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CARDIOVASCULAR ANESTHESIOLOGY

Phenoxybenzamine in the Treatment of Hypoplastic Left Heart Syndrome: A Core Review

From the Department of Anesthesiology, Emory University School of Medicine, Children's Healthcare of Atlanta at Egleston, Atlanta, Georgia.

Address correspondence and reprint requests to Nina A. Guzzetta, MD, Department of Anesthesiology, Emory University School of Medicine, Children's Healthcare of Atlanta at Egleston, 1405 Clifton Road NE, Atlanta, GA 30322. Address e-mail to nina.guzzetta{at}emoryhealthcare.org.

Abstract

Perioperative management of neonates after the Norwood procedure is extremely complex. Limited reserve of the neonatal single ventricle and the parallel arrangement of the pulmonary and systemic circuits result in a tenuous balance between pulmonary and systemic blood flows. Precise manipulations of both pulmonary and systemic vascular resistance are necessary to prevent excessive pulmonary blood flow at the expense of systemic oxygen delivery. An emerging treatment strategy aimed at improving early mortality is the intraoperative administration of phenoxybenzamine, a profound systemic vasodilator. Maximum systemic vasodilation is thought to reduce afterload of the single ventricle and produce a more stable parallel circulation by ameliorating the postoperative fluctuations in systemic vascular resistance. Although this strategy has gained popularity at many centers, it is not without scrutiny. The following review provides an overview of the pharmacology of phenoxybenzamine, the surgical and physiologic implications of the Norwood procedure, and a discussion of the pros and cons of phenoxybenzamine administration.

Neonates who have undergone the Norwood procedure remain anatomically uncorrected, with a single ventricle supplying both systemic and pulmonary circulations and shunt-dependent pulmonary blood flow. High mortality after this procedure has been attributed to low cardiac output and maldistribution of blood flow between the systemic and pulmonary circulations (1). Unexpected cardiovascular collapse and death are common (2,3). In an effort to improve postoperative mortality, a number of new treatment strategies have emerged, including the use of potent vasodilators such as phenoxybenzamine. The goal of treatment with phenoxybenzamine is to assist in balancing the post-Norwood circulation by decreasing systemic vascular resistance (SVR) and encouraging systemic blood flow as opposed to pulmonary blood flow. However, there is as yet no definite consensus concerning its use and effectiveness. This lack of consensus is the focus of this pro–con debate. In this article, I will first review the basic pharmacology of phenoxybenzamine as well as the surgical and physiological results of the Norwood procedure.

Phenoxybenzamine (Dibenzyline: Wellspring Pharmaceutical Corporation, Bradenton, FL) is a haloalkylamine that blocks both -1 and -2 adrenergic receptors with a slightly higher affinity for the -1 receptor (4). Blockade by phenoxybenzamine develops relatively slowly, reaching a peak effect in 1 h or more after IV administration. Likewise, it is a long-acting drug with a half-life of approximately 24 h. Its high lipid solubility leads to an accumulation in adipose tissue after large doses or repeated administration (5). As a result of the irreversible covalent bond that phenoxybenzamine forms with the -adrenergic receptor, responsiveness to an agonist requires the synthesis of new receptors. Hamilton et al. demonstrated that only 50% of -1 receptors had recovered 8 days after the administration of phenoxybenzamine (6). Similar studies showed that the recovery of -2 receptors was shorter, with 50% of these receptors restored in 2–3 days (7). The true duration of action of phenoxybenzamine is therefore related more to the synthesis of new receptors than to the actual half-life of the drug (Table 1). Consequently, one potential problem with phenoxybenzamine is prolonged vasodilation refractory to the usual array of -agonists. Vasopressin, which acts on the V1 receptor of smooth muscle, has preserved activity even in the presence of phenoxybenzamine and is an effective antidote to refractory hypotension (8).

The predominant action of phenoxybenzamine is systemic vasodilation because of direct blockade of -adrenergic receptors in vascular smooth muscle. Pulmonary arteries and veins also dilate, but to a lesser degree than the systemic vasculature (5). Thus the major hemodynamic effects of phenoxybenzamine manifest as a marked decrease in SVR and central venous pressure along with a compensatory increase in cardiac output (Table 2) (9). Increases in coronary artery blood flow accompany the increases in cardiac performance. Cerebral and renal blood flows are affected very little by phenoxybenzamine as long as arterial blood pressure remains within the range of autoregulation (5). The use of phenoxybenzamine during cardiac surgery facilitates higher pump flow rates during cardiopulmonary bypass (CPB) and is associated with less metabolic acidosis postoperatively (10). Additionally, phenoxybenzamine was found to be more effective than sodium nitroprusside in improving tissue perfusion postbypass, as measured by smaller peripheral-to-core temperature gradients and lower base deficits in phenoxybenzamine-treated patients (9). Though there is no clear consensus on the benefits of phenoxybenzamine during the Norwood procedure, many centers administer 0.25 mg/kg of phenoxybenzamine at the commencement of CPB in an attempt to optimize systemic organ perfusion during deep hypothermic CPB and postoperatively (Table 3).

The three-staged reconstruction for hypoplastic left heart syndrome (HLHS) requires the creation of separate pulmonary and systemic circulations both supported by a single right ventricle. The initial stage of this approach, known as the Norwood procedure, was first described by Norwood et al. in 1983 (11). The procedure, typically the most physiologically challenging of the three stages, involves the creation of a common atrium to provide unobstructed delivery of pulmonary venous blood from the single right ventricle to the aorta and coronary arteries and a fixed source of pulmonary blood flow through a systemic-to-pulmonary artery shunt (Fig. 1). Historically, the most common shunt used was a modified Blalock-Taussig (BT) shunt in which a graft is used to connect the right subclavian or innominate artery to the right pulmonary artery. However, many surgeons have begun to question the use of this shunt because of concerns regarding the potential for diastolic run-off and subsequent coronary artery steal (12). Coronary artery blood flow occurs primarily during diastole and placement of a modified BT shunt has been shown by Doppler echocardiography to result in significant forward flow reversal in the descending aorta during diastole (13). Thus there is speculation that a modified BT shunt may contribute to the decreased coronary artery blood flow and myocardial dysfunction that may be seen after the Norwood procedure. In 2003, Sano et al. popularized the use of a right ventricular-to-pulmonary artery shunt, which thereby eliminates the risk of aortic diastolic run-off and coronary artery steal (14). A multicenter protocol is currently underway to determine whether one shunt may be more efficacious than the other in the long term.

View larger version (45K): [in this window] [in a new window]   Figure 1. The Norwood reconstruction. AP = aortopulmonary interposition shunt (Gore-Tex, W. L. Gore and Associates, Inc., Flagstaff, AZ) from the innominate artery to pulmonary artery provides pulmonary blood flow to the pulmonary circulation, RV = right ventricle. Reproduced with permission from Ohye RG, Mosca RS, Bove EL, Backer CL, Mavroudis C. Pediatric cardiac surgery. 3rd ed, 2003, 565, ©Mosby.

Although the introduction of a staged operative approach has dramatically improved survival for neonates born with HLHS and other similar variants, the Norwood procedure itself remains challenging, and with a relatively high mortality (2). The immediate postbypass management of neonates after this procedure is particularly complex. One of the complexities is that even healthy neonates have a limited cardiac reserve. The neonatal myocardium and its contractile tissue are immature. Contractile tissue in neonatal hearts is only 30% of the myocardial mass when compared with 60% in adults, and is characterized by a lower velocity of shortening and a diminished length-tension relationship (15). Thus, the neonatal heart has a reduced compliance, a relatively fixed stroke volume, and a cardiac output that is heart-rate dependent. As a result, the neonatal heart responds poorly to increases in after load. Neonates undergoing a Norwood procedure suffer from the above intrinsic limitations as well as from other factors unique to HLHS. First, functional limitations of the postoperative Norwood myocardium are further compounded by myocardial depression from cardioplegia and CPB. Second, the single ventricle must perform the work of both a pulmonary and systemic ventricle in a setting that may include a low diastolic pressure and alterations in coronary artery blood flow (16). Third, sympathetic responses to stress that result in increases in SVR and subsequent increases in the pulmonary-to-systemic flow ratio (Qp/Qs) further reduce myocardial performance and systemic organ perfusion (16). Consequently, perioperative management strategies to increase survival have mainly focused on improving postbypass myocardial function and systemic organ perfusion. Such strategies have included continuous monitoring of mixed venous oxygen saturation, minimization of circulatory arrest time with low flow continuous cerebral perfusion, amelioration of the inflammatory response to CPB by the use of antifibrinolytic drugs and modified ultrafiltration, and reductions in SVR by the use of vasodilators such as phenoxybenzamine. This pro–con debate addresses the latter treatment.

Early mortality after the Norwood procedure has been associated with pulmonary over-circulation (Fig. 2) (1). Efforts to achieve a balanced Qp/Qs have traditionally centered on increasing pulmonary vascular resistance (PVR). Elevations in PVR are achieved readily in neonates by manipulation of inspired gases, either limiting the fraction of inspired oxygen or inducing hypercapnia. Such manipulations are useful both before and after Stage I reconstruction to promote this balance. Similarly surgical reductions in the size of the systemic-to-pulmonary artery shunt have been performed in an attempt to prevent increases in pulmonary blood flow. An arterial oxygen saturation within a range of 75%–80% is targeted, and thought to indicate a balanced Qp/Qs.

View larger version (9K): [in this window] [in a new window]   Figure 2. Mean calculated Qp/Qs ratio versus time over the first 24 h after admission to the intensive care unit. The graph depicts 13 patients who did not receive phenoxybenzamine during the Norwood procedure: 11 patients survived, 2 patients died. In the absence of phenoxybenzamine pulmonary over-circulation is universally present in the first 12 h postoperative. Qp/Qs ratios >2.5:1 were associated with nonsurvival. Reproduced with permission from Rossi AF, Sommer RJ, Lotvin A, Gross RP, Steinberg LG, Kipel G, Golinko RJ, Griepp RB. Am J Cardiol, 1994, 73, 1122, ©Excerpta Medica.

However, several clinical studies have demonstrated a wide variability in systemic organ perfusion, as measured by systemic venous oxygen saturation (Svo₂), despite maintenance of arterial oxygen saturation within the target range (Fig. 3) (16–19). Svo₂ monitoring in the post-CPB period revealed that most episodes of systemic venous desaturation and poor systemic organ perfusion were because of the abrupt increases in SVR rather than decreases in PVR (16). Because of the potential to increase Qp/Qs through the systemic-to-pulmonary artery shunt, increases in SVR do not necessarily result in an increase in arterial blood pressure and may, in fact, result in a quantitative decrease in the output of the single ventricle. Further vasoconstriction from inotropes or other vasoconstrictors administered in response to decreasing Svo₂ often worsens ventricular function and systemic perfusion. These studies underscore the importance of monitoring Svo₂ to detect critical reductions in systemic oxygen delivery and have led to the investigation of phenoxybenzamine for aggressive afterload reduction in the immediate postbypass period. Profound vasodilation of the systemic circuit will, theoretically, prevent the acute, unexpected increases in SVR seen after CPB and the accompanying over-circulation of the pulmonary circuit at the expense of systemic perfusion. Furthermore, a low SVR will decrease the energy requirements of the fragile post-CPB neonatal myocardium by allowing it to eject blood into a low resistance circulation. In this way, it is believed that potent vasodilation of the systemic circulation results in an increase in systemic oxygen delivery and improved end-organ perfusion. Although some studies claim that failure to use phenoxybenzamine is a risk factor for early cardiovascular collapse (2,16,20), the benefits of its use have not been clearly established. The following discussion further debates the advantages and disadvantages of using phenoxybenzamine while caring for these challenging neonates.

View larger version (29K): [in this window] [in a new window]   Figure 3. Multichannel recording during the first 4 h after admission to the intensive care unit of arterial saturation, mean arterial blood pressure, and superior vena cava saturation of a Norwood patient who did not receive phenoxybenzamine intraoperatively. The y axis indicates both percent saturation and the mean arterial blood pressure. The x axis indicates time. Severe impairments of systemic oxygen delivery are uncovered by superior vena cava saturation and are presumably the result of sudden increases in systemic afterload. These lead to a near-fatal event at 18:10 that is not tracked by either arterial saturation or mean arterial blood pressure monitoring. Sao2 = arterial saturation, MAP = mean arterial blood pressure, Svo2 = superior vena cava saturation, ICU = intensive care unit. Reproduced with permission from Tweddell JS, Hoffman GM, Fedderly RT, Berger S, Thomas JP, Ghanayem NS, Kessel MW, Litwin SB. Ann Thorac Surg, 1999, 67, 165, ©Elsevier.

Footnotes

Accepted for publication May 14, 2007.

REFERENCES

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