Vasopressin

CLASS

• bioactive neuroendocrine nonapeptide
• endogenously produced by the magnocellular neurone cell bodies of the paraventricular and supraoptic nuclei of the posterior hypothalamus

MECHANISM OF ACTION

Vasopressin on multiple receptors (GPCRs; g protein coupled receptors) (Holmes et al, 2003)

• V1
  • vascular smooth muscle of the systemic, splanchnic, renal, and coronary circulations -> potent vasoconstriction
  • vasoconstriction of renal efferent arterioles -> increased GFR
• V2
  • renal collecting ducts -> anti-diuresis
  • haemostatic system -> induces the release of Von Willebrand Factor (VWF) and Factor VIII:coagulant (FVIII:c) from endothelial cells -> increased platelet aggregation
• V3
  • pituitary -> stimulates release of ACTH and hence increased cortisol secretion
• OTR
  • oxytocin receptor subtypes -> myometrium and vascular smooth muscle
• P2
  • purinergic -> potential effects of smooth muscle vasodilation and cardiac contractility
• Likely binds to other receptor subtypes as well

Effects are preserved during hypoxia and severe acidosis and catecholamine-resistant states

Other effects

• less pulmonary artery vasoconstriction than noradrenaline, may even cause pulmonary artery vasodilation
• less arrhythmia than noradrenaline

PHARMACEUTICS

• clear, colourless solution in a glass ampoule containing 1 ml
• concentration of 20 IU/ml (= 0.4 mg)

DOSE

• 0.01-0.1U/min (onset: fast, offset: fast for vascular, long for kidneys)

ROUTE

• IV; also SC or IM

INDICATIONS

• diabetes insipidus
• refractory vasodilatory shock, e.g. septic shock, post-cardiac surgery vasoplegia
  • administered to about 17% of septic shock patients (Vale et al, 2016; Venkatesh et al, 2018)
  • Supported by Surviving Sepsis Guidelines as an option for refractory hypotension but not recommended as first line vasopressor (Dellinger et al, 2012)
• cardiac arrest (40U bolus)
• haemostasis in bleeding oesophageal varicies
• haemophilia
• von Willibrands disease

ADVERSE EFFECTS

• splanchnic vasoconstriction
• uterine contraction
• ischaemia (e.g. digital)
• oliguria

Tends to cause no or less increase in pulmonary artery pressure (compared to noradrenaline, for instance)

PHARMACOKINETICS

• Absorption – IV usually for vasopressin
• Distribution — VD of 0.14 l/kg
• Metabolism – peptidases in the liver and kidney (vasopressinases)
• Elimination – t1/2 = 10-20min; 65% of argipressin exreted unchanged

EVIDENCE

Nagendran et al, ICM 2019

• Individual patient data meta-analysis (IDMA) of 4 RCTs of vasopressin (compared with other vasoactive agents) for septic shock
• Findings
  • no effect on 28-day mortality: relative risk (RR) 0.98, 95% CI 0.86–1.12; however, wide CIs cannot exclude meaningful harm or benefit
  • no difference in serious adverse events (RR 1.02, 95% CI 0.82–1.26)
  • Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%–3.2%] but fewer arrhythmias (ARD −2.8%, 95% CI −0.2% to −5.3%)
  • Mesenteric ischaemia and acute coronary syndrome events were similar between groups
  • Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74–0.99), but this finding was not robust to sensitivity analyses
  • No statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion)
• Commentary and criticisms
  • still lacks power (wide CIs)
  • digital ischaemia may have implications for longterm quality of life
  • vasopressin generally used in addition to noradrenaline; findings do not inform use of vasopressin as first line or as an adjunct to other vasoactive agents (e.g. adrenaline)

VANISH trial, JAMA 2016

• Factorial (2×2) multicenter, double blind, randomised controlled trial
• n = 409 septic shock patients
• Vasopressin (titrated up to 0.06 U/min) +/-Hydrocortisone (50mg q6h and then weaned) versus noradrenaline (titrated up to 12 μg/min +/-Hydrocortisone (50mg q6h and then weaned)
• If the patient was still hypotensive after the first dose of study drug 2 then additional open-label catecholamine vasopressors could be administered
• no difference in number of days alive and free of kidney failure (defined by AKIN group stage 3)
• no difference with the addition of steroids

Serpa Neto meta-analysis, 2011

• Nine trials, n = 998 participants
• meta-analysis using a fixed-effect model
• Vasopressin decreased norepinephrine requirement
• Vasopressin may decrease mortality
  • all patients: reduced mortality (relative risk (RR), 0.87 (0.77 to 0.99); P = 0.04).
  • compared with norepinephrine
    • in adults:  decreased mortality  (RR, 0.87 (0.76 to 1.00); P = 0.05)
    • in patients with septic shock (42.5% vs. 49.2%, respectively; RR, 0.87 (0.75 to 1.00); P = 0.05; number needed to treat, 1 to 15)
• Vasopressin use in vasodilatory shock is safe
  • no difference in adverse events between the vasopressin and control groups (RR, 0.98 (0.65 to 1.47); P = 0.92).

VAAST Trial, NEJM 2008

• multicenter double blind, randomised controlled trial
• n = 780 septic shock patients
• patients on low dose noradrenaline randomised to vasopressin (up to 0.03U/min) versus higher dose noradrenaline
• no significant difference in mortality at 28 days
  • lower severity patients (baseline noradrenaline 5-14mcg/min) had a trend towards lower 28-day mortality with vasopressin (35.7% vs 26.5%, p=0.05) and 90-day mortality (46.1% vs 35.8%, p=0.04, NNT 10)
• vasopressin administration had a significant noradrenaline-sparing effect
• no significant overall difference in adverse events
  • trend towards a higher rate of cardiac arrest in the noradrenaline group
  • trend towards an increased incidence of digital ischaemia in the vasopressin group
• led to a recommendation for use as an adjunctive pressor agent (up to 0.03U/min) in the 2008 update to the Surviving Sepsis Guidelines

Tsuneyoshi et al, 2001 (CCM)

• hemodynamic and metabolic effects of low-dose vasopressin infusions in septic shock
• n = 16 with septic shock refractory to fluid + catecholamines -> vasopressin 0.04 u/min for 16 hrs
• immediate, significant increase MAP, SVR, UO, decrease lactate(NS)
• no adverse cardiac effect, no effect pO2, BSL, electrolytes

Malay et al, 1999 (Trauma)

• 0.04 u/min = permissive replacement dose

Landry et al, 1996 (Circulation)

• secretion of vasopressin was significantly suppressed in patients with septic shock compared to those with cardiogenic shock

References and Links

LITFL

• CCC — Noradrenaline
• CCC — Initial management of septic shock
• CCC — Inotropes, vasopressors, and other vasoactive drugs

Journal articles

• Dellinger RP, et al; Surviving Sepsis Campaign Guidelines (SSG) Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. PubMed PMID: 23353941. [free full text]
• Gordon AC. Vasopressin in Septic Shock. JICS 2011 Jan; 12(1):11-14. [Free Full Text]
• Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1–receptor physiology. Crit Care. 2003;7(6):427-34. [pubmed] [article]
• Holmes CL, Landry DW, Granton JT. Science Review: Vasopressin and the cardiovascular system part 2 – clinical physiology. Crit Care. 2004;8(1):15-23. [pubmed] [article]
• Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. The New England journal of medicine. 345(8):588-95. 2001. [pubmed]
• Malay MB, Ashton RC, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. The Journal of trauma. 47(4):699-703; discussion 703-5. 1999. [pubmed]
• Nagendran M, Russell JA, Walley KR, et al. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019; [pubmed]
• Romand JA, Treggiari-Venzi M. Is vasopressin an ideal vasopressor to treat hypotension in septic shock? Intensive care medicine. 25(7):763-4. 1999. [pubmed]
• Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. PMID: 18305265. [Free Full Text]
• Russell JA. Bench-to-bedside review: Vasopressin in the management of septic shock. Critical care . 15(4):226. 2011. [pubmed]
• Serpa Neto A, Nassar AP, Cardoso SO. Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials. Critical care (London, England). 16(4):R154. 2012. [pubmed]
• Sharman A, Low J. Vasopressin and its role in critical care. Contin Educ Anaesth Crit Care Pain (2008) 8 (4): 134-137. doi: 10.1093/bjaceaccp/mkn021 [Free Full Text]
• Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Critical care medicine. 29(3):487-93. 2001. [pubmed]
• Vail EA, Gershengorn HB, Hua M, Walkey AJ, Wunsch H (2016) Epidemiology of vasopressin use for adults with septic shock. Ann Am Thorac Soc 13:1760–1767
• Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J, Investigators AT, The Australian-New Zealand Intensive Care Society Clinical Trials G (2018) Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 378:797–808
• Young PJ, Dleany A, Venkatesh B. Vasopressin in septic shock: what we know and where to next? Intensive Care Med. 2019; [article]

FOAM and web resources

• The Bottom Line — VANISH