The Effects and Safety of Vasopressin Receptor Agonists in Patients With Septic Shock

A Meta-analysis and Trial Sequential Analysis

Libing Jiang; Yi Sheng; Xia Feng; Jing Wu

Disclosures

Crit Care. 2019;23(91) 

In This Article

Discussion

In this meta-analysis, the authors evaluated the effects and safety of vasopressin receptor agonists in patients with septic shock. The results showed vasopressin receptor agonist administration might be associated with increased survival in septic shock patients and further studies are required. However, their use could increase the risk of digital ischemia. There were no effects on ICU length of stay, duration of mechanical ventilation, cardiovascular ischemia events, arrhythmia, cerebrovascular ischemia events, mesenteric ischemia, diarrhea, and hypomania.

Generally, catecholamines, especially norepinephrine, are used as the first-line vasopressors in septic shock patients.[3,33–35] However, with a better understanding of the pathophysiology of septic shock and growing attention to the side effects of catecholamines, alternative vasopressors are searched. Vasopressin is an endogenous hormone, and the supraoptic and paraventricular hypothalamic nuclei are the principal sources.[36,37] Plasma vasopressin level in normal subjects does not exceed 4 pg/ml. But in patients with septic shock, the level of plasma vasopressin is reported to be abnormally low.[36–39] Moreover, exogenously administered vasopressin could increase the responsiveness to infused catecholamines and reduce the dose of catecholamines.[40–42]

Vasopressin in Septic Shock Trial (VASST) failed to find a statistical difference in short-term and long-term mortality between septic shock patients who received vasopressin and norepinephrine.[31] In the present meta-analysis, we find the use of vasopressin receptor agonists is associated with increased survival when compared with those that received catecholamines alone, and this positive association may be more obvious in patients with cirrhosis who received terlipressin. Terlipressin, a synthetic analogue of vasopressin with a longer half-life, acts via V1 receptors on arteriolar smooth muscle cells. Terlipressin is generally used for hepatorenal syndrome and esophageal variceal bleeding.[43,44] Previous small studies found a continuous infusion of terlipressin might be more effective than vasopressin in restoring hemodynamic status with less adverse events.[16,25,45] In the study by Choudhury et al.,[22] the authors even found terlipressin is effective in improving survival of cirrhotics with septic shock, and they suggested early introduction of terlipressin rather than after failure of monotherapy. This is in agreement with the results of our study. The survival advantage of terlipressin is more obvious in cirrhotics with septic shock perhaps because it can reduce the portal pressure and result in redistribution of splanchnic blood. Additionally, terlipressin use may be useful in renal function recovery.[22] Selepressin, a more selective V1a receptor agonist, was reported to be effective in the improvement of hemodynamics in septic shock animal models and decreasing pulmonary capillary leak when used early or as first-line agent.[46–48] One small phase IIb human study reported selepressin was safe and effective in septic shock patients.[49]

Several meta-analyses reached conflict conclusions.[32,50–54] Possible reasons include different inclusion criteria. In this present study, both studies in full text and abstract were eligible. In order to reduce patient heterogeneity, only septic shock patients were included in the present study. Additionally, different endpoints and statistical methods may also account for the inconsistent outcomes.

The Limitation of This Study

Several limitations of the present study should be concerned. Firstly, although there was no statistical significance of Egger's test, the possibility of publication bias cannot be completely excluded. Secondly, some endpoints were not reported in studies, which were published in the abstract. Thirdly, ICU mortality, 24 h mortality, hospital mortality, and 28/30-day mortality were regarded to be equal in the present study, and this might bias the outcome. Finally, long-term endpoints, like 90-day mortality, and some surrogate outcomes were not reported in the present study.

The Implication for Clinical Practice and Further Studies

The results of this meta-analysis showed vasopressin receptor agonists improved survival with a higher risk of digital ischemia. The following reasons may account for the higher incidence of digital ischemia in the study by Liu et al. Firstly, 94% of patients with digital ischemia in their study received terlipressin and open-label noradrenaline. Furthermore, the maximum dose of terlipressin used in their study was higher than that reported in other studies.[27] However, no patient needed surgical interventions for digital ischemia. Another concern of using vasopressin in patients with septic shock is its effects on cardiac output and oxygen delivery. Vasopressin has previously been reported to be associated with a reduction of cardiac output,[55] although this association is not found in other studies.[16,56] Factors including different infusion method and dose of vasopressin, different period of fluid resuscitation, and additional medication use (inotropic infusion) may partially explain the diverse results.[56] Neto et al., in their meta-analysis, pointed that vasopressin use did not result in decreased cardiac output, except for high dose of terlipressin.[52] Additionally, Gordon et al. and Neto et al., in their studies, found vasopressin administration was associated with a significant decrease in heart rate, and this may play important role in effect on the cardiac output of vasopressin.[52,56] In most published studies, patients in the intervention group received both vasopressin and open-label catecholamines, and this may bias the outcome. And more head-to-head comparative randomized evidence is required. The VASST study found the survival advantage of concomitant vasopressin and norepinephrine therapy was obvious in patients with less severe shock.[57] In another study, lactate concentration was reported to be associated with the hemodynamic response of vasopressin.[58] In the study by Nascente et al., they found vasopressin administration is likely to improve microcirculation in septic shock patients whose baseline noradrenaline dose was higher than 0.38 μg/kg/min.[59] Therefore, uncovering specific subgroups of septic patients who are most likely to respond to early initiation of vasopressin is important.[58] A post hoc analysis pointed that the adjunctive use of corticosteroids could increase the survival benefit of vasopressin. And in these patients, the serum vasopressin concentration significantly increased.[60] Although this association did not been observed in the following randomized controlled trial,[19] adjunctive treatments with vasopressin in septic shock patients are another point requiring more studies. Moreover, the best dose, time of use,[10,61–64] infusion method (continuous or intermittent), and discontinuation strategies are also a hot topic and remain unclear.[65]

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