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J Thorac Cardiovasc Surg 2004;127:692-704
© 2004 The American Association for Thoracic Surgery
Surgery for congenital heart disease |
a Division of Cardiothoracic Anesthesiology, The Cardiac Center at The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
b Division of Neuroradiology, The Cardiac Center at The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
c Division of Pediatric Cardiology, The Cardiac Center at The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
d Division of Neurology, The Cardiac Center at The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
e Division of Cardiothoracic Surgery, The Cardiac Center at The Children's Hospital of Philadelphia, Philadelphia, Pa, USA
f Department of Medicine (Medical Genetics), University of Washington, Seattle, Wash, USA
g Division of Pediatric Cardiology, Emory University School of Medicine, Atlanta, Ga, USA
h Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
i Department of Neurology, Duke University Medical Center, Durham, NC, USA
Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.
* Address for reprints: J. W. Gaynor, MD, Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Suite 8527, Philadelphia, PA 19104, USA.
gaynor{at}email.chop.edu
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Abstract |
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METHODS: Magnetic resonance imaging of the brain was performed 6 to 14 days after cardiac surgery utilizing cardiopulmonary bypass with or without deep hypothermic circulatory arrest in 105 neonates and infants 
6 months of age.
RESULTS: Median age at surgery was 6 days (range 1-178), with 82 neonates (age 30 days). Periventricular leukomalacia was found in 44 of the neonates (54%) compared with 1 of 23 infants (4%). Forward logistic regression using age at surgery as a continuous variable identified a model containing longer total support time (cardiopulmonary bypass plus deep hypothermic circulatory arrest), lower systolic blood pressure at cardiac intensive care unit admission postoperatively, lower minimum diastolic blood pressure, and PO2 in the first 48 hours after surgery. When age at surgery was considered as a dichotomous variable (neonate versus infant), younger age at surgery replaced systolic blood pressure, PO2, and total support time in the model. Lower minimum diastolic blood pressure was a significant risk factor in both models.
CONCLUSIONS: Periventricular leukomalacia was found in >50% of neonates after cardiac surgery but rarely in older infants. Hypoxemia and hypotension in the early postoperative period, particularly diastolic hypotension, may be important risk factors for periventricular leukomalacia.
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Methods |
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6 months of age undergoing CPB, with or without DHCA, for repair of CHD were eligible. Exclusion criteria included (1) multiple congenital anomalies; (2) recognizable genetic or phenotypic syndrome other than chromosome 22q11 microdeletions; and (3) language other than English spoken in the home. The study was approved by the Institutional Review Board at The Children's Hospital of Philadelphia. Informed consent was obtained from the parent or guardian.
Operative management
Surgery was performed by 4 cardiac surgeons with a dedicated team of cardiac anesthesiologists. Alpha-stat blood gas management was utilized. DHCA was utilized at the surgeon's discretion. Prior to DHCA, patients underwent core cooling with topical hypothermia of the head to a nasopharyngeal temperature of 18°C. Modified ultrafiltration was performed in all patients.
Data collection
Data collected included gestational age, head circumference, birth weight, and Apgar scores, which were obtained from birth records. Weight and age at surgery and type of surgery were recorded, along with CPB time, aortic crossclamp time, and duration of DHCA. Total support time was calculated as CPB time plus DHCA time. Postoperative hemodynamic data including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and right atrial pressure (RAP) were retrospectively recorded from the cardiac intensive care unit (CICU) flow sheet at 4-hour intervals for the first 48 hours postoperatively. Arterial blood gas data including pH, PO2, and PCO2 were recorded at the same intervals.
Postoperative MRI
MRI of the brain was performed in the early postoperative period between 3 and 14 days after surgery. All patients were transported to and from the MRI scanner, cared for, and, if necessary, sedated and/or anesthetized by cardiac anesthesiologists for the MRI examination. No patient was intubated exclusively for MRI and all patients recovered in the CICU.
MRI was performed with a 1.5 Tesla Magnetom magnet (Siemens, Munich, Germany). T1- and T2-weighted images were performed in the axial plane, with T1 imaging also acquired in the sagittal and coronal planes. A gradient echo T2 axial scan was done for the susceptibility effects of blood products. All MRIs were reviewed and interpreted by a single neuroradiologist (R.A.Z.), using a scoring system for localizing and grading cerebral injury developed for this project. Most PVL is seen in this population as areas of increased signal intensity on T1-weighted images in the periventricular white matter. Small punctate areas (1 or more) of increased T1 signal (less than 3 mm) were classified as mild PVL. These usually occur in the frontal and parietal regions and may be bilateral. When there were multiple small areas of increased T1 signal, between 3 mm and 1 cm in size, the PVL was classified as moderate. These may be bilateral in the frontal, parietal, and temporal regions but are not confluent. Larger confluent areas with plaques greater than 1 cm, often bilateral, in the frontal, parietal, and sometimes temporal regions were classified as severe PVL.
APOE genotype determination
Whole blood was obtained prior to surgery and stored at 4°C. Genomic DNA was prepared and used to determine APOE genotypes utilizing a previously published method.10
Data analysis
Patients were coded according to a previously described classification incorporating cardiac anatomy and perioperative physiology, which has been shown to be predictive of perioperative mortality.11 Class I is 2 ventricles with no aortic arch obstruction; class II is 2 ventricles with aortic arch obstruction; class III is single ventricle with no arch obstruction; and class IV is single ventricle with arch obstruction. Patients with tetralogy of Fallot (TOF) and transposition of the great arteries (TGA) are class I, while patients with hypoplastic left heart syndrome (HLHS) or variants are class IV. Patients were also grouped according to specific cardiac diagnoses: patients with HLHS; patients with conotruncal defects (TOF, TGA, truncus arteriosus, etc); and all other defects.
Statistical methods
Data are presented as median and range, where appropriate. All predictors of PVL considered are listed in Table 1. Monitoring data (PO2, PCO2, pH, SBP, DBP, RAP, HR) had repeated measures from time zero (CICU admission) to 48 hours taken at 4-hour intervals. For each of these monitoring variables, the minimum and maximum values during the study period were identified and only time zero, minimum, and maximum values were considered. For SBP, for example, the variables SBPadm, SBPmin, and SBPmax were considered. Three quantitative predictors were also dichotomized: gestational age (gestational age 2) was grouped as premature (less than 37 weeks) or not (
37 weeks); age at surgery (age at surgery 2) was grouped as neonate (up to 30 days of age) or not (31 days of age or older); and use of DHCA was grouped as "yes" or "no."
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2 group (22 and 23), the 33 group, and the 4 group (34 and 44). Because of the opposing effects of 2 and 4 in Alzheimer's disease, patients with 24 were excluded. These were then considered as 2 dummy variables (2 vs 3 and 4 vs 3). Any predictor of PVL that was found to have a P value of .1 or less was considered in a forward stepwise logistic regression to determine a model for prediction of PVL. Gestational age and age at surgery were coded as both continuous and dichotomous in separate regressions. Use of DHCA was also considered separately from the quantitative variable length of DHCA use. The relationship of all quantitative variables in the final model for PVL prediction was plotted. The correlation structure of all predictive variables was also evaluated. All analyses used SPSS 10.0 for Windows. |
Results |
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There were 44 girls and 61 boys. The median gestational age was 39 weeks (range 28-42) with a median birth weight of 3125 g (range 739-4528). Twelve patients (11%) were younger than 37 weeks gestational age. The median head circumference at birth was 34 cm (range 24-38, n = 103). Microcephaly (birth head circumference less than fifth percentile for gestational age) was present in 17% of the patients.
The median age at surgery was 6 days (range 1-178). Eighty-two patients underwent surgery as neonates. Median weight at surgery was 3.4 kg (range 1.5-6.9). Forty-four patients were class I, 11 were class II, 9 were class III, and 41 were class IV. HLHS was present in 33 infants, conotruncal defects in 51, and other defects in 21. DHCA was utilized in 64 patients with a median duration of 38 minutes (range 1-86). Median cooling time prior to DHCA was 15 minutes (range 8-35). Only 2 patients were cooled for less than 15 minutes. The median total support time was 88 minutes (range 13-242). The median hematocrit after hemodilution on CPB was 27% (range 20-37).
APOE genotype was completed for 98 of 105 patients (93%). Eight were 22 or 23 and 26 were 34 or 44. The 33 genotype was present in 61 patients. There were 3 patients with 24.
The median postoperative day for performance of MRI was 7 (range 3-14). PVL was identified in 45 infants (43%; Figure 1). PVL was identified in 44 of 82 neonates (54%) compared with only 1 of 23 (4%) older infants. The severity of PVL was mild in 36 of 45 (80%), moderate in 8 (18%), and severe in 1 (2%). The PVL was unilateral in 16 of 45 (36%) and bilateral in 29 (64%). PVL was identified in 25% of class I patients, 36% of class II patients, 33% of class III patients, and 60% of class IV patients.
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.1 level were examined for their correlations. As expected, many of these variables are highly correlated (Table 2). Gestational age did not remain in the final model, regardless of whether it was quantitative or qualitative; however, the coding of age at surgery (dichotomous vs continuous) did affect the final model. In addition, no APOE genotype effect on the risk of PVL was identified. Forward logistic regression considering age at surgery as a quantitative variable identified a model containing the minimum DBP (DBPmin) and PO2 (PO2min), the SBP at CICU admission (SBPadm), and longer total support time as significant predictors of PVL (Table 3). It is important to note that given the highly correlated nature of the other predictors, this may not be the only useful predictive model for this set of risk factors. However, given these variables, none of the other predictors improved prediction of PVL. The direction of these effects was as expected: lower DBPmin, lower PO2min, and lower SBPadm all increased risk of PVL, as did longer total support time. To aid in the visualization of the relationship of these 4 variables with PVL, the subjects were grouped according to the predictor and the proportion of subjects in each group with PVL plotted (Figure 2). However, when age at surgery was dichotomized (30 days or >30 days), it remained in the final model (Table 3), replacing PO2min, SBPadm, and total support time as significant predictors of PVL. When the analysis was restricted to the 82 neonates, DBPmin and SBPadm remained significant predictors of PVL in the multivariable analysis with age at surgery considered as a continuous variable. PO2min and longer total support time were no longer significant.
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Discussion |
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PVL was described as a specific entity in 1962 by the neuropathologic studies of Banker and Larroche.12 PVL is defined by the presence of focal necrosis of all cellular elements in the deep white matter surrounding the walls of the lateral ventricles and a more diffuse injury to oligodendroglial precursors.13-16 PVL was recognized initially as a pathologic condition relatively specific to the preterm neonate; however, appreciation of its clinical significance was overshadowed by its common coexistence with more dramatic-appearing lesions such as germinal matrix, intraventricular, and parenchymal hemorrhages. Cranial ultrasonography has demonstrated that PVL may be detected in 7% to 26% of preterm infants. PVL in preterm infants is highly associated with subsequent cerebral palsy, mental retardation, learning disabilities, visual-motor deficits, and ADHD.13-16 PVL may be encountered in the term infant following significant asphyxia, hypoglycemia, meningitis, CHD, and other conditions.17 The late consequences of PVL in term infants without CHD are comparable to those in prematurity and resemble the long-term neurodevelopmental "signature" of some children following surgical repair of CHD.17
One of the key developmental processes in premature and very young infant is progression of myelination, in which precursors of myelin are created, mature, and eventually envelop axons in the cerebral hemispheres, cerebellum, brain stem, and spinal cord. There is an age-dependent window of vulnerability to injury of developing white matter. PVL is one of the hallmarks of brain injury in premature and some term infants but is much less common thereafter. The target for diffuse white matter injury in PVL is the early differentiating oligodendrocyte, histologically distinguished from its mature counterpart by the absence of myelin basic protein staining.16 Whereas mature oligodendroglia are relatively resistant to injury from conditions such as hypoxia-ischemia, differentiating oligodendrocytes are exquisitely sensitive to a variety of insults, including hypoxia, ischemia, reactive oxygen species, and inflammatory mediators.13-16,18 In addition to direct toxic effects, oligodendrocyte maturation may be disrupted. Clinical conditions in preterm infants that result in cerebral ischemia, such as respiratory distress syndrome, patent ductus arteriosus, hypotension, and impaired autoregulation of cerebral blood flow, are associated with the development of PVL. Previous studies have also suggested that hyperventilation producing hypocarbia is a risk factor for PVL, possibly secondary to alteration in cerebral blood flow resulting in cerebral ischemia.19 Hypocarbia was not identified as a risk factor in our study.
Cytokine networks play important roles in normal brain development. However, in some pathologic conditions, cytokines [such as tumor necrosis factor-
(TNF-) and interleukin-6 (IL-6)] may be directly toxic to vulnerable, immature oligodendroglia while others are indirectly toxic through glial stimulation of nitric oxide, reactive oxygen species, and excitatory amino acids.13-16,18 There is in vitro evidence that IL-6 may alter the developmental pathways of oligodendrocyte precursors away from myelinating oligodendrocytes toward astrocyte development. There is increasing evidence that the systemic inflammatory response of the fetus and neonate is an important mechanism of white matter injury.13-16 The role of the systemic inflammatory response induced by CPB as a mediator of white matter injury is not known.
Children with CHD are at risk for cerebral hypoperfusion and hypoxemia before, during, and after cardiac surgery.6 Use of DHCA results in a period of global cerebral ischemia. Postoperative hemodynamic instability with low cardiac output and hypotension may also decrease cerebral perfusion. Many infants are hypoxemic before and after reconstructive surgery. In addition, use of CPB for the repair of CHD initiates a systemic inflammatory response.6 Exposure of blood to the foreign surface of the bypass circuit results in activation of complement as well as activation of the coagulation and fibrinolytic pathways. The systemic inflammatory response includes cytokine production, neutrophil activation, and endothelial cell activation. Dramatic increases of circulating cytokines for 24 to 48 hours have been reported in many studies of patients undergoing CPB including TNF- and IL-6, as well as other cytokines.
These potential risk factors do not fully explain the frequency or pattern of neurodevelopmental dysfunction. There is significant interindividual variation in developmental outcome, even among children with the same cardiac defect, suggesting that other patient-specific factors may be important determinants of CNS injury. In a recent study we demonstrated that APOE genotype, specifically the APOE 2 allele, was predictive of a worse neurodevelopmental outcome at 1 year of age following neonatal and infant cardiac surgery.20 In the current study we were unable to demonstrate an effect of APOE genotype as a predictor of PVL. However, given the relatively small size of the study population and the rarity of the APOE 2 allele (approximately 8% of the population), the statistical power to demonstrate a genotype effect is very limited.
Prior neuropathology and autopsy studies have demonstrated that PVL is a common finding in patients with CHD. A study of 33 children with CHD who were older than 1 year of age at death demonstrated white matter injury in 75% of the brains examined postmortem.7 A neuropathologic study conducted at our institution examined expired infants with HLHS.8 Both congenital and acquired abnormalities were demonstrated. The most common acquired ischemic neuropathologic lesions were PVL, present in over 25% of those examined, and localized strokes.
A recent study at our institution utilizing serial MRIs (preoperative, early postoperative, and late postoperative) in 24 patients demonstrated that PVL is common early after neonatal cardiac surgery (50% of neonates), consistent with another study.21 Interestingly, PVL was present in 16% of the infants preoperatively, suggesting that in utero or early postnatal CNS injury had occurred. However, over 50% of the infants demonstrated new or worsened PVL on the early postoperative MRI consistent with CNS injury occurring in the intraoperative and early postoperative periods. However, PVL could no longer be demonstrated 3 to 6 months after surgery. This apparent resolution of PVL does not imply that white matter injury did not occur, but rather that more sensitive imaging techniques may be necessary after resolution of the acute injury. Few other studies have evaluated infants with brain MRI following cardiac surgery, especially in the early postoperative period. Miller and associates9 evaluated MRI of the brain in 23 children who had undergone cardiac surgery. MRI was performed at least 2 years following cardiac surgery. Ten patients had undergone neonatal cardiac surgery. White matter injury was demonstrated in 10 of 23 patients (43%) and in 8 of 10 (80%) of patients who had undergone neonatal heart surgery. At the 1-year follow-up evaluation of the Boston Circulatory Arrest Study, MRI of the brain was performed in 142 children.2 Definite abnormalities were present in 22 patients (15%) and possible abnormalities in 11 (8%). PVL was not reported. In this study the prevalence of an MRI abnormality was related to preoperative acidosis but not to use or duration of DHCA.
There are several limitations to the current study. There is a possibility of selection bias, as not all parents of enrolled patients consented to the MRI.21 Some potential patients were discharged before the MRI could be obtained and others were deemed unstable to undergo MRI until after the study period, thus both well and ill children were excluded. Preoperative MRI was not performed; therefore, it is possible PVL was present in some patients prior to surgery. In the study by Mahle and associates,21 however, PVL was present in only 16% of patients prior to surgery and new or worsened PVL was found in 52% of patients on the early postoperative MRI. This suggests that the white matter injury most commonly occurs intraoperatively or during the early postoperative period. In addition, because PVL is an evolving lesion the time variability in the performance of the postoperative study may result in an underestimation of the incidence. Serial imaging studies may be necessary. Finally, many of the variables were highly correlated as expected (Table 2). There might be other useful risk models based on other predictors; however, none of the available predictors improved the occurrence of PVL.
In conclusion, this study demonstrates that cerebral white matter injury manifested as PVL is found in more than 50% of neonates early following cardiac surgery but is rare in older infants. Prolonged exposure to CPB (with or without DHCA) and hypoxia and hypotension in the early postoperative period were associated with PVL in this population. Future studies are necessary to determine the long-term significance of PVL identified on early postoperative MRI as a marker for long-term neurodevelopmental function in these patients. Future clinical neuroprotection trials and outcome studies should include CNS imaging and detailed collection of preoperative, intraoperative, and postoperative hemodynamic variables, as these may yield important insights into the mechanisms of CNS injury in children with CHD
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Discussion |
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I do have the following questions for you. First, if you could please tell us a little bit more about periventricular leukomalacia. Is it specific for certain kinds of injury and outcome, or is it a general MRI finding that can have many causes and correlate with variable outcomes?
Second, have you looked for PVL in neonates without cardiac disease, specifically those who are hypoxemic, such as with lung disease, or those who have diastolic hypotension, such as those who have sepsis, as opposed to just all the neonates in general who are not cardiac patients? Can you see if that break point of yours is even more notable in those patients who are hypoxemic or hypotensive? In patients with postoperative hypoxemia (a PO2 of less than 40) or postoperative hypotension (a diastolic blood pressure less than 35), both of which were break points in your study, was there a correlation when this occurred in the postoperative period and the likelihood of PVL? That is, is hypoxemia or hypotension worse from the standpoint of leading to or being associated with PVL if it occurs in the first 2 days after surgery rather than if it occurs on postoperative day 4, for example?
It is interesting that you include the CPB period, since all of the patients in your study had some episode of hypotension. If you consider that there was a mean blood pressure lower than the diastolic pressure break point on CPB for most of these patients, was there any correlation between mean blood pressure on pump and PVL?
Can you tell us anything more about the follow-up correlation of PVL in your study patients and their neurologic outcomes? Obviously that's going to be very critical to knowing the importance of this study.
And finally, the implication of this study is that in our zeal to operate on neonates, we may be subjecting them to risks for neuroneural behavioral outcomes that might be different if we could wait until they were outside the neonatal period. Alternatively, it may simply be that neonates who require cardiac repair have an inherent risk for adverse neurologic outcome. It would be interesting if you could reexamine your data in a manner that could help us understand that. For example, is there a difference between babies with a single diagnosis such as TOF with respect to their association with PVL related to the timing of operation?
Dr Gaynor. Thank you very much, Dr Ungerleider. I will try to go through your questions.
PVL represents cerebral white matter injury, that is, axonal injury, oligodendrocyte injury. PVL specifically affects the white matter tracts and that has been confirmed in pathologic studies. There is some unpublished data from our institution comparing MRI findings with the pathologic findings in a small group of infants who died. Our radiologists and neuropathologists have demonstrated that these MRI findings are specific for PVL. So it is not really a general MRI finding. It is specific for white matter injury and correlates with injury to the white matter tracts. There is often subsequent delayed myelination. The findings seen on early MRI may be related to the edema and other changes associated with early cell injury; therefore, later MRIs may not show white matter injury. You see loss of volume, with increased ventricles and decreased brain volume, suggesting white matter loss, but the acute effects of edema have all resolved.
We haven't looked for PVL in neonates without cardiac disease, but the patient population in which PVL was described is in the neonatal intensive care unit, in the preterm infants, and it has been associated with a variety of factors, with hypoxemia, with respiratory distress syndrome in these infants, and with hypotension. So these are risk factors in the neonatal patient without cardiac disease, but most of those studies have been done in preterm infants.
Regarding the break points, we didn't specifically look for break points. We were just looking at the graphs. It does look like there are break points, particularly for the PO2 and the diastolic blood pressure.
We don't know whether intervention to improve oxygenation or raise the blood pressure would prevent PVL. That's obviously the next study. I don't think you can make that leap from this study, that if we can avoid hypoxemia of less than 40 and a diastolic blood pressure of less than 35 we will prevent PVL, but I think that could be an important hypothesis for future studies.
And I do think that the timing of the occurrence of hypoxemia and hypotension probably is very important. The early postoperative period after an episode of bypass or a period of deep hypothermic circulatory arrest, or even if the children had been sick preoperatively, is a vulnerable period that even if you had not irreversibly injured neurons or the oligodendrocytes, an additional insult in that early postoperative period results in neuronal death. So I think if you are further past surgery, you may be less vulnerable to injury. Again, that will need to be tested.
We did not look at the mean pressures on bypass. That would be an interesting future study.
These infants have come back for neurodevelopmental evaluation at 1 year of age, assessed with a neurologic exam and the Bailey's scales of infant development, but we haven't analyzed the data yet. That hopefully will be a future presentation.
As far as the implications regarding the elective neonatal surgery, when we looked at the distribution in the first month of life, it was pretty much even, whether it was week 1, 2, 3, or 4, and the real break point occurred at about 30 days. Now, I don't know if it is colinear with cardiac diagnosis (the reason the children are having the surgery) or whether it is related to the physiology and the maturation of the oligodendrocytes.
I think it would be interesting to study in the future whether or not it's better to operate on patients with TOF when they are 1 week old if they are asymptomatic or if it's better to wait until they are 2 months old, taking risk of increasing cyanosis. But I think we should consider that operating on neonates who may be vulnerable simply because we feel it is better to do this in the neonatal period may not always for every child be the best option.
Dr James S. Tweddell (Milwaukee, Wis). My question really involves the finding of decreased diastolic pressure as a risk factor. Obviously pressure is dependent on the systemic vascular resistance and total cardiac output, or cardiac output. I was wondering if you could give us any insight into which of those 2 factors seem to have the most impact on the development of PVL, or if you are able to sort that out at all? Really, it relates to whether a patient with good cardiac output and a low diastolic pressure is at greater risk as a patient whose diastolic hypotension is due primarily to low output.
Dr Gaynor. Well, we weren't able to evaluate that in the study, but I think that's a very interesting question. What controls cerebral blood flow in the early postoperative period, and how is the blood flow distributed through the body? Is it systemic vascular resistance? Is it cerebrovascular resistance? I know you are going to present some data later on looking at that. I'm sure total cardiac output is important. One of the really important messages of this article is that the early postoperative period is a time of risk for these children. We have focused so much on what we do in the operating room and the use versus nonuse of DHCA that we sometimes do not consider the intensive care unit. We have to concentrate on protecting the brain in the early postoperative period. We need to do studies where we actually assess the adequacy of cerebral blood flow, either looking at cerebral oxygenation or some measure of cerebral blood flow, and then determine whether an intervention that will increase blood pressure by increasing systemic vascular resistance will improve cerebral blood flow. Alternatively we can try to increase cardiac output and hope that the flow distribution will improve cerebral blood flow.
I think that's something we really need to begin to look at. We are not able to answer that from that study, but I think this is something that is clearly important as we go forward.
Dr Glen Van Arsdell (Toronto, Ontario, Canada). That was a beautiful presentation and study and has some important implications for us, and you've alluded to some. I wanted to just see whether I could get you to further delineate how you analyzed this.
Obviously, one of the simmering debates is the timing of repair in certain lesions, and the Boston neurologic outcome data have suggested that if you have prolonged intubation, it may well affect your long-term neurologic outcome. Have you tried to correlate the 2 factors, time of intubation and age at repair, to see whether or not that had any impact on PVL? And second, have you looked at a continuous variable to preoperative oxygen saturation and whether or not that had any impact on PVL?
Dr Gaynor. We haven't looked at those factors specifically. We did do a study with Dean Kurth, who is now at Cincinnati, using near-infrared spectroscopy to look at cerebral oxygenation preoperatively. In some subgroups, particularly patients with hypoplastic left heart syndrome, it can be dangerously low in the preoperative period. That was not measured in this study, and this does not occur in every infant. Some of these children were infants who came in for elective surgery.
But I think it is important to focus on the preoperative period, the potential for injury in the preoperative period. How we are setting these patients up for surgery? Can we optimize their condition, their cerebral blood flow, in the preoperative period, so perhaps they are less vulnerable for the operative period?
In our previous study, the incidence of PVL prior to surgery or at the time of surgery is fairly low, 16%, compared with approximately 50% postoperatively. So I think most of the injury is occurring either intraoperatively or in the early postoperative period. But we may be setting kids up. If we take a patient who has dangerously low cerebral oxygenation to the operating room, he may be more vulnerable than another child.
We did not look at duration of ventilation. I don't know that the problem is the duration of ventilation per se, it may be, or is it just a surrogate for some other marker of illness, or if there is some other problem going on. I don't know. We didn't look at that in these data. We could go back and look at that, but we haven't thus far.
Dr Frank L. Hanley (Stanford, Calif). The most dramatic finding you showed, Bill, was the difference in the insult between neonates and nonneonates. On initial assessment of these findings, it seems clear that that there is either something very different in the way neonates and relatively young infants respond or there is something different in your management techniques between neonates and nonneonates. One or both of these may be very important here. The similarities and differences in the management schemes of these 2 groups were not presented. Can you review whether you use different bypass techniques, hematocrits, or other factors when treating neonates as compared with older infants that could give us some insights into the overall management differences during and shortly after bypass between the 2 groups?
Dr Gaynor. The management strategies and the bypass strategies are fairly similar. The older children probably have a lower incidence of deep hypothermic circulatory arrest, but obviously the neonate state is colinked to many other variables, particularly diagnosis. The patients with HLHS were all neonates. That means the neonates had a greater incidence of the use of circulatory arrest. So there may be some colinking there, and these other factors are important. But there are also physiologic differences in the neonatal brain. The oligodendrocytes are not fully mature at birth. There is a maturation period that occurs after birth; it may be that the oligodendrocytes in the neonate are more vulnerable to injury than those of the older infants. I think there are a lot of things that are related, and we need to sort out what those factors are.
Dr Hanley. Can you give us just a very brief overview of when you did not use DHCA? What was the standard so-called "continuous bypass management," in terms of did you go low flow, how low, for how long a period of time, things like that?
Dr Gaynor. That again, we would have to go back and look at it specifically because it is highly variable between the surgeons doing the cases. Some of these children were 6 months old who underwent ventricular septal defect closure and had continuous bypass at full flow with mild to moderate hypothermia; others were neonates who had fairly deep hypothermia and low flow bypass for a period of time. We haven't broken that out in terms of the specific bypass strategies. That is something we could look at, but it is not a uniform technique for this study and wasn't controlled as a factor for this study.
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Footnotes |
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References |
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 P. S. McQuillen Magnetic Resonance Imaging in Congenital Heart Disease: What to Do With What We See and Don't See? Circulation, February 10, 2009; 119(5): 660 - 662. [Full Text] [PDF]
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C. J. Petit, J. J. Rome, G. Wernovsky, S. E. Mason, D. M. Shera, S. C. Nicolson, L. M. Montenegro, S. Tabbutt, R. A. Zimmerman, and D. J. Licht Preoperative Brain Injury in Transposition of the Great Arteries Is Associated With Oxygenation and Time to Surgery, Not Balloon Atrial Septostomy Circulation, February 10, 2009; 119(5): 709 - 716. [Abstract] [Full Text] [PDF]
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 G Dohlen, R R Chaturvedi, L N Benson, A Ozawa, G S Van Arsdell, D S Fruitman, and K-J Lee Stenting of the right ventricular outflow tract in the symptomatic infant with tetralogy of Fallot Heart, January 15, 2009; 95(2): 142 - 147. [Abstract] [Full Text] [PDF]
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K. Watanabe, M. Matsui, J. Matsuzawa, C. Tanaka, K. Noguchi, N. Yoshimura, K. Hongo, M. Ishiguro, S. Wanatabe, K. Hirono, et al. Impaired neuroanatomic development in infants with congenital heart disease. J. Thorac. Cardiovasc. Surg., January 1, 2009; 137(1): 146 - 153. [Abstract] [Full Text] [PDF]
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 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]
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 R. van der Rijken, G. Hulstijn-Dirkmaat, F. Kraaimaat, L. Nabuurs-Kohrman, A. Nijveld, B. Maassen, and O. Daniels Open-heart surgery at school age does not affect neurocognitive functioning Eur. Heart J., November 1, 2008; 29(21): 2681 - 2688. [Abstract] [Full Text] [PDF]
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 W. Deng, J. Pleasure, and D. Pleasure Progress in Periventricular Leukomalacia Arch Neurol, October 1, 2008; 65(10): 1291 - 1295. [Abstract] [Full Text] [PDF]
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 G. Wernovsky The Paradigm Shift Toward Surgical Intervention for Neonates With Hypoplastic Left Heart Syndrome Arch Pediatr Adolesc Med, September 1, 2008; 162(9): 849 - 854. [Full Text] [PDF]
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 A. Farouk, M. Karimi, M. Henderson, J. Ostrowsky, E. Siwik, and H. Hennein Cerebral regional oxygenation during aortic coarctation repair in pediatric population. Eur. J. Cardiothorac. Surg., July 1, 2008; 34(1): 26 - 31. [Abstract] [Full Text] [PDF]
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C. Pizarro, K. A. Murdison, C. D. Derby, and W. Radtke Stage II Reconstruction After Hybrid Palliation for High-Risk Patients With a Single Ventricle Ann. Thorac. Surg., April 1, 2008; 85(4): 1382 - 1388. [Abstract] [Full Text] [PDF]
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 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]
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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]
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J. W. Newburger, R. A. Jonas, J. Soul, B. D. Kussman, D. C. Bellinger, P. C. Laussen, R. Robertson, J. E. Mayer Jr, P. J. del Nido, E. A. Bacha, et al. Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 347 - 354. [Abstract] [Full Text] [PDF]
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J. Li, G. Zhang, H. Holtby, A.-M. Guerguerian, S. Cai, T. Humpl, C. A. Caldarone, A. N. Redington, and G. S. Van Arsdell The influence of systemic hemodynamics and oxygen transport on cerebral oxygen saturation in neonates after the Norwood procedure J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 83 - 90. [Abstract] [Full Text] [PDF]
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I. Zeltser, G. P. Jarvik, J. Bernbaum, G. Wernovsky, A. S. Nord, M. Gerdes, E. Zackai, R. Clancy, S. C. Nicolson, T. L. Spray, et al. Genetic factors are important determinants of neurodevelopmental outcome after repair of tetralogy of Fallot J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 91 - 97. [Abstract] [Full Text] [PDF]
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J. A. Ballweg, G. Wernovsky, R. F. Ittenbach, J. Bernbaum, M. Gerdes, P. R. Gallagher, T. E. Dominguez, E. Zackai, R. R. Clancy, S. C. Nicolson, et al. Hyperglycemia After Infant Cardiac Surgery Does Not Adversely Impact Neurodevelopmental Outcome Ann. Thorac. Surg., December 1, 2007; 84(6): 2052 - 2058. [Abstract] [Full Text] [PDF]
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 S. P. Miller, P. S. McQuillen, S. Hamrick, D. Xu, D. V. Glidden, N. Charlton, T. Karl, A. Azakie, D. M. Ferriero, A. J. Barkovich, et al. Abnormal Brain Development in Newborns with Congenital Heart Disease N. Engl. J. Med., November 8, 2007; 357(19): 1928 - 1938. [Abstract] [Full Text] [PDF]
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M. V. Johnston Congenital Heart Disease and Brain Injury N. Engl. J. Med., November 8, 2007; 357(19): 1971 - 1973. [Full Text] [PDF]
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 S. P Miller and P. S McQuillen Neurology of congenital heart disease: insight from brain imaging Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2007; 92(6): F435 - F437. [Full Text] [PDF]
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 S. A. Back and S. P. Miller Cerebral White Matter Injury: The Changing Spectrum in Survivors of Preterm Birth NeoReviews, October 1, 2007; 8(10): e418 - e424. [Abstract] [Full Text] [PDF]
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J. A. DiNardo Phenoxybenzamine Is Indicated in Treatment of Hypoplastic Left Heart Syndrome: Con Anesth. Analg., August 1, 2007; 105(2): 310 - 311. [Full Text] [PDF]
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A. Sarajuuri, E. Jokinen, R. Puosi, M. Eronen, L. Mildh, I. Mattila, L. Valanne, and T. Lonnqvist Neurodevelopmental and neuroradiologic outcomes in patients with univentricular heart aged 5 to 7 years: Related risk factor analysis J. Thorac. Cardiovasc. Surg., June 1, 2007; 133(6): 1524 - 1532. [Abstract] [Full Text] [PDF]
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J. W. Gaynor, G. Wernovsky, G. P. Jarvik, J. Bernbaum, M. Gerdes, E. Zackai, A. S. Nord, R. R. Clancy, S. C. Nicolson, and T. L. Spray Patient characteristics are important determinants of neurodevelopmental outcome at one year of age after neonatal and infant cardiac surgery J. Thorac. Cardiovasc. Surg., May 1, 2007; 133(5): 1344 - 1353. [Abstract] [Full Text] [PDF]
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 G. D. Williams and C. Ramamoorthy Brain monitoring and protection during pediatric cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2007; 11(1): 23 - 33. [Abstract] [PDF]
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S. D. Markowitz, R. N. Ichord, G. Wernovsky, J. W. Gaynor, and S. C. Nicolson Surrogate markers for neurological outcome in children after deep hypothermic circulatory arrest. Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2007; 11(1): 59 - 65. [Abstract] [PDF]
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B. D. Kussman, K. Gauvreau, J. A. DiNardo, J. W. Newburger, A. S. Mackie, K. L. Booth, P. J. del Nido, S. J. Roth, and P. C. Laussen Cerebral perfusion and oxygenation after the Norwood procedure: Comparison of right ventricle-pulmonary artery conduit with modified Blalock-Taussig shunt J. Thorac. Cardiovasc. Surg., March 1, 2007; 133(3): 648 - 655. [Abstract] [Full Text] [PDF]
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P. S. McQuillen, A. J. Barkovich, S. E.G. Hamrick, M. Perez, P. Ward, D. V. Glidden, A. Azakie, T. Karl, and S. P. Miller Temporal and Anatomic Risk Profile of Brain Injury With Neonatal Repair of Congenital Heart Defects Stroke, February 1, 2007; 38(2): 736 - 741. [Abstract] [Full Text] [PDF]
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B. Alsoufi, J. Bennetts, S. Verma, and C. A. Caldarone New Developments in the Treatment of Hypoplastic Left Heart Syndrome Pediatrics, January 1, 2007; 119(1): 109 - 117. [Abstract] [Full Text] [PDF]
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M. A. Padula and A. M. Ades Neurodevelopmental Implications of Congenital Heart Disease NeoReviews, July 1, 2006; 7(7): e363 - e369. [Full Text] [PDF]
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G. M. Hoffman Neurologic Monitoring on Cardiopulmonary Bypass: What Are We Obligated to Do? Ann. Thorac. Surg., June 1, 2006; 81(6): S2373 - S2380. [Abstract] [Full Text] [PDF]
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T.-Y. Hsia and P. J. Gruber Factors Influencing Neurologic Outcome After Neonatal Cardiopulmonary Bypass: What We Can and Cannot Control Ann. Thorac. Surg., June 1, 2006; 81(6): S2381 - S2388. [Abstract] [Full Text] [PDF]
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J. R. Kaltman, G. P. Jarvik, J. Bernbaum, G. Wernovsky, M. Gerdes, E. Zackai, R. R. Clancy, S. C. Nicolson, T. L. Spray, and J. W. Gaynor Neurodevelopmental outcome after early repair of a ventricular septal defect with or without aortic arch obstruction J. Thorac. Cardiovasc. Surg., April 1, 2006; 131(4): 792 - 798. [Abstract] [Full Text] [PDF]
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B. Jungwirth, G. B. Mackensen, M. Blobner, F. Neff, B. Reichart, E. F. Kochs, and G. Nollert Neurologic outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats: Description of a new model J. Thorac. Cardiovasc. Surg., April 1, 2006; 131(4): 805 - 812. [Abstract] [Full Text] [PDF]
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J. W. Gaynor, G. Wernovsky, and R. Clancy Invited commentary Ann. Thorac. Surg., March 1, 2006; 81(3): 967 - 967. [Full Text] [PDF]
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P. S. McQuillen, S. E.G. Hamrick, M. J. Perez, A. J. Barkovich, D. V. Glidden, T. R. Karl, D. Teitel, and S. P. Miller Balloon Atrial Septostomy Is Associated With Preoperative Stroke in Neonates With Transposition of the Great Arteries Circulation, January 17, 2006; 113(2): 280 - 285. [Abstract] [Full Text] [PDF]
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E. A. Bacha, S. Daves, J. Hardin, R.-i. Abdulla, J. Anderson, M. Kahana, P. Koenig, B. N. Mora, M. Gulecyuz, J. P. Starr, et al. Single-ventricle palliation for high-risk neonates: The emergence of an alternative hybrid stage I strategy J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 163 - 171. [Abstract] [Full Text] [PDF]
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A. H. Schultz, G. P. Jarvik, G. Wernovsky, J. Bernbaum, R. R. Clancy, J. A. D'Agostino, M. Gerdes, D. McDonald-McGinn, S. C. Nicolson, T. L. Spray, et al. Effect of congenital heart disease on neurodevelopmental outcomes within multiple-gestation births J. Thorac. Cardiovasc. Surg., December 1, 2005; 130(6): 1511 - 1516. [Abstract] [Full Text] [PDF]
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F. L. Hanley Religion, politics...deep hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1236 - 1236. [Full Text] [PDF]
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J. W. Gaynor, S. C. Nicolson, G. P. Jarvik, G. Wernovsky, L. M. Montenegro, N. B. Burnham, D. M. Hartman, A. Louie, T. L. Spray, and R. R. Clancy Increasing duration of deep hypothermic circulatory arrest is associated with an increased incidence of postoperative electroencephalographic seizures J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1278 - 1286. [Abstract] [Full Text] [PDF]
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G. M. Hoffman, K. A. Mussatto, C. L. Brosig, N. S. Ghanayem, N. Musa, R. T. Fedderly, R. D.B. Jaquiss, and J. S. Tweddell Systemic venous oxygen saturation after the Norwood procedure and childhood neurodevelopmental outcome J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 1094 - 1100. [Abstract] [Full Text] [PDF]
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A. Azakie, J. Muse, M. Gardner, K. L. Skidmore, S. P. Miller, T. R. Karl, and P. S. McQuillen Cerebral oxygen balance is impaired during repair of aortic coarctation in infants and children J. Thorac. Cardiovasc. Surg., September 1, 2005; 130(3): 830 - 836. [Abstract] [Full Text] [PDF]
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