Intraoperative methylprednisolone and neurodevelopmental outcomes in infants after cardiac surgery

Abstract

Background:

Neurodevelopmental impairment is a significant consequence for survivors of surgery for critical congenital heart disease. This study sought to determine if intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes.

Methods:

A planned secondary analysis of a two-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery was performed. A brain injury biomarker was measured perioperatively. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two sample t-tests and generalized linear models were used.

Results:

There were 129 participants (n=61 methylprednisolone, n=68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between the two treatment groups. Participants who underwent a palliative (vs. corrective) procedure had lower mean BSID-III cognitive (101±15 vs. 106±14, p=0.03) and motor scores (85±18 vs. 94±16, p<0.01). Longer ventilation time was associated with lower motor scores. Longer cardiac intensive care unit (CICU) stay was associated with lower cognitive, language, and motor scores. Cardiopulmonary bypass time, aortic cross clamp time, and deep hypothermic circulatory arrest were not associated with BSID-III scores.

Conclusions:

Neurodevelopmental outcomes were not associated with intraoperative methylprednisolone or intraoperative variables. Participants who underwent a neonatal palliative (vs. corrective) procedure had longer CICU stays and worse neurodevelopmental outcomes at 1 year. This work suggests that interventions focused solely on the operative period may not be associated with a long-term neurodevelopmental benefit.

Neurodevelopmental impairment is the most significant consequence for survivors of critical congenital heart disease and its treatment.^1,2 Specifically, children who have undergone cardiac surgery during infancy have increased risk for deficits in language and social skills, reasoning, executive function, and attention. Such neurocognitive impairments can negatively impact academic performance, psychosocial and adaptive functioning, employability, and quality of life.^3–7 Given the importance of neurodevelopmental sequelae for children living with congenital heart disease, the American Heart Association and the American Academy of Pediatrics issued a joint scientific statement on guidelines for systematic surveillance, screening, and evaluation throughout childhood.⁸

Intraoperative practices have received much attention as potentially modifiable factors to improve both short and long term outcomes in infants undergoing cardiac surgery.^9–12 Specifically, intraoperative steroids have been utilized to ameliorate inflammation and end-organ damage related to cardiopulmonary bypass (CPB) and ischemia-reperfusion injury.^13–18 However, the potential neuroprotective effects of intraoperative steroids in children undergoing cardiac surgery remain poorly understood.

The primary aim of this study was to determine whether intraoperative methylprednisolone in neonates undergoing cardiac surgery with cardiopulmonary bypass was associated with neurodevelopmental outcomes at 12 months of age. The secondary aims were to identify risk factors for adverse neurodevelopmental outcomes and to determine whether intraoperative methylprednisolone was associated with circulating levels of the brain injury biomarker glial fibrillary acidic protein (GFAP).

Patients and Methods

This was a planned secondary analysis of the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial. Details of the original trial have been previously published.¹² Briefly, the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial was a double-blind, randomized, placebo-controlled study of intraoperative methylprednisolone in neonates undergoing cardiac surgery with cardiopulmonary bypass (ClinicalTrials.gov: NCT01579513). Patients were recruited from 2 centers in North America. Inclusion criteria consisted of infants younger than 1 month of age undergoing cardiac surgery with CPB. Exclusion criteria included prematurity defined as <37 weeks post gestational age at the time of surgery, steroids within the 2 days before surgery, suspected infection, a hypersensitivity that would be a contraindication to methylprednisolone, or use of mechanical circulatory support or active resuscitation at the time of proposed randomization. Participants were included in the analysis if they had completed a Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) at 12 months of age.¹⁹ The protocol was approved by the institutional review board at each center, and written informed consent was obtained from a parent/guardian before randomization.

Randomization

Study participants were randomly assigned in a 1:1 ratio to receive either intravenous methylprednisolone (30 mg/kg of body weight) or placebo after the induction of anesthesia. Patients were assigned by permuted block randomization within strata according to the planned procedure being palliative or corrective and by the surgeon/center. The study drug was infused intravenously after the induction of anesthesia prior to skin incision. All patients, caregivers, health care providers, and investigation personnel were blinded to the treatment allocation until the close of the study. In all other respects, study participants were managed accordingly to the usual practices at each center.

At site 1, general perfusion strategies included full-flow bypass at 2.6 l/min/m2 at 32°C, or low flow bypass at 1.3 l/min/m2 between 20–25°C. Regional antegrade cerebral perfusion was utilized during aortic arch reconstructions, generally carried out at a temperature of 20°C and a flow of 50 mL/kg/min, with monitoring of cerebral near-infrared spectroscopy (NIRS) with a target goal of > 90%. Cold-blood cardioplegia was given at 20 minute intervals during periods of aortic cross-clamping. Deep hypothermic circulatory arrest (DHCA) as performed at 20 °C, when necessary Acid-base management was by a pH stat strategy with a hematocrit goal of 28% while on CPB. Conventional and modified ultrafiltration were used in all cases. At site 2, full-flow bypass was considered 200 mL/kg/min at 36°C and flow is decreased as patient temperature decreases to meet mean arterial pressure goals of 30–35 mmHg. Generally, this resulted in a flow of 80–100 mL/kg/min at 18°C. Regional antegrade cerebral perfusion was utilized during arch reconstructions either at 18°C at a flow of 30 mL/kg/min with monitoring of cerebral NIRS with a target goal of >90%; or at 25°C at a flow of 60–80 mL/kg/min with monitoring of cerebral NIRS, but without a specific target depending on the surgeon. Circulatory arrest was performed at moderate hypothermia (around 25°C), typically for very brief periods, when needed. Cold-blood cardioplegia was given at 45–90 minute intervals during periods of aortic cross-clamping. Acid-base management was by a pH-stat strategy with a hematocrit goal of 30% while on CPB at 20°C or lower. Alpha-stat management was used for periods of warming. Conventional ultrafiltration was used in all cases. Modified ultrafiltration was used in the vast majority of cases.

GFAP was measured in blood at 4 time points: 1) before skin incision; 2) immediately after the completion of modified ultrafiltration at the end of CPB; 3) at 4 hours postoperatively and 4) at 24 hours postoperatively. All samples were batched and assayed simultaneously to avoid potential laboratory variance. GFAP was assayed at Johns Hopkins University using an electrochemiluminescent sandwich immunoassay as previously described.^20–23

Neurodevelopmental Assessment

Neurodevelopment was assessed at 12 months of age with an in-person evaluation by a trained psychologist experienced with the BSID-III.¹⁹ The BSID-III is a standardized test for children aged 1 through 42 months and is widely accepted to have good inter-rater reliability. The BSID-III yields cognitive, language, and motor composite scores. The mean ± standard deviation for each of the composite scores in the normative population is 100 ± 15. Administration of the BSID-III followed manual guidelines.¹⁹ The BSID-III was only administered in English or Spanish, and it was administered in the dominant language spoken at home. Testing personnel were blinded to the treatment assignment.

Statistical Analysis

Standard descriptive statistics were used to summarize the general demographic and clinical data. Continuous demographic characteristics are listed as means and associated standard deviations and were compared between groups using students t-test or Wilcoxon Rank-Sum tests. Categorical characteristics are expressed as number and percentage of subjects and were compared between groups using chi-squared or fisher’s exact test. Generalized linear models were used to identify significant prognostic variables for each of the BSID scores. Log transformations were used for non-normal data. Statistical analyses were performed with SAS, version 9.4 (SAS Institute, Inc; Cary, NC).

Results

There were 129 participants (n = 61 methylprednisolone, n = 68 placebo) included in the analysis (Figure 1). The study participants had cardiac surgery at a mean age of 9.0 ± 5.5 days. Pre-operative demographic and operative characteristics are shown in Table 1. The methylprednisolone group was slightly younger in gestational age at the time of birth compared to the placebo group. Otherwise, there were no significant differences between groups with respect to pre-operative demographics, operative characteristics, and surgical case complexity.

Figure 1.

Study enrollment flowchart

Table 1.

Demographic, Clinical, and Surgical Characteristics of the Methylprednisolone and Placebo Groups

Characteristic	All (N=129)	Methylprednisolone (N=61)	Placebo (N=68)	P-values
Demographics
Gestational age at birth, weeks	38.9 (1.2)	38.6 (1.3)	39.1 (1.1)	0.04
Female sex	52 (40%)	28 (46%)	24 (35%)	0.22
Race				0.60
White	87 (67%)	42 (69%)	45 (66%)
Black	31 (24%)	15 (25%)	16 (24%)
Asian	2 (2%)	0 (0%)	2 (3%)
American Indian or Alaska Native	1 (1%)	0 (0%)	1 (1%)
Other	8 (6%)	4 (7%)	4 (6%)
Ethnicity Hispanic	8 (6%)	3 (5%)	5 (7%)	0.55
Procedure and Diagnoses
Corrective	83 (64%)	39 (64%)	44 (65%)	0.93
Transposition of the great arteries	38 (29%)	19 (31%)	19 (28%)
Aortic arch hypoplasia with VSD	21 (16%)	9 (15%)	12 (18%)
Truncus arteriosus	7 (5%)	3 (5%)	4 (6%)
Tetralogy of Fallot	0 (0%)	0 (0%)	0 (%)
Other	17 (13%)	8 (13%)	9 (13%)
Palliative	46 (36%)	22 (36%)	24 (35%)
Hypoplastic left heart syndrome	19 (15%)	9 (15%)	10 (15%)
Other single ventricle lesions	19 (15%)	9 (15%	10 (15%
Tetralogy of Fallot with PA	5 (4%)	3 (5%)	2 (3%)
Other	3 (2%)	1 (2%)	2 (3%)
Intraoperative Characteristics
Age at surgery, days	9.0 (5.5)	9.4 (5.3)	8.7 (5.7)	0.50
Weight at surgery, kg	3.3 (0.5)	3.2 (0.5)	3.4 (0.5)	0.10
STAT mortality risk category				0.49
1	1 (1%)	1 (2%)	0 (0%)
2	2 (2%)	0 (0%)	2 (3%)
3	30 (23%)	16 (26%)	14 (21%)
4	67 (52%)	31 (51%)	36 (53%)
5	29 (22%)	13 (21%)	16 (24%)
CPB duration, min	182 (63.6)	185 (63)	179 (64)	0.57
Aortic cross clamp duration, min	83 (37.1)	81 (37)	85 (37)	0.58
Use of DHCA	28 (22%)	13 (21%)	15 (22%)	0.92
DCHA duration, min	15 (17.7)	22 (21)	10 (12)	0.10
Modified ultrafiltration	127 (98%)	61 (100%)	66 (97%)	0.18

Values are mean ± standard deviation or number (%) as appropriate. CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; n, number; PA, pulmonary atresia; STAT, Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery; VSD, ventricular septal defect

BSID-III scores

The mean age at the time of BSID-III was 12.6 ± 0.6 months of age. Mean BSID-III composite scores were 104.4 ± 14.5 for cognitive, 100.8 ± 13.9 for language, and 90.7 ± 17.5 for motor. The study cohort as a whole scored below the normative population in the motor domain. There were no significant differences in cognitive (105 ± 15 vs 104 ± 14, p=0.85), language (101 ± 15 vs 100 ± 13, p=0.68), and motor (90 ± 16 vs 91 ± 19, p=0.68) domain scores respectively between the methylprednisolone and placebo groups. However, in the comparison between the palliative versus corrective surgery groups, the palliative group had worse scores in both the cognitive and motor domains (Figure 2). When stratified by site, there were no significant differences in BSID-III scores between the methylprednisolone and placebo groups.

Figure 2.

Bayley cognitive, language, and motor scores according to surgery type (palliative vs. corrective). The upper and lower borders of the box represent the upper and lower quartiles. The middle horizontal line represents the median. The upper and lower whiskers represent the maximum and minimum values of non-outliers. Extra dots represent outliers.

In the secondary analysis to identify early prognostic post-operative variables and associations with BSID-III outcomes, longer duration of time spent on a ventilator was associated with lower BSID-III motor composite scores (p<0.01). Longer CICU length of stay was associated with lower BSID-III cognitive (<0.01), language (p<0.01), and motor scores (p<0.01). However, cardiopulmonary bypass time, aortic cross clamp time, and DHCA were not associated with BSID-III scores.

GFAP levels

In the analysis of perioperative GFAP levels, there was a peak immediately after the completion of modified ultrafiltration at the end of CPB. There were no significant differences in levels between the methylprednisolone and placebo groups for all four time points (Figure 3).

Figure 3.

Perioperative GFAP levels by treatment group (methylprednisolone vs. placebo). Before skin incision GFAP levels were low for both the methylprednisolone and placebo groups. Immediately upon completion of CPB there was an almost 100-fold increase, followed by a rapid tapering by 4 hours. There were no significant differences in levels between the methylprednisolone and placebo groups for all four time points. The upper and lower whiskers represent the upper and lower values. The shape represents the median. GFAP, glial fibrillary acidic protein. Pre-op, pre-operative. Post-op, post-operative. Methlypr, methylprednisolone.

Comment

In this planned secondary analysis of a double blind, randomized, placebo-controlled trial, intraoperative use of methylprednisolone was not associated with improved or decreased BSID-III scores at 12 months of age in children who underwent neonatal cardiac surgery with cardiopulmonary bypass. The benefit of intra-operative corticosteroids on hospital outcomes is controversial but its specific impact on neurodevelopmental outcomes in infants has not been previously studied.²⁴ These findings are important given concerns that corticosteroid use for the treatment of bronchopulmonary dysplasia in premature infants is associated with poorer neurodevelopmental outcomes.²⁵

The intraoperative variables of CPB time, aortic cross clamp time, and use of DHCA were not associated with BSID-III scores. These findings are consistent with previous studies supporting the hypothesis that the cause of neurodevelopmental impairment is less related to intraoperative strategies but rather multifactorial including innate patient, sociodemographic, and perioperative factors.^1,5,26–27 In the Single Ventricle Reconstruction trial of the Norwood procedure with modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary artery shunt, neurodevelopment was assessed by in-person evaluation with the Bayley Scales of Infant Development 2^nd edition (BSID-II) at 14 months after randomization.¹¹ In this prespecified secondary analysis that included a multicenter cohort of 314 infants, there was a high prevalence of neurodevelopmental impairment. However, there was no significant difference in BSID-II scores between those who received a modified Blalock-Taussig shunt and those who received a right-ventricle-to-pulmonary artery shunt. Additionally, specific DHCA or perfusion strategy did not emerge as an independent risk factor for worse developmental outcomes. In contrast, lower BSID-II scores were predicted by innate patient factors and measures of greater severity of illness including genetic syndromes or other anomalies, lower maternal education, lower birth weight, longer postoperative mechanical ventilation, longer hospital length of stay, and greater number of complications after Norwood hospital discharge.⁵ Similar findings were reported in a larger study of 1770 subjects from 22 institutions that underwent cardiac surgery for a broad range of diagnoses between January 1, 1998 and December 31, 2009.¹ In this study cohort, BSID-II scores at a mean age of 14 ± 3.7 months were below population means. After adjustment for center and type of congenital heart disease, there were no significant improvements in BSID-II in recent years. Risk factors for worse BSID-II scores included lower birth weight, white race, male gender, presence of a genetic/extracardiac anomaly, and less maternal education. After adjustment for these innate patient risk factors, there was modest improvement in neurodevelopmental outcomes over time.¹

Given the prolonged time lapse between neonatal surgery and neurodevelopmental testing coupled with the multifactorial etiology of neurodevelopmental deficits, it is difficult to elucidate if a specific intraoperative intervention was effective in reducing brain injury. GFAP, an astrocyte intermediate filament protein, is a promising diagnostic brain injury biomarker that is normally absent in blood and released as a result of astrocyte injury or necrosis.²⁸ GFAP levels measured acutely in adults with traumatic brain injury and those surviving cardiac arrest have been associated with neurological disability.^29–31 More recently, higher GFAP levels at the time of neonatal cardiac surgery were shown to be independently associated with decreased BSID-III motor scores at 12 months of age.³² In our study, intraoperative methylprednisolone was not associated with an alteration in perioperative GFAP levels. This finding supports our primary finding that intraoperative methylprednisolone is not associated with improved neurodevelopmental outcomes and also suggests that methylprednisolone offers little neuroprotective benefit in neonates undergoing cardiac surgery.

This planned secondary analysis study design identified associations but was unable to determine causality. The data collection did not include prenatal and fetal data, maternal education, socioeconomic status, and data related to neurodevelopmental care practices in the CICU. However, the randomized study design minimizes confounding factors and allocation bias, balancing the groups with respect to unknown variables such as home environment and post-hospital discharge neurodevelopmental follow-up care.

In conclusion, the causes of neurodevelopmental outcomes in children living with congenital heart defects are complex, cumulative, and multifactorial. The findings of our study suggest that isolated neuroprotective interventions focused solely on the operative period may not be associated with a long-term benefit and that our efforts must extend deeper into operative management strategies, the cardiac intensive care unit, and after hospital discharge. Identifying brain injury biomarkers that are reliably diagnostic and predictive of long-term neurodevelopmental outcomes will be important next steps to testing potential neuroprotective interventions.