Overview
Vasopressors are vasoactive drugs used to restore and maintain mean arterial pressure (MAP) in haemodynamically unstable patients. Their effects are mediated through adrenergic and non-adrenergic receptors on vascular smooth muscle, the myocardium, and other tissues.
Receptor Pharmacology
Adrenoceptors
| Receptor | Location | Effect |
|---|---|---|
| α₁ | Vascular smooth muscle | Vasoconstriction ↑ SVR |
| α₂ | Presynaptic terminals | ↓ noradrenaline release |
| β₁ | Myocardium, SA node | ↑ HR, ↑ contractility |
| β₂ | Bronchi, peripheral vessels | Bronchodilation, vasodilation |
Non-adrenergic receptors
| Receptor | Agonist | Effect |
|---|---|---|
| V1 (vasopressin) | Vasopressin | Vascular smooth muscle contraction |
| Dopaminergic (DA1) | Dopamine (low dose) | Renal/mesenteric vasodilation |
Individual Agents
Noradrenaline (Norepinephrine)
- Primary action: Potent α₁ agonist; weak β₁ agonism at higher doses
- Net haemodynamic effect: ↑ SVR, ↑ MAP; cardiac output maintained or mildly reduced
- First-line vasopressor in septic shock (Surviving Sepsis Campaign guidelines)
- Dose: 0.01–1 mcg/kg/min (titrate to MAP target, typically ≥65 mmHg)
- Caution: peripheral and mesenteric ischaemia at high doses
Adrenaline (Epinephrine)
- Primary action: Mixed α and β agonism; β effects predominate at lower doses
- Net haemodynamic effect: ↑ HR, ↑ contractility, ↑ SVR at higher doses
- Indications: Anaphylaxis (first-line), cardiac arrest, refractory septic shock
- Dose: 0.01–1 mcg/kg/min
- Note: causes significant lactic acidosis (β₂-mediated glycogenolysis) which does not reflect tissue hypoperfusion
Vasopressin
- Mechanism: V1 receptor agonist; promotes calcium-mediated vascular smooth muscle contraction independently of adrenoceptors
- Rationale in septic shock: relative vasopressin deficiency occurs; restores vascular tone
- Role: adjunct to noradrenaline to reduce noradrenaline requirements ("noradrenaline-sparing")
- Fixed dose: 0.03–0.04 units/min (not weight-based, not titrated)
- VASST trial: no mortality difference vs noradrenaline alone, but post-hoc benefit in less severe shock (noradrenaline dose <15 mcg/min — note: mcg per minute, not per kg)
Phenylephrine
- Primary action: Pure α₁ agonist; no β activity
- Net haemodynamic effect: ↑ SVR, ↑ MAP; reflex bradycardia, ↓ cardiac output
- Indications: Vasodilatory shock when tachycardia is problematic; spinal/neuraxial anaesthesia-induced hypotension
- Avoid in cardiogenic shock or where cardiac output is already impaired
Dopamine
- Dose-dependent receptor activation:
- Low (1–5 mcg/kg/min): DA1 — renal/mesenteric vasodilation (no evidence of renoprotection)
- Moderate (5–10 mcg/kg/min): β₁ — ↑ HR, ↑ contractility
- High (>10 mcg/kg/min): α₁ — vasoconstriction
- More arrhythmogenic than noradrenaline (SOAP II trial: higher mortality in cardiogenic shock subgroup)
- Largely superseded by noradrenaline
Physiological Framework
Determinants of MAP
MAP ≈ CO × SVR (+ CVP, which is negligible in most clinical contexts)
CO = HR × SV
Vasopressors primarily target SVR (α₁ effect). Positive inotropes increase CO. Many agents do both.
Frank-Starling and vasopressor use
Vasopressors increase afterload. In a volume-deplete or failing ventricle, this may reduce stroke volume. Ensure adequate preload and consider inodilator support (e.g. dobutamine) if cardiac output falls.
Vascular tone in distributive shock
Sepsis causes profound vasodilation via:
- ↑ NO synthase activity (iNOS) → excess nitric oxide
- Vasopressin depletion
- Inflammatory mediator-driven smooth muscle relaxation
Vasopressors counteract these mechanisms to restore perfusion pressure.
Key Trials
| Trial | Question | Finding |
|---|---|---|
| SOAP II (De Backer 2010) | Dopamine vs noradrenaline in shock | No overall mortality difference; ↑ arrhythmias and mortality in cardiogenic shock with dopamine |
| VASST (Russell 2008) | Vasopressin + noradrenaline vs noradrenaline alone in septic shock | No mortality difference overall; possible benefit in less severe shock subgroup |
| VANISH (Gordon 2016) | Vasopressin ± hydrocortisone vs noradrenaline ± hydrocortisone | No mortality difference; less renal replacement therapy with vasopressin |
| SEPSISPAM (Asfar 2014) | MAP target 65–70 mmHg vs 80–85 mmHg in septic shock | No mortality difference; higher target reduced RRT in chronically hypertensive subgroup |
Clinical Pearls
- Centralise early: vasopressors should ideally run via central venous access; short peripheral administration is acceptable as a bridge
- MAP target: ≥65 mmHg is appropriate for most patients; higher targets (80–85 mmHg) may benefit chronic hypertensives (SEPSISPAM trial)
- Lactic acidosis on adrenaline does not equate to worsening tissue hypoperfusion — interpret in clinical context and use other markers (ScvO₂, lactate trend, UO)
- Noradrenaline dose >0.25 mcg/kg/min is a threshold commonly used to define high-dose vasopressor requirement and trigger consideration of adjuncts (vasopressin, hydrocortisone)
- Receptor downregulation: prolonged catecholamine exposure leads to adrenoceptor downregulation — one mechanism for catecholamine-refractory shock and a rationale for vasopressin as a non-adrenergic adjunct
Viva Questions
1. What are the key receptor targets of vasopressors and how do they translate to haemodynamic effects?
α₁ receptors on vascular smooth muscle mediate vasoconstriction, increasing SVR and MAP. β₁ receptors on the myocardium increase heart rate and contractility, increasing cardiac output. V1 receptors on vascular smooth muscle cause contraction independently of adrenoceptors. Noradrenaline acts predominantly via α₁, raising MAP through SVR with minimal chronotropy. Adrenaline stimulates both α and β receptors, increasing both CO and SVR but causing tachycardia. Vasopressin acts solely via V1, making it useful when adrenoceptors are downregulated or catecholamine-refractory shock is present.
2. Why does adrenaline cause a lactic acidosis and how should you interpret it clinically?
Adrenaline stimulates β₂ receptors in skeletal muscle, promoting glycogenolysis and gluconeogenesis and producing lactate as a byproduct. It also inhibits pyruvate dehydrogenase, reducing lactate clearance. This is a Type B lactic acidosis — not due to tissue hypoperfusion. It should not prompt dose escalation or interpretation as clinical deterioration. Reassurance comes from assessing other perfusion markers: ScvO₂, urine output, clinical improvement, and lactate trend in context of adrenaline dose. Importantly, the lactate will improve when adrenaline is weaned, not when perfusion worsens.
3. What is the rationale for adding vasopressin in septic shock, and what does the evidence show?
In septic shock, endogenous vasopressin stores become depleted, contributing to catecholamine-refractory vasodilation. Vasopressin acts via V1 receptors independently of adrenoceptors, restoring tone even when receptors are downregulated. The VASST trial (Russell 2008) showed no overall 28-day mortality benefit versus noradrenaline alone, but a post-hoc subgroup suggested benefit in less severe shock (noradrenaline <15 mcg/min). The VANISH trial (Gordon 2016) showed less renal replacement therapy with vasopressin, with no mortality difference. It is used at a fixed dose of 0.03–0.04 units/min as an adjunct to reduce noradrenaline requirements rather than as a primary agent.
4. A patient in septic shock remains hypotensive on noradrenaline 0.4 mcg/kg/min. What are your next steps?
First reassess the basics: is fluid resuscitation adequate, is there an uncontrolled source, is the diagnosis correct? Then consider adjuncts in parallel. Add vasopressin 0.03–0.04 units/min — noradrenaline-sparing via a non-adrenergic mechanism. Consider hydrocortisone 200 mg/day — addresses relative adrenal insufficiency and sensitises the vasculature to catecholamines. Perform bedside echo to exclude an occult cardiogenic component; if cardiac output is low, add dobutamine or switch to adrenaline. If tachycardia is the limiting factor preventing further noradrenaline, phenylephrine (pure α₁) avoids β₁ stimulation. Escalating noradrenaline beyond 0.5–1 mcg/kg/min without adjuncts is generally not recommended.
5. What MAP target should you aim for in septic shock, and how would you individualise it?
The Surviving Sepsis Campaign recommends an initial MAP target of ≥65 mmHg. The SEPSISPAM trial compared 65–70 mmHg vs 80–85 mmHg targets and found no difference in 28-day mortality overall, but in the subgroup with chronic hypertension, the higher target was associated with less renal replacement therapy. The OVATION pilot trial showed similar findings. In practice: target ≥65 mmHg as a default, use 70–80 mmHg for known hypertensives or those with evidence of end-organ hypoperfusion despite 65 mmHg, and avoid excessive targets which increase vasopressor exposure, arrhythmia risk, and digital ischaemia. Integrate MAP with other perfusion markers — lactate clearance, urine output, and clinical response — rather than treating the number in isolation.