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J Thorac Cardiovasc Surg 2007;133:1524-1532
© 2007 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Neurodevelopmental and neuroradiologic outcomes in patients with univentricular heart aged 5 to 7 years: Related risk factor analysis

^a Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
^b Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
^c Department of Anesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland
^d Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
^e Hospital for Children and Adolescents, and the Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.

Received for publication September 18, 2006; revisions received November 24, 2006; accepted for publication December 13, 2006.

^_* Address for reprints: Anne Maria Hannele Sarajuuri, MD, Helsinki University Central Hospital, Hospital for Children and Adolescents, Department of Child Neurology, Lastenlinnante 2, 00029 HUS, Helsinki, Finland.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Objective: Despite improved survival and neurodevelopmental outcome, children with hypoplastic left heart syndrome and other forms of univentricular heart remain at increased risk for cognitive, motor, and other neurologic deficits.

Methods: We examined 27 children with hypoplastic left heart syndrome or other forms of univentricular heart at a median age of 5.70 years (range 4.99–7.51 years) and performed brain computed tomography or magnetic resonance imaging on 20. Possible risk factors were correlated with outcome.

Results: Mean full-scale IQ among patients with hypoplastic left heart syndrome was 86.7; that among patients with other forms of univentricular heart was 89.1, with both differing significantly from the expected population mean (P = .015 and P = .029, respectively). Cerebral palsy was diagnosed in 1 of 7 patients with hypoplastic left heart syndrome and 2 of 20 with other forms of univentricular heart. Brain computed tomography or magnetic resonance imaging revealed ischemic changes and infarcts or atrophy in 5 of 8 patients who had undergone the Norwood procedure and in 2 of 12 of those who had not (P = .062). Abnormal computed tomographic findings correlated significantly with lower full-scale IQ (P = .045) and verbal IQ (P = .02). In the multiple linear regression model, diuresis the third day after the primary operation and cardiopulmonary bypass time in the bidirectional Glenn operation correlated significantly with the primary outcome of full-scale IQ.

Conclusion: In children with univentricular heart, intellectual and neurologic deficits are common. Perioperative and postoperative risk factors related to the primary phase and bidirectional Glenn operation contribute to these deficits.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Because of increased survival rates, the focus in congenital heart surgery is increasingly on quality of life. Patients with univentricular heart (UVH) remain at increased risk for neurodevelopmental sequelae caused by several brain mechanisms.^1-3 Hypoplastic left heart syndrome (HLHS) is associated with the poorest outcome.^4-7 Because of developments in surgical methods and preoperative and postoperative care, recent results are better than those of the first reports, which noted that most patients with HLHS have mental retardation.^4,8 Reported mean full-scale IQ (FIQ) of patients with HLHS has ranged from 86 to 94, remaining clearly below the mean level of the normal population, unlike the 93 to 107 seen in patients with other forms of UVH. In most studies, prevalences of mental retardation have ranged from 10% to 18% for HLHS and from 0% to 8% for other forms of UVH.^5-7,9-11 Cerebral palsy was present in 17% of the children with HLHS examined by Mahle and colleagues,¹⁰ and problems with both gross and fine motor development occurred in almost half. The same study reported a high incidence (69%) of attention deficit hyperactivity disorder among children with HLHS.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patient Population
All children aged 5 to 7 years who had previously undergone surgery for UVH at the Hospital for Children and Adolescents of Helsinki University Central Hospital had the option of taking part in a neurodevelopmental and neuroradiologic evaluation between October 2002 and April 2004 as part of follow-up. The study protocol was approved by the ethics committee of our hospital.

During the visits, parents were interviewed regarding such topics as socioeconomic status,¹² occurrence of possible neurodevelopmental problems in the family, and use of any rehabilitation. Patient records were analyzed thoroughly concerning perinatal and preoperative, perioperative, and postoperative clinical factors and laboratory results: Apgar scores at 1, 5, and 10 minutes; weight, height, and head circumference at birth; preoperative use of alprostadil infusion and inotropic agents, age at diagnosis; and cardiac ejection fraction and ductal flow on echocardiography before the primary operation. Figures on durations of cardiopulmonary bypass (CPB), deep hypothermic cardiac arrest (DHCA), aortic crossclamp time, hypothermia, cooling, and rewarming; on level of hypothermia; and on occurrence of any perioperative or postoperative complications were collected for every operation. Preoperative heart failure was assessed according to the New York Pediatric Heart Failure Index.¹³ The following postoperative data were collected: times spent on a respirator and in the intensive care unit (ICU), amount of diuresis in the first 3 postoperative days (milliliters per kilogram per hour), use of inotropic agents, and number of days of nitric oxide inhalation needed. The following laboratory values were collected during the periods of 0 to 6, 6 to 24, 24 to 48, and 48 to 72 postoperative hours: the lowest and highest arterial pH values, lowest venous oxyhemoglobin saturation, and the lowest and highest blood glucose levels. The normalization time of arterial pH was recorded. Follow-up echocardiographic data were analyzed for cardiac function (ejection fraction >55% regarded as normal), nonphysiologic atrioventricular valve regurgitation, recoarctation of the aorta, and other possible abnormal findings. Possible catheterization complications were recorded, as well as any clinical seizures or resuscitations during any phase. Cumulative CPB, DHCA, and aortic crossclamp times were recorded. All these data were analyzed for association with the primary outcome of FIQ in the univariate analysis.

View larger version (19K): [in this window] [in a new window]   Figure 1. A, Correlations of full-scale IQ (FIQ) with perfusion time in Glenn operation (A), duration of hypothermia in Glenn operation (B), third postoperative day diuresis after primary operation (C), cumulative arrest time (D), highest blood glucose 0 to 6 hours after Glenn operation (E), and natural log of stay in intensive care unit (ICU) after primary operation (F).

Imaging of the Brain
Either magnetic resonance imaging (MRI, Siemens Vision 1.5 T; Siemens, Erlangen, Germany) or computed tomographic scan (CT, GE Lightspeed 8; GE Medical Systems, Milwaukee, Wis) was performed on 20 children. CT was performed if MRI was impossible because of pacemaker wires or poor anesthesia tolerance. The images were analyzed by a single neuroradiologist (L.V.) blinded to cardiac diagnosis and developmental test results.

Cognitive Testing
The Wechsler Preschool and Primary Scale of Intelligence—Revised¹⁵ served as a test of cognition. Three verbal and three performance subtests were administered, and verbal IQ (VIQ), performance IQ (PIQ), and FIQ were calculated according to the test manual. The IQ points of 1 moderately mentally handicapped child were counted as developmental age divided by calendar age times 100 because the tables did not score that low.

The neuropsychologic assessment was carried out with the Finnish Neuropsychologic Investigation of Children¹⁶ (Table 4). Each subtest was scored and analyzed separately. The Visual Motor Integration Test—Revised¹⁷ served as a specific measure of visuospatial functions.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patient Characteristics
Of 32 eligible children, 27 underwent a neurologic examination and 26 took part in cognitive testing at the median age of 5.70 years (range 4.99-7.51 years). Two could not be reached, and the parents of 3 children refused. One of the latter group had already been followed up neurologically because of verbal dyspraxia and had received speech therapy. The others were not known to have any neurodevelopmental problems. All 27 patients examined had undergone total cavopulmonary connection (TCPC), and all 7 patients with HLHS and 2 with double-outlet right ventricle were operated on with the Norwood procedure during the neonatal period (Table 1). Norwood operations with DHCA and a modified Blalock–Taussig shunt were performed at our hospital from 1995 to 1999; since that time, we have used selective cerebral perfusion. Six patients underwent 1 additional operation, and 1 patient with HLHS underwent 3 additional operations before the study began. The median durations of DHCA and CPB are listed in Table 2. Twelve patients were subjected to DHCA, 4 for 1 period, 7 for 2 periods, and 1 for 3 periods.

Neurologic Outcome
One patient in the UVH group had previously had diagnosed intellectual disability, and 3 had cerebral palsy, defined as disordered motor function as result of brain dysfunction evident in early infancy and characterized by changes in muscle tone, muscle weakness, involuntary movements, or ataxia. Two of these patients with cerebral palsy had mild hemiplegia, and 1 had spastic and ataxic features. The last-mentioned child, born prematurely at the 33rd gestational week, had hydrocephalus caused by aqueductal stenosis diagnosed at 9 months; there were no signs of intracerebral hemorrhage or ischemia on MRI, and the child underwent a ventriculoperitoneal shunt. All other children were term. One child with cerebral palsy was blind in one eye as a result of optic nerve atrophy. Cerebral palsy prevalences were 10.0% (2/20) in the UVH group and 14.3% (1/7) in the HLHS group. One patient with HLHS had a sensorineural hearing deficit and needed a hearing aid. Of all patients, 62.9% had been counseled by some therapist: 29.6% by a physiotherapist, 37.0% by a speech therapist, and 29.6% by an occupational therapist. One child received antiepileptic medication, and 3 others had received a postoperative anticonvulsant.

Mild hypotonia (62.9%) and difficulties in maintaining balance (76.0%) were common findings. Neurologic status was otherwise normal in 2 patients with HLHS (28.6%) and 10 with other forms of UVH (50.0%). Of the whole group, 34.6% had difficulties in gross motor function and 44.4% in fine motor function, the last-mentioned being more prevalent among children with HLHS (5/7) than among those with other forms of UVH (7/20). Three patients with other forms of UVH had mild abnormalities in cranial nerve function (squinting in 2 and ptosis in 1).

Cognitive Results
General intelligence
Mean FIQ, VIQ, and PIQ values (Table 3) did not significantly differ between the HLHS and UVH groups. As a prognostic factor, the Norwood operation seemed in this study population to be more important than the diagnosis itself, although it was not significant, with mean FIQs of 81.0 among those who had undergone the Norwood operation and 92.4 among those who had not (n = 17). The cognitive performance was at the level of intellectual disability in 2 children in the UVH group (FIQ <70). FIQ values of all patients in the HLHS group were above 70.

Neuropsychologic profile
Results of the Finnish Neuropsychologic Investigation of Children subtests and Visual Motor Integration Test—Revised for children with HLHS and those with other forms of UVH are presented in Table 4, along with the difference for the whole group relative to the expected population mean of 10. No significant differences existed between the HLHS and UVH groups on any of the subtests. A lower mean in the picture recognition test in children with HLHS approached significance (P = .06).

Signs of attention deficit hyperactivity disorder appeared in 57.1% of children with HLHS and in 52.6% of children with other forms of UVH. Occurrence of attention deficit hyperactivity disorder features correlated with neither any of the risk factors mentioned in Table 5 or the binary risk factors, nor was it associated with abnormal imaging findings.

Risk Factor Analysis
The results of those continuous and categorical factors that correlated significantly with the primary outcome FIQ at a level of P = .05 in the univariate analysis are presented in Table 5. Of the binary risk factor variables, only the occurrence of relevant atrioventricular valve regurgitation before the bidirectional Glenn (BDG) operation (FIQ 68.6 vs 93.2, P = .015) and postoperative complications afterward (FIQ 79.7 vs 98.8, P = .008) were significant. No variables concerning the TCPC operation were significantly correlated with FIQ values. Only 4 children had a fetal diagnosis, and their mean FIQ was similar to that of the remaining children. In multiple linear regression analysis, only the amount of diuresis on the third postoperative day after the primary-phase operation (P = .008) and the perfusion time in the BDG operation (P = .019) correlated significantly with FIQ.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In our study, mean FIQ levels differed significantly from the population mean for the whole study population and for both HLHS and UVH subgroups, as did mean VIQ levels for the whole group and for the UVH subgroup. The mean FIQ value of our patients with HLHS was similar to values reported by other investigators, but at the lower end. The mean FIQ value in our UVH group was even lower than in earlier studies, but because of our relatively small study group was greatly influenced by the results of a single moderately intellectually disabled child who had undergone resuscitation and sustained hypoxic-ischemic brain damage in connection with her Norwood operation. The fact that our study group included 2 bilingual children, 1 mainly Swedish-speaking child, and 1 child who used a hearing aid explains at least in part our lower VIQ than PIQ values, contrary to others’ results.^5-7,10-11 These children’s VIQ values also reduced the mean FIQ values to some extent. Surprisingly, socioeconomic status did not correlate significantly with FIQ, perhaps because of the limitations of our occupational scale and the presence of more potent factors that overwhelmed the effect of socioeconomic status. Unlike some earlier reports,^7,10 occurrence of clinically evident seizures during follow-up did not correlate significantly with FIQ, although a trend emerged toward lower FIQ in patients with clinically evident seizures.

The results for domain-specific neuropsychologic tests are for most part relative to the comparatively low overall intelligence level of the children with HLHS and other forms of UVH. In accordance with other studies,¹⁸ however, certain neurocognitive deficits occurred in fine motor function and visuospatial skills. Deficiencies also appeared in visual memory and auditory attention, reflecting higher-order cognitive functioning. In adult studies, deficiencies in more complex cognitive functions have been associated with cerebral anoxia.¹⁹ On the basis of these findings, we speculate that hypoxia may have more effect on the associative than on the primary areas.

Relative deficiencies were also evident in language functions, such as phonologic segmentation and comprehension of instructions. Difficulties in phonologic awareness have been associated with DHCA in children.²⁰

One interesting finding in our study was a relationship between the neuroradiologic ischemic findings in CT and the FIQ and VIQ values. Because CT is less precise method than MRI, detecting only the more extensive lesions, it is logical that these lesions may have had more effect on general intelligence. In an earlier study, Goldberg and colleagues⁷ found signs of previous ischemia or infarction on brain MRI in 13 of 29 (44.8%) children with HLHS or other forms of UVH. These signs were associated with a slightly lower mean FIQ, but the difference was not significant (P = .21). Neuroradiologic evidence of ischemic changes in patients with UVH has been described in few other studies. Kern and associates⁹ found ischemic changes or infarcts in 3 of their 7 neuroradiologically examined patients with HLHS and cerebral atrophy in 1. Miller and colleagues²¹ found abnormalities on brain MRI in 74% of 20 children after surgery with CPB or DHCA at a mean age of 66 months for various forms of congenital heart disease. In 1 case, the abnormality was a congenital structural anomaly, whereas in the others, there were ischemic changes. These findings suggested an association between abnormal results of brain MRI and abnormal results of neurologic examination, as well as lower IQ. Early postoperative—possibly reversible—periventricular leukomalacia changes have been reported in more than 50% of patients with congenital heart disease, especially in neonates.^22,23 The role of these early lesions in long-term functional outcome remains unknown, but these findings confirm that perioperative brain insult is common.

Our univariate risk factor analysis (Table 5) revealed that several factors related to the primary and BDG operations, but none related to the TCPC operation, correlated significantly with the primary outcome of FIQ. With respect to support times, the CPB time in the BDG operation correlated especially significantly with outcome in both univariate and multivariate analyses. The mechanisms by which CPB damages the brain are well known and include microembolic injury,²⁴ triggering of complex inflammatory microvasculopathy,²⁵ and disturbance of cerebral vascular autoregulation.²⁶ In our study population, DHCA was used in only 12 patients, among whom cumulative DHCA duration seemed to correlate clearly with outcome, although the correlation was not significant because of the small sample (P = .07). Some studies on neurodevelopmental outcome of patients with HLHS and other forms of UVH show a correlation between either use or duration of DHCA,^5-7,9,11 whereas others do not.¹⁰ The significances of length of intensive care unit stay after the first and second operations and of postoperative complications after the BDG operation reflect the vulnerability in the acute postoperative period and probably capture several differing mechanisms of brain damage. The role of postoperative diuresis after the primary operation as a prognostic factor for neurodevelopmental outcome can be explained by the effect of postoperative cardiac output on vital organs such as the kidney and brain and serves as a simple indicator of hemodynamic state. In postoperative Norwood physiology, the balance between systemic and pulmonary circulation is of great importance, especially in the acute postoperative period. Normal blood pH is a prerequisite for this. According to our findings, arterial blood pH should be allowed to vary little in either direction from normal limits.

When the superior vena cava (SVC) is connected to the pulmonary artery in the BDG operation, the venous return from the brain changes as a result of the absence of the downstream pump (ie, right atrium and ventricle) and of the perfusion injury in the lungs. The longer the CPB time, the more extensive is the lung injury, leading to increased resistance of the pulmonary circulation and inhibition of the venous return from the brain. This may cause SVC syndrome—described in connection with BDG²⁷ and other pediatric cardiac surgery²⁸—with possible neurologic manifestations and even a communicating hydrocephalus. Signs of SVC syndrome were found in 3 patients after the BDG operation according to our retrospective analysis of patient records. Especially at times of lower blood pressure, the elevated SVC pressure and intracranial venous pressure may lead to low cerebral perfusion pressure and thus neurologic sequelae. We were unable retrospectively to trace SVC pressure changes reliably in our patients, but we speculate that this mechanism may at least partially explain the effect of BDG-related factors, such as CPB time, venous blood oxyhemoglobin saturation, and postoperative complications, on the neurodevelopmental outcome.

Evidence is growing regarding the deleterious effect of hyperglycemia on the prognosis of critically ill pediatric patients.²⁹ Among pediatric cardiac surgical patients in the prospective Boston circulatory arrest study, however, intraoperative and postoperative hyperglycemia was not associated with worse neurodevelopmental outcome.³⁰ Our findings, in contrast, suggest a correlation of higher blood glucose levels 0 to 6 hours after BDG operation with lower FIQ values, with a similar but not significant tendency 0 to 6 hours after the TCPC operation (P = .058).

The limitations of our study are its relatively small and heterogeneous study population, with various operations performed in the primary phase, and its retrospective nature. Neurologic events such as clinically detected seizures were only documented in medical records, and no routine postoperative electroencephalographic recording was performed to detect subclinical seizures. Thus it may be difficult to trace definitely the point and circumstances at which brain injury has occurred.

We conclude that intellectual and neurologic deficits are common findings in children with UVH. Neuroradiologic evidence of ischemia was frequent among patients who had undergone Norwood surgery and was associated with low FIQ and VIQ if only CT results were considered. On the basis of our risk factor analysis, we emphasize the role of acute postoperative hemodynamic stability after the primary and BDG operations in addition to the well-known neurodevelopmental risk factors related to support times and mechanisms.

	Acknowledgments

 
We thank Professor Seppo Sarna for statistical advice and reviewing the statistical analysis of this study.

	Footnotes

 
Supported by grants from Arvo and Lea Ylppö foundation, Lastenlinna Foundation, and the Foundation for Pediatric Research, Finland.

	References

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