Sepsis and Septic Shock

Chapter: Sepsis and Septic Shock
McMaster Section Editor(s): Waleed Alhazzani, Deborah Cook
Section Editor(s) in Interna Szczeklika: Piotr Zaborowski, Jerzy Stefaniak, Miłosz Parczewski, Weronika Rymer, Agnieszka Wroczyńska
McMaster Author(s): Waleed Alhazzani, Andrew Rhodes, Roman Jaeschke
Author(s) in Interna Szczeklika: Andrzej Kübler, Miłosz Jankowski
Additional Information

DEFINITION, ETIOLOGY, PATHOGENESIS Top

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.

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 >12,000/microL or <4000/microL, 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 organs or systems (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 <100,000/microL 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 degree of hypoxia and hypotension, platelet count, bilirubin level, urine output and creatinine level, and neurologic function (the 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 dose 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 count <150,000/microL (1 point), then an additional point for each of <100,000/microL, <50,000/microL, and <20,000/microL.

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 level >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 lactate level >2 mmol/L (18 mg/dL) despite adequate fluid resuscitation.

Comparison of 2001 and 2016 definitions and concepts: Table 8.14-1.

Etiology

The etiology of sepsis does not always determine its clinical course. Pathogens may be undetectable in the bloodstream or other tissues. In the majority of 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; acute kidney injury (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 8.14-2. 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 suspected of 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. PubMed 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. PubMed 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. PubMed 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.

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.

It was recently proposed that during the first hour after clinical recognition of sepsis several aspects of diagnosis and management are performed: obtaining blood cultures, measuring 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 is questioned by many clinicians.

Treatment of Infection

1. Antimicrobial treatment: Start empiric antimicrobial therapy as soon as possible, that is, 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). High Quality of Evidence (high confidence that we know true effects of the intervention). 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. PubMed 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. PubMed 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. PubMed PMID: 24717459.  It is important to collect appropriate samples for microbiological testing before the treatment (but only if it does not delay treatment by more than a short period of time, eg, up to 30-45 minutes; see Diagnosis, Etiology, Pathogenesis, above). In sepsis administer at least one IV broad-spectrum antibiotic; 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 after 48 to 72 hours, 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 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 drain rather than open abdominal washout). In the case of infected pancreatic necrosis, a stepwise approach rather than a 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. PubMed 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. For clinicians who are less experienced or who prefer to use an algorithm for resuscitation, the reasonable early goal-directed therapy (EGDT) hemodynamic targets are:

1) Central venous pressure (CVP) 8 to 12 mm Hg (11-16 cm H2O) or 12 to 15 mm Hg (16-20 cm H2O) in patients treated with positive airway pressure mechanical ventilation or with elevated abdominal pressures (intra-abdominal hypertension or abdominal compartment syndrome). Bedside ultrasonography may also be used to identify patients with hypovolemia.Evidence 4Weak 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 presence of small observational studies with no patient-important outcomes—imprecision, indirectness, and risk of bias. Siva B, Hunt A, Boudville N. The sensitivity and specificity of ultrasound estimation of central venous pressure using the internal jugular vein. J Crit Care. 2012 Jun;27(3):315.e7-11. doi: 10.1016/j.jcrc.2011.09.008. Epub 2011 Dec 1. PubMed PMID: 22137379.

2) MAP ≥65 mm is the standard of treatment.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). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (not blinded) and studies being underpowered (lower than expected mortality). 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. PubMed PMID: 24635770. Possible exceptions may occur in patients with hypertension in whom higher MAP (up to 80 mm Hg) may be acceptable.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 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. PubMed PMID: 24635770.

3) Spontaneous urine output ≥0.5 mL/kg/h.

4) Central venous oxygen saturation (superior vena cava) (ScvO2) ≥70% or mixed venous oxygen saturation ≥65% (measurement of lactate levels has a similar clinical significance and could be used instead).Evidence 7Weak 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. 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. PubMed PMID: 20179283; PubMed Central PMCID: PMC2918907. Jansen TC, van Bommel J, Schoonderbeek FJ, et 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. PubMed PMID: 20463176. Recently managing patients according to capillary refill assessed every half hour was again shown to be equivalent.Evidence 8Strong 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). Hernández G, Ospina-Tascón GA, Damiani LP, et al; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN). 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. PubMed PMID: 30772908; PubMed Central PMCID: PMC6439620.

To achieve these goals, use fluid resuscitation (see below). In patients in whom despite achieving the target CVP and MAP (including the patients treated with vasopressors; see below) the target ScvO2 or lactate clearance has not been obtained within 6 hours, it is suggested to use, depending on the circumstances (heart rate, left ventricular function, previous hemodynamic response to fluid, hemoglobin [Hb] level) one or more of the following: continued fluid resuscitation, transfusion of packed red blood cells (PRBCs) to achieve hematocrit ≥30%, dobutamine (maximum dose, 20 microg/kg/min).Evidence 9Weak 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 fact that this particular set of goals and interventions was originally used in a study examining multiple concurrent interventions (indirectness towards each of those separately) tested against another protocol (indirectness towards regular care), with some indirect evidence dissimilar in results (transfusion; see Evidence #19). Newer evidence points to the possibility that other goals may not be inferior, at least in subgroups of patients. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. PubMed PMID: 11794169. 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. PubMed PMID: 24635770. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18. PubMed PMID: 24635773; PubMed Central PMCID: PMC4101700. Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/NEJMoa1500896. Epub 2015 Mar 17. PubMed PMID: 25776532.

Clinicians trained in resuscitation and sepsis management can use bedside dynamic volume status and perfusion assessment (eg, echocardiography, ultrasonography, cardiac index, capillary refill time, urine output, and others), and laboratory values such as serum lactate level when available, avoiding measurement of ScvO2, transfusing PRBCs only for Hb <70g/dL, and with lower use of dobutamine.Evidence 10Strong 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). 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. PubMed PMID: 28320242. The key is frequent assessment of the patient.

2. Treatment of cardiovascular dysfunction:

1) Maintain adequate intravascular volume. In patients with tissue hypoperfusion and suspected hypovolemia, start with a rapid infusion of crystalloids (reasonable amount may be ≥30 mL/kg; alternatively clinicians use 500-1000 mL boluses with frequent reassessment) while watching for volume overload (part of this volume may be substituted by equivalent volumes of albumin); repeat depending on the effects on arterial pressure, urine output, and possible adverse effects (symptoms of volume overload). Some patients may require rapid administration of higher fluid volumes. Administration of colloids other than albumin, and particularly of hydroxyethyl starch (HES), may result in kidney injury and increased mortality, and thus it is recommended not to use HES in patients with sepsis or septic shock.Evidence 11Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Moderate quality of evidence (moderate level of confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness (starches frequently in high chloride solutions tested occasionally against more balanced solutions). 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. Review. PubMed PMID: 23418281; PubMed Central 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. Review. Erratum in: JAMA. 2013 Mar 27;309(12):1229. PubMed PMID: 23423413. Until further data are available, we also suggest avoiding a rapid use of larger volumes (eg, >2 L) of unbalanced crystalloids with a high concentration of chloride (typically 0.9% NaCl).Evidence 12Weak 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. PubMed 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. Review. PubMed PMID: 25047428.

 2) Vasopressors: If hypotension persists in spite of 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. PubMed PMID: 22036860. Vasopressin (dosage: see Shock) could be used when reduction of the dose of norepinephrine is attemptedEvidence 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. PubMed PMID: 18305265. or as an early addition to norepinephrine (rather than major increase in the dose of norepinephrine) as it may reduce the risk of death, atrial fibrillation, and need for renal replacement therapy at the expense of increased risk of digital ischemia.Evidence 15Weak 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 result inconsistency between the low and high risk of bias studied that was involved in the meta-analysis.   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. PubMed PMID: 29801010; PubMed Central PMCID: PMC6583502. 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 necessary). 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 tried on the basis of physiologic rationale in patients with low stroke volumes in spite of adequate fluid resuscitation, although the benefit of such action is unclear. Coexisting or developing hypotension may require the addition of a vasopressor.

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

4. Treatment of renal failure: Hemodynamic stabilization (normalization of arterial pressure) is essential. Use renal replacement therapy (RRT) when necessary; the effects of early versus late institution of RRT in critically ill patients are not clear as is not clear the choice between intermittent and continuous RRT, although the latter may result in less hemodynamic instability.Evidence 16Low 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. Karvellas CJ, Farhat MR, Sajjad I, et al. A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Crit Care. 2011;15(1):R72. doi: 10.1186/cc10061. Epub 2011 Feb 25. Review. PubMed PMID: 21352532; PubMed Central PMCID: PMC3222005. Rabindranath K, Adams J, Macleod AM, Muirhead N. Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003773. Review. PubMed PMID: 17636735. Bagshaw SM, Berthiaume LR, Delaney A, Bellomo R. Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: a meta-analysis. Crit Care Med. 2008 Feb;36(2):610-7. doi: 10.1097/01.CCM.0B013E3181611F552. Review. PubMed PMID: 18216610.

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 recent evidence suggests that its use is likely beneficial, particularly among patients with 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. PubMed 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). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity of results and imprecision. Patel GP, Balk RA. Systemic steroids in severe sepsis and septic shock. Am J Respir Crit Care Med. 2012 Jan 15;185(2):133-9. doi: 10.1164/rccm.201011-1897CI. Epub 2011 Jun 16. Review. PubMed PMID: 21680949.  (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). High Quality of Evidence (high 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. 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. PubMed PMID: 21062514; PubMed Central 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). High Quality of Evidence (high 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. 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. PubMed 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. PubMed 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 <10,000/microL; it may be also beneficial in patients with platelet counts 10,000 to 20,000/microL and increased risk of bleeding (including severe sepsis and septic shock). A reasonable target platelet count for larger invasive procedures may be ≥50,000/microL.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 administered in patients with risk factors of bleeding.Evidence 24Strong 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 heterogeneity. 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. PubMed 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. PubMed PMID: 29199388; PubMed Central 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. PubMed 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. PubMed 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 acute respiratory distress syndrome and PaO2/FiO2 <150 mm Hg, consider using neuromuscular blocking agents 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). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to unclear data on weakness and limitation to one geographical area (directness). 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. PubMed PMID: 23497608; PubMed Central 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.

TablesTop

Table 8.14-1. Definitions and criteria for the diagnosis of sepsis and septic shock

Consensus criteria

Previous (1991, 2001)

Current (2016)

Sepsis

Systemic inflammatory response caused by infection. Criteria for SIRS are considered to be met if ≥2 of the following occur:

 1) Body temperature >38°C or <36°C

2) Heart rate >90/mina

3) Respiratory rate >20/min or PaCO2 <32 mm Hg

4) Leukocyte count >12,000/microL or <4000/microL or >10% immature neutrophil

Life-threatening organ dysfunction caused by a dysregulated host response to infection, which causes organ damage (corresponds to the previous concept of severe sepsis)

 

Severe sepsis

Sepsis causing failure or severe malfunction of ≥1 organ or system (corresponds to the current concept of sepsis)

Sepsis, as above

Organ dysfunction

– Cardiovascular system: Hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or SBP drop >40 mm Hg)

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

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

– Metabolism: Elevated serum lactate levels

– Hemostasis: Platelet count <100,000/microL or INR >1.5

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

–CNS: Features of encephalopathy (anxiety, confusion, agitation, delirium, coma)

Patient with suspected or documented infection and ≥2 points increase from baseline on SOFA (see text)b

 

Septic shock

Severe sepsis with acute circulatory failure characterized by persistent hypotension (SBP <90 mm Hg, mean <65 mm Hg or decrease in SBP by >40 mm Hg) despite adequate fluid resuscitation (thus requiring use of vasoconstrictive drugs)

Subset of sepsis with underlying circulatory and cellular metabolism abnormalities profound enough to substantially increase mortality. Clinical criteria include presence of sepsis and vasopressor therapy needed to elevate MAP ≥65 mm Hg and lactate level >2 mmol/L (18 mg/dL) despite adequate fluid resuscitation

Scale proposed for early isolation of patients at risk of death

Not specified; SIRS, organ dysfunction, and extended criteria for diagnosis of sepsis were used

qSOFA: ≥2 of:

1) Disturbance of consciousness

2) SBP ≤100 mm Hg

3) Respiratory rate ≥22/min

a This may not occur in patients receiving beta-blockers.

b In patients without acute organ dysfunction the SOFA score is usually 0.

Based on Intensive Care Med. 2003;29(4):530-8 and JAMA. 2016 23;315(8):801-10.

CNS, central nervous system; FiO2, fraction of inspired oxygen; INR, international normalized ratio; MAP, mean arterial pressure; PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, arterial partial pressure of oxygen; qSOFA, quick sequential organ failure assessment; SBP, systolic blood pressure; SIRS, syndrome of systemic inflammatory response; SOFA, sequential organ failure assessment.

Table 8.14-2. Clinical consequences and diagnostic features of sepsis

Infection (documented or suspected) and some of the following:

General variables:

– Fever >38.3 degrees Celsius or hypothermia <36 degrees Celsius

– Tachycardia >90/min

– Tachypnea >30/min (or mechanical ventilation)

– Sudden deterioration of mental status

– Significant edema or positive fluid balance (>20 mL/kg/d)

– Hyperglycemia (>7.7 mmol/L [140 mg/dL]) in the absence of diabetes

Inflammatory variables:

– Leukocytosis (WBC count >12,000/microL) or leukopenia (WBC count <4000/microL)

– More than 10% of immature neutrophil forms in WBC differential counts

– Plasma CRP >2 SD above mean value

– Plasma procalcitonin >2 SD above mean value

Hemodynamic and tissue perfusion variables:

– Arterial hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or SBP drop >40 mm Hg)

– Serum lactate levels >ULN

– Decreased capillary refill

Emerging or worsening organ dysfunction variables:

– Hypoxemia (PaO2/FiO2 <300 mm Hg; <200 mm Hg in patients with primary diseases of the respiratory tract)

– Acute oliguria (urine output <0.5 mL/kg/h over >2 hours with adequate volume status)

– Increase in creatinine levels by ≥44.2 micromol/L (≥0.5 mg/dL) over 48 hours

– Coagulation abnormalities (platelet count <100,000/microL, INR >1.5, aPTT >60 seconds)

– Total serum bilirubin levels >70 micromol/L (4 mg/dL)

– Ileus (absent bowel sounds)

Adapted from Crit Care Med. 2013;41(2):580-637.

aPTT, activated partial thromboplastin time; CRP, C-reactive protein; INR, international normalized ratio; MAP, mean arterial pressure; SBP, systolic blood pressure; SD, standard deviation; ULN, upper limit of normal; WBC, white blood cell.

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