Neurodevelopmental Outcomes After Infant Cardiac Surgery With Circulatory Arrest and Intermittent Perfusion Christian Pizarro, MD, Erica D. Sood, PhD, Paul Kerins, CCP, Daniel Duncan, CCP, Ryan R. Davies, MD, and Edward Woodford, MPAS Nemours Cardiac Center, and Division of Behavioral Health, Alfred I. duPont Hospital for Children, Wilmington, Delaware
Background. Optimal perfusion strategies for neuroprotection during infant cardiac surgery remain undefined. Despite encouraging experimental data, neurodevelopmental (ND) outcomes after cardiac surgery in neonates and infants using deep hypothermic circulatory arrest (DHCA) with a period of intermittent perfusion have not been reported, and it is not known whether it can extend DHCA while preserving ND outcomes. Methods. Cross-sectional ND evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition was conducted at 24 months of age. Retrospective clinical data were extracted from the electronic medical record. Results. Forty patients underwent cardiac surgery during the first year of life using a period of uninterrupted DHCA (24 patients) or DHCA interrupted by a period of intermittent perfusion (16 patients). Total duration of DHCA ranged from 5 to 74 minutes and did not predict ND scores. Despite a longer exposure to
DHCA in the intermittent perfusion group (55 minutes [1,3 interquartile [IQ] 45.3 to 65.5] versus 38 minutes [1,3 IQ 32 to 40.8]), no differences in ND scores were detected. Significant comorbidities, duration of intensive care unit and hospital stay, as well as multiple procedures with DHCA were independent predictors of ND outcomes at 24 months of age. Conclusions. Despite extended duration of total DHCA, the use of a period of intermittent perfusion to limit uninterrupted DHCA periods to less than 45 minutes could lead to ND outcomes similar to those of patients exposed to brief periods of DHCA. Deep hypothermic circulatory arrest with intermittent perfusion may facilitate implementation of prospective studies to identify the optimal cerebral perfusion strategy.
N
40 minutes interrupted by a period of total body intermittent perfusion (IP) exists [17, 18]. This study seeks to document ND outcomes at 24 months of age in patients who underwent cardiac surgery with DHCA with or without IP during the first year of life, and to explore whether the use of a period of IP can extend the total duration of DHCA while preserving ND outcomes.
eurodevelopmental (ND) impairment is the most common morbidity affecting quality of life in children after surgical intervention for congenital heart disease [1]. Deep hypothermic circulatory arrest (DHCA) offers distinct technical advantages, most notably in procedures involving the aortic arch and in those performed on the smallest patients [2–8]. However, extended periods of DHCA have been associated with neurologic injury and adverse ND outcomes [9–12]. Several experimental studies have demonstrated that limiting the duration of uninterrupted DHCA (U-DHCA) using a period of total body reperfusion results in preservation of the brain microvascular structure and improved cerebral metabolic recovery, despite total duration of DHCA beyond 60 minutes [13–16]. These observations suggest that this strategy could ameliorate the impact of cerebral ischemia and improve neurologic outcomes. However, no published data on the neurodevelopment of children exposed to DHCA beyond Accepted for publication Feb 20, 2014. Address correspondence to Dr Pizarro, Nemours Cardiac Center, Alfred I. duPont Hospital for Children, 1600 Rockland Rd, Wilmington, Delaware 19803; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
Patients and Methods Study Design and Participants Participants were enrolled in a cross-sectional study examining neurodevelopmental outcome at 24 months of age after newborn or infant cardiac surgery performed between 2007 and 2010. Forty patients exposed to DHCA during open-heart surgery were stratified into 2 groups based on the use of IP; 16 patients had a total of 40 to 74 minutes of DHCA with IP (IP-DHCA), and 24 patients had 45 minutes or less of uninterrupted DHCA (U-DHCA). In order to avoid potential confounders known to adversely affect ND outcomes, patients with chromosomal anomalies, birth asphyxia, or a previous history of resuscitation or perioperative mechanical support were excluded. Subsequent procedures with DHCA 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.02.042
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were performed in 12 patients prior to ND assessment. Five patients in the U-DHCA group had additional exposure to U-DHCA (26 to 45 minutes), and among 7 patients in the IP-DHCA group, 2 had additional exposure to DHCA with IP (53 to 69 minutes) and 5 had U-DHCA (5 to 45 minutes); therefore, no patient was exposed to U-DHCA greater than 45 minutes without a period of IP. Clinical and perioperative data were extracted from the electronic medical records. The Nemours Institutional Review Board approved this research, and parental consent was obtained from the parents or legal guardians prior to the ND assessment and data extraction.
Operative Management Patients were managed in a dedicated cardiac intensive care unit. Perfusion management included pH-stat strategy during cooling with a target hematocrit of 30%, the use of fresh whole blood, single dose of steroids in the cardiopulmonary (CPB) prime, and the use of conventional ultrafiltration. Total body IP was performed at the discretion of the surgeon when a period of DHCA greater than 40 minutes was anticipated. This was accomplished by placing the arterial cannula in the proximal aorta, in order to perfuse all the brachiocephalic vessels and the descending aorta. Target flow was 100 cc kg1 min1. Perfusion was continued for a minimum of 1 minute for every 10 minutes of DHCA, while maintaining the nasopharyngeal temperature at 18 C.
Neurodevelopmental Testing Children were administered the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 24 3 months of age by a clinical psychologist according to standardization. The Bayley-III assesses the developmental functioning of infants and young children through items administered in a structured play format [19]. This measure allows for the calculation of separate cognitive, receptive communication, and expressive communication scaled scores (previously combined into the Mental Development Index) and separate fine and gross motor scaled scores (previously combined into the Psychomotor Development Index).
Analytic Strategy Descriptive analyses examined sociodemographic and clinical characteristics of the cohort. Procedure-related characteristics referred to the first (index) open-heart procedure. The ND scores and prevalence of delay (defined as > 1 SD below normative mean) were examined for the entire cohort as well as for each perfusion strategy group. Exploratory analyses using the MannWhitney test and Fisher exact test were used to compare ND outcomes across groups. Nonparametric tests were chosen due to non-normal distributions of ND scores within each group. Correlations (Kendall s) between DHCA duration and ND scores were examined for the entire cohort. Correlations between reperfusion duration, flow rate, and ND
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scores were also explored. Lastly, forward stepwise linear regression analyses were conducted on the entire cohort to identify the best models for the prediction of ND scores. Clinical and sociodemographic characteristics significantly associated with ND scores in univariable correlation analyses (p < 0.05) were used as candidate predictors for multivariable modeling. The entry criterion was set at a p value less than 0.05 and the removal criterion was set at a p value of 0.10 or greater. Explained variance for all models was calculated by adjusted R2 values. Analyses were conducted utilizing SPSS software version 19 (2010; SPSS Inc, Chicago, IL). Considering the number of subjects (40) this study was powered to detect large differences (12 to 14 points) on the Bayley-III composite scores (Cohen d ¼ .95), which represents 1 standard deviation (scores have a mean of 100 and a standard deviation of 15).
Results Clinical Characteristics Clinical characteristics of participants are shown in Table 1. Patients in the IP-DHCA group were exposed to longer periods of DHCA and CPB; they also had longer intensive care unit and hospital stays compared with patients exposed to U-DHCA. In addition, patients in the IP-DHCA group demonstrated a tendency to be younger at the time of surgery, be in the intensive care unit preoperatively, and have a higher Aristotle complexity score as well as an increased number of procedures with DHCA prior to ND evaluation. Case mix was similar between groups; however, procedures involving the aortic arch (Norwood, VSD plus coarctation) predominated in the IP-DHCA group. Regarding sociodemographic characteristics, no differences were observed between groups (Table 2).
Group Comparisons on Neurodevelopmental Outcome Median ND scores for each perfusion strategy are shown in Table 3. Despite a total DHCA time being longer than 40 minutes and up to 74 minutes, the use of IP separating 2 periods of DHCA led to neurodevelopmental scores similar to or slightly better than those in the U-DHCA group (Table 3). In addition, the proportion of patients exhibiting delay in each ND domain did not differ significantly between patients exposed to IP-DHCA versus U-DHCA.
DHCA Duration, Reperfusion Characteristics, and Neurodevelopmental Outcome The duration of DHCA was not associated with ND scores (correlations ranging from .16 to .15; p values > 0.20). Neurodevelopmental scores and the proportion of children with delays in each domain also did not differ significantly between patients who had less than 40 or 40 or greater minutes of DHCA. In the IP-DHCA group, the 3 patients with the longest total exposure to DHCA (as high as 70 to 74 minutes) had average cognitive scores. Available data in 2 of the 3 patients also showed average
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Table 1. Clinical Characteristics Characteristic Median (IQ-3Q) Age at surgery (days) Weight at surgery (kg) ACS CPB support (min) DHCA (min) Reperfusion (min) IP flow (cc/kg/min) ICU stay (days) Hospital stay (days) Lifetime DHCA (min) Frequency (%) Premature birth Significant comorbiditya Single ventricle Preoperative ICU Preoperative cyanosis Multiple procedures Multiple DHCA Frequency (%) Procedure Norwood VSD Coarct TOF AS VSD Arch repair DORV Hemi-Fontan TAPVC Ross-Konno arch Other
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IP-DHCA
5.4 3.3 14.2 128.5 55 8 70.6 10 21 73.5
(3–18) (2.9–4.1) (10.2–17.1) (113–145.5) (45.3–65.5) (5–12.8) (48.6–98) (6.8–15) (15.3–28.5) (47.8–109.5)
2 (12.5%) 5 (31.3%)
Table 2. Sociodemographic Characteristics U-DHCA
p Value
33 3.6 10.8 77.5 38
(6–57) 0.06 (3.2–4.2) 0.17 (7.1–15.3) 0.15 (73.3–108.5) 0.2 0.06 >0.2 >0.2 0.17
5 3 1 1 2 2 0 1 1 0
(31.3%) (18.8%) (6.3%) (6.3%) (12.5%) (12.5%) (0%) (6.3%) (6.3%) (0%)
3 4 4 3 2 0 2 1 1 4
(12.5%) (16.7%) (16.7%) (12.5%) (8.3%) (0%) (8.3%) (4.2%) (4.2%) (16.7%)
>0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2
Significant comorbidities included: gestational age 0.20).
Multivariable Linear Regression Models Significant univariable associations (p < 0.05) of neurodevelopmental scores with sociodemographic and clinical characteristics are summarized in Table 4. Factors included in the final multivariable models for each
Characteristic Race Caucasian African American Other Household income < $39,999 $40,000 – $69,999 $70,000 – $99,999 > $100,000 Education level of accompanying parent College degree Education level of spouse/partner College degree
IP-DHCA
U-DHCA
p Value
12 (75%) 3 (18.8%) 1 (6.3%)
18 (75%) 4 (16.7%) 2 (8.3%)
>0.2 >0.2 >0.2
(33.3%) (9.5%) (28.6%) (28.6%)
>0.2 >0.2 >0.2 >0.2
8 (50%)
9 (39.1%)
>0.2
7 (50%)
10 (47.6%)
>0.2
3 6 5 2
(18.8%) (37.5%) (31.3%) (12.5%)
7 2 6 6
neurodevelopmental outcome are shown in Table 5. The final multivariable model for cognitive outcome consisted of length of hospital stay and the presence of a significant comorbidity, which together accounted for 24% of the variance. Similarly, receptive communication outcome was influenced by the presence of a significant comorbidity, which accounted for 9% of the variance. In the motor domain, fine motor outcome was influenced by the length of intensive care unit stay, which accounted for 9% of the variance, while gross motor outcome was influenced by a history of multiple
Table 3. Neurodevelopmental Outcomes Variable
DHCA þ IP
Median (IQ-3Q)a Cognitive 95 (82.5–100) Language 103 (81–109) Receptive 10 (7–11.75) Expressive 10 (7–12) Motor 95.5 (94–97) Fine motor 11 (9.5–11.5) Gross motor 8 (8–8.75) Frequency (%) of delayb Cognitive 4 (25%) Language 4 (30.8%) Receptive 3 (18.8%) Expressive 2 (15.4%) Motor 1 (8.3%) Fine motor 1 (7.7%) Gross motor 1 (8.3%)
U-DHCA
95 94 9 9 91 9.5 8 2 7 6 5 3 2 4
p Volume
(90–105) (79–106) (6–13) (7–10) (89.5–98.5) (8–11) (7–9)
>0.2 >0.2 >0.2 >0.2 >0.2 0.13 >0.2
(8.7%) (30.4%) (26.1%) (21.7%) (14.3%) (9.1%) (18.2%)
>0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2
a
Bayley-III composite scores have a mean and median of 100 (15) and b Delay defined as subtest scores have a mean and median of 10 (3). >1 SD below normative mean.
DHCA ¼ deep hypothermic circulatory arrest; perfusion; U ¼ uninterrupted.
IP ¼ intermittent
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Table 4. Candidate Predictors for Multivariable Modeling (p < 0.05) Univariable Correlations With Neurodevelopmental Outcome Variable Cognitive Single ventricle physiologya Significant comorbiditya Length of ICU stay Length of hospital stay Multiple DHCAa Receptive communication Significant comorbidity Expressive communication None a
r
p
.35 .42 .37 .43 .32
0.03 0.01 0.02 0.01 0.049
.33
0.04
Fine motor Length of ICU stay Gross motor Significant comorbidity Multiple DHCA Cumulative DHCA Length of hospital stay
r
p
.35
0.04
.38 .44 .37 .37
0.03 0.01 0.03 0.03
Dichotomous variables present (1) or absent (0).
DHCA ¼ deep hypothermic circulatory arrest;
ICU ¼ intensive care unit.
favorable effect on magnetic resonance imaging-detected brain injury and ND outcomes, including a prospective randomized trial, have failed to provide such evidence [21, 22]. Despite the intuitive notion that RCP is protective, this concept has been challenged by Gunn and colleagues [23] who reported a 33% incidence of perioperative seizures in a cohort of patients undergoing arch reconstruction while utilizing RCP between 18 and 25 C. These seizures were commonly left-sided and usually present during the period of RCP. In addition, the reduction in left-hemispheric cerebral oxygenation reported by near infrared spectroscopy during RCP [24] brings into question the effectiveness of this approach in its current form. Experimental studies indicate that limiting the duration of extended U-DHCA through an interval period of complete cerebral (all brachiocephalic vessels) reperfusion is associated with preservation of the cerebral vascular bed integrity and improvement of cerebral metabolism, providing direct evidence of neuroprotection, and suggesting the potential to improve
procedures with DHCA and presence of a significant comorbidity, which together accounted for 25% of the variance.
Comment Despite widespread recognition of a higher incidence of neurodevelopmental impairment among children with complex congenital heart disease and the priority assigned to research for neuroprotective strategies, little evidence regarding the optimal intraoperative perfusion strategy is available [1, 17, 18, 20]. Deep hypothermic circulatory arrest has been used in many centers due to its distinct technical advantages and the ability to ameliorate the morbidity associated with CPB exposure, particularly in neonates and the smallest patients [2–8]. However, extended periods of DHCA have been shown to be associated with neurologic injury leading to adverse ND outcomes [9–12]. Regional cerebral perfusion (RCP) has become a popular strategy to minimize the exposure to DHCA; however, studies aiming to demonstrate a Table 5. Final Stepwise Linear Regression Models Variable Regression 1: cognitive Length of hospital stay Significant comorbiditya,b Regression 2: receptive communication Significant comorbidity Regression 3: Fine motor Length of ICU stay Regression 4: Gross motor Multiple DHCAb Significant comorbidity
B
SE (B)
95% CI
b
p
0.04 2.36
0.02 1.06
.07 – .004 4.5 – .20
.34 .33
0.03 0.03
2.85
1.34
5.6 – .14
.33
0.04
0.04
0.02
.07 – .002
.35
0.04
1.35 1.18
0.53 0.56
2.4 – .27 2.3 – .04
.39 .32
0.02 0.04
R2 .24
.09 .09 .25
Significant comorbidities included prematurity < 35 weeks gestational age, arrhythmia, necrotizing enterocolitis, depressed myocardial function, protein losing enteropathy/right ventricle dysfunction/pacemaker, history of prolonged mechanical ventilation/portal hypertension/pneumonia, seizure, and b Dichotomous variables present (1) or absent (0). pancreatic insufficiency.
a
CI ¼ confidence interval;
DHCA ¼ deep hypothermic circulatory arrest.
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neurologic outcomes [14-16]. However, data on the neurodevelopmental outcomes of children exposed to DHCA with IP have never been reported [17, 18]. In this study, patients in the IP-DHCA group had similar ND outcomes at 24 months as those in the UDCHA group despite exposure to total DHCA times well beyond 45 minutes. These findings contrast with the report by Forbess and colleagues [10] as well as Wypij [11] and colleagues demonstrating that patients exposed to greater than 39 or 41 minutes of DHCA, respectively, had worse neurodevelopmental outcomes than patients exposed to shorter periods of DHCA. In light of the experimental data it is possible our observations represent the clinical corollary of the neuroprotective effect conferred by IP. Given the sample size, this study was powered to only detect large differences (12 points or greater) between groups. While we can conclude that patients exposed to IP-DHCA do not exhibit large differences in ND outcomes compared with patients exposed to shorter periods of U-DHCA, lesser differences may exist. However, it should be noted that the median scores for the IP-DHCA group were similar or slightly higher in every domain tested. In fact, despite a broad range of DHCA from 4 to as long as 74 minutes, duration of DHCA evaluated as a continuum or using the 40minute threshold was not associated with ND outcomes in any domain. Previous reports have documented that the incidence of postoperative electroencephalographic seizures varies between 20% and 11% among infants undergoing cardiac surgery, with clinical seizures being apparent in one third of them, particularly when DHCA exceeds 40 minutes [11, 12]. Although in our study the duration of DHCA in the IP-DHCA group was considerably longer than 40 minutes, no clinical seizures were observed in this cohort. However, in the absence of continuous postoperative electroencephalogram monitoring the true incidence of seizures remains unknown and will remain a matter of speculation. Nevertheless, likely there is a threshold for the duration of DHCA below which the incidence of seizure activity is low and no different from patients who do not undergo DHCA. Based on the experimental observation of preservation of microvascular structure and brain metabolism, it is possible that a period of IP could influence that threshold. Previous studies have attempted to define a safe threshold for DHCA to prevent central nervous system injury and subsequent ND issues. However, there is increasing evidence that even the continuous use of CPB is not entirely safe and can be associated with seizures, neurologic injury, and adverse ND sequelae [25]. Patient-related characteristics, such as the presence of a significant comorbidity, as well as total length of hospital stay, were robust predictors of neurodevelopment, whereas when IP perfusion was used to limit U-DHCA to less than 45 minutes, DHCA duration was not. Although the frequency of delays was similar between groups, a difference greater than 10% in the cognitive domain at first glance could be quickly attributed to the duration of DHCA despite IP; this should be interpreted in light of
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the higher complexity and severity of illness of these patients, variables which were the most important predictors in the multivariable analysis. Numerous reports have documented relationships between innate patient characteristics and other clinical variables and neurodevelopmental outcomes, often far exceeding the variance accounted for by intraoperative management strategies [26–28]. For example, innate patient factors and measures of greater severity of illness, but not DHCA use or duration, emerged as independent risk factors for neurodevelopment outcome at 14 months of age for patients enrolled in the Single Ventricle Reconstruction trial [28]. As demonstrated by the recent survey of preferences and attitudes toward perfusion techniques during neonatal arch reconstruction [17], there is an absolute paucity of robust and conclusive data to inform this decision, concluding that the use of DHCA, RCP, and DHCA with IP remains largely based on personal experience and surgeons’ own beliefs. In this scenario we provide the first report on neurodevelopmental outcomes associated with the use of DHCA with IP. This data could inform a surgeon’s decision about the advisability of IP when confronted with the need to extend a period of DHCA.
Limitations Important limitations of this study include its retrospective design and its limited sample size. The relatively uniform conduct of the reperfusion strategy make it difficult to define the influence of temperature, flow, hematocrit, and pH-strategy on ND outcomes. The lack of routine perioperative neuroimaging and electroencephalogram monitoring did not allow analysis of potential differences regarding incidence of preoperative and postoperative brain injury as well as the true incidence of seizures. While representative of current clinical practice, the shorter durations of DHCA among patients who did not receive IP precluded comparisons of prolonged DHCA with or without IP. Although almost half of the participants in this study had multiple cardiac procedures and almost a third had multiple procedures with DHCA, subsequent exposures to DHCA were shorter and the IP strategy continued to be used for patients with extended exposures. It should be noted that difficulties remaining engaged and cooperative for up to 90 minutes is not atypical for 2-year olds, it is also possible that these difficulties are a surrogate for impairments in attention and emotional regulation, which have been previously documented in children with congenital heart disease [24, 26].
Conclusions This study documents that children exposed to total DHCA beyond 40 minutes during cardiac surgery in the first year of life did not exhibit large differences in ND outcomes, compared with those who underwent shorter periods of DHCA, when IP was used to limit duration of U-DHCA to less than 45 minutes.
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The use of DHCA with IP could provide a valid perfusion strategy to be compared against regional perfusion techniques in a randomized controlled trial. The limits of neuroprotection associated with IP remain to be defined. We would like to thank Julie S. Benzaquen, PhD, for her contribution to the neurodevelopmental evaluations. This research was supported by a grant from the Nemours Foundation (Grant number 16-07700-001) and was also made possible through the generosity of donors (Nemours Fund for Children’s Health).
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13. 14.
15. 16.
17.
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Background. Optimal perfusion strategies for neuroprotection during infant cardiac surgery remain undefined. Despite encouraging experimental data, neurodevelopmental (ND) outcomes after cardiac surgery in neonates and infants using deep hypothermic circulatory arrest (DHCA) with a period of intermittent perfusion have not been reported, and it is not known whether it can extend DHCA while preserving ND outcomes. Methods. Cross-sectional ND evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition was conducted at 24 months of age. Retrospective clinical data were extracted from the electronic medical record. Results. Forty patients underwent cardiac surgery during the first year of life using a period of uninterrupted DHCA (24 patients) or DHCA interrupted by a period of intermittent perfusion (16 patients). Total duration of DHCA ranged from 5 to 74 minutes and did not predict ND scores. Despite a longer exposure to
DHCA in the intermittent perfusion group (55 minutes [1,3 interquartile [IQ] 45.3 to 65.5] versus 38 minutes [1,3 IQ 32 to 40.8]), no differences in ND scores were detected. Significant comorbidities, duration of intensive care unit and hospital stay, as well as multiple procedures with DHCA were independent predictors of ND outcomes at 24 months of age. Conclusions. Despite extended duration of total DHCA, the use of a period of intermittent perfusion to limit uninterrupted DHCA periods to less than 45 minutes could lead to ND outcomes similar to those of patients exposed to brief periods of DHCA. Deep hypothermic circulatory arrest with intermittent perfusion may facilitate implementation of prospective studies to identify the optimal cerebral perfusion strategy.
N
40 minutes interrupted by a period of total body intermittent perfusion (IP) exists [17, 18]. This study seeks to document ND outcomes at 24 months of age in patients who underwent cardiac surgery with DHCA with or without IP during the first year of life, and to explore whether the use of a period of IP can extend the total duration of DHCA while preserving ND outcomes.
eurodevelopmental (ND) impairment is the most common morbidity affecting quality of life in children after surgical intervention for congenital heart disease [1]. Deep hypothermic circulatory arrest (DHCA) offers distinct technical advantages, most notably in procedures involving the aortic arch and in those performed on the smallest patients [2–8]. However, extended periods of DHCA have been associated with neurologic injury and adverse ND outcomes [9–12]. Several experimental studies have demonstrated that limiting the duration of uninterrupted DHCA (U-DHCA) using a period of total body reperfusion results in preservation of the brain microvascular structure and improved cerebral metabolic recovery, despite total duration of DHCA beyond 60 minutes [13–16]. These observations suggest that this strategy could ameliorate the impact of cerebral ischemia and improve neurologic outcomes. However, no published data on the neurodevelopment of children exposed to DHCA beyond Accepted for publication Feb 20, 2014. Address correspondence to Dr Pizarro, Nemours Cardiac Center, Alfred I. duPont Hospital for Children, 1600 Rockland Rd, Wilmington, Delaware 19803; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
Patients and Methods Study Design and Participants Participants were enrolled in a cross-sectional study examining neurodevelopmental outcome at 24 months of age after newborn or infant cardiac surgery performed between 2007 and 2010. Forty patients exposed to DHCA during open-heart surgery were stratified into 2 groups based on the use of IP; 16 patients had a total of 40 to 74 minutes of DHCA with IP (IP-DHCA), and 24 patients had 45 minutes or less of uninterrupted DHCA (U-DHCA). In order to avoid potential confounders known to adversely affect ND outcomes, patients with chromosomal anomalies, birth asphyxia, or a previous history of resuscitation or perioperative mechanical support were excluded. Subsequent procedures with DHCA 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.02.042
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were performed in 12 patients prior to ND assessment. Five patients in the U-DHCA group had additional exposure to U-DHCA (26 to 45 minutes), and among 7 patients in the IP-DHCA group, 2 had additional exposure to DHCA with IP (53 to 69 minutes) and 5 had U-DHCA (5 to 45 minutes); therefore, no patient was exposed to U-DHCA greater than 45 minutes without a period of IP. Clinical and perioperative data were extracted from the electronic medical records. The Nemours Institutional Review Board approved this research, and parental consent was obtained from the parents or legal guardians prior to the ND assessment and data extraction.
Operative Management Patients were managed in a dedicated cardiac intensive care unit. Perfusion management included pH-stat strategy during cooling with a target hematocrit of 30%, the use of fresh whole blood, single dose of steroids in the cardiopulmonary (CPB) prime, and the use of conventional ultrafiltration. Total body IP was performed at the discretion of the surgeon when a period of DHCA greater than 40 minutes was anticipated. This was accomplished by placing the arterial cannula in the proximal aorta, in order to perfuse all the brachiocephalic vessels and the descending aorta. Target flow was 100 cc kg1 min1. Perfusion was continued for a minimum of 1 minute for every 10 minutes of DHCA, while maintaining the nasopharyngeal temperature at 18 C.
Neurodevelopmental Testing Children were administered the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 24 3 months of age by a clinical psychologist according to standardization. The Bayley-III assesses the developmental functioning of infants and young children through items administered in a structured play format [19]. This measure allows for the calculation of separate cognitive, receptive communication, and expressive communication scaled scores (previously combined into the Mental Development Index) and separate fine and gross motor scaled scores (previously combined into the Psychomotor Development Index).
Analytic Strategy Descriptive analyses examined sociodemographic and clinical characteristics of the cohort. Procedure-related characteristics referred to the first (index) open-heart procedure. The ND scores and prevalence of delay (defined as > 1 SD below normative mean) were examined for the entire cohort as well as for each perfusion strategy group. Exploratory analyses using the MannWhitney test and Fisher exact test were used to compare ND outcomes across groups. Nonparametric tests were chosen due to non-normal distributions of ND scores within each group. Correlations (Kendall s) between DHCA duration and ND scores were examined for the entire cohort. Correlations between reperfusion duration, flow rate, and ND
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scores were also explored. Lastly, forward stepwise linear regression analyses were conducted on the entire cohort to identify the best models for the prediction of ND scores. Clinical and sociodemographic characteristics significantly associated with ND scores in univariable correlation analyses (p < 0.05) were used as candidate predictors for multivariable modeling. The entry criterion was set at a p value less than 0.05 and the removal criterion was set at a p value of 0.10 or greater. Explained variance for all models was calculated by adjusted R2 values. Analyses were conducted utilizing SPSS software version 19 (2010; SPSS Inc, Chicago, IL). Considering the number of subjects (40) this study was powered to detect large differences (12 to 14 points) on the Bayley-III composite scores (Cohen d ¼ .95), which represents 1 standard deviation (scores have a mean of 100 and a standard deviation of 15).
Results Clinical Characteristics Clinical characteristics of participants are shown in Table 1. Patients in the IP-DHCA group were exposed to longer periods of DHCA and CPB; they also had longer intensive care unit and hospital stays compared with patients exposed to U-DHCA. In addition, patients in the IP-DHCA group demonstrated a tendency to be younger at the time of surgery, be in the intensive care unit preoperatively, and have a higher Aristotle complexity score as well as an increased number of procedures with DHCA prior to ND evaluation. Case mix was similar between groups; however, procedures involving the aortic arch (Norwood, VSD plus coarctation) predominated in the IP-DHCA group. Regarding sociodemographic characteristics, no differences were observed between groups (Table 2).
Group Comparisons on Neurodevelopmental Outcome Median ND scores for each perfusion strategy are shown in Table 3. Despite a total DHCA time being longer than 40 minutes and up to 74 minutes, the use of IP separating 2 periods of DHCA led to neurodevelopmental scores similar to or slightly better than those in the U-DHCA group (Table 3). In addition, the proportion of patients exhibiting delay in each ND domain did not differ significantly between patients exposed to IP-DHCA versus U-DHCA.
DHCA Duration, Reperfusion Characteristics, and Neurodevelopmental Outcome The duration of DHCA was not associated with ND scores (correlations ranging from .16 to .15; p values > 0.20). Neurodevelopmental scores and the proportion of children with delays in each domain also did not differ significantly between patients who had less than 40 or 40 or greater minutes of DHCA. In the IP-DHCA group, the 3 patients with the longest total exposure to DHCA (as high as 70 to 74 minutes) had average cognitive scores. Available data in 2 of the 3 patients also showed average
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Table 1. Clinical Characteristics Characteristic Median (IQ-3Q) Age at surgery (days) Weight at surgery (kg) ACS CPB support (min) DHCA (min) Reperfusion (min) IP flow (cc/kg/min) ICU stay (days) Hospital stay (days) Lifetime DHCA (min) Frequency (%) Premature birth Significant comorbiditya Single ventricle Preoperative ICU Preoperative cyanosis Multiple procedures Multiple DHCA Frequency (%) Procedure Norwood VSD Coarct TOF AS VSD Arch repair DORV Hemi-Fontan TAPVC Ross-Konno arch Other
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IP-DHCA
5.4 3.3 14.2 128.5 55 8 70.6 10 21 73.5
(3–18) (2.9–4.1) (10.2–17.1) (113–145.5) (45.3–65.5) (5–12.8) (48.6–98) (6.8–15) (15.3–28.5) (47.8–109.5)
2 (12.5%) 5 (31.3%)
Table 2. Sociodemographic Characteristics U-DHCA
p Value
33 3.6 10.8 77.5 38
(6–57) 0.06 (3.2–4.2) 0.17 (7.1–15.3) 0.15 (73.3–108.5) 0.2 0.06 >0.2 >0.2 0.17
5 3 1 1 2 2 0 1 1 0
(31.3%) (18.8%) (6.3%) (6.3%) (12.5%) (12.5%) (0%) (6.3%) (6.3%) (0%)
3 4 4 3 2 0 2 1 1 4
(12.5%) (16.7%) (16.7%) (12.5%) (8.3%) (0%) (8.3%) (4.2%) (4.2%) (16.7%)
>0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2
Significant comorbidities included: gestational age 0.20).
Multivariable Linear Regression Models Significant univariable associations (p < 0.05) of neurodevelopmental scores with sociodemographic and clinical characteristics are summarized in Table 4. Factors included in the final multivariable models for each
Characteristic Race Caucasian African American Other Household income < $39,999 $40,000 – $69,999 $70,000 – $99,999 > $100,000 Education level of accompanying parent College degree Education level of spouse/partner College degree
IP-DHCA
U-DHCA
p Value
12 (75%) 3 (18.8%) 1 (6.3%)
18 (75%) 4 (16.7%) 2 (8.3%)
>0.2 >0.2 >0.2
(33.3%) (9.5%) (28.6%) (28.6%)
>0.2 >0.2 >0.2 >0.2
8 (50%)
9 (39.1%)
>0.2
7 (50%)
10 (47.6%)
>0.2
3 6 5 2
(18.8%) (37.5%) (31.3%) (12.5%)
7 2 6 6
neurodevelopmental outcome are shown in Table 5. The final multivariable model for cognitive outcome consisted of length of hospital stay and the presence of a significant comorbidity, which together accounted for 24% of the variance. Similarly, receptive communication outcome was influenced by the presence of a significant comorbidity, which accounted for 9% of the variance. In the motor domain, fine motor outcome was influenced by the length of intensive care unit stay, which accounted for 9% of the variance, while gross motor outcome was influenced by a history of multiple
Table 3. Neurodevelopmental Outcomes Variable
DHCA þ IP
Median (IQ-3Q)a Cognitive 95 (82.5–100) Language 103 (81–109) Receptive 10 (7–11.75) Expressive 10 (7–12) Motor 95.5 (94–97) Fine motor 11 (9.5–11.5) Gross motor 8 (8–8.75) Frequency (%) of delayb Cognitive 4 (25%) Language 4 (30.8%) Receptive 3 (18.8%) Expressive 2 (15.4%) Motor 1 (8.3%) Fine motor 1 (7.7%) Gross motor 1 (8.3%)
U-DHCA
95 94 9 9 91 9.5 8 2 7 6 5 3 2 4
p Volume
(90–105) (79–106) (6–13) (7–10) (89.5–98.5) (8–11) (7–9)
>0.2 >0.2 >0.2 >0.2 >0.2 0.13 >0.2
(8.7%) (30.4%) (26.1%) (21.7%) (14.3%) (9.1%) (18.2%)
>0.2 >0.2 >0.2 >0.2 >0.2 >0.2 >0.2
a
Bayley-III composite scores have a mean and median of 100 (15) and b Delay defined as subtest scores have a mean and median of 10 (3). >1 SD below normative mean.
DHCA ¼ deep hypothermic circulatory arrest; perfusion; U ¼ uninterrupted.
IP ¼ intermittent
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Table 4. Candidate Predictors for Multivariable Modeling (p < 0.05) Univariable Correlations With Neurodevelopmental Outcome Variable Cognitive Single ventricle physiologya Significant comorbiditya Length of ICU stay Length of hospital stay Multiple DHCAa Receptive communication Significant comorbidity Expressive communication None a
r
p
.35 .42 .37 .43 .32
0.03 0.01 0.02 0.01 0.049
.33
0.04
Fine motor Length of ICU stay Gross motor Significant comorbidity Multiple DHCA Cumulative DHCA Length of hospital stay
r
p
.35
0.04
.38 .44 .37 .37
0.03 0.01 0.03 0.03
Dichotomous variables present (1) or absent (0).
DHCA ¼ deep hypothermic circulatory arrest;
ICU ¼ intensive care unit.
favorable effect on magnetic resonance imaging-detected brain injury and ND outcomes, including a prospective randomized trial, have failed to provide such evidence [21, 22]. Despite the intuitive notion that RCP is protective, this concept has been challenged by Gunn and colleagues [23] who reported a 33% incidence of perioperative seizures in a cohort of patients undergoing arch reconstruction while utilizing RCP between 18 and 25 C. These seizures were commonly left-sided and usually present during the period of RCP. In addition, the reduction in left-hemispheric cerebral oxygenation reported by near infrared spectroscopy during RCP [24] brings into question the effectiveness of this approach in its current form. Experimental studies indicate that limiting the duration of extended U-DHCA through an interval period of complete cerebral (all brachiocephalic vessels) reperfusion is associated with preservation of the cerebral vascular bed integrity and improvement of cerebral metabolism, providing direct evidence of neuroprotection, and suggesting the potential to improve
procedures with DHCA and presence of a significant comorbidity, which together accounted for 25% of the variance.
Comment Despite widespread recognition of a higher incidence of neurodevelopmental impairment among children with complex congenital heart disease and the priority assigned to research for neuroprotective strategies, little evidence regarding the optimal intraoperative perfusion strategy is available [1, 17, 18, 20]. Deep hypothermic circulatory arrest has been used in many centers due to its distinct technical advantages and the ability to ameliorate the morbidity associated with CPB exposure, particularly in neonates and the smallest patients [2–8]. However, extended periods of DHCA have been shown to be associated with neurologic injury leading to adverse ND outcomes [9–12]. Regional cerebral perfusion (RCP) has become a popular strategy to minimize the exposure to DHCA; however, studies aiming to demonstrate a Table 5. Final Stepwise Linear Regression Models Variable Regression 1: cognitive Length of hospital stay Significant comorbiditya,b Regression 2: receptive communication Significant comorbidity Regression 3: Fine motor Length of ICU stay Regression 4: Gross motor Multiple DHCAb Significant comorbidity
B
SE (B)
95% CI
b
p
0.04 2.36
0.02 1.06
.07 – .004 4.5 – .20
.34 .33
0.03 0.03
2.85
1.34
5.6 – .14
.33
0.04
0.04
0.02
.07 – .002
.35
0.04
1.35 1.18
0.53 0.56
2.4 – .27 2.3 – .04
.39 .32
0.02 0.04
R2 .24
.09 .09 .25
Significant comorbidities included prematurity < 35 weeks gestational age, arrhythmia, necrotizing enterocolitis, depressed myocardial function, protein losing enteropathy/right ventricle dysfunction/pacemaker, history of prolonged mechanical ventilation/portal hypertension/pneumonia, seizure, and b Dichotomous variables present (1) or absent (0). pancreatic insufficiency.
a
CI ¼ confidence interval;
DHCA ¼ deep hypothermic circulatory arrest.
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neurologic outcomes [14-16]. However, data on the neurodevelopmental outcomes of children exposed to DHCA with IP have never been reported [17, 18]. In this study, patients in the IP-DHCA group had similar ND outcomes at 24 months as those in the UDCHA group despite exposure to total DHCA times well beyond 45 minutes. These findings contrast with the report by Forbess and colleagues [10] as well as Wypij [11] and colleagues demonstrating that patients exposed to greater than 39 or 41 minutes of DHCA, respectively, had worse neurodevelopmental outcomes than patients exposed to shorter periods of DHCA. In light of the experimental data it is possible our observations represent the clinical corollary of the neuroprotective effect conferred by IP. Given the sample size, this study was powered to only detect large differences (12 points or greater) between groups. While we can conclude that patients exposed to IP-DHCA do not exhibit large differences in ND outcomes compared with patients exposed to shorter periods of U-DHCA, lesser differences may exist. However, it should be noted that the median scores for the IP-DHCA group were similar or slightly higher in every domain tested. In fact, despite a broad range of DHCA from 4 to as long as 74 minutes, duration of DHCA evaluated as a continuum or using the 40minute threshold was not associated with ND outcomes in any domain. Previous reports have documented that the incidence of postoperative electroencephalographic seizures varies between 20% and 11% among infants undergoing cardiac surgery, with clinical seizures being apparent in one third of them, particularly when DHCA exceeds 40 minutes [11, 12]. Although in our study the duration of DHCA in the IP-DHCA group was considerably longer than 40 minutes, no clinical seizures were observed in this cohort. However, in the absence of continuous postoperative electroencephalogram monitoring the true incidence of seizures remains unknown and will remain a matter of speculation. Nevertheless, likely there is a threshold for the duration of DHCA below which the incidence of seizure activity is low and no different from patients who do not undergo DHCA. Based on the experimental observation of preservation of microvascular structure and brain metabolism, it is possible that a period of IP could influence that threshold. Previous studies have attempted to define a safe threshold for DHCA to prevent central nervous system injury and subsequent ND issues. However, there is increasing evidence that even the continuous use of CPB is not entirely safe and can be associated with seizures, neurologic injury, and adverse ND sequelae [25]. Patient-related characteristics, such as the presence of a significant comorbidity, as well as total length of hospital stay, were robust predictors of neurodevelopment, whereas when IP perfusion was used to limit U-DHCA to less than 45 minutes, DHCA duration was not. Although the frequency of delays was similar between groups, a difference greater than 10% in the cognitive domain at first glance could be quickly attributed to the duration of DHCA despite IP; this should be interpreted in light of
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the higher complexity and severity of illness of these patients, variables which were the most important predictors in the multivariable analysis. Numerous reports have documented relationships between innate patient characteristics and other clinical variables and neurodevelopmental outcomes, often far exceeding the variance accounted for by intraoperative management strategies [26–28]. For example, innate patient factors and measures of greater severity of illness, but not DHCA use or duration, emerged as independent risk factors for neurodevelopment outcome at 14 months of age for patients enrolled in the Single Ventricle Reconstruction trial [28]. As demonstrated by the recent survey of preferences and attitudes toward perfusion techniques during neonatal arch reconstruction [17], there is an absolute paucity of robust and conclusive data to inform this decision, concluding that the use of DHCA, RCP, and DHCA with IP remains largely based on personal experience and surgeons’ own beliefs. In this scenario we provide the first report on neurodevelopmental outcomes associated with the use of DHCA with IP. This data could inform a surgeon’s decision about the advisability of IP when confronted with the need to extend a period of DHCA.
Limitations Important limitations of this study include its retrospective design and its limited sample size. The relatively uniform conduct of the reperfusion strategy make it difficult to define the influence of temperature, flow, hematocrit, and pH-strategy on ND outcomes. The lack of routine perioperative neuroimaging and electroencephalogram monitoring did not allow analysis of potential differences regarding incidence of preoperative and postoperative brain injury as well as the true incidence of seizures. While representative of current clinical practice, the shorter durations of DHCA among patients who did not receive IP precluded comparisons of prolonged DHCA with or without IP. Although almost half of the participants in this study had multiple cardiac procedures and almost a third had multiple procedures with DHCA, subsequent exposures to DHCA were shorter and the IP strategy continued to be used for patients with extended exposures. It should be noted that difficulties remaining engaged and cooperative for up to 90 minutes is not atypical for 2-year olds, it is also possible that these difficulties are a surrogate for impairments in attention and emotional regulation, which have been previously documented in children with congenital heart disease [24, 26].
Conclusions This study documents that children exposed to total DHCA beyond 40 minutes during cardiac surgery in the first year of life did not exhibit large differences in ND outcomes, compared with those who underwent shorter periods of DHCA, when IP was used to limit duration of U-DHCA to less than 45 minutes.
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The use of DHCA with IP could provide a valid perfusion strategy to be compared against regional perfusion techniques in a randomized controlled trial. The limits of neuroprotection associated with IP remain to be defined. We would like to thank Julie S. Benzaquen, PhD, for her contribution to the neurodevelopmental evaluations. This research was supported by a grant from the Nemours Foundation (Grant number 16-07700-001) and was also made possible through the generosity of donors (Nemours Fund for Children’s Health).
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13. 14.
15. 16.
17.
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