Surgical modifications and perioperative management

Factors Affecting Systemic Oxygen Delivery After Norwood Procedure With Sano Modification Yuji Naito, MD, Mitsuru Aoki, MD, Manabu Watanabe, MD, Nobuyuki Ishibashi, MD, Kouta Agematsu, MD, Koichi Sughimoto, MD, and Tadashi Fujiwara, MD Department of Cardiovascular Surgery, Chiba Children s Hospital, Chiba, Japan Background. The physiologic goal of management after a Norwood procedure is to optimize systemic oxygen delivery, as indicated by oxygen excess factor (OEF). Factors were examined that might affect systemic oxygen delivery after the Norwood procedure with right ventricle-to-pulmonary artery (RV-PA) conduit as the pulmonary blood supply. Methods. Hemodynamic data of 9 patients (mean age, 25.0 days; mean weight, 2.9 kg) who underwent a modified Norwood operation for hypoplastic left heart syndrome (HLHS) between April 2003 and April 2008 were retrospectively analyzed. Variables were obtained by manometry and oximetry from indwelling catheters in the systemic artery, pulmonary artery, and superior vena cava at 3- to 6-hour intervals for 72 hours postoperatively. Systemic (Qs) and pulmonary (Qp) blood flow, systemic vascular resistance (SVR), and pulmonary vascular resistance (PVR) were calculated. Results. A significant increase in SVR and decrease in PVR occurred during the first 6 hours, which might be inductive to sudden cardiovascular collapse. SVR and PVR significantly decreased over time through 24 hours, followed by a lower steady increase. OEF was closely correlated with SVR (p < 0.0001). No correlation of OEF with PVR (p 0.65) was noted among the assumed variables. Mixed venous oxygen saturation (SVO 2 ) and OEF were strongly correlated. Pulmonary arterial pressure and OEF were weakly correlated. Conclusions. Postoperative management strategies to maintain a low SVR, rather than manipulating PVR, appear to be rational to achieve adequate oxygen delivery after a Norwood procedure with Sano modification. The SVO 2 provides reliable prediction of OEF during postoperative hemodynamic recovery. (Ann Thorac Surg 2010;89:168 73) 2010 by The Society of Thoracic Surgeons Surgical modifications and perioperative management improvements have led to increased survival after the first-stage Norwood palliation of hypoplastic left heart syndrome (HLHS). Modulating a balance between pulmonary blood flow (Qp) and systemic blood flow (Qs) is a key issue that determines postoperative outcomes in these challenging patients. A mathematic model developed by Barnea and colleagues [1] suggests that maximal systemic oxygen delivery occurs at a Qp/Qs of less than 1. A number of clinical and experimental studies [2] have analyzed the effect of manipulation of Qp or Qs and its relationship to systemic oxygen delivery. Recently, Li and colleague [3] reported that the systemic oxygen delivery is strongly influenced by systemic vascular resistance (SVR) during the early postoperative period in patients undergoing the Norwood procedure with a systemic pulmonary shunt. However, little information is available on the effects of these factors in postoperative neonates undergoing a Sano modification of the Norwood procedure with a right ventricle-to-pulmonary artery (RV-PA) shunt [4]. This report describes the factors that may Accepted for publication Sept 15, 2009. Presented at the Poster Session of the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26 28, 2009. Address correspondence to Dr Naito, Department of Cardiovascular Surgery, Chiba Children s Hospital, 579-1, Heta-cho, Midori-ku, Chiba, 266-0007, Japan; e-mail: ujinaito@aol.com. contribute to optimizing systemic oxygen delivery after the Norwood procedure with the Sano modification. Patients and Methods This study was approved by the Institutional Review Board at The Chiba Children s Hospital, and parents informed consent was obtained. Patients Hemodynamic data of 9 consecutive patients who underwent a modified Norwood operation for HLHS between April 2003 and April 2008 were retrospectively analyzed. Age, weight, diagnosis, and preceding operation are summarized in Table 1. Operative Procedure General anesthesia was maintained with inhaled isoflurane, intravenous fentanyl, and pancuronium bromide. After a median sternotomy, a 3- or 3.5-mm polytetrafluoroethylene graft (PTFE) was anastomosed to the brachiocephalic artery for regional cerebral circulation, and venous cannulas were inserted into superior and inferior vena cavae. An 8F Biomedicus arterial cannula (Medtronic, Minneapolis, MN) was inserted into the thoracic descending aorta with Seldinger method for perfusion of the lower body. Thus, during cardiopulmonary bypass, 2010 by The Society of Thoracic Surgeons 0003-4975/10/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2009.09.032

Ann Thorac Surg NAITO ET AL 2010;89:168 73 OXYGEN DELIVERY AFTER SANO NORWOOD 169 the complete avoidance of circulatory arrest through the entire procedure was feasible. The aortic arch reconstruction was performed by direct anastomosis of the pulmonary trunk to the combination of transverse arch and descending aorta. Pulmonary blood flow was supplied through the RV-PA conduit with the PTFE graft in all patients. The diameters of the conduit used are reported in Table 1. Postoperative Care Patients received time-cycled mechanical ventilation with pressure support. Sedation was maintained with a continuous intravenous infusion of fentanyl (2 to 4 g/ kg/h), pancuronium bromide (0.05 to 0.1 mg/kg/h), and midazolam (0.1 to 0.2 mg/kg/h). Dopamine (3 to 10 g/kg/min), dobutamine (3 to 10 g/kg/min), and epinephrine (0.05 to 0.2 g/kg/min) were used as inotropic agents. Pulmonary vascular resistance was maximally decreased with oxygen (100%), nitric oxide gas inhalation, and nitroglycerin (2 to 4 g/kg/min). Milrinone (0.25 to 0.75 g/kg/min) was used to decrease both SVR and PVR. Patients received transfusions of packed red blood cells to maintain a hemoglobin value of no less than 12 g/dl. Table 1. Patient Profiles Variable No. or Mean SD (Range) Age, d 25.0 19.1 (5 55) Weight, kg 2.9 0.5 (2.3 3.8) Diagnosis MA, AA 5 MS, AS 2 MA, AS 1 MS, AA 1 Preceding operation Bilateral PA banding 3 RV-PA shunt size 5mm 7 4mm 2 AA aortic atresia; AS aortic stenosis; MA mitral atresia; MS mitral stenosis; PA pulmonary artery; RV right ventricle; SD standard deviation. Table 2. Equation Used for Calculating Hemodynamics and Systemic Oxygen Delivery Variables Data Collection The mean systemic arterial pressure, PA pressure (PAP), and central venous pressure were continuously monitored with percutaneously inserted indwelling catheters. Systemic arterial and venous blood gases and blood lactate levels were measured on admission to the intensive care unit and every 3 to 6 hours for postoperative day 1, and every 6 to 12 hours through postoperative day 3. Systemic arterial (Sao 2 ) and venous (Svo 2 ) oxygen saturation were measured by oximetry of blood samples. Pulmonary venous saturation (Spvo 2 ) was assumed to be 98%. Measured saturations and the direct Fick equation were used to obtain Qp and Qs, with assumption that systemic oxygen consumption was 160 ml/min/m 2. The oxygen excess factor (OEF, ) [5] was calculated as (systemic oxygen delivery)/(systemic oxygen consumption), or [Cao 2 Qs]/[(Cao 2 Cvo 2 ) Qs] Sao 2 /(Sao 2 Svo 2 ); where Cao 2 is the oxygen content of systemic arterial blood and Cvo 2 is the oxygen content of systemic venous blood. If oxygen consumption remains constant, then the OEF is directly proportional to systemic oxygen delivery [6]. Each equation is detailed in Table 2. Statistics All data were expressed as mean value standard deviations. Generalized simple linear regression analysis was used to determine the nature of any time trend of the measures during the 24-hour period, and polynomial transformations were tested for given measures. Simple linear regression was used to determine the correlation between measured variables and OEF. A value of p 0.05 was considered significant. All statistical analyses were performed with SPSS 11.5 software (SPSS Inc, Chicago, Ill). Results Equations Qp, L/min/m 2 VO 2 /(Cpvo 2 Cao 2 ) Qs, L/min/m 2 VO 2 /(Cao 2 Cvo 2 ) CO, L/min/m 2 Qs Qp SVR, WU m 2 (MAP CVP)/Qs PVR, WU m 2 (PAP CVP)/Qp OEF, Sao 2 /(Sao 2 Svo 2 ) Cao 2 oxygen content of systemic arterial blood; CO total cardiac output; Cpvo 2 oxygen content of pulmonary venous blood; Cvo 2 oxygen content of systemic venous blood; CVP central venous pressure; MAP mean arterial pressure; OEF oxygen excess factor; PAP pulmonary artery pressure; PVR pulmonary vascular resistance; Qp pulmonary blood flow; Qs systemic blood flow; Sao 2 systemic arterial oxygen saturation; Svo 2 systemic venous oxygen saturation; SVR systemic vascular resistance; VO 2 oxygen consumption; WU Wood unit. The mean cardiopulmonary bypass time was 187 24.5 minutes and aortic cross clamp time was 49.0 14.0 minutes. Mortality During the study period, 9 patients underwent the modified Norwood procedure. There was one early death due to sudden cardiovascular collapse at postoperative day 14. There were two interstage deaths. One patient died 2 months postoperatively of necrotizing enterocolitis, and the other patient died 5 months postoperatively of low cardiac output with sepsis. Profiles of Direct Measurements of Hemodynamics and OEF The direct measurements of hemodynamics and OEF are shown in Figure 1. SVR showed an initial rapid increase in the first 6 hours, followed by a slow decrease during first

170 NAITO ET AL Ann Thorac Surg OXYGEN DELIVERY AFTER SANO NORWOOD 2010;89:168 73 Fig 1. Profiles of direct measurements of hemodynamics and oxygen excess factor (OEF) are shown with the standard deviations (error bars). CO cardiac output; PAP pulmonary artery pressure; PVR pulmonary vascular resistance; Qp pulmonary blood flow; Qs systemic blood flow; Svo 2 systemic venous oxygen saturation; SVR systemic vascular resistance. 24-hour period. PVR showed an initial rapid decrease in the first 6 hours, which was opposite the SVR trend, with subsequent decline during first 24-hour period. The distinctive initial trend between SVR and PVR might be indicative of sudden cardiovascular collapse. PVR showed a small increase during next 24-hour period with a subsequent plateau, whereas SVR showed fluctuating values during next 48-hour period. Qp, Qs, cardiac output, and Svo 2 showed small but significant linear increases over time (p 0.05 for all 4 variables) during first 24-hour period. Qp peaked at 30 hours postoperatively and decreased over time subsequently, whereas Qs showed a fluctuating course after 24 hours. PAP showed a significant liner decrease over time during the first 24 hours, followed by a slow increase that peaked at about 42 hours. There was a similar trend as PVR. OEF showed a similar trend as Qs, namely, a significant linear increase over time (p 0.001) during first 24 hours, followed by fluctuating course. Arterial blood chemistry revealed that the lactate level was decreased roughly by half during first 24 hours and restored to normal value in a polynomial function (p 0.001). The mean Qp/Qs value of all measured data was 1.5 1.0. It showed a fluctuating trend but ranged between 1.0 and 2.0 over time. Interrelationships Between OEF and Other Variables Figure 2 and Table 3 present the generalized linear model correlation. For the assumed variables: SVR showed a close linear correlation with OEF (r 0.78, p 0.91), but PVR showed no correlation with OEF (r 0.04; p 0.65). For the directly measured variables: Svo 2 showed strong correlation with OEF (r 0.78, p 0.0001). There was a tendency that a lower lactate value yielded the higher OEF, but this was not statistically significance (r 0.16, p 0.07). The PAP showed a significant but weak correlation with OEF (r 0.21, p 0.019). Systemic arterial pressure showed no correlation with OEF (r 0.16, p 0.08).

Ann Thorac Surg NAITO ET AL 2010;89:168 73 OXYGEN DELIVERY AFTER SANO NORWOOD 171 Fig 2. Interrelationships are shown between oxygen excess factor (OEF) and the variables of systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), lactate, systemic venous oxygen saturation (Svo 2 ), systemic arterial pressure (AoP), and pulmonary artery pressure (PAP). Comment The Pathophysiology of Sudden Cardiovascular Collapse Sudden death during the early postoperative period is a significant cause of death in patients with HLHS after Norwood palliation. According to the report from the Children s Hospital of Philadelphia, which enrolled 840 patients with the Norwood procedure, approximately half of the hospital deaths occurred within the first 48 hours after first-stage reconstructive surgery [7]. In the large pathologic study of 122 postmortem cases [8], the most important cause of death after stage I palliation for Table 3. Statistical Analysis Using the Generalized Linear Model for Repeated Measures of the Correlations Between Variables Variables Independent Dependent Pearson R R 2 Intercept Coefficient p Value SVR OEF 0.78 0.60 5.61 0.14 0.0001 PVR OEF 0.041 0.002 3.16 0.02 0.65 Svo 2 OEF 0.78 0.60 1.27 0.091 0.0001 Lactate OEF 0.16 0.03 3.36 0.01 0.071 AoP OEF 0.16 0.03 0.91 0.04 0.08 PAP OEF 0.21 0.05 3.94 0.05 0.019 AoP systemic arterial pressure; OEF oxygen excess factor; PAP pulmonary artery pressure; PVR pulmonary vascular resistance; Svo 2 systemic venous oxygen saturation; SVR systemic vascular resistance.

172 NAITO ET AL Ann Thorac Surg OXYGEN DELIVERY AFTER SANO NORWOOD 2010;89:168 73 HLHS was impairment of coronary perfusion, which might be the consequence of elevated SVR with preexisted compromised coronary flow from surgical errors. The distinctive trend of a rapid increase in SVR concomitant with a decrease in PVR, which might account for sudden cardiovascular collapse, was similarly demonstrated in other clinical studies [9]. Oxygen delivery is significantly decreased at 6 postoperative hours unrelated to the Qp/Qs value [10]. With the notion that extreme vulnerability to change of the Qp/Qs ratio occurring early postoperative period was the fate of the Norwood procedure, the maximal SVR reduction took effect for a stable postoperative course. Compared with non-hlhs patients, however, elevated SVR persisted for long time in patients with HLHS undergoing the Norwood procedure [11, 12]. The pathophysiology of persisted elevated SVR was reported to relate the shape of the reconstructed aorta [12]; however, further study must be conducted to address this issue to improve both early and late outcome. Hemodynamic Assessment During the Early Postoperative Period Norwood palliation has historically resulted in high rates of cardiogenic shock, impaired oxygen delivery, endorgan dysfunction, and subsequent death due to the limited cardiac output of the single right ventricle combined with the volatility of parallel circulation. Monitoring during the early postoperative period has historically included a physical examination, blood pressure, heart rate, central venous pressure, and measurement of systemic arterial oxygen saturation using pulse oximetry. People who engaged in postoperative care sought to examine the reliable monitoring methodology for improved outcome. LACTATE. Serial measurements of blood lactate level have been used as a guide for the management of patients after Norwood procedure. Increasing blood lactate level was reported to be an accurate predictor of death or the requirement for extracorporeal membrane oxygenator support for recipients of complex neonatal cardiac operations [13]. VENOUS OXYGEN SATURATION. The analysis of continuous monitoring of Svo 2 as an indicator of tissue anaerobic metabolism revealed that the risk of anaerobic metabolism increased when Svo 2 was below 30% [14]. NEAR-INFRARED SPECTROSCOPY. Near-infrared spectroscopy gives a noninvasive estimate of regional venous oxygen saturation, which can be used like venous oximetry to monitor oxygen supply-demand relationships [15, 16]. OXYGEN EXCESS FACTOR ( ). The OEF is the quotient of systemic oxygen delivery and systemic oxygen consumption and was proposed by Buheitel and colleagues [5] in the setting of postoperative care for congenital heart disease. Barnea and colleagues [6] integrated its concept into the univentricular parallel circulation as a better index to maximize systemic oxygen delivery. Analysis for a Significant Contributory Factor for Systemic Oxygen Delivery The several investigations for postoperative management strategy of the Norwood procedure had convinced us that keeping the SVR low is a more effective measure to maximize systemic oxygen delivery than to manipulate PVR [17]. Li and colleagues [3] conducted minute investigations for postoperative management strategy focusing on the calculation of oxygen delivery with derivatives of Fick s equations. Their methodology was based on the Norwood procedure using a Blalock-Taussig shunt and that measurement of PVR was calculated with inclusion of pressure gradient through a Blalock-Taussig shunt. In addition, the major restriction of pulmonary blood flow after a Norwood operation occurs within the Blalock- Taussig shunt, and PVR itself is relatively unimportant in determining pulmonary blood flow, particularly that relevant to cardiovascular collapse. The validation of these hypotheses was not established in the setting of the Norwood procedure using an RV-PA shunt, however. In the setting of an RV-PA shunt, it was deemed difficult to measure the PVR with the pressure gradient between the RV and the left atrium; therefore, we directly placed an indwelling catheter into PA to obtain an actual value of PAP. The overall results of this study were identical to that of the clinical setting in patients with Norwood procedure using the Blalock- Taussig shunt. The result of this investigation might be subject to misinterpretation that respiratory management has no role in postoperative management. Animal models and clinical experience have demonstrated the effect of respiratory carbon dioxide and oxygen manipulation against PVR [18 20]. We speculate that there was little effect on PVR during the postoperative period of neonatal open heart operations, where high PVR persisted due to detrimental effects of cardiopulmonary bypass. PVR decreased in accordance with the improvement of pulmonary gas exchange function where the partial pressure of oxygen would increase over time. Study Limitations Several study limitations should be raised in this clinical investigation. The limited number of patients eliminated the comparison of investigated study results with actual clinical outcomes. Assumption of VO 2 and Spvo 2 may result in an inaccurate measurement of hemodynamic data. In our study cohort, 3 of the 9 patients had undergone bilateral PA banding before the Norwood procedure. The effect of the bilateral PA banding on subsequent Norwood operation needs further analysis. Conclusion Postoperative management strategy should be aimed to maintain a low SVR, rather than manipulating PVR, to maximize the systemic oxygen delivery after Norwood procedure with Sano modification.

Ann Thorac Surg NAITO ET AL 2010;89:168 73 OXYGEN DELIVERY AFTER SANO NORWOOD 173 References 1. Barnea O, Austin EH, Richman B, Santamore WP. Balancing the circulation: theoretic optimization of pulmonary/ systemic flow ratio in hypoplastic left heart syndrome. J Am Coll Cardiol 1994;24:1376 81. 2. Bradley SM, Atz AM, Simsic JM. Redefining the impact of oxygen and hyperventilation after the Norwood procedure. J Thorac Cardiovasc Surg 2004;127:473 80. 3. Li J, Zhang G, McCrindle BW, et al. Profiles of hemodynamics and oxygen transport derived by using continuous measured oxygen consumption after the Norwood procedure. J Thorac Cardiovasc Surg 2007;133:441 8. 4. Sano S, Ishino K, Kawada M, et al. Right ventriclepulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2003;126: 504 9; discussion 509 10. 5. Buheitel G, Scharf J, Hofbeck M, Singer H. Estimation of cardiac index by means of the arterial and the mixed venous oxygen content and pulmonary oxygen uptake determination in the early post-operative period following surgery of congenital heart disease. Intensive Care Med 1994;20:500 3. 6. Barnea O, Santamore WP, Rossi A, et al. Estimation of oxygen delivery in newborns with a univentricular circulation. Circulation 1998;98:1407 13. 7. Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark BJ, 3rd.Survival after reconstructive surgery for hypoplastic left heart syndrome: a 15-year experience from a single institution. Circulation 2000;102:III136 41. 8. Bartram U, Grunenfelder J, Van Praagh, R. Causes of death after the modified Norwood procedure: a study of 122 postmortem cases. Ann Thorac Surg 1997;64:1795 802. 9. Bradley SM, Simsic JM, McQuinn TC, et al. Hemodynamic status after the Norwood procedure: a comparison of right ventricle-to-pulmonary artery connection versus modified Blalock-Taussig shunt. Ann Thorac Surg 2004;78:933 41; discussion 933 41. 10. Charpie JR, Dekeon MK, Goldberg CS, et al. Postoperative hemodynamics after Norwood palliation for hypoplastic left heart syndrome. Am J Cardiol 2001;87:198 202. 11. Wright GE, Crowley DC, Charpie JR, et al. High systemic vascular resistance and sudden cardiovascular collapse in recovering Norwood patients. Ann Thorac Surg 2004;77: 48 52. 12. Sundareswaran KS, Kanter KR, Kitajima HD, et al. Impaired power output and cardiac index with hypoplastic left heart syndrome: a magnetic resonance imaging study. Ann Thorac Surg 2006;82:1267 75; discussion 1275 7. 13. Charpie JR, Dekeon MK, Goldberg CS, et al. Serial blood lactate measurements predict early outcome after neonatal repair or palliation for complex congenital heart disease. J Thorac Cardiovasc Surg 2000;120:73 80. 14. Hoffman GM, Ghanayem NS, Kampine JM, et al. Venous saturation and the anaerobic threshold in neonates after the Norwood procedure for hypoplastic left heart syndrome. Ann Thorac Surg 2000;70:1515 20; discussion 1521. 15. Hoffman GM, Ghanayem NS, Tweddell JS. Noninvasive assessment of cardiac output. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2005:12 21. 16. Johnson BA, Hoffman GM, Tweddell JS, et al. Near-Infrared Spectroscopy in Neonates Before Palliation of Hypoplastic Left Heart Syndrome. Ann Thorac Surg 2009;87:571 9. 17. Nakano T, Kado H, Shiokawa Y, et al. The low resistance strategy for the perioperative management of the Norwood procedure. Ann Thorac Surg 2004;77:908 12. 18. Mora GA, Pizarro C, Jacobs ML, Norwood WI. Experimental model of single ventricle. Influence of carbon dioxide on pulmonary vascular dynamics. Circulation 1994;90:II43 6. 19. Jobes DR, Nicolson SC, Steven JM, et al. Carbon dioxide prevents pulmonary overcirculation in hypoplastic left heart syndrome. Ann Thorac Surg 1992;54:150 1. 20. Riordan CJ, Randsbeck F, Storey JH, et al. Effects of oxygen, positive end-expiratory pressure, and carbon dioxide on oxygen delivery in an animal model of the univentricular heart. J Thorac Cardiovasc Surg 1996;112:644 54.