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From the Department of Anesthesiology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Wisconsin.
Address correspondence to Eckehard Stuth, MD, Department of Anesthesiology, Medical College of Wisconsin, Children's Hospital of Wisconsin, 9000 West Wisconsin Avenue, Milwaukee, WI 53201. Address e-mail to estuth{at}mcw.edu.
Dr Guzetta's review (1) prominently refers to our experience with phenoxybenzamine (POB) at Children's Hospital of Wisconsin (2–5) and she chose to highlight the risk of sudden increases in systemic afterload on systemic oxygen delivery after the Norwood procedure with one of our published recordings (Fig. 4 in Refs. 1 and 6). Although publications on the use of POB are few, the available data provide persuasive evidence in favor of intense and sustained afterload reduction for Norwood palliation.
Cardiopulmonary bypass with deep hypothermia, surgical trauma, and arterial hypoxemia contribute to an intense perioperative stress response during Norwood palliation of hypoplastic left heart syndrome, which results in significant morbidity (7). This stress response is characterized by potent activation of the sympathetic nervous system (8) and the renin-angiotensin axis (9,10), and leads to pronounced vasoconstriction of regional vascular beds, in particular the mesenteric circulation (8–10). Such vasoconstriction can result in end-organ ischemia and multiple-organ dysfunction. Use of POB at initiation of pediatric cardiopulmonary bypass results in more effective and homogenous warming and cooling of children during cardiopulmonary bypass and a lower perioperative base deficit, suggesting better organ perfusion and peripheral circulation (11,12).
In the postoperative Norwood circulation, the size of the systemic to pulmonary artery interposition shunt is the main determinant of total pulmonary resistance to blood flow and constrains the pulmonary to systemic blood flow (Qp/Qs) ratio (13). A Qp/Qs close to 1:1 results in a balanced parallel circulation which minimizes single ventricle work (13,14). In a full-term neonate (
3 kg) a 3.5-mm diameter interposition shunt is most likely to result in a balanced circulation after full myocardial and circulatory recovery. This shunt size provides optimal systemic oxygen delivery, even if endogenous pulmonary vascular resistance is moderately increased (13), whereas larger interposition shunts lead to pulmonary over-circulation with the risk of systemic hypoperfusion (13). Smaller, more restrictive shunts avoid pulmonary over-circulation but can result in severe perioperative hypoxemia and need for revision. The single ventricle after Norwood palliation is highly afterload-sensitive. Ventricular output and systemic oxygen delivery decline exponentially with increasing systemic vascular resistance in the Norwood circulation, even in the presence of an optimally sized shunt (13). Therefore, rational postoperative management should be directed at controlling systemic afterload. Although randomized trials that compare afterload-reducing strategies have not been performed, sustained afterload reduction with POB is supported by prospective physiological data showing perioperative stabilization of the parallel circulation, improved oxygen delivery (3,4), and excellent outcomes (5,15). Conversely, in the absence of sustained afterload reduction, sudden unexpected circulatory collapse has been reported with distressing frequency in the early postoperative period after Norwood palliation. Such unexpected circulatory collapse has been associated with sudden fluctuations in systemic vascular resistance (15,16), which can lead to ventricular dysfunction, pulmonary over-circulation with systemic hypoperfusion and myocardial ischemia.
A single initial loading dose of POB (0.25 mg/kg) results in low systemic vascular resistance on cardiopulmonary bypass (3,4) and sustained postoperative afterload reduction, which may persist for 72 hours. Our prospective database suggests that such a sustained effect is advantageous, because sudden, unpredictable increases in systemic afterload during the postoperative period are reliably prevented or blunted (15), and systemic oxygen delivery is optimized by "clamping" the Qp/Qs closer to unity (3). Sustained stable afterload reduction facilitates recovery of single ventricle function and stabilizes the parallel circulation during the most vulnerable first 72 hours. In a consecutive series of 105 patients undergoing the Norwood operation at the Hospital for Sick Children in Toronto, 25 patients had acute circulatory collapse in the first 72 hours postoperatively. Thirteen of these patients appeared clinically stable, but had early sudden collapse without apparent cause. Sixteen of the 25 neonates died. In those patients in whom the operation was deemed technically successful, intense afterload reduction with POB reduced the incidence of early sudden circulatory collapse from 31% to 5% (15). Similarly, multivariate analysis in 115 neonates undergoing Norwood palliation at Children's Hospital of Wisconsin, which compared the patient survival from the pre-POB era to the POB era, showed that intense afterload reduction with POB and continuous venous saturation monitoring were the factors significantly associated with improved survival. POB not only decreases systemic vascular resistance, minimizes Qp/Qs imbalance, and improves systemic oxygen delivery (3), but also simplifies postoperative ventilatory and inspiratory gas management. During afterload reduction with POB systemic oxygen delivery remains adequate, even at high arterial oxygen saturations, whereas in the absence of adequate afterload reduction high arterial oxygen saturations are associated with pulmonary over-circulation and systemic hypoperfusion (4). This uncoupling of arterial oxygen saturation from systemic oxygen delivery by POB is advantageous because it allows the use of higher inspired oxygen concentrations postoperatively, which prevents unrecognized pulmonary venous desaturation and its deleterious effect on systemic oxygen delivery (17).
A POB-based strategy results in low systemic vascular resistance with the goal of achieving high systemic flows. This strategy is only safe and successful with strict adherence to well-defined hemodynamic and oxygen delivery goals, which requires not only arterial blood pressure monitoring but also continuous monitoring of oxygen delivery with such modalities as continuous venous (superior vena cava) oximetry and two-site near-infrared spectroscopy (3,6,18). POB profoundly changes the way adjunctive vasoactive drugs are used. We routinely use milrinone, but injudicious use of adrenaline can lead to hypotension via ß-adrenergically mediated vasodilatation in the presence of 
-adrenergic blockade. Therefore, noradrenalin should be used initially as the primary catecholamine. High doses of noradrenalin and adrenaline (up to 0.5 µg · kg–1 · min–1) may be required to separate from bypass, but catecholamine infusions can usually be decreased rapidly to more moderate rates (0.05–0.2 µg · kg–1 · min–1) during modified ultrafiltration. We also routinely use high-dose opiate (7) and high-dose aprotinin regimens, delayed sternal closure, corticosteroids, and modified ultrafiltration. Most importantly, we closely monitor mean arterial blood pressure, systemic oxygen delivery, and regional oxygenation with continuous venous oximetry and two-site near infrared spectroscopy (18). It is crucial to promptly correct inadequate mean arterial blood pressures (<45 mm Hg) and impairments in systemic oxygen delivery (venous saturation <50%) by optimizing preload, hematocrit, and inotropes. Recent data from our institution suggest that POB is also beneficial for managing the Sano modification of Stage 1 palliation (19). Because IV POB is not approved for the described indication, Food and Drug Administration approval and an investigational drug number are required as part of a protocol for research or compassionate use. The decision to incorporate POB into a perioperative Norwood management strategy requires careful planning and full engagement of the entire perioperative team to realize improvements in outcome.
ACKNOWLEDGMENTS
The authors acknowledges and thanks Professor George Hoffman, MD, Medical Director of Pediatric Anesthesia and Co-director of the Pediatric Intensive Care Unit, Children's Hospital of Wisconsin for his expert advice and review.
Footnotes
Accepted for publication May 8, 2007.
REFERENCES
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