Survival of children who undergo surgical intervention for congenital heart disease (CHD) has increased over the past decades. As a result, increasing awareness of neurologic abnormalities associated with CHD has heightened investigations of patient and process-related factors contributing to brain injury in this population of patients.1
Neurologic injury is among the most critical acute complications among patients supported with extracorporeal membrane oxygenation (ECMO) and is associated with significant mortality and long-term morbidity.2–5 Several studies have identified factors associated with neurologic complications after ECMO support both in the general pediatric population6 and in neonates.7,8
Although much is known about the epidemiology and predictors of neurologic complications in neonates support with ECMO for all indications, information specific to neonates with CHD supported with ECMO have been previously characterized only in single center experience.7,9 Neonates with CHD supported with ECMO may be at higher risk for neurologic injury due to brain immaturity associated with CHD, exposure to cardiac surgery utilizing cardiopulmonary bypass, hemodynamic instability, and need for cardiopulmonary resuscitation before ECMO deployment. Thus, information on factors associated with neurologic injury in this population is useful to provide specific care for this population increasingly supported with ECMO. We therefore sought to ascertain the incidence of neurologic injury in neonates with CHD and supported with ECMO and to evaluate patient demographic, pre-ECMO, and ECMO support-related variables associated with acute neurologic injury in these patients.
Materials and Methods
Data for purposes of this study were obtained from the ECMO registry of the extracorporeal life support organization. The characteristics of the registry have been described elsewhere.8
Our article presents a subanalysis of data previously used to describe neurologic injury and factors associated with neurologic injury in neonates supported with ECMO for all indications.8 For these analyses, data from all patients less than 30 days of age at the time of ECMO deployment and a diagnosis of CHD during the calendar years 2005–2010 were selected.
Neurologic Injury in Neonates on Extracorporeal Membrane Oxygenation
We defined neurologic injury as patients who had an ECMO registry neurologic injury complication code for stroke or intracranial hemorrhage (ICH).3,6 Stroke and ICH reported to the registry were diagnosed using ultrasound or computerized tomography imaging of the head. Nineteen patients with a complication code for brain death and two patients with seizures were excluded from the analysis.
Variables for Analysis
Variables used included patient demographics, diagnosis and procedure-related information, type and duration of ECMO support, reason for discontinuation of ECMO, pre-ECMO mechanical ventilator settings and patient support details, lowest pre-ECMO pH in the 6 hours before ECMO, and in-hospital mortality. Decisions regarding patient selection, patient management before, on, or after ECMO, and the use of imaging for assessment of neurologic injury were not standardized across the reporting institutions, and thus were subject to practice variability.
Primary and Secondary International Classification of Diseases 9th edition (ICD-9) diagnosis codes reported to the registry were used to create the diagnostic category of “CHD.” Patients were then further assigned to the following subgroup categories according to the main pathophysiology of the cardiac lesion: “transposition of the great arteries (TGA)” (i.e., dextro- or congenitally corrected-TGA), “single ventricle (SV) physiology” (i.e., hypoplastic left heart syndrome), “right ventricular obstruction” (i.e., Tetralogy of Fallot, pulmonary stenosis), “left ventricular obstruction” (i.e., aortic stenosis, coarctation of the aorta), “cyanosis-increased pulmonary blood flow” (i.e., truncus arteriosus), “orthotopic heart transplantation/cardiomyopathy/myocarditis,” “total anomalous pulmonary venous connection” (TAVPR), and “others.”
Primary indication for ECMO included “pulmonary,” “cardiac,” and extracorporeal cardiopulmonary resuscitation (ECPR) based on definitions created by the ECMO registry. Patients were categorized as cannulated through the “neck” for ECMO if an internal jugular vein or carotid artery was reported as one of the cannulation sites. Similarly, patients were categorized as cannulated through the “chest” if the right atrium or aorta was used for cannulation. Racial groups were designated as white and non-white. Non-white patients included those whose race was categorized as “Asian,” “Black,” “Hispanic,” or “Other.”10
For patients (n = 116) who had more than one ECMO run, only data from the first run were included for analysis. Patients with an ECMO registry neurologic injury complication code for seizures and brain death were excluded from the control population. Demographic, pre-ECMO, and ECMO support details were compared for patients with or without acute neurologic injury using Mann–Whitney U test for continuous data, and the χ2 test for categorical data. The Fisher’s exact test was used when expected counts in more than 20% of cells were less than 5. A χ2 test for linear trend was used to study trends in incidence of acute neurologic injury over time for ECMO patients.
Multivariable logistic regression model was created to evaluate the association of factors related to demographic, pre-ECMO, and ECMO support obtained at the time of ECMO support and acute neurologic injury. Candidate variables for inclusion in the multivariable model were chosen from the univariate analysis with criteria for variable selection set at a p value less than 0.1. A backward selection procedure was used for entry of variables into the model, and criteria for variable inclusion in the model was set at a p value less than 0.05.
Because birth weight and weight at the time of ECMO initiation, diagnostic groups, and indication for ECMO were collinear variables, only weight at ECMO and indication for ECMO were considered for inclusion in the model as data were more complete in these variables. Variables with data missing from more than 10% of cases were not considered for inclusion in the model to prevent loss of information. Subjects with missing values from one or more independent variables were excluded from the multivariable model.
Continuous variables (e.g., weight at ECMO, gestational age [GA]) retained in the logistic regression model were tested for a linear association with outcome by categorizing them and refitting them in the regression model. Continuous variables that failed assumption of linearity were retained as categorical variables. STATA data analysis and statistical software (Version 11.1, StataCorp LP, College Station, TX) were used for the analysis. Data are reported as frequency (n) with proportion (%), median values with interquartile range (IQR: 10th, 90th percentile) or odds ratios with 95% confidence intervals. Statistical significance was set at a p value less than 0.05.
A total of 1,898 ECMO runs were reported to the ECMO registry during the calendar years 2005–2010. All patients had a diagnosis of CHD. The median patient age at ECMO was 7 days (IQR: 1, 20), 58% of the patients were males, and 60% of the patients were white race. Indications for ECMO included cardiac failure (n = 1,505, 79%), respiratory failure (n = 124, 7%), and ECMO to aid cardiopulmonary resuscitation (ECPR; n = 269, 14%). The median duration of ECMO was 113 (IQR: 38, 307) hours. The overall mortality rate for neonates with CHD undergoing ECMO was 56% (n = 1,057). A total of 273 (14%) patients had evidence of neurologic injury in this cohort. Of those, 232 (12%) developed ICH, whereas 41 (2%) were showed signs of stroke. The incidence of neurologic injury in ECMO neonates did not vary by year (χ2 for linear trend, p = 0.19).
Comparison of Patients with and without Acute Neurologic Injury
Table 1 shows demographic features of neonates with and without acute neurologic injury during ECMO. Patients with neurologic injury had lower birth weight, GA, and weight at the time of ECMO deployment than those without neurologic injury. Patients with neurologic injury were also less likely to have chromosomal abnormalities. There were no significant differences in age, race, or gender between the two groups. Cardiac diagnostic category and indication for ECMO support were not significantly different between patients with or without neurologic injury. Patients with neurologic injury had a significantly higher in-hospital mortality (73%) compared with those without (53%).
Pre-Extracorporeal Membrane Oxygenation and Extracorporeal Membrane Oxygenation Support Data
Pre-extracorporeal membrane oxygenation and ECMO details of patients with and without neurologic injury are shown in Table 2. Time from admission to ECMO cannulation, pre-ECMO ventilator settings and duration of ventilation before ECMO, use of inhaled nitric oxide, surfactant, and high-frequency oscillatory ventilation were similar between the two groups. Arterial blood gas pH, standardized bicarbonate level, peripheral oxygen saturation (SaO2), and systolic and mean blood pressure were significantly lower in patients with neurologic injury.
Multivariable Logistic Regression Models of Factors Associated with Neurologic Injury
Pre-extracorporeal membrane oxygenation factors associated with acute neurologic injury in multivariable logistic regression models are shown in Table 3. Weight less than 3 kg at ECMO, the need for cardiopulmonary resuscitation before ECMO and pre-ECMO pH were independently associated with increased odds of neurologic injury.
Comparison of Surgical and Nonsurgical Patients
A total of 1,602 (84%) neonates underwent cardiac surgery. Table 4 summarizes demographic, pre-ECMO, and ECMO support details that significantly differed between surgical and nonsurgical neonates. There were no differences in terms of acute neurologic injury between the neonates who underwent pre-ECMO cardiac surgery and those who did not. Patients who did not undergo cardiac surgery before ECMO were more likely to have cardiomyopathy/myocarditis and TAVPR. Moreover, pulmonary indication for ECMO, the use of VV ECMO mode, inhaled nitric oxide, surfactant, and high-frequency oscillatory ventilation were more frequent among nonsurgical patients.
Neurologic injury in neonates with CHD supported with ECMO is a frequent complication. In our study of 1,898 neonates, we found a stroke and ICH rate of 14% that is lower than the reported 17% in the general neonatal population.8 The only demographic factor independently associated with neurologic injury was weight at the time of ECMO deployment. Other pre-ECMO factors included occurrence of cardiac arrest and pre-ECMO pH. Consistent with previous studies, neonates with neurologic injury had increased mortality compared with those without (73% vs. 53%).3,6
Cerebral immaturity increases the vulnerability of neonates to ICH and oxidative reperfusion injury. Additionally, the presence of CHD may further increase the potential for brain injury as altered cerebral blood flow and impaired cerebral oxygen delivery impact brain development.11,12 In neonates with CHD altered cerebral blood flow with impaired cerebral oxygen delivery, both in utero13 and after birth14 may impact later brain development. The brain therefore is less mature and more vulnerable at birth than suggested by GA.15 The neonatal period is a critical time for brain maturation, myelination, and development of neural networks. Impaired cerebral blood flow and brain immaturity during this vulnerable time may lead to increased susceptibility to neurologic injury.16 Cardiopulmonary bypass and deep hypothermic cardiac arrest during neonatal heart surgery may result in cerebral macroemboli and microemboli to the central nervous system (CNS).17,18,19 Nevertheless to date, with the exception of higher hematocrit during cardiopulmonary bypass (CPB), no intraoperative interventions or specific procedural modifications have shown improved neurodevelopmental outcomes.20 A recent report from Beca et al.21 showed how white matter injury occurred at the same rate in infants undergoing surgery without CPB as in those with CPB. Consistently, we could not find any association between cardiac surgery and neurologic injury.
Our data failed to show an association between type of cardiac lesions and CNS injury. Two forms of CHD, TGA and SV physiology are thought to share increased vulnerability to brain injury reflecting impaired brain development possibly caused by reduced in utero cerebral oxygen delivery.22 SV physiology has been identified as a risk factor for new postoperative brain lesions.23,24 Recently, the severity of postoperative neurologic lesions in infants with CHD was shown to be strongly associated with the type of cardiac physiology and occurred at the highest rates in infants having either SV or arch surgery compared with infants with two-ventricle physiology.21 We could not find a significant association between these or any other types of cardiac lesions and acute neurologic injury. Dimitropoulos et al.25 recently demonstrated that higher preoperative neonatal illness severity score, lower preoperative oxygen saturation, and hypotension are predictive of preoperative neurologic injuries, whereas newly acquired postoperative brain injuries are more strongly influenced by perioperative factors such as lower postoperative systolic and mean blood pressure. Consistently, our data suggest that in a population of critically ill patients such as neonates with CHD undergoing ECMO, pre-ECMO severity of hemodynamic impairment, and timing of ECMO deployment more than cardiac lesion-specific physiology are the main risk factors for the development of neurologic injury.
Consistent with previous studies in this population, we found an association between lower weight and the presence of neurologic injury.7,26 Organ immaturity is considered one of the most prominent risk factor for developing ICH.27 Extracorporeal membrane oxygenation patients weighing less than 2 kg are 50% more prone to develop ICH than those weighing more than 2 kg.28
Limitations of our data set and our definition of neurologic injury require careful consideration when interpreting the data presented here. Data are reported to the extracorporeal life support organization registry on a voluntary basis and are therefore subject to reporting bias, so neurologic complications may be underreported. The data analyzed here were not specifically collected for studying neurologic complications in neonates supported with ECMO. Information on the severity of neurologic injury was not collected and could not be used to classify neurologic complications. We cannot determine the timing of neurologic injury and imaging modality used, and thus some patients in our cohort may have had injury before the initiation of ECMO. Data regarding the presence of coagulation disorders and anticoagulation management were not available for studying the influence of these important issues on neurologic complications during ECMO. Important information on functional outcomes and quality of life in survivors with neurologic complications was not available. Finally, diagnosis codes are provided via ICD-9 coding, which may not include potential confounding diagnoses and may be subject to misclassification bias.
Despite these many limitations, our data show that neonates with CHD undergoing ECMO are highly vulnerable to acute neurologic injury. Strict real-time neurologic monitoring may represent an innovative way to minimize the impact of neurologic injury in this high-risk group of patients. Brain biomarkers such as glial fibrillary acidic protein to follow during the ECMO period may indicate ongoing brain injury and allow timely intervention to reduce the impact of further neurologic injury.29 Perioperative seizures are consistently associated with adverse neurodevelopmental outcomes.30 Continuous electroencephalographic monitoring may mitigate later neurodevelopmental issues by early detection and management of on-ECMO seizures. Regardless of cardiac lesion-specific physiology or the occurrence of cardiac surgery, neurologic injuries in this population are higher in sicker patients. Severity of illness should therefore become the main target for improvement. Thus, timing of ECMO deployment may influence the development of ECMO complications. Future research into evaluating whether earlier deployment of ECMO and the use of neuroprotective therapies such as therapeutic hypothermia may help reduce the incidence of neurologic injury in neonates supported with ECMO should be undertaken in the future.
1. Wernovsky G. Improving neurologic and quality-of-life outcomes in children with congenital heart disease: Past, present, and future. J Thorac Cardiovasc Surg. 2008;135:240–242
2. Thiagarajan RR, Laussen PC, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation to aid cardiopulmonary resuscitation in infants and children. Circulation. 2007;116:1693–1700
3. Barrett CS, Bratton SL, Salvin JW, Laussen PC, Rycus PT, Thiagarajan RR. Neurological injury after extracorporeal membrane oxygenation use to aid pediatric cardiopulmonary resuscitation. Pediatr Crit Care Med. 2009;10:445–451
4. Lequier L, Joffe AR, Robertson CM, et al.Western Canadian Complex Pediatric Therapies Program Follow-up Group. Two-year survival, mental, and motor outcomes after cardiac extracorporeal life support at less than five years of age. J Thorac Cardiovasc Surg. 2008;136:976–983
5. Costello JM, O’Brien M, Wypij D, et al. Quality of life of pediatric cardiac patients who previously required extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2012;13:428–434
6. Cengiz P, Seidel K, Rycus PT, Brogan TV, Roberts JS. Central nervous system complications during pediatric extracorporeal life support: Incidence and risk factors. Crit Care Med. 2005;33:2817–2824
7. Hardart GE, Fackler JC. Predictors of intracranial hemorrhage during neonatal extracorporeal membrane oxygenation. J Pediatr. 1999;134:156–159
8. Polito A, Barrett CS, Wypij D, et al. Neurologic complications in neonates supported with extracorporeal membrane oxygenation. An analysis of ELSO registry data. Intensive Care Med. 2013;39:1594–1601
9. Bhat P, Hirsch JC, Gelehrter S, et al. Outcomes of infants weighing three kilograms or less requiring extracorporeal membrane oxygenation after cardiac surgery. Ann Thorac Surg. 2013;95:656–661
10. Lasa JJ, Cohen MS, Wernovsky G, Pinto NM. Is race associated with morbidity and mortality after hospital discharge among neonates undergoing heart surgery? Pediatr Cardiol. 2013;34:415–423
11. Ferriero DM. Neonatal brain injury. N Engl J Med. 2004;351:1985–1995
12. Marino BS, Lipkin PH, Newburger JW, et al.American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, and Stroke Council. Neurodevelopmental outcomes in children with congenital heart disease: Evaluation and management: A scientific statement from the American Heart Association. Circulation. 2012;126:1143–1172
13. Kaltman JR, Di H, Tian Z, Rychik J. Impact of congenital heart disease on cerebrovascular blood flow dynamics in the fetus. Ultrasound Obstet Gynecol. 2005;25:32–36
14. Licht DJ, Wang J, Silvestre DW, et al. Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc Surg. 2004;128:841–849
15. Licht DJ, Shera DM, Clancy RR, et al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg. 2009;137:529–536 discussion 536
16. Limperopoulos C, Tworetzky W, McElhinney DB, et al. Brain volume and metabolism in fetuses with congenital heart disease: Evaluation with quantitative magnetic resonance imaging and spectroscopy. Circulation. 2010;121:26–33
17. Kurth CD, Steven JM, Nicolson SC, Jacobs ML. Cerebral oxygenation during cardiopulmonary bypass in children. J Thorac Cardiovasc Surg. 1997;113:71–78 discussion 78
18. Newburger JW, Jonas RA, Wernovsky G, et al. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med. 1993;329:1057–1064
19. Jonas RA, Wypij D, Roth SJ, et al. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: Results of a randomized trial in infants. J Thorac Cardiovasc Surg. 2003;126:1765–1774
20. Hirsch JC, Jacobs ML, Andropoulos D, et al. Protecting the infant brain during cardiac surgery: A systematic review. Ann Thorac Surg. 2012;94:1365–1373 discussion 1373
21. Beca J, Gunn JK, Coleman L, et al. New white matter brain injury after infant heart surgery is associated with diagnostic group and the use of circulatory arrest. Circulation. 2013;127:971–979
22. Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007;357:1928–1938
23. Galli KK, Zimmerman RA, Jarvik GP, et al. Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg. 2004;127:692–704
24. Dent CL, Spaeth JP, Jones BV, et al. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg. 2006;131:190–197
25. Dimitropoulos A, McQuillen PS, Sethi V, et al. Brain injury and development in newborns with critical congenital heart disease. Neurology. 2013;81:241–248
26. Revenis ME, Glass P, Short BL. Mortality and morbidity rates among lower birth weight infants (2000 to 2500 grams) treated with extracorporeal membrane oxygenation. J Pediatr. 1992;121:452–458
27. Sarkar S, Bhagat I, Dechert R, Schumacher RE, Donn SM. Severe intraventricular hemorrhage in preterm infants: Comparison of risk factors and short-term neonatal morbidities between grade 3 and grade 4 intraventricular hemorrhage. Am J Perinatol. 2009;26:419–424
28. Rozmiarek AJ, Qureshi FG, Cassidy L, et al. How low can you go? Effectiveness and safety of extracorporeal membrane oxygenation in low-birth-weight neonates. J Pediatr Surg. 2004;39:845–847
29. Stewart A, Tekes A, Huisman TA, et al. Glial fibrillary acidic protein as a biomarker for periventricular white matter injury. Am J Obstet Gynecol. 2013;209:27
30. Gaynor JW, Jarvik GP, Gerdes M, et al. Postoperative electroencephalographic seizures are associated with deficits in executive function and social behaviors at 4 years of age following cardiac surgery in infancy. J Thorac Cardiovasc Surg. 2013;146:132–137