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Background Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18–22 months after neonatal encephalopathy, in LMICs. Methods We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1–2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. Discussion Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. Trial registration ClinicalTrials.gov, NCT02387385 . Registered on 27 February 2015.

Background For patients with painful knee osteoarthritis, long-term symptomatic relief may improve quality of life. Cooled radiofrequency ablation (CRFA) has demonstrated significant improvements in pain, physical function and health-related quality of life compared with conservative therapy with intra-articular steroid (IAS) injections. This study aimed to establish the cost-effectiveness of CRFA compared with IAS for managing moderate to severe osteoarthritis-related knee pain, from the US Medicare system perspective. Methods We conducted a cost-effectiveness analysis utilizing efficacy data (Oxford Knee Scores) from a randomized, crossover trial on CRFA (NCT02343003), which compared CRFA with IAS out to 6 and 12 months, and with IAS patients who subsequently crossed over to receive CRFA after 6 months. Outcomes included health benefits (quality-adjusted life-years [QALYs]), costs and cost-effectiveness (expressed as cost per QALY gained). QALYs were estimated by mapping Oxford Knee Scores to the EQ-5D generic utility measure using a validated algorithm. Secondary analyses explored differences in the settings of care and procedures used in-trial versus real-world clinical practice. Results CRFA resulted in an incremental QALY gain of 0.091 at an incremental cost of $1711, equating to a cost of US$18,773 per QALY gained over a 6-month time horizon versus IAS. Over a 12-month time horizon, the incremental QALY gain was 0.229 at the same incremental cost, equating to a cost of US$7462 per QALY gained versus IAS. Real-world cost assumptions resulted in modest increases in the cost per QALY gained to a maximum of US$21,166 and US$8296 at 6 and 12 months, respectively. Sensitivity analyses demonstrated that findings were robust to variations in efficacy and cost parameters. Conclusions CRFA is a highly cost-effective treatment option for patients with osteoarthritis-related knee pain, compared with the US$100,000/QALY threshold typically used in the US.

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: The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles The temperature profile of encephalopathic infants with standard care The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome The feasibility of neurodevelopmental follow-up at 18-22 months of age Methods/Design Ethical approval was obtained from Makerere Unive r sity 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

Hypothermia is a common adverse event during continuous renal replacement therapy (CRRT), affecting multiple organ systems and increasing risk of poor health outcomes among patients with acute kidney injury (AKI) undergoing CRRT. TheraMax blood warmers are the next generation of extracorporeal blood warmers which reduce risk of hypothermia during CRRT. The purpose of this study is to elucidate the potential health economic impacts of avoiding CRRT-induced hypothermia by using the novel TherMax blood warming device. This study compares health care costs associated with use of the new TherMax blood warmer unit integrated with the PrisMax system compared to CRRT with a standalone blood warming device to avoid hypothermia in continuous renal replacement therapy (CRRT). An economic model was developed in which relevant health states for each intervention were normothermia, hypothermia, discharge, and death. Clinical inputs and costs were obtained from a combination of retrospective chart review and publicly available summary estimates. The proportion of AKI patients treated with CRRT who became hypothermic (<36°C) during CRRT treatment was 34.5% in the TherMax group compared to 71.9% in the ‘standalone warmer’ group. Given the 78.7-year average life expectancy in the US and the assumed average patient age at discharge/death of 65.4 years, the total life-years gained by avoiding mortality related to hypothermia was 9.0 in the TherMax group compared to 8.0 in the ‘standalone warmer’ group. Cost per life-year gained was$8,615 in the TherMax group versus $ 10,115 in the ‘standalone warmer’ group for a difference of -$1,501 favoring TherMax. The incremental cost-effectiveness ratio was negative, indicating superior cost-effectiveness for TherMax versus ‘standalone warmer’. The TherMax blood warming device used with the PrisMax system is associated with lower risk of hypothermia, which our model indicates leads to lower costs, lower risk of mortality due to hypothermia, and superior cost-effectiveness.

ObjectiveTo assess the impact of hypothermic neural rescue for perinatal asphyxia at birth on healthcare costs of survivors aged 6–7 years, and to quantify the relationship between costs and overall disability levels.Design6–7 years follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial.SettingCommunity study including a single parental questionnaire to collect information on children’s healthcare resource use.Patients130 UK children (63 in the control group, 67 in the hypothermia group) whose parents consented and returned the questionnaire.InterventionsIntensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone.Main outcome measuresHealthcare resource usage and costs over the preceding 6 months.ResultsAt 6–7 years, mean (SE) healthcare costs per child were £1543 (£361) in the hypothermia group and £2549 (£812) in the control group, giving a saving of −£1005 (95% CI −£2734 to £724). Greater levels of overall disability were associated with progressively higher costs, and more parents in the hypothermia group were employed (64% vs 47%). Results were sensitive to outlying observations.ConclusionsCost results although not significant favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. Estimates were however sensitive to the care requirements of two seriously ill children in the control group. A quantification of the relationship between costs and levels of disability experienced will be useful to healthcare professionals, policy makers and health economists contemplating the long-term economic consequences of perinatal asphyxia and hypothermic neural rescue.Trial registration numberThis study reports on the follow-up of the TOBY clinical trial: ClinicalTrials. gov number NCT01092637.

Hypothermia is an established method of treating severe forms of perinatal hypoxia in newborns. Some of them develop neonatal encephalopathy, which is associated with high morbidity and mortality. Therefore, prophylaxis of this pathology is important as well as determining environmental factors in mothers of newborns affected by this pathology. The aim of the study was to assess of selected environmental factors in mothers of newborns qualified for hypothermia. The material consisted of 102 subjects, including 51 mothers of newborns with hypoxic-ischemic encephalopathy referred for hypothermia treatment (group I) and 51 mothers of newborns without signs of hypoxia (group II). The case-control study was carried out in the third level reference centre. It is 1 of 20 centers of therapeutic hypothermia for newborn in Poland. Data was collected based on a data collection sheet. Study groups were compared in terms of demographic and environmental data. The odds ratio (OR) was determined and the logistic regression analysis of univariate and multivariate regression was used to determine the probability of the need for hypothermia in the study group. The groups did not differ in terms of age, BMI and place of living. The need to use hypothermia increased in pregnant women living together with their parents (OR = 6.8, 95% CI: 2.4-19.6) also in case of exposure to factors at the workplace, i.e., noise (OR = 4.1, 95% CI: 1.1-15.5). Based on the results of our case-control study we postulate to pay attention during preconception care to proper preparation for pregnancy especially in younger women exposed to nuisance in the work environment and at home. In this area postulated activities should include education programs, in close cooperation occupational medicine practitioners and obstetricians even before the conception as a part of pre-conception counseling. Int J Occup Med Environ Health. 2023;36(1):59-68.

Delay in implementing new treatments into clinical practice results in considerable health and economic opportunity costs. Data from the UK TOBY Cooling Register provides the opportunity to examine how one new effective therapy for newborn infants suspected of suffering asphyxial encephalopathy--therapeutic hypothermia- was implemented in the UK. We analysed returned data forms from inception of the Register in December 2006 to the end of July 2011. Data forms were received for 1384 (67%) of the 2069 infants registered. The monthly rate of notifications increased from median {IQR} 18 {15-31} to 33 {30-39} after the announcement of the results of the recent TOBY trial, and to 50 {36-55} after their publication. This rate further increased to 70 {64-83} following official endorsement of the therapy, and is now close to the expected numbers of eligible infants. Cooling was started at 3.3 {1.5-5.5} hours after birth and the time taken to achieve the target 33-34 °C rectal temperature was 1 {0-3} hours. The rectal temperature was in the target range in 83% of measurements. From 2006 to 2011 there was evidence of extension of treatment to slightly less severely affected infants. 278 of 1362 (20%) infants died at 2.9 {1.4-4.1} days of age. The rates of death fell slightly over the period of the Register and, at two years of age cerebral palsy was diagnosed in 22% of infants; half of these were spastic bilateral. Factors independently associated with adverse outcome were clinical seizures prior to cooling (p<0.001) and severely abnormal amplitude integrated EEG (p<0.001). Therapeutic hypothermia was implemented appropriately within the UK, with significant benefit to patients and the health economy. This may be due in part to participation by neonatal units in clinical trials, the establishment of the national Register, and its endorsement by advisory bodies.

Introduction There is an extensive body of research regarding neurological outcomes following neonatal hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH), with limited data on growth outcomes. We examined perinatal characteristics associated with postnatal growth in this population. Methods Convenience cohort of 66 infants with HIE who underwent TH and participated in follow-up at 24 months of age were included. Regression modeling including perinatal anthropomorphics, markers of HIE, and systemic injury was used to evaluate growth at 24 months. Results Birth head circumference was associated with weight ( p  = 0.036). MRI severity, pH at admission and birth head circumference were associated with height ( p  = 0.043, p  = 0.015 and p  = 0.043 respectively). MRI severity and length of intubation were associated with head circumference ( p  = 0.038 and p  < 0.001 respectively). Conclusion There was a significant association between specific early factors and growth at 24 months among infants with HIE treated with TH.

Hypoxic ischaemic encephalopathy (HIE) is a major cause of neonatal mortality and disability in the United Kingdom (UK) and has significant human and financial costs. Therapeutic hypothermia (TH), which consists of cooling down the newborn’s body temperature, is the current standard of treatment for moderate or severe cases of HIE. Timely initiation of treatment is critical to reduce risk of mortality and disability associated with HIE. Very expensive servo-controlled devices are currently used in high-income settings to induce TH, whereas low-income settings rely on the use of low-tech devices such as water bottles, ice packs or fans. Cooling mattresses made with phase change materials (PCMs) were recently developed as a safe, efficient, and affordable alternative to induce TH in low-income settings. This frugal innovation has the potential to become a reverse innovation for the National Health Service (NHS) by providing a simple, efficient, and cost-saving solution to initiate TH in geographically remote areas of the UK where cooling equipment might not be readily available, ensuring timely initiation of treatment while waiting for neonatal transport to the nearest cooling centre. The adoption of PCM cooling mattresses by the NHS may reduce geographical disparity in the availability of treatment for HIE in the UK, and it could benefit from improvements in coordination across all levels of neonatal care given challenges currently experienced by the NHS in terms of constraints on funding and shortage of staff. Trials evaluating the effectiveness and safety of PCM cooling mattresses in the NHS context are needed in support of the adoption of this frugal innovation. These findings may be relevant to other high-income settings that experience challenges with the provision of TH in geographically remote areas. The use of promising frugal innovations such as PCM cooling mattresses in high-income settings may also contribute to challenge the dominant narrative that often favours innovation from North America and Western Europe, and consequently fight bias against research and development from low-income settings, promoting a more equitable global innovation landscape.

Background With increasing survival rates following pediatric intensive care unit (PICU) hospitalization, assessing functional outcomes is imperative. We compared children’s psychosocial and adaptive functioning six weeks and six months after discharge from the PICU with children hospitalized in a general ward. Methods This prospective observational cohort study followed 100 children aged 2 to 11 years after PICU and ward discharge (control group) for six months. The two groups were compared for psychosocial and adaptive functioning using the Behavioral Assessment System for Children, Third Edition (BASC-3) parent report scale. Parents also completed the Parenting Stress Index-Short Form scale to assess parenting stress. Multivariate regression analysis adjusted for demographics, PICU-related factors, and parental stress was used to investigate the potential variables associated with children’s psychosocial and adaptive functioning six weeks and six months after PICU discharge. Results Our findings indicated that children experienced greater psychosocial problems and worse adaptive functioning up to six months after PICU discharge than children after ward discharge, P  < 0.05. The number of intervention procedures and parental stress were common factors associated with impaired psychosocial and adaptive functioning post-PICU discharge. Six months after PICU discharge, younger age and length of stay were associated with psychosocial problems, while internalizing and externalizing problems were associated with poorer adaptive functioning, P  < 0.05. Conclusion Given the impact of PICU experience on children’s psychosocial and adaptive outcomes, it is crucial to implement psychological assessments with a follow-up plan extended longitudinally after PICU discharge. This study underscores the need to integrate adaptive behavior assessment in children’s psychological evaluation to identify significant deficits, develop relevant behavioral management plans, and monitor their progress.