Cooling during transportation of newborns with hypoxic ischemic encephalopathy using phase change material mattresses in low-resource settings: a randomized controlled trial in Hanoi, Vietnam

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T. T. Tran, Dien. M. Tran, Ha. T. Le, Lena Hellström-Westas, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4243358/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Aug, 2024 Read the published version in BMC Pediatrics → Version 1 posted 10 You are reading this latest preprint version Abstract Objective To determine the effectiveness of phase-change-material mattress (PCM) during transportation of newborns with hypoxic ischemic encephalopathy (HIE). Study design: Randomized controlled trial of newborns with HIE from June 2016 to December 2019. Patients were randomized to transport with PCM or without PCM (control) when transferred to a cooling center in northern Vietnam. Result 52 patients in PCM-group and 61 in control group. Median rectal temperature upon arrival was 34.5°C (IQR 33.5–34.8) in PCM-group and 35.1°C (IQR 34.5–35.9) in control group (p = 0.023). Median time from birth to reach target temperature was 5.0 ± 1.4 hours and 5.5 ± 1.2 hours in the respective groups (p = 0.065). 80.8% of those transported with PCM versus 62.3% of infants transported without (p = 0.049) had reached target temperature within the 6-hour timeframe. There was no record of overcooling ( 0.05). Conclusion Phase-change-material can be used as a safe and effective cooling method during transportation of newborns with HIE in low-resource settings. Asphyxia Cooling Encephalopathy Low-income setting Phase change materials Figures Figure 1 Figure 2 BACKGROUND Neonatal hypoxic-ischemic encephalopathy (HIE), caused by a lack of blood flow and oxygen to the brain at birth, occurs in 10–20/1000 live births in low-middle-income countries (LMICs) ( 1 ). In Vietnam, birth asphyxia accounts for 14% of all neonatal mortality ( 2 ), with regional variation and reported rates as high as 33% in certain regions ( 3 , 4 ). Although the incidence of birth asphyxia in Vietnam is high, there is still limited experience with therapeutic hypothermia (TH) treatment, as in other LMICs. Meta-analysis of studies from high-income countries (HICs) shows that induced hypothermia is associated with reduced risk of death or major neurodevelopmental disability by 18 months of age ( 5 , 6 ). The benefits of cooling, however, is insufficiently studied and requires further evaluation in LMICs ( 7 , 8 ). Evidence from animal and newborn studies has indicated that the window of opportunity to start cooling is within 6 hours after birth ( 9 , 10 ); hence, transportation time could delay hypothermia treatment, consequently altering the safety or effectiveness of TH treatment and neurological outcomes( 11 ). In order to optimize the neuroprotective effect in newborns with HIE, cooling should start as early as possible, both actively and passively. Several studies have shown that passive cooling (e.g., removal of clothes, turning off heating devices to allow the baby to cool down naturally) is less effective and has a higher risk of overcooling compared to active cooling using servo-controlled equipment ( 12 – 14 ). Despite the demonstrated benefits of servo-controlled devices when used in transport ( 13 , 15 ) more recent studies continue to show achieving target temperature within the 6-hour window remains a challenge for THs even in HIC settings with proportions between 55% and 63% ( 16 ) let alone in LMICs like Vietnam. Phase change material (PCM) has been well studied in both animals and newborn infants for its effectiveness and safety in therapeutic hypothermia treatment ( 17 , 18 ). A PCM-based device has been shown to be comparable to standard servo-controlled equipment in maintaining the target temperature ( 19 , 20 ). A pilot study implementing PCM to cool asphyxiated newborns in Vietnam has proven that it is an effective yet easy to use method of cooling in a low-resource neonatal intensive care unit ( 21 ). Following from our previous study, the aim of this study was to determine the feasibility and effectiveness of phase-change-material mattresses during transportation of asphyxiated newborns with suspected HIE, with the aim of reducing the time to initiate therapeutic cooling in low-resource settings. PARTICIPANTS AND METHODS Participants : Following a pilot study showing that PCM is feasible and safe for inducing TH ( 21 ), we conducted a randomized controlled trial study of patients from seven hospitals within up to 200km transport distance to a tertiary center. The inclusion criteria were: infants ≥ 36 weeks gestational age and ≤ 6 hours after birth with either Apgar score ≤ 5 at 10 minutes or continued need for resuscitation, 10 mins or pH 16 mmol/L and sign of moderate to severe encephalopathy (altered consciousness, abnormal tone). Infants were excluded if > 6 hours after birth at time of referral/evaluation, coagulopathy with active bleeding, prenatally diagnosed syndromes, malformations or metabolic disorders not compatible with survival ( 22 ). Prior to the study, visits to assess the capacity of all hospital and training sessions had been organized to enhance neonatal unit doctors and nurses at all sites concerning the background of the study, the use of a PCM mattress, data recording, and assessment of patients. Parents/guardians of asphyxiated newborns were approached regarding participation in the study once the patient met criteria for cooling. The study was registered in Clinical Trials (04/05/2022, NCT05361473). This study was intended to be a feasibility study to assess the safety and applicability of using PCM for transportation of asphyxiated newborns compared to passive cooling (standard care). The aim was to recruit 70 newborns for each group in order to cover differences in severity of HIE, transport distances, and time of day, etc. Study design and intervention Each hospital was provided with sealed envelopes containing papers for PCM or control by the study team. Once cooling criteria were met, patients were randomized to a group cooled by PCM mattress (Medical Cooling Sweden AB; by TST AB, Kinna, Sweden) during transportation or a control group, in which patients were passively cooled by turning off all external heating sources. The babies were transported in road ambulances, placed on an ambulance stretcher with only one layer of clothes on, no extra cover by blanket (all the referring hospitals do not have transport incubator) during transportation, which enabled the babies to chill spontaneously at air temperature. Skin temperature in the axilla and environment temperature were measured before transport and every 30 minutes during the transportation for both groups. The infant’s clinical condition was clinically monitored by the accompanying hospital staff, but there was no continuous monitoring of heart rate or oxygen saturation during transport. On arrival at VNCH, the infants were evaluated for continuation of cooling or initiation of cooling, respectively. All received hypothermia treatment with PCM mattress. Both groups received cooling therapy with a target temperature of 33.5–34.5°C for 72 hours and standard medical care. On admission, the severity of the infant’s encephalopathy was assessed by modified Sarnat score and neonatal encephalopathy scores (Thompson score) were used at 24, 48 and 72 hours as part of clinical assessment ( 23 ). Short-term adverse effects of cooling, such as respiratory cardiovascular complications (bradycardia, hypotension, pulmonary hypertension), electrolyte imbalance (hypokalemia, hyponatremia), and coagulopathy – platelet dysfunction, were recorded during treatment. Outcome measures Outcome measures were the same for both groups: Rectal temperature on arrival, time to reach target temperature 33.5°C (postnatal age), neurology assessment on arrival and at discharge (for survivors), death before discharge, complications, including hypotension (with/without inotropes), pneumothorax, uncontrollable seizures, sepsis during treatment. Statistical analyses Demographic factors and clinical characteristics were summarized with counts (percentages) for categorical variables, mean (standard deviation [SD]) for normally distributed continuous variables or median (interquartile or entire range) for other continuous variables. For each group, differences were assessed using Student’s t test (normal distribution) or the Mann Whitney U test (skewed distribution). Data were analyzed by using SPSS. P value < 0.05 was considered statistically significant. RESULTS During the three-year study period (from September 1st 2016 to December 31st 2019), there were in total 118 infants transferred from the seven study hospitals: 55 in the PCM group, and 63 in the control group. The average time for transfer of each patient was two to three hours, or more during rush hours. Upon arrival at VNCH, during re-evaluation, the encephalopathy was mild in five patients (3 in PCM group, 2 in non-PCM group), and cooling was therefore stopped for these children, and they were excluded from the analysis. The study participants are summarized in Fig. 1 . Baseline maternal and neonatal characteristics for both groups are presented in Table 1 . Table 1 Maternal and neonatal baseline characteristics. Figures are numbers (percentages) and means (standard deviation). Characteristic PCM group (n = 52) Control group (n = 61) P value Maternal Age – years 27 ± 5 26 ± 6 0.160 Intrapartum complications – no. (%) 43 44 0.083 Fetal heart-rate deceleration 15 ( 29 ) 18 ( 34 ) Cord prolapses 2 ( 4 ) 0 (0) Shoulder dystocia 3 ( 6 ) 2 ( 4 ) Maternal hemorrhage 2 ( 4 ) 3 ( 6 ) Mode of delivery – no. (%) 0.671 Vaginal delivery/Instrumental Delivery 28 (54) 34 (56) Emergency caesarean delivery 24 (46) 27 (44) Neonatal Male – no. (%) 37 (71%) 39 (64%) 0.522 Gestational (weeks) 39 (±1.1) 39 (±1.2) 0.634 Birthweight (grams) 3210 (±1040) 3165 (±416) 0.754 Apgar score ≤ 5 – no. (%) at 10 min * 22 (100%) 28 (100%) Age at randomization – hour 2 ± 0.5 2 ± 0.4 0.254 Age at admission (hours from birth) 3.6 ± 1.4 3.9 ± 1.4 0.119 Transport distance, hours by road ambulance (Median, range) 2.1 (0.5–2.8) 2.2 (0.5–3) 0.204 Time to reach target temp 33.5 °C to 34.5°C – (hours from birth) 5.0 ± 1.4 5.5 ± 1.2 0.065 Number of patients reaching target temp within 6 hours of birth – no. (%) 42 (80.8%) 38 (62.3%) 0.049 Rectal temp at randomization, before transport (°C) 35.8 ± 0.6 36 ± 0.8 0.125 Seizure on admission – no. (%) 5 ( 10 ) 3 ( 5 ) Level of encephalopathy – no. (%) 0.625 Moderate - Sarnat stage II (n) 18 ( 35 ) 23 ( 38 ) Severe - Sarnat stage III (n) 34 (65) 38 (62) * Apgar score at 5 min and 10 min were available for only 22 newborns in PCM group and 28 newborns in control group Newborns had a mean gestation of 39 (±1.1) weeks in both groups, and the majority were male, with 37 (71%) in the PCM group versus 39 (64%) in the control group. There was no significant difference between the two groups in terms of maternal age or mode of delivery. Close to 50% of cases required emergency c-sections due to intrapartum complications such as fetal distress, cord prolapse, bleeding, or other complications. Eligibility criteria for transportation and evaluation for cooling were adapted to previous multicenter studies ( 22 ) and based on either Apgar scores or need for continuation of resuscitation at 10 minutes, because blood gases were not routinely reported or assessed. In the PCM group, 15 (29%) newborns had clinical seizures on admission, with a mean age at admission of 3.6 hours ± 1.4. In the non-PCM group, 23 (38%) newborns had clinical seizures on admission, with a mean age at admission of 3.9 hours ± 1.4. Anticonvulsant was used similarly in both groups. Figure 2 shows the mean temperature of the newborns in both groups at two different time points: on departure from the referring hospital and on arrival at VNCH. Upon arrival to VNCH, the mean rectal temperature in the PCM group was significantly lower than in the control one: 34.5°C (IQR 33.5–34.8) compared to 35.1°C (IQR 34.5–35.9) (p = 0.023). There was no record of excessive hypothermia (< 32°C) on admission for any of the groups. Consequently, the median time to reach target cooling temperature from birth in the PCM group was 5 ± 1.4 hours, while it took 5.5 ± 1.2 hours for the control group to reach the target cooling temperature (p = 0.065). 42/52 patients (81%) of those transported with PCM versus 38/61 (62%) of infants transported without (p = 0.049) had reached target temperature within the 6-hour timeframe. There was no significant difference in Thompson scores between the two groups on arrival and on consequent days. In total, 38 newborns died before discharge from hospital: 17 in the PCM group and 21 in the control group. In the PCM group, the newborns died from the following causes: encephalopathy-related complications (n = 13 [74%]), persistent pulmonary hypertension (n = 3 [18%]), and sepsis (n = 1 [6%]). In the control group, the primary cause of death was also encephalopathy-related complications (n = 18 [86%]); other causes including persistent pulmonary hypertension (n = 2 [4%]) and pneumothorax (n = 1 [2%]). The proportion of deaths according to Sarnat stage was similar across groups (Table 2 ). Among the 87 survivors, 69 (79%) completed follow-up until 18 months. Nineteen children developed cerebral palsy (8 diplegia, 3 hemiplegia, 8 dyskinetic), and 11 had delayed neurodevelopment ( 24 ). Table 2 Clinical outcomes Variables PCM group (n = 52) Control group (n = 61) P value Encephalopathy score (Thompson score) Day 1, Mean, min-max 16 ( 9 – 21 ) 17 ( 9 – 22 ) n.s At discharge, Mean, min-max 5 (0–18) 6 (0–18) n.s Complications during cooling – no. (%) Hypotension ± inotropes 30 (58) 33 (54) n.s Pneumothorax 2 ( 4 ) 0 n.s Uncontrollable seizures 4 ( 8 ) 3 ( 5 ) n.s Sepsis 10 ( 19 ) 10 ( 16 ) n.s MRI at day 7–10 – no. (%) White matter injury 10 ( 19 ) 11 ( 18 ) n.s Cerebral hemorrhage 3 ( 6 ) 1 ( 2 ) n.s Brain edema 2 ( 4 ) 1 ( 2 ) n.s Brain atrophy 0 1 ( 2 ) n.s Deaths – n (%) Total 17 (33%) 21 (34%) n.s Sarnat stage II 2 3 n.s Sarnat stage III 15 18 n.s DISCUSSION In this control study we show that phase changing material (PCM) can be used as a safe and effective cooling method during transportation of newborns with HIE. Target temperature was reached faster in the group where PCM was used during transportation, and there were no complications during transportation. The transfer of patients took an average of two to three hours with a median temperature on arrival 0.6°C lower in the PCM group (34.5°C) than in the control group (35.1°C). In a subtropical region like Vietnam, average temperatures range from high of 35.6°C (96.1°F) to low of 14.6°C (58.3°F), with an average yearly temperature of 24.8°C (76.7°F)". Under such thermal conditions, passive cooling may be less effective than more efficient methods of cooling. When comparing the temperature on arrival with other studies from similar settings, it was lower than in both the NICHD trial (36.6 ± 1.0°C) ( 25 ), where all patients were inborn, and in the Thayil S et al. trial (35.2 ± 1.3°C) ( 20 ). The target temperature of 33.5°C was achieved at a median age of 1.5 hours earlier for the PCM group than the control group, which is a possible advantage, since earlier studies showed that reaching the target temperature early is often associated with better motor outcomes at 18 months in surviving newborns ( 10 ). In a large cohort of 207 infants in Canada who received cooling for HIE, it was shown that initiating cooling before and during transfer is critical for achieving the target temperature sooner, which is a key factor for improving outcomes ( 26 , 27 ). Lemyre et al. also suggested that the severity of the encephalopathy was associated with the time to reach the target core temperature. We did not demonstrate a statistically significant difference in time to reach target temperature between groups (p = 0.062). However, we did demonstrate a significant difference in the proportion of infants reaching target temperature by 6 hours of age between groups (80.8% in infants transported with PCM versus 62.3% of infants transported without, p = 0.049). This difference means that a larger proportion of infants received neuroprotection within the narrow six-hour timeframe shown to be efficacious in animal and human studies of TH for HIE. Transport over both short and long distances makes achieving and maintaining target temperature a great challenge globally. Studies in both LMICs and HICs show that delays in the initiation of cooling therapy (even though still within the six-hour window of the protocol) requires longer time to attain target temperatures and is likely to result in a worse outcome ( 28 , 29 ). In our study, no patient in either of the two groups developed severe hypothermia (< 32°C). However, several authors have raised concerns that initiation of cooling during transport may increase the risk of excessive cooling ( 30 , 31 ). In comparison, removal of an external heat supply in 18 transported newborns in Sweden resulted in 3 (17%) newborns becoming overcooled to below 32°C ( 31 ). Similarly, Zanelli et al. reported that in their study of 11 newborns, two newborns were significantly overcooled (29.2°C and 29.6°C) upon arrival at the hospital by passive cooling. In another study of 35 newborns, where active cooling was conducted by placing cool packs in an incubator, 34% of newborns had core temperatures below 32°C on arrival at the cooling center ( 32 ). Carreras et al. has shown that severity of HIE and acidosis at birth is associated with the increased risk of overcooling ( 33 ). In the present study, the overall mortality rate was 34%, which was significantly higher in comparison to 19% in previous trials from high-income countries ( 25 ). However, the mortality rate was similar to other LMIC settings, such as Nepal (31%) ( 34 ), and even slightly lower than, e.g., India, Sri Lanka, and Bangladesh (42%) ( 8 ). The proportion of deaths according to Sarnat stage was similar across groups, and up to 50% of infants with Sarnat stage III encephalopathy died. Indeed, studies from Nepal have shown that, in settings where long-term ventilation and stabilization are not available, the mortality rate for newborns with Sarnat stage III neonatal encephalopathy can be as high as 100% ( 34 ). Comparable to many cooling studies, there were no differences between the two groups in the present study in terms of adverse events, such as hypotension, arrhythmias, coagulation dysfunction, skin injury due to cooling, or infection ( 35 ). A recently published RCT that included seven study cites and 408 newborns, the HELIX study showed that therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months, and thus, as not recommended as a treatment for HIE in LMIC settings ( 8 ). The results from our study, with combined infant mortality and severe neurological disability of 55% in infants treated with TH ( 24 ), were comparable to both the results in the randomized HELIX trial, in part performed during the same time as the present study, and to a case–control study in Nepal, performed almost 20 years earlier in the mid 1990s ( 34 ). Possible explanations for the worse outcomes in LMICs include the larger proportion of newborns requiring transport and referral from other hospitals, longer duration of the hypoxic insult, and a higher proportion of newborns having clinical seizures, all of which are comparable to the findings of this study. Since there are multiple factors that could influence the results of hypothermic neuroprotection, the question of whether or not we should stop cooling newborns with HIE in LMICs should be investigated further. There are many differences in the epidemiology and outcome of newborns with encephalopathy in low-resource settings. There is a higher incidence of hospital-acquired infections like sepsis or pneumonia in Vietnam’s hospitals ( 36 ). These differences could alter the safety or effectiveness of therapeutic hypothermia treatment as well as the neurological outcomes. There is evidence that antenatal insults such as maternal nutrition, comorbidities, and complications during labor may be associated with established brain injury before birth, in which the initiation of cooling at birth may already be too late. Additionally, there is convincing evidence that suggests that a combination of infection and ischemia results in more severe brain injuries and increases in the risk of adverse outcomes ( 37 , 38 ), which is possibly one of the factors responsible for the poorer neurological outcome reported from low and mid-resource settings ( 34 ), and it is unknown whether therapeutic hypothermia would be neuroprotective in such situations. Given the narrow window of opportunity for hypothermia treatment (within 6 hours after birth), differentiating between HIE and other pathologies is not possible because: ( 1 ) inborn errors of metabolism, or neuromuscular diseases cannot be quickly diagnoses in LMICs and ( 2 ) sepsis cannot be quickly or accurately diagnosed given the poor predictive accuracy of complete blood count and CRP at this postnatal age. Studies showed that 5–12% of neonates treated with TH have early-onset sepsis (EOS) and the clinical features may be indistinguishable ( 5 , 39 ). Among the 113 patients in this study, we suspected early-onset sepsis by history in 10 patients, only 2 patients (0.2%) were diagnosed with sepsis by positive blood cultures. In our study, none of the children had documented metabolic disorders. The initial diagnosis of HIE was made after telephone consultation about patient history, need for prolonged resuscitation and early signs of encephalopathy. On admission to the VNCH, all patients got cranial ultrasounds to rule out other patterns of brain injury. During treatment course, all patients who required significant mechanical ventilation, HFOV or iNO for persistent pulmonary hypertension (PPHN) or who had unresolved metabolic acidosis were investigated for other underlying causes such as sepsis or IMD. In order to improve outcomes for newborns HIE in LMICs, it is important to enhance resuscitation care and the early initiation of hypothermia. There is therefore an important need for validation of ‘low tech’, safe, and economical cooling methods that are feasible during transport, as transport facilities in LMICs are generally inadequate in terms of both quantity and quality. As a matter of fact, ambulances in most LMIC settings are used solely for transport and not as an emergency care vehicle, due to poorly equipped facilities and lack of trained medical staff ( 40 , 41 ). CONCLUSION Initiating therapeutic hypothermia with a PCM mattress during ambulance transportation is feasible and safe, and allows for significantly earlier initiation and attainment of target temperatures, possibly providing further benefit for neonates with hypoxic-ischemic encephalopathy. List Of Abbreviations HICs: high-income countries; HIE: hypoxic ischemic encephalopathy; LMICs: Low-middle income countries; NICU: neonatal intensive care unit; PCM: phase change materials; TH: therapeutic hypothermia; VNCH: Vietnam National Children’s Hospital. Declarations ACKNOWLEDGEMENT We would like to acknowledge all participants in our studies, all referring hospitals: Hanoi OBGY Hospital, Ha Dong General Hospital, Hung Yen Provincial hospital of Obstetrics and Pediatrics, Thai Binh Provincial Hospital Pediatrics, Hai Duong Provincial hospital of Pediatrics, Bac Giang Provincial hospital of Obstetrics and Pediatrics, Vinh Phuc Provincial hospital of Obstetrics and Pediatrics and Dr Linus Olson from TRAC who have student exchange and capacity building between Sweden and Vietnam possible. The Swedish research council, VR for support. FUNDING None AUTHOR CONTRIBUTIONS All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Dr H.T.T.T had primary responsibility for protocol development, patient screening, enrollment, outcome assessment, preliminary and final data analysis and writing the manuscript; Dr T.A and Dr L.O supervised the design and execution of the study and contributed to the writing of the manuscript; Drs H.T.L participated in the patient screening, enrollment and data collection; Drs D.M.T, L.H.W supervised the execution of the study and contributed to the writing of the manuscript. COMPETING INTERESTS Authors state no conflict of interest. INFORMED CONSENT WRITTEN INFORMED consent was obtained from the participants' parent/legal guardian to participate in the study prior to treatment. ETHICAL APPROVAL This study was approved by the Ethical Review Board of National Hospital of Pediatrics (renamed as Vietnam National Children’s Hospital since 2017) Research Institute for Child Health (RICH) (NHP - RICH- 13-002). The study was performed in accordance with the Declaration of Helsinki. 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Efficacy of passive hypothermia and adverse events during transport of asphyxiated newborns according to the severity of hypoxic-ischemic encephalopathy. J Pediatr (Rio J). 2018;94(3):251–7. Ellis M, Manandhar N, Manandhar DS, Costello AM. Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case-control study. BMJ. 2000;320(7244):1229–36. Shankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008;122(4):e791–8. Tran DM, Larsson M, Olson L, Hoang NTB, Le NK, Khu DTK, et al. High prevalence of colonisation with carbapenem-resistant Enterobacteriaceae among patients admitted to Vietnamese hospitals: Risk factors and burden of disease. J Infect. 2019;79(2):115–22. Eklind S, Mallard C, Leverin AL, Gilland E, Blomgren K, Mattsby-Baltzer I, et al. Bacterial endotoxin sensitizes the immature brain to hypoxic–ischaemic injury. Eur J Neurosci. 2001;13(6):1101–6. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ (Clinical Res ed. 1998;317(7172):1554–8. Hage L, Jeyakumaran D, Dorling J, Ojha S, Sharkey D, Longford N, et al. Changing clinical characteristics of infants treated for hypoxic-ischaemic encephalopathy in England, Wales and Scotland: a population-based study using the National Neonatal Research Database. Arch Dis Child Fetal Neonatal Ed. 2021;106(5):501–8. Suryanto u, Plummer V, Boyle M. EMS Systems in Lower-Middle Income Countries: A Literature Review. Prehosp Disaster Med. 2017;32(1):64–70. Aggarwal KC, Gupta R, Sharma S, Sehgal R, Roy MP. Mortality in newborns referred to tertiary hospital: An introspection. J Family Med Prim Care. 2015;4(3):435–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 08 Aug, 2024 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 26 Jun, 2024 Reviews received at journal 25 Jun, 2024 Reviews received at journal 10 Jun, 2024 Reviewers agreed at journal 10 Jun, 2024 Reviewers agreed at journal 04 Jun, 2024 Reviewers invited by journal 03 Jun, 2024 Editor assigned by journal 03 Jun, 2024 Editor invited by journal 16 May, 2024 Submission checks completed at journal 16 May, 2024 First submitted to journal 09 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4243358","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304178608,"identity":"e6de1f69-f464-45b8-bcb2-4d1e80908d50","order_by":0,"name":"Hang. T. T. Tran","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBACAxDx4YeEHIg+8IBYLYwzeyyMwVoSiNXCzMNWkdgA4hGlxZz97OEXPDwS6fPDDj8E2mInp9tAQItlT16ahYSFRO7G22kGQC3JxmYHCDnsQI6ZgQEPUMvsBJCWA4nbCGo5/8bMIIFNIt1wdvoHIrXcyDF+cIBNIkFeOodYW268MWNs7JEw3CCdU3AgwYAYv5zPMf7850edvPzs9M0fPlTYyRHUAgRsEmC9YJUGhJWDAPMHECnfQJzqUTAKRsEoGIEAAKalRz1A5AroAAAAAElFTkSuQmCC","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Hang.","middleName":"T. T.","lastName":"Tran","suffix":""},{"id":304178609,"identity":"9c20b0f6-b5ca-4b21-9841-fad433d8db5f","order_by":1,"name":"Dien. M. Tran","email":"","orcid":"","institution":"Vietnam National Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dien.","middleName":"M.","lastName":"Tran","suffix":""},{"id":304178610,"identity":"b0a5895e-1dc5-4863-b0d1-e84679b1cda8","order_by":2,"name":"Ha. T. Le","email":"","orcid":"","institution":"Vietnam National Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ha.","middleName":"T.","lastName":"Le","suffix":""},{"id":304178611,"identity":"8e0194f6-a923-48db-a84a-c8e627c4b675","order_by":3,"name":"Lena Hellström-Westas","email":"","orcid":"","institution":"Uppsala University","correspondingAuthor":false,"prefix":"","firstName":"Lena","middleName":"","lastName":"Hellström-Westas","suffix":""},{"id":304178612,"identity":"ad3b566a-3fe2-40d8-b770-176ecd86f57f","order_by":4,"name":"Tobias Alfvén","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Tobias","middleName":"","lastName":"Alfvén","suffix":""},{"id":304178613,"identity":"68d28113-47b3-4693-b1b2-b4605b3f1ee4","order_by":5,"name":"Linus Olson","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Linus","middleName":"","lastName":"Olson","suffix":""}],"badges":[],"createdAt":"2024-04-09 16:59:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4243358/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4243358/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-024-04987-6","type":"published","date":"2024-08-08T15:57:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57517656,"identity":"19c44569-4606-4198-b450-e6113bcfc0de","added_by":"auto","created_at":"2024-05-31 20:24:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47885,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEnrolment, Randomization of the study participants\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4243358/v1/661af919b10f16b5260f432d.png"},{"id":57517655,"identity":"cc6f9d7d-835c-4720-a4d0-3f7706acb9e0","added_by":"auto","created_at":"2024-05-31 20:24:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":77333,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBox plot for temperature measurement at referring hospital and on arrival at VNCH. The area between the redlines shows the target temperature range of 33.5°C to 34.5°C\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4243358/v1/d7c7b255a777b69c81efa89d.png"},{"id":62298298,"identity":"b8731317-5919-4a33-a271-2a3b2b824885","added_by":"auto","created_at":"2024-08-12 16:11:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":706826,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4243358/v1/6ba94a14-e8d2-45e1-b7ef-33976f62a02d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cooling during transportation of newborns with hypoxic ischemic encephalopathy using phase change material mattresses in low-resource settings: a randomized controlled trial in Hanoi, Vietnam","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eNeonatal hypoxic-ischemic encephalopathy (HIE), caused by a lack of blood flow and oxygen to the brain at birth, occurs in 10\u0026ndash;20/1000 live births in low-middle-income countries (LMICs) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In Vietnam, birth asphyxia accounts for 14% of all neonatal mortality (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), with regional variation and reported rates as high as 33% in certain regions (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Although the incidence of birth asphyxia in Vietnam is high, there is still limited experience with therapeutic hypothermia (TH) treatment, as in other LMICs.\u003c/p\u003e \u003cp\u003eMeta-analysis of studies from high-income countries (HICs) shows that induced hypothermia is associated with reduced risk of death or major neurodevelopmental disability by 18 months of age (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The benefits of cooling, however, is insufficiently studied and requires further evaluation in LMICs (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEvidence from animal and newborn studies has indicated that the window of opportunity to start cooling is within 6 hours after birth (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e); hence, transportation time could delay hypothermia treatment, consequently altering the safety or effectiveness of TH treatment and neurological outcomes(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIn order to optimize the neuroprotective effect in newborns with HIE, cooling should start as early as possible, both actively and passively. Several studies have shown that passive cooling (e.g., removal of clothes, turning off heating devices to allow the baby to cool down naturally) is less effective and has a higher risk of overcooling compared to active cooling using servo-controlled equipment (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Despite the demonstrated benefits of servo-controlled devices when used in transport (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) more recent studies continue to show achieving target temperature within the 6-hour window remains a challenge for THs even in HIC settings with proportions between 55% and 63% (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) let alone in LMICs like Vietnam.\u003c/p\u003e\u003cp\u003ePhase change material (PCM) has been well studied in both animals and newborn infants for its effectiveness and safety in therapeutic hypothermia treatment (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). A PCM-based device has been shown to be comparable to standard servo-controlled equipment in maintaining the target temperature (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). A pilot study implementing PCM to cool asphyxiated newborns in Vietnam has proven that it is an effective yet easy to use method of cooling in a low-resource neonatal intensive care unit (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFollowing from our previous study, the aim of this study was to determine the feasibility and effectiveness of phase-change-material mattresses during transportation of asphyxiated newborns with suspected HIE, with the aim of reducing the time to initiate therapeutic cooling in low-resource settings.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"PARTICIPANTS AND METHODS","content":"\u003cp\u003e \u003cb\u003eParticipants\u003c/b\u003e: Following a pilot study showing that PCM is feasible and safe for inducing TH (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), we conducted a randomized controlled trial study of patients from seven hospitals within up to 200km transport distance to a tertiary center. The inclusion criteria were: infants\u0026thinsp;\u0026ge;\u0026thinsp;36 weeks gestational age and \u0026le;\u0026thinsp;6 hours after birth with either Apgar score\u0026thinsp;\u0026le;\u0026thinsp;5 at 10 minutes or continued need for resuscitation, 10 mins or pH\u0026thinsp;\u0026lt;\u0026thinsp;7.0 and/or base deficit\u0026thinsp;\u0026gt;\u0026thinsp;16 mmol/L and sign of moderate to severe encephalopathy (altered consciousness, abnormal tone). Infants were excluded if\u0026thinsp;\u0026gt;\u0026thinsp;6 hours after birth at time of referral/evaluation, coagulopathy with active bleeding, prenatally diagnosed syndromes, malformations or metabolic disorders not compatible with survival (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Prior to the study, visits to assess the capacity of all hospital and training sessions had been organized to enhance neonatal unit doctors and nurses at all sites concerning the background of the study, the use of a PCM mattress, data recording, and assessment of patients. Parents/guardians of asphyxiated newborns were approached regarding participation in the study once the patient met criteria for cooling. The study was registered in Clinical Trials (04/05/2022, NCT05361473). This study was intended to be a feasibility study to assess the safety and applicability of using PCM for transportation of asphyxiated newborns compared to passive cooling (standard care). The aim was to recruit 70 newborns for each group in order to cover differences in severity of HIE, transport distances, and time of day, etc.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and intervention\u003c/h2\u003e \u003cp\u003eEach hospital was provided with sealed envelopes containing papers for PCM or control by the study team. Once cooling criteria were met, patients were randomized to a group cooled by PCM mattress \u003cem\u003e(Medical Cooling Sweden AB; by TST AB, Kinna, Sweden)\u003c/em\u003e during transportation or a control group, in which patients were passively cooled by turning off all external heating sources. The babies were transported in road ambulances, placed on an ambulance stretcher with only one layer of clothes on, no extra cover by blanket (all the referring hospitals do not have transport incubator) during transportation, which enabled the babies to chill spontaneously at air temperature.\u003c/p\u003e \u003cp\u003eSkin temperature in the axilla and environment temperature were measured before transport and every 30 minutes during the transportation for both groups. The infant\u0026rsquo;s clinical condition was clinically monitored by the accompanying hospital staff, but there was no continuous monitoring of heart rate or oxygen saturation during transport. On arrival at VNCH, the infants were evaluated for continuation of cooling or initiation of cooling, respectively. All received hypothermia treatment with PCM mattress.\u003c/p\u003e \u003cp\u003eBoth groups received cooling therapy with a target temperature of 33.5\u0026ndash;34.5\u0026deg;C for 72 hours and standard medical care. On admission, the severity of the infant\u0026rsquo;s encephalopathy was assessed by modified Sarnat score and neonatal encephalopathy scores (Thompson score) were used at 24, 48 and 72 hours as part of clinical assessment (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Short-term adverse effects of cooling, such as respiratory cardiovascular complications (bradycardia, hypotension, pulmonary hypertension), electrolyte imbalance (hypokalemia, hyponatremia), and coagulopathy \u0026ndash; platelet dysfunction, were recorded during treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cp\u003eOutcome measures were the same for both groups: Rectal temperature on arrival, time to reach target temperature 33.5\u0026deg;C (postnatal age), neurology assessment on arrival and at discharge (for survivors), death before discharge, complications, including hypotension (with/without inotropes), pneumothorax, uncontrollable seizures, sepsis during treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eDemographic factors and clinical characteristics were summarized with counts (percentages) for categorical variables, mean (standard deviation [SD]) for normally distributed continuous variables or median (interquartile or entire range) for other continuous variables. For each group, differences were assessed using Student\u0026rsquo;s t test (normal distribution) or the Mann Whitney U test (skewed distribution). Data were analyzed by using SPSS. P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eDuring the three-year study period (from September 1st 2016 to December 31st 2019), there were in total 118 infants transferred from the seven study hospitals: 55 in the PCM group, and 63 in the control group. The average time for transfer of each patient was two to three hours, or more during rush hours. Upon arrival at VNCH, during re-evaluation, the encephalopathy was mild in five patients (3 in PCM group, 2 in non-PCM group), and cooling was therefore stopped for these children, and they were excluded from the analysis. The study participants are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBaseline maternal and neonatal characteristics for both groups are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMaternal and neonatal baseline characteristics. Figures are numbers (percentages) and means (standard deviation).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePCM group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge \u0026ndash; years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 \u0026plusmn; 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 \u0026plusmn; 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntrapartum complications \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal heart-rate deceleration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCord prolapses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShoulder dystocia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMode of delivery \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.671\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaginal delivery/Instrumental Delivery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency caesarean delivery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeonatal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.522\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (\u0026plusmn;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (\u0026plusmn;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.634\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirthweight (grams)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3210 (\u0026plusmn;1040)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3165 (\u0026plusmn;416)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.754\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar score \u0026le; 5 \u0026ndash; no. (%) at 10 min\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at randomization \u0026ndash; hour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 \u0026plusmn; 0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 \u0026plusmn; 0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at admission (hours from birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.6 \u0026plusmn; 1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9 \u0026plusmn; 1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransport distance, hours by road ambulance (Median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1 (0.5\u0026ndash;2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2 (0.5\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.204\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to reach target temp 33.5 \u0026deg;C to 34.5\u0026deg;C \u0026ndash; (hours from birth)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.0 \u0026plusmn; 1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5 \u0026plusmn; 1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients reaching target temp within 6 hours of birth \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003cp\u003e(80.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (62.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRectal temp at randomization, before transport (\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.8 \u0026plusmn; 0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 \u0026plusmn; 0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizure on admission \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLevel of encephalopathy \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate - Sarnat stage II (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere - Sarnat stage III (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003e* Apgar score at 5 min and 10 min were available for only 22 newborns in PCM group and 28 newborns in control group\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNewborns had a mean gestation of 39 (\u0026plusmn;1.1) weeks in both groups, and the majority were male, with 37 (71%) in the PCM group versus 39 (64%) in the control group. There was no significant difference between the two groups in terms of maternal age or mode of delivery. Close to 50% of cases required emergency c-sections due to intrapartum complications such as fetal distress, cord prolapse, bleeding, or other complications. Eligibility criteria for transportation and evaluation for cooling were adapted to previous multicenter studies (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and based on either Apgar scores or need for continuation of resuscitation at 10 minutes, because blood gases were not routinely reported or assessed.\u003c/p\u003e \u003cp\u003eIn the PCM group, 15 (29%) newborns had clinical seizures on admission, with a mean age at admission of 3.6 hours \u0026plusmn; 1.4. In the non-PCM group, 23 (38%) newborns had clinical seizures on admission, with a mean age at admission of 3.9 hours \u0026plusmn; 1.4. Anticonvulsant was used similarly in both groups.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the mean temperature of the newborns in both groups at two different time points: on departure from the referring hospital and on arrival at VNCH. Upon arrival to VNCH, the mean rectal temperature in the PCM group was significantly lower than in the control one: 34.5\u0026deg;C (IQR 33.5\u0026ndash;34.8) compared to 35.1\u0026deg;C (IQR 34.5\u0026ndash;35.9) (p\u0026thinsp;=\u0026thinsp;0.023). There was no record of excessive hypothermia (\u0026lt;\u0026thinsp;32\u0026deg;C) on admission for any of the groups. Consequently, the median time to reach target cooling temperature from birth in the PCM group was 5 \u0026plusmn; 1.4 hours, while it took 5.5 \u0026plusmn; 1.2 hours for the control group to reach the target cooling temperature (p\u0026thinsp;=\u0026thinsp;0.065). 42/52 patients (81%) of those transported with PCM versus 38/61 (62%) of infants transported without (p\u0026thinsp;=\u0026thinsp;0.049) had reached target temperature within the 6-hour timeframe.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere was no significant difference in Thompson scores between the two groups on arrival and on consequent days.\u003c/p\u003e \u003cp\u003eIn total, 38 newborns died before discharge from hospital: 17 in the PCM group and 21 in the control group. In the PCM group, the newborns died from the following causes: encephalopathy-related complications (n\u0026thinsp;=\u0026thinsp;13 [74%]), persistent pulmonary hypertension (n\u0026thinsp;=\u0026thinsp;3 [18%]), and sepsis (n\u0026thinsp;=\u0026thinsp;1 [6%]). In the control group, the primary cause of death was also encephalopathy-related complications (n\u0026thinsp;=\u0026thinsp;18 [86%]); other causes including persistent pulmonary hypertension (n\u0026thinsp;=\u0026thinsp;2 [4%]) and pneumothorax (n\u0026thinsp;=\u0026thinsp;1 [2%]). The proportion of deaths according to Sarnat stage was similar across groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the 87 survivors, 69 (79%) completed follow-up until 18 months. Nineteen children developed cerebral palsy (8 diplegia, 3 hemiplegia, 8 dyskinetic), and 11 had delayed neurodevelopment (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePCM group (n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group (n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eEncephalopathy score (Thompson score)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 1, Mean, min-max\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt discharge, Mean, min-max\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0\u0026ndash;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (0\u0026ndash;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eComplications during cooling \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotension \u0026plusmn; inotropes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUncontrollable seizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMRI at day 7\u0026ndash;10 \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite matter injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebral hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain atrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDeaths \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarnat stage II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarnat stage III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.s\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this control study we show that phase changing material (PCM) can be used as a safe and effective cooling method during transportation of newborns with HIE. Target temperature was reached faster in the group where PCM was used during transportation, and there were no complications during transportation.\u003c/p\u003e \u003cp\u003eThe transfer of patients took an average of two to three hours with a median temperature on arrival 0.6\u0026deg;C lower in the PCM group (34.5\u0026deg;C) than in the control group (35.1\u0026deg;C). In a subtropical region like Vietnam, average temperatures range from high of 35.6\u0026deg;C (96.1\u0026deg;F) to low of 14.6\u0026deg;C (58.3\u0026deg;F), with an average yearly temperature of 24.8\u0026deg;C (76.7\u0026deg;F)\". Under such thermal conditions, passive cooling may be less effective than more efficient methods of cooling. When comparing the temperature on arrival with other studies from similar settings, it was lower than in both the NICHD trial (36.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u0026deg;C) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), where all patients were inborn, and in the Thayil S et al. trial (35.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u0026deg;C) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The target temperature of 33.5\u0026deg;C was achieved at a median age of 1.5 hours earlier for the PCM group than the control group, which is a possible advantage, since earlier studies showed that reaching the target temperature early is often associated with better motor outcomes at 18 months in surviving newborns (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In a large cohort of 207 infants in Canada who received cooling for HIE, it was shown that initiating cooling before and during transfer is critical for achieving the target temperature sooner, which is a key factor for improving outcomes (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Lemyre et al. also suggested that the severity of the encephalopathy was associated with the time to reach the target core temperature. We did not demonstrate a statistically significant difference in time to reach target temperature between groups (p\u0026thinsp;=\u0026thinsp;0.062). However, we did demonstrate a significant difference in the proportion of infants reaching target temperature by 6 hours of age between groups (80.8% in infants transported with PCM versus 62.3% of infants transported without, p\u0026thinsp;=\u0026thinsp;0.049). This difference means that a larger proportion of infants received neuroprotection within the narrow six-hour timeframe shown to be efficacious in animal and human studies of TH for HIE. Transport over both short and long distances makes achieving and maintaining target temperature a great challenge globally. Studies in both LMICs and HICs show that delays in the initiation of cooling therapy (even though still within the six-hour window of the protocol) requires longer time to attain target temperatures and is likely to result in a worse outcome (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, no patient in either of the two groups developed severe hypothermia (\u0026lt;\u0026thinsp;32\u0026deg;C). However, several authors have raised concerns that initiation of cooling during transport may increase the risk of excessive cooling (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). In comparison, removal of an external heat supply in 18 transported newborns in Sweden resulted in 3 (17%) newborns becoming overcooled to below 32\u0026deg;C (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Similarly, Zanelli et al. reported that in their study of 11 newborns, two newborns were significantly overcooled (29.2\u0026deg;C and 29.6\u0026deg;C) upon arrival at the hospital by passive cooling. In another study of 35 newborns, where active cooling was conducted by placing cool packs in an incubator, 34% of newborns had core temperatures below 32\u0026deg;C on arrival at the cooling center (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Carreras et al. has shown that severity of HIE and acidosis at birth is associated with the increased risk of overcooling (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the present study, the overall mortality rate was 34%, which was significantly higher in comparison to 19% in previous trials from high-income countries (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). However, the mortality rate was similar to other LMIC settings, such as Nepal (31%) (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), and even slightly lower than, e.g., India, Sri Lanka, and Bangladesh (42%) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The proportion of deaths according to Sarnat stage was similar across groups, and up to 50% of infants with Sarnat stage III encephalopathy died. Indeed, studies from Nepal have shown that, in settings where long-term ventilation and stabilization are not available, the mortality rate for newborns with Sarnat stage III neonatal encephalopathy can be as high as 100% (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Comparable to many cooling studies, there were no differences between the two groups in the present study in terms of adverse events, such as hypotension, arrhythmias, coagulation dysfunction, skin injury due to cooling, or infection (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA recently published RCT that included seven study cites and 408 newborns, the HELIX study showed that therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months, and thus, as not recommended as a treatment for HIE in LMIC settings (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The results from our study, with combined infant mortality and severe neurological disability of 55% in infants treated with TH (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), were comparable to both the results in the randomized HELIX trial, in part performed during the same time as the present study, and to a case\u0026ndash;control study in Nepal, performed almost 20 years earlier in the mid 1990s (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Possible explanations for the worse outcomes in LMICs include the larger proportion of newborns requiring transport and referral from other hospitals, longer duration of the hypoxic insult, and a higher proportion of newborns having clinical seizures, all of which are comparable to the findings of this study. Since there are multiple factors that could influence the results of hypothermic neuroprotection, the question of whether or not we should stop cooling newborns with HIE in LMICs should be investigated further. There are many differences in the epidemiology and outcome of newborns with encephalopathy in low-resource settings. There is a higher incidence of hospital-acquired infections like sepsis or pneumonia in Vietnam\u0026rsquo;s hospitals (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). These differences could alter the safety or effectiveness of therapeutic hypothermia treatment as well as the neurological outcomes.\u003c/p\u003e \u003cp\u003eThere is evidence that antenatal insults such as maternal nutrition, comorbidities, and complications during labor may be associated with established brain injury before birth, in which the initiation of cooling at birth may already be too late. Additionally, there is convincing evidence that suggests that a combination of infection and ischemia results in more severe brain injuries and increases in the risk of adverse outcomes (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e), which is possibly one of the factors responsible for the poorer neurological outcome reported from low and mid-resource settings (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), and it is unknown whether therapeutic hypothermia would be neuroprotective in such situations. Given the narrow window of opportunity for hypothermia treatment (within 6 hours after birth), differentiating between HIE and other pathologies is not possible because: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) inborn errors of metabolism, or neuromuscular diseases cannot be quickly diagnoses in LMICs and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) sepsis cannot be quickly or accurately diagnosed given the poor predictive accuracy of complete blood count and CRP at this postnatal age. Studies showed that 5\u0026ndash;12% of neonates treated with TH have early-onset sepsis (EOS) and the clinical features may be indistinguishable (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Among the 113 patients in this study, we suspected early-onset sepsis by history in 10 patients, only 2 patients (0.2%) were diagnosed with sepsis by positive blood cultures. In our study, none of the children had documented metabolic disorders. The initial diagnosis of HIE was made after telephone consultation about patient history, need for prolonged resuscitation and early signs of encephalopathy. On admission to the VNCH, all patients got cranial ultrasounds to rule out other patterns of brain injury. During treatment course, all patients who required significant mechanical ventilation, HFOV or iNO for persistent pulmonary hypertension (PPHN) or who had unresolved metabolic acidosis were investigated for other underlying causes such as sepsis or IMD.\u003c/p\u003e \u003cp\u003eIn order to improve outcomes for newborns HIE in LMICs, it is important to enhance resuscitation care and the early initiation of hypothermia. There is therefore an important need for validation of \u0026lsquo;low tech\u0026rsquo;, safe, and economical cooling methods that are feasible during transport, as transport facilities in LMICs are generally inadequate in terms of both quantity and quality. As a matter of fact, ambulances in most LMIC settings are used solely for transport and not as an emergency care vehicle, due to poorly equipped facilities and lack of trained medical staff (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eInitiating therapeutic hypothermia with a PCM mattress during ambulance transportation is feasible and safe, and allows for significantly earlier initiation and attainment of target temperatures, possibly providing further benefit for neonates with hypoxic-ischemic encephalopathy.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003eHICs: high-income countries; HIE: hypoxic ischemic encephalopathy; LMICs: Low-middle income countries; NICU: neonatal intensive care unit; PCM: phase change materials; TH: therapeutic hypothermia; VNCH: Vietnam National Children\u0026rsquo;s Hospital.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge all participants in our studies, all referring hospitals: Hanoi OBGY Hospital,\u0026nbsp;Ha Dong General Hospital, Hung Yen Provincial hospital of Obstetrics and Pediatrics, Thai Binh Provincial\u0026nbsp;Hospital Pediatrics, Hai\u0026nbsp;Duong Provincial hospital of Pediatrics, Bac Giang Provincial hospital of Obstetrics\u0026nbsp;and Pediatrics, Vinh Phuc Provincial hospital of Obstetrics and Pediatrics and Dr Linus Olson from TRAC who\u0026nbsp;have student exchange and capacity building between Sweden and Vietnam possible. The Swedish\u0026nbsp;research council, VR for support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have accepted responsibility for the entire content of this manuscript and approved its submission.\u003c/p\u003e\n\u003cp\u003eDr H.T.T.T had primary responsibility for protocol development, patient screening, enrollment, outcome assessment, preliminary and final data analysis and writing the manuscript; Dr T.A and Dr L.O supervised the design and execution of the study and contributed to the writing of the manuscript; Drs H.T.L participated in the patient screening, enrollment and data collection; Drs D.M.T, L.H.W supervised the execution of the study and contributed to the writing of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors state no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eINFORMED CONSENT\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWRITTEN INFORMED consent was obtained from the participants' parent/legal guardian to participate in the study prior to treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICAL APPROVAL\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethical Review Board of National Hospital of Pediatrics (renamed as\u0026nbsp;Vietnam National Children’s Hospital since 2017) Research Institute for Child Health (RICH) (NHP - RICH-\u0026nbsp;13-002). The study was performed in accordance with the Declaration of Helsinki. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is not available due to ethical reasons. Further enquiries can be directed to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLiu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016;388(10063):3027\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO-MCEE estimates for child causes of death. 2000\u0026ndash;2015. 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Therapeutic hypothermia during neonatal transport at Regional Perinatal Centers: active vs. passive cooling. J Perinat Med. 2019;47(3):365\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkula VP, Joe P, Thusu K, Davis AS, Tamaresis JS, Kim S, et al. A randomized clinical trial of therapeutic hypothermia mode during transport for neonatal encephalopathy. J Pediatr. 2015;166(4):856\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e.e1-2\u003c/span\u003e\u003cspan address=\"http://.e1-2\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKendall GS, Kapetanakis A, Ratnavel N, Azzopardi D, Robertson NJ. Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy. Arch Dis Child. 2010;95(6):F408\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaudhary RF, Broster K, McRitchie S. Austin, Topun. Active Versus Passive Cooling During Neonatal Transport. Pediatrics. 2013;132:841\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorre Monmany N, Behrsin J, Leslie A. Servo-controlled cooling during neonatal transport for babies with hypoxic-ischaemic encephalopathy is practical and beneficial: Experience from a large UK neonatal transport service. J Paediatr Child Health. 2019;55(5):518\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas N, Abiramalatha T, Bhat V, Varanattu M, Rao S, Wazir S, et al. Phase Changing Material for Therapeutic Hypothermia in Neonates with Hypoxic Ischemic Encephalopathy - A Multi-centric Study. Indian Pediatr. 2018;55(3):201\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAker K, St\u0026oslash;en R, Eikenes L, Martinez-Biarge M, Nakken I, H\u0026aring;berg AK, et al. Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN study): a randomised controlled trial. Arch Dis Child. 2020;105(4):405\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins RD, Raju T, Edwards AD, Azzopardi DV, Bose CL, Clark RH, et al. Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop. J Pediatr. 2011;159(5):851\u0026ndash;e81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThayyil S, Shankaran S, Wade A, Cowan FM, Ayer M, Satheesan K, et al. Whole-body cooling in neonatal encephalopathy using phase changing material. Arch Dis Child Fetal Neonatal Ed. 2013;98(3):F280\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTran HTT, Le HTT, Tran HTP, Khu DTK, Lagercrantz H, Tran DM et al. Hypothermic treatment for neonatal asphyxia in low-resource settings using phase-changing material-An easy to use and low-cost method. Acta Paediatr. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzzopardi D, Brocklehurst P, Edwards D, Halliday H, Levene M, Thoresen M, et al. The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr. 2008;8:17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson CMPALL, Hann FM, van der Elst CW, Molteno CD. The value of a scoring system for hypoxic-ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Pediatr. 1997;86:757.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTran HTTLH, Tran DM, et al. 10.1136/ e, bmjpo-2023-00220. Therapeutic hypothermia after perinatal asphyxia in Vietnam: mediumterm outcomes at 18 months \u0026ndash; a prospective cohort study. BMJ Paediatrics Open. 2024;8:e002208.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLemyre B, Ly L, Chau V, Chacko A, Barrowman N, Whyte H, et al. Initiation of passive cooling at referring centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns. Paediatr Child Health. 2017;22(5):264\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavies A, Wassink G, Bennet L, Gunn AJ, Davidson JO. Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy? Neural Regen Res. 2019;14(10):1678\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLindsay NM, Healy GN, Colditz PB, Lingwood BE. Use of the Ages and Stages Questionnaire to predict outcome after hypoxic-ischaemic encephalopathy in the neonate. J Paediatr Child Health. 2008;44(10):590\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNatarajan G, Pappas A, Shankaran S, Laptook AR, Walsh M, McDonald SA, et al. Effect of inborn vs. outborn delivery on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy: secondary analyses of the NICHD whole-body cooling trial. Pediatr Res. 2012;72(4):414\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Reilly D, Labrecque M, O'Melia M, Bacic J, Hansen A, Soul JS. Passive cooling during transport of asphyxiated term newborns. J Perinatol. 2013;33(6):435\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHallberg B, et al. Passive induction of hypothermia during transport of asphyxiated infants: A risk of excessive cooling. Acta Paediatr. 2009;98:942\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010;30(5):324\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarreras N, Alsina M, Alarcon A, Arca-D\u0026iacute;az G, Agut T, Garc\u0026iacute;a-Alix A. Efficacy of passive hypothermia and adverse events during transport of asphyxiated newborns according to the severity of hypoxic-ischemic encephalopathy. J Pediatr (Rio J). 2018;94(3):251\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEllis M, Manandhar N, Manandhar DS, Costello AM. Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case-control study. BMJ. 2000;320(7244):1229\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008;122(4):e791\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTran DM, Larsson M, Olson L, Hoang NTB, Le NK, Khu DTK, et al. High prevalence of colonisation with carbapenem-resistant Enterobacteriaceae among patients admitted to Vietnamese hospitals: Risk factors and burden of disease. J Infect. 2019;79(2):115\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEklind S, Mallard C, Leverin AL, Gilland E, Blomgren K, Mattsby-Baltzer I, et al. Bacterial endotoxin sensitizes the immature brain to hypoxic\u0026ndash;ischaemic injury. Eur J Neurosci. 2001;13(6):1101\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ (Clinical Res ed. 1998;317(7172):1554\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHage L, Jeyakumaran D, Dorling J, Ojha S, Sharkey D, Longford N, et al. Changing clinical characteristics of infants treated for hypoxic-ischaemic encephalopathy in England, Wales and Scotland: a population-based study using the National Neonatal Research Database. Arch Dis Child Fetal Neonatal Ed. 2021;106(5):501\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuryanto u, Plummer V, Boyle M. EMS Systems in Lower-Middle Income Countries: A Literature Review. Prehosp Disaster Med. 2017;32(1):64\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAggarwal KC, Gupta R, Sharma S, Sehgal R, Roy MP. Mortality in newborns referred to tertiary hospital: An introspection. J Family Med Prim Care. 2015;4(3):435\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Asphyxia, Cooling, Encephalopathy, Low-income setting, Phase change materials","lastPublishedDoi":"10.21203/rs.3.rs-4243358/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4243358/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo determine the effectiveness of phase-change-material mattress (PCM) during transportation of newborns with hypoxic ischemic encephalopathy (HIE).\u003c/p\u003e\u003ch2\u003eStudy design:\u003c/h2\u003e \u003cp\u003eRandomized controlled trial of newborns with HIE from June 2016 to December 2019. Patients were randomized to transport with PCM or without PCM (control) when transferred to a cooling center in northern Vietnam.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003e52 patients in PCM-group and 61 in control group. Median rectal temperature upon arrival was 34.5\u0026deg;C (IQR 33.5\u0026ndash;34.8) in PCM-group and 35.1\u0026deg;C (IQR 34.5\u0026ndash;35.9) in control group (p\u0026thinsp;=\u0026thinsp;0.023). Median time from birth to reach target temperature was 5.0 \u0026plusmn; 1.4 hours and 5.5 \u0026plusmn; 1.2 hours in the respective groups (p\u0026thinsp;=\u0026thinsp;0.065). 80.8% of those transported with PCM versus 62.3% of infants transported without (p\u0026thinsp;=\u0026thinsp;0.049) had reached target temperature within the 6-hour timeframe. There was no record of overcooling (\u0026lt;\u0026thinsp;32\u0026deg;C) in any of the groups. The mortality rate was 33% and 34% respectively (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePhase-change-material can be used as a safe and effective cooling method during transportation of newborns with HIE in low-resource settings.\u003c/p\u003e","manuscriptTitle":"Cooling during transportation of newborns with hypoxic ischemic encephalopathy using phase change material mattresses in low-resource settings: a randomized controlled trial in Hanoi, Vietnam","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-31 20:24:01","doi":"10.21203/rs.3.rs-4243358/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-26T09:34:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-25T18:10:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-10T16:13:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14454257076560149366830282433546713995","date":"2024-06-10T13:43:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"19764072340165552576501295839659782568","date":"2024-06-04T18:35:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-03T18:43:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-03T18:32:04+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-16T12:05:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-16T12:02:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2024-04-09T16:58:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d46a3817-8db2-4d6a-894f-53efe0675642","owner":[],"postedDate":"May 31st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T16:01:27+00:00","versionOfRecord":{"articleIdentity":"rs-4243358","link":"https://doi.org/10.1186/s12887-024-04987-6","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2024-08-08 15:57:16","publishedOnDateReadable":"August 8th, 2024"},"versionCreatedAt":"2024-05-31 20:24:01","video":"","vorDoi":"10.1186/s12887-024-04987-6","vorDoiUrl":"https://doi.org/10.1186/s12887-024-04987-6","workflowStages":[]},"version":"v1","identity":"rs-4243358","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4243358","identity":"rs-4243358","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}