Sections

Septic Shock

Workup

Approach Considerations

Early recognition and management are key in patients with sepsis or septic shock. Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are indicated in patients with septic shock. These measures are necessary because these patients often require admission to an intensive care unit (ICU) for invasive monitoring and support. Once patients are stabilized, clinicians can determine their approach to the diagnostic workup.

Investigative studies include laboratory tests, imaging modalities, and possibly lumbar puncture/spinal fluid testing to detect a clinically suspected focal infection, the presence of a clinically occult focal infection, and complications of sepsis and septic shock.

Complete blood cell count with differential

The white blood cell (WBC) count and the WBC differential can be somewhat helpful in predicting bacterial infection, though an elevated WBC count is not specific to infection. In the setting of fever without localizing signs of infection, a WBC count higher than 15,000/µL or a neutrophil band count higher than 1500/µL has about a 50% correlation with bacterial infection. WBC counts higher than 50,000/µL or lower than 300/µL are associated with significantly decreased survival rates.

Hemoglobin concentration dictates oxygen-carrying capacity in blood, which is crucial in shock to maintain adequate tissue perfusion. Although there is no specific hematocrit or hemoglobin target, keeping the hemoglobin concentration above 7 g/dL is usually practiced, and studies comparing this versus 9 g/dL have shown no increased survival benefit from either arm.

Platelets, as acute-phase reactants, usually increase at the onset of any serious stress and are typically elevated in the setting of inflammation. However, the platelet count will fall with persistent sepsis, and disseminated intravascular coagulation (DIC) may develop.

Coagulation studies

Coagulation status should be assessed by measuring the prothrombin time (PT) and the activated partial thromboplastin time (aPTT). Patients with clinical evidence of a coagulopathy require additional tests to detect the presence of DIC. The PT and the aPTT are elevated in DIC, fibrinogen levels are decreased, and fibrin split products are increased.

Blood chemistries

At regular intervals, metabolic assessment should be carried out by measuring serum levels of electrolytes, including magnesium, calcium, phosphate, and glucose. Sodium and chloride levels are abnormal in severe dehydration. Decreased bicarbonate can point to acute acidosis—however, sodium bicarbonate therapy is not recommended to improve hemodynamics or replace vasopressor requirements in patients with metabolic acidemia from hypoperfusion whose pH level is 7.15 or greater.^{[11, 60]}

Glucose control is important in the management of sepsis: Hyperglycemia is associated with higher mortality.

Serum lactate is perhaps the best serum marker for tissue perfusion, in that it is elevated under conditions of anaerobic metabolism, which occurs when tissue oxygen demand exceeds supply. This can result from decreased arterial oxygen content (hypoxemia), decreased perfusion pressure (hypotension), maldistribution of flow, and decreased diffusion of oxygen across capillary membranes to target tissues, as well as decreased oxygen utilization on a cellular level.

There is also evidence that lactate can be elevated in sepsis in the absence of tissue hypoxia, as a consequence of mitochondrial dysfunction and downregulation of pyruvate dehydrogenase, which is the first step in oxidative phosphorylation.^[61]

Lactate levels higher than 2.5 mmol/L are associated with an increase in mortality. The higher the serum lactate, the worse the degree of shock and the higher the mortality. Lactate levels higher than 4 mmol/L in patients with suspected infection have been shown to yield a 5-fold increase in the risk of death and are associated with a mortality approaching 30%.^[62]It has been hypothesized that lactate clearance is a measure of tissue reperfusion and an indication of adequate therapy.^{[63, 64]}

Renal and hepatic function should be assessed with the following chemistry studies:

Serum creatinine level
Blood urea nitrogen (BUN) level
Bilirubin level
Alkaline phosphatase (ALP) level
Alanine aminotransferase (ALT) level
Aspartate aminotransferase (AST) level
Albumin level

Liver function tests (LFTs) and levels of bilirubin, ALP, and lipase are important in evaluating multiorgan dysfunction or a potential causative source (eg, biliary disease, pancreatitis, or hepatitis). Increased BUN and creatinine levels can point to severe dehydration or renal failure.

In severely ill patients suspected of having adrenal insufficiency, a delta cortisol level below 9 µg/dL (after administration of 250 µg of cosyntropin) or a random total cortisol level below 10 µg/dL is diagnostic.^[65]It should be kept in mind that the adrenocorticotropic hormone (ACTH) stimulation test is not recommended for identifying the subset of patients with septic shock or acute respiratory distress syndrome (ARDS) who should receive corticosteroid therapy.^[65]

The American College of Critical Care Medicine (ACCCM) does not recommend the routine use of free cortisol measurements in critically ill patients.^[65]There are no clear parameters for the normal range of free cortisol in such patients, and the free cortisol assay is not widely available, despite its advantages over the total serum cortisol assay.^[65]

Blood cultures

Blood cultures should be obtained in patients with suspected sepsis (or blood infection) to facilitate isolation of a specific organism and tailoring of antibiotic therapy. These cultures are the primary means of diagnosing intravascular infections (eg, endocarditis) and infections of indwelling intravascular devices. Individuals at high risk for endocarditis are intravenous (IV) drug abusers and patients with prosthetic heart valves.

Patients at risk for bacteremia include adults who are febrile with an elevated WBC or neutrophil band count, elderly patients who are febrile, and neutropenic patients who are febrile. These populations have a 20-30% incidence of bacteremia. The incidence of bacteremia increases to at least 50% in patients with sepsis and evidence of end-organ dysfunction.

The Surviving Sepsis Campaign recommends obtaining at least 2 blood cultures before antibiotics are administered, with 1 percutaneously drawn and the other(s) obtained through each vascular access (unless the device was inserted < 48 hours beforehand).^{[11, 60]}Again, however, it must be remembered that blood cultures are positive in fewer than 50% of cases of sepsis.^{[3, 4, 5]}

To optimize recovery of aerobic bacteria from patients with suspected intra-abdominal infection, 1-10 mL of fluid can be directly inoculated into an aerobic blood culture; an additional 0.5 mL of fluid should be sent for Gram staining and, if indicated, fungal cultures.^[2]For anaerobic bacteria, 1-10 mL of fluid can also be directly inoculated into an anaerobic blood culture bottle.

Susceptibility testing for organisms that have a high risk for resistance (eg, Pseudomonas, Proteus, Acinetobacter, Staphylococcus aureus, and predominant [moderate to heavy growth] Enterobacteriaceae) should be performed.^[2]Unfortunately, in patients with community-acquired intra-abdominal infection, blood cultures are not of much clinical utility; Gram staining of the infected material also is not generally useful in such cases.

Urinalysis and urine culture

Urinalysis and urine culture are indicated for every patient who is in a septic state. Urinary tract infection (UTI) is a common source for sepsis, especially in elderly individuals. Adults who are febrile without localizing symptoms or signs have a 10-15% incidence of occult UTI. Obtaining a culture is important for isolating a specified organism and tailoring antibiotic therapy.

Gram stain and culture of secretions and tissue

The Gram stain is the only immediately available test that can document the presence of bacterial infection and guide the choice of initial antibiotic therapy. Secretions or tissue for Gram stain and culture from the sites of potential infection (eg, cerebrospinal fluid [CSF], wounds, respiratory secretions, or other body fluids) may be are obtained as they are identified, preferably before administering antibiotic therapy.^{[11, 60]}

At least 1 mL of fluid or tissue is needed for cultures.^[2]For aerobic or anaerobic cultures, 0.5 mL of fluid or 0.5 g of tissue should be transported to the laboratory in the appropriate aerobic or anaerobic transport medium.^[2]

If pneumonia is suspected, a sputum specimen should be obtained for Gram stain and culture, provided that the patient has a productive cough and that a good-quality specimen can be obtained.^[66]Any abscess should be drained promptly and purulent material sent to the microbiology laboratory for analysis. If meningitis is suspected, a CSF specimen should be obtained.

Routine culture and susceptibility studies should be obtained in the following cases^[2]:

Perforated appendicitis and other community-acquired intra-abdominal infections in which there is significant resistance of a common community isolate to an antimicrobial regimen in widespread use locally
Higher-risk patients who have a greater risk of harboring resistant pathogens, such as those with previous antibiotic exposure

Although Gram staining may be helpful for identifying healthcare-related infections (eg, presence of yeast), it has not proved to be of clinical value in community-acquired intra-abdominal infections.^[2]Anaerobic cultures are not necessary for community-acquired intra-abdominal infections if empiric antimicrobial therapy against common anaerobic pathogens is administered.

Chest

Because most patients who present with sepsis have pneumonia, and because the clinical examination is unreliable for the detection of pneumonia (especially in elderly patients), a chest radiograph is warranted. Chest radiography detects infiltrates in about 5% of febrile adults without localizing signs of infection; accordingly, it should be routine in adults who are febrile without localizing symptoms or signs and in patients who are febrile with neutropenia and without pulmonary symptoms.

Chest radiography is useful in detecting radiographic evidence of ARDS (see the images below), which carries a high mortality. The discovery of such evidence on a chest radiograph should prompt consideration of early intubation and mechanical ventilation, even if the patient has not yet shown signs of overt respiratory distress.

Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.

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Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.

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A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed acute respiratory distress syndrome (ARDS) and multiorgan failure.

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In early ARDS, the chest radiograph may appear normal. The typical findings of noncardiogenic pulmonary edema are bilateral hazy, symmetric homogeneous opacities, which may demonstrate air bronchograms. The margins of pulmonary vessels become indistinct and obscured with disease progression.

The usual findings of metastatic pulmonary edema, such as Kerley A or B lines, are not usually observed; a perihilar distribution of opacities is also absent. Furthermore, other findings of cardiogenic pulmonary edema, such as cardiomegaly, vascular redistribution, and pleural effusions, are absent as well.

With disease progression, the ground-glass opacities change into heterogeneous linear or reticular infiltrates. Days to weeks later, either persistent chronic fibrosis may develop or the chest radiograph appearance becomes more normal. Periodic chest radiographs during the management of ARDS are particularly important for diagnosing barotrauma, confirming adequate positioning of an endotracheal tube or intravascular catheters, and detecting nosocomial pneumonia.

Abdomen

Supine and upright or lateral decubitus abdominal radiographs should be obtained; these may be useful when an intra-abdominal source of sepsis is suspected. Abdominal plain films should be obtained if clinical evidence of bowel obstruction or perforation exists. However, if obvious signs of diffuse peritonitis are present and immediate surgical intervention is planned, further diagnostic imaging is not required.^[2]

In adult patients with suspected intra-abdominal infection who are not undergoing immediate laparotomy, computed tomography (CT) of the abdomen is preferable to abdominal radiography.^[2]

Extremities

Plain radiographs of the extremities may be helpful when deep soft-tissue infection is suspected. These films can show evidence of soft-tissue gas formation; however, it is important to emphasize that necrotizing fasciitis is a clinical diagnosis (signaled, for example, by extreme pain, crepitus, bullae, hemorrhage, and foul-smelling exudates).

If clinical suspicion of necrotizing fasciitis is high, a surgical consultation should be obtained immediately, and the patient should be taken promptly to the operating room for intervention, often without the need for any imaging. CT and magnetic resonance imaging (MRI) cannot be relied on to make this diagnosis.

Plain radiographs can also show evidence of osteomyelitis. However, MRI is much more sensitive for making this diagnosis.

Ultrasonography

Abdominal ultrasonography is indicated when patients have evidence of acute cholecystitis or ascending cholangitis exists^[2](eg, right upper quadrant abdominal tenderness, fever, vomiting, elevated LFT results, elevated bilirubin level, or elevated alkaline phosphatase level). Surgery or endoscopic retrograde cholangiopancreatography (ERCP) may be urgently necessary in the setting of sepsis with acute cholecystitis or ascending cholangitis.

Echocardiography has a number of uses in assessing patients with septic shock and may be considered.^[67]This imaging modality can provide a comprehensive cardiac evaluation in patients with hemodynamic instability and can be helpful for guiding fluid therapy and monitoring treatment effects. Other conditions that can be assessed include sepsis-induced myocardial dysfunction, right heart failure, dynamic left ventricular obstruction, and tamponade.^[67]

CT and MRI

CT is the imaging modality of choice for excluding an intra-abdominal abscess or a retroperitoneal source of infection. Obesity or the presence of excessive intestinal gas markedly interferes with abdominal imaging by ultrasonography; therefore, CT is preferred in this setting.

Obtain an abdominal CT scan if the patient has abdominal or flank tenderness in the setting of sepsis. Certain abdominal processes (eg, diverticular abscess, ischemic bowel, appendicitis, perinephric abscess) may necessitate urgent operative intervention.

When clinical evidence of a deep soft tissue infection exists, such as crepitus, bullae, hemorrhage, or foul-smelling exudate, obtain a plain radiograph. The presence of soft-tissue gas often dictates surgical exploration.

Although either CT or MRI may reveal evidence of subcutaneous and deep-tissue inflammation, neither modality is sensitive or specific in the setting of necrotizing deep-tissue infection, and neither should be relied upon to make this diagnosis. MRI is much more sensitive for osteomyelitis than plain radiography is.

If there is evidence of increased intracranial pressure (eg, papilledema) or focal mass lesions (focal defects, preceding sinusitis or otitis, or recent intracranial surgery), antibiotic therapy should be initiated, and a head CT scan should be obtained. Antibiotics will not begin to affect CSF cultures for at least several hours; therefore, proper antibiotic administration should not be delayed by the procedure if there is a high suspicion for meningitis.

If bacterial meningitis is strongly suspected, a lumbar puncture should be performed promptly, without any delay to obtain a CT scan.

Lumbar Puncture

A lumbar puncture (spinal fluid test) is indicated when there is clinical evidence or suspicion of meningitis or encephalitis. If the opening pressure is elevated, only as much CSF as is needed for culture should be obtained. Broad-spectrum antibiotics to cover meningitis should be administered before the start of the procedure. In patients with an acute fulminant presentation, rapid onset of septic shock, and severely impaired mental status, this procedure is used to rule out bacterial meningitis.

Treatment & Management

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Media Gallery

Strawberry tongue in a child with staphylococcal toxic shock syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.
A 26-year-old woman developed rapidly progressive shock associated with purpura and signs of meningitis. Her blood culture results confirmed the presence of Neisseria meningitidis. The skin manifestation seen in this image is characteristic of severe meningococcal infection and is called purpura fulminans.
Gram stain of blood showing the presence of Neisseria meningitidis.
Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This photomicrograph shows early stage (exudative stage) DAD.
Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This is a high-powered photomicrograph of early stage (exudative stage) DAD.
Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has occurred; hyaline membranes as well as collagen and fibroblasts are present.
Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue, which may develop into fibrotic stage of DAD.
Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.
Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.
A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed acute respiratory distress syndrome (ARDS) and multiorgan failure.
An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare causes of septic shock.
A 28-year-old woman who was a former intravenous drug user (human immunodeficiency virus [HIV] status: negative) developed septic shock secondary to bilateral pneumococcal pneumonia.
Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.
Soft-tissue infection secondary to group A streptococci, leading to toxic shock syndrome.
Necrotizing cellulitis of toxic shock syndrome.
Necrosis of the little toe of the right foot and cellulitis of the foot secondary to group A streptococcal infection.
Group A streptococci cause beta hemolysis on blood agar.
Gram stain of blood showing group A streptococci that was isolated from a patient who developed toxic shock syndrome. Image courtesy of T. Matthews.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The leg was incised to exclude underlying necrotizing infection. Image courtesy of Rob Green, MD.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). This patient also had streptococcal pharyngitis. Image courtesy of Rob Green, MD.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. Image courtesy of Rob Green, MD.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. He improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over his palms and soles. Image courtesy of Rob Green, MD.
Progression of soft-tissue swelling to vesicle or bullous formation is an ominous sign and suggests streptococcal shock syndrome. Image courtesy of S. Manocha.
Extensive debridement of necrotizing fasciitis of the hand.
Healing of the hand after aggressive surgical debridement of necrotizing fasciitis (same patient as in previous image).
A 58-year-old patient presented in septic shock. On physical examination, progressive swelling of the right groin was observed. On exploration, necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). Computed tomography (CT) scanning helped to evaluate the extent of the infection and to exclude other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema.
Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema (same lesion as shown in previous computed tomography image).

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Table 1. Sepsis-Related SOFA Score (adapted from Singer et al)

System

0 Points

1 Point

2 Points

3 Points

4 Points

Respiration

PaO₂^a/FiO₂^b

≥400 mm Hg

< 400 mm Hg

< 300 mm Hg

< 200 mm Hg

(with respiratory support)

< 100 mm Hg

(with respiratory support)

Coagulation

Platelet count

≥150 x 10³/µL

< 150 x 10³/µL

< 100 x 10³/µL

< 50 x 10³/µL

< 20 x 10³/µL

Liver

Bilirubin level

< 1.2 mg/dL

1.2-1.9 mg/dL

2-5.9 mg/dL

6-11.9 mg/dL

>12 mg/dL

Cardiovascular

MAP^c ≥70 mm Hg

MAP >70 mm Hg

Dopamine < 5 or

dobutamine (any dose)^e

Dopamine 5.1-15 or

epinephrine ≤0.1 or

norepinephrine ≤0.1^e

Dopamine >15 or

epinephrine >0.1 or

norepinephrine >0.1^e

Central nervous system

GCS^d score

13-14

10-12

6-9

< 6

Renal

Creatinine

Urine output

< 1.2 mg/dL

1.2-1.9 mg/dL

2-3.4 mg/dL

3.5-4.9 mg/dL

< 500 mL/day

>5 mg/dL

< 200 mL/day

^aPaO₂=Partial pressure of oxygen.

^bFiO₂=Fraction of inspired oxygen.

^cMAP=Mean arterial pressure.

^dGCS=Glasgow Coma Scale (range, 3-15, with higher indicating better function).

^eCatecholamine doses administered as µg/kg/min for ≥1 hour.

Table 2. Surviving Sepsis Guidelines Criteria for Organ Dysfunction

Organ System	Sepsis Criteria	Severe Sepsis Criteria
Pulmonary	Arterial hypoxemia: PaO₂/FIO₂< 300	Arterial hypoxemia: PaO₂/FIO₂< 250 in absence of pneumonia and < 200 in presence of pneumonia
Hepatic	Hyperbilirubinemia: Plasma total bilirubin >4 mg/dL or 70 µmol/L	Hyperbilirubinemia: Plasma total bilirubin >2 mg/dL or 34.2 µmol/L
Renal	Creatinine increase >0.5 mg/dL or 44.2 µmol/L Acute oliguria: Urine output < 0.5 mL/kg/hr for ≥2 hr despite adequate fluid resuscitation	Creatinine >2 mg/dL or 176.8 µmol/L Acute oliguria: Urine output < 0.5mL/kg/hr for ≥2 hr despite adequate fluid resuscitation
Gastrointestinal	Ileus: Absent bowel sounds
Hematologic	INR >1.5, aPTT >60 s, or platelets < 100,000/µL	INR >1.5 or platelets < 100,000/µL
Cardiovascular	Hyperlactatemia >1 mmol/L; decreased capillary refill or mottling Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg	Hyperlactatemia: Above upper limits of laboratory normal Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg
Central nervous system	Confusion, lethargy, coma

aPTT = activated partial thromboplastin time; FIO₂ = fraction of inspired oxygen; INR = international normalized ratio; MAP = mean arterial pressure; PaO₂ = partial pressure of oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time; SBP = systolic blood pressure. Source: Dellinger RP, Levy MM, Rhodes A, et al, for the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.^[11]

Table 3. Mediators of Sepsis

Type	Mediator	Activity
Cellular mediators	LPS	Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators
	Lipoteichoic acid
	Peptidoglycan
	Superantigens
	Endotoxin
Humoral mediators	Cytokines	Activate inflammatory pathways
	TNF-α and IL-1β	Potent proinflammatory effect
	IL-6	Acts as pyrogen, stimulates B- and T-cell proliferation
	IL-8	Neutrophil chemotactic factor, activation and degranulation of neutrophils
	IL-10	Inhibits cytokine production, induces immunosuppression
	MIF	Activates macrophages and T cells
	G-CSF	Promotes neutrophil and macrophage, platelet activation
	Complement	Promotes neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects
	Nitric oxide	Involved in hemodynamic alterations of septic shock; cytotoxic, augments vascular permeability, contributes to shock
	Lipid mediators	Enhance vascular permeability and contribute to lung injury
	Phospholipase A2
	PAF
	Eicosanoids
	Arachidonic acid metabolites	Augment vascular permeability
	Adhesion molecules	Enhance neutrophil-endothelial cell interaction, regulate leukocyte migration and adhesion, and play a role in pathogenesis of sepsis; increased levels of VAP-1 activity and anchor protein SDC-1 content have been found in critically ill patients with septic shock^[12]
	Selectins
	Leukocyte integrins
	High mobility box–1	Late mediator of endotoxin-induced lethality and tissue repair
G-CSF = granulocyte colony-stimulating factor; IL = interleukin; LPS = lipopolysaccharide; MIF = macrophage inhibitory factor; PAF = platelet-activating factor; SDC-1 = syndecan-1; TNF = tumor necrosis factor; VAP-1 = vascular adhesion protein–1. Source: Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan;37(1):291-304.^[13]

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Author

Andre Kalil, MD, MPH Professor of Medicine, Department of Medicine, Section of Infectious Diseases, University of Nebraska College of Medicine; Director, Transplant ID Program, University of Nebraska Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Kristina L Bailey, MD Assistant Professor, Department of Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center

Kristina L Bailey, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Research Society on Alcoholism

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science 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, Dr(HC), FCCP, FAPS, MCCM is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American Thoracic Society, European Society of Intensive Care Medicine, Society of Critical Care Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Baxter Medical, Exostat, LiDCO<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights from iNTELOMED.

Acknowledgements

Fatima Al Faresi, MD Dermatologist, Tawam Hospital, Al Ain, UAE