Vasopressin pressor effects in critically ill children during evaluation for brain death and organ recovery

Abstract

Background: Vasopressin (VP) shows promise as a pressor agent in animals and adult human cardiac arrest and resuscitation, but has not been studied for pressor effect in critically ill or arrested children. VP infusion is routine treatment for diabetes insipidus during brain death evaluation and organ recovery. We hypothesized that low dose VP infusion during organ recovery in critically ill children exerts a pressor effect, without major organ toxicity. Methods: 34 VP-treated and 29 age-matched critically ill controls (C) ≤18 years were retrospectively reviewed during brain death evaluation and organ recovery. VP infusion protocol titrated VP dose clinically to urine output, with high variability. Pressor and inotrope management was titrated clinically to BP, cerebral perfusion and central venous pressures (when available) and peripheral perfusion with similar protocol targets for pre-load in VP and C groups. Outcome measures include dose, type and number of pressors and inotropes. Organ function was assessed at recovery and 48 h post-transplant by independent surgeon and transplant program organ function criteria. Analysis by Odds Ratio (OR), and chi-square. Results: VP dose averaged 0.041±0.069 U/kg/h. Average baseline mean arterial pressure (MAP) before VP infusion was 79±17 mmHg VP and 76±14 mmHg C (P=0.6). Subsequent average MAP were: 82±21 mmHgVP after VP infusion versus 71±16 mmHg C (P=0.01) and 80±14 mmHg VP versus 68±22 mmHg C (P=0.01). Ability to wean/stop pressors and inotropes was: dopamine (14/23) 42% VP versus (10/26) 38% C (P=0.75), dobutamine (4/7) 57% VP versus (0/6) 0% C (P=0.026), epinephrine (4/5) 80% VP versus (0/6) 0% C (P=0.006), norepinephrine/phenylephrine (4/4) 100% VP versus (2/5) 40% C (P=0.057). Alpha agonist pressor dependence was successfully weaned from 7/9 (78%) VP versus 0/9 (0%) C: odds ratio=7.3, (P<0.01). There was no VP induced dysrhythmia, hypertension, anuria or toxicity reported. Good organ recovery function was not significantly different at recovery or 48 h post-transplant for kidney (79% VP versus 69% C, P=0.068), liver (87% VP versus 95% C, P=0.533), or heart (90% VP versus 71% C, P=0.11). Conclusions: Low dose vasopressin infusion exerts a pressor effect in critically ill children treated for diabetes insipidus during brain death and organ recovery. VP treated patients were 7.3 times more likely to wean from alpha agonists than comparably managed age matched controls, without adverse affect on transplant organ function. We speculate that further prospective assessment of VP safety and efficacy as a pressor adjunct for resuscitation of critically ill children is warranted.

Introduction

Survival outcome following cardiac arrest remains dismal despite implementation of advanced cardiac life support interventions. The utility of epinephrine, considered the ‘gold standard’ drug for cardiac resuscitation, has recently been questioned and may be no more effective than placebo in some circumstances [1]. Consequently, alternative therapies have been explored, including the hormone vasopressin (pitressin, antidiuretic hormone, or ADH). Endogenous levels of arginine vasopressin are elevated in patients suffering cardiac arrest, and return of spontaneous circulation is associated with elevated vasopressin levels [2]. In ventricular fibrillation animal models, vasopressin administration results in a very powerful vasoconstrictive effect, increasing coronary perfusion pressure and mean arterial pressure more than epinephrine, while preserving myocardial and cerebral blood flow [3]. Vasopressin enhances myocardial oxygen delivery and increased cardiac contractility without increasing myocardial oxygen demand. The mechanism of vasopressin's action may be related to V1 receptor stimulation and augmentation of endogenous catecholamines [3]. Recently, adult trials of VP treatment of refractory ventricular fibrillation showed promise in terms of increased 24-hour survival compared with those who received epinephrine [2], [4]. Vasopressin is reported to significantly increase coronary perfusion pressure in prolonged human pulseless electrical activity (PEA) and asystole during CPR [5]. Additionally, vasopressin administration in porcine PEA models resulted in a significant increase in left ventricular myocardial and cerebral blood flow during CPR and a higher rate of return of spontaneous circulation (ROSC) compared with animals receiving high-dose epinephrine [6]. Endobronchial administration of vasopressin in porcine cardiac arrest models has demonstrated improved resuscitation outcome and survival [7]. Vasopressin has also been investigated as an alternative pressor in adults with septic shock and vasodilatory shock after cardiac surgery, and reduced the need for other catecholamine pressors [8], [9].

The use of vasopressin as either a pressor or resuscitation drug in the pediatric population, however, has not been examined. Vasopressin has been used safely and effectively for management of diabetes insipidus, nocturnal enuresis, and gastrointestinal hemorrhage in children [10], [11]. The pressor effectiveness has not been independently evaluated previously, and it has not been studied in cardiac arrest or brain death. The Gift of Life Donor Program adopted a protocol titrating vasopressin infusion to treat diabetes insipidus in children meeting clinical brain-death criteria during the organ-recovery period. This population, although not in cardiopulmonary arrest, is often critically-ill and pressor-dependent. The recent reports of vasopressin use in adult resuscitation stimulated a retrospective review of the effect of vasopressin infusion on pressor-dependent children. The purpose of this study was to determine whether low dose vasopressin infusions exerted pressor effects, maintained a stable hemodynamic profile, allowed weaning of other alpha agonists, and preserved organ quality at organ recovery in these patients. This data may encourage appropriate evaluation of vasopressin as an adjunct or alternative pressor medication for use in pediatric cardiopulmonary arrest, resuscitation, and support of critically ill children.