CHAPTER 108  Shock Syndromes Related to Sepsis

 
685

108 
SHOCK SYNDROMES RELATED TO SEPSIS
JAMES A. RUSSELL

DEFINITION
Sepsis is defined by presence of at least two of the four signs of the systemic
inflammatory response syndrome (SIRS): (1) fever (>38° C) or hypothermia
(<36° C); (2) tachycardia (>90 beats/minute); (3) tachypnea (>20 breaths/
minute), hypocapnia (partial pressure of carbon dioxide <32 mm Hg), or the
need for mechanical ventilatory assistance; and (4) leukocytosis (>12,000
cells/μL), leukopenia (<4000 cells/μL), or a left shift (>0% immature band
cells) in the circulating white blood cell differential and suspected or proven
infection. Bacteremia is defined as the growth of bacteria in blood cultures,
but infection does not have to be proved to diagnose sepsis at the onset. Severe
sepsis is sepsis in addition to dysfunction of one or more organ systems (e.g.,
hypoxemia, oliguria, lactic acidosis, thrombocytopenia, decreased Glasgow
Coma Scale score). Septic shock is defined as severe sepsis in addition to
hypotension (systolic blood pressure <90 mm Hg or a >40 mm Hg decrease
from baseline) despite adequate fluid resuscitation.1

EPIDEMIOLOGY
Approximately 750,000 cases of severe sepsis or septic shock occur every year
in the United States. Sepsis causes as many deaths as acute myocardial infarc-
tion, and septic shock and its complications are the most common causes of
death in noncoronary intensive care units (ICUs). The medical care costs
associated with sepsis are approximately $16.7 billion a year in the United
States alone. The frequency of septic shock is increasing as physicians perform
more aggressive surgery, as more resistant organisms are present in the envi-
ronment, and as the prevalence of immune compromise resulting from
disease and immunosuppressive drugs increases. Studies suggest that African
Americans have a higher incidence of severe sepsis than whites do (6.0 vs.
3.6 per 1000 population) and a higher mortality in ICUs (32.1 vs. 29.3%; P
< .0001), even after adjustment for poverty levels. The mechanisms of this
apparent difference in risk for and mortality from sepsis are not known.
Gram-positive or gram-negative bacteria, fungi, and, very rarely, protozoa
or rickettsiae can cause septic shock. Increasingly common causes of septic
shock are gram-positive bacteria, especially methicillin-resistant Staphylococ-
cus aureus, vancomycin-resistant enterococci, penicillin-resistant Streptococ-
cus pneumoniae, and resistant gram-negative bacilli.
The common infections causing septic shock are pneumonia, peritonitis,
pyelonephritis, abscess (especially intra-abdominal), primary bacteremia,
cholangitis, cellulitis, necrotizing fasciitis, and meningitis. Nosocomial pneu-
monia is the most common cause of death from nosocomial infection.

PATHOBIOLOGY
At onset, septic shock activates inflammation, leading to enhanced coagula-
tion, activated platelets, increased neutrophils and mononuclear cells, and
686 CHAPTER 108  Shock Syndromes Related to Sepsis
diminished fibrinolysis. After several days, a compensatory anti-inflammatory
response with immunosuppression may contribute to death. Several path-
ways amplify one another: inflammation triggers coagulation, and coagula-
tion triggers inflammation, resulting in a positive feedback loop that is
proinflammatory and procoagulant. Tissue hypoxia in septic shock also
amplifies inflammation and coagulation. Many mediators that are critical for
the homeostatic control of infection may be injurious to the host (e.g., tumor
necrosis factor-α [TNF-α]), so therapies that fully neutralize such mediators
are largely ineffective.
Widespread endothelial injury is an important feature of septic shock; an
injured endothelium is more permeable, so the flux of protein-rich edema
fluid into tissues such as the lung increases. Injured endothelial cells release
nitric oxide, a potent vasodilator that is a key mediator of septic shock. Septic
shock also injures epithelial cells of the lung and intestine. Intestinal epithelial
injury increases intestinal permeability; this leads to epithelial translocation
of intestinal bacteria and endotoxin, which further augments the inflamma-
tory phenotype of septic shock.
Early Infection, the Innate Immune Response,
Inflammation, and the Endothelium
Host defense is organized into innate and adaptive immune responses. The
innate immune system responds by using pattern recognition receptors (e.g.,
toll-like receptors [TLRs]) to pathogen-associated molecular patterns, which
are extremely well conserved molecules of microorganisms. Surface mole-
cules of gram-positive and gram-negative bacteria (peptidoglycan and lipo-
polysaccharide, respectively) bind to TLR-2 and TLR-4, respectively (E-Fig.
108-1). TLR-2 and TLR-4 binding initiates an intracellular signaling cascade
that culminates in nuclear transport of the transcription factor nuclear factor
κB (NF-κB), which triggers transcription of cytokines such as TNF-α and
interleukin (IL)–6. Cytokines upregulate adhesion molecules of neutrophils
and endothelial cells, and neutrophil activation leads to bacterial killing.
However, cytokines also directly injure host endothelial cells, as do activated
neutrophils, monocytes, and platelets. Inhibition of early cytokine mediators
of sepsis, such as TNF-α and IL-1β, has not proved successful, probably
because TNF-α and IL-1β peak and then decline quickly, before these antag-
onist therapies can be applied clinically.
After the early cytokine inflammatory response, immune cells, including
macrophages and neutrophils, release later mediators, such as high-mobility
group box 1 (HMGB-1). HMGB-1 activates neutrophils, monocytes, and
endothelium. Unlike TNF-α antagonists, inhibitors of HMGB-1 decrease
mortality even when they are given 24 hours after the induction of experi-
mental peritonitis.
Another adverse effect of sepsis is widespread endothelial injury that leads
to increased endothelial permeability with loss of protein and fluids to the
interstitial space. This endothelial permeability is a final common pathway for
widespread tissue injury. Cytokines and other inflammatory mediators
induce intercellular endothelial cell gaps by disrupting intercellular junctions,
by changing cytoskeletal structure, or by direct damage to endothelial cells.
Several pathways of altered endothelial permeability have been implicated in
sepsis, including protease-activated receptor 1 (PAR-1) and disruption of the
intercellular VE-cadherin, β-catenin, and p120-catenin complex. PAR-1
binding by activated protein C and low-dose thrombin is cytoprotective,
whereas PAR-1 stimulation by high-dose thrombin increases endothelial per-
meability. Binding of Slit to Robo4 maintains the integrity of the intercellular
VE-cadherin, β-catenin, and p120-catenin complexes and thus maintains
healthy endothelial permeability.
Adaptive Immunity Adds Specificity and
Amplifies the Immune Response
Microorganisms stimulate specific humoral and cell-mediated adaptive
immune responses that amplify innate immunity. B cells release immuno-
globulins that bind to microorganisms and thereby facilitate delivery of
microorganisms to natural killer cells and neutrophils. In sepsis, type 1 helper
T (TH1) cells generally secrete proinflammatory cytokines (TNF-α, IL-1β),
and type 2 helper T (TH2) cells secrete anti-inflammatory cytokines (IL-4,
IL-10).
Coagulation Response to Infection
Septic shock activates the coagulation system (E-Fig. 108-2) and ultimately
converts fibrinogen to fibrin, which is bound to platelets to form microvascular
thrombi. Microvascular thrombi further amplify endothelial injury by the
release of mediators and by tissue hypoxia because of obstruction to blood flow.
Normally, natural anticoagulants (protein C, protein S, antithrombin, and
tissue factor pathway inhibitor) dampen coagulation, enhance fibrinolysis,
and remove microthrombi. Thrombin-α binds to thrombomodulin, which
activates protein C when protein C is bound to the endothelial protein C
receptor (EPCR). Activated protein C dampens the procoagulant phenotype
because it inactivates factors Va and VIIIa and inhibits the synthesis of plas-
minogen activator inhibitor 1 (PAI-1). Activated protein C also decreases
apoptosis, leukocyte activation and adhesion, and production of cytokines.
Septic shock decreases the levels of the natural anticoagulants protein C,
protein S, antithrombin, and tissue factor pathway inhibitor. Furthermore,
lipopolysaccharide and TNF-α decrease thrombomodulin and EPCR,
thereby limiting the activation of protein C. Lipopolysaccharide and TNF-α
also increase levels of PAI-1, inhibiting fibrinolysis.
Tissue Hypoxia in Septic Shock
Tissue hypoxia independently activates inflammation (by activation of
NF-κB and cytokines, synthesis of nitric oxide, and activation of HMGB-1),
induces coagulation (through tissue factor and PAI-1), and activates neutro-
phils, monocytes, and platelets. Hypoxia induces hypoxia-inducible factor-
1α (HIF-1α), which upregulates erythropoietin, and vascular endothelial
growth factor (VEGF). Erythropoietin is protective to brain and other
tissues. VEGF inhibits fibrinolysis and increases inducible nitric oxide syn-
thase, which augments nitric oxide–induced vasodilation. Nitric oxide has a
further injurious effect: excessive nitric oxide inhibits the beneficial actions
of HIF-1α (e.g., upregulating synthesis of erythropoietin) during hypoxia.
Late Septic Shock, Immunosuppression, and Apoptosis of
Immune and Epithelial Cells
After about 1 week of septic shock, death can result from immunosuppres-
sion, which is suggested by anergy, lymphopenia, hypothermia, and nosoco-
mial infection (E-Fig. 108-3). Multiple organ dysfunction may be an
anti-inflammatory phenotype because of the apoptosis of immune, epithelial,
and endothelial cells. Activated CD4+ T cells evolve into either a TH1 proin-
flammatory (TNF-α, IL-1β) or a TH2 anti-inflammatory (IL-4, IL-10) phe-
notype. Sepsis leads to migration from a TH1 to a TH2 phenotype; for
example, persistent elevation of IL-10 is associated with an increased risk of
death. Immunosuppression also develops because of apoptosis of lympho-
cytes. Proinflammatory cytokines, activated B and T cells, and glucocorti-
coids induce lymphocyte apoptosis, whereas TNF-α and endotoxin induce
apoptosis of lung and intestinal epithelial cells. The fact that glucocorticoids
also stimulate apoptosis could be the biologic explanation for the observation
that patients with septic shock who are treated with hydrocortisone have
more superinfections than do patients treated with placebo.
Death from infectious disease appears to be highly heritable. Sepsis is a
prime example of a polygenic disease related to the interaction of multiple
genes and an environmental insult (infection). Single-nucleotide polymor-
phisms of cytokines (TNF-α, IL-6, IL-10), coagulation factors (protein C,
fibrinogen-β), the catecholamine pathway (β-adrenergic receptor), and
innate immunity genes (CD14, TLR-1, TLR-2) have been variably associated
with an increased risk of death from sepsis.
Cardiovascular Dysfunction
Inadequate tissue perfusion and tissue hypoxia are the cardinal features of all
types of shock. Early in septic shock, most patients have sinus tachycardia
and, by definition, decreased blood pressure (<90 mm Hg systolic, a decrease
of ≥40 mm Hg from baseline systolic pressure, or mean arterial pressure
<65 mm Hg; Table 108-1). Septic shock is the classic form of distributive
shock (Chapter 106), characterized by increased pulse pressure (bounding
pulses), decreased systemic vascular resistance (warm, flushed skin), and
functional hypovolemia (low jugular venous pressure). Distributive shock
means that the distribution of systemic blood flow is abnormal, such that
areas of both low flow (and low venous oxygen saturation) and high flow (and
increased venous oxygen saturation) are present. Nevertheless, about one
third of patients with septic shock initially present with findings more typical
of hypovolemic shock (low central venous pressure and low central venous
oxygen saturation) because the clinical features depend on the stage and
severity of septic shock as well as on the degree of fluid resuscitation that has
occurred. After fluid resuscitation, patients typically develop the characteris-
tic clinical and hemodynamic features of classic distributive shock.
Ventricular preload is commonly decreased in early septic shock, for several
reasons.2 First, patients may be volume depleted because of decreased fluid
intake and because of increased fluid losses as a result of fever, vomiting, and
 CHAPTER 108  Shock Syndromes Related to Sepsis
 
686.e1

PAMPs Gram + ve
Gram – ve Vascular lumen
LPS DAMPs
CD14
TLR2 Complement
TLR4 activation
Flow
TNFα Prostaglandins
Leukotrienes
PO2 Neutrophil
NFκB IL1β
Reactive
IL-6 Necrotic cell death oxygen
TNFα Monocyte Proteases species
HMG B1
ICAM
iNOS iNOS
NO
NO
L-arginine L-arginine

NO Increased
endothelial
permeability
E-FIGURE 108-1.  Inflammatory responses to sepsis. Gram-positive and gram-negative bacteria, viruses, and fungi have unique cell wall molecules called pathogen-associated
molecular patterns (PAMPs) that bind to pattern recognition receptors (called toll-like receptors [TLRs]) on the surface of immune cells as well as C-type lectin receptors, retinoic acid
inducible gene 1–like receptors, and nucleotide-binding oligomerization domain–like receptors. Nucleotide-binding oligomerization domain–like receptors alter protein complexes
in the inflammasome. The lipopolysaccharide (LPS) of gram-negative bacilli binds to LPS-binding protein–CD14 complex. The peptidoglycan of gram-positive bacteria and the LPS of
gram-negative bacteria bind to TLR-2 and TLR-4, respectively. TLR-2 and TLR-4 binding activates intracellular signal transduction pathways that lead to the activation of the cytosolic
transcription factor nuclear factor κB (NF-κB). Activated NF-κB moves from the cytoplasm to the nucleus, binds to transcription start sites, and increases the transcription of proin-
flammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Increased necrotic cell death releases damage-associated molecular
patterns (DAMPs or alarmins) that bind to TLRs and thus feedback to further amplify the proinflammatory response. TNF-α, IL-1β, and IL-6 are proinflammatory cytokines that activate
the adaptive immune response but also cause both direct and indirect host injury (e.g., by complement activation). Sepsis increases the activity of inducible nitric oxide synthase
(iNOS), which increases the synthesis of nitric oxide (NO), a potent vasodilator. Cytokines activate endothelial cells by upregulating adhesion receptors such as intercellular adhesion
molecule (ICAM), and they injure endothelial cells by the activation and binding of neutrophils, monocytes, macrophages, and platelets to endothelial cells. These effector cells release
mediators such as proteases, reactive oxygen species, prostaglandins, and ICAM leukotrienes. Cytokines also activate the coagulation cascade.

Apoptosis of dendritic,
B and T cells

T regulatory cell
Anti-inflammatory expansion
cytokines
(e.g., IL-10) Impaired phagocytosis
Soluble cytokine
receptors
Monocyte
(e.g., IL-1Ra)

Gut
epithelial cell
apoptosis

E-FIGURE 108-2.  Procoagulant response in sepsis. Sepsis initiates coagulation by activating the endothelium to increase tissue factor. Protease-activated receptors (PARs), espe-
cially PAR-1, link the inflammatory and coagulation responses to sepsis. Activation of factors Va and VIIIa leads to the formation of thrombin-α, which converts fibrinogen to fibrin.
Fibrin binds to platelets that adhere to endothelial cells, forming microvascular thrombi. Microvascular thrombi amplify injury by the release of mediators and by microvascular
obstruction, which causes distal ischemia and tissue hypoxia. Normally, natural anticoagulants—protein C (PC), protein S (PS), antithrombin, and tissue factor pathway inhibitor
(TFPI)—dampen coagulation, enhance fibrinolysis, and remove microthrombi. Thrombin-α binds to thrombomodulin on endothelial cells and thus activates the binding of PC to
endothelial PC receptor (EPCR). PC forms a complex with its cofactor PS. PC binding to EPCR increases the activation of PC to activated PC (APC). APC proteolytically inactivates factors
Va and VIIIa and decreases the synthesis of plasminogen activator inhibitor 1 (PAI-1). Sepsis decreases levels of PC, PS, antithrombin, and TFPI. Lipopolysaccharide and tumor necrosis
factor-α (TNF-α) decrease thrombomodulin and EPCR, thus decreasing the activation of PC. PAR-1 binding by activated protein C and low-dose thrombin is cytoprotective, whereas
PAR-1 stimulation by high-dose thrombin increases endothelial permeability. Lipopolysaccharide and TNF-α also inhibit PAI-1, so fibrinolysis is inhibited. HIFα = hypoxia-inducible
factor-α; NO = nitric oxide; tPA = tissue plasminogen activator; VEGF = vascular endothelial growth factor.
686.e2 CHAPTER 108  Shock Syndromes Related to Sepsis
 

HIFα VEGF NO

Blood vessel PO 2 tPA

PAI1
Tissue factor Plasminogen
Plasmin
Va
Flow VIIIa Thrombin
Fibrin
APC
PO 2 Thrombin High-dose Fibrinogen Low-dose
thrombin thrombin
PC APC
Platelet
Thrombomodulin EPCR
PAR-1 PAR-1 PAR-1

Increased Cytoprotection
endothelial
permeability
E-FIGURE 108-3.  Anti-inflammatory, immunosuppressive, and proapoptotic responses in sepsis. In parallel with the proinflammatory response, the host generates anti-
inflammatory, immunosuppressive, and proapoptotic responses. Activated neutrophils increase the transcription of anti-inflammatory cytokines such as interleukin-10 (IL-10), and
IL-10 then inactivates macrophages and has other anti-inflammatory effects. Apoptosis of dendritic cells, T and B cells, and gut epithelial cells leads to sometimes profound immu-
nosuppression that increases the risk of secondary nosocomial infections. There is also increased production of T-regulatory cells that then impair phagocytosis of organisms. Initially
increased pituitary adrenocorticotropic hormone (ACTH)–induced adrenal release of cortisol inhibits the proinflammatory response by regulating transcription of many cytokines
and other mediators of inflammation.
 CHAPTER 108  Shock Syndromes Related to Sepsis
TABLE 108-1  HEMODYNAMIC VARIABLES, ABBREVIATIONS,
AND NORMAL VALUES
Arterial pressure: systolic pressure (SAP) (>100 mm Hg), diastolic pressure, pulse
pressure, mean arterial pressure (MAP) (>65 mm Hg)
Central venous pressure (CVP): normal, 6-12 mm Hg
Pulmonary artery pressure (PAP): normal, 25/15 mm Hg
Pulmonary vascular resistance (PVR): normal, 150-250 dynes/sec/cm
( )
PAP − PAOP
≡ × 80
CO
Pulmonary artery occlusion pressure (PAOP) or pulmonary artery wedge pressure
(PAWP): normal, 8-15 mm Hg
Systemic vascular resistance (SVR): normal, 900-1400 dynes/sec/cm
( ≡
MAP − CVP
CO
× 80 ) preload (because of decreased intake, fluid losses, third spacing resulting
Cardiac output (CO): normal, 5 L/min
Left ventricular stroke work index (LVSWI): normal, (60-100 grams × meters/
beats) = (SV × [MAP – PAWP] × 0.0136)
Oxygen delivery (Do2): normal, 1 L/min (= CO × [Hg × 1.38 × Sao2] + [0.003 ×
Po2])
Oxygen consumption (Vo2): normal, 250 mL/min (= CO × Hg × 1.38 × [Sao2 –
Svo2] + [0.003 × (Pao2 – Pvo2)])
Oxygen extraction ratio: normal, 0.23-0.32 (= Vo2/Do2)
Hemodynamic variables are often normalized to account for different body mass by
dividing by body surface area (BSA)
   Pulmonary vascular resistance index (PVRI): normal (= PVR/BSA)
   Systemic vascular resistance index (SVRI): normal (= SVR/BSA)
   Cardiac index (CI): normal, 2.5-4.2 L/min/m2 (= CO/BSA)
   Left ventricular stroke work index (LVSWI): normal (= LVSW/BSA)
   Oxygen delivery index (Do2I): normal, 460-650 mL/min/m2 (= Do2/BSA)
   Oxygen consumption index (Vo2I): normal, 95-170 mL/min/m2 (= Vo2/BSA)
diarrhea if gastrointestinal disease is present. Second, fluid loss from the intra-
vascular to the interstitial space (capillary leak) is caused by mediators that
induce widespread endothelial injury, which increases capillary permeability.
Increased capillary permeability leads to loss of protein-rich edema fluid into
the interstitial space. In the lung, increased permeability is a key component
of acute lung injury. A third reason that ventricular preload is decreased in
septic shock is venodilation induced by mediators such as nitric oxide. Veno-
dilation increases venous capacitance, leading to relative volume depletion,
which compounds the absolute volume depletion. Ventricular afterload is
decreased because of excessive release of potent vasodilators such as nitric
oxide, prostaglandin I2, adenosine diphosphate, and other vasodilators.
In addition to abnormal vasodilation, patients have concurrent microvas-
cular vasoconstriction. Microvascular vasoconstriction may not be apparent
clinically or hemodynamically, but it can lead to tissue hypoxia, detected by
increased arterial lactate concentrations. Microvascular vasoconstriction is
caused by increased norepinephrine, thromboxanes, and other local vasocon-
strictors. Microvascular vasoconstriction causes focal hypoxia, which is exac-
erbated by microvascular obstruction by platelets and leukocytes.
The abnormal mismatch of oxygen delivery to oxygen demand can disturb
the global relationship of oxygen delivery to oxygen consumption. Normally,
oxygen consumption is independent of oxygen delivery over a wide range.
When oxygen delivery decreases to less than the critical oxygen delivery level,
oxygen consumption decreases and leads to a state in which oxygen con-
sumption depends on oxygen delivery. At levels lower than the critical oxygen
delivery level, arterial lactate increases as a result of tissue hypoxia. The clini-
cal implication is that oxygen delivery should be increased (e.g., by increasing
cardiac output by volume resuscitation, infusion of dobutamine, or transfu-
sion of erythrocytes) to more than the critical level.
Cardiovascular function is further compromised in septic shock because
of decreased ventricular contractility.3 Decreased ventricular contractility
may be difficult to detect clinically and may be diagnosed only by hemody-
namic or echocardiographic assessment. Numerous circulating mediators of
sepsis, including endotoxin, cytokines (e.g., IL-6, TNF-α), and nitric oxide
(locally released into the coronary circulation), decrease contractility. Endo-
toxin signals through TLRs to upregulate the expression of proteins such as
S110A8 and S100A9 to cause a receptor for advanced glycation end products
(RAGE)–dependent decrease in calcium flux, which decreases the ejection
fraction. Coronary ischemia resulting from microvascular obstruction by leu-
kocytes and oxygen free radicals, which are released by neutrophils adherent
687
to the coronary capillary endothelium, is another mechanism of decreased
contractility.
Early in septic shock, patients who survive have increased left ventricular
end-diastolic volume, which likely allows them to maintain cardiac output
despite decreased contractility. In contrast, nonsurvivors do not have
increased left ventricular end-diastolic volume, so their cardiac output is com-
promised. In some patients with septic shock, concurrent acute lung injury
and secondary pulmonary hypertension increase right ventricular afterload,
with a secondary shift of the interventricular septum from right to left. This
septal shift decreases left ventricular end-diastolic volume and can also limit
cardiac output.
CLINICAL MANIFESTATIONS
Cardiovascular dysfunction in septic shock is characterized by decreased
from increased permeability, and venodilation), decreased afterload, and
often decreased ventricular contractility. Decreased ventricular volume is
detected clinically by low jugular venous pressure and hemodynamically by
decreased central venous pressure. Left ventricular resistance, or afterload, is
also commonly decreased and is detected clinically by warm, flushed skin and
hemodynamically by decreased systemic vascular resistance.
DIAGNOSIS
Even as the diagnostic evaluation is beginning, the initial assessment of a
critically ill patient must focus immediately on the airway (need for intuba-
tion), breathing (respiratory rate, respiratory distress, pulse oximetry), circu-
lation (heart rate, blood pressure, jugular venous pressure, skin perfusion),
and rapid initiation of resuscitation (Fig. 108-1). Vital signs and the leukocyte
count quickly establish whether the patient has SIRS (two of the four crite-
ria). Arterial blood gases and lactate levels are useful complementary tests. A
secondary survey is designed to determine the likely source of infection and
the status of organ function. Pneumonia (Chapter 97) is suggested by cough,
sputum, and respiratory distress; empyema (Chapter 99) is suggested by
pleuritic chest pain. Signs of peritonitis, an abdominal mass, and right upper
quadrant tenderness suggest abdominal sepsis. Pyelonephritis (Chapter 284)
is likely in patients with dysuria and costovertebral angle tenderness. Integu-
mentary assessment for erythema (cellulitis), line site erythema (line sepsis),
tenderness (necrotizing fasciitis), crepitus (anaerobic myonecrosis), and
petechiae and purpura (meningococcemia) can be illuminating. Headache,
stiff neck, and signs of meningismus raise the suspicion of meningitis
(Chapter 412). Focal neurologic signs suggest brain abscess (Chapter 413).
Laboratory investigations that are helpful to identify the source of infec-
tion include appropriate cultures and Gram stains (blood, sputum, urine,
fluids, and cerebrospinal fluid). Blood cultures are positive in 40 to 60% of
patients who have septic shock. The chest radiograph aids in the diagnosis of
pneumonia, empyema, and acute lung injury. Abdominal ultrasound and
computed tomography are indicated if abdominal sepsis is suspected.
Hemodynamic assessment of the patient includes diagnostic central
venous or pulmonary artery catheterization. In early septic shock, central
venous pressure is usually low and increases in response to volume resuscita-
tion. Central venous oxygen saturation, cardiac output, and ventricular filling
pressures may be determined continuously. Pulmonary artery pressure is
usually normal but may be increased because septic shock can cause pulmo-
nary hypertension. Pulmonary artery occlusion (or wedge) pressure is usually
low before resuscitation, but it may be normal or increased if the patient has
underlying preexisting heart disease (e.g., heart failure or coronary artery
disease with prior myocardial infarction) or if left ventricular contractility is
decreased by sepsis. Cardiac output may be low or normal before fluid resus-
citation and typically increases to higher than normal after fluid resuscitation.
If fluid resuscitation increases central venous pressure and pulmonary artery
occlusion pressure but cardiac output does not increase, left ventricular dys-
function is presumably present.
Echocardiographic features of decreased ventricular contractility include
decreased right and left ventricular ejection fractions and increased end-
diastolic and end-systolic volumes. Early in septic shock, the left ventricular
ejection fraction is decreased, and it remains low in nonsurvivors. In survi-
vors, the left ventricular ejection fraction usually returns to normal during 5
to 10 days. Bedside echocardiography can also be used to assess intravascular
volume status, which can be diagnosed on the basis of collapse of the inferior
vena cava, and valvular dysfunction.
Renal, hepatic, and coagulation function tests are helpful to evaluate organ
function. After determination of the source of sepsis, it is crucial to address
688 CHAPTER 108  Shock Syndromes Related to Sepsis
 

Clinical Evaluation Laboratory Evaluation Management

Airway A. Airway—high risk intubation

Breathing B. Breathing—oxygen, tidal volume 6
• RR mL/kg IBW if ventilated
• Distress C. Circulation—goal-directed therapy
• Pulse oximetry • ABGs protocol
Circulation • Arterial lactate • Fluids, vasopressors, inotropes,
• HR, BP transfusion
• Skin
• MAP > 65 mm Hg
• JVP + • CVP 8-12 mm Hg
• Hct > 30%
SIRS SIRS • ScvO2 > 70% (optional)
(2 of 4) • CBC Consider pulmonary artery catheter or
• HR (>90 min–1) echocardiogram especially if known CV disease
• WBC differential
• RR (>20 min–1) or PaCO2 < 32 mm Hg
or mechanical ventilation +
• T (>38°C) or T (<36°C)
• WBC (>12,000 mm–3) or WBC D. Drugs
(<4,000 mm–3)
+ Antibiotics: broad spectrum
Consider hydrocortisone
Consider vasopressin
Source of Infection Source of Infection
• Respiratory (pneumonia, empyema) • C&S, Gram stain: blood, sputum, urine, +
• Abdominal (peritonitis, abscess, +/– fluids, +/– CSF
cholangitis) • CXR E. Evaluate source of sepsis
• Skin (cellulitis, fasciitis) • U/S, CT scan
• Pyelonephritis
+
• CNS (meningitis, brain abscess)
+ F. Fix source of sepsis
• Abscess, empyema
• Cholecystitis, cholangitis
Organ Function Organ Function • Urinary obstruction
• Peritonitis, bowel infarct
CNS • Renal function: electrolytes, BUN, • Necrotizing fasciitis
• LOC, focal signs creatinine • Gas gangrene
Renal function • Hepatic function: bilirubin, AST, AlkPhos
• Urine output • Coagulation: INR, PTT, platelets, D-dimer

FIGURE 108-1.  Algorithm for the clinical and laboratory evaluation and management of septic shock. ABGs = arterial blood gases; AlkPhos = alkaline phosphatase; AST = aspartate
aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; C&S = culture and sensitivity; CBC = complete blood count; CNS = central nervous system; CSF = cerebrospinal
fluid; CT = computed tomography; CV = cardiovascular; CVP = central venous pressure; CXR = chest radiograph; Hct = hematocrit; HR = heart rate; IBW = ideal body weight;
INR = international normalized ratio; JVP = jugular venous pressure; LOC = level of consciousness; MAP = mean arterial pressure; PaCO2 = partial pressure of carbon dioxide;
PTT = partial thromboplastin time; RR = respiratory rate; ScvO2 = central venous oxygen saturation; SIRS = systemic inflammatory response syndrome; T = temperature; U/S = ultra-
sound; WBC = white blood cell count.

that source by draining abscesses and empyemas; radiologically or surgically
correcting urinary tract obstruction; and surgically managing peritonitis,
bowel infarction, cholecystitis, cholangitis, necrotizing fasciitis, and gas
gangrene.
Differential Diagnosis
The major differential diagnoses of classic septic shock are other nonseptic
causes of SIRS, such as acute pancreatitis (Chapter 144), acute respiratory
distress syndrome (Chapter 104), aspiration pneumonitis (Chapter 94),
multiple trauma (Chapter 111), and recent major surgery without infection
(Chapter 433). Other causes of distributive shock are anaphylactic shock
(suggested by angioedema and hives; Chapter 440), spinal shock (recent
trauma and paraplegia; Chapter 399), acute adrenal insufficiency (“tanned
skin,” hyperkalemia, metabolic alkalosis; Chapter 227), and acute or acute-
on-chronic hepatic failure (jaundice, ascites, encephalopathy; Chapter 153).
The differential diagnosis of septic shock must include the other causes of
shock: hypovolemic, cardiogenic, and obstructive shock (Chapters 106 and
107). Patients with hypovolemic shock (from internal or external fluid losses,
hemorrhage) present with a suggestive history and signs of hypovolemia (low
jugular venous pressure) and skin hypoperfusion (cool, clammy, cyanotic
extremities). Cardiogenic shock (resulting from myocardial infarction or
acute-on-chronic congestive heart failure or occurring after cardiovascular
surgery) is suggested by the history, signs of increased filling pressure
(increased jugular venous pressure, crackles, S3, pulmonary edema, cardio-
megaly), and skin hypoperfusion (Chapter 107). Some patients who have
acute myocardial infarction and cardiogenic shock have features of SIRS
without infection. Obstructive shock (from pulmonary thromboembolism,
cardiac tamponade, pneumothorax) is manifested similarly to cardiogenic
shock.
PREVENTION
Measures to prevent sepsis include handwashing, elevation of the head of the
bed, scrupulous sterile techniques for the insertion of catheters, and possibly
the use of antibiotic-impregnated catheters. New catheter insertion sites for
catheter changes, isolation of patients who have resistant organisms, and
isolation of significantly immunocompromised patients may also prevent
infection.
Preventing the progression from sepsis to septic shock requires early
diagnosis and aggressive resuscitation.4 Early fluid resuscitation, lung-protec-
tive ventilation, and antibiotics are critical therapies in early septic shock
(Table 108-2).
TREATMENT 
Respiratory Therapy
All patients in septic shock require oxygen initially, and many require
mechanical ventilation. Mechanical ventilation is required in most patients
who have septic shock because acute lung injury is the most common com-
plication. Lung-protective ventilation (mechanical ventilation that minimizes
lung injury by using a relatively low tidal volume, such as >6 mL/kg of
 CHAPTER 108  Shock Syndromes Related to Sepsis
 
689

TABLE 108-2  POTENTIAL ANTIBIOTIC REGIMENS FOR PATIENTS WITH SEPTIC SHOCK*
SOURCE OF SEPSIS INITIAL ANTIBIOTIC REGIMEN ALTERNATIVE ANTIBIOTIC REGIMEN
Community-acquired pneumonia Third-generation cephalosporin (cefotaxime 2 g IV q6h; Piperacillin-tazobactam 3.375 g IV q6h plus
ceftriaxone 2 g IV q12h; ceftizoxime 2 g IV q8h) plus Fluoroquinolone or
Fluoroquinolone (e.g., ciprofloxacin 400 mg IV q12h, Macrolide
levofloxacin 750 mg IV q24h, moxifloxacin 400 mg
IV q24h) or
Macrolide (azithromycin 500 mg IV q24h)
Hospital-acquired pneumonia Imipenem 0.5 g IV q6h or Fluoroquinolone (ciprofloxacin 400 mg IV q12h) plus
Meropenem 1 g IV q8h Vancomycin 1.5 g IV q12h or
Piperacillin-tazobactam 3.375 g IV q6h plus
Tobramycin 1.5 mg/kg q8h plus
Vancomycin
Abdominal (mixed aerobic/anaerobic) Piperacillin-tazobactam 3.375 g IV q6h or Ampicillin 2 g IV q4h plus
Imipenem 0.5 g IV q6h (or meropenem 1 g IV q8h) Metronidazole 500 mg IV q8h plus
Fluoroquinolone (ciprofloxacin 400 mg IV q12h)
Urinary tract Fluoroquinolone (ciprofloxacin 400 mg IV q12h) Ampicillin 2 g IV q4h plus
Gentamicin 1.5 mg/kg IV q8h or
Third-generation cephalosporin (cefotaxime 2 g IV q6h,
ceftriaxone 2 g IV q12h, or ceftizoxime 2 g IV q8h)
Necrotizing fasciitis Imipenem 0.5 g IV q6h Penicillin G (if confirmed group A streptococci)
Primary bacteremia (normal host) Piperacillin-tazobactam 3.375 g IV q6h plus Imipenem 0.5 g IV q6h plus
Vancomycin 1.5 g IV q12h Vancomycin 1.5 g IV q12h
Primary bacteremia (intravenous drug user) Vancomycin 1.5 g IV q12h plus Piperacillin-tazobactam 3.375 g IV q6h plus
Fluoroquinolone (ciprofloxacin 400 mg IV q12h) Vancomycin 1.5 g IV q12h
Febrile neutropenia Cefepime 2 g IV q8h plus Piperacillin-tazobactam 3.375 g IV q6h plus
Vancomycin 1.5 g IV q12h Gentamicin 1.5 mg/kg q8h or
Imipenem 0.5 g IV q6h plus
Gentamicin 1.5 mg/kg q8h
Bacterial meningitis Ceftriaxone 2 g IV q12h plus Gram-positive cocci: vancomycin plus ceftriaxone 2 g IV q12h
Ampicillin 3 g IV q6h plus Gram-negative diplococci: cefotaxime 2 g IV q4-6h
Vancomycin 1.5 g IV q12h plus Gram-positive bacilli: ampicillin 3 g IV q6h plus gentamicin
Dexamethasone 0.15 mg/kg IV q6h for 2-4 days Gram-negative bacilli: ceftazidime 2 g IV q8h plus gentamicin
1.5 mg/kg IV q8h
All above plus dexamethasone
Cellulitis Ciprofloxacin 400 mg IV q12h plus Imipenem 0.5 g IV q6h
Clindamycin 900 mg IV q8h
*Most antibiotic doses must be adjusted if there is hepatic or renal dysfunction. Some antibiotics require adjustment based on levels (e.g., gentamicin). In selecting a drug, carefully consider the patient’s
history of antibiotic (especially penicillin) allergy.

predicted body weight) decreases mortality from acute lung injury and acute
respiratory distress syndrome (Chapter 105). A1  eter. Patients whose acute lung injury is managed after 24 to 48 hours with a
Patients who require ventilation need adequate but not excessive sedation,
which can worsen hemodynamic instability, prolong ventilation, and increase
the risk for development of nosocomial pneumonia. Sedation should be
titrated by objective assessment. Daily interruption of sedation decreases the
duration of mechanical ventilation and intensive care. Weaning from mechani-
cal ventilation is often associated with fluid overload from prior fluid resuscita-
tion and from the reduction in intrathoracic pressure. Patients whose weaning
is guided by brain natriuretic peptide levels are weaned more quickly and have
more ventilator-free days because they generally receive more aggressive
diuretic therapy, without a concomitant increased need for vasopressors, an
increased risk of renal dysfunction, or more electrolyte abnormalities. A2  than 70%, packed red cell transfusions should be used to maintain a hemato-
Circulatory Therapy
Early therapy is the cornerstone of emergency management, but such
therapy need not achieve specific central hemodynamic targets or require the
placement of a central venous catheter or the administration of inotropic
agents or blood transfusions. A3  A4  Standard therapies should have the goal of
,
increasing tissue oxygen delivery by increasing profoundly low blood pres-
sure, increasing inadequate blood flow, increasing low arterial oxygen satura-
tion, and increasing mixed venous oxygen saturation. Although oxygen
delivery is higher in survivors than in nonsurvivors, it is not clear that a specific
oxygen delivery target is more beneficial than clinical end points. Several trials
have shown that supernormal global oxygen delivery does not decrease mor-
tality rates in sepsis and septic shock.
A mean arterial blood pressure goal of 65 to 70 mm Hg is as good as a goal
of 80 to 85 mm Hg. A5  However, a higher mean arterial pressure target (80 to
85 mm Hg) may decrease the risk of renal injury and the need for renal
replacement therapy in patients with preexisting hypertension. In patients
who have acute lung injury, no difference in outcomes is seen with  approach to persistent hypotension despite adequate fluid resuscitation, a
management using a pulmonary artery catheter versus a central venous cath-
conservative fluid strategy (compared with a liberal fluid strategy) have signifi-
cantly improved lung function and shorter duration of ventilation and ICU
stay.
Fluids should be used to maintain central venous pressure at 8 to 12 mm Hg;
at present, no convincing data indicate that albumin is better than normal
saline solution.5, A6  In patients with severe sepsis, large randomized trials
confirm that modified lactated Ringer solution or albumin is preferred to 10%
hetastarch (a colloid) because of lower rates of acute kidney injury, less need
for renal replacement therapy, and fewer deaths. A7  As a result, hetastarch
should not be used in septic shock. If central venous oxygen saturation is less
crit greater than 30%.
Vasopressors (e.g., norepinephrine, 1 to 50 µg/minute; epinephrine, 1 to 30
µg/minute) should be added if the mean arterial pressure is less than
65 mm Hg. Dobutamine (2.5 to 20 µg/kg/minute) is required if central venous
pressure, mean arterial pressure, and hematocrit are optimized but the central
venous oxygen saturation remains less than 70%. In a randomized trial of
patients with septic shock, the combination of norepinephrine plus dobuta-
mine resulted in a mortality similar to that with epinephrine alone, with no
differences in organ dysfunction, time to resolution of shock, or adverse
events. A8  In another randomized trial, norepinephrine was slightly but not
significantly better than dopamine for reducing mortality when used as the
first-line vasopressor for patients with septic shock A9 ; however, norepineph-
rine was associated with a lower rate of arrhythmias, especially atrial fibrilla-
tion. These accumulated data suggest that norepinephrine may be preferable
to dopamine as the first vasopressor in septic shock.
Clinicians can use epinephrine alone, norepinephrine alone, or norepineph-
rine plus dobutamine in patients with low cardiac output. As a strategic
690 CHAPTER 108  Shock Syndromes Related to Sepsis
vasopressor such as norepinephrine (1 to 50 µg/minute) can be added first. If
the cardiac index is low or if the mixed venous oxygen saturation is low (>70%)
despite an adequate central venous pressure, an inotropic agent such as dobu-
tamine should be added, initially at approximately 2 to 5 µg/kg/minute and
increasing until the mixed venous oxygen saturation is adequate. In some
patients in septic shock, the cardiac index is inadequate, as reflected by a low
mixed venous oxygen saturation despite a high central venous pressure
(>12 mm Hg) or pulmonary artery wedge pressure (>18 mm Hg) because of
underlying cardiovascular dysfunction or because of acute left ventricular dys-
function resulting from sepsis. In such patients, earlier use of an inotropic
agent such as dobutamine should be considered to increase left ventricular
contractility. The overall goal is to achieve an adequate mean arterial pressure
(>65 mm Hg), central venous pressure, and mixed venous oxygen saturation
while other indices of adequate perfusion are monitored, such as hourly urine
output (>0.5 mL/kg/hour), arterial lactate levels (<2 mmol/L), mental status,
and skin perfusion. To assess the adequacy of early resuscitation of severe
sepsis and septic shock and to guide ongoing therapy, a central venous
oxygen saturation goal greater than 70% or a lactate clearance of at least 10%
is an equally good measure. A10 
Fever, which is common in septic shock, may have some beneficial effects
for resisting infection but also increases oxygen demand. Reducing fever can
decrease the need for vasopressors and possibly the risk of septic encepha-
lopathy. In one large trial, external cooling for 48 hours to maintain core body
temperature between 36.5° C and 37° C was safe and decreased the need for
vasopressors as well as 14-day mortality rates (from 34% to 19%). A11  Cooling
to reduce fever to normothermia is especially promising for febrile septic
shock patients who are receiving high doses of vasopressors, require inotropic
agents, or have marked tachycardia.
Transfusion of Erythrocytes and Erythropoietin
Anemia is common in septic shock, but the optimal hemoglobin level for
resuscitation has been controversial. Recently, however, a randomized trial of
transfusion in critically ill patients with septic shock found that a transfusion
threshold of a hemoglobin level of 7 g/dL was equivalent to a threshold of 9
g/dL in terms of ischemic events, the need for life support, or death, while
reducing transfusions from a median of 4 units to a median of 1 unit. A12  its associated morbidity, mortality, and resource use (Fig. 108-2). In critically ill
Drugs
Antibiotics
The infected site and infecting organisms of septic shock are often not
known initially, and clinicians usually need to decide on an empirical antibiotic
regimen before knowing culture results in patients with septic shock. After
appropriate culture specimens are obtained, intravenous broad-spectrum
antibiotics should be administered on an emergency basis (within 1 hour)
while considering host factors such as immune and allergic status (Chapters
280 and 281; see Fig. 108-1). Emergency, empirical antibiotic therapy (Table
108-2) should be guided by the greater frequency of gram-positive bacteria,
the possibility of resistant organisms, and the local bacteriologic features. In
one large trial, meropenem alone was equivalent to the combination of
meropenem and moxifloxacin in terms of mortality rates and organ dysfunc-
tion. A13  Adding empirical fluconazole treatment does not result in better out-
comes in critically ill, non-neutropenic patients.
Because outcomes in patients with septic shock are worse if the organisms
causing the sepsis are not sensitive to the initial antibiotic regimen, a central
question is the relative value of using a single antibiotic compared with mul-
tiple antibiotics. Broad-spectrum antibiotics should be used for as short a time
as possible. If a causative organism is identified (<20% of septic patients have
negative cultures), the antibiotic regimen should be quickly narrowed with 3
to 5 days to decrease the emergence of resistant organisms. The duration of
antibiotics should be guided by the cause of septic shock, but patients gener-
ally require 10 to 14 days of therapy.
Corticosteroids
High-dose corticosteroids do not improve outcomes in the full spectrum of
patients with sepsis or acute respiratory distress syndrome, but the evidence
supporting the use of low-dose corticosteroids in septic shock is controversial.
In one trial, corticosteroids (hydrocortisone, 50 mg intravenously every 6
hours, plus fludrocortisone, 50-µg tablet/day per nasogastric tube or orally for
7 days) increased survival in septic patients whose serum cortisol response
after stimulation with an intravenous infusion of 250 µg of corticotropin
was 9 µg/dL or less. In a subsequent randomized trial of hydrocortisone (50 mg
every 6 hours intravenously for 5 days) versus placebo, however, mortality was
not improved, regardless of the patient’s response to corticotropin stimula-
tion. A14  Adding fludrocortisone to hydrocortisone does not appear to be
better than hydrocortisone alone, and aggressive insulin therapy to address
the hyperglycemia that often accompanies corticosteroid treatment is no
better than usual glucose control. A15  Hydrocortisone treatment is often associ-
ated with a shorter duration of septic shock but can increase the risk of super-
infections. Current sepsis guidelines suggest that corticosteroids should be
considered only in patients who are poorly responsive to vasopressors.
Corticosteroids administered before antibiotics also decrease the neuro-
logic sequelae of bacterial, especially pneumococcal, meningitis (Chapter
412). Enthusiasm for corticosteroid therapy must be tempered by the risk 
of complications such as superinfection, neuromyopathy, hyperglycemia,
immune suppression, and impaired wound healing.
Recombinant Human Activated Protein C
In septic shock, a deficiency of activated protein C is nearly universal, 
and low levels of activated protein C are associated with increased mortality.
However, recombinant human activated protein C infusion does not 
reduce mortality in patients who receive guideline-driven therapy for septic
shock, A16  and the drug has been removed from the worldwide market.
Vasopressin
Although vasopressin deficiency and downregulation of vasopressin recep-
tors are common findings in septic shock, a low-dose vasopressin infusion
added to norepinephrine is not significantly better than a norepinephrine
infusion alone in septic shock. A17  Whether vasopressin infusion may be benefi-
cial in patients with less severe shock is uncertain.
Hyperglycemia and Intensive Insulin Therapy
Hyperglycemia and insulin resistance are common in septic shock, but
intensive insulin therapy to control hyperglycemia is not beneficial in patients
in medical ICUs because of significantly higher rates of hypoglycemia and
perhaps increased mortality. A18  Therefore, intensive insulin therapy cannot be
recommended for patients with septic shock.
Renal Dysfunction and Dialysis
Acute renal failure is an important complication of septic shock because of
patients who have acute kidney injury, hemodialysis six times per week is no
better than conventional hemodialysis, and intensive renal replacement
therapy is no better than standard therapy overall or in patients who have
sepsis. A19 
Low-dose dopamine (2 to 4 µg/kg/minute) does not decrease the need for
renal support, does not improve outcomes, and is not recommended. Lactic
acidosis is a common complication of septic shock, but administration of
sodium bicarbonate in the setting of lactic acidosis does not improve hemo-
dynamics or the response to vasopressors.
A small randomized controlled trial evaluated the use of polymyxin B hemo-
perfusion in patients with abdominal sepsis to reduce blood endotoxin levels.
Polymyxin B hemoperfusion increased blood pressure, decreased vasopressor
requirements, improved organ dysfunction, and reduced mortality by one
third. However, this intervention requires further evaluation before it can be
recommended.
Other Therapies
Deep venous thrombosis prophylaxis with low-dose heparin is recom-
mended for patients who do not have active bleeding, coagulopathy, or a
contraindication to heparin (see Fig. 108-2). Low-molecular-weight heparin
does not decrease risk of deep venous thrombosis compared with unfraction-
ated heparin, but it may decrease the risk of pulmonary emboli in the critically
ill. A20  Stress ulcer prophylaxis with H2-receptor antagonists decreases the risk
of gastrointestinal hemorrhage. Proton pump inhibitors may also be effective,
but they have not been fully evaluated in septic shock.
Enteral nutrition is generally safer and more effective than total parenteral
nutrition A21 , but total parenteral nutrition is sometimes required in patients
with abdominal sepsis, surgery, or trauma.6 Initial trophic feeding, which pro-
vides about 25% of normal calorie requirements, appears to be as good as full
enteral feeding and is therefore recommended after stabilization of patients
in septic shock. A22  The use of sedation, neuromuscular blocking agents, and
corticosteroids should be minimized because they can exacerbate septic
encephalopathy and the polyneuropathy or myopathy of sepsis. Neutropenic
patients may benefit from granulocyte colony-stimulating factor (Chapter
167). The risk of nosocomial infection is decreased by narrow-spectrum anti-
biotics, early weaning from ventilation, and periodic removal and replacement
of catheters (Chapter 282).

B. Breathing—Oxygen, with a tidal volume 6 mL/kg IBW if ventilated.
Wean according to ARDSNet protocol (Chapters 105 and 106)
C. Circulation
• Fluids, vasopressors, inotropes, transfusion; goals include:
• MAP > 65 mm Hg
• CVP 8-12 mm Hg
• Hg 70-90 g/L
• ScvO2 > 70% (optional)
Consider pulmonary artery catheter or echocardiogram
especially if known cardiovascular disease; goals include:
• Wedge pressure 8-15 mm Hg
• Cardiac index: normal or increased
D. Drugs:
• Antibiotics: Narrow spectrum to cause of infection
• Hydrocortisone (if evidence of relative adrenal insufficiency
[see text]): hydrocortisone 50 mg intravenously every 6 hours
and fludrocortisone 50-µg tab orally or per NG tube daily for 7
days
Other Organ Support
• Renal function: Continuous renal replacement
• DVT prophylaxis: Low-dose heparin 5000 IU subcutaneously every
12 hours
• Stress ulcer prophylaxis: H2-receptor antagonist
(e.g., ranitidine 50 mg intravenously every 8 hours)
• Nutrition: Enteral preferred
• Sedation: Intermittent with daily awakening
FIGURE 108-2.  Ongoing critical care support and management in septic shock. CVP
= central venous pressure; DVT = deep venous thrombosis; Hg = hemoglobin; IBW = ideal
body weight; MAP = mean arterial pressure; NG = nasogastric; ScvO2 = central venous
oxygen saturation.
PROGNOSIS
The 28-day mortality of septic shock has decreased during the past 20 years
from about 50% to about 25 to 35%,7 especially in academic centers,8 prob-
ably because of the earlier initiation of appropriate therapies at appropriate
doses for limited periods. Early deaths (in the first 72 hours) are usually the
result of refractory, progressive shock despite escalating life support. Later
deaths from septic shock (after day 3) are usually secondary to multiple organ
dysfunction. The number of dysfunctional organs and the progression or lack
of improvement of organ dysfunction are indicators of increased risk of death.
Other factors that portend a poor prognosis are increased age, underlying
medical conditions, more severe illness, increased arterial lactate concentra-
tions, and the need for high-dose vasopressors. Furthermore, a delay in
achieving adequate resuscitation is associated with increased mortality.
As the number of survivors of septic shock has increased, so have the
numbers with significant long-term sequelae, including cognitive dysfunc-
tion,9 depression, and post-traumatic stress disorder. Survivors of septic
shock who also had acute lung injury (Chapter 104) can have weakness,
fatigue, and dyspnea on exertion after hospital discharge due to pulmonary
dysfunction, neuromuscular dysfunction, or other persistent organ dysfunc-
tion. Patients who have an episode of acute kidney injury during septic shock
have a significantly decreased long-term survival than patients without it.10
Overall, the survival and quality of life after hospital discharge after septic
shock remain poorer than expected for at least the next 10 years.11,12
A3. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic
shock. N Engl J Med. 2014;370:1683-1693.
A4. Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic
shock. N Engl J Med. 2014;371:1496-1506.
A5. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic
shock. N Engl J Med. 2014;370:1583-1593.
A6. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic
shock. N Engl J Med. 2014;370:1412-1421.
A7. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and
network meta-analysis. Ann Intern Med. 2014;161:347-355.
A8. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone
for management of septic shock: a randomized trial. Lancet. 2007;370:676-684.
A9. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the
treatment of septic shock. N Engl J Med. 2010;362:779-789.
A10. Jones AE, Shapiro NI, Trzeziak S, et al. Lactate clearance vs. central venous oxygen saturation as
goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303:739-746.
A11. Schortgen F, Clabault K, Katsahian S, et al. Fever control using external cooling in septic shock: a
randomized controlled trial. Am J Respir Crit Care Med. 2012;185:1088-1095.
A12. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion
in septic shock. N Engl J Med. 2014;371:1381-1391.
A13. Brunkhorst FM, Oppert M, Marx G, et al. Effect of empirical treatment with moxifloxacin and
meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a
randomized trial. JAMA. 2012;307:2390-2399.
A14. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl
J Med. 2008;358:111-124.
A15. Annane D, Cariou A, Maxime V, et al. Corticosteroid treatment and intensive insulin therapy for
septic shock in adults: a randomized controlled trial. JAMA. 2010;303:341-348.
A16. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock.
N Engl J Med. 2012;366:2055-2064.
A17. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with
septic shock. N Engl J Med. 2008;358:877-887.
A18. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill
patients. N Engl J Med. 2009;360:1283-1297.
A19. Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support in critically ill patients with
acute kidney injury. N Engl J Med. 2008;359:7-20.
A20. Cook D, Meade M, Guyatt G, et al. Dalteparin versus unfractionated heparin in critically ill
patients. N Engl J Med. 2011;364:1305-1314.
A21. Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically
ill adults. N Engl J Med. 2014;371:1673-1684.
A22. Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with
acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795-803.
GENERAL REFERENCES
For the General References and other additional features, please visit Expert Consult
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A1. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared
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agement during ventilator weaning: a randomized controlled trial. Am J Respir Crit Care Med.
2012;186:1256-1263.
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1. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840-851.
2. Funk DJ, Jacobsohn E, Kumar A. The role of venous return in critical illness and shock—part I:
physiology. Crit Care Med. 2013;41:255-262.
3. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369:1726-1734.
4. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for
management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.
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8. Walkey AJ, Wiener RS. Hospital case volume and outcomes among patients hospitalized with severe
sepsis. Am J Respir Crit Care Med. 2014;189:548-555.
9. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical
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decreased long-term survival in the critically ill. Am J Respir Crit Care Med. 2014;189:1075-1081.
11. Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional disability
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2211-2218.
691.e2 CHAPTER 108  Shock Syndromes Related to Sepsis
 

REVIEW QUESTIONS 2. Septic shock has not been shown to be associated with which of the fol-
lowing complications during post-hospitalization recovery?
1. Which of the following statements about dopamine in septic shock is
correct? A. Cognitive dysfunction
B. Decreased long-term survival
A. Low-dose dopamine is effective in decreasing the risk of acute kidney C. Neuromuscular dysfunction
injury. D. Impaired quality of life
B. Dopamine infusion was associated with increased cardiovascular E. Recurrent seizure disorder
adverse effects compared with norepinephrine in a large mortality-
powered randomized controlled trial. Answer: E  Cognitive function, long-term survival, neuromuscular function,
C. Dopamine increases mean arterial pressure excessively compared with and quality of life are all reduced among survivors of severe sepsis. However,
norepinephrine. survivors of septic shock do not have increased risk of recurrent seizures.
D. Dopamine alters dopaminergic receptor neurologic functions and (Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive
alters mental status in septic shock. impairment after critical illness. N Engl J Med. 2013;369:1306-1316. Her-
E. Randomized controlled trial evidence shows that dopamine infusion ridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after acute
shortens the duration of vasopressor support compared with respiratory distress syndrome. N Engl J Med. 2011;364:1293-1304. Iwashyna
norepinephrine. TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional
disability among survivors of severe sepsis. JAMA. 2010;304:1787-1794.)
Answer: B  Dopamine infusion is associated with increased cardiovascular
adverse effects compared with norepinephrine (De Backer D, Biston P, Devr-
iendt J, et al. Comparison of dopamine and norepinephrine in the treatment
of septic shock. N Engl J Med. 2010;362:779-789; Patel GP, Grahe JS, Sperry
M, et al. Efficacy and safety of dopamine versus norepinephrine in the man-
agement of septic shock. Shock. 2010;33:375-380.). Low-dose dopamine
does not decrease the risk of acute kidney injury (Bellomo R, Chapman M,
Finfer S, et al. Australian and New Zealand Intensive Care Society Clinical
Trials Group. Low dose dopamine in patients with early renal dysfunction: a
placebo controlled randomised trial. Lancet. 2000;356:2139-2143.) and is
not recommended in the surviving sepsis guidelines (Dellinger RP, Levy
MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines
for management of severe sepsis and septic shock: 2012. Crit Care Med.
2013;41:580-637.) for this reason. There is no convincing evidence that
dopamine increases mean arterial pressure excessively compared with nor-
epinephrine; both are given as continuous infusions that can be effectively
titrated to a target mean arterial pressure. Although there are dopaminergic
neurons, there is no evidence that dopamine infusion alters dopaminergic
receptor neurologic functions or alters mental status in septic shock. There
is no evidence that dopamine shortens the duration of vasopressor support
compared with norepinephrine (De Backer D, Biston P, Devriendt J, et al.
Comparison of dopamine and norepinephrine in the treatment of septic
shock. N Engl J Med. 2010;362:779-789.).