As noradrenaline doses escalate (commonly about 0.25-0.5 mcg/kg/min), add vasopressin; give IV hydrocortisone for ongoing vasopressor need; add dobutamine or use adrenaline for cardiac dysfunction; avoid vitamin C, beta-blockers, terlipressin and levosimendan.
At the bedside
Timed steps- 1
Add vasopressin
NA escalatingSSC 2026 suggests adding vasopressin 0.03 units/min when noradrenaline doses are escalating (conditional, moderate certainty), rather than escalating noradrenaline further. No start dose is mandated: about 0.25-0.5 mcg/kg/min is common practice, and VASSPR (2026) found no mortality difference between starting at 0.1 or 0.4 mcg/kg/min.
- 2
Start hydrocortisone
Ongoing vasopressor needSSC 2026 suggests IV corticosteroids in septic shock (conditional, low certainty). Usual regimen: hydrocortisone 50 mg IV every 6 h or 200 mg/day infusion. A common unit trigger is NA or adrenaline ≥ 0.25 mcg/kg/min for ≥ 4 h (the 2021 remark); 2026 sets no threshold. Do not wait for a cortisol level.
- 3
Echo for septic cardiomyopathy
NextIf cardiac dysfunction with low output and hypoperfusion persists despite adequate fluid and MAP: add dobutamine to noradrenaline, or use adrenaline alone (SSC 2026). Inotropes go with, not instead of, a vasopressor. Do not use levosimendan. With known cardiac dysfunction either noradrenaline or adrenaline is a reasonable first vasopressor (noradrenaline if tachyarrhythmia, adrenaline if bradycardia).
- 4
Add adrenaline and look for causes
Still refractoryIf MAP is still low on noradrenaline + vasopressin, add adrenaline 0.05-0.3 mcg/kg/min (SSC 2026); where vasopressin is unavailable, add adrenaline to noradrenaline alone. Check for a missed source, bleeding, tamponade, pneumothorax, abdominal compartment syndrome, adrenal crisis, low ionised calcium, severe acidosis.
- 5
Things that do not help
AvoidSSC 2026 suggests against: IV vitamin C (LOVIT harm), beta-blockers (esmolol, landiolol) to treat shock, terlipressin, levosimendan, IV immunoglobulin, blood purification (including polymyxin B haemoperfusion) and vitamin D. Bicarbonate only if pH ≤ 7.2 with AKI (AKIN 2-3). No dopamine first line. Methylene blue: no recommendation (rescue only, consultant decision).
- 6
Stop in order
WeaningWean noradrenaline first (to about 0.1), then taper vasopressin. Stop hydrocortisone once off vasopressors (tapering optional).
Second vasopressor
Vasopressin
- Dose
- 0.03 units/min (fixed)
- Range
- 0.01–0.04 units/min
- Preparation
- 20 units in 50 mL NS = 0.4 units/mL
- Worked example
- 0.03 units/min × 60 = 1.8 units/h ÷ 0.4 units/mL = 4.5 mL/h
Start when noradrenaline doses are escalating (commonly 0.25-0.5 mcg/kg/min). If vasopressin is unavailable, SSC 2026 allows adding adrenaline instead.
Open infusion calculatorSteroid for vasopressor-dependent septic shock
Hydrocortisone
- Dose
- 50 mg every 6 h (200 mg/day)
- Preparation
- Bolus: 100 mg vial in 2 mL water for injection. Infusion: 200 mg in 50 mL NS at 2.1 mL/h.
Usually 5-7 days, or until vasopressors stop. SSC 2026 does not set a dose, start threshold or duration; 200 mg/day is the trial dose (ADRENAL, APROCCHSS).
Optional mineralocorticoid add-on
Fludrocortisone
- Dose
- 50 mcg once daily for 7 days
Third agent in refractory shock
Adrenaline (epinephrine)
- Dose
- 0.05-0.3 mcg/kg/min
- Range
- 0.05–0.5 mcg/kg/min
- Preparation
- 4 mg in 50 mL (80 mcg/mL)
- Worked example
- 70 kg at 0.1 mcg/kg/min = 5.25 mL/h
Inotrope for septic cardiomyopathy with low output
Dobutamine
- Dose
- 2.5-10 mcg/kg/min
- Range
- 2.5–20 mcg/kg/min
- Preparation
- 250 mg in 50 mL (5000 mcg/mL)
- Worked example
- 70 kg at 5 mcg/kg/min: 5 × 70 × 60 ÷ 5000 = 4.2 mL/h
Calculators for this topic
Infusion rate from mcg/kg/min
Pump rate in mL/h for drugs dosed in mcg/kg/min (noradrenaline, adrenaline, dobutamine, milrinone, nitroglycerin by weight).
Infusion rate from a fixed hourly or per-minute dose
Pump rate for non-weight-based infusions such as vasopressin (U/min), labetalol (mg/min) or amiodarone (mg/h).
References
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Escalation in refractory septic shock
Step 1 of ~4
Decision: NA escalating (about ≥ 0.25 mcg/kg/min)?
Based on Prescott HC, Antonelli M, Alhazzani W, et al. Educational use; follow local protocol.
Pathophysiology
Septic shock causes relative vasopressin deficiency (pituitary stores deplete within 24-48 h), catecholamine receptor down-regulation and critical illness-related corticosteroid insufficiency (CIRCI). Steroids restore vascular responsiveness to catecholamines; vasopressin acts on non-adrenergic V1 receptors.
Evidence
- VASST (2008): vasopressin 0.01-0.03 U/min added to noradrenaline did not lower 28-day mortality overall; possible benefit in less severe shock.
- ADRENAL (2018, n = 3800): hydrocortisone 200 mg/day did not reduce 90-day mortality but hastened shock resolution and shortened ventilation.
- APROCCHSS (2018, n = 1241): hydrocortisone + fludrocortisone reduced 90-day mortality (43.0% vs 49.1%).
- SSC 2026: suggests IV corticosteroids in septic shock (conditional; certainty downgraded from moderate to low). A 45-RCT meta-analysis (9,543 patients) found a possible small mortality reduction (RR 0.92, 95% CI 0.83-1.01) and more shock reversal by day 7, with more hyperglycaemia and hypernatraemia. The 2021 trigger (NA or adrenaline ≥ 0.25 mcg/kg/min for ≥ 4 h) is not part of the 2026 statement.
- Vasopressors in 2026: noradrenaline first line over dopamine, adrenaline or selepressin (strong); over vasopressin or angiotensin II only conditional (downgraded from strong). Add vasopressin on escalating noradrenaline (conditional, moderate certainty); add adrenaline if MAP stays low on both (conditional, very low certainty). New: suggest against terlipressin; with cardiac dysfunction, either noradrenaline or adrenaline first line.
- Inotropes: suggest an inotrope (with a vasopressor) for cardiac dysfunction with persistent hypoperfusion; dobutamine added to noradrenaline or adrenaline alone; insufficient data for dobutamine vs milrinone; suggest against levosimendan.
- Other adjuncts: suggest against IV vitamin C, IV immunoglobulin, blood purification, polymyxin B haemoperfusion, vitamin D and (new) beta-blockers; insufficient evidence for methylene blue and oral midodrine.
- VASSPR (JAMA 2026, n ≈ 3,960): starting vasopressin at 0.1 vs 0.4 mcg/kg/min noradrenaline-equivalent did not change 28-day mortality (31.8% vs 33.0%); published after SSC 2026.
- LOVIT (2022): IV vitamin C increased the composite of death or persistent organ dysfunction.
Controversies
- Whether fludrocortisone adds benefit: APROCCHSS was positive while ADRENAL used hydrocortisone alone; there is no head-to-head RCT.
- Methylene blue: SSC 2026 makes no recommendation (insufficient evidence); it may raise BP but survival benefit is unproven, and 69% of panellists never or almost never use it. Angiotensin II is not routinely available in India.
- Terlipressin as a vasopressin substitute (common in India because of cost): SSC 2026 now suggests against terlipressin in septic shock (conditional, low certainty); it has different pharmacology and higher ischaemic risk.
🇮🇳 India notes
- Vasopressin availability and cost vary. Some units use terlipressin instead, but SSC 2026 suggests against terlipressin; where vasopressin is unavailable it allows adding adrenaline to noradrenaline.
- Hydrocortisone 100 mg vials are widely available; make sure the 6-hourly schedule is not missed overnight.
References
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