Vasopressin in septic shock : Tapering and atrial fibrillation

In last few weeks, two studies on Vasopressin(AVP) were published which shed some light on its profile and use.

In the first studyWilliam F. McIntyre, Kevin J. Um et el published a meta analysis and systemic review of use of vasopressin and vasopressin plus catecholamines in distributive shock in JAMA.

Authors searched Medline, Embase and Central databases, and study 23 randomized clinical trials which included 3088 patients.

They looked at the randomized clinical trials, which included adults with distributive shock including septic shock, post cardiovascular surgery shock, neurogenic shock, anaphylaxis, which compared administration of vasopressin or its analogues , with or without concomitant catecholamines compared with catecholamines alone.

The primary outcome was atrial fibrillation and the secondary outcomes were mortality, requirement of renal replacement therapy, myocardial injury, ventricular arrhythmia, stroke and length of stay in the intensive care unit.

Data was analyzed, and categorized into high-quality evidence, intermediate quality and low quality.

RESULTS

Based on high-quality evidence with low risk of bias,  a lower rate of atrial fibrillation was associated with the vasopressin use when used for treatment of distributive shock.

Low risk of mortality as well as renal replacement therapy was noted when trials with High risk of bias were included.

In the second study, Kyeongman Jeon, Jae-Uk Song, Chi Ryang Chung et el studied comparison of tapering vasopressin vs tapering catecholamines in septic shock.  Discontinuation Order of Vasopressors in the management of Septic Shock (DOVSS) was conducted at Samsung Medical
Center (a 1979-bed, university-affiliated, tertiary referral hospital in Seoul, South Korea) between January 2012 and February 2014. It was a randomized double blind controlled trial. 

INCLUSION CRITERIA

All patients, 20 yrs or older, admitted with septic shock with documented site of infection, who are on catecholamines(Norepinephrine) and AVP who have maintained MAP of 65 for at least 2 hrs after reducing Norepinephrine dose to 0.03mcg/kg/min.

METHODS

Above patients were randomized to 2 groups. In the NE group, NE was discontinued at
the rate 0.1 mcg/kg/min every hour, keeping the AVP infusion at 0.03 U/min; next, AVP was weaned at a rate 0.01 U/min every hour if the MAP was maintained above 65 mmHg for 2 h after successful termination of NE. Care of septic shock was per surviving sepsis guidelines. They checked serum copeptin level in both groups.

While tapering either vasopressor, if hypotension developed, they followe following protocol

Administration of a fluid challenge (of at least 30 mL/kg of IV crystalloid or equivalent volume of colloid over 30 min) was initially performed to keep CVP >8 mmHg. If CVP was ≥ 8, the discontinued vasopressor was increased up to its dose prior to the hypotension, and then increased according to the protocol (NE, 0.1mcg/kg/min and AVP, 0.0 l unit/min) to maintain the target MAP. If the target
MAP was not achieved despite these interventions, the NE dose was increased by 0.1mcg/kg/min every hour until the MAP stabilized.

RESULTS

This study was stopped early because there was significant higher incidence of hypotension in norepinephrine group. NE tapering was significantly associated with hypotension during the study
period (hazard ratio, 2.221; 95% confidence interval, 1.106–4.460; p = 0.025). The serum copeptin level was lower in patients in whom hypotension developed during tapering of AVP than it was in those without hypotension.

VASOPRESSIN

Vasopressin(AVP) is an endogenous peptide, produced in the hypothalamic supraoptic nuclei and paraventricular nuclei (known as osmoreceptors). It is stored in the posterior pituitary. Important triggers for its release and synthesis include hyperosmolar plasma/urine, hypotension, and hypovolemia. AVP is a non-specific V1a, V1b (V3) and V2 receptors agonist. Its vasoconstriction effect ismainly through V1a receptor stimulation in the smooth muscles of the vasculature.

Other proposed effects from V1a receptor activation include vasodilator effects in the pulmonary and coronary vasculature. The proposed mechanism is through release of nitric oxide (NO) from
the endothelium.

V2 receptor activation leads to water channel aquaphorin 2 expression and translocation in the principal cells of the collecting tubule in the kidney.

Measurement of circulating AVP is problematic due to its short half-life, instability, and cumbersome detection methods . In contrast, copeptin is a stable fragment that is located at the C terminal of provasopressin. Copeptin levels directly mirror AVP levels because of its stoichiometric synthesis.

ROLE IN SEPTIC SHOCK

Low levels of vasopressin are found in patients with septic shock.  Prior to VASST trial, there were several experimental studies regarding use of vasopressin in septic shock. VASST trial   showed that low-dose vasopressin did not reduce mortality rates as compared with norepinephrine in septic shock but a later analysis showed patients with less severe septic shock had a better survival outcome when low dose AVP therapy was administered.  Also showed that there was a 50% reduction in end-stage renal failure in the AVP group and dialysis requirement. 

VANCS trial showed that vasopressin can be used as a first-line vasopressor agent in postcardiac surgery vasoplegic shock and improves clinical outcomes.

VANISH trial (Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock) showed that among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. 

At present, at the standard therapeutic dose, vasopressin is considered a “catecholamine sparing”
agent in severe sepsis, and is used most often in conjunction with norepinephrine.

BOTTOMLINE

Early introduction of vasopressin in patients with septic shock who have adequately volume resuscitated may lower the incidence of atrial fibrillation as well as renal failure. However, once patients are stable, its better to taper vasopressin first.

 

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