Regional Low-Flow Perfusion Versus Circulatory Arrest in Neonates: One-Year Neurodevelopmental Outcome

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1 Regional Low-Flow Perfusion Versus Circulatory Arrest in Neonates: One-Year Neurodevelopmental Outcome Karen J. Visconti, PhD, David Rimmer, MS, Kimberlee Gauvreau, ScD, Pedro del Nido, MD, John E. Mayer, Jr, MD, Ikou Hagino, MD, and Frank A. Pigula, MD Departments of Cardiovascular Surgery and Cardiology, Children s Hospital, and Department of Surgery, Harvard Medical School, Boston, Massachusetts Background. Regional low-flow perfusion of the brain is a bypass technique commonly used during stage 1 reconstruction in neonates with hypoplastic left heart syndrome and related variants. The neurodevelopmental outcome of these children is unknown. Methods. Twenty-nine infants (22 boys, 7 girls) with hypoplastic left heart syndrome or variant requiring single ventricle palliation and aortic arch reconstruction were studied between 1999 and Mental Developmental Index (MDI) and Psychomotor Developmental Index were assessed using Bayley Scales of Infant Development and correlated with intraoperative and perioperative variables. Results are reported as mean standard deviation. Results. Average age at stage 1 operation and at bidirectional Glenn was 7 8 days and months, respectively. The MDI was in the low average range ( ). The Psychomotor Developmental Index was in the mildly delayed range ( ). Regional low-flow perfusion was used in 31% (9 of 29 patients), with an average circulatory arrest time of minutes. Deep hypothermia and circulatory arrest was used as the primary operative strategy in 69% of patients (20 of 29 patients), with an average circulatory arrest time of minutes (p 0.003). No differences in MDI or Psychomotor Developmental Index scores were observed between the regional low-flow perfusion and non regional low-flow perfusion groups (MDI, versus ; p 0.93, respectively; Psychomotor Developmental Index, versus ; p 0.93, respectively). Lowest operative temperature (<16 C) and birth order (<2 versus >3) significantly related to MDI (89.6 versus 72.8; p 0.047). Conclusions. At 1 year of age, neurodevelopmental outcomes of patients undergoing stage 1 using regional low-flow perfusion were similar to outcomes observed in children exposed to circulatory arrest. The association of birth order and MDI suggests that early intervention may benefit these patients. (Ann Thorac Surg 2006;82: ) 2006 by The Society of Thoracic Surgeons Current survival of stage 1 palliation for hypoplastic left heart syndrome and related variants now approach 90% in dedicated centers [1 3]. As a consequence of improved survival, attention is focusing on the neurodevelopmental outcomes of these survivors. Traditionally these surgeries have been performed during deep hypothermic circulatory arrest (DHCA). Prolonged DHCA is associated with brain injury, but the safe duration of circulatory arrest remains unknown. In the Boston Circulatory Arrest Study of neonates undergoing repair of transposition of the great arteries, neonates repaired during DHCA showed significant developmental deficits at 1 year when compared with children repaired during low-flow cardiopulmonary bypass (CPB) Accepted for publication June 9, Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30 Feb 1, Address correspondence to Dr Pigula, Department of Cardiovascular Surgery, Children s Hospital, 300 Longwood Ave, Boston, MA 02115; frank.pigula@cardio.tch.harvard.edu. [4]. Some of these deficits persisted, and at age 4 years those exposed to DHCA had persistent deficits in motor skills [5]. Eight-year follow-up of this cohort documented persistent deficits in measures of motor function, apraxia, visual motor tracking, and phonologic awareness in the DHCA group, whereas those repaired during low-flow CPB exhibited more impulsive behaviors [6]. Subanalysis of these data suggests that neurodevelopmental outcomes for these patients were not adversely affected unless the duration of DHCA exceeded a threshold of 41 minutes [7]. Thus, methods by which DHCA can be reduced, or even avoided, are of interest. The introduction of regional low-flow perfusion (RLFP) into clinical practice has provided an alternative to DHCA, and has been adopted by many centers. Some of these centers have reported improved stage 1 survival with the technique, but none have reported developmental data. The association between DHCA and later development is still an active area of investigation. At this institution, 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 2208 VISCONTI ET AL Ann Thorac Surg REGIONAL PERFUSION AND NEURODEVELOPMENTAL OUTCOME 2006;82: we have developed a database registry tracking the neurodevelopmental progress of children with congenital heart disease [8 10]. Although the use of DHCA alone has not been found to be predictive of neurodevelopmental outcomes of children at 5 years of age, the duration of DHCA exposure was predictive. Exposure to a cumulative duration of DHCA of more than 33 minutes was associated with lower IQ scores at 5 years of age [8]. Similar findings have been reported in previous reports among children with both single [8, 11 13] and biventricular anatomy [4]. Because of these findings, surgical techniques designed to reduce or eliminate the need for DHCA have been developed. Although there have been animal models that have shown significant neurologic and histopathologic advantage to RLFP, improved neurodevelopmental outcomes in patients have not been demonstrated. The purpose of the current study was performed to compare the 1-year neurodevelopmental outcomes of children undergoing the Norwood operation with RLFP versus DHCA. Patients and Methods Patients This is a retrospective study consisting of infants who underwent the Norwood procedure for repair of single ventricle at Children s Hospital (Boston, MA) between June 1999 and April Infants were invited to participate in a developmental follow-up examination if they underwent the Norwood procedure at Children s Hospital, Boston, and were 1 year of age at time of assessment, English-speaking, residents of New England, and free of additional congenital syndromes known to severely impact cognition (ie, Down syndrome). We identified 49 patients who met the criteria. Of these eligible patients, 29 (59%) participated. Nine (18%) refused to participate, and 11 (22%) were unavailable or failed to respond. This study was approved by the Children s Hospital Committee on Clinical Investigation and was conducted in accordance with institutional guidelines. Informed consent was obtained from the parents of all participating patients. Medical Record Review Information was obtained from each patient s medical records concerning anatomic diagnosis, age at repair, and use of RLFP or right ventricle to pulmonary artery conduit (Sano modification). The following intraoperative variables were obtained: duration of CPB, duration of hypothermic circulatory arrest, minimum hematocrit during CPB, lowest rectal temperature attained during CPB, duration of hospital stay, and days from surgery until removal of feeding tube. Perfusion Methods Perfusion management (DHCA or RLFP) was determined at the discretion of the operating surgeon. Blood gas management is by the ph stat technique. All patients received methylprednisolone (Solu-Medrol), phentolamine, and furosemide (Lasix) during cooling. When used, DHCA was initiated at a rectal temperature of 18 C after at least 20 minutes of systemic cooling. Regional low-flow perfusion rates were maintained between 30 and 40 ml kg 1 min 1, maintaining a left radial artery pressure between 20 and 25 mm Hg. Developmental Assessment All patients were administered the Bayley Scales of Infant Development [14]. The Bayley Scales of Infant Development is a standardized measure used to assess infant cognitive and gross motor development. This test yields two scales: Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI). The mean score is 100, with a standard deviation of 15. Information on family characteristics was obtained from interviews with the parents. Parental IQ was assessed with the Kaufman Brief Intelligence Test [15]. Socioeconomic status was determined with the Hollingshead Four Factor Index of Social Status [16]. This index calculates socioeconomic status on the basis of parental occupation and educational level. Parental occupations are stratified into nine categories (eg, 1 for laborer, 6 for technician, and 9 for a professional). Education is scored on a scale of 1 to 7 (eg, 1 for 7th-grade education and 7 for graduate degree). All evaluations were conducted by the same psychologist (K.J.V) at Boston Children s Hospital. Statistical Analysis Patient and surgical characteristics were compared for individuals in the RLFP group and DHCA group using the two-sample Student s t test. Mean MDI and PDI scores were compared across categories using the twosample Student s t test for two categories and one-way analysis of variance for three or more categories. If a variable was found to be significantly associated with MDI or PDI, linear regression analysis was used to examine the relationship, with adjustment for parental IQ or socioeconomic status. Groups were compared with respect to surgical characteristics and developmental outcome by the use of Student s t tests for continuous variables. Results Patient Characteristics Of the 29 patients, 23 were diagnosed with hypoplastic left heart syndrome and 6 had single ventricles with aortic arch obstruction. The median age at time of operation was 5 days (range, 2 to 34 days). Regional low-flow perfusion was used in 9 patients (31%). Mean hypothermic circulatory arrest time in RLFP patients was 23.5 minutes (standard deviation, 13.4 minutes). The Sano modification was used in 7 patients (24%). Patients who underwent RLFP received significantly shorter periods of hypothermic circulatory arrest than patients in the non- RLFP group (23.5 minutes versus 44.3 minutes; p 0.003).

3 Ann Thorac Surg VISCONTI ET AL 2006;82: REGIONAL PERFUSION AND NEURODEVELOPMENTAL OUTCOME 2209 Table 1. Comparison of Medical Variables of Regional Low-Flow Perfusion and Hypothermic Circulatory Arrest Patients Regional Low-Flow Perfusion Group (n 9) Hypothermic Circulatory Arrest Group (n 20) Variable Mean SD Mean SD p Value Stage 1 Age at repair (days) Duration of HCA (min) Duration of CPB (min) Temperature (coldest, C) Hematocrit (%, minimum) Length of hospital stay (days) Stage 2 Age at repair (months) Duration of CPB Temperature (coldest, C) Hematocrit (%, minimum) Length of hospital stay (days) CPB cardiopulmonary bypass; HCA hypothermic circulatory arrest; SD standard deviation. A summary of additional medical variables comparing the two groups is presented in Table 1. All 29 patients had undergone the bidirectional Glenn procedure at the time of the evaluation. The mean age at bidirectional Glenn procedure was 6 months (range, 2 to 10 months). In general, families of patients who had undergone the Norwood procedure were intact, white, and middle class (Table 2). There were 22 male (76%) and 7 female (24%) patients. Twenty-four patients (83%) were first or second in birth order. Developmental Testing MENTAL INDEX. Mean MDI score was within 1 standard deviation ( 15) of the normative population mean of 100. In the group as a whole, mean MDI was 87.7 (standard deviation, 13.2), representing performance in the low average range (Fig 1A). Age at operation, duration of DHCA, duration of CPB, lowest hematocrit, and postoperative hospital stay did not correlate with MDI scores. Table 2. Sociodemographic Variables (n 29) Variable Mean SD Parents marital status (% married) 93% Ethnicity (% white) 66% Birth order (% first born) 45% Sex (% males) 76% Social class (mean SD) a Parental IQ (mean SD) b Composite Vocabulary Matrices a Score on the Hollingshead Four Factor Index of Social Class, with higher score indicating higher social class. b Score on the Kaufman Brief Intelligence Test. SD standard deviation. Significant differences in MDI scores were not found to exist between patients who underwent RLFP and those who did not (mean MDI, 88.0 versus 87.6; p 0.93). Infants who underwent the Sano did not perform significantly different from those who did not undergo the Sano (92.4 versus 86.2; p 0.20). Patients who underwent temperatures lower than 16 C during surgery performed less well than patients who underwent higher temperatures (mean MDI, 82.0 versus 92.0, respectively; p 0.05). Birth order significantly predicted MDI scores. Patients who were first or second born scored higher than children whose ordinal position in the family was 3 or greater. Mean MDI for first and second born children was 89.6 (standard deviation, 12.1). Mean MDI of third or later born was 72.8 (standard deviation, 11.2; p 0.05). PSYCHOMOTOR INDEX. Mean PDI was 75.2 (standard deviation, 14.5), indicating performance in the mildly delayed range (Fig 1B). Duration of hypothermic circulatory arrest, duration of CPB, coldest temperature, lowest hematocrit, and postoperative hospital stay did not correlate with PDI scores. There were no differences in PDI scores between patients who underwent RLFP and those who did not (mean PDI, 75.5 versus 75.0; p 0.93). Age at repair was predictive of PDI scores. Patients who underwent surgery before 7 days of age received higher PDI scores than patients who underwent repair when they were 7 days or older (78.2 versus 67.1, respectively; p 0.05). Birth order approached significance for predicting PDI scores. First and second born children performed better than later born children (76.4 versus 63.8; p 0.07). Comment Regional low-flow perfusion falls into a category of CPB management techniques designed to reduce the neuro-

4 2210 VISCONTI ET AL Ann Thorac Surg REGIONAL PERFUSION AND NEURODEVELOPMENTAL OUTCOME 2006;82: Fig 1. (A) Mental Development Index for children at 1 year of age after stage1 palliation during regional low-flow perfusion (RLFP) and deep hypothermia circulatory arrest (DHCA). There were no differences between groups, and, on average these children functioned at the low average range. (B) Psychomotor Developmental Index for children at 1 year of age after stage1 palliation during regional low-flow perfusion and deep hypothermia circulatory arrest. There were no differences between groups, and, on average these children functioned in the mildly delayed range. morbidity associated with DHCA. Others include intermittent cerebral perfusion, in which brief periods (15 minutes) of circulatory arrest are interrupted for a short period (1 to 10 minutes) of cerebral perfusion. Animal studies of both techniques suggest that they are effective in maintaining both cerebral metabolism and cerebral cellular architecture [17 20]. Although there are no clinical reports describing the use of intermittent cerebral perfusion, clinical series have reported that RLFP is a safe technique that appears to provide physiologically significant cerebral and somatic circulatory support [21, 22]. Some groups have reported that RLFP improves 1-month and 1-year survival after single ventricle palliation in the neonate [23]. Children born with single ventricle physiology have been reported to have IQ scores in the average range, although significantly lower than the general population [8, 13, 24]. In a previous publication from this institute, we reported IQ scores in our sample of 5-year-old single ventricle patients to be 89.9 [8]. However, few studies have examined the neurodevelopment of children younger than school age, and none examined the impact of the use of RLFP. The findings from this study reveal that infants with single ventricles perform in the low to below average range in development. Development seems particularly impaired in the area of gross motor development. This finding is in accordance with findings from the Boston Circulatory Arrest Trial, which reported that patients who underwent circulatory arrest as a predominant support strategy were at a greater risk of delayed motor development at 1 year at age [1]. The connection between duration of DHCA and delays in development has been reported by others in the literature [4 10]. However, the connection has not been uniform. In the present study, we failed to find a significant association between duration of DHCA and scores on a test of infant development. The lack of differences in neurodevelopmental outcomes at 1 year may be attributable to several factors. Potential relationships may not be apparent owing to small sample size or selection bias. Alternatively, it should be recognized that, despite using RLFP, this group still experienced an average DHCA time of 23 minutes, and reflects differences in technique among the surgical staff. This substantial period of DHCA among RLFP patients may obscure the potential advantages of the technique. This explanation seems unlikely, however, as DHCA time was not related to MDI or PDI by multivariate analysis. Finally, one must consider the possibility that the intraoperative CPB management of these patients may be unable to significantly influence subsequent neurodevelopmental achievement. There is an increasing awareness that patients born with severe congenital heart defects demonstrate significant anatomic and metabolic cerebral derangements preoperatively. Using magnetic resonance imaging, Licht and colleagues [25] have reported structural brain lesions occur in 53% of neonates, as well as decreased cerebral blood flow with abnormal carbon dioxide reactivity. Dent and associates [26] performed preoperative and postoperative magnetic resonance imaging on children undergoing the Norwood operation using RLFP. Preoperative neurostructural abnormalities were identified in more than 50% of patients. Postoperative examination revealed new or exacerbated lesions in 73% of patients, which were correlated with prolonged postoperative cerebral desaturation. These results suggest that neonates suffering from severe congenital heart disease present with significant preoperative cerebral injury or abnormality that may be compounded by postoperative physiology. This concept is supported by a report from Mahle and coworkers [27] that finds that neurodevelopmental deficits are prevalent among school-aged children with hypoplastic left heart syndrome, regardless of the surgical strategy pursued (single ventricle palliation versus primary heart transplantation). In this study, transplanted patients were generally spared the hemodynamic and oxygenation fluctuations that characterize the postoperative stage 1

5 Ann Thorac Surg VISCONTI ET AL 2006;82: REGIONAL PERFUSION AND NEURODEVELOPMENTAL OUTCOME 2211 procedure [27]. As such, any intraoperative intervention may be ineffective in improving neurodevelopmental outcome, and greater attention to preoperative (even prenatal) and postoperative issues may be beneficial. A surprising finding was the impact of birth order on MDI scores, and suggests the potential for postoperative interventions to impact developmental outcomes. Infants who were first or second born received higher MDI or PDI scores than infants born later. The reason for this is speculative. The stress associated with having a child with congenital heart disease has been reported in the literature [28]. It is conceivable that parents of first and second born children with CHD may be better able to meet the demands associated with caring for their children. They may have greater resources and fewer time constraints. However, as families grow, parents may already be overwhelmed with caring for older siblings and may not have additional resources to care for their children who require greater attention. In summary, no difference between 1-year neurodevelopmental outcomes was identified in patients undergoing stage 1 palliation with RLFP or DHCA. Larger, controlled studies are required, and consideration should be given to the impact that preexisting preoperative and postoperative factors may have on neurodevelopmental outcomes. The authors would like to acknowledge the contribution of patients to this study by Richard A. Jonas, MD. References 1. Azakie A, Martinez D, Sapru A, et al. Impact of right ventricle to pulmonary artery conduit on outcome of the modified Norwood procedure. Ann Thorac Surg 2004;77: Mair R, Tulzer G, Sames E, et al. Right ventricular to pulmonary artery conduit instead of modified Blalock- Taussig shunt improves postoperative hemodynamics in newborns after the Norwood operation. J Thorac Cardiovasc Surg 2003;126: Tweddell JS, Hoffman GM, Mussatto KA, et al. Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Circulation 2002;106(12 Suppl 1): Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurological status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;332: Bellinger DC, Wypij D, Kuban KCK, et al. Developmental and neurologic status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999;100: Bellinger DC, Wypij D, duduplessis AJ, et al. Neurodevelopmental status after 8 years in children with dextroposition of the great arteries: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003;126: Wypij D, Newburger JW, Rappaport LA, et al. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003;126: Forbess JM, Visconti KJ, Hancock-Friesen C, Howe RC, Bellinger DC, Jonas RA. Neurodevelopmental outcome after congenital heart surgery: results from an institutional registry. Circulation 2002;106; Forbess JM, Visconti KJ, Bellinger DC, Jonas RA. Neurodevelopmental outcomes in children after the Fontan operation. Circulation 2001;104(Suppl 1):I-127 I Forbess JM, Visconti KJ, Bellinger DC, Howe RJ, Jonas RA. Neurodevelopmental outcomes after biventricular repair of congenital heart defects. J Thorac Cardiovasc Surg 2002;123: Kern JH, Hinton VJ, Nereo NE, Hayes CJ, Gersony WM. Early developmental outcome after the Norwood procedure for hypoplastic left heart syndrome. Pediatrics 1998;102: Uzark K, Lincoln A, Lamberti JJ, Mainwarning RD, Spicer RL, Moore JW. Neurodevelopmental outcomes in children with Fontan repair of functional single ventricle. Pediatrics 1998;101: Wernovsky G, Stiles KM, Gauvreau K, et al. Cognitive development after the Fontan operation. Circulation 2000; 102: Bayley N. Manual for the Bayley scales of infant development, 2nd ed. San Antonio: Psychological Corporation, Kaufman A, Kaufman N. Kaufman brief intelligence test. Circle Pines, MN: American Guidance Service, Hollingshead A. Four factor index of social status. New Haven, CT: Yale University Press, Kimura T, Muraoka R, Chiba Y, et al. Effect of intermittent deep hypothermic circulatory arrest on brain metabolism. J Thorac Cardiovasc Surg 1994;108: Langley SM, Chai PJ, Miller SER, et al. Intermittent perfusion protects the brain during deep hypothermic circulatory arrest. Ann Thorac Surg 1999;68: Myung RJ, Petko M, Judkins AR, et al. Regional low-flow perfusion improved neurologic outcome compared with deep hypothermic circulatory arrest in neonatal piglets. J Thorac Cardiovasc Surg 2004;127: Decampli WM. Laboratory studies regarding regional low flow perfusion for neonatal cardiac surgery. Cardiol Young 2005;15(Suppl 1): Pigula FA, Nemoto EM, Griffith BP, et al. Regional low flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg 2000;19: Pigula FA, Gandhi SK, Siewers RD, et al. Regional lowflow perfusion provides somatic circulatory support during neonatal aortic arch surgery. Ann Thorac Surg 2001; 72: Hannan RL, Ybarra MA, Ojito JW, et al. Complex neonatal single ventricle palliation using antegrade cerebral perfusion instead of prolonged deep hypothermic circulatory arrest. Abstract presented at the 42nd STS annual meeting, Jan 31, 2006, Chicago. 24. Mahle WT, Clancy RR, Moss EM, Gerdes M, Jobes DR, Wernovsky G. Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypoplastic left heart syndrome. Pediatrics 2000;105: Licht DJ, Wang J, Silvestre DW, et al. Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc Surg 2004;128: Dent CL, Spaeth JP, Jones BV, et al. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2006;131: Mahle WT, Visconti KJ, Freier MC, et al. Relationship of surgical approach to neurodevelopmental outcomes in hypoplastic left heart syndrome. Pediatrics 2006;117:e DeMaso DR, Campis LK, Wypij D, Bertram S, Lipshitz M, Freed M. The impact of maternal perceptions and medical severity on the adjustment of children with congenital heart defects. J Pediatr Psych 1990;16;

6 2212 VISCONTI ET AL Ann Thorac Surg REGIONAL PERFUSION AND NEURODEVELOPMENTAL OUTCOME 2006;82: DISCUSSION DR EDWARD L. BOVE (Ann Arbor, MI): I rise to congratulate you on this study, and I think it s terribly important that we perform just these kinds of analyses before we all jump to various treatments that have really no data to support them. The other reason I rise to comment is to mention that we have just completed a 1-year analysis of a very similar randomized, prospective study in Ann Arbor, the results of which are going to be presented at the AATS meeting this spring in Philadelphia. Our results essentially mimic those you have just presented here. In our series of just under 80 patients, we found that there were no important differences between the two groups at 1 year of follow-up. PDI scores lagged behind the MDI, just as you ve shown and has also been shown in virtually every other study that I m aware of. In addition, the regional low-flow patients fared consistently worse than the circulatory arrest patients. There were some differences in our study compared to yours. The number of patients was larger, the developmental scales were higher for both groups, and the circulatory arrest times were lower. But all in all, I would support your conclusions and certainly congratulate you for doing this study. Thank you. DR MICHAEL D. BLACK (San Francisco, CA): I think a true comparison between selective cerebral perfusion and circulatory arrest can only be made when one group is exposed to circulatory arrest and the other is not. A further important variable(s) remains temperature. We know that under 18 Centigrade there is intense vasoparesis of the vasculature within the cerebrum. And I think that if you re going to do selective cerebral perfusion and really drop the temperature to profound temperatures, you re going to have an additional effect that you can t control. Furthermore, in the postoperative phase, we demonstrated years ago, using retrograde jugular bulb thermistors, that the brain temperature, after warming a patient to normothermia, can be 5 hotter in the cerebral cortex than using either rectal or nasopharyngeal temperature monitoring. That is, an additional injury from either technique may be encountered postoperatively. Once you cool somebody to 18, whether you perform selective cerebral perfusion or circulatory arrest, I think you have quite a multifactorial mechanism of injury in all phases of care, the preoperative period, the intraoperative experience, and the postoperative recovery period. It would have been wonderful to see the two groups separated based solely on temperature and flow. So I would have preferred to see the comparison between a no circulatory arrest cohort with perhaps moderate hypothermia versus total circulatory arrest cohort and deep hypothermia. I think it would have been perhaps a little bit more valuable or informative. But it s a very good paper, I enjoyed it. DR PIGULA: Thank you. But I would note that some groups have tried using this technique with more moderate temperatures, in the 24 or so, and I ve always been hesitant. And there have been some experiences where there has been renal dysfunction and other morbid sequelae of that. So I ve never really pursued that approach to it. DR BLACK: I think the main thing, as we heard today, some institutions maintain cardiopulmonary flows at 40 ml kg 1 min 1 using the radial artery (we, too, try to keep the mean pressure at what it would be normally on pump using standard techniques), and we have not had issues with renal malperfusion or increased lactates postoperatively. DR PIGULA: At warmer temperatures? DR BLACK: Yes. And once you use circulatory arrest, lactates are very high. If you use selective cerebral and even (selective) coronary perfusion, limiting all forms of ischemia, lactates are very, very low coming out of the operating room. DR PIGULA: I ve been concerned and this is getting a little more into the esoteric aspects of this but a concern, of course, always with the perfusion rate is you really don t want to overperfuse a brain. You can kill a brain by overperfusion as well as underperfusion. And at least experimentally, the work that Bill Gaynor did in Philadelphia, they found that in the animal model, the higher flow rates, they really had worse outcomes. They were using 20 and 40 ml kg 1 min 1. And the pig is not the human. But I think that that does raise a red flag for me and it makes me a little bit concerned about that. DR BLACK: One other comment. I think there is a lot of literature, once you cool profoundly, there is a dissociation between flow and pressure. So you could have immense flow with little to no pressure or a good pressure with little flow. So I think the secret with this technique, if it s going to be optimized, is trying to maintain moderate hypothermia, not uncoupling pressure and flow, which has been shown in many models to occur. Doing so, you come out of the operating room with good urine output on pump, normal lactates postoperatively, and we ve shown no seizures postoperatively. I believe that they will do overall better. DR PIGULA: Well, you know, there is nothing like success. But there is no question that there is a cold-induced cerebral vasoparesis. And where that happens isn t exactly known. My understanding is it s always been a little bit warmer, in the low 20s. So you d have to have your temperatures up above that to provide that benefit. DR JOSEPH M. FORBESS (Dallas, TX): Was there a difference in the two groups as far as the number that got full coarctectomies versus the more traditional patch on the underside of the aortic arch? DR PIGULA: I don t know that detail, I m sorry, Joe. DR THOMAS L. SPRAY (Philadelphia, PA): Just one minor question. I mean, I love the study because it confirms my own prejudice, and we always love those studies. But this study looks at a 5-year period and you had 29 patients or so. I mean, obviously, there has to be some selection bias here. And I guess my question is, how did you select the patients that you included in this study? It had to be retrospective, I assume. And I m assuming that these were patients who were coming back for neurodevelopmental testing for some other reason or they were local or some other selection, and would that have changed the socioeconomic factors that you found in the comparisons of the groups?

7 Ann Thorac Surg VISCONTI ET AL 2006;82: REGIONAL PERFUSION AND NEURODEVELOPMENTAL OUTCOME 2213 DR PIGULA: Well, there is no question there is a selection bias. And the patients really had to meet multiple selection criteria. They had to be local, for instance. They had to be English-speaking. They had to be willing to come back. They had to consent for this, because this was an IRB-approved study. And this represents a small number of patients who underwent this type of operation over that time period. So there is no question that there is a select bias, but it s the best we have at the moment. That s an obvious limitation. DR SPRAY: It still seems like a relatively small population for a center that must be doing, I m assuming, 35 or 40 a year stage I operations. And this is a 5-year period, so it s 10%, basically, of the potential patients that could be included in the study. DR PIGULA: Patients were lost, but that s because of some personnel changes as well in the institution. But again, there is no question there is a selection bias here. DR FRANÇOIS G. LACOUR-GAYET (Denver, CO): I have a few comments and two questions. First of all, I noticed that in the group that you call regional perfusion, you have a good number of patients with circulatory arrest. I wonder if your group is really a pure group of brain perfusion. Second of all, it is not justified to use the term low flow to describe the flow that is given to the brain. It is a normal flow to the brain through the cannula placed in the innominate artery; giving 40 ml kg 1 min 1, or even more, I give myself 60 to 70 ml kg 1 min 1. The purpose is to deliver a normal brain flow. Third, there is some evidence from the literature that brain perfusion with deep hypothermia is not very good for systemic resistances. The other comment is that when using brain perfusion, you can decrease the cross-clamp time and myocardial ischemia. There is a way to reconstruct the terminal end of the aortic arch with perfusing the ascending aorta. I have two questions. Do you believe that 1 year of age is the right time to evaluate the brain? I mean the intelligence, abstraction, let s say the neocortical functions. These are not very developed at 1 year of age. And finally, to be a bit provocative you know, 2 days ago it was the anniversary of Mozart s birth do you believe if he had circulatory arrest he would have done just as he did? DR PIGULA: I enjoyed that last question so much I forgot the first one. Well, with your question about regarding the best time to evaluate the brain, I don t know the answer to that. I m not a psychologist or a neurodevelopmentalist. But I can tell you that there are clearly differences and changes in the maturation in the brain as we grow, and there are gender differences. That s come out in the lay press recently, in the last Newsweek edition, that they can identify changes in the physiology and in some cases the anatomy of the developing brain between boys and girls up to 10 years of age. So the right time to evaluate the brain and the right time to say, well, we have no effect at this age, but we may have an effect at age 5, for instance. And I don t know that. I think that the studies do need to be performed and to be performed longitudinally to try to answer that question. And the second question that you asked about Mozart is interesting, because I think that there is an important point there. And that point that I tried to make with the last slide is that we are understanding that there is pathology going on long before we ever see the patient and long before the patient is ever born. There are abnormalities in the cerebral blood flow patterns, blood flows, as well as strictly cerebral anatomic abnormalities, and we re finding that that happens in utero, as well as before we operate on them. So the fact of the matter is what we do in the operating room, while we like to think may make a big difference, may not be that important, and the die is cast by the time that we re involved. Either that, or the die is cast, because we have to accept the physiology after the operation that we have little option about and that further problems happen at that point, with the cerebral desaturations, for instance, that clearly overwhelm anything we can do in the operating room. So I think that we need to take a look at the whole picture and try to find out exactly what things we are able to have an impact over and what we are not and go from there. DR TARA KARAMLOU (Toronto, Ontario, Canada): I was intrigued by the birth order falling out as a significant factor. And I wonder, you just alluded to it, about placental insufficiency, I wonder if you looked at maternal age and whether you think that that may have something to do with the generally unfavorable value of older birth order? DR PIGULA: Well, that s a good question. But no, we haven t, is the short answer. But I think that that s an interesting perspective on it. DR HENRY L. WALTERS III (Detroit, MI): I congratulate you on trying to find out if there are any cognitive benefits to regional low-flow perfusion in this context. Another question we should also be asking is whether there are any technical liabilities associated with this technique? I notice, for example, that the regional low-flow perfusion group underwent the second stage at a significantly earlier age than the deep hypothermic circulatory arrest group. Was there a higher incidence of shunt-related complications, either early or late, perhaps related to the need to occlude the proximal innominate artery proximal to the shunt that could have led to the need to perform earlier second stage palliation? Do you think there are any technical liabilities that may be associated with the technique? DR PIGULA: I don t think that happened in any of these patients. But what my concern would be, primarily, is the adequacy of the arch reconstruction. And that s one thing we haven t looked at in a larger series, and we didn t look at it in this series, whether or not patients required any further arch reconstruction. I can tell you 2 patients were disqualified because at the time they came back for their Glenn, they had arch augmentation under circulatory arrest, so they were not included in the analysis. But both of those patients were in the circulatory arrest group. So I think that s a good question. Because you certainly don t want to compromise your operation to perform a technique that you re not sure is providing a benefit. And I think that s an important question and something that we still need to pay attention to.