Abstract
Objective
To evaluate the association between sedation-analgesia (SA) during initial 72 hours and death/disability at 18 months of age in neonatal hypoxic-ischemic encephalopathy (HIE).
Design
This was a secondary analysis of the NICHD therapeutic hypothermia (TH) randomized controlled trial in moderate or severe HIE. Receipt of SA and anticonvulsant medications at 5 time points were considered: prior to and at baseline, 24, 48 and 72 hours of TH or normothermia. Disability was defined as mental developmental index <85, cerebral palsy, blindness, hearing impairment or Gross Motor Function Classification System 2-5.
Results
Of the 208 RCT participants, 38 (18%) infants had no exposure to SA or anticonvulsants at any of the 5 time points, 20 (10%) received SA agents only, 81 (39%) received anticonvulsants only and 69 (33%) received both SA and anticonvulsants. SA category drugs were not administered in 57% of infants while 18% received SA at ≥3 time points; 72% infants received anticonvulsants during 72 hours of intervention. At 18 months of age, disability among survivors and death/disability was more frequent in the groups receiving anticonvulsants, with (48 and 65%) or without (37 and 58%) SA, compared to groups with no exposure (14 and 34%) or SA (13 and 32%) alone. Severe HIE (aOR 3.60; 1.59-8.13), anticonvulsant receipt (aOR 2.48; 1.05-5.88) and mechanical ventilation (aOR 7.36; 3.15-17.20) were independently associated with 18-month death/disability whereas TH (aOR 0.28; 0.13-0.60) was protective. SA exposure showed no association with outcome.
Conclusions
The risk-benefits of SA in HIE needs further investigation.
Introduction
Despite the significant benefits of therapeutic hypothermia (TH) for neonatal hypoxic-ischemic encephalopathy (HIE), death and disability remain considerable [1]. Infants with HIE are subjected to the stresses of an adverse perinatal event, resuscitation, TH itself and painful procedures. Whether use of medications for sedation/analgesia (SA) to mitigate the pain /stress response improves outcomes in HIE is unclear. Thoresen et al reported that mild hypothermia was not protective after hypoxia-ischemia in unsedated piglets but reduced the severity of brain damage in piglets receiving halothane or intravenous anesthesia [2, 3, 4]. However, neuroprotection with prolonged TH after hypoxia-ischemia has been consistently observed in unsedated fetal sheep and neonatal rodents [5, 6]. In adults, SA medications during TH are associated with earlier attainment and better maintenance of target temperatures [7]. Of the neonatal trials of TH, only the Neo-nEURO study treated all infants with morphine or an equivalent dose of fentanyl [8]. In the Total Body Hypothermia for Neonatal Encephalopathy trial, infants underwent sedation with morphine infusions or chloral hydrate if they “appeared to be distressed” [9]. In all other trials of TH for neonatal HIE, SA administration was provider-driven; there has not been an analysis of SA use from any of the randomized controlled trials (RCTs) [10–13].
SA used during TH for neonatal HIE may affect neuromonitoring of infants, duration of mechanical ventilation and hemodynamic status. TH, in turn, may alter drug pharmacokinetics and potentially increase their adverse effects. Roka and colleagues found serum morphine concentrations at 24 to 72 hours after birth to be higher in the 10 infants who underwent TH, compared to 6 normothermic infants, at similar morphine infusion rates and doses [14]. In addition to SA, infants with HIE may receive concomitant neuromuscular blocking agents and anticonvulsants, which may affect neurodevelopmental outcomes, either through an unclear causal pathway or because of altered systemic concentrations or as markers of global severity of illness. These effects have not been previously explored.
We sought to address this knowledge gap using data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) TH RCT [10]. We describe patterns of use of SA, anticonvulsants and neuromuscular blocking agents during the initial days of life. Our primary hypothesis was that, among participants of the NICHD NRN whole body cooling RCT for neonatal HIE, SA administration during the 72 hours of TH or normothermia would be associated with an increased risk of death/moderate or severe disability at 18-22 months of age, after adjustment for center, HIE severity, TH, and clinical markers of severity of the infant’s underlying illness during the 72 hours.
Methods
This was a secondary analysis of data from the NICHD NRN whole body cooling RCT for moderate or severe HIE in term or late preterm (gestational age ≥ 36 weeks) infants (10). Eligibility criteria for the original trial included cord blood or postnatal acidosis and/or clinical criteria (acute perinatal event and either a 10 minute Apgar score of 5 or less or assisted ventilation). Further, enrolled infants (n=208) had moderate or severe HIE on standardized neurologic examination or had seizures. Infants in the RCT were randomized to normothermia or TH to achieve an esophageal temperature of 33.5°C for 72 hours. The trial was approved by the Institutional Review Boards at all participating sites.
Prospectively collected data were available on SA administration and type at 5 time points, (each treated as a window from the previous): prior to baseline, baseline (defined as the time of initiation of TH when the cooling blanket was turned on or the time of randomization for the normothermic group of infants) and at 24, 48 and 72 hours of intervention (TH or normothermia). Included SA medications were morphine, fentanyl, chloral hydrate, midazolam and phenobarbital and other. Data on anticonvulsants were coded as phenobarbital, lorazepam, phenytoin, paraldehyde and other. In addition, data on neuromuscular blocking agent (pancuronium, vecuronium, rocuronium and other) administration were collected. For initial analyses, we classified infants into groups who received no SA or anticonvulsants, only SA, only anticonvulsants and both SA and anticonvulsant agents. Since SA use was the variable of interest, we further described degree of exposure to SA as a factor count by the number of SA agents and number of time points (0-5) at which they were administered. For example, receipt of 2 agents at 3 time points would give a count of 6.
Time to achieve target esophageal temperature and esophageal temperature fluctuations >2°C after 4 hours of cooling were noted for infants who underwent TH. Hypocarbia was defined as pCO2 less than 35 mm Hg and hypercarbia as pCO2 greater than 55 mmHg on blood gases (temperature-corrected in the TH group) obtained at 4, 8, 12, 24, 48 and 72 hours of intervention [15]. Demographic and birth characteristics and data on the use of pressors and neuromuscular blockers at the 5 time points through the 72 hour intervention, persistent encephalopathy, defined as moderate or severe encephalopathy without improvement on examinations at 24, 48 and 72 hours and anticonvulsants at discharge and outcomes at 18-22 months of age were compared between the 4 groups.
The primary outcome was death or moderate/severe disability at 18-22 months of age, defined as in the main RCT [10]. Neuromotor disability was defined on the basis of cerebral palsy (CP), and functional disability was graded according to the Gross Motor Function Classification System (GMFCS) [16]. Cognitive outcome was assessed with Bayley Scales of Infant Development (BSID-II), where the population mean (SD) scores were 100 (15) on the mental developmental index (MDI) and psychomotor developmental index (PDI). Severe disability was defined as any of the following: MDI score below 70, a GMFCS grade of level 3 to 5, hearing impairment requiring hearing aids for > 60 db testing, or bilateral blindness. Moderate disability was defined as MDI score 70 to 84 in addition to one or more of the following: a GMFCS grade of level 2, hearing impairment with no amplification, or a persistent seizure disorder.
Statistical Analysis
Descriptive statistics included median and inter-quartile (IQR) ranges for continuous variables and frequencies and proportions for categorical variables. ANOVA, Wilcoxon-Rank sum and chi-square tests were used, as appropriate, to compare infant characteristics and outcomes between the 4 groups of infants as defined. Logistic regression model for the association between SA exposure (factor count as a continuous variable) and death/disability at 18-22 months of age was developed, adjusting for severity of HIE, TH, anticonvulsant use through the 72 hours and center (as a random variable), in addition to clinical markers of severity of illness in the 72 hours of intervention (receipt of pressors through the 5 time points, mechanical ventilation at baseline, 24, 48 and 72 hours, and hypocarbia or hypercarbia at any time in the 72 hours). Adjusted odds ratios (ORs) and 95% C.I. were computed. All P values were based on 2-tailed tests and values < 0.05 were taken as significant. We decided a priori to evaluate the subgroups of cooled and normothermic infants separately, only if the p value for interaction test between SA and intervention (TH vs. normothermia) was < 0.1.
Results
Of the 208 RCT participants, 38 (18%) infants had no exposure to SA or anticonvulsants at any of the 5 time points, 20 (10%) received SA agents only, 81 (39%) received anticonvulsants only and 69 (33%) received both SA and anticonvulsant at some time point. Only two infants received phenobarbital as a sedative. There were no differences rates of TH in the 4 groups (55% in the no exposure, 50% in the SA only, 49% in the anticonvulsant only and 45% in those who received both classes; p=0.78). Table 1 is a comparison of demographic and birth characteristics of these 4 groups. Significant differences between groups were noted in the proportion of infants who were outborn, had severe HIE and received chest compressions in the delivery room (DR) and at 10 minutes and received resuscitation medications in the DR as well as in the median 1 and 5-minute Apgar score and cord pH. Infants who received anticonvulsants alone or along with SA had lower Apgar scores and cord pH, received chest compressions and had severe HIE more often. Table 2 is a detailed description of the receipt of SA, anticonvulsants, neuromuscular blocking agents and pressors at each time point. More than half (57%) the infants had no exposure to SA agents, with 18% receiving SA agents at 3 or more of the 5 time points. The commonly used drugs were morphine, fentanyl and midazolam (18-21% each). Anticonvulsants were administered to 72% of infants, with 46% receiving them for 3 or more time points.
Table 1.
Comparison of demographic and birth characteristics between groups of infants with SA and/or anticonvulsant (AC) receipt during the 72 hours of study intervention
| Characteristic Mean ± SD or Median (IQR) or n(%) | No SA or AC N=38 | Any SA without ACN=20 |
Any AC without SAN=81 |
Both SA and AC N=69 |
p-value |
|---|---|---|---|---|---|
|
| |||||
| Outborn, n (%) | 11 (29%) | 4 (20%) | 35 (43%) | 43 (62%) | 0.0005 |
|
| |||||
| Apgar scores at 1 min | 1 (0-2) | 2 (1-2) | 1 (0-1) | 0 (0-1) | 0.0002 |
|
| |||||
| Apgar scores at 5 min | 3 (2-4) | 3.5 (3-5) | 2 (0-4) | 2 (0-4) | 0.003 |
|
| |||||
| Apgar scores at 10 min | 4 (3-6) | 4 (3.5-6) | 4 (2-4) | 3 (2-5) | 0.15 |
|
| |||||
| Birth weight (Grams) | 3310 ± 666 | 3339 ± 763 | 3466 ± 649 | 3320 ± 541 | 0.45 |
|
| |||||
| Gestational age (Weeks) | 38.7 ± 1.64 | 39.6 ± 1.76 | 38.9 ± 1.49 | 38.8 ± 1.63 | 0.25 |
|
| |||||
| Male sex, n (%) | 20 (53%) | 11 (55%) | 43 (53%) | 43 (62%) | 0.67 |
|
| |||||
| Uterine rupture, n (%) | 3 (8%) | 1 (5%) | 16 (20%) | 9 (13%) | 0.23 |
|
| |||||
| DR resuscitation, n (%) | 38 (100%) | 20 (100%) | 81 (100%) | 69 (100%) | N/A |
| Oxygen | 38 (100%) | 20 (100%) | 81 (100%) | 69 (100%) | N/A |
| Bag/mask | 37 (97%) | 18 (90%) | 78 (96%) | 66 (96%) | 0.57 |
| Chest compressions | 18 (47%) | 3 (15%) | 50 (63%) | 52 (75%) | <0.0001 |
| Intubation | 34 (89%) | 18 (90%) | 78 (96%) | 65 (94%) | 0.33 |
| Drugs | 18 (47%) | 3 (15%) | 44 (55%) | 47 (68%) | 0.0003 |
|
| |||||
| Continued resuscitation at 10 m, n (%) | 34 (89%) | 18 (90%) | 76 (94%) | 67 (97%) | 0.31 |
| Oxygen | 33 (97%) | 18 (100%) | 75 (99%) | 67 (100%) | 0.58 |
| Bag/mask | 20 (59%) | 6 (33%) | 43 (57%) | 41 (61%) | 0.21 |
| Chest compressions | 8 (24%) | 1 (6%) | 26 (35%) | 25 (37%) | 0.03 |
| Intubation | 31 (91%) | 16 (89%) | 72 (95%) | 58 (87%) | 0.35 |
| Drugs | 10 (29%) | 4 (22%) | 26 (34%) | 30 (45%) | 0.23 |
|
| |||||
| Time to spontaneous respiration ≥10 m, n (%) | 15 (42%) | 10 (56%) | 15 (20%) | 17 (25%) | 0.007 |
|
| |||||
| Cord pH | 6.95 ± 0.22 | 6.95 ± 0.20 | 6.81 ± 0.19 | 6.82 ± 0.19 | 0.005 |
|
| |||||
| Cord base deficit (meq/L) | 16.4 ± 8.09 | 16.6 ± 7.18 | 20.0 ± 7.68 | 20.9 ± 7.39 | 0.08 |
|
| |||||
| Postnatal gas pH | 7.07 ± 0.22 | 7.05 ± 0.19 | 7.08 ± 0.22 | 7.01 ± 0.25 | 0.30 |
|
| |||||
| Postnatal gas base deficit (meq/L) | 19.0 ± 6.60 | 16.8 ± 7.71 | 17.8 ± 8.06 | 18.1 ± 8.00 | 0.90 |
|
| |||||
| Encephalopathy at randomization: | 0.008 | ||||
| Moderate | 30 (79%) | 17 (85%) | 43 (53%) | 44 (65%) | |
| Severe | 8 (21%) | 3 (15%) | 38 (47%) | 24 (35%) | |
|
| |||||
| TH, n (%) | 21 (55%) | 10 (50%) | 40 (49%) | 31 (45%) | 0.78 |
|
| |||||
| Time to target esophageal temp* | 0.95 ± 0.48 | 1.17 ± 0.96 | 0.85 ± 0.39 | 0.81 ± 0.30 | 0.78 |
|
| |||||
| Temp fluctuations >2°, n (%)* | 1 (5%) | 3 (33%) | 2 (5%) | 3 (10%) | 0.09 |
Only among cooled infants in each group
Table 2.
Description of the receipt of SA, anticonvulsants, neuromuscular blocking agents and pressors at each time point.
| Sedation-analgesia | Any | Number of timepoints | ||||||
|---|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 | |||
| Any SA | 89 (43%) | 119 (57%) | 29 (14%) | 22 (11%) | 19 (9%) | 15 (7%) | 4 (2%) | |
| Specific drugs | ||||||||
| Morphine | 38 (18%) | 170 (82%) | 23 (11%) | 7 (3%) | 5 (2%) | 2 (1%) | 1 (0%) | |
| Fentanyl | 44 (21%) | 164 (79%) | 11 (5%) | 9 (4%) | 15 (7%) | 7 (3%) | 2 (1%) | |
| Chloral hydrate | 1 (0%) | 207 (100%) | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | |
| Midazolam | 42 (20%) | 166 (80%) | 15 (7%) | 10 (5%) | 11 (5%) | 4 (2%) | 2 (1%) | |
| Phenobarbital | 2 (1%) | 206 (99%) | 1 (0%) | 0 (0%) | 1 (0%) | 0 (0%) | 0 (0%) | |
| Other | 5 (2%) | 203 (98%) | 3 (1%) | 2 (1%) | 0 (0%) | 0 (0%) | 0 (0%) | |
| Other Classes of Medications | ||||||||
| Medication Type | Any | 0 | 1 | 2 | 3 | 4 | 5 | |
| Anticonvulsants | 150(72%) | 58 (28%) | 33 (16%) | 21 (10%) | 32 (15%) | 19 (9%) | 45 (22%) | |
| Neuromuscular blockage agents | 32 (15%) | 176 (85%) | 14 (7%) | 12 (6%) | 3 (1%) | 2 (1%) | 1 (0%) | |
| Pressors | 116(56%) | 92 (44%) | 12 (6%) | 22 (11%) | 35 (17%) | 15 (7%) | 32 (15%) | |
Table 3 is a comparison of clinical characteristics during the 72 hours and outcomes in the 4 groups of infants. There were significant differences between groups in the receipt of neuromuscular blockers. Infants who had no exposure to SA or anticonvulsants had lower rates of unchanged HIE severity through the 72 hours, and had shorter durations of mechanical ventilation and supplemental oxygen. Mean length of hospital stay in survivors was significantly longer in the SA only group of infants, compared to the group without SA or anticonvulsant exposure. At 18 months of age, disability among survivors and death/disability was more frequent in the groups receiving anticonvulsants, with or without SA. Nineteen infants underwent one or more surgical procedures during hospitalization, the commonest being gastrostomy (n=9), gastrostomy and fundoplication (n=4), and ECMO (n=3). Surgical procedures were equally distributed between groups. Two infants had multiple surgeries, including fundoplication and unspecified surgery (n=1) and tracheostomy, fundoplication, and gastrostomy (n=1); one infant had “other” surgery.
Table 3.
Comparison of outcomes between groups of infants with SA and/or anticonvulsant exposure
| Characteristic Mean ± SD or Median (IQR) or n(%) | No SA/AC N=38 |
SA without AC N=20 |
AC without SA N=81 |
SA and AC N=69 |
p-value |
|---|---|---|---|---|---|
|
| |||||
| Pressors at all time points | 2 (5%) | 5 (25%) | 11 (14%) | 14 (20%) | 0.10 |
|
| |||||
| AC at all time points | 0 (0%) | 0 (0%) | 24 (30%) | 21 (30%) | 1.0* |
|
| |||||
| Neuromuscular blocker at any time point | 1 (3%) | 6 (30%) | 1 (1%) | 24 (35%) | <0.0001 |
|
| |||||
| Unchanged HIE severity from randomization to: | |||||
| 24 hrs (N=179) | 10 (32%) | 11 (69%) | 50 (70%) | 39 (64%) | 0.003 |
| 48 hrs (N=175) | 6 (19%) | 12 (71%) | 44 (64%) | 34 (59%) | 0.0001 |
| 72 hrs (N=170) | 6 (20%) | 8 (44%) | 38 (55%) | 27 (51%) | 0.01 |
|
| |||||
| In-hospital death, n (%) | 6 (16%) | 4 (20%) | 21 (26%) | 18 (26%) | 0.63 |
|
| |||||
| Days on ventilator | 2.6 ± 2.3 | 9.1 ± 6.8 | 5.4 ± 5.8 | 6.9 ± 6.6 | <0.0001 |
|
| |||||
| Days on oxygen | 4.7 ± 7.5 | 11.2 ± 8.7 | 8.1 ± 12.7 | 9.0 ± 8.1 | 0.0001 |
|
| |||||
| Major surgery in NICU | 1 (3%) | 1 (5%) | 11 (14%) | 6 (9%) | 0.26 |
|
| |||||
| Days of tube feedings | 6.4 ± 13.2 | 6.4 ± 12.5 | 9.0 ± 14.1 | 8.0 ± 14.5 | 0.23 |
|
| |||||
| Age at full oral feeds, days | 8.0 ± 10.1 | 13.2 ± 11.1 | 9.5 ± 16.3 | 10.8± 11.7 | 0.04 |
|
| |||||
|
Length of stay, days N=199 |
13.6 ± 13.3 9 (7-15) |
23.9 ± 22.1 19 (9.5-26.5) |
18.9 ± 17.3 13 (9-22) |
16.3 ± 15.8 13 (7-20) |
0.08 0.07 |
|
| |||||
|
Length of stay in survivors N=150 |
15.8 ± 13.4 11 (8-17) |
26.4 ± 23.4 22 (10-26.5) |
21.3 ± 15.2 15.5(11-23) |
20.4 ± 16.4 14 (10-26) |
0.04 0.15 |
|
| |||||
| Discharge gavage/gastrostomy feeds, n (%) (N=152) | 3 (10%) | 1 (6%) | 18 (31%) | 10 (21%) | 0.051 |
|
| |||||
| Anticonvulsant at discharge, n (%) (N=152) | 2 (6%) | 0 (0%) | 31 (53%) | 26 (55%) | <0.0001 |
|
| |||||
| 18 months outcomes | |||||
| Death (N=206) | 9 (24%) | 4 (21%) | 26 (33%) | 23 (33%) | 0.61 |
| Disability (N=144) | 4 (14%) | 2 (13%) | 20 (37%) | 22 (48%) | 0.006 |
| Death or disability (N=206) | 13 (34%) | 6 (32%) | 46 (58%) | 45 (65%) | 0.003 |
P-value only compares the latter two columns, since absence of anticonvulsants is part of the definition for the first two columns.
Data unavailable in 9 infants who were transferred out before discharge
Further analyses of exposure to SA were conducted using the factor count. Table 4 is a description of rates of death or disability in infants with varying exposure to SA, by the factor count. Rates of death/disability were 50%, 52% and 59% respectively for infants with no exposure to SA, a single agent at 1 time point and those with greater exposure.
Table 4.
Description of number of infants in each SA factor count (range 0-15, for up to 5 time points and up to 3 drugs) group and corresponding rates of death/disability at 18 months of age
| SA factor count | N (%) | Death or disability (N=206) |
|---|---|---|
| 0 | 119 (57%) | 59/118 (50%) |
| 1 | 25 (12%) | 13 (52%) |
| 2 | 23 (11%) | 15/22 (68%) |
| 3 | 11 (5%) | 8 (73%) |
| 4 | 9 (4%) | 4 (44%) |
| 5 | 4 (2%) | 2 (50%) |
| 6 | 7 (3%) | 3 (43%) |
| 7 | 3 (1%) | 1 (33%) |
| 8 | 2 (1%) | 2 (100%) |
| 9 | 2 (1%) | 2 (100%) |
| 10 | 3 (1%) | 1 (33%) |
| 11-15 | 0 (0%) | 110/206 (53%) |
Logistic regression on the association between level of SA exposure using factor count and the primary outcome, adjusting for severity of HIE, TH, center, anticonvulsant and pressor receipt and mechanical ventilation at all time points, and hypocarbia/hypercarbia at any time point with the adjusted OR and 95% C.I. for each included variable are shown (Table 5). The c-statistics for the models were 0.819 for death or disability. Severe HIE, anticonvulsant receipt and mechanical ventilation were independently associated with death or disability whereas TH was protective. SA exposure and hypocarbia or hypercarbia were not associated with death or disability.
Table 5.
Adjusted logistic regression for association between SA exposure (factor count) and primary outcome at 18 months of age
| Variable | AOR (95% CI) | P-value |
|---|---|---|
| SA factor count (0-15) | 0.93 (0.79-1.10) | 0.42 |
| HIE severity | 3.60 (1.59-8.13) | 0.002 |
| TH | 0.28 (0.13-0.60) | 0.001 |
| Center (as random effect) | N/A | |
| Pressors at all 5 time points (prior to baseline, baseline, 24H, 48H, 72H) | 0.43 (0.16-1.13) | 0.09 |
| Anticonvulsants at all 5 time points (prior to baseline, baseline, 24H, 48H, 72H) | 2.48 (1.05-5.88) | 0.04 |
| Mechanical ventilation at all 4 time points (baseline, 24H, 48H, 72H) | 7.36 (3.15-17.2) | <0.0001 |
| Hypocarbia (PCO2 < 35) and/or hypercarbia (PC02 > 55) at any time point (baseline, 4H, 8H, 12H, 24H, 48H, 72H) | 2.96 (0.82-10.7) | 0.10 |
Discussion
In this secondary analysis of data from the NICHD NRN whole body cooling RCT, 57% of infants received no SA drug; SA administration for prolonged durations was uncommon; SA administration did not significantly differ between cooled and normothermic infants. A greater proportion of infants who were administered anticonvulsants, alone or in combination with SA, at any of 5 time points during the 72 hours of trial intervention had severe HIE, lower median 1 and 5-minute Apgar scores and cord pH and required chest compressions. They also had higher rates of death/disability at 18 months and of disability alone. Infants without SA or anticonvulsant exposure had significantly less unchanged HIE severity, shorter durations of mechanical ventilation and supplemental oxygen. On logistic regression, severe HIE, TH and anticonvulsant receipt during the 72 hours were found to be associated with death or disability at 18 months of age, whereas degree of exposure to SA was not.
Current practice guidelines recommend SA and neuromuscular blocking administration during TH in adult comatose patients after cardiac arrest although variability in practice has been reported [17–19]. In the Therapeutic Hypothermia after Pediatric out-of-hospital cardiac arrest RCT, children were sedated and pharmacologically paralyzed during TH [20]. SA use in adults and older children is to prevent shivering during TH induction and maintenance, which may increase temperature if not suppressed. The newborn is distinctly different since non-shivering thermogenesis is the primary response to a cold stress.
There are currently no data on the association between SA in the neonatal period and neurodevelopmental outcomes in term infants with HIE. In all except one RCT of TH in neonatal HIE, SA practices were heterogenous and determined by center and clinician preferences [8–13]. Despite this, the results from the trials have been remarkably similar. Our data underscore the complexity of examining the relationship between an important care practice such as SA associated with TH and outcomes. In the current data set, less than half the infants received SA agents during the intervention. While we did not find an association between level of SA exposure and death or disability at 18 months, whether SA affected other variables such as mechanical ventilation and anticonvulsant exposure which did show an association with outcome is unclear. Nonetheless, the results highlight the need for a careful approach when considering the risks/benefits of SA agents in infants with HIE. We statistically adjusted for severity of HIE and multiple other markers of acuity of illness in the logistic regression model; however, we may have adjusted for some variables intermediate in the causal pathway between SA exposure and outcome.
In other neonatal populations, there are no clear benefits of “routine” SA use. Among term neonates, longer duration or higher cumulative dose of SA in the neonatal period have been shown to adversely affect performance IQ and visual motor integration scores [21], and neuromuscular blockade to increase the risk of mortality [22]. Among mechanically ventilated preterm participants of the NEOPAIN RCT, pre-emptive morphine infusions did not reduce the frequency of brain injury or death, but intermittent open-label morphine was associated with an increased rate [23]. Other studies in preterm populations have not shown an effect of SA exposure on neurodevelopment [24–26].
The current data, while exploratory, suggest that careful, rather than routine SA administration in infants with HIE during the initial 72 hours of life, may not be harmful. Only 10% of infants received SA alone, making it difficult to ascertain their effects. Preclinical data are conflicting; neonatal morphine administration has been shown to induce apoptosis in microglial cells and behavioral changes have been demonstrated in some animal models [6, 27–29] and reduced survival but no significant differences in the volume of infarction, or behavioral outcomes in others [30].
We recognize the limitations of this exploratory secondary analysis. There were no defined protocols for SA in the NRN RCT and the categorization of levels of SA using a factor count, while designed to assess both number of agents and duration of exposure, was arbitrary. We attempted to account also for anticonvulsants and, neuromuscular blocking agents, which may be less driven by practice variation. However, we did not have indications for SA, doses or pain scores available, and could not discriminate the effect of each class of medication. The BSID-II has been shown to have systematic differences from the BSID-III current version. Our sample size precluded subgroup analysis of normothermic and cooled groups of infants separately and only 10% of the cohort received SA alone. Lastly, data on maternal education level which is a surrogate of socio-economic status and strongly influences outcome, was incomplete.
Nonetheless, the current study addresses a largely unstudied issue in a high-risk population of neonates and provides novel insights into potential associations of SA in the initial days of life among infants with HIE and neurodevelopmental outcomes. While it is difficult to unravel the relative contributions of the brain injury, the pain-stress of neurocritical care and SA administration on neurodevelopment, our data emphasize the need for further systematic investigation into the risk-benefits of SA in HIE, in an era when TH is widely disseminated.
Acknowledgments
Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. One behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Mr. Scott A. McDonald (DCC Statistician) had full access to all of the data in the study, and with the NRN Center Principal Investigators, take responsibility for the integrity of the data and accuracy of the data analysis.
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chairs: Alan H. Jobe, MD PhD, University of Cincinnati (2003-2006); Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006-present). Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Betty R. Vohr, MD; William Oh, MD; Angelita M. Hensman, RN BSN; Bonnie E. Stephens, MD; Theresa M. Leach, MEd CAES; Lucy Noel; Victoria E. Watson, MS CAS.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80) – Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Deanne E. Wilson-Costello, MD; Nancy Bass, MD; Harriet G. Friedman MA; Nancy S. Newman, BA RN; Bonnie S. Siner, RN. Cincinnati Children’s Hospital Medical Center and University of Cincinnati Medical Center (U10 HD27853, M01 RR8084) – Kurt Schibler, MD; Edward F. Donovan, MD; Kate Bridges, MD; Kimberly Yolton, PhD; Jean J. Steichen, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Holly L. Mincey, RN BSN; Jody Hessling, RN; Teresa L. Gratton, PA.
Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, M01 RR30) – Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Kathryn E. Gustafson, PhD; Ricki F. Goldstein, MD; Kathy J. Auten, MSHS; Katherine A. Foy, RN; Kimberley A. Fisher, PhD FNP-BC IBCLC; Sandy Grimes, RN BSN; Melody B. Lohmeyer, RN MSN.
Emory University, Grady Memorial Hospital and Emory University Hospital Midtown (U10 HD27851, M01 RR39) – Barbara J. Stoll, MD; David P. Carlton, MD; Lucky Jain, MD; Ira Adams-Chapman, MD; Ann M. Blackwelder, RNC BS MS; Ellen C. Hale, RN BS CCRC; Sobha Fritz, PhD; Sheena Carter, PhD; Maureen Mulligan LaRossa, RN.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Linda L. Wright, MD; Elizabeth M. McClure, MEd; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750) – Brenda B. Poindexter, MD MS; James A. Lemons, MD; Anna M. Dusick, MD FAAP; Diana D. Appel, RN BSN; Jessica Bissey, PsyD HSPP; Dianne E. Herron, RN; Lucy C. Miller, RN BSN CCRC; Leslie Richard, RN; Leslie Dawn Wilson, BSN CCRC.
RTI International (U10 HD36790) – W. Kenneth Poole, PhD; Jane Hammond, PhD; Jeanette O’Donnell Auman, BS; Margaret Crawford, BS; Betty K. Hastings; Jamie E. Newman, PhD MPH; Carolyn M. Petrie Huitema, MS; Kristin M. Zaterka-Baxter, RN BSN.
Stanford University and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70) –Krisa P. Van Meurs, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Maria Elena DeAnda, PhD; Barry E. Fleisher, MD; Anne M. DeBattista, RN PNP; Joan M. Baran, PhD; Julie C. Lee-Ancajas, PhD.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32) – Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Kathleen G. Nelson, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Vivien A. Phillips, RN BSN; Laurie Lou Smith, EdS NCSP; Fred J. Biasini, PhD; Kirstin J. Bailey, PhD.
University of California-San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461) – Neil N. Finer, MD; David Kaegi, MD; Maynard R. Rasmussen, MD; Yvonne E. Vaucher, MD MPH; Martha G. Fuller, RN MSN; Radmila West PhD; Kathy Arnell, RNC; Chris Henderson, RCP CRTT; Wade Rich, BSHS RRT.
University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521, M01 RR44) – Dale L. Phelps, MD; Gary J. Myers, MD; Diane Hust, MS RN CS; Linda J. Reubens, RN CCRC.
University of Miami Holtz Children’s Hospital (U10 HD21397, M01 RR16587) – Shahnaz Duara, MD; Charles R. Bauer, MD; Sylvia Hiriart-Fajardo, MD; Mary Allison, RN; Maria Calejo, MS;Ruth Everett-Thomas, RN MSN; Silvia M. Frade Eguaras, MA; Susan Gauthier, BA. University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – Pablo J. Sánchez, MD; R. Sue Broyles, MD; Abbot R. Laptook, MD; Charles R. Rosenfeld, MD; Walid A. Salhab, MD; Roy J. Heyne, MD; Cathy Boatman, MS CIMI; Cristin Dooley, PhD LSSP; Gaynelle Hensley, RN; Jackie F. Hickman, RN; Melissa H. Leps, RN; Susie Madison, RN; Nancy A. Miller, RN; Janet S. Morgan, RN; Lizette E. Torres, RN; Alicia Guzman; Elizabeth Heyne, PA-C; Linda A. Madden, BSN RN CPNP; Sally Adams, PNP.
University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373, M01 RR2588) – Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Esther G. Akpa, RN BSN; Patty A. Cluff, RN; Patricia W. Evans, MD; Claudia I. Franco, RN BSN; Charles Green, PhD; Anna E. Lis, RN, BSN; Georgia E. McDavid, RN; Patti L. Pierce Tate, RCP; Nora I. Alaniz, BS; Pamela J. Bradt, MD MPH; Magda Cedillo; Susan Dieterich, PhD; Margarita Jiminez, MD; Terri Major-Kincade, MD MPH; Brenda H. Morris, MD; M. Layne Poundstone, RN BSN; Stacey Reddoch, BA; Saba Siddiki, MD; Maegan C. Simmons, RN; Laura L. Whitely, MD; Sharon L. Wright, MT; Lourdes M. Valdés PhD.
Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385) – Rebecca Bara, RN BSN; Yvette R. Johnson, MD MPH; Laura A. Goldston, MA; Geraldine Muran, RN BSN; Deborah Kennedy, RN BSN; Patrick J. Pruitt, BS.
Yale University, Yale-New Haven Children’s Hospital (U10 HD27871, M01 RR125, UL1 RR24139) – Richard A. Ehrenkranz, MD; Patricia Gettner, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Elaine Romano, MSN; Joanne Williams, RN BSN; Susan DeLancy, MA CAS.
Statement of Financial Support: Please see acknowledgement section U10 HD27904; U10 HD21364; M01 RR80, U10 HD27853; M01 RR8084; U10 HD40492, M01 RR30; U10 HD27851, M01 RR39; U10 HD27856, M01 RR750; U10 HD36790; U10 HD27880, M01 RR70; U10 HD34216, M01 RR32; U10 HD40461; U10 HD40521, M01 RR44; U10 HD21397, M01 RR16587; U10 HD40689, M01 RR633; U10 HD21373, M01 RR2588; U10 HD21385; U10 HD27871, M01 RR125, UL1 RR24139
This is a secondary study of the trial listed at NCT00005772
Footnotes
Disclosure statement: None of the coauthors have any conflicts of interest to disclose.
No honorarium or grant was paid to the corresponding author for the initial draft of the manuscript
Category of Study: Clinical
References
- 1.Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic-ischemic encephalopathy. Cochrane Database Syst Rev. 2013;1:CD003311. doi: 10.1002/14651858.CD003311.pub3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res. 2001;50:405e11. doi: 10.1203/00006450-200109000-00017. [DOI] [PubMed] [Google Scholar]
- 3.Haaland K, Loberg EM, Steen PA, Thoresen M. Posthypoxic hypothermia in newborn piglets. Pediatr Res. 1997;41:505e12. doi: 10.1203/00006450-199704000-00009. [DOI] [PubMed] [Google Scholar]
- 4.Chakkarapani E, Dingley J, Liu X, Hoque N, Aquilina K, Porter H, et al. Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Ann Neurol. 2010;68:330e41. doi: 10.1002/ana.22016. [DOI] [PubMed] [Google Scholar]
- 5.Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx. 2006;3:154e69. doi: 10.1016/j.nurx.2006.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wassink G, Lear CA, Gunn KC, Dean JM, Bennet L, Gunn AJ. Analgesics, sedatives, anticonvulsant drugs, and the cooled brain. Semin Fetal Neonatal Med. 2015;20(2):109–14. doi: 10.1016/j.siny.2014.10.003. [DOI] [PubMed] [Google Scholar]
- 7.DellAnna AM, Taccone FS, Halenarova K, Citerio G. Sedation after cardiac arrest and during therapeutic hypothermia. Minerva Anestesiol. 2014;80:954–62. [PubMed] [Google Scholar]
- 8.Simbruner G, Mittal RA, Rohlmann F, Muche R, neo.nEURO.network Trial Participants Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO. network RCT Pediatrics. 2010;126(4):e771–8. doi: 10.1542/peds.2009-2441. [DOI] [PubMed] [Google Scholar]
- 9.Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. TOBY Study Group Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349–58. doi: 10.1056/NEJMoa0900854. [DOI] [PubMed] [Google Scholar]
- 10.Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. National Institute of Child Health and Human Development Neonatal Research Network Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84. doi: 10.1056/NEJMcps050929. [DOI] [PubMed] [Google Scholar]
- 11.Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365(9460):663–70. doi: 10.1016/S0140-6736(05)17946-X. [DOI] [PubMed] [Google Scholar]
- 12.Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Infant Cooling Evaluation Collaboration Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165(8):692–700. doi: 10.1001/archpediatrics.2011.43. [DOI] [PubMed] [Google Scholar]
- 13.Zhou WH, Cheng GQ, Shao XM, Liu XZ, Shan RB, Zhuang DY, et al. China Study Group Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010;157(3):367–72. doi: 10.1016/j.jpeds.2010.03.030. [DOI] [PubMed] [Google Scholar]
- 14.Róka A, Melinda KT, Vásárhelyi B, Machay T, Azzopardi D, Szabó M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121(4):e844–9. doi: 10.1542/peds.2007-1987. [DOI] [PubMed] [Google Scholar]
- 15.Pappas A, Shankaran S, Laptook AR, Langer JC, Bara R, Ehrenkranz RA, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2011;158(5):752–758. doi: 10.1016/j.jpeds.2010.10.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Palisano R, Rossenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39:214–223. doi: 10.1111/j.1469-8749.1997.tb07414.x. [DOI] [PubMed] [Google Scholar]
- 17.Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, Smith GB, et al. European Resuscitation Council Guidelines For Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation. 2010;81:1305–52. doi: 10.1016/j.resuscitation.2010.08.017. [DOI] [PubMed] [Google Scholar]
- 18.Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. American Heart Association Part 9: Post-cardiac Arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S768–86. doi: 10.1161/CIRCULATIONAHA.110.971002. [DOI] [PubMed] [Google Scholar]
- 19.Chamorro C, Borrallo JM, Romera MA, Silva JA, Balandín B. Anesthesia and Analgesia Protocol During Therapeutic Hypothermia After Cardiac Arrest: A Systematic Review. Anesth Analg. 2010;110:1328–35. doi: 10.1213/ANE.0b013e3181d8cacf. [DOI] [PubMed] [Google Scholar]
- 20.Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. THAPCA Trial Investigators Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children. N Engl J Med. 2015;372(20):1898–1908. doi: 10.1056/NEJMoa1411480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Guerra GG, Robertson CMT, Alton GY, Joffe AR, Cave DA, Yasmin F, et al. Western Canadian Complex Pediatric Therapies Follow-up Group Neurotoxicity of sedative and analgesia drugs in young infants with congenital heart disease: 4-year follow-up. Pediatric Anesthesia. 2014;24:257–265. doi: 10.1111/pan.12257. [DOI] [PubMed] [Google Scholar]
- 22.Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent Pulmonary Hypertension of the Newborn in the Era Before Nitric Oxide: Practice Variation and Outcomes. Pediatrics. 2000;105:14–20. doi: 10.1542/peds.105.1.14. [DOI] [PubMed] [Google Scholar]
- 23.Anand KJ, Whit Hall R, Desai N, Shephard B, Bergqvist LL, Young TE, et al. NEOPAIN Trial Investigators Group Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004;363:1673–82. doi: 10.1016/S0140-6736(04)16251-X. [DOI] [PubMed] [Google Scholar]
- 24.Roze JC, Denizot S, Carbajal R, Ancel PY, Kaminski M, Arnaud C, et al. Prolonged Sedation and/or Analgesia and 5-Year Neurodevelopment Outcome in Very Preterm Infants. Arch Pediatr Adolesc Med. 2008;162(8):728–733. doi: 10.1001/archpedi.162.8.728. [DOI] [PubMed] [Google Scholar]
- 25.MacGregor R, Evans D, Sudgen D, Gaussen T, Levene M. Outcome at 5–6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79(1):F40–F43. doi: 10.1136/fn.79.1.f40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.de Graaf J, van Lingen RA, Simons SH, Anand KJ, Duivenvoorden HJ, Weisglas-Kuperus N, et al. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: five-year follow-up of a randomized controlled trial. Pain. 2011;152(6):1391–7. doi: 10.1016/j.pain.2011.02.017. [DOI] [PubMed] [Google Scholar]
- 27.Hu S, Sheng WS, Lokensgard JR, Peterson PK. Morphine induces apoptosis of human microglia and neurons. Neuropharmacology. 2002;42:829–836. doi: 10.1016/s0028-3908(02)00030-8. [DOI] [PubMed] [Google Scholar]
- 28.Handelmann GE, Dow-Edwards D. Modulation of brain development by morphine: Effects on central motor systems and behavior. Peptides. 1985;6(Suppl 2):29–34. doi: 10.1016/0196-9781(85)90131-7. [DOI] [PubMed] [Google Scholar]
- 29.Attarian S, Tran LC, Moore A, Stanton G, Meyer E, Moore RP. The Neurodevelopmental Impact of Neonatal Morphine Administration. Brain Sci. 2014;4:321–334. doi: 10.3390/brainsci4020321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Festekjian A, Ashwal S, Obenaus A, Angeles DM, Denmark TK. The role of morphine in a rat model of hypoxic-ischemic injury. Pediatr Neurol. 2011;45:77e82. doi: 10.1016/j.pediatrneurol.2011.04.004. [DOI] [PubMed] [Google Scholar]