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J Thorac Cardiovasc Surg 2007;133:880-887
© 2007 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

A randomized clinical trial of regional cerebral perfusion versus deep hypothermic circulatory arrest: Outcomes for infants with functional single ventricle

^a Division of Pediatric Cardiology, University of Michigan, Ann Arbor, Mich
^b Section of Cardiac Surgery, University of Michigan, Ann Arbor, Mich
^c Division of Pediatric Psychology, University of Michigan, Ann Arbor, Mich
^d School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, Mich.

Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.

Received for publication June 20, 2006; revisions received November 8, 2006; accepted for publication November 20, 2006.

^_* Address for reprints: Caren S. Goldberg, MD, C.S. Mott Children’s Hospital, L1221 Women’s Box 0204, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0204. (Email: cgoldber{at}umich.edu).

	Abstract

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Objective: Regional cerebral perfusion has been adopted as a means to improve neuroprotection during aortic arch reconstruction. The purpose of this study was to determine whether a strategy of regional cerebral perfusion rather than one of deep hypothermic circulatory arrest during aortic arch reconstruction would improve neurodevelopment without increasing morbidity or mortality for patients undergoing the Norwood operation.

Methods: A randomized trial was performed in infants with single ventricle anatomy undergoing the Norwood operation. Participants were randomized to deep hypothermic circulatory arrest or regional cerebral perfusion. Neurodevelopment was measured before second-stage surgery and at 1 year by the Bayley Scales of Infant Development-II, Psychomotor Development Index and Mental Development Index. Intent-to-treat analysis was performed.

Results: Seventy-seven patients were enrolled. Survival to hospital discharge was 88% and to 1-year follow-up, 75%, without a significant difference between groups. For the entire cohort, the mean (SD) psychomotor development index score was 77 (20) and the mean mental development index score was 92 (21), with psychomotor development index lower than mental development index both before second-stage surgery (P < .0001) and at 1 year (P < .0001). There were no statistical differences in mental development or psychomotor development scores between the groups at pre–second-stage operation or 1-year follow-up, although the point estimates were consistently lower for the regional cerebral perfusion group.

Conclusion: Infant development is delayed after the Norwood operation. Pilot data do not suggest that regional cerebral perfusion improves infant development. Further study with a multicenter clinical trial is imperative to address this important question.

	Introduction

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Major advances in surgical techniques, medical management, and perioperative care have resulted in marked improvements in survival rates for children with hypoplastic left heart syndrome (HLHS). Although survival rates have improved,^1-4 associated morbidities remain significant. Neurodevelopmental outcomes are among the major concerns. Multiple studies in the past decade have demonstrated that although children with complex congenital heart diseases, including HLHS, can have good neurodevelopmental outcomes, these children are at increased risk for neurologic abnormalities and developmental delay.^5-9 Multiple factors including preoperative presentation, associated syndromes, and postoperative instability are likely to contribute to the risk of neurologic abnormalities. The use of deep hypothermic circulatory arrest (DHCA) is among the factors understood to negatively affect neurodevelopment.

For infants undergoing the Norwood operation, DHCA has been the standard intraoperative perfusion technique used during aortic arch reconstruction. Circulatory arrest allows for a bloodless field and diminishes the risk of embolism. Deep hypothermia at nasopharyngeal temperatures of 18°C is used to lower the metabolic needs of the brain. However, despite this technique, the use of circulatory arrest has been associated with neurologic and developmental abnormalities.^10-12

In an effort to protect the brain, regional cerebral perfusion (RCP) has been adopted by some centers as an alternative to DHCA. RCP is performed by cooling the patient as with DHCA. Through a polytetrafluoroethylene graft anastomosed to the innominate artery, blood can then be directed to the cerebral circulation. Flow rates of 20 mL · kg^–1 · min^–1 are generally used. RCP has been demonstrated to be technically feasible,^13-15 but no randomized prospective study has compared functional neurodevelopmental outcomes for children undergoing the Norwood operation with the use of RCP with those after the Norwood operation with DHCA. The purpose of this study was therefore to determine whether the use of RCP rather than DHCA during aortic arch reconstruction in infants with HLHS and other functional single ventricle malformations is associated with improved neurodevelopment without increasing morbidity or mortality.

	Materials and Methods

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Enrollment Criteria
A randomized controlled clinical trial was conducted at the University of Michigan Congenital Heart Center. Participants were enrolled from October 2001 through February 2005. Study inclusion required that the participants be born with HLHS or another single ventricle malformation requiring aortic arch reconstruction and that they be less then 30 days of age at the time of the Norwood operation. Patients were excluded from recruitment if the birth weight was less than 2 kg, gestational age was less than 32 weeks, if there was an identified genetic syndrome known to be associated with abnormal neurodevelopment, or if there was a known history of maternal substance abuse. Guidelines of the institutional review board were followed and informed consent was obtained from the parents of all study participants.

Stratification and Randomization
Study participants were stratified by surgeon and by risk group. (Three congenital heart surgeons participated in this study). Patients with pulmonary venous obstruction, patients less then 36 weeks’ gestation and/or less than 2.5 kg, and patients with clinical shock or clinical seizures preoperatively were randomized within the higher risk strata. Within strata, randomization used block randomization with random block size.

Of note, although it was obviously not possible to blind the surgeon and the surgical team, the family and the other research team members, including the pediatric psychologists, were masked to the assigned technique.

Surgical Technique
Standard technique at the University of Michigan Congenital Heart Center at the time of this study was to perform a modified Norwood operation with a modified Blalock–Taussig shunt as previously described by our group.¹⁶ DHCA involved active cooling during cardiopulmonary bypass to less than 18°C by nasopharyngeal temperature probe over a period of greater than 20 minutes. Topical cooling was also used by applying ice bags to the patient’s head.

All patients were managed throughout bypass with alpha-stat monitoring and underwent 10 minutes of modified ultrafiltration at the conclusion of bypass. Hematocrit was maintained at a target of 30% during bypass, with higher values at separation from bypass to achieve a post–modified ultrafiltration value in the mid to high 40s.

For participants randomized to RCP, at the time of the aortic arch reconstruction, the patient’s body and head were cooled to 18°C, as with DHCA. The proximal end of the Blalock–Taussig shunt was anastomosed at the distal innominate artery. The arterial bypass cannula was placed into the Blalock–Taussig shunt and RCP initiated at 5 mL · kg^–1 · min^–1, gradually increasing to 20 mL · kg^–1 · min^–1 (Figure 1). Near-infrared spectroscopy (INVOS 5100A; Somanetics, Troy, Mich) was used to measure cerebral oxygenation. At the conclusion of the arch reconstruction, the patient was returned to cardiopulmonary bypass and rewarmed, as with the standard technique.

View larger version (38K): [in this window] [in a new window]   Figure 1. llustration of RCP. Arrows represent flow of blood from cardiopulmonary bypass circuit through polytetrafluoroethylene graft anastomosed to the innominate artery. RCP, regional cerebral perfusion.

Outcome Measurements
Measures of safety
Safety information was collected in multiple ways. Each day while the patient was in the hospital, a member of the study team rounded on that patient to collect any information relating to morbidities. In addition, each family was contacted by telephone before the second-stage operation and again at 10 months of age. During all hospitalizations, including at the time of the second-stage operation, the patients were tracked as well. Echocardiograms and catheterizations are performed routinely as part of the clinical practice at the University of Michigan Congenital Heart Center before the second-stage procedure. The echocardiographic data were reviewed at hospital discharge after the Norwood operation and before the second stage to assess diaphragm function. Catheterization data before the second stage were used to determine the presence of aortic recoarctation. Need for cardiopulmonary resuscitation, need for extracorporeal membrane oxygenation, cardiac transplantation, vocal cord paresis, and/or diaphragm paresis before the second-stage operation were noted.

All mortalities were categorized as follows: (1) death before discharge after the Norwood operation, (2) interstage death before the second-stage procedure, or (3) death after the second-stage procedure.

Measures of neurologic and developmental outcome
Infant development was measured before the second-stage operation and again at 1 year of age with the Bayley Scales of Infant Development II (BSID-II). The BSID-II was administered by one of three pediatric psychologists. (E.M., E.S., S.T.) The pediatric psychologists were masked to the perfusion technique assignment. The BSID-II includes two scales or indices, the Mental Development Index (MDI) and the Psychomotor Development Index (PDI). The MDI is used primarily to assess memory, habituation, problem solving, early receptive and expressive language, social skills, and early number concepts. The PDI measures primarily gross and fine motor functioning. The mean score for the general population for each index is 100 points with a standard deviation of 15 points.¹⁷

Socioeconomic status was measured using the Hollingshead Four Factor Index of Social Status for all participants who returned for developmental assessment before the second stage and/or at 1 year.

Statistical Analysis
The primary method of analysis was based on intention-to-treat methods to compare those participants randomly assigned to RCP with participants randomly assigned to DHCA.

² or Fisher exact analysis was used to compare the differences in dichotomous variables between treatment groups. All normally distributed variables, such as scores on the PDI and MDI, were compared between treatment groups by the Student t test. Paired t test was used to compare two continuous variables between two time points or on two indices, the MDI before second-stage operation to the MDI at 1 year, or the MDI to PDI. Regression modeling was performed to adjust for impact of demographic variables on the BSID II scores, such as fetal diagnosis and socioeconomic status.

	Results

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Demographics of Participants
Seventy-seven patients were enrolled in the study. Twenty-three (30%) were within the high-risk strata. Thirty-eight were randomized to DHCA and 39 to RCP. In the case of 1 patient who was randomized to RCP, a very small right carotid artery was identified in the operating room, which was not thought to be amenable to placement of a modified Blalock–Taussig shunt. For this reason a central shunt was used and the aortic arch reconstruction was performed with the use of DHCA. Because of the intent-to-treat analysis, this patient was included in the RCP group for morbidity and mortality data. Unfortunately, this patient died before the second-stage operation and therefore is not included in the analysis of BSID-II scores.

Preoperative demographics showed no statistical difference in sex, gestational age, birth weight, or cardiac anatomy. Socioeconomic status measured with the Hollingshead Four Factor Index was not different between groups for the participants who returned for developmental follow-up. All participants had a single ventricle and required a Norwood operation. The majority of the participants had HLHS (67/77); 32 (84%) of 38 in the DHCA treatment group and 35 (90%) of 39 in the RCP treatment group. Overall, the diagnosis was made by prenatal ultrasound in 77% of the participants. A fetal diagnosis was made in 66% of patients randomly assigned to DHCA and 85% of those randomly assigned to RCP (P = .06). Thirty percent of the study cohort were within the high-risk strata, 31% of the RCP group and 29% of the DHCA group (P = .86) (Table 1).

Survival
Overall hospital survival for the study cohort was 88%. There were 3 predischarge deaths in the RCP subgroup (8%) and 6 predischarge deaths in the DHCA subgroup (16%) (P = .31). After discharge, but before the second-stage operation, 8 patients died from the RCP group (8/36, 22%) and 2 from the DHCA subgroup (2/32, 6%), P = .08. At 1 year, survival was 75% for the entire cohort, 69% for the RCP group, and 79% for the DHCA group (P = .33) (Figure 2).

View larger version (30K): [in this window] [in a new window]   Figure 2. Survival for the RCP and DHCA treatment groups at hospital discharge after Norwood operation, to second-stage operation, and to 1 year of age. RCP, retrograde cerebral perfusion; DHCA, deep hypothermic circulatory arrest.

Before the second-stage operation, the mean (SD) MDI and PDI scores for the entire cohort were 87.4 (14) and 71.5 (15), respectively. There was a tendency toward higher scores for the entire study group at 1 year, 91.8 (21) and 77.1 (21) for the MDI (P = .21) and PDI (P = .07), respectively. The MDI scores were significantly higher than the PDI scores both before the second-stage (P < .0001) operation and at 1 year (P < .0001) (Figure 3).

View larger version (15K): [in this window] [in a new window]   Figure 3. PDI and MDI scores are plotted on the y-axis compared with MDI scores on the x-axis at pre–second stage (A) and at 1 year (B). PDI, Psychomotor Development Index; MDI, Mental Development Index.

View larger version (15K): [in this window] [in a new window]   Figure E1. Box plots demonstrate comparison of DHCA and RCP groups for PDI pre–second stage (A), MDI pre–second stage (B), PDI at 1 year (C), and MDI at 1 year (D). DHCA, deep hypothermic circulatory arrest; RCP, regional cerebral perfusion; PDI, Psychomotor Development Index; MDI, Mental Development Index.

Models including fetal diagnosis and socioeconomic status were created to determine whether adjustment for these factors would provide a different understanding of the impact of RCP on MDI and PDI scores at the pre–second-stage and 1-year evaluations. The magnitude of the differences between groups was unchanged.

	Discussion

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In recent years, multiple centers have evaluated neurocognitive outcomes of children with HLHS and other single ventricle anomalies. Although individual patients can have normal development, studies consistently demonstrate that these patients are at an increased risk for developmental abnormalities.^5-9 It is widely understood that the etiology of the neurologic deficits in this patient group are multifactorial. The use of DHCA is among the modifiable factors thought to increase the risk of neurocognitive abnormalities in children with complex congenital heart abnormalities. For this reason, alternatives to DHCA, including RCP, have recently garnered attention.

Myung and colleagues¹⁸ compared the impact of RCP to DHCA on neurologic function in a fetal pig model. Fetal pigs were randomized to a 90-minute period of either RCP or DHCA. The authors found that postoperative neurobehavioral scores were more likely to be abnormal in the DHCA group than in the RCP group and that the RCP subgroup had less evidence of apoptosis on autopsy. However, there have been no data demonstrating improved outcomes with the use of RCP in infants.

Dent and colleagues¹⁹ from the University of Cincinnati have performed head magnetic resonance imaging studies of children with HLHS preoperatively and after the Norwood operation to determine whether RCP protects against hypoxic-ischemic injury evident structurally. Head magnetic resonance imaging was performed before the Norwood operation and during the early postoperative period in 15 newborn infants, all of whom had aortic arch reconstruction performed with the use of RCP. The investigators found that 73% of study participants had worsened or new evidence of cerebral ischemia after the Norwood operation despite the use of RCP during aortic arch reconstruction.¹⁹ There was no direct control group in this study and the RCP time averaged 83 minutes, significantly longer than the 41 minutes of DHCA time that Wypij and colleagues²⁰ found to be relatively safe.

The primary aim of this study was to investigate the hypothesis that RCP would improve neurodevelopmental outcomes without significantly affecting morbidity and mortality. We have studied too few patients thus far to draw definitive conclusions regarding the impact of RCP rather than DHCA on neurodevelopmental outcome on survival for children undergoing Norwood palliation. However, our data do not support the hypothesis that RCP improves neurodevelopmental outcomes. Since its initial description, RCP has been adopted by surgeons at some congenital heart centers with the belief that cerebral perfusion will provide better protection of the brain than DHCA.

Although we measured no statistical difference in morbidity and mortality outcomes between the two treatment groups, we could not demonstrate any beneficial effect of RCP on neurodevelopment.

This study was stratified for a composite high-risk group and for surgeon. Fetal diagnosis was not stratified and was somewhat different between the two groups. Mahle and colleagues²¹ have found that fetal diagnosis is associated with lower rates of neurologic events in patients with HLHS. In this study there was a higher rate of fetal diagnosis in the RCP subgroup. This may be expected to bias the RCP group to improved neurodevelopment. Adjustment for fetal diagnosis was therefore performed with regression modeling, but although the tendency was for improved scores in patients with a fetal diagnosis, the difference between the RCP and DHCA treatment groups was not found to be statistically different.

There are a number of limitations to our study. Whereas the exposure to DHCA or RCP occurs during the newborn period at the Norwood operation, the primary outcome measure was performed at 1 year of age. Thus, all participants underwent a second-stage operation, before the 1-year BSID-II evaluation. It was for this reason that the BSID-II was administered before the second stage as well. It is interesting to note that many of the participants had higher scores on the BSID-II at 1 year than at the pre–second-stage evaluation, suggesting that the second stage is not typically associated with new neurologic insults. By the 1-year follow-up, more time generally has passed since the last hospitalization and thus the patient has potentially had more time to progress developmentally. Longer-term follow-up will be important to discern if developmental catch-up will be more likely to occur in either the RCP or DHCA treatment groups.

This study is also limited by the relatively small sample size. When the findings of a planned early look at the data were analyzed, the estimated required sample size to address the study hypothesis was substantially increased and it was determined that a multicenter study would be more appropriate to address this question efficiently. However, although the sample size is relatively small, there was a consistent trend for the RCP treatment group to have lower developmental scores.

As with all trials comparing a new technique with a standard technique, this study is subject to a learning curve bias. Although RCP was used at our center selectively for approximately 1 year before the initiation of this trial, we recognize that this is still limited experience compared with the experience with DHCA at our center. To further investigate for evidence of a developing learning curve, we have analyzed the total bypass time for patients randomized to RCP over time and find that there is no change in bypass time over the study period (data not shown).

Finally, the method of RCP used in this study was based on the published experience at the time this trial was developed. Since that time, the method of RCP delivery has evolved at some centers. We do recognize that this study has only tested a single method of providing RCP and that there may be variations that would lead to different results.

The data from this trial do demonstrate that mental and psychomotor development as measured by the BSID-II is delayed in infants after the Norwood operation. These data also demonstrate significantly lower scores on the PDI than on the MDI, as previously shown.^22,23 The reason for this result remains unclear, although the finding is consistently reproducible and likely represents a predisposition for particular areas of central nervous system insult.

	Conclusions

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Consistent with the findings of others, these data demonstrate that development in children with HLHS and other related single ventricle malformations is delayed, with lower scores on the PDI than on the MDI. RCP was not associated with improved neurodevelopmental outcomes when compared with DHCA. Although this was a randomized controlled clinical trial, the sample size was limited and these pilot data are unfortunately inconclusive. As centers have adopted the RCP technique as a standard of care, these data support the need for a multicenter randomized clinical trial to compare safety and neurodevelopmental outcomes of RCP with those of DHCA before broad institutionalization on RCP.

	Footnotes

 
Funded by the Doris Duke Charitable Foundation, University of Michigan General Clinical Research Center.

^_* Hollingshead AB. Four-factor index of social status. Unpublished manuscript, Yale University, Department of Sociology, New Haven [CT]. 1975.

	References

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1. Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark 3rd BJ. Survival after reconstructive surgery for hypoplastic left heart syndrome: a 15 year experience from a single institution. Circulation 2000;102(19 suppl 3):III136-III141.[Medline]
   
2. Bove EL, Lloyd TR. Staged reconstruction for hypoplastic left heart syndrome. Contemporary results. Ann Surg 1996;224:387-394.[Medline]
   
3. Tweddell JS, Hoffman GM, Mussatto KA, Fedderly RT, Berger S, Jaquiss RD, et al. Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Circulation 2002;106(suppl I):I82-I89.[Medline]
   
4. Kern JH, Hayes JH, Michler RE, Gersony WM, Quagebeur JM. Survival and risk factor analysis for the Norwood procedure for hypoplastic left heart syndrome. Am J Cardiol 1997;80:170-174.[Medline]
   
5. Goldberg CS, Schwartz EM, Brunberg JA, Mosca RS, Bove EL, Schork MA, et al. Neurodevelopmental outcome of patients after the Fontan operation: a comparison between children with hypoplastic left heart syndrome and other functional single ventricle lesions. J Pediatr 2000;137:646-652.[Medline]
   
6. 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;105:1082-1089.[Abstract/Free Full Text]
   
7. Kern JH, Hinton VJ, Nereo NE, Hayes CJ, Gersony WM. Early developmental outcome after the Norwood procedure for hypoplastic left heart syndrome. Pediatrics 1998;102:1148-1152.[Abstract/Free Full Text]
   
8. Wernovsky G, Stiles KM, Gauvreau K, Gentles TL, duPlessis AJ, Bellinger DC, et al. Cognitive development after the Fontan operation. Circulation 2000;102:883-889.[Abstract/Free Full Text]
   
9. Uzark K, Lincoln A, Lamberti JJ, Mainwaring RD, Spicer RL, Moore JW. Neurdevelopmental outcomes in children with Fontan repair of functional single ventricle. Pediatrics 1998;101:630-633.[Abstract/Free Full Text]
   
10. Oates RK, Simpson JM, Turnbull JAB, Cartmill TB. The relationship between intelligence and duration of circulatory arrest with deep hypothermia. J Thorac Cardiovasc Surg 1995;110:786-792.[Abstract/Free Full Text]
    
11. Newburger JW, Jonas RA, Wernovsky G, Wypij D, Hickey PR, Kuban KC, et al. A comparison of perioperative neurologic effects of hypothermic circulatory arrest versus low flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 1993;329:1057-1064.[Medline]
    
12. Bellinger DC, Wypij D, Kuban KC, Rappaport LA, Hickey PR, Wernovsky G, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999;100:526-532.[Abstract/Free Full Text]
    
13. Pigula FA, Nemoto EM, Griffith BP, Siewers RD. Regional low-flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg 2000;119:331-339.[Abstract/Free Full Text]
    
14. Asou T, Kado H, Imoto Y, Shiokawa Y, Tominaga R, Kawachi Y, et al. Selective cerebral perfusion technique during aortic arch repair in neonates. Ann Thorac Surg 1996;61:1546-1548.[Abstract/Free Full Text]
    
15. Tchervenkov CI, Chu VF, Shum-Tim D, Laliberte E, Reyes TU. Norwood operation without circulatory arrest: a new surgical technique. Ann Thorac Surg 2000;70:1730-1733.[Abstract/Free Full Text]
    
16. Bove EL. Current status of staged reconstruction for hypoplastic left heart syndrome. Pediatr Cardiol 1998;19:308-315.[Medline]
    
17. Bayley N. Bayley Scales of Infant Development. 2nd ed.. San Antonio: Pychological Corp; 1993.
    
18. Myung RJ, Petko M, Judkins AR, Schears G, Ittenbach RF, Waibel RJ, et al. Regioanl low-flow perfusion improves neurologic outcome compared with deep hypothermic circulatory arrest in neonatal piglets. J Thorac Cardiovasc Surg 2004;127:1051-1057.[Abstract/Free Full Text]
    
19. Dent CL, Spaeth JP, Jones BV, Schwartz SM, Glauser TA, Hallinan B, et al. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2006;131:190-197.[Abstract/Free Full Text]
    
20. Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, 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;126:1397-1403.[Abstract/Free Full Text]
    
21. Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ. Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with hypoplastic left heart syndrome. Pediatrics 2001;107:1277-1282.[Abstract/Free Full Text]
    
22. Gaynor JW, Gerdes M, Zackai EH, Bernbaum J, Wernovsky G, Clancy RR, et al. Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg. 2003;126:1736-1745.[Abstract/Free Full Text]
    
23. Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ, du Plessis AJ, et al. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg 2003;126:1765-1774.[Abstract/Free Full Text]
    

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				H. Sasaki, K. J. Guleserian, R. Rose, C. Fotiadis, P. J. Boyer, and J. M. Forbess Hypothermic extracorporeal circulation in immature swine: a comparison of continuous cardiopulmonary bypass, selective antegrade cerebral perfusion and circulatory arrest Eur J Cardiothorac Surg, December 1, 2009; 36(6): 992 - 997. [Abstract] [Full Text] [PDF]

				C. A. Joynt, C. M.T. Robertson, P.-Y. Cheung, A. Nettel-Aguirre, A. R. Joffe, R. S. Sauve, W. S.G. Biggs, N. J. Leonard, D. B. Ross, I. M. Rebeyka, et al. Two-year neurodevelopmental outcomes of infants undergoing neonatal cardiac surgery for interrupted aortic arch: A descriptive analysis J. Thorac. Cardiovasc. Surg., October 1, 2009; 138(4): 924 - 932. [Abstract] [Full Text] [PDF]

				J. D. Salazar, R. D. Coleman, S. Griffith, J. D. McNeil, M. Steigelman, H. Young, B. Hensler, P. Dixon, J. Calhoon, F. Serrano, et al. Selective Cerebral Perfusion: Real-Time Evidence of Brain Oxygen and Energy Metabolism Preservation Ann. Thorac. Surg., July 1, 2009; 88(1): 162 - 169. [Abstract] [Full Text] [PDF]

				R. G. Ohye, C. S. Goldberg, J. Donohue, J. C. Hirsch, M. Gaies, M. L. Jacobs, J. G. Gurney, and Michigan Congenital Heart Outcomes Research and Di The quest to optimize neurodevelopmental outcomes in neonatal arch reconstruction: The perfusion techniques we use and why we believe in them J. Thorac. Cardiovasc. Surg., April 1, 2009; 137(4): 803 - 806. [Full Text] [PDF]

				A. Sarajuuri, T. Lonnqvist, L. Mildh, I. Rajantie, M. Eronen, I. Mattila, and E. Jokinen Prospective follow-up study of children with univentricular heart: Neurodevelopmental outcome at age 12 months J. Thorac. Cardiovasc. Surg., January 1, 2009; 137(1): 139 - 145. [Abstract] [Full Text] [PDF]

				R. L. Sherlock, P. S. McQuillen, S. P. Miller, and on behalf of aCCENT Preventing Brain Injury in Newborns With Congenital Heart Disease: Brain Imaging and Innovative Trial Designs Stroke, January 1, 2009; 40(1): 327 - 332. [Abstract] [Full Text] [PDF]

				J. Atallah, I. A. Dinu, A. R. Joffe, C. M.T. Robertson, R. S. Sauve, J. D. Dyck, D. B. Ross, I. M. Rebeyka, and the Western Canadian Complex Pediatric Therapies F Two-Year Survival and Mental and Psychomotor Outcomes After the Norwood Procedure: An Analysis of the Modified Blalock-Taussig Shunt and Right Ventricle-to-Pulmonary Artery Shunt Surgical Eras Circulation, September 30, 2008; 118(14): 1410 - 1418. [Abstract] [Full Text] [PDF]

				B. Alsoufi and C. A. Caldarone Reply Ann. Thorac. Surg., July 1, 2008; 86(1): 352 - 353. [Full Text] [PDF]

				A. J. Shillingford, M. M. Glanzman, R. F. Ittenbach, R. R. Clancy, J. W. Gaynor, and G. Wernovsky Inattention, Hyperactivity, and School Performance in a Population of School-Age Children With Complex Congenital Heart Disease Pediatrics, April 1, 2008; 121(4): e759 - e767. [Abstract] [Full Text] [PDF]

				S. Tabbutt, A. S. Nord, G. P. Jarvik, J. Bernbaum, G. Wernovsky, M. Gerdes, E. Zackai, R. R. Clancy, S. C. Nicolson, T. L. Spray, et al. Neurodevelopmental Outcomes After Staged Palliation for Hypoplastic Left Heart Syndrome Pediatrics, March 1, 2008; 121(3): 476 - 483. [Abstract] [Full Text] [PDF]

				J. G.T. Augoustides The conduct of experimental circulatory arrest: the search for clinical relevance. J. Thorac. Cardiovasc. Surg., November 1, 2007; 134(5): 1381 - 1382. [Full Text] [PDF]

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