Sepsis & Septic Shock — CritCare.in

📘 1 · Washington Manual of Critical Care, 4th Ed

Washington Manual Summary

"Sepsis is a medical emergency requiring immediate and simultaneous diagnostic evaluation and therapeutic intervention. Every hour of delay in appropriate antibiotic therapy increases mortality by approximately 7%."

Washington Manual of Critical Care, 4th Ed. (Kollef & Witt, eds.) Wolters Kluwer 2023. Chapter: Sepsis and Septic Shock.

Clinical Synopsis

Sepsis: Life-threatening acute organ dysfunction from dysregulated host response to infection. SOFA ≥2 from baseline = sepsis. Hospital mortality ~10–30%.
Septic Shock: Sepsis requiring vasopressors to maintain MAP ≥65 mmHg AND lactate >2 mmol/L despite adequate resuscitation. Mortality >40%.
Recognition: Use NEWS2/MEWS/SIRS (not qSOFA alone) for screening — SSC 2026 Strong recommendation.
Epidemiology: ~49 million cases/year worldwide; 13 million sepsis-related deaths annually. Leading cause of ICU mortality in India. Most common sources: urinary, pneumonia, abdominal, bacteraemia.
Time-sensitive: Every 30 min delay in antibiotics measurably increases mortality. Treat as urgently as STEMI.

Diagnostic Criteria at a Glance

Tool	Variables	Threshold	Use
SOFA	Resp, Coag, Liver, CVS, CNS, Renal (0–4 pts each)	≥2 from baseline = Sepsis	Diagnoses sepsis; each point ↑ mortality ~10%
NEWS2	RR, SpO₂, O₂, SBP, HR, Consciousness, Temp	≥5 = high risk	Best screening — SSC 2026 Strong rec over qSOFA
qSOFA	RR ≥22 \| GCS <15 \| SBP ≤100	≥2 points	Prognostic only — NOT for sepsis screening (SSC 2026)
Lactate	Serum lactate (mmol/L)	>2 = septic shock; >4 = very high risk	Septic shock criterion; clearance ≥10%/2h = goal

📗 2 · Marino's The ICU Book, 5th Edition (2025)

Marino Physiology — Why Sepsis Kills

🔬 How sepsis progresses to multi-organ failure

TriggerInfection — microbial invasion (PAMPs recognised by the host)

Neutrophil activation → respiratory burst & reactive oxygen speciesoxidant injury spills onto host endothelium

Dysregulated cytokine surge — TNF-α, IL-1, IL-6 ("malignant inflammation")

Endothelial NO → vasodilatation + capillary leak↓↓ SVR & hypovolaemia — warm/hyperdynamic shock

Mitochondrial dysfunctionimpaired O₂ utilisation (cytopathic hypoxia); lactate rises

Microcirculatory failure + splanchnic hypoperfusion → gut-barrier failure

Pathological stateMulti-organ dysfunction — AKI, ARDS, septic cardiomyopathy, encephalopathy

"The mortality rate in sepsis is not related to the causative organism, including multidrug-resistant organisms. This observation is consistent with the notion that the major problem in sepsis is not the infection, but the host response to infection."

Marino PL. The ICU Book, 5th Ed. Ch.17: Inflammatory Shock Syndromes. Wolters Kluwer; 2025. p.305

Step 1 — Neutrophil Activation and the Respiratory Burst

📗 Marino Ch.17, p.300–303

Invading microbes trigger circulating neutrophils → respiratory burst (20-fold ↑ in O₂ consumption, lasting 15–20 min). NADPH oxidase activates → generates reactive oxygen species (ROS): superoxide radical → hydrogen peroxide → hypochlorite. ROS kill microbes but also damage the host's vascular endothelium, proteins, lipids, and DNA = oxidant injury.

Critical insight: this inflammatory injury can become self-sustaining (malignant inflammation) — injury triggers more inflammation → multi-organ failure cascade.

Step 2 — Haemodynamic Consequences (Hyperdynamic/Warm Shock)

📗 Marino Ch.17, p.305–307

Proinflammatory cytokines (TNF-α, IL-1, IL-6) → endothelial NO release → profound vasodilation → ↓↓ SVR — the dominant haemodynamic lesion
Oxidant injury to endothelium → capillary leak → hypovolaemia (fluid leaves the intravascular compartment)
Cardiac output is typically increased (tachycardia + ↓ afterload) — this defines "warm/hyperdynamic shock"
Splanchnic blood flow reduced despite ↑ overall CO → gut mucosal disruption → bacterial translocation → worsens sepsis
Late sepsis → cytokine-mediated septic cardiomyopathy → ↓ CO → poor prognosis

Step 3 — The Critical Insight: Mitochondrial Dysfunction

📗 Marino Ch.17, p.307 — "Two Very Important Implications"

Organ dysfunction in sepsis results from mitochondrial dysfunction: oxidative damage to the electron transport chain + cytokine inhibition of pyruvate dehydrogenase → ↓ mitochondrial O₂ consumption → ↑ tissue PO₂ (paradoxically elevated O₂ in skeletal muscle). Marino cites direct measurements showing elevated muscle PO₂ in severe sepsis patients.

Implication 1 (Marino, p.307): Since tissue O₂ levels are NOT impaired in septic shock, the liberal use of supplemental O₂ to "promote tissue oxygenation" is not justified, and could be harmful (by promoting oxidant stress).

Implication 2 (Marino, p.307): Elevated plasma lactate in septic shock is NOT the result of inadequate tissue oxygenation. Lactate is an alternative energy source during metabolic stress. Therefore ScvO₂ is inappropriately elevated in sepsis (↓ O₂ extraction from microcirculation) and is unreliable as a resuscitation endpoint.

Step 4 — Organ Failure Cascade (Marino Table 17.1)

Organ System	Clinical Condition	Mechanism
Brain	Septic encephalopathy	Microglial activation, BBB disruption, neurotransmitter imbalance
Bone Marrow	Anaemia of critical illness	Inflammatory suppression of erythropoiesis
Heart/Vasculature	Septic shock, cardiomyopathy	Cytokine-mediated systolic + diastolic dysfunction
Kidneys	Acute Kidney Injury (AKI)	Endothelial dysfunction, microvascular coagulation
Lungs	ARDS	Neutrophil-mediated alveolar capillary injury
Peripheral Nerves	Critical illness polyneuropathy	Axonal degeneration from microvascular disease
Skeletal Muscle	ICU-acquired weakness	Rhabdomyolysis, critical illness myopathy

Mortality rises directly with number of organ failures: each additional organ failing adds ~15–20% absolute mortality (Marino Figure 17.2 — data from US and European surveys).

📋 3 · SSC 2026 — International Guidelines

Latest Guideline Recommendations

Prescott HC, et al. Surviving Sepsis Campaign 2026. Crit Care Med. 2026;54(4):725–812 | 129 statements | Evidence through June 2025

A. Screening

Statement 4 Strong · Moderate certainty

Use NEWS, NEWS2, MEWS, or SIRS over qSOFA as a single screening tool. Upgraded from 2021

B. Fluid Resuscitation

Statement 10 Conditional · Low certainty

At least 30 mL/kg IV crystalloid in first 3 hours if hypoperfusion or lactate ≥4 mmol/L. (In BMI >30: calculate using adjusted/ideal body weight)

Statement 44 Conditional · Moderate certainty

Balanced crystalloids over 0.9% saline. Upgraded from Low certainty | Exception: TBI → 0.9% saline

Statement 45 Conditional · Moderate certainty

Crystalloids ALONE over albumin. Changed from 2021 | Exception: large crystalloid volumes already given; cirrhosis. Avoid albumin in TBI.

Statement 89 Conditional · Very low certainty NEW 2026

After acute resuscitation phase: active fluid removal (diuretics; if insufficient → ultrafiltration) to achieve deresuscitation.

C. Vasopressors

Statement 13 Strong · Moderate certainty

Initial MAP target ≥65 mmHg. New remark: range ±5 mmHg acceptable (60–70 mmHg).

Statement 14 Conditional · Low certainty NEW 2026

For adults ≥65 years: initial MAP range 60–65 mmHg over higher ranges. (Permissive hypotension reduces vasopressor burden; meta-analysis showed reduced mortality in elderly)

Statement 42 Conditional · Very low certainty

Either invasive OR non-invasive BP monitoring acceptable. Changed from 2021 (EVERDAC trial: non-invasive non-inferior). Arterial line for: high-dose vasopressors, escalating doses, frequent ABGs.

Statement 55 Conditional — over vasopressin/Ang II

Norepinephrine first-line vasopressor. Downgraded from Strong over vasopressin/Ang II | Still STRONG over dopamine, epinephrine, selepressin

D. Antimicrobials

Statement 16 Strong · Very low certainty

Administer antibiotics within 1 hour of recognising septic shock.

Statement 33 Strong · Moderate certainty Upgraded to Strong

Prolonged (extended) infusion of beta-lactams for maintenance after loading dose. Loading: 30 min; Maintenance: 3–4h infusion. Maximises time above MIC for time-dependent antibiotics.

Statement 36 Strong · Very low certainty Upgraded to Strong

De-escalate antimicrobial therapy when confirmed microbiological diagnosis + susceptibility available.

Statement 28 Conditional NEW 2026

Without anaerobic infection risk factors: no anaerobic coverage in empirical regimen. Anaerobic risk: intra-abdominal, deep gynae/obstetric, necrotizing soft tissue, head/neck, CNS abscess.

Statement 27 Conditional · Low certainty

Against routine empirical antifungal. Changed from dual 2021 rec | Consider case-by-case: immunocompromised, prolonged antibiotics/hospitalisation, intra-abdominal source.

E. Adjuncts

Statement 79 Conditional · Low certainty

IV corticosteroids in septic shock. Certainty downgraded from Moderate | Trigger: NE ≥0.25 mcg/kg/min. Dose: Hydrocortisone 50 mg IV q6h (200 mg/day) × 7 days. Marino (p.309): hastens shock reversal ~1.5 days but does NOT improve survival.

💊 4 · Drug Doses & Dilutions

Drug Doses, Ampoule Compositions & Dilutions

Per Marino 5th Ed Table 17.2 + SSC 2026 + ISCCM 2020. Doses based on Ideal Body Weight (IBW).

IBW (Devine): Male = 50 + 2.3 × (Ht inches − 60) | Female = 45.5 + 2.3 × (Ht inches − 60)
Rate (ml/hr) = Dose (mcg/kg/min) × IBW (kg) × 60 ÷ Concentration (mcg/ml)

Drug	Ampoule	Standard Dilution	Starting Dose	Range	When
Noradrenaline	4 mg/4 ml	4 mg in 46 ml NS = 80 mcg/ml	0.05–0.1 mcg/kg/min	0.01–3 mcg/kg/min	1st line. Peripheral OK <12h.
Vasopressin	20 IU/1 ml	20 IU in 19 ml NS = 1 IU/ml → 1.8 ml/hr	0.03 IU/min — FIXED	0.03 IU/min only	NE >0.25 mcg/kg/min (Marino Table 17.2)
Adrenaline	1 mg/ml (1:1000)	5 mg in 45 ml NS = 100 mcg/ml	0.05–0.1 mcg/kg/min	0.01–1 mcg/kg/min	3rd vasopressor (Marino Table 17.2)
Dobutamine	250 mg/20 ml	250 mg in 250 ml NS = 1000 mcg/ml	2.5–5 mcg/kg/min	2.5–20 mcg/kg/min	Low CO: cold peripheries, ScvO₂ <65%, low EF on echo
Hydrocortisone	100 mg vial	200 mg in 50 ml NS = 4 mg/ml	50 mg IV q6h	200 mg/day × 7 days	NE ≥0.25 mcg/kg/min (Marino p.309; SSC 2026)

NE Dose-to-Rate Table (80 mcg/ml solution)

Dose (mcg/kg/min)	50 kg	60 kg	70 kg	80 kg	Clinical Note
0.05	1.9 ml/hr	2.3 ml/hr	2.6 ml/hr	3.0 ml/hr	Starting dose
0.1	3.8 ml/hr	4.5 ml/hr	5.3 ml/hr	6.0 ml/hr	Usual starting
0.25	9.4 ml/hr	11.3 ml/hr	13.1 ml/hr	15.0 ml/hr	ADD vasopressin here (Marino + SSC 2026)
0.5	18.8 ml/hr	22.5 ml/hr	26.3 ml/hr	30.0 ml/hr	High dose — refractory shock

Antibiotics — Extended Infusion Protocol (SSC 2026 Strong Recommendation)

Source	Likely Pathogen	Loading Dose (30 min)	Extended Infusion Maintenance
Septic shock — unknown source	GNB + MRSA risk	Meropenem 1g IV over 30 min	1g over 3h q8h + Vancomycin 25 mg/kg load if MRSA risk
Urosepsis — ESBL+	Klebsiella, E.coli ESBL	Meropenem 1g IV over 30 min	1g over 3h q8h (no metronidazole — no anaerobic risk)
HAP/VAP — MDR	Pseudomonas, Acinetobacter	Pip-Taz 4.5g IV over 30 min	4.5g over 4h q6h
Abdominal sepsis	GNB + Anaerobes	Meropenem 1g IV over 30 min	1g over 3h q8h (Meropenem covers anaerobes)
XDR Acinetobacter	Acinetobacter XDR	Colistin 9 MIU IV load	Colistin 4.5 MIU q12h + Meropenem 2g over 3h q8h

🗺 5 · Clinical Flowchart

Step-by-Step Clinical Algorithm

Based on Marino 5th Ed Table 17.2 + SSC 2026 Statements 10, 13, 55 + ISCCM 2020

Recognition — Screen with NEWS2/MEWS

Suspected infection + NEWS2 ≥5 OR qSOFA ≥2 → Sepsis Alert. Septic shock = vasopressors needed + lactate >2 mmol/L despite fluids. Begin resuscitation immediately — do not sequence, do simultaneously.

Hour-1 Bundle (All 5 Simultaneously)

Blood cultures × 2 before antibiotics (aerobic + anaerobic, 2 sites)
Lactate — if >2 mmol/L: re-measure at 2h; if >4: high risk regardless of BP
Antibiotics within 1 hour (septic shock) — see drug table above
Crystalloid 30 ml/kg IBW IV if MAP <65 or SBP <90 or lactate ≥4
Vasopressors if MAP <65 during/after fluids — peripheral start is OK (SSC 2026)

Vasopressor Escalation (per Marino Table 17.2 + SSC 2026)

Step 1: Noradrenaline → titrate to MAP 65–70 (60–65 if age ≥65 — NEW SSC 2026)
Step 2: NE >0.25 mcg/kg/min → add Vasopressin 0.03 IU/min (FIXED dose)
Step 3: Still refractory → add Adrenaline + Hydrocortisone 200 mg/day
Step 4: Echo: low EF + cold extremities + ScvO₂ <65% → add Dobutamine 5 mcg/kg/min

Fluid Reassessment (Beyond 30 ml/kg)

Use dynamic parameters: Passive Leg Raise (CO ↑ ≥10% = fluid responsive) | PPV ≥13% (ventilated, SR) | IVC collapsibility >50%. Avoid fluid overload — target neutral balance from 24–48h after stabilisation (Marino Ch.11).

Antibiotic Strategy (SSC 2026)

Loading dose (30 min) → Switch to extended infusion (3–4h) = STRONG REC. Review cultures at 48–72h → de-escalate (STRONG REC). No routine anaerobic coverage unless risk factors. Duration: 7 days adequate for most. PCT-guided de-escalation where available.

Monitoring Targets

Deresuscitation (NEW SSC 2026 Statement 89)

Once haemodynamically stable (off or low vasopressors): furosemide 40–80 mg IV to achieve negative fluid balance. Fluid overload (>10% body weight gain) independently increases mortality. Target neutral/negative balance from 24–48h after stabilisation.

⚠️ 6 · Common Mistakes

Common Mistakes — What NOT to Do

❌ Mistake 1 — Waiting for CVC Before Starting Vasopressors

SSC 2026 explicitly: start noradrenaline peripherally (antecubital/wrist). Do not delay 30 minutes inserting a CVC while MAP is 50. Peripheral NE is safe ≤12h with site monitoring q30 min.

❌ Mistake 2 — Using Dopamine as First-Line

SOAP II (De Backer NEJM 2010): dopamine → more arrhythmias (24% vs 12%); worse mortality in cardiogenic shock subgroup. SSC 2026: STRONG recommendation for NE over dopamine. Marino (p.308) also endorses this.

❌ Mistake 3 — Titrating Vasopressin Dose Up

Vasopressin = 0.03 IU/min ONLY (fixed). Increasing dose causes catastrophic mesenteric + coronary ischaemia, skin necrosis. It is not titrated — it is on or off. (Marino Table 17.2; SSC 2026)

❌ Mistake 4 — Giving Albumin Routinely

SSC 2026 CHANGED: crystalloids alone preferred (moderate certainty). Updated meta-analysis: albumin has no mortality benefit in sepsis. Use only if: cirrhosis or already gave large crystalloid volumes. Avoid in TBI.

❌ Mistake 5 — Not De-escalating Antibiotics at 48–72h

SSC 2026 UPGRADED to STRONG recommendation. Culture results at 48–72h → narrow spectrum. 14-day courses cause CDiff, AMR, nephrotoxicity without benefit. 7 days adequate for most infections.

❌ Mistake 6 — Using ScvO₂ as Resuscitation Endpoint

Marino (Ch.17 p.307): mitochondrial dysfunction → ↓ O₂ extraction → ScvO₂ inappropriately ELEVATED. ScvO₂ is unreliable in sepsis. Use lactate clearance (≥10%/2h) as the primary resuscitation endpoint instead.

❌ Mistake 7 — Routine Anaerobic Coverage for All Sepsis

NEW SSC 2026: no anaerobic coverage unless specific risk factors. Lung/urinary/unknown source sepsis does NOT need metronidazole. Unnecessary = hepatotoxicity + CDiff risk + AMR selection.

❌ Mistake 8 — Liberal Supplemental O₂ to "Promote Tissue Oxygenation"

Marino (Ch.17 p.307): tissue O₂ is NOT impaired in sepsis — mitochondria cannot use it. Liberal supplemental O₂ in normoxic sepsis is NOT justified and is potentially harmful (oxidant stress). Target SpO₂ 92–96% only.

🎓 7 · Exam Pearls — DrNB / PDCC / IFCCM / EDIC

Exam Pearls

Q: Define sepsis vs septic shock (Sepsis-3, 2016).
Sepsis = life-threatening organ dysfunction (SOFA ≥2) from dysregulated host response to infection. Septic shock = sepsis + vasopressors to maintain MAP ≥65 + lactate >2 mmol/L despite adequate fluids. Mortality: sepsis ~15%; septic shock >40%.

Q: SSC 2026 — which screening tool is now recommended over qSOFA?
NEWS, NEWS2, MEWS, or SIRS (Strong recommendation, moderate certainty). qSOFA is a prognostic tool — it predicts ICU admission/death but misses ~40% of sepsis at presentation. Four systematic reviews confirmed EWS scores are more sensitive.

Q: NEW SSC 2026 — MAP target for patients ≥65 years in septic shock?
60–65 mmHg (Conditional recommendation, low certainty). NEW in 2026. Meta-analysis: lower target associated with reduced mortality in elderly. Less vasopressor exposure without harming organ perfusion.

Q: Per Marino 5th Ed — why is lactate elevated in septic shock? Is it anaerobic?
NO. Marino (Ch.17, p.307): mitochondrial dysfunction (pyruvate dehydrogenase inhibition + oxidative damage to electron transport chain) → ↓ mitochondrial O₂ consumption → lactate is produced as alternative energy source during metabolic stress. It does NOT indicate tissue hypoxia. Tissue PO₂ is actually elevated in sepsis.

Q: Extended infusion of beta-lactams — what grade in SSC 2026? Why?
STRONG recommendation (moderate certainty) — upgraded from Conditional in 2021. Loading dose (30 min) → maintenance by 3–4h infusion. Beta-lactams are time-dependent antibiotics: keeping drug levels above MIC for longer = better bactericidal effect.

Q: What changed about albumin in SSC 2026?
Changed from 2021. Now: crystalloids ALONE preferred (Conditional, moderate certainty). Updated meta-analysis: albumin has no effect on sepsis mortality. Exceptions: large crystalloid volumes already given; cirrhosis. Always avoid albumin in TBI.

Q: Trigger and dose for hydrocortisone in septic shock (Marino + SSC 2026)?
Trigger: NE ≥0.25 mcg/kg/min (SSC 2026) or NE ≥0.25–0.5 mcg/kg/min (Marino Table 17.2). Dose: Hydrocortisone 50 mg IV q6h (= 200 mg/day) × 7 days. Marino (p.309): hastens shock reversal ~1.5 days but does NOT improve survival rate.

Q: Why is ScvO₂ unreliable in septic shock? (Marino insight)
Marino Ch.17: mitochondrial dysfunction → ↓ O₂ extraction from microcirculation → ScvO₂ is inappropriately ELEVATED (not because O₂ delivery is adequate, but because the mitochondria cannot use it). Use lactate clearance ≥10%/2h as the reliable resuscitation target instead.

📚 8 · References

References

Marino PL. Marino's The ICU Book, 5th edition. Chapter 17: Inflammatory Shock Syndromes (pp.300–319). Philadelphia, PA: Wolters Kluwer; 2025. ISBN: 978-1-975176-71-6.
Marino PL. Marino's The ICU Book, 5th edition. Chapter 14: Approaches to Clinical Shock (pp.249–272). Philadelphia, PA: Wolters Kluwer; 2025.
Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Crit Care Med. 2026;54(4):725–812.
Prescott HC, Antonelli M, Alhazzani W, et al. Executive Summary: Surviving Sepsis Campaign 2026. Crit Care Med. 2026;54(4):715–724.
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810.
Myatra SN, et al. ISCCM Position Statement on Sepsis and Septic Shock 2020. Indian J Crit Care Med. 2020;24(S1):S1–S28.
De Backer D, Biston P, Devriendt J, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock (SOAP II). N Engl J Med. 2010;362(9):779–789.
Russell JA, Walley KR, Singer J, et al. Vasopressin versus Norepinephrine in Septic Shock (VASST). N Engl J Med. 2008;358(9):877–887.
Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS). N Engl J Med. 2018;378(9):809–818.
NICE-SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med. 2009;360(13):1283–1297.
Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults (SMART). N Engl J Med. 2018;378(9):829–839.
Asfar P, Meziani F, Hamel JF, et al. High versus Low Blood-Pressure Target in Septic Shock (SEPSISPAM). N Engl J Med. 2014;370(17):1583–1593.
Washington Manual of Critical Care, 4th Edition. Kollef MH, Witt CA (eds). Chapter: Sepsis and Septic Shock. Philadelphia, PA: Wolters Kluwer; 2023.
Oh TE (ed). Oh's Intensive Care Manual, 8th edition. Chapters 65–67: Sepsis and SIRS. Elsevier; 2018.