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Sepsis: Etiology, Pathogenesis, ICU Care, and 2026 SSC Guidelines

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1. Definition (Sepsis-3, 2016 - Still Current)

• Persistent hypotension requiring vasopressor support (MAP <65 mmHg despite adequate volume resuscitation), AND
• Serum lactate >2 mmol/L

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2. Etiology

Pathogens

• ~88% of sepsis cases are community-onset (detected within 48 h of hospitalization); ~12% are hospital-onset
• ~53% of U.S. cases are bacterially culture-positive, with roughly equal split between gram-positive and gram-negative organisms
• Gram-positive organisms: Staphylococcus aureus (including MRSA), Streptococcus spp., Enterococcus spp. (13.6% antibiotic-resistant)
• Gram-negative organisms: Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa (13.2% resistant to ceftriaxone, extended-spectrum beta-lactams, or carbapenems)
• Viruses, fungi, and parasites can also cause sepsis

Sites of Infection (most common)

Risk Factors

• Extremes of age, immunosuppression, malignancy
• Chronic diseases (diabetes, CKD, liver disease, HIV)
• Recent surgery, invasive devices (lines, catheters)
• Genetic polymorphisms in immune-response genes

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3. Pathogenesis

3a. Pattern Recognition and Innate Immune Activation

• Pathogen-associated molecular patterns (PAMPs) - e.g., LPS (lipopolysaccharide) from gram-negative bacteria, lipoteichoic acid from gram-positive bacteria - bind to pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) on neutrophils, macrophages, and endothelial cells
• Damage-associated molecular patterns (DAMPs) from injured host cells amplify this signal
• TLR activation triggers NF-kB signaling, leading to massive release of proinflammatory cytokines: TNF-alpha, IL-1beta, IL-6, IL-8, and others

3b. The Cytokine Storm

• The initial hyperinflammatory phase drives fever, vasodilation, capillary leak, and organ dysfunction
• Subsequently, a compensatory anti-inflammatory response (CARS) with IL-10, TGF-beta may lead to immune paralysis/immunosuppression - the "two-hit" model
• This immunosuppressive phase is associated with secondary infections and prolonged ICU stays

3c. Endothelial Dysfunction and Microvascular Failure

• Cytokines and activated neutrophils injure the endothelium, disrupting the glycocalyx
• Results in: increased vascular permeability (capillary leak, edema), loss of vasomotor tone, impaired microcirculatory flow
• This is a key driver of distributive shock - markedly decreased systemic vascular resistance (SVR) with initially elevated cardiac output

3d. Coagulation Cascade Activation

• Cytokines induce tissue factor expression on endothelium and monocytes, activating the extrinsic coagulation pathway
• Simultaneous suppression of antithrombotic molecules (antithrombin III, activated protein C, TFPI) and activation of antifibrinolytic molecules
• Results in microvascular thrombi -> organ ischemia, and paradoxically bleeding via factor/platelet consumption
• Up to 35% of septic shock patients meet DIC criteria (thrombocytopenia + elevated fibrin split products + decreased fibrinogen + prolonged PT/INR)
• Sepsis-induced coagulopathy (SIC) scoring (platelets + PT + SOFA) is more sensitive for early detection

3e. Mitochondrial Dysfunction and Cellular Metabolic Failure

• Even with adequate macro-circulation, cells cannot use oxygen effectively ("cytopathic hypoxia")
• Reactive oxygen species (ROS) and nitric oxide (NO) - massively upregulated via iNOS - impair mitochondrial function
• Leads to lactic acidosis even without tissue hypoperfusion

3f. Organ-Specific Consequences

• Lungs: Neutrophil sequestration, diffuse alveolar damage -> ARDS
• Kidneys: Tubular epithelial injury, reduced renal blood flow, microvascular inflammation -> AKI (due to sepsis itself, nephrotoxic drugs, contrast)
• Liver: Aminotransferase elevation, bilirubin rise; the liver also participates as a mediator source
• Brain: Sepsis-associated encephalopathy from impaired cerebral microcirculation, BBB disruption, cerebral edema
• Heart: Septic cardiomyopathy (myocardial depression), partly reversible, attributed to TNF-alpha, IL-1, nitric oxide excess
• Adrenals: Relative adrenal insufficiency is common in severe sepsis

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4. ICU Care (Standard Evidence-Based Management)

4a. Screening and Recognition

• Use SOFA score for diagnosis in ICU settings
• qSOFA as a rapid screening tool outside the ICU
• Measure serum lactate: lactate ≥2 mmol/L = tissue hypoperfusion; ≥4 mmol/L = high mortality risk even without hypotension

4b. Blood Cultures and Source Control

• Obtain at least 2 sets of blood cultures (aerobic and anaerobic) before antibiotics - but do NOT delay antibiotics more than 45 minutes for cultures
• Identify and control the source: drain abscesses, remove infected devices, debride infected tissue - ideally within 6-12 hours

4c. Antimicrobial Therapy

• Start broad-spectrum empiric IV antibiotics as early as possible (within 1 hour of recognition in septic shock)
• Tailor choice to likely source, local resistance patterns, immune status, and risk of MDR organisms
• De-escalate based on culture results and clinical improvement
• Recommended duration: typically 7-10 days (shorter in uncomplicated urinary/soft tissue source); procalcitonin-guided de-escalation is supported

4d. Hemodynamic Resuscitation

• 30 mL/kg IV crystalloid (balanced crystalloids preferred over 0.9% NaCl) within the first 3 hours - but guided by dynamic assessments of fluid responsiveness
• Avoid excessive fluids (liberal fluids not superior to conservative strategy after initial resuscitation)

• Target MAP ≥65 mmHg
• Norepinephrine is the first-line vasopressor
• Add vasopressin (0.03 units/min) if norepinephrine doses are escalating or to spare norepinephrine
• Epinephrine as add-on or alternative
• Dopamine: only in selected patients (bradycardia, low cardiac output), not first-line
• Avoid dopamine as first-line vasopressor (more arrhythmias, higher mortality vs. norepinephrine)

• Central venous access; arterial line for continuous BP monitoring
• Point-of-care ultrasound (POCUS) for cardiac function assessment
• Dynamic fluid responsiveness tests (pulse pressure variation, straight-leg raise)

4e. Corticosteroids

• Hydrocortisone 200 mg/day (IV infusion or intermittent dosing) in septic shock not responding to adequate fluids AND vasopressors (shock reversal faster, but no clear mortality benefit at 90 days)
• Do NOT use in sepsis without shock

4f. Mechanical Ventilation (if ARDS develops)

• Lung-protective ventilation: tidal volume 6 mL/kg ideal body weight; plateau pressure <30 cmH2O
• PEEP titration to maintain oxygenation
• High PEEP in moderate-severe ARDS
• Prone positioning (≥16 hours/day) in moderate-severe ARDS (PaO2/FiO2 <150)
• Neuromuscular blockade: consider short-course cisatracurium in severe early ARDS
• HFNC and non-invasive ventilation: consider before intubation in hypoxemic respiratory failure

4g. Glucose Control

• Maintain blood glucose 140-180 mg/dL (7.8-10 mmol/L)
• Avoid hypoglycemia; intensive insulin therapy (target <110 mg/dL) increases hypoglycemia risk without benefit

4h. Renal Replacement Therapy (RRT)

• Indicated for AKI with metabolic acidosis, uremia, hyperkalemia, or volume overload refractory to diuresis
• Continuous RRT (CRRT) preferred in hemodynamically unstable patients
• No proven benefit to early initiation of RRT in the absence of absolute indications

4i. Blood Transfusion

• Transfuse packed RBCs when hemoglobin <7.0 g/dL (restrictive threshold)
• Higher threshold (8-9 g/dL) in active myocardial ischemia, severe hypoxemia, or acute hemorrhage
• Platelets: transfuse if <50 x10^9/L with active bleeding; cryoprecipitate if fibrinogen <150 mg/dL
• LMWH preferred over UFH for VTE prophylaxis

4j. Nutrition

• Start enteral nutrition within 48 hours if hemodynamically stable
• Avoid parenteral nutrition in the first 7 days if enteral is feasible
• Avoid overfeeding

4k. Sedation and Analgesia (PADIS Bundle)

• Analgesia-first approach
• Minimize sedation depth; target light sedation (RASS -1 to -2) unless specific indications for deeper sedation
• Daily awakening trials + spontaneous breathing trials
• Delirium: regular monitoring (CAM-ICU or ICDSC); non-pharmacological prevention preferred (avoid benzodiazepines)

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5. The 2026 Surviving Sepsis Campaign (SSC) Guidelines - Key Updates

Major New and Updated Recommendations

Screening and Recognition

• Emphasizes early recognition across all settings, including pre-hospital
• In probable sepsis with hypotension and time to in-hospital evaluation >60 minutes: administer antibiotics in the ambulance (pre-hospital antibiotic initiation - a new recommendation)

Antimicrobial Therapy (Antibiotic Optimization)

• Reinforces rapid antibiotic administration but with nuance: not every suspected sepsis patient requires the same urgency
• Updated guidance on antimicrobial de-escalation and stewardship: narrow therapy early once cultures return
• New statements on antibiotic optimisation based on pharmacokinetic/pharmacodynamic (PK/PD) principles (extended infusions, therapeutic drug monitoring)
• Coverage for drug-resistant organisms addressed more specifically

Hemodynamic Management

• MAP target: 65 mmHg remains standard, BUT new recommendation for lower MAP targets (60-65 mmHg) in older adults (>75 years) - reduces vasopressor exposure without apparent harm
• Fluid resuscitation: More conservative approach supported - the 30 mL/kg bolus is conditional, not mandatory for all patients; reassess fluid responsiveness continuously
• Fluid removal after resuscitation: New explicit guidance on active fluid removal (diuresis or ultrafiltration) in the de-resuscitation phase once shock is controlled - to prevent fluid overload complications
• Balanced crystalloids remain preferred over saline
• Albumin: conditional recommendation in patients requiring large volumes of crystalloids

Post-Discharge and Long-Term Care (New Domain)

• New statements on continuity of care post-discharge, including:
  • Screening for post-ICU syndrome (PICS): cognitive, psychological, and physical impairments
  • Psychological rehabilitation and counseling for sepsis survivors
  • Physical rehabilitation planning
  • Follow-up in post-ICU/post-sepsis clinics
• Recognition that 30-40% of sepsis survivors face lasting health issues

Respiratory Support

• Updated guidance on HFNC vs. NIV vs. early intubation decision-making
• POCUS: now a conditional recommendation for guiding resuscitation (especially in pediatrics, but also supported in adults)

Pediatric Guidelines (Parallel Publication)

• A new data-driven definition of pediatric sepsis replaces the previous organ-dysfunction-based criteria
• 20 new topics addressed
• POCUS conditional recommendation for guiding pediatric resuscitation
• Post-sepsis morbidity and long-term follow-up now explicitly included

Summary Table: SSC 2026 vs. SSC 2021 - Key Differences

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6. Epidemiology (Global Burden)

• 48.9 million sepsis cases annually worldwide
• 11 million sepsis deaths/year = 1 in 5 global deaths
• 85% of deaths occur in low- and middle-income countries
• US: ~1.7 million cases/year; ~350,000 deaths or discharges to hospice
• Overall mortality: ~15% in hospitalized adults; up to 40% in septic shock
• Cost: $16,324/sepsis admission; $38,298/septic shock admission (U.S., 2016 data)

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Sources

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapter 315 - Sepsis and Septic Shock
• Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Prescott H, Antonelli M, et al. Crit Care Med. 2026. DOI: 10.1097/CCM.0000000000007075
• SSC 2026 Pediatric Guidelines (Weiss SL et al., Pediatr Crit Care Med. 2026. PMID: 41869844)
• ESICM/SCCM official SSC 2026 releases (March 23, 2026)

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Sepsis - Complete Comprehensive Review (Continued)

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4. ICU Care - Detailed & Complete

4a. Diagnosis & Initial Assessment

• CBC with differential (leukocytosis >12,000/uL or leukopenia <4,000/uL, bandemia ≥10%)
• Basic metabolic panel + liver function tests
• Serum lactate - the single most important prognostic marker: ≥2 mmol/L = tissue hypoperfusion; ≥4 mmol/L = very high mortality
• Coagulation panel (PT/INR, aPTT, fibrinogen, D-dimer) - for DIC/SIC assessment
• Urinalysis + culture
• Blood cultures x2 sets (aerobic + anaerobic) - before antibiotics but never delay antibiotics >45 min

• Chest X-ray (pneumonia, pulmonary edema)
• CT abdomen/pelvis if intra-abdominal source suspected
• POCUS for rapid cardiac function assessment, volume status, IVC collapsibility, pleural/pericardial effusions

• Heart failure, cardiac arrest
• Non-infectious COPD exacerbation
• Mesenteric ischemia, IBD
• Adrenal insufficiency, pulmonary embolism, hypovolemia

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4b. The "Hour-1 Bundle" (SSC 2018, reaffirmed 2021/2026)

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4c. Antimicrobial Therapy (Complete)

• Septic shock: antibiotics within 1 hour (every hour of delay increases mortality by ~7%)
• Sepsis without shock: within 3 hours (2026 SSC: a "diagnostic pause" is acceptable in stable patients to avoid overuse, but not at the expense of significant delay)
• Pre-hospital (new in SSC 2026): if transport time to hospital >60 min, administer antibiotics in the ambulance

• Add echinocandin (micafungin, caspofungin) if: prolonged broad-spectrum antibiotics, immunocompromised, Candida isolated from multiple sites, or abdominal surgery with perforation

• Narrow to targeted therapy as soon as cultures return
• Discontinue if infection is ruled out
• Procalcitonin-guided de-escalation reduces duration without increasing mortality
• Typical course: 7 days for most infections; shorter is acceptable for urinary/skin sources
• Extended/continuous infusions of beta-lactams (PK/PD optimization) - new emphasis in SSC 2026 for serious infections (improves time above MIC)

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4d. Fluid Resuscitation (Complete & Updated)

• 30 mL/kg IV crystalloid as initial bolus for hypotension or lactate ≥4 mmol/L - recommended conditionally (SSC 2026: low-certainty evidence, individualize based on patient context)
• The ARISE FLUIDS trial (NEJM, June 2026) - the most recent major RCT - tested vasopressor-first vs. fluid-first strategy in early septic shock. Results: vasopressor-early strategy was not inferior; did not refute the need for initial fluid, but supported earlier vasopressor initiation alongside reduced fluid volumes
• Balanced crystalloids (Plasma-Lyte, Ringer's lactate) preferred over 0.9% normal saline - NS associated with hyperchloremic metabolic acidosis and AKI
• Albumin: consider in patients receiving large cumulative volumes of crystalloids (conditional recommendation); evidence from ALBIOS and EARSS trials; not first-line

• Passive leg raise (PLR) test - increases venous return; a >10% rise in cardiac output = fluid-responsive
• Pulse pressure variation (PPV) >13% in mechanically ventilated patients
• Stroke volume variation (SVV) via advanced monitoring
• POCUS: IVC collapsibility index

• Reassess volume status continuously
• Avoid fluid creep (ongoing maintenance fluids not evidence-based in stable resuscitated patients)

• Active fluid removal once shock is controlled: use furosemide or ultrafiltration/RRT to achieve negative fluid balance
• Cumulative fluid overload is independently associated with increased mortality, AKI, longer ventilation
• CLASSIC trial (NEJM 2022): restrictive fluid strategy after initial resuscitation reduced 90-day mortality vs. standard strategy
• The concept of ROSE (Resuscitation, Optimization, Stabilization, Evacuation) formalizes the four phases of fluid management

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4e. Vasopressors and Hemodynamic Support (Complete)

• Alpha-1 + beta-1 agonist; increases SVR and MAP without excessive tachycardia
• Start at 0.01-0.1 mcg/kg/min, titrate to MAP ≥65 mmHg
• SSC 2026: lower MAP target of 60-65 mmHg acceptable in patients >75 years (SEPSIS-ACT trial data) - reduces vasopressor dose/duration without harm

• Add vasopressin 0.03 units/min when norepinephrine dose is escalating (typically >0.25 mcg/kg/min) or to spare catecholamines
• Acts on V1 receptors; particularly useful in vasodilatory (high-renin state) septic shock
• Catecholamine-sparing strategy reduces cardiac arrhythmias, myocardial injury, and immunosuppression

• New vasoconstrictor acting on RAAS; useful in catecholamine-refractory septic shock (especially high-renin phenotype)
• Conditional use; can reduce norepinephrine requirements

• Third-line or in cardiac arrest/severe myocardial depression
• Increases heart rate and metabolic rate; can worsen lactic acidosis

• No longer first-line (SOAP II trial: more arrhythmias, no mortality benefit vs. norepinephrine)
• Limited role: low-dose dopamine for renal protection is NOT recommended (disproven)

• For septic cardiomyopathy with evidence of low cardiac output (cold, clammy extremities, elevated filling pressures, low ScvO2)
• Start at 2-5 mcg/kg/min; do NOT use to increase cardiac output above normal (supranormal oxygen delivery strategy failed in trials)

• Arterial line (intra-arterial BP monitoring): essential in all vasopressor-dependent patients
• Central venous catheter: CVP measurement (less reliable alone), medication delivery
• Advanced monitoring: pulmonary artery catheter (PAC) in refractory cases; transpulmonary thermodilution (PiCCO); continuous cardiac output monitors
• ScvO2 (central venous oxygen saturation) target ≥70% as surrogate for oxygen delivery/consumption balance
• Lactate clearance ≥10% per 2 hours as treatment response marker - target lactate normalization

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4f. Corticosteroids (Complete)

• Adequate fluid resuscitation AND
• Norepinephrine ≥0.25 mcg/kg/min (or equivalent vasopressor)

• Hydrocortisone 200 mg/day IV (as continuous infusion or 50 mg every 6 hours)
• Fludrocortisone 50 mcg/day (oral/NG) may be added based on APROCCHSS protocol - remains an option per SSC 2026
• Duration: until vasopressor weaning, typically 5-7 days; taper not necessary if given <7 days

• ADRENAL trial (2018): hydrocortisone reduced time to shock reversal but no 90-day mortality benefit
• APROCCHSS trial (2018): hydrocortisone + fludrocortisone improved 90-day mortality vs. placebo (43.0% vs. 49.1%)
• Net effect: accelerates shock reversal; mortality benefit remains debated
• Do NOT use in sepsis without shock (no benefit, potential harm)
• Do NOT use dexamethasone for shock (no mineralocorticoid activity, longer duration)
• Future direction: genomic/phenotype-based corticosteroid targeting (SRS2 endotype, CIRCI identification)

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4g. Mechanical Ventilation (Complete)

• Refractory hypoxemia (SpO2 <90% despite HFNC/NIV)
• Worsening respiratory fatigue
• Encephalopathy compromising airway protection
• Hemodynamic deterioration

• Tidal volume: 6 mL/kg ideal body weight (IBW)
• Plateau pressure: <30 cmH2O
• Driving pressure: target <15 cmH2O (tidal volume / respiratory system compliance)
• PEEP: titrated to oxygenation (FiO2/PEEP table or ARDSnet protocol)
• Target SpO2 92-96% (avoid hyperoxia - independently harmful)

• Prone positioning: ≥16 hours/day - the PROSEVA trial showed 28-day mortality reduction from 32.8% to 16% (NNT = 6)
• High PEEP strategy
• Neuromuscular blocking agents (NMBAs): short-course cisatracurium (48 hours) in early severe ARDS - remains conditional; recent re-analysis supports use in PaO2/FiO2 <120
• ECMO (VV-ECMO): last resort for refractory ARDS; centers with expertise

• High-Flow Nasal Cannula (HFNC): up to 60 L/min; reduces work of breathing, dead space washout, positive airway pressure; shown to reduce intubation rates vs. standard O2 in hypoxemic respiratory failure (FLORALI trial)
• Non-invasive ventilation (NIV/CPAP/BiPAP): effective in COPD, cardiac pulmonary edema, selected immunocompromised patients; avoid if patient is deteriorating or exhausted

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4h. Acute Kidney Injury in Sepsis (Complete)

• Renal microvascular dysfunction and impaired autoregulation
• Tubular epithelial injury from cytokines, ROS, and nephrotoxins
• Abdominal compartment syndrome (if present)
• Iatrogenic contributions: aminoglycosides, contrast, NSAIDs, ACE inhibitors

• Optimize perfusion pressure (MAP ≥65 mmHg, or higher if pre-existing hypertension)
• Avoid nephrotoxins
• RRT Indications: metabolic acidosis (pH <7.1), uremia (BUN >100 mg/dL with uremic symptoms), refractory hyperkalemia (K+ >6.5 mmol/L), fluid overload refractory to diuretics
• Mode: CRRT preferred over intermittent HD in hemodynamically unstable patients (more stable fluid removal)
• Timing: No mortality benefit from early prophylactic RRT in the absence of absolute indications (STARRT-AKI trial)
• Use KDIGO AKI staging (creatinine rise and urine output criteria) to monitor progression

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4i. Septic Cardiomyopathy

• Mechanism: TNF-alpha, IL-1beta, nitric oxide directly suppress myocardial contractility
• Manifests as: reduced EF on echo, elevated filling pressures despite normal/high MAP
• Echo (TTE/TEE): essential - assess LV/RV function, wall motion, rule out tamponade, guide fluid status
• Treatment: reduce vasopressors if tolerated; add dobutamine; correct metabolic derangements
• Prognosis: recovers in 7-10 days in survivors; lack of recovery is a poor sign

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4j. Coagulation Management (Complete)

• Treat the underlying sepsis
• Cryoprecipitate: fibrinogen <150 mg/dL
• Fresh frozen plasma (FFP): prolonged PT/INR + active bleeding
• Platelet transfusion: <50 x10^9/L + active bleeding; lower threshold for high-risk patients
• LMWH (preferred over UFH): for VTE prophylaxis in all septic patients unless contraindicated
• Full anticoagulation: NOT recommended prophylactically; reserved for confirmed DVT/PE

• Platelet count (0-2 points) + PT ratio (0-2 points) + SOFA score (0-2 points)
• SIC score ≥4: start intervention (treat underlying sepsis; anticoagulation with heparin in selected cases per Japanese guidelines)

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4k. Nutritional Support

• Avoid gastric residual volume monitoring routinely
• Use post-pyloric feeding if high aspiration risk
• Vitamin C: IV high-dose vitamin C NOT recommended (VITAMINS trial, CITRIS-ALI trial: no benefit)
• Thiamine: replace in patients with suspected deficiency (alcohol use, malnutrition)

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4l. Glycemic Control

• Target blood glucose 140-180 mg/dL (7.8-10 mmol/L)
• Use continuous insulin infusion with hourly glucose monitoring when insulin is required
• Avoid intensive insulin therapy (target 80-110 mg/dL): NICE-SUGAR trial showed increased mortality and 3x more severe hypoglycemia events
• Hypoglycemia (BGL <70 mg/dL) is independently associated with increased mortality

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4m. Sedation, Analgesia, and Delirium (PADIS Bundle)

• IV opioids (fentanyl/morphine/hydromorphone) titrated to comfort
• Consider non-opioid adjuncts (ketamine, acetaminophen) to minimize opioid doses

• Target light sedation (RASS -1 to -2) - deeper sedation increases ICU LOS, mortality, and post-ICU cognitive impairment
• Preferred agents: propofol or dexmedetomidine (less delirium vs. benzodiazepines)
• Avoid benzodiazepines (midazolam/lorazepam): associated with more delirium and prolonged mechanical ventilation
• Daily spontaneous awakening trials (SAT) + spontaneous breathing trials (SBT) ("wake and wean"): reduces ICU LOS and mortality (ABC trial)

• Assess with CAM-ICU or ICDSC every shift
• Non-pharmacological prevention: ABCDEF bundle (Assess, Both SAT + SBT, Choice of analgesia/sedation, Delirium assessment, Early mobilization, Family engagement)
• Pharmacological: no agent proven to prevent ICU delirium; haloperidol/quetiapine for symptomatic management only
• Dexmedetomidine (alpha-2 agonist): can reduce delirium in mechanically ventilated patients, allows cooperative sedation

• Passive + active physiotherapy from day 1-2
• Reduces ICU-acquired weakness, delirium, and long-term functional impairment

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4n. Source Control

• Mandatory and time-sensitive: identify and eliminate the infectious focus
• Drain abscesses percutaneously or surgically
• Remove infected intravascular catheters, urinary catheters, implanted devices
• Debride necrotizing fasciitis (within 6 hours - surgical emergency)
• Resect perforated bowel/appendix
• Rule: least invasive effective procedure first; timing ideally within 6-12 hours of diagnosis

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5. The 2026 Surviving Sepsis Campaign - Full Detail

Structure

• 129 adult statements (46 new), endorsed by 24 professional societies
• Developed by 69 panelists from 23 countries; 38% from LMICs
• Companion pediatric guidelines (Weiss SL et al., PMID: 41869844): 20 new topics, new pediatric sepsis definition

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Key New and Updated Recommendations (Adult Guidelines)

Domain 1: Screening and Rapid Treatment

Domain 2: Antimicrobial Therapy

Domain 3: Hemodynamic Resuscitation

Domain 4: Ventilation and Respiratory

Domain 5: Adjunctive Therapies

Domain 6: Post-Discharge and Rehabilitation (New Domain - SSC 2026)

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6. Post-Sepsis Syndrome (PICS)

• Early post-discharge follow-up at 2-4 weeks
• Neuropsychological evaluation at 3 and 6 months
• Physiotherapy and occupational therapy
• Psychological support/CBT for PTSD
• Patient and caregiver education (sepsis survivor networks)

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7. Biomarkers in Sepsis

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8. Emerging and Future Therapies

• Anti-TNF-alpha (etanercept, infliximab)
• Anti-IL-1 (anakinra - failed in unselected sepsis, but active trials in IL-1 high phenotype)
• Anti-TLR-4 (eritoran)
• Anti-C5a
• Activated protein C (drotrecogin alfa - withdrawn)
• Antithrombin III
• Polymyxin-B hemoperfusion (EUPHRATES, TIGRIS trials: no benefit)
• High-dose IV vitamin C (CITRIS-ALI, VITAMINS: no benefit)

• Precision/phenotype-guided therapy: using transcriptomic endotypes (SRS1/SRS2) to select patients likely to respond to immunomodulation
• Angiotensin II (Giapreza): catecholamine-sparing in high-renin septic shock phenotype
• IL-7: immune reconstitution in immunosuppressed/lymphopenic sepsis phase (trials ongoing)
• Thymosin-alpha 1: immune restoration (positive signals in Asia)
• Gut microbiome modulation: fecal microbiota transplant in post-antibiotic dysbiosis
• CRRT with cytokine removal (e.g., oXiris filter, CytoSorb): removing cytokines from circulation - trials ongoing, not yet standard of care
• Single-cell transcriptomics, proteomics, metabolomics: identifying novel targets and patient subgroups
• AI/ML-based early warning systems: sepsis alert algorithms in EHR; meta-analysis (PMID: 39037814) confirms improved adherence and mortality when combined with clinical pathways

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9. Summary Quick-Reference Table

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Sources

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapters 314-315 - Shock & Sepsis
• Surviving Sepsis Campaign 2026 - Prescott H, Antonelli M, et al. Crit Care Med / Intensive Care Med. March 23, 2026. DOI: 10.1097/CCM.0000000000007075
• ARISE FLUIDS Trial. Vasopressors or Fluids in Early Septic Shock. NEJM. June 11, 2026
• SSC 2026 Pediatric Guidelines - Weiss SL et al. Pediatr Crit Care Med. PMID: 41869844
• Managing Sepsis in the Era of Precision Medicine. Acute Crit Care. 2026;41(2):189-200
• Rosen's Emergency Medicine 10e; Fischer's Mastery of Surgery 8e; Tintinalli's Emergency Medicine 9e