Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion and acute failure of multiple organs, including the lungs, kidneys, and liver, can occur. Common causes in immunocompetent patients include many different species of gram-positive and gram-negative bacteria. Patients who are immunocompromised may have uncommon bacterial or fungal species as a cause. Signs include fever, hypotension, oliguria, and confusion. Diagnosis is primarily clinical combined with culture results showing infection; early recognition and treatment are critical. Treatment is aggressive fluid resuscitation, antibiotics, surgical excision of infected or necrotic tissue and drainage of pus, and supportive care.
(See also Shock and Intravenous Fluid Resuscitation.)
Sepsis represents a spectrum of disease with mortality risk ranging from moderate (eg, 10%) to substantial (eg, > 40%) (1), depending on various pathogen and host factors along with the timeliness of recognition and provision of appropriate treatment.
Septic shock is a subset of sepsis with significantly increased mortality due to severe abnormalities of circulation and/or cellular metabolism. Septic shock involves persistent hypotension (defined as the need for vasopressors to maintain mean arterial pressure ≥ 65 mm Hg, and a serum lactate level > 18 mg/dL [2 mmol/L] despite adequate volume resuscitation [2]).
The concept of the systemic inflammatory response syndrome (SIRS), defined by certain abnormalities of vital signs and laboratory results, has long been used to identify early sepsis (2). However, SIRS criteria have been found to lack sensitivity and specificity for increased mortality risk, which is the main consideration for using such a conceptual model. The lack of specificity may be because the SIRS response is often adaptive rather than pathologic.
General references
1. Rangel-Frausto MS, Pittet D, Costigan M, et al: The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273(2):117–123, 1995.
2. Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810, 2016. doi:10.1001/jama.2016.0287
Etiology of Sepsis and Septic Shock
Most cases of septic shock are caused by hospital-acquired gram-negative bacilli or gram-positive cocci and often occur in patients who are immunocompromised and in patients with chronic and debilitating diseases (1). Rarely, it is caused by Candida or other fungi. A postoperative infection should be suspected as the cause of septic shock in patients who have recently had surgery. A unique, uncommon form of shock caused by staphylococcal and streptococcal toxins is called toxic shock syndrome.
Septic shock occurs more often in neonates (see Neonatal Sepsis), older adults, and pregnant people. Predisposing factors include
Leukopenia (especially that associated with cancer or treatment with cytotoxic medications)
Invasive devices (including endotracheal tubes, vascular or urinary catheters, drainage tubes, and other foreign materials)
Prior treatment with antibiotics or corticosteroids
Recent hospitalization (especially in an intensive care unit)
Common causative sites of infection include the lungs and the urinary, biliary, and gastrointestinal tracts.
Etiology reference
1. Rudd KE, Johnson SC, Agesa KM, et al: Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395(10219):200–211, 2020. doi:10.1016/S0140-6736(19)32989-7
Pathophysiology of Sepsis and Septic Shock
The pathogenesis of septic shock is not completely understood. An inflammatory stimulus (eg, a bacterial toxin) triggers production of pro-inflammatory mediators, including tumor necrosis factor (TNF) and interleukin (IL)-1. These cytokines cause neutrophil–endothelial cell adhesion, activate the clotting mechanism, and generate microthrombi. They also release numerous other mediators, including leukotrienes, lipoxygenase, histamine, bradykinin, serotonin, and IL-2. They are opposed by anti-inflammatory mediators, such as IL-4 and IL-10, resulting in a negative feedback mechanism.
Initially, arteries and arterioles dilate, decreasing peripheral arterial resistance; cardiac output typically increases. This stage has been referred to as warm shock. Later, cardiac output may decrease, blood pressure falls (with or without an increase in peripheral resistance), and typical features of hypoperfusion appear.
Even in the stage of increased cardiac output, vasoactive mediators cause blood flow to bypass capillary exchange vessels (a distributive defect). Poor capillary flow resulting from this shunting, along with capillary obstruction by microthrombi, decreases delivery of oxygen and impairs removal of carbon dioxide and waste products. Decreased perfusion causes dysfunction and sometimes failure of ≥ 1 organs, including the kidneys, lungs, liver, brain, and heart.
Coagulopathy may develop because of intravascular coagulation with consumption of major clotting factors, excessive fibrinolysis in reaction thereto, and more often a combination of both.
Symptoms and Signs of Sepsis and Septic Shock
With sepsis (without septic shock), patients typically have fever, tachycardia, diaphoresis, and tachypnea; blood pressure remains normal. Other signs of the causative infection may be present.
Symptoms and signs of sepsis can be subtle and often easily mistaken for manifestations of other disorders (eg, primary cardiac dysfunction, pulmonary embolism, delirium, or infectious gastroenteritis). It can be particularly difficult to recognize clinical manifestations of sepsis in patients with immunosupression or in postoperative patients.
As sepsis worsens or septic shock develops, an early sign, particularly in older adults or the very young, may be confusion or decreased alertness. Blood pressure decreases, yet the skin is paradoxically warm. Later, extremities become cool and pale, with peripheral cyanosis and mottling. Organ dysfunction causes additional symptoms and signs specific to the organ involved (eg, oliguria, dyspnea).
Diagnosis of Sepsis and Septic Shock
History and physical examination
Blood pressure (BP), heart rate, and oxygen monitoring
Complete blood count (CBC) with differential, electrolyte panel, creatinine, and lactate
Invasive central venous pressure (CVP), partial pressure of arterial oxygen (PaO2), and central venous oxygen saturation (ScvO2) readings
Cultures of blood, urine, and other potential sites of infection, including wounds in surgical patients
Sepsis is suspected when a patient with a known infection develops systemic signs of inflammation or organ dysfunction (1). Similarly, a patient with otherwise unexplained signs of systemic inflammation should be evaluated for infection by history, physical examination, and imaging or laboratory testing. Tests include urinalysis and urine culture (particularly in patients who have indwelling catheters), blood cultures, and cultures of other suspect body fluids. Blood levels of C-reactive protein and procalcitonin are often elevated in severe sepsis and may facilitate diagnosis, but they are not specific. In patients with a suspected surgical or occult cause of sepsis, ultrasonography (eg, Rapid Ultrasound for Shock and Hypotension (RUSH) Examination), CT, or MRI may be required, depending on the suspected source. Ultimately, the diagnosis is clinical.
Other causes of shock (eg, hypovolemia, myocardial infarction [MI]) should be ruled out via history, physical examination, ECG, and serum cardiac biomarker measurement as clinically indicated. Even in the absence of MI, hypoperfusion caused by sepsis may result in ECG findings of cardiac ischemia including nonspecific ST-T wave abnormalities, T-wave inversions, and supraventricular and ventricular arrhythmias.
It is important to detect organ dysfunction as early as possible. A number of scoring systems have been devised for early detection of sepsis, but the sequential organ failure assessment score (SOFA score) and the quick SOFA score (qSOFA) have been validated with respect to mortality risk and are relatively simple to use. The qSOFA score is based on the blood pressure, respiratory rate, and the Glasgow Coma Scale and does not require waiting for lab results.
For patients with a suspected infection who are not in the intensive care unit (ICU), the qSOFA score is a better predictor of inpatient mortality than the SIRS criteria and SOFA score. For patients with a suspected infection who are in the ICU, the SOFA score is a better predictor of in-patient mortality than the SIRS criteria and qSOFA score (2).
Patients with ≥ 2 of the following criteria meet criteria for SIRS and should have further clinical investigation:
Temperature > 38° C (100.4° F) or < 36° C (96.8° F)
Heart rate > 90 beats per minute
Respiratory rate > 20 breaths per minute or partial pressure of arterial carbon dioxide (PaCO2) < 32 mm Hg
White blood cell (WBC) count > 12,000/mcL (12 × 109/L), < 4,000/mcL (4 × 109/L), or > 10% immature (band) forms
Patients with ≥ 2 of the following qSOFA criteria should have further clinical and laboratory investigation:
Respiratory rate ≥ 22 breaths per minute
Altered mentation
Systolic blood pressure ≤ 100 mm Hg
The SOFA score is somewhat more robust when patients are treated in the ICU, but this score requires laboratory testing (see table Sequential Organ Failure Assessment Score). There are other scoring systems in clinical use (3).
Sequential Organ Failure Assessment (SOFA) Score
Parameter | Score: 0 | Score: 1 | Score: 2 | Score: 3 | Score: 4 |
|---|---|---|---|---|---|
PaO2/FIO2 | ≥ 400 mm Hg (53.3 kPa) | < 400 mm Hg (53.3 kPa) | < 300 mm Hg (40 kPa) | < 200 mm Hg (26.7 kPa) with respiratory support | < 100 mm Hg (13.3 kPa) with respiratory support |
Platelets | ≥ 150 × 103/mcL (≥ 150 × 109/L) | < 150 × 103/mcL (< 150 × 109/L) | < 100 × 103/mcL (< 100 × 109/L) | < 50 × 103/mcL (< 50 × 109/L) | < 20 × 103/mcL (< 20 × 109/L) |
Bilirubin | < 1.2 mg/dL (20 micromole/L) | 1.2–1.9 mg/dL (20–32 micromole/L) | 2.0–5.9 mg/dL (33–101 micromole/L) | 6.0–11.9 mg/dL (102–204 micromole/L) | > 12.0 mg/dL (204 micromole/L) |
Cardiovascular (with medication doses given for ≥ 1 hour) | MAP ≥ 70 mm Hg | MAP < 70 mm Hg | < 5 mcg/kg/minute or | or ≤ 0.1 mcg/kg/minute or ≤ 0.1 mcg/kg/minute | > 15 mcg/kg/minute or > 0.1 mcg/kg/minute or > 0.1 mcg/kg/minute |
Glasgow Coma Scale score* | 15 points | 13–14 points | 10–12 points | 6–9 points | < 6 points |
Creatinine | < 1.2 mg/dL (110 micromole/L) | 1.2-1.9 mg/dL (110–170 micromole/L) | 2.0-3.4 mg/dL (171–299 micromole/L) | 3.5-4.9 mg/dL (300–400 micromole/L) | > 5.0 mg/dL (440 micromole/L) |
Urine output | — | — | — | < 500 mL/day | < 200 mL/day |
* A higher score indicates better neurologic function. | |||||
FIO2 = fraction of inspired oxygen; kPa = kilopascals; MAP = mean arterial pressure; PaO2 = arterial oxygen partial pressure. | |||||
Adapted from Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810, 2016. doi:10.1001/jama.2016.0287 | |||||
CBC, arterial blood gases (ABGs), chest x-ray, serum electrolytes, BUN (blood urea nitrogen), creatinine, partial pressure of carbon dioxide (PCO2), and liver function are monitored. Serum lactate levels, ScvO2, or both can be determined to help guide treatment. WBC count may be decreased (< 4,000/mcL [< 4 × 109/L]) or increased (> 15,000/mcL [> 15 × 109/L]), and polymorphonuclear leukocytes may be as low as 20%. During the course of sepsis, the WBC count may fluctuate, depending on the severity of sepsis or shock, the patient's immunologic status, and the etiology of the infection. Concurrent corticosteroid use may elevate WBC count and thus mask WBC changes due to trends in the illness.
Hyperventilation with respiratory alkalosis (low PaCO2 and increased arterial pH) occurs early, in part as compensation for lactic acidemia. Serum bicarbonate is usually low, and serum and blood lactate levels increase. As shock progresses, metabolic acidosis worsens, and blood pH decreases. Early hypoxemic respiratory failure leads to a decreased PaO2/fraction of inspired oxygen (FIO2) ratio and sometimes overt hypoxemia with PaO2 < 70 mm Hg. Diffuse infiltrates may appear on the chest x-ray due to acute respiratory distress syndrome (ARDS). BUN and creatinine usually increase progressively as a result of renal insufficiency. Bilirubin and transaminases may rise, although overt hepatic failure is uncommon in patients with normal baseline liver function.
Hemodynamic measurements with a central venous or pulmonary artery catheter can be used when the specific type of shock is unclear or when large fluid volumes (eg, > 4 to 5 L balanced crystalloid within 6 to 8 hours) are needed.
Bedside echocardiography in the ICU is a practical and noninvasive alternative method of hemodynamic monitoring. In septic shock, cardiac output is increased and peripheral vascular resistance is decreased, whereas in other forms of shock, cardiac output is typically decreased and peripheral resistance is increased.
Neither CVP nor pulmonary artery occlusive pressure (PAOP) is likely to be abnormal in septic shock, unlike in hypovolemic, obstructive, or cardiogenic shock.
Many patients with severe sepsis develop relative adrenal insufficiency (ie, normal or slightly elevated baseline cortisol levels that do not increase significantly in response to further stress or exogenous adrenocorticotropic hormone [ACTH]). Adrenal function may be tested by measuring serum cortisol at 8 AM; a level < 5 mcg/dL (< 138 nmol/L) is inadequate. Alternatively, cortisol can be measured before and after injection of 250 mcg of synthetic ACTH; a rise of < 9 mcg/dL (< 248 nmol/L) is considered insufficient.
Diagnosis references
1. Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810, 2016. doi:10.1001/jama.2016.0287
2. Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of clinical criteria for sepsis: For the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 215(8):762–774, 2016. doi: 10.1001/jama.2016.0288
3. Covino M, Sandroni C, Della Polla D, et al: Predicting ICU admission and death in the Emergency Department: A comparison of six early warning scores. Resuscitation 190:109876, 2023. doi:10.1016/j.resuscitation.2023.109876
Treatment of Sepsis and Septic Shock
Perfusion restored with IV fluids and sometimes vasopressors
Oxygen support
Broad-spectrum antibiotics
Source control
Patients with septic shock should be treated in an ICU. The following should be monitored frequently (as often as hourly):
Volume status using CVP, PAOP, serial ultrasonography, and/or ScvO2
ABGs
Blood glucose, lactate, and electrolyte levels
Renal function
Arterial oxygen saturation should be measured continuously via pulse oximetry. Urine output, a good indicator of renal perfusion, should be measured (in general, indwelling urinary catheters should be avoided unless they are essential). The onset of oliguria (eg, < approximately 0.5 mL/kg/hour) or anuria, or rising creatinine may signal impending renal failure.
Following evidence-based guidelines and formal protocols for timely diagnosis and treatment of sepsis has been shown to decrease mortality and length of stay in the hospital (1, 2).
Perfusion restoration
Initially, 1 L of crystalloid is given rapidly. Most patients require a minimum of 30 mL/kg in the first 4 to 6 hours. However, the goal of therapy is not to administer a specific volume of fluid but to achieve tissue reperfusion without causing pulmonary edema due to fluid overload.
Estimates of successful reperfusion include ScvO2 and lactate clearance (ie, percent change in serum lactate levels over 6 to 8 hours). Target ScvO2 is ≥ 70%. Lactate clearance target is 10 to 20%.
Risk of pulmonary edema can be controlled by optimizing preload; fluids should be given until CVP reaches 8 mm Hg (10 cm water) or PAOP reaches 12 to 15 mm Hg; however, patients on mechanical ventilation may require higher CVP levels. The quantity of fluid required often far exceeds the normal blood volume and may reach 10 L over 4 to 12 hours. PAOP or echocardiography can identify limitations in left ventricular function and incipient pulmonary edema due to fluid overload. Point-of-care ultrasonography can also be used to assess volume status, including inferior vena cava (IVC) distention or collapsibility, cardiac function, and presence of pulmonary edema.
Oxygen support
Oxygen is given by mask, nasal prongs, or noninvasive positive pressure ventilation. Tracheal intubation and mechanical ventilation may be needed subsequently for respiratory failure (see Mechanical ventilation in ARDS).
Antibiotics
Parenteral antibiotics should be given as soon as possible after specimens of blood, body fluids, and wound sites have been taken for Gram stain and culture. Prompt empiric therapy, started immediately after sepsis is suspected, is essential and may be lifesaving. Antibiotic selection requires an educated guess based on the suspected source (eg, pneumonia, urinary tract infection), clinical setting, knowledge or suspicion of causative organisms and of sensitivity patterns common to that specific inpatient unit or institution, and previous culture results.
Pearls & Pitfalls
|
Source control
The source of infection should be controlled as early as possible. IV and urinary catheters and endotracheal tubes should be removed if possible or changed. Abscesses must be drained, and necrotic and devitalized tissues (eg, gangrenous gallbladder, necrotizing soft-tissue infection) must be surgically excised. If excision is not possible (eg, because of comorbidities or hemodynamic instability), surgical drainage may help. If the source is not controlled, the patient’s condition will continue to deteriorate despite antibiotic therapy.
Other supportive measures
< 400 mg IV per day in divided doses) is indicated for patients with adrenal insufficiency documented by cortisol testing. However, in refractory septic shock (systolic blood pressure < 90 mm Hg for more than 1 hour following both adequate fluid resuscitation and vasopressor administration, attainment of source control, and antibiotics), no cortisol testing is required before starting corticosteroid therapy (4). Continued treatment is based on patient response.
Treatment references
1. Bhattacharjee P, Edelson DP, Churpek MM: Identifying patients with sepsis on the hospital wards. Chest 151:898–907, 2017. doi: 10.1016/j.chest.2016.06.02T
2. Evans L, Rhodes A, Alhazzani W, et al: Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med 49(11):e1063–e1143, 2021. doi:10.1097/CCM.0000000000005337
3. Zarychanski R, Abou-Setta AM, Turgeon AF, et al: Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis [published correction appears in JAMA 309(12):1229, 2013]. JAMA 309(7):678–688, 2013. doi:10.1001/jama.2013.430
4. Annane D, Pastores SM, Rochwerg B, et al: Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med 43(12):1751-1763, 2017. doi: 10.1007/s00134-017-4919-5
Prognosis for Sepsis and Septic Shock
Overall mortality in patients with septic shock is decreasing and is about 20% (with a wide range, depending on patient characteristics) (1). Poor outcomes often follow failure to institute early aggressive therapy (eg, within 6 hours of suspected diagnosis). Once severe lactic acidosis with decompensated metabolic acidosis becomes established, especially in conjunction with multiorgan failure, septic shock is likely to be irreversible and fatal. Mortality can be estimated with different scores, including the mortality in emergency department sepsis (MEDS) score. The multiple organ dysfunction score (MODS) measures dysfunction of 6 organ systems and correlates strongly with risk of mortality.
Prognosis reference
1. Rudd KE, Johnson SC, Agesa KM, et al: Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395(10219):200–211, 2020. doi:10.1016/S0140-6736(19)32989-7
Key Points
Sepsis and septic shock are increasingly severe clinical syndromes of life-threatening organ dysfunction caused by a dysregulated response to infection.
An important component is critical reduction in tissue perfusion, which can lead to acute failure of multiple organs, including the lungs, kidneys, and liver.
Early recognition and treatment are key to improved survival.
Resuscitate with intravenous fluids and sometimes vasopressors titrated to optimize central venous oxygen saturation and preload, and to lower serum lactate levels.
Control the source of infection by removing catheters, tubes, and infected and/or necrotic tissue and by draining abscesses.
Give empiric broad-spectrum antibiotics directed at most likely organisms and switch quickly to more specific medications based on culture and sensitivity results.
