Multiple Organ Dysfunction Syndrome in Sepsis

Updated: Jan 27, 2020
Author: Ali H Al-Khafaji, MD, MPH, FACP, FCCP, FCCM; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM 



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 Ches Stages of sepsis based on American College of Chest Physicians/Society of Critical Care Medicine Consensus Panel guidelines.

Infection is usually 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. However, viral infections can be indistinguishable from bacteria infections in their presentation.

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 a nonspecific presentation of these insults and 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). That sepsis and SIRS are phenotypically similar underscores a common inflammatory pathway causing both.

Venn diagram showing overlap of infection, bactere Venn diagram showing overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

In early 2016, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force to address definitions and clinical criteria for sepsis.[4] The task force concluded that sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction is represented by an increase in the Sequential [sepsis-related] Organ Failure Assessment (SOFA) score[5] of 2 points or more, which is associated with an in-hospital mortality greater than 10%.

Septic shock is defined as a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.

Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%.

In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least two of the following clinical criteria that together constitute a new bedside clinical score termed quick SOFA (qSOFA)[6] : respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.

The task force recommended that these updated definitions and clinical criteria should replace previous definitions

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.


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. 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.

Although uncontrolled, once MODS develops systemic evidence of both proinflammatory and anti-inflammatory up-regulation are usually present, suggesting that failure of host defense homeostasis is the final pathway from sepsis to MODS, rather than simple hypotension-induced end-organ injury, as may occur with hemorrhagic shock. Survival from severe sepsis with MODS is usually associated with a generalized reduction in both the proinflammatory and anti-inflammatory response.

A novel hypothesis has recently emerged that survival from severe sepsis requires a generalized down-regulation of the body’s immune response, energetic functions, and associated organ performance. Thus, MODS may by the host’s adaptive response to overwhelming inflammation, allowing inflammation to clear without causing permanent end-organ harm. As discussed below, all organs reveal a generalized hyporesponsiveness that is clearly abnormal in health but may mark a survival strategy in severe sepsis.

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 since vascular endothelium is universally affected by the circulating inflammatory mediators. Although it is unclear if microcirculatory abnormalities are the cause or an innocent bystander of the end-organ injury, clear microvascular dysfunction is seen. A decrease in the number of perfused capillaries is seen, although with application of vasodilator therapies, full microvascular recruitment occurs. Mitochondrial dysfunction also occurs and is often associated with reduced mitochondrial transmembrane potential gradients, which are necessary to drive oxidative phosphorylation. The end result is an apparent inability of end-organs to extract oxygen maximally.

Debate continues as to whether this failure of energy metabolism is an adaptive cytoprotective mechanism similar to hibernation or reflects primary mitochondrial pathology. These are areas of active research but do not presently translate into clear clinical practice guidelines. Increased capillary endothelial permeability leads to widespread protein-rich tissue edema.

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. The two characteristics of this acute stress myocardial depression are impaired adrenergic responsiveness and diastolic dysfunction leading to relative catecholamine resistance and small rather than dilated hearts. 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 dysoxia therefore persists. This condition is termed microcirculatory and mitochondrial distress syndrome (MMDS).[7] 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. Indeed, sepsis and pneumonia are the most common causes of ARDS.

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, endotoxins, and normal digestive proteases 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. Excess NO production is thought to be the causative agent of sepsis-induced ileus. 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 (“shocked 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 kidney injury (AKI) often accompanies sepsis. Different etiologies for AKI have been reported, and the cause is typically thought to be multifactorial.[8] The mechanism of AKI is complex but likely 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. Still, most animal studies show that renal blood flow is increased, not decreased, in sepsis, though associated with impaired tubular function and a lack of significant histologic evidence of tubular 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.


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. Protease-activated receptors (PARs), especially PAR 1, form the molecular link between coagulation and inflammation; PAR1 exerts cytoprotective effects when stimulated by activated protein C or low-dose thrombin but exerts disruptive effects on endothelial-cell barrier function when activated by high-dose thrombin.[9]

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 (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.


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.

Host response and other 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.

The host response to sepsis is characterized by both proinflammatory responses and anti-inflammatory immunosuppressive responses. The direction, extent, and duration of these reactions are determined by both host factors (eg, genetic characteristics, age, coexisting illnesses, medications) and pathogen factors (eg, microbial load, virulence).[10]

Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding oligomerization domain–like receptors [NLRs]).[10]

The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation at least in part by acting on the same pattern-recognition receptors triggered by pathogens.[10]


Estimating the exact incidence of sepsis throughout the world is difficult. Studies vary in their methods of determining the incidence of sepsis.[11] [#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).[12] These figures may be usefully compared with those reported by Martin et al[13] and by Blanco et al.[14] Approximately 40% of patients with sepsis may develop septic shock. Patients who are at risk include those with positive blood cultures.


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.[15]

A multicenter prospective study published in the Journal of the American Medical Association reported a mortality of 56% during ICU stay.[16] 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.[17]




Symptoms of sepsis are usually nonspecific and include fever, chills, and constitutional symptoms of fatigue, malaise, anxiety, or confusion.[18] 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.


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.

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.[19]

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.

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 associated with acute lung injury or right-sided heart failure require either right-heart catheterization with a pulmonary artery (Swan-Ganz) catheter or a transpulmonary thermodilution device (eg, PiCCO, Vigileo) to guide therapy. These catheters provide an 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 from the pulmonary artery catheter is helpful in determining the status of tissue oxygenation.

Dynamic hemodynamic monitoring devices using pulse pressure and stroke volume variation are used in some centers when the patients are in sinus rhythm and on mechanical ventilation without spontaneous breathing to define volume responsiveness and assess dynamic arterial tone, both useful in deciding on resuscitation treatment options.

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.


There are two 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 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 i 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) 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 Organizing diffuse alveolar damage in a different location showing disorganization of pulmonary architecture.
A high-power view of organizing diffuse alveolar d 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


Hypoxia or hypercarbia necessitating assisted ventilation for 3-5 days

ARDS requiring PEEP >10 cm H2 O and FI O2< 0.5


Bilirubin 2-3 mg/dL or other liver function tests >2 × normal, PT elevated to 2 × normal

Jaundice with bilirubin 8-10 mg/dL


Oliguria (< 500 mL/day) or increasing creatinine (2-3 mg/dL)



Intolerance of gastric feeding for more than 5 days

Stress ulceration with need for transfusion, acalculous cholecystitis


aPTT >125% of normal, platelets < 50-80,000



Decreased ejection fraction with persistent capillary leak

Hyperdynamic state not responsive to pressors




Peripheral nervous system

Mild sensory neuropathy

Combined motor and sensory 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 three 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 used 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.

General management is as follows[20] :

  • Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion

  • Goals during the first 6 hours of resuscitation are (1) central venous pressure 8-12 mm Hg, (2) mean arterial pressure (MAP) above 65 mm Hg, (3) urine output above 0.5 mL/kg/h, (4) central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively

  • In patients with elevated lactate levels, targeting resuscitation to normalize lactate as rapidly as possible

  • Screening for sepsis and performance improvement

Diagnosis is as follows[20] :

  • Cultures as clinically appropriate before antimicrobial therapy if no significant delay (45 min) in the start of antimicrobial(s)

  • At least 2 sets of blood cultures obtained before antimicrobial therapy

  • Imaging studies performed promptly to confirm a potential source of infection

Antimicrobial therapy is as follows[20] :

  • Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy

  • Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis

  • Antimicrobial regimen should be reassessed daily for potential deescalation

  • Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic but have no subsequent evidence of infection

  • Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens

  • Duration of therapy typically 7-10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with Staphylococcus aureus, some fungal and viral infections, or immunologic deficiencies (including neutropenia)

  • Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin

  • Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause

Source control is as follows[20] :

  • A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible

  • Intervention be undertaken for source control within the first 12 hours after the diagnosis is made, if feasible

Infection prevention is as follows[20] :

  • Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; this infection control measure can then be instituted in healthcare settings and regions where this methodology is found to be effective

  • Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associate pneumonia in ICU patients with severe sepsis

Choice of resuscitation fluid is as follows[20] :

  • Surviving Sepsis Campaign: Recommend using crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock and recommend against the use of hydroxyethyl starches (HES). Albumin can be used in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids.

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 norepinephrine, epinephrine, vasopressin, dopamine, 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 65 mm Hg) on the basis of clinical indices for organ perfusion.

Norepinephrine is the first-choice vasopressor. Epinephrine (added to and potentially substituted for norepinephrine) can be used when an additional agent is needed to maintain adequate blood pressure. Vasopressin at 0.03 units/minute can be added to norepinephrine with the intent of either raising MAP or decreasing norepinephrine dosage. Dopamine as an alternative vasopressor agent to norepinephrine is used only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). Phenylephrine is not recommended in the treatment of septic shock, except in circumstances when norepinephrine is associated with serious arrhythmias, cardiac output is known to be high and blood pressure is persistently low, or as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve MAP target.[20]


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 0.2-1.35 µg/kg/min; doses as high as 3.3 µg/kg/min have been used because alpha-receptor down-regulation 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.[21, 22]

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 adequate cardiac output is maintained.


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.


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 only partially 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

In healthy volunteers, infusion of dopamine at low doses (0.5-2 mg/kg/min) increases both renal blood flow and the glomerular filtration rate by selective stimulation of renal dopaminergic receptors. However, “beneficial” effects of such renal-dose dopamine in sepsis are unsubstantiated. 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.


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.

Angiotensin II

Angiotensin II targets the renin-angiotensin-aldosterone system (RAAS), a powerful mediator of arterial blood pressure. Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial was conducted to determine whether the addition of angiotensin II to background vasopressors would improve blood pressure in patients with catecholamine-resistant vasodilatory shock.[23] In that study, 321 patients with vasodilatory shock were randomized to receive either angiotensin II (163 patients) or placebo (158 patients). Enrolled patients had shock despite receiving more than 0.2 μg/kg/min of norepinephrine or another vasopressor in a similar dose. The primary endpoint was a response with respect to MAP at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. The primary endpoint was reached by more patients in the angiotensin II group than in the placebo group. At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score was greater in the angiotensin II group than in the placebo group. There was no statistically significant difference in mortality between the two groups.

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. However, if there is inadequate cardiac index, MAP, mixed venous oxygen saturation, and urine output despite optimal volume resuscitation and vasopressor therapy, a trial of dobutamine infusion up to 20 µg/kg/min be administered or added to 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%).[24] 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.[25] 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, hydrocortisone can be given at 200-300 mg/day for up to 7 days or until vasopressor support is no longer required for patients with refractory septic shock.

Trials have demonstrated positive results from administration of stress-dose corticosteroids to patients in severe and refractory shock.[26] Large clinical trials have documented a clear benefit of hydrocortisone plus fludrocortisone for adults with septic shock, reducing the time on ventilator and the severity of acute kidney injury, along with overall lower Sequential Organ Failure Assessment (SOFA) scores.[27] Thus, it is reasonable to provide stress-dose steroid coverage plus mineralocorticoid supplement to septic shock patients, and especially those 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 useful to identify patients with relative adrenal insufficiency, defined as failure to raise levels above 9 µg/dL.

Tight Glycemic Control

A protocolized approach to blood glucose management in ICU patients with severe sepsis is recommended, commencing insulin dosing when 2 consecutive blood glucose levels are of more than 180 mg/dL. This approach should target an upper blood glucose level equal or more than 180 mg/dL rather than an upper target blood glucose of equal or less than 110 mg/dL.[20]


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 7 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

Long-term outcomes

For patients who survive sepsis and MODS, the road to recovery is often long and challenging. Post hospital discharge, patients may have physical, emotional, and cognitive consequences. In addition, these patients have a higher risk of repeat sepsis episodes. Aggressive rehabilitation programs, including psychological treatments, may be helpful.[28]


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 systematic review by Nathens presented no benefit in medical patients but a reduced mortality in surgical trauma patients.[29] 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.


Class Summary

Isotonic crystalloids are the standard for initial volume resuscitation. Fluids are drugs and should be used that way. When given in quantity, they 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. Large volume NS resuscitation causes a hyperchloremic metabolic acidosis and in large population-based clinical trials was associated with worse outcomes than patients treated with balanced salt solutions like LR. However, these mortality differences were small. Fluid resuscitation should not be delayed to use a balanced salt solution if NS is the only fluid available.

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.

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. The use of albumin in resuscitation has not been shown to alter outcome.

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.

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.

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.

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.

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.

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.

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.

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.

Clindamycin (Cleocin)

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

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.

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.

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.


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.

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.

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.


Questions & Answers


What is multiple organ dysfunction syndrome (MODS)?

What is sepsis and what is its clinical progression?

What is systemic inflammatory response syndrome (SIRS)?

How are sepsis and systemic inflammatory response syndrome (SIRS) differentiated?

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What is the role of epinephrine in the management of multiple organ dysfunction syndrome (MODS) in sepsis?

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