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The role of vasopressin in sepsis

Created: 16/5/2007
 

The Role of Vasopressin in Sepsis

Dr John Griffiths DICM MRCP FRCA MA
CriticalCareUK Editor



Focus on vasopressin

Vasopressin is an endogenous nonapeptide hormone released by the posterior pituitary in response to hypovolaemia and hypertonicity. It is also commonly know as antidiuretic hormone (ADH) and DDAVP. Its release is regulated by a combination of arterial baroreceptors in the carotid sinus and aortic arch, and osmoreceptors located near to the supraoptic nucleus (Figure 1). Release is normally constantly inhibited by volume receptors in the cardiac cavities.
Normal levels of plasma vasopressin are 0-4 pg/ml. Levels of 5-7 pg/ml cause maximum urinary concentration. Vasopressin at higher concentrations causes vasoconstriction via V1 receptors, and potentiates cortisol release via V3 receptors. It is metabolised by aminopeptidases throughout the body, and has a half-life of about 10 minutes.


Figure 1: Mechanisms of action and production of vasopressin



Focus on vasopressin levels and septic shock

Vasopressin levels are initially appropriately high in septic shock but invariably decline in the late phase (36 hours onwards) of septic shock. The cause of this decline is uncertain but may be due to depletion of pituitary stores after extensive release in the initial period of shock coupled with autonomic dysfunction and increased atrial stretch due to fluid boluses leading to reduced production. The situation is further complicated by the fact that high concentrations of noradrenaline (norepinephrine) (and nitric oxide) seem to inhibit vasopressin secretion.

Focus on the use of vasopressin in septic shock

In sepsis, the effects of vasopressin are believed to be mediated by V1R receptors found in vascular smooth muscle via the phosphoinositide pathway (Table 1). Infusion of 0.01 U/min of vasopressin has been shown to restore plasma concentrations to early shock levels. However, the use of vasopressin in septic shock does not have a great evidence base. There have been two pertinent randomised controlled trials of vasopressin in catecholamine-resistant vasodilatory shock but none looking at its effect on mortality. Both trials showed significant decreases in noradrenaline requirements. The first (a trial of 24 patients who underwent a 4-hour blinded study) showed a significant improvement in renal function in the vasopressin group, despite similar mean arterial pressures (the main objective of the study) when compared with the placebo group. There were no differences in cardiac output or gastric mucosal carbon dioxide tension. The second (randomising 48 patients to vasopressin and noradrenaline or noradrenaline alone for a 48-hour period, and monitoring broadly similar variables), infused vasopressin at a constant rate of 4 U/h until no noradrenaline was required, and then reduced vasopressin infusion rates in a stepwise manner depending on haemodynamic variables. The investigators showed significant improved cardiac indices, fewer tachyarrhythmias and improved gastric mucosal carbon dioxide tensions in the vasopressin group. They did, however, note a significant increase in plasma bilirubin levels.
There are, however, some areas of concern. Vasopressin use has been associated with increases in gastric-arterial carbon dioxide tension suggestive of gastrointestinal hypoperfusion. There has also been inconsistent evidence of decreased cardiac output, provoking concerns about oxygen delivery. Clearly, the platelet effects will lead to increased aggregation - an effect that could be deleterious in the hypercoagulable sepsis environment. Finally, the reported increase in plasma bilirubin may be indicative of decreased hepatocellular blood flow or direct toxicity.

Table 1. Distribution and effector response of the body’s Vasopressin receptors.

Receptors

Tissues

Principal Effects

Intracellular Signalling

V1R

Vascular smooth muscle

Kidney, platelets, spleen

Direct and indirect vasodilation

Phospholipase C

Increased intracellular Ca2+

V2R

Renal collecting duct

Endothelium

Increased permeability to water

Vasodilation

Increased cAMP

NO mediated

V3R

Pituitary

Neurotransmitter

ACTH release

Increased cAMP

OTR

Endothelium

Vasodilation

NO mediated



Focus on current recommendations for vasopressin use in sepsis

The combination of these concerns with the absence of a randomised controlled trial powered to show a survival benefit means that the Surviving Sepsis Campaign currently only recommends vasopressin (at a regimen of 0.01-0.04 U/min) as adjunctive therapy in patients with refractory shock despite adequate fluid resuscitation and high-dose conentional vasopressors. There is currently a multicentred study powered to examine the effects of vasopressin on outcome in septic shock, ‘The Vasopressin versus Norepinephrine in Septic Shock Study’ (VASST). The hypothesis is that treatment with vasopressin will reduce mortality from septic shock at 28 days. The results of this study are eagerly anticipated.

Key learning points

  • Vasopressin has been consistently shown to have a beneficial effect on blood pressure in the presence of septic shock.
  • However, at the current time there is insufficient benefit to justify the routine use of vasopressin in septic shock.
  • Vasopressin should be considered as a salvage mechanism in cases of septic shock refractory to increasing doses of inotropes.

Key references

Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest 2001; 120: 989-1002.

Kam PCA, Williams S, Yoong FFY. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia 2004; 59: 993-1001.

Dunser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W, Friesenecker B, Hasibeder WR. Arginine vasopressin in advanced vasodilatory shock. A prospective randomized controlled study. Circulation 2003;107: 2313-2319.

Patel B, Chittock D, Russell J, Walley K. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002; 96: 576-582.

Holmes C, Walley K, Chittock R, Lehman T, Russell J. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001; 27: 1416-1421.

Mount Sinai Hospital Critical Care Research Vasopressin vs. Norepinephrine in Septic Shock Study. Prime investigator James Russell.


ArticleDate:20070516
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