Surviving Sepsis Campaign — International Guidelines for Management of Sepsis and Septic Shock

Important note: The SSC publishes guidelines periodically; the most recent published version is SSC 2021 (Evans et al., Critical Care Medicine, 2021;49(11):e1063). As of early 2025, SSC 2026 guidelines have not yet been published — they are anticipated but not available in the medical literature. The following note is based on the current SSC 2021 recommendations as reflected in the most up-to-date medical textbooks available, including Harrison's Principles of Internal Medicine, 22nd Edition (2025), The Washington Manual of Medical Therapeutics, and Rosen's Emergency Medicine.

1. Definitions (Sepsis-3, 2016 — Current Standard)

Sepsis

• Operationally defined as an acute increase in SOFA score ≥ 2 from baseline in a patient with suspected infection.
• Replaces the old SIRS-based "Sepsis-2" definition.

Septic Shock

• Persistent hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg AND
• Serum lactate > 2 mmol/L despite adequate volume resuscitation
• In-hospital mortality: ~40%

SOFA Score (Sequential Organ Failure Assessment)

qSOFA (Quick SOFA) — Bedside Screening Tool

• Altered mental status (GCS < 15)
• Respiratory rate ≥ 22 breaths/min
• Systolic BP ≤ 100 mmHg qSOFA ≥ 2 = prompt further assessment for sepsis

Prior SIRS criteria (temp <36°C or >38°C, HR >90, RR >20 or PaCO₂ <32, WBC <4,000 or >12,000 or >10% bands) are now considered outdated and superseded.

2. Epidemiology

• ~88% of cases are community-onset (within 48 h of hospitalization)
• ~12% are hospital-onset (after 48 h)
• ~53% of U.S. sepsis cases are culture-positive
• Most common gram-positive organisms: S. aureus, Streptococcus spp., Enterococcus spp. (13.6% antibiotic-resistant including MRSA, VRE)
• Most common gram-negative organisms: E. coli, Klebsiella spp., Pseudomonas aeruginosa (13.2% resistant to ceftriaxone, extended-spectrum β-lactams, or carbapenems)
• Most frequent primary infection sites: urinary tract (48.9%), respiratory tract (32.9%), intraabdominal (13.6%), skin/soft tissue (10.3%)

3. Pathophysiology

• Innate immune activation: PAMPs (pathogen-associated) and DAMPs (damage-associated molecular patterns) trigger pattern recognition receptors (PRRs) on monocytes and neutrophils
• Cytokine storm: IL-1β, IL-6, TNF-α drive systemic inflammation
• Coagulation cascade: Tissue factor upregulation → fibrin generation → microthrombi (NETs + leukocytes + platelets + fibrin bound by vWF) → disseminated intravascular coagulation (DIC)
• Endothelial injury: Loss of VE-cadherin and tight junctions → capillary leak, interstitial edema, decreased oxygen diffusion
• Vasodilation: Excess nitric oxide → distributive shock, hypoperfusion
• Immunosuppression: Myeloid-derived suppressor cells impair T-cell, B-cell, and NK-cell function — contributing to late-phase immune paralysis
• Mitochondrial dysfunction: Cellular metabolic failure even with adequate O₂ delivery

4. Diagnosis & Workup

Laboratory Tests

Microbiology

• Blood cultures (×2 peripheral sites), urine culture, sputum, CSF if indicated, wound swabs — all before antibiotics if possible
• Urinalysis essential, especially in elderly

Imaging

• Chest X-ray, directed imaging (CT abdomen/pelvis, ultrasound) to identify source of infection

5. The Hour-1 Bundle (SSC 2018 Update, reaffirmed 2021)

6. Fluid Resuscitation

• Initial bolus: 30 mL/kg IV crystalloid within the first hour
  • Adjust down if heart failure or pulmonary edema is present
  • Give more if patient remains fluid-responsive after initial bolus
• Preferred fluid: Balanced crystalloids (Lactated Ringer's) — RCTs show lower rates of renal dysfunction and possible improved mortality vs. normal saline
• Albumin: Multiple trials have not shown significant benefit over crystalloids in septic patients; not recommended as first-line
• Hydroxyethyl starches (HES): Avoid — associated with increased renal failure and mortality
• Fluid responsiveness assessment: Use dynamic parameters (pulse pressure variation, stroke volume variation, passive leg raise test) to guide ongoing fluid administration and prevent fluid overload

7. Vasopressors & Cardiovascular Support

• Target MAP: ≥ 65 mmHg (higher targets, e.g., 80–85 mmHg, not shown to improve outcomes in most patients)
• Insert arterial line for continuous MAP monitoring in patients on vasopressors

8. Antimicrobials

Timing

• Administer within 1 hour of sepsis/septic shock recognition
• Every hour of delay is associated with increased mortality
• Draw blood cultures first if this does not delay antibiotics >45 minutes

Empirical Antibiotic Selection

• Suspected site of infection
• Community vs. hospital/ICU onset
• Prior culture history and local resistance patterns
• Immunocompromised status

• Add MRSA coverage (vancomycin or linezolid) if: MRSA risk factors, known colonization, hospital-acquired, or catheter-related
• Add antifungal (echinocandin) if: immunocompromised, prolonged antibiotics, TPN, abdominal surgery, Candida colonization

De-escalation & Duration

• Procalcitonin-guided de-escalation: Serial procalcitonin measurements support antibiotic stewardship and stopping antibiotics earlier
• Narrow spectrum as soon as culture results return
• Reassess need for antibiotics daily

9. Source Control

• Identify and control the anatomic source of infection as soon as medically feasible
• Drainage of abscesses, debridement of infected/necrotic tissue (e.g., necrotizing fasciitis), removal of infected devices, management of bowel perforations
• Surgical or interventional radiology procedures should not be delayed once sepsis is recognized
• Principle: remove/drain the nidus of infection to prevent ongoing bacterial seeding

10. Corticosteroids

• Indication: Septic shock not responding to adequate fluid resuscitation and vasopressors
• Regimen: Hydrocortisone 200 mg/day IV (50 mg q6h or continuous infusion)
• Do not use ACTH stimulation test to guide steroid use (outdated)
• Taper when vasopressors are no longer required
• Mechanism: Relative adrenal insufficiency (critical illness–related corticosteroid insufficiency, CIRCI) is common in refractory septic shock

11. Blood Glucose Control

• Target blood glucose: 140–180 mg/dL (7.8–10 mmol/L)
• Use insulin infusion protocols
• Avoid hypoglycemia (< 70 mg/dL) — associated with increased mortality
• Tight glycemic control (80–110 mg/dL) is not recommended — NICE-SUGAR trial showed increased mortality with intensive glucose control

12. Mechanical Ventilation (Sepsis-Induced ARDS)

• Low tidal volume ventilation: 6 mL/kg predicted body weight
• Plateau pressure: Keep ≤ 30 cmH₂O
• PEEP: Titrate to maintain oxygenation; higher PEEP in moderate–severe ARDS
• Prone positioning: For patients with PaO₂/FiO₂ < 150 — reduces mortality in severe ARDS
• Conservative fluid strategy after initial resuscitation to reduce ventilator days
• Spontaneous breathing trials (SBT): Daily assessment for weaning/extubation readiness

13. Blood Transfusion

• Restrictive transfusion strategy: Transfuse RBCs when Hgb < 7 g/dL in most patients
• Exception: Higher threshold (Hgb < 9 g/dL) in: active coronary ischemia, acute hemorrhage
• No benefit from transfusing to higher Hgb in hemodynamically stable patients
• Platelets: Transfuse if < 10,000/mm³ (prophylactic) or < 20,000/mm³ if bleeding risk; < 50,000/mm³ if active bleeding or procedure planned
• Fresh Frozen Plasma: Only for active bleeding or planned invasive procedure with coagulopathy

14. Renal Replacement Therapy (RRT)

• Initiate for standard indications: severe AKI with oliguria, azotemia, refractory hyperkalemia, severe metabolic acidosis, or volume overload unresponsive to diuretics
• Continuous RRT (CRRT) preferred in hemodynamically unstable patients over intermittent hemodialysis

15. DVT / VTE Prophylaxis

• Pharmacologic prophylaxis with heparin (unfractionated or LMWH) in all septic patients without contraindications
• Mechanical prophylaxis (compression devices) when pharmacologic is contraindicated

16. Stress Ulcer Prophylaxis

• Use proton pump inhibitor (PPI) or H₂ blocker in patients with risk factors for GI bleeding (mechanical ventilation, coagulopathy, prior GI ulcer/bleeding)

17. Nutrition

• Early enteral nutrition preferred over parenteral nutrition when gut is functional
• Begin within 24–48 hours of ICU admission
• Avoid overfeeding; target caloric requirements based on indirect calorimetry or predictive equations
• Parenteral nutrition: Only if enteral route is contraindicated or insufficient after several days

18. Lactate Clearance & Monitoring Goals

Note on EGDT: Early Goal-Directed Therapy (Rivers protocol, 2001) — targeting CVP 8–12, ScvO₂ ≥70%, MAP ≥65 — was widely adopted but three major multicenter RCTs (ProCESS, ARISE, ProMISe) showed no mortality benefit over usual care, largely because usual care had already incorporated many of these principles.

19. Immunomodulation & Emerging/Investigational Therapies

• Intravenous immunoglobulin (IVIG): Not routinely recommended; insufficient evidence
• Activated Protein C (Xigris/drotrecogin alfa): Withdrawn from market — trials showed no benefit and increased bleeding risk
• Thiamine (Vitamin B₁): Sepsis causes thiamine depletion; supplementation studied but not yet standard of care
• Vitamin C + hydrocortisone + thiamine (HAT therapy): Randomized trials (CITRIS-ALI, VITAMINS) did not confirm early positive observational results — not recommended as routine
• Anti-cytokine therapies: IL-6 receptor antagonists (tocilizumab, sarilumab) being studied in select inflammatory contexts

20. Long-Term Sequelae — Post-Sepsis Syndrome

• Cognitive impairment and dementia
• Psychological sequelae: PTSD, anxiety, depression
• Physical disability: Muscle weakness, ICU-acquired neuromyopathy
• Immune dysregulation: Persistent immunosuppression → recurrent infections
• Increased mortality for years after discharge
• Regular follow-up, rehabilitation, and psychological support are recommended

Quick-Reference Summary Card

SEPSIS RECOGNITION → SOFA ≥2 + suspected infection
SEPTIC SHOCK → vasopressors needed + lactate >2 after fluids

HOUR-1 BUNDLE:
  ✓ Measure lactate (repeat if >2 mmol/L)
  ✓ Blood cultures ×2 before antibiotics
  ✓ Broad-spectrum antibiotics IMMEDIATELY
  ✓ 30 mL/kg IV crystalloid (LR preferred) if hypotensive or lactate ≥4
  ✓ Vasopressors if MAP <65 → Norepinephrine first-line

VASOPRESSORS: NE → Vasopressin → Epi (dopamine: avoid)
ANTIBIOTICS: Broad-spectrum within 1 hour, de-escalate per cultures
SOURCE CONTROL: Drain/debride as soon as feasible
STEROIDS: Hydrocortisone 200 mg/day for refractory shock only
GLUCOSE: Target 140–180 mg/dL
TRANSFUSION: Hgb <7 g/dL trigger (restrictive)
VENT: 6 mL/kg IBW, plateau ≤30 cmH₂O
NUTRITION: Early enteral feeding within 24–48 h
DVT/VTE: Heparin prophylaxis in all