Hypothermia For Hypoxic-ischemic Encephalopathy Research Articles

Elevated Morphine Concentrations in Neonates Treated With Morphine and Prolonged Hypothermia for Hypoxic Ischemic Encephalopathy

Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants. Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33 degrees C to 34 degrees C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth. Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137-767 ng/mL) in the hypothermia-treated infants and 206 ng/mL (88-327 ng/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL/min per kg (0.58-1.21 mL/min per kg) in hypothermic group and 0.89 mL/min per kg (0.65-1.33 mL/min per kg) in infants on normothermia. Serum morphine concentrations >300 nL/mL occurred more often in the hypothermia group and when the morphine infusion rate was >10 microg/kg per h. Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates >10 microg/kg per h.

Implementation of a ‘Hypothermia for HIE’ program: 2-year experience in a single NICU

Hypothermia has been shown to be neuroprotective in some newborns with moderate-to-severe perinatal hypoxic-ischemic encephalopathy (HIE). In 2006, the American Academy of Pediatrics recommended that institutions that choose to use therapeutic hypothermia do so in the context of a rigorous protocol, with systematic collection of patient data including neurodevelopmental follow-up. In this report, we describe our experience with implementation of a 'Hypothermia for HIE' program in a single tertiary care Neonatal Intensive Care Unit (NICU). Important components of the program include detailed protocols, staff and outreach education, early initiation of cooling in both inborn and outborn patients, maintaining stable hypothermia during neonatal transport, and comprehensive neurologic evaluation including serial EEGs, brain MRI and neurodevelopmental follow-up. In the first 2 years of the program, we have used hypothermia therapy in 21 patients, 18 with perinatal and 3 with early postnatal events leading to HIE. Eleven of fifteen outborn patients were cooled prior to and during transport, resulting in initiation of therapy 3 h sooner than if therapy had been delayed until arrival at our center. While lowering the body temperature of encephalopathic newborns is not difficult, addressing the complex medical problems of this vulnerable group of patients requires an experienced multidisciplinary team in regional referral centers.

Hypothermia for the Treatment of Neonatal Ischemic Encephalopathy: Is the Genie out of the Bottle?

Evidence suggests that hypothermia for hypoxic ischemic encephalopathy in the term neonate may decrease the risk of death or neurodevelopmental impairment. The objective of this study was to determine how hypothermia has been incorporated into practice. An anonymous survey was sent to medical directors of United States neonatal intensive care units (NICUs) in October 2005. We received completed surveys from 441 (54.5%) of 809 of NICUs. Only 6.4% of respondents used hypothermia. The most common method was total body cooling (64.3%) compared with head cooling (25%) or both (10.7%). At centers that did not offer hypothermia, 29% transferred infants to an institution that did. Centers that offered hypothermia were more likely at academic institutions (76.9%) compared with private practices (11.5%; p < 0.001). Hypothermia was more likely offered at institutions that offered extracorporeal membrane oxygenation (ECMO; 57%) than centers where ECMO was not offered (43%; p < 0.001). There has not been widespread use of hypothermia. There are a variety of protocols used. As results of further outcome studies become available, educational efforts and national practice guidelines will be essential.

Outcome Prediction of Neonatal Hypoxic-Ischemic Encephalopathy

Data for 205 neonates from the multicenter National Institute of Child Health trial of hypothermia in hypoxic-ischemic encephalopathy (HIE) were analyzed by using clinical and laboratory variables obtained in the NICUs within 6 hours of birth, with death or moderate/severe disability at 18-22 months or death as the outcomes.

Predicting Outcomes of Neonates Diagnosed With Hypoxemic-Ischemic Encephalopathy

The goals were to identify predictor variables and to develop scoring systems and classification trees to predict death/disability or death in infants with hypoxic-ischemic encephalopathy. Secondary analysis of data from the multicenter, randomized, controlled, National Institute of Child Health and Human Development Neonatal Research Network trial of hypothermia in hypoxic-ischemic encephalopathy was performed. Data for 205 neonates diagnosed as having hypoxic-ischemic encephalopathy were studied. Logistic regression analysis was performed by using clinical and laboratory variables available within 6 hours of birth, with death or moderate/severe disability at 18 to 22 months or death as the outcomes. By using the identified variables and odds ratios, scoring systems to predict death/disability or death were developed, weighting each predictor in proportion to its odds ratio. In addition, classification and regression tree analysis was performed, with recursive partitioning and automatic selection of optimal cutoff points for variables. Correct classification rates for the scoring systems, classification and regression tree models, and early neurologic examination were compared. Correct classification rates were 78% for death/disability and 71% for death with the scoring systems, 80% and 77%, respectively, with the classification and regression tree models, and 67% and 73% with severe encephalopathy in early neurologic examination. Correct classification rates were similar in the hypothermia and control groups. Among neonates diagnosed as having hypoxic-ischemic encephalopathy, the classification and regression tree model, but not the scoring system, was superior to early neurologic examination in predicting death/disability. The 3 models were comparable in predicting death. Only a few components of the early neurologic examination were associated with poor outcomes. These scoring systems and classification trees, if validated, may help in assessments of prognosis and may prove useful for risk-stratification of infants with hypoxic-ischemic encephalopathy for clinical trials.

A cool way to treat hypoxic encephalopathy?

The commentary by Higgins et al summarizes the conclusions of the recent National Institute of Child Health and Human Development workshop on hypothermia as a potential treatment for perinatal hypoxic ischemic encephalopathy (HIE). The authors review current knowledge of the pathogenesis of HIE and the mechanisms of cerebral hypothermia. They provide a balanced view of the outcomes of the completed clinical trials that use hypothermia for HIE and describe the major gaps in our understanding. Most importantly, they have developed a list of thoughtful and practical recommendations for the practicing neonatologist to consider while waiting for future information about this promising but still nascent therapy.

HYPOTHERMIA FOR ASPHYXIA

Objective: This lecture will cover the results of the two published trials of hypothermia for hypoxic ischemic encephalopathy recently reported. There will be a discussion of the methods of selection, criteria, and outcomes of the studies, as well as future directions for further trials.