Approach to the Patient with Shock

Shock is the clinical syndrome that results from

inadequate tissue perfusion.
Irrespective of cause, the hypoperfusion-induced
imbalance between the delivery of and requirements for
oxygen and substrate leads to cellular dysfunction.
Then cellular injury created induces the production and
release of damage-associated molecular patterns (DAMPs
or "danger signals") and inflammatory mediators that
further compromise perfusion through functional and
structural changes within the microvasculature.
This leads to a vicious cycle in which impaired perfusion
is responsible for cellular injury that causes
maldistribution of blood flow, further compromising
cellular perfusion; the latter ultimately causes multiple
organ failure (MOF) and, if the process is not interrupted,
leads to death.
Shock-induced vicious cycle.

The fundamental approach to management is to recognize

overt and impending shock in a timely fashion and to
intervene emergently to restore perfusion.
Clinical shock is usually accompanied by hypotension
( (MAP <60 mmHg in previously normotensive persons).
 Classification of Shock
Hypovolemic Septic
Traumatic   Hyperdynamic (early)
Cardiogenic   Hypodynamic (late)
  Intrinsic Neurogenic
  Compressive Hypoadrenal

Pathogenesis and Organ Response

Microcirculation
Normally when CO falls, SVR rises to maintain a level of
systemic pressure that is adequate for perfusion of the
heart and brain at the expense of other tissues.
The metabolic rates of the heart and brain are high, and
their stores of energy substrate are low. These organs are
critically dependent on a continuous supply of oxygen and
nutrients, and neither tolerates severe ischemia for more
than brief periods (minutes).
Autoregulation is critical in sustaining cerebral and
coronary perfusion despite significant hypotension.
However, when MAP drops to less than 60 mmHg, blood
flow to these organs falls, and their function deteriorates.
Arteriolar vascular smooth muscle has both alpha and
beta adrenergic receptors.
Efferent sympathetic fibers release norepinephrine, which
acts primarily on receptors as one of the most
fundamental compensatory responses to reduced
perfusion pressure.
Other constrictor substances that are increased in most
forms of shock include angiotensin II, vasopressin,
endothelin 1, and thromboxane A2.
Circulating vasodilators in shock include PG I2, nitric
oxide (NO), and, importantly, products of local
metabolism such as adenosine that match flow to the
tissue's metabolic needs.
The balance between these various vasoconstrictors
and vasodilators influences acting upon the
microcirculation determines local perfusion.
Impairment of the microcirculation in the late stages of all
forms of shock, results in the derangement of cellular
metabolism that is ultimately responsible for organ
failure.
The endogenous response to mild or moderate
hypovolemia is an attempt at restitution of intravascular
volume through alterations in hydrostatic pressure and
osmolarity.
When filtration is reduced while intravascular oncotic
pressure remains constant or rises, there is net
reabsorption of fluid into the vascular bed.
Metabolic changes raise extracellular osmolarity, leading
to an osmotic gradient that increases interstitial and
intravascular volume at the expense of intracellular
volume.

Cellular Responses
Interstitial transport of nutrients is impaired leading to a
decline in intracellular high-energy phosphate stores.
Mitochondrial dysfunction is the most likely causes for
decreased amounts of ATP.
As a consequence, there is an accumulation of hydrogen
ions, lactate, and other products of anaerobic metabolism.
As shock progresses, these vasodilator metabolites
override vasomotor tone, causing further hypotension and
hypoperfusion.
Dysfunction of cell membranes is associated increase in
intracellular sodium and water, leading to cell swelling.
Neuroendocrine Response
Hypovolemia, hypotension, and hypoxia are sensed by
baroreceptors and chemoreceptors that contribute to an
autonomic response that attempts to restore blood volume,
maintain central perfusion, and mobilize metabolic
substrates.
Hypotension disinhibits the vasomotor center, resulting in
increased adrenergic output and reduced vagal activity.
–result in maintenance of central organ perfusion and
increases the heart rate and cardiac output.
The effects of circulating epinephrine largely causing
increased glycogenolysis and gluconeogenesis and
reduced pancreatic insulin release.
Severe pain or other stresses contributes to decreased
peripheral uptake of glucose and amino acids, enhances
lipolysis, and increases gluconeogenesis.
Increased pancreatic secretion of glucagon during stress
accelerates hepatic gluconeogenesis and further elevates
blood glucose concentration.
Renin induces the formation angiotensin II, an extremely
potent vasoconstrictor and stimulator of aldosterone
release.
Aldosterone contributes to the maintenance of
intravascular volume by enhancing renal tubular
reabsorption of sodium, resulting in the excretion of a
low-volume, concentrated, sodium-free urine.
Cardiovascular Response
Ventricular filling (preload), the resistance to ventricular
ejection (afterload), and myocardial contractility—are
paramount in controlling stroke volume.
Hypovolemia leads to decreased ventricular preload that
in turn reduces the stroke volume.
Restoration of intravascular volume may return stroke
volume to normal but only at elevated filling pressures.
In addition, sepsis, ischemia, myocardial infarction (MI),
severe tissue trauma, hypothermia, general anesthesia,
prolonged hypotension, and acidemia may all also impair
myocardial contractility and reduce the stroke volume at
any given ventricular end-diastolic volume.

The resistance to ventricular ejection is significantly

influenced by the systemic vascular resistance, which is
elevated in most forms of shock.
However, resistance is depressed in the early
hyperdynamic stage of septic shock or neurogenic shock,
thereby initially allowing the cardiac output to be
maintained or elevated.
Venous dilation, as occurs in neurogenic shock, reduces
ventricular filling and hence stroke volume and
potentially cardiac output.
Pulmonary Response
Shock-induced tachypnea reduces tidal volume and
increases both dead space and minute ventilation.
Relative hypoxia and the subsequent tachypnea induce a
respiratory alkalosis.
Reduce functional residual capacity and may lead to
atelectasis.
Shock and, in particular, resuscitation-induced oxidant
radical generation, is recognized as a major cause of acute
lung injury and subsequent acute respiratory distress
syndrome.
Noncardiogenic pulmonary edema secondary to diffuse
pulmonary capillary endothelial and alveolar epithelial
injury, hypoxemia, and bilateral diffuse pulmonary
infiltrates.

Renal Response
Acute kidney injury, a serious complication of shock and
hypoperfusion.
Acute tubular necrosis is result of the interactions of
shock, sepsis, the administration of nephrotoxic agents,
and rhabdomyolysis.
The physiologic response of the kidney to hypoperfusion
is to conserve salt and water.
Metabolic Derangements
Disruption of the normal cycles of carbohydrate, lipid,
and protein metabolism.
With reduced availability of oxygen, the breakdown of
glucose to pyruvate, and ultimately lactate, represents an
inefficient cycling of substrate with minimal net energy
production.
Significant rise in serum triglyceride concentrations.
Inflammatory Responses
Plays a significant role in the progression of shock and
contributes importantly to the development of MOD, and
MOF.
Adaptive immunity is suppressed and the patient is highly
susceptible to secondary nosocomial infections.
Direct complement fixation to injured tissues can progress
to the C5-C9 attack complex, causing further cell damage.
Activation of the coagulation cascade causes
microvascular thrombosis, with subsequent fibrinolysis
leading to repeated episodes of ischemia and reperfusion.
Tumor necrosis factor produced by activated
macrophages, reproduces many components of the shock
state, including hypotension, lactic acidosis, and
respiratory failure.
Interleukin 1 "endogenous pyrogen" and produced by
tissue-fixed macrophages, is critical to the inflammatory
response.
Multiple inflammatory cells, including neutrophils,
macrophages, and platelets, are major contributors to
inflammation-induced injury.
Release of high levels of reactive oxygen
intermediates/species (ROI/ROS) rapidly consumes
endogenous essential antioxidants and generates diffuse
oxygen radical damage.
Treatment
Monitoring
BP, pulse, and respiratory rate should be monitored
continuously; a Foley catheter should be inserted to
follow urine flow; and mental status should be assessed
frequently.

Normal Hemodynamic Parameters

Parameter Calculation Normal
Values
Cardiac output (CO) SV x HR 4–8 L/min
Cardiac index (CI) CO/BSA 2.6–4.2
(L/min)/m2
 
Stroke volume (SV) CO/HR 50–100
mL/beat
Systemic vascular [(MAP – 700–1600
resistance (SVR) RAP)/CO] x 80 dynes · s/cm5
 
Pulmonary vascular [(PAPm – 20–130 dynes ·
resistance (PVR) PCWP)/CO] x 80 s/cm5
    
Left ventricular SV(MAP – 60–80 g-m/beat
stroke work (LVSW) PCWP) x 0.0136
Right ventricular SV(PAPm – RAP) 10–15 g-m/beat
stroke work  
(RVSW)
Determinations of oxygen content in arterial and venous
blood, together with cardiac output and hemoglobin
concentration, allow calculation of oxygen delivery,
oxygen consumption, and oxygen-extraction ratio.
Oxygen-carrying capacity of hemoglobin   1.39 mL/g
In resuscitation from shock, it is critical to restore tissue
perfusion and optimize oxygen delivery, hemodynamics,
and cardiac function rapidly.
A reduction in systemic vascular resistance accompanying
an increase in cardiac output indicates that compensatory
vasoconstriction is reversing due to improved tissue
perfusion.
An algorithm for the resuscitation of the patient in
shock.
Specific Forms of Shock
Hypovolemic Shock
Results either from the loss of red blood cell mass and
plasma from hemorrhage or from the loss of plasma
volume alone due to extravascular fluid sequestration or
GI, urinary, and insensible losses.
The normal physiologic response to hypovolemia is to
maintain perfusion of the brain and heart while attempting
to restore an effective circulating blood volume.
Mild hypovolemia (20% of the blood volume)
-mild tachycardia but relatively few external signs,
especially in a supine young patient.
Moderate hypovolemia (20–40% of the blood volume),
anxious and tachycardic; there may be significant postural
hypotension and tachycardia.
Hypovolemia is severe (40% of the blood volume), the
classic signs of shock appear; the blood pressure declines
and becomes unstable even in the supine position, and the
patient develops marked tachycardia, oliguria, and
agitation or confusion.
Hence, mental obtundation is an ominous clinical sign.
Hypovolemic Shock
Mild Moderate (20– Severe (>40%BV)
(<20%BV) 40%BV)
Coo extremities Same, plus: Same, plus:
Increased     Tachycardia     Hemodynamic
capillary refill instability
time     Tachypnea
    Marked
Diaphoresis     Oliguria tachycardia
Collapsed veins     Postural     Hypotension
changes
Anxiety     Mental status
deterioration (coma)
Diagnosis
Signs of hemodynamic instability and the source of
volume loss is obvious.
The diagnosis is more difficult when the source of blood
loss is occult.
Even after acute hemorrhage, hemoglobin and hematocrit
values do not change until compensatory fluid shifts have
occurred or exogenous fluid is administered.
Plasma losses cause hemoconcentration, and free water
loss leads to hypernatremia.
It is essential to distinguish between hypovolemic and
cardiogenic shock because, definitive therapy differs
significantly.
The findings in cardiogenic shock of jugular venous
distention, rales, and an S3 gallop.

Treatment
Initial resuscitation requires rapid reexpansion of the
circulating intravascular blood volume.
Volume resuscitation is initiated with the rapid infusion of
either isotonic saline or a balanced salt solution such as
Ringer's lactate.
The infusion of 2–3 L of salt solution over 20–30 min
should restore normal hemodynamic parameters.
Continuing acute blood loss, with hemoglobin
concentrations declining to less than 10 g/dL, should
initiate blood transfusion.
Supplemental oxygen should always be provided, and
endotracheal intubation may be necessary to maintain
arterial oxygenation.
Cardiogenic Shock
Cardiogenic shock and pulmonary edema are life-
threatening conditions that should be treated as medical
emergencies.
The most common etiology for both is severe left
ventricular (LV) dysfunction that leads to pulmonary
congestion and/or systemic hypoperfusion.
Pathophysiology of cardiogenic shock.

Cardiogenic Shock
-characterized by systemic hypoperfusion due to severe
depression of the cardiac index [<2.2 (L/min)/m2] and
sustained systolic arterial hypotension (<90 mmHg)
despite an elevated filling pressure [PCWP >18 mmHg].
It is associated with in-hospital mortality rates >50%.
The major causes are acute myocardial infarction
(MI) and less frequently by cardiomyopathy or
myocarditis, cardiac tamponade, or critical valvular heart
disease.
Incidence
CS is the leading cause of death of patients hospitalized
with MI.
Early reperfusion therapy for acute MI decreases the
incidence of CS.
Shock typically is associated with ST elevation MI
(STEMI) and is less common with non-ST elevation MI.
LV failure accounts for ~80% of cases of CS
complicating acute MI.
Acute severe MR, VSR, predominant RV failure, and free
wall rupture or tamponade account for the remainder.

Pathophysiology
-characterized by a vicious circle in which depression of
myocardial contractility, usually due to ischemia, results
in reduced cardiac output and arterial pressure (BP),
which result in hypoperfusion of the myocardium and
further ischemia and depression of cardiac output.
Reduced coronary perfusion leads to worsening ischemia
and progressive myocardial dysfunction and a rapid
downward spiral, which, if uninterrupted, is often fatal.
Lactic acidosis from poor tissue perfusion and hypoxemia
from pulmonary edema may result from pump failure and
then contribute to the vicious circle by worsening
myocardial ischemia and hypotension.
Patient Profile
In patients with acute MI, older age, female sex, prior MI,
diabetes, and anterior MI location are all associated with
an increased risk of CS.
Reinfarction soon after MI increases the risk of CS.
Timing
On admission in only one-quarter of patients develop CS
complicating MI; one-quarter develop within 6 h of MI
onset.
Another quarter develop shock later on the first day.

Diagnosis
A focused history and physical examination should be
performed, blood specimens sent to the laboratory, and an
ECG and chest x-ray.
Clinical Findings
Continuing chest pain and dyspnea and appear pale,
apprehensive, and diaphoretic.
Mentation may be altered, with somnolence, confusion,
and agitation.
The pulse is typically weak and rapid(90–110 )beats/min,
or severe bradycardia due to high-grade heart block may
be present.
SBP is reduced (<90 mmHg) with a narrow pulse pressure
(<30 mmHg.
Tachypnea, Cheyne-Stokes respirations, and jugular
venous distention may be present.
The precordium is typically quiet, with a weak apical
pulse.
Systolic murmurs .
Rales are audible in most patients with LV failure.
Oliguria (urine output <30 mL/h) is common.

Laboratory Findings
WBC count is typically elevated with a left shift.
Blood urea nitrogen and creatinine rise progressively.
Hepatic transaminases may be markedly elevated due to
liver hypoperfusion.
Poor tissue perfusion may result in an anion-gap acidosis
and elevation of the lactic acid level.
Cardiac markers are markedly elevated.
Electrocardiogram
Q waves and/or >2-mm ST elevation.
Chest Roentgenogram
Pulmonary vascular congestion and often pulmonary
edema.
The heart is enlarged when it occurs in a patient with a
previous MI.
Echocardiogram
Pulmonary Artery Catheterization
Treatment: Acute Myocardial Infarction
Maintaining adequate systemic and coronary perfusion by
raising systemic BP with vasopressors.
Hypoxemia and acidosis must be corrected.
Negative inotropic agents should be discontinued.
Hyperglycemia should be controlled with insulin.
Recurrent ventricular tachycardia or rapid atrial
fibrillation may require immediate treatment.

Vasopressors
Norepinephrine should be started at a dose of 2 to 4
microg/min and titrated upward as necessary.
Max dose of 15 microg/min, it is unlikely that a further
increase will be beneficial.
Dopamine; at low doses ( 2 microg/kg per min), it dilates
the renal vascular bed, at moderate doses (2–10 microg/kg
per min), it has positive chronotropic and inotropic effects
as a consequence of beta adrenergic receptor stimulation.
At higher doses, a vasoconstrictor effect results from
alpha receptor stimulation.
It is started at an infusion rate of 2–5 microg/kg per min,
and the dose is increased every 2–5 min to a maximum of
20–50 microg/kg per min.
Reperfusion-Revascularization
Early revascularization with PCI or coronary artery
bypass graft (CABG).
Pulmonary Edema
Diagnosis
Acute pulmonary edema usually presents with the rapid
onset of dyspnea at rest, tachypnea, tachycardia, and
severe hypoxemia.
Rales and wheezing due to airway compression.
Hypertension is usually present due to release of
endogenous catecholamines.

Pulmonary edema associated with electrocardiographic

ST elevation and evolving Q waves is usually diagnostic
of acute MI.
Brain natriuretic peptide levels, when substantially
elevated, support heart failure as the etiology of acute
dyspnea with pulmonary edema.
Pulmonary artery catheterization is indicated when the
etiology of the pulmonary edema is uncertain, when it is
refractory to therapy, or when it is accompanied by
hypotension.
Treatment
Depends on the specific etiology.
In addition, conditions that frequently complicate
pulmonary edema, such as infection, acidemia, anemia,
and renal failure, must be corrected.
Support of Oxygenation and Ventilation
Cardiogenic pulmonary edema can be rapidly treated,
with improvement in gas exchange.
Oxygen Therapy
Positive-Pressure Ventilation
Pulmonary edema increases the work of breathing and the
O2 requirements of this work.
Mechanical ventilation with positive end-expiratory
pressure can have multiple beneficial effects on
pulmonary edema:

(1) decreases both preload and afterload

(2) redistributes lung water from the intraalveolar and
(3) increases lung volume to avoid atelectasis.
Diuretics
Furosemide are effective in most forms of pulmonary
edema, even in the presence of hypoalbuminemia,
hyponatremia, or hypochloremia.
The initial dose of furosemide should be 0.5 mg/kg, but a
higher dose (1 mg/kg) is required in patients with renal
insufficiency, chronic diuretic use, or hypervolemia or
after failure of a lower dose.
Nitrates
Sublingual nitroglycerin (0.4 mg x 3 every 5 min) is first-
line therapy for acute cardiogenic pulmonary edema.
If pulmonary edema persists in the absence of
hypotension, sublingual may be followed by IV
nitroglycerin, commencing at 5–10micro g/min.
Morphine
Given in 2- to 4-mg IV boluses, morphine is a transient
venodilator that reduces preload while relieving dyspnea
and anxiety.
Angiotensin-Converting Enzyme (ACE) Inhibitors
Reduce both afterload and preload and are recommended
for hypertensive patients.

Physical Methods
Reduction of venous return reduces preload.
Digitalis Glycosides
May be useful for control of ventricular rate in patients
with rapid atrial fibrillation or flutter and LV dysfunction
The emergency management of patients with
cardiogenic shock, acute pulmonary edema.
Severe Sepsis and Septic Shock: Introduction
Definitions
Fever or hypothermia, leukocytosis or leukopenia,
tachypnea, and tachycardia are the cardinal signs of the
systemic response, that is often called the SIRS.
SIRS may have an infectious or a noninfectious etiology.
If infection is suspected or proven, a patient with SIRS is
said to have sepsis.
When sepsis is associated with dysfunction of organs
distant from the site of infection, the patient has severe
sepsis.
When hypotension cannot be corrected by infusing fluids,
the diagnosis is septic shock.

Definitions Used to Describe the Condition of Septic Patients

Bacteremia Presence of bacteria in blood, as evidenced by positive blood cultures
Septicemia Presence of microbes or their toxins in blood
Systemic Two or more of the following conditions:
inflammatory (1) fever (oral temperature >38°C) or hypothermia (<36°C);
response syndrome (2) tachypnea (>24 breaths/min);
(SIRS) (3) tachycardia (heart rate >90 beats/min);
(4) leukocytosis (>12,000/microL), leucopenia (<4,000/microL), or >10% bands
Sepsis SIRS that has a proven or suspected microbial etiology
Severe sepsis Sepsis with one or more signs of organ dysfunction—for example:
(similar to "sepsis
syndrome")
  1. Cardiovascular:
Arterial SP  less than 90 mmHg or mean arterial pressure less than 70 mmHg that responds
to administration of intravenous fluid
  2. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate fluid resuscitation 
  4. Hematologic:
Platelet count <80,000/microL or 50% decrease in platelet count from highest value
recorded over previous 3 days 
  5. Unexplained metabolic acidosis:
A pH less than 7.30
 
Septic shock Sepsis with hypotension (ABP <90 mmHg systolic, or 40 mmHg less than patient's normal
blood pressure) for at least 1 h despite adequate fluid resuscitation;
  or 
  Need for vasopressors to maintain systolic blood pressure greater than 90 mmHg or mean
arterial pressure greater than 70 mmHg 
Refractory septic Septic shock that lasts for >1 h and does not respond to fluid or pressor administration
shock
MODS Dysfunction of more than one organ, requiring intervention to maintain homeostasis
Etiology
In fact, blood cultures yield bacteria or fungi in only –20–
40% of cases of severe sepsis and 40–70% of cases of
septic shock.
Individual gram-negative or gram-positive bacteria
account for 70% of these isolates; the remainder are
fungi or a mixture of microorganisms.

Gram-negative bacteria
Enterobacteriaceae, pseudomonads, Haemophilus spp.,
other gram-negative bacteria.
Gram-positive bacteria
Staphylococcus aureus, coagulase-negative staphylococci,
enterococci, Streptococcus pneumoniae, other gram-
positive bacteria.
Classic pathogens
Neisseria meningitidis, S. pneumoniae, Haemophilus
influenzae, and Streptococcus pyogenes.

Epidemiology
Sepsis-related incidence and mortality rates increase with
age and preexisting comorbidity.
The widespread use of immunosuppressive drugs,
indwelling catheters, and mechanical devices also plays a
role.
Pathophysiology
Most cases of severe sepsis are triggered by bacteria or
fungi that do not ordinarily cause systemic disease in
immunocompetent hosts.
The septic response may also be induced by microbial
exotoxins that act as superantigens (e.g., toxic shock
syndrome toxin) as well as by many pathogenic viruses.
Host Mechanisms for Sensing Microbes
A host protein (LPS-binding protein) binds lipid A and
transfers the LPS to CD14 on the surfaces of monocytes,
macrophages, and neutrophils.
LPS then is passed to MD-2, that is bound to toll-like
receptor (TLR) 4 to form a molecular complex that
transduces the LPS recognition signal to the interior of the
cell.
This signal rapidly triggers the production and release of
mediators, such as tumor necrosis factor, that amplify the
LPS signal and transmit it to other cells and tissues.

Cytokines and Other Mediators

Cytokines can exert endocrine, paracrine, and autocrine
effects.
TNF alpha stimulates leukocytes and vascular endothelial
cells to release other cytokines, to express cell-surface
molecules that enhance neutrophil-endothelial adhesion at
sites of infection, and to increase prostaglandin and
leukotriene production.
Coagulation Factors
Intravascular thrombosis, a hallmark of the local
inflammatory response, may help wall off invading
microbes and prevent infection and inflammation from
spreading to other tissues.
Clotting is also favored by impaired function of the
protein C–protein S inhibitory pathway and depletion of
antithrombin and proteins C and S, while fibrinolysis is
prevented by increased plasma levels of plasminogen
activator inhibitor 1.
Septic Shock
The hallmark of septic shock is a decrease in peripheral
vascular resistance that occurs despite increased levels of
vasopressor catecholamines.
Fluid administration is usually followed by the
hyperdynamic, vasodilatory phase during which cardiac
output is normal (or even high) and oxygen consumption
declines despite adequate oxygen delivery.
Severe Sepsis
Pathogenesis
Circulating bacteria and their products almost certainly
elicit multiorgan dysfunction and hypotension by directly
stimulating inflammatory responses within the
vasculature.
Inflammatory mediators or neural signals arising from the
local site seem to be the key triggers for severe sepsis and
septic shock.
Site of primary infection:bacteremia arising from a
pulmonary or abdominal source was eightfold more likely
to be associated with severe sepsis than was bacteremic
urinary tract infection.
A third pathogenesis may be represented by severe sepsis
due to superantigen-producing Staphylococcus aureus or
Streptococcus pyogenes.
The pathogenesis of severe sepsis thus may differ
according to the infecting microbe, the ability of the host's
innate defense mechanisms to sense it, the site of the
primary infection, the presence or absence of immune
defects, and the prior physiologic status of the host.

Clinical Manifestations
The manifestations of the septic response are
superimposed on the symptoms and signs of the patient's
underlying illness and primary infection.
Individual variations in presentation.
For example,the absence of fever is most common in
neonates, in elderly patients, and in persons with uremia
or alcoholism.
Hyperventilation is often an early sign of the septic
response.
Disorientation, confusion, and other manifestations of
encephalopathy.
Focal neurologic signs are uncommon, although
preexisting focal deficits may become more prominent.
Hypotension and DIC.
Cellulitis, pustules, bullae, or hemorrhagic lesions may
develop when hematogenous bacteria or fungi seed the
skin or underlying soft tissue.
When sepsis is accompanied by cutaneous petechiae or
purpura, infection with N. meningitidis should be
suspected.
Generalized erythroderma in a septic patient suggests the
toxic shock syndrome due to S. aureus or S. pyogenes.

Gastrointestinal manifestations such as nausea, vomiting,

diarrhea, and ileus may suggest acute gastroenteritis.
Stress ulceration can lead to upper gastrointestinal
bleeding.
Prolonged or severe hypotension may induce acute
hepatic injury or ischemic bowel necrosis.
Major Complications
Cardiopulmonary Complications
Ventilation-perfusion mismatching produces a fall in
arterial PO2 early in the course.
In the absence of pneumonia or heart failure, progressive
diffuse pulmonary infiltrates and arterial hypoxemia
(PaO2/FIO2, <300) indicate the development of acute lung
injury; more severe hypoxemia (PaO2/FIO2, <200) denotes
the acute respiratory distress syndrome (ARDS).
Acute lung injury or ARDS develops in 50% of
patients with severe sepsis or septic shock.
Sepsis-induced hypotension usually results initially from
a generalized maldistribution of blood flow and blood
volume and from hypovolemia that is due, at least in part,
to diffuse capillary leakage of intravascular fluid.
During early septic shock, systemic vascular resistance is
usually elevated and cardiac output may be low.
After fluid repletion, in contrast, cardiac output typically
increases and systemic vascular resistance falls.
Indeed, normal or increased cardiac output and decreased
systemic vascular resistance distinguish septic shock from
cardiogenic, extracardiac obstructive, and hypovolemic
shock; other processes that can produce this combination
include anaphylaxis, beriberi, cirrhosis, and overdoses of
nitroprusside or narcotics.
Depression of myocardial function,develops within 24 h
in most patients with severe sepsis.
Cardiac output is maintained despite the low ejection
fraction because ventricular dilatation permits a normal
stroke volume.
Adrenal Insufficiency
The diagnosis of adrenal insufficiency may be very
difficult in critically ill patients.
Whereas a plasma cortisol level of less than15 microg/mL
(10 microg/mL if the serum albumin concentration is <2.5
mg/dL) indicates adrenal insufficiency.
Although CIRCI may result from structural damage to the
adrenal gland, it is more commonly due to reversible
dysfunction of the hypothalamic-pituitary axis or to tissue
corticosteroid resistance.
The major clinical manifestation of CIRCI is hypotension
that is refractory to fluid replacement and requires pressor
therapy.

Some classic features of adrenal insufficiency, such as

hyponatremia and hyperkalemia, are usually absent;
others, such as eosinophilia and modest hypoglycemia,
may sometimes be found.
Renal Complications
Oliguria, azotemia, proteinuria, and nonspecific urinary
casts are frequently found.
Most renal failure is due to acute tubular necrosis induced
by hypotension or capillary injury.
Coagulopathy
Although thrombocytopenia occurs in 10–30% of
patients, the underlying mechanisms are not understood.
Platelet counts are usually very low (<50,000/microL) in
patients with DIC; these low counts may reflect diffuse
endothelial injury or microvascular thrombosis.
Laboratory Findings
Leukocytosis with a left shift, thrombocytopenia,
hyperbilirubinemia, and proteinuria.
Leukopenia may develop.
Active hemolysis suggests clostridial bacteremia, malaria,
a drug reaction, or DIC; in the case of DIC,
microangiopathic changes may be seen on a blood smear.
During early sepsis, hyperventilation induces respiratory
alkalosis.

With respiratory muscle fatigue and the accumulation of

lactate, metabolic acidosis typically supervenes.
Evaluation of arterial blood gases reveals hypoxemia that
is initially correctable with supplemental oxygen but
whose later refractoriness to 100% oxygen inhalation
indicates right-to-left shunting.
Most diabetic patients with sepsis develop hyperglycemia.
Severe infection may precipitate diabetic ketoacidosis that
may exacerbate hypotension.
Hypoglycemia occurs rarely.
The serum albumin level declines as sepsis continues.
Hypocalcemia is rare.
Diagnosis
There is no specific diagnostic test for the septic response.
Diagnostically sensitive findings in a patient with
suspected or proven infection include fever or
hypothermia, tachypnea, tachycardia, and leukocytosis or
leukopenia; acutely altered mental status,
thrombocytopenia, an elevated blood lactate level, or
hypotension also should suggest the diagnosis.
The septic response can be quite variable, however.
Definitive etiologic diagnosis requires isolation of the
microorganism from blood or a local site of infection.

At least two blood samples should be obtained (from two

different venipuncture sites) for culture.
Gram's staining and culture of material from the primary
site of infection or from infected cutaneous lesions may
help establish the microbial etiology.
Treatment: Severe Sepsis and Septic Shock
Successful management requires urgent measures to treat
the infection, to provide hemodynamic and respiratory
support, and to eliminate the offending microorganisms.
These measures should be initiated within 1 h of the
patient's presentation with severe sepsis or septic shock.
Antimicrobial Agents
The interval between the onset of hypotension and the
administration of appropriate antimicrobial chemotherapy
was the major determinant of outcome; a delay of as little
as 1 h was associated with lower survival rates.
Maximal recommended doses of antimicrobial drugs
should be given intravenously, with adjustment for
impaired renal function when necessary.
When culture results become available, the regimen can
often be simplified, as a single antimicrobial agent is
usually adequate for the treatment of a known pathogen.
Aminoglycoside monotherapy for P. aeruginosa
bacteremia is less effective than the combination of an
aminoglycoside with an antipseudomonal beta lactam
agent.

Empirical antifungal therapy

-patient is already receiving broad-spectrum antibiotics or
parenteral nutrition, has been neutropenic for 5 days, has
had a long-term central venous catheter, or has been
hospitalized in an intensive care unit for a prolonged
period.

Initial Antimicrobial Therapy for Severe Sepsis with No Obvious Source in Adults with Normal Renal Function
Clinical Condition Antimicrobial Regimens (Intravenous Therapy)
Immunocompetent (1) piperacillin-tazobactam (3.375 g q4–6h);
adult (2) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h); or
(3) cefepime (2 g q12h).
If the patient is allergic to beta lactam agents, use ciprofloxacin (400 mg q12h) or
levofloxacin (500–750 mg q12h) plus clindamycin (600 mg q8h). Vancomycin (15
mg/kg q12h) should be added to each of the above regimens.
Neutropenia (<500 (1) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q8h);
neutrophils/microL) (2) piperacillintazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h).
Vancomycin (15 mg/kg q12h) should be added if the patient has an indwelling vascular
catheter.
Empirical antifungal therapy with an echinocandin (for caspofungin: a 70-mg loading
dose, then 50 mg daily).
Splenectomy Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used.
If the patient is allergic to -lactam drugs, vancomycin (15 mg/kg q12h) plus either
moxifloxacin (400 mg q24h) or levofloxacin (750 mg q24h) or aztreonam (2 g q8h)
should be used.
IV drug user Vancomycin (15 mg/kg q12h)
AIDS Cefepime (2 g q8h) or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7
mg/kg q24h) should be used.
If the patient is allergic to -lactam drugs, ciprofloxacin (400 mg q12h) or levofloxacin
(750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin should be used.
Most patients require antimicrobial therapy for at least 1
week.
Removal of the Source of Infection

Hemodynamic, Respiratory, and Metabolic Support

The primary goals are to restore adequate oxygen and
substrate delivery to the tissues as quickly as possible and
to improve tissue oxygen utilization and cellular
metabolism.
Circulatory adequacy is assessed by measurement of
arterial blood pressure and monitoring of parameters such
as mentation, urine output, and skin perfusion.
Initial management of hypotension should include the
administration of IV fluids, typically beginning with 1–2
L of normal saline over 1–2 h.
The urine output rate should be kept at >0.5 mL/kg per
hour by continuing fluid administration; a diuretic such as
furosemide may be used if needed.
In patients with septic shock, plasma vasopressin levels
increase transiently but then decrease dramatically.
CIRCI should be strongly considered in patients who
develop hypotension that does not respond to fluid
replacement therapy.
Hydrocortisone (50 mg IV every 6 h) should be given; if
clinical improvement occurs over 24–48 h, continue
hydrocortisone therapy for 5–7 days before slowly
tapering and discontinuing it.

Stress-ulcer prophylaxis with a histamine H2-receptor

antagonist may decrease the risk of gastrointestinal
hemorrhage in ventilated patients.
Erythrocyte transfusion is generally recommended when
the blood hemoglobin level decreases to less than 7 g/dL,
with a target level of 9 g/dL in adults.
Bicarbonate is sometimes administered for severe
metabolic acidosis (arterial pH <7.2.
General Support
Nutritional supplementation may reduce the impact of
protein hypercatabolism.
Prophylactic heparinization to prevent deep venous
thrombosis is indicated for patients who do not have
active bleeding or coagulopathy.
Recovery is also assisted by prevention of skin
breakdown, nosocomial infections, and stress ulcers.
Using insulin only if it is needed to maintain the blood
glucose concentration below 150 mg/dL.
Patients receiving intravenous insulin must be monitored
frequently (every 1–2 h) for hypoglycemia.
Prognosis
Approximately 20–35% of patients with severe sepsis and
40–60% of patients with septic shock die within 30 days.
Others die within the ensuing 6 months.
Late deaths often result from poorly controlled infection,
immunosuppression, complications of intensive care,
failure of multiple organs, or the patient's underlying
disease.
Age and prior health status are probably the most
important risk factors.
Septic shock is also a strong predictor of short- and long-
term mortality.
The most commonly identified etiologic agents in patients
who die are Staphylococcus aureus, Streptococcus
pyogenes, S. pneumoniae, and Neisseria meningitidis.
Individuals with preexisting comorbidities are at greater
risk of dying of severe sepsis at any age.
Prevention
Reducing the number of invasive procedures undertaken
Reducing the incidence and duration of profound
neutropenia (<500 neutrophils/miccroL), and
By more aggressively treating localized nosocomial
infections.
Neurogenic Shock
Interruption of sympathetic vasomotor input after a high
cervical spinal cord injury, spinal anesthesia, or
devastating head injury.
In addition to arteriolar dilation, venodilation causes
pooling in the venous system, which decreases venous
return and cardiac output.
The extremities are often warm, in contrast to the usual
sympathetic vasoconstriction-induced coolness in
hypovolemic or cardiogenic shock.

Excessive volumes of fluid may be required to restore

normal hemodynamics if given alone.
Once hemorrhage has been ruled out, norepinephrine may
be necessary to augment vascular resistance and maintain
an adequate mean arterial pressure.
Hypoadrenal Shock
-occurs in settings in which unrecognized adrenal
insufficiency complicates the host response to the stress
induced by acute illness or major surgery.
-chronic administration of high doses of exogenous
glucocorticoids.
-critical illness, including trauma and sepsis, may induce a
relative hypoadrenal state.
The shock is characterized by reductions in systemic
vascular resistance, hypovolemia, and reduced cardiac
output.
Treatment
Unstable patient, dexamethasone sodium phosphate, 4
mg, should be given intravenously.
The patient has a reduced risk of death if treated with
hydrocortisone, 100 mg every 6–8 h, and tapered as the
patient achieves hemodynamic stability.
Simultaneous volume resuscitation and pressor support
are required.

Adjunctive Therapies
Dobutamine, dopamine, and norepinephrine are widely
used in the treatment of all forms of shock.
Dobutamine is inotropic with simultaneous afterload
reduction, thus minimizing cardiac-oxygen consumption
increases as cardiac output increases.
Rewarming
Hypothermia is a frequent adverse consequence of
massive volume resuscitation.
Hypothermia may depress cardiac contractility and
thereby further impair cardiac output and oxygen
delivery/utilization.
Hypothermia, particularly temperatures <35°C directly
impairs the coagulation pathway, sometimes causing a
significant coagulopathy.
Rapid rewarming to >35°C (>95°F) significantly
decreases the requirement for blood products and
produces an improvement in cardiac function.

Miesso(MD)