Vasoactive drugs in resuscitation

The vasoactive drugs are the agents that restore the perfusion pressure and the cardiac output when the fluid resuscitation is exhausted or contraindicated, and they are the most dangerous drugs the emergency physician wields — a dose misjudged by a decimal point stops a heart or opens a vessel catastrophically. The Fellowship candidate must know the receptor that each agent acts on (because the receptor predicts the effect — the alpha-1 receptor constricts the vasculature and raises the pressure, the beta-1 receptor raises the heart rate and the contractility, the beta-2 receptor dilates and bronchodilates, the V1 receptor of the vasopressin constricts independently of the catecholamine pathway, and the dopamine receptor is dose-dependent and unreliable), must match the agent to the shock type (the vasopressor for the distributive shock, the inotrope for the cardiogenic, the combined agent for the mixed), and must know the doses, the routes, and the complications cold.[3]

The receptor framework — the science behind every choice

The catecholamines and the vasopressin analogues act through a small number of G-protein-coupled receptors, and the receptor engaged determines the haemodynamic effect. The Fellowship candidate who memorises the receptor profile of each agent reasons from the physiology rather than rote, and answers any question on any agent — including the unfamiliar — by reading the receptor.[3]

The alpha-1 adrenergic receptor (a Gq-coupled receptor on the vascular smooth muscle) activates the phospholipase C pathway, raises the intracellular calcium, and produces the arteriolar vasoconstriction that is the basis of every vasopressor. The beta-1 adrenergic receptor (a Gs-coupled receptor on the myocardium) raises the cyclic AMP, the calcium influx, and therefore the heart rate (the chronotropy), the contractility (the inotropy), and the conduction velocity (the dromotropy). The beta-2 adrenergic receptor (a Gs-coupled receptor on the bronchial and the vascular smooth muscle) relaxes the smooth muscle, producing the bronchodilation and a peripheral vasodilation that can drop the pressure. The dopamine-1 (D1) receptor dilates the renal, mesenteric and the cerebral vasculature and was the basis of the historical "renal dose dopamine" myth — discredited, because the low-dose dopamine does not protect the kidney in the shock. The V1 (V1a) receptor of the vasopressin is a Gq-coupled receptor on the vascular smooth muscle that produces a catecholamine-independent vasoconstriction — the value of the vasopressin as a catecholamine-sparing adjunct in the refractory vasoplegia.[3]

[3] [2]

The agent-by-agent pharmacology

The vasoactive armamentarium is small — six core agents and a handful of adjuncts. Each is profiled by its receptor profile, its onset, its titratability, and its complications, and the choice of the agent is the choice of the receptor profile that the patient needs.[1]

[3] [1] [4] [3] [1] [3] [3]

The selection of the agent by the shock type

The shocked patient has a shock type, and the shock type decides the vasoactive agent. The four shock types — the distributive (the septic, the anaphylactic, the neurogenic, the drug-induced), the cardiogenic, the hypovolaemic and the obstructive — each have a preferred pharmacology, and the bedside echocardiogram and the fluid response narrow the diagnosis in the minutes that matter.[2]

[4] [4] [4]

The dosing reference — the full weight-based table

The vasoactive doses are weight-based (the microgram per kilogram per minute), titrated to the perfusion target (the mean arterial pressure of 65, the lactate trend, the urine output, the capillary refill), and infused through a syringe driver or a volumetric pump with the dedicated lumen. The Fellowship candidate must know the dose, the starting point, the titration range and the maximum, because these are the numbers that are asked and the numbers that are fatal if misjudged.[4]

[2] [3]

Peripheral versus central administration — the question that matters in the first hour

The traditional teaching was that the vasopressor requires a central line, and that the patient must wait for the central access before the pressor is started. The contemporary evidence — and the Surviving Sepsis Campaign 2021 — accepts the peripheral vasopressor as a safe and appropriate temporising measure in the first hour of the resuscitation, because the harm of the delayed pressor (the prolonged hypotension, the deepening ischaemia) exceeds the small risk of the extravasation.[6]

The peripheral administration rules: use a large, proximal vein (the antecubital fossa or the forearm, never the dorsum of the hand or the wrist); use a cannula that is well flushed and well secured; avoid the limbs with the poor perfusion, the vascular disease or the dialysis fistula; monitor the site continuously for the swelling, the blanching or the pain; dilute the standard concentration (the noradrenaline at 4 mg in 50 mL or 8 mg in 250 mL is the peripheral-safe dilution); and plan the central access early — the peripheral line is a bridge, not the destination, and any patient on a sustained pressor needs a central line within the first hours.[3]

The central administration is preferred for the high-dose or the multi-agent infusion (more than one pressor or an inotrope), the vasopressin (the high extravasation risk, the tissue necrosis), and the long-acting agents (the milrinone, the terlipressin). The site is the internal jugular (the lowest infection and thrombosis risk, the ultrasound-guided insertion) or the subclavian (the lower infection but the pneumothorax risk in the coagulopathic or the ventilated patient); the femoral is the rapid-access option in the arrest and the deeply shocked patient but carries the higher infection risk.[2]

[6] [2]

The septic-shock resuscitation — the first 60 minutes

The septic shock is the commonest application of the vasoactive drugs in the resuscitation bay, and the Surviving Sepsis Campaign hour-1 bundle is the framework. The fluids are given first (the 30 mL per kilogram of the balanced crystalloid for the hypotension or the lactate over 4), and the vasopressor is started early — even before the full fluid challenge is complete if the patient is profoundly hypotensive — to restore the mean arterial pressure to 65. The CLOVERS trial has refined this by showing that the early vasopressor with the restrictive fluid is at least as safe as the liberal-fluid-then-pressor strategy, supporting the early pressor in the right patient.[7]

[6]

The targets — the MAP, the lactate, and the SEPSISPAM question

The vasoactive agent is titrated to the mean arterial pressure of 65 mmHg (the threshold below which the autoregulation of the cerebral, the coronary and the renal beds is lost), the lactate trend (the clearance of 10 per cent per hour in the first hours, or the trend rather than the single value), and the urine output (over 0.5 mL per kilogram per hour). The capillary refill (under three seconds) and the mottling are the bedside adjuncts.[4]

The SEPSISPAM trial asked whether a higher target (the MAP of 80 to 85) was better than the standard 65 for the patients with the septic shock, and the answer was no — there was no mortality difference overall, but the higher target required more catecholamines, more arrhythmias, and a signal of harm in the subgroup with the chronic hypertension (more acute kidney injury). The lesson: the target is 65 for most patients, with a higher target (the 75 to 80) considered only for the patient with the chronic hypertension who had a higher baseline and who clinically appears under-perfused at 65.[4]

[4]

The catecholamine-sparing strategy and the adjuncts

The high catecholamine dose is independently associated with the arrhythmia, the myocardial ischaemia, the immunosuppression and the mortality — and the catecholamine-sparing strategy aims to reduce the catecholamine burden without sacrificing the perfusion. The two adjuncts are the vasopressin (the V1-receptor vasoconstrictor that is catecholamine-independent) and the corticosteroid (the hydrocortisone that restores the vascular responsiveness and the adrenal function).[2]

The VASST trial (Russell 2008) compared the vasopressin against the noradrenaline in the septic shock and found no overall mortality difference, but a signal of benefit in the less severe shock (the lactate under 4); the VANISH trial (Gordon 2016) compared the early vasopressin against the noradrenaline and found no difference in the kidney failure-free days, but a lower rate of the renal-replacement therapy. The Surviving Sepsis Campaign suggests the vasopressin as a catecholamine-sparing adjunct at a fixed 0.03 units per minute when the noradrenaline dose is rising.[3]

The APROCCHSS trial (Annane 2018) randomised the septic-shock patients to the hydrocortisone plus the fludrocortisone versus the placebo and found a reduction in the 90-day mortality (43 per cent versus 49 per cent) — the strongest evidence for the corticosteroid in the vasopressor-refractory shock. The Surviving Sepsis Campaign suggests the intravenous hydrocortisone 200 mg per day for the patient on the rising vasopressor dose (typically over 0.25 mcg/kg/min of the noradrenaline).[5]

[5]

The early vasopressor versus the early fluid — the CLOVERS question

The Surviving Sepsis Campaign hour-1 bundle mandates the 30 mL per kilogram of the fluid for the hypotension or the lactate over 4, but the contemporary evidence — the CLOVERS trial — has refined the role of the early fluid. The CLOVERS trial (Self 2023, NEJM) randomised the sepsis-induced hypotension to a restrictive fluid strategy (the early vasopressor, the smaller fluid boluses, the dynamic assessment) versus a liberal fluid strategy (the standard 30 mL per kilogram, the vasopressor only for the refractory hypotension) and found no difference in the 90-day mortality — and a trend toward fewer days on the vasopressor and less fluid overload in the restrictive arm.[7]

The lesson is not that the fluid is harmful but that the early vasopressor, used judiciously in the patient who is not clearly volume-responsive, is safe and may reduce the fluid overload. The dynamic assessment (the passive leg raise, the fluid challenge, the bedside echocardiogram) is the tool that distinguishes the patient who will benefit from the fluid from the patient who needs the pressor — and the Fellowship candidate must know both.[7]

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The special situations

Anaphylaxis — the intramuscular adrenaline

The anaphylactic shock is the one shock in which the intramuscular adrenaline is the first, the second and the third therapy — not an infusion, not a vasopressor, but the 0.5 mg of the 1:1000 adrenaline into the anterolateral thigh (the vastus lateralis), repeated every five minutes until the response. The alpha-1 arrests the angio-oedema and the vasodilation, the beta-2 the bronchospasm, and the beta-1 supports the heart. The intravenous adrenaline infusion (0.05 to 0.5 mcg/kg/min) is reserved for the refractory shock, the patient on the beta-blocker (where the glucagon is added), or the peri-arrest. The adjuncts — the fluid, the antihistamine (the chlorphenamine), the hydrocortisone, the bronchodilator — are the second-line; the adrenaline is the first.[2]

The cardiac arrest and the post-ROSC shock

The cardiac arrest uses the 1 mg of the 1:10,000 adrenaline intravenously every three to five minutes (the standard ALS algorithm), with the vasopressin no longer recommended by the ILCOR (the adrenaline alone is the standard). The post-ROSC patient with the stunned myocardium and the vasodilatory post-arrest syndrome frequently needs the noradrenaline infusion (the MAP of 65 and the systolic over 90, the normoxia and the normocapnia, the targeted temperature management), and the dobutamine is added for the low-output state. The post-arrest bradycardia and the heart block may need the isoprenaline or the pacing.[2]

[2]

The beta-blocker and the calcium-channel-blocker overdose

The beta-blocker and the calcium-channel-blocker overdose is the drug-induced shock with a specific antidotal pathway: the high-dose insulin and the euglycaemia (the 1 unit per kilogram bolus of the regular insulin, then the 0.5 to 1 unit per kilogram per hour, with the glucose to maintain the euglycaemia), the calcium (the 10 to 20 mL of the 10 per cent calcium chloride or the 30 to 60 mL of the 10 per cent calcium gluconate), the vasopressor (the noradrenaline or the adrenaline, high-dose), and the lipid emulsion for the refractory. The vasopressin is ineffective alone in this setting (the V1 pathway is intact but the catecholamine and the calcium pathways are blocked) — do not rely on it. The glucagon is added for the beta-blocker overdose (the 5 to 10 mg bolus then the infusion). The mechanical circulatory support is the rescue for the refractory.[2]

The right-heart failure and the pulmonary hypertension

The right-heart failure (the right-ventricular infarct, the massive pulmonary embolism, the decompensated pulmonary hypertension) is the shock in which the milrinone is preferred over the dobutamine — the milrinone lowers the pulmonary vascular resistance (the afterload of the right ventricle) and the inotropy supports the output, without the tachyarrhythmia of the dobutamine. The noradrenaline holds the systemic pressure (the coronary perfusion pressure of the right ventricle, supplied in the systole and the diastole, depends on it), the volume loading is cautious (the right ventricle is preload-responsive up to a point, then it fails), and the vasodilators are avoided. The inhaled pulmonary vasodilators (the nitric oxide, the nebulised epoprostenol) are the adjunct for the refractory.[3]

The neurogenic shock

The neurogenic shock (the spinal cord lesion above the T6) is the loss of the sympathetic tone — the hypotension with the bradycardia (the unopposed vagal tone), the warm periphery (the loss of the alpha tone), and the hypothermia. The noradrenaline is the first-line vasopressor (the alpha-1 to restore the systemic vascular resistance), with the atropine 0.5 mg or the isoprenaline infusion for the symptomatic bradycardia. The fluid is given for the associated injuries but the pressor is the main therapy. The distinguishing feature from the spinal shock (the transient areflexia of the acute cord injury) is the persistent hypotension with the bradycardia.[2]

The complications and the pitfalls

The complications of the vasoactive therapy are the predictable consequences of the receptor pharmacology: the extravasation and the tissue necrosis (the alpha-1 vasoconstriction at the cannula site), the arrhythmia (the beta-1 chronotropy — the tachycardia, the atrial fibrillation, the ventricular ectopy, the ischaemia), the digital and mesenteric ischaemia (the vasopressin at the high dose), the hyponatraemia (the vasopressin), the lactate rise on the adrenaline (the beta-2 glycolysis), the hypotension on the milrinone (the vasodilation, the long half-life), and the immunosuppression and the hyperglycaemia (the high-dose catecholamine).[2]

The pitfalls are the inverse of the pharmacology: using the dopamine as the first-line pressor; using the pure alpha-agonist (the phenylephrine, the metaraminol) alone in the cardiogenic shock (the afterload rise drops the stroke volume); delaying the pressor for the central line; titrating the vasopressin above 0.04 units per minute; forgetting the phentolamine for the extravasation; using the milrinone at the full dose in the acute kidney injury; chasing the rising lactate on the adrenaline with more fluid; and treating the blood pressure number rather than the perfusion.[3]

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The monitoring and the weaning

The patient on the vasoactive therapy needs the arterial line (the beat-to-beat pressure, the accurate titration), the central venous access (the reliable infusion, the multiple agents), the continuous ECG (the arrhythmia), the urine output (the catheter, the hourly charting), the lactate (the trend), and the bedside echocardiogram (the cardiac output, the volume status, the response to the inotrope). The advanced monitoring — the pulse contour cardiac output, the pulmonary artery catheter, the point-of-care ultrasound — is used for the complex or the refractory shock.[2]

[6]

The weaning of the vasopressor begins when the cause is treated (the antibiotic working in the septic shock, the revascularisation done in the cardiogenic), the lactate is clearing, the urine output is recovering, and the perfusion is restored. The noradrenaline is weaned in the 0.05 mcg/kg/min decrements as the patient tolerates, the vasopressin is discontinued first (the longer duration of action, the catecholamine-sparing achieved), and the inotrope is weaned last. The premature weaning (before the cause is treated) precipitates the rebound hypotension; the prolonged weaning (out of caution) prolongs the intensive-care stay and the catheter risk.[6]

The prognosis and the disposition

The mortality of the septic shock is 30 to 40 per cent with the prompt resuscitation, higher with the delay. The patients on the rising catecholamine dose, the vasopressin, and the hydrocortisone carry the higher mortality. Every patient on the vasoactive therapy is admitted to the intensive care, with the continuous monitoring, the cause-directed therapy, and the daily reassessment for the weaning.[6]

The special populations

The elderly carry the higher baseline pressure and the chronic hypertension, and may need the higher MAP target (the 75 to 80) per the SEPSISPAM subgroup. The pregnant patient with the septic shock is managed with the same noradrenaline (it is safe in the pregnancy; the phenylephrine is the alternative for the obstetric anaesthesia-induced hypotension). The paediatric patient is dosed by the weight and started on the adrenaline (the first-line pressor in the paediatric septic shock per the PALS guidelines) rather than the noradrenaline. The patient with the chronic heart failure needs the inotrope early (the dobutamine or the milrinone) and the cautious pressor. The patient with the pulmonary hypertension needs the milrinone and the inhaled pulmonary vasodilator.[4]

The evidence and the regional guidelines

The contemporary framework is the Surviving Sepsis Campaign 2021 (the noradrenaline first-line, the vasopressin the adjunct at 0.03 units per minute, the hydrocortisone 200 mg per day for the refractory shock, the target MAP of 65)[6] — the sepsis-specific evidence. The SOAP II (noradrenaline over dopamine)[1], the VASST and the VANISH (the vasopressin)[2][3], the SEPSISPAM (the MAP target)[4], the APROCCHSS (the hydrocortisone)[5], and the CLOVERS (the early vasopressor versus the fluid)[7] are the landmark trials the Fellowship candidate must cite.

[1] [4] [3] [4] [5] [2] [3]

Exam pearls

• Noradrenaline is the first-line vasopressor for the septic and the distributive shock — dopamine is no longer first-line (SOAP II — more arrhythmia, no mortality benefit).
• Noradrenaline is alpha-greater-than-beta — the alpha-1 restores the systemic vascular resistance and the pressure, the mild beta-1 supports the output without the dopamine tachyarrhythmia. Dose 0.05 to 1.0 mcg/kg/min to a MAP of 65.
• Anaphylaxis is the intramuscular adrenaline into the anterolateral thigh — 0.5 mg of 1:1000 every five minutes; the infusion (0.05 to 0.5 mcg/kg/min) is only for the refractory.
• Vasopressin is the V1-receptor catecholamine-sparing adjunct — fixed 0.01 to 0.04 units per minute, never titrated higher (mesenteric and digital ischaemia), never the first pressor. VASST and VANISH support the adjunctive role.
• Dobutamine is the beta-1 inotrope — 2.5 to 20 mcg/kg/min, the cardiogenic shock and the septic cardiomyopathy. Watch the tachyarrhythmia, the ischaemia, and the hypotension if volume-deplete.
• Milrinone is the PDE-3 inodilator — the right heart and the pulmonary vasculature; 0.125 to 0.75 mcg/kg/min; halve the dose in the AKI; the half-life is hours (hard to switch off).
• The MAP target is 65 — the SEPSISPAM showed no benefit of the higher target and a signal of harm in the chronic-hypertension subgroup. The 75 to 80 is reserved for the selected chronic-hypertension patient.
• Do not delay the pressor for the central line — start the peripheral noradrenaline through a well-sited, proximal cannula, and plan the central access within the first hours (the Surviving Sepsis Campaign 2021).
• Extravasation is the emergency — stop, aspirate, leave the cannula in situ, and inject the phentolamine 5 to 10 mg in 10 mL saline subcutaneously within twelve hours.
• Adrenaline raises the lactate through the beta-2 aerobic glycolysis — a rising lactate on the adrenaline infusion is not by itself the sign of the worsening shock.
• The pure alpha-agonist (phenylephrine, metaraminol) in the cardiogenic shock — the number improves while the patient dies (the afterload rise drops the stroke volume of the failing ventricle).
• The catecholamine-sparing: add the vasopressin 0.03 units per minute and the hydrocortisone 200 mg per day for the patient on the rising noradrenaline dose (over 0.25 mcg/kg/min) — the APROCCHSS mortality benefit.
• The dopamine is dose-dependent (D1, beta, alpha) and unpredictable — avoid first-line; reserve for the bradycardia-induced shock and the temporary bridge.
• CLOVERS (2023): the early vasopressor with the restrictive fluid is at least as safe as the liberal-fluid-then-pressor strategy — the dynamic assessment (the passive leg raise, the bedside echo) distinguishes the patient who needs the fluid from the patient who needs the pressor.
• The right-heart failure and the pulmonary hypertension — the milrinone is preferred over the dobutamine (lowers the pulmonary vascular resistance); the noradrenaline holds the systemic pressure; avoid the vasodilators.
• The beta-blocker/CCB overdose — the high-dose insulin/euglycaemia, the calcium, the noradrenaline or the adrenaline, and the lipid emulsion; the vasopressin is ineffective alone (do not rely on it).
• Read the agent through the receptor — the receptor engaged predicts the effect, and the receptor is the answer to any question on any vasoactive agent, including the unfamiliar.[7]

Red flags

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References

1. [1]De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock (SOAP II). New England Journal of Medicine, 2010.PMID 20200382
2. [2]Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock (VASST). New England Journal of Medicine, 2008.PMID 18305265
3. [3]Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock (VANISH). JAMA, 2016.PMID 27483065
4. [4]Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock (SEPSISPAM). New England Journal of Medicine, 2014.PMID 24635770
5. [5]Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS). New England Journal of Medicine, 2018.PMID 29490185
6. [6]Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Medicine, 2021.PMID 34599691
7. [7]National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Shapiro NI, Douglas IS, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension (CLOVERS). New England Journal of Medicine, 2023.PMID 36688507