Vasoplegic and vasopressor-refractory shock: methylene blue, vasopressin, adjuncts · ICU Topics

vasoplegic vasopressor refractory shock clinical overview for ICU fellowship exams — FigureExam overview — key physiology, red flags and first-hour management.

Management algorithm for vasoplegic vasopressor refractory shock — FigureStepwise ICU management: immediate priorities, disease-specific therapy, escalation.

Cinematic ICU scene of a vasoplegic patient on high-dose noradrenaline with a vasoactive infusion pump stack, methylene blue and vasopressin syringes drawn up, a cardiac monitor showing refractory hypotension, clinical-blue lighting, no faces, no text — FigureVasoplegic shock — distributive shock refractory to catecholamines, driven by nitric-oxide-mediated vasodilation. After source control and first-line norepinephrine, escalate to vasopressin, add corticosteroids, and reserve methylene blue (a soluble guanylate cyclase inhibitor) for the truly refractory case.

Vasopressor agents in vasoplegic shock

Agent	Receptor	Role	Evidence	Notes
Noradrenaline	α1 (vasoconstriction), β1 (some)	FIRST-LINE	SSC 2021	Most septic shock responds. Titrate to MAP ≥65
Vasopressin	V1 (vasoconstriction)	SECOND-LINE (add to NA)	VANISH, VASST	Fixed dose 0.03 U/min. Catecholamine-sparing. Different pathway (not catecholamine). Don't titrate (fixed)
Adrenaline	α1, β1, β2	THIRD-LINE/add-on	SSC	For refractory or inotrope need. Lactate rises (β2 → glycolysis) — don't misinterpret
Hydrocortisone	Glucocorticoid	ADJUNCT (CIRCI)	ADRENAL, APROCCHSS	200 mg/day if vasopressor-dependent. Reduces vasopressor dose/duration
Methylene blue	Inhibits NO-cGMP	RESCUE (refractory)	Emerging	1-2 mg/kg IV. Blocks NO pathway. AVOID with serotonergic drugs (SSRI interaction)
Angiotensin II	AT1 receptor	RESCUE (refractory)	ATHOS-3	For vasodilatory shock refractory to conventional. Increased BP, reduced vasopressor dose

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Vasopressor escalation in refractory septic shock

OPTIMISE VOLUME (but not over-resuscitate) — Use dynamic measures (passive leg raise, fluid challenge, IVC ultrasound) to assess fluid responsiveness. Give 250-500 mL crystalloid bolus only if responsive. AVOID blanket 30 mL/kg if already euvolaemic (fluid overload worsens outcomes — avoid positive balance >3-5 L). Target: MAP ≥65 mmHg, lactate clearance, urine output
NORADRENALINE (first-line) — Start when MAP <65 despite adequate volume. Dose: 0.05-0.5 mcg/kg/min (titrate to MAP ≥65). Central line preferred (but peripheral acceptable if urgent — US guidelines). If needing >0.25-0.5 mcg/kg/min → refractory → escalate
ADD VASOPRESSIN (second-line) — Add when noradrenaline >0.25-0.5 mcg/kg/min or rising. FIXED dose 0.03 U/min (don't titrate — flat dose). Mechanism: V1 receptor (different from catecholamine). Catecholamine-sparing (reduces noradrenaline dose). VANISH trial: no mortality benefit vs noradrenaline, but reduced atrial fibrillation and renal replacement therapy in subgroup. May allow noradrenaline weaning
ADD HYDROCORTISONE (CIRCI) — If still vasopressor-dependent (noradrenaline + vasopressin, MAP <65). Hydrocortisone 200 mg/day (continuous or 50 mg q6h). ADRENAL trial: no mortality benefit overall, but faster shock reversal. APROCCHSS: hydrocortisone + fludrocortisone + vitamin C reduced mortality (controversial — French trial). Consider cosyntropin test (but don't delay treatment)
METHYLENE BLUE (rescue, refractory vasoplegia) — If refractory to noradrenaline + vasopressin + steroids. Methylene blue 1-2 mg/kg IV over 20-60 min (then infusion 0.25-2 mg/kg/hr if needed). Mechanism: inhibits soluble guanylate cyclase → blocks NO-cGMP pathway → restores vascular tone. Evidence: observational + small RCTs — increases MAP, reduces vasopressor dose. AVOID: SSRI (serotonin syndrome risk), G6PD deficiency (haemolysis), pregnancy. Interferes with pulse oximetry (spurious SpO2 drop)
ANGIOTENSIN II / ADRENALINE (rescue) — Angiotensin II (Giapreza): ATHOS-3 trial — increased BP in refractory vasodilatory shock, reduced catecholamine dose. For refractory. Adrenaline: add for inotropy or refractory (note lactate rises from β2 — don't misinterpret as worsening). Consider extracorporeal support (VA-ECMO) if cardiogenic component or refractory to all
ADDRESS CAUSE + SOURCE CONTROL — (a) Antibiotics (within 1 hour — broad-spectrum). (b) Source control (drain abscess, remove infected line, surgery for perforation). (c) Exclude/treat adrenal insufficiency (cortisol, cosyntropin test). (d) Correct electrolytes (Mg, Ca, phosphate — affect vascular tone). (e) Correct acidosis (pH <7.1 impairs vasopressor response). (f) Treat hypoxaemia. (g) Consider echocardiogram (exclude cardiogenic/septic cardiomyopathy component)

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SAQ — Vasopressor-refractory septic shock: escalation, second agents, and rescue therapy

10 minutes · 10 marks

A 65-year-old woman in septic shock from a cholangitis receives 30 mL/kg balanced crystalloid, piperacillin-tazobactam, and is on noradrenaline 0.7 mcg/kg/min. MAP is 60 mmHg, lactate 5.0 mmol/L, ScvO2 75%, temperature 38.5°C. Echocardiography shows a hyperdynamic LV with no regional wall motion abnormality. The registrar asks what to do next as the noradrenaline keeps rising.

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SAQ — Post-cardiac surgery vasoplegia and the role of methylene blue and vasopressin

10 minutes · 10 marks

A 72-year-old man is admitted to ICU 2 hours after an elective on-pump CABG. He is on noradrenaline 0.6 mcg/kg/min, MAP 58 mmHg, warm peripherally with a wide pulse pressure, SVR 480 dyn·s·cm⁻⁵, cardiac index 3.5 L/min/m², lactate 1.8 mmol/L, and a TEG shows no coagulopathy. He was on an ACE inhibitor pre-operatively and received protamine. The cardiac surgical registrar asks what this syndrome is and how you will manage it.

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Clinical pearls

High-yield vasoplegic shock points for CICM/FFICM exam

Pathophysiology — NO-cGMP pathway. (1) In sepsis, inflammatory cytokines (TNF, IL-1) induce iNOS (inducible nitric oxide synthase) in vascular smooth muscle. (2) iNOS produces large amounts of NITRIC OXIDE (NO). (3) NO diffuses to vascular smooth muscle → activates SOLUBLE GUANYLATE CYCLASE → converts GTP to cGMP. (4) cGMP activates protein kinase G → myosin light chain dephosphorylation → VASCULAR SMOOTH MUSCLE RELAXATION → VASODILATION. (5) This NO-mediated vasodilation is RELATIVEly RESISTANT to catecholamines (alpha-1 agonists work via different pathway — IP3/DAG → calcium → contraction, but the NO-cGMP pathway overrides). (6) This is WHY septic shock can be 'vasopressor-refractory' — the NO pathway is overwhelming the catecholamine pathway. METHYLENE BLUE blocks this pathway (guanylate cyclase inhibitor).[1] }
Exclude REVERSIBLE causes before 'refractory'. Before declaring vasopressor-refractory shock, EXCLUDE: (1) HYPOVOLAEMIA (still under-filled — give fluid challenge, reassess with passive leg raise/IVC). (2) CARDIOGENIC COMPONENT (septic cardiomyopathy — LV dysfunction in sepsis → echo shows poor LV function → add inotrope, not just vasopressor). (3) ADRENAL INSUFFICIENCY (CIRCI — check cortisol, give hydrocortisone). (4) ACIDOSIS (pH <7.15 → vasopressors ineffective → correct). (5) HYPOCALCAEMIA / HYPOPHOSPHATAEMIA / HYPOMAGNESAEMIA (affect vascular tone + cardiac function). (6) ONGOING SOURCE (uncontrolled infection — abscess not drained, line not removed, perforation not fixed). (7) ANAPHYLAXIS (try adrenaline, not just noradrenaline). Each is TREATABLE — address before escalating to rescue agents.[1] }
Noradrenaline — first-line, why. (1) ALPHA-1 agonist → vasoconstriction (increases SVR → raises BP). (2) BETA-1 (mild) → some inotropy (unlike pure alpha phenylephrine). (3) SSC 2021: preferred first vasopressor in septic shock (vs dopamine — which has higher arrhythmia rate; SOAP II trial). (4) DOSE: 0.05-0.5 mcg/kg/min (start low, titrate to MAP ≥65). (5) CENTRAL LINE preferred (extravasation → necrosis), but PERIPHERAL acceptable if urgent (monitor site). (6) If needing >0.5 mcg/kg/min → refractory → add vasopressin + steroids. (7) Side effects: peripheral/ischaemic (digits, bowel), arrhythmia (less than dopamine).[2] }
Vasopressin — second-line, evidence. (1) MECHANISM: V1 receptor on vascular smooth muscle → phospholipase C → IP3 → calcium → vasoconstriction (DIFFERENT pathway from catecholamines — why it works when catecholamines failing). (2) FIXED DOSE 0.03 U/min (don't titrate — flat dose — higher doses cause ischaemia). (3) VASST trial (2008): vasopressin vs noradrenaline — no overall mortality difference, but trend toward benefit in LESS severe shock (noradrenaline 5-14 mcg/min). (4) VANISH trial (2016): vasopressin vs noradrenaline as initial — no mortality difference, but reduced atrial fibrillation + reduced RRT in subgroup (suggests renal benefit). (5) CATECHOLAMINE-SPARING: adding vasopressin allows noradrenaline dose to be reduced (less alpha-1 toxicity). (6) SIDE EFFECTS: ischaemia (digits, mesenteric, cardiac — rare at 0.03 U/min), hyponatraemia (V2 effect — weak), mesenteric.[4] }
Hydrocortisone — CIRCI, when to give. (1) CIRCI (Critical Illness-Related Corticosteroid Insufficiency): relative adrenal insufficiency in critical illness → reduced cortisol response → contributes to vasoplegia (cortisol normally supports vascular tone + catecholamine effect). (2) ADRENAL trial (2018, NEJM): hydrocortisone 200 mg/day vs placebo in septic shock — NO mortality benefit overall, BUT faster shock reversal (fewer days on vasopressors). (3) APROCCHSS (2018, NEJM): hydrocortisone + fludrocortisone + vitamin C (HAT therapy) — REDUCED mortality (controversial — single-centre French trial, criticized). (4) SSC 2021: SUGGEST hydrocortisone for septic shock NOT responding to adequate fluid + vasopressor (weak recommendation). (5) DOSE: hydrocortisone 200 mg/day (continuous infusion or 50 mg q6h). (6) Don't delay for cosyntropin test — give empirically if vasopressor-dependent, stop if not needed.[2] }
Methylene blue — mechanism and evidence. (1) MECHANISM: inhibits soluble GUANYLATE CYCLASE → blocks NO-cGMP pathway → restores vascular tone (reverses NO-mediated vasodilation). (2) DOSE: 1-2 mg/kg IV bolus over 20-60 min, then infusion 0.25-2 mg/kg/hr (if needed). (3) EVIDENCE: mostly observational + small RCTs. Increases MAP, reduces vasopressor dose, may improve mortality (small studies). Not yet in SSC guidelines (insufficient RCT evidence). (4) USE: refractory vasoplegia (post-cardiac surgery, septic shock unresponsive to conventional). (5) ONSET: minutes (rapid). DURATION: hours (may need infusion). (6) CONTRAINDICATIONS: G6PD deficiency (haemolysis), renal failure (caution), pregnancy, serotonergic drugs (SSRI — risk of serotonin syndrome — methylene blue is MAO inhibitor). (7) MONITORING: turns urine/secretions blue (harmless), interferes with pulse oximetry (spurious low SpO2 — use arterial blood gas), may affect ECG. (8) RISKS: excessive vasoconstriction (mesenteric, cardiac ischaemia), serotonin syndrome (with SSRI).[5] }
Angiotensin II — ATHOS-3 trial. (1) MECHANISM: angiotensin II (endogenous vasoconstrictor — RAAS) acts on AT1 receptor → vasoconstriction (different from catecholamine + vasopressin pathways). (2) ATHOS-3 trial (2017, NEJM): angiotensin II vs placebo in vasodilatory shock (mostly septic) refractory to conventional vasopressors → angiotensin II increased MAP (69% vs 23% met primary), reduced catecholamine dose. (3) DOSE: start 20 ng/kg/min, titrate to MAP. (4) USE: refractory vasodilatory shock (not first-line — for those failing conventional). (5) SIDE EFFECTS: thrombosis (ATHOS-3 — increased venous thrombosis — add prophylaxis), digital ischaemia. (6) AVAILABLE as Giapreza (synthetic angiotensin II). (7) CONTROVERSIAL: small trial, selected population, thrombosis risk — not yet standard, but option for refractory.[3] }
Post-cardiac surgery vasoplegia — specific syndrome. (1) 5-25% of cardiac surgery patients (especially CPB). (2) FEATURES: hypotension (low SVR), normal/high cardiac output, vasopressor-refractory, ongoing vasodilation post-CPB. (3) RISK FACTORS: pre-op ACEi/ARB, long CPB time, low pre-op ejection fraction, redo surgery, use of PDE inhibitors (milrinone), protamine reaction. (4) MECHANISM: inflammatory response to CPB (complement activation, cytokines) → NO release → vasoplegia (same NO-cGMP pathway as sepsis). (5) TREATMENT: noradrenaline first; vasopressin; METHYLENE BLUE particularly effective here (NO pathway dominant); steroids; correct hypocalcaemia (calcium improves tone + contractility). (6) PREVENTION: consider pre-op ACEi/ARB hold (controversial), minimise CPB time.[1] }
Adrenaline — when to add. (1) THIRD-LINE (after noradrenaline + vasopressin) or if INOTROPE needed (poor cardiac output — septic cardiomyopathy). (2) MECHANISM: alpha-1 (vasoconstriction) + beta-1 (inotropy + chronotropy) + beta-2 (bronchodilation, glycolysis). (3) DOSE: 0.05-0.5 mcg/kg/min (titrate). (4) CAVEAT — LACTATE RISES: beta-2 stimulation → aerobic glycolysis → pyruvate → lactate. So adrenaline causes lactate to RISE (not from hypoperfusion — from glycolysis). DON'T misinterpret rising lactate on adrenaline as 'worsening shock' — it may be drug effect. (5) SIDE EFFECTS: arrhythmia (more than noradrenaline — beta-1), ischaemia (digits, mesenteric, cardiac), hyperglycaemia, lactate rise, tachycardia. (6) CAT trial: adrenaline vs noradrenaline + dobutamine — equivalent outcomes; adrenaline more lactate/tachyarrhythmia.[6] }
Fluid overload worsens septic shock outcomes. (1) Excessive fluid resuscitation (positive balance >3-5 L in first days) → tissue oedema (including gut, lungs, kidney) → organ dysfunction. (2) CLASSIC trial (2019, NEJM): liberal vs restrictive fluid in septic shock — no mortality difference, but restrictive group received less fluid (and did just as well — fluid isn't always good). (3) CLOVERS trial (2023, NEJM): restrictive vs liberal — similar outcomes (no benefit of liberal). (4) APPROACH: dynamic assessment (passive leg raise, fluid challenge, IVC) — give fluid only if responsive. Don't 'chase the MAP' with fluid if not responsive (use vasopressors instead). (5) Consider earlier vasopressors (peripheral noradrenaline while fluid-resuscitating — CLOVERS supports this). (6) Avoid albumin (ALBIOS — no benefit) unless large colloid needed.[2] }
Vitamin C (ascorbate) + thiamine + steroids (HAT therapy) — controversial. (1) MARIK (2017, Chest): before-after study — HAT therapy (hydrocortisone + ascorbic acid + thiamine) reduced mortality in sepsis (8.5% vs 40%). Huge interest. (2) SUBSEQUENT TRIALS: (a) VICTAS (2020) — no difference in SOFA at 7 days (primary). (b) ACTS (2021) — no difference in SOFA. (c) LOVIT (2022, NEJM) — ascorbate (vitamin C) ALONE increased death/organ dysfunction vs placebo (HARM). (3) CURRENT CONSENSUS: HAT therapy NOT recommended (insufficient evidence, potential harm). (4) VITAMIN C: high-dose ascorbate may help refractory vasoplegia (antioxidant — reduces NO), but LOVIT shows harm — DON'T give routinely. (5) THIAMINE: give if alcoholism/malnutrition (prevents Wernicke, may help lactic acidosis).[2] }
Mean arterial pressure target — 65 mmHg. (1) SSC 2021: target MAP ≥65 mmHg (not higher). (2) SEPSISPAM trial (2014, NEJM): high target (80-85) vs standard (65-70) — no mortality difference overall; subgroup with chronic hypertension trended toward less AKI with high target (but more arrhythmia). (3) PRACTICAL: 65 mmHg is sufficient for most; consider higher (75-80) in chronic hypertensives (may need higher perfusion pressure). (4) INDIVIDUALISE: if lactate rising, urine output dropping, mottled skin, altered mental state → target may be too low (increase). If digits ischaemic → target too high (lower if possible). (5) Don't chase a number — assess PERFUSION (lactate, urine, skin, mental state).[2] }
Peripheral vasopressors — safe when needed. (1) SSC 2021: peripheral noradrenaline ACCEPTABLE (initial, urgent) — don't delay for central line if shocked. (2) EVIDENCE: large observational studies — low extravasation rate (<2%) when monitored. (3) PRACTICE: start peripheral (large vein, forearm — not hand/antecubital), monitor site hourly, switch to central when line placed. (4) Extravasation: STOP infusion, leave cannula, aspirate, phentolamine (alpha-blocker) infiltration (5-10 mg in 10 mL saline — counteracts alpha-1 vasoconstriction). (5) AVOID: weak veins (dorsal hand), lower limb (poor flow), high concentration peripherally.[6] }
Vasoplegia + cardiac failure — the 'mixed' shock. (1) Septic cardiomyopathy: sepsis causes myocardial depression (cytokines, NO) → LV dysfunction (reduced EF) → CONTRIBUTES to shock (not just vasoplegia). (2) ECHOCARDIOGRAM: shows poor LV function (hyperdynamic would suggest pure vasoplegia; poor LV suggests cardiogenic component). (3) TREATMENT: add INOTROPE (dobutamine — beta-1; adrenaline; milrinone — PDE inhibitor) if cardiac output low despite adequate preload + vasopressor. (4) DON'T just escalate vasopressors if the heart is failing (more alpha won't help a failing heart — may worsen afterload). (5) VA-ECMO: if refractory cardiogenic + vasoplegic (mixed) shock unresponsive to inotropes + vasopressors. (6) ALWAYS echo in refractory shock — distinguish vasoplegic (high CO, low SVR) from cardiogenic (low CO, high SVR) or mixed.[1] }

Red flags

Prognosis

Vasoplegic and refractory shock evidence

Noradrenaline first-line (SOAP II — dopamine higher arrhythmia; SSC 2021). Vasopressin (VASST 2008, VANISH 2016 — no mortality benefit, catecholamine-sparing, reduced AF/RRT subgroup). Hydrocortisone (ADRENAL 2018 — no mortality, faster shock reversal; APROCCHSS — HAT reduced mortality, controversial). Angiotensin II (ATHOS-3 2017 — increased BP in refractory). Methylene blue (observational/small RCTs — increases MAP, reduces vasopressors; not in SSC). MAP target 65 (SEPSISPAM — no benefit of higher). CLASSIC/CLOVERS — restrictive fluid not inferior (avoid over-resuscitation). Vitamin C (LOVIT 2022 — HARM; HAT not recommended). Refractory septic shock mortality 40-60% (very high — these are the sickest patients).

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Pathophysiology — deep dive

Pathophysiology of vasoplegic vasopressor refractory shock — FigureCore mechanism linking insult to organ failure — CICM/FFICM viva scaffold.

The four mechanisms of vasoplegia — exam answer

iNOS / NO / cGMP over-activation. Sepsis cytokines (TNF-α, IL-1β, IFN-γ) induce inducible nitric oxide synthase (iNOS) in vascular smooth muscle and endothelium. iNOS produces sustained, supraphysiological NO (100–1000× basal eNOS output). NO activates soluble guanylate cyclase (sGC) → ↑cGMP → PKG activation → myosin light chain dephosphorylation → sustained vasodilation. cGMP also activates BK(Ca) potassium channels → smooth muscle hyperpolarisation → closes voltage-gated Ca²⁺ channels → further relaxation. Methylene blue inhibits sGC; vasopressin bypasses this entirely (PLC/IP3 pathway).[1] }
Vasopressin deficiency. Septic shock depletes neurohypophyseal vasopressin stores (magnocellular neuron exhaustion + inhibited baroreflex-mediated release). Plasma vasopressin is inappropriately LOW in septic shock vs cardiogenic shock of equivalent severity. This is the rationale for fixed-dose replacement (0.03 U/min) — restoring physiological concentration rather than pharmacological vasoconstriction.[4] }
RAAS dysregulation + angiotensin II resistance. Reduced angiotensin-converting enzyme activity (ACE consumed/glycated by inflammation), reduced AT1 receptor sensitivity, and increased angiotensin II type-2 receptor (AT2 — vasodilatory) expression all impair the renin-angiotensin axis. The lung (ACE-rich) is particularly affected in ARDS/sepsis. Rationale for exogenous angiotensin II (ATHOS-3).[3] }
Adrenal insufficiency (CIRCI). Critical illness reduces cortisol response to stress (suppressed HPA axis, corticosteroid-binding-globulin depletion, tissue corticosteroid resistance). Cortisol normally upregulates α1-receptor expression and supports catecholamine signalling. Without cortisol, catecholamine vasopressors are blunted — basis for hydrocortisone in refractory shock.
K_ATP channel opening. Lactate, acidosis and ADP open ATP-sensitive K⁺ channels → hyperpolarisation → vasodilation. Explains why correcting acidosis restores pressor responsiveness (avoid sodium bicarbonate empirically — treat the cause).

Causes of vasoplegic / catecholamine-refractory shock

Category	Specific cause	Mechanism	Clue
Septic (commonest)	Gram-negative / Gram-positive sepsis, fungal	iNOS induction, NO-cGMP, vasopressin deficiency, RAS dysregulation	Fever, source, lactate, leucocytosis
Post-cardiac surgery	Post-CPB vasoplegia (5–25% of CPB cases)	Complement, cytokine release, haemodilution, protamine, pre-op ACEi/ARB	On-pump time, low SVR with high CO within hours of surgery
Anaphylaxis	IgE mast-cell degranulation	Histamine, PAF, leukotrienes → NO + direct vasodilation	Trigger (drug, contrast, food), urticaria, bronchospasm, epinephrine first
Drug-induced	ACEi, ARB, PDE inhibitors (milrinone/sildenafil), protamine, anaesthetic agents, narcotics	Direct vasodilation or receptor blockade	Temporal link to drug exposure
Post-reperfusion	Post-embolisation, post-clamping, post-transplant revascularisation, reperfusion of ischaemic limb/bowel	Reperfusion injury — ROS, cytokines, NO	Acute event after revascularisation
Adrenal crisis	CIRCI, steroid withdrawal, adrenal haemorrhage (Waterhouse-Friderichsen), etomidate	Loss of cortisol-mediated α1-upregulation	Prior steroid use, etomidate exposure, hyperpigmentation, hyponatraemia + hyperkalaemia
Hepatic failure	Cirrhosis, acute liver failure	Endotoxin clearance failure, splanchnic vasodilation, NO excess	Jaundice, coagulopathy, ascites
Neurogenic	Spinal cord injury (T6 above)	Loss of sympathetic tone → unopposed parasympathetic	Trauma, bradycardia, warm dry skin, priapism
Toxidromes	β-blocker / CCB overdose, cyanide, CO	Receptor blockade / cellular hypoxia	Bradycardia (BB/CCB), lactate, exposure history

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Rescue agents in depth

Rescue vasopressors — practical dosing and receptor pharmacology

Agent	Receptor / target	Starting dose	Titration	Onset / half-life	Trial evidence	Key cautions
Noradrenaline	α1 ≫ β1	0.05 mcg/kg/min	↑ every 5 min to MAP ≥65	Onset seconds, t½ 2.4 min	SSC 2021 first-line; SOAP II (vs dopamine)	Extravasation necrosis, arrhythmia, digital ischaemia
Vasopressin	V1 (smooth muscle)	0.03 U/min FIXED	Do NOT titrate (flat dose)	Onset minutes, t½ 10–35 min	VASST 2008; VANISH 2016	Mesenteric/digital ischaemia at higher dose; hyponatraemia
Adrenaline	α1, α2, β1, β2	0.05 mcg/kg/min	↑ q5–10 min	Onset seconds, t½ 2 min	CAT trial (vs noradrenaline + dobutamine)	Lactate rise (β2 glycolysis), arrhythmia, hyperglycaemia, mesenteric vasoconstriction
Hydrocortisone	Glucocorticoid	200 mg/day (50 mg q6h or continuous)	Not titrated	Hours	ADRENAL; APROCCHSS	Hyperglycaemia, infection, neuromyopathy; do NOT use etomidate for intubation
Methylene blue	Inhibits sGC → ↓cGMP	1–2 mg/kg IV bolus over 20–60 min → 0.25–2 mg/kg/hr infusion	Repeat bolus if effect wanes	Onset minutes, effect 2–6 h	Observational + small RCTs	G6PD haemolysis; SSRI serotonin syndrome; spurious pulse ox drop; PBS rejection after IV Ig
Angiotensin II (Giapreza)	AT1	20 ng/kg/min	Titrate q5 min, max 80 ng/kg/min	Onset minutes, t½ <1 min	ATHOS-3 2017	VTE — give prophylaxis; digital ischaemia
Terlipressin	V1 (long-acting vasopressin analogue)	1–2 mg IV q4–6h (or infusion 1.3–6.7 mcg/kg/hr)	q4h	Onset min, t½ 6 h	CONFIRM trial (hepatorenal); emerging in shock	Hypoxaemia (pulmonary vasoconstriction), ischaemia
Phenylephrine	Pure α1	0.5–5 mcg/kg/min	↑ q10–15 min	Onset seconds	No sepsis RCT — second-line/tachyarrhythmia	Reflex bradycardia, reduced stroke volume — avoid in low CO

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Methylene blue protocol for refractory vasoplegia

Indication. Vasodilatory shock (septic, post-CPB, post-reperfusion) refractory to noradrenaline + vasopressin ± steroids, OR rapidly escalating pressor requirement with adequate volume.
Pre-administration checklist. (a) G6PD status — if unknown, ask (no time to test in emergency; avoid if known deficiency → haemolysis). (b) Concomitant SSRI/SNRI/MAOI — risk of serotonin syndrome; weigh risk–benefit. (c) Pregnancy — relative contraindication. (d) Renal failure — caution (MB excreted renally).
Dose. 1–2 mg/kg IV in 50–100 mL 5% dextrose over 20–60 min. (Some protocols use up to 2 mg/kg; total cumulative ceiling commonly cited as 4–7 mg/kg.) Follow with infusion 0.25–2 mg/kg/hr titrated to MAP.
Effect. Onset within minutes; peak 30–60 min; duration 2–6 h. Expect rise in SVR and fall in noradrenaline requirement by 30–60%.
Monitor. MAP, lactate, vasopressor dose, urine output, distal perfusion. Pulse oximetry artefact: MB discolours plasma → SpO₂ may read 80–85% spuriously for 1–2 h; use ABG/CO-oximetry if concerned. Haemoglobin measurement may also be artefactually altered.
Weaning. Once shock resolves and catecholamine dose low, taper infusion by 0.25 mg/kg/hr q2–4h. Rebound hypotension possible — wean slowly.
Adverse effects. Skin/urine blue-green discolouration (benign), nausea, dizziness, haemolysis (G6PD), serotonin syndrome (SSRI), pseudomethaemoglobinaemia, interference with phototherapy/PBS measurement.

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Approach to escalating vasopressors (practical algorithm)

Stage 0 — confirm shock + check volume. Map MAP, lactate, mottling, urine. Bedside echo (cardiac vs distributive). Dynamic fluid responsiveness (PLR, IVC). If responsive → 250–500 mL crystalloid. If not → go to pressors; do NOT chase MAP with fluid.
Stage 1 — Noradrenaline. Peripheral or central, titrate to MAP ≥65. Target dose 0.05–0.25 mcg/kg/min.
Stage 2 — Add vasopressin 0.03 U/min. When noradrenaline >0.25–0.5 mcg/kg/min or escalating. Fixed dose. Expect noradrenaline-sparing effect.
Stage 3 — Steroids. Hydrocortisone 200 mg/day if still vasopressor-dependent on noradrenaline + vasopressin. Add fludrocortisone 50 mcg/day per APROCCHSS (controversial).
Stage 4 — Address reversible factors. Echo (mixed shock → inotrope), cortisol ± cosyntropin, Ca²⁺/Mg²⁺/PO₄³⁻, pH, exclude source, treat anaphylaxis with epinephrine.
Stage 5 — Methylene blue. For refractory NO-mediated vasoplegia. Use early rather than as last-ditch (best evidence in post-CPB and septic).
Stage 6 — Angiotensin II / terlipressin. If still refractory. ATHOS-3 dosing. Add VTE prophylaxis.
Stage 7 — Mechanical support. VA-ECMO for refractory mixed/cardiogenic shock; consider early in selected centres.
Throughout — source control, daily sedation hold, normoxia/normocapnia/normoglycaemia, VTE prophylaxis, stress ulcer prophylaxis, early enteral nutrition, glycaemic control 140–180 mg/dL.

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Clinical pearls (additional — exam high-yield)

Vasoplegic shock — exam pearls (set 2)

VASST (2008, NEJM) — vasopressin in septic shock. Multicentre RCT, 778 patients, vasopressin (up to 0.04 U/min) vs noradrenaline in septic shock with MAP <65 on ≥5 mcg/min noradrenaline. No difference in 28-day mortality (35.4% vs 39.3%). Pre-specified subgroup with LESS severe shock (5–14 mcg/min NA at baseline) trended toward mortality benefit. Heavy ischaemic side-effects at higher doses → practice standardised at fixed 0.03 U/min. Established vasopressin as SAFE second-line; not superior to NA.[4] }
VANISH (2016, JAMA) — vasopressin vs noradrenaline as initial, with optional open-label catecholamine. 409 patients. Up to 0.06 U/min vasopressin. No difference in kidney-failure-free days (primary). Subgroup: vasopressin + hydrocortisone interaction — vasopressin patients had less RRT and less atrial fibrillation than noradrenaline. Reinforces catecholamine-sparing role + synergy with steroids.[4] }
ADRENAL (2018, NEJM) — hydrocortisone in septic shock. 3,658 patients, hydrocortisone 200 mg/day vs placebo. No 90-day mortality difference (27.9% vs 28.7%). Faster shock reversal (median 5.6 vs 7.0 ICU vasopressor-free days). More superinfections, hyperglycaemia. → Hydrocortisone NOT routine; reserve for shock not responding to fluids + vasopressor.
APROCCHSS (2018, NEJM) — HAT (hydrocortisone + fludrocortisone + ascorbic acid) in severe septic shock. 1241 patients. Lower 90-day mortality (24% vs 33%) with HAT vs placebo. Single French centre; vitamin C dose 50 mg q6h IV (50 mg/kg/day). Criticised: results not replicated; high baseline mortality in placebo arm. VICTAS/LOVIT subsequently refuted vitamin C benefit. Hydrocortisone + fludrocortisone alone remains defensible in very severe shock.
LOVIT (2022, NEJM) — high-dose vitamin C HARM. 872 patients with sepsis, IV vitamin C 50 mg/kg q6h × 96 h vs placebo. PRIMARY OUTCOME WORSE — composite of death or persistent organ dysfunction at 28 days higher with vitamin C (44% vs 38%). → High-dose vitamin C is NOT recommended and may harm.[2] }
ATHOS-3 (2017, NEJM) — angiotensin II for high-output vasodilatory shock. 344 patients with vasodilatory shock despite ≥0.2 mcg/kg/min catecholamine. Angiotensin II (Giapreza) titrated 20–200 ng/kg/min. Primary endpoint (MAP ↑ ≥10 mmHg or ≥75 mmHg at 3 h) met in 69.9% vs 23.4% placebo. No mortality difference. More VTE (initiate prophylaxis). Best response in the renin-low subgroup. Useful in truly refractory vasodilatory shock.[3] }
Post-cardiac surgery vasoplegia syndrome (VPS). Incidence 5–25% post-CPB; mortality 20–30% if refractory. Predictors: pre-op ACEi/ARB, low EF, redo surgery, long CPB/cross-clamp, blood products, protamine. Mechanism = complement + cytokine + NO. Methylene blue has its best evidence here — given intra-op/early post-op (1–2 mg/kg) reduces vasopressor requirement; multiple small RCTs and meta-analyses show MAP benefit. Vasopressin 0.03–0.04 U/min also effective. Avoid empiric vitamin C.
Anaphylactic vasoplegia is DIFFERENT — epinephrine first. Histamine-mediated, mast cell tryptase rise. IM adrenaline 0.5 mg is first-line, NOT noradrenaline. Refractory anaphylaxis: adrenaline infusion (0.05–0.5 mcg/kg/min), add glucagon (1–5 mg/hr) in β-blocked patients (glucagon bypasses β-receptor), H1/H2 blockers, fluid. Vasopressin and methylene blue are rescue if catecholamine-resistant. Methylene blue has case-series evidence in anaphylaxis refractory to adrenaline (inhibits histamine-induced NO).
Etomidate causes adrenal suppression — avoid in septic intubation. Single dose etomidate inhibits 11β-hydroxylase for ≥24 h → CIRCI → worsened vasoplegia. Use ketamine (1–2 mg/kg) for RSI in septic shock. If etomidate used, consider empirical hydrocortisone (controversial — EtaProof/KETASED trials mixed).
Calcium and vasopressor sensitivity. Hypocalcaemia (ionised Ca²⁺ <1.0 mmol/L) is common in sepsis and impairs smooth muscle contraction + cardiac contractility. Correct ionised calcium to ≥1.1 mmol/L — often dramatically improves vasopressor responsiveness (give calcium gluconate 1–2 g). Same for Mg²⁺ and PO₄³⁻. Always check before labelling 'refractory'.
Acidosis and vasopressor resistance. pH <7.15 reduces α-receptor responsiveness and catecholamine binding. Treat the CAUSE (hypoperfusion) rather than giving bicarbonate. Bicarbonate empirically does not improve haemodynamics in lactic acidosis and may worsen intracellular acidosis / sodium load. If pH <7.1 with hyperkalaemia/arrhythmia, controlled bicarbonate to pH 7.15–7.20 only.
Vasopressor spiral + peripheral ischaemia — when to stop escalating. If digits/nose/ears mottled or dusky despite pressors, further escalation trades perfusion for MAP. Reassess: inotrope? obstructive component (tension PTX, tamponade)? mixed shock? Consider de-escalation + accepting lower MAP (60 mmHg) with lactate/urine monitoring. Mesenteric ischaemia risk rises with noradrenaline + vasopressin + terlipressin combined.
Terlipressin in septic shock. Long-acting V1 agonist (prodrug). CONFIRM trial (hepatorenal syndrome) showed efficacy but HRS patients. In septic shock: limited RCTs — improved MAP, NA-sparing, but meta-analyses show no mortality benefit and possible excess respiratory failure. Reserve for rescue when vasopressin unavailable or for hepatorenal-driven shock. Dose 1–2 mg IV q4–6h or infusion 1.3–6.7 mcg/kg/hr.
Septic cardiomyopathy — always echo. ~40–50% of septic shock has myocardial depression (LV EF <50% or S' < 8 cm/s). Differentiates "vasoplegic only" from "mixed". Echo findings: hyperdynamic = pure vasoplegia; reduced EF ± RV dysfunction = mixed → add inotrope (dobutamine or milrinone; milrinone vasodilates — pair with vasopressor). Sepsis-induced cardiomyopathy is REVERSIBLE over 7–10 days.[1] }

Mortality prediction in refractory vasoplegic shock

Mortality prediction tools used at the bedside

Tool	Components	Use	Refractory-shock discrimination
SOFA	6 organ systems (0–4 each)	Daily ICU mortality tracking	SOFA ≥11 → ~80% mortality; rise over 48 h prognostic
APACHE II	Physiologic + age + chronic health	Admission prediction	Score ≥30 in septic shock → 50–70% mortality
qSOFA	RR ≥22, SBP ≤100, GCS <15	Ward/ED sepsis screen	2 of 3 → high risk; less sensitive in ICU
mNUTRIC	Age, APACHE II, SOFA, comorbidity, LOS, starvation	Malnutrition-inflammation risk in ICU	Score ≥5 → ↑mortality; relevant in chronic shock
NOREPINEPHRINE equivalent dose	Sum of catecholamine equivalents at 24 h	Vasopressor burden	>0.5 mcg/kg/min NA-equivalent at 24 h → ↑mortality
VIS (Vasoactive-Inotropic Score)	Catecholamines + milrinone + vasopressin	Daily vasoactive load	Persistent VIS ≥50 → ↑mortality in paediatric + adult
Lactate + lactate clearance	Initial lactate + 6-h clearance	Perfusion adequacy	Lactate >4 with <10% clearance at 6 h → ↑mortality

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Mortality prediction pearls

Noradrenaline-equivalent dose ≥1 mcg/kg/min at 24 h predicts 50%+ mortality. Each 0.1 mcg/kg/min increment in NA-equivalent dose at 6 h, 12 h, and 24 h is independently associated with rising 28-day mortality (Jentzer 2018). Patients on triple vasopressors (NA + vasopressin + epinephrine) at 24 h have approximately 60% mortality.[1] }
Refractory septic shock by SSC definition = lactate >2 mmol/L AND vasopressor need to keep MAP ≥65 after adequate fluids. 28-day mortality 35–50%. Truly refractory (failing above despite combination therapy) mortality 50–70%.
SOFA + lactate combined is the bedside test. SOFA ≥10 + lactate ≥4 mmol/L at 24 h → ~70% mortality. Falling SOFA over first week predicts survival; rising SOFA predicts death.
Vasopressor requirement trajectory matters more than peak. A patient on escalating pressors at 48 h has worse prognosis than one on a stable high dose that is now falling. Daily VIS trend guides family conversation + prognostication.
CIRCI diagnosis is pragmatic, not biochemical. Random cortisol <10 mcg/dL OR delta cortisol <9 mcg/dL after 250 mcg cosyntropin suggests CIRCI. But do not delay steroids for the test — treat empirically if shocked on two pressors. Steroid trial (ADRENAL/APROCCHSS) supports empirical use in vasopressor-dependent shock.

Red flags (additional)

Vasoplegic shock — exam red flags (set 2)

Noradrenaline-equivalent ≥1 mcg/kg/min at 24 h → mortality 50%+; escalate + discuss goals of care.[1] }
Etomidate for intubation in septic shock → relative adrenal suppression; choose ketamine; consider empirical hydrocortisone.
Anaphylaxis → IM adrenaline FIRST, not noradrenaline. Glucagon if β-blocked. Vasopressin/MB only as rescue.
Methylene blue + SSRI = serotonin syndrome risk; MB + G6PD deficiency = haemolysis; MB spuriously drops SpO₂ reading.
Angiotensin II (ATHOS-3) increased VTE — start pharmacological VTE prophylaxis on initiation.[3] }
Terlipressin can cause hypoxaemia (pulmonary vasoconstriction) — monitor SpO₂; avoid in ARDS unless essential.
Adrenaline raises lactate via β2 glycolysis — do NOT misinterpret as worsening shock; trending lactate on adrenaline is unreliable.[6] }
Hypocalcaemia + acidosis + hypophosphataemia mimic 'refractory' shock — check and correct before escalating pressors.
Pure α1 escalation (phenylephrine) in low-CO state reduces stroke volume — add inotrope, not pure vasoconstrictor.
Vitamin C (LOVIT) → harm; HAT therapy not recommended; do NOT give high-dose ascorbate.[2] }

Trial evidence in detail

Vasopressin vs norepinephrine — VASST (2008) and VANISH (2016)

VASST (Russell, NEJM 2008): n=778 septic shock on ≥5 mcg/min NA. Vasopressin 0.01–0.04 U/min vs NA. 28-day mortality 35.4% vs 39.3% (NS). Less-severe-shock subgroup favoured vasopressin. Safety signal encouraging. VANISH (Gordon, JAMA 2016): n=409, early vasopressin (up to 0.06 U/min) ± hydrocortisone vs NA ± hydrocortisone. Primary (kidney-failure-free days) NS. Less RRT and less AF in vasopressin group. Take-home: vasopressin is SAFE, catecholamine-sparing, not superior — use as add-on second agent at fixed 0.03 U/min.

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Corticosteroids — ADRENAL vs APROCCHSS vs CACTUS vs COIITSS

ADRENAL (2018, NEJM): n=3,658, hydrocortisone 200 mg/day vs placebo. No 90-day mortality benefit (27.9% vs 28.7%); faster shock reversal. APROCCHSS (2018, NEJM): n=1,241 severe septic shock; hydrocortisone + fludrocortisone + vitamin C reduced 90-day mortality (24% vs 33%). CACTUS (2018): hydrocortisone stopped earlier without harm. COIITSS (2010): hydrocortisone ± fludrocortisone — no benefit. SSC 2021: suggest hydrocortisone for septic shock NOT responding to adequate fluids + vasopressors (weak, low-quality). Avoid steroids if pregnant sepsis + chorioamnionitis may worsen.

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Rescue agents — ATHOS-3, methylene blue, terlipressin

ATHOS-3 (Khanna, NEJM 2017): n=344 refractory vasodilatory shock; angiotensin II 20–200 ng/kg/min. MAP response 69.9% vs 23.4% at 3 h; reduced catecholamine dose; no mortality difference; ↑VTE. Methylene blue: systematic reviews (Nguyen 2018, Jang 2022, Pakrah 2022) — ↑MAP, ↓catecholamine dose, possible mortality benefit in subgroup. Best evidence in post-CPB vasoplegia. Terlipressin: small RCTs in septic shock; NA-sparing; CONFIRM trial in HRS showed efficacy; risk of respiratory failure. No rescue agent has shown convincing mortality benefit — all are BP/dose-sparing.

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MAP target, fluid strategy, vitamin C — the negative trials that shaped practice

SEPSISPAM (2014, NEJM): high (80–85) vs low (65–70) MAP target — no mortality difference; chronic hypertensives had less AKI but more arrhythmia. MAP ≥65 is the standard. CLASSIC (2019, NEJM) + CLOVERS (2023, NEJM): restrictive vs liberal fluid — restrictive non-inferior; liberal fluid offers no benefit, may harm. Don't chase MAP with fluid in non-responders. LOVIT (2022, NEJM): high-dose IV vitamin C (50 mg/kg q6h) increased death or persistent organ dysfunction (44% vs 38%). HAT therapy and high-dose vitamin C are NOT recommended.

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Special circumstances

Special circumstances — pregnancy, liver failure, pulmonary hypertension

Pregnancy / peripartum vasoplegia. Septic abortion, chorioamnionitis, amniotic fluid embolism (AFE → catastrophic vasoplegia + coagulopathy). Left lateral tilt (avoid aortocaval compression). Noradrenaline is SAFE and first-line (VASST subgroup, observational). Vasopressin is safe. Avoid angiotensin II (placental vasoconstriction). Methylene blue — relative contraindication (theoretical fetal haemolysis, G6PD). Hydrocortisone safe. AFE: rapid onset, Coombs-negative haemolysis, DIC, abrupt cardiovascular collapse — give cryoprecipitate (fibrinogen), early delivery, vasopressors, consider V-A ECMO.
Cirrhosis / acute liver failure vasoplegia. Splanchnic vasodilation, NO excess, low SVR, high CO, low MAP. Terlipressin is first-choice second agent (splanchnic-selective, evidence in HRS). Albumin resuscitation preferred. Watch for hepatorenal syndrome. Avoid high-dose vitamin C (hepatic encephalopathy from oxalate). Transjugular intrahepatic portosystemic shunt (TIPS) post-procedure vasoplegia — use terlipressin.
Pulmonary hypertension + vasoplegia. Right ventricle fails with systemic hypotension (reduced coronary perfusion to RV → spiral). Avoid pure α1 (raises PVR — phenylephrine). Use vasopressin (splanchnic/systemic vasoconstriction without raising PVR). Milrinone for RV inotropy (vasodilates — pair with vasopressin). Inhaled NO or inhaled epoprostenol for RV afterload reduction. Methylene blue CONTRAINDICATED in pulmonary hypertension (raises PVR — pulmonary vasoconstriction).
Post-anaphylaxis / tryptase-positive shock. If refractory after IM adrenaline + infusion + fluid + H1/H2: vasopressin 0.03–0.04 U/min, methylene blue 1–2 mg/kg (inhibits histamine-driven NO — case series show response), glucagon in β-blocked (50 mcg/kg bolus then 1–5 mg/hr). Send tryptase at 1–2 h, 4 h, 24 h. Refer to allergy/immunology.
Right-heart failure mimics refractory vasoplegia. Acute cor pulmonale (massive PE, ARDS, RV infarct) shows low CO + low SVR + high CVP. Pure α1 escalation worsens RV ischaemia. Use echo, inhaled pulmonary vasodilator + dobutamine + vasopressin, consider VA-ECMO / pulmonary artery catheter.

[1]

Weaning and de-escalation

Vasopressor weaning once shock resolves

Confirm resolution. Lactate <2 mmol/L (or trending down ≥10%/2 h), MAP ≥65 on stable/low doses, urine output >0.5 mL/kg/hr, mottling resolved, mental status improved.
Wean in order of last added → first added. Typical: stop angiotensin II / terlipressin → wean methylene blue → reduce adrenaline (β2 effects) → reduce hydrocortisone (taper to avoid rebound) → wean noradrenaline last → wean vasopressin.
Vasopressin weaning. Reduce by 0.005 U/min every 1–2 h; some centres stop without taper (short t½). Watch for rebound hypotension.
Steroid taper. Hydrocortisone 200 mg/day → 100 mg/day × 1 day → 50 mg/day × 1 day → stop. If prolonged use (>7 days), slower taper (HPA suppression).
Noradrenaline wean. Decrease by 0.02–0.05 mcg/kg/min q15–30 min if MAP stable. Pause peripheral line early (safety).
Failure to wean. Reassess: ongoing source, adrenal suppression (cosyntropin test), cardiac function (echo), fluid overload (negative balance with diuretics/CRRT), septic cardiomyopathy recovery.
Avoid rebound. Stop methylene blue slowly (NO pathway reactivation). Stop vasopressin carefully in vasopressin-deficient septic shock.

[1]

References (additional)

Russell JA, et al. VASST. NEJM 2008;358:877–887. pmid: 18305265.
Gordon AC, et al. VANISH. JAMA 2016;316:1709–1719. pmid: 27673307.
Khanna A, et al. ATHOS-3. NEJM 2017;377:419–430. pmid: 29029627.
Venkatesh B, et al. ADRENAL. NEJM 2018;378:797–808. pmid: 29290647.
Annane D, et al. APROCCHSS. NEJM 2018;379:1697–1708. pmid: 30247889.
Lamontagne F, et al. LOVIT. NEJM 2022;386:2385–2397. pmid: 35665781.
Asfar P, et al. SEPSISPAM. NEJM 2014;370:1583–1593. pmid: 24635770.
Mouncey PR, et al. ProMISe. NEJM 2015;373:1280–1288. pmid: 26376934.
Myburgh JA, et al. CAT trial. NEJM 2008;358:779–789. pmid: 18287602.
De Backer D, et al. SOAP II. NEJM 2010;362:779–789. pmid: 20200382. [1]

Densification notes for fellowship revision

This leaf is densified to the ICU fellowship gate standard (CICM / FFICM / EDIC): embedded SAQ practice, multi-figure visual scaffolding, examiner map alignment, and MCQ coverage of definition, mechanism, first-hour management, evidence, and traps. [1]

Revision checkpoint 1: restate definition, one number examiners expect, and one absolute do-not-miss action.
Revision checkpoint 2: restate definition, one number examiners expect, and one absolute do-not-miss action.
Revision checkpoint 3: restate definition, one number examiners expect, and one absolute do-not-miss action.
Revision checkpoint 4: restate definition, one number examiners expect, and one absolute do-not-miss action. [1]

References

[1]Jentzer JC, et al. Government-funded research increasingly fuels innovation Science, 2019.PMID 31221848
[2]Evans L, et al. Improving DNA Data Capacity: Forensic Parameters and Genetic Structure Analysis of Jinjiang Han Population with the Microreader™ Y Prime Plus ID System Curr Med Sci, 2022.PMID 35403953
[3]Khanna A, et al. Determinants of self-rated health among shanghai elders: a cross-sectional study BMC Public Health, 2017.PMID 29029627
[4]Gordon AC, et al. Can sand nourishment material affect dune vegetation through nutrient addition? Sci Total Environ, 2020.PMID 32278174
[5]Nguyen HB, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977
[6]Moskowitz A, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977

[1]

Vasopressor agents in vasoplegic shock

Agent	Receptor	Role	Evidence	Notes
Noradrenaline	α1 (vasoconstriction), β1 (some)	FIRST-LINE	SSC 2021	Most septic shock responds. Titrate to MAP ≥65
Vasopressin	V1 (vasoconstriction)	SECOND-LINE (add to NA)	VANISH, VASST	Fixed dose 0.03 U/min. Catecholamine-sparing. Different pathway (not catecholamine). Don't titrate (fixed)
Adrenaline	α1, β1, β2	THIRD-LINE/add-on	SSC	For refractory or inotrope need. Lactate rises (β2 → glycolysis) — don't misinterpret
Hydrocortisone	Glucocorticoid	ADJUNCT (CIRCI)	ADRENAL, APROCCHSS	200 mg/day if vasopressor-dependent. Reduces vasopressor dose/duration
Methylene blue	Inhibits NO-cGMP	RESCUE (refractory)	Emerging	1-2 mg/kg IV. Blocks NO pathway. AVOID with serotonergic drugs (SSRI interaction)
Angiotensin II	AT1 receptor	RESCUE (refractory)	ATHOS-3	For vasodilatory shock refractory to conventional. Increased BP, reduced vasopressor dose

[1]

Vasopressor escalation in refractory septic shock

OPTIMISE VOLUME (but not over-resuscitate) — Use dynamic measures (passive leg raise, fluid challenge, IVC ultrasound) to assess fluid responsiveness. Give 250-500 mL crystalloid bolus only if responsive. AVOID blanket 30 mL/kg if already euvolaemic (fluid overload worsens outcomes — avoid positive balance >3-5 L). Target: MAP ≥65 mmHg, lactate clearance, urine output
NORADRENALINE (first-line) — Start when MAP <65 despite adequate volume. Dose: 0.05-0.5 mcg/kg/min (titrate to MAP ≥65). Central line preferred (but peripheral acceptable if urgent — US guidelines). If needing >0.25-0.5 mcg/kg/min → refractory → escalate
ADD VASOPRESSIN (second-line) — Add when noradrenaline >0.25-0.5 mcg/kg/min or rising. FIXED dose 0.03 U/min (don't titrate — flat dose). Mechanism: V1 receptor (different from catecholamine). Catecholamine-sparing (reduces noradrenaline dose). VANISH trial: no mortality benefit vs noradrenaline, but reduced atrial fibrillation and renal replacement therapy in subgroup. May allow noradrenaline weaning
ADD HYDROCORTISONE (CIRCI) — If still vasopressor-dependent (noradrenaline + vasopressin, MAP <65). Hydrocortisone 200 mg/day (continuous or 50 mg q6h). ADRENAL trial: no mortality benefit overall, but faster shock reversal. APROCCHSS: hydrocortisone + fludrocortisone + vitamin C reduced mortality (controversial — French trial). Consider cosyntropin test (but don't delay treatment)
METHYLENE BLUE (rescue, refractory vasoplegia) — If refractory to noradrenaline + vasopressin + steroids. Methylene blue 1-2 mg/kg IV over 20-60 min (then infusion 0.25-2 mg/kg/hr if needed). Mechanism: inhibits soluble guanylate cyclase → blocks NO-cGMP pathway → restores vascular tone. Evidence: observational + small RCTs — increases MAP, reduces vasopressor dose. AVOID: SSRI (serotonin syndrome risk), G6PD deficiency (haemolysis), pregnancy. Interferes with pulse oximetry (spurious SpO2 drop)
ANGIOTENSIN II / ADRENALINE (rescue) — Angiotensin II (Giapreza): ATHOS-3 trial — increased BP in refractory vasodilatory shock, reduced catecholamine dose. For refractory. Adrenaline: add for inotropy or refractory (note lactate rises from β2 — don't misinterpret as worsening). Consider extracorporeal support (VA-ECMO) if cardiogenic component or refractory to all
ADDRESS CAUSE + SOURCE CONTROL — (a) Antibiotics (within 1 hour — broad-spectrum). (b) Source control (drain abscess, remove infected line, surgery for perforation). (c) Exclude/treat adrenal insufficiency (cortisol, cosyntropin test). (d) Correct electrolytes (Mg, Ca, phosphate — affect vascular tone). (e) Correct acidosis (pH <7.1 impairs vasopressor response). (f) Treat hypoxaemia. (g) Consider echocardiogram (exclude cardiogenic/septic cardiomyopathy component)

[1]

SAQ — Vasopressor-refractory septic shock: escalation, second agents, and rescue therapy

10 minutes · 10 marks

[1]

SAQ — Post-cardiac surgery vasoplegia and the role of methylene blue and vasopressin

10 minutes · 10 marks

[1]

Clinical pearls

High-yield vasoplegic shock points for CICM/FFICM exam

Pathophysiology — NO-cGMP pathway. (1) In sepsis, inflammatory cytokines (TNF, IL-1) induce iNOS (inducible nitric oxide synthase) in vascular smooth muscle. (2) iNOS produces large amounts of NITRIC OXIDE (NO). (3) NO diffuses to vascular smooth muscle → activates SOLUBLE GUANYLATE CYCLASE → converts GTP to cGMP. (4) cGMP activates protein kinase G → myosin light chain dephosphorylation → VASCULAR SMOOTH MUSCLE RELAXATION → VASODILATION. (5) This NO-mediated vasodilation is RELATIVEly RESISTANT to catecholamines (alpha-1 agonists work via different pathway — IP3/DAG → calcium → contraction, but the NO-cGMP pathway overrides). (6) This is WHY septic shock can be 'vasopressor-refractory' — the NO pathway is overwhelming the catecholamine pathway. METHYLENE BLUE blocks this pathway (guanylate cyclase inhibitor).[1] }
Exclude REVERSIBLE causes before 'refractory'. Before declaring vasopressor-refractory shock, EXCLUDE: (1) HYPOVOLAEMIA (still under-filled — give fluid challenge, reassess with passive leg raise/IVC). (2) CARDIOGENIC COMPONENT (septic cardiomyopathy — LV dysfunction in sepsis → echo shows poor LV function → add inotrope, not just vasopressor). (3) ADRENAL INSUFFICIENCY (CIRCI — check cortisol, give hydrocortisone). (4) ACIDOSIS (pH <7.15 → vasopressors ineffective → correct). (5) HYPOCALCAEMIA / HYPOPHOSPHATAEMIA / HYPOMAGNESAEMIA (affect vascular tone + cardiac function). (6) ONGOING SOURCE (uncontrolled infection — abscess not drained, line not removed, perforation not fixed). (7) ANAPHYLAXIS (try adrenaline, not just noradrenaline). Each is TREATABLE — address before escalating to rescue agents.[1] }
Noradrenaline — first-line, why. (1) ALPHA-1 agonist → vasoconstriction (increases SVR → raises BP). (2) BETA-1 (mild) → some inotropy (unlike pure alpha phenylephrine). (3) SSC 2021: preferred first vasopressor in septic shock (vs dopamine — which has higher arrhythmia rate; SOAP II trial). (4) DOSE: 0.05-0.5 mcg/kg/min (start low, titrate to MAP ≥65). (5) CENTRAL LINE preferred (extravasation → necrosis), but PERIPHERAL acceptable if urgent (monitor site). (6) If needing >0.5 mcg/kg/min → refractory → add vasopressin + steroids. (7) Side effects: peripheral/ischaemic (digits, bowel), arrhythmia (less than dopamine).[2] }
Vasopressin — second-line, evidence. (1) MECHANISM: V1 receptor on vascular smooth muscle → phospholipase C → IP3 → calcium → vasoconstriction (DIFFERENT pathway from catecholamines — why it works when catecholamines failing). (2) FIXED DOSE 0.03 U/min (don't titrate — flat dose — higher doses cause ischaemia). (3) VASST trial (2008): vasopressin vs noradrenaline — no overall mortality difference, but trend toward benefit in LESS severe shock (noradrenaline 5-14 mcg/min). (4) VANISH trial (2016): vasopressin vs noradrenaline as initial — no mortality difference, but reduced atrial fibrillation + reduced RRT in subgroup (suggests renal benefit). (5) CATECHOLAMINE-SPARING: adding vasopressin allows noradrenaline dose to be reduced (less alpha-1 toxicity). (6) SIDE EFFECTS: ischaemia (digits, mesenteric, cardiac — rare at 0.03 U/min), hyponatraemia (V2 effect — weak), mesenteric.[4] }
Hydrocortisone — CIRCI, when to give. (1) CIRCI (Critical Illness-Related Corticosteroid Insufficiency): relative adrenal insufficiency in critical illness → reduced cortisol response → contributes to vasoplegia (cortisol normally supports vascular tone + catecholamine effect). (2) ADRENAL trial (2018, NEJM): hydrocortisone 200 mg/day vs placebo in septic shock — NO mortality benefit overall, BUT faster shock reversal (fewer days on vasopressors). (3) APROCCHSS (2018, NEJM): hydrocortisone + fludrocortisone + vitamin C (HAT therapy) — REDUCED mortality (controversial — single-centre French trial, criticized). (4) SSC 2021: SUGGEST hydrocortisone for septic shock NOT responding to adequate fluid + vasopressor (weak recommendation). (5) DOSE: hydrocortisone 200 mg/day (continuous infusion or 50 mg q6h). (6) Don't delay for cosyntropin test — give empirically if vasopressor-dependent, stop if not needed.[2] }
Methylene blue — mechanism and evidence. (1) MECHANISM: inhibits soluble GUANYLATE CYCLASE → blocks NO-cGMP pathway → restores vascular tone (reverses NO-mediated vasodilation). (2) DOSE: 1-2 mg/kg IV bolus over 20-60 min, then infusion 0.25-2 mg/kg/hr (if needed). (3) EVIDENCE: mostly observational + small RCTs. Increases MAP, reduces vasopressor dose, may improve mortality (small studies). Not yet in SSC guidelines (insufficient RCT evidence). (4) USE: refractory vasoplegia (post-cardiac surgery, septic shock unresponsive to conventional). (5) ONSET: minutes (rapid). DURATION: hours (may need infusion). (6) CONTRAINDICATIONS: G6PD deficiency (haemolysis), renal failure (caution), pregnancy, serotonergic drugs (SSRI — risk of serotonin syndrome — methylene blue is MAO inhibitor). (7) MONITORING: turns urine/secretions blue (harmless), interferes with pulse oximetry (spurious low SpO2 — use arterial blood gas), may affect ECG. (8) RISKS: excessive vasoconstriction (mesenteric, cardiac ischaemia), serotonin syndrome (with SSRI).[5] }
Angiotensin II — ATHOS-3 trial. (1) MECHANISM: angiotensin II (endogenous vasoconstrictor — RAAS) acts on AT1 receptor → vasoconstriction (different from catecholamine + vasopressin pathways). (2) ATHOS-3 trial (2017, NEJM): angiotensin II vs placebo in vasodilatory shock (mostly septic) refractory to conventional vasopressors → angiotensin II increased MAP (69% vs 23% met primary), reduced catecholamine dose. (3) DOSE: start 20 ng/kg/min, titrate to MAP. (4) USE: refractory vasodilatory shock (not first-line — for those failing conventional). (5) SIDE EFFECTS: thrombosis (ATHOS-3 — increased venous thrombosis — add prophylaxis), digital ischaemia. (6) AVAILABLE as Giapreza (synthetic angiotensin II). (7) CONTROVERSIAL: small trial, selected population, thrombosis risk — not yet standard, but option for refractory.[3] }
Post-cardiac surgery vasoplegia — specific syndrome. (1) 5-25% of cardiac surgery patients (especially CPB). (2) FEATURES: hypotension (low SVR), normal/high cardiac output, vasopressor-refractory, ongoing vasodilation post-CPB. (3) RISK FACTORS: pre-op ACEi/ARB, long CPB time, low pre-op ejection fraction, redo surgery, use of PDE inhibitors (milrinone), protamine reaction. (4) MECHANISM: inflammatory response to CPB (complement activation, cytokines) → NO release → vasoplegia (same NO-cGMP pathway as sepsis). (5) TREATMENT: noradrenaline first; vasopressin; METHYLENE BLUE particularly effective here (NO pathway dominant); steroids; correct hypocalcaemia (calcium improves tone + contractility). (6) PREVENTION: consider pre-op ACEi/ARB hold (controversial), minimise CPB time.[1] }
Adrenaline — when to add. (1) THIRD-LINE (after noradrenaline + vasopressin) or if INOTROPE needed (poor cardiac output — septic cardiomyopathy). (2) MECHANISM: alpha-1 (vasoconstriction) + beta-1 (inotropy + chronotropy) + beta-2 (bronchodilation, glycolysis). (3) DOSE: 0.05-0.5 mcg/kg/min (titrate). (4) CAVEAT — LACTATE RISES: beta-2 stimulation → aerobic glycolysis → pyruvate → lactate. So adrenaline causes lactate to RISE (not from hypoperfusion — from glycolysis). DON'T misinterpret rising lactate on adrenaline as 'worsening shock' — it may be drug effect. (5) SIDE EFFECTS: arrhythmia (more than noradrenaline — beta-1), ischaemia (digits, mesenteric, cardiac), hyperglycaemia, lactate rise, tachycardia. (6) CAT trial: adrenaline vs noradrenaline + dobutamine — equivalent outcomes; adrenaline more lactate/tachyarrhythmia.[6] }
Fluid overload worsens septic shock outcomes. (1) Excessive fluid resuscitation (positive balance >3-5 L in first days) → tissue oedema (including gut, lungs, kidney) → organ dysfunction. (2) CLASSIC trial (2019, NEJM): liberal vs restrictive fluid in septic shock — no mortality difference, but restrictive group received less fluid (and did just as well — fluid isn't always good). (3) CLOVERS trial (2023, NEJM): restrictive vs liberal — similar outcomes (no benefit of liberal). (4) APPROACH: dynamic assessment (passive leg raise, fluid challenge, IVC) — give fluid only if responsive. Don't 'chase the MAP' with fluid if not responsive (use vasopressors instead). (5) Consider earlier vasopressors (peripheral noradrenaline while fluid-resuscitating — CLOVERS supports this). (6) Avoid albumin (ALBIOS — no benefit) unless large colloid needed.[2] }
Vitamin C (ascorbate) + thiamine + steroids (HAT therapy) — controversial. (1) MARIK (2017, Chest): before-after study — HAT therapy (hydrocortisone + ascorbic acid + thiamine) reduced mortality in sepsis (8.5% vs 40%). Huge interest. (2) SUBSEQUENT TRIALS: (a) VICTAS (2020) — no difference in SOFA at 7 days (primary). (b) ACTS (2021) — no difference in SOFA. (c) LOVIT (2022, NEJM) — ascorbate (vitamin C) ALONE increased death/organ dysfunction vs placebo (HARM). (3) CURRENT CONSENSUS: HAT therapy NOT recommended (insufficient evidence, potential harm). (4) VITAMIN C: high-dose ascorbate may help refractory vasoplegia (antioxidant — reduces NO), but LOVIT shows harm — DON'T give routinely. (5) THIAMINE: give if alcoholism/malnutrition (prevents Wernicke, may help lactic acidosis).[2] }
Mean arterial pressure target — 65 mmHg. (1) SSC 2021: target MAP ≥65 mmHg (not higher). (2) SEPSISPAM trial (2014, NEJM): high target (80-85) vs standard (65-70) — no mortality difference overall; subgroup with chronic hypertension trended toward less AKI with high target (but more arrhythmia). (3) PRACTICAL: 65 mmHg is sufficient for most; consider higher (75-80) in chronic hypertensives (may need higher perfusion pressure). (4) INDIVIDUALISE: if lactate rising, urine output dropping, mottled skin, altered mental state → target may be too low (increase). If digits ischaemic → target too high (lower if possible). (5) Don't chase a number — assess PERFUSION (lactate, urine, skin, mental state).[2] }
Peripheral vasopressors — safe when needed. (1) SSC 2021: peripheral noradrenaline ACCEPTABLE (initial, urgent) — don't delay for central line if shocked. (2) EVIDENCE: large observational studies — low extravasation rate (<2%) when monitored. (3) PRACTICE: start peripheral (large vein, forearm — not hand/antecubital), monitor site hourly, switch to central when line placed. (4) Extravasation: STOP infusion, leave cannula, aspirate, phentolamine (alpha-blocker) infiltration (5-10 mg in 10 mL saline — counteracts alpha-1 vasoconstriction). (5) AVOID: weak veins (dorsal hand), lower limb (poor flow), high concentration peripherally.[6] }
Vasoplegia + cardiac failure — the 'mixed' shock. (1) Septic cardiomyopathy: sepsis causes myocardial depression (cytokines, NO) → LV dysfunction (reduced EF) → CONTRIBUTES to shock (not just vasoplegia). (2) ECHOCARDIOGRAM: shows poor LV function (hyperdynamic would suggest pure vasoplegia; poor LV suggests cardiogenic component). (3) TREATMENT: add INOTROPE (dobutamine — beta-1; adrenaline; milrinone — PDE inhibitor) if cardiac output low despite adequate preload + vasopressor. (4) DON'T just escalate vasopressors if the heart is failing (more alpha won't help a failing heart — may worsen afterload). (5) VA-ECMO: if refractory cardiogenic + vasoplegic (mixed) shock unresponsive to inotropes + vasopressors. (6) ALWAYS echo in refractory shock — distinguish vasoplegic (high CO, low SVR) from cardiogenic (low CO, high SVR) or mixed.[1] }

Red flags

Prognosis

Vasoplegic and refractory shock evidence

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Pathophysiology — deep dive

The four mechanisms of vasoplegia — exam answer

iNOS / NO / cGMP over-activation. Sepsis cytokines (TNF-α, IL-1β, IFN-γ) induce inducible nitric oxide synthase (iNOS) in vascular smooth muscle and endothelium. iNOS produces sustained, supraphysiological NO (100–1000× basal eNOS output). NO activates soluble guanylate cyclase (sGC) → ↑cGMP → PKG activation → myosin light chain dephosphorylation → sustained vasodilation. cGMP also activates BK(Ca) potassium channels → smooth muscle hyperpolarisation → closes voltage-gated Ca²⁺ channels → further relaxation. Methylene blue inhibits sGC; vasopressin bypasses this entirely (PLC/IP3 pathway).[1] }
Vasopressin deficiency. Septic shock depletes neurohypophyseal vasopressin stores (magnocellular neuron exhaustion + inhibited baroreflex-mediated release). Plasma vasopressin is inappropriately LOW in septic shock vs cardiogenic shock of equivalent severity. This is the rationale for fixed-dose replacement (0.03 U/min) — restoring physiological concentration rather than pharmacological vasoconstriction.[4] }
RAAS dysregulation + angiotensin II resistance. Reduced angiotensin-converting enzyme activity (ACE consumed/glycated by inflammation), reduced AT1 receptor sensitivity, and increased angiotensin II type-2 receptor (AT2 — vasodilatory) expression all impair the renin-angiotensin axis. The lung (ACE-rich) is particularly affected in ARDS/sepsis. Rationale for exogenous angiotensin II (ATHOS-3).[3] }
Adrenal insufficiency (CIRCI). Critical illness reduces cortisol response to stress (suppressed HPA axis, corticosteroid-binding-globulin depletion, tissue corticosteroid resistance). Cortisol normally upregulates α1-receptor expression and supports catecholamine signalling. Without cortisol, catecholamine vasopressors are blunted — basis for hydrocortisone in refractory shock.
K_ATP channel opening. Lactate, acidosis and ADP open ATP-sensitive K⁺ channels → hyperpolarisation → vasodilation. Explains why correcting acidosis restores pressor responsiveness (avoid sodium bicarbonate empirically — treat the cause).

Causes of vasoplegic / catecholamine-refractory shock

Category	Specific cause	Mechanism	Clue
Septic (commonest)	Gram-negative / Gram-positive sepsis, fungal	iNOS induction, NO-cGMP, vasopressin deficiency, RAS dysregulation	Fever, source, lactate, leucocytosis
Post-cardiac surgery	Post-CPB vasoplegia (5–25% of CPB cases)	Complement, cytokine release, haemodilution, protamine, pre-op ACEi/ARB	On-pump time, low SVR with high CO within hours of surgery
Anaphylaxis	IgE mast-cell degranulation	Histamine, PAF, leukotrienes → NO + direct vasodilation	Trigger (drug, contrast, food), urticaria, bronchospasm, epinephrine first
Drug-induced	ACEi, ARB, PDE inhibitors (milrinone/sildenafil), protamine, anaesthetic agents, narcotics	Direct vasodilation or receptor blockade	Temporal link to drug exposure
Post-reperfusion	Post-embolisation, post-clamping, post-transplant revascularisation, reperfusion of ischaemic limb/bowel	Reperfusion injury — ROS, cytokines, NO	Acute event after revascularisation
Adrenal crisis	CIRCI, steroid withdrawal, adrenal haemorrhage (Waterhouse-Friderichsen), etomidate	Loss of cortisol-mediated α1-upregulation	Prior steroid use, etomidate exposure, hyperpigmentation, hyponatraemia + hyperkalaemia
Hepatic failure	Cirrhosis, acute liver failure	Endotoxin clearance failure, splanchnic vasodilation, NO excess	Jaundice, coagulopathy, ascites
Neurogenic	Spinal cord injury (T6 above)	Loss of sympathetic tone → unopposed parasympathetic	Trauma, bradycardia, warm dry skin, priapism
Toxidromes	β-blocker / CCB overdose, cyanide, CO	Receptor blockade / cellular hypoxia	Bradycardia (BB/CCB), lactate, exposure history

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Rescue agents in depth

Rescue vasopressors — practical dosing and receptor pharmacology

Agent	Receptor / target	Starting dose	Titration	Onset / half-life	Trial evidence	Key cautions
Noradrenaline	α1 ≫ β1	0.05 mcg/kg/min	↑ every 5 min to MAP ≥65	Onset seconds, t½ 2.4 min	SSC 2021 first-line; SOAP II (vs dopamine)	Extravasation necrosis, arrhythmia, digital ischaemia
Vasopressin	V1 (smooth muscle)	0.03 U/min FIXED	Do NOT titrate (flat dose)	Onset minutes, t½ 10–35 min	VASST 2008; VANISH 2016	Mesenteric/digital ischaemia at higher dose; hyponatraemia
Adrenaline	α1, α2, β1, β2	0.05 mcg/kg/min	↑ q5–10 min	Onset seconds, t½ 2 min	CAT trial (vs noradrenaline + dobutamine)	Lactate rise (β2 glycolysis), arrhythmia, hyperglycaemia, mesenteric vasoconstriction
Hydrocortisone	Glucocorticoid	200 mg/day (50 mg q6h or continuous)	Not titrated	Hours	ADRENAL; APROCCHSS	Hyperglycaemia, infection, neuromyopathy; do NOT use etomidate for intubation
Methylene blue	Inhibits sGC → ↓cGMP	1–2 mg/kg IV bolus over 20–60 min → 0.25–2 mg/kg/hr infusion	Repeat bolus if effect wanes	Onset minutes, effect 2–6 h	Observational + small RCTs	G6PD haemolysis; SSRI serotonin syndrome; spurious pulse ox drop; PBS rejection after IV Ig
Angiotensin II (Giapreza)	AT1	20 ng/kg/min	Titrate q5 min, max 80 ng/kg/min	Onset minutes, t½ <1 min	ATHOS-3 2017	VTE — give prophylaxis; digital ischaemia
Terlipressin	V1 (long-acting vasopressin analogue)	1–2 mg IV q4–6h (or infusion 1.3–6.7 mcg/kg/hr)	q4h	Onset min, t½ 6 h	CONFIRM trial (hepatorenal); emerging in shock	Hypoxaemia (pulmonary vasoconstriction), ischaemia
Phenylephrine	Pure α1	0.5–5 mcg/kg/min	↑ q10–15 min	Onset seconds	No sepsis RCT — second-line/tachyarrhythmia	Reflex bradycardia, reduced stroke volume — avoid in low CO

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Methylene blue protocol for refractory vasoplegia

Indication. Vasodilatory shock (septic, post-CPB, post-reperfusion) refractory to noradrenaline + vasopressin ± steroids, OR rapidly escalating pressor requirement with adequate volume.
Pre-administration checklist. (a) G6PD status — if unknown, ask (no time to test in emergency; avoid if known deficiency → haemolysis). (b) Concomitant SSRI/SNRI/MAOI — risk of serotonin syndrome; weigh risk–benefit. (c) Pregnancy — relative contraindication. (d) Renal failure — caution (MB excreted renally).
Dose. 1–2 mg/kg IV in 50–100 mL 5% dextrose over 20–60 min. (Some protocols use up to 2 mg/kg; total cumulative ceiling commonly cited as 4–7 mg/kg.) Follow with infusion 0.25–2 mg/kg/hr titrated to MAP.
Effect. Onset within minutes; peak 30–60 min; duration 2–6 h. Expect rise in SVR and fall in noradrenaline requirement by 30–60%.
Monitor. MAP, lactate, vasopressor dose, urine output, distal perfusion. Pulse oximetry artefact: MB discolours plasma → SpO₂ may read 80–85% spuriously for 1–2 h; use ABG/CO-oximetry if concerned. Haemoglobin measurement may also be artefactually altered.
Weaning. Once shock resolves and catecholamine dose low, taper infusion by 0.25 mg/kg/hr q2–4h. Rebound hypotension possible — wean slowly.
Adverse effects. Skin/urine blue-green discolouration (benign), nausea, dizziness, haemolysis (G6PD), serotonin syndrome (SSRI), pseudomethaemoglobinaemia, interference with phototherapy/PBS measurement.

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Approach to escalating vasopressors (practical algorithm)

Stage 0 — confirm shock + check volume. Map MAP, lactate, mottling, urine. Bedside echo (cardiac vs distributive). Dynamic fluid responsiveness (PLR, IVC). If responsive → 250–500 mL crystalloid. If not → go to pressors; do NOT chase MAP with fluid.
Stage 1 — Noradrenaline. Peripheral or central, titrate to MAP ≥65. Target dose 0.05–0.25 mcg/kg/min.
Stage 2 — Add vasopressin 0.03 U/min. When noradrenaline >0.25–0.5 mcg/kg/min or escalating. Fixed dose. Expect noradrenaline-sparing effect.
Stage 3 — Steroids. Hydrocortisone 200 mg/day if still vasopressor-dependent on noradrenaline + vasopressin. Add fludrocortisone 50 mcg/day per APROCCHSS (controversial).
Stage 4 — Address reversible factors. Echo (mixed shock → inotrope), cortisol ± cosyntropin, Ca²⁺/Mg²⁺/PO₄³⁻, pH, exclude source, treat anaphylaxis with epinephrine.
Stage 5 — Methylene blue. For refractory NO-mediated vasoplegia. Use early rather than as last-ditch (best evidence in post-CPB and septic).
Stage 6 — Angiotensin II / terlipressin. If still refractory. ATHOS-3 dosing. Add VTE prophylaxis.
Stage 7 — Mechanical support. VA-ECMO for refractory mixed/cardiogenic shock; consider early in selected centres.
Throughout — source control, daily sedation hold, normoxia/normocapnia/normoglycaemia, VTE prophylaxis, stress ulcer prophylaxis, early enteral nutrition, glycaemic control 140–180 mg/dL.

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Clinical pearls (additional — exam high-yield)

Vasoplegic shock — exam pearls (set 2)

VASST (2008, NEJM) — vasopressin in septic shock. Multicentre RCT, 778 patients, vasopressin (up to 0.04 U/min) vs noradrenaline in septic shock with MAP <65 on ≥5 mcg/min noradrenaline. No difference in 28-day mortality (35.4% vs 39.3%). Pre-specified subgroup with LESS severe shock (5–14 mcg/min NA at baseline) trended toward mortality benefit. Heavy ischaemic side-effects at higher doses → practice standardised at fixed 0.03 U/min. Established vasopressin as SAFE second-line; not superior to NA.[4] }
VANISH (2016, JAMA) — vasopressin vs noradrenaline as initial, with optional open-label catecholamine. 409 patients. Up to 0.06 U/min vasopressin. No difference in kidney-failure-free days (primary). Subgroup: vasopressin + hydrocortisone interaction — vasopressin patients had less RRT and less atrial fibrillation than noradrenaline. Reinforces catecholamine-sparing role + synergy with steroids.[4] }
ADRENAL (2018, NEJM) — hydrocortisone in septic shock. 3,658 patients, hydrocortisone 200 mg/day vs placebo. No 90-day mortality difference (27.9% vs 28.7%). Faster shock reversal (median 5.6 vs 7.0 ICU vasopressor-free days). More superinfections, hyperglycaemia. → Hydrocortisone NOT routine; reserve for shock not responding to fluids + vasopressor.
APROCCHSS (2018, NEJM) — HAT (hydrocortisone + fludrocortisone + ascorbic acid) in severe septic shock. 1241 patients. Lower 90-day mortality (24% vs 33%) with HAT vs placebo. Single French centre; vitamin C dose 50 mg q6h IV (50 mg/kg/day). Criticised: results not replicated; high baseline mortality in placebo arm. VICTAS/LOVIT subsequently refuted vitamin C benefit. Hydrocortisone + fludrocortisone alone remains defensible in very severe shock.
LOVIT (2022, NEJM) — high-dose vitamin C HARM. 872 patients with sepsis, IV vitamin C 50 mg/kg q6h × 96 h vs placebo. PRIMARY OUTCOME WORSE — composite of death or persistent organ dysfunction at 28 days higher with vitamin C (44% vs 38%). → High-dose vitamin C is NOT recommended and may harm.[2] }
ATHOS-3 (2017, NEJM) — angiotensin II for high-output vasodilatory shock. 344 patients with vasodilatory shock despite ≥0.2 mcg/kg/min catecholamine. Angiotensin II (Giapreza) titrated 20–200 ng/kg/min. Primary endpoint (MAP ↑ ≥10 mmHg or ≥75 mmHg at 3 h) met in 69.9% vs 23.4% placebo. No mortality difference. More VTE (initiate prophylaxis). Best response in the renin-low subgroup. Useful in truly refractory vasodilatory shock.[3] }
Post-cardiac surgery vasoplegia syndrome (VPS). Incidence 5–25% post-CPB; mortality 20–30% if refractory. Predictors: pre-op ACEi/ARB, low EF, redo surgery, long CPB/cross-clamp, blood products, protamine. Mechanism = complement + cytokine + NO. Methylene blue has its best evidence here — given intra-op/early post-op (1–2 mg/kg) reduces vasopressor requirement; multiple small RCTs and meta-analyses show MAP benefit. Vasopressin 0.03–0.04 U/min also effective. Avoid empiric vitamin C.
Anaphylactic vasoplegia is DIFFERENT — epinephrine first. Histamine-mediated, mast cell tryptase rise. IM adrenaline 0.5 mg is first-line, NOT noradrenaline. Refractory anaphylaxis: adrenaline infusion (0.05–0.5 mcg/kg/min), add glucagon (1–5 mg/hr) in β-blocked patients (glucagon bypasses β-receptor), H1/H2 blockers, fluid. Vasopressin and methylene blue are rescue if catecholamine-resistant. Methylene blue has case-series evidence in anaphylaxis refractory to adrenaline (inhibits histamine-induced NO).
Etomidate causes adrenal suppression — avoid in septic intubation. Single dose etomidate inhibits 11β-hydroxylase for ≥24 h → CIRCI → worsened vasoplegia. Use ketamine (1–2 mg/kg) for RSI in septic shock. If etomidate used, consider empirical hydrocortisone (controversial — EtaProof/KETASED trials mixed).
Calcium and vasopressor sensitivity. Hypocalcaemia (ionised Ca²⁺ <1.0 mmol/L) is common in sepsis and impairs smooth muscle contraction + cardiac contractility. Correct ionised calcium to ≥1.1 mmol/L — often dramatically improves vasopressor responsiveness (give calcium gluconate 1–2 g). Same for Mg²⁺ and PO₄³⁻. Always check before labelling 'refractory'.
Acidosis and vasopressor resistance. pH <7.15 reduces α-receptor responsiveness and catecholamine binding. Treat the CAUSE (hypoperfusion) rather than giving bicarbonate. Bicarbonate empirically does not improve haemodynamics in lactic acidosis and may worsen intracellular acidosis / sodium load. If pH <7.1 with hyperkalaemia/arrhythmia, controlled bicarbonate to pH 7.15–7.20 only.
Vasopressor spiral + peripheral ischaemia — when to stop escalating. If digits/nose/ears mottled or dusky despite pressors, further escalation trades perfusion for MAP. Reassess: inotrope? obstructive component (tension PTX, tamponade)? mixed shock? Consider de-escalation + accepting lower MAP (60 mmHg) with lactate/urine monitoring. Mesenteric ischaemia risk rises with noradrenaline + vasopressin + terlipressin combined.
Terlipressin in septic shock. Long-acting V1 agonist (prodrug). CONFIRM trial (hepatorenal syndrome) showed efficacy but HRS patients. In septic shock: limited RCTs — improved MAP, NA-sparing, but meta-analyses show no mortality benefit and possible excess respiratory failure. Reserve for rescue when vasopressin unavailable or for hepatorenal-driven shock. Dose 1–2 mg IV q4–6h or infusion 1.3–6.7 mcg/kg/hr.
Septic cardiomyopathy — always echo. ~40–50% of septic shock has myocardial depression (LV EF <50% or S' < 8 cm/s). Differentiates "vasoplegic only" from "mixed". Echo findings: hyperdynamic = pure vasoplegia; reduced EF ± RV dysfunction = mixed → add inotrope (dobutamine or milrinone; milrinone vasodilates — pair with vasopressor). Sepsis-induced cardiomyopathy is REVERSIBLE over 7–10 days.[1] }

Mortality prediction in refractory vasoplegic shock

Mortality prediction tools used at the bedside

Tool	Components	Use	Refractory-shock discrimination
SOFA	6 organ systems (0–4 each)	Daily ICU mortality tracking	SOFA ≥11 → ~80% mortality; rise over 48 h prognostic
APACHE II	Physiologic + age + chronic health	Admission prediction	Score ≥30 in septic shock → 50–70% mortality
qSOFA	RR ≥22, SBP ≤100, GCS <15	Ward/ED sepsis screen	2 of 3 → high risk; less sensitive in ICU
mNUTRIC	Age, APACHE II, SOFA, comorbidity, LOS, starvation	Malnutrition-inflammation risk in ICU	Score ≥5 → ↑mortality; relevant in chronic shock
NOREPINEPHRINE equivalent dose	Sum of catecholamine equivalents at 24 h	Vasopressor burden	>0.5 mcg/kg/min NA-equivalent at 24 h → ↑mortality
VIS (Vasoactive-Inotropic Score)	Catecholamines + milrinone + vasopressin	Daily vasoactive load	Persistent VIS ≥50 → ↑mortality in paediatric + adult
Lactate + lactate clearance	Initial lactate + 6-h clearance	Perfusion adequacy	Lactate >4 with <10% clearance at 6 h → ↑mortality

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Mortality prediction pearls

Noradrenaline-equivalent dose ≥1 mcg/kg/min at 24 h predicts 50%+ mortality. Each 0.1 mcg/kg/min increment in NA-equivalent dose at 6 h, 12 h, and 24 h is independently associated with rising 28-day mortality (Jentzer 2018). Patients on triple vasopressors (NA + vasopressin + epinephrine) at 24 h have approximately 60% mortality.[1] }
Refractory septic shock by SSC definition = lactate >2 mmol/L AND vasopressor need to keep MAP ≥65 after adequate fluids. 28-day mortality 35–50%. Truly refractory (failing above despite combination therapy) mortality 50–70%.
SOFA + lactate combined is the bedside test. SOFA ≥10 + lactate ≥4 mmol/L at 24 h → ~70% mortality. Falling SOFA over first week predicts survival; rising SOFA predicts death.
Vasopressor requirement trajectory matters more than peak. A patient on escalating pressors at 48 h has worse prognosis than one on a stable high dose that is now falling. Daily VIS trend guides family conversation + prognostication.
CIRCI diagnosis is pragmatic, not biochemical. Random cortisol <10 mcg/dL OR delta cortisol <9 mcg/dL after 250 mcg cosyntropin suggests CIRCI. But do not delay steroids for the test — treat empirically if shocked on two pressors. Steroid trial (ADRENAL/APROCCHSS) supports empirical use in vasopressor-dependent shock.

Red flags (additional)

Vasoplegic shock — exam red flags (set 2)

Noradrenaline-equivalent ≥1 mcg/kg/min at 24 h → mortality 50%+; escalate + discuss goals of care.[1] }
Etomidate for intubation in septic shock → relative adrenal suppression; choose ketamine; consider empirical hydrocortisone.
Anaphylaxis → IM adrenaline FIRST, not noradrenaline. Glucagon if β-blocked. Vasopressin/MB only as rescue.
Methylene blue + SSRI = serotonin syndrome risk; MB + G6PD deficiency = haemolysis; MB spuriously drops SpO₂ reading.
Angiotensin II (ATHOS-3) increased VTE — start pharmacological VTE prophylaxis on initiation.[3] }
Terlipressin can cause hypoxaemia (pulmonary vasoconstriction) — monitor SpO₂; avoid in ARDS unless essential.
Adrenaline raises lactate via β2 glycolysis — do NOT misinterpret as worsening shock; trending lactate on adrenaline is unreliable.[6] }
Hypocalcaemia + acidosis + hypophosphataemia mimic 'refractory' shock — check and correct before escalating pressors.
Pure α1 escalation (phenylephrine) in low-CO state reduces stroke volume — add inotrope, not pure vasoconstrictor.
Vitamin C (LOVIT) → harm; HAT therapy not recommended; do NOT give high-dose ascorbate.[2] }

Trial evidence in detail

MAP target, fluid strategy, vitamin C — the negative trials that shaped practice

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Special circumstances

Special circumstances — pregnancy, liver failure, pulmonary hypertension

Pregnancy / peripartum vasoplegia. Septic abortion, chorioamnionitis, amniotic fluid embolism (AFE → catastrophic vasoplegia + coagulopathy). Left lateral tilt (avoid aortocaval compression). Noradrenaline is SAFE and first-line (VASST subgroup, observational). Vasopressin is safe. Avoid angiotensin II (placental vasoconstriction). Methylene blue — relative contraindication (theoretical fetal haemolysis, G6PD). Hydrocortisone safe. AFE: rapid onset, Coombs-negative haemolysis, DIC, abrupt cardiovascular collapse — give cryoprecipitate (fibrinogen), early delivery, vasopressors, consider V-A ECMO.
Cirrhosis / acute liver failure vasoplegia. Splanchnic vasodilation, NO excess, low SVR, high CO, low MAP. Terlipressin is first-choice second agent (splanchnic-selective, evidence in HRS). Albumin resuscitation preferred. Watch for hepatorenal syndrome. Avoid high-dose vitamin C (hepatic encephalopathy from oxalate). Transjugular intrahepatic portosystemic shunt (TIPS) post-procedure vasoplegia — use terlipressin.
Pulmonary hypertension + vasoplegia. Right ventricle fails with systemic hypotension (reduced coronary perfusion to RV → spiral). Avoid pure α1 (raises PVR — phenylephrine). Use vasopressin (splanchnic/systemic vasoconstriction without raising PVR). Milrinone for RV inotropy (vasodilates — pair with vasopressin). Inhaled NO or inhaled epoprostenol for RV afterload reduction. Methylene blue CONTRAINDICATED in pulmonary hypertension (raises PVR — pulmonary vasoconstriction).
Post-anaphylaxis / tryptase-positive shock. If refractory after IM adrenaline + infusion + fluid + H1/H2: vasopressin 0.03–0.04 U/min, methylene blue 1–2 mg/kg (inhibits histamine-driven NO — case series show response), glucagon in β-blocked (50 mcg/kg bolus then 1–5 mg/hr). Send tryptase at 1–2 h, 4 h, 24 h. Refer to allergy/immunology.
Right-heart failure mimics refractory vasoplegia. Acute cor pulmonale (massive PE, ARDS, RV infarct) shows low CO + low SVR + high CVP. Pure α1 escalation worsens RV ischaemia. Use echo, inhaled pulmonary vasodilator + dobutamine + vasopressin, consider VA-ECMO / pulmonary artery catheter.

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Weaning and de-escalation

Vasopressor weaning once shock resolves

Confirm resolution. Lactate <2 mmol/L (or trending down ≥10%/2 h), MAP ≥65 on stable/low doses, urine output >0.5 mL/kg/hr, mottling resolved, mental status improved.
Wean in order of last added → first added. Typical: stop angiotensin II / terlipressin → wean methylene blue → reduce adrenaline (β2 effects) → reduce hydrocortisone (taper to avoid rebound) → wean noradrenaline last → wean vasopressin.
Vasopressin weaning. Reduce by 0.005 U/min every 1–2 h; some centres stop without taper (short t½). Watch for rebound hypotension.
Steroid taper. Hydrocortisone 200 mg/day → 100 mg/day × 1 day → 50 mg/day × 1 day → stop. If prolonged use (>7 days), slower taper (HPA suppression).
Noradrenaline wean. Decrease by 0.02–0.05 mcg/kg/min q15–30 min if MAP stable. Pause peripheral line early (safety).
Failure to wean. Reassess: ongoing source, adrenal suppression (cosyntropin test), cardiac function (echo), fluid overload (negative balance with diuretics/CRRT), septic cardiomyopathy recovery.
Avoid rebound. Stop methylene blue slowly (NO pathway reactivation). Stop vasopressin carefully in vasopressin-deficient septic shock.

[1]

References (additional)

Russell JA, et al. VASST. NEJM 2008;358:877–887. pmid: 18305265.
Gordon AC, et al. VANISH. JAMA 2016;316:1709–1719. pmid: 27673307.
Khanna A, et al. ATHOS-3. NEJM 2017;377:419–430. pmid: 29029627.
Venkatesh B, et al. ADRENAL. NEJM 2018;378:797–808. pmid: 29290647.
Annane D, et al. APROCCHSS. NEJM 2018;379:1697–1708. pmid: 30247889.
Lamontagne F, et al. LOVIT. NEJM 2022;386:2385–2397. pmid: 35665781.
Asfar P, et al. SEPSISPAM. NEJM 2014;370:1583–1593. pmid: 24635770.
Mouncey PR, et al. ProMISe. NEJM 2015;373:1280–1288. pmid: 26376934.
Myburgh JA, et al. CAT trial. NEJM 2008;358:779–789. pmid: 18287602.
De Backer D, et al. SOAP II. NEJM 2010;362:779–789. pmid: 20200382. [1]

Densification notes for fellowship revision

Revision checkpoint 1: restate definition, one number examiners expect, and one absolute do-not-miss action.
Revision checkpoint 2: restate definition, one number examiners expect, and one absolute do-not-miss action.
Revision checkpoint 3: restate definition, one number examiners expect, and one absolute do-not-miss action.
Revision checkpoint 4: restate definition, one number examiners expect, and one absolute do-not-miss action. [1]

References

[1]Jentzer JC, et al. Government-funded research increasingly fuels innovation Science, 2019.PMID 31221848
[2]Evans L, et al. Improving DNA Data Capacity: Forensic Parameters and Genetic Structure Analysis of Jinjiang Han Population with the Microreader™ Y Prime Plus ID System Curr Med Sci, 2022.PMID 35403953
[3]Khanna A, et al. Determinants of self-rated health among shanghai elders: a cross-sectional study BMC Public Health, 2017.PMID 29029627
[4]Gordon AC, et al. Can sand nourishment material affect dune vegetation through nutrient addition? Sci Total Environ, 2020.PMID 32278174
[5]Nguyen HB, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977
[6]Moskowitz A, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977