Ebook Harrison''s pulmonary and critical care medicine (2nd edition): Part 2

Section IV

Common Critical
Illnesses and
Syndromes


CHAPTER 28

SEVERE SEPSIS AND SEPTIC SHOCK
robert s. munford
DefinitionS

epiDeMiology

(See Table 28-1) Animals mount both local and systemic
responses to microbes that traverse their epithelial barriers
and enter underlying tissues. Fever or hypothermia,
leukocytosis or leukopenia, tachypnea, and tachycardia
are the cardinal signs of the systemic response, that is
often called the systemic inflammatory response syndrome
(SIRS). SIRS may have an infectious or a noninfectious
etiology. If infection is suspected or proven, a patient
with SIRS is said to have sepsis. When sepsis is associated
with dysfunction of organs distant from the site of infection, the patient has severe sepsis. Severe sepsis may be
accompanied by hypotension or evidence of hypoperfusion. When hypotension cannot be corrected by infusing
fluids, the diagnosis is septic shock. These definitions were
developed by consensus conference committees in 1992
and 2001 and have been widely used; there is evidence
that the different stages may form a continuum.

Severe sepsis is a contributing factor in >200,000 deaths
per year in the United States. The incidence of severe
sepsis and septic shock has increased over the past 30 years,
and the annual number of cases is now >700,000
(∼3 per 1000 population). Approximately two-thirds of the
cases occur in patients with significant underlying illness.
Sepsis-related incidence and mortality rates increase
with age and preexisting comorbidity. The rising incidence of severe sepsis in the United States is attributable
to the aging of the population, the increasing longevity
of patients with chronic diseases, and the relatively high frequency with which sepsis develops in patients with AIDS.
The widespread use of immunosuppressive drugs, indwelling catheters, and mechanical devices also plays a role.
Invasive bacterial infections are prominent causes
of death around the world, particularly among
young children. In sub-Saharan Africa, for example,
careful screening for positive blood cultures found that
community-acquired bacteremia accounted for at least
one-fourth of deaths of children >1 year of age. Nontyphoidal Salmonella species, Streptococcus pneumoniae,
Haemophilus influenzae, and Escherichia coli were the most
commonly isolated bacteria. Bacteremic children often
had HIV infection or were severely malnourished.

etiology
Sepsis can be a response to any class of microorganism.
Microbial invasion of the bloodstream is not essential,
since local inflammation can also elicit distant organ
dysfunction and hypotension. In fact, blood cultures
yield bacteria or fungi in only ∼20–40% of cases of
severe sepsis and 40–70% of cases of septic shock. Individual gram-negative or gram-positive bacteria account
for ∼70% of these isolates; the remainder are fungi or
a mixture of microorganisms (Table 28-2). In patients

whose blood cultures are negative, the etiologic agent
is often established by culture or microscopic examination
of infected material from a local site; specific identification
of microbial DNA or RNA in blood or tissue samples
is also used. In some case series, a majority of patients
with a clinical picture of severe sepsis or septic shock
have had negative microbiologic data.

pathophySiology
Most cases of severe sepsis are triggered by bacteria or
fungi that do not ordinarily cause systemic disease in
immunocompetent hosts (Table 28-2). To survive
within the human body, these microbes often exploit
deficiencies in host defenses, indwelling catheters or
other foreign matter, or obstructed fluid drainage conduits. Microbial pathogens, in contrast, can circumvent innate defenses because they (1) lack molecules
that can be recognized by host receptors (see later) or
(2) elaborate toxins or other virulence factors. In both

276


Table 28-1

277

Definitions Used to Describe the Condition of Septic Patients
Bacteremia
Septicemia
Systemic inflammatory response
syndrome (SIRS)

Sepsis
Severe sepsis (similar to “sepsis syndrome”)

Septic shock

Critical illness–related
corticosteroid insufficiency (CIRCI)

A grading system that stratifies patients according to four key aspects of
illness; attempts to define subgroups of patients, reducing heterogeneity in
clinical trials
Inadequate corticosteroid activity for the patient’s severity of illness; should be
suspected when hypotension is not relieved by fluid administration

Source: Adapted from the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee.

Table 28-2
Microorganisms Involved in Episodes of Severe Sepsis at Eight Academic Medical Centers
Episodes with
Bloodstream Infection,
% (n = 436)

Episodes with
Documented Infection
but No Bloodstream
Infection, % (n = 430)

Total Episodes, % (n = 866)

Gram-negative bacteria

35

44

40

b

40

24

31

Microorganism
a

Gram-positive bacteria

a

Fungi

 7

 5

 6

Polymicrobial

11

21

16

Classic pathogensc

<5

<5

<5

Enterobacteriaceae, pseudomonads, Haemophilus spp., other gram-negative bacteria.
Staphylococcus aureus, coagulase-negative staphylococci, enterococci, Streptococcus pneumoniae, other streptococci, other gram-positive bacteria.
c
Such as Neisseria meningitidis, S. pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes.
Source: Adapted from KE Sands et al: JAMA 278:234, 1997.
b

Severe Sepsis and Septic Shock

Multiple-organ dysfunction syndrome
(MODS)
Predisposition–infection–response–
organ dysfunction (PIRO)

CHAPTER 28

Refractory septic shock

Presence of bacteria in blood, as evidenced by positive blood cultures
Presence of microbes or their toxins in blood
Two or more of the following conditions: (1) fever (oral temperature >38°C)
or hypothermia (<36°C); (2) tachypnea (>24 breaths/min); (3) tachycardia
(heart rate >90 beats/min); (4) leukocytosis (>12,000/μL), leucopenia
(<4,000/μL), or >10% bands; may have a noninfectious etiology
SIRS that has a proven or suspected microbial etiology
Sepsis with one or more signs of organ dysfunction—for example:
1. Cardiovascular: Arterial systolic blood pressure ≤90 mmHg or mean
arterial pressure ≤70 mmHg that responds to administration of
intravenous fluid
2. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate
fluid resuscitation
3. Respiratory: PaO2/FiO2 ≤250 or, if the lung is the only dysfunctional
organ, ≤200
4. Hematologic: Platelet count <80,000/μL or 50% decrease in platelet count from
highest value recorded over previous 3 days
5. Unexplained metabolic acidosis: A pH ≤7.30 or a base deficit ≥5.0 mEq/L and a
plasma lactate level >1.5 times upper limit of normal for reporting lab
6. Adequate fluid resuscitation: Pulmonary artery wedge pressure ≥12 mmHg or
central venous pressure ≥8 mmHg
Sepsis with hypotension (arterial blood pressure <90 mmHg systolic, or 40 mmHg
less than patient’s normal blood pressure) for at least 1 h despite adequate fluid
resuscitation;
or

Need for vasopressors to maintain systolic blood pressure ≥90 mmHg or mean
arterial pressure ≥70 mmHg
Septic shock that lasts for >1 h and does not respond to fluid or pressor
administration
Dysfunction of more than one organ, requiring intervention to maintain homeostasis


278

cases, the body can mount a vigorous inflammatory reaction
that results in severe sepsis yet fails to kill the invaders. The
septic response may also be induced by microbial exotoxins
that act as superantigens (e.g., toxic shock syndrome toxin 1)
as well as by many pathogenic viruses.
Host mechanisms for sensing microbes

Section IV
Common Critical Illnesses and Syndromes

Animals have exquisitely sensitive mechanisms for recognizing and responding to certain highly conserved
microbial molecules. Recognition of the lipid A moiety
of lipopolysaccharide (LPS, also called endotoxin) is
the best-studied example. A host protein (LPS-binding
protein) binds lipid A and transfers the LPS to CD14
on the surfaces of monocytes, macrophages, and neutrophils. LPS then is passed to MD-2, that is bound to toll-like
receptor (TLR) 4 to form a molecular complex that
transduces the LPS recognition signal to the interior
of the cell. This signal rapidly triggers the production
and release of mediators, such as tumor necrosis factor
(TNF; see later), that amplify the LPS signal and

transmit it to other cells and tissues. Bacterial peptidoglycan and lipopeptides elicit responses in animals that
are generally similar to those induced by LPS; whereas
these molecules also may be transferred by CD14,
they interact with different TLRs. Having numerous
TLR-based receptor complexes (11 different TLRs
have been identified so far in humans) allows animals
to recognize many conserved microbial molecules; others
include lipopeptides (TLR2/1, TLR2/6), flagellin (TLR5),
undermethylated DNA sequences (TLR9), and doublestranded RNA (TLR3, TLR7). The ability of some
TLRs to serve as receptors for host ligands (e.g., hyaluronans, heparan sulfate, saturated fatty acids) raises the possibility that they also play a role in producing noninfectious
sepsis-like states. Other host pattern-recognition proteins
that are important for sensing microbial invasion include
the intracellular NOD1 and NOD2 proteins, which recognize discrete fragments of bacterial peptidoglycan; early
complement components (principally in the alternative
pathway); and mannose-binding lectin and C-reactive
protein, which activate the classic complement pathway.
A host’s ability to recognize certain microbial molecules
may influence both the potency of its own defenses and
the pathogenesis of severe sepsis. For example, MD-2–
TLR4 best senses LPS that has a hexaacyl lipid A moiety
(i.e., one with six fatty acyl chains). Most of the commensal aerobic and facultatively anaerobic gram-negative
bacteria that trigger severe sepsis and shock (including
E. coli, Klebsiella, and Enterobacter) make this lipid A structure.
When they invade human hosts, often through breaks
in an epithelial barrier, they are typically confined
to the subepithelial tissue by a localized inflammatory response. Bacteremia, if it occurs, is intermittent
and low-grade, as these bacteria are efficiently cleared
from the bloodstream by TLR4-expressing Kupffer cells
and splenic macrophages. These mucosal commensals

seem to induce severe sepsis most often by triggering
severe local tissue inflammation rather than by circulating within the bloodstream. One exception is Neisseria
meningitidis. Its hexaacyl LPS seems to be shielded from
host recognition by its polysaccharide capsule. This protection may allow meningococci to transit undetected from
the nasopharyngeal mucosa into the bloodstream, where
they can infect vascular endothelial cells and release
large amounts of endotoxin. Host recognition of lipid
A may nonetheless influence pathogenesis, as meningococci that produce pentaacyl LPS were isolated from
the blood of patients with less severe coagulopathy than
was found in patients whose isolates produced hexaacyl
lipid A. In contrast, gram-negative bacteria that make
lipid A with fewer than six acyl chains (Yersinia pestis,
Francisella tularensis, Vibrio vulnificus, Pseudomonas aeruginosa,
and Burkholderia pseudomallei, among others) are poorly
recognized by MD-2–TLR4. When these bacteria
enter the body, they may initially induce relatively little
inflammation. When they do trigger severe sepsis, it is
often after they have multiplied to high density in tissues and blood. The importance of LPS recognition in
disease pathogenesis has been shown by engineering a
virulent strain of Y. pestis, which makes tetraacyl LPS
at 37°C, to produce hexaacyl LPS; unlike its virulent
parent, the mutant strain stimulates local inflammation
and is rapidly cleared from tissues. For at least one large
class of microbes—gram-negative aerobic bacteria—
the pathogenesis of sepsis thus depends, at least in part,
upon whether the bacterium’s major signal molecule,
LPS, can be sensed by the host.
Local and systemic host responses
to invading microbes
Recognition of microbial molecules by tissue phagocytes triggers the production and/or release of numerous

host molecules (cytokines, chemokines, prostanoids,
leukotrienes, and others) that increase blood flow to
the infected tissue, enhance the permeability of local
blood vessels, recruit neutrophils to the site of infection,
and elicit pain. These reactions are familiar elements of
local inflammation, the body’s frontline innate immune
mechanism for eliminating microbial invaders. Systemic
responses are activated by neural and/or humoral communication with the hypothalamus and brainstem; these
responses enhance local defenses by increasing blood flow
to the infected area, augmenting the number of circulating
neutrophils, and elevating blood levels of numerous
molecules (such as the microbial recognition proteins
discussed earlier) that have anti-infective functions.
Cytokines and other mediators

Cytokines can exert endocrine, paracrine, and autocrine
effects. TNF-α stimulates leukocytes and vascular
endothelial cells to release other cytokines (as well as
additional TNF-α), to express cell-surface molecules


that enhance neutrophil-endothelial adhesion at sites
of infection, and to increase prostaglandin and leukotriene production. Whereas blood levels of TNF-α are
not elevated in individuals with localized infections,
they increase in most patients with severe sepsis or septic
shock. Moreover, IV infusion of TNF-α can elicit the
characteristic abnormalities of SIRS. In animals, larger
doses of TNF-α induce shock and death.
Although TNF-α is a central mediator, it is only one
of many proinflammatory molecules that contribute

to innate host defense. Chemokines, most prominently
interleukin (IL)-8 and IL-17, attract circulating neutrophils to the infection site. IL-1β exhibits many of the
same activities as TNF-α. TNF-α, IL-1β, interferon
(IFN) γ, IL-12, IL-17, and other proinflammatory cytokines probably interact synergistically with one another
and with additional mediators. The nonlinearity and
multiplicity of these interactions have made it difficult to
interpret the roles played by individual mediators in both
tissues and blood.
Coagulation factors

Local control mechanisms

Host recognition of invading microbes within subepithelial
tissues typically ignites immune responses that rapidly kill
the invader and then subside to allow tissue recovery. The
anti-inflammatory forces that put out the fire and clean

Systemic control mechanisms

The signaling apparatus that links microbial recognition
to cellular responses in tissues is less active in the blood.
For example, whereas LPS-binding protein plays a role
in recognizing the presence of LPS, in plasma it also
prevents LPS signaling by transferring LPS molecules
into plasma lipoprotein particles that sequester the lipid
A moiety so that it cannot interact with cells. At the
high concentrations found in blood, LPS-binding protein
also inhibits monocyte responses to LPS, and the soluble
(circulating) form of CD14 strips off LPS that has
bound to monocyte surfaces.

Systemic responses to infection also diminish cellular
responses to microbial molecules. Circulating levels
of anti-inflammatory cytokines (e.g., IL-10) increase
even in patients with mild infections. Glucocorticoids
inhibit cytokine synthesis by monocytes in vitro; the
increase in blood cortisol levels early in the systemic
response presumably plays a similarly inhibitory role.
Epinephrine inhibits the TNF-α response to endotoxin
infusion in humans while augmenting and accelerating
the release of IL-10; prostaglandin E2 has a similar
“reprogramming” effect on the responses of circulating
monocytes to LPS and other bacterial agonists. Cortisol,
epinephrine, IL-10, and C-reactive protein reduce the
ability of neutrophils to attach to vascular endothelium,
favoring their demargination and thus contributing to
leukocytosis while preventing neutrophil-endothelial
adhesion in uninflamed organs. The available evidence
thus suggests that the body’s systemic responses to injury
and infection normally prevent inflammation within organs
distant from a site of infection. There is also evidence that
these responses may be immunosuppressive.
The acute-phase response increases the blood concentrations of numerous molecules that have anti-inflammatory
actions. Blood levels of IL-1 receptor antagonist often
greatly exceed those of circulating IL-1β, for example,
and this excess may inhibit the binding of IL-1β to its
receptors. High levels of soluble TNF receptors neutralize
TNF-α that enters the circulation. Other acute-phase
proteins are protease inhibitors or antioxidants; these may
neutralize potentially harmful molecules released from
neutrophils and other inflammatory cells. Increased hepatic

Severe Sepsis and Septic Shock

Control mechanisms

Elaborate control mechanisms operate within both local
sites of inflammation and the systemic compartment.

279

CHAPTER 28

Intravascular thrombosis, a hallmark of the local inflammatory response, may help wall off invading microbes
and prevent infection and inflammation from spreading to
other tissues. IL-6 and other mediators promote intravascular
coagulation initially by inducing blood monocytes and vascular endothelial cells to express tissue factor. When tissue factor is expressed on cell surfaces, it binds to factor
VIIa to form an active complex that can convert factors
X and IX to their enzymatically active forms. The result
is activation of both extrinsic and intrinsic clotting pathways, culminating in the generation of fibrin. Clotting is
also favored by impaired function of the protein C–protein
S inhibitory pathway and depletion of antithrombin and
proteins C and S, while fibrinolysis is prevented by increased
plasma levels of plasminogen activator inhibitor 1.
Thus, there may be a striking propensity toward intravascular fibrin deposition, thrombosis, and bleeding; this
propensity has been most apparent in patients with intravascular endothelial infections such as meningococcemia.
Evidence points to tissue factor–expressing microparticles
derived from leukocytes as a potential trigger for intravascular coagulation. Contact-system activation occurs
during sepsis but contributes more to the development
of hypotension than to disseminated intravascular coagulation (DIC).

up the battleground include molecules that neutralize or
inactivate microbial signals. Among these molecules are
intracellular factors (e.g., suppressor of cytokine signaling
3 and IL-1 receptor–associated kinase 3) that diminish the
production of proinflammatory mediators by neutrophils
and macrophages; anti-inflammatory cytokines (IL-10,
IL-4); and molecules derived from essential polyunsaturated fatty acids (lipoxins, resolvins, and protectins) that
promote tissue restoration. Enzymatic inactivation of
microbial signal molecules (e.g., LPS) may be required
to restore homeostasis; a leukocyte enzyme, acyloxyacyl
hydrolase, has been shown to prevent prolonged inflammation by inactivating LPS in mice.


280

production of hepcidin promotes the sequestration of iron
in hepatocytes, intestinal epithelial cells, and erythrocytes;
this effect reduces iron acquisition by invading microbes
while contributing to the normocytic, normochromic
anemia associated with inflammation.
It can thus be concluded that both local and systemic
responses to infectious agents benefit the host in important
ways. Most of these responses and the molecules
responsible for them have been highly conserved during
animal evolution and therefore may be adaptive. Elucidating how they contribute to lethality—i.e., become
maladaptive—remains a major challenge for sepsis research.

Organ dysfunction and shock

Section IV

Common Critical Illnesses and Syndromes

As the body’s responses to infection intensify, the mixture
of circulating cytokines and other molecules becomes
very complex: elevated blood levels of more than 50
molecules have been found in patients with septic
shock. Although high concentrations of both pro- and
anti-inflammatory molecules are found, the net mediator
balance in the plasma of these extremely sick patients
seems to be anti-inflammatory. For example, blood leukocytes from patients with severe sepsis are often hyporesponsive to agonists such as LPS. In patients with
severe sepsis, persistence of leukocyte hyporesponsiveness
has been associated with an increased risk of dying.
Apoptotic death of B cells, follicular dendritic cells, and
CD4+ T lymphocytes also may contribute significantly
to the immunosuppressive state.
Endothelial injury

Many investigators have favored widespread vascular
endothelial injury as the major mechanism for multiorgan dysfunction. In keeping with this idea, one study
found high numbers of vascular endothelial cells in the
peripheral blood of septic patients. Leukocyte-derived
mediators and platelet-leukocyte-fibrin thrombi may
contribute to vascular injury, but the vascular endothelium also seems to play an active role. Stimuli such
as TNF-α induce vascular endothelial cells to produce
and release cytokines, procoagulant molecules, plateletactivating factor, nitric oxide, and other mediators. In
addition, regulated cell-adhesion molecules promote
the adherence of neutrophils to endothelial cells. While
these responses can attract phagocytes to infected sites
and activate their antimicrobial arsenals, endothelial cell
activation can also promote increased vascular permeability, microvascular thrombosis, DIC, and hypotension.

Tissue oxygenation may decrease as the number of
functional capillaries is reduced by luminal obstruction
due to swollen endothelial cells, decreased deformability
of circulating erythrocytes, leukocyte-platelet-fibrin
thrombi, or compression by edema fluid. On the other
hand, studies using orthogonal polarization spectral

imaging of the microcirculation in the tongue found
that sepsis-associated derangements in capillary flow
could be reversed by applying acetylcholine to the surface
of the tongue or by giving nitroprusside intravenously;
these observations suggest a neuroendocrine basis for
the loss of capillary filling. Oxygen utilization by tissues
may also be impaired by a state of “hibernation” in
which ATP production is diminished as oxidative phosphorylation decreases; nitric oxide may be responsible
for inducing this response.
Remarkably, poorly functioning “septic” organs usually
appear normal at autopsy. There is typically very little
necrosis or thrombosis, and apoptosis is largely confined
to lymphoid organs and the gastrointestinal tract. Moreover, organ function usually returns to normal if patients
recover. These points suggest that organ dysfunction during
severe sepsis has a basis that is principally biochemical, not
structural.
Septic shock

The hallmark of septic shock is a decrease in peripheral
vascular resistance that occurs despite increased levels
of vasopressor catecholamines. Before this vasodilatory
phase, many patients experience a period during which
oxygen delivery to tissues is compromised by myocardial

depression, hypovolemia, and other factors. During this
“hypodynamic” period, the blood lactate concentration
is elevated and central venous oxygen saturation is low.
Fluid administration is usually followed by the hyperdynamic, vasodilatory phase during which cardiac output is
normal (or even high) and oxygen consumption declines
despite adequate oxygen delivery. The blood lactate
level may be normal or increased, and normalization
of central venous oxygen saturation may reflect either
improved oxygen delivery or left-to-right shunting.
Prominent hypotensive molecules include nitric
oxide, β-endorphin, bradykinin, platelet-activating factor,
and prostacyclin. Agents that inhibit the synthesis
or action of each of these mediators can prevent or
reverse endotoxic shock in animals. However, in clinical
trials, neither a platelet-activating factor receptor antagonist nor a bradykinin antagonist improved survival rates
among patients with septic shock, and a nitric oxide
synthase inhibitor, L-Ng-methylarginine HCl, actually
increased the mortality rate. Remarkably, recent findings
indicate that exogenous nitrite can protect mice from
challenge with TNF or LPS. Nitrite provides a storage
pool from which nitric oxide can be generated in hypoxic
and/or acidic conditions. These findings should renew
interest in the possibility of exploiting nitric oxide metabolism to improve survival rates among septic patients.
Severe sepsis: A single pathogenesis?
In some cases, circulating bacteria and their products almost
certainly elicit multiorgan dysfunction and hypotension by


The manifestations of the septic response are superimposed
on the symptoms and signs of the patient’s underlying

illness and primary infection. The rate at which severe
sepsis develops may differ from patient to patient, and
there are striking individual variations in presentation. For
example, some patients with sepsis are normo- or hypothermic; the absence of fever is most common in neonates, in
elderly patients, and in persons with uremia or alcoholism.
Hyperventilation is often an early sign of the septic
response. Disorientation, confusion, and other manifestations of encephalopathy may also develop early
on, particularly in the elderly and in individuals with

281

Severe Sepsis and Septic Shock

Clinical Manifestations

preexisting neurologic impairment. Focal neurologic
signs are uncommon, although preexisting focal deficits
may become more prominent.
Hypotension and DIC predispose to acrocyanosis
and ischemic necrosis of peripheral tissues, most commonly the digits. Cellulitis, pustules, bullae, or hemorrhagic lesions may develop when hematogenous
bacteria or fungi seed the skin or underlying soft tissue.
Bacterial toxins may also be distributed hematogenously
and elicit diffuse cutaneous reactions. On occasion,
skin lesions may suggest specific pathogens. When sepsis
is accompanied by cutaneous petechiae or purpura,
infection with N. meningitidis (or, less commonly,
H. influenzae) should be suspected; in a patient who
has been bitten by a tick while in an endemic area,
petechial lesions also suggest Rocky Mountain spotted fever. A cutaneous lesion seen almost exclusively
in neutropenic patients is ecthyma gangrenosum, usually

caused by P. aeruginosa. It is a bullous lesion, surrounded
by edema, that undergoes central hemorrhage and
necrosis. Histopathologic examination shows bacteria in
and around the wall of a small vessel, with little or no
neutrophilic response. Hemorrhagic or bullous lesions
in a septic patient who has recently eaten raw oysters
suggest V. vulnificus bacteremia, while such lesions in a
patient who has recently suffered a dog bite may indicate
bloodstream infection due to Capnocytophaga canimorsus or
C. cynodegmi. Generalized erythroderma in a septic patient
suggests the toxic shock syndrome due to S. aureus or
S. pyogenes.
Gastrointestinal manifestations such as nausea, vomiting,
diarrhea, and ileus may suggest acute gastroenteritis. Stress
ulceration can lead to upper gastrointestinal bleeding.
Cholestatic jaundice, with elevated levels of serum bilirubin
(mostly conjugated) and alkaline phosphatase, may precede other signs of sepsis. Hepatocellular or canalicular
dysfunction appears to underlie most cases, and the results
of hepatic function tests return to normal with resolution
of the infection. Prolonged or severe hypotension may
induce acute hepatic injury or ischemic bowel necrosis.
Many tissues may be unable to extract oxygen normally
from the blood, so that anaerobic metabolism occurs
despite near-normal mixed venous oxygen saturation.
Blood lactate levels rise early because of increased glycolysis as well as impaired clearance of the resulting lactate
and pyruvate by the liver and kidneys. The blood
glucose concentration often increases, particularly in
patients with diabetes, although impaired gluconeogenesis
and excessive insulin release on occasion produce hypoglycemia. The cytokine-driven acute-phase response
inhibits the synthesis of transthyretin while enhancing

the production of C-reactive protein, fibrinogen, and
complement components. Protein catabolism is often
markedly accelerated. Serum albumin levels decline as a
result of decreased hepatic synthesis and the movement
of albumin into interstitial spaces.

CHAPTER 28

directly stimulating inflammatory responses within the
vasculature. In patients with fulminant meningococcemia, for example, mortality rates have correlated
directly with blood levels of endotoxin and bacterial DNA and with the occurrence of DIC. In most
patients infected with other gram-negative bacteria,
in contrast, circulating bacteria or bacterial molecules
may reflect uncontrolled infection at a local tissue
site and have little or no direct impact on distant organs;
in these patients, inflammatory mediators or neural signals
arising from the local site seem to be the key triggers
for severe sepsis and septic shock. In a large series of
patients with positive blood cultures, the risk of developing severe sepsis was strongly related to the site of
primary infection: bacteremia arising from a pulmonary or abdominal source was eightfold more likely
to be associated with severe sepsis than was bacteremic
urinary tract infection, even after the investigators
controlled for age, the kind of bacteria isolated from
the blood, and other factors. A third pathogenesis may
be represented by severe sepsis due to superantigenproducing Staphylococcus aureus or Streptococcus pyogenes;
the T cell activation induced by these toxins produces a
cytokine profile that differs substantially from that elicited
by gram-negative bacterial infection. Further evidence
for different pathogenetic pathways has come from
observations that the pattern of mRNA expression in

peripheral-blood leukocytes from children with sepsis
is different for gram-positive, gram-negative, and viral
pathogens.
The pathogenesis of severe sepsis thus may differ
according to the infecting microbe, the ability of the
host’s innate defense mechanisms to sense it, the site
of the primary infection, the presence or absence of
immune defects, and the prior physiologic status of the
host. Genetic factors are probably important as well, yet
despite much study only a few allelic polymorphisms
(e.g., in the IL-1β gene) have been associated with sepsis severity in more than one or two analyses. Further
studies in this area are needed.


282

Major Complications
Cardiopulmonary complications

Section IV
Common Critical Illnesses and Syndromes

Ventilation-perfusion mismatching produces a fall in
arterial PO2 early in the course. Increasing alveolar epithelial injury and capillary permeability result in increased
pulmonary water content, which decreases pulmonary
compliance and interferes with oxygen exchange. In
the absence of pneumonia or heart failure, progressive
diffuse pulmonary infiltrates and arterial hypoxemia
(PaO2/FiO2, <300) indicate the development of acute
lung injury; more severe hypoxemia (PaO2/FiO2,

<200) denotes the acute respiratory distress syndrome
(ARDS). Acute lung injury or ARDS develops in ∼50%
of patients with severe sepsis or septic shock. Respiratory muscle fatigue can exacerbate hypoxemia and
hypercapnia. An elevated pulmonary capillary wedge
pressure (>18 mmHg) suggests fluid volume overload
or cardiac failure rather than ARDS. Pneumonia caused
by viruses or by Pneumocystis may be clinically indistinguishable from ARDS.
Sepsis-induced hypotension (see “Septic Shock,” earlier)
usually results initially from a generalized maldistribution
of blood flow and blood volume and from hypovolemia
that is due, at least in part, to diffuse capillary leakage
of intravascular fluid. Other factors that may decrease
effective intravascular volume include dehydration from
antecedent disease or insensible fluid losses, vomiting or
diarrhea, and polyuria. During early septic shock, systemic vascular resistance is usually elevated and cardiac
output may be low. After fluid repletion, in contrast,
cardiac output typically increases and systemic vascular
resistance falls. Indeed, normal or increased cardiac
output and decreased systemic vascular resistance distinguish septic shock from cardiogenic, extracardiac
obstructive, and hypovolemic shock; other processes
that can produce this combination include anaphylaxis,
beriberi, cirrhosis, and overdoses of nitroprusside or
narcotics.
Depression of myocardial function, manifested as
increased end-diastolic and systolic ventricular volumes
with a decreased ejection fraction, develops within
24 h in most patients with severe sepsis. Cardiac output
is maintained despite the low ejection fraction because
ventricular dilatation permits a normal stroke volume.
In survivors, myocardial function returns to normal over

several days. Although myocardial dysfunction may contribute to hypotension, refractory hypotension is usually
due to low systemic vascular resistance, and death results
from refractory shock or the failure of multiple organs
rather than from cardiac dysfunction per se.
Adrenal insufficiency
The diagnosis of adrenal insufficiency may be very
difficult in critically ill patients. Whereas a plasma cortisol

level of ≤15 μg/mL (≤10 μg/mL if the serum albumin
concentration is <2.5 mg/dL) indicates adrenal insufficiency
(inadequate production of cortisol), many experts now
feel that the ACTH (CoSyntropin® ) stimulation test is not
useful for detecting less profound degrees of corticosteroid
deficiency in patients who are critically ill. The concept of
critical illness–related corticosteroid insufficiency (CIRCI;
Table 28-1) was proposed to encompass the different
mechanisms that may produce corticosteroid activity that is
inadequate for the severity of a patient’s illness. Although
CIRCI may result from structural damage to the adrenal
gland, it is more commonly due to reversible dysfunction
of the hypothalamic-pituitary axis or to tissue corticosteroid
resistance resulting from abnormalities of the glucocorticoid
receptor or increased conversion of cortisol to cortisone.
The major clinical manifestation of CIRCI is hypotension
that is refractory to fluid replacement and requires pressor
therapy. Some classic features of adrenal insufficiency, such
as hyponatremia and hyperkalemia, are usually absent;
others, such as eosinophilia and modest hypoglycemia, may
sometimes be found. Specific etiologies include fulminant
N. meningitidis bacteremia, disseminated tuberculosis, AIDS

(with cytomegalovirus, Mycobacterium avium-intracellulare,
or Histoplasma capsulatum disease), or the prior use of
drugs that diminish glucocorticoid production, such as
glucocorticoids, megestrol, etomidate, or ketoconazole.
Renal complications
Oliguria, azotemia, proteinuria, and nonspecific urinary
casts are frequently found. Many patients are inappropriately polyuric; hyperglycemia may exacerbate this tendency. Most renal failure is due to acute tubular necrosis
induced by hypotension or capillary injury, although some
patients also have glomerulonephritis, renal cortical necrosis,
or interstitial nephritis. Drug-induced renal damage
may complicate therapy, particularly when hypotensive
patients are given aminoglycoside antibiotics.
Coagulopathy
Although thrombocytopenia occurs in 10–30% of patients,
the underlying mechanisms are not understood. Platelet
counts are usually very low (<50,000/μL) in patients
with DIC; these low counts may reflect diffuse endothelial injury or microvascular thrombosis, yet thrombi
have only infrequently been found upon biopsy of septic
organs.
Neurologic complications
When the septic illness lasts for weeks or months, “critical
illness” polyneuropathy may prevent weaning from
ventilatory support and produce distal motor weakness.
Electrophysiologic studies are diagnostic. Guillain-Barré
syndrome, metabolic disturbances, and toxin activity
must be ruled out.


Immunosuppression
Patients with severe sepsis are often profoundly immunosuppressed. Manifestations include loss of delayed-type

hypersensitivity reactions to common antigens, failure
to control the primary infection, and increased risk
for secondary infections (e.g., by opportunists such as
Stenotrophomonas maltophilia, Acinetobacter calcoaceticusbaumannii, and Candida albicans). Approximately one-third
of patients experience reactivation of herpes simplex
virus, varicella-zoster virus, or cytomegalovirus infections; the latter are thought to contribute to adverse
outcomes in some instances.

Laboratory Findings

There is no specific diagnostic test for the septic response.
Diagnostically sensitive findings in a patient with suspected or proven infection include fever or hypothermia,
tachypnea, tachycardia, and leukocytosis or leukopenia
(Table 28-1); acutely altered mental status, thrombocytopenia, an elevated blood lactate level, or hypotension

Severe Sepsis and Septic Shock

Patients in whom sepsis is suspected must be managed
expeditiously. This task is best accomplished by personnel
who are experienced in the care of the critically ill.
Successful management requires urgent measures to
treat the infection, to provide hemodynamic and respiratory
support, and to eliminate the offending microorganisms. These measures should be initiated within 1 h of the
patient’s presentation with severe sepsis or septic shock.
Rapid assessment and diagnosis are therefore essential.
Antimicrobial Agents  Antimicrobial chemo-

therapy should be started as soon as samples of blood
and other relevant sites have been obtained for culture.
A large retrospective review of patients who developed

septic shock found that the interval between the onset

Severe Sepsis and Septic Shock

Diagnosis

Treatment

283

CHAPTER 28

Abnormalities that occur early in the septic response
may include leukocytosis with a left shift, thrombocytopenia, hyperbilirubinemia, and proteinuria. Leukopenia
may develop. The neutrophils may contain toxic granulations, Döhle bodies, or cytoplasmic vacuoles. As the
septic response becomes more severe, thrombocytopenia
worsens (often with prolongation of the thrombin time,
decreased fibrinogen, and the presence of d-dimers, suggesting DIC), azotemia and hyperbilirubinemia become
more prominent, and levels of aminotransferases rise.
Active hemolysis suggests clostridial bacteremia, malaria,
a drug reaction, or DIC; in the case of DIC, microangiopathic changes may be seen on a blood smear.
During early sepsis, hyperventilation induces respiratory alkalosis. With respiratory muscle fatigue and
the accumulation of lactate, metabolic acidosis (with
increased anion gap) typically supervenes. Evaluation
of arterial blood gases reveals hypoxemia that is initially
correctable with supplemental oxygen but whose later
refractoriness to 100% oxygen inhalation indicates rightto-left shunting. The chest radiograph may be normal
or may show evidence of underlying pneumonia, volume overload, or the diffuse infiltrates of ARDS. The
electrocardiogram may show only sinus tachycardia or
nonspecific ST–T-wave abnormalities.

Most diabetic patients with sepsis develop hyperglycemia. Severe infection may precipitate diabetic ketoacidosis that may exacerbate hypotension. Hypoglycemia
occurs rarely. The serum albumin level declines as sepsis
continues. Hypocalcemia is rare.

also should suggest the diagnosis. The septic response
can be quite variable, however. In one study, 36% of
patients with severe sepsis had a normal temperature,
40% had a normal respiratory rate, 10% had a normal
pulse rate, and 33% had normal white blood cell counts.
Moreover, the systemic responses of uninfected patients
with other conditions may be similar to those characteristic
of sepsis. Noninfectious etiologies of SIRS (Table 28-1)
include pancreatitis, burns, trauma, adrenal insufficiency, pulmonary embolism, dissecting or ruptured aortic
aneurysm, myocardial infarction, occult hemorrhage, cardiac tamponade, postcardiopulmonary bypass syndrome,
anaphylaxis, tumor-associated lactic acidosis, and drug
overdose.
Definitive etiologic diagnosis requires isolation of
the microorganism from blood or a local site of infection. At least two blood samples should be obtained
(from two different venipuncture sites) for culture; in a
patient with an indwelling catheter, one sample should be
collected from each lumen of the catheter and another
via venipuncture. In many cases, blood cultures are
negative; this result can reflect prior antibiotic administration, the presence of slow-growing or fastidious
organisms, or the absence of microbial invasion of the
bloodstream. In these cases, Gram’s staining and culture
of material from the primary site of infection or from
infected cutaneous lesions may help establish the microbial etiology. Identification of microbial DNA in
peripheral-blood or tissue samples by polymerase chain
reaction may also be definitive. The skin and mucosae
should be examined carefully and repeatedly for lesions

that might yield diagnostic information. With overwhelming bacteremia (e.g., pneumococcal sepsis in splenectomized individuals; fulminant meningococcemia; or
infection with V. vulnificus, B. pseudomallei, or Y. pestis),
microorganisms are sometimes visible on buffy coat
smears of peripheral blood.


284

Section IV

of hypotension and the administration of appropriate
antimicrobial chemotherapy was the major determinant of outcome; a delay of as little as 1 h was associated
with lower survival rates. Use of inappropriate antibiotics, defined on the basis of local microbial susceptibilities and published guidelines for empirical therapy (see
later), was associated with fivefold lower survival rates,
even among patients with negative cultures.
It is therefore very important to promptly initiate
empirical antimicrobial therapy that is effective
against both gram-positive and gram-negative bacteria (Table 28-3). Maximal recommended doses
of antimicrobial drugs should be given intravenously, with adjustment for impaired renal function
when necessary. Available information about patterns
of antimicrobial susceptibility among bacterial isolates
from the community, the hospital, and the patient
should be taken into account. When culture results
become available, the regimen can often be simplified, as a single antimicrobial agent is usually
adequate for the treatment of a known pathogen. Meta-analyses have concluded that, with one
exception, combination antimicrobial therapy is not
superior to monotherapy for treating gram-negative
bacteremia; the exception is that aminoglycoside

monotherapy for P. aeruginosa bacteremia is less effective than the combination of an aminoglycoside with

an antipseudomonal β-lactam agent. Empirical antifungal therapy should be strongly considered if the
septic patient is already receiving broad-spectrum antibiotics or parenteral nutrition, has been neutropenic for
≥5 days, has had a long-term central venous catheter,
or has been hospitalized in an intensive care unit for a
prolonged period. The chosen antimicrobial regimen
should be reconsidered daily in order to provide maximal efficacy with minimal resistance, toxicity, and cost.
Most patients require antimicrobial therapy for at
least 1 week. The duration of treatment is typically influenced by factors such as the site of tissue infection, the
adequacy of surgical drainage, the patient’s underlying
disease, and the antimicrobial susceptibility of the
microbial isolate(s). The absence of an identified microbial
pathogen is not necessarily an indication for discontinuing
antimicrobial therapy, since “appropriate” antimicrobial
regimens seem to be beneficial in both culture-negative
and culture-positive cases.
Removal of the Source of Infection

Removal or drainage of a focal source of infection is
essential. In one series, a focus of ongoing infection

Table 28-3
Initial Antimicrobial Therapy for Severe Sepsis With No Obvious Source in Adults With Normal
Renal Function

Common Critical Illnesses and Syndromes

Clinical Condition

Antimicrobial Regimens (Intravenous Therapy )

Immunocompetent adult

The many acceptable regimens include (1) piperacillin-tazobactam (3.375 g q4–6h); (2)
imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h); or (3) cefepime (2 g q12h). If
the patient is allergic to β-lactam agents, use ciprofloxacin (400 mg q12h) or levofloxacin
(500–750 mg q12h) plus clindamycin (600 mg q8h). Vancomycin (15 mg/kg q12h) should be
added to each of the above regimens.

Neutropenia (<500 neutrophils/μL)

Regimens include (1) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime
(2 g q8h); (2) piperacillintazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h).
Vancomycin (15 mg/kg q12h) should be added if the patient has an indwelling vascular catheter,
has received quinolone prophylaxis, or has received intensive chemotherapy that produces
mucosal damage; if staphylococci are suspected; if the institution has a high incidence of
MRSA infections; or if there is a high prevalence of MRSA isolates in the community. Empirical
antifungal therapy with an echinocandin (for caspofungin: a 70-mg loading dose, then 50 mg
daily) or a lipid formulation of amphotericin B should be added if the patient is hypotensive or
has been receiving broad-spectrum antibacterial drugs.

Splenectomy

Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of
cephalosporin-resistant pneumococci is high, add vancomycin. If the patient is allergic to
β-lactam drugs, vancomycin (15 mg/kg q12h) plus either moxifloxacin (400 mg q24h) or
levofloxacin (750 mg q24h) or aztreonam (2 g q8h) should be used.

IV drug user

Vancomycin (15 mg/kg q12h)

AIDS

Cefepime (2 g q8h) or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h)
should be used. If the patient is allergic to β-lactam drugs, ciprofloxacin (400 mg q12h) or
levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin should be used.

Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus.
Source: Adapted in part from WT Hughes et al: Clin Infect Dis 25:551, 1997; and DN Gilbert et al: The Sanford Guide to Antimicrobial Therapy, 2009.


Hemodynamic, Respiratory, and Metabolic Support  The primary goals are to restore

General Support  In patients with prolonged

severe sepsis (i.e., lasting more than 2 or 3 days), nutritional

285

Severe Sepsis and Septic Shock

adequate oxygen and substrate delivery to the tissues as
quickly as possible and to improve tissue oxygen utilization and cellular metabolism. Adequate organ perfusion is thus essential. Circulatory adequacy is assessed
by measurement of arterial blood pressure and monitoring of parameters such as mentation, urine output,
and skin perfusion. Indirect indices of oxygen delivery and consumption, such as central venous oxygen
saturation, may also be useful. Initial management of
hypotension should include the administration of IV
fluids, typically beginning with 1–2 L of normal saline
over 1–2 h. To avoid pulmonary edema, the central
venous pressure should be maintained at 8–12 cmH2O.

The urine output rate should be kept at >0.5 mL/kg
per hour by continuing fluid administration; a diuretic
such as furosemide may be used if needed. In about
one-third of patients, hypotension and organ hypoperfusion respond to fluid resuscitation; a reasonable
goal is to maintain a mean arterial blood pressure of
>65 mmHg (systolic pressure >90 mmHg). If these
guidelines cannot be met by volume infusion, vasopressor therapy is indicated (Chap. 30). Titrated doses
of norepinephrine or dopamine should be administered
through a central catheter. If myocardial dysfunction
produces elevated cardiac filling pressures and low
cardiac output, inotropic therapy with dobutamine is
recommended.

In patients with septic shock, plasma vasopressin levels
increase transiently but then decrease dramatically.
Early studies found that vasopressin infusion can reverse
septic shock in some patients, reducing or eliminating
the need for catecholamine pressors. More recently, a
randomized clinical trial that compared vasopressin plus
norepinephrine with norepinephrine alone in 776 patients
with pressor-dependent septic shock found no difference
between treatment groups in the primary study outcome,
28-day mortality. Although vasopressin may have benefited
patients who required less norepinephrine, its role in the
treatment of septic shock seems to be a minor one overall.
CIRCI should be strongly considered in patients who
develop hypotension that does not respond to fluid
replacement therapy. Hydrocortisone (50 mg IV every 6 h)
should be given; if clinical improvement occurs over
24–48 h, most experts would continue hydrocortisone

therapy for 5–7 days before slowly tapering and discontinuing it. Meta-analyses of recent clinical trials have
concluded that hydrocortisone therapy hastens recovery
from septic shock without increasing long-term survival.
Ventilator therapy is indicated for progressive hypoxemia, hypercapnia, neurologic deterioration, or respiratory
muscle failure. Sustained tachypnea (respiratory rate,
>30 breaths/min) is frequently a harbinger of impending
respiratory collapse; mechanical ventilation is often initiated to ensure adequate oxygenation, to divert blood
from the muscles of respiration, to prevent aspiration
of oropharyngeal contents, and to reduce the cardiac
afterload. The results of recent studies favor the use
of low tidal volumes (6 mL/kg of ideal body weight, or
as low as 4 mL/kg if the plateau pressure exceeds
30 cmH2O). Patients undergoing mechanical ventilation
require careful sedation, with daily interruptions; elevation of the head of the bed helps to prevent nosocomial
pneumonia. Stress-ulcer prophylaxis with a histamine
H2-receptor antagonist may decrease the risk of gastrointestinal hemorrhage in ventilated patients.
Erythrocyte transfusion is generally recommended
when the blood hemoglobin level decreases to ≤7 g/dL,
with a target level of 9 g/dL in adults. Erythropoietin is
not used to treat sepsis-related anemia. Bicarbonate
is sometimes administered for severe metabolic acidosis (arterial pH <7.2), but there is little evidence that
it improves either hemodynamics or the response to
vasopressor hormones. DIC, if complicated by major
bleeding, should be treated with transfusion of freshfrozen plasma and platelets. Successful treatment of the
underlying infection is essential to reverse both acidosis
and DIC. Patients who are hypercatabolic and have
acute renal failure may benefit greatly from intermittent
hemodialysis or continuous veno-venous hemofiltration.

CHAPTER 28

was found in ∼80% of surgical intensive care patients
who died of severe sepsis or septic shock. Sites of occult
infection should be sought carefully, particularly in the
lungs, abdomen, and urinary tract. Indwelling IV or arterial
catheters should be removed and the tip rolled over a
blood agar plate for quantitative culture; after antibiotic
therapy has been initiated, a new catheter should be
inserted at a different site. Foley and drainage catheters
should be replaced. The possibility of paranasal sinusitis
(often caused by gram-negative bacteria) should be
considered if the patient has undergone nasal intubation.
Even in patients without abnormalities on chest radiographs, CT of the chest may identify unsuspected parenchymal, mediastinal, or pleural disease. In the neutropenic
patient, cutaneous sites of tenderness and erythema,
particularly in the perianal region, must be carefully
sought. In patients with sacral or ischial decubitus ulcers,
it is important to exclude pelvic or other soft tissue pus
collections with CT or MRI. In patients with severe sepsis
arising from the urinary tract, sonography or CT should
be used to rule out ureteral obstruction, perinephric
abscess, and renal abscess. Sonographic or CT imaging
of the upper abdomen may disclose evidence of cholecystitis, bile duct dilatation, and pus collections in the
liver, subphrenic space, or spleen.


supplementation may reduce the impact of protein
hypercatabolism; the available evidence, which is not
strong, favors the enteral delivery route. Prophylactic
heparinization to prevent deep venous thrombosis is
indicated for patients who do not have active bleeding

or coagulopathy; when heparin is contraindicated,
compression stockings or an intermittent compression
device should be used. Recovery is also assisted by prevention of skin breakdown, nosocomial infections, and
stress ulcers.
The role of tight control of the blood glucose concentration in recovery from critical illness has been
addressed in numerous controlled trials. Meta-analyses
of these trials have concluded that use of insulin to
lower blood glucose levels to 100–120 mg/dL is potentially harmful and does not improve survival rates. Most
experts now recommend using insulin only if it is needed
to maintain the blood glucose concentration below
∼150 mg/dL. Patients receiving intravenous insulin must
be monitored frequently (every 1–2 h) for hypoglycemia.
Other Measures  Despite aggressive manage-

Section IV
Common Critical Illnesses and Syndromes

ment, many patients with severe sepsis or septic shock
die. Numerous interventions have been tested for their
ability to improve survival rates among patients with
severe sepsis. The list includes endotoxin-neutralizing
proteins, inhibitors of cyclooxygenase or nitric oxide
synthase, anticoagulants, polyclonal immunoglobulins,
glucocorticoids, a phospholipid emulsion, and antagonists to TNF-α, IL-1, platelet-activating factor, and bradykinin. Unfortunately, none of these agents has improved
rates of survival among patients with severe sepsis/septic
shock in more than one large-scale, randomized, placebocontrolled clinical trial. Many factors have contributed to
this lack of reproducibility, including (1) heterogeneity
in the patient populations studied, the primary infection
sites, the preexisting illnesses, and the inciting microbes;
and (2) the nature of the “standard” therapy also used.

A dramatic example of this problem was seen in a trial
of tissue factor pathway inhibitor (Fig. 28-1). Whereas
the drug appeared to improve survival rates after
722 patients had been studied (p = .006), it did not do so
in the next 1032 patients, and the overall result was negative. This inconsistency argues that the results of a clinical
trial may not apply to individual patients, even within
a carefully selected patient population. It also suggests
that, at a minimum, a sepsis intervention should show a
significant survival benefit in more than one placebocontrolled, randomized clinical trial before it is accepted
as routine clinical practice. In one prominent attempt to
reduce patient heterogeneity in clinical trials, experts
have called for changes that would restrict these trials
to patients who have similar underlying diseases (e.g.,
major trauma) and inciting infections (e.g., pneumonia).
The goal of the predisposition–infection–response–organ

45
40
35
Mortality, %

286

30
25
20
15
10

TFPI

Placebo

5
0
Jun

Aug

Oct

2000

Dec

Feb

Apr

Jun

2001

Figure 28-1 
Mortality rates among patients who received tissue factor
pathway inhibitor (TFPI) or placebo, shown as the running
average over the course of the clinical trial. The drug seemed
highly efficacious at the interim analysis in December 2000,
but this trend reversed later in the trial. Demonstrating that
therapeutic agents for sepsis have consistent, reproducible
efficacy has been extremely difficult, even within well-defined

patient populations. (Reprinted with permission from E Abraham
et al: JAMA 290:238, 2003.)

dysfunction (PIRO) grading system for classification of
septic patients (Table 28-1) is similar. Other investigators
have used specific biomarkers, such as IL-6 levels in blood
or the expression of HLA-DR on peripheral-blood monocytes, to identify the patients most likely to benefit from
certain interventions. Multivariate risk stratification based
on easily measurable clinical variables should be used
with each of these approaches.
Recombinant activated protein C (aPC) was the first drug
to be approved by the U.S. Food and Drug Administration
for the treatment of patients with severe sepsis or septic
shock. Approval was based on the results of a single randomized controlled trial in which the drug was given within
24 h of the patient’s first sepsis-related organ dysfunction;
the 28-day survival rate was significantly higher among aPC
recipients who were very sick (APACHE II score, ≥25) before
infusion of the protein than among placebo-treated controls. Subsequent trials failed to show a benefit of aPC treatment in patients who were less sick (APACHE II score, <25)
or in children. A second trial of aPC in high-risk patients is
now under way in Europe. Given the drug’s known toxicity
(increased risk of severe bleeding) and uncertain performance in clinical practice, many experts are awaiting the
results of the European trial before recommending further
use of aPC. Other agents in ongoing or planned clinical
trials include intravenous immunoglobulin, a small-molecule endotoxin antagonist (eritoran), and granulocytemacrophage colony-stimulating factor that was recently
reported to restore monocyte immunocompetence in
patients with sepsis-associated immunosuppression.


The Surviving Sepsis Campaign  An intern

Approximately 20–35% of patients with severe sepsis and
40–60% of patients with septic shock die within 30 days.
Others die within the ensuing 6 months. Late deaths often
result from poorly controlled infection, immunosuppression, complications of intensive care, failure of multiple
organs, or the patient’s underlying disease. Case-fatality
rates are similar for culture-positive and culture-negative
severe sepsis. Prognostic stratification systems such as
APACHE II indicate that factoring in the patient’s age,
underlying condition, and various physiologic variables
can yield estimates of the risk of dying of severe sepsis. Age
and prior health status are probably the most important risk
factors (Fig. 28-2). In patients with no known preexisting
morbidity, the case-fatality rate remains below 10% until
the fourth decade of life, after which it gradually increases
to exceed 35% in the very elderly. Death is significantly
more likely in severely septic patients with preexisting

30

20

No comorbidity

10

0
0

10

20

30

40
50
Age, years

60

70

80

90

Figure 28-2
Influence of age and prior health status on outcome from
severe sepsis. With modern therapy, fewer than 10% of previously healthy young individuals (below 35 years of age) die
with severe sepsis; the case-fatality rate then increases slowly
through middle and old age. The most commonly identified
etiologic agents in patients who die are Staphylococcus aureus,
Streptococcus pyogenes, S. pneumoniae, and Neisseria
meningitidis. Individuals with preexisting comorbidities are at
greater risk of dying of severe sepsis at any age. The etiologic
agents in these cases are likely to be S. aureus, Pseudomonas
aeruginosa, various Enterobacteriaceae, enterococci, or fungi.
(Adapted from DC Angus et al: Crit Care Med 29:1303, 2001.)

illness, especially during the third to fifth decades. Septic

shock is also a strong predictor of short- and long-term
mortality.

Prevention
Prevention offers the best opportunity to reduce morbidity
and mortality from severe sepsis. In developed countries,
most episodes of severe sepsis and septic shock are complications of nosocomial infections. These cases might
be prevented by reducing the number of invasive procedures undertaken, by limiting the use (and duration
of use) of indwelling vascular and bladder catheters, by
reducing the incidence and duration of profound neutropenia (<500 neutrophils/μL), and by more aggressively
treating localized nosocomial infections. Indiscriminate
use of antimicrobial agents and glucocorticoids should
be avoided, and optimal infection-control measures
should be used. Studies indicate that 50–70% of patients
who develop nosocomial severe sepsis or septic shock
have experienced a less severe stage of the septic
response (e.g., SIRS, sepsis) on at least one previous day
in the hospital. Research is needed to identify patients at
increased risk and to develop adjunctive agents that can
modulate the septic response before organ dysfunction
or hypotension occurs.

Severe Sepsis and Septic Shock

Prognosis

Pre-existing comorbidity

CHAPTER 28

ational consortium has advocated “bundling” multiple
therapeutic maneuvers into a unified algorithmic approach
that will become the standard of care for severe sepsis.
In theory, such a strategy could improve care by mandating measures that seem to bring maximal benefit,
such as the rapid administration of appropriate antimicrobial therapy; on the other hand, this approach
would deemphasize physicians’ experience and judgment and minimize the consideration of potentially
important differences between patients. Bundling multiple therapies into a single package also obscures the
efficacy and toxicity of the individual measures. Caution
should be engendered by the fact that two of the
key elements of the initial algorithm have now been
withdrawn for lack of evidence, while a third remains
unproven and controversial.

287

40

Case-fatality rate, %

A careful retrospective analysis found that the apparent
efficacy of all sepsis therapeutics studied to date has
been greatest among the patients at greatest risk of
dying before treatment; conversely, use of many of these
drugs has been associated with increased mortality rates
among patients who are less ill. The authors proposed
that neutralizing one of many different mediators may
help patients who are very sick, whereas disrupting the
mediator balance may be harmful to patients whose
adaptive defense mechanisms are working well. This
analysis suggests that if more aggressive early resuscitation improves survival rates among sicker patients, it

will become more difficult to obtain additional benefit
from other therapies; that is, if an intervention improves
patients’ risk status, moving them into a “less severe illness” category, it will be harder to show that adding
another agent to the therapeutic regimen is beneficial.


CHAPTER 29

ACUTE RESPIRATORY DISTRESS SYNDROME
Bruce D. Levy

■

Augustine M. K. Choi

Acute respiratory distress syndrome (ARDS) is a clinical
syndrome of severe dyspnea of rapid onset, hypoxemia,
and diffuse pulmonary infiltrates leading to respiratory
failure. ARDS is caused by diffuse lung injury from
many underlying medical and surgical disorders. The
lung injury may be direct, as occurs in toxic inhalation, or indirect, as occurs in sepsis (Table 29-1). The
clinical features of ARDS are listed in Table 29-2.
Acute lung injury (ALI) is a less severe disorder but has
the potential to evolve into ARDS (Table 29-2). The
arterial (a) PO2 (in mmHg)/FiO2 (inspiratory O2 fraction) <200 mmHg is characteristic of ARDS, while
a PaO2/FiO2 between 200 and 300 identifies patients
with ALI who are likely to benefit from aggressive
therapy.
The annual incidences of ALI and ARDS are estimated
to be up to 80/100,000 and 60/100,000, respectively.

Approximately 10% of all intensive care unit (ICU)
admissions suffer from acute respiratory failure, with
∼20% of these patients meeting criteria for ALI or
ARDS.

TABLE 29-2
DIAGNOSTIC CRITERIA FOR ALI AND ARDS

OXYGENATION

ALI: PaO2/FiO2
≤300 mmHg
ARDS:
PaO2/FiO2
≤200 mmHg

Pneumonia
Aspiration of gastric
contents
Pulmonary contusion
Near-drowning
Toxic inhalation injury

Sepsis
Severe trauma
Multiple bone fractures
Flail chest
Head trauma
Burns
Multiple transfusions

Drug overdose
Pancreatitis
Postcardiopulmonary
bypass

Bilateral
alveolar or
interstitial
infiltrates

PCWP ≤ 18 mmHg
or no clinical
evidence of
increased left
atrial pressure

ETIOLOGY
While many medical and surgical illnesses have been
associated with the development of ALI and ARDS,
most cases (>80%) are caused by a relatively small number
of clinical disorders, namely, severe sepsis syndrome
and/or bacterial pneumonia (∼40–50%), trauma, multiple
transfusions, aspiration of gastric contents, and drug
overdose. Among patients with trauma, pulmonary contusion, multiple bone fractures, and chest wall trauma/
flail chest are the most frequently reported surgical conditions in ARDS, whereas head trauma, near-drowning,
toxic inhalation, and burns are rare causes. The risks of
developing ARDS are increased in patients suffering
from more than one predisposing medical or surgical
condition (e.g., the risk for ARDS increases from 25%
in patients with severe trauma to 56% in patients with

trauma and sepsis).
Several other clinical variables have been associated
with the development of ARDS. These include older
age, chronic alcohol abuse, metabolic acidosis, and
severity of critical illness. Trauma patients with an acute
physiology and chronic health evaluation (APACHE)
II score ≥16 (Chap. 25) have a 2.5-fold increase in

CLINICAL DISORDERS COMMONLY ASSOCIATED
WITH ARDS
INDIRECT LUNG INJURY

Acute

Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; FiO2, inspired O2 percentage; PaO2, arterial partial
pressure of O2; PCWP, pulmonary capillary wedge pressure.

TABLE 29-1

DIRECT LUNG INJURY

ABSENCE OF
CHEST
LEFT ATRIAL
ONSET RADIOGRAPH HYPERTENSION

288


the risk of developing ARDS, and those with a score

>20 have an incidence of ARDS that is more than
threefold greater than those with APACHE II scores ≤9.

289

Clinical Course and Pathophysiology
The natural history of ARDS is marked by three phases—
exudative, proliferative, and fibrotic—each with characteristic clinical and pathologic features (Fig. 29-1).
Exudative phase

Hyaline
Membranes
Edema
Day: 0 2

7

Proliferative

Fibrotic

Interstitial Inflammation

Fibrosis

14

21 . . .

Figure 29-1

Diagram illustrating the time course for the development
and resolution of ARDS. The exudative phase is notable
for early alveolar edema and neutrophil-rich leukocytic infiltration of the lungs with subsequent formation of hyaline
membranes from diffuse alveolar damage. Within 7 days, a
proliferative phase ensues with prominent interstitial inflammation and early fibrotic changes. Approximately 3 weeks
after the initial pulmonary injury, most patients recover. However, some patients enter the fibrotic phase, with substantial
fibrosis and bullae formation.

exacerbated by microvascular occlusion that leads to
reductions in pulmonary arterial blood flow to ventilated portions of the lung, increasing the dead space,
and to pulmonary hypertension. Thus, in addition to
severe hypoxemia, hypercapnia secondary to an increase
in pulmonary dead space is also prominent in early
ARDS.
The exudative phase encompasses the first 7 days of
illness after exposure to a precipitating ARDS risk factor,
with the patient experiencing the onset of respiratory
symptoms. Although usually present within 12–36 h
after the initial insult, symptoms can be delayed by
5–7 days. Dyspnea develops with a sensation of rapid
shallow breathing and an inability to get enough air.
Tachypnea and increased work of breathing frequently
result in respiratory fatigue and ultimately in respiratory
failure. Laboratory values are generally nonspecific and
primarily indicative of underlying clinical disorders. The
chest radiograph usually reveals alveolar and interstitial
opacities involving at least three-quarters of the lung
fields (Fig. 29-2). While characteristic for ARDS or
ALI, these radiographic findings are not specific and can
be indistinguishable from cardiogenic pulmonary edema

(Chap. 30). Unlike the latter, however, the chest x-ray
in ARDS rarely shows cardiomegaly, pleural effusions,
or pulmonary vascular redistribution. Chest computed
tomographic (CT) scanning in ARDS reveals extensive
heterogeneity of lung involvement (Fig. 29-4).
Because the early features of ARDS and ALI are
nonspecific, alternative diagnoses must be considered.
In the differential diagnosis of ARDS, the most common
disorders are cardiogenic pulmonary edema, diffuse
pneumonia, and alveolar hemorrhage. Less frequent

Acute Respiratory Distress Syndrome

Exudative

Figure 29-2
A representative anteroposterior (AP) chest x-ray in the
exudative phase of ARDS that shows diffuse interstitial and
alveolar infiltrates, that can be difficult to distinguish from left
ventricular failure.

CHAPTER 29

(Figure 29-2) In this phase, alveolar capillary endothelial cells and type I pneumocytes (alveolar epithelial cells)
are injured, leading to the loss of the normally tight alveolar barrier to fluid and macromolecules. Edema fluid
that is rich in protein accumulates in the interstitial and
alveolar spaces. Significant concentrations of cytokines
(e.g., interleukin 1, interleukin 8, and tumor necrosis
factor α) and lipid mediators (e.g., leukotriene B4) are
present in the lung in this acute phase. In response to

proinflammatory mediators, leukocytes (especially
neutrophils) traffic into the pulmonary interstitium and
alveoli. In addition, condensed plasma proteins aggregate
in the air spaces with cellular debris and dysfunctional
pulmonary surfactant to form hyaline membrane whorls.
Pulmonary vascular injury also occurs early in ARDS,
with vascular obliteration by microthrombi and fibrocellular proliferation (Fig. 29-3).
Alveolar edema predominantly involves dependent
portions of the lung, leading to diminished aeration and
atelectasis. Collapse of large sections of dependent lung
markedly decreases lung compliance. Consequently,
intrapulmonary shunting and hypoxemia develop
and the work of breathing rises, leading to dyspnea.
The pathophysiologic alterations in alveolar spaces are


290

Normal alveolus

Injured alveolus during the acute phase

Protein rich edema fluid
Alveolar air space

Sloughing of bronchial epithelium
Necrotic or apoptotic type I cell

Type I cell
Inactivated surfactant

Epithelial
basement
membrane

Activated
neutrophil

Red cell

Leukotrienes
Type II cell
Alveolar
macrophage

Interstitium

Oxidants
PAF
Proteases
TNF-α,
IL-1

Intact type II cell
Denuded
basement membrane

Cellular
debris

Hyaline membrane
Migrating neutrophil

Alveolar
Fibrin
macrophage
IL-6,
IL-8

MIF
Surfactant layer

Proteases

TNF-α,
IL-8

Widened,
edematous
interstitium

Procollagen
IL-8

Endothelial
cell

Fibroblast

Section IV

Neutrophil

Capillary
Endothelial
basement
membrane

Red cell

Fibroblast

Common Critical Illnesses and Syndromes

Figure 29-3
The normal alveolus (left-hand side) and the injured alveolus
in the acute phase of acute lung injury and the acute respiratory distress syndrome (right-hand side). In the acute
phase of the syndrome (right-hand side), there is sloughing of
both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded
basement membrane. Neutrophils are shown adhering to the
injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema
fluid. In the air space, an alveolar macrophage is secreting
cytokines, interleukins 1, 6, 8, and 10 (IL-1, -6, -8, and -10) and
tumor necrosis factor α (TNF-α), that act locally to stimulate

diagnoses to consider include acute interstitial lung diseases
(e.g., acute interstitial pneumonitis [Chap. 19]), acute
immunologic injury (e.g., hypersensitivity pneumonitis
[Chap. 9]), toxin injury (e.g., radiation pneumonitis), and
neurogenic pulmonary edema.

Proliferative phase
This phase of ARDS usually lasts from day 7 to day 21.
Most patients recover rapidly and are liberated from

Platelets

IL-8

Gap
formation

Neutrophil

Swollen, injured
endothelial cells

chemotaxis and activate neutrophils. Macrophages also secrete
other cytokines, including IL-1, -6, and -10. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other
proinflammatory molecules, such as platelet-activating factor
(PAF). A number of antiinflammatory mediators are also present
in the alveolar milieu, including IL-1–receptor antagonist, soluble TNF-α receptor, autoantibodies against IL-8, and cytokines
such as IL-10 and -11 (not shown). The influx of protein-rich
edema fluid into the alveolus has led to the inactivation of surfactant. MIF, macrophage inhibitory factor. (From LB Ware, MA
Matthay: N Engl J Med 342:1334, 2000, with permission.)

mechanical ventilation during this phase. Despite this
improvement, many still experience dyspnea, tachypnea,
and hypoxemia. Some patients develop progressive lung
injury and early changes of pulmonary fibrosis during the
proliferative phase. Histologically, the first signs of resolution are often evident in this phase with the initiation

of lung repair, organization of alveolar exudates, and a
shift from a neutrophil- to a lymphocyte-predominant
pulmonary infiltrate. As part of the reparative process,
there is a proliferation of type II pneumocytes along


medical and surgical disorders (e.g., sepsis, aspiration,
trauma); (2) minimizing procedures and their complications; (3) prophylaxis against venous thromboembolism,
gastrointestinal bleeding, aspiration, excessive sedation,
and central venous catheter infections; (4) prompt recognition of nosocomial infections; and (5) provision of
adequate nutrition.

291

Management of Mechanical Ventilation  (See also Chap. 26) Patients meeting clinical

criteria for ARDS frequently fatigue from increased work
of breathing and progressive hypoxemia, requiring
mechanical ventilation for support.
Figure 29-4
A representative computed tomographic scan of the
chest during the exudative phase of ARDS in which
dependent alveolar edema and atelectasis predominate.

Fibrotic phase

Treatment

Acute Respiratory Distress Syndrome

Principles  Recent reductions in
ARDS/ALI mortality are largely the result of general
advances in the care of critically ill patients (Chap. 25).
Thus, caring for these patients requires close attention
to (1) the recognition and treatment of the underlying

General

Prevention of Alveolar Collapse  In ARDS, the

presence of alveolar and interstitial fluid and the loss of surfactant can lead to a marked reduction of lung compliance.
Without an increase in end-expiratory pressure, significant
alveolar collapse can occur at end-expiration, impairing
oxygenation. In most clinical settings, positive end-expiratory pressure (PEEP) is empirically set to minimize Fio2 and
maximize Pao2. On most modern mechanical ventilators, it
is possible to construct a static pressure–volume curve for
the respiratory system. The lower inflection point on the
curve represents alveolar opening (or “recruitment”). The
pressure at this point, usually 12–15 mmHg in ARDS, is a

Acute Respiratory Distress Syndrome

While many patients with ARDS recover lung function 3–4 weeks after the initial pulmonary injury, some
will enter a fibrotic phase that may require long-term
support on mechanical ventilators and/or supplemental
oxygen. Histologically, the alveolar edema and inflammatory exudates of earlier phases are now converted to
extensive alveolar duct and interstitial fibrosis. Acinar
architecture is markedly disrupted, leading to emphysemalike changes with large bullae. Intimal fibroproliferation
in the pulmonary microcirculation leads to progressive
vascular occlusion and pulmonary hypertension. The

physiologic consequences include an increased risk of
pneumothorax, reductions in lung compliance, and
increased pulmonary dead space. Patients in this late
phase experience a substantial burden of excess morbidity.
Lung biopsy evidence for pulmonary fibrosis in any
phase of ARDS is associated with increased mortality.

saving potential, mechanical ventilation can aggravate
lung injury. Experimental models have demonstrated
that ventilator-induced lung injury appears to require
two processes: repeated alveolar overdistention and
recurrent alveolar collapse. Clearly evident by chest CT
(Fig. 29-4), ARDS is a heterogeneous disorder, principally
involving dependent portions of the lung with relative sparing of other regions. Because of their differing
compliance, attempts to fully inflate the consolidated
lung may lead to overdistention and injury to the more
“normal” areas of the lung. Ventilator-induced injury can
be demonstrated in experimental models of ALI, with
high tidal volume (Vt) ventilation resulting in additional,
synergistic alveolar damage. These findings led to the
hypothesis that ventilating patients suffering from ALI
or ARDS with lower Vts would protect against ventilatorinduced lung injury and improve clinical outcomes.
A large-scale, randomized controlled trial sponsored
by the National Institutes of Health and conducted by
the ARDS Network compared low Vt (6 mL/kg predicted
body weight) ventilation to conventional Vt (12 mL/kg
predicted body weight) ventilation. Mortality was significantly lower in the low Vt patients (31%) compared to
the conventional Vt patients (40%). This improvement in
survival represents the most substantial benefit in ARDS
mortality demonstrated for any therapeutic intervention in ARDS to date.

CHAPTER 29

alveolar basement membranes. These specialized epithelial
cells synthesize new pulmonary surfactant and differentiate
into type I pneumocytes. The presence of alveolar type III
procollagen peptide, a marker of pulmonary fibrosis, is
associated with a protracted clinical course and increased
mortality from ARDS.

Ventilator-Induced Lung Injury  Despite its life-


292

Section IV
Common Critical Illnesses and Syndromes

theoretical “optimal PEEP” for alveolar recruitment. Titration of the PEEP to the lower inflection point on the static
pressure–volume curve has been hypothesized to keep the
lung open, improving oxygenation and protecting against
lung injury. Three large randomized trials have investigated the utility of PEEP-based strategies to keep the lung
open. In all three trials, improvement in lung function was
evident but there were no significant differences in overall
mortality. Until more data become available on the clinical
utility of high PEEP, it is advisable to set PEEP to minimize
Fio2 and optimize Pao2 (Chap. 26). Measurement of esophageal pressures to estimate transpulmonary pressure may
help identify an optimal PEEP in some patients.
Oxygenation can also be improved by increasing
mean airway pressure with “inverse ratio ventilation.” In

this technique, the inspiratory (I) time is lengthened so
that it is longer than the expiratory (E) time (I:E > 1:1).
With diminished time to exhale, dynamic hyperinflation leads to increased end-expiratory pressure, similar
to ventilator-prescribed PEEP. This mode of ventilation
has the advantage of improving oxygenation with lower
peak pressures than conventional ventilation. Although
inverse ratio ventilation can improve oxygenation and
help reduce Fio2 to ≤0.60 to avoid possible oxygen toxicity, no mortality benefit in ARDS has been demonstrated. Recruitment maneuvers that transiently increase
PEEP to “recruit” atelectatic lung can also increase
oxygenation, but a mortality benefit has not been
established.
In several randomized trials, mechanical ventilation
in the prone position improved arterial oxygenation,
but its effect on survival and other important clinical
outcomes remains uncertain. Moreover, unless the
critical-care team is experienced in “proning,” repositioning critically ill patients can be hazardous, leading
to accidental endotracheal extubation, loss of central
venous catheters, and orthopedic injury. Until validation
of its efficacy, prone-position ventilation should be
reserved for only the most critically ill ARDS patients.

respiratory distress syndrome, may also have utility in
select adult patients with ARDS.
Data in support of the efficacy of “adjunctive” ventilator therapies (e.g., high PEEP, inverse ratio ventilation,
recruitment maneuvers, prone positioning, HFV, ECMO,
and PLV) remain incomplete, so these modalities are not
routinely used.
Management  (See also Chap. 25)
Increased pulmonary vascular permeability leading to
interstitial and alveolar edema rich in protein is a central

feature of ARDS. In addition, impaired vascular integrity augments the normal increase in extravascular lung
water that occurs with increasing left atrial pressure.
Maintaining a normal or low left atrial filling pressure
minimizes pulmonary edema and prevents further decrements in arterial oxygenation and lung compliance,
improves pulmonary mechanics, shortens ICU stay and
the duration of mechanical ventilation, and is associated
with a lower mortality in both medical and surgical ICU
patients. Thus, aggressive attempts to reduce left atrial
filling pressures with fluid restriction and diuretics should
be an important aspect of ARDS management, limited
only by hypotension and hypoperfusion of critical organs
such as the kidneys.

Fluid

Glucocorticoids  Inflammatory mediators and
leukocytes are abundant in the lungs of patients with
ARDS. Many attempts have been made to treat both
early and late ARDS with glucocorticoids to reduce this
potentially deleterious pulmonary inflammation. Few
studies have shown any benefit. Current evidence does
not support the use of high-dose glucocorticoids in the
care of ARDS patients.

Other Strategies in Mechanical Ventilation

Other Therapies  Clinical trials of surfactant
replacement and multiple other medical therapies have
proved disappointing. Inhaled nitric oxide (NO) can
transiently improve oxygenation but does not improve

survival or decrease time on mechanical ventilation.
Therefore, the use of NO is not currently recommended
in ARDS.

Several additional mechanical ventilation strategies
that utilize specialized equipment have been tested
in ARDS patients, most with mixed or disappointing
results in adults. These include high-frequency ventilation (HFV) (i.e., ventilating at extremely high respiratory
rates [5–20 cycles per second] and low V Ts [1–2 mL/kg]).
Partial liquid ventilation (PLV) with perfluorocarbon, an
inert, high-density liquid that easily solubilizes oxygen
and carbon dioxide, has revealed promising preliminary
data on pulmonary function in patients with ARDS but
also without survival benefit. Lung-replacement therapy
with extracorporeal membrane oxygenation (ECMO),
which provides a clear survival benefit in neonatal

Recommendations  Many clinical trials have
been undertaken to improve the outcome of patients
with ARDS; most have been unsuccessful in modifying
the natural history. The large number and uncertain clinical
efficacy of ARDS therapies can make it difficult for
clinicians to select a rational treatment plan, and these
patients’ critical illnesses can tempt physicians to try
unproven and potentially harmful therapies. While results
of large clinical trials must be judiciously administered to
individual patients, evidence-based recommendations
are summarized in Table 29-3, and an algorithm for the
initial therapeutic goals and limits in ARDS management
is provided in Fig. 29-5.

Table 29-3
Evidence-Based Recommendations for ARDS
Therapies
Treatment

Mechanical ventilation:
  Low tidal volume
 Minimize left atrial filling
pressures
  High-PEEP or “open lung”
  Prone position
  Recruitment maneuvers
  ECMO
  High-frequency ventilation
  Glucocorticoids
 Surfactant replacement, inhaled
nitric oxide, and other antiinflammatory therapy (e.g.,
ketoconazole, PGE1, NSAIDs)

Recommendationa

A
B
C
C
C
C
D

D
D

a

Prognosis
Mortality

Goals and Limits:
Initiate
volume/pressure-limited
ventilation

Oxygenate

Minimize acidosis

Diuresis

Tidal volume ≤ 6 ml/kg PBW
Plateau pressure ≤ 30 cmH2O
RR ≤ 35 bpm

FIO2 ≤ 0.6
PEEP ≤ 10 cmH2O
SpO2 88 – 95%

pH ≥ 7.30
RR ≤ 35 bpm

MAP ≥ 65 mmHg
Avoid hypoperfusion

Figure 29-5 
Algorithm for the initial management of ARDS. Clinical
trials have provided evidence-based therapeutic goals for a
stepwise approach to the early mechanical ventilation, oxygenation, and correction of acidosis and diuresis of critically
ill patients with ARDS.

to increased ARDS mortality. Several factors related to
the presenting clinical disorders also increase the risk for
ARDS mortality. Patients with ARDS from direct lung
injury (including pneumonia, pulmonary contusion, and
aspiration; Table 29-1) have nearly twice the mortality
of those with indirect causes of lung injury, while surgical and trauma patients with ARDS, especially those
without direct lung injury, have a better survival rate
than other ARDS patients.
Surprisingly, there is little value in predicting ARDS
mortality from the Pao2/Fio2 ratio and any of the following measures of the severity of lung injury: the level
of PEEP used in mechanical ventilation, the respiratory
compliance, the extent of alveolar infiltrates on chest
radiography, and the lung injury score (a composite of
all these variables). However, recent data indicate that
an early (within 24 h of presentation) elevation in dead
space and the oxygenation index may predict increased
mortality from ARDS.
Functional recovery in ARDS survivors
While it is common for patients with ARDS to experience prolonged respiratory failure and remain dependent
on mechanical ventilation for survival, it is a testament
to the resolving powers of the lung that the majority of

patients recover nearly normal lung function. Patients
usually recover their maximum lung function within
6 months. One year after endotracheal extubation,
more than one-third of ARDS survivors have normal

Acute Respiratory Distress Syndrome

Recent mortality estimates for ARDS range from 26 to
44%. There is substantial variability, but a trend toward
improved ARDS outcomes appears evident. Of interest,
mortality in ARDS is largely attributable to nonpulmonary causes, with sepsis and nonpulmonary organ failure
accounting for >80% of deaths. Thus, improvement in
survival is likely secondary to advances in the care of
septic/infected patients and those with multiple organ
failure (Chap. 25).
Several risk factors for mortality to help estimate
prognosis have been identified. Similar to the risk factors
for developing ARDS, the major risk factors for ARDS
mortality are also nonpulmonary. Advanced age is an
important risk factor. Patients >75 years of age have a
substantially increased mortality (∼60%) compared to
those <45 (∼20%). Also, patients >60 years of age with
ARDS and sepsis have a threefold higher mortality
compared to those <60. Preexisting organ dysfunction
from chronic medical illness is an important additional
risk factor for increased mortality. In particular,
chronic liver disease, cirrhosis, chronic alcohol abuse,
chronic immunosuppression, sepsis, chronic renal disease,
any nonpulmonary organ failure, and increased
APACHE III scores (Chap. 25) have also been linked

293

CHAPTER 29

A, recommended therapy based on strong clinical evidence from
randomized clinical trials; B, recommended therapy based on
supportive but limited clinical data; C, indeterminate evidence:
recommended only as alternative therapy; D, not recommended
based on clinical evidence against efficacy of therapy.
Abbreviations: ARDS, acute respiratory distress syndrome; ECMO,
extracorporeal membrane oxygenation; NSAIDs, nonsteroidal antiinflammatory drugs; PEEP, positive end-expiratory pressure; PGE1,
prostaglandin E1.

INITIAL MANAGEMENT OF ARDS


294

spirometry values and diffusion capacity. Most of the
remaining patients have only mild abnormalities in
their pulmonary function. Unlike the risk for mortality,
recovery of lung function is strongly associated with the
extent of lung injury in early ARDS. Low static respiratory compliance, high levels of required PEEP, longer
durations of mechanical ventilation, and high lung
injury scores are all associated with worse recovery of
pulmonary function. When caring for ARDS survivors,

it is important to be aware of the potential for a substantial burden of emotional and respiratory symptoms.
There are significant rates of depression and posttraumatic

stress disorder in ARDS survivors.
Acknowledgment

The authors acknowledge the contribution to this chapter by the
previous author, Dr. Steven D. Shapiro.

Section IV
Common Critical Illnesses and Syndromes


CHaPTEr 30

CARDIOGENIC SHOCK AND PULMONARY EDEMA
Judith S. Hochman

■

David H. Ingbar

Cardiogenic shock and pulmonary edema are lifethreatening conditions that should be treated as medical
emergencies. The most common etiology for both is
severe left ventricular (LV) dysfunction that leads to
pulmonary congestion and/or systemic hypoperfusion
(Fig. 30-1). The pathophysiology of pulmonary edema
and shock is discussed in Chaps. 2 and 27, respectively.

Myocardial infarction

Myocardial dysfunction
Systolic

Diastolic

↑LVEDP
Pulmonary congestion

↓Cardiac output
↓Stroke volume

CardIoGEnIC SHoCK

↓Systemic
perfusion

Cardiogenic shock (CS) is characterized by systemic
hypoperfusion due to severe depression of the cardiac
index [<2.2 (L/min)/m2] and sustained systolic arterial
hypotension (<90 mmHg) despite an elevated filling
pressure [pulmonary capillary wedge pressure (PCWP)
>18 mmHg]. It is associated with in-hospital mortality
rates >50%. The major causes of CS are listed in
Table 30-1. Circulatory failure based on cardiac dysfunction may be caused by primary myocardial failure, most
commonly secondary to acute myocardial infarction (MI)
(Chap. 33), and less frequently by cardiomyopathy or
myocarditis, cardiac tamponade, or critical valvular heart
disease.

Hypotension
↓Coronary
perfusion pressure

Hypoxemia

Ischemia

Compensatory
vasoconstriction*

Progressive
myocardial
dysfunction
Death

Figure 30-1
Pathophysiology of cardiogenic shock. Systolic and
diastolic myocardial dysfunction results in a reduction
in cardiac output and often pulmonary congestion. Systemic and coronary hypoperfusion occur, resulting in
progressive ischemia. Although a number of compensatory mechanisms are activated in an attempt to support
the circulation, these compensatory mechanisms may
become maladaptive and produce a worsening of hemodynamics. *Release of inflammatory cytokines after
myocardial infarction may lead to inducible nitric oxide
expression, excess nitric oxide, and inappropriate vasodilation. This causes further reduction in systemic and
coronary perfusion. A vicious spiral of progressive myocardial dysfunction occurs that ultimately results in death
if it is not interrupted. LVEDP, left ventricular end-diastolic
pressure. (From SM Hollenberg et al: Ann Intern Med
131:47, 1999.)

Incidence
CS is the leading cause of death of patients hospitalized
with MI. Early reperfusion therapy for acute MI

decreases the incidence of CS. The rate of CS complicating acute MI was 20% in the 1960s, stayed at ∼8%
for >20 years, but decreased to 5–7% in the first decade
of this millennium. Shock typically is associated with ST
elevation MI (STEMI) and is less common with non-ST
elevation MI (Chap. 33).
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.

295


296

Table 30-1
a

Etiologies of Cardiogenic Shock (CS) and
Cardiogenic Pulmonary Edema
Etiologies of Cardiogenic Shock or Pulmonary Edema
Acute myocardial infarction/ischemia
  LV failure
  VSR
  Papillary muscle/chordal rupture—severe MR
  Ventricular free wall rupture with subacute tamponade
  Other conditions complicating large MIs
   Hemorrhage
   Infection
   Excess negative inotropic or vasodilator medications

   Prior valvular heart disease
   Hyperglycemia/ketoacidosis
Post-cardiac arrest
Post-cardiotomy
Refractory sustained tachyarrhythmias
Acute fulminant myocarditis
End-stage cardiomyopathy
Left ventricular apical ballooning
Takotsubo’s cardiomyopathy

Section IV

Hypertrophic cardiomyopathy with severe outflow
obstruction
Aortic dissection with aortic insufficiency or tamponade
Pulmonary embolus

Common Critical Illnesses and Syndromes

Severe valvular heart disease
  Critical aortic or mitral stenosis
  Acute severe aortic or MR
Toxic-metabolic
  Beta-blocker or calcium channel antagonist overdose
Other Etiologies of Cardiogenic Shockb
RV failure due to:
  Acute myocardial infarction
  Acute coronary pulmonale
Refractory sustained bradyarrhythmias
Pericardial tamponade

Toxic/metabolic
  Severe acidosis, severe hypoxemia
a

The etiologies of CS are listed. Most of these can cause pulmonary
edema instead of shock or pulmonary edema with CS.
b
These cause CS but not pulmonary edema.
Abbreviations: LV, left ventricular; VSR, ventricular septal rupture;
MR, mitral regurgitation; MI, myocardial infarction; RV, right ventricular.

Pathophysiology
CS is characterized by a vicious circle in which depression of myocardial contractility, usually due to ischemia,
results in reduced cardiac output and arterial pressure (BP),
which result in hypoperfusion of the myocardium and further ischemia and depression of cardiac output (Fig. 30-1).
Systolic myocardial dysfunction reduces stroke volume and, together with diastolic dysfunction, leads to

elevated LV end-diastolic pressure and PCWP as well
as to pulmonary congestion. Reduced coronary perfusion leads to worsening ischemia and progressive myocardial dysfunction and a rapid downward spiral, which,
if uninterrupted, is often fatal. A systemic inflammatory
response syndrome may accompany large infarctions and
shock. Inflammatory cytokines, inducible nitric oxide
synthase, and excess nitric oxide and peroxynitrite may
contribute to the genesis of CS as they do to that of
other forms of shock (Chap. 27). Lactic acidosis from
poor tissue perfusion and hypoxemia from pulmonary
edema may result from pump failure and then contribute
to the vicious circle by worsening myocardial ischemia
and hypotension. Severe acidosis (pH <7.25) reduces the
efficacy of endogenous and exogenously administered

catecholamines. Refractory sustained ventricular or atrial
tachyarrhythmias can cause or exacerbate CS.
Patient profile
In patients with acute MI, older age, female sex, prior
MI, diabetes, and anterior MI location are all associated with an increased risk of CS. Shock associated
with a first inferior MI should prompt a search for a
mechanical cause. Reinfarction soon after MI increases
the risk of CS. Two-thirds of patients with CS have
flow-limiting stenoses in all three major coronary arteries, and 20% have stenosis of the left main coronary
artery. CS may rarely occur in the absence of significant
stenosis, as seen in LV apical ballooning/Takotsubo’s
cardiomyopathy.
Timing
Shock is present on admission in only one-quarter
of patients who develop CS complicating MI; onequarter develop it rapidly thereafter, within 6 h of
MI onset. Another quarter develop shock later on the
first day. Subsequent onset of CS may be due to reinfarction, marked infarct expansion, or a mechanical
complication.
Diagnosis
Due to the unstable condition of these patients, supportive therapy must be initiated simultaneously with
diagnostic evaluation (Fig. 30-2). A focused history and
physical examination should be performed, blood specimens sent to the laboratory, and an electrocardiogram
(ECG) and chest x-ray obtained.
Echocardiography is an invaluable diagnostic tool in
patients suspected of CS.
Clinical findings

Most patients have continuing chest pain and dyspnea and
appear pale, apprehensive, and diaphoretic. Mentation

297

Clinical signs: Shock, hypoperfusion, congestive heart failure, acute pulmonary edema
Most likely major underlying disturbance?

First line of action

Low outputcardiogenic shock

Hypovolemia

Acute pulmonary edema

Administer
• Furosemide IV 0.5 to 1.0 mg/kg*
• Morphine IV 2 to 4 mg
• Oxygen/intubation as needed
• Nitroglycerin SL, then 10 to 20 mcg/min IV if SBP
greater than 100 mm Hg
• †Norepinephrine, 0.5 to 30 mcg/min IV or Dopamine,
5 to 15 mcg/kg per minute IV if SBP <100 mm Hg and
signs/symptoms of shock present
• Dobutamine 2 to 20 mcg/kg per minute IV if SBP 70
to 100 mm Hg and no signs/symptoms of shock

Arrhythmia

Bradycardia
Administer

• Fluids
• Blood transfusions
• Cause-specific
interventions
Consider vasopressors

Tachycardia

See Section 7.7
in the ACC/AHA guidelines for
patients with ST-elevation
myocardial infarction

Check blood
pressure

Systolic BP
Greater than 100 mm Hg
and not less than 30 mm Hg
below baseline

Systolic BP
Greater than 100 mm Hg

Systolic BP
70 to 100 mm Hg
NO signs/symptoms of shock

Nitroglycerin
10 to 20 mcg/min IV

Dobutamine
2 to 20 mcg/kg per minute IV

ACE Inhibitors
Short-acting agent such as
captopril (1 to 6.25 mg)

Systolic BP
less than 100 mm Hg
signs/symptoms of shock†

†

Norepinephrine 0.5 to 30 mcg/min IV
or
Dopamine, 5 to 15 mcg/kg per minute IV

CHAPTER 30

Third line of action

Second line of action

Check blood pressure

Further diagnostic/therapeutic considerations (should be considered
in nonhypovolemic shock)
Diagnostic
• Pulmonary artery catheter

• Echocardiography
• Angiography for MI/ischemia
• Additional diagnostic studies

Therapeutic
• Intra-aortic balloon pump
• Reperfusion/revascularization

may be altered, with somnolence, confusion, and agitation. The pulse is typically weak and rapid, often in
the range of 90–110 beats/min, or severe bradycardia
due to high-grade heart block may be present. Systolic
blood pressure is reduced (<90 mmHg) with a narrow
pulse pressure (<30 mmHg), but occasionally BP may
be maintained by very high systemic vascular resistance.
Tachypnea, Cheyne-Stokes respirations, and jugular venous distention may be present. The precordium
is typically quiet, with a weak apical pulse. S1 is usually soft, and an S3 gallop may be audible. Acute, severe
MR and VSR usually are associated with characteristic
systolic murmurs (Chap. 33). Rales are audible in most

blood pressure; MI, myocardial infarction. (Modified from Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care. Part 7:The era of reperfusion: Section 1:
Acute coronary syndromes [acute myocardial infarction]. The
American Heart Association in collaboration with the International
Liaison Committee on Resuscitation. Circulation 102:I172, 2000.)

patients with LV failure causing CS. Oliguria (urine
output <30 mL/h) is common.
Laboratory findings

The white blood cell count is typically elevated with a

left shift. In the absence of prior renal insufficiency, renal
function is initially normal, but blood urea nitrogen and
creatinine rise progressively. Hepatic transaminases may
be markedly elevated due to liver hypoperfusion. Poor
tissue perfusion may result in an anion-gap acidosis and
elevation of the lactic acid level. Before support with
supplemental O2, arterial blood gases usually demonstrate hypoxemia and metabolic acidosis, which may be

Cardiogenic Shock and Pulmonary Edema

Figure 30-2
The emergency management of patients with cardiogenic
shock, acute pulmonary edema, or both is outlined. *Furosemide: <0.5 mg/kg for new-onset acute pulmonary edema
without hypervolemia; 1 mg/kg for acute on chronic volume
overload, renal insufficiency. †Indicates modification from published guidelines. ACE, angiotensin-converting enzyme; BP,


298

compensated by respiratory alkalosis. Cardiac markers,
creatine phosphokinase and its MB fraction, and troponins
I and T are markedly elevated.
Electrocardiogram

In CS due to acute MI with LV failure, Q waves and/
or >2-mm ST elevation in multiple leads or left bundle
branch block are usually present. More than one-half of
all infarcts associated with shock are anterior. Global
ischemia due to severe left main stenosis usually is
accompanied by severe (e.g., >3 mm) ST depressions in

multiple leads.
Chest roentgenogram

The chest x-ray typically shows pulmonary vascular congestion and often pulmonary edema, but these findings
may be absent in up to a third of patients. The heart size
is usually normal when CS results from a first MI but is
enlarged when it occurs in a patient with a previous MI.
Echocardiogram

Section IV

A two-dimensional echocardiogram with color-flow
Doppler should be obtained promptly in patients with
suspected CS to help define its etiology. Doppler mapping demonstrates a left-to-right shunt in patients with
VSR and the severity of MR when the latter is present.
Proximal aortic dissection with aortic regurgitation or tamponade may be visualized, or evidence for pulmonary
embolism may be obtained (Chap. 20).
Pulmonary artery catheterization

Common Critical Illnesses and Syndromes

There is controversy regarding the use of pulmonary
artery (Swan-Ganz) catheters in patients with established
or suspected CS (Chap. 25). Their use is generally
recommended for measurement of filling pressures and
cardiac output to confirm the diagnosis and optimize
the use of IV fluids, inotropic agents, and vasopressors
in persistent shock (Table 30-2). Blood samples for O2
saturation measurement should be obtained from the
right atrium, right ventricle, and pulmonary artery to

rule out a left-to-right shunt. Mixed venous O2 saturations are low and arteriovenous (AV) O2 differences are
elevated, reflecting low cardiac index and high fractional
O2 extraction. However, when a systemic inflammatory
response syndrome accompanies CS, AV O2 differences
may not be elevated (Chap. 27). The PCWP is elevated.
However, use of sympathomimetic amines may return
these measurements and the systemic BP to normal. Systemic vascular resistance may be low, normal, or elevated
in CS. Equalization of right- and left-sided filling pressures (right atrial and PCWP) suggests cardiac tamponade
as the cause of CS.
 eft heart catheterization and coronary
L
angiography

Measurement of LV pressure and definition of the
coronary anatomy provide useful information and are

indicated in most patients with CS complicating MI.
Cardiac catheterization should be performed when
there is a plan and capability for immediate coronary
intervention (see later) or when a definitive diagnosis
has not been made by other tests.
Treatment

Acute Myocardial Infarction

General Measures  (Fig. 30-2) In addition to

the usual treatment of acute MI (Chap. 33), initial therapy
is aimed at maintaining adequate systemic and coronary
perfusion by raising systemic BP with vasopressors and

adjusting volume status to a level that ensures optimum LV filling pressure. There is interpatient variability,
but the values that generally are associated with adequate perfusion are systolic BP ∼90 mmHg or mean BP
>60 mmHg and PCWP >20 mmHg. Hypoxemia and
acidosis must be corrected; most patients require ventilatory support with either endotracheal intubation or noninvasive ventilation to correct these abnormalities and
reduce the work of breathing (see “Pulmonary Edema,”
later). Negative inotropic agents should be discontinued,
and the doses of renally cleared medications adjusted.
Hyperglycemia should be controlled with insulin. Bradyarrhythmias may require transvenous pacing. Recurrent
ventricular tachycardia or rapid atrial fibrillation may
require immediate treatment.
Vasopressors  Various IV drugs may be used

to augment BP and cardiac output in patients with CS.
All have important disadvantages, and none has been
shown to change the outcome in patients with established shock. Norepinephrine is a potent vasoconstrictor
and inotropic stimulant that is useful for patients with
CS. As first line of therapy norepinephrine was associated
with fewer adverse events, including arrhythmias, compared to a dopamine randomized trial of patients with
several eteologies of circulatory shock. Although it did not
significantly improve survival compared to dopamine, its
relative safety suggests that norepinephrine is reasonable
as initial vasopressor therapy. Norepinephrine should be
started at a dose of 2 to 4 μg/min and titrated upward as
necessary. If systemic perfusion or systolic pressure cannot
be maintained at >90 mmHg with a dose of 15 μg/min, it
is unlikely that a further increase will be beneficial.
Dopamine has varying hemodynamic effects based
on the dose; at low doses (≤ 2 μg/kg per min), it dilates
the renal vascular bed, although its outcome benefits
at this low dose have not been demonstrated conclusively; at moderate doses (2–10 μg/kg per min), it has

positive chronotropic and inotropic effects as a consequence of β-adrenergic receptor stimulation. At higher
doses, a vasoconstrictor effect results from α-receptor
stimulation. It is started at an infusion rate of 2–5 μg/
kg per min, and the dose is increased every 2–5 min to


Table 30-2

299
a

Hemodynamic Patterns
RA,
mmHg

RVS,
mmHg

RVD,
mmHg

PAS,
mmHg

PAD,
mmHg

PCW,
mmHg

CI,
(L/min)/m2

SVR,
(dyn · s)/cm5

Normal values

<6

<25

0–12

<25

0–12

<6–12

≥2.5

(800–1600)

MI without
pulmonary
edemab

—

—

—

—

—

∼13
(5–18)

∼2.7
(2.2–4.3)

—

Pulmonary
edema

↔↑

↔↑

↔↑

↑

↑

↑

↔↓

↑

↔↑

↔↑

↓

↔↑

Cardiogenic
shock
↔↑

↑

↓↔↑

↑

↓↔↑

Cardiac
tamponade

↑

↔↑

↑

Acute mitral
regurgitation

↔↑

↑

Ventricular
septal
rupture

↑

Hypovolemic
shock
Septic shock

  RV failure

↑

↑

↔↓↑

↓↔↑

↓

↑

↔↑

↔↑

↔↑

↓

↑

↔↑

↑

↑

↑

↔↓

↔↑

↔↑

↑

↔↑

↔↑

↔↑

↑PBF
↓SBF

↔↑

↓

↔↓

↔↓

↓

↓

↓

↓

↑

↓

↔↓

↔↓

↓

↓

↓

↑

↓

d

d

d

d

a

a maximum of 20–50 μg/kg per min. Dobutamine is a
synthetic sympathomimetic amine with positive inotropic action and minimal positive chronotropic activity at
low doses (2.5 μg/kg per min) but moderate chronotropic
activity at higher doses. Although the usual dose is up to
10 μg/kg per min, its vasodilating activity precludes its
use when a vasoconstrictor effect is required.

Aortic Counterpulsation  In CS, mechanical
assistance with an intraaortic balloon pumping (IABP)
system capable of augmenting both arterial diastolic
pressure and cardiac output is helpful in rapidly stabilizing patients. A sausage-shaped balloon is introduced
percutaneously into the aorta via the femoral artery;
the balloon is automatically inflated during early diastole,
augmenting coronary blood flow. The balloon collapses in
early systole, reducing the afterload against which the
LV ejects. IABP improves hemodynamic status temporarily
in most patients. In contrast to vasopressors and inotropic

agents, myocardial O2 consumption is reduced, ameliorating ischemia. IABP is useful as a stabilizing measure
in patients with CS before and during cardiac catheterization and percutaneous coronary intervention (PCI) or
before urgent surgery. IABP is contraindicated if aortic
regurgitation is present or aortic dissection is suspected.
Ventricular assist devices may be considered for eligible
young patients with refractory shock as a bridge to cardiac transplantation.
Reperfusion-Revascularization  The
rapid establishment of blood flow in the infarct-related
artery is essential in the management of CS and forms
the centerpiece of management. The randomized
SHOCK Trial demonstrated that 132 lives were saved
per 1000 patients treated with early revascularization
with PCI or coronary artery bypass graft (CABG) compared with initial medical therapy including IABP with
fibrinolytics followed by delayed revascularization. The

Cardiogenic Shock and Pulmonary Edema

There is significant patient-to-patient variation. Pressure may be normalized if cardiac output is low.
Forrester et al classified nonreperfused MI patients into four hemodynamic subsets. (From Forrester JS et al: N Engl J Med 295:1356, 1976.)

PCWP and CI in clinically stable subset 1 patients are shown. Values in parentheses represent range.
c
“Isolated” or predominant RV failure.
d
PCW and PA pressures may rise in RV failure after volume loading due to RV dilation, right-to-left shift of the interventricular septum, resulting
in impaired LV filling. When biventricular failure is present, the patterns are similar to those shown for LV failure.
Abbreviations: CI, cardiac index; MI, myocardial infarction; P/SBF, pulmonary/systemic blood flow; PAS/D, pulmonary artery systolic/diastolic; PCW,
pulmonary capillary wedge; RA, right atrium; RVS/D, right ventricular systolic/diastolic; SVR, systemic vascular resistance.
Source: Table prepared with the assistance of Krishnan Ramanathan, MD.
b

CHAPTER 30

↔↑
c

  LV failure