Sepsis & Septic Shock

Meet the patient

A 68-year-old man arrives from a nursing home with new confusion and a cough. He is afebrile, his respiratory rate is 28, his systolic BP is 92, and he cannot tell you the year. No one has measured his lactate yet.[1][3]

This is sepsis hiding behind a normal temperature and a near-normal pressure — the picture that kills because it is written up as a urinary tract infection. His qSOFA is already 3 of 3 (tachypnoea, altered mentation, hypotension), and every minute spent waiting for confirmation is paid for in mortality.[1][4]

Overview & Definition

Sepsis is the commonest preventable cause of in-hospital death worldwide and the archetypal time-critical medical emergency. The clinical skill is early recognition (suspected infection plus a deranged physiological screen — qSOFA at least 2 — plus clinical gestalt) followed by immediate execution of the Hour-1 bundle without waiting for confirmation, because each hour of delay in effective antibiotics and resuscitation measurably increases mortality.[4]

The conceptual shift that defines modern sepsis is the abandonment of SIRS (Systemic Inflammatory Response Syndrome) as a defining criterion and its replacement with organ dysfunction (SOFA). Under the older 1992 (Sepsis-1) and 2001 (Sepsis-2) definitions, sepsis was "infection plus two or more SIRS criteria," severe sepsis was sepsis with organ dysfunction, and septic shock was sepsis with refractory hypotension. SIRS is sensitive but non-specific (present after exercise, pancreatitis, trauma and surgery), it under-detects the genuinely deteriorating patient, and the term "severe sepsis" was redundant (sepsis is organ-dysfunctional by definition). The Sepsis-3 task force (2016) retired SIRS and "severe sepsis," redefined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, and gave an operational bedside handle — an acute change in total SOFA score of 2 or more points consequent to infection.[1]

Septic shock — the most severe phenotype — is defined operationally as sepsis with vasopressor requirement to maintain a mean arterial pressure (MAP) of at least 65 mmHg AND a serum lactate over 2 mmol/L despite adequate volume resuscitation. The combination of vasoplegia and a raised lactate identifies a population with a hospital mortality exceeding 40 percent, distinctly worse than sepsis alone.[1]

The three core pathophysiological abnormalities — vasoplegia, capillary leak and cellular hypoxia (mitochondrial dysfunction) — explain every clinical feature and every element of therapy: fluids and vasopressors restore the macrocirculation, source control removes the trigger, and supportive organ support buys time for the host response to reset.[1][2]

Exam application bank (NEET-PG / INICET)

One-line answer

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3 definition, Singer 2016). Operationally it is identified at the bedside as an acute change in total SOFA score of 2 or more points consequent to infection. Septic shock is a subset of sepsis with circulatory and cellular/metabolic abnormalities substantial enough to substantially increase mortality — clinically hypotension requiring vasopressors to maintain a mean arterial pressure of at least 65 mmHg AND a serum lactate over 2 mmol/L despite adequate volume resuscitation, carrying a hospital mortality over 40 percent. Common sources are respiratory, abdominal, urinary, skin/soft tissue and device-related. Recognition is clinical (suspected infection with qSOFA at least 2: RR 22 or more, altered mentation, SBP 100 or less), and management is the Surviving Sepsis Campaign Hour-1 bundle — measure lactate, obtain blood cultures, give broad-spectrum antibiotics immediately (within 1 hour in septic shock), give at least 30 mL/kg crystalloid within the first 3 hours for sepsis-induced hypoperfusion, and start vasopressors for hypotension — plus source control and organ support.[1][2]

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose/route if drug therapy is standard. [1]

Stem 2 — Unstable / complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote, or reperfusion — and what you do in the first 15 minutes. [1]

Stem 3 — Atypical group. Elderly, pregnancy, child, or immunocompromised: how presentation and thresholds change. [1]

Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. [1]

Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU/ICU/theatre, and what follow-up is mandatory. [1]

Rapid viva checklist

1. Definition + classification
2. Pathophysiology chain
3. Bedside signs / criteria
4. Score with exact components (if any)
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline/trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Sepsis & Septic Shock.

Classification

Sepsis is classified along three axes: the clinical severity ladder (infection -> sepsis -> septic shock), the source (which determines the antibiotic choice and the source-control strategy), and the haemodynamic phenotype (warm vasoplegic vs cold decompensated), which guides resuscitation. [1]

[1]

[1]

The haemodynamic phenotype is the second classification axis and is clinically useful at the bedside: [1]

• Warm shock (early, vasoplegic / distributive) — the patient is warm, flushed, vasodilated with a wide pulse pressure, a bounding pulse and a low diastolic pressure. Cardiac output is high; systemic vascular resistance is low. This is the dominant picture of early septic shock and is norepinephrine-responsive (restores vascular tone).
• Cold shock (late, decompensated) — the patient is cold, clammy, mottled with prolonged capillary refill, a narrow pulse pressure and oliguria. Cardiac output has fallen (myocardial depression, hypovolaemia from capillary leak). This signals decompensation and demands aggressive resuscitation plus an inotrope if cardiac output remains low.[1]

The source classification drives empirical antibiotic selection and the source-control plan and is covered in detail under Management. [1]

Epidemiology & Risk Factors

Sepsis is a leading cause of death worldwide. The Global Burden of Disease analysis (Rudd et al, 2020) estimated 48.9 million incident cases and 11.0 million sepsis-related deaths in 2017, accounting for 19.7 percent of all global deaths. Although age-standardised sepsis mortality fell by about half between 1990 and 2017 (driven by vaccination, clean water and antimicrobials), the absolute burden remains enormous and is disproportionately borne by low- and middle-income countries — 84 percent of sepsis cases occur in these settings, and sub-Saharan Africa, South Asia and East Asia carry the highest age-standardised mortality. Almost half of all sepsis deaths occur in children under 5.[3]

Septic shock carries a hospital mortality of 30 to 40 percent — by the Sepsis-3 operational definition, over 40 percent.[1] The single largest modifiable determinant of that mortality is the time to effective antimicrobial therapy and adequate resuscitation: in the landmark Kumar cohort of septic shock, survival decreased by an average of 7.6 percent for each hour of delay before the initiation of effective antimicrobial therapy after the onset of recurrent or persistent hypotension.[4]

[1]

Host risk factors for sepsis: [1]

• Extremes of age — neonates (immature immunity) and the elderly (immunosenescence, comorbidity, frailty). The very young and very old account for a disproportionate share of sepsis deaths.
• Immunocompromise — HIV/AIDS, chemotherapy-induced neutropenia, solid-organ or stem-cell transplant, long-term corticosteroids or other immunosuppressants, biologics (anti-TNF, anti-IL-6, anti-CD20), haematological and solid malignancy, diabetes mellitus, chronic liver disease (cirrhosis), chronic kidney disease, and asplenia / hyposplenism (surgical, sickle-cell, coeliac).
• Chronic organ failure — CKD, COPD, heart failure, cirrhosis.
• Breakdown of barriers and devices — indwelling central venous and arterial lines, urinary catheters, endotracheal tubes, prosthetic material, burns, chronic wounds, pressure ulcers, recent surgery.
• Pregnancy and the puerperium — chorioamnionitis, septic abortion, puerperal sepsis, pyelonephritis of pregnancy.
• Iatrogenic and environmental — broad-spectrum antibiotics (selection pressure for resistant organisms and C. difficile), immunosuppressants, residence in a long-term care facility, and (in resource-limited settings) household air pollution and unsafe water. [1]

Organisms. The microbial spectrum is dominated by Gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter species) and Gram-positive cocci (Staphylococcus aureus including MRSA, Streptococcus pneumoniae, enterococci, Group A strep). Fungal sepsis (candidaemia) is an important cause in the critically ill, the immunocompromised, and patients with prolonged ICU stay, central lines and total parenteral nutrition. The rising global threat is multidrug resistance — extended-spectrum beta-lactamase (ESBL) producers, carbapenem-resistant Enterobacterales (CRE), Pseudomonas and Acinetobacter resistant to carbapenems, vancomycin-resistant enterococci (VRE) and MRSA — which forces empiric broad-spectrum regimens and worsens outcome.[2]

Pathophysiology

The entire clinical syndrome of sepsis flows from a single organising event — a dysregulated host response in which the normally protective inflammatory, coagulation and endothelial responses to infection escape their regulatory checks, simultaneously over- and under-shooting, and damaging the host. Understanding this cascade explains every clinical feature (vasoplegia, capillary leak, multi-organ failure, lactate rise) and every element of therapy. [1]

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1. Initiation: PAMPs and pattern-recognition receptors

The innate immune system does not recognise "sepsis" — it recognises microbial signatures. Pathogens shed conserved pathogen-associated molecular patterns (PAMPs): lipopolysaccharide (LPS/endotoxin) from the outer membrane of Gram-negative bacteria, lipoteichoic acid and peptidoglycan from Gram-positive cell walls, flagellin from motile bacteria, unmethylated CpG DNA from bacteria, beta-glucans from fungi, and viral RNA/DNA. These are detected by pattern-recognition receptors (PRRs) — the Toll-like receptors (TLR4/MD2/CD14 complex for LPS; TLR2 for lipoteichoic acid) and the intracellular NOD-like receptors — on monocytes, macrophages, dendritic cells and endothelial cells. Host tissue damage also releases damage-associated molecular patterns (DAMPs) (HMGB1, histones, mitochondrial DNA, ATP) which activate the same receptors, explaining why non-infectious insults (trauma, pancreatitis, burns) produce a sepsis-like picture.[1]

2. The inflammatory response: SIRS, CARS and their dysregulation

Receptor engagement activates the NF-kB transcription factor pathway, driving synthesis of the pro-inflammatory cytokines — tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and interferon-gamma (IFN-gamma) — which recruit and activate neutrophils, up-regulate adhesion molecules, generate fever and drive the acute-phase response. Simultaneously, a counter-regulatory anti-inflammatory response (CARS) is mounted, dominated by interleukin-10 (IL-10), the IL-1 receptor antagonist and transforming growth factor-beta (TGF-beta), which dampens immune activation to prevent uncontrolled inflammation. [1]

In health, SIRS (the pro-inflammatory surge) and CARS (the anti-inflammatory brake) are tightly balanced and resolve together as the infection clears. In sepsis, this balance is dysregulated: some patients have uncontrolled hyper-inflammation (early cytokine storm), others develop immunoparalysis (excessive CARS, with reactivation of latent viruses and secondary infections), and most oscillate between the two over the course of illness. This explains why a single anti-cytokine strategy has repeatedly failed in trials — the host response is heterogeneous and time-dependent, not a uniform cytokine excess.[1]

3. Endothelial dysfunction and capillary leak

The cytokine storm directly injures the vascular endothelium and its protective glycocalyx (the carbohydrate-rich lining of the vascular lumen). Glycocalyx degradation, junctional disruption and endothelial apoptosis produce three consequences: [1]

• Nitric oxide (NO) over-production (driven by inducible NO synthase, iNOS) — produces generalised vasodilation (vasoplegia), the haemodynamic hallmark of distributive shock, lowering systemic vascular resistance and the diastolic blood pressure.
• Increased vascular permeability (capillary leak) — albumin and fluid extravasate into the interstitium, causing hypovolaemia, tissue oedema (pulmonary oedema in ARDS, soft-tissue swelling) and haemoconcentration. This is why large fluid volumes are often needed initially, but also why excessive fluid is harmful (positive fluid balance is an independent predictor of mortality).
• Loss of vascular tone regulation and microcirculatory heterogeneity — even when the macrocirculation (MAP) is restored, the microcirculation may remain dysfunctional, with shunted, non-perfused capillaries — the basis for lactate elevation despite an adequate blood pressure.[1]

4. The procoagulant shift and disseminated intravascular coagulation

Sepsis drives a systemic procoagulant, antifibrinolytic state. Cytokines induce tissue factor expression on monocytes and endothelium, activating the extrinsic coagulation cascade and generating thrombin and fibrin, which deposit as microvascular thrombi throughout the capillary bed. Simultaneously, the natural anticoagulant pathways are consumed and down-regulated — activated protein C, antithrombin and tissue-factor-pathway inhibitor (TFPI) fall — and fibrinolysis is suppressed by a marked rise in plasminogen activator inhibitor-1 (PAI-1). The net effect is microvascular thrombosis with consumption of platelets and clotting factors — disseminated intravascular coagulation (DIC) — which causes both ischaemic organ injury (the microthrombi) and bleeding (consumption of platelets and factors). DIC is a strong independent predictor of sepsis mortality.[1]

5. Mitochondrial dysfunction and cytopathic hypoxia

The most counter-intuitive and important pathophysiological insight in modern sepsis is cytopathic hypoxia: in established sepsis, cells become unable to utilise oxygen even when oxygen delivery is adequate. Nitric oxide and reactive oxygen species inhibit cytochrome c oxidase (complex IV) of the electron transport chain, stalling oxidative phosphorylation; cells switch to anaerobic glycolysis and lactate accumulates. This is a dysoxic (type B/C) lactate rise — distinct from the hypoxic (type A) lactate rise of pure hypoperfusion — and it explains why simply maximising oxygen delivery (the rationale of the now-abandoned early goal-directed therapy protocol) does not reliably reverse organ failure. The cell must recover its mitochondrial function for the organ to recover, and this is a matter of time and supportive care, not of more oxygen or more fluid.[1]

Integration: why a normal blood pressure does not exclude sepsis

The three abnormalities — vasoplegia, capillary leak and cellular hypoxia — do not progress in lock-step. A patient can have significant tissue hypoperfusion (rising lactate, falling urine output, confusion) while the systemic blood pressure is still normal, because compensatory vasoconstriction, tachycardia and the stress response maintain MAP until reserve is exhausted. By the time hypotension appears, the patient is already decompensating. This is why sepsis recognition must not wait for hypotension — the qSOFA screen, lactate and clinical gestalt identify the at-risk patient earlier.[1]

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Clinical Presentation

Sepsis presents as an acute, evolving, multi-system illness built on a focus of infection. The tempo is hours to days, and the discriminating features are the source, the systemic features, and the atypical presentations in the vulnerable. [1]

Shared systemic features

• Fever or hypothermia — fever is typical, but hypothermia can occur and is a recognized danger sign in the elderly and immunocompromised patient.
• Tachycardia — usually present; a heart rate that fails to rise appropriately in the face of severe illness is concerning.
• Tachypnoea — a respiratory rate of 22 per minute or more is a qSOFA component and often an early warning sign; it reflects both metabolic acidosis compensation and incipient ARDS.
• Altered mental status — new confusion, agitation, drowsiness or reduced GCS (a qSOFA component) — sepsis-associated encephalopathy is a metabolic encephalopathy without focal neurological signs or CNS infection.
• Reduced urine output — falling urine output reflecting renal hypoperfusion and incipient acute kidney injury.
• Skin changes — warm, flushed (early vasoplegia) or cold, clammy, mottled with prolonged capillary refill in decompensated shock; abnormal peripheral perfusion markers are associated with organ dysfunction and mortality.[1][18]

Source-specific presentations

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Atypical presentation in the elderly and immunocompromised

The classic febrile, tachycardic picture is frequently absent in the most vulnerable patients, and this is the single most common reason sepsis is missed: [1]

• The elderly often present with no fever or with hypothermia, and with new-onset confusion, a fall, incontinence, lethargy, anorexia or simply 'off legs'. A maternal or elderly relative who has 'just gone off' may be in septic shock. The threshold to screen, culture and treat must be very low.
• The immunocompromised (neutropenia, transplant, steroids, HIV, biologics) may have attenuated fever and inflammation, a broader organism differential (opportunists — Pneumocystis, fungi, CMV, mycobacteria), and rapid deterioration. Neutropenic sepsis is a medical emergency — empirical broad-spectrum antibiotics within one hour of presentation, before confirmatory cultures.[2]
• Diabetics, the cirrhotic, and those on beta-blockers or steroids may have blunted tachycardia, masking severity.

Paediatric presentation

Suspect sepsis in any child with fever and altered behaviour, abnormal colour (pale, mottled, ashen), prolonged capillary refill, tachypnoea, grunting, increased work of breathing, lethargy or reduced feed intake. Paediatric septic shock is recognised by decompensated (cold) shock — weak peripheral pulses, prolonged capillary refill, mottled or cool skin, hypotension (a late sign in children). Structured paediatric early-warning tools support recognition. Where intensive care is available, SSC paediatric guidelines suggest up to 40 to 60 mL/kg over the first hour as 10 to 20 mL/kg balanced-crystalloid boluses titrated to clinical markers of cardiac output; weight-based antibiotic and vasopressor dosing applies (see Special Populations).[15]

Maternal and neonatal sepsis

• Maternal / puerperal — chorioamnionitis, puerperal endometritis, septic abortion, pyelonephritis, wound infection, mastitis. The pregnant patient has a physiologically raised baseline RR and HR and a leukocytosis — interpret these cautiously. Group A strep, E. coli, anaerobes and (globally) Gram-negative sepsis dominate. Deliver if the uterus is the source and chorioamnionitis is established. Safe antibiotics in pregnancy: beta-lactams, cephalosporins; avoid aminoglycosides, tetracyclines, chloramphenicol, quinolones where possible.[2]
• Neonatal sepsis — early-onset (under 72 hours) from vertical transmission (Group B strep, E. coli, Listeria monocytogenes), risk factors PROM, maternal GBS colonisation, prematurity, intrapartum fever; versus late-onset (over 72 hours), usually nosocomial (coagulase-negative staph, Klebsiella, S. aureus, Candida). Presents with non-specific features — temperature instability, respiratory distress, poor feeding, lethargy, apnoea, jaundice. Treat empirically within one hour.

Differential Diagnosis

The useful framing is the differential of acute circulatory shock with a systemic inflammatory phenotype — a picture dominated by hypotension, tachycardia, a raised lactate and multi-organ disturbance, where sepsis is the commonest but not the only cause. [1]

The discriminating features examiners expect, with the bedside tests that separate them: [1]

[1]

Non-infectious SIRS-mimics

Several non-infectious insults produce a sepsis-like systemic inflammatory picture and must be considered, because the management differs: acute pancreatitis, major trauma, burns, major surgery, transfusion reaction, tumour lysis syndrome, drug reactions (DRESS, neuroleptic malignant syndrome, serotonin syndrome, malignant hyperthermia), heat stroke, thyrotoxic storm, aspiration/chemical pneumonitis, mesenteric ischaemia, acute adrenal crisis, and severe diabetic ketoacidosis. The history, the source and the bedside tests (lipase, drug history, thyroid function, cortisol) usually separate them. Many of these patients still benefit from the sepsis resuscitation principles (fluids, vasopressors, organ support) while the underlying cause is addressed. [1]

Causes of a raised lactate other than sepsis

A raised lactate is not synonymous with sepsis. Distinguish: [1]

• Type A (hypoxic / hypoperfusion) — sepsis, shock (any cause), severe hypoxaemia, mesenteric ischaemia, seizures, severe exercise, shivering.
• Type B (impaired metabolism / clearance) — metformin-associated lactic acidosis, malignancy (Warburg effect), mitochondrial toxicity (antiretrovirals, linezolid, propofol infusion syndrome), severe hepatic failure (impaired lactate clearance), beta-agonists (salbutamol), ethanol, thiamine deficiency, carbon monoxide and cyanide poisoning, inhaled nitric oxide. [1]

A rising or persistently raised lactate in a 'treated' septic patient prompts a search for ongoing hypoperfusion (inadequate resuscitation), an undrained source, bowel ischaemia, a secondary complication (limb ischaemia, mesenteric ischaemia), or hepatic failure.[1]

Clinical & Bedside Assessment

The bedside assessment of suspected sepsis is structured (ABCDE), time-critical, and source-seeking. The goals are to recognise, resuscitate, localise the source, and quantify the severity. [1]

ABCDE priorities

• Airway — patency; protect if reduced GCS (under 8 -> intubation); assess for stridor (anaphylaxis, epiglottitis).
• Breathing — respiratory rate (the earliest and most sensitive vital sign), SpO2, oxygen target 94 to 98 percent (88 to 92 percent in COPD at risk of CO2 retention), auscultation, work of breathing; consider ABG/VBG if hypoxaemic or to measure lactate; mechanical ventilation for respiratory failure, ARDS or GCS under 8.
• Circulation — heart rate, blood pressure and MAP (target at least 65 mmHg), capillary refill time, mottling score, JVP (flat in hypovolaemia, raised in cardiogenic/obstructive), pulses, two large-bore IV cannulae, full monitoring; identify shock phenotype (warm vs cold).
• Disability — GCS / AVPU, pupils, blood glucose (hypoglycaemia is common and dangerous), sepsis-associated encephalopathy.
• Exposure — full examination to find the source (see below); temperature; skin for rashes (meningococcal petechiae, cellulitis, necrotising fasciitis, line sites). [1]

The focused source-seeking examination

This is the highest-yield part of the assessment. Inspect every potential focus: [1]

• Skin — cellulitis, abscess, necrotising fasciitis (pain out of proportion, dusky skin, haemorrhagic bullae, crepitus), infected wounds, ulcers, diabetic foot, burns, surgical sites, pressure ulcers.
• Lines and devices — inspect EVERY central line, PICC, peripheral cannula, dialysis catheter, urinary catheter, drain, pacemaker pocket for erythema, purulence, tenderness; palpate along the track.
• Respiratory — consolidation, effusion, crackles, bronchial breathing.
• Abdomen — peritonism (guarding, rigidity, rebound), biliary tenderness (Murphy sign), distension (obstruction, ileus, ischaemia), bladder (retention), organomegaly, ascites.
• Genitourinary — prostate tenderness, testicular (epididymo-orchitis, torsion), pelvic (PID, septic abortion), retained products.
• CNS — neck stiffness, photophobia, petechiae (meningococcaemia), Kernig/Brudzinski signs; focal signs (abscess).
• Ears, throat, sinuses, teeth — otitis media, quinsy, dental abscess, sinusitis.
• Joints and bones — septic arthritis, osteomyelitis, prosthetic joint infection. [1]

The qSOFA bedside screen (reproduce verbatim)

[1]

Bedside observations and severity markers

• Respiratory rate — a rate of 22 per minute or more is a qSOFA component and an early warning sign.
• Blood pressure and MAP — MAP under 65 indicates shock; a falling diastolic and widening pulse pressure signal early vasoplegia even with a preserved systolic.
• Capillary refill time — prolonged CRT signals abnormal peripheral perfusion; in the ANDROMEDA-SHOCK trial, a resuscitation strategy targeting CRT normalisation was tested against lactate normalisation with no significant mortality difference, and CRT-guided patients had less organ dysfunction at 72 hours.[18]
• Skin mottling — a graded marker of peripheral perfusion used at the bedside in septic shock.
• Temperature — fever is typical, but hypothermia occurs and marks severe disease in the vulnerable patient.
• GCS / confusion — altered mentation is a qSOFA component; new confusion is sepsis until proven otherwise.
• Urine output — catheterise and measure hourly; falling urine output signals renal hypoperfusion and evolving AKI.
• Lactate — the key biochemical marker of tissue hypoperfusion; over 2 mmol/L is significant, 4 mmol/L or above is severe. [1]

Assessment of fluid responsiveness

Before giving more fluid, assess whether the heart will eject it — SSC 2021 recommends dynamic measures over static ones. Bedside methods: passive leg raise with a real-time cardiac-output measure (e.g. echocardiography or pulse-contour analysis), a fluid challenge with reassessment of stroke volume, and (in ventilated patients with an arterial line) pulse pressure variation / stroke volume variation. If the patient is not fluid-responsive, start vasopressors/inotropes rather than fluid-loading.[2]

Investigations

The goals of investigation are to confirm infection, quantify organ dysfunction, localise the source, identify the organism, grade the severity, and exclude mimics. Do NOT delay the Hour-1 bundle while waiting for results — cultures are taken in parallel with bundle delivery, and empirical therapy is started before organism identification. [1]

First-line investigations

• Blood cultures — before antimicrobials if this causes no substantial delay; two or more sets (aerobic and anaerobic bottles) from separate sites are standard practice to maximise yield and detect contaminants.[2]
• Full blood count — leukocytosis or leukopenia or a left shift (band forms); thrombocytopenia (a marker of severity and DIC); haemoglobin (acute bleed or anaemia of chronic disease).
• CRP and procalcitonin — CRP is a non-specific acute-phase reactant; procalcitonin is more specific for bacterial infection and can guide antibiotic duration and cessation (a procalcitonin algorithm safely shortens antibiotic courses).
• Urea and electrolytes — creatinine (AKI is a SOFA component); sodium (hyponatraemia in severe sepsis, Legionella), potassium.
• Liver function tests — bilirubin (a SOFA component), AST/ALT, albumin.
• Coagulation — INR, APTT, fibrinogen and D-dimer to screen for DIC (use the ISTH overt-DIC score, below).
• Venous blood gas with lactate — lactate, pH, base excess, glucose; an arterial gas if hypoxaemic or to assess ventilation.
• Glucose — hypoglycaemia is common and dangerous; hyperglycaemia is a stress response.
• Creatinine kinase, troponin, amylase/lipase — as directed by the suspected source.
• Urinalysis and urine culture — nitrites and leucocyte esterase; culture before antibiotics; catheter specimen if necessary.
• Chest X-ray — for a pulmonary source, ARDS, pulmonary oedema, line position.
• Source-directed imaging — CT abdomen/pelvis (peritonism, obstruction, abscess, pancreatic source), CT head then lumbar puncture (meningitis), CT pulmonary angiogram (PE), echocardiography (endocarditis — Duke criteria; cardiac dysfunction), ultrasound (biliary, obstructed renal tract, abdominal collection, line site, lung). [1]

The SOFA score (reproduce verbatim)

The Sequential Organ Failure Assessment (SOFA) score grades six organ systems from 0 (normal) to 4 (severe failure); an acute change in total SOFA of 2 or more points consequent to infection defines sepsis operationally. [1]

(Baseline SOFA is assumed to be 0 in a previously well patient; in a patient with known chronic organ failure, the change from baseline is used.) A SOFA of 2 or more points has an in-hospital mortality over 10 percent.[1]

Lactate — interpretation and re-measurement

[1]

A lactate over 2 mmol/L with infection indicates tissue hypoperfusion (the 'severe sepsis' phenotype of the old definitions). A lactate of 4 mmol/L or above defines severe hypoperfusion for which the Hour-1 bundle directs at least 30 mL/kg crystalloid. Re-measure the lactate at 2 to 4 hours to guide resuscitation: in the Jones randomised trial, targeting a lactate clearance of at least 10 percent per 2 hours was non-inferior to targeting an ScvO2 of 70 percent or above for early sepsis therapy, and serial clearance is a practical bedside goal.[2][17]

The ISTH overt-DIC score (reproduce verbatim)

[1]

Procalcitonin — role and limitations

Procalcitonin rises specifically with bacterial infection (and is suppressed by viral infection via interferon-gamma), making it a useful adjunct to guide the initiation and, more importantly, the duration and cessation of antibiotics — a procalcitonin-based algorithm safely shortens antibiotic exposure without excess adverse outcomes. Limitations: it is also raised after major surgery, trauma, burns, cardiogenic shock and in small-cell lung cancer; it should never override clinical judgement.[2]

Management — Resuscitation

Sepsis is a time-critical emergency. The resuscitation bundle must be delivered concurrently, not sequentially, and within one hour of recognition — the Surviving Sepsis Campaign Hour-1 bundle. The philosophy is: recognise, resuscitate, sample, source-control, support. [1]

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The Surviving Sepsis Campaign 2021 Hour-1 bundle (reproduce verbatim)

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Oxygen and the airway

Give supplemental oxygen to target SpO2 of 94 to 98 percent (or 88 to 92 percent in COPD at risk of CO2 retention). Escalate to high-flow nasal cannulae or non-invasive ventilation for moderate hypoxaemic respiratory failure; intubate and mechanically ventilate for severe respiratory failure, ARDS, falling GCS (under 8), or inability to protect the airway. In the ventilated patient with sepsis-associated ARDS, use lung-protective ventilation (see Definitive management).[2]

Fluid resuscitation — principles and the evidence

• Fluid of choice: balanced crystalloid (Hartmann's / Ringer's lactate / Plasma-Lyte). The SMART trial (Semler 2018) showed that balanced crystalloids reduce the composite of death, new dialysis or persistent renal dysfunction compared with normal saline in critically ill adults — saline, given in volume, causes hyperchloraemic metabolic acidosis, renal vasoconstriction and acute kidney injury.[8]
• Initial volume: at least 30 mL/kg IV crystalloid within the first 3 hours for sepsis-induced hypoperfusion (hypotension or lactate 4 mmol/L or above). Reassess frequently using the markers of perfusion (MAP, lactate, capillary refill, urine output) and dynamic measures of fluid responsiveness (e.g. passive leg raise with a cardiac-output measure, or fluid challenge against stroke-volume/pressure-variation indices).[2]
• Avoid excessive fluid. Positive fluid accumulation is associated with prolonged ventilation, progression of acute kidney injury and increased mortality. The CLOVERS trial (2023) found that an early restrictive strategy (earlier vasopressors, less IV fluid) did not result in significantly lower or higher 90-day mortality (14.0 vs 14.9 percent) than a liberal strategy, while giving about 2 litres less fluid by 72 hours.[2][10]
• Albumin may be added to crystalloid when patients require substantial amounts of fluid (weak); starches are recommended against in sepsis (renal risk).[2]

Vasopressors

• Norepinephrine (noradrenaline) is first-line (strong) — an alpha-agonist (predominantly) that restores vascular tone and MAP; titrate to a target MAP of 65 mmHg.[2]
• Add vasopressin (0.03 units/min fixed dose — a catecholamine-sparing agent) rather than escalating norepinephrine, commonly when norepinephrine reaches around 0.25 to 0.5 mcg/kg/min.
• Epinephrine may be added (or substituted) when an adequate MAP cannot otherwise be maintained (weak); it has alpha and beta activity (risk of arrhythmia and lactate rise).
• Target MAP 65 mmHg. The SEPSISPAM trial (Asfar 2014) found no significant difference in 28- or 90-day mortality between targeting 80 to 85 and 65 to 70 mmHg; the higher target caused more newly diagnosed atrial fibrillation, although among patients with chronic hypertension the high-target group required less renal-replacement therapy.[9]
• Start vasopressors EARLY — if the patient is hypotensive during or after the initial fluid bolus, do NOT wait to finish a full 30 mL/kg before starting norepinephrine; CLOVERS supports early vasopressor use. Norepinephrine and vasopressin may be run peripherally short-term while central access is established (most patients achieve the MAP target within 1 hour).[2][10]

Early source control

Source control — the physical removal of the infective focus — is as important as antibiotics and must be achieved as soon as medically and logistically practical, ideally within 6 to 12 hours of recognition. The principle: drain infected fluid (abscess, empyema, collection), debride infected tissue (necrotising fasciitis, myonecrosis, infarcted bowel), and remove infected devices and lines (central lines, cannulae, urinary catheters, prosthetic material where feasible). An undrained focus is a frequent cause of refractory shock and must be sought actively with imaging. For the surgical abdomen (perforation, ischaemia, cholangitis), surgery or ERCP is definitive and antibiotics are adjunctive.[2]

The legacy of early goal-directed therapy (EGDT)

The protocolised central-venous-oxygen-saturation-targeted (ScvO2 over 70 percent) resuscitation of early goal-directed therapy (EGDT, Rivers 2001) was the dominant paradigm for a decade but was NOT supported by the three large pragmatic trials — ProCESS (2014)[5], ARISE (2014)[6] and ProMISe (2015)[7] — which showed that protocolised EGDT was not superior to usual care and was associated with more fluid, more vasopressors and more central lines. The modern Hour-1 bundle is simpler and centred on lactate, cultures, antibiotics, judicious fluid, and early vasopressors.[2]

Management — Definitive & Stepwise

The definitive management builds on resuscitation with source-directed and resistance-guided antibiotics, source control, organ support, and the prevention of complications. The escalation triggers are explicit. [1]

Antibiotic principles

• Broad-spectrum, source-guided, and local-resistance-guided — cover the likely organisms for the source and the patient's risk profile (MRSA, Pseudomonas, ESBL/CRE).
• Within one hour of recognition in septic shock or high-likelihood sepsis — every hour of delay increases mortality.[4]
• IV at maximum dose; reassess daily.
• De-escalate to culture and sensitivity results within 48 to 72 hours — stop redundant agents, narrow to the narrowest effective spectrum.
• Duration: typically 7 to 10 days for most sepsis; procalcitonin-guided shortening is reasonable; longer courses for undrained foci, S. aureus bacteraemia (minimum 14 days, often longer), fungaemia, and the immunocompromised.[2]

Empirical antibiotic regimens (adapt to local resistance)

[2]

The vasopressor/inotrope ladder

1. Norepinephrine (alpha over beta) — the recommended first-line agent (strong); titrate to an initial target MAP of 65 mmHg.
2. Vasopressin 0.03 units/min (fixed dose) — add rather than escalating norepinephrine (weak); commonly started when norepinephrine is around 0.25 to 0.5 mcg/kg/min. Catecholamine-sparing.
3. Epinephrine — suggested as the next agent to be added (or substituted) when adequate MAP cannot be maintained (weak); may cause arrhythmia and a lactate rise.
4. Dobutamine — add to norepinephrine (or use epinephrine alone) for myocardial dysfunction with persisting hypoperfusion or elevated cardiac filling pressures (weak); the septic heart is often depressed (sepsis-induced cardiomyopathy).[2]

Corticosteroids in septic shock

IV hydrocortisone is suggested (weak recommendation, low-quality evidence) for adults with septic shock with an ongoing vasopressor requirement (e.g. norepinephrine or epinephrine at 0.25 mcg/kg/min or more for at least 4 hours) — not for sepsis without shock. Dose: hydrocortisone 200 mg/day by continuous infusion OR 50 mg IV every 6 hours. The APROCCHSS trial (Annane, NEJM 2018) randomly assigned vasopressor-dependent septic shock patients to hydrocortisone (50 mg IV every 6 hours) plus fludrocortisone (50 mcg daily) for 7 days or placebo, and found lower 90-day mortality with the combination (43.0 vs 49.1 percent; relative risk 0.88); patients also had more vasopressor-free days. Earlier, Annane (JAMA 2002) showed a mortality benefit of hydrocortisone 50 mg every 6 hours plus fludrocortisone 50 mcg daily for 7 days in patients whose shock did not respond to corticotropin. Taper as shock resolves.[2][11][12]

Lung-protective ventilation for sepsis-associated ARDS

• Low tidal volume (6 mL/kg predicted body weight) with plateau pressure 30 cmH2O or less for sepsis-induced respiratory failure with ARDS.
• Titrate PEEP to optimise oxygenation without compromising venous return.
• Prone ventilation for more than 12 hours per day is recommended for sepsis-induced moderate-to-severe ARDS.
• Avoid positive fluid accumulation where possible once resuscitated — fluid overload is associated with prolonged ventilation, AKI progression and increased mortality.
• For early ARDS with PaO2/FiO2 under 150, intermittent or as-needed neuromuscular blockade by bolus is suggested over continuous infusion; ECMO for the most severe, refractory cases.[2]

Supportive measures

• VTE prophylaxis — the critically ill patient is at high VTE risk; SSC 2021 recommends pharmacologic prophylaxis with LMWH over unfractionated heparin and recommends against adding mechanical prophylaxis to pharmacologic prophylaxis (use mechanical alone only when anticoagulation is contraindicated).
• Stress-ulcer prophylaxis — a proton-pump inhibitor for patients with risk factors for gastrointestinal bleeding; not routinely for all.
• Glycaemic control — initiate insulin when glucose is 180 mg/dL (10 mmol/L) or above, targeting approximately 144 to 180 mg/dL (8 to 10 mmol/L); avoid hypoglycaemia and avoid tight control.
• Nutrition — initiate early enteral nutrition within 72 hours (weak recommendation) where feasible; parenteral only if enteral is not.
• Renal replacement therapy — for AKI with refractory hyperkalaemia, acidosis, fluid overload or uraemia; either continuous or intermittent RRT is acceptable, with continuous often used in haemodynamic instability.
• Transfusion — restrictive strategy (strong): transfuse at a haemoglobin threshold of 70 g/L in the absence of ischaemia, acute haemorrhage or myocardial infarction; avoid routine erythropoietin and FFP in the absence of bleeding.[2]

Controversies that are NOT supported

• Vitamin C / thiamine / hydrocortisone ('HAT' or Marik protocol) — the LOVIT trial (Lamontagne 2022) showed that high-dose IV vitamin C increased the risk of death or persistent organ dysfunction compared with placebo in critically ill patients with sepsis; vitamin C is NOT recommended.[13]
• Extracorporeal blood purification (polymyxin B haemoperfusion, CytoSorb) — not routinely supported by evidence.
• Erythropoietin, selenium, IV immunoglobulin (for septic shock without specific indication) — not recommended.

Specific Subtypes & Scenarios

Neonatal sepsis

Early-onset (under 72 hours) — vertical transmission; organisms Group B strep (Streptococcus agalactiae), E. coli, Listeria monocytogenes. Risk factors: PROM over 18 hours, maternal intrapartum fever over 38 deg C, maternal GBS colonisation, prematurity, chorioamnionitis. Presents with non-specific features (temperature instability, respiratory distress, apnoea, poor feeding, lethargy, jaundice, irritability). Empirical therapy: benzylpenicillin + gentamicin (or ampicillin + gentamicin; add cefotaxime if meningitis). Maternal intrapartum GBS prophylaxis (IV benzylpenicillin in labour) reduces early-onset GBS disease. [1]

Late-onset (over 72 hours) — usually nosocomial; organisms coagulase-negative staphylococci (line-related), Klebsiella, S. aureus, Candida. Empirical therapy is guided by the unit's resistance patterns; remove/change central lines.[2]

Paediatric sepsis

Suspect sepsis in any febrile child with altered behaviour, abnormal colour, prolonged capillary refill, tachypnoea, grunting or lethargy. Decompensated (cold) shock is recognised by weak pulses, mottled cool skin, prolonged capillary refill and hypotension (a late sign). Where intensive care is available, SSC paediatric guidelines suggest up to 40 to 60 mL/kg over the first hour, given as 10 to 20 mL/kg balanced-crystalloid boluses titrated to clinical markers of cardiac output, stopping for signs of fluid overload (hepatomegaly, crackles, rising oxygen requirement). Where intensive care is NOT available and the child is not hypotensive, fluid boluses are recommended against: in the FEAST trial (NEJM 2011), bolus fluids increased 48-hour mortality in African children with severe febrile illness and impaired perfusion. Give antimicrobials as soon as possible, within 1 hour of recognising septic shock, and use epinephrine or norepinephrine for fluid-refractory shock; admit to PICU.[15][16]

Sepsis in the immunocompromised and neutropenia

Neutropenic sepsis (neutrophil count under 0.5 x10^9/L, or under 1.0 and falling) is a medical emergency — empirical broad-spectrum antibiotics within one hour of presentation, BEFORE confirmatory cultures. Initial regimen: an anti-pseudomonal beta-lactam (piperacillin-tazobactam, ceftazidime or meropenem) as monotherapy; add vancomycin for suspected line infection, haemodynamic instability, severe mucositis, or known MRSA colonisation. Consider empirical antifungal (echinocandin or mould-active azole) in high-risk neutropenia with persistent fever over 4 to 7 days; antiviral (aciclovir) if mucocutaneous HSV. G-CSF per unit protocol; low threshold for CT chest (looking for invasive fungal disease — halo sign, angioinvasion) and bronchoalveolar lavage. Do not delay antibiotics for cultures.[2]

Surgical abdomen as the source

Perforation (diverticular, appendiceal, peptic ulcer), mesenteric ischaemia, cholangitis, post-operative collection, obstructed infected biliary or urinary system — urgent source control is definitive (surgery, ERCP, percutaneous drainage), and antibiotics are adjunctive. Empirical cover must include anaerobes and Enterobacterales (piperacillin-tazobactam or ceftriaxone + metronidazole). Do not delay surgery for 'stabilisation' that cannot be achieved without source control.[2]

Puerperal and obstetric sepsis; septic abortion

Sources: chorioamnionitis, puerperal endometritis, septic abortion, wound infection, mastitis, retained products of conception. Organisms: Group A strep (rapidly progressive, high mortality), E. coli, anaerobes, and (globally) Gram-negative sepsis. Remove retained products (uterine evacuation), explore and debride wounds, broad-spectrum antibiotics including anaerobic and Group A strep cover (piperacillin-tazobactam + clindamycin for toxin suppression if GAS). Deliver the baby if chorioamnionitis is the source and the pregnancy is viable. Safe antibiotics in pregnancy and breastfeeding: beta-lactams, cephalosporins, macrolides; avoid aminoglycosides, tetracyclines, chloramphenicol, and quinolones where possible.[2]

Toxic shock syndrome and meningococcaemia as sepsis phenotypes

• Toxic shock syndrome — a superantigen-mediated cytokine storm; priorities are urgent source control (remove tampon/foreign body; debride necrotising fasciitis) and antibiotic cover that includes a protein-synthesis inhibitor (e.g. clindamycin) alongside a beta-lactam for toxin suppression. See the dedicated TSS topic.
• Meningococcaemia — Neisseria meningitidis septicaemia with a petechial/purpuric non-blanching rash progressing to purpura fulminans (DIC) and Waterhouse-Friderichsen syndrome (adrenal haemorrhage); treat immediately with a third-generation cephalosporin, and give chemoprophylaxis to close contacts. [1]

Sepsis in cirrhosis and chronic liver disease

The cirrhotic patient is functionally immunocompromised (reticuloendothelial dysfunction, portosystemic shunting, low complement) and prone to spontaneous bacterial peritonitis (SBP), bacteraemia and infection with Gram-negative organisms. SBP presents with ascites, abdominal pain, fever or encephalopathy; diagnose by a raised neutrophil count on diagnostic paracentesis; treat with a third-generation cephalosporin plus IV albumin 1.5 g/kg at diagnosis and 1 g/kg on day 3 — in the Sort trial this combination reduced renal impairment (10 vs 33 percent) and in-hospital mortality (10 vs 29 percent) versus cephalosporin alone. Watch for variceal bleeding risk (coagulopathy, portal hypertension).[19]

Complications & Pitfalls

Early complications

• Refractory vasoplegic shock — mortality from persistent vasodilation, myocardial depression and capillary leak.
• Acute respiratory distress syndrome (ARDS) — bilateral pulmonary infiltrates, refractory hypoxaemia (PaO2/FiO2 under 300); manage with lung-protective ventilation.
• Acute kidney injury — from hypoperfusion, nephrotoxic drugs and inflammation; may require RRT.
• Hepatic dysfunction — cholestatic and hepatocellular; hyperbilirubinaemia.
• Disseminated intravascular coagulation — bleeding and microvascular thrombosis; manage the cause.
• Metabolic — hypoglycaemia or hyperglycaemia; lactic acidosis; electrolyte derangement.
• Ileus, stress ulceration, abdominal compartment syndrome — from fluid overload and splanchnic oedema.
• Sepsis-associated encephalopathy (SAE) — delirium, reduced GCS without CNS infection or focal signs; reversible with resolution of sepsis but associated with longer-term cognitive impairment. [1]

Late complications

• Critical-illness polyneuropathy and myopathy (ICU-acquired weakness) — difficulty weaning from the ventilator, profound limb weakness, slow recovery over months.
• Post-intensive-care syndrome — the triad of physical (weakness, breathlessness), cognitive (impaired memory, executive function) and psychological (PTSD, depression, anxiety) morbidity that persists for months to years.
• Post-sepsis immunoparalysis — increased susceptibility to secondary and nosocomial infections (ventilator-associated pneumonia, C. difficile, candiduria, reactivation of latent viruses — CMV, HSV, EBV).
• Recurrence — survivors are at increased risk of a further sepsis episode in the following year. [1]

Classic errors and pitfalls

1. Delay in antibiotics — the single most preventable cause of avoidable death; in the Kumar cohort survival fell by an average of 7.6 percent per hour of delay.[4]
2. Inadequate or delayed source control — an undrained abscess, an infected line left in situ, or infarcted bowel not resected causes refractory shock; smaller studies favour source control within 6 to 12 hours.[2]
3. Excessive fluid — fluid accumulation risks prolonged ventilation, progression of acute kidney injury and increased mortality; use dynamic measures of fluid responsiveness and stop bolusing when the patient is not fluid-responsive.[2]
4. Delayed vasopressors — waiting to complete the full 30 mL/kg before starting norepinephrine in a profoundly hypotensive patient prolongs hypoperfusion; an early-vasopressor strategy was not harmful in CLOVERS.[2][10]
5. Missing resistant organisms — SSC 2021 recommends empiric MRSA coverage only at high MRSA risk, and empiric antifungal therapy only at high fungal risk — cover accordingly.[2]
6. Forgetting glucose — hyperglycaemia above 180 mg/dL (10 mmol/L) should trigger insulin, but hypoglycaemia is easily missed and dangerous.[2]
7. Failure to de-escalate antibiotics — prolonged broad-spectrum therapy drives resistance; SSC 2021 suggests daily assessment for de-escalation and shorter courses when source control is adequate.[2]
8. Not screening for the source — a 'sepsis of unknown origin' demands active imaging to find and control the focus.[2]
9. Over-reliance on a single number — a normal blood pressure, a normal white count, or a single normal lactate does not exclude sepsis; the trend and the clinical picture decide.

Fluid overload — recognise and avoid

A positive cumulative fluid balance is an independent predictor of mortality in septic shock. Recognise it by rising oxygen requirements, pulmonary crepitations, widespread B-lines on lung ultrasound, abdominal distension and rising ventilator pressures (abdominal compartment syndrome), and peripheral and sacral oedema. Avoid it by reassessing fluid responsiveness before every bolus, starting vasopressors early, and adopting a conservative (de-resuscitative) fluid strategy once the patient is stabilised — guided by perfusion markers and lactate clearance rather than by protocolised volume targets.[10]

Prognosis & Disposition

Case-fatality

• Sepsis: approximately 10 percent in-hospital mortality.
• Septic shock: 30 to 40 percent; by the Sepsis-3 operational definition (vasopressor-dependent hypotension with lactate over 2 after fluids), over 40 percent.[1]
• Predictors of poor outcome: high and non-clearing lactate, high SOFA/APACHE II score, age, immunocompromise, cirrhosis, malignancy, an uncontrollable source, a multidrug-resistant organism, and delayed antibiotics and resuscitation.[3][4]

The effect of time

The single largest modifiable determinant of mortality is the time to effective antimicrobial therapy and adequate resuscitation. In septic shock, each additional hour of delay to effective antimicrobials after the onset of hypotension was associated with an average decrease in survival of 7.6 percent per hour in the Kumar cohort.[4] Early recognition and bundle delivery — the entire point of the Hour-1 bundle — exist to compress this interval.

Disposition

• ICU (level 3): any patient requiring vasopressors, mechanical ventilation, or renal replacement therapy, or with rapidly escalating organ failure.
• HDU (level 2): the patient with single-organ failure or requiring close monitoring but not advanced organ support.
• Ward: the stable septic patient who has been resuscitated, is off vasopressors, and has a controlled source. [1]

Mobilise critical care, the infectious diseases team, microbiology, and (for a surgical source) surgery early. Communicate clearly with the patient and family, including realistic prognostic discussions and escalation plans, and consider goals of care in the setting of advanced comorbidity. [1]

Long-term outcomes — the post-sepsis syndrome

Survivors of sepsis face an increased risk of death and morbidity for months to years afterward — the post-sepsis syndrome. This includes physical impairment (weakness, breathlessness, fatigue — critical-illness polyneuropathy/myopathy), cognitive decline (impaired memory and executive function, especially in the elderly), psychological morbidity (PTSD, depression, anxiety), recurrent infection, and a high rate of rehospitalisation. Survivors have a higher long-term mortality than matched controls. Comprehensive follow-up — rehabilitation, vaccination, functional and cognitive assessment, and management of new or worsened comorbidity — is essential and is increasingly delivered through post-ICU clinics.[3]

Special Populations

Paediatrics

Recognition is harder because the presentation is non-specific; structured paediatric early-warning tools support recognition.[15] Weight-based fluids: in systems with intensive care, SSC paediatric guidelines suggest up to 40 to 60 mL/kg over the first hour as 10 to 20 mL/kg boluses titrated to clinical markers of cardiac output, stopping for signs of fluid overload — but where intensive care is not available, bolus fluid is recommended against in the absence of hypotension (FEAST: boluses increased 48-hour mortality in African children with severe infection).[15][16] Give antimicrobials as soon as possible, within 1 hour of recognising septic shock, and choose epinephrine or norepinephrine (no single first-line agent was recommended) for fluid-refractory shock; either may run peripherally if central access is not immediate.[15] Admit to PICU.

Pregnancy and the puerperium

The pregnant patient has a physiologically raised baseline respiratory rate and heart rate and a mild leukocytosis — interpret these cautiously, and have a low threshold to investigate and treat. Sources: chorioamnionitis, pyelonephritis, appendicitis (right-lower quadrant pain, often higher in pregnancy), cholecystitis, pneumonia, puerperal sepsis, septic abortion. Safe antibiotics: beta-lactams, cephalosporins, macrolides, nitrofurantoin (avoid near term). Avoid (where possible): aminoglycosides (fetal ototoxicity), tetracyclines (teeth/bone), chloramphenicol (grey baby — historical), quinolones (cartilage — caution), trimethoprim (first trimester — neural tube). Left lateral tilt to relieve aortocaval compression during resuscitation. Deliver if the uterus is the source and chorioamnionitis is established.[2]

The elderly

Blunted fever (may be afebrile or hypothermic); atypical presentation (confusion, falls, incontinence, anorexia, 'off legs'); multiple comorbidities and polypharmacy (beta-blockers blunt the tachycardic response, steroids mask inflammation); a lower threshold to escalate; and a higher mortality. The "new confusion in an elderly patient is sepsis until proven otherwise" rule saves lives. [1]

The immunocompromised

Neutropenia, transplant, HIV with low CD4, steroids, biologics — a broader differential (opportunists — Pneumocystis jirovecii pneumonia, invasive fungal disease, CMV, mycobacteria), empirical broad cover, a low threshold for bronchoalveolar lavage and tissue biopsy, and early antifungal and antiviral coverage. Neutropenic sepsis is treated empirically within one hour before cultures.[2]

Asplenia / hyposplenism

Overwhelming post-splenectomy infection (OPSI) is a medical emergency — encapsulated organisms (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, and Capnocytophaga canimorsus after dog bites) cause fulminant, often fatal sepsis with DIC and adrenal haemorrhage. Management: empirical broad-spectrum cover immediately (ceftriaxone; add vancomycin if meningitis), standby emergency antibiotics at home (amoxicillin), and lifelong vaccination (pneumococcal, meningococcal, Haemophilus influenzae type b, influenza annual). See the dedicated asplenia topic. [1]

Chronic liver disease / cirrhosis

Functional immunoparalysis (reticuloendothelial dysfunction, low complement, portosystemic shunting); high risk of spontaneous bacterial peritonitis, bacteraemia, and sepsis with Gram-negatives and enterococci; coagulopathy and variceal bleeding risk complicate management. In cirrhotic patients with SBP and renal impairment, albumin (1.5 g/kg at diagnosis and 1 g/kg on day 3) plus cefotaxime reduced renal impairment (10 vs 33 percent) and in-hospital mortality (10 vs 29 percent) compared with cefotaxime alone (Sort, NEJM 1999); guideline practice is albumin 1.5 g/kg then 1 g/kg for SBP with renal dysfunction. Prognosis is worse than in the non-cirrhotic.[19]

Anticoagulated and dialysis-dependent

Manage DIC (the ISTH overt-DIC score) — transfuse platelets and plasma for bleeding or before invasive procedures; reversal of therapeutic anticoagulation if life-threatening bleeding (warfarin: vitamin K + prothrombin complex concentrate; DOAC: andexanet alfa or PCC; heparin: protamine). Adjust antibiotic doses for renal function (meropenem, piperacillin-tazobactam, vancomycin (level/trough-guided), ceftriaxone needs no adjustment; linezolid needs no adjustment). Vasopressors are safe in dialysis patients — do not withhold them. Ensure VTE prophylaxis despite bleeding risk (use mechanical prophylaxis if pharmacological is contraindicated). [1]

Evidence, Guidelines & Regional Differences

Landmark trials and guidelines

The Surviving Sepsis Campaign 2021 guidelines (Evans, PMID 34599691)

The SSC 2021 guidelines are the global standard. Key recommendations:[2]

• Hour-1 bundle — measure lactate (re-measure if raised), obtain cultures before antibiotics where this causes no substantial delay, broad-spectrum antimicrobials immediately (ideally within 1 h for shock; within 3 h acceptable for possible sepsis without shock), at least 30 mL/kg crystalloid within the first 3 h for sepsis-induced hypoperfusion, vasopressors for hypotension.
• Balanced crystalloids suggested over normal saline for resuscitation (weak recommendation); starches recommended against (strong).
• Norepinephrine first-line (strong); add vasopressin 0.03 units/min rather than escalating norepinephrine; initial target MAP 65 mmHg (strong).
• Restrictive transfusion strategy (strong; trigger typically haemoglobin 70 g/L).
• IV hydrocortisone 200 mg/day suggested (weak) for septic shock with an ongoing vasopressor requirement.
• Lung-protective ventilation (6 mL/kg, plateau pressure 30 cmH2O or less) and prone ventilation over 12 h/day for moderate-severe sepsis-induced ARDS.
• Insulin at glucose 180 mg/dL (10 mmol/L) or above with a typical target of 144 to 180 mg/dL (8 to 10 mmol/L); early (within 72 h) enteral nutrition (weak); pharmacologic VTE prophylaxis (LMWH over UFH); stress-ulcer prophylaxis for patients with GI-bleeding risk factors.
• Do NOT use vitamin C (LOVIT, 2022). [2][13]

Regional deltas

[1] [1] [1]

Current controversies

• Vitamin C / thiamine / hydrocortisone (HAT) — the LOVIT trial (2022) showed harm from high-dose vitamin C; the HAT protocol is not recommended.[13]
• Extracorporeal blood purification (polymyxin B haemoperfusion, CytoSorb) — not routinely supported.
• The optimal MAP target — 65 to 70 mmHg is standard; a higher target may help selected patients with chronic hypertension but is not routine.[9]
• Point-of-care ultrasound (POCUS)-guided resuscitation — increasingly used to assess cardiac function, volume status and the source.
• Restrictive vs liberal fluids — the modern trend is restrictive (early vasopressors), supported by CLOVERS.[10]

Ward-round test

Stem 1. A 72-year-old diabetic woman is confused, afebrile, respiratory rate 26, BP 96/50, lactate 3.2 mmol/L. What is your first move, and what result must you refuse to wait for?[1][2]

Show the answer

Start the Hour-1 bundle now and in parallel: measure lactate, obtain blood cultures before antibiotics (without substantial delay), give broad-spectrum IV antibiotics immediately, give at least 30 mL/kg balanced crystalloid within the first 3 hours for her hypotension, and start vasopressors if MAP stays under 65. Do NOT wait for the SOFA score, the culture result, or the white cell count — suspected sepsis with qSOFA 2 or more and a lactate over 2 mandates bundle activation now.[1][2]

Stem 2. After initial crystalloid resuscitation his MAP is 58 mmHg and his lactate has risen to 5. Name the first drug, the dose target, and what you add next.[2]

Show the answer

Start norepinephrine (noradrenaline) — the first-line agent — and titrate to an initial target MAP of 65 mmHg; do not chase it with more fluid first. Rather than escalating norepinephrine further, add vasopressin at its usual fixed dose of 0.03 units/min (commonly started when norepinephrine is around 0.25 to 0.5 mcg/kg/min). If the vasopressor requirement is ongoing, add hydrocortisone 200 mg/day.[2]

Stem 3. A ward patient "looks septic" but the blood pressure is 124/70 and the lactate is normal. Can you safely exclude sepsis?[1]

Show the answer

No. A normal blood pressure does not exclude sepsis. Compensatory vasoconstriction and tachycardia hold the MAP until reserve is exhausted, and cytopathic hypoxia can raise the lactate late. New confusion, tachypnoea, or a qSOFA of at least 2 in an elderly or immunocompromised patient is sepsis until proven otherwise.[1]

Exam Pearls

• Sepsis = life-threatening organ dysfunction from a dysregulated host response to infection (Sepsis-3); operationally an acute SOFA increase of 2 or more points. SIRS is retired as a defining criterion.[1]
• Septic shock = vasopressor-dependent hypotension (MAP at least 65) AND lactate over 2 despite adequate fluids; mortality over 40 percent.[1]
• qSOFA = RR 22 or more, altered mentation (GCS under 15), SBP 100 or less (2 of 3); bedside escalation tool — SSC 2021 recommends against using it as the sole screen.[1][2]
• Hour-1 bundle: measure lactate (re-measure if raised), blood cultures before antibiotics, broad-spectrum antibiotics immediately, at least 30 mL/kg crystalloid within the first 3 hours for hypoperfusion, vasopressors for hypotension.[2]
• Norepinephrine is first-line vasopressor; target MAP at least 65; add vasopressin; hydrocortisone 200 mg/day for refractory shock.[2]
• Balanced crystalloids preferred over saline for resuscitation (SMART, SSC 2021); an early restrictive fluid strategy with earlier vasopressors did not change 90-day outcome (CLOVERS); starches are recommended against.[2][8][10]
• Measure lactate; re-measure if raised — a clearance target of at least 10 percent per 2 hours is an accepted resuscitation goal (Jones trial, non-inferior to ScvO2 targeting).[17]
• Antibiotics immediately, ideally within one hour, in possible septic shock; survival fell by an average 7.6 percent per hour of delay in the Kumar cohort.[2][4]
• Source control (drain, debride, remove lines) alongside antibiotics; smaller studies favour achieving it within 6 to 12 hours.[2]
• Common sources: lung, abdomen, urinary tract, skin/soft tissue, line/device, CNS, endovascular — with the highest burden in sub-Saharan Africa, south Asia and east Asia.[3]
• Suspect adrenal crisis in refractory vasopressor-dependent shock; give empirical hydrocortisone.[11]
• DIC in sepsis: low platelets, low fibrinogen, raised PT/APTT, raised D-dimer; treat the cause (sepsis), support with blood products only if bleeding/procedure.
• Sepsis-associated encephalopathy = delirium/reduced GCS without CNS infection or focal signs.
• Warm shock (early vasoplegic) vs cold shock (late decompensated) — guides resuscitation.
• Procalcitonin guides antibiotic duration, not the diagnosis of sepsis.

References

1. [1]Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA, 2016.PMID 26903338
2. [2]Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 Intensive Care Med, 2021.PMID 34599691
3. [3]Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study Lancet, 2020.PMID 31954465
4. [4]Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Crit Care Med, 2006.PMID 16625125
5. [5]Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock N Engl J Med, 2014.PMID 24635773
6. [6]Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock N Engl J Med, 2014.PMID 25272316
7. [7]Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock N Engl J Med, 2015.PMID 25776532
8. [8]Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults N Engl J Med, 2018.PMID 29485925
9. [9]Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock N Engl J Med, 2014.PMID 24635770
10. [10]Shapiro NI, Douglas IS, Brower RG, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension N Engl J Med, 2023.PMID 36688507
11. [11]Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA, 2002.PMID 12186604
12. [12]Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock N Engl J Med, 2018.PMID 29490185
13. [13]Lamontagne F, Masse MH, Menard J, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit N Engl J Med, 2022.PMID 35704292
14. [14]Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 Intensive Care Med, 2017.PMID 28101605
15. [15]Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children Intensive Care Med, 2020.PMID 32030529
16. [16]Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection N Engl J Med, 2011.PMID 21615299
17. [17]Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial JAMA, 2010.PMID 20179283
18. [18]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.PMID 30772908
19. [19]Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis N Engl J Med, 1999.PMID 10432325