Septic shock

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Jason Le, B.S.[2]

Overview

• Septic shock is the most severe clinical phenotype of Sepsis and is associated with circulatory, cellular, and metabolic dysfunction and a substantially increased risk of death. Within the Sepsis-3 framework, septic shock is operationally defined by vasopressor requirement to maintain a mean arterial pressure (MAP) of 65 mm Hg or greater and serum lactate greater than 2 mmol/L despite adequate volume resuscitation and in the absence of hypovolemia.
• Septic shock is a form of distributive (vasodilatory) shock characterized by vasoplegia, endothelial and microcirculatory dysfunction, impaired oxygen utilization, and variable myocardial depression.
• The operational criteria are intended for clinical and epidemiologic classification and should not delay resuscitation when septic shock is clinically suspected.
• Management requires simultaneous treatment of infection, circulatory failure, and tissue hypoperfusion.

Definition and Diagnostic Criteria

• Septic shock is diagnosed within the Sepsis-3 framework in a patient with Sepsis (an acute SOFA score increase of 2 or more points attributable to infection) when, after adequate volume resuscitation and in the absence of hypovolemia, both of the following are present:

• Vasopressor requirement to maintain MAP 65 mm Hg or greater.
• Serum lactate greater than 2 mmol/L.

• The combination identifies a population with hospital mortality greater than 40%.
• SSC 2026 issued a strong recommendation favoring NEWS, NEWS2, MEWS, or SIRS over qSOFA as a single screening tool, because qSOFA has poor sensitivity (approximately 32%-65%) for sepsis. A positive qSOFA should still prompt evaluation for sepsis.

Criterion	Operational definition
Sepsis	Acute SOFA score increase of 2 or more points attributable to infection
Vasopressor requirement	Vasopressor therapy required to maintain MAP 65 mm Hg or greater
Lactate	Serum lactate greater than 2 mmol/L in the absence of hypovolemia after adequate volume resuscitation

Pathophysiology

• Septic shock results from a dysregulated host response to infection producing vasodilation, maldistribution of blood flow, endothelial injury, capillary leak, microvascular thrombosis, impaired cellular oxygen utilization, and variable myocardial depression.
• Innate immune activation: pathogen-associated molecular patterns and damage-associated molecular patterns activate pattern-recognition receptors, including Toll-like receptors, with downstream NF-kB activation and release of inflammatory mediators.
• Vasoplegia: increased inducible nitric oxide synthase activity and nitric oxide signaling promote profound vascular smooth-muscle relaxation and catecholamine hyporesponsiveness. Prostacyclin and relative vasopressin deficiency may contribute.
• Nonselective nitric-oxide synthase inhibition can increase blood pressure but has not improved outcomes and may increase mortality, underscoring the complex role of nitric oxide in septic shock.
• Endothelial injury and capillary leak: inflammatory signaling damages the endothelial glycocalyx and intercellular junctions, increasing vascular permeability and producing interstitial edema and intravascular volume depletion.
• Coagulopathy and microvascular thrombosis: tissue-factor activation, impaired endogenous anticoagulant pathways, and suppressed fibrinolysis promote microvascular thrombosis and may progress to disseminated intravascular coagulation.
• Microcirculatory and mitochondrial dysfunction: heterogeneous capillary perfusion, microthrombi, impaired red-cell deformability, and mitochondrial dysfunction impair oxygen utilization. This can produce cytopathic hypoxia, in which cellular oxygen utilization is impaired despite apparently adequate oxygen delivery, and contributes to persistent lactate elevation.
• Myocardial depression: inflammatory mediators can produce reversible septic cardiomyopathy. Cardiac output is often preserved or increased early but may decrease with myocardial depression or inadequate preload.

Causes

• The lung is the most common source of infection in septic shock, followed by intra-abdominal, genitourinary, bloodstream, and skin/soft-tissue infections. The distribution varies with age and geography.
• Bacteria account for most identified pathogens. Common gram-negative pathogens include Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa; common gram-positive pathogens include Staphylococcus aureus and Streptococcus species.
• Fungal septic shock, particularly due to Candida species, is more likely with prolonged critical illness, indwelling vascular devices, total parenteral nutrition, and immunocompromise.
• Multidrug-resistant organisms should be considered when healthcare exposure, prior microbiology, or other resistance risk factors are present.
• No pathogen is identified in a substantial proportion of cases; culture-negative septic shock does not exclude the diagnosis.

History and Symptoms

• Suspect septic shock in a patient with suspected or confirmed infection who develops hypotension requiring vasopressors and/or hyperlactatemia.
• Presentations may be heterogeneous or subtle early in the course.
• General/constitutional findings: fever or hypothermia, rigors, malaise, and diaphoresis.
• Source-localizing symptoms: cough or dyspnea with pulmonary infection; dysuria or flank pain with genitourinary infection; abdominal pain with intra-abdominal infection; and focal erythema or pain with skin/soft-tissue infection.
• Organ dysfunction: altered mentation or confusion, tachypnea or dyspnea, oliguria, and peripheral hypoperfusion.
• Altered mentation, hypotension, and tachypnea are particularly concerning in a patient with infection, but their absence does not exclude septic shock. Beta-blockers and antipyretics may blunt tachycardia and fever.

Physical Examination

• Assess hemodynamics, tissue perfusion, organ function, and the likely infectious source.
• Important findings include hypotension, tachycardia, tachypnea, altered mentation, oliguria, mottling, cool extremities, and prolonged capillary refill.
• Capillary refill time is a bedside marker of peripheral perfusion and can be used with other perfusion measures to guide ongoing resuscitation.
• The evidence base for capillary-refill-guided resuscitation includes the ANDROMEDA-SHOCK trial (28-day mortality 34.9% vs 43.4% with lactate-guided care; HR 0.75, 95% CI 0.55-1.02) and the subsequent multicenter ANDROMEDA-SHOCK-2 trial (n=1467), in which a CRT-targeted personalized resuscitation protocol was superior to usual care for a hierarchical composite of mortality, duration of vital support, and length of stay (win ratio 1.16, 95% CI 1.02-1.33).
• The ANDROMEDA-SHOCK-2 CRT-personalized hemodynamic resuscitation algorithm provides a structured approach to using peripheral perfusion findings alongside other clinical and hemodynamic variables.
• In ANDROMEDA-SHOCK-2, the benefit was driven predominantly by reduced duration of vital support rather than a mortality difference; there was no significant difference in 28-day all-cause mortality between groups.

Laboratory Findings

• Serum lactate greater than 2 mmol/L is a component of the Sepsis-3 septic shock definition and is also a prognostic and resuscitation marker.
• Serial lactate measurements and assessment of lactate clearance can help evaluate the response to resuscitation, but persistent lactate elevation should be interpreted in the context of perfusion, adrenergic stimulation, metabolic abnormalities, and impaired cellular oxygen utilization.
• Other findings may include leukocytosis or leukopenia, bandemia, hyperglycemia, elevated creatinine, and other abnormalities reflecting organ dysfunction.

Medical Therapy

• Treatment should proceed simultaneously in three domains: rapid antimicrobial therapy and source control, restoration of effective circulation, and correction of persistent tissue hypoperfusion.

Antimicrobial Therapy

• Administer broad-spectrum antimicrobial therapy immediately when septic shock is suspected.
• Empiric antimicrobial selection should reflect the likely source, local resistance patterns, prior microbiology, healthcare exposure, and individual risk factors for resistant or fungal pathogens.
• Collect blood cultures, ideally two sets, as soon as possible and before antimicrobials when feasible, without delaying antimicrobial therapy. Blood-culture sensitivity falls substantially after antimicrobial administration.
• De-escalate or narrow antimicrobial therapy when microbiology and susceptibility results permit.
• Routine empiric antifungal therapy is not suggested in sepsis or septic shock; antifungal treatment should be reserved for patients with specific clinical risk factors for invasive fungal infection.

Source Control

• An anatomic source of infection that is amenable to intervention should be identified and controlled promptly as part of septic shock management.
• Detailed procedural management is addressed in the Source control microchapter.

Fluid Resuscitation

• Use IV crystalloids as the initial fluid; balanced crystalloids are preferred over 0.9% saline.
• SSC 2026 suggests at least 30 mL/kg IV crystalloid within the first 3 hours for sepsis-induced hypoperfusion or septic shock, with a conditional recommendation and low certainty of evidence. Dosing is based on actual body weight, with adjusted or ideal body weight suggested when BMI is greater than 30 kg/m2.
• The 2025 ESICM guideline made no recommendation for or against restrictive versus liberal fluid resuscitation; both SSC 2026 and ESICM acknowledge equivalence between strategies and support a personalized approach. The optimal individualized initial volume remains uncertain.
• Reassess frequently for fluid responsiveness and evidence of fluid overload. Dynamic measures such as passive leg raising and pulse-pressure variation are preferred over static filling pressures (e.g., CVP) for predicting fluid responsiveness.

Vasopressor Therapy

• Norepinephrine is the first-line vasopressor and is recommended over dopamine, epinephrine, and selepressin; it is also generally preferred to vasopressin and angiotensin II as initial therapy.
• Add vasopressin when norepinephrine requirements are escalating.
• Add epinephrine if MAP remains inadequate despite norepinephrine and vasopressin. Where vasopressin is unavailable, epinephrine may be added to norepinephrine.
• Terlipressin is suggested against in septic shock.
• When septic shock is accompanied by cardiac dysfunction, either norepinephrine or epinephrine may be used as first-line vasopressor therapy. Norepinephrine may be preferable when tachyarrhythmia is present and epinephrine may be useful when bradyarrhythmia is present.
• Vasopressors should be started promptly when hypotension is severe or persists. In unstable shock, vasopressors may be initiated concurrently with fluid administration and may be started through a peripheral IV rather than delaying therapy for central venous access.

Blood Pressure and Perfusion Targets

• Target an initial MAP of approximately 65 mm Hg during vasopressor-supported resuscitation.
• For adults 65 years old or older with septic shock, SSC 2026 makes a conditional recommendation (low certainty) for an initial MAP range of 60-65 mm Hg over higher targets. This is supported by the 65 trial (90-day mortality 41.0% vs 43.8%; adjusted OR 0.82, 95% CI 0.68-0.98), which also reduced vasopressor exposure.
• Do not use MAP alone to assess adequacy of resuscitation. Serial lactate assessment, capillary refill time, clinical examination, urine output, and other markers of tissue perfusion should inform ongoing therapy.

Inotropic Support

• For persistent hypoperfusion despite adequate intravascular volume and arterial pressure, add dobutamine or use epinephrine for inotropic support.

Corticosteroids

• SSC 2026 conditionally recommends IV hydrocortisone for septic shock with ongoing vasopressor requirement.
• The typical regimen is hydrocortisone 200 mg/day, administered as 50 mg every 6 hours or by continuous infusion.
• Corticosteroids increase the probability of shock reversal; the effect on 28-day mortality is small and uncertain. Hyperglycemia and hypernatremia occur more frequently with corticosteroid therapy.
• The SSC 2021 practical trigger was norepinephrine or epinephrine at least 0.25 microg/kg/min for at least 4 hours; this threshold was derived from prior guideline practice and should not be treated as a validated universal initiation threshold.
• The 2024 SCCM focused update supports hydrocortisone for septic shock and describes hydrocortisone 200 mg/day with or without fludrocortisone 50 microg enterally daily for approximately 7 days or until ICU discharge; the incremental benefit and routine use of fludrocortisone remain uncertain.

Important Updates Compared With Older Teaching

• SIRS-based severe sepsis terminology is obsolete. Sepsis-3 removed the severe-sepsis category, and SIRS is not an adequate standalone definition of sepsis or septic shock.
• qSOFA is not the preferred single screening tool. SSC 2026 strongly favors NEWS, NEWS2, MEWS, or SIRS over qSOFA because of qSOFA's poor sensitivity; a positive qSOFA nevertheless warrants evaluation for sepsis.
• Traditional early goal-directed therapy protocols based on routine central venous pressure and central venous oxygen saturation targets are no longer standard care after ProCESS, ARISE, and ProMISe demonstrated no outcome advantage over contemporary usual care.
• Current resuscitation emphasizes dynamic assessment of fluid responsiveness and serial perfusion measures such as lactate and capillary refill time.
• Current vasopressor escalation is generally norepinephrine -> vasopressin -> epinephrine, with peripheral initiation acceptable when necessary to avoid treatment delays.
• Corticosteroids have moved from a narrow refractory-shock concept toward use in septic shock with ongoing vasopressor requirements, reflecting a reliable shock-reversal benefit despite uncertain mortality benefit.

Areas of Uncertainty

• Initial fluid volume and vasopressor timing: the optimal individualized fluid volume and precise timing of vasopressor initiation remain uncertain. The multicenter CLOVERS and 2026 ARISE FLUIDS RCTs found no mortality or patient-centered benefit of a restricted-fluid/early-vasopressor strategy versus greater fluid with later vasopressors, supporting flexible rather than fixed resuscitation strategies.
• Corticosteroid regimen and timing: the optimal initiation threshold and timing remain uncertain, and prior vasopressor-dose thresholds should not be interpreted as validated dosing rules.
• Fludrocortisone: evidence suggests possible additional benefit when added to hydrocortisone, but the certainty and generalizability of this finding remain uncertain; no specific routine recommendation is established.
• Vasopressin timing: the norepinephrine dose or duration at which vasopressin should be added is not definitively established.
• Mortality effect of corticosteroids: available evidence supports improved shock reversal, whereas the mortality effect remains limited by imprecision and heterogeneity.

High-Yield Clinical Pearls

• Lactate elevation in septic shock reflects more than tissue hypoperfusion; aerobic glycolysis, adrenergic stimulation, and mitochondrial dysfunction can contribute. Persistent lactate elevation therefore warrants reassessment of the entire clinical picture rather than automatic administration of additional fluid.
• Do not use nitric-oxide synthase inhibition as a strategy to treat septic vasoplegia; increased blood pressure does not translate into improved outcomes and may increase mortality.
• Peripheral norepinephrine is acceptable when necessary to avoid delaying vasopressor therapy while central access is obtained.
• Capillary refill time is a practical bedside marker that can complement lactate and other measures of perfusion during resuscitation.
• Culture-negative septic shock is common; failure to identify a pathogen does not exclude septic shock.

Common Pitfalls

• Delaying antimicrobial therapy or source control while awaiting definitive microbiologic or diagnostic confirmation.
• Administering repeated fixed-volume fluid boluses without reassessing fluid responsiveness or signs of fluid overload.
• Using qSOFA or SIRS as the primary diagnostic framework for septic shock rather than integrating clinical assessment, organ dysfunction, and hemodynamics.
• Missing septic shock because fever or tachycardia is absent, particularly in patients receiving antipyretics or beta-blockers.
• Withholding corticosteroids solely because a mortality benefit has not been definitively demonstrated despite evidence for improved shock reversal in patients with ongoing vasopressor requirements.
• Using dopamine instead of norepinephrine as the default first-line vasopressor.