Sepsis and Septic Shock — Part 4: Corticosteroids & Organ Support
Corticosteroid indications and evidence in septic shock, mechanical ventilation in sepsis-induced ARDS, renal replacement therapy, blood product management, glucose management, DVT and stress ulcer prophylaxis, and nutrition.
1. Corticosteroids in Septic Shock
1.1 Guideline Recommendation
Recommendation: For adults with septic shock and an ongoing requirement for vasopressor therapy, the panel suggests using IV corticosteroids.
Strength: Weak recommendation, moderate quality of evidence1
Specific regimen:
- Hydrocortisone 200 mg/day administered as either:
- 50 mg IV every 6 hours, OR
- 100 mg IV bolus followed by continuous infusion of 200 mg/day (8.3 mg/hour)
- Duration: Continue for the duration of vasopressor therapy; taper when vasopressors are discontinued or weaned to low doses (norepinephrine < 0.05–0.1 μg/kg/min)
- Fludrocortisone: The addition of fludrocortisone (50 μg enterally once daily) is optional; the APROCCHSS trial included fludrocortisone, while the ADRENAL trial did not2 3
1.2 When to Initiate Corticosteroids
The guidelines do not specify a precise vasopressor dose threshold for initiating corticosteroids, but the following is a reasonable clinical approach:
- Consider initiation when norepinephrine dose reaches ≥ 0.25 μg/kg/min and has been sustained for ≥ 4 hours despite adequate fluid resuscitation
- Strongly consider when norepinephrine dose reaches ≥ 0.5 μg/kg/min or when escalation to a second vasopressor is required
- Some experts recommend early initiation (within 6 hours of vasopressor requirement) based on the APROCCHSS trial design3
- Corticosteroids are not recommended for sepsis without shock1
1.3 Key Evidence — Landmark Trials
| Trial | Year | Design | N | Intervention | Primary Outcome | Key Finding |
|---|---|---|---|---|---|---|
| ADRENAL | 2018 | Multicenter, double-blind RCT | 3,658 | Hydrocortisone 200 mg/day continuous infusion × 7 days vs. placebo | 90-day mortality | No significant difference: 27.9% vs. 28.8% (OR 0.95, 95% CI 0.82–1.10, p = 0.50). Faster shock reversal, shorter ICU and hospital stay, less transfusion with hydrocortisone2 |
| APROCCHSS | 2018 | Multicenter, double-blind RCT | 1,241 | Hydrocortisone 50 mg IV q6h + Fludrocortisone 50 μg daily × 7 days vs. placebo | 90-day mortality | Significant mortality reduction: 43.0% vs. 49.1% (RR 0.88, 95% CI 0.78–0.99, p = 0.03). NNT = 163 |
| Annane et al. | 2002 | Multicenter, double-blind RCT | 300 | Hydrocortisone 50 mg IV q6h + Fludrocortisone 50 μg daily × 7 days vs. placebo | 28-day mortality in non-responders to ACTH stimulation test | Significant mortality reduction in non-responders (53% vs. 63%, p = 0.02)4 |
| CORTICUS | 2008 | Multicenter, double-blind RCT | 499 | Hydrocortisone 50 mg IV q6h × 5 days then taper vs. placebo | 28-day mortality | No mortality benefit overall (34.3% vs. 31.5%, p = 0.51). Faster shock reversal with hydrocortisone. More hyperglycemia and superinfections5 |
1.4 Reconciling the Evidence
- The two largest trials (ADRENAL and APROCCHSS) reached different conclusions regarding mortality, likely because APROCCHSS enrolled sicker patients (higher baseline mortality ~46%) while ADRENAL enrolled less severely ill patients (baseline mortality ~28%)
- Consistent findings across all trials: Corticosteroids accelerate shock reversal (earlier cessation of vasopressors by approximately 1–2 days)
- The benefit of corticosteroids appears greatest in patients with more severe shock (higher vasopressor requirements, longer duration of shock)
- ACTH stimulation testing is NOT recommended to guide corticosteroid use in septic shock — treat based on clinical severity, not cortisol levels1
1.5 Adverse Effects of Corticosteroids in Sepsis
| Adverse Effect | Incidence | Management |
|---|---|---|
| Hyperglycemia | 30–50% | Insulin infusion protocol; target glucose 140–180 mg/dL |
| Hypernatremia | 10–20% | Monitor electrolytes; adjust IV fluids |
| Secondary infections | Possibly increased (CORTICUS data) | Maintain infection surveillance; unclear clinical significance |
| ICU-acquired weakness | Theoretical concern | Minimize duration; combine with early mobilization |
| GI bleeding | Rare | Stress ulcer prophylaxis (see Section 7) |
2. Mechanical Ventilation in Sepsis-Induced ARDS
2.1 Sepsis-Induced ARDS
Sepsis is the most common cause of acute respiratory distress syndrome (ARDS), accounting for approximately 30–50% of all ARDS cases. Sepsis-induced ARDS carries a mortality of 35–50% depending on severity.6
Berlin Definition of ARDS:
| Feature | Criteria |
|---|---|
| Timing | Within 1 week of known clinical insult or new/worsening respiratory symptoms |
| Chest imaging | Bilateral opacities not fully explained by effusions, atelectasis, or nodules |
| Origin of edema | Respiratory failure not fully explained by cardiac failure or fluid overload |
| Oxygenation (PaO2/FiO2) | |
| — Mild | 200–300 mmHg (with PEEP or CPAP ≥ 5 cmH2O) |
| — Moderate | 100–200 mmHg (with PEEP ≥ 5 cmH2O) |
| — Severe | ≤ 100 mmHg (with PEEP ≥ 5 cmH2O) |
2.2 Lung-Protective Ventilation
Recommendation: For adults with sepsis-induced respiratory failure, the panel recommends using low tidal volume ventilation (6 mL/kg predicted body weight) rather than high tidal volume (> 10 mL/kg PBW).
Strength: Strong recommendation, high quality of evidence1
Recommendation: For adults with sepsis-induced ARDS, the panel recommends targeting an upper limit of plateau pressure of 30 cmH2O.
Strength: Strong recommendation, moderate quality of evidence1
Recommendation: For adults with moderate-severe sepsis-induced ARDS, the panel suggests using higher PEEP rather than lower PEEP.
Strength: Weak recommendation, moderate quality of evidence1
Recommendation: For adults with sepsis-induced ARDS, the panel recommends using a conservative fluid strategy over a liberal fluid strategy.
Strength: Weak recommendation, low quality of evidence (applied as best practice)1
Lung-Protective Ventilation Protocol
| Parameter | Target / Setting |
|---|---|
| Mode | Volume-assist control (preferred initially) |
| Tidal volume | 6 mL/kg predicted body weight (range 4–8 mL/kg PBW) |
| Respiratory rate | Adjust to maintain pH > 7.25–7.30 (typically 20–35 breaths/min) |
| Plateau pressure | ≤ 30 cmH2O (if > 30, reduce Vt to minimum of 4 mL/kg PBW) |
| Driving pressure | < 15 cmH2O (plateau pressure − PEEP; associated with mortality in observational data)7 |
| PEEP | Use FiO2/PEEP table (see below); higher PEEP strategy for moderate-severe ARDS |
| FiO2 | Minimum to maintain SpO2 88–95% (PaO2 55–80 mmHg) |
| I:E ratio | 1:1 to 1:3 |
Predicted Body Weight Calculation:
- Male: PBW (kg) = 50 + 2.3 × (height in inches − 60)
- Female: PBW (kg) = 45.5 + 2.3 × (height in inches − 60)
PEEP / FiO2 Tables
Lower PEEP / Higher FiO2 Strategy:
| FiO2 | 0.3 | 0.4 | 0.4 | 0.5 | 0.5 | 0.6 | 0.7 | 0.7 | 0.7 | 0.8 | 0.9 | 0.9 | 0.9 | 1.0 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PEEP | 5 | 5 | 8 | 8 | 10 | 10 | 10 | 12 | 14 | 14 | 14 | 16 | 18 | 18–24 |
Higher PEEP / Lower FiO2 Strategy (for moderate-severe ARDS):
| FiO2 | 0.3 | 0.3 | 0.3 | 0.3 | 0.4 | 0.4 | 0.5 | 0.5 | 0.5–0.8 | 0.8 | 0.9 | 1.0 | 1.0 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PEEP | 5 | 8 | 10 | 12 | 14 | 16 | 16 | 18 | 20 | 22 | 22 | 22 | 24 |
2.3 Prone Positioning
Recommendation: For adults with sepsis-induced moderate-severe ARDS (PaO2/FiO2 < 150 mmHg), the panel recommends prone positioning for more than 12 hours per day.
Strength: Strong recommendation, moderate quality of evidence1
Evidence: The PROSEVA trial (2013) demonstrated that prone positioning for ≥ 16 hours per day in severe ARDS (PaO2/FiO2 < 150) reduced 28-day mortality from 32.8% to 16.0% (HR 0.39, 95% CI 0.25–0.63, p < 0.001).8
Practical guidance:
- Initiate within 12–24 hours of ARDS onset with moderate-severe hypoxemia
- Maintain prone position for ≥ 16 hours per session
- Continue daily prone sessions until PaO2/FiO2 > 150 mmHg with FiO2 ≤ 0.6 and PEEP ≤ 10 cmH2O in the supine position
- Contraindications: spinal instability, open abdomen, elevated intracranial pressure, recent sternotomy (relative)
2.4 Neuromuscular Blockade
Recommendation: For adults with sepsis-induced moderate-severe ARDS, the panel suggests against routine use of continuous neuromuscular blocking agents (NMBAs).
Strength: Weak recommendation, moderate quality of evidence1
Evidence: The ROSE trial (2019) found no benefit of early continuous cisatracurium (48 hours) compared with usual care (lighter sedation without NMBAs) in moderate-severe ARDS (90-day mortality 42.5% vs. 42.8%).9 However, short-course or bolus-dose NMBAs may be used for ventilator dyssynchrony, refractory hypoxemia, or during prone positioning.
2.5 Recruitment Maneuvers
Recommendation: For adults with sepsis-induced ARDS, the panel suggests against using recruitment maneuvers routinely.
Strength: Weak recommendation, moderate quality of evidence1
Evidence: The ART trial (2017) demonstrated that lung recruitment maneuvers with PEEP titration by decremental best-compliance strategy increased 28-day mortality compared with low PEEP strategy in moderate-severe ARDS (55.3% vs. 49.3%, p = 0.041).10
3. Renal Replacement Therapy (RRT) in Sepsis
3.1 Indications for RRT
Recommendation: For adults with sepsis or septic shock and acute kidney injury (AKI) who require renal replacement therapy, the panel suggests using either continuous or intermittent RRT.
Strength: Weak recommendation, low quality of evidence1
Recommendation: For adults with sepsis or septic shock and AKI with no definitive indication for RRT, the panel suggests against initiating RRT.
Strength: Weak recommendation, low quality of evidence1
Definitive (Emergent) Indications for RRT
| Indication | Clinical Threshold |
|---|---|
| Refractory hyperkalemia | K+ > 6.5 mEq/L or K+ > 6.0 with ECG changes despite medical management |
| Refractory metabolic acidosis | pH < 7.15 despite optimization of ventilation and bicarbonate |
| Refractory fluid overload | Pulmonary edema with respiratory failure not responsive to diuretics |
| Uremic complications | Encephalopathy, pericarditis, uremic bleeding |
| Certain toxic ingestions | Methanol, ethylene glycol, lithium, salicylates, metformin |
3.2 Timing of RRT in Sepsis-Associated AKI
Key trials on RRT timing:
| Trial | Year | N | Comparison | Key Finding |
|---|---|---|---|---|
| AKIKI | 2016 | 619 | Early (within 6 hours of AKI stage 3) vs. delayed (emergent indications) RRT | No difference in 60-day mortality (48.5% vs. 49.7%, p = 0.79). Delayed group: 49% never required RRT11 |
| IDEAL-ICU | 2018 | 488 | Early (within 12 hours) vs. delayed (≥ 48 hours) RRT in septic shock with AKI | No difference in 90-day mortality (58% vs. 54%, p = 0.38). Trial stopped early for futility12 |
| STARRT-AKI | 2020 | 2,927 | Accelerated (within 12 hours of AKI eligibility) vs. standard (emergent indications or AKI > 72 hours) RRT | No difference in 90-day mortality (43.9% vs. 43.7%). Accelerated group had more RRT-related adverse events and greater RRT dependence at 90 days13 |
Clinical recommendation: Initiate RRT for definitive indications. In the absence of emergent indications, a “watchful waiting” strategy is reasonable — monitor closely and initiate RRT if indications develop or clinical trajectory worsens.
3.3 RRT Modality
| Modality | Description | Advantages | Disadvantages |
|---|---|---|---|
| Continuous RRT (CRRT) | Continuous venovenous hemofiltration/hemodialysis/hemodiafiltration | Better hemodynamic tolerance; superior fluid management; preferred in hemodynamically unstable patients | Resource-intensive; requires continuous anticoagulation; immobilization |
| Intermittent hemodialysis (IHD) | 3–4 hour sessions, typically daily or every other day | More rapid solute clearance; less anticoagulation requirement; allows mobilization | Hemodynamic instability; less precise fluid management |
| Prolonged intermittent RRT (PIRRT/SLED) | 6–12 hour sessions | Compromise between CRRT and IHD; reasonable hemodynamic tolerance; resource-efficient | Less well-studied |
Recommended CRRT dose: 20–25 mL/kg/hr of effluent (prescribed dose should be 25–30 mL/kg/hr to account for downtime).1
4. Blood Product Management
4.1 Red Blood Cell Transfusion
Recommendation: For adults with sepsis or septic shock, the panel suggests using a restrictive (rather than liberal) red blood cell transfusion strategy: transfuse when hemoglobin concentration decreases to < 7.0 g/dL in the absence of extenuating circumstances (active hemorrhage, myocardial ischemia, severe hypoxemia).
Strength: Weak recommendation, moderate quality of evidence1
Evidence: The TRISS trial (2014) randomized 998 patients with septic shock to a hemoglobin threshold of 7 g/dL vs. 9 g/dL. No difference in 90-day mortality (43.0% vs. 45.0%, RR 0.94, p = 0.44) or in ischemic events. The lower-threshold group received 50% fewer transfusions.14
4.2 Platelet Transfusion
Recommendation:1
- Transfuse platelets when the count is < 10,000/μL regardless of bleeding risk
- Transfuse platelets when the count is < 20,000/μL if there is a high risk of bleeding
- Transfuse platelets when the count is < 50,000/μL for active bleeding, surgery, or invasive procedures
4.3 Fresh Frozen Plasma (FFP)
The guidelines do not recommend prophylactic FFP transfusion solely to correct laboratory coagulation abnormalities in the absence of bleeding or planned invasive procedures.1
4.4 Erythropoietin
Recommendation: The panel suggests against using erythropoiesis-stimulating agents for the treatment of anemia associated with sepsis.
Strength: Weak recommendation, moderate quality of evidence1
5. Glucose Management
5.1 Recommendations
Recommendation: For adults with sepsis or septic shock, the panel suggests initiating insulin therapy when two consecutive blood glucose levels are > 180 mg/dL (10 mmol/L), targeting an upper blood glucose level of ≤ 180 mg/dL (10 mmol/L) rather than a target ≤ 110 mg/dL.
Strength: Weak recommendation, moderate quality of evidence1
5.2 Target Glucose Range
| Parameter | Recommendation |
|---|---|
| Initiation threshold | 2 consecutive readings > 180 mg/dL |
| Target range | 140–180 mg/dL (7.8–10 mmol/L) |
| Lower limit alert | < 110 mg/dL — reduce insulin rate; check for hypoglycemia risk factors |
| Hypoglycemia | < 70 mg/dL — treat immediately; hold insulin |
| Severe hypoglycemia | < 40 mg/dL — medical emergency; IV dextrose |
5.3 Key Evidence
NICE-SUGAR trial (2009): In 6,104 ICU patients, intensive glucose control (target 81–108 mg/dL) resulted in higher 90-day mortality compared with conventional control (target ≤ 180 mg/dL) — 27.5% vs. 24.9% (OR 1.14, 95% CI 1.02–1.28, p = 0.02). The intensive group had significantly more severe hypoglycemia (6.8% vs. 0.5%, p < 0.001).15
5.4 Insulin Protocol Principles
- Use a validated IV insulin infusion protocol with standardized titration algorithms
- Monitor blood glucose every 1–2 hours during initial stabilization, then every 4 hours once stable
- Use point-of-care arterial blood glucose measurements when possible (capillary/fingerstick may be inaccurate in patients with shock, edema, or vasopressor use)
- Provide a dextrose source (D5W or D10W infusion, enteral nutrition, or parenteral nutrition) to prevent hypoglycemia during insulin infusion
- Transition to subcutaneous insulin when the patient is eating and hemodynamically stable, with an overlap period of 1–2 hours
6. Venous Thromboembolism (VTE) Prophylaxis
6.1 Recommendations
Recommendation: For adults with sepsis or septic shock, the panel recommends pharmacologic VTE prophylaxis unless a contraindication exists.
Strength: Strong recommendation, moderate quality of evidence1
Recommendation: The panel suggests using low-molecular-weight heparin (LMWH) rather than unfractionated heparin (UFH) for VTE prophylaxis.
Strength: Weak recommendation, moderate quality of evidence1
6.2 VTE Prophylaxis Regimens
| Agent | Standard Dose | Renal Adjustment (CrCl < 30 mL/min) | Notes |
|---|---|---|---|
| Enoxaparin (preferred) | 40 mg SC once daily | 30 mg SC once daily | LMWH preferred for consistency and lower HIT risk |
| Heparin (UFH) | 5,000 units SC q8–12h | No adjustment | Alternative when CrCl < 30 or high bleeding risk |
| Fondaparinux | 2.5 mg SC once daily | Contraindicated if CrCl < 30 | Alternative; very low HIT risk |
6.3 Mechanical Prophylaxis
Recommendation: The panel suggests against using mechanical VTE prophylaxis in addition to pharmacologic prophylaxis, unless pharmacologic prophylaxis is contraindicated.
Strength: Weak recommendation, low quality of evidence1
- Intermittent pneumatic compression (IPC) devices should be used when pharmacologic prophylaxis is contraindicated (active bleeding, thrombocytopenia < 30,000–50,000/μL, recent CNS surgery or hemorrhage)
- Graduated compression stockings alone are NOT recommended for VTE prophylaxis in critically ill patients (CLOTS trials demonstrated no benefit and potential harm)16
7. Stress Ulcer Prophylaxis
7.1 Recommendations
Recommendation: For adults with sepsis or septic shock who have risk factors for gastrointestinal bleeding, the panel suggests using stress ulcer prophylaxis.
Strength: Weak recommendation, moderate quality of evidence1
7.2 Risk Factors for Stress Ulceration
| Major Risk Factors (Each Independently Increases Risk) | Minor Risk Factors |
|---|---|
| Mechanical ventilation > 48 hours | Sepsis |
| Coagulopathy (platelets < 50,000, INR > 1.5, or aPTT > 2× normal) | ICU stay > 1 week |
| Corticosteroid use | |
| Occult or overt GI bleeding during admission | |
| Hepatic failure | |
| Renal failure | |
| Burns > 35% TBSA | |
| Head/spinal injury |
7.3 Agent Selection
Recommendation: The panel suggests using either proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) when stress ulcer prophylaxis is indicated.
Strength: Weak recommendation, low quality of evidence1
| Agent | Dose | Advantages | Disadvantages |
|---|---|---|---|
| Pantoprazole (PPI) | 40 mg IV or PO once daily | More effective acid suppression; once-daily dosing | Possible increased risk of C. difficile infection; possible increased risk of pneumonia; possible hypomagnesemia with prolonged use |
| Famotidine (H2RA) | 20 mg IV q12h | May have lower risk of C. difficile and pneumonia; available IV and PO | Less potent acid suppression; tachyphylaxis with prolonged use |
| Sucralfate | 1 g PO/NG q6h | No acid suppression → no infectious risks | Less effective than PPIs; requires enteral access; may interfere with drug absorption |
Evidence: The SUP-ICU trial (2018) randomized 3,298 ICU patients to pantoprazole 40 mg IV daily vs. placebo. No significant difference in 90-day mortality (31.1% vs. 30.4%, p = 0.76). Clinically important GI bleeding was lower with pantoprazole (2.5% vs. 4.2%, p = 0.009), but the absolute difference was small.17
8. Nutrition in Sepsis
8.1 Recommendations
Recommendation: For adults with sepsis or septic shock who can be fed enterally, the panel suggests early initiation of enteral nutrition (within 72 hours) rather than early parenteral nutrition or no nutrition.
Strength: Weak recommendation, very low quality of evidence1
8.2 Nutrition Timing and Approach
| Parameter | Recommendation |
|---|---|
| Timing | Initiate enteral nutrition within 24–48 hours of ICU admission in hemodynamically stable patients (stable or decreasing vasopressor doses, lactate trending down) |
| Route | Gastric feeding preferred initially; post-pyloric (nasojejunal) if gastric intolerance (high residuals > 500 mL, vomiting, aspiration risk) |
| Initial rate | Start at trophic/hypocaloric rates (10–20 mL/hr or ~500 kcal/day) for the first 24–48 hours |
| Advancement | Advance to goal rate over 48–72 hours as tolerated |
| Caloric target | 25–30 kcal/kg/day by day 3–7 (some guidelines recommend lower initial targets of 15–20 kcal/kg/day in the first week)18 |
| Protein target | 1.2–2.0 g/kg/day (higher end for patients with ongoing catabolism, burns, or obesity) |
| Parenteral nutrition | Do NOT initiate early (within the first 7 days) in patients who can be fed enterally. Consider supplemental or total parenteral nutrition after day 7 if enteral targets cannot be met |
8.3 When to Hold Enteral Nutrition
- Hemodynamic instability requiring escalating vasopressors or rising lactate
- Uncontrolled shock (MAP < 60 mmHg despite maximal support)
- Active GI bleeding
- Bowel obstruction, perforation, or ischemia
- High-output fistula (relative)
- After initiation of prone positioning (hold briefly, resume when stable in prone position)
8.4 Key Evidence
- CALORIES trial (2014): In 2,400 ICU patients, early parenteral nutrition vs. early enteral nutrition showed no difference in 30-day mortality (33.1% vs. 34.2%, p = 0.57). Enteral nutrition was associated with fewer episodes of hypoglycemia and vomiting.19
- EPaNIC trial (2011): Late initiation of parenteral nutrition (day 8) was superior to early initiation (day 3) with lower ICU infections, shorter ICU and hospital stay, and lower cost.20
9. Bicarbonate Therapy
Recommendation: For adults with septic shock and a pH ≥ 7.15, the panel suggests against using sodium bicarbonate therapy to improve hemodynamics or reduce vasopressor requirements.
Strength: Weak recommendation, moderate quality of evidence1
For patients with severe acidemia (pH < 7.15) and AKI (AKIN stage 2 or 3), the BICAR-ICU trial (2018) suggested that sodium bicarbonate (4.2% solution targeted to pH ≥ 7.30) may reduce the composite of 28-day mortality and organ failure at day 7, and may reduce the need for RRT.21
References
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Jaber S, Paugam C, Futier E, et al. “Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.” Lancet. 2018;392(10141):31-40. DOI: 10.1016/S0140-6736(18)31080-8 ↩︎