acids leading to the production
of ketoacids: acetoacetate, and beta-hydroxybutyrate. This ketogenesis is
a hallmark of DKA.
• Growth hormone, cortisol and catecholamines all enhance
gluconeogenesis, block glucose uptake by muscle and promote lipolysis. 
Acidosis
• Overproduction of ketoacids, beta-hydroxybutyric acid, acetoacetic acid

DKA & HHS

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intra-cellular water shifts to the extra-cellular matrix due to increased serum osmolality.  K+ • There is profound total body [K+] depletion in DKA and HHS. lead to total body [K+] depletion. inadequate oral intake. In normal circumstances. plasma [Na+] is usually low or normal in DKA – i. which may underestimate the degree of ketosis.  Dehydration • Hyperglycemia induces osmotic diuresis leading to total body water deficit often to 10-15% of body weight. but in DKA it may be as high as 15:1.+ HCO3-). this is an important pathway by which excess acid is discarded by the body. The lungs or the kidneys in turn can excrete acetone. the water loss exceeds the NaCl loss. in general are as follows: o Na+: 5-13 mmol/kg o Cl-: 3-7 mmol/kg o K+: 3-15 mmol/kg o PO4/Mg/Ca++: 1-2mmol/kg of each  NaCl • With the osmotic diuresis.6 meq/L of [Na+] for every 100mg/dL above 100mg/dL elevation in glucose. the plasma [Na+] can be increased. The kidney can re-absorb glucose with serum levels up to 180mg/dL above which glucose is wasted and water follows. • The measured [Na+] can be corrected by adding 1. Commonly used tests measure acetoacetate levels well but measure acetone poorly and don’t measure beta-hydroxybutyrate at all.• • • • • 2 ketoacids dissociated at physiologic pH ⇒ excess hydrogen ions ⇒ bind bicarbonate ⇒ decreased serum bicarbonate levels ⇒ circulating ketone bodies in anion form ⇒ lead to the anion gap acidosis of DKA Anion gap = [Na+ – (Cl. and emesis. • Electrolytes follow free water and are therefore also lost in the urine.and intra-cellular space. which are typical in DKA. Keep in mind that the measured sodium level is the “actual” [Na] in the blood and that the “corrected” Na is a theoretical calculation that is a useful guideline for hydration. the ratio of B-hydroxybutyrate / acetoacetate is 2-3:1. Urinary losses with osmotic diuresis. DKA & HHS 2 . In HHS however.e. normal anion gap = 12 Acetoacetate is converted to acetone by a spontaneous nonenzymatic process in direct proportion to its serum concentration. • Because of the osmotic shift of water in both the extra. Extreme lipemia can also decrease the measured Na value and is an artifact. • Deficits of electrolytes.

Although replacement of PO4 is of theoretical benefit and it is standard of care in most institutions. Diagnosis:  Clinical Presentation • History: polyuria. however. lean patients with type 1 diabetes. • In maintaince fluids. and proteolysis. the Na-K-ATPase pump is triggered by insulin driving [K+] into the cells. respiratory failure. • Physical exam clues that help differentiate DKA from HHS: o Acanthosis in axilla or neck area – typical in Type 2 DM o Assess thyroid – palpable thyroid maybe consistent with autoimmune mediated endocrinopathy – type I DM o Kussmaul respirations – deep respirations seen with type I DM o Acetone on breath – c/w type I DM o Body habitus—lean or large DKA & HHS 3 .3-DPG which decreases the P50 of oxyhemoglobin (shifts the oxyHb curve leftward increasing O2 affinity). and weight loss over the preceding weeks • Precipitating factor: often infections. polyphagia. obese. polydipsia. type 2 diabetes patients and symptoms may develop more slowly. Initially.) Once insulin therapy is initiated. Etiologies for this [K+] shift include hyperglycemia / low insulin levels. acidosis. K+ PO4++ rather than K+ Cl. vomiting and altered sensorium • Physical exam: lethargy. arrhythmias. studies have shown no clear benefit. • HHS is more likely in older. therefore repletion should be initiated early in treatment.  PO4/Mg/Ca++ • Profound hypophosphatemia often occurs in DKA resulting in depressed levels of erythrocyte 2. or severe acidosis  Differentiating DKA and HHS • DKA typically develops in younger. acidosis counterbalances this by increasing the P50.can be used to avoid the hyperchloremic acidosis sometimes seen during therapy. altered level of consciousness.• • At the time of presentation. hypokalemia is unmasked. • PO4++ replacement can result in decreased levels of Mg/Ca++. but often unidentifiable • Presenting signs: abdominal pain. dehydration. therefore these levels must also be closely monitored. hyperpnea and acetone (“bitter almonds”) detected on their breath and often acutely ill • PICU admission: patients with profound shock. plasma [K+] is normal or elevated because of the shift that occurs from intracellular to extracellular space. (Recall that one of the treatments for hyperkalemia is glucose / insulin.

borderline or low BP). C-peptide • • • • • • • Hemoglobin A-1C T4.  3 components to fluid management in DKA: • Deficit DKA & HHS 4 . Begin with 10-20ml/kg bolus of isotonic crystalloid (NS) and repeat if shock persists (i. • Initial fluid therapy should be aimed at resuscitation and reversal of shock. poor perfusion. Laboratory Findings DKA: • Serum glucose >300 mg/dl • Blood pH < 7.CXR and EKG Head CT if comatose Management of DKA in the PICU  Fluids • DKA patients usually present with severe dehydration of 10-15% deficit. urine culture +/. HHS: • • • • • • Hyperglycemia is more severe Blood pH may be > 7. i. TSH Anti-Islet cell Ab. • For patients in DKA.8] +[2(Na + K)]  Other laboratory values that can be abnormal in DKA patients but may not represent significant comorbid disease are as follows: • Elevated WBC: usually due to stress & dehydration • Elevated amylase: usually nonpancreatic source. parotid. lipase must be checked since pancreatitis is associated with HHS • Prolonged PT. There is concern of rapid hydration inciting cerebral edema and no clear data exists to date supporting or refuting this theory.Blood. anti-insulin Ab (for new onset) U/A +/.30 Absent/trace ketones in urine [HCO3-] may not be low Serum osmolality >320 mmol/kg Osm = [glu/18] +[BUN/2.e. PTT: etiology unclear  Admission labs / studies for DKA patient: • Comprehensive chemistry panel • ABG / VBG • CBC w/diff • Serum osmoles • Urine ketones • Serum beta-hydroxybutyrate • Serum lactate • Insulin.3 • Ketonuria. tachycardia. fluids must be administered to correct shock but over aggressive rapid hydration should be avoided. glucosuria • [HCO3-] < 15 mEq/L • Elevated betahydroxybutyrate in blood.e.

0 mEq/L) and in the presence of adequate renal function.– as discussed previously). start D10 NS • 2 bag system: one bag containing D5 fluids and a second bag with NS along with each bag having 20 meq K+Cl. emesis) o Some patients will continue to have a significant ongoing osmotic diuresis throughout the early part of therapy.5%. These losses should be accounted for and replaced to prevent persistent shock.e. the replacement can be stopped. D5 NS o Blood sugar < 200mg/dL. She receives 30ml/kg of NS in the ED – 600ml. 200 cc of NS x2hrs)  Adding Dextrose • Change IVF when o Blood sugar < 300mg/dL.+ 20 meq K+PO4. Once the urine output has normalized.and half as K+PO4.9%NaCl (NS). DKA & HHS 5 . o On going losses: Suppose the same 20kg child is voiding 200 ml/hr. o For example: if the blood glucose is 230mg/dL with IVF at 160 ml/hr. Typically isotonic fluids (NS) are preferable in order to keep the serum Na+ from dropping during rehydration and to help prevent cerebral edema. o Maintaince: = 60 ml/hr (per the 4/2/1 rule) Total hourly fluid rate = deficit + maint + ongoing losses = 100ml/hr + 60ml/hr + urine replacement (i. o In the absence of hyperkalemia (K+ <5. Na+ > 155) the maintenance fluids can be changed to 1/2 or 3/4NS. start D5%NS bag at 80 ml/hr and decrease NS bag to 80 ml/hr = total fluids 160 ml/hr at D2. 40 mEq/L of K+ can be added to the fluids (generally half as K+Cl. if with therapy the corrected serum Na+ is becoming quite high (i. <5cc/kg/hr. Either NS or ½NS can be used for replacement depending on the corrected serum Na. the losses can be replaced with either intermittent fluid blouses or with a urine output replacement – cc per cc or ½cc per cc every 24hrs.are titrated to maintain a blood glucose of 150-250 mg/dL. Example of a 20kg child: o Deficit: patient presents 15% dehydrated – the calculated deficit is 3 Liters. Ongoing losses (urine. However. Maintenance o Isotonic maintenance fluids are started as 0.e. The remainder of the fluid deficit should be replaced over 24 hrs: 3000 – 600 = 2400 or 100ml/hr of IVF.• • • o The fluid deficit is typically replaced over the first 24 hours once the shock state is treated.

the insulin drip may require titration to achieve the desired rate of fall of glucose and to improve the hyperosmolar state. the insulin infusion should be run through the tubing for 5-30 minutes prior to being attached to the patient to provide a consistent dose of drug delivery.1 U/kg/hr. By appropriately titrating the glucose intake. Therefore. consistent drop in glucose o Potentially. o Hypoglycemia is generally avoided with a predictable. Heplock the dextrose containing IVF only after confirming adequate oral intake without emesis in order to avoid hypoglycemia.3 o Anion gap < 12 o Improved level of consciousness (GCS 15) o Able to tolerate oral intake • Transitioning from continuous infusion to SQ insulin: order of events o Check glucose.> 18 o Blood pH > 7.• o Suppose next glucose is 180mg/dL – increase the D5% bag to 100 ml/hr and decrease the NS bag to 60 ml/hr. Patients with HHS are typically type-2 diabetics and are insulin resistant rather than deficient and therefore may require more insulin to correct the hyperosmolar state. and then stop the insulin drip. • Hyperglycemia corrects prior to the acidosis.1 U/kg and no data to support subcutaneous insulin administration for DKA. The insulin infusion is continued until the following conditions are met: o HCO3. rapid blood sugar decrease to hypoglycemic levels can be prevented. dextrose should be added to the IVF but the insulin infusion should continue at the same rate since it is the primary treatment to correct the acidosis.  Insulin therapy • A continuous infusion of regular insulin at 0. o AT this point. less hypokalemia and more inhibition of lipolysis occurs with a consistent dose of insulin • There is no established need for an initial IV bolus of 0. • *Note: Insulin attaches to IV tubing and glass. let the patient eat/drink. o If the blood glucose levels are decreasing too quickly. DKA & HHS 6 . 2-4 grams of glucose per unit of insulin is required to maintain a stable blood glucose level. • In HHS patients. This rate should produce a gradual decrease in glucose levels of about 50-100 mg/dl per hour. administer SQ dose per sliding scale. the endocrinologist can initiate recommendations regarding a regular and long acting insulin regimen. o It’s easily adjustable and safe.

(These are meant to be basic guidelines.) 1) Ensure 2 large bore IVs are present. The IV fluids can be “Y” together to achieve the desired dextrose concentration to maintain blood glucose levels between 200-300 mg/dl. Ca. the acidosis will only correct with appropriate insulin administration. 8) The insulin drip should not be titrated. Serum glucose should be monitored hourly and a chem.0 7) NaHCO3 should not be administered to DKA patients despite the severity of acidosis.-10 with Na. PO4 along with a blood gas should be done every 4 hours. 5) With ongoing therapy and rehydration the serum sodium should rise. Fatal arrhythmias can occur at values <2. The risk of mortality and CNS complication are increased by bicarbonate administration. pupillary changes. acute change in LOC) 10) Order several bags of IV fluids with and without dextrose at the time of admission to seamlessly transition the patient to dextrose containing fluids as the blood sugars decrease to 300 mg/dL. 10 key elements to managing DKA in the ICU: Attention to detail is important. 2) All patients should be placed on a cardiac monitor.e. 4) Obtain hourly neuro assessments including a GCS. Mg. 6) A K+ level less than 3. K. 9) Mannitol (0. A central venous catheter would not be a first choice due to risk of thrombosis unless the patient presents in shock. A decreasing sodium level can be a risk factor for cerebral edema. A line for lab draws should be established: a large bore PIV or an arterial line.25 gm/kg) should be at the bedside for acute cerebral edema (i. 3) A Foley to monitor urine output is critical to assess ongoing losses and to direct fluid therapy.0mEq/L should be corrected aggressively. DKA & HHS 7 .

o Once intubated. if the patient is hyperventilating to a CO2 level of 11. The length of insulin therapy is not prolonged due to hyperchloremic metabolic acidosis. DKA & HHS 8 .e.Complications  Cerebral Edema: This is the most serious complication of DKA. assure the mechanical ventilation matches the patient’s CO2 level prior to intubation. The potential etiologies include: o Vasogenic edema: leaking of fluid across the blood-brain-barrier o Cytotoxic edema: neuronal swelling due to cellular injury or rapid extracellular osmolar changes • Risk factors for cerebral edema include: o Children < 5 years of age o High BUN suggesting greater dehydration o Severity of acidosis o Bicarbonate administration o New diagnosis of diabetes o Sodium levels don’t rise as expected with insulin treatment (i. fall in serum osmolality) • Assure serum Na+ level is rising with rehydration • Hourly neuro checks should be done for 12 hours after treatment initiation. Therefore the patient’s hydration status should be closely monitored and fluids aggressively replaced. • Mannitol should be administered. use the appropriate medications to blunt a spike in the ICP.5 gm/kg IV slow push. consider hypertonic saline 3%NS in a small bolus of 3-5cc/kg. • Hypoglycemia can also present with mental status changes and must be ruled out while evaluating a patient with sudden drop in GCS. urine ketones should be followed to assure the DKA is resolving.e. if acidosis persists after the first 24 hours. Any changes in neurologic status necessitate a stat head CT. • The pathophysiology is unclear. 0. for acute mental status changes. consult neurosurgery for potential need of ICP monitoring. • If head CT reveals cerebral edema or the patient has deteriorating neurologic status.  Hyperchloremic metabolic acidosis • May occur as part of normal rehydration therapy and has no has no significant clinical consequences. • Patients with a GCS <8 necessitate intubation. match it to prevent worsening ICP elevation. Assure a foley is placed for the ensuing diuresis. • However. • If the serum Na+ is dropping with therapy. o For intubation induction. • Persistent dehydration can also present with mental status changes. i.

 Hypokalemia • Can be avoided with frequent monitoring and meticulous attention to fluid management. Saline boluses. • Hypokalemia can cause fatal arrhythmias. every effort should be made to maintain a level of 4. or calcium can amplify the decrease in potassium levels. Therefore. Thrombii have particularly been noted with femoral lines. Rapid fluid shifts during resuscitation and rehydration may lead to capillary leak and interstitial pulmonary edema and ARDS.  Hypoglycemia • Assure the IVF and insulin therapy is appropriately managed to prevent low blood sugar levels. DKA patients present in shock and may have low albumin at the time of presentation due to poor nutrition. Consider low dose heparin drip (10 U/kg/hr) to help prevent clot formation. ARDS • Occasionally. a risk of thrombosis is present with central line placement. It is a rare complication in the pediatric population. • Consider subclavian or IJ lines for patients in shock that require CVP monitoring or in whom access is difficult. DKA & HHS 9 .0 mEq/L.  Thrombosis • Because of severe dehydration and a general low flow state.