An elderly man presented with an acute abdomen. At operation, he was found to have four-quadrant peritonitis due to a perforating sigmoid tumour. He underwent a hemicolectomy and had a defunctioning stoma formed. Postoperatively, he required 0.7mcg/kg/min noradrenaline to maintain a MAP 65mmHg. A vasopressin infusion was commenced and his noradrenaline requirements decreased. However, he developed acute kidney injury and subsequent multiorgan failure. Treatment was withdrawn around 48 hours post-operatively.

Is vasopressin safe to use in septic shock? What are the benefits?

David Garry

 

Catecholamines are currently the vasopressor of choice in adult patients with septic shock, but their effectiveness may be limited by a loss of pressor responsiveness secondary to the development of adrenergic hyposensitivity. Catecholamines can also have adverse effects, including reductions in oxygen delivery, arrythmias, organ ischaemia, deleterious effects on immune function, thrombogenicity, effects on metabolic efficiency and stimulation of bacterial growth.

Vasopressin is produced in the hypothalamus and released by the posterior pituitary in response to an increase in plasma osmolality, a decrease in BP or a decrease in circulating volume. It acts on V1 receptors (vasoconstriction, including the potentiation of catecholamines), V2 receptors (increased water re-absorption) and V3 receptors (modulation of ACTH secretion). Although endogenous levels increase in early septic shock it is increasingly recognised that patients on intensive care in vasodilatory shock have very low levels of vasopressin.

Existing studies looking at the use of vasopressin in patients with septic shock have produced conflicting results. The largest study to date is the VASST trial (1), looking at septic shock patients already receiving noradrenaline. It enrolled 778 patients already on noradrenaline to receive either additional noradrenaline or vasopressin (0.01-0.03 U/min). It found no difference in 28-day mortality (35.4% vs 39.3%, p=0.26) but on sub-group analysis 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). There were no significant differences in the overall rates of serious adverse events. Of note, the trial was very underpowered (mortality in the control group was lower than anticipated).

In 2012 Neto A et al. published a systematic review and meta-analysis of 9 studies with a total of 998 patients (of note 778 were from the study by Russell et al.). Seven studies in the meta-analysis used vasopressin, 2 used terlipressin, one evaluated both.

Their primary outcome (overall survival) showed:
• Association of vasopressin with a decreased dose of noradrenaline infusion reduced mortality (RR: 0.87 [0.76-1.00]; p=0.05).
• Effect on mortality disappeared after the analysis without the study by Russell et al.

Their secondary outcomes were:
1 – change in haemodynamic and biochemical variables:
• Significant reduction in the noradrenaline requirement among patients receiving vasopressin
• Vasopressin significantly decreased heart rate without changes in cardiac output.
• Vasopressin did not decrease cardiac or oxygen delivery indices

2 – A decrease in catecholamine requirements:
• Significant reduction in the noradrenialine requirement among patients receiving vasopressin

3 – Assessment of adverse events:
• No difference in adverse events between the vasopressin and control groups (RR: 0.98 [0.65-1.47]; p=0.92

Current practice often sees vasopressin used as a “rescue” vasopressor in the face of spiralling catecholamine requirements. This practice is supported by the results of the VASST trial as it didn’t show a higher rate of adverse effects with vasopressin. The meta-analysis also failed to reveal any safety concerns with the use of vasopressin. Interestingly it showed that the use of vasopressin is associated with an overall reduced mortality.

The meta-analysis also showed that vasopressin reduced heart rate without changes in cardiac output. This is an interesting finding, as it could have a role in the prevention or development of septic shock/tachycardia associated myocardial dysfunction. Diastolic dysfunction is a major prediction of mortality in patients with septic shock, reducing heart rate could help in achieving adequate filling.

One outstanding question concerns the potential use of vasopressin as a first line vasopressor. The VANISH study is a multicentre randomised controlled trial that is currently recruiting patients, comparing early vasopressin vs noradrenaline as the initial vasopressor in patients who have septic shock. The primary outcome measure is rate of acute kidney injury at 28 days, the secondary outcome measures include 28 day, ICU and hospital mortality.

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Lessons learnt
A combination of vasopressin with noradrenaline reduces noradrenaline requirements in patients with vasodilatory shock. Vasopressin does not seem to be associated with adverse effects, and according to the results of the meta-analysis by Neto et al. it is associated with a reduced overall mortality.

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References
1 Russell JA, Walley KR, Singer J et al; VASST Investigators: Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med 2008, 358:877-87
2 Neto A, Nassar A, Cardoso et al. Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials. Crit Care. 2012 Aug 14;16(4):R154
3 Landry D, Oliver J. The Pathogenesis of Vasodilatory Shock. NEJM 2001;345:588-595