Patients at Risk for Low Systemic Oxygen Delivery After the Norwood Procedure

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1 Patients at Risk for Low Systemic Oxygen Delivery After the Norwood Procedure James S. Tweddell, MD, George M. Hoffman, MD, Raymond T. Fedderly, MD, Nancy S. Ghanayem, MD, John M. Kampine, MD, Stuart Berger, MD, Kathleen A. Mussatto, RN, and S. Bert Litwin, MD Departments of Surgery (Cardiothoracic Surgery), Anesthesia, and Pediatrics (Divisions of Cardiology and Critical Care), Children s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin Background. Identification of patients at risk for inadequate systemic oxygen delivery following the Norwood procedure could allow for application of more intensive monitoring, provide for earlier intervention of decreased cardiac output, and result in improved outcome. Methods and Results. Superior vena cava saturation (SvO 2 ) and arteriovenous oxygen content difference were prospectively monitored as indicators of systemic oxygen delivery and recorded hourly for the first 48 hours in 29 of 33 consecutive patients following the Norwood procedure. Risk factors were evaluated using multiple linear regression to determine their impact on SvO 2 and arteriovenous oxygen content difference. Age less than 8 days, weight less than 2.5 kg, aortic atresia, and prolonged cardiopulmonary bypass time were risk factors for low SvO 2 and wide arteriovenous oxygen content difference (p < 0.05). Phenoxybenzamine and increasing time after operation were associated with higher SvO 2 and narrower arteriovenous oxygen content difference (p < 0.05). Thirty-day survival was 97% and hospital survival was 94%. The earliest death occurred on postoperative day 20. Survival to bidirectional cavopulmonary shunt was 77%. Preoperative mechanical ventilation was the only risk factor identified for late death. Conclusions. Aortic atresia, low weight, younger age, and prolonged cardiopulmonary bypass, previously identified risk factors for mortality, were associated with decreased SvO 2 and narrower arteriovenous oxygen content difference in the early postoperative period. The impact of this hemodynamic vulnerability on mortality was minimized by continuous SvO 2 monitoring. (Ann Thorac Surg 2000;69:1893 9) 2000 by The Society of Thoracic Surgeons Although results from stage I palliation for hypoplastic left heart syndrome (HLHS) are improving, early mortality remains at 25% even at experienced centers [1 3]. The mechanism of death is presumed to be inadequate systemic oxygen delivery [4 6]. Postoperative management strategies that target systemic oxygen delivery and a balanced circulation have achieved improved results [7 11]. Recently, small oximetric catheters have become available that are suitable for use in the neonate. Starting in July of 1996 we began routine placement of oximetric catheters in the superior vena cava of patients following the Norwood procedure to identify periods of low systemic oxygen delivery. A prospective database was developed containing demographic and hemodynamic data including superior vena cava oxygen saturation. This study is an evaluation of that database to identify risk factors for decreased systemic oxygen delivery in the early postoperative period following the Norwood procedure. Accepted for publication Dec 9, Address reprint requests to Dr Tweddell, Division of Cardiothoracic Surgery, Children s Hospital of Wisconsin, 9000 W Wisconsin Ave, MS 715, Milwaukee, WI 53226; jstwedde@mcw.edu. Material and Methods Between July of 1996 and September 1998, 33 patients underwent a Norwood procedure at the Children s Hospital of Wisconsin. Superior vena cava saturation was continuously monitored (4F oximetric catheter; Abbott Labs, North Chicago, IL) and used as an approximation of mixed venous oxygen saturation (SvO 2 ). Hourly hemodynamic data were also collected for the first 48 hours, as were demographic and survival data. All patients underwent a Norwood procedure consisting of relief of arch obstruction, anastomosis of the pulmonary artery to the ascending aorta combined with augmentation of the ascending aorta, transverse arch and proximal descending aorta with pulmonary homograft, placement of a systemic-to-pulmonary artery shunt, and creation of a nonrestrictive atrial septal defect. The systemic-topulmonary artery shunt was constructed from the innominate artery to the central pulmonary artery confluence. All patients in this study had single ventricle anatomy. Postoperative management was standardized, guided by the oximetric data and aimed at achieving adequate systemic oxygen delivery defined as an SvO 2 greater than or equal to 50%, an arteriovenous oxygen content difference ( AVO 2 ) less than or equal to 5 ml/dl with a pulmonary-to-systemic flow ratio near 1. Our strategy to 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 1894 TWEDDELL ET AL Ann Thorac Surg OXYGEN DELIVERY AFTER NORWOOD PROCEDURE 2000;69: Table 1. Patient Characteristics Patient Characteristic (n 33) optimize systemic oxygen delivery primarily targeted a reduction of systemic vascular resistance with the use of vasodilators rather than an elevation of pulmonary vascular resistance through the use of ventilator management. This study spanned the introduction of phenoxybenzamine (POB), an irreversible -blocker, to our routine perioperative management. The last 26 patients received POB, 0.25 mg/kg in the cardiopulmonary bypass (CPB) circuit at commencement of CPB. At the completion of the Norwood procedure before weaning from CPB, nitroprusside or norepinephrine (used only in patients receiving POB) infusions were adjusted to target a systemic vascular resistance index of 10 Wood units, corresponding to a mean arterial pressure of at least 30 mm Hg at a flow of 3.0 L min 1 m 2. Norepinephrine was used for its -agonist effect, to overcome any excessive vasodilatation because of POB. All patients underwent modified ultrafiltration after successful separation from CPB. All patients received neuromuscular blockade and a continuous of fentanyl for the first 12 hours after admission to the intensive care unit. In addition, all patients were placed in servo-controlled infant warmers (Ohio, Infant Warmer System; Ohmeda Inc, Columbia, MD) and maintained at normothermia. A patient with a low SvO 2 and wide AVO 2 was managed first by making certain of an atrioventricular rhythm, augmenting preload to a central venous pressure as high as 12 mm Hg, adding afterload reduction if the mean arterial pressure was greater than 45 mm Hg and finally, increasing inotropic support. All patients received milrinone (50 g/kg loading dose) before weaning from CPB, followed by a continuous infusion of 0.5 g kg 1 min 1 and dopamine at no more than 3 g kg 1 min 1.If additional inotropic support was required, epinephrine was added. Control of pulmonary blood flow through manipulation of mechanical ventilation was used only in patients who did not receive POB. If arterial saturation (SaO 2 ) was elevated and SvO 2 remained low (elevated pulmonary-to-systemic flow ratio), the fraction of inspired oxygen was weaned toward 21% and hypercapnia (partial pressure of carbon dioxide 45 mm Hg and 60 mm Hg) was permitted. The addition of CO 2 to the inspired gas was not used. Preoperative (age at operation, weight, anatomic subtype, mechanical ventilation and inotropic support) and operative (shunt size, duration of hypothermic circulatory arrest [HCA], and duration of CPB) factors were evaluated for their impact on postoperative oxygen delivery. Previously, we have reported the impact of POB on the systemic oxygen delivery in a subset of patients following the Norwood procedure [11]. Because of the prior documentation of the significance of POB on early postoperative hemodynamics, we included POB as a potential independent risk factor in this study. Shunt size was normalized as cross-sectional area divided by patient body weight. Indicators of systemic oxygen delivery included SvO 2 and AVO 2. Arteriovenous oxygen content difference was calculated using the formula: AVO 2 (SaO 2 SvO 2 ) times; 1.34 hemoglobin. Potential risk factors for decreased systemic oxygen delivery were entered into stepwise multiple linear regression and retained when p was less than 0.2. Continuous variables were dichotomized at either the 25th percentile (weight), 50th percentile (normalized shunt size) or 75th percentile (age, CPB duration, HCA duration), to create categorical variables. The effect of categorical variables was then evaluated individually with two-way analysis of variance. This was corrected for repeated measures factor including post-hoc Bonferroni test for between groups comparison (repeated measures analysis of variance). Risk factors for decreased systemic oxygen delivery were then evaluated for their impact on late survival. Survival curves were calculated using the Kaplan-Meier method and compared using the log rank test. Statistical analysis was performed using STATA software (College Station, TX) and differences were considered significant when p less than Results Mean Standard Error Range Age (days) Weight (kg) CPB time (min) HCA time (min) Normalized shunt size (mm 2 /kg) CPB cardiopulmonary bypass, not including duration of hypothermic circulatory arrest; HCA hypothermic circulatory arrest. Thirty-day survival was 97% (32 of 33 patients) and hospital survival was 94% (31 of 33). The early death occurred in an infant of a diabetic mother patient with aortic atresia and severe ventricular hypertrophy. The early postoperative course of this patient was marked by restrictive cardiac physiology. This patient was placed on extracorporeal membrane oxygenator support at postoperative hour 9. Although he was successfully weaned from extracorporeal membrane oxygenator, he died on postoperative day 20. Hemodynamic data on extracorporeal membrane oxygenator support were excluded from analysis. A second hospital death occurred in a patient with aortic atresia who, after a benign early postoperative course, sustained a cardiac arrest and died on postoperative day 50. Patient characteristics are summarized in Table 1. Two patients required two periods of HCA with their total HCA time included in the average and range reported in Table 1. The anatomic subtype of HLHS is summarized in Table 2. Aortic atresia was present in 58% (19 of 33) of the patients. Preoperative inotropic support was used in 39% (13 of 33) and preoperative mechanical ventilation in 67% (22 of 33 patients). Either mechanical ventilation or inotropic support was used in 70% (23 of 33) and both forms of preoperative support were used in 36% (12 of 33 patients). An attempt was made to match shunt size to body

3 Ann Thorac Surg TWEDDELL ET AL 2000;69: OXYGEN DELIVERY AFTER NORWOOD PROCEDURE 1895 Table 2. Anatomy Anatomy (n 33) Number HLHS (n 31) AA/MA 15 AA/MS 3 AA/unbal AVC 1 AS/MA 3 AS/MS 9 Single LV with TGA (n 2) DILV with l-tga 1 TA with d-tga 1 AA aortic atresia; AS aortic stenosis; unbal AVC unbalanced atrioventricular canal; d dextro; DI double inlet; HLHS hypoplastic left heart syndrome; l levo; LV left ventricle; MA mitral atresia; MS mitral stenosis; TA tricuspid atresia; TGA transposition of the great vessels. weight. Two patients weighing 2.6 and 2.8 kg received a 3.0-mm diameter shunt. One patient more than 4 weeks of age and weighing 4.0 kg received a 5.0-mm shunt. Fourteen patients weighing kg (range, 2.39 to 3.30 kg) received a 3.5-mm shunt and 16 patients weighing kg (range, 2.7 to 4.1 kg) received a 4.0-mm shunt. Continuous SvO 2 monitoring was possible in 29 of 33 patients. In these 29 patients, there were 1,357 hourly data points available for analysis. Anatomic and technical factors prevented us from obtaining SvO 2 data in 4 patients. There were no complications, including thrombosis, bleeding necessitating reoperation, or line infection, related to the use of the oximetric catheter. Postoperative inotropic support was common. In addition to the routine use of milrinone and low-dose dopamine outlined in the methods section, 31 of 33 patients received continuous epinephrine infusions at a median dose of 0.07 g kg 1 min 1. Continuous infusions of Table 3. Impact of Risk Factors on Early Systemic Oxygen Delivery (by Multiple Linear Regression) Variables SvO 2 (n 1,357, R ) AVO 2 (n 1,357, R ) Coef. p Value Coef. p Value Risk factors for 2SvO 2 and 1 AVO 2 Weight 2.5 kg Aortic atresia HCA 77 min CPB 158 min Risk factors for 1SvO 2 and 2 AVO 2 POB Preop inotropes Age 8 days Hour postop Constant AVO 2 atrioventricular oxygen content; Coef. coefficient; CPB cardiopulmonary bypass; HCA hypothermic circulatory arrest; POB phenoxybenzamine; postop postoperative; Preop preoperative; SvO 2 superior vena cava saturation. Fig 1. Patients with aortic atresia had lower superior vena cava saturation (SvO 2 ) (A) (p 0.04, repeated measures analysis of variance) and wider arteriovenous oxygen content ( AVO 2 ) (B) (p 0.006, repeated measures analysis of variance) during the first 48 hours after the Norwood procedure. norepinephrine at a median dose of 0.03 g kg 1 min 1 were used in 14 of the 26 patients receiving POB. The impact of risk factors on early postoperative systemic oxygen delivery is summarized in Table 3. Age less than 8 days, aortic atresia, weight less than 2.5 kg, and prolonged CPB time were risk factors for decreased systemic oxygen delivery. The use of POB and time from operation were risk factors for improved systemic oxygen delivery. The duration of HCA was a risk factor for only decreased SvO 2 but not wide AVO 2. The impact of aortic atresia, age, and CPB duration on systemic oxygen delivery can be seen in Figures 1 to 3. Univariate analysis showed that larger normalized shunt size was associated with a higher SvO 2 and narrower AVO 2 during hours 4 to 24 (p 0.05, repeated measures analysis of variance) (Fig 4). Multiple linear regression did not identify an independent impact of shunt size on SvO 2 or AVO 2. Actuarial survival, including operative mortality, for the entire group was 77% at 200 days and is equal to the survival rate to bidirectional cavopulmonary shunt (Fig 5). There were no deaths at the time of bidirectional cavopulmonary shunt and all patients undergoing bidirectional cavopulmonary shunt are still alive. The most recent 20 patients have a 200-day survival of 90%. The only risk factor for late death was preoperative mechanical ventilation (p , by log rank) (Fig 6). Aortic atresia was not a risk factor for late mortality (Fig 7).

4 1896 TWEDDELL ET AL Ann Thorac Surg OXYGEN DELIVERY AFTER NORWOOD PROCEDURE 2000;69: Fig 2. Age less than 8 days was associated with a borderline lower superior vena cava saturation (SvO 2 ) (A) (p 0.05, repeated measures analysis of variance) and wider arteriovenous oxygen content ( AVO 2 ) (B) (p 0.01, repeated measures analysis of variance) during the first 48 hours after the Norwood procedure. Comment Fig 3. Prolonged cardiopulmonary bypass time (CPB) ( 158 minutes) resulted in a lower superior vena cava saturation (SvO 2 ) (A) (p 0.05 hours 2 to 8, repeated measures analysis of variance) and wider arteriovenous oxygen content ( AVO 2 ) (B) (p 0.05 hours 3, 4, 8, 9, and 14, repeated measures analysis of variance) after the Norwood procedure. Postoperative management of the patient following the Norwood procedure is complicated by the limited reserve of the neonatal single ventricle, as well as the parallel arrangement of the systemic and pulmonary circuits. Excessive pulmonary blood flow at the expense of systemic blood flow is a common postoperative scenario that can lead to death [4, 6]. Analysis of SvO 2 and SaO 2 data are the only methods to differentiate the possible causes of decreased systemic oxygen delivery, permitting early intervention. Although the identification of lactic acidosis has been suggested as a clinically useful indicator of decreased systemic oxygen delivery, the development of lactic acidosis predictably lags the period of inadequate tissue oxygen delivery. Uncomplicated survivors of the Norwood procedure have an elevated lactic acid in the early postoperative period [12]. Furthermore, abrupt life-threatening decreases in systemic oxygen delivery can occur and lead to death before lactic acid becomes elevated [13]. Previously, we have identified episodes of abrupt decreases in the SvO 2 of patients after the Norwood procedure [11]. Despite routine invasive monitoring these episodes would not be identified without the oximetric catheter and the rapidity with which these episodes occurred makes intermittent sampling to identify lactic acidosis unlikely to be fruitful. We have not experienced any complications related to the use of the oximetric catheter; specifically, we have not had any thrombosis or significant bleeding. The purpose of this study was to identify risk factors for low systemic oxygen delivery, which will contribute to mortality without early recognition and treatment. Death following the Norwood procedure likely occurs in patients with critically low levels of systemic oxygen delivery who might otherwise survive but are subjected to additional, possibly random stresses. Therefore, death as the only outcome end point will not identify all patients at increased risk for mortality. Aortic atresia has been identified as a risk factor for decreased early and late survival following the Norwood procedure [14, 15]. Although aortic atresia was not a risk factor for either early or late mortality in this series, it was an independent risk factor for decreased systemic oxygen delivery in the early postoperative period (Fig 1). In addition, it is noteworthy that both hospital deaths in this series occurred in patients with aortic atresia, although outside of the period of continuous SvO 2 monitoring. Aortic atresia represents the most extreme form of HLHS. These patients have only a single right ventricle

5 Ann Thorac Surg TWEDDELL ET AL 2000;69: OXYGEN DELIVERY AFTER NORWOOD PROCEDURE 1897 Fig 6. Actuarial survival among patients who were supported with preoperative mechanical ventilation was significantly lower than patients who were not mechanically ventilated in the preoperative period, p , by log rank. Fig 4. Larger shunt size was associated with increased superior vena cava saturation (SvO 2 ) (A) and narrower arteriovenous oxygen content ( AVO 2 ) (B) (p 0.05 hours 4 to 24, repeated measures analysis of variance). When entered into multivariate linear regression, shunt size was not an independent predictor of superior vena cava saturation (SvO 2 ) or arteriovenous oxygen content ( AVO 2 ). These data indicate that within the range of shunt size used in this study, larger shunt size did not adversely affect systemic oxygen delivery. without the contribution of even a small left ventricle and total ventricular mass may be decreased. The ascending aorta can be quite small complicating the anastomosis of the proximal ascending aorta to the pulmonary artery, resulting in coronary insufficiency. In addition, coronary abnormalities have been identified in patients with aortic atresia [16]. Interestingly, aortic atresia was not a risk factor for mortality before bidirectional cavopulmonary shunt suggesting that if early risk can be overcome, late survival is good (Fig 7). Low birth weight neonates have been reported to be at increased risk for mortality following the Norwood procedure [17]. We found that lower weight patients were at increased risk for decreased systemic oxygen delivery. The adverse effects of CPB, HCA, as well as technical issues related to the operation are likely to have a greater impact in the small patient. Lower weight was not a risk factor for late survival and therefore, within the weight range evaluated in this study, lower weight should not be used to exclude patients from Norwood palliation. Cardiopulmonary bypass results in a whole body inflammatory response resulting in multiorgan dysfunction. The pulmonary and systemic endothelium are injured and vasoactive products are formed resulting in alterations of vasomotor tone, including an increase in the systemic vascular resistance that may contribute to difficulties achieving a balanced circulation and adequate systemic oxygen delivery in the postoperative Norwood patient [3, 11, 18, 19]. It is not surprising that prolonged CPB has an adverse impact on patients following the Norwood procedure (Fig 3). Prolonged circulatory arrest time results in injury to many organ systems most notably the central nervous system and has been reported to be a risk factor for death following the Norwood proce- Fig 5. Actuarial survival including early deaths. Survival to bidirectional cavopulmonary shunt was 77%. Fig 7. Actuarial survival and the impact of aortic atresia. There was not a significant difference in survival to bidirectional cavopulmonary shunt between patients with and without aortic atresia.

6 1898 TWEDDELL ET AL Ann Thorac Surg OXYGEN DELIVERY AFTER NORWOOD PROCEDURE 2000;69: dure [3]. Prolonged duration of HCA was predictive of decreased SvO 2, but not a wide AVO 2, indicating only a marginal impact on systemic oxygen delivery. Prolonged HCA duration is to be avoided but within the range of duration of HCA in this study, which is within the range reported by other researchers, there was only a marginal impact on early postoperative hemodynamics [10]. The preoperative status of patients with HLHS has been reported to have an impact on outcome following the Norwood procedure [3, 14, 15]. Patients in whom the diagnosis is made early in life or even prenatally may have a benign preoperative course. Patients presenting later with impending ductal closure may require intense and prolonged resuscitation. The degree of preoperative metabolic acidosis has been reported to predict poor outcome after surgical intervention [14, 15]. In this study we looked at the use of preoperative support in the form of mechanical ventilation or preoperative inotropic support as risk factors for decreased systemic oxygen delivery in the postoperative period. Neither mechanical ventilation nor preoperative inotropic support was found to be a risk factor for decreased systemic oxygen delivery. In fact, preoperative inotropic support was found to be associated with a higher postoperative SvO 2 and borderline decrease in AVO 2. The preoperative status of the neonate with HLHS has been used to select candidates for the Norwood procedure. Our data would indicate that preoperative support does not by itself increase the risk of decreased systemic oxygen delivery in the early postoperative period and therefore, should not be used as a selection tool. Although patients older than 1 month of age have been shown to be at increased risk following the Norwood procedure, little data are available to determine the optimal timing of operation of younger patients [15, 20, 21]. The indications for the timing of operation in this study were not determined. Younger age was determined to be a risk factor for decreased systemic oxygen delivery, but may be a surrogate for other factors. Patients presenting and undergoing operation at an earlier age may have inherent differences making them more likely to have decreased systemic oxygen delivery such as poor myocardial function or lower pulmonary vascular resistance. In this study only 2 patients were more than 2 weeks of age and therefore, the impact of older age on outcome could not be determined. Despite these limitations we found that age less than 8 days is a risk factor for decreased systemic oxygen delivery in the early postoperative period (Fig 3). The identification of increased pulmonary blood flow at the expense of systemic blood flow has led some surgeons to construct smaller systemic-to-pulmonary artery shunts. Whether or not smaller shunts improve systemic oxygen delivery is unknown. In this study, larger shunts were associated with a narrower AVO 2 and higher SvO 2 in the early postoperative period (Fig 4). Although multiple linear regression analysis did not identify shunt size as an independent predictor of systemic oxygen delivery, the data indicate that larger shunt size was not associated with decreased systemic oxygen delivery. The optimal size shunt for patients undergoing the Norwood procedure has not been identified, but within the range of shunts used in this series, larger shunt size combined with management to reduce systemic vascular resistance resulted in increased systemic oxygen delivery. Survival to bidirectional cavopulmonary shunt, including early mortality was 77% (Fig 5). Only preoperative support in the form of mechanical ventilation was a risk factor for late mortality (Fig 6). Patients who require preoperative mechanical ventilation for resuscitation and stabilization frequently have difficulties with excessive pulmonary blood flow and decreased systemic oxygen delivery and thus, these patients may be more prone to develop circulatory imbalance even after stage I palliation. Risk factors for decreased systemic oxygen delivery in the early postoperative period were not the same as risk factors for late mortality. Our findings support the suggestion that strategies to improve early postoperative survival are not simply delaying inevitable mortality and that improvements in early postoperative outcome should improve overall survival [4, 22]. Limitations of this Study Although the data in this study were prospectively collected, interventions were not randomized or blinded. The evaluated risk factors were chosen for clinical and historic reasons and the significance of important covariates cannot be assessed by this study. For hemodynamic end points, only SvO 2 and AVO 2 were analyzed; however, SvO 2 and AVO 2 are probably the best indicators of the adequacy of postoperative hemodynamic management. In addition, very few studies exist that evaluate or include indicators for systemic oxygen delivery in the postoperative management in patients following the Norwood procedure. By limiting the assessment to two outcome variables, we limited the potential for error because of multiple comparisons. In conclusion, previously identified risk factors for early mortality following the Norwood procedure, such as aortic atresia, low weight, younger age, prolonged CPB, and HCA duration were risk factors for decreased systemic oxygen delivery in the early postoperative period. Decreased systemic oxygen delivery is likely to be a significant mechanism of death. The impact of these risk factors on early mortality can be ameliorated with the use of continuous SvO 2 monitoring. Furthermore, the addition of POB to a strategy to achieve circulatory balance will result in improved systemic oxygen delivery in the early postoperative period. Decreasing early mortality following the Norwood procedure through intensive early monitoring will improve long-term outcome of palliation for HLHS. References 1. Murdison KA, Baffa JM, Farrell PE, et al. Hypoplastic left heart syndrome, outcome after initial reconstruction and

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