vasoactive drugs

MAP = CO x SVR. Every vasoactive drug works by raising one or both. Fix preload first — pressors on an empty tank buy numbers, not perfusion. Norepinephrine is the default for nearly all shock; vasopressin is the first add-on; epinephrine is the rescue/arrest/anaphylaxis drug; phenylephrine is the niche alpha-only agent for tachyarrhythmia and LVOT obstruction. Inotropes (dobutamine, milrinone) fix flow, not pressure, and usually need a pressor alongside them.

vasopressors

drug	receptors	usual adult dose	HR	CO	SVR	primary role	headline caution
norepinephrine	alpha-1 +++, beta-1 ++	0.01–0.5 mcg/kg/min (2–40 mcg/min); no true ceiling	↔/↑	↔/↑	↑↑	first-line for nearly all shock	extravasation (→ phentolamine); useless if hypovolaemic
vasopressin	V1 (V2)	fixed 0.03 U/min (range 0.01–0.04). Not titrated	↔/↓	↔/↓	↑↑	first add-on in septic shock; RV failure/PHTN	digital/mesenteric/coronary ischaemia; don’t wean abruptly
epinephrine	alpha-1 +++, beta-1 +++, beta-2 ++	infusion 0.01–0.5 mcg/kg/min. Anaphylaxis 0.5 mg IM. Arrest 1 mg IV q3–5 min	↑↑	↑↑	↑	anaphylaxis, cardiac arrest; rescue in refractory shock	arrhythmia; type B lactic acidosis; worse in cardiogenic shock
phenylephrine	alpha-1 ++++ (pure)	bolus 50–200 mcg; infusion 25–200 mcg/min (0.25–3 mcg/kg/min)	↓	↓	↑↑	peri-operative hypotension; tachyarrhythmia; LVOT obstruction	avoid in LV failure — afterload without inotropy
dopamine	dose-dependent D1 → beta-1 → alpha-1	2–20 mcg/kg/min	↑↑	↑	↑	largely historical. Symptomatic bradycardia	2x arrhythmia rate vs norepi; ↑mortality in cardiogenic shock
*angiotensin II* (Giapreza)	AT1	start 20 ng/kg/min; ≤80 ng/kg/min first 3 h; maintenance ≤40 ng/kg/min	↔	↔	↑↑	catecholamine-refractory distributive shock	thrombosis — needs VTE prophylaxis. Cost. Rarely available
*methylene blue*	sGC/NOS inhibitor	1–2 mg/kg IV over 20–60 min	↔	↔	↑	vasoplegia post-cardiac surgery; refractory sepsis	serotonin syndrome (SSRI); G6PD haemolysis; falsely low SpO2
*midodrine*	alpha-1 (oral prodrug)	5–15 mg PO TID	↓	↔	↑	ward/HRS/orthostatic; ICU weaning adjunct	supine hypertension; bradycardia; not a substitute for IV pressors
*terlipressin*	V1 (long-acting)	2–12 mg/day infusion	↔/↓	↔/↓	↑↑	HRS-AKI (gold standard globally; SAP in Canada)	respiratory failure; ischaemia; no inotropy

inotropes

drug	mechanism	usual dose	HR	CO	SVR/PVR	primary role	headline caution
*dobutamine*	beta-1 ++, beta-2 +	2.5–20 mcg/kg/min	↑	↑↑	↓	cardiogenic shock; sepsis with cardiomyopathy	hypotension, tachyarrhythmia, tachyphylaxis at 48–72 h
*milrinone*	PDE3 inhibitor	0.125–0.75 mcg/kg/min (loading dose usually omitted)	↑	↑↑	↓↓ (PVR)	RV failure / pulmonary HTN; beta-blocked patient	t1/2 2–4 h → prolonged hypotension; renally cleared, avoid/reduce in AKI
*levosimendan*	Ca2+ sensitiser + K-ATP opener	0.1–0.2 mcg/kg/min x 24 h	↑	↑↑	↓	beta-blocked patient; ischaemic cardiomyopathy	metabolite OR-1896 lasts 5–9 days — you cannot turn it off
*isoproterenol*	beta-1 +++, beta-2 +++	2–10 mcg/min	↑↑↑	↑	↓	bradyarrhythmia, denervated (transplant) heart, torsades/Brugada niche	profound hypotension, ischaemia, arrhythmia

rough norepinephrine-equivalent doses

For comparing “how sick is this patient” across charts and papers. 1 unit = 0.1 mcg/kg/min of norepinephrine ≈

epinephrine 0.1 mcg/kg/min
phenylephrine 1 mcg/kg/min
dopamine 15 mcg/kg/min
vasopressin 0.04 U/min

Roughly: >0.5 mcg/kg/min norepi-equivalent = high dose; >1 = refractory shock with mortality commonly >60–80%.

receptor reference

receptor	location	effect when stimulated	clinical translation
alpha-1	vascular smooth muscle	vasoconstriction	↑SVR → ↑MAP (venoconstriction also ↑ venous return)
alpha-2	presynaptic nerve terminal	↓NE release	why clonidine/dexmedetomidine drop BP
beta-1	cardiomyocyte, SA node	↑inotropy, ↑chronotropy, ↑dromotropy	↑CO, but ↑MVO2 and ↑arrhythmia
beta-2	vascular smooth muscle, bronchi, mast cells	vasodilation, bronchodilation, mast-cell stabilisation, aerobic glycolysis	↓SVR; bronchospasm relief; ↑lactate without ischaemia
V1	vascular smooth muscle	vasoconstriction	works independent of pH and catecholamine receptors
V2	renal collecting duct	water reabsorption	antidiuresis; hyponatraemia (minimal at pressor doses)
AT1	vascular smooth muscle	vasoconstriction (+ aldosterone)	third, non-adrenergic pathway
D1	renal/splanchnic vessels	vasodilation	the “renal dose” myth — no clinical benefit
PDE3	cardiomyocyte + vessel (enzyme, not receptor)	↑cAMP → inotropy + vasodilation	works downstream of beta-blockade

Vasoplegia can be attacked through three pathways — adrenergic (alpha-1), vasopressinergic (V1), and RAAS (AT1). Combining them (decatecholaminisation) caps the dose of any single agent and limits catecholamine toxicity: arrhythmia, immunosuppression, hypermetabolism, tachyphylaxis.

picking an agent by shock phenotype

shock type	CO	SVR	CVP / filling	first move	vasoactive plan
septic / distributive	↑ or ↔	↓↓	↓	fluids + antibiotics + source control	norepi → + vasopressin → + epi (± angiotensin II, steroids)
cardiogenic	↓↓	↑	↑	revascularise / treat cause	norepi for MAP ± dobutamine or milrinone for flow
hypovolaemic / haemorrhagic	↓	↑	↓↓	volume / blood + stop the bleeding	pressors are a bridge only — norepi at lowest dose
obstructive (PE, tamponade, tension PTX, auto-PEEP)	↓	↑	↑	relieve the obstruction	norepi ± vasopressin; avoid dropping preload
RV failure / pulmonary HTN	↓	↑	↑↑	optimise oxygenation/CO2/pH (all raise PVR)	norepi + vasopressin (spares PVR) + milrinone/inhaled pulmonary vasodilator. Avoid phenylephrine
anaphylactic	↑	↓↓	↓	IM epinephrine, fluids, remove trigger	epi infusion if refractory; glucagon if beta-blocked
neurogenic	↔/↓	↓	↓	fluids, MAP target for cord perfusion	norepi (alpha + beta-1 covers the bradycardia)

standard escalation ladders

Septic shock: norepinephrine → add vasopressin once norepi ≈ 0.25–0.5 mcg/kg/min → add epinephrine and/or hydrocortisone 200 mg/day → consider angiotensin II / methylene blue
Cardiogenic shock: norepinephrine to restore coronary perfusion pressure ± dobutamine or milrinone for flow → mechanical support (IABP/Impella/VA-ECMO)
Anaphylaxis: epinephrine 0.5 mg IM anterolateral thigh, repeat q5–15 min → fluids → epi infusion → adjuncts (antihistamines/steroids are not first-line and don’t treat shock)
Symptomatic bradycardia: atropine → dopamine 5–20 mcg/kg/min or epinephrine 2–10 mcg/min → transcutaneous/transvenous pacing

targets

Default: MAP ≥ 65 mmHg for most shock states
SEPSISPAM (2014): high (80–85) vs low (65–70) MAP target → no mortality difference; less RRT in the chronic-hypertension subgroup at the higher target, but more AF
65 Trial (2020): permissive MAP 60–65 in patients ≥65 y on vasopressors → reduced vasopressor exposure; 90-day mortality not significantly different on primary unadjusted analysis (adjusted analysis favoured permissive). Reasonable to accept 60–65 in the elderly
Beyond MAP, judge perfusion: lactate clearance, cap refill, urine output, mentation, mottling

practical points

peripheral vasopressors

Start norepinephrine peripherally rather than delaying for central access. Rules of thumb: ≥20G cannula, proximal to the antecubital fossa (upper arm/AC — never hand, wrist, or foot), documented good flush/blood return, hourly site checks, defined time limit per local policy. Extravasation ~3%, tissue injury rare when these rules are followed.

extravasation

Norepinephrine/phenylephrine/dopamine: stop the infusion, leave the cannula in and aspirate, then infiltrate phentolamine 5–10 mg in 10 mL NS around the site. Alternatives: topical nitroglycerin 2% paste, terbutaline infiltration. Elevate the limb.

why the pressor “isn’t working”

Before escalating, screen for: hypovolaemia (commonest), severe acidaemia (pH <7.2 desensitises adrenergic receptors), ionised hypocalcaemia, hypoxaemia/hypercapnia, hypothermia, adrenal insufficiency, occult bleeding, tamponade / tension pneumothorax / auto-PEEP, drug error (wrong bag, disconnected line, tissued IV), and failed source control.

Tachyphylaxis — catecholamines (norepi, epi, dopamine, dobutamine) lose potency with prolonged exposure via receptor downregulation. Non-catecholamines — vasopressin, angiotensin II, milrinone, levosimendan — do not
Acidaemia — vasopressin keeps working at pH <7.15 when catecholamine receptors are desensitised → main reason it’s the preferred add-on
Weaning order — wean norepinephrine first, vasopressin last. Retrospective data show more rebound hypotension when vasopressin is stopped first
Base vs salt — norepinephrine is dosed as base in some countries and as the bitartrate salt in others (2 mg bitartrate = 1 mg base). Explains apparent dose discrepancies between papers
Phenylephrine causes reflex bradycardia — baroreceptor-mediated; combined with the afterload rise, CO falls. Useful in tachyarrhythmia/LVOTO, harmful in heart failure
Central line ≠ requirement to start, but required to continue high-dose or prolonged infusions
Arterial line for anyone on more than a transient pressor — cuff pressures are unreliable in vasoconstricted shock

what NOT to do

Adding vasopressin at “0.25–0.5 mcg/kg/min” refers to the norepinephrine dose trigger, not the vasopressin dose. Vasopressin is fixed at 0.03 U/min
Epinephrine raises lactate without ischaemia (beta-2 → aerobic glycolysis, type B lactic acidosis) — don’t escalate resuscitation for this alone; reassess the whole picture
Phenylephrine in cardiogenic shock — afterload without inotropy → CO falls further
Dopamine is not renoprotective at any dose — no prevention of AKI, no renal outcome benefit
Milrinone in AKI accumulates → hours of refractory hypotension
Levosimendan is a one-way door — the active metabolite lasts up to 9 days
Terlipressin has no inotropy → afterload + volume without contractility support = pulmonary oedema

key trials summary

trial	question	bottom line
SOAP II (NEJM 2010)	dopamine vs norepinephrine, all shock	no overall mortality difference; 2x arrhythmias with dopamine; ↑mortality in cardiogenic shock subgroup → norepi wins
VASST (NEJM 2008)	vasopressin + norepi vs norepi	no overall mortality benefit; possible benefit in less severe shock; established the sparing role
VANISH (JAMA 2016)	vasopressin first-line vs norepi	no difference in kidney-failure-free days; less RRT with vasopressin
ATHOS-3 (NEJM 2017)	angiotensin II in refractory distributive shock	↑MAP response (~70% vs 23%); no mortality benefit; thrombosis signal
65 Trial (JAMA 2020)	permissive MAP 60–65 in ≥65 y	less vasopressor exposure, no clear mortality harm
SEPSISPAM (NEJM 2014)	MAP 80–85 vs 65–70	neutral overall; less RRT in chronic hypertensives
CENSER (AJRCCM 2019)	early low-dose norepi in sepsis	better shock control at 6 h; no mortality difference
CLOVERS (NEJM 2023)	restrictive fluids/early pressors vs liberal fluids	no mortality difference — both strategies acceptable
Levy et al. (JACC 2018) + meta-analyses	epi vs norepi in cardiogenic shock	epi → more refractory shock, more lactate, signal toward ↑mortality → norepi preferred
DOREMI (NEJM 2021)	milrinone vs dobutamine in cardiogenic shock	no difference in composite outcome — pick on side-effect profile
PARAMEDIC-2 (NEJM 2018)	epi vs placebo in OHCA	↑ROSC and ↑30-day survival, no improvement in favourable neurological outcome
ADRENAL / APROCCHSS (NEJM 2018)	hydrocortisone in septic shock	faster shock reversal both; mortality benefit in APROCCHSS (hydrocortisone + fludrocortisone)

individual agents

Core pressors — norepinephrine · epinephrine · vasopressin · phenylephrine · dopamine

Inotropes — dobutamine · milrinone · levosimendan · isoproterenol

Rescue / niche — angiotensin II · methylene blue · hydroxocobalamin · midodrine · terlipressin

Related pages — septic shock · cardiogenic shock · hepatorenal syndrome · anaphylaxis