Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery

II. Background

1. Description of the Problem One of the effects of cardiac operations involving cardiopulmonary bypass is reversible myocardial dysfunction lasting a number of days postoperatively. Typically this period of myocardial dysfunction is treated with vasoactive drugs aimed at improving contractility and reducing afterload. Problems exist with the current vasodilator therapy, including: variable response, inadequate response, complications of delivery mechanism with the potential for swings in blood pressure and ongoing dose adjustments. These are necessary due to the patients' autonomic nervous system reactivity changes during the post-cardiopulmonary bypass period. Evidence to support therapies targeting control of systemic vascular resistance include randomized controlled studies looking at the outcome of high risk neonates undergoing open cardiac procedures with very high dose synthetic narcotic anesthesia. This is known to reduce sympathetic nervous system activity. There exist numerous, uncontrolled but widely accepted, studies documenting the adjunctive use of vasodilators such as sodium nitroprusside, nitroglycerin and alpha-adrenergic blockers including phenoxybenzamine in the perioperative period. The results of all of these studies point towards a salutatory effect of measures to control vasoconstrictor responses on blood flow to the organs at risk, primarily the organs in the splenic circulation: the liver, kidneys, and intestines. Ischemia to these organs is responsible for a significant amount of morbidity in the post-bypass period including late onset sepsis and renal dysfunction. In addition, after myocardial injury the natural vasoconstrictor responses that mammalian organisms have to falling cardiac output are counterproductive and may initiate a cascade of responses, necessitating medical interventions culminating in overt myocardial pump failure. This then can lead to patient death or need for institution of extracorporeal circulatory support after the initial cardiopulmonary bypass period.
2. Physiologic Role of Phenoxybenzamine Numerous reports have demonstrated that with nearly complete blockage of alpha-adrenergic receptors (i.e. phenoxybenzamine) that both infusions of exogenous catecholamines and the neural release of endogenous catecholamines result not in vasoconstrictor responses but instead augmented myocardial contractility without increases in afterload. While medical interventions to effect circulatory responses are already in use commonly in the perioperative period, including synthetic narcotic analgesia and the use of short-acting vasodilator agents, these measures alone have not been universally effective in preventing the sort of hemodynamic deterioration described above. Therefore, we propose to use phenoxybenzamine, a drug which irreversibly binds to alpha-adrenergic receptors and some dopamine receptors, as an adjunct to the management of the perioperative vascular tone abnormalities in high risk infants and children undergoing cardiopulmonary bypass for open heart procedures.
3. Existing pharmacologic and clinical data Phenoxybenzamine (Dibenzyline: Wellspring Pharmaceutical Corporation, Bradenton, FL) is a haloalkylamine that irreversibly blocks both α-1 and α-2 adrenergic receptors. The drug exhibits a slightly higher affinity for the α-1 receptor. 12 There exists a body of literature concerning intravenous administration of phenoxybenzamine in the setting of congenital heart disease surgery, specifically in the Norwood repair for hypoplastic left heart syndrome. The use of phenoxybenzamine during cardiac surgery has been demonstrated to facilitate higher pump flow rates during cardiopulmonary bypass (CPB) and is associated with attenuation of postoperative metabolic acidosis. 13 Specifically, phenoxybenzamine has been shown to be more effective than sodium nitroprusside in improving tissue perfusion postbypass (as demonstrated by a comparison of rewarming characteristics), with lower base deficits in patients treated with phenoxybenzamine. 14 Indeed, to date there are many congenital heart disease surgical centers in the United States who, prior to the Norwood procedure, administer 0.25 mg/kg of phenoxybenzamine at the initiation of cardiopulmonary bypass in an attempt to optimize systemic organ perfusion in the perioperative period. Such a protocol, at this dose specifically, has been described to improve systemic oxygen delivery in patients undergoing the Norwood procedure for hypoplastic left heart syndrome, as well as an improvement in survival to future surgical palliations. 10

III. Aims and Objectives

Our general hypothesis is that a blockade of vasoconstrictor responses in the period around cardiopulmonary bypass will result in better organ preservation and improvement in cardiac output postoperatively. More specifically, as serum lactate serves as a surrogate for demonstrating the adequacy of end organ perfusion, we will utilize this continuous variable as our primary endpoint for the purposes of this protocol. Our hypothesis is that the use of phenoxybenzamine in this select population will reduce initial postoperative lactate levels by a clinically-relevant level of 25%, relative to historical controls. Secondary endpoints evaluated as well will include utilization of inotropic support, duration of hospitalization, and time to resolution of postoperative lactic acidosis. Both physiologic and outcome variables will be examined and compared to a matched cohort of patients drawn from our recent experience without the use of phenoxybenzamine.

IV. Patient Selection and Clinical Management