History
Sepsis or septic shock is systemic inflammatory response syndrome (SIRS) secondary to a documented infection (see Shock Classification, Terminology, and Staging). Detrimental host responses to infection occupy a continuum that ranges from sepsis to septic shock and multiple organ dysfunction syndrome (MODS). The specific clinical features depend on where the patient falls on that continuum. Symptoms of sepsis are often nonspecific and include the following:
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Fever (usually >101°F [38°C]), chills, and rigors
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Confusion
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Anxiety
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Difficulty breathing
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Fatigue and malaise
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Nausea and vomiting
These symptoms are not pathognomonic for sepsis syndromes and may be present in a wide variety of other conditions. Alternatively, typical symptoms of systemic inflammation may be absent in sepsis, especially in elderly individuals. In sepsis, symptoms may include decreased urine output and cyanosis (blueish discoloration of the lips and/or digits).
Fever is a common symptom, though it may be absent in elderly or immunosuppressed patients. The hypothalamus resets in sepsis, so that heat production and heat loss are balanced in favor of a higher temperature. An inquiry should be made about fever onset (abrupt or gradual), duration, and maximal temperature. These features have been associated with increased infectious burden and severity of illness. However, fever alone is an insensitive indicator of sepsis; in fact, hypothermia is more predictive of illness severity and death.
Chills are a secondary symptom associated with fever, developing as a consequence of increased muscular activity that produces heat and raises the body temperature. Sweating occurs when the hypothalamus returns to its normal set point and senses the higher body temperature, stimulating perspiration to evaporate excess body heat.
Mental function is often altered. Mild disorientation or confusion is especially common in elderly individuals. Apprehension, anxiety, agitation, and, eventually, coma are manifestations of sepsis. The exact cause of metabolic encephalopathy is not known; altered amino acid metabolism may play a role.
Hyperventilation with respiratory alkalosis is a common feature of patients with sepsis. This feature results from stimulation of the medullary respiratory center by endotoxins and other inflammatory mediators.
Localizing symptoms referable to organ systems may provide useful clues to the etiology of sepsis. Such symptoms include the following:
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Head and neck infections – Severe headache, neck stiffness, altered mental status, earache, sore throat, sinus pain or tenderness, and cervical or submandibular lymphadenopathy
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Chest and pulmonary infections – Cough (especially if productive), pleuritic chest pain, dyspnea, dullness on percussion, bronchial breath sounds, localized rales, or any evidence of consolidation
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Cardiac infections – Any new murmur, especially in patients with a history of injection or intravenous (IV) drug use
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Abdominal and gastrointestinal (GI) infections – Diarrhea, abdominal pain, abdominal distention, guarding or rebound tenderness, and rectal tenderness or swelling
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Pelvic and genitourinary (GU) infections – Pelvic or flank pain, adnexal tenderness or masses, vaginal or urethral discharge, dysuria, frequency, and urgency
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Bone and soft-tissue infections – Localized limb pain or tenderness, focal erythema, edema, and swollen joint, crepitus in necrotizing infections, and joint effusions
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Skin infections – Petechiae, purpura, erythema, ulceration, bullous formation, and fluctuance
Physical Examination
The hallmarks of sepsis and septic shock are changes that occur at the microvascular and cellular level with diffuse activation of inflammatory and coagulation cascades, vasodilation and vascular maldistribution, capillary endothelial leakage, and dysfunctional utilization of oxygen and nutrients at the cellular level. The challenge for clinicians is to recognize that this process is under way when it may not be clearly manifested in the vital signs or clinical examination.
The physical examination should first involve assessment of the patient’s general condition, including an assessment of airway, breathing, and circulation (ie, the ABCs), as well as mental status. An acutely ill, flushed, and toxic appearance is observed universally in patients with serious infections.
Examine vital signs, and observe for signs of hypoperfusion. Carefully examine the patient for evidence of localized infection. Ensure that the patient’s body temperature is measured accurately. Rectal temperatures should be obtained, as oral and tympanic temperatures are not always reliable. Fever may be absent, but patients generally have tachypnea and tachycardia.
Pay attention to the patient’s skin color and temperature. Pallor or grayish or mottled skin are signs of poor tissue perfusion seen in septic shock. In the early stages of sepsis, cardiac output is well maintained or even increased. The vasodilation may result in warm skin, warm extremities, and normal capillary refill (warm shock). As sepsis progresses, stroke volume and cardiac output fall. The patients begin to manifest the signs of poor perfusion, including cool skin, cool extremities, and delayed capillary refill (cold shock). In sepsis, symptoms may include decreased urine output and cyanosis (blueish discoloration of the lips and/or digits).
Petechiae or purpura (see the image below) can be associated with disseminated intravascular coagulation (DIC). These findings are an ominous sign.
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.
Tachycardia is a common feature of sepsis and indicative of a systemic response to stress; it is the physiologic mechanism by which cardiac output, and thus oxygen delivery to tissues, is increased. Tachycardia indicates hypovolemia and the need for intravascular fluid repletion; however, an increased heart rate often persists in sepsis despite adequate fluid repletion. Narrow pulse pressure and tachycardia are considered the earliest signs of shock. Tachycardia may also be a result of fever itself.
Tachypnea is a common and often underappreciated feature of sepsis. It is an indicator of pulmonary dysfunction and is commonly found in pneumonia and acute respiratory distress syndrome (ARDS), both of which are associated with increased mortality in sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators is a possible cause. As tissue hypoperfusion ensues, the respiratory rate also rises to compensate for metabolic acidosis. The patient often feels short of breath or appears mildly anxious.
Altered mental status is another common feature of sepsis. It is considered a sign of organ dysfunction and is associated with increased mortality. Mild disorientation or confusion is especially common in elderly individuals. Other manifestations include apprehension, anxiety, and agitation. Profound cases may involve obtundation or comatose states. The cause of these mental status abnormalities is not entirely understood, but in addition to cerebral hypoperfusion, altered amino acid metabolism has been proposed as a causative factor.
In septic shock, it is important to identify any potential source of infection. This is particularly important in cases where a site of infection can be removed or drained, as in certain intra-abdominal infections, soft-tissue abscesses and fasciitis, or perirectal abscesses. The following physical signs help localize the source of an infection:
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Central nervous system (CNS) infection – Profound depression in mental status and signs of meningismus (neck stiffness)
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Head and neck infections – Inflamed or swollen tympanic membranes, sinus tenderness, nasal congestion or exudate, pharyngeal erythema and exudates, inspiratory stridor, and cervical lymphadenopathy
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Chest and pulmonary infections – Dullness on percussion, bronchial breath sounds, localized rales, or any evidence of consolidation
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Cardiac infections – Any new murmur, especially in patients with a history of injection or IV drug use
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Abdominal and GI infections – Abdominal distention, localized tenderness, guarding or rebound tenderness, and rectal tenderness or swelling
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Pelvic and GU infections – Costovertebral angle tenderness, pelvic tenderness, pain on cervical motion, adnexal tenderness or masses, and cervical discharge
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Bone and soft-tissue infections – Focal erythema, edema, tenderness, crepitus in necrotizing infections, fluctuance, pain with joint range of motion, and joint effusions and associated warmth or erythema
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Skin infections – Petechiae, purpura, erythema, ulceration, bullous formation, and fluctuance
Complications
End-organ failure is a major contributor to mortality in sepsis and septic shock. The complications with the greatest adverse effect on survival are ARDS, DIC, and acute kidney injury (AKI; previously termed acute renal failure [ARF]).
Acute respiratory distress syndrome
Acute lung injury (ALI)—mild ARDS, by the Berlin Definition [10] —leading to moderate or severe ARDS is a major complication of sepsis and septic shock. The incidence of ARDS is approximately 18% in patients with septic shock, and mortality approaches 50%. ARDS also leads to prolonged intensive care unit (ICU) stays and an increased incidence of ventilator-associated pneumonia.
ARDS secondary to sepsis demonstrates the manifestations of underlying sepsis and the associated multiple organ dysfunction. Pulmonary manifestations include acute respiratory distress and acute respiratory failure resulting from severe hypoxemia caused by intrapulmonary shunting. Fever and leukocytosis may be present secondary to the lung inflammation.
The severity of ARDS may range from mild lung injury to severe respiratory failure. The onset of ARDS usually is within 12-48 hours of the inciting event. The patients demonstrate severe dyspnea at rest, tachypnea, and hypoxemia; anxiety and agitation are also present.
The frequency of ARDS in sepsis has been reported to range from 18% to 38% (with gram-negative sepsis, 18-25%). Sepsis and multiorgan failure are the most common cause of death in ARDS patients. Approximately 16% of patients with ARDS die of irreversible respiratory failure. Most patients who show improvement achieve maximal recovery by 6 months, with lung function improving to 80-90% of predicted values.
Acute kidney injury
Sepsis is the most common cause of AKI (ARF), which affects 40-70% of all critically ill patients, depending on how AKI is defined (eg, according to the RIFLE [risk, injury, failure, loss, and end stage] or AKIN [Acute Kidney Injury Network] classifications]). [43] AKI complicates therapy and worsens the overall outcome. [53] There is an increased risk of mortality when urosepsis is present with sepsis and septic shock [54] ; however, the global prognosis for patients with urosepsis is better than that for those with sepsis from other infectious sites.
Other complications in septic shock
Other complications include the following:
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DIC (also occurring in 40% of patients with septic shock)
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Chronic renal dysfunction
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Myocardial ischemia and dysfunction
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Liver failure
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Other complications related to prolonged hypotension and organ dysfunction
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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.
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Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.
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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.
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Gram stain of blood showing the presence of Neisseria meningitidis.
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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.
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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.
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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.
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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.
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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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An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare causes of septic shock.
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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.
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Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.
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Soft-tissue infection secondary to group A streptococci, leading to toxic shock syndrome.
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Necrotizing cellulitis of toxic shock syndrome.
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Necrosis of the little toe of the right foot and cellulitis of the foot secondary to group A streptococcal infection.
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Group A streptococci cause beta hemolysis on blood agar.
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Gram stain of blood showing group A streptococci that was isolated from a patient who developed toxic shock syndrome. Image courtesy of T. Matthews.
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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.
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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.
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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.
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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.
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Progression of soft-tissue swelling to vesicle or bullous formation is an ominous sign and suggests streptococcal shock syndrome. Image courtesy of S. Manocha.
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Extensive debridement of necrotizing fasciitis of the hand.
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Healing of the hand after aggressive surgical debridement of necrotizing fasciitis (same patient as in previous image).
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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).
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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).
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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).
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Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema.
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Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema (same lesion as shown in previous computed tomography image).
Tables
System |
0 Points |
1 Point |
2 Points |
3 Points |
4 Points |
Respiration PaO2a/FiO2b |
≥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 |
MAPc ≥70 mm Hg |
MAP >70 mm Hg |
Dopamine < 5 or dobutamine (any dose)e |
Dopamine 5.1-15 or epinephrine ≤0.1 or norepinephrine ≤0.1e |
Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1e |
Central nervous system GCSd score |
15 |
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. |
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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 |
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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 |
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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] |
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Type |
Mediator |
Activity |
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Cellular mediators |
LPS |
Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators |
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Lipoteichoic acid |
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Peptidoglycan |
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Superantigens |
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Endotoxin |
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Humoral mediators |
Cytokines |
Activate inflammatory pathways |
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Potent proinflammatory effect |
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Acts as pyrogen, stimulates B- and T-cell proliferation |
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Neutrophil chemotactic factor, activation and degranulation of neutrophils |
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Inhibits cytokine production, induces immunosuppression |
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Activates macrophages and T cells |
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Promotes neutrophil and macrophage, platelet activation |
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Complement |
Promotes neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects |
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Nitric oxide |
Involved in hemodynamic alterations of septic shock; cytotoxic, augments vascular permeability, contributes to shock |
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Lipid mediators |
Enhance vascular permeability and contribute to lung injury |
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Arachidonic acid metabolites |
Augment vascular permeability |
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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] |
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Late mediator of endotoxin-induced lethality and tissue repair |
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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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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- General Treatment Guidelines in Septic Shock
- Goals of Hemodynamic Support
- Fluid Resuscitation
- Vasopressor Therapy
- Inotropic Therapy and Augmented Oxygen Delivery
- Empiric Antimicrobial Therapy
- Corticosteroid Therapy
- Glycemic Control
- DVT Prophylaxis and Management of DIC
- Management of Acute Respiratory Distress Syndrome
- Surgical Treatment
- Prevention
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- Questions & Answers
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