Sepsis and Septic Shock

DEFINITION, ETIOLOGY, PATHOGENESISTop

The most widely used definition for the sepsis spectrum was based on the 2001 International Sepsis Definitions Conference criteria. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) were published. Comparison of 2001 and 2016 definitions and concepts: Table 1.

2001 International Sepsis Definitions Conference Criteria

Systemic inflammatory response syndrome (SIRS) refers to an acute onset of ≥2 of the following symptoms:

1) Temperature >38.3 degrees Celsius or <36 degrees Celsius.

2) Heart rate >90 beats/min (this may be absent in patients treated with beta-blockers).

3) Respiratory rate >20 breaths/min or partial pressure of carbon dioxide in arterial blood (PaCO2) <32 mm Hg.

4) White blood cell (WBC) count >12×109/L or <4×109/L, or >10% of immature neutrophils in the differential WBC count.

Infection is an inflammatory response to microorganisms in tissues, body fluids, or cavities that are sterile under normal conditions.

Microbiologically documented infection refers to isolation of a pathogen from the normally sterile body fluid or tissue (or, alternatively, detection of its antigens or genetic material).

Clinically suspected infection refers to the presence of clinical features strongly suggestive of infection, for instance, leukocytes found in the normally sterile body fluid (other than blood), visceral perforation, radiographic features of pneumonia accompanied by purulent respiratory secretions, or an infected wound.

Sepsis is defined as a systemic inflammatory response caused by infection.

Severe sepsis is sepsis causing failure or severe malfunction of ≥1 organ or system (other causes must be excluded; diagnostic criteria are relative), including:

1) Cardiovascular system: Hypotension (systolic blood pressure [SBP] <90 mm Hg, mean arterial pressure [MAP] <70 mm Hg, or an SBP drop >40 mm Hg).

2) Respiratory system: PaO2/FiO2 <300 mm Hg (<200 mm Hg in patients with primary diseases of the respiratory tract).

3) Kidneys: Urine output <0.5 mL/kg/h over >2 hours with adequate fluid intake/resuscitation or a serum creatinine level increase by >0.5 mg/dL (44.2 micromol/L).

4) Metabolism: Elevated serum lactate levels.

5) Hemostasis: Platelet count <100×109/L or international normalized ratio (INR) >1.5.

6) Liver: Serum bilirubin levels >34.2 micromol/L (2 mg/dL).

7) Central nervous system (CNS): Features of encephalopathy (anxiety, confusion, agitation, delirium, coma).

Septic shock is severe sepsis with persistent hypotension refractory to fluid resuscitation, requiring administration of vasopressors.

Multiple organ dysfunction syndrome (MODS) refers to severe functional organ disturbances in an acutely ill patient, which are indicative of the failure to maintain homeostasis without therapeutic intervention.

Bacteremia is the presence of live bacteria in the bloodstream. Viremia is the presence of a replication-competent virus in the bloodstream. Fungemia is the presence of live fungi in the bloodstream (candidemia: presence of live Candida spp in the bloodstream).

Sepsis-3 Definition and Diagnostic Criteria

Quick sequential organ failure assessment (qSOFA) includes prognostic criteria that predict poor outcomes. It should not be used to screen patients for sepsis (as it may lead to substantial underdiagnosis) but it may prompt clinicians to monitor and assess the patient for the possibility of sepsis. A positive qSOFA score implies ≥2 of the following 3 criteria are met: altered mental status, SBP ≤100 mm Hg, and respiratory rate ≥22/min.

Sepsis is now defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.

Clinical diagnostic criteria for sepsis: A suspected or documented infection and ≥2 points increase from the baseline on the sequential (sepsis-related) organ failure assessment (SOFA) score.

The SOFA score (available at mdcalc.com) assesses dysfunction of different organs by measuring the degree of hypoxia and hypotension, platelet count, bilirubin level, urine output and creatinine level, and neurologic function (Glasgow Coma Scale [GCS]). One point is granted after meeting each of the following thresholds:

1) MAP <70 mm Hg (1 point) and then additional points for use of low (2 points), medium (3 points), or high doses of vasopressors (4 points).

2) A ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <400 mm Hg (1 point), then an additional point for each of <300 mm Hg, 200 mm Hg, and 100 mm Hg.

3) A GCS score of 13 to 14 (1 point), then an additional point for each score in the range of 10 to 12; 6 to 9; and <6 points.

4) Platelet counts <150×109/L (1 point), then an additional point for each of <100×109/L, <50×109/L, and <20×109/L.

5) Bilirubin >20 micromol/L (1.2 mg/dL) (1 point), then an additional point for each of >32 micromol/L (1.9 mg/dL), >101 micromol/L (5.9 mg/dL), and >204 micromol/L (12 mg/dL).

6) Creatinine levels >110 micromol/L (1.2 mg/dL) (1 point), then additional points for each of 171 micromol/L (2.0 mg/dL), 300 micromol/L (3.5 mg/dL), and >440 micromol/L (5.0 mg/dL). Urine output <200 mL/d carries 4 points and <500 mL/d, 3 points.

Septic shock is now defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality. Clinical diagnostic criteria for septic shock include the presence of sepsis, vasopressor therapy needed to elevate MAP ≥65 mm Hg, and a lactate level >2 mmol/L (18 mg/dL) despite adequate fluid resuscitation.

Etiology

The etiology of sepsis does not always determine its clinical course. Pathogens may be undetectable in the bloodstream or other tissues. In most patients there is no history of immunodeficiency (although it is an important risk factor for sepsis).

Infection and inflammation that eventually lead to the development of sepsis initially affect various sites, such as the abdominal organs (eg, peritonitis, acute pancreatitis), urinary system (eg, pyelonephritis), respiratory system (eg, pneumonia, empyema), CNS (eg, meningitis, encephalitis), musculoskeletal system (eg, septic arthritis, osteomyelitis), and skin and subcutaneous tissue (eg, injury-related and surgical wounds, pressure ulcers). Location of the primary infection site is frequently occult (eg, periodontal sites, sinuses, tonsils, endocardium, gallbladder and biliary tract, reproductive system including gestational sac infections).

Iatrogenic risk factors include intravascular catheters, urinary catheters, implantable prostheses and devices, endotracheal tube, parenteral nutrition, surgical wounds, and drug-induced immunodeficiency.

Pathophysiology

Sepsis is a pathologic response to infection involving several factors such as pathogen antigens, endotoxins, as well as proinflammatory and anti-inflammatory mediators produced by the host (cytokines, chemokines, eicosanoids, and other mediators causing SIRS) and substances causing cell damage (eg, free radicals).

Septic shock (hypotension and tissue hypoperfusion) is a consequence of inflammatory mediators, which cause relative hypovolemia (inadequate intravascular volume resulting from vasodilation and reduced systemic vascular resistance), absolute hypovolemia (increased vascular permeability), or less commonly myocardial dysfunction (in septic shock the stroke volume is usually increased as long as the intravascular volume is maintained). Hypotension and hypoperfusion lead to decreased tissue oxygen delivery and hypoxia. Ultimately, this results in increased cellular anaerobic metabolism and lactic acidosis. Other manifestations of septic shock may include acute respiratory distress syndrome (ARDS); acute kidney injury (initially in the form of prerenal acute kidney injury); altered mental status resulting from CNS hypoperfusion and the effects of inflammatory mediators; gastrointestinal system disturbances, including ileus or gut ischemia, that predispose to intestinal mucosal disruption, which causes bleeding (acute hemorrhagic gastropathy and stress ulcers, ischemic colitis) or bacterial translocation from the intestinal lumen to the bloodstream; acute hepatic insufficiency or failure; relative adrenal insufficiency; and disturbances of hemostasis (disseminated intravascular coagulation; usually beginning with thrombocytopenia).

CLINICAL FEATURES AND NATURAL HISTORYTop

Clinical manifestations of SIRS and severe sepsis: see Definition, Etiology, Pathogenesis, above and Table 2. Additional signs and symptoms depend on the involvement of particular organs and systems. If the spread of infection and/or the host response to infection is not attenuated at an early stage, functional impairment of other organs and systems will follow (see Definition, Etiology, Pathogenesis, above). If adequate treatment is not started, the symptoms of septic shock can progress to MODS and death.

DIAGNOSISTop

Diagnostic Tests

1. Laboratory tests: Assessment of organ dysfunction including arterial and venous blood gases, serum lactate level (when possible, it should be measured even within the first hour of the onset of symptoms of [severe] sepsis), coagulation tests, kidney and liver function tests, and inflammatory markers (complete blood count [CBC], C-reactive protein [CRP], or procalcitonin [PCT]). Negative PCT or similar markers may support the decision to shorten the course of empiric antimicrobial therapy in patients with suspected sepsis.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity of data and indirectness to specific clinical situations. Kopterides P, Siempos II, Tsangaris I, Tsantes A, Armaganidis A. Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med. 2010 Nov;38(11):2229-41. doi: 10.1097/CCM.0b013e3181f17bf9. Review. PMID: 20729729. Jensen JU, Hein L, Lundgren B, et al; Procalcitonin And Survival Study (PASS) Group. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011 Sep;39(9):2048-58. doi: 10.1097/CCM.0b013e31821e8791. PMID: 21572328. Heyland DK, Johnson AP, Reynolds SC, Muscedere J. Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Crit Care Med. 2011 Jul;39(7):1792-9. doi: 10.1097/CCM.0b013e31821201a5. Review. PMID: 21358400. Oliveira CF, Botoni FA, Oliveira CR, et al. Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial. Crit Care Med. 2013 Oct;41(10):2336-43. doi: 10.1097/CCM.0b013e31828e969f. PubMed PMID: 23921272. Some of those tests (eg, CRP, PCT, or interleukin 6 [IL-6]) may not be routinely available.

2. Microbiology:

1) Blood: ≥2 samples including ≥1 from a noncatheterized vessel (separate venipuncture) and 1 from each vascular catheter (especially if inserted prior to the development of sepsis).

2) Other samples: Depending on the suspected etiology, the samples should be obtained from the respiratory tract, urine, other body fluids (cerebrospinal fluid, pleural effusion), or wound discharge.

3. Imaging studies (as suggested by symptoms, signs, and laboratory tests): Radiography (particularly chest radiographs), ultrasonography, and computed tomography (CT) (particularly of the abdomen).

TREATMENTTop

Antimicrobial and other supportive treatment should be started urgently and simultaneously. Prognosis is determined primarily by the prompt administration of antibiotics and IV fluids.

Some practice guidelines (Surviving Sepsis Campaign) proposed that during the first hour after clinical recognition of sepsis several aspects of diagnosis and management are performed: obtaining blood cultures, measurement of the lactate level, delivery of antibiotics, beginning of fluid resuscitation, and application of vasopressors if needed to maintain SBP >65 mm Hg. The ability to achieve all this in clinical practice could be challenging in many clinical settings.

Treatment of Infection

1. Antimicrobial treatment: Start empiric antimicrobial therapy as soon as possible in patients with possible septic shock, ideally within 1 hour of presentation (each hour of delay may increase mortality by 8%, especially in septic shock).Evidence 2Strong recommendations (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered to low due to observational nature of data and increased to moderate due to size of effect. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010 Apr;38(4):1045-53. doi: 10.1097/CCM.0b013e3181cc4824. PMID: 20048677. Kumar A, Haery C, Paladugu B, et al. The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels. J Infect Dis. 2006 Jan 15;193(2):251-8. Epub 2005 Dec 13. PMID: 16362889. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014 Aug;42(8):1749-55. doi: 10.1097/CCM.0000000000000330. PMID: 24717459. In patients with possible sepsis without shock, it is important to collect appropriate samples for microbiologic testing before treatment and to rapidly assess the likelihood of infectious versus noninfectious causes of acute illness, but only if this does not delay treatment by more than a short period of time (see Diagnosis, Etiology, Pathogenesis, above). In sepsis administer at least one IV broad-spectrum antibiotic or a specific agent if the causative agent is known; consider the coverage of the most likely etiologic organisms (bacteria, fungi) and the penetration of the antibiotic to the sites of infection, as well as local pathogen resistance patterns. Treatment may be modified, usually within days, depending on available microbiology results and the clinical course. Targeted treatment should be implemented as soon as possible. Monotherapy is preferred; combination therapy may be used, for instance, in the case of suspected or confirmed Pseudomonas (patterns of use differ) or Acinetobacter infection. In septic shock with bacteremia caused by Streptococcus pneumoniae, combine a beta-lactam with a macrolide. The duration of treatment is usually 7 to 10 days (it may be longer in the case of delayed clinical response to treatment, if local infection sites cannot be adequately drained or eradicated, if patients are immunodeficient, or if the infections are due to particularly virulent pathogens). Antimicrobial treatment in patients with neutropenia: see Febrile Neutropenia.

2. Source control should include infected tissues or organs (eg, gallbladder, necrotic segment of bowel), infected catheters, implantable prostheses and devices. Drainage of any abscesses, empyema, and other infected collections in closed spaces is also of key importance, as long as the likely benefits and risks of procedures are considered. The preferred treatment should generally be kept as noninvasive as maintaining efficacy allows (eg, percutaneous drainage rather than open abdominal washout). In the case of infected pancreatic necrosis, a stepwise approach rather than complete removal of infected tissue is suggested.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision/small number of patients. van Santvoort HC, Besselink MG, Bakker OJ, et al; Dutch Pancreatitis Study Group. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010 Apr 22;362(16):1491-502. doi: 10.1056/NEJMoa0908821. PMID: 20410514.

Supportive Treatment

1. Initial treatment of shock should be started as soon as possible (prior to the intensive care unit admission). A prompt recognition and initiation of treatment by clinicians experienced in resuscitation with frequent reassessment are likely at least as important as following any specific algorithm or obtaining specific values. While early goal-directed therapy (EGDT), an algorithmic-based approach to resuscitation, was previously recommended, it has since been demonstrated to be no better than the current usual care and results in greater resource use.Evidence 4Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). PRISM Investigators; Rowan KM, Angus DC, Bailey M, et al. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. N Engl J Med. 2017 Jun 8;376(23):2223-2234. doi: 10.1056/NEJMoa1701380. Epub 2017 Mar 21. PMID: 28320242. Instead, a rapid, individualized approach to resuscitation should be undertaken, recognizing that sepsis is a life-threatening emergency. Of note, this approach utilizes lessons gained from using EGDT and examining the influence of its individual components:

1) Administration of 30 mL/kg of IV crystalloid within the first 3 hours of resuscitation.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and risk of bias. Kuttab HI, Lykins JD, Hughes MD, et al. Evaluation and Predictors of Fluid Resuscitation in Patients With Severe Sepsis and Septic Shock. Crit Care Med. 2019 Nov;47(11):1582-1590. doi: 10.1097/CCM.0000000000003960. PMID: 31393324; PMCID: PMC8096207. PRISM Investigators; Rowan KM, Angus DC, Bailey M, et al. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. N Engl J Med. 2017 Jun 8;376(23):2223-2234. doi: 10.1056/NEJMoa1701380. Epub 2017 Mar 21. PMID: 28320242. Ehrman RR, Gallien JZ, Smith RK, et al. Resuscitation Guided by Volume Responsiveness Does Not Reduce Mortality in Sepsis: A Meta-Analysis. Crit Care Explor. 2019 May 23;1(5):e0015. doi: 10.1097/CCE.0000000000000015. PMID: 32166259; PMCID: PMC7063966. Further fluid administration can be guided on the basis of dynamic measures such as fluid challenge, passive leg raise, stroke volume, stroke volume variation, pulse pressure variation, or echocardiography rather than physical examination or static parameters.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due risk of bias and indirectness. Ehrman RR, Gallien JZ, Smith RK, et al. Resuscitation Guided by Volume Responsiveness Does Not Reduce Mortality in Sepsis: A Meta-Analysis. Crit Care Explor. 2019 May 23;1(5):e0015. doi: 10.1097/CCE.0000000000000015. PMID: 32166259; PMCID: PMC7063966.

2) MAP ≥65 mm Hg is the standard of treatment and it is recommended in patients on vasopressors over higher blood pressure targets.Evidence 7Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to subgroup analysis. Asfar P, Meziani F, Hamel JF, et al; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056/NEJMoa1312173. Epub 2014 Mar 18. PMID: 24635770.

3) Guided resuscitation targeted to decreasing serum lactate (in patients with elevated serum lactate levels)Evidence 8 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158. PMID: 20179283; PMCID: PMC2918907. Jansen TC, van Bommel J, Schoonderbeek FJ, al; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. doi: 10.1164/rccm.200912-1918OC. Epub 2010 May 12. PMID: 20463176. or normalization of capillary refill time (<3 s, measured using a glass slide applied to the index finger to blanch the skin, and then held for 10 s).Evidence 9Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness (difficult to standardize intervention). Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071. PMID: 30772908; PMCID: PMC6439620.

4) Frequent reassessment of the patient for signs of improving organ function, including spontaneous urine output ≥0.5 mL/kg/h and improved mentation.

2. Fluids and vasopressors for septic shock:

1) Choice of fluids: In patients receiving crystalloid boluses for resuscitation (eg, 30 mL/kg), balanced solutions (eg, Ringer lactate or Plasma-Lyte solutions) are preferred over alternatives such as 0.9% normal saline, as they may reduce the risk of worsening metabolic acidosis and possibly improve other patient outcomes (studies on the topic are still ongoing).Evidence 10Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of studies (cohort) or indirectness and imprecision of comparisons from network meta-analysis. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. doi: 10.1001/jama.2012.13356. PMID: 23073953. Rochwerg B, Alhazzani W, Sindi A, et al; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014 Sep 2;161(5):347-55. doi: 10.7326/M14-0178. PMID: 25047428. In patients receiving large volumes of IV fluids, albumin may be added to crystalloid.Evidence 11Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate quality of evidence (moderate level of confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. Martin GS, Bassett P. Crystalloids vs. colloids for fluid resuscitation in the Intensive Care Unit: A systematic review and meta-analysis. J Crit Care. 2019 Apr;50:144-154. doi: 10.1016/j.jcrc.2018.11.031. Epub 2018 Nov 30. PMID: 30540968. Administration of colloids other than albumin, and particularly of hydroxyethyl starch (HES), may result in kidney injury and increased mortality, and thus HES should not be used in patients with sepsis or septic shock.Evidence 12Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). High quality of evidence (high level of confidence that we know true effects of the intervention). Haase N, Perner A, Hennings LI, et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ. 2013 Feb 15;346:f839. doi: 10.1136/bmj.f839. PMID: 23418281; PMCID: PMC3573769. 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. JAMA. 2013 Feb 20;309(7):678-88. doi: 10.1001/jama.2013.430. Erratum in: JAMA. 2013 Mar 27;309(12):1229. PMID: 23423413.

2) Vasopressors: If hypotension persists despite adequate fluid resuscitation, we recommend norepinephrine (rather than dopamine) as a first-line vasopressor.Evidence 13Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Applies to the norepinephrine versus dopamine comparison. De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med. 2012 Mar;40(3):725-30. doi: 10.1097/CCM.0b013e31823778ee. PMID: 22036860. Vasopressin (dosage: see Shock) can be used as a second-line agent for patients not meeting the MAP target of 65 mmHg despite norepinephrine administration,Evidence 14Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the study being underpowered and lower mortality rate than expected. Russell JA, Walley KR, Singer J, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. PMID: 18305265. McIntyre WF, Um KJ, Alhazzani W, et al. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2018.4528. Review. PMID: 29801010; PMCID: PMC6583502 remembering that the risk of atrial fibrillation and kidney replacement therapy (KRT) is lowered while the risk or severity of limb ischemia is increased. Epinephrine can be used as an alternative to norepinephrine if the patient is unresponsive to vasopressors or if additional vasopressors are required to support hemodynamics.

Administer the vasopressor agent as soon as practical through a central venous catheter under invasive intra-arterial pressure monitoring (arterial catheterization is usually performed). The use of dopamine should be limited to patients with bradycardia, reduced stroke volumes, and those at low risk of arrhythmias.

3) Inotropic therapy: Dobutamine (dosage: see Shock) may be added to norepinephrine, or epinephrine can be substituted for norepinephrine in patients with cardiac dysfunction and persistent hypoperfusion despite adequate fluid resuscitation and seemingly adequate arterial blood pressure.Evidence 15 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and risk of bias. Belletti A, Benedetto U, Biondi-Zoccai G, et al. The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials. J Crit Care. 2017 Feb;37:91-98. doi: 10.1016/j.jcrc.2016.08.010. Epub 2016 Aug 13. PMID: 27660923. Annane D, Vignon P, Renault A, et al; CATS Study Group. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 Aug 25;370(9588):676-84. doi: 10.1016/S0140-6736(07)61344-0. Erratum in: Lancet. 2007 Sep 22;370(9592):1034. PMID: 17720019.

3. Treatment of respiratory failure (see Respiratory Failure). Usually mechanical ventilation is necessary. Also see Pneumonia.

4. Treatment of renal failure: Early versus late institution of KRT in critically ill patients has no impact on short-term mortality (28 days), but early KRT results in more patients receiving KRT and likely a higher risk of line infection and possibly similar rates of KRT dependence at ≥90 days. Thus, KRT should be initiated once there is a definitive indication; the choice between intermittent and continuous KRT is less clear and is generally based upon the expertise and staffing requirements for continuous renal replacement therapy (CRRT), intermittent hemodialysis (IHD), or sustained low-efficiency hemodialysis (SLED).Evidence 16 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Medium Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity of results and risk of bias in primary studies. Naorungroj T, Neto AS, Yanase F, et al. Time to Initiation of Renal Replacement Therapy Among Critically Ill Patients With Acute Kidney Injury: A Current Systematic Review and Meta-Analysis. Crit Care Med. 2021 Aug 1;49(8):e781-e792. doi: 10.1097/CCM.0000000000005018. PMID: 33861550. Ye Z, Wang Y, Ge L, et al. Comparing Renal Replacement Therapy Modalities in Critically Ill Patients With Acute Kidney Injury: A Systematic Review and Network Meta-Analysis. Crit Care Explor. 2021 May 12;3(5):e0399. doi: 10.1097/CCE.0000000000000399. PMID: 34079944; PMCID: PMC8162503.

5. Treatment of acidosis: The main goal of acidosis treatment should be directed at removing the underlying cause. The use of IV NaHCO3 to raise pH in patients with significant acidosis has been controversial, but evidence suggests that its use is likely beneficial, particularly among patients with sepsis and metabolic acidosis and renal dysfunction.Evidence 17Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and subgroup analysis.Jaber S, Paugam C, Futier E, et al, Jung B; BICAR-ICU Study Group. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018 Jul 7;392(10141):31-40. doi: 10.1016/S0140-6736(18)31080-8. Epub 2018 Jun 14. Erratum in: Lancet. 2018 Dec 8;392(10163):2440. PMID: 29910040.

6. Glucocorticoids: In patients with persistent hypotension despite adequate fluid resuscitation and vasopressor therapy, low-dose IV hydrocortisone (200 mg/d) may be usedEvidence 18Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and indirectness. Rochwerg B, Oczkowski SJ, Siemieniuk RAC, et al. Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med. 2018 Sep;46(9):1411-1420. doi: 10.1097/CCM.0000000000003262. PMID: 29979221. (at least until the symptoms of shock resolve).

7. Glucose control: In the case of severe sepsis associated hyperglycemia (>10 mmol/L [180 mg/dL]), it is recommended to control glucose with target levels <10 mmol/L (180 mg/dL) rather than <6.1 mmol/L (110 mg/dL).Evidence 19Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Applies to the comparison of target 10 mmol/L vs 6 mmol/L. Other comparisons may have lower Quality of Evidence data. Quality of Evidence lowered due to indirectness. Friedrich JO, Chant C, Adhikari NK. Does intensive insulin therapy really reduce mortality in critically ill surgical patients? A reanalysis of meta-analytic data. Crit Care. 2010;14(5):324. doi: 10.1186/cc9240. Epub 2010 Oct 21. PMID: 21062514; PMCID: PMC3219247. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24. PubMed PMID: 19318384. If IV insulin infusion is used, in the initial phase of insulin therapy check glucose levels every 1 to 2 hours, and after stabilization of blood glucose, every 4 to 6 hours. Avoid hypoglycemia. In patients with hypoperfusion the glucose levels in capillary blood should be interpreted with caution; venous or arterial blood measurements are more reliable.

8. Other supportive treatment:

1) Transfusions of blood products:

a) Transfuse PRBCs in patients with an Hb <7 g/dL (rather than with an Hb <10 g/L) to achieve a target Hb of 7 to 9 g/dL.Evidence 20Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Applies to the 70 g/L vs 90-100 g/L comparison. Other comparisons may have lower Quality of Evidence data. Quality of Evidence lowered due to indirectness. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-17. Erratum in: N Engl J Med 1999 Apr 1;340(13):1056. PMID: 9971864. Holst LB, Haase N, Wetterslev J, et al; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1. PMID: 25270275. Exceptions may include transfusion of PRBCs in patients with an Hb >7 g/dL and tissue hypoperfusion (acute septic shock may represent such a situation), active bleeding, or significant coronary artery disease.

b) Platelet transfusion: It is suggested to transfuse platelets in patients with platelet counts <10×109/L; it may be also beneficial in patients with platelet counts 10×109/L to 20×109/L and increased risk of bleeding (including severe sepsis and septic shock). A reasonable target platelet count for larger invasive procedures may be ≥50×109/L.Evidence 21Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of studies. Applies to all recommendation under this section. Opinion consistent with 2012 Surviving Sepsis Campaign suggestions based on a very low quality of data.

c) Fresh-frozen plasma (FFP) and cryoprecipitate are used mainly in the case of active bleeding or preparation for invasive procedures.Evidence 22Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of studies. Applies to all recommendation under this section. Opinion consistent with 2012 Surviving Sepsis Campaign suggestions based on a very low quality of data.

2) Nutrition should preferably be via the enteral route. The volumes should not exceed the level tolerated by the patient (covering the full caloric requirement initially is not mandatory). The patient-important consequences of using prokinetics are not clear.Evidence 23Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due imprecision and indirectness to patient-important outcomes. http://criticalcarenutrition.com/docs/cpgs2012/5.2.pdf

3) Stress ulcer prophylaxis is suggested in patients with risk factors of bleeding.Evidence 24Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity. Krag M, Marker S, Perner A, et al; SUP-ICU trial group. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018 Dec 6;379(23):2199-2208. doi: 10.1056/NEJMoa1714919. Epub 2018 Oct 24. PMID: 30354950. Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med. 2010 Nov;38(11):2222-8. doi: 10.1097/CCM.0b013e3181f17adf. Review. PMID: 20711074. Proton pump inhibitors may be preferred over H2-receptor antagonists.Evidence 25Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to individual studies bias, lack of data on Clostridium difficile infection. Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med. 2018 Jan;44(1):1-11. doi: 10.1007/s00134-017-5005-8. Epub 2017 Dec 4. Erratum in: Intensive Care Med. 2017 Dec 11. PMID: 29199388; PMCID: PMC5770505.

4) Deep vein thrombosis prophylaxis (see Deep Vein Thrombosis) should be used unless the risk of bleeding is judged prohibitive.Evidence 26Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Alhazzani W, Lim W, Jaeschke RZ, Murad MH, Cade J, Cook DJ. Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013 Sep;41(9):2088-98. doi: 10.1097/CCM.0b013e31828cf104. Review. PMID: 23782973. We suggest low-molecular-weight heparin rather than unfractionated heparin.Evidence 27Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Alhazzani W, Lim W, Jaeschke RZ, Murad MH, Cade J, Cook DJ. Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013 Sep;41(9):2088-98. doi: 10.1097/CCM.0b013e31828cf104. Review. PMID: 23782973.

5) Management of patients treated with mechanical ventilation: Administer sedatives in the lowest possible doses to achieve the target (lowest well-tolerated) level of sedation. Avoid long-term administration of neuromuscular blocking agents; however, in patients with ARDS and PaO2/FiO2 <150 mm Hg, consider using intermittent neuromuscular blocking agents rather than continuous infusions for 48 hours of mechanical ventilation.Evidence 28Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19. PMID: 31112383; PMCID: PMC6741345. Alhazzani W, Alshahrani M, Jaeschke R, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care. 2013 Mar 11;17(2):R43. doi: 10.1186/cc12557. PMID: 23497608; PMCID: PMC3672502. Maintain the head of the bed elevated at 30 to 45 degrees and, until future evidence helps to clarify current controversies, consider the use of oropharyngeal decontamination with chlorhexidine gluconate or selective decontamination of the digestive tract to prevent ventilator-associated pneumonia.

6) Treatment of disseminated intravascular coagulation (see Disseminated Intravascular Coagulation). Treatment of the underlying causes of sepsis is crucial.

7) Other adjunctive therapies such as IV vitamin C, IV immunoglobulins, or polymyxin B hemoperfusion lack sufficient evidence demonstrating safety and effectiveness to justify widespread use outside of clinical trials.

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