2243 Sepsis and Septic Shock CHAPTER 304

immunopathologic damage will determine whether uncomplicated

infection becomes sepsis.

Initiation of Inflammation Over the past decade, our knowledge

of pathogen recognition has increased tremendously. Host response

to infection is initiated when pathogens are recognized and bound by

innate immune cells, particularly macrophages (Chap. 349). Pathogen

recognition receptors (PRRs) present on the surface of immune cells

bind pathogen-associated molecular patterns (PAMPs), which are

structures conserved across microbial species. The interaction of PRRs

with PAMPs results in upregulation of inflammatory gene transcription and activation of innate immunity (Fig. 304-1). Four main PRR

classes are prominent: Toll-like receptors (TLRs), RIG-I-like receptors,

C-type lectin receptors, and NOD-like receptors; the activity of the last

group occurs partially in protein complexes called inflammasomes. Up

to 10 TLRs have been identified in humans. Although many PAMPs

have been described, including viral RNAs and flagellin, a common

PAMP is the lipid A moiety of lipopolysaccharide (LPS or endotoxin)

found in the outer membrane of gram-negative bacteria. LPS first

attaches to the LPS-binding protein on the surface of monocytes,

macrophages, and neutrophils. It is then transferred to and signals via

TLR4 to produce and release proinflammatory cytokines such as tumor

necrosis factor and interleukin 1 (IL-1) that grow the signal and alert

other cells and tissues.

In addition to pathogen recognition, PRRs also sense endogenous

molecules released from injured cells—so-called damage-associated

molecular patterns (DAMPs). DAMPs, or “alarmins,” are nuclear, cytoplasmic, or mitochondrial structures that are released from cells as a

result of infection, tissue injury, or cell necrosis. Examples of DAMPs

include high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones. Once released into the extracellular environment, DAMPs are recognized by PRRs on immune cells, resulting

in upregulation of proinflammatory cytokine production. Other cellular elements released during infection include reactive oxygen species,

microparticles, proteolytic enzymes, and neutrophil extracellular traps,

which can also influence inflammatory processes.

Concurrent to macrophage activation, polymorphonuclear leukocyte (PMN) surface receptors also bind microbial components. This

interaction results in the expression of surface adhesion molecules that

cause PMN aggregation and margination to the vascular endothelium.

Through a multistep process of rolling, adhesion, diapedesis, and chemotaxis, PMNs migrate to the site of infection, releasing inflammatory

mediators responsible for local vasodilation, hyperemia, and increased

microvascular permeability.

Sepsis occurs when these local proinflammatory immune processes

become exaggerated, resulting in a generalized immune response.

Though it remains unclear why this malignant transition occurs, direct

effects of the invading microorganism, overproduction of proinflammatory mediators, and activation of the complement system have all

been implicated.

Coagulation Abnormalities Sepsis is commonly associated with

coagulation disorders and frequently leads to disseminated intravascular coagulation. Abnormalities in coagulation are thought to isolate

invading microorganisms and/or to prevent the spread of infection and

inflammation to other tissues and organs. Excess fibrin deposition is

Electron transport chain activity

ATP

Lactate/H+

DO2

CELL INTERSTITIUM MICROCIRCULATION

Inflammation

Hypotension

Hypovolemia

Vasodilation

 DO2

 Barrier function

 Tissue

oxygenation

Thrombus/

Platelets

 Antithrombin

 Tissue factor

pathway inhibitor

 Tissue factor

 Protein C

 Activated

protein C

 Fibrinolysis

 Tissue edema

 Increased

O2 diffusion

distance

Activated

leukocyte

Endothelial

leak/dysfunction

Cytokines

Activated endothelium

ICAM, VCAM-1 expression

Innate immune

cells

Pathogens

PAMPs

TLR,

NLR, or

CLR

DAMPs

Inflammatory

mediators

 Adhesion

Transmigration

 Tissue

damage

 Lactate/H+

Altered

microvascular

flow

Mitochondrial

dysfunction

FIGURE 304-1 Select mechanisms implicated in the pathogenesis of sepsis-induced organ and cellular dysfunction. The host response to sepsis involves multiple

mechanisms that lead to decreased oxygen delivery (DO2

) at the tissue level. The duration, extent, and direction of these interactions are modified by the organ under threat,

host factors (e.g., age, genetic characteristics, medications), and pathogen factors (e.g., microbial load and virulence). The inflammatory response is typically initiated by

an interaction between pathogen-associated molecular patterns (PAMPs) expressed by pathogens and pattern recognition receptors expressed by innate immune cells

on the cell surface (Toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors

and nucleotide-binding oligomerization domain–like receptors [NLRs]). The resulting tissue damage and necrotic cell death lead to release of damage-associated molecular

patterns (DAMPs) such as uric acid, high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones. These molecules promote the activation

of leukocytes, leading to greater endothelial dysfunction, expression of intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule 1 (VCAM-1) on the

activated endothelium, coagulation activation, and complement activation. This cascade is compounded by macrovascular changes such as vasodilation and hypotension,

which are exacerbated by greater endothelial leak tissue edema, and relative intravascular hypovolemia. Subsequent alterations in cellular bioenergetics lead to greater

glycolysis (e.g., lactate production), mitochondrial injury, release of reactive oxygen species, and greater organ dysfunction.

2244 PART 8 Critical Care Medicine

driven by coagulation via tissue factor, a transmembrane glycoprotein

expressed by various cell types; by impaired anticoagulant mechanisms, including the protein C system and antithrombin; and by compromised fibrin removal due to depression of the fibrinolytic system.

Coagulation (and other) proteases further enhance inflammation via

protease-activated receptors. In infections with endothelial predominance (e.g., meningococcemia), these mechanisms can be common

and deadly.

Organ Dysfunction Although the mechanisms that underlie

organ failure in sepsis are only partially known, both cellular and

hemodynamic alterations play a key role. Key contributing factors

include aberrant inflammatory response, cellular alterations, endothelial dysfunction, and circulatory abnormalities. Aberrant inflammation

causes cellular damage, increasing the risk of organ dysfunction. Cellular alterations, including impaired cell death pathways, mitochondrial

dysfunction, and intracellular handling of reactive oxygen species, play

a key role. For example, mitochondrial damage due to oxidative stress

and other mechanisms impairs cellular oxygen utilization. The slowing

of oxidative metabolism, in parallel with impaired oxygen delivery,

reduces cellular O2

 extraction. Yet energy (i.e., ATP) is still needed to

support basal, vital cellular function, which derives from glycolysis and

fermentation and thus yields H+ and lactate. With severe or prolonged

insult, ATP levels fall beneath a critical threshold, bioenergetic failure

ensues, toxic reactive oxygen species are released, and apoptosis leads

to irreversible cell death and organ failure. Endothelial dysfunction is

also critical to the pathogenesis of multiple organ failure common to

sepsis. Cell-cell connections in the vascular endothelium are disrupted

in sepsis due to a number of factors, resulting in loss of barrier integrity, giving rise to subcutaneous and body-cavity edema. Endothelial

glycocalyx disruption also contributes to endothelial permeability and

edema formation. Circulatory dysfunction, both at the systemic and

microcirculatory level, is also common in sepsis and contributes to the

development of organ failure. Uncontrolled release of nitric oxide from

cellular damage causes vasomotor collapse, opening of arteriovenous

shunts, and pathologic shunting of oxygenated blood from susceptible

tissues. Microcirculatory complications, including microthrombosis

and decreased capillary density, also impair tissue oxygen delivery,

resulting in the development of organ dysfunction.

Emerging evidence suggests the gut may also play an independent

role in the development of sepsis-associated organ dysfunction. Proposed hypotheses include bacterial translocation through impaired

mucosal integrity, release of toxic mediators by injured gut mucosa,

and even alteration in gut microbiome due to critical illness. The

resulting morphologic changes in sepsis-induced organ failure are also

complex. Generally, organs such as the lung undergo extensive microscopic changes, while other organs may undergo rather few histologic

changes. In fact, some organs (e.g., the kidney) may lack significant

structural damage while still having significant tubular-cell changes

that impair function.

Anti-inflammatory Mechanisms The immune system harbors

humoral, cellular, and neural mechanisms that may exacerbate the

potentially harmful effects of the proinflammatory response. Phagocytes can switch to an anti-inflammatory phenotype that promotes

tissue repair, while regulatory T cells and myeloid-derived suppressor

cells further reduce inflammation. The so-called neuroinflammatory reflex may also contribute: sensory input is relayed through the

afferent vagus nerve to the brainstem, from which the efferent vagus

nerve activates the splenic nerve in the celiac plexus, with consequent

norepinephrine release in the spleen and acetylcholine secretion by a

subset of CD4+ T cells. The acetylcholine release targets α7 cholinergic

receptors on macrophages, reducing proinflammatory cytokine release.

Disruption of this neural-based system by vagotomy renders animals

more vulnerable to endotoxin shock, while stimulation of the efferent

vagus nerve or α7 cholinergic receptors attenuates systemic inflammation in experimental sepsis.

Immune Suppression Patients who survive early sepsis but

remain dependent on intensive care occasionally demonstrate evidence

of a suppressed immune system. These patients may have ongoing

infectious foci despite antimicrobial therapy or may experience the

reactivation of latent viruses. Multiple investigations have documented

reduced responsiveness of blood leukocytes to pathogens in patients

with sepsis; these findings were recently corroborated by postmortem

studies revealing strong functional impairments of splenocytes harvested from ICU patients who died of sepsis. Immune suppression was

evident in the lungs as well as the spleen; in both organs, the expression

of ligands for T cell–inhibitory receptors on parenchymal cells was

increased. Enhanced apoptotic cell death, especially of B cells, CD4+

T cells, and follicular dendritic cells, has been implicated in sepsisassociated immune suppression and death. In a cohort of >1000

ICU admissions for sepsis, secondary infections developed in 14% of

patients, and the associated genomic response at the time of infection

was consistent with immune suppression, including impaired glycolysis

and cellular gluconeogenesis. The most common secondary infections

included catheter-related bloodstream infections, ventilator-associated

infections, and abdominal infections. Efforts are ongoing to identify

those sepsis patients who have hyperinflamed rather than immunosuppressed phenotypes. Improved identification and monitoring of

host immune response could be helpful for guiding immunologic

therapies. The dynamic nature of the immune response (i.e., response

can vary at different stages of sepsis and change rapidly) and unclear

understanding of whether the dysfunctional immune system is driving

organ dysfunction or whether the immune system itself is just another

dysfunctional organ, remain challenges.

APPROACH TO THE PATIENT

Sepsis and Septic Shock

At the bedside, a clinician begins by asking, “Is this patient septic?” Consensus criteria for sepsis and septic shock agree on core

diagnostic elements, including suspected or documented infection

accompanied by acute, life-threatening organ dysfunction. If infection is documented, the clinician must determine the inciting cause

and the severity of organ dysfunction, usually by asking: “What

just happened?” Severe infection can be evident, but it is often

quite difficult to recognize. Many infection-specific biomarkers

and molecular diagnostics are under study to help discriminate

sterile inflammation from infection, but these tools are not commonly used. The clinician’s acumen is still crucial to the diagnosis

of infection. Next, the primary physiologic manifestations of organ

dysfunction can be assessed quickly at the bedside with a sixorgan framework, yielding the SOFA score. Particular focus should

then be placed on the presence or absence of shock, which constitutes a clinical emergency. The general manifestations of shock

include arterial hypotension with evidence of tissue hypoperfusion

(e.g., oliguria, altered mental status, poor peripheral perfusion, or

hyperlactemia).

■ CLINICAL MANIFESTATIONS

The specific clinical manifestations of sepsis are quite variable, depending on the initial site of infection, the offending pathogen, the pattern

of acute organ dysfunction, the underlying health of the patient, and

the delay before initiation of treatment. The signs of both infection

and organ dysfunction may be subtle. Guidelines provide a long list of

potential warning signs of incipient sepsis (Table 304-1). Once sepsis

has been established and the inciting infection is assumed to be under

control, the temperature and white blood cell (WBC) count often

return to normal. However, organ dysfunction typically persists.

Cardiorespiratory Failure Two of the most commonly affected

organ systems in sepsis are the respiratory and cardiovascular systems.

Respiratory compromise classically manifests as acute respiratory

distress syndrome (ARDS), defined as hypoxemia and bilateral infiltrates of noncardiac origin that arise within 7 days of the suspected

infection. ARDS can be classified by Berlin criteria as mild (Pao2

/Fio2

,

201–300 mmHg), moderate (101–200 mmHg), or severe (≤100 mmHg).

2245 Sepsis and Septic Shock CHAPTER 304

A common competing diagnosis is hydrostatic

edema secondary to cardiac failure or volume

overload. Although traditionally identified

by elevated pulmonary capillary wedge measurements from a pulmonary artery catheter

(>18 mmHg), cardiac failure can be objectively

evaluated on the basis of clinical judgment or

focused echocardiography.

Cardiovascular compromise typically

presents as hypotension. The cause can be

frank hypovolemia, maldistribution of blood

flow and intravascular volume due to diffuse

capillary leakage, reduced systemic vascular

resistance, or depressed myocardial function.

After adequate volume expansion, hypotension frequently persists, requiring the use of

vasopressors. In early shock, when volume

status is reduced, systemic vascular resistance

may be quite high with low cardiac output;

after volume repletion, however, this picture

may rapidly change to low systemic vascular

resistance and high cardiac output.

Kidney Injury Acute kidney injury (AKI) is

documented in >50% of septic patients, increasing the risk of in-hospital death by six- to eightfold. AKI manifests as oliguria, azotemia, and

rising serum creatinine levels and frequently

requires dialysis. The mechanisms of sepsisinduced AKI are incompletely understood.

AKI may occur in up to 25% of patients in the

absence of overt hypotension. Current mechanistic work suggests that a combination of diffuse microcirculatory

blood-flow abnormalities, inflammation, and cellular bioenergetic

responses to injury contribute to sepsis-induced AKI beyond just organ

ischemia.

Neurologic Complications Typical central nervous system dysfunction presents as coma or delirium. Imaging studies typically show

no focal lesions, and electroencephalographic findings are usually

consistent with nonfocal encephalopathy. Sepsis-associated delirium is

considered a diffuse cerebral dysfunction caused by the inflammatory

response to infection without evidence of a primary central nervous

system infection. Consensus guidelines recommend delirium screening with valid and reliable tools such as the Confusion Assessment

Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care

Delirium Screening Checklist (ICDSC). Critical-illness polyneuropathy and myopathy are also common, especially in patients with a prolonged course. For survivors of sepsis, neurologic complications can

be severe. Postsepsis syndrome, an emerging pathologic entity characterized by long-term cognitive impairment and functional disability,

affects 25−50% of sepsis survivors. In a national (U.S.) representative

prospective cohort of >1000 elderly patients with severe sepsis, moderate to severe cognitive impairment increased by 10.6 percentage points

among patients who survived severe sepsis (odds ratio, 3.34; 95% CI,

1.53–7.25) over that among survivors of nonsepsis hospitalizations.

Many of these limitations persisted for up to 8 years. The mechanisms

of the neurocognitive derangements in postsepsis syndrome are not

fully understood; however, a combination of cerebrovascular injury,

metabolic derangements, and neuroinflammation is proposed.

Additional Manifestations Many other abnormalities occur in

sepsis, including ileus, elevated aminotransferase levels, altered glycemic control, thrombocytopenia and disseminated intravascular coagulation, adrenal dysfunction, and sick euthyroid syndrome. Adrenal

dysfunction in sepsis is widely studied and is thought to be related

more to reversible dysfunction of the hypothalamic-pituitary axis or

tissue glucocorticoid resistance than to direct damage to the adrenal

gland. The diagnosis is difficult to establish. Recent clinical practice

guidelines do not recommend use of the adrenocorticotropic hormone

stimulation test or determination of the plasma cortisol level to detect

relative glucocorticoid insufficiency.

■ DIAGNOSIS

Laboratory and Physiologic Findings A variety of laboratory

and physiologic changes are found in patients with suspected infection

who are at risk for sepsis. In a 12-hospital cohort of electronic health

records related to >70,000 encounters (Fig. 304-2), only tachycardia

(heart rate, >90 beats/min) was present in >50% of encounters; the

most common accompanying abnormalities were tachypnea (respiratory rate, >20 breaths/min), hypotension (systolic blood pressure,

≤100 mmHg), and hypoxia (SaO2

, ≤90%). Leukocytosis (WBC count,

>12,000/μL) was present in fewer than one-third of patients and leukopenia (WBC count, <4000/μL) in fewer than 5%. Notably, many

features that may identify acute organ dysfunction, such as platelet

count, total bilirubin, or serum lactate level, are measured in only a

small minority of at-risk encounters. If measured, metabolic acidosis

with anion gap may be detected, as respiratory muscle fatigue occurs

in sepsis-associated respiratory failure. Other, less common findings

include serum hypoalbuminemia, troponin elevation, hypoglycemia,

and hypofibrinogenemia.

Diagnostic Criteria There is no specific test for sepsis, nor is there

a gold-standard method for determining whether a patient is septic. In

fact, the definition of sepsis can be written as a logic statement:

sepsis = f (threat to life | organ dysfunction | dysregulated host response

| infection),

where sepsis is the dependent variable, which in turn is a function of

four independent variables linked in a causal pathway, with—from left

to right—one conditional upon the other. There may be uncertainty

about whether each variable exists, whether it can be measured, and

whether the causal and conditional relationships hold. If we assume

that organ dysfunction exists and can be measured, then attributing

the marginal degradation in function to a dysregulated host response

is not simple and requires the ability to determine preexisting dysfunction, other noninfectious contributions to organ dysfunction,

Heart rate

Respiratory rate

Temperature

White blood cell count

Temperature

White blood cell count

Bands

Systolic blood pressure

Serum creatinine

PaO2/FiO2 ratio

Platelets

Glasgow coma scale

Bilirubin

Mechanical ventilation

Vasopressors

Vasopressors

≤100 mmHg

≥1.2 mmHg

≤300

≤150 k/µL

<15

≥1.2 mg/dL

>90 BPM

>20 BPM

<36 C

>12 k/µL

<4 k/µL

>38 C

>10 %

Present/absent

Present/absent

More than one

Variable

SIRS

variables

SOFA

variables

Threshold Units

FIGURE 304-2 Distribution of systemic inflammatory response syndrome (SIRS) and sequential (or sepsisrelated) organ failure assessment (SOFA) variables among infected patients at risk for sepsis, as documented

in the electronic health record. Dark green bars represent the proportion of such patients with abnormal

findings; light green bars, the proportion with normal findings; and white bars, the proportion with missing

data. (Adapted from CW Seymour et al: Assessment of clinical criteria for sepsis: For the Third International

Consensus Definitions for Sepsis and Septic Shock [Sepsis-3]. JAMA 315:762, 2016.)

2246 PART 8 Critical Care Medicine

Health Health

Organ

dysfunction

Uncomplicated

infection

Sepsis Sepsis

Uncomplicated

Organ infection

dysfunction

FIGURE 304-3 Schematic of the importance of accurate, easy-to-use criteria for sepsis and its components, infection and organ dysfunction. In the ideal case (left), criteria

clearly distinguish sepsis patients from other patients with uncomplicated infection or organ dysfunction. The reality (right), however, is that existing criteria fail to make

clear distinctions, leaving a significant proportion of patients in areas of uncertainty. (Reproduced with permission from DC Angus et al: A framework for the development

and interpretation of different sepsis definitions and clinical criteria. Crit Care Med 44:e113, 2016.)

and—ideally—the mechanism by which the host response to an infection causes organ dysfunction.

In order to sort through these complex details, clinicians need simple bedside criteria to operationalize the logic statement (Fig. 304-3).

The Sepsis Definitions Task Force, with the introduction of Sepsis-3,

has recommended that, once infection is suspected, clinicians consider

whether it has caused organ dysfunction by determining a SOFA score.

The SOFA score ranges from 0 to 24 points, with up to 4 points accrued

across six organ systems. The SOFA score is widely studied in the ICU

among patients with infection, sepsis, and shock. With ≥2 new SOFA

points, the infected patient is considered septic and may be at ≥10%

risk of in-hospital death.

To aid in early identification of infected patients, the quick SOFA

(qSOFA) and the National Early Warning Score (NEWS) scores are proposed as clinical prompts to identify patients at high risk of sepsis outside

the ICU, whether on the medical ward or in the emergency department.

The qSOFA score ranges from 0 to 3 points, with 1 point each for systolic

hypotension (≤100 mmHg), tachypnea (≥22 breaths/min), or altered

mentation. A qSOFA score of ≥2 points has a predictive value for sepsis

similar to that of more complicated measures of organ dysfunction. The

National Early Warning Score (NEWS) is an aggregate scoring system

derived from six physiologic parameters, including respiratory rate, oxygen saturation, systolic blood pressure, heart rate, altered mentation, and

temperature. Recent work has also shown that, although SIRS criteria may

be fulfilled in sepsis, they sometimes are not and do not meaningfully

contribute to the identification of patients with suspected infection who

are at greater risk of a poor course, ICU admission, or death—outcomes

more common among patients with sepsis than among those without.

Septic shock is a subset of sepsis in which circulatory and cellular/

metabolic abnormalities are profound enough to substantially increase

mortality risk, but the application of this definition as a criterion for

enrollment of patients varies significantly in clinical trials, observational studies, and quality improvement work. For clarity, criteria are

proposed for septic shock that include (1) sepsis plus (2) the need for

vasopressor therapy to elevate mean arterial pressure to ≥65 mmHg,

with (3) a serum lactate concentration >2.0 mmol/L after adequate

fluid resuscitation.

Arterial lactate is a long-studied marker of tissue hypoperfusion,

and hyperlactemia and delayed lactate clearance are associated with

a greater incidence of organ failure and death in sepsis. In a study of

>1200 patients with suspected infection, 262 (24%) of 1081 patients

exhibited an elevated lactate concentration (≥2.5 mmol/L) even in the

setting of normal systolic blood pressure (>90 mmHg) and were at elevated risk of 28-day in-hospital mortality. However, lactic acidosis may

occur in the presence of alcohol intoxication, liver disease, diabetes

mellitus, administration of total parenteral nutrition, or antiretroviral

treatment, among other conditions. Furthermore, in sepsis, an elevated

lactate concentration may simply be the manifestation of impaired

clearance. These factors may confound the use of lactate as a standalone biomarker for the diagnosis of sepsis; thus, it should be used in

the context of other markers of infection and organ dysfunction.

TREATMENT

Sepsis and Septic Shock

EARLY TREATMENT OF SEPSIS AND SEPTIC SHOCK

Recommendations for sepsis care begin with prompt diagnosis.

Recognition of septic shock by a clinician constitutes an emergency in which immediate treatment can be life-saving. Up-to-date

guidelines for treatment are derived from international clinical

practice guidelines provided by the Surviving Sepsis Campaign.

This consortium of critical care, infectious disease, and emergency

medicine professional societies has issued three iterations of clinical

guidelines for the management of patients with sepsis and septic

shock (Table 304-2).

The initial management of infection requires several steps: forming a probable diagnosis, obtaining samples for culture, initiating

empirical antimicrobial therapy, and achieving source control. More

than 30% of patients with sepsis require source control, mainly for

abdominal, urinary, and soft-tissue infections. The mortality rate is

lower among patients with source control than among those without, although the timing of intervention is debated. Antibiotic delay

may be deadly. For every 1-h delay among septic patients, a 3−7%

increase in the odds of in-hospital death is reported. Thus, international clinical practice guidelines recommend the administration of

appropriate broad-spectrum antibiotics within 1 h of recognition of

sepsis or septic shock. For empirical therapy, the appropriate choice

depends on the suspected site of infection, the location of infection

onset (i.e., the community, a nursing home, or a hospital), the

patient’s medical history, and local microbial susceptibility patterns

(Table 304-3). In a single-center study of >2000 patients with bacteremia, the number of patients who needed to receive appropriate

antimicrobial therapy in order to prevent one patient death was 4.0

(95% CI, 3.7–4.3). Empirical antifungal therapy should be administered only to septic patients at high risk for invasive candidiasis.

The treatment elements listed above form the basis for a 1-h

bundle of care, replacing the previous guidelines recommending treatment initiation within 3−6 h. This management bundle

includes five components: (1) measurement of serum lactate levels,

(2) collection of blood for culture before antibiotic administration,

(3) administration of appropriate broad-spectrum antibiotics, (4)

initiation of a 30 mL/kg crystalloid bolus for hypotension or lactate

≥4 mmol/L, and (5) treatment with vasopressors for persistent

2247 Sepsis and Septic Shock CHAPTER 304

TABLE 304-2 Elements of Care in Sepsis and Septic Shock: Recommendations Adapted from International Consensus Guidelines

Resuscitation

Sepsis and septic shock constitute an emergency, and treatment should begin right away.

Resuscitation with IV crystalloid fluid (30 mL/kg) should begin within the first 3 h.

Saline or balanced crystalloids are suggested for resuscitation.

If the clinical examination does not clearly identify the diagnosis, hemodynamic assessments (e.g., with focused cardiac ultrasound) can be considered.

In patients with elevated serum lactate levels, resuscitation should be guided toward normalizing these levels when possible.

In patients with septic shock requiring vasopressors, the recommended target mean arterial pressure is 65 mmHg.

Hydroxyethyl starches and gelatins are not recommended.

Norepinephrine is recommended as the first-choice vasopressor.

Vasopressin should be used with the intent of reducing the norepinephrine dose.

The use of dopamine should be avoided except in specific situations—e.g., in those patients at highest risk of tachyarrhythmias or relative bradycardia.

Dobutamine use is suggested when patients show persistent evidence of hypoperfusion despite adequate fluid loading and use of vasopressors.

Red blood cell transfusion is recommended only when the hemoglobin concentration decreases to <7.0 g/dL in the absence of acute myocardial infarction, severe

hypoxemia, or acute hemorrhage.

Infection Control

So long as no substantial delay is incurred, appropriate samples for microbiologic cultures should be obtained before antimicrobial therapy is started.

IV antibiotics should be initiated as soon as possible (within 1 h); specifically, empirical broad-spectrum therapy should be used to cover all likely pathogens.

Antibiotic therapy should be narrowed once pathogens are identified and their sensitivities determined and/or once clinical improvement is evident.

If needed, source control should be undertaken as soon as is medically and logistically possible.

Daily assessment for de-esclation of antimicrobial therapy should be conducted.

Respiratory Support

A target tidal volume of 6 mL/kg of predicted body weight (compared with 12 mL/kg in adult patients) is recommended in sepsis-induced ARDS.

A higher PEEP rather than a lower PEEP is used in moderate to severe sepsis-induced ARDS.

In severe ARDS (Pao2

/Fio2

, <150 mmHg), prone positioning is recommended, and recruitment maneuvers and/or neuromuscular blocking agents for ≤48 h are suggested.

A conservative fluid strategy should be used in sepsis-induced ARDS if there is no evidence of tissue hypoperfusion.

Routine use of a pulmonary artery catheter is not recommended.

Spontaneous breathing trials should be used in mechanically ventilated patients who are ready for weaning.

General Supportive Care

Patients requiring a vasopressor should have an arterial catheter placed as soon as is practical.

Hydrocortisone is not suggested in septic shock if adequate fluids and vasopressor therapy can restore hemodynamic stability.

Continuous or intermittent sedation should be minimized in mechanically ventilated sepsis patients, with titration targets used whenever possible.

A protocol-based approach to blood glucose management should be used in ICU patients with sepsis, with insulin dosing initiated when two consecutive blood glucose

levels are >180 mg/dL.

Continuous or intermittent renal replacement therapy should be used in patients with sepsis and acute kidney injury.

Pharmacologic prophylaxis (unfractionated heparin or low-molecular-weight heparin) against venous thromboembolism should be used in the absence of

contraindications.

Stress ulcer prophylaxis should be given to patients with risk factors for gastrointestinal bleeding.

The goals of care and prognosis should be discussed with patients and their families.

Abbreviations: ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PEEP, positive end-expiratory pressure.

Source: Adapted from A Rhodes et al: Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med 45:486, 2017.

hypotension or shock. Serum lactate levels should be remeasured if

initial level ≥2 mmol/L.

Other elements of the management bundle are cardiorespiratory

resuscitation and mitigation of the immediate threats of uncontrolled infection. Early resuscitation requires a structured approach

including the administration of IV fluids and vasopressors, with

oxygen therapy and mechanical ventilation to support injured

organs. The exact components required to optimize resuscitation,

such as choice and amount of fluid, appropriate type and intensity

of hemodynamic monitoring, and role of adjunctive vasoactive

agents, all remain controversial.

Evidence suggests that protocolized treatment bundles may confer a greater survival advantage than clinical assessments of organ

perfusion and management without a protocol. Though the cornerstone of all sepsis treatment bundles is early antibiotic administration and rapid restoration of perfusion, bundle timing and intensity

remain controversial. Arguably the first protocol-based sepsis treatment strategy—early, goal-directed therapy (EGDT)—included

an aggressive resuscitation protocol with specific hemodynamic

thresholds for fluid administration, blood transfusion, and use

of inotropes. Given the many controversial features of this older

single-center trial, subsequent trials, including ProCESS, ARISE,

and ProMISe, compared protocol-based standard care with protocol-based EGDT and usual care. Each found that EGDT offered no

mortality benefit in early septic shock but did increase treatment

intensity and cost. Multiple subsequent meta-analyses of these trials

confirmed that EGDT offers no mortality benefit while increasing health care utilization and ICU admission in well-resourced

countries. Modified versions of EGDT were also tested in lowerresourced settings, with no change in outcome. Thus, EGDT is no

longer recommended as the primary strategy for early resuscitation

in septic shock. More contemporary treatment bundles recommended initiating treatment within 3−6 h, but these management

protocols were replaced with the “hour-1” treatment bundle to

enforce the necessity of beginning resuscitation and management

immediately. Met with controversy about feasibility and safety,

the “hour-1 bundle” continues to be the focus of investigation and

debate.

2248 PART 8 Critical Care Medicine

TABLE 304-3 Initial Antimicrobial Therapy for Severe Sepsis with No

Obvious Source in Adults with Normal Renal Function

CLINICAL

CONDITION ANTIMICROBIAL REGIMENSa

Septic shock

(immunocompetent

adult)

The many acceptable regimens include (1) piperacillintazobactam (4.5 g q6h), (2) cefepime (2 g q8h), or (3)

meropenem (1 g q8h) or imipenem-cilastatin (0.5 g q6h).

If the patient is allergic to β-lactam antibiotics, use (1)

aztreonam (2 g q8h) or (2) ciprofloxacin (400 mg q12h) or

levofloxacin (750 mg q24h). Add vancomycin (loading dose

of 25–30 mg/kg, then 15–20 mg/kg q8–12h) to each of the

above regimens.

Neutropenia (<500

neutrophils/μL)

Regimens include (1) cefepime (2 g q8h), (2) meropenem

(1 g q8h) or imipenem-cilastatin (0.5 g q6h) or doripenem

(500 mg q8h), or (3) piperacillin-tazobactam (3.375 g q4h).

Add vancomycin (as above) if the patient has a suspected

central line–associated bloodstream infection, severe

mucositis, skin/soft tissue infection, or hypotension. Add

tobramycin (5–7 mg/kg q24h) plus vancomycin (as above)

plus caspofungin (one dose of 70 mg, then 50 mg q24h) if

the patient has severe sepsis/septic shock.

Splenectomy Use ceftriaxone (2 g q24h, or—in meningitis—2 g q12h).

If the local prevalence of cephalosporin-resistant

pneumococci is high, add vancomycin (as above). If the

patient is allergic to β-lactam antibiotics, use levofloxacin

(750 mg q24h) or moxifloxacin (400 mg q24h) plus

vancomycin (as above).

a

All agents are administered by the intravenous route. Beta-lactam antibiotics may

exhibit unpredictable pharmacodynamics in sepsis; therefore, continuous infusions

are often used.

Source: Adapted in part from DN Gilbert et al: The Sanford Guide to Antimicrobial

Therapy, 47th ed, 2017; and from RS Munford: Sepsis and septic shock, in DL Kasper

et al (eds). Harrison’s Principles of Internal Medicine, 19th ed. New York,

McGraw-Hill, 2015, p. 1757.

Nonetheless, some form of resuscitation is considered essential,

and a standardized approach, akin to the use of “trauma teams,”

has been advocated to ensure prompt care. The patient should be

moved to an appropriate setting, such as the ICU, for ongoing care.

SUBSEQUENT TREATMENT OF SEPSIS AND SEPTIC SHOCK

After initial resuscitation, attention is focused on monitoring and

support of organ function, avoidance of complications, and deescalation of care when possible.

Monitoring Hemodynamic monitoring devices may clarify the

primary physiologic manifestations in sepsis and septic shock. The

clinical usefulness of these monitoring devices can be attributable

to the device itself, the algorithm linked to the device, or the static/

dynamic target of the algorithm. Decades ago, the standard care of

shock patients included invasive devices like the pulmonary artery

catheter (PAC), also known as the continuous ScvO2

 catheter. The

PAC can estimate cardiac output and measure mixed venous oxygen

saturation, among other parameters, to refine the etiology of shock

and potentially influence patient outcomes. Recently, a Cochrane

review of 2923 general-ICU patients (among whom the proportion

of patients in shock was not reported) found no difference in mortality with or without PAC management, and therefore, the PAC is no

longer recommended for routine use. Instead, a variety of noninvasive monitoring tools, such as arterial pulse contour analysis (PCA)

or focused echocardiography, can provide continuous estimates of

parameters such as cardiac output, beat-to-beat stroke volume, and

pulse pressure variation. These tools, along with passive leg-raise

maneuvers or inferior vena cava collapsibility on ultrasound, can help

determine a patient’s volume responsiveness but require that a variety

of clinical conditions be met (e.g., patient on mechanical ventilation,

sinus rhythm); in addition, more evidence from larger randomized

trials on the impact of these tools in daily management is needed.

Support of Organ Function The primary goal of organ support is

to improve delivery of oxygen to the tissues as quickly as possible.

Depending on the underlying physiologic disturbance, this step

may require administration of IV fluids or vasopressors, blood

transfusions, or ventilatory support.

Many crystalloids can be used in septic shock, including 0.9% normal saline, Ringer’s lactate, Hartmann’s solution, and Plasma-Lyte.

Because crystalloid solutions vary in tonicity and inorganic/organic

anions, few of these preparations closely resemble plasma. Normal

saline is widely used in the United States. Colloid solutions (e.g.,

albumin, dextran, gelatins, or hydroxyethyl starch) are the most

widely used fluids in critically ill patients, with variability across

ICUs and countries. A clinician’s choice among colloids is influenced

by availability, cost, and the desire to minimize interstitial edema.

Many think that a greater intravascular volume is gained by use of

colloids in shock, but the effects of colloids are modified by molecular weight and concentration as well as by vascular endothelial

changes during inflammation. A network meta-analysis using direct

and indirect comparisons in sepsis found evidence of higher mortality with starch than with crystalloids (relative risk [RR], 1.13; 95%

CI, 0.99–1.30 [high confidence]) and no difference between albumin

(RR, 0.83; 95% CI, 0.65–1.04 [moderate confidence]) or gelatin (RR,

1.24; 95% CI, 0.61–2.55 [very low confidence]) and crystalloids. In

general, crystalloids are recommended on the basis of strong evidence as first-line fluids for sepsis resuscitation, with specific caveats; their use is guided by resolution of hypotension, oliguria, altered

mentation, and hyperlactemia. Inconsistent evidence supports the

use of balanced crystalloids, and guidelines recommend against

using hydroxyethyl starches for intravascular volume replacement.

When circulating fluid volume is adequate, vasopressors are

recommended to maintain perfusion of vital organs. Vasopressors

such as norepinephrine, epinephrine, dopamine, and phenylephrine

differ in terms of half-life, β- and α-adrenergic stimulation, and

dosing regimens. Recent evidence comes from the SOAP II trial,

a double-blind randomized clinical trial at eight centers comparing norepinephrine with dopamine in 1679 undifferentiated ICU

patients with shock, of whom 63% were septic. Although no difference was observed in 28-day mortality or in predefined septic shock

subgroup, arrhythmias were significantly greater with dopamine.

These findings were confirmed in a subsequent meta-analysis. As

a result, expert opinion and consensus guidelines recommend norepinephrine as the first-choice vasopressor in septic shock. Levels of

the endogenous hormone vasopressin may be low in septic shock,

and the administration of vasopressin can reduce the norepinephrine dose. Consensus guidelines suggest adding vasopressin (up to

0.03 U/min) in patients without a contraindication to norepinephrine, with the intent of raising mean arterial pressure or decreasing

the norepinephrine dose. There may be select indications for use of

alternative vasopressors—e.g., when tachyarrhythmias from dopamine or norepinephrine, limb ischemia from vasopressin, or other

adverse effects dictate.

The transfusion of red blood cells to high thresholds (>10 g/

dL) had been suggested as part of EGDT in septic shock. However,

the Scandinavian TRISS trial in 1005 septic shock patients demonstrated that a lower threshold (7 g/dL) resulted in 90-day mortality

rates similar to those with a higher threshold (9 g/dL) and reduced

transfusions by almost 50%. Thus, red blood cell transfusion should

be reserved for patients with a hemoglobin level ≤7 g/dL.

Significant hypoxemia (Pao2

, <60 mmHg or SaO2

, <90%), hypoventilation (rising Paco2

), increased work of breathing, and inadequate

or unsustainable compensation for metabolic acidosis (pH <7.20) are

common indications for mechanical ventilatory support. Endotracheal intubation protects the airway, and positive-pressure breathing

allows oxygen delivery to metabolically active organs in favor of

inspiratory muscles of breathing and the diaphragm. An experiment

in dogs showed that the relative proportion of cardiac output delivered to respiratory muscles in endotoxic shock decreased by fourfold

with spontaneous ventilation over that with mechanical ventilation.

During intubation, patients in shock should be closely monitored for

vasodilatory effects of sedating medications or compromised cardiac output due to increased intrathoracic pressure, both of which

may cause hemodynamic collapse. With hemodynamic instability,

2249 Sepsis and Septic Shock CHAPTER 304

noninvasive mask ventilation may be less suitable in patients experiencing sepsis-associated acute respiratory failure.

Adjuncts One of the great disappointments in sepsis management

over the past 30 years has been the failure to convert advances in

our understanding of the underlying biology into new therapies.

Researchers have tested both highly specific agents and those with

more pleotropic effects. The specific agents can be divided into

those designed to interrupt the initial cytokine cascade (e.g., antiLPS or anti-proinflammatory cytokine strategies) and those that

interfere with dysregulated coagulation (e.g., antithrombin or activated protein C). Recombinant activated protein C (aPC) was one of

the first agents approved by the U.S. Food and Drug Administration

and was the most widely used. A large, randomized, double-blind,

placebo-controlled, multicenter trial of aPC in severe sepsis (the

PROWESS trial) was reported in 2001; the data suggested an absolute risk reduction of up to 6% among aPC-treated patients with

severe sepsis. However, subsequent phase 3 trials failed to confirm

this effect, and the drug was withdrawn from the market. It is no

longer recommended in the care of sepsis or septic shock.

Many adjunctive treatments in sepsis and septic shock target

changes in the innate immune response and coagulation cascade.

Specific adjuncts like glucocorticoids in septic shock have continued to be widely used despite inconsistent evidence. A large

negative clinical trial and a conflicting systematic review in 2009

extended the debate about whether glucocorticoids lower 28-day

mortality or improve shock reversal. Two subsequent randomized

trials demonstrated faster shock resolution together with mortality

benefit when glucocorticoids were administered in combination

with mineralocorticoids. Conversely, however, multiple major trials and meta-analyses found no difference between patients with

severe sepsis who were treated with glucocorticoids and control

patients in terms of the development of shock or the mortality rate.

These data and others led to a suggestion in international clinical

practice guidelines against using IV hydrocortisone to treat septic

shock if adequate fluid resuscitation and vasopressor therapy are

able to restore hemodynamic stability. If not, the guidelines suggest

the administration of IV hydrocortisone at a dose of 200 mg/d

(weak recommendation, low quality of evidence).

Among other adjuncts, high-dose IV ascorbic acid, either alone

or in combination with thiamine and hydrocortisone, has been proposed as an inflammatory modulator and antioxidant in sepsis, but

studies have produced variable results. IV immunoglobulin may be

associated with potential benefit, but significant questions remain

and such treatment is not part of routine practice. Despite a large

number of observational studies suggesting that statin use mitigates

the incidence or outcome of sepsis and severe infection, there are

no confirmatory randomized controlled trials, and statins are not

an element in routine sepsis care.

De-Escalation of Care Once patients with sepsis and septic shock

are stabilized, it is important to consider which therapies are no longer required and how care can be minimized. The de-escalation of

initial broad-spectrum therapy, which observational evidence indicates is safe, may reduce the emergence of resistant organisms as well

as potential drug toxicity and costs. The added value of combination

antimicrobial therapy over that of adequate single-agent antibiotic

therapy in severe sepsis has not been established. Current guidelines

recommend combination antimicrobial therapy only for neutropenic

sepsis and sepsis caused by Pseudomonas. U.S. trials and metaanalyses investigating the role of serum biomarkers like procalcitonin in minimizing antibiotic exposure had mixed results. One

randomized open-label trial reported a mortality benefit when

antibiotic duration was guided by normalization of procalcitonin

levels, but others have failed to replicate these findings. European

trials are indicating that this biomarker may lead to a reduction in

the duration of treatment and in daily defined doses in critically ill

patients with a presumed bacterial infection. Ultimately, there is no

consensus on antibiotic de-escalation criteria.

■ PROGNOSIS

Before modern intensive care, sepsis and septic shock were highly

lethal, with infection leading to compromise of vital organs. Even

with intensive care, nosocomial mortality rates for septic shock often

exceeded 80% as recently as 30 years ago. Now, the U.S. Burden of

Disease Collaborators report that the primary risk factor for sepsis and

septic shock—i.e., infection—is the fifth leading cause of years of productive life lost because of premature death. More than half of sepsis

cases require ICU admission, representing 10% of all ICU admissions.

However, with advances in training, surveillance, monitoring, and

prompt initiation of supportive care for organ dysfunction, the mortality rate from sepsis and septic shock is now closer to 20% in many

series. Although some data suggest that mortality trends are even lower,

attention has been focused on the trajectory of recovery among survivors. Patients who survive to hospital discharge after sepsis remain at

increased risk of death in the following months and years. Those who

survive often suffer from impaired physical or neurocognitive dysfunction, mood disorders, and low quality of life. In many studies, it is

difficult to determine the causal role of sepsis. However, an analysis of

the Health and Retirement Study—a large longitudinal cohort study of

aging Americans—suggested that severe sepsis significantly accelerated

physical and neurocognitive decline. Among survivors, the rate of hospital readmission within 90 days after sepsis exceeds 40%.

■ PREVENTION

In light of the persistently high mortality risk in sepsis and septic

shock, prevention may be the best approach to reducing avoidable

deaths, but preventing sepsis is a challenge. The aging of the population, the overuse of inappropriate antibiotics, the rising incidence of

resistant microorganisms, and the use of indwelling devices and catheters contribute to a steady burden of sepsis cases. The number of cases

could be reduced by avoiding unnecessary antibiotic use, limiting use

of indwelling devices and catheters, minimizing immune suppression

when it is not needed, and increasing adherence to infection control

programs at hospitals and clinics. To facilitate earlier treatment, such

pragmatic work could be complemented by research into the earliest pathophysiology of infection, even when symptoms of sepsis are

nascent. In parallel, the field of implementation science could inform

how best to increase adoption of infection control in high-risk settings

and could guide appropriate care.

■ FURTHER READING

Angus DC et al: Epidemiology of severe sepsis in the United States:

Analysis of incidence, outcome, and associated costs of care. Crit

Care Med 29:1303, 2001.

Boomer JS et al: Immunosuppression in patients who die of sepsis and

multiple organ failure. JAMA 306:2594, 2011.

De Backer D et al: Comparison of dopamine and norepinephrine in

the treatment of shock. N Engl J Med 362:779, 2010.

Fleischmann C et al: Assessment of global incidence and mortality

of hospital-treated sepsis. Current estimates and limitations. Am J

Respir Crit Care Med 193:259, 2016.

Levy MM et al: The surviving sepsis campaign bundle: 2018 update.

Intensive Care Med 44:925, 2018.

Medzhitov R et al: Disease tolerance as a defense strategy. Science

335:936, 2012.

Rochwerg B et al: Fluid resuscitation in sepsis: A systematic review

and network meta-analysis. Ann Intern Med 161:347, 2014.

Rudd K et al: Global, regional, and national sepsis incidence and

mortality, 1990-2017: Analysis for the global burden of disease study.

Lancet 395:10219, 2020.

Seymour CW et al: Assessment of clinical criteria for sepsis: For the

Third International Consensus Definitions for Sepsis and Septic

Shock (Sepsis-3). JAMA 315:762, 2016.

Vincent JL et al: The SOFA (sepsis-related organ failure assessment)

score to describe organ dysfunction/failure. On behalf of the Working

Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707, 1996.

2250 PART 8 Critical Care Medicine

Cardiogenic shock and pulmonary edema are each life-threatening

high-acuity conditions that require treatment as medical emergencies,

usually in an intensive care unit (ICU) or cardiac intensive care unit

(CICU). The most common joint etiology is severe left ventricular

(LV) dysfunction from myocardial infarction (MI) that leads to pulmonary congestion and/or systemic hypoperfusion (Fig. 305-1). The

pathophysiologies of pulmonary edema and shock are discussed in

Chaps. 37 and 303, respectively.

CARDIOGENIC SHOCK

Cardiogenic shock (CS) is a low cardiac output state resulting in

life-threatening end-organ hypoperfusion and hypoxia. The clinical presentation is typically characterized by persistent hypotension

(<90 mmHg systolic blood pressure [BP]) or <60-65 mmHg mean

arterial pressure unresponsive to volume replacement or by the use of

vasopressors needed to maintain adequate BP (systolic >90 mmHg) and

is accompanied by clinical features of peripheral hypoperfusion, such as

elevated arterial lactate (>2 mmol/L). Objective hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure can

help confirm a cardiogenic cause of shock but are not mandatory. The

in-hospital mortality rates range from 40 to 60%, depending on shock

severity and the associated underlying cause. Recently, the new Society

for Cardiovascular Angiography and Interventions (SCAI) classification

305

of CS has been introduced including five categories: (A) at risk, (B) beginning or preshock, (C) classical, (D) deteriorating, and (E) extremis CS

(Fig. 305-2). Preshock is defined as clinical evidence of relative hypotension or tachycardia without hypoperfusion. These patients should be

monitored closely and treated early to avoid development of classical

CS. Extremis CS includes cases in which considerations about futility of

treatment should be done and possibly palliative care initiated.

Although declining in incidence, acute MI with LV dysfunction

remains the most frequent cause of CS, with other causes listed in

Table 305-1. Circulatory failure based on cardiac dysfunction may

be caused by primary myocardial failure, most commonly secondary

to acute MI (Chap. 275), and less frequently by cardiomyopathy or

myocarditis (Chap. 259), cardiac tamponade (Chap. 270), arrhythmias

(Chap. 254), or critical valvular heart disease (Chap. 261).

Incidence The incidence of CS complicating acute MI has decreased

to 5–10%, largely due to increasing use of early mechanical reperfusion

therapy for acute MI. Shock is more common with ST-segment elevation MI (STEMI) than with non-STEMI (Chap. 275).

LV failure accounts for ~80% of cases of CS complicating acute MI.

Acute severe mitral regurgitation (MR), ventricular septal rupture

(VSR), predominant right ventricular (RV) failure, and free wall rupture or tamponade account for the remainder. A recently recognized

uncommon cause of transient CS is the takotsubo syndrome.

Pathophysiology The understanding of the complex pathophysiology of CS has evolved over the past decades. In general, a profound

depression of myocardial contractility results in a deleterious spiral of

reduced cardiac output, low BP, and ongoing myocardial ischemia, followed by further contractility reduction (Fig. 305-1). This vicious cycle

usually leads to death if not interrupted. CS can result in both acute and

subacute derangements to the entire circulatory system. Hypoperfusion

Cardiogenic Shock and

Pulmonary Edema

David H. Ingbar, Holger Thiele

Acute Myocardial Infarction

SIRS

Ventilation

Fluids

inotropes/

vasopressors

+ +

+

+

Mechanical

support

device

Reperfusion:

PCI/CABG

Bleeding/

transfusion

eNOS

iNOS Peripheral perfusion ↓

Vasoconstriction

Fluid retention

NO ↑

Peroxynitrite ↑

Interleukins ↑

TNF-α ↑

LVEDP ↑

Lung edema ↑

Cardiac output ↓

Stroke volume ↓

SVR ↓

Pro-inflammation

Catecholamine sensitivity ↓

Contractility ↓

Coronary

perfusion ↓

Hypoxia Hypotension

Ischemia

Progressive

left ventricular

dysfunction

Death

Left ventricular dysfunction

systolic diastolic

FIGURE 305-1 Pathophysiology of cardiogenic shock and potential treatment targets. The pathophysiologic concept of the expanded cardiogenic shock spiral and treatment

targets. CABG, coronary artery bypass grafting; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; LVEDP, left ventricular end-diastolic pressure;

NO, nitric oxide; PCI, percutaneous coronary intervention; SIRS, systemic inflammatory response syndrome; SVR, systemic vascular resistance; TNF, tumor necrosis factor.

(Reproduced with permission from H Thiele et al: Shock in acute myocardial infarction: The Cape Horn for trials? Eur Heat J 31:1828, 2010.)