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10% bands) are now considered outdated and superseded.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

• BP 90/60 mmHg
• HR 120 bpm
• Pallor
• Active massive PR bleeding

Diverticulitis and Colon Cancer Risk

What the Evidence Says

Clinical Implication: Post-Diverticulitis Colonoscopy

Colonoscopy 4–8 weeks after an acute episode of presumptive diverticulitis to exclude colorectal cancer

• A first episode of uncomplicated diverticulitis
• Any episode of complicated diverticulitis
• Before planning elective surgical resection

Summary

• Post-op day 3 (very early post-operative period)
• Following cholecystectomy
• Jaundice + right hypochondriac pain

Why Option A is Correct

• Jaundice within days of surgery (onset day 2–5 is classic)
• Pain from biliary distension
• Possible bile leak if the duct is not fully occluded

Why the Others Are Less Likely

Clinical Approach After Suspecting CBD Clip Injury

1. Urgent MRCP — confirms and delineates the level of obstruction
2. ERCP — diagnostic + therapeutic (stenting if partial injury)
3. Surgical re-exploration — if complete transection/clip; Roux-en-Y hepaticojejunostomy is the definitive repair
4. Early surgical consultation is mandatory — delayed repair worsens outcomes

The earlier the injury is recognised and repaired, the better the long-term biliary function outcome.

CBD Stones, Obstructive Jaundice, and RHC Mass

Do CBD Stones Cause Obstructive Jaundice?

• CBD stones (choledocholithiasis) do cause obstructive jaundice when they partially or completely block bile flow
• Biliary obstruction → ↑ intrabiliary pressure → conjugated bilirubin regurgitates into bloodstream → jaundice + dark urine + pale stools + pruritus
• Serum bilirubin in CBD stones is typically 2–5 mg/dL, rarely exceeding 12–15 mg/dL
• Alkaline phosphatase rises early and rapidly; GGT is the most commonly elevated enzyme
• Jaundice from stones is often intermittent (stones may pass spontaneously) or accompanied by pain (biliary colic or Charcot's triad)

If bilirubin ≥ 20 mg/dL (342 μmol/L), this strongly suggests neoplastic obstruction rather than stones. — Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Do CBD Stones Cause a Palpable RHC Mass?

"In a patient with obstructive jaundice, a palpably enlarged gallbladder is unlikely to be due to gallstones (CBD stones), and suggests malignant obstruction instead."

So What Causes a Palpable RHC Mass with Jaundice?

• Carcinoma of the head of pancreas (most common)
• Periampullary carcinoma
• Cholangiocarcinoma (Klatskin tumour)
• Gallbladder carcinoma with CBD involvement
• Metastatic lymph nodes compressing the CBD

Bottom Line

Carbimazole vs Methimazole at 20 Weeks of Pregnancy

The Trimester-Based Switch Principle

At 20 Weeks Specifically

1. Organogenesis is complete — the teratogenic window for methimazole-associated embryopathy has passed (ends ~10–12 weeks)
2. PTU hepatotoxicity risk — propylthiouracil carries an FDA black box warning for severe hepatitis and liver failure; this risk is especially concerning when use extends into the 2nd/3rd trimester
3. Carbimazole is a prodrug of methimazole — it is converted to methimazole after absorption. They are clinically equivalent; carbimazole is used in the UK, Australia, and much of Asia/Europe; methimazole is used in the US

"Due to the hepatotoxicity of propylthiouracil, the FDA has limited indications for its use to the first trimester of pregnancy, the treatment of thyroid storm, and patients with minor adverse reactions to methimazole." — Harrison's Principles of Internal Medicine, 22nd Edition (2025)

"Methimazole is usually avoided in the first trimester in favor of propylthiouracil due to methimazole-associated embryopathy, and then methimazole is used for the remainder of the pregnancy due to the concern for propylthiouracil-associated liver failure." — Goodman & Gilman's Pharmacological Basis of Therapeutics

Dosing Guidance (2nd Trimester Onward)

• Carbimazole: 10–20 mg every 12 hours initially; maintenance 2.5–10 mg/day
• Methimazole: same doses (1:1 ratio with carbimazole)
• Use the lowest effective dose — target free T4 in the upper half of normal range (slightly elevated is acceptable)
• Do not target normal TSH — keeping fT4 slightly above normal prevents fetal hypothyroidism, since antithyroid drugs cross the placenta

Other Key Points at 20 Weeks

• Radioiodine is absolutely contraindicated throughout pregnancy
• Graves' disease often improves as pregnancy progresses (immune tolerance) — dose reduction or even stopping is often possible in the third trimester
• Expect postpartum flare — close monitoring after delivery is essential
• Methimazole up to 20 mg/day is safe in breastfeeding — minimal transfer into breast milk

Summary

At 20 weeks POA: Methimazole or Carbimazole — safer maternal profile, teratogenic risk is no longer relevant, and PTU should be avoided to protect the mother's liver.

1. ESCC responds better to chemoradiotherapy (pCR ~40% vs ~23% for EAC) — this is why definitive CRT alone is a viable curative option for ESCC (especially cervical location), but surgery adds survival benefit in EAC.
2. Barrett's oesophagus is the pivotal concept for EAC — the metaplasia-dysplasia-carcinoma sequence is the only established preventable pathway, making surveillance and RFA ablation key prevention strategies.
3. HER2 testing is mandatory in metastatic EAC — trastuzumab is added to chemotherapy in HER2-positive cases (ToGA trial showed survival benefit).
4. Nivolumab adjuvant therapy (CheckMate-577) applies to both histologies with residual pathologic disease after neoadjuvant CRT — this is a practice-changing trial for both.
5. Obesity protects against ESCC but causes EAC — a unique and frequently tested paradox.