Withdrawal of Life-Support in Neonatal Hypoxic-Ischemic Encephalopathy.

PURPOSE: We describe the frequency and timing of withdrawal of life-support (WLS) in moderate or severe hypoxic-ischemic encephalopathy (HIE) and examine its associations with medical and sociodemographic factors. PROCEDURES: We undertook a secondary data analysis of a prospective multicenter data registry of regional level IV Neonatal Intensive Care Units participating in the Children's Hospitals Neonatal Database. Infants ≥36 weeks gestational age with HIE admitted to a Children's Hospitals Neonatal Database Neonatal Intensive Care Unit between 2010 and 2016, who underwent therapeutic hypothermia were categorized as (1) infants who died following WLST and (2) survivors with severe HIE (requiring tube feedings at discharge). RESULTS: Death occurred in 267/1,925 (14%) infants with HIE, 87.6% following WLS. Compared to infants with WLS (n = 234), the survived severe group (n = 74) had more public insurance (73% vs 39.3%, P = 0.00001), lower household income ($37,020 vs $41,733, P = 0.006) and fewer [20.3% vs 35.0%, P = 0.0212] were from the South. Among infants with WLS, electroencephalogram was performed within 24 hours in 75% and was severely abnormal in 64% cases; corresponding rates for MRI were 43% and 17%, respectively. Private insurance was independently associated with WLS, after adjustment for HIE severity and center. CONCLUSIONS: In a multicenter cohort of infants with HIE, WLS occurred frequently and was associated with sociodemographic factors. The rationale for decision-making for WLS in HIE require further exploration.

Intercenter Cost Variation for Perinatal Hypoxic-Ischemic Encephalopathy in the Era of Therapeutic Hypothermia.

OBJECTIVE: To quantify intercenter cost variation for perinatal hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia across children's hospitals. STUDY DESIGN: Prospectively collected data from the Children's Hospitals Neonatal Database and Pediatric Health Information Systems were linked to evaluate intercenter cost variation in total hospitalization costs after adjusting for HIE severity, mortality, length of stay, use of extracorporeal support or nitric oxide, and ventilator days. Secondarily, costs for intensive care unit bed, electroencephalography (EEG), and laboratory and neuroimaging testing were also evaluated. Costs were contextualized by frequency of favorable (survival with normal magnetic resonance imaging) and adverse (death or need for gastric tube feedings at discharge) outcomes to identify centers with relative low costs and favorable outcomes. RESULTS: Of the 822 infants with HIE treated with therapeutic hypothermia at 19 regional neonatal intensive care units, 704 (86%) survived to discharge. The median cost/case for survivors was $58 552 (IQR $32 476-$130 203) and nonsurvivors $29 760 (IQR $16 897-$61 399). Adjusting for illness severity and select interventions, intercenter differences explained 29% of the variation in total hospitalization costs. The widest cost variability across centers was EEG use, although low cost and favorable outcome centers ranked higher with regards to EEG costs. CONCLUSIONS: There is marked intercenter cost variation associated with treating HIE across regional children's hospitals. Our investigation may help establish references for cost and enhance quality improvement and resource utilization projects related to HIE.

The long-term health, social, and financial burden of hypoxic-ischaemic encephalopathy.

Infants who suffer hypoxic-ischaemic encephalopathy (HIE) at term are at risk of dying or developing severe cerebral palsy (CP). Children with severe CP often have other neurodevelopmental disabilities, which may affect their quality of life as much as the CP itself. New treatments for HIE, such as cooling, may improve motor outcomes, but affected infants may still have significant cognitive or communication problems. Infants who have experienced HIE and develop CP will require significant medical input throughout childhood and adult life. The costs of this medical input are high, but the indirect costs to the child, his or her family, and the relevant social services and education systems are many times greater. When demonstrating the cost-effectiveness of interventions aimed at preventing or treating HIE, these additional costs should be taken into account.

A quantitative analysis of optimal treatment capacity for perinatal asphyxia.

OBJECTIVE: In centers electing to offer therapeutic hypothermia for treating hypoxic-ischemic encephalopathy (HIE), determining the optimal number of cooling devices is not straightforward. The authors used computer-based modeling to determine the level of service as a function of local HIE caseload and number of cooling devices available. METHODS: The authors used discrete event simulation to create a model that varied the number of HIE cases and number of cooling devices available. Outcomes of interest were percentage of HIE-affected infants not cooled, number of infants not cooled, and percentage of time that all cooling devices were in use. RESULTS: With 1 cooling device, even the smallest perinatal center did not achieve a cooling rate of 99% of eligible infants. In contrast, 2 devices ensured 99% service in centers treating as many as 20 infants annually. In centers averaging no more than 1 HIE infant monthly, the addition of a third cooling device did not result in a substantial reduction in the number of infants who would not be cooled. CONCLUSION: Centers electing to offer therapeutic hypothermia with only a single cooling device are at significant risk of being unable to provide treatment to eligible infants, whereas 2 devices appear to suffice for most institutions treating as many as 20 annual HIE cases. Three devices would rarely be needed given current caseloads seen at individual institutions. The quantitative nature of this analysis allows decision makers to determine the number of devices necessary to ensure adequate availability of therapeutic hypothermia given the HIE caseload of a particular institution.

Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18-22 month follow-up for neonatal encephalopathy in a low resource hospital setting in Uganda: study protocol.

BACKGROUND: There is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective. AIMS: Under the UCL Uganda Women's Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine:(i) The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles(ii) The temperature profile of encephalopathic infants with standard care(iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome(iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age METHODS/DESIGN: Ethical approval was obtained from Makerere University and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months. DISCUSSION: We will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future. TRIAL REGISTRATION: Current controlled trials ISRCTN92213707.

Cost-effectiveness of therapeutic hypothermia to treat neonatal encephalopathy.

OBJECTIVE: To estimate the cost-effectiveness (CE) of total body hypothermia plus intensive care versus intensive care alone to treat neonatal encephalopathy. METHODS: Decision analytic modeling was used to synthesize mortality and morbidity data from three randomized controlled trials, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), National Institute of Child Health and Human Development (NICHD), and CoolCap trials. Cost data inputs were informed by TOBY, the sole source of prospectively collected resource utilization data for encephalopathic infants. CE was expressed in terms of incremental cost per disability-free life year (DFLY) gained. Probabilistic sensitivity analysis was performed to generate CE acceptability curves (CEACs). RESULTS: Cooling led to a cost increase of £3787 (95% confidence interval [CI]: -2516, 12,360) (€5115; 95% CI: -3398-16,694; US$5344; 95% CI: -3598, 26,356; using 2006 Organisation for Economic Co-operation and Development (OECD) purchasing power parities) and a DFLY gain of 0.19 (95%CI: 0.07-0.31) over the first 18 months after birth. The incremental cost per DFLY gained was £19,931 (€26,920; US$28,124). The baseline CEAC showed that if decision-makers are willing to pay £30,000 for an additional DFLY, there is a 69% probability that cooling is cost-effective. The probability of CE exceeded 99% at this threshold when the throughput of infants was increased to reflect the national incidence of neonatal encephalopathy or when the time horizon of the economic evaluation was extended to 18 years after birth. CONCLUSIONS: The probability that cooling is a cost-effective treatment for neonatal encephalopathy is finely balanced over the first 18 months after birth but increases substantially when national incidence data or an extended time horizon are considered.