Danish S. Malik1, Gabriela Bambrick‐Santoyo2, Karen McKenna3, Rachael Schneider3, and Richard Lee4
1 St Luke’s Cornwall Hospital, Newburgh, NY, USA
2 Mountainside Medical Center, Montclair, NJ, USA
3 Mount Sinai Morningside‐West, New York, NY, USA
4 Icahn School of Medicine at Mount Sinai, New York, NY, USA
In 2016 a new consensus definition of sepsis was published by the Society of Critical Care Medicine. However, the acceptance of these criteria and their impact are not yet established. There is ongoing debate regarding the specific definition and disease classifications of sepsis.
Sepsis is an inflammatory host response to infection that can lead to life‐threatening organ dysfunction.
Major international organizations differ in their definition and classification system of sepsis (Table 43.1).
In the USA there are approximately 970 000 sepsis cases per year.
The incidence rose almost 9% annually during the past two decades.
Sepsis mortality overall is greater than 50% and increases linearly with severity of disease, ranging from 10% to 80%.
Accounts for 40% of ICU expenditures.
Average length of stay is 75% higher than most other conditions, increasing with disease severity.
Cost per hospitalization also increases with disease severity, from $16 000 to $38 000 in the USA.
USA annual cost was $24 billion in 2013, 13% of total hospital costs, but accounting for only 3.6% of hospital admissions.
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference, 2001
Sepsis: clinical syndrome defined by both the presence of infection and more than one of the systemic inflammatory response syndrome (SIRS) criteria:
Temperature >38°C or <36°C
Heart rate >90 bpm
Respiratory rate >20 breaths/min or a PaCO2 of <32 mmHg
WBC >12 000 or <4000 mg/dL
Severe sepsis: sepsis complicated with end‐organ dysfunction. (See also Table 1 in the original paper for a list of non‐specific physical, hemodynamic, and laboratory variables consistent with sepsis)
Septic shock: state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes
Hypotension: systolic arterial pressure below 90 mmHg, a MAP <60, or a reduction in SBP of >40 mmHg from baseline, despite adequate volume resuscitation, in the absence of other causes for hypotension
Surviving Sepsis Campaign (used by the National Quality Forum (NQF) and Centers for Medicare and Medicaid Services (CMS))
Sepsis: suspected infection in the setting of two or more of the SIRS criteria:
Temperature >38.3°C or <36°C
Heart rate >90 bpm
Respiratory rate >20 breaths/min or a PaCO2 of <32 mmHg
WBC >12 000 or <4000 mg/dL; >10% bands
Severe sepsis: defined as sepsis with markers of end‐organ dysfunction, or lactic acidosis above upper limit laboratory normal (usually >2 mmol/L)
Septic shock: a lactic acidosis >4 at any time, or fluid‐resistant hypotension
SCCM/ESICM Task Force, 2016
Consensus definition published in 2016, not yet endorsed by all medical societies and has not yet been incorporated into sepsis treatment protocols SIRS has been removed as part of the definition, and terminology such as severe sepsis, sepsis syndrome, and septicemia have been eliminated
Sepsis: life‐threatening organ dysfunction caused by a dysregulated host response to infection. Outside the ICU, patients with suspected or presumed infection who are highly likely to have poor outcomes can be clinically identified using the quick sequential organ failure assessment (qSOFA) score (SBP <100 mmHg, respiratory rate >22 breaths/min, altered mental status) In the ICU, patients with suspected or presumed infection who are highly likely to have poor outcomes can be clinically identified by the presence of 2 or more SOFA points or a change in SOFA score by 2 or more points from baseline
Septic shock: subset of sepsis in which profound circulatory, metabolic, and cellular abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP ≥65 mmHg and having a serum lactate >2 mmol/L after adequate fluid resuscitation
Sepsis can occur as a result of both community‐acquired and healthcare–associated infection of any source and type (fungal, bacterial, viral).
Pneumonia is the most common cause, accounting for about half of all cases, followed by intra‐abdominal and urinary tract infections.
Blood cultures are typically positive in only one‐third of cases.
The pathogenic mechanisms underlying sepsis and septic shock are complex.
Microorganisms at the port of infection enter the bloodstream. In response, a large number of host pro‐ and anti‐inflammatory mediators are released from cells (endothelial cells, monocyte macrophages, neutrophils) and plasma proteins (coagulation, fibrinolytic, and complement systems). These host‐released mediators have major physiologic effects on multiple organ systems.
The balance between the pro‐ and anti‐inflammatory response will determine the degree of organ damage or infection proliferation.
The direction, extent, and duration of these reactions are determined by both host (genetic characteristics, age, coexisting illnesses, medications) and pathogen (microbial load and virulence) factors.
Septic shock can cause dysregulation in the cardiovascular, respiratory, renal, metabolic, hematologic, hepatic, and nervous systems.
Severe sepsis is frequently associated with altered coagulation in some cases leading to disseminated intravascular coagulation (DIC).
Age >65 years.
Chronic lung disease.
Tremulousness, hypertension, tongue fasciculation, restlessness, seizures, history of alcohol abuse
High grade fevers, rigors, cough, tachycardia, variable presentation from well appearing to toxic
Vomiting and diarrhea, nausea, abdominal discomfort without focal pain or tenderness, afebrile or low grade temperature, otherwise well appearing
Focal warmth, induration, fluctuance, crepitations, pain out of proportion to exam findings
Duration and progression of symptoms.
Known sick contacts.
Recent antibiotic use.
History of infections.
Recent hospitalizations or surgeries.
Change in urine output.
Evidence of immunosuppression.
Chronic disease states.
Assess the presence of any of the SIRS criteria (see Table 43.1).
One in eight cases of sepsis have been found to be SIRS negative.
Hypotension (MAP <65) or capillary refill >2 seconds may be markers of poor end‐organ perfusion, although absence of these findings does not exclude it.
Examine any foreign bodies (indwelling catheters, implanted medical devices) for warmth, induration, tenderness, or purulent drainage.
Focus the physical exam based on the kind of infection(s) suspected (Table 43.2) such as pneumonia, urinary tract infection (UTI), cellulitis, central nervous system or intra‐abdominal infection, or infection of foreign bodies.
Useful clinical decision rules and calculators
In the 2016 SCCM/ESICM sepsis definition (see Table 43.1) the sequential organ failure assessment (SOFA) score is used to identify patients at higher risk of dying from sepsis. The applicability of this definition will require future prospective validation.
The SOFA score is an illness severity score which is mainly used to predict the mortality of critically ill patients. It is helpful in assessing the severity of end‐organ damage in sepsis, using clinical parameters to predict mortality risk.
In the ICU, patients with suspected infection who are likely to have poor outcomes can be identified by the presence of 2 or more SOFA points or a change in SOFA score by 2 or more points from baseline (Table 43.3).
Outside the ICU, these patients can be identified using the qSOFA score (any two of three elements: SBP <100 mmHg, RR >22 breaths/min, altered mental status).
Dopamine >5a or epinephrine ≤ 0.1a or norepinephrine 0.1a
Dopamine >5a or epinephrine ≤ 0.1a or norepinephrine 0.1a
Hematologic: platelet count (1×103)
Neurologic: GCS score
a Adrenergic agents administered for more than 1 hour (doses in μg/kg/min).
Disease severity classification
According to the 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference, sepsis is classified as the presence of SIRS criteria with a source of infection.
Severe sepsis is classified as evidence of end‐organ dysfunction in the setting of infection (see next section for parameters of end‐organ dysfunction).
Septic shock is classified as sepsis‐induced hypotension that is refractory to appropriate fluid bolus.
List of diagnostic tests
All patients suspected of sepsis should receive: CBC, basic metabolic panel, at least two sets of blood cultures, CXR, and serum lactate.
Cultures should be drawn prior to initiation of antibiotics unless it would lead to a significant (>45 minutes) delay to antibiotic administration.
Coagulation testing (PTT, PT/INR) and hepatic function tests may be necessary if severe sepsis or septic shock is suspected.
CXR if the lungs are a suspected source of infection.
Patients may have a leukocytosis, leukopenia, or bandemia. They may also demonstrate signs of end‐organ damage such as hypoxemia, acute oliguria, elevated creatinine (>2 mg/dL) or bilirubin (>2 mg/dL), thrombocytopenia (platelets <100 000/μL), or coagulopathy (INR >1.7 or PTT >60sec).
Urinalysis and urine cultures should be sent if there is strong suspicion for urinary infection.
Lumbar puncture, thoracentesis, paracentesis, and wound culture may be indicated depending on clinical scenario and suspected source of sepsis.
List of imaging techniques
CXR for patients with signs or symptoms of respiratory dysfunction.
Advanced imaging may be warranted depending on the suspected source: e.g. CT scan for intra‐abdominal, intracranial, or deep tissue infections; MRI for suspected spinal epidural abscess.
Bedside point‐of‐care ultrasound to assess volume status and fluid responsiveness.
Potential pitfalls/common errors made regarding diagnosis of sepsis
Failure to consider sepsis, thereby delaying identification and treatment.
Failure to obtain serum lactate to identify ‘occult’ sepsis or stratify severity of sepsis.
Failure in obtaining cultures of blood, urine, or other potential sources of sepsis prior to initiating antibiotic therapy.
Being falsely reassured by patient’s clinical appearance, vital signs, or low serum lactate.
Ruling out a source of infection based on poorly sensitive physical exam findings, e.g. normal lung exam, minimal abdominal tenderness, well‐appearing patient.
Cornerstones of treatment include fluid resuscitation, controlling the source of infection, administration of antimicrobials, and supporting vital signs and end‐organ function.
Time to antimicrobials is a critical determinant of survival in severe sepsis/septic shock.
If sepsis is strongly suspected, empiric broad spectrum antibiotics should be started without waiting for confirmation by imaging or lab analysis. If the patient is found to be in severe sepsis or septic shock, antibiotics should be administered ideally within 1 hour of sepsis presentation.
If the patient is in good health at baseline, well appearing, with a reassuring serum lactate and a confirmed source of infection, a more targeted antimicrobial regimen may be considered.
Remove any indwelling catheters or medical devices if suspected to be a source of infection.
Emergent subspecialty consultation is crucial when solid‐organ infection is suspected (appendicitis, cholecystitis, endometritis, abscesses).
Fluid bolus of 30 mL/kg.
Goal is a mean arterial pressure >65 mmHg.
In the setting of lactic acidosis, trend serum lactate until it reaches normal limits.
Supportive care measures
Fluid administration as mentioned earlier Start vasopressors if patient deemed poor candidate for further fluid boluses Initial vasopressor of choice: norepinephrine 0.1–3 μg/kg/min, titrate to goal MAP Second choice: add epinephrine as second agent, dobutamine (in the setting of myocardial dysfunction), phenylephrine (in hyperdynamic shock), or vasopressin (0.02–0.04 U/min) Consider corticosteroids (hydrocortisone 100 mg IV) if hypotension is refractory to fluids and vasopressors
Identify cause (fever versus hypovolemia) Often the first clinical sign of hypovolemia Fluid administration as mentioned earlier
Passive rewarming (warm blankets, external temperature device, warm saline boluses)
May be marker of hypovolemia or end‐organ dysfunction Target urine output is >0.5 mL/kg/h In oliguric or anuric patients, consider placement of urinary catheter for closer monitoring of urine output
Administer regular insulin if blood sugar >200 mg/dL Goal blood sugar is 140–180 mg/dL
Maintain hemoglobin >7 g/dL in most patients Maintain hemoglobin >8–9 g/dL if showing signs of ongoing cardiac ischemia
Managing the hospitalized patient
The level of care will depend on the severity of sepsis, the response to antibiotics, and the initial treatment given. Patients requiring vasopressors and with hemodynamic instability should be admitted to the ICU until hemodynamically stable.
The initial choice of antibiotics should take into consideration the risk for multidrug‐resistant organisms. Risk factors for such organisms include antimicrobial therapy over the past 90 days, current hospitalization of 5 days or more, high frequency of antibiotic resistance in the community or hospital, and level of immunosuppression.
Once cultures are resulted, antibiotics should be adjusted based on speciation and sensitivities. The length of treatment depends on the infected site/source, organism, and clinical response.
Prevention/management of complications
Remove indwelling urinary and central venous catheters as soon as they are not needed to prevent catheter‐related infections.
De‐escalate broad spectrum antibiotics as soon as possible in order to help prevent antibiotic resistance as well as Clostridium difficile infections secondary to antibiotic use.