The multiple organ dysfunction syndrome

John C Marshall, M.D.

Department of Surgery, The Toronto General Hospital, University Health Network, and the
University of Toronto

The most common cause of death for patients admitted to a contemporary intensive care unit
(ICU) is a clinical condition that owes its existence to the development of the ICU. Variously
known as the multiple organ dysfunction syndrome (MODS), multi-organ failure, multiple
systems organ failure, or through some of its more prominent manifestations, as the acute
respiratory distress syndrome (ARDS) or disseminated intravascular coagulation (DIC), MODS
is as poorly understood as it is prevalent. Even its terminology merits comment. Although
originally described as multiple organ failure, it is evident that normal physiologic function of
the failing organ systems can be restored in survivors. Thus characterization of the process as
multiple organ dysfunction is more appropriate. And although the syndrome involves the
dysfunction of many organs, it also affects physiologic systems not classically thought of as
organs, including the hematologic system, immune system, or the endocrine system. Finally,
although it is described as a syndrome, its clinical course and causes are highly variable, and
there is only the most general form of consensus regarding the organs whose dysfunction
comprises the syndrome, or the criteria that should be used to describe this dysfunction.

The Multiple Organ Dysfunction Syndrome (MODS) can be defined as the development of
potentially reversible physiologic derangement involving two or more organ systems not
involved in the disorder that resulted in ICU admission, and arising in the wake of a potentially
life-threatening physiologic insult.

Organ system specific support is the raison d'être for the ICU, and it is not surprising, therefore,
that the need for such support has become a model for describing the clinical course of the
critically ill patient. The observation that critically ill patients die, not as a result of the
progression of the disorder that precipitated ICU admission, but of a complex series of
physiologic derangements that develop following resuscitation and management in the ICU was
first made in the 1960's. Baue, in 1975, published a landmark editorial in which he commented
on the striking similarity of the post mortem findings in patients dying in an ICU and suggested
that it was not the failure of a single system, but the concomitant failure of multiple
interdependent organ systems that was the unsolved problem in critical care. Subsequent reports
highlighted the important role of occult, uncontrolled infection in the pathogenesis of MODS,
although control of infection did not necessarily result in reversal of the physiologic
derangements, nor was infection universally present in patients with the syndrome.

MODS: Clinical and pathologic description

Organ dysfunction in a critically ill patient can be described in one of two ways — as the clinical
intervention that was employed to support the failing organ system (mechanical ventilation,
hemodialysis, inotropic or vasopressor agents, parenteral nutrition etc), or as the acute
physiologic derangement that made such support necessary. The first descriptions of the
syndrome generally counted the number of failing systems, using as descriptors, the need for
clinical intervention. More recently several similar descriptive scales have been developed, based
on the quantification of organ dysfunction as a numeric scale. Each uses the same six organ
systems to characterize MODS - the respiratory, cardiovascular, renal, hepatic, neurologic, and
hematologic systems. They differ in minor ways with respect to the selected parameters to
describe cardiovascular dysfunction, and in the timing and weighting of the variables selected.
The Multiple Organ Dysfunction (MOD) score, a scale that uses physiologic variables
exclusively is presented in table I.

Table I

The multiple organ dysfunction (MOD) score.

Regardless of how MODS is characterized, it is apparent that the risk of ICU death increases as
the severity of organ dysfunction - whether the number of failing organs (table II), or the overall
degree of dysfunction (fig. 1) increases.

Table II

Prognosis in multiple organ failure.

The histologic features of the organs involved in MODS are less well characterized, but
generally include evidence of edema, inflammation, tissue ischemia or necrosis, and variable
degrees of fibrosis and repair. These alterations, in turn, are responsible for the clinical features
of MODS in each of its component systems.

Lung
The characteristic abnormality of the lung in MODS is a failure of normal gas exchange,
reflected predominantly in arterial hypoxemia. Multiple pathologic factors contribute to impaired
gas exchange. Early in the course of lung injury, atelectasis and intravascular thrombosis or
altered regional flow contribute to ventilation/perfusion mismatch, while increased capillary
permeability leads to alveolar flooding and an increased diffusion distance for oxygen. Regional
injury resulting from infection or trauma contributes to compromised lung function. With the
institution of ventilatory support, lung injury can be aggravated through what has been termed
volutrauma and barotrauma, leading to further atelectasis in dependent lung zones, and cyst
formation in the anti-dependent zones. Finally, the process of tissue repair, initiated with the
influx of inflammatory cells into the injured lung, results in fibrosis and hyaline membrane
formation, the cardinal pathologic features of late ARDS.

Kidney

Renal dysfunction in MODS is reflected in impairment of normal selective excretory function,

initially in oliguria despite adequate intravascular volume, but later in a rising creatinine level,
and fluid and electrolyte derangements of sufficient magnitude that dialysis is required. Its
causes are both pre-renal and renal. Reduced renal blood flow secondary to systemic
hypotension, altered regional perfusion, or increased intra-abdominal pressure is an early risk
factor; evolution of the disorder is compounded by pre-existing physiologic deficit and the
effects of nephrotoxic drugs. Obstructive causes must be considered and ruled out. As is the case
for lung injury, ICU interventions contribute to the evolution of the syndrome: vasopressor
agents cause further reductions in renal blood flow, while potentially nephrotoxic drugs are a key
part of the anti-infective arsenal used in the ICU.

Heart and cardiovascular system

The acute cardiovascular derangements of MODS consist of five features:

1.

a generalized reduction in peripheral vascular tone, mediated largely through the local
vasodilatory activity of nitric oxide

2.

a generalized increase in capillary permeability producing diffuse capillary leak and

edema, and contributing to further dysfunction in other organ systems

3.

alterations in regional blood flow to specific organ beds

4.
 microvascular plugging and stasis, resulting from occlusion of the microvasculature by
abnormally rigid erythrocytes and leukocytes, and resulting in arteriovenous shunting that
contributes to a high mixed venous saturation

5.

myocardial depression, affecting the right side of the heart in particular

It is readily apparent that these abnormalities predispose to impaired oxygen delivery, and
therefore contribute to the injury of other organ systems. Since their net physiologic consequence
is hypotension that is refractory to increased preload, we have used a measure called the
pressure-adjusted heart rate (PAR) to quantify cardiovascular dysfunction in the MOD score.
Calculated as the product of the heart rate and the ratio of central venous to mean arterial
pressure (HR × CVP/MAP), it is, like the PO2/FIO2 ratio, a reflection of physiology, corrected
for therapy; increasing values reflect worsening cardiovascular dysfunction.

Gastrointestinal/hepatic

Gastrointestinal dysfunction in critical illness likely results from the interacting effects of
reduced regional blood flow, impaired motility, and alterations in the normal microbial flora. In
the past, upper gastrointestinal bleeding or stress ulceration was the most common manifestation
of gut dysfunction; this complication has become uncommon with improvements in
hemodynamic support, earlier diagnosis of infection, and the appropriate use of effective
prophylaxis. Intolerance of enteral feeding, reflected in bloating and diarrhea is another
manifestation of gut dysfunction. However, in contrast to other organ systems, simple clinical
measures of gut dysfunction are not readily available.

Hepatic dysfunction in MODS is reflected in hyperbilirubinemia and cholestasis, rather than in

biochemical evidence of hepatocellular injury or synthetic dysfunction. A stereotypical pattern of
altered hepatic protein synthesis - the acute phase response - typically accompanies MODS as a
non-specific manifestation of systemic inflammation. Serum levels of C reactive protein and
alpha-1 anti-trypsin are elevated as part of the acute phase response, whereas levels of albumin, a
negative acute phase reactant, are depressed.

Neurologic

An altered level of consciousness, reflected in a reduction in the Glasgow Coma Score, is the
most readily recognizable manifestation of the neurologic dysfunction of MODS. Its causes are
multiple, including the iatrogenic effects of sedatives and analgesics, metabolic alterations,
subclinical cerebral edema and reduced cerebral perfusion pressure, and, perhaps, micro-
abscesses in the brain. A peripheral neuropathy - the so-called ‘critical illness polyneuropathy’ -
is commonly present, though harder to measure.

Hematologic
Leucocytosis is an adaptive response to a variety of acute stresses and therefore commonly
present, although not truly a manifestation of organ dysfunction. Similarly a mild anemia
resulting from both bone marrow suppression and iatrogenic blood-taking is common. However
the most widely cited manifestation of dysfunction of the hematologic system in MODS is
thrombocytopenia, in its most extreme form resulting in disseminated intravascular coagulation
(DIC). Like other manifestations of MODS, the causes of thrombocytopenia in critical illness are
many - heparin-induced thrombocytopenia, intravascular consumption, and reduced production
to name a few.

Immunologic

Multiple abnormalities of non-specific and specific immune function are described in the
critically ill patient, including impaired delayed type hypersensitivity responsiveness, altered
production of antibodies, and a complex spectrum of abnormalities in the regulation of
lymphocyte responses. The most readily evident, and clinically relevant manifestation of altered
immunity in MODS is the development of nosocomial ICU-acquired infection, caused by
relatively avirulent organisms. The characteristic flora of ICU-acquired infection in MODS
includes coagulase-negative Staphylococci, Enterococci, Candida, and Pseudomonas.

Endocrine/metabolic

Multiple metabolic and endocrine abnormalities are evident during MODS, although they are
less well-characterized, Hyperglycemia and relative insulin resistance is both common and
readily detected. Less accessible abnormalities include the sick euthyroid syndrome, and relative
adrenal insufficiency. The latter has recently gained prominence as a promising therapeutic
target for the patient with prolonged inflammation and organ dysfunction.

Prevention of MODS
MODS is less a syndrome to be treated than a complication to be prevented. Iatrogenic factors,
or processes amenable to prophylactic intervention figure prominently in the expression of the
syndrome.

Because the syndrome almost invariably arises following the activation of a host inflammatory
response, MODS can be considered to be the maladaptive consequence of acute inflammation,
the systemic equivalent of functio laesa, or loss of function, a cardinal sign of acute localized
inflammation. To date, however, interventions targeted at the host inflammatory response have
not proven effective in preventing MODS or minimizing its evolution. Other simpler approaches
are more promising. Table III summarizes ICU interventions for which there is evidence of
significant benefit, reflected in reduced organ dysfunction, or improved ICU survival. The list is
a sampling that is of necessity inadequate. Any intervention that can prevent death or bring
physiologic benefit to critically ill patients might reasonably be included; on the other hand,
rigorous evaluation of most commonly accepted ICU interventions has not been undertaken.
Table III

The prevention of MODS in critical illness.

Conclusion
The multiple organ dysfunction syndrome is both a syndrome and a form of clinical shorthand
for the approach to patient care that is exemplified by contemporary ICU practice. As a
syndrome, it is intimately linked to the adaptive host response to injury or infection, and it is to
be expected that interventions that can modulate the expression of this response will ultimately
prove effective in improving clinical outcome. As a clinical shorthand, it categorizes the range of
interventions available to support critically ill patients, and underlines the prime importance of
recognizing the potential for iatrogenic harm implicit in the increasingly complex and
technological repertoire we use to care for them.

References
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inflammatory response and organ dysfunction. JAMA. (1994);271:226–233. [PubMed]
3.
Vincent J L. Prevention and therapy of multiple organ failure. World J Surg.
(1996);20:465–470. [PubMed]
4.
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for multiple organ system failure and death in critically injured patients. Surgery.
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Sauaia A, Moore F A, Moore E E, Haenel J B, Read R A, Lezotte D C. Early predictors
of postinjury multiple organ failure. Arch Surg. (1994);129:39–45. [PubMed]
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Marshall J C, Cook D J, Christou N V, Bernard G R, Sprung C L, Sibbald W J. Multiple
organ dysfunction score: A reliable descriptor of a complex clinical outcome. Crit Care
Med. (1995);23:1638–1652. [PubMed]
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 Vincent J L, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart K,
Suter P, Thijs L G. The sepsis-related organ failure assessment (SOFA) score to describe
organ dysfunction/failure. Intens Care Med. (1996);22:707–710. [PubMed]
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Garber B G, Hébert P C, Yelle J D, Hodder R V, McGowan J. Adult respiratory distress
syndrome: A systematic overview of incidence and risk factors. Crit Care Med.
(1996);24:687–695. [PubMed]
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Petty T L. Acute respiratory distress syndrome: Consensus, definitions, and future
directions. Crit Care Med. (1996);24:555–556. [PubMed]
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Brivet F G, Kleinknecht D J, Loirat P, Landais P J M, Bedock B, Bleichner G, Richard C,
Coste F, Brun-Buisson C, Sicot C, Tenaillon A, Gajdos P, Blin F, Saulnier F, Agostini M
M, Nicolas F, Fery-Lemonnier E, Staikowski F, Carlet J, Guivarch G, Fraisse F, Ricome
J, Tempe J D, Mezzarobba P. Acute renal failure in intensive care units - Causes,
outcome, and prognostic factors of hospital mortality: A prospective, multicenter study.
Crit Care Med. (1996);24:192–198. [PubMed]
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Hebert P C, Wells G, Blajchman M A, Marshall J, Martin C, Pagliarello G, Tweeddale
M, Schweitzer I, Yetisir E. the Transfusion Requirements in Critical Care Investigators
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[PubMed]
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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.

Multiple Organ Dysfunction Syndrome in

Sepsis

 Overview
 Presentation
 DDx
 Workup
 Treatment
 Medication

Updated: Apr 12, 2012

 Background
 Pathophysiology
 Epidemiology
 Prognosis
 Show All

Multimedia Library
Tables
References

Background
Multiple organ dysfunction syndrome (MODS) is a continuum, with incremental degrees of
physiologic derangements in individual organs; it is a process rather than a single event.
Alteration in organ function can vary widely from a mild degree of organ dysfunction to
completely irreversible organ failure. The degree of organ dysfunction has a major clinical
impact.

In a classic 1975 editorial by Baue, the concept of “multiple, progressive or sequential systems
failure” was formulated as the basis of a new clinical syndrome.[1] Several different terms were
proposed thereafter (eg, multiple organ failure, multiple system organ failure, and multiple organ
system failure) to describe this evolving clinical syndrome of otherwise unexplained progressive
physiologic failure of several interdependent organ systems.

Eventually, the term MODS was proposed as a more appropriate description. MODS is defined
as a clinical syndrome characterized by the development of progressive and potentially reversible
physiologic dysfunction in 2 or more organs or organ systems that is induced by a variety of
acute insults, including sepsis.

For patient education resources, see the Blood and Lymphatic System Center, as well as Sepsis
(Blood Infection).

Clinical continuum of sepsis

Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic
inflammation and widespread tissue injury. A continuum of severity from sepsis to septic shock
and MODS exists. The clinical process usually begins with infection, which potentially leads to
sepsis and organ dysfunction.[2] A consensus panel of the American College of Chest Physicians
and the Society of Critical Care Medicine developed definitions of the various stages of this
process (see the image below).[3]

Stages of sepsis based on American College of Chest

Physicians/Society of Critical Care Medicine Consensus Panel guidelines.

Infection is a microbial phenomenon in which an inflammatory response to the presence of

microorganisms or the invasion of normally sterile host tissue by these organisms is
characteristic.

Bacteremia is the presence of viable bacteria in the blood.

Systemic inflammatory response syndrome (SIRS) may follow a variety of clinical insults,
including infection, pancreatitis, ischemia, multiple trauma, tissue injury, hemorrhagic shock, or
immune-mediated organ injury. SIRS is defined by the presence of 2 or more of the following:

 Temperature greater than 38.0°C or less than 36.0°C

 Heart rate higher than 90 beats/min
 Respiratory rate higher than 20 breaths/min or arterial carbon dioxide tension below 32
mm Hg
 White blood cell (WBC) count higher than 12,000/µL, lower than 4000/µL, or including
more than 10% bands

Sepsis is a systemic response to infection. It is identical to SIRS, except that it must result
specifically from infection rather than from any of the noninfectious insults that may also cause
SIRS (see the image below).

Venn diagram showing overlap of infection, bacteremia, sepsis,

systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

Septic shock is sepsis with hypotension (systolic blood pressure < 90 mm Hg or a reduction of
40 mm Hg from baseline) despite adequate fluid resuscitation. Concomitant organ dysfunction or
perfusion abnormalities (eg, lactic acidosis, oliguria, and coma) are present in the absence of
other known causes.

MODS is the presence of altered organ function in an acutely ill patient such that homeostasis
cannot be maintained without intervention. Primary MODS is the direct result of a well-defined
insult in which organ dysfunction occurs early and can be directly attributable to the insult itself.
Secondary MODS develops as a consequence of a host response and is identified within the
context of SIRS. The inflammatory response of the body to toxins and other components of
microorganisms causes the clinical manifestations of sepsis.

Pathophysiology
Malignant intravascular inflammation

Sepsis has been referred to as a process of malignant intravascular inflammation. Normally, a

potent, complex, immunologic cascade ensures a prompt protective response to microorganism
invasion in humans. A deficient immunologic defense may allow infection to become
established; however, an excessive or poorly regulated response may harm the host through
maladaptive release of indigenously generated inflammatory compounds (see the image below).
 Pathogenesis of sepsis and multiorgan failure.

Lipid A and other bacterial products release cytokines and other immune modulators that
mediate the clinical manifestations of sepsis. Interleukins, tumor necrosis factor (TNF)-α,
interferon gamma (IFN-γ), and other colony-stimulating factors are produced rapidly within
minutes or hours after interactions of monocytes and macrophages with lipid A.

Inflammatory mediator release becomes a self-stimulating process, and release of other such
mediators, including interleukin (IL)-1, platelet activating factor, IL-2, IL-6, IL-8, IL-10, and
nitric oxide (NO), further increases cytokine levels. This leads to continued activation of
polymorphonuclear leukocytes (PMNs), macrophages, and lymphocytes; proinflammatory
mediators recruit more of these cells. All of these processes create a state of destructive
immunologic dissonance.

Sepsis is described as an autodestructive process that permits extension of the normal

pathophysiologic response to infection to involve otherwise normal tissues and results in MODS.
Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is
immune from the consequences of the inflammatory excesses of sepsis. Mortality increases as
organ failure increases.

Dysfunction of organ systems

Circulatory derangement

Significant derangement in autoregulation of circulation is typical of sepsis. Vasoactive

mediators cause vasodilatation and increase microvascular permeability at the site of infection.
NO plays a central role in the vasodilatation of septic shock. Also, impaired secretion of
vasopressin may occur, which may permit persistence of vasodilatation.

Changes in both systolic and diastolic ventricular performance occur in sepsis. Through the use
of the Frank-Starling mechanism, cardiac output often is increased to maintain blood pressure in
the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to
increase their cardiac output appropriately.

Regionally, sepsis interferes with the normal distribution of systemic blood flow to organ
systems. Consequently, core organs may not receive appropriate oxygen delivery, and the result
is what is known as regional hypoperfusion.
Microcirculation is the key target organ for injury in sepsis. A decrease in the number of
functional capillaries causes an inability to extract oxygen maximally, which is caused by
intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood
cells. Increased endothelial permeability leads to widespread tissue edema involving protein-rich
fluid.

Septic shock and SIRS are characterized by reversible myocardial depression, which can prove
resistant to catecholamine and fluid administration. Circulating “myocardial depressant factor”—
probably representing the synergistic effects of TNF-α, IL-1β, other cytokines, and NO—is
implicated in pathogenesis. Macrovascular myocardial ischemia and hypoperfusion are unlikely
contributors.

In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression
cause regional tissue distress, and regional hypoxia therefore persists. This condition is termed
microcirculatory and mitochondrial distress syndrome (MMDS).[4] Sepsis-induced inflammatory
autoregulatory dysfunction persists, and oxygen need is not matched by supply, leading to
MODS.

Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone,
diminished venous return from venous dilation, and release of myocardial depressant substances
causes hypotension.

Pulmonary dysfunction

Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and
enhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil
entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar
capillary membranes. Acute lung injury and acute respiratory distress syndrome (ARDS) are
frequent manifestations of these effects.

Gastrointestinal dysfunction

The gastrointestinal (GI) tract may help propagate the injury of sepsis. Overgrowth of bacteria in
the upper GI tract may be aspirated into the lungs, producing nosocomial or aspiration
pneumonia. The normal barrier function of the gut may be affected, allowing translocation of
bacteria and endotoxins into the systemic circulation and extending the septic response.

Septic shock can cause paralytic ileus that can lead to a delay in the institution of enteral feeding.
The optimal level of nutritional intake is interfered with in the face of high protein and calorie
requirements. Narcotics and muscle relaxants can further worsen GI tract motility.

Liver dysfunction

As a consequence of the role the liver plays in host defense, the abnormal synthetic functions
caused by liver dysfunction can contribute to both the initiation and progression of sepsis. The
reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria and their
products; liver dysfunction leads to a spillover of these products into systemic circulation.

Liver failure (“shock liver”) can be manifested by elevations in liver enzymes and bilirubin,
coagulation defects, and failure to excrete toxins such as ammonia, which lead to worsening
encephalopathy.

Renal dysfunction

Acute renal failure often accompanies sepsis due to acute tubular necrosis. The mechanism is
complex but involves a decrease in effective intravascular volume resulting from systemic
hypotension, direct renal vasoconstriction, release of cytokines, and activation of neutrophils by
endotoxins and other peptides, which contribute to renal injury.

Central nervous system dysfunction

Involvement of the central nervous system (CNS) in sepsis produces encephalopathy and
peripheral neuropathy. The pathogenesis is poorly defined but is probably related to systemic
hypotension, which can lead to brain hypoperfusion.

Coagulopathy

Subclinical coagulopathy, signaled by a mild elevation of the thrombin time (TT) or activated
partial thromboplastin time (aPTT) or a moderate reduction in the platelet count, is extremely
common; however, overt disseminated intravascular coagulation (DIC) may also develop.
Coagulopathy is caused by deficiencies in coagulation system proteins, including protein C,
antithrombin III, and tissue factor inhibitors.

Mechanisms of organ dysfunction and injury

The precise mechanisms of cell injury and resulting organ dysfunction in sepsis are not fully
understood. MODS is associated with widespread endothelial and parenchymal cell injury, some
of which can be explained by the following 4 proposed mechanisms.

Hypoxic hypoxia

The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue
oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial
abnormalities contribute to the septic microcirculatory defect in sepsis. The reactive oxygen
species, lytic enzymes, and vasoactive substances (eg, NO and endothelial growth factors) lead
to microcirculatory injury, which is compounded by the inability of the erythrocytes to navigate
the septic microcirculation.

Direct cytotoxicity
Endotoxin, TNF-α, and NO may cause damage to mitochondrial electron transport, leading to
disordered energy metabolism. This is called cytopathic or histotoxic anoxia, an inability to
utilize oxygen even when it is present.

Apoptosis

Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells are
normally eliminated. The proinflammatory cytokines may delay apoptosis in activated
macrophages and neutrophils, but other tissues (eg, gut epithelium), may undergo accelerated
apoptosis. Therefore, derangement of apoptosis plays a critical role in the tissue injury of sepsis.

Immunosuppression

The interaction between proinflammatory and anti-inflammatory mediators may lead to an

imbalance between them. An inflammatory reaction or an immunodeficiency may predominate,
or both may be present.

Clinical factors influencing outcome

Clinical characteristics that relate to the severity of sepsis include the host response to infection,
the site and type of infection, the timing and type of antimicrobial therapy, the offending
organism, the development of shock, the underlying disease, the patient’s long-term health
condition, and the number of failed organs. Factors that lead to sepsis and septic shock may not
be essential in determining the ultimate outcome.

Epidemiology
Estimating the exact incidence of sepsis throughout the world is difficult. Studies vary in their
methods of determining the incidence of sepsis.[5] [#IntroductionFrequencyUnitedStates]Current
estimates suggest that the incidence of sepsis is greater than 500,000 cases per year. Reported
prevalence rates for SIRS of sepsis range from 20% to 60%. A French study found that severe
sepsis was present in 6.3% of all admissions to the intensive care unit (ICU).[6] These figures
may be usefully compared with those reported by Martin et al[7] and by Blanco et al.[8]
Approximately 40% of patients with sepsis may develop septic shock. Patients who are at risk
include those with positive blood cultures.

Prognosis
Mortality from MODS remains high. Mortality from ARDS alone is 40-50%; once additional
organ system dysfunction occurs, mortality increases as much as 90%. Several clinical trials
have demonstrated a mortality ranging from 40% to 75% in patients with MODS arising from
sepsis.
The poor prognostic factors are advanced age, infection with a resistant organism, impaired host
immune status, and poor prior functional status. Development of sequential organ failure despite
adequate supportive measures and antimicrobial therapy is a harbinger of a poor outcome.

There is a graded severity from SIRS to sepsis, severe sepsis, and septic shock, with associated
28-day mortality rates of approximately 10%, 20%, 20-40%, and 40-60%, respectively.[9]

A multicenter prospective study published in the Journal of the American Medical Association
reported a mortality of 56% during ICU stay.[10] Of all deaths, 27% occurred within 2 days of the
onset of severe sepsis, and 77% of all deaths occurred within the first 14 days. The risk factors
for early mortality in this study were a higher severity of illness score, the presence of 2 or more
acute organ failures at the time of sepsis, shock, and a low blood pH (< 7.3).

Lobo et al determined that MODS is the primary cause of death in high-risk patients after
surgery; the risk factors for death due to multiple organ failure should be considered in
determining risk stratification.[11]

Proceed to Clinical Presentation

Author

Ali H Al-Khafaji, MD, MPH Associate Professor of Critical Care Medicine, Director,
Transplant Intensive Care Unit, University of Pittsburgh School of Medicine

Ali H Al-Khafaji, MD, MPH is a member of the following medical societies: American College
of Chest Physicians, American College of Gastroenterology, American College of Physicians,
and International Liver Transplantation Society

Disclosure: Nothing to disclose.

Coauthor(s)

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department
of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface
General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of
Sleep Medicine, American College of Chest Physicians, American College of Physicians-
American Society of Internal Medicine, American Thoracic Society, Canadian Medical
Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine,
Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Gregg Eschun, MD Assistant Professor, Department of Internal Medicine, Sections of

Respirology and Critical Care, St Boniface Hospital, University of Manitoba Faculty of
Medicine, Canada

Gregg Eschun, MD is a member of the following medical societies: American College of Chest
Physicians, American Thoracic Society, Canadian Medical Association, and College of
Physicians and Surgeons of Manitoba

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, FCCP, FCCM Professor of Critical Care Medicine,
Bioengineering, Cardiovascular Disease and Anesthesiology, Vice-Chair of Academic Affairs,
Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of
Pittsburgh School of Medicine

Michael R Pinsky, MD, CM, FCCP, FCCM is a member of the following medical societies:
American College of Chest Physicians, American College of Critical Care Medicine, American
Heart Association, American Thoracic Society, Association of University Anesthetists, European
Society of Intensive Care Medicine, Shock Society, and Society of Critical Care Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board
membership; Edwards Lifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria
Consulting; Cheetah Medical Consulting fee Consulting

Additional Contributors

Cory Franklin, MD Professor, Department of Medicine, Rosalind Franklin University of

Medicine and Science; Director, Division of Critical Care Medicine, Cook County Hospital

Cory Franklin, MD is a member of the following medical societies: New York Academy of
Sciences and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University
School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service,
Henry Ford Health System

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American
College of Chest Physicians and American Thoracic Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska

Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment

History
Symptoms of sepsis are usually nonspecific and include fever, chills, and constitutional
symptoms of fatigue, malaise, anxiety, or confusion.[12] These symptoms are not pathognomonic
for infection and may also be observed in a wide variety of noninfectious inflammatory
conditions. In addition, they may be absent in patients with serious infections, especially in
elderly individuals.

Because systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and multiple
organ dysfunction syndrome (MODS) represent a clinical continuum (see Overview), the
specific features exhibited in any given case depend on where the patient falls on that continuum.

Fever is a common feature of sepsis. Fever of infectious origin results from resetting the
hypothalamus so that heat production and heat loss are balanced to maintain a higher
temperature. An abrupt onset of fever usually is associated with a large infectious load.

Chills are a secondary symptom associated with fever and result from increased muscular
activity in an attempt to produce heat and thereby raise the body temperature to the level required
to reset the hypothalamus.

Sweating occurs when the hypothalamus returns to its normal set point and senses that the body
temperature is above the desired level. Perspiration is stimulated to offload excess body heat
through evaporative cooling.

Altered mental function is often observed. Mild disorientation or confusion is especially

common in elderly individuals. More severe manifestations include apprehension, anxiety, and
agitation, and in some cases, coma may eventually ensue. The mechanism by which mental
function is altered is not known, but altered amino acid metabolism has been proposed as a cause
of metabolic encephalopathy.

Hyperventilation with respiratory alkalosis is a common feature of sepsis. Stimulation of the

medullary ventilatory center by endotoxins and other inflammatory mediators has been proposed
as the cause of hyperventilation.

The following localizing symptoms are some of the most useful clues to the etiology of both
fever and sepsis:

 Head and neck infections - Earache, sore throat, sinus pain, or swollen lymph glands
 Chest and pulmonary infections - Cough (especially if productive), pleuritic chest pain,
and dyspnea
 Abdominal and gastrointestinal (GI) infections - Abdominal pain, nausea, vomiting, and
diarrhea
 Pelvic and genitourinary (GU) infections - Pelvic or flank pain, vaginal or urethral
discharge, urea, frequency, urgency
  Bone and soft tissue infections - Focal pain or tenderness, focal erythema, edema

Physical Examination
The physical examination focuses first on the general condition of the patient. Assess the
patient’s overall hemodynamic condition to search for signs of hyperperfusion. Look for signs
suggestive of a focal infection. An acutely ill, toxic appearance is a common feature in patients
with serious infections.

The vital signs may suggest sepsis, even if fever is absent. As noted (see above), tachypnea is
common; tachycardia with an increased pulse pressure also is common.

Measure the body temperature accurately. Because oral temperatures are often unreliable, rectal
temperatures should be obtained.

Investigate signs of systemic tissue perfusion. In the early stages of sepsis, cardiac output is well
maintained or even increased. Along with the effects of vasodilatory mediators, this may result in
warm skin, warm extremities, and normal capillary refill. As sepsis progresses, stroke volume
and cardiac output fall. Patients begin to manifest signs of poor distal perfusion, including cool
skin, cool extremities, and delayed capillary refill.

The following physical signs suggest focal, usually bacterial, infection:

 Central nervous system (CNS) infection - Profound depression in mental status and
meningismus
 Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness,
pharyngeal exudates, stridor, cervical lymphadenopathy
 Chest and pulmonary infections - Localized rales or evidence of consolidation
 Cardiac infections - Regurgitant valvular murmur
 Abdominal and GI infections - Focal tenderness, guarding or rebound, rectal tenderness,
or swelling
 Pelvic and GU infections - Costovertebral angle tenderness, pelvic tenderness, cervical
motion pain, and adnexal tenderness
 Bone and soft tissue infections - Focal erythema, edema, infusion, and tenderness
 Skin infections - Petechiae and purpura
 Approach Considerations
 Laboratory tests are useful in cases of suspected sepsis or septic shock to assess the
general hematologic and metabolic condition of the patient. The microbiologic studies
provide results that may indicate occult bacterial infection or bacteremia and identify the
causative pathogen or pathogens.
 Various imaging modalities are employed to diagnose clinically suspected focal
infection, detect the presence of a clinically occult focal infection, and evaluate
complications of sepsis and septic shock.
 Laboratory Studies
 A complete blood cell (CBC) count with differential should be obtained. An adequate
hemoglobin concentration is necessary to ensure oxygen delivery in shock; hemoglobin
should be maintained at a level of 8 g/dL.
 Acute-phase reactants and platelets usually increase at the onset of any serious stress.
With persistent sepsis, the platelet count will fall, and disseminated intravascular
coagulation (DIC) may develop.
 The white blood cell (WBC) differential and the WBC count may predict the existence of
a bacterial infection. In adults who are febrile, a WBC count higher than 15,000/µL or a
neutrophil band count higher than 1500/µL is associated with a high likelihood of
bacterial infection.[13]
 A metabolic assessment should be performed with measurement of serum electrolytes,
including magnesium, calcium, phosphate, and glucose, at regular intervals. Renal and
hepatic function should be assessed with measurement of serum creatinine, blood urea
nitrogen (BUN), bilirubin, alkaline phosphate, and alanine aminotransferase (ALT).
 Arterial blood gas testing is indicated.
 Measurement of serum lactate provides an assessment of tissue hypoperfusion. Elevated
serum lactate indicates that significant tissue hypoperfusion exists with the shift from
aerobic to anaerobic metabolism. This signals a worse degree of shock and a higher
mortality.
 Coagulation status should by assessed by measuring the prothrombin time (PT) and the
activated partial thromboplastin time (aPTT). Patients with clinical evidence of
coagulopathy require additional tests to detect the presence of DIC.
 Although indiscriminate use of blood cultures has low utility, blood culture is the primary
modality for facilitating the diagnosis of intravascular infections (eg, endocarditis) and
infections of indwelling intravascular devices. Two populations—people who abuse
intravenous (IV) drugs and patients with prosthetic heart valves—are at high risk for
endocarditis.
 Patients at risk for bacteremia include adults who are febrile with elevated WBC or
neutrophil band counts, elderly patients who are febrile, and patients who are febrile and
neutropenic. These populations have a 20-30% incidence of bacteremia. The incidence of
bacteremia is at least 50% in patients with sepsis and evidence of end-organ dysfunction.
 A urinalysis and a urine culture should be ordered for every patient who is in a septic
state. Urinary infection is a common source of sepsis, especially in elderly individuals.
Adults who are febrile without localizing symptoms or signs have a 10-15% incidence of
occult urinary tract infection (UTI).
 Secretions or tissue for Gram stain and culture should be obtained from sites of potential
infection. Generally, the Gram stain is the only available test for immediately
documenting the presence of bacterial infection and guiding the choice of initial
antibiotic therapy.
 Plain Radiography, Ultrasonography, and CT
 In patients with severe sepsis, a chest radiograph should be obtained because the clinical
examination is unreliable for diagnosing pneumonia. Clinically occult infiltrates have
been detected by routine use of chest radiography in adults who are febrile without
localizing symptoms or signs and in patients who are febrile and neutropenic without
pulmonary symptoms. Supine and upright or lateral decubitus abdominal films may be
useful when an intra-abdominal source is suspected.
 Ultrasonography is the imaging modality of choice when a biliary tract infection is
suspected of being the source of sepsis.
 Computed tomography (CT) is the imaging modality of choice for excluding an intra-
abdominal abscess or a retroperitoneal source of infection. A CT scan of the head should
be obtained when there is evidence of increased intracranial pressure (papilledema), when
factors suggesting focal mass lesions (eg, focal defects, previous sinusitis or otitis, recent
intracranial surgery) are present, or before lumbar puncture (LP) when meningitis is
suspected.
 When clinical evidence of a deep soft tissue infection exists (eg, crepitus, bullae,
hemorrhage, or a foul-smelling exudate), a plain radiograph should be obtained. The
presence of soft tissue gas and the spread of infection beyond the clinically detectable
disease may necessitate surgical exploration.
 Other Diagnostic and Supportive Procedures
 When meningitis or encephalitis is suspected, LP must be performed on an urgent basis.
In patients with an acute fulminant presentation, rapid onset of septic shock, and severe
impairment of mental status, bacterial meningitis must be ruled out by means of LP.
 Procedures such as cardiac monitoring, noninvasive blood pressure monitoring, and pulse
oximetry are necessary because patients often require admission to the intensive care unit
(ICU) for invasive monitoring and support. Supplemental oxygen is provided during
initial stabilization and resuscitation.
 In all patients in septic shock, adequate venous access for volume resuscitation is
necessary. A central venous line can also be used to monitor central venous pressure for
assessment of intravascular volume status.
 An indwelling urinary catheter used to monitor urinary output can serve as a marker for
adequate renal perfusion and cardiac output.
 Patients in whom septic shock has developed require right-heart catheterization with a
pulmonary artery (Swan-Ganz) catheter. This catheter provides an accurate assessment of
the volume status of a patient who is in a septic state. Cardiac output measurements can
be obtained. Furthermore, determination of mixed venous oxygenation is helpful in
determining the status of tissue oxygenation.
 Most patients who are in a septic state experience respiratory distress secondary to severe
sepsis or as a manifestation of septic shock. Pulmonary dysfunction of sepsis (ie, acute
respiratory distress syndrome [ARDS]) also may occur. These patients need intubation
and mechanical ventilation for optimum respiratory support.
 Staging
 There are 2 well-defined forms of multiple organ dysfunction syndrome (MODS). In
both, the development of acute lung injury (ALI) or ARDS is of key importance to the
natural history. ARDS is the earliest manifestation in all cases (see the images below).
 Acute respiratory distress syndrome (ARDS) present in
this chest x-ray (CXR) film is a common organ system affected in multiorgan failure of

sepsis. Acute respiratory distress syndrome (ARDS)

shown in this chest x-ray (CXR) film is a common complication of septic shock. Note
bilateral airspace infiltration, absence of cardiomegaly, vascular redistribution, and

Kerley B lines. Organizing phase of diffuse alveolar

damage (ARDS) secondary to septic shock shows diffuse alveolar injury and infiltration

with inflammatory cells. Organizing diffuse alveolar

damage in a different location showing disorganization of pulmonary architecture.
 A high-power view of organizing diffuse alveolar damage
(ARDS) shows hyperplasia of type II pneumocytes and hyaline membrane deposits.
 In the more common form of MODS, the lungs are the predominant—and often the
only—organ system affected until very late in the disease. These patients most often
present with a primary pulmonary disorder, such as pneumonia, aspiration, contusion,
near drowning, exacerbation of chronic obstructive pulmonary disease (COPD),
hemorrhage, or pulmonary embolism.
 Lung disease progresses to meet ARDS criteria. Encephalopathy or mild coagulopathy
may accompany pulmonary dysfunction, which persists for 2-3 weeks. At this time, the
patient either begins to recover or progresses to fulminant dysfunction in another organ
system. Once another major organ dysfunction occurs (see Table 1 below), these patients
frequently do not survive.
 Table. Criteria for Organ Dysfunction (Open Table in a new window)

Organ System Mild Criteria Severe Criteria

Pulmonary Hypoxia or hypercarbia necessitating ARDS requiring PEEP >10 cm H2
assisted ventilation for 3-5 days O and FI O2 < 0.5
Hepatic Bilirubin 2-3 mg/dL or other liver Jaundice with bilirubin 8-10
function tests >2 × normal, PT elevated mg/dL
to 2 × normal
Renal Oliguria (< 500 mL/day) or increasing Dialysis
creatinine (2-3 mg/dL)
Gastrointestinal Intolerance of gastric feeding for moreStress ulceration with need for
than 5 days transfusion, acalculous
cholecystitis
Hematologic aPTT >125% of normal, platelets < 50- DIC
80,000
Cardiovascular Decreased ejection fraction with Hyperdynamic state not
persistent capillary leak responsive to pressors
CNS Confusion Coma
Peripheral nervous Mild sensory neuropathy Combined motor and sensory
system deficit
aPTT = activated partial thromboplastin time; ARDS = acute respiratory distress syndrome; CNS
= central nervous system; DIC = disseminated intravascular coagulation; FI O2 = fraction of
inspired oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time.
  The second form of MODS presents quite differently. These patients often have an
inciting source in organs other than the lungs—most commonly, intra-abdominal sepsis,
extensive blood loss, pancreatitis, or vascular catastrophes. ALI or ARDS develops early,
and dysfunction in other organ systems (hepatic, hematologic, cardiovascular, and renal)
also develops much sooner than in the first form of MODS. Patients remain in a pattern
of compensated dysfunction for several weeks, at which time they either recover or
deteriorate further and die.
 Surgical Drainage and Debridement
 Patients with infected foci should be taken for definitive surgical treatment after initial
resuscitation and administration of antibiotics. When an infected focus persists, there is
little to be gained from spending hours on attempting to stabilize the patient.
 Infectious processes require expeditious surgical drainage or debridement for source
control, even if the patient does not appear stable. Without emergency surgical treatment,
the patient’s condition may not improve.

Approach Considerations
Treatment of patients with septic shock has the following 3 major goals:

 To resuscitate the patient from septic shock, using supportive measures to correct
hypoxia, hypotension, and impaired tissue oxygenation
 To identify the source of infection and treat it with antimicrobial therapy, surgery, or both
 To maintain adequate organ system function, guided by cardiovascular monitoring, and
to interrupt the pathogenesis of multiple organ dysfunction syndrome (MODS)

Current management principles employed in addressing these goals include the following:

 Early recognition
 Early hemodynamic resuscitation
 Early and adequate antibiotic therapy
 Source control
 Continued hemodynamic support
 Corticosteroids (refractory vasopressor-dependent shock)
 Tight glycemic control
 Proper ventilator management with low tidal volume in patients with acute respiratory
distress syndrome (ARDS)

Recognition of septic shock requires identification of features of the systemic inflammatory

response syndrome (SIRS)—mental changes, hyperventilation, distributive hemodynamics,
hyperthermia or hypothermia, and a reduced, elevated, or left-shifted white blood cell (WBC)
count—along with the existence of a potential source of infection.

Patients in septic shock require immediate cardiorespiratory stabilization with large volumes of
intravenous (IV) fluids, infusion of vasoactive drugs, and, often, endotracheal intubation and
mechanical ventilation.
Empiric IV antimicrobial therapy should be immediately directed toward all potential infectious
sources.

The drugs used for hemodynamic support of patients with sepsis have adverse effects on
splanchnic circulation. Accordingly, the ideal hemodynamic therapy in these patients has not
been determined. After adequate fluid resuscitation, therapy with dopamine may be initiated,
followed by norepinephrine when dopamine fails. Alternatively, therapy may be initiated with
norepinephrine, with dobutamine used if inotropic support is needed. The use of epinephrine as a
single agent in septic shock is not recommended.

Manipulation of oxygen delivery by increasing the cardiac index has either yielded no
improvement or has worsened morbidity and mortality. Routine use of hemodynamic drugs to
raise cardiac output to supranormal levels is not recommended.

Drotrecogin alfa (activated protein C) was the only widely accepted drug specific to the therapy
of sepsis. However, in a clinical trial (PROWESS-SHOCK trial), this agent failed to show a
survival benefit for patients with severe sepsis and septic shock. The results of the trial led to the
withdrawal of drotrecogin alfa from the worldwide market on October 25, 2011. The adverse
side effect of drotrecogin alfa is bleeding.

Lactic acidosis of septic shock usually causes anion gap metabolic acidosis. Administration of
bicarbonate has the potential to worsen intracellular acidosis. Correction of acidemia with
sodium bicarbonate has not been proved to improve hemodynamics in critically ill patients with
increased blood lactate levels. Nevertheless, bicarbonate therapy has been used in cases where
the pH is less than 7.20 or the bicarbonate level is lower than 9 mmol/L, though no data to
support this practice exist.

The pathogenesis of septic shock and MODS derives from mediators produced because of the
immune response of the host. Despite encouraging data from animal studies, immunosuppressive
agents, such as high-dose corticosteroids, have not shown any benefit in humans.

The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should be
kept at less than 150 mg/dL.

Research has focused on modifying the host response to sepsis via a number of approaches,
including the following:

 Antibodies against gram-negative endotoxin

 Gamma globulins
 Monoclonal antibodies against tumor necrosis factor
 Blockade of eicosanoid production
 Blockade of interleukin (IL)–1 activity
 Inhibition of nitric oxide (NO) synthase

These approaches have met with modest success in animal experiments, but at present, they
cannot be recommended for general use in humans.
A study by Jaimes et al was not able to demonstrate beneficial effects of unfractionated heparin
in patients with sepsis on length of hospital stay, MODS, and mortality at 28 days when
compared to placebo.[14]

General Supportive Care and Resuscitation

Initial treatment includes support of respiratory and circulatory function, administration of
supplemental oxygen, mechanical ventilation, and volume infusion. Beyond these supportive
measures, treatment includes a combination of several parenteral antibiotics, removal or drainage
of infected foci, treatment of complications, and pharmacologic interventions to prevent further
harmful host responses (see below).

Administer supplemental oxygen to any patient who is septic with hypoxia or respiratory
distress. If the patient’s airway is not secure or respirations are inadequate, perform endotracheal
intubation and mechanical ventilation.

All patients with sepsis require supplemental fluids. Assessment of the patient’s volume and
cardiovascular status guides the amount and rate of infusion. For adult patients who are
hypotensive, administer an isotonic crystalloid solution (sodium chloride 0.9% or lactated Ringer
solution) in boluses of 500 mL (10 mL/kg in children), with repeat clinical assessments after
each bolus. Administer repeat boluses until signs of adequate perfusion are restored. A total of 4-
6 L may be required.

Monitor patients for signs of volume overload, such as dyspnea, pulmonary crackles, and
pulmonary edema, on chest radiographs. Improvement, stabilization, and normalization of the
patient’s mental status, heart rate, blood pressure, capillary refill, and urine output indicate
adequate volume resuscitation.

In some patients, clinical assessment of the response to volume infusion may be difficult. By
monitoring the response of the central venous pressure (CVP) or the pulmonary artery occlusion
pressure (PAOP) to fluid boluses, the physician can assess these patients.

A CVP of 10-15 mm Hg, a PAOP greater than 18 mm Hg, or a rise in the PAOP by 5 mm Hg or
more after a fluid bolus indicates adequate volume resuscitation. Because such patients are
susceptible to volume overload, any further fluid must be administered carefully. Colloid
resuscitation (with albumin or pentastarch) has no proven benefit over isotonic crystalloid
resuscitation (with normal saline or lactated Ringer solution).

If patients are treated initially in the wards or in the emergency department (ED), after initial
attempts at stabilization, they should be transferred to the intensive care unit (ICU) for invasive
monitoring and support.

Empiric Antimicrobial Therapy

Initial selection of particular antimicrobial agents is empiric and is based on an assessment of the
patient’s underlying host defenses, the potential sources of infection, and the most likely
pathogens.

Antibiotics must be broad-spectrum and must cover gram-positive, gram-negative, and anaerobic
bacteria because all of these classes of organisms produce identical clinical pictures. Administer
antibiotics parenterally in doses high enough to achieve bactericidal serum levels. Many studies
have found that clinical improvement correlates with the achievement of serum bactericidal
levels rather than with the number of antibiotics administered.

Coverage directed against anaerobes is particularly important in the treatment of patients with
intra-abdominal or perineal infections. Antipseudomonal coverage is indicated in patients with
neutropenia or burns.

Patients who are immunocompetent generally can be treated with a single drug that provides
broad-spectrum coverage, such as a third-generation cephalosporin. However, patients who are
immunocompromised usually must be treated with 2 broad-spectrum antibiotics that provide
overlapping coverage. Within these general guidelines, no single combination of antibiotics is
clearly superior to any other.

Vasopressor Therapy
When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion,
initiate therapy with vasopressor agents. The agents used are dopamine, norepinephrine,
epinephrine, and phenylephrine. These drugs maintain adequate blood pressure during life-
threatening hypotension and preserve perfusion pressure for optimizing flow in various organs.
Maintain the mean BP required for adequate splanchnic and renal perfusion (mean arterial
pressure [MAP] of 60 or 65 mm Hg) on the basis of clinical indices for organ perfusion.

If the patient remains hypotensive despite volume infusion and moderate-dose dopamine, start a
direct vasoconstrictor (eg, norepinephrine at a dose of 0.5 µg/kg/min), titrating the dose to
support a systolic BP of 90 mm Hg.

Although potent vasoconstrictors such as norepinephrine traditionally have been avoided because
of their adverse events on cardiac output and renal perfusion, data from human studies have
shown that norepinephrine can reverse septic shock in patients unresponsive to volume and
dopamine. These patients require invasive hemodynamic monitoring with arterial lines and
pulmonary artery catheters.

Dopamine

A precursor of norepinephrine and epinephrine, dopamine has varying effects, depending on the
dose administered. A dose lower than 5 µg/kg/min results in vasodilation of renal, mesenteric,
and coronary beds. At a dose of 5-10 µg/kg/min, beta1 -adrenergic effects induce an increase in
cardiac contractility and heart rate. At doses of about 10 µg/kg/min, alpha-adrenergic effects lead
to arterial vasoconstriction and an increase in blood pressure.
Dopamine is effective in increasing MAP in patients who are hypotensive with septic shock after
volume resuscitation. The blood pressure increases primarily as a result of an inotropic effect,
which is useful in patients who have concomitant reduced cardiac function. The undesirable
effects are tachycardia, increased pulmonary shunting, potentially decreased splanchnic
perfusion, and increased PAOP.

Renal-dose dopamine

The use of renal-dose dopamine in sepsis is a controversial issue. In the past, low-dose dopamine
was routinely used in many units because of the presumed kidney-protecting effects. Dopamine
at a dose of 2-3 µg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy
animals and volunteers. However, multiple studies have not demonstrated a beneficial effect with
prophylactic or therapeutic low-dose dopamine administration in patients who are critically ill.

Administering low-dose dopamine does not protect the patient from developing acute renal
failure, and there is no evidence that it preserves mesenteric profusion. Consequently, routine use
of this practice is not recommended. Aggressively resuscitating patients with septic shock,
maintaining adequate perfusion pressure, and avoiding excessive vasoconstriction are effective
measures for protecting the kidneys.

Epinephrine

Epinephrine can increase MAP by increasing the cardiac index, stroke volume, systemic vascular
resistance, and heart rate. It may increase oxygen delivery and consumption and decreases
splanchnic blood flow. Administration of epinephrine is associated with an elevation of systemic
and regional lactate concentrations.

The use of epinephrine is recommended in patients who are unresponsive to traditional agents.
The undesirable effects of this agent include increased lactate concentration, potential production
of myocardial ischemia and arrhythmias, and reduced splanchnic flow.

Norepinephrine

Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist

effects. It can successfully increase blood pressure in patients who are in a septic state and
remain hypotensive after fluid resuscitation and dopamine. Doses range from 0.2 to 1.35
µg/kg/min; doses as large as 3.3 µg/kg/min have been used because alpha-receptor
downregulation may occur in sepsis.

In patients with sepsis, indices of regional perfusion (eg, urine flow and lactate concentration)
have improved after norepinephrine infusion. In recent controlled trials, no significant difference
was noted in the rate of death between patients with shock who were treated with dopamine and
those who were treated with norepinephrine; the use of dopamine was associated with a greater
number of adverse events, which were mostly cardiac arrhythmias.[15, 16]
Accordingly, use norepinephrine early, and do not withhold it as a last resort. Norepinephrine
therapy appears to have no effects on splanchnic oxygen consumption and hepatic glucose
production, provided that adequate cardiac output is maintained.

Phenylephrine

Phenylephrine is a selective alpha1 -adrenergic receptor agonist that is primarily used in

anesthesia to increase blood pressure. Although the data are limited, phenylephrine has been
found to increase MAP in patients with sepsis who are hypotensive with an increase in oxygen
consumption and potential to reduce cardiac output. Phenylephrine may be a good choice when
tachyarrhythmias limit therapy with other vasopressors.

Role of inotropic therapy

Although myocardial performance is altered during sepsis and septic shock, cardiac output is
usually maintained in patients with sepsis who have undergone volume resuscitation. Data from
the 1980s and 1990s suggested a linear relation between oxygen delivery and oxygen
consumption (pathologic supply dependency), indicating that oxygen delivery was likely
insufficient to meet the metabolic needs of the patient.

However, subsequent investigations challenged the concept of pathologic supply dependency

and the practice of elevating cardiac index and oxygen delivery (hyperresuscitation) on the
grounds that these interventions have not been shown to improve patient outcome. Therefore, the
role of inotropic therapy is uncertain unless the patient has an inadequate cardiac index, MAP,
mixed venous oxygen saturation, and urine output despite optimal volume resuscitation and
vasopressor therapy.

Recombinant Human Activated Protein C Therapy

Activated protein C is an endogenous protein that not only promotes fibrinolysis and inhibits
thrombosis and inflammation but also may modulate the coagulation and inflammation of severe
sepsis. Sepsis reduces the level of protein C and inhibits conversion of protein C to activated
protein C. Administration of recombinant activated protein C inhibits thrombosis and
inflammation, promotes fibrinolysis, and modulates coagulation and inflammation.

An early publication by the Recombinant Human Activated Protein C Worldwide Evaluation in

Severe Sepsis (PROWESS) study group demonstrated that administration of recombinant human
activated protein C (drotrecogin alfa) resulted in lower mortality (24.7%) in the treatment group
than in the placebo group (30.8%).[17] Treatment with drotrecogin alfa was associated with a
19.4% relative reduction in the risk of death and a 6.1% absolute reduction in the risk of death.

After that early publication, the efficacy and safety of drotrecogin alfa were widely debated.
Drotrecogin alfa was withdrawn from the worldwide market on October 25, 2011, after analysis
of the PROWESS-SHOCK clinical trial, in which the drug failed to demonstrate a statistically
significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic
shock.[18] Trial results observed a 28-day all-cause mortality of 26.4% in patients treated with
drotrecogin alfa, compared with 24.2% in the placebo group.

Corticosteroid Therapy
Despite the theoretical and experimental animal evidence supporting the use of large doses of
corticosteroids in those with severe sepsis and septic shock, all randomized human studies of this
practice (except a single study from 1976) found that corticosteroids did not prevent the
development of shock, reverse the shock state, or improve 14-day mortality. Therefore, routine
use of high-dose corticosteroids in patients with severe sepsis or septic shock is not indicated.

Although further research is required to address this issue definitively, there are some
recommendations that can be made at present. Trials have demonstrated positive results from
administration of stress-dose corticosteroids to patients in severe and refractory shock.[19] These
results await further confirmation, but it is reasonable to provide stress-dose steroid coverage
should be provided to patients who have the possibility of adrenal suppression.

The following key points summarize current use of corticosteroids in septic shock:

 Older, traditional trials of corticosteroids in sepsis probably failed to show good results
because they used high doses and did not select patients appropriately
 Subsequent trials with low-dose (physiologic) dosages in select patient populations
(vasopressor-dependent patients and those with potential relative adrenal insufficiency)
reported improved outcomes
 Corticosteroids should be initiated for patients with vasopressor-dependent septic shock

A cosyntropin stimulation test may be performed to identify patients with relative adrenal
insufficiency, defined as failure to raise levels above 9 µg/dL.

Tight Glycemic Control

Tight glycemic control has become a prominent emphasis in the care of critically ill patients, and
data have been extrapolated for potential application to patients with sepsis. A 2001 Belgian
study of surgical ICU patients who remained in the ICU for more than 5 days showed a 10%
mortality benefit in those with tighter glycemic control.[20] The glucose levels for these patients
were maintained between 80 and 110 mg/dL through the use of intensive insulin therapy.

Tight glycemic control has been shown to improve mortality in postoperative surgical patients
including and particularly those patients with sepsis. The benefit of glycemic control appears to
result more from aggressive avoidance of the detrimental effects of hyperglycemia than from the
potential therapeutic effect of insulin. On the basis of the current evidence, the Surviving Sepsis
Campaign recommends maintaining a glucose level of less than 150 mg/dL.[21]

Consultations
Seek consultation with an appropriate surgeon for patients with suspected or known infected
foci, especially for patients with a suspected abdominal source.

Patients who do not respond to therapy or are in septic shock require admission to an ICU for
continuous monitoring and observation. Consultation with a critical care physician or internist
with expertise is appropriate.

Long-Term Monitoring
The major focus of resuscitation from septic shock is supporting cardiac and respiratory
functions. To prevent MODS, these patients require a very close monitoring and institution of
appropriate therapy for major organ function. Problems encountered in these patients include the
following:

 Temperature control – Fever generally requires no treatment, except in patients with

limited cardiovascular reserve, because of increased metabolic requirements; antipyretic
drugs and physical cooling methods, such as sponging or cooling blankets, may be used
to lower the temperature
 Metabolic support – Patients with septic shock develop hyperglycemia and electrolyte
abnormalities; serum glucose should be kept in normal range with insulin infusion;
regular measurement and correction of electrolyte deficiency (including hypokalemia,
hypomagnesemia, hypocalcemia and hypophosphatemia) is recommended
 Anemia and coagulopathy – Hemoglobin as low as 8 g/dL is well tolerated and does not
warrant transfusion unless the patient has poor cardiac reserve or demonstrates evidence
of myocardial ischemia; thrombocytopenia and coagulopathy are common in sepsis and
do not necessitate replacement with platelets or fresh frozen plasma, unless the patient
develops active clinical bleeding
 Renal dysfunction – Closely monitor urine output and renal function in all patients with
sepsis; any abnormalities of renal function should prompt attention to adequacy of
circulating blood volume, cardiac output, and blood pressure; correct these if they are
inadequate
 Nutritional support – Early nutritional support is of critical importance in patients with
septic shock; the enteral route is preferred unless the patient has an ileus or other
abnormality; gastroparesis is observed commonly and can be treated with motility agents
or placement of a small bowel feeding tube

Prevention
Patients with impaired host defense mechanisms are at greatly increased risk for sepsis and
MODS. The main causes are chemotherapeutic drugs, malignancy, severe trauma, burns,
diabetes mellitus, renal or hepatic failure, old age, ventilatory support, and invasive catheters.

One way of helping to prevent severe sepsis is to avoid invasive catheters or remove them as
soon as possible. Prophylactic antibiotics in the perioperative phase, particularly after
gastrointestinal surgery, may be beneficial. Use of topical antibiotics around invasive catheters
and as part of a dressing for patients with burns is helpful. Maintenance of adequate nutrition,
administration of pneumococcal vaccine to patients who have undergone splenectomy, and early
enteral feeding are other preventive measures.

Topical or systemic antibiotics have been given to prevent sepsis and MODS in high-risk
patients. The use of nonabsorbable antibiotics in the stomach to prevent translocation of bacteria
and occurrence of bacteremia has been a controversial issue. Numerous trials have been
performed over the years using either topical antibiotics alone or a combination of topical and
systemic antibiotics.

A systemic review by Nathens presented no benefit in medical patients but a reduced mortality in
surgical trauma patients.[22] The beneficial effect was from a combination of systemic and topical
antibiotics, predominantly involving reduction of lower respiratory tract infections in patients
who were treated.

Medication Summary
The proven medical treatments for septic shock are restoration of intravascular volume and
broad-spectrum empiric antibiotic coverage. All other medical therapies, though theoretically
attractive, have not been shown to reduce morbidity or mortality.

Electrolytes
Class Summary

Isotonic crystalloids are the standard for initial volume resuscitation. These fluids expand the
intravascular and interstitial fluid spaces. Typically, approximately 30% of administered isotonic
fluid remains intravascular; therefore, large quantities may be required to maintain an adequate
circulating volume.

Normal saline and lactated Ringer solution

Both normal saline (NS) and lactated Ringer solution (LR) are essentially isotonic and have
equivalent volume restorative properties. Whereas some differences exist between the 2 solutions
with respect to the metabolic changes observed with administration of large quantities, for
practical purposes and in most situations, the differences are clinically irrelevant. No
demonstrable difference in hemodynamic effect, morbidity, or mortality exists between
resuscitation with NS and resuscitation with LR.

The amounts of intravascular fluid required are related to the degree of vascular endothelial
injury and impaired vasomotor tone; thus, not only may very large quantities of fluids be
required initially, but continual fluid resuscitation also is often required during the initial days of
management.
Blood Components
Class Summary

Colloids are used for resuscitation because they provide an oncotically active substance that
expands plasma volume to a greater degree than isotonic crystalloids do while reducing the
tendency toward pulmonary and cerebral edema. Approximately 50% of the administered colloid
remains intravascular.

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Albumin 5% (Albuminar, Buminate, Kedbumin)

Albumin is used for treatment of certain types of shock or impending shock. It is useful for
plasma volume expansion and maintenance of cardiac output. A solution of NS and 5% albumin
is available for volume resuscitation.

Antibiotics, Other
Class Summary

Besides resuscitation fluids, empiric antibiotics that cover the infecting organism and are started
early are the only other proven medical treatment for septic shock. Administer all initial
antibiotics intravenously (IV) in patients with septic shock.

The necessary coverage is achieved by giving a single broad-spectrum agent or multiple

antibiotics. In adults who are not immunocompromised, monotherapy with either an
antipseudomonal penicillin or a carbapenem is possible. Combination therapy in adults involves
either a third-generation cephalosporin plus anaerobic coverage (clindamycin or metronidazole)
or a fluoroquinolone plus clindamycin.

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Cefotaxime (Claforan)

Cefotaxime is used for treatment of bloodstream infection (BSI), as well as for treatment of
gynecologic infections caused by susceptible organisms. It is a third-generation cephalosporin
with enhanced gram-negative coverage, especially of Escherichia coli, Proteus species, and
Klebsiella species. It has variable activity against Pseudomonas species.

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Ceftriaxone (Rocephin)

Ceftriaxone is used because of the increasing prevalence of penicillinase-producing

microorganisms. It inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-
binding proteins. Bacteria eventually lyse as a consequence of the ongoing activity of cell wall
autolytic enzymes while cell wall assembly is arrested.

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Cefuroxime (Zinacef, Ceftin)

Cefuroxime is a second-generation cephalosporin that maintains the gram-positive activity of the

first-generation cephalosporins and adds activity against E coli, Klebsiella pneumoniae, Proteus
mirabilis, Haemophilus influenzae, and Moraxella catarrhalis. The condition of the patient, the
severity of the infection, and the susceptibility of the microorganism determine the proper dose
and route of administration.

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Ticarcillin-clavulanate (Timentin)

Ticarcillin-clavulanate is a combination of an antipseudomonal penicillin with a beta-lactamase

inhibitor that provides coverage against most gram-positive organisms (variable coverage against
Staphylococcus epidermidis and none against methicillin-resistant Staphylococcus aureus
[MRSA]), most gram-negative organisms, and most anaerobes.

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Piperacillin-tazobactam (Zosyn)

Piperacillin-tazobactam inhibits the biosynthesis of cell wall mucopeptide and is effective during
the stage of active multiplication. It has antipseudomonal activity.

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Imipenem-cilastatin (Primaxin)
Imipenem cilastatin is a carbapenem with activity against most gram-positive organisms (except
MRSA), gram-negative organisms, and anaerobes. It is used for treatment of polymicrobial
infections in which other agents do not have wide-spectrum coverage or are contraindicated
because of their potential for toxicity.

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Meropenem (Merrem)

Meropenem is a carbapenem that, compared with imipenem, has slightly increased activity
against gram-negative organisms and slightly decreased activity against staphylococci and
streptococci.

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Clindamycin (Cleocin)

Clindamycin is primarily used for its activity against anaerobes. It has some activity against
streptococcus and methicillin-sensitive S aureus (MSSA).

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Metronidazole (Flagyl)

Metronidazole is an imidazole ring-based antibiotic that is active against various anaerobic

bacteria and protozoa. It is usually employed in combination with other antimicrobial agents,
except when it is used for Clostridium difficile enterocolitis, in which case monotherapy is
appropriate.

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Ciprofloxacin (Cipro)

Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently,

growth by inhibiting DNA gyrase and topoisomerases, which are required for replication,
transcription, and translation of genetic material. Quinolones have broad activity against gram-
positive and gram-negative aerobic organisms. Ciprofloxacin has no activity against anaerobes.
Continue treatment for at least 2 days (typically, 7-14 days) after signs and symptoms have
disappeared.

Activated Protein C Analogues

Class Summary

Activated protein C analogues exert antithrombotic effects, have indirect profibrinolytic activity,
and may have anti-inflammatory effects.

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Drotrecogin alfa (Xigris)

October 25, 2011: Withdrawn from worldwide market. Drotrecogin alfa was indicated for
reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and
at high risk of death.

Drotrecogin alfa is a recombinant form of activated protein C that exerts antithrombotic effects
by inhibiting factors Va and VIIIa. It has indirect profibrinolytic activity by inhibiting
plasminogen activator inhibitor-1 and limiting formation of activated thrombin-activatable
fibrinolysis inhibitor. It may exert anti-inflammatory effects by inhibiting human tumor necrosis
factor production by monocytes, blocking leukocyte adhesion to selectins, and limiting
thrombin-induced inflammatory responses within microvascular endothelium.

Cardiovascular, Other
Class Summary

If a patient does not respond to several liters of isotonic crystalloid (usually 4 L or more), or if
evidence of volume overload is present, the depressed cardiovascular system can be stimulated
by inotropic and vasoconstrictive agents.

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Dopamine

Dopamine is used to treat hypotension in fluid-resuscitated patients. It stimulates both adrenergic

and dopaminergic receptors. The hemodynamic effect depends on the dose. Lower doses
stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation in
healthy volunteers but probably have no measurable effect in patients who are critically ill.
Higher doses produce cardiac stimulation, tachycardia, and vasoconstriction.

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Norepinephrine (Levophed)

Norepinephrine, like dopamine, is used to treat hypotension after adequate fluid resuscitation. It
stimulates beta1-adrenergic and alpha-adrenergic receptors, which increase arterial tone and
cardiac contractility. As a result, systemic blood pressure and coronary blood flow increase with
norepinephrine, though myocardial oxygen demand also may increase.

Once a response has been obtained, adjust the infusion rate to maintain a mean arterial pressure
greater than 60 mm Hg. Blood pressures below this threshold are insufficient to perfuse vital
organs; however, raising pressures much above 70 mm Hg with vasopressors does not further
increase tissue blood flow.

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Vasopressin (Pitressin)

Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. Although it does not
increase blood pressure in healthy subjects, it markedly increases vasomotor tone in patients with
septic shock. It also increases water resorption at the distal renal tubular epithelium (ADH effect)
and promotes smooth muscle contraction throughout the vascular bed of the renal tubular
epithelium (vasopressor effects). Vasoconstriction also is increased in splanchnic, portal,
coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels.

Vasopressin is not yet routinely used to treat hypotension in septic shock. The dosage of
vasopressin used for hypotension is 10% of that used to treat upper gastrointestinal bleeding
from varices.