Short-Term Effects of Opioid Use During Therapeutic Hypothermia for Neonatal Encephalopathy

doi:10.21203/rs.3.rs-3218180/v1

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Short-Term Effects of Opioid Use During Therapeutic Hypothermia for Neonatal Encephalopathy

https://doi.org/10.21203/rs.3.rs-3218180/v1

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Objective

To examine the effects of opioids during therapeutic hypothermia (TH) on short-term clinical outcomes in neonates with neonatal encephalopathy (NE).

Methods

Multicenter retrospective study of neonates with moderate/severe NE. Opioid exposure was classified as positive (> 0.1 mg/kg) or negative (no exposure or ≤ 0.1 mg/kg) based on cumulative morphine milligram equivalents (MME). Negative binomial regression models were used to evaluate clinical outcomes.

Results

One hundred and twenty neonates were included. Positive opioid exposure was associated with an increase in: 1) length of hospitalization, 2) hypotension/use of vasopressors, and 3) need for and longer duration of mechanical ventilation. Findings were seen with morphine and fentanyl (continuous infusion or intermittent bolus) and were worse with concurrent administration of antiepileptics.

Conclusions

Opioid use during TH was associated with adverse effects on short term clinical outcomes. Caution should be exercised when using opioids during TH until longer-term neurodevelopmental outcome studies can be examined in larger cohorts.

Health sciences/Diseases/Neurological disorders/Paediatric neurological disorders

Health sciences/Diseases/Neurological disorders/Brain injuries

Therapeutic hypothermia (TH) is the recommended treatment for infants with signs and symptoms of neonatal encephalopathy (NE) occurring after a significant perinatal event. The clinical presentation of NE includes depressed level of consciousness, decreased spontaneous movement, low muscle tone, poor sucking reflex, and seizures. This commonly occurs in the context of a perinatal sentinel event (e.g., cord prolapse, placental abruption) and can be associated with end-organ involvement and long-term neurodevelopmental sequela. NE is traditionally categorized as mild, moderate, and severe using modified Sarnat scoring and other assessment tools, with TH considered standard treatment for moderate and severe NE (1, 2). Published data demonstrates the benefits of initiating TH in neonates prior to 6 hours of life and continued for 72 hours (2, 3, 4).

In many centers around the country, agitation, discomfort, and pain during TH are routinely treated with opioids such as morphine and fentanyl (continuous infusion and/or intermittent bolus administration) (1). Morphine has anti-nociceptive properties and reduces the release of glutamate and the sensitivity of glutamate receptors. Glutamate is an excitatory neurotransmitter and is responsible for triggering apoptosis during secondary energy failure characteristic of neonatal NE. Inhibition of glutamate release and reduction of glutamate receptor sensitivity is thought to result in neuroprotection (5). Angeles et al found that neonates who were given morphine during TH had less evidence of hypoxic injury on magnetic resonance imaging compared to those who did not receive opioids (5).

There is concern that repeated neonatal pain is associated with adverse neurodevelopmental outcomes. Williams and Lascelles suggested that there are long-term consequences of untreated neonatal pain including associated adverse sensorimotor/cognitive development and subsequent future responses to pain (6). Walker also reviewed long-term effects of neonatal pain on neurodevelopment and suggested that there were distinct differences when morphine is administered as a sedative in the absence of pain and/or tissue damage compared to when it is used as an analgesic for true pain (7). Gunderson et al reported on their prospectively collected cohort of 282 neonates with HIE treated with TH who were exposed to opioids for sedation and analgesia and found no adverse effects on neurodevelopmental outcomes at 18–24 months (8).

Natarajan et al. demonstrated that sedation during TH does not correlate with neurological outcomes and suggested that sedation should be further studied in neonates exposed to TH (9). Liow et al. performed a secondary analysis from a large multinational prospective observational study to examine the association between morphine infusion during TH on brain injury and neurodevelopmental outcomes (10). They concluded that morphine does not offer any neuroprotective benefits and may be associated with a prolonged hospital stay (10). Additionally, Frymoyer et al conducted a pharmacokinetic study in 20 neonates receiving morphine and found the clearance to be significantly lower in this category of patients compared to full term babies without NE (11). Similarly, Roka et al found that serum morphine concentrations during the 24 to 72 hours after birth were higher in infants who underwent TH compared to their normothermic controls despite similar morphine infusion rates and doses (12). The potential adverse effects of opioids (e.g., hypotension, respiratory depression) are especially concerning given that clearance is decreased during TH (11, 12).

The goal of the present study was to determine whether opioid use during TH for moderate and severe NE affects short-term clinical outcomes including length of hospitalization, duration and mode of respiratory support, and need for vasopressor medications for blood pressure support. Our hypothesis was that morphine or fentanyl administration during TH for NE does not significantly impact short-term clinical outcomes.

This is a multicenter retrospective study of neonates receiving TH for moderate or severe NE at Tufts Medical Center (TMC) in Boston MA, Norton Children’s Hospital (NCH) in Louisville KY, and Brenner Children’s Hospital at Wake Forest (WF) in Winston Salem NC. At all three centers, the severity of NE was determined using Sarnat scoring and neonates with mild NE were excluded even if they received TH. Opioid use for sedation during TH is not routine at TMC but is standard of care at NCH (morphine continuous infusion) and WF (fentanyl continuous infusion). Fentanyl is about 100 times more potent than morphine; a dose of only 100 micrograms (0.1 mg) can produce equivalent analgesia to approximately 10 mg of morphine (13).

Charts were examined from neonates undergoing TH for moderate or severe NE from January 2013 – February 2021. Demographic information related to the prenatal, intrapartum, and postpartum care was collected including pregnancy complications, delivery information, need for neonatal resuscitation, and data regarding the diagnosis of NE and eligibility for TH. Laboratory and imaging data were used as a surrogate assessment for severity of illness. De-identified data from each center were entered into a REDCap database. Due to the retrospective nature of this study, not all data were available for all patients in the study.

Primary Outcome Measures in Relation to Opioid Use

The primary outcomes examined in this study were: 1) length of hospitalization, 2) duration and type of respiratory support, and 3) use of vasopressor medications for blood pressure support. Secondary outcomes included time to full oral feeds, duration of parenteral nutrition, and total time a central line was in place. The major focus of this study was exposure to opioids (e.g., morphine, fentanyl) which was classified as positive or negative based on cumulative morphine milligram equivalents (MME). Positive opioid exposure was defined as > 0.1 mg/kg cumulative MME and negative as no opioid doses or a total of ≤ 0.1 mg/kg received during TH.

Statistical Analyses

The clinical and laboratory characteristics of the two opioid exposure groups were analyzed using Wilcoxon rank sum tests for continuous variables and chi-square tests for categorical variables. The clinical and laboratory characteristics of each center was analyzed using Kruskal-Wallis tests for continuous variables and chi-square tests for categorical variables. We used negative binomial regression models to evaluate the association between opioid exposure and length of hospitalization, length of vasopressor use, duration of noninvasive ventilation, time to come off parenteral nutrition, total time a central line was in place, and time to full oral feeds. We used linear regression to evaluate the association between opioid exposure and log-transformed duration of invasive ventilation. We used logistic regression to evaluate the association between opioid exposure and vasopressor use. All models were adjusted for center and the use of anti-seizure medications. A two-sided 0.05 level of significance was used. All analyses were conducted using SAS Enterprise Guide software, Version 8.3 Update 3 (SAS Institute Inc., Cary, NC).

We included 129 neonates in the study: 52 at TMC, 39 at NCH, and 29 at WF. Table IA and IB show the maternal and neonatal demographic and perinatal characteristics for neonates in the study, by center and by cumulative MME category or opiate exposure (positive or negative) respectively. There were no statistically significant differences between the sites with respect to sex, race, ethnicity, birth weight, and mode of delivery. Most neonates receiving TH at all three centers were outborn (14).

More neonates from WF had severe NE (31%) compared to the other centers (Table IA). NCH had a significantly higher number of mothers with a history of substance use. A significantly higher incidence of depression and anxiety was noted in mothers from TMC. Significant difference was noted in the documentation of non-reassuring fetal heart rate tracings with TMC having more cases compared to NCH and WF.

The use of resuscitative measures, delivery complications, and laboratory data were comparable among centers, including the degree of acidosis on the cord and/or first postnatal blood gas (Table IA). The severity of acidosis was similar between sites, defined as the lowest bicarbonate value on an electrolyte panel during cooling and rewarming periods (first 6 days of the hospital stay).

The unadjusted analysis of the primary outcomes is shown in Tables IIA and IIB. Table IIA compares both the exposure and the outcomes across centers, and Table IIB compares both the exposure and outcomes between exposure categories. The cumulative opioid dosing analysis showed that 68% of all neonates in the study were exposed to > 0.1 mg/kg MME. The WF group was exposed to a median (first quartile [Q1] to third quartile [Q3]) of 3.3 (0.8 to 8.1) mg/kg MME compared to 0.9 (0.8 to 1.6) mg/kg at NCH and 0.2 (0.1 to 0.4) mg/kg at TMC (Table IIA) (p < 0.0001). At NCH, 97.4% of neonates had a positive exposure to opioids compared to 72.4% at WF, and 44.2% at TMC (p < 0.0001). The median (Q1 to Q3) length of hospital stay was 23 (10 to 34) days at WF compared to 14 (12 to 22) days at NCH and 9 (8 to 20) days at TMC (p = 0.004). The use of vasopressors was 66.7% at NCH compared to 41.4% at WF and 23.1% at TMC (p = 0.0002). The median (Q1 to Q3) duration of mechanical ventilation was 5 (1 to 8) days at WF compared to 3 (2 to 6) days at NCH and 2 (1 to 3) days at TMC (p = 0.01). The median (Q1 to Q3) duration of central line use was 8 (7 to 10) days at NCH compared to 7 (6 to 10) days at WF and 6 (5 to 8) days at TMC (p = 0.003). Consistent with these data, the median (Q1 to Q3) time to full oral feeds was 9 (7 to 14) days at NCH compared to 8 (7 to 15) days at WF and 6 (5 to 7) days at TMC (p = 0.0002).

After adjusting for center and use of anti-seizure medications, neonates with a positive exposure to opioids had a 8% longer average length of stay in the hospital compared to the negative opioid dose group (ratio of means 1.08, 95% CI 0.85–1.38), 1.30 times the odds of requiring vasopressors (odds ratio 1.30, 95% CI 0.47–3.63), a 44% longer average duration of vasopressor use (ratio of means 1.23, 95% CI 0.70–2.64), and a 32% longer average time needing invasive ventilation (ratio of means 1.32, 95% CI 0.91–1.89). The positive dose group had a 31% shorter average time receiving non-invasive ventilatory support (ratio of means 0.69, 95% CI 0.44–1.07) compared to the negative group. None of these findings, however, were found to be statistically significant.

Exposure to anti-seizure medications was common in neonates with moderate to severe NE. Neonates receiving these medications were more likely to require a longer duration of mechanical ventilation and more vasopressor use. These neonates also had a 61% longer average length of stay in the hospital (ratio of means 1.61, 95% CI 1.31–1.97), and 2.35 times of odds of requiring vasopressors compared to those not exposed to anti-seizure medications (odds ratio 2.35, 95% CI 1.00-5.48).

The benefits and risks of opiate use during therapeutic hypothermia remain controversial. While some pre-clinical models suggest that morphine may enhance the neuroprotective effects of TH by reducing oxidative stress, other animal studies have suggested that morphine induces neuronal apoptosis which could be harmful (2, 15, 16).

The aim of this study was to examine short-term outcomes in neonates requiring TH and exposed to no or minimal doses of opioids compared to higher MME at three academic medical centers. The results of this study suggests that higher cumulative doses of MME during TH for NE (often via continuous infusions) is associated with a greater need and longer duration of mechanical ventilatory support, vasopressors to support blood pressure, and a longer hospital stay. The TH protocols at the three centers are very similar except for the approach for sedation. At TMC intermittent morphine doses (0.05–0.1 mg/kg) are used only as needed while NCH routinely administers morphine by continuous infusion throughout the 72 hours of TH, and WF administers fentanyl by continuous infusion. Our analysis demonstrated that the cumulative MME dose was significantly different among the three sites which was somewhat unexpected since the general perception is that continuous infusion decreases the cumulative MME amount required for pain control and comfort. The substantial difference in the cumulative MME dose at WF compared to the other two centers is related to the preferential use of fentanyl, with significantly higher potency (100 times) compared to morphine.

Although patient demographics at the three centers were similar, some differences were seen, related to the geographical and socio-economic environment. Most neonates receiving TH at all three centers were outborn which is consistent with current evidence (14). There was a higher number of mothers with substance use disorder in the NCH cohort (17). The higher incidence of anxiety and depression diagnosed among mothers in the TMC group could be related to better access to mental health resources in Massachusetts (18).

The data showed minor differences among sites with respect to modes of ventilation, fluid resuscitation, laboratory data, and initiation of feeds (Table IIIA), likely due to variation in practice patterns between the three sites.

Even though neonates exposed to antiepileptics required a longer hospitalization, a greater need for vasopressors and duration of vasopressor use as well as need for invasive ventilation, none of these differences were found to be statistically significant.

Given the retrospective nature of this study and the real-world data that was obtained, the differences in clinical practice at the three institutions were inherent. But this is a pragmatic study which enabled the comparison of effect of opioids on short term outcomes at three centers with similar TH management, despite some differences in clinical practice. The difference in pressor use could be partially related to variations in the approach to blood pressure measurement at the three institutions. At TMC and WF, the use of intraarterial lines for blood pressure monitoring is less common than at NCH. Intraarterial line blood pressure measurements are considered the gold standard and values tend to be lower than those measured by a sphygmomanometer (19). This may result in more vasopressor use at NCH which could also impact the need and duration of central line use. Higher use of vasopressors would also result in slower advancement of feeds and could partially explain why the NCH group started trophic feeds later.

The main limitations of our study include the relatively small sample size, retrospective data collection (with some data collected that is approximately 10 years old), and inherent clinical practice variations between the three institutions despite very similar TH protocols. Since the concomitant use of anti-seizure medication could be a confounding variable with impact on the primary and secondary outcomes, this variable was adjusted for in our final analysis and the differences were not found to be statistically significant. Another limitation was the lack of an objective tool to more accurately compare the severity of NE and the pain/discomfort associated with TH. Information used as a surrogate biomarker included: APGAR scores, blood gases, the presence of multiorgan involvement, and Sarnat scoring. Data collected in this study showed that neonates with a diagnosis of severe NE did not consistently have evidence of multiorgan involvement or the most severe MRI findings.

Although the use of MRI as a biomarker of underlying brain injury is still being debated, MRI findings do correlate with future neurodevelopmental outcomes associated with NE (20). The discrepancy between unfavorable short-term outcomes and MRI results as a long-term prognostic tool emphasizes the need for long-term outcome data to definitively determine benefit or harm of opioid use in the management of neonatal NE during TH. For this study’s subjects, each center’s MRIs were interpreted by their own pediatric neuroradiologist. We were not able to have a single blinded radiologist interpret the results for all the MRIs and this prevented us from formulating statistical conclusions regarding the MRI findings.

The cumulative impact of opioids on long-term neurodevelopmental outcomes after TH could not be analyzed given the limited amounts of follow-up data available from the three centers. Long-term outcomes are critical to establish safety of these medication practices. The optimal therapeutic approach to neonatal pain management using opioids is still unresolved and a standardized approach is lacking. Newer sedatives such as dexmedetomidine are emerging as alternative options and their use in neonates is becoming much more widespread without sufficient compelling data on safety and dosing, especially during TH when the metabolism of many drugs changes (21).

This study is one of the few involving the generation of real-world data, an important approach for more evidence considering the current paucity of data on the safety and efficacy of opioid use in neonates (especially those with underlying brain injury). While the current results raise concerns regarding the use of opioids in neonates undergoing TH, a larger prospective multicenter trial with detailed pharmacokinetic analyses and comprehensive neurodevelopmental follow-up will ultimately be needed to further investigate the short- and long-term safety and efficacy of opioids during TH.

Acknowledgements:

We would like to acknowledge the Tufts Clinical and Translational Science Institute for their assistance in data analysis for this project.

Additional Information:

Conflict of Interest: The authors have no conflicts of interest to disclose.

Funding source: No funding was obtained or utilized for this study.

Ethics Approval and Consent to Participate: This study was reviewed and approved by the Tufts Health Sciences Institutional Review Board (IRB), # 13467. Data use agreements were in place for participating centers. The study was performed in accordance with the Declaration of Helsinki.

Authors Contributions:

Tina Jumani, DO, conceptualized and designed the study, oversaw collection of data, drafted the manuscript, and reviewed and revised the manuscript.
Rodica Turcu, MD conceptualized and designed the study, reviewed data analyses, and reviewed and revised the manuscript.
Jonathan Davis, MDconceptualized and designed the study, reviewed data analyses, and reviewed and revised the manuscript.
Tonya Robinson, MD participated in designing the study, oversaw collection of data, drafted the manuscript, and reviewed and revised the manuscript.
Jeffrey Shenberger, MD participated in designing the study, oversaw collection of data, drafted the manuscript, and reviewed and revised the manuscript.
Benjamin Sweigart, completed the statistical analysis and reviewed and revised the manuscript
Priya Mishra MD, participated in data collection, reviewed and revised the manuscript

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Table IA: Maternal and Neonatal Demographics by Center

Variable	All (N=120)	TMC (N=52)	NCH (N=39)	WF (N=29)	p-value
Severe encephalopathy, n (%)	14 (11.7)	5 (9.6)	0 (0.0)	9 (31.0)	0.0003
Inborn (yes), n (%)	10 (8.3)	4 (7.7)	2 (5.1)	4 (13.8)	0.40
Male sex, n (%)	75 (63.0) [N=119]	32 (61.5)	25 (64.1)	18 (64.3) [N=28]	0.96
Race, n (%)
White	73 (60.8)	28 (53.9)	29 (74.4)	16 (55.2)	0.01
Black	17 (14.2)	6 (11.5)	4 (10.3)	7 (24.1)
Hispanic	14 (11.7)	10 (19.2)	4 (10.3)	0 (0.0)
Asian	6 (5.0)	4 (7.7)	0 (0.0)	2 (6.9)
Birth Weight (g), mean (SD)	3349.6 (616.1)	3371.9 (607.7)	3408.9 (506.2)	3229.8 (756.5)	0.47
Gestational Age (weeks), mean (SD)	38.7 (1.6)	39.0 (1.4)	39.0 (1.4)	37.8 (1.8)	0.003
Mode of Delivery, n (%)
C-Section	75 (62.5)	31 (59.6)	24 (61.5)	20 (69.0)	0.16
Spontaneous Vaginal Delivery	33 (27.5)	12 (23.1)	14 (35.9)	7 (24.1)
Vacuum-Assisted Vaginal Delivery	12 (10.0)	9 (17.3)	1 (2.6)	2 (6.9)
Maternal Medical History, n (%)
Hypertension, n (%)	17 (14.2)	8 (15.4)	8 (20.5)	1 (3.5)	0.13
Pre-eclampsia, n (%)	8 (6.7)	2 (3.9)	5 (12.8)	1 (3.5)	0.21
Substance use, n (%)	19 (15.8)	4 (7.7)	11 (28.2)	4 (13.8)	0.03
Chorioamnionitis, n (%)	19 (15.8)	10 (19.2)	7 (18.0)	2 (6.9)	0.31
Diabetes - diet controlled, n (%)	11 (9.2)	4 (7.7)	6 (15.4)	1 (3.5)	0.28
Diabetes - insulin, n (%)	13 (10.8)	8 (15.4)	1 (2.6)	4 (13.8)	0.11
Obesity, n (%)	15 (12.5)	7 (13.5)	6 (15.4)	2 (6.9)	0.61
Depression/Anxiety, n (%)	10 (8.3)	7 (13.5)	0 (0.0)	3 (10.3)	0.04
Maternal Indication for Delivery, n (%)
Abruption	18 (15.0)	5 (9.6)	8 (20.5)	5 (17.2)	0.51
Chorioamnionitis	10 (8.3)	6 (11.5)	4 (10.3)	0 (0.0)
Chronic Hypertension	4 (3.3)	3 (5.8)	0 (0.0)	1 (3.5)
Gestational Diabetes	3 (2.5)	2 (3.9)	0 (0.0)	1 (3.5)
Maternal Fever	1 (0.8)	1 (1.9)	0 (0.0)	0 (0.0)
Pre-eclampsia	4 (3.3)	1 (1.9)	1 (2.6)	2 (6.9)
Vaginal Bleeding	2 (1.7)	1 (1.9)	1 (2.6)	0 (0.0)
Fetal Indications for Delivery, n (%)
NFHRT/fetal decelerations, n (%)	56 (46.7)	30 (57.7)	12 (30.8)	14 (48.3)	0.04
Failure to progress, n (%)	7 (5.8)	2 (3.9)	2 (5.1)	3 (10.3)	0.54
Post-dates, n (%)	7 (5.8)	6 (11.5)	1 (2.6)	0 (0.0)	0.07
Cord Prolapse, n (%)	7 (5.8)	3 (5.8)	3 (7.7)	1 (3.5)	0.89
Delivery data
Apgar 1min, median (IQR)	1 (1-2)	1 (1-2)	1 (1-2)	1 (0-2)	0.45
Apgar 5min, median (IQR)	3 (2-5)	3 (2-4)	4 (2-6)	3 (1-4)	0.03
Apgar 10min, median (IQR)	5 (3-7) [N=109]	5 (4-6) [N=50]	6 (3-7) [N=35]	5 (2-7) [N=24]	0.28
Cord arterial blood pH, mean (SD)	7.0 (0.2) [N=59]	7.0 (0.2) [N=29]	6.9 (0.2) [N=17]	7.0 (0.1) [N=13]
Cord arterial BE, mean (SD)	-15.3 (5.5) [N=48]	-14.4 (5.6) [N=21]	-15.9 (5.3) [N=18]	-16.4 (6.0) [N=9]
Cord venous blood pH, mean (SD)	7.0 (0.2) [N=59]	7.0 (0.2) [N=32]	7.0 (0.2) [N=18]	7.0 (0.2) [N=9]
Cord venous BE, mean (SD)	-14.5 (6.5) [N=41]	-13.3 (4.2) [N=15]	-15.0 (7.2) [N=17]	-15.7 (8.6) [N=9]
First neonatal gas pH, mean (SD)	7.1 (0.2) [N=108]	7.1 (0.2) [N=44]	7.1 (0.2) [N=36]	7.1 (0.2) [N=28]	0.70
First neonatal gas BE, mean (SD)	-15.1 (6.3) [N=77]	-15.7 (6.6) [N=19]	-14.5 (6.0) [N=33]	-15.5 (6.5) [N=25]
Delivery Complications, n (%)
Meconium, n (%)	28 (23.3)	7 (13.5)	14 (35.9)	7 (24.1)	0.04
Shoulder Dystocia, n (%)	15 (12.5)	7 (13.5)	6 (15.4)	2 (6.9)	0.61
Nuchal cord, n (%)	15 (12.5)	7 (13.5)	5 (12.8)	3 (10.3)	1.00
Breech/Footling Breech, n (%)	5 (4.2)	0 (0.0)	1 (2.6)	4 (13.8)
Neonatal resuscitation at delivery, n (%)
CPAP, n (%)	18 (15.0)	13 (25.0)	0 (0.0)	5 (17.2)	0.004
PPV with Bag/ mask/O2, n (%)	113 (94.2)	47 (90.4)	39 (100.0)	27 (93.1)	0.14
Intubation, n (%)	87 (72.5)	35 (67.3)	31 (79.5)	21 (72.4)	0.44
Normal Saline, n (%)	23 (19.2)	5 (9.6)	9 (23.1)	9 (31.0)	0.04
Epinephrine, n (%)	22 (18.3)	7 (13.5)	5 (12.8)	10 (34.5)	0.05

NRFHT – non-reassuring fetal heart tracing, BE – base excess, PPV – positive pressure ventilation

Table IB: Maternal and Neonatal Demographics by Cumulative Morphine Equivalent Categories/Opiate exposure

Variable	All (N=120)	Positive exposure (>0.1 mg/kg) (N=82)	Negative exposure (≤0.1 mg/kg) (N=38)	p-value
Severe encephalopathy, n (%)	14 (11.7)	8 (9.8)	6 (15.8)	0.37
Inborn (yes), n (%)	10 (8.3)	5 (6.1)	5 (13.2)	0.29
Male sex, n (%)	75 (63.0) [N=119]	52 (63.4)	23 (62.2) [N=37]	0.90
Hospital, n (%)
TMC	52 (43.3)	23 (28.1)	29 (76.3)	<0.0001
NCH	39 (32.5)	38 (46.3)	1 (2.6)
WF	29 (24.2)	21 (25.6)	8 (21.1)
Race, n (%)
White	73 (60.8)	53 (64.6)	20 (52.6)	0.44
Black	17 (14.2)	11 (13.4)	6 (15.8)
Hispanic	14 (11.7)	10 (12.2)	4 (10.5)
Asian	6 (5.0)	4 (4.9)	2 (5.3)
Birth Weight (g), mean (SD)	3349.6 (616.1)	3449.7 (584.8)	3133.6 (634.1)	0.01
Gestational Age (weeks), mean (SD)	38.7 (1.6)	38.8 (1.4)	38.4 (1.8)	0.20
Mode of Delivery, n (%)
C-Section	75 (62.5)	51 (62.2)	24 (63.2)	0.65
Spontaneous Vaginal Delivery	33 (27.5)	24 (29.3)	9 (23.7)
Vacuum-Assisted Vaginal Delivery	12 (10.0)	7 (8.5)	5 (13.2)
Maternal Medical History
Hypertension, n (%)	17 (14.2)	10 (12.2)	7 (18.4)	0.36
Pre-eclampsia, n (%)	8 (6.7)	6 (7.3)	2 (5.3)	1.00
Substance use, n (%)	19 (15.8)	13 (15.9)	6 (15.8)	0.99
Chorioamnionitis, n (%)	19 (15.8)	11 (13.4)	8 (21.1)	0.29
Diabetes - diet controlled, n (%)	11 (9.2)	9 (11.0)	2 (5.3)	0.50
Diabetes - insulin, n (%)	13 (10.8)	10 (12.2)	3 (7.9)	0.75
Obesity, n (%)	15 (12.5)	13 (15.9)	2 (5.3)	0.14
Depression/Anxiety, n (%)	10 (8.3)	3 (3.7)	7 (18.4)	0.01
Maternal Indication for Delivery, n (%)
Abruption	18 (15.0)	13 (15.9)	5 (13.2)	0.48
Chorioamnionitis	10 (8.3)	5 (6.1)	5 (13.2)
Chronic Hypertension	4 (3.3)	2 (2.4)	2 (5.3)
Gestational Diabetes	3 (2.5)	3 (3.7)	0 (0.0)
Maternal Fever	1 (0.8)	0 (0.0)	1 (2.6)
Pre-eclampsia	4 (3.3)	2 (2.4)	2 (5.3)
Vaginal Bleeding	2 (1.7)	1 (1.2)	1 (2.6)
Fetal Indications for Delivery, n(%)
NFHRT/fetal decelerations, n (%)	56 (46.7)	35 (42.7)	21 (55.3)	0.20
Failure to progress, n (%)	7 (5.8)	5 (6.1)	2 (5.3)
Post-dates, n (%)	7 (5.8)	6 (7.3)	1 (2.6)
Cord Prolapse, n (%)	7 (5.8)	5 (6.1)	2 (5.3)
Delivery information
Apgar 1min, median (IQR)	1 (1-2)	1 (0-2)	1 (1-2)	0.23
Apgar 5min, median (IQR)	3 (2-5)	3 (1-5)	3 (2-4)	0.84
Apgar 10min, median (IQR)	5 (3-7) [N=109]	5 (3-7) [N=73]	5 (3-7) [N=36]	0.69
Cord arterial blood pH, mean (SD)	7.0 (0.2) [N=59]	7.0 (0.2) [N=35]	6.9 (0.2) [N=24]
Cord arterial BE, mean (SD)	-15.3 (5.5) [N=48]	-14.8 (5.1) [N=31]	-16.2 (6.3) [N=17]
Cord venous blood pH, mean (SD)	7.0 (0.2) [N=59]	7.0 (0.2) [N=38]	7.0 (0.1) [N=21]
Cord venous BE, mean (SD)	-14.5 (6.5) [N=41]	-13.3 (6.6) [N=30]	-17.9 (5.2) [N=11]
First neonatal gas obtained pH, mean (SD)	7.1 (0.2) [N=108]	7.1 (0.2) [N=73]	7.1 (0.2) [N=35]	0.16
First neonatal gas BE, mean (SD)	-15.1 (6.3) [N=77]	-15.0 (6.6) [N=58]	-15.4 (5.3) [N=19]
Delivery Complications, n (%)
Meconium, n (%)	28 (23.3)	23 (28.1)	5 (13.2)	0.07
Shoulder Dystocia, n (%)	15 (12.5)	13 (15.9)	2 (5.3)	0.14
Nuchal cord, n (%)	15 (12.5)	10 (12.2)	5 (13.2)	1.00
Breech/Footling Breech, n (%)	5 (4.2)	3 (3.7)	2 (5.3)
Neonatal resuscitation at delivery, n (%)
CPAP, n (%)	18 (15.0)	10 (12.2)	8 (21.1)	0.21
PPV with Bag/mask/O2, n (%)	113 (94.2)	79 (96.3)	34 (89.5)	0.21
Intubation, n (%)	87 (72.5)	60 (73.2)	27 (71.1)	0.81
Normal Saline, n (%)	23 (19.2)	18 (22.0)	5 (13.2)	0.26
Epinephrine, n (%)	22 (18.3)	19 (23.2)	3 (7.9)	0.04

NRFHT – non-reassuring fetal heart tracing, BE – base excess, PPV – positive pressure ventilation

Table IIA: Primary and Secondary Outcomes by Center

Variable	All (N=120)	TMC (N=52)	NCH (N=39)	WF (N=29)	p-value
Opioids administered, n (%)
Morphine alone	75 (62.5)	37 (71.2)	38 (97.4)	0 (0.0)	<0.0001
Fentanyl alone	22 (18.3)	0 (0.0)	0 (0.0)	22 (75.9)
Morphine and Fentanyl	1 (0.8)	0 (0.0)	0 (0.0)	1 (3.5)
None	22 (18.3)	15 (28.9)	1 (2.6)	6 (20.7)
Cumulative morphine equivalent (mg/kg), median (IQR)	0.8 (0.2-1.6) [N=98]	0.2 (0.1-0.4) [N=37]	0.9 (0.8-1.6) [N=38]	3.3 (0.8-8.1) [N=23]	<0.0001
Cumulative morphine equivalent categories, n (%)
High (>0.1 mg/kg)	82 (68.3)	23 (44.2)	38 (97.4)	21 (72.4)	<0.0001
Low (≤0.1 mg/kg)	38 (31.7)	29 (55.8)	1 (2.6)	8 (27.6)	<0.0001
Outcome variables
Length of stay (days), median (IQR)	13 (9-23)	9 (8-20)	14 (12-22)	23 (10-34)	0.004
Vasopressors, n (%)	50 (41.7)	12 (23.1)	26 (66.7)	12 (41.4)	0.0002
Multiple Vasopressors, n (%)	18 (15.0)	4 (7.7)	7 (18.0)	7 (24.1)	0.11
Duration of Vasopressor use (days), median (IQR)	3 (2-5) [N=50]	3 (1-4) [N=12]	4 (3-5) [N=26]	3 (2-6) [N=12]	0.10
Invasive Ventilation, n (%)	93 (77.5)	35 (67.3)	33 (84.6)	25 (86.2)	0.06
Length of invasive ventilation (days), median (IQR)	2 (1-5) [N=93]	2 (1-3) [N=35]	3 (2-6) [N=33]	5 (1-8) [N=25]	0.01
Noninvasive Ventilation, n (%)	87 (72.5)	36 (69.2)	39 (100.0)	12 (41.4)	<0.0001
Length of noninvasive ventilation (days), median (IQR)	3 (2-4) [N=87]	2 (1-4) [N=36]	3 (2-4)	4 (1-7) [N=12]	0.35
Duration of time off PN prior to discharge (days), median (IQR)	6 (3-13) [N=117]	3 (2-11) [N=51]	7 (4-10) [N=38]	13 (5-19) [N=28]	0.01
Duration of central line (days), median (IQR)	7 (5-9) [N=119]	6 (5-8)	8 (7-10)	7 (6-10) [N=28]	0.003
Time to full oral feeds (DOL), median (IQR)	7 (6-12) [N=106]	6 (5-7) [N=45]	9 (7-14)	8 (7-15) [N=22]	0.0002

PN – parenteral nutrition, DOL – day of life

Table IIB: Primary and Secondary Outcomes by Dose Category

		Cumulative Morphine Equivalent Categories
Variable	All (N=120)	Positive exposure (>0.1 mg/kg) (N=82)	Negative exposure. (≤0.1 mg/kg) (N=38)	p-value
Morphine alone	75 (62.5)	61 (74.4)	14 (36.8)	<0.0001
Fentanyl alone	22 (18.3)	20 (24.4)	2 (5.3)
Morphine and Fentanyl	1 (0.8)	1 (1.2)	0 (0.0)
None	22 (18.3)	0 (0.0)	22 (57.9)
Cumulative morphine equivalent (mg/kg), median (IQR)	0.5 (0.1-1.2)	0.9 (0.4-2.0)	0.0 (0.0-0.1)
Outcome variables
Length of stay (days), median (IQR)	13 (9-23)	14 (9-24)	11 (8-21)	0.12
Vasopressors, n (%)	50 (41.7)	40 (48.8)	10 (26.3)	0.02
Multiple Vasopressors, n (%)	18 (15.0)	13 (15.9)	5 (13.2)	0.70
Duration of Vasopressor use (days), median (IQR)	3 (2-5) [N=50]	4 (2-5) [N=40]	3 (1-3) [N=10]	0.08
Invasive Ventilation, n (%)	93 (77.5)	65 (79.3)	28 (73.7)	0.50
Length of invasive ventilation (days), median (IQR)	2 (1-5) [N=93]	3 (1-7) [N=65]	2 (1-3) [N=28]	0.03
Noninvasive Ventilation, n (%)	87 (72.5)	65 (79.3)	22 (57.9)	0.01
Length of noninvasive ventilation (days), median (IQR)	3 (2-4) [N=87]	3 (2-4) [N=65]	3 (1-7) [N=22]	0.60
Duration of time off PN prior to discharge (days), median (IQR)	6 (3-13) [N=117]	7 (3-13) [N=79]	4 (2-11)	0.11
Duration of central line (days), median (IQR)	7 (5-9) [N=119]	7 (6-10)	6 (5-7) [N=37]	0.01
Time to full oral feeds (DOL), median (IQR)	7 (6-12) [N=106]	8 (6-13) [N=73]	6 (5-7) [N=33]	0.01

PN – parenteral nutrition, DOL – day of life

Table IIIA: Clinical and Lab Findings by Center

Variable	All (N=120)	TMC (N=52)	NCH (N=39)	WF (N=29)	p-value
Clinical Findings
Sepsis, n (%)	5 (4.2)	1 (1.9)	3 (7.7)	1 (3.5)	0.44
Pneumothorax, n (%)	8 (6.7)	3 (5.8)	3 (7.7)	2 (6.9)	1.00
Intraventricular hemorrhage, n (%)	9 (7.6) [N=119]	1 (1.9)	3 (7.7)	5 (17.9) [N=28]	0.03
Nitric Oxide use, n (%)	18 (15.0)	4 (7.7)	6 (15.4)	8 (27.6)	0.05
Steroids use, n (%)	25 (20.8)	2 (3.9)	13 (33.3)	10 (34.5)	0.0003
Initiation of trophic feeds (day of life), median (IQR)	4 (4-5) [N=118]	4 (4-4)	5 (4-7)	4 (3-6) [N=27]	0.001
Gastrostomy tube at discharge, n (%)	11 (9.2)	5 (9.6)	0 (0.0)	6 (20.7)	0.01
Laboratory values
AST (highest), median (IQR)	161 (101-326) [N=119]	150 (88-383) [N=51]	191 (109-326)	161 (81-288)	0.76
ALT (highest), median (IQR)	66 (29-163) [N=119]	64 (28-160) [N=51]	96 (41-239)	44 (18-127)	0.02
BUN (highest), median (IQR)	20 (14-27)	23 (19-29)	16 (11-20)	22 (14-27)	<0.0001
Creatinine (highest), median (IQR)	0.9 (0.8-1.2)	1.0 (0.8-1.4)	0.8 (0.7-0.9)	1.0 (0.8-1.3)	0.002
Bicarbonate (lowest), median (IQR)	15 (12-18) [N=102]	15 (12-18) [N=51]	16 (13-20) [N=22]	14 (11-17)	0.30
Prothrombin Time (PT) (highest), median (IQR)	17.4 (15.7-22.8) [N=97]	16.8 (15.6-21.5) [N=47]	18.2 (15.7-22.8)	17.7 (14.7-26.1) [N=11]	0.78
Partial Thromboplastin time (PTT) (highest), median (IQR)	59.7 (43.5-80.9) [N=95]	60.6 (48.5-93.4) [N=47]	62.4 (45.2-77.4)	39.6 (30.0-71.3) [N=9]	0.06
INR, median (IQR)	1.5 (1.4-2.0) [N=97]	1.5 (1.4-1.9) [N=47]	1.6 (1.3-2.1)	1.7 (1.4-2.6) [N=11]	0.44
Fibrinogen (lowest), median (IQR)	154 (116-191) [N=95]	152 (103-172) [N=46]	159 (133-225)	134 (105-176) [N=10]	0.26
Hematocrit, median (IQR)	42.0 (34.5-47.2)	43.3 (35.8-47.5)	39.3 (32.9-47.0)	40.1 (32.8-47.0)	0.44
Platelets (lowest), median (IQR)	133 (71-182) [N=119]	147 (92-202) [N=51]	102 (62-161)	139 (69-195)	0.04
Phosphorous (lowest), median (IQR)	4.7 (4.2-5.8) [N=74]	4.7 (4.2-5.7) [N=45]	NA	4.7 (3.9-5.8)	0.89
Potassium (lowest), median (IQR)	3.5 (3.1-4.0) [N=98]	3.4 (3.2-3.8)	4.8 (4.3-5.1) [N=17]	3.2 (2.8-3.6)	<0.0001
Alkaline Phosphatase (highest), median (IQR)	150 (111-204) [N=96]	169 (144-211) [N=50]	125 (105-137) [N=17]	124 (100-170)	0.001
Total Bilirubin (highest), median (IQR)	5.8 (3.9-8.2) [N=97]	6.7 (4.6-8.8) [N=51]	4.6 (3.9-6.9) [N=17]	5.8 (4.1-8.8)	0.33
White Blood Cell Count (highest), median (IQR)	20.0 (14.2-26.5) [N=119]	21.4 (16.4-26.4) [N=51]	19.5 (14.5-31.5)	19.2 (12.6-23.4)	0.36
Hemoglobin (lowest), median (IQR)	14.3 (11.8-16.1) [N=113]	15.0 (12.4-16.3) [N=51]	13.7 (11.8-16.0) [N=33]	13.3 (11.0-15.5)	0.26
Seizure classification
No Seizures, n (%)	66 (55.0)	33 (63.5)	21 (53.9)	12 (41.4)	0.15
Clinical Seizures, n (%)	32 (26.7)	10 (19.2)	14 (35.9)	8 (27.6)	0.20
EEG-Confirmed, n (%)	24 (20.0)	9 (17.3)	4 (10.3)	11 (37.9)	0.02
Anti-Seizure medications, n (%)	59 (49.2)	20 (38.5)	18 (46.2)	21 (72.4)	0.01
Head Ultrasound Findings, n (%)
Normal	69 (57.5)	28 (53.9)	33 (84.6)	8 (27.6)	<0.0001
Abnormal	25 (20.8)	8 (15.4)	6 (15.4)	11 (37.9)
Not done	26 (21.7)	16 (30.8)	0 (0.0)	10 (34.5)
MRI #1, n (%)
Normal	38 (31.7)	12 (23.1)	24 (61.5)	2 (6.9)	<0.0001
No signs of hypoxic injury	34 (28.3)	22 (42.3)	7 (18.0)	5 (17.2)
Mild hypoxic ischemic injury	16 (13.3)	4 (7.7)	4 (10.3)	8 (27.6)
Profound hypoxic ischemic injury	27 (22.5)	14 (26.9)	4 (10.3)	9 (31.0)
Not done	4 (3.3)	0 (0.0)	0 (0.0)	4 (13.8)
Unknown	1 (0.8)	0 (0.0)	0 (0.0)	1 (3.5)
MRI #2, n (%)
Normal	10 (8.3)	6 (11.5)	1 (2.6)	3 (10.3)	<0.0001
No signs of hypoxic injury	14 (11.7)	14 (26.9)	0 (0.0)	0 (0.0)
Mild hypoxic ischemic injury	1 (0.8)	1 (1.9)	0 (0.0)	0 (0.0)
Profound hypoxic ischemic injury	8 (6.7)	7 (13.5)	0 (0.0)	1 (3.5)
Not done	87 (72.5)	24 (46.2)	38 (97.4)	25 (86.2)

AST – aspartate transaminase, ALT – alanine transaminase, EEG - electroencephalogram

Table IIIB: Clinical and Lab Findings by Cumulative Morphine Equivalent Categories

Variable	All (N=120)	Positive exposure (>0.1 mg/kg) (N=82)	Negative exposure (≤0.1 mg/kg) (N=38)	p-value
Clinical Findings
Pneumothorax, n (%)	8 (6.7)	6 (7.3)	2 (5.3)	1.00
Intraventricular hemorrhage, n (%)	9 (7.6) [N=119]	8 (9.9) [N=81]	1 (2.6)	0.27
Nitric Oxide use, n (%)	18 (15.0)	14 (17.1)	4 (10.5)	0.35
Steroids use, n (%)	25 (20.8)	22 (26.8)	3 (7.9)	0.02
Initiation of trophic feeds (day of life), median (IQR)	4 (4-5) [N=118]	4 (4-5) [N=80]	4 (3-5)	0.01
Gastrostomy tube at discharge, n (%)	11 (9.2)	7 (8.5)	4 (10.5)	0.74
Laboratory values
AST (highest), median (IQR)	161 (101-326) [N=119]	150 (95-326) [N=81]	210 (105-298)	0.45
ALT (highest), median (IQR)	66 (29-163) [N=119]	57 (31-160) [N=81]	83 (28-163)	0.97
BUN (highest), median (IQR)	20 (14-27)	20 (13-26)	21 (17-29)	0.09
Creatinine (highest), median (IQR)	0.9 (0.8-1.2)	0.8 (0.7-1.1)	1.1 (0.8-1.6)	0.0006
Bicarbonate (lowest), median (IQR)	15 (12-18) [N=102]	15 (12-19) [N=64]	14 (12-17)	0.03
Prothrombin Time (PT) (highest), median (IQR)	17.4 (15.7-22.8) [N=97]	17.5 (15.6-23.4) [N=66]	17.0 (15.7-21.1) [N=31]	0.80
Partial Thromboplastin time (PTT) (highest), median (IQR)	59.7 (43.5-80.9) [N=95]	54.3 (42.1-73.7) [N=65]	71.4 (44.9-116.1) [N=30]	0.06
INR, median (IQR)	1.5 (1.4-2.0) [N=97]	1.5 (1.4-2.1) [N=66]	1.5 (1.4-1.9) [N=31]	0.68
Fibrinogen (lowest), median (IQR)	154 (116-191) [N=95]	157 (117-209) [N=64]	151 (105-172) [N=31]	0.31
Hematocrit, median (IQR)	42.0 (34.5-47.2)	41.2 (34.5-46.6)	43.0 (34.4-47.8)	0.87
Platelets (lowest), median (IQR)	133 (71-182) [N=119]	114 (70-171)	147 (93-200) [N=37]	0.11
Phosphorous (lowest), median (IQR)	4.7 (4.2-5.8) [N=74]	4.7 (3.5-5.8) [N=42]	4.9 (4.5-5.8) [N=32]	0.17
Potassium (lowest), median (IQR)	3.5 (3.1-4.0) [N=98]	3.6 (3.3-4.2) [N=61]	3.3 (3.0-3.8) [N=37]	0.03
Alkaline Phosphatase (highest), median (IQR)	150 (111-204) [N=96]	137 (106-205) [N=59]	165 (128-198) [N=37]	0.11
Total Bilirubin (highest), median (IQR)	5.8 (3.9-8.2) [N=97]	5.8 (3.3-8.8) [N=60]	6.8 (5.1-7.9) [N=37]	0.68
White Blood Cell Count (highest), median (IQR)	20.0 (14.2-26.5) [N=119]	19.6 (15.1-26.4)	21.3 (14.0-26.5) [N=37]	0.67
Hemoglobin (lowest), median (IQR)	14.3 (11.8-16.1) [N=113]	14.2 (11.6-15.9) [N=76]	14.7 (12.3-16.5) [N=37]	0.94
Seizure classification, n (%)
No Seizures, n (%)	66 (55.0)	45 (54.9)	21 (55.3)	0.97
Clinical Seizures, n (%)	32 (26.7)	24 (29.3)	8 (21.1)	0.34
EEG-Confirmed, n (%)	24 (20.0)	14 (17.1)	10 (26.3)	0.24
Anti-Seizure medications, n (%)	59 (49.2)	39 (47.6)	20 (52.6)	0.61
Head Ultrasound Findings, n (%)
Normal	69 (57.5)	49 (59.8)	20 (52.6)	0.42
Abnormal	25 (20.8)	18 (22.0)	7 (18.4)
Not done	26 (21.7)	15 (18.3)	11 (29.0)
MRI #1, n (%)
Normal	38 (31.7)	33 (40.2)	5 (13.2)	0.02
No signs of hypoxic injury	34 (28.3)	20 (24.4)	14 (36.8)
Mild hypoxic ischemic injury	16 (13.3)	12 (14.6)	4 (10.5)
Profound hypoxic ischemic injury	27 (22.5)	13 (15.9)	14 (36.8)
Not done	4 (3.3)	3 (3.7)	1 (2.6)
Unknown	1 (0.8)	1 (1.2)	0 (0.0)
MRI #2, n (%)
Normal	10 (8.3)	4 (4.9)	6 (15.8)	0.01
No signs of hypoxic injury	14 (11.7)	8 (9.8)	6 (15.8)
Mild hypoxic ischemic injury	1 (0.8)	0 (0.0)	1 (2.6)
Profound hypoxic ischemic injury	8 (6.7)	3 (3.7)	5 (13.2)
Not done	87 (72.5)	67 (81.7)	20 (52.6)

AST – aspartate transaminase, ALT – alanine transaminase, EEG - electroencephalogram

There is NO conflict of interest to disclose.

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Short-Term Effects of Opioid Use During Therapeutic Hypothermia for Neonatal Encephalopathy

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