Vasopressin

Contents

Overview

Vasopressin (antidiuretic hormone, ADH) is a nonapeptide hormone produced in the hypothalamus and released from the posterior pituitary. In critical illness, particularly vasodilatory septic shock, endogenous vasopressin levels are initially elevated and then fall paradoxically — a phenomenon termed relative vasopressin deficiency. Exogenous vasopressin at low doses restores vascular tone, reduces noradrenaline requirements, and may offer renal benefits in septic shock.

Pharmacology

Synthesis and Release

Vasopressin is synthesised in the supraoptic and paraventricular nuclei of the hypothalamus and transported along axons to the posterior pituitary for storage and release. Stimuli for release include:

  • Rising plasma osmolality (sensed by hypothalamic osmoreceptors): primary stimulus
  • Hypovolaemia and hypotension (sensed by baroreceptors): at larger volume deficits, baroreceptor input overrides osmotic regulation

Receptor Profile

V1a receptors (vascular smooth muscle, myometrium, platelets): Gq-coupled → IP3/DAG pathway → calcium release → vasoconstriction. This is the predominant haemodynamic mechanism.

V1b receptors (anterior pituitary): Modulate ACTH release. Relevant in the stress response to critical illness.

V2 receptors (renal collecting duct principal cells): Gs-coupled → cAMP → insertion of aquaporin-2 (AQP2) water channels into the apical membrane → water reabsorption. This is the antidiuretic mechanism.

Oxytocin receptors: Minor activity — uterine contraction, central effects.

At low doses used in vasodilatory shock (0.01–0.04 units/min), V1a-mediated vasoconstriction dominates without significant systemic toxicity.

Pharmacokinetics

  • Half-life: approximately 5–20 minutes
  • Administered as continuous IV infusion only (too short-acting for bolus use in shock)
  • No significant hepatic or renal dose adjustment required
  • Cleared by vasopressinase (placental enzyme in pregnancy), hepatic peptidases, and renal excretion

Relative Vasopressin Deficiency in Septic Shock

In early septic shock, vasopressin levels rise appropriately as part of the stress response. However, as shock is sustained, vasopressin levels fall disproportionately — often to levels lower than expected for the degree of hypotension. Proposed mechanisms include:

  • Depletion of posterior pituitary stores from sustained stimulation
  • Suppression by elevated catecholamines (noradrenaline inhibits vasopressin release at high concentrations)
  • Autonomic neuropathy reducing the baroreceptor-hypothalamic axis sensitivity

This relative deficiency provides the rationale for low-dose vasopressin replacement in septic shock.

Vasopressin in Vasodilatory Shock

Mechanism of Benefit

In vasodilatory septic shock, nitric oxide-mediated and prostaglandin-mediated arteriolar vasodilation reduces systemic vascular resistance. Vasopressin counteracts this through direct V1a-mediated vasoconstriction of vascular smooth muscle. Additionally, vasopressin may:

  • Sensitise adrenergic receptors (restoring catecholamine responsiveness)
  • Reduce NO production by inhibiting inducible NO synthase
  • Have V2-mediated effects on renal tubules, potentially increasing urine output in volume-resuscitated patients
  • Potentiate corticosteroid effects

Dosing in Septic Shock

Vasopressin is used as a fixed low-dose infusion, not titrated:

  • Dose: 0.01–0.04 units/min (usually 0.03 units/min as standard)
  • Started as an adjunct to noradrenaline when noradrenaline dose is rising and additional vasomotor support is needed
  • Not titrated upward based on MAP (unlike noradrenaline): higher doses cause disproportionate vasoconstriction with ischaemic complications
  • Typically discontinued before noradrenaline when weaning vasopressors

SSC guidelines recommend vasopressin (up to 0.03 units/min) as an adjunct to noradrenaline with the intention of raising MAP to target or reducing noradrenaline dose. It is not recommended as a sole first-line vasopressor.

The VANISH Trial

The VANISH trial (Gordon et al., JAMA 2016) was a 2×2 factorial RCT of 421 patients with septic shock, comparing vasopressin vs noradrenaline (first-line vasopressor) and hydrocortisone vs placebo.

Primary outcome: Kidney failure-free days at 28 days. Vasopressin was not superior to noradrenaline for this outcome.

Key secondary findings:

  • Vasopressin was associated with reduced rates of renal replacement therapy (25.4% vs 35.3% with noradrenaline), but this did not reach statistical significance after multiple testing adjustment in the original analysis
  • In the subgroup without corticosteroids, vasopressin was associated with more kidney failure-free days — a hypothesis-generating finding suggesting interaction between vasopressin and corticosteroids
  • No difference in 28-day mortality

Context: VANISH followed the VASST trial (Russell et al., NEJM 2008), which compared vasopressin + noradrenaline vs noradrenaline alone. VASST found no overall mortality benefit, but a pre-specified subgroup with less severe shock showed reduced mortality with vasopressin. VANISH was designed to test vasopressin as a first-line agent.

Conclusion: Vasopressin is a reasonable alternative to noradrenaline as an initial vasopressor in septic shock and may reduce RRT requirements, but it is not superior in terms of major outcomes. Its use is justified by its different pharmacological mechanism (avoiding further escalation of catecholamine dose) and its inclusion in international guidelines.

See the VANISH journal club entry for further detail.

Comparison with Terlipressin

Vasopressin and terlipressin are both vasopressin analogues but differ in pharmacokinetics, receptor selectivity, and clinical indications:

Feature Vasopressin Terlipressin
Structure Native nonapeptide Prodrug of lysine vasopressin
Half-life 5–20 minutes ~6 hours (prodrug)
Administration Continuous infusion IV bolus or infusion
V1:V2 selectivity Balanced Greater V1 selectivity
Licensed indications Vasodilatory shock (off-label in UK), central DI HRS type 1, variceal haemorrhage
Primary use Septic shock adjunct Hepatorenal syndrome

Vasopressin has more balanced V1/V2 activity and a shorter half-life. Terlipressin's longer duration and greater V1 selectivity make it better suited for intermittent dosing in HRS and variceal haemorrhage.

Diabetes Insipidus

Vasopressin (specifically desmopressin, DDAVP — a synthetic V2-selective analogue) is the treatment for central diabetes insipidus. In the ICU, central DI occurs most commonly following:

  • Traumatic brain injury
  • Pituitary or hypothalamic surgery
  • Subarachnoid haemorrhage with hypothalamic involvement
  • Brain death (DI is near-universal in brain death and can complicate management of potential organ donors)

Diagnosis: Polyuria (>200–300 mL/hour), low urine osmolality (<300 mOsm/kg), high serum osmolality (>295 mOsm/kg), and rising serum sodium.

Management:

  • Desmopressin (DDAVP): 1–4 micrograms IV/SC BD-TDS. V2-selective — antidiuretic without V1-mediated vasoconstriction.
  • In brain-dead potential organ donors, vasopressin infusion (0.01–0.04 units/min) is often used instead — it also provides vasopressor support alongside the antidiuretic effect.
  • Hypotonic fluid replacement to correct free water deficit.

Adverse Effects

Adverse effects of vasopressin in septic shock at standard doses (0.01–0.04 units/min):

Mesenteric ischaemia: Vasoconstriction of splanchnic vessels can reduce intestinal blood flow, causing ischaemic colitis — particularly at higher doses or in patients with pre-existing vascular disease.

Myocardial ischaemia: Coronary vasoconstriction may precipitate ischaemia in susceptible patients.

Peripheral ischaemia: Digital and limb ischaemia — similar to noradrenaline; more prominent at high doses.

Hyponatraemia: V2-mediated water reabsorption can cause dilutional hyponatraemia, particularly with excessive free water administration.

Bradycardia: Reflex bradycardia from increased systemic vascular resistance. Generally mild at standard doses.

Reduced cardiac output: Vasoconstriction increases afterload; in patients with impaired cardiac function, cardiac output may fall.

At doses of 0.03 units/min, these adverse effects are generally less frequent than with equivalent doses of noradrenaline, but clinical vigilance is still required.

Viva Questions

What is relative vasopressin deficiency in septic shock and what is the rationale for giving exogenous vasopressin?

In septic shock, endogenous vasopressin levels initially rise as part of the stress response to hypotension. However, in sustained shock, vasopressin levels fall paradoxically — often to levels lower than expected for the severity of hypotension. This is termed relative vasopressin deficiency. Proposed mechanisms include depletion of hypothalamic-posterior pituitary stores from sustained hyperstimulation, catecholamine-mediated suppression of vasopressin release at high noradrenaline concentrations, and impaired baroreceptor-hypothalamic signalling. The vasodilatory state of septic shock is driven partly by excess nitric oxide and prostaglandins, which cause pathological arteriolar vasodilation. Replacing vasopressin at physiological doses (0.01–0.04 units/min) restores V1a-mediated vascular smooth muscle tone, raising systemic vascular resistance and MAP. It may also restore catecholamine receptor sensitivity and suppress inducible NO synthase. This provides a mechanistically different vasopressor action from noradrenaline, allowing reduction of catecholamine doses with their associated risks (tachycardia, arrhythmia, direct myocardial toxicity at high doses).

What did the VANISH trial show and how has it influenced the use of vasopressin in septic shock?

The VANISH trial (JAMA 2016) was a factorial RCT comparing vasopressin vs noradrenaline as the initial vasopressor in septic shock, and hydrocortisone vs placebo. The primary outcome was kidney failure-free days at 28 days. Vasopressin was not superior to noradrenaline for this outcome. However, vasopressin was associated with numerically fewer patients requiring renal replacement therapy (25.4% vs 35.3%), though this did not meet the pre-specified statistical threshold. There was a suggestion of interaction between vasopressin and the absence of corticosteroids — vasopressin appeared to be more beneficial without concurrent hydrocortisone, though this was a secondary finding. The trial confirmed that vasopressin is a safe and effective alternative to noradrenaline as a first-line vasopressor and did not demonstrate safety concerns at standard doses. Combined with the earlier VASST trial, the evidence supports vasopressin as an adjunct to noradrenaline in septic shock — reducing noradrenaline requirements and potentially reducing RRT rates. It is incorporated into SSC guidelines as an adjunct to be added when noradrenaline requirements are escalating, at a fixed dose of up to 0.03–0.04 units/min.

How does vasopressin cause antidiuresis and how do you use this property in the ICU?

Vasopressin acts on V2 receptors in the principal cells of the renal collecting duct. V2 receptor activation triggers Gs-protein signalling, increasing intracellular cAMP, which activates protein kinase A. PKA phosphorylates aquaporin-2 (AQP2) water channel proteins in intracellular vesicles, causing them to translocate to and insert into the apical membrane of the principal cell. This greatly increases the water permeability of the apical membrane, allowing water to move down the osmotic gradient from the tubular lumen into the hypertonic medullary interstitium and ultimately into the bloodstream. The result is concentrated urine and water conservation. In the ICU, this antidiuretic property is clinically important in central diabetes insipidus, where ADH production or release is impaired. Central DI presents with large volumes of dilute urine (urine osmolality <300 mOsm/kg, specific gravity <1.005), rising serum sodium, and increasing serum osmolality. Treatment is with desmopressin (DDAVP), a synthetic V2-selective analogue with negligible V1 activity, given 1–4 micrograms IV or SC BD-TDS. In brain-dead potential organ donors, vasopressin infusion is preferred as it provides both antidiuretic and vasopressor effects simultaneously. Aqueous vasopressin can also be used for central DI when precise titration of the antidiuretic effect alongside haemodynamic support is desired.