CoolCot Study: Active methods of therapeutic hypothermia for newborns with hypoxic ischaemic encephalopathy (HIE) during neonatal transport: a study protocol for a randomised controlled trial comparing battery enabled servo-controlled cooling blankets and ice-gel pack methods

CoolCot Study: Active methods of therapeutic hypothermia for newborns with hypoxic ischaemic encephalopathy (HIE) during neonatal transport: a study protocol for a randomised controlled trial comparing battery enabled servo-controlled cooling blankets and ice-gel pack methods | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article CoolCot Study: Active methods of therapeutic hypothermia for newborns with hypoxic ischaemic encephalopathy (HIE) during neonatal transport: a study protocol for a randomised controlled trial comparing battery enabled servo-controlled cooling blankets and ice-gel pack methods Adam Heathcote, Kate Hooper, Sebastian Lee, Fan Tang, Matt Cooper, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6407483/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Sep, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background . Impaired oxygen delivery or blood flow to the brain around the time of birth can cause injury. Hypoxic ischaemic encephalopathy (HIE) is a leading cause of death and disability in term and near-term infants. Therapeutic hypothermia (TH) (reducing body temperature to 33–34°C for 72 hours after birth) is the only intervention available for infants with moderate-to-severe encephalopathy. TH should be initiated within 6 hours of birth for maximum benefit. Many infants worldwide are not born in a centre where TH is possible, and transport is required for active TH. In Australia, the current method of active TH during transport involves ice‒gel packs. There have been no prospective studies comparing active methods of TH in neonatal transport reporting short- and long-term outcomes. We aim to compare two active TH modalities: a battery servo-controlled cooling blanket (Criticool mini (Belmont Medical Technologies, MA, USA)) and standard care (ice‒gel packs) for TH during the transport of newborns with HIE. Methods . The CoolCot study will be conducted in the Newborn Emergency Transport Service of Western Australia (NETS WA), a single state-wide transport service. Eligible infants with confirmed or suspected HIE will be referred to NETS WA from healthcare facilities without tertiary health (TH) capacity in Western Australia. Following the arrival of the transport team, infants with informed consent will be randomly assigned to battery-enabled servo-controlled TH or standard care (ice‒gel packs). The primary outcome will be the proportion of patients with a temperature in the range of 33.0°C–34.0°C on arrival at the receiving unit. The secondary outcomes include the time to achieve the therapeutic temperature, the time spent out of the temperature range, the degree of temperature fluctuation, and safety. Long-term measures: MRI brain findings (days 5-10 of life) and Bayley Scales of Infant Development assessment at 2 years. Discussion : The CoolCot study is the first RCT to prospectively compare the effectiveness of active cooling methods in neonatal emergency transport. Reducing the time needed to achieve the target temperature is crucial in optimising neurodevelopmental outcomes. A key feature of this study is the neurodevelopmental assessment conducted at age two. Trial registration : WHO ICTRP Registry/Australian New Zealand Clinical Trials Registry: ACTRN12623001298606p. The date of registration was 13 December 2023. Hypoxic ischaemic encephalopathy Therapeutic hypothermia Servo-controlled cooling Neonatal transport Randomised control trial Figures Figure 1 Figure 2 Figure 3 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (1). Title {1} COOLCOT Study: Active methods of therapeutic hypothermia for newborns with hypoxic ischaemic encephalopathy (HIE) during neonatal transport: a study protocol for a randomised controlled trial comparing battery servo-controlled cooling blankets and ice-gel pack methods. Trial registration {2a and 2b}. WHO ICTRP Registry/Australian New Zealand Clinical Trials Registry: ACTRN12623001298606p. Date or registration – 13 Dec 202 Protocol version {3} Protocol version 4.1, June 2025 Funding {4} Funding provided to cover consumables for the study, statistical support, publication of protocol, dissemination of results, personnel FTE to coordinate the running of the trial. Funding provided by the Perth Children’s Hospital Foundation (PCHF). Indemnity and insurance provided by Child and Adolescent Health Service (CAHS) governance. Author details {5a} Dr Adam Heathcote 1,2 , Dr Kate Hooper 1,2 , Sebastian Lee 2 , Fan Tang 2 , Dr Matt Cooper 4 , Dr Vamsi Batta 1,2 , Dr Saumil Desai 1,2,3 , Dr Jacqueline Gardiner 1,2 , Alex Wilson 1,2,3 Tess Watson 1,2 , Kylie McDonald 1,2 Alysha Timoney 2 , Dr Jonathan Davis 1,2,3,4 Newborn Emergency Transport Service of Western Australia, Perth Neonatology, Child and Adolescent Health Service, Perth, Western Australia School of Medicine, University of Western Australia, Monash Avenue, Nedlands, Western Australia, Australia. The Kids Research Institute Australia, Perth, Western Australia, Australia. Name and contact information for the trial sponsor {5b} A/Prof Jonathan Davis, Newborn Emergency Transport Service, Perth Children's Hospital, 15 Hospital Avenue, Nedlands WA 6009 Australia, +61 0864565392, [email protected] Role of sponsor {5c} The trial Sponsor is responsible for the initiation, management and controlling the financing of the trial and carries the medicolegal responsibility associated with its conduct The Sponsor is also responsible for ensuring that appropriate approvals are obtained prior to the commencement of the clinical trial, that conditions of any approvals are adhered to during the course of the clinical trial and ensuring that the ethics principles of research merit and integrity, justice, beneficence and respect are applied to the conduct of clinical trials. The Sponsor also ensures that the trial is appropriately monitored for compliance with the protocol The Trial Steering Committee, chaired by JD, is responsible for the study design, management and analysis of data, and decision to publish the results. Background and rationale {6a} Hypoxic ischemic encephalopathy (HIE) results from a lack of cerebral blood flow or oxygen delivery around the time of birth. It is a leading cause of death and neurodevelopmental impairment in term and near-term infants (2). Therapeutic hypothermia (TH) is the only proven treatment for moderate to severe HIE (3). TH involves whole-body cooling to a target temperature of 33–34°C for 72 hours, followed by 12 hours of rewarming. Infants with moderate to severe HIE who undergo TH within 6 hours of life demonstrate improved survival and reduced neurodevelopmental impairment (4). In Western Australia, there are approximately 30,000 births each year, and 30-60 infants are born annually with HIE who require TH (incidence is 1-2 per 1,000 births). Most of these infants (50 to 85%) are born in hospitals that do not provide TH and need to be transported by NETS WA to one of two tertiary centres. A large UK study reported that 50% of patients with moderate to severe HIE are born outside centers capable of providing TH (5). As the benefits of TH are greatest when treatment is initiated early (6), NETS WA begins active cooling (using ice‒gel packs) upon arrival and continues during transport. Generally, TH is achieved via one of three methods: passive cooling, active cooling with ice-gel packs, or a servo-controlled cooling blanket (7, 8). Passive cooling removes clothing and any external heat source from the infant and allows the temperature to fall without active intervention. The temperature is monitored with a continuous rectal thermometer or intermittent axillary measurements. Ice-gel packs were storedin the refrigerator, carried with the transport team on the outbound journey to the patient and kept cool in a portable insulated picnic cooler. These packs are applied to the baby’s body to induce TH. A treatment algorithm guides the number and distribution of cold packs applied, and the core temperature is continuously monitored via an indwelling rectal thermometer (9). A servo-controlled cooling blanket actively functions via a cooling/heating pump, which circulates water to regulate the temperature. A control unit constantly monitors the patient’s core temperature through skin and rectal probes and uses a temperature control algorithm at very short intervals, and the optimum water temperature is delivered to reach the desired setpoint temperature. The cooling/heating pump brings the water to the required temperature and circulates it through a wrap or blanket. TH has been reported to be most effective in moderate to severe HIE when the target temperature is reached earlier (6, 10). Accurate temperature maintenance within the desired range is necessary to avoid the adverse effects associated with lower temperatures (<33°C) (11). Reports have described the superiority of active TH in neonatal transport (8, 12-16). The impact of active TH during transport has not been assessed in terms of long-term neurodevelopmental outcomes (7). Ice-gel packs are the standard active TH method used during neonatal transport in Australia (17), and maintaining the temperature in the therapeutic range with ice-gel packs is challenging (17, 18). No prospective studies have compared active methods of TH during neonatal transport. We hypothesise that infants receiving servo-controlled TH will reach the target temperature sooner, spend more between 33 and 34°C and arrive at the TH centre with temperatures in the target range in greater proportions than infants receiving the current standard of care (ice‒gel packs). We also hypothesise that long-term neurodevelopmental outcomes will be improved by the use of servo-controlled methods compared with ice‒gel packs. Objectives {7} We aim to compare the effectiveness of two active TH methods: a battery-enabled servo-controlled TH device (Criticool Mini, Belmont Medical Technologies, MA, USA) with the current standard ice‒gel packs for providing TH during transport to newborns with HIE. Aims To determine whether battery-enabled servo-control or standard care with ice gel packs achieves the target TH temperature (33–34°C) upon arrival at the receiving or destination unit. To determine whether servo-controlled management achieves the target temperature faster than current stand care does with ice gel packs. Monitoring the duration of time spent within the target temperature range during the transport journey. To compare the number of safety events between methods of active TH during neonatal transport. To assess the long-term impact of active TH in transport and compare differences among methods via 2-year Bayley IV developmental assessment. Trial design {8} Single-centre (service) randomised controlled superiority trials of TH management with a battery-enabled servo-controlled system (Criticool Mini, Belmont Medical Technologies MA, USA) or ice‒gel packs (standard care) during neonatal transport of infants with HIE. The null hypothesis is that there is no difference between modalities of active TH in the described outcomes below. Methods: Participants, interventions and outcomes Study setting {9} The study will be conducted in Western Australia (WA) during the transportation of infants by the Newborn Emergency Transport Service of WA (NETS WA). The newborn emergency transport infrastructure in Western Australia has been described previously (19). Eligibility criteria {10} The eligibility criteria for the study will follow the institutional criteria for TH in the Child and Adolescent Health Service based at King Edward Memorial and Perth Children’s Hospital in Perth Western Australia (20). In short, infants born at > 35 weeks gestation with moderate or severe HIE who are referred to NETS WA for transport for TH will be eligible for screening. Inclusion criteria i. Moderate to severe HIE was defined according to institutional guidelines. ii. Require transport for TH iii. Informed parental consent. Evidence of asphyxia was defined as the presence of at least two of the following four criteria (20): 1. Any acute perinatal event that may result in HIE (e.g., abruption of the placenta, cord prolapse, severe fetal heart rate abnormality). 2. Patients with an Apgar score < 6 at 10 minutes or who continued to need resuscitation with positive pressure ventilation +/- chest compressions at 10 minutes of age. 3. A pH < 7.0 or a base deficit of 12 or more was used. 4. If cord pH is not available, pH 12 mmol/L should be used within 60 minutes of birth on postnatal blood gas. Moderate or severe encephalopathy was defined by at least one of the following 3 criteria: 1. ≥3 criteria in the moderate/severe category on the basis of the modified Sarnat classification (21) (see Table 1 below). 2. Seizures 3. Abnormal aEEG (Hellström‒Westas classification (22); discontinuous normal voltage, burst suppression, low voltage, flat trace seizures). Table 1. Clinical features of moderate to severe (stages 2 to 3) HIE based on the Sarnat Classification (21) Exclusion criteria 1. Major congenital abnormalities that require urgent surgery in the first 72 hours of life 2. Gastrointestinal abnormality in which a rectal probe cannot be inserted 3. Active bleeding and coagulopathy, which TH is likely to exacerbate 4. Infants who appear moribund and whose treatment is likely futile 5. Refusal of consent Who will provide informed consent? {26a} Consent is obtained in a two-stage process. The parent(s) of infants who meet the criteria will be approached by the trial-trained NETS team (doctor or nurse), who will explain the proposed management and introduce the CoolCot study. At the start of the transfer process, when the transport team arrives at the referring hospital, parent(s) will receive a description of the study and will be given an explanatory leaflet. They will be asked to provide verbal consent. Following this, the study team will use a REDcap randomisation module to assign the therapeutic group. If parents decline to give consent, the baby will receive standard care, with an ice‒gel pack delivering TH. Following admission and within 72 hours of life, parents will be given the detailed Participant Information and Consent Form (PICF) before being asked for written consent. Additional consent provisions for the collection and use of participant data and biological specimens {26b} Not applicable – There are no current plans to use data for ancillary studies, although the data will be stored and may be used for separate studies in the future. Interventions Explanation for the choice of comparators {6b} Active cooling using ice-gel (current standard care) . This is the standard of care for neonatal transport teams across Australia (and other parts of the world). It is inexpensive and easy to use and requires very little additional equipment. One study reported that it is inferior in providing target thermoregulation, but there was no difference in long-term neurodevelopmental outcomes compared with servo-controlled devices in the NICU (23). It is embedded as a standard of care, and staff are very accustomed to its practice. Active cooling using a battery-enabled servo-controlled device (Criticool Mini, Belmont Medical Technologies, MA, USA). Devices similar to this have provided proven, safe and effective TH to infants with HIE who are inpatients in the NICU and during transport (24). This device was chosen owing to the portable (battery) power supply. Most servo-controlled devices are connected to a ‘mains’ supply by the bedside and in the vehicle during neonatal transport. A ‘mains’ power supply is unavailable during transit between these settings. The Criticool Mini is battery-enabled and allows maintenance of the cold chain throughout transport. The infant will receive active TH from initiating the device until arriving at the receiving TH centre. The only other prospective RCT of TH in transport used a device that would only operate if connected to ‘mains’ power (25). Our study is the first to investigate continuous, uninterrupted TH throughout the transport process. Intervention description {11a} The NETS team will be dispatched with the capacity to provide both active methods: standard ice‒gel packs and servo-controlled TH. The decision to commence TH will be made before the arrival of the transport team. Before the arrival of NETS, the referring team is advised to commence passive TH. This is performed by undressing the infant on a radiant warmer switched off (e.g., GE Panda™️ Warmer) and undressing to the nappy (23). The infant will then have 15-minute axillary temperatures to monitor before the transport team’s arrival. The treating team cannot be blinded to the study intervention. Following consent and group allocation (randomisation), the intervention will be applied from arrival at the referring healthcare facility until admission to the NICU at one of the tertiary TH centres in Perth, the state capital of Western Australia. All infants in the study will be transported in a portable incubator and neonatal transport system (Mansell, Toowoomba, QLD) with a mounted Criticool mini (Belmont Technologies MA, USA), as shown in Figure 1. 1. Ice-gel packs (current standard care) The transport incubator was switched off, and the infants were placed inside for transport. Ice gel packs are applied to the infant depending on the recorded internal temperature (rectal temperature probe) per the institutional treatment algorithm (9) (Table 2). They are placed into cotton bags to avoid direct contact with the skin and to avoid adverse reactions, e.g., cold burns. The infant’s temperature will be monitored continuously via an in-dwelling rectal thermometer read every 15 minutes via the Criticool mini set to standby mode (no thermoregulation provided). This allows continuous temperature data to be recorded via the internal Criticool recording system (Clinilogger, Belmont Medical Technologies, MA, USA). If the rectal temperature falls < 33.0°C, the transport incubator warmer (on manual) is switched on and gradually adjusted to maintain the rectal temperature at 33.0–34.0°C. The incubator heater was turned off once the temperature reached 33.5°C. The infant will receive this method of TH until admission to the receiving unit, and the final admission temperature will be recorded. Table 2. Ice gel pack treatment algorithm for active TH based on institutional guidelines (9) Temperature algorithm (Celsius) Number of cool packs to be applied Areas to apply >37.0 4 Head, shoulders, neck, trunk 36.1 – 37.0 3 Shoulders, neck, trunk 35.1 – 36.0 2 Shoulders, neck 34.1 – 36.0 1 Shoulders, trunk 33.0 – 34.0 0 Nil 2. Battery-enabled servo-controlled mattress The infants will be placed in the switched-off transport incubator, and their temperature will be managed via a battery-enabled servo-controlled Criticool mini and infant wrap (Curewrap, Belmont Medical Technologies, MA, USA; Figure 2). The device uses a rectal and skin thermometer, which is read by the neonatal transport staff every 15 minutes. It weighs 11 kg and has a 60-minute battery life if disconnected from the ‘mains’ supply. The temperature was set at 33.5°C in the targeted temperature management mode on the device. The infant will be wrapped in infant wrap (Curewrap, Belmont Medical Technologies, MA, USA), a single-use, one-piece, body-shaped, flexible garment that is easy to wrap around and secure for the patient. A pressure relief algorithm periodically drains the water from the wrap for slight repositioning of the infant. Specially designed channels within the garment distribute pressure. The infant will receive this method of TH until admission to the receiving unit, and the final admission temperature will be recorded. Criteria for discontinuing or modifying allocated interventions {11b} Discontinuation of the allocated intervention will only occur in circumstances where there is catastrophic failure of the battery-enabled servo control system, if there is risk of extreme harm to the infant using the intervention, or if ice‒gel packs completely thaw. As clinical care may be compromised in this situation, an alternate TH method will be used instead. Nonadherence to the study protocol will be declared and described in any published manuscript of results, and analysis will be by intention to treat. Strategies to improve adherence to interventions {11c} Intervention packs have been created as ‘grab bags’. These will include patient recruitment materials, consent forms, temperature probes, infant wrap (Curewrap, Belmont Medical Technologies, MA, USA) and action cards for a step-by-step guide for TH via both methods and data collection. The battery-enabled servo-controlled device is mounted on a transport system and is taken on each transport for HIE. Staff training is recurrent and cyclical, and recruitment remains a regular educational focus. Staff are regularly trained on the use of the device. Relevant concomitant care permitted or prohibited during the trial {11d} Passive cooling and supportive care can be utilised before the transport team arrives. Active cooling prior to NETS WA’s arrival and any additional cooling methods beyond the designated intervention are not allowed during this trial. Provisions for post-trial care {30} All participants will receive standard institutional care for HIE following transport by NETS. Acute care includes 72 hours of TH, 12 hours of rewarming, and all necessary supportive care. As part of routine management, all infants will receive an MRI scan on day 5 of life. The same standard post-discharge follow-up included developmental assessments at 4, 8, and 12 months and a BSID-IV at 2 years. The latter will be the study's secondary outcome. Outcomes {12} The outcomes will be reported as primary (immediate arrival) or secondary (short-term: transport, safety, inpatient; long-term: 2-year developmental assessment). They will be stratified by means of transport: road versus air transport. Primary outcome: The proportion of infants whose temperature was within the target thermal range (33– 34°C) upon admission to the receiving NICU. Secondary outcomes: Short-term a) The proportion of time spent in the target thermal range b) The length of time taken to reach the target thermal range c) The highest and lowest recorded temperatures of the baby during transport d) Comparison of MRI brain findings on days 5-10 (routine care) Safety assessments Adverse events from active TH methods during transport will be recorded. The risks of using the Criticool mini and infant wrap (Curewrap, Belmont Medical Technologies, MA, USA ) devices are associated with the cooling process and may involve the presence of ice packs. These risks include skin complications (fat necrosis), increased bleeding, and discomfort. Long-term Comparison of 2-year cognitive and motor scores based on the BSID-IV assessment performed at the 2-year follow-up (part of routine care). Participant timeline {13} Sample size {14} Based on local data from 2018-2022 of the 130 infants who met the criteria and were transported for cooling by NETS WA, 64 (49.2%) arrived at temperatures outside the desired range. To detect a reduction from 50% (in the control arm) to 10% (in the intervention arm), with over 85% power and a 0.05 alpha, 23 participants would be required in each arm (based on a test of two independent proportions); 26 participants would be recruited per arm to accommodate up to 10% data loss. Recruitment should occur within 12 to 18 months at current operating rates. Recruitment {15} All suspected cases of HIE in Western Australia (born outside the sole tertiary perinatal centre) are referred through NETS WA for TH assessment and transferred to Perth Children’s Hospital. Both written and verbal information is provided, and consent is obtained verbally at the reference site. Written consent will be confirmed within 72 hours of arrival at the tertiary TH centre. This phased two-step approach has previously been used in clinical research within NETS WA (27), and similar processes in neonatal clinical trials have been reported successfully(). Assignment of interventions and allocation Sequence generation {16a} The infants will be randomly assigned to a battery-enabled, servo-controlled system (intervention arm) or standard care (ice-gel pack or control arm) at a 1:1 ratio, according to a computer-generated, block-randomised sequence produced by the Redcap randomisation module(29). The randomised block sizes range from 4--6. Multiple births will be randomised as individuals since they are transferred independently. Concealment mechanism {16b} It is not possible to conceal the intervention from the treating team. The interventions use different external equipment. To minimise bias, the team will travel with the capacity to provide THs via both active methods. Randomisation occurs after the transport team arrives. Deidentified data will only be extracted from the database for analysis by the study team and biostatistician. Implementation {16c} One of five authorised and trial-trained neonatal transport consultants will allocate and randomise infants through the Redcap randomisation module. The study team can access only deidentified data. Data reidentification is only possible for a tiny group of authorised team members and would only be necessary for rare safety, risk, or open disclosure purposes. Description of allocation, interventions and assessments are described in the Spirit diagram (Figure 3). Assignment of interventions: Blinding Who will be blinded {17a} No blinding of the intervention will occur to the treating clinical team. Blinding is not possible owing to the physical nature of the intervention. The statistician conducting the analysis will be blinded to the group allocations. Procedure for unblinding if needed {17b} No blinding of the intervention will occur. Data collection and management Plans for assessment and collection of outcomes {18a} At the end of each transport of every infant in WA, a REDcap form is used to collect a standard set of transport data. In addition to this standard form, a trial case report will be completed simultaneously. Data will be collected from the electronic transport database, patient medical records, and trial database. Copies of consent forms and case report forms will be saved in a dedicated password-protected trial file on a secure government server in Western Australia. Plans to promote participant retention and complete follow-up {18b} The participants will remain within the health service for two years for follow-up as standard care. This includes routine appointments with a neonatologist at 4, 8, and 12 months of age and correspondence to promote regular communication. The infants will be reviewed for formal developmental assessments at 2 years. Data management {19} A study database will be established on the WA Health Instance of REDCap. This database is password-protected and accessible from a WA Health-registered iPad, tablet, computer, or laptop. Study-approved members of the NETS Team will have access to the database. Data can be entered directly into the REDCap database for the duration of transport. Data collection Demographic, outcome, and other trial data will be collected via a mixed method. The transport service routinely gathers all required baseline, treatment, and observational data through a standard REDcap data entry form. An individualised REDCap data collection form captures specific trial data, including aspects related to HIE diagnosis (maternal, delivery, and infant), detailed TH information (passive and active), and temperature data, encompassing the primary and secondary outcome components. Continuous temperature data are recorded via skin and rectal probes and stored by the Clinilogger (Belmont Medical Technologies, v1.6.3, MA, USA) module attached to the servo-controlled device via the Criticool mini. The clinilogger is removed from the Criticool mini, and data are extracted once the cot has returned to the base and the patient has been handed over. The continuous data are extracted as a CSV file. Baseline data from standard transport collection will be ‘cross-piped’ with trial data to form a composite trial database. Clinical staff transporting trial infants will enter the data, which the NETS transport research nurse will check to ensure quality and consistency. Information from (days 5–10) MRI will be scored via a current best practice scoring system, e.g., Weeke (30), Barkovitch (31), or other future published scoring systems. Neurodevelopmental impairment will be assessed via the BSID IV at a 2-year appointment. Severe NDI will be defined by a BSID-IV cognitive score below 70 at age 2. Severity will be assigned using the worst cognitive or motor outcome. The BSID-IV cognitive outcome is defined as normal (≥90), mild (85-89), or moderate (70-84) (32). Data security and confidentiality Data in the REDCap database contain patient identifiers. REDCap automatically assigns a study ID number. Only deidentified data will be extracted from the REDCap database for analysis by the study team and biostatistician. Reidentification is only possible by study team members with authorised access to the REDCap database. Any hard copies of source documents will be filed in a locked cabinet. The study team and study biostatistician will perform the data analysis and reporting. The data will be archived and stored for 25 years at the end of the trial, as detailed in the Western Australian Sector Disposal Authority, Section 12.4.4. 8 Data will be destroyed per the CAHS policy, documented and listed with the disposal authority to retain and dispose of research records. Physical files are shredded and disposed of in confidential waste. At the end of the archive period, the digital records will be erased. The study team collecting data will consist of individuals, including associate investigators, the project nurse, the medical team, and assigned medical students. During regular study meetings, the project coordinator will oversee the data collection and source documents. Once a month, the project coordinator will verify the information gathered in the study database and address any missing data or errors in data entry. Confidentiality {27} The data in the REDCap database contain patient identifiers. REDCap automatically assigns a study ID number. Only deidentified data will be extracted from the REDCap database for analysis by the study team and biostatistician. Reidentification is only possible by study team members with authorised access to the REDCap database. Any hard copies of source documents will be filed in a locked cabinet. The study team and study biostatistician will perform the data analysis and reporting. Disposal Authority, Section 12.4.4. 8 Data will be destroyed in accordance with the CAHS policy, documented and listed with the disposal authority to retain and dispose of research records. Physical files are shredded and disposed of in confidential waste. The digital records will be erased. The study team collecting data will consist of team members, including associate investigators, project nurses, and the medical team. During regular study meetings, the project coordinator will oversee the data collection and source documents. Once a month, the project coordinator will verify the information collected in the study database and check for any missing data or errors in data entry. All the data are stored on the WA Health REDCap system and are accessible only to the study team under WA Health security access protocols. No identifiable data will be used in the analysis or reporting of outcomes. No participant will be identified in any form of reporting or analysis. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable, no biological specimens were collected as part of this trial Statistical methods Statistical methods for primary and secondary outcomes {20a} Descriptive statistics will be reported by group, including counts (and percentages) for dichotomous and categorical data and either medians (and interquartile ranges) or means (and standard deviations) for continuous data. The primary outcome will be analysed via logistic regression, where the odds ratio (OR) and 95% confidence interval for the group effect (intervention group relative to the control group) will be reported, alongside the proportion of infants whose temperature is in the range of each group. An unadjusted OR will be reported, in addition to an adjusted OR from a model that includes adjustment for potential confounders, including gestational age (weeks), birth weight, duration of transfer (hours), temperature prior to transfer, and month of year. Analysis of secondary and additional outcomes, where dichotomous, will follow the same framework as outlined above. Continuous outcomes (for example, the length of time taken to reach the target thermal range) will be analysed via linear regression (assuming that model assumptions are met), where the unadjusted and adjusted (based on the potential confounders listed above) between-group mean differences (and 95% confidence intervals) will be reported. Interim analyses {21b} Data will be accessible only to the study team in accordance with WA health security access protocols. Interim analysis of the primary outcome and adverse events will conducted for the data monitoring and safety committee at 26 recruits (50%). The study will only be terminated if there is substantial, consistent, and identifiable life or limb-threatening harm to the infant as a direct result of the use of the battery-enabled servo-controlled cooling system. This decision may be communicated by the CAHS Human Research Ethics Committee at any point during the study or by the coordinating principal investigator. Methods for additional analyses (e.g., subgroup analyses) {20b} Assuming that sufficient data within each group are available, both primary and secondary outcomes will be analysed stratified by mode of transport (air or land-based transport). Further exploratory analysis may look to understand the impact of ‘mission critical events’, related to transport or required emergency interventions that directly impact TH, on study outcomes. However, it is acknowledged that the study is not powered for these events. Methods in analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c} The primary analysis will be based on an intention-to-treat population of all randomised infants. Imputation (via multiple-chained equations) for missing data will be considered and carried out if missing data are problematic and if the method assumptions are satisfactorily met; otherwise, complete case analysis will be utilised. Plans to give access to the full protocol, participant-level data and statistical code {31c} The entire protocol will be shared for publication. Participant-level data and statistical code will not be shared. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} The trial is coordinated by the Newborn Emergency Transport Service Western Australia (NETS WA), which is part of the neonatology division of the Child and Adolescent Health Service (CAHS; WA Health) and is based at Perth Children’s Hospital in Perth, the state capital of WA. The trial steering committee, which includes the CPI, PI, AI, senior medical and nursing staff, and a dedicated trial nurse, meets monthly. The trial is discussed weekly with the operational team, and feedback is obtained from the CPI and trial nurse. Composition of the data monitoring committee, its role and reporting structure {21a} The data safety and monitoring committee is external and independent of the trial team and includes neonatal experts in TH and HIE and an independent statistician. The committee is made up of three individuals. The DSMC meets six months and prepares a report for the CPI. The CPI provides 12 monthly submissions to the Human Research Ethics Committee of the Child and Adolescent Health Service and reports on the safety of the device, ethics of recruitment, and results. Adverse event reporting and harms {22} Safety reporting from the CoolCot Trial will adhere to standards from the 2016 recommendations of the National Health and Medical Research Council (NHMRC), Australia (33). Any potential or realised adverse events will be documented in REDCap. Newborns in neonatal intensive care are at a greater risk of clinical incidents than are patients in other areas. Any adverse event (AE) identified while the infant is an inpatient will be recorded accordingly in the trial documentation. In infants receiving intensive care, several AEs may occur that are not ultimately related to the trial intervention. This study will maintain a low threshold for reporting and documenting AEs, and the responsibility for identification will rest with the CPI and PIs in conjunction with the treating NICU team. Frequency and plans for auditing trial conduct {23} The trial will be reviewed every six months in conjunction with the DMSC review. The consent procedure, data entry, and temperature management processes will be reviewed specifically to ensure consistency and quality. Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} A single service conducts the trial. Protocol changes will be a last resort and avoided as much as possible. If necessary, they will be amended and approved through the Child and Adolescent Human Ethics Amendment process. The team will be informed of these changes through regular education communication and sessions. The trial registry will be updated. Dissemination plans {31a} We intend to publish the protocol and project results in a peer-reviewed journal. We hope that selected data will be submitted and presented nationally and internationally at appropriate scientific meetings through the neonatal network in Western Australia and, more widely, through the Perinatal Society of Australia and New Zealand. Importantly, we will share through regular updates of consumer groups that were consulted to support the funding and ethics applications. Acquittal reports and outcomes will be prepared for the funding organisation, the Perth Children’s Hospital Foundation, and associated partners. Discussion TH has been established as an effective treatment for moderate to severe HIE (24). Many infants are born in hospitals without neonatal intensive care or access to TH; the neonatal transport team plays a key role in establishing and maintaining TH during transfer to larger treatment centres (34). Rapid access to active TH is necessary to reach the target temperature and improve outcomes (35). Methods of active TH have not been prospectively compared, nor has the long-term impact of TH during neonatal transport (7). The trial is powered to detect differences in arrival temperature, demonstrating the direct efficacy of servo-controlled methods. This study will address gaps in the evidence concerning active methods of thermoregulation in infants with HIE who require neonatal transport. The trial is embedded in clinical practice and pragmatic in its design, simplifying the approach to patient care and the intervention. An important secondary outcome is longer-term development, assessed by the BSID-IV. Assessment of surviving infants at 2 years of age will provide evidence of the long-term efficacy and safety of active TH in transport. Owing to the complexity of the clinical environment, randomised controlled trials in neonatal emergency transport are rarely conducted. In approximately 50% of cases, infants with HIE are not born in centres equipped to provide necessary TH(5). This study aims to demonstrate the feasibility of such acute care trials in this setting and address a treatment gap for infants in these circumstances. Data from this trial should inform other trials both nationally and internationally. Trial status This published protocol is Version 4.1 as of 7 th June 2025. Recruitment began on 1st July 2023 and is ongoing; it is expected to be complete by 30 th June 2027. Abbreviations HIE Hypoxic ischaemic encephalopathy TH Therapeutic Hypothermia PCH Perth Children’s Hospital NETS WA Newborn Emergency Transport Service NICU Neonatal intensive care unit TGA Therapeutic Goods Administration CAHS Child and Adolescent Health Service BSID IV–Bayley Scales of Infant and Toddler Development, 4th Edition PICF Participant Information and Consent Form Declarations Acknowledgements We would like to thank the parents of the infants enrolled in this trial. We appreciate the trust you place in NETS WA. The authors wish to acknowledge the hard work and dedication of the nurses and doctors from the Newborn Emergency Transport Service Western Australia for their commitment to identifying and consenting patients and collecting the data. The authors also wish to thank Ms. Jennifer Mountain for her support in preparing the manuscript and for helping to bring the project to life. Authors’ contributions {31b} JD, the chief investigator, conceived the study, led the proposal and protocol development, partially wrote, and approved the final manuscript. AH and KH wrote and developed the protocol and supervised SL and FT in the protocol manuscript. AH and KH submitted the protocol for ethics and governance with the support of JM. VB, JG, SD, AW, AT, and KM are members of the trial steering committee and provided input on developing the protocol and the important practical aspects of the trial and its execution. TW was the trial nurse and supervised data collection and quality control. MC is the trial statistician and is advised on all aspects of data collection, randomisation, group allocation, and analysis. Funding {4} The Perth Children’s Foundation generously provided funds to conduct the trial, including support for staffing and publication. They had no role in the design, collection, analysis, interpretation or writing of the manuscript. Availability of data and materials {29} The CPI and trial statisticians will have access to the completed trial database. There are no contractual agreements in place. The complete deidentified CoolCot trial database will be available 6 months after the publication of the primary outcome. The study protocol and documentation have been submitted for publication in a journal. An application to obtain data may be made to the CPI ( [email protected] ). The final decision to share data will be made by the trial steering committee. Ethics approval and consent to participate {24} The Human Ethics Research Committee of the Child and Adolescent Health Service, Perth Western Australia, provided granted trial approval. RGS000006472. Consent for publication {32} The CoolCot trial steering committee is willing to provide a model consent form on written request. Competing interests {28} The authors declare that they have no competing interests. Authors’ information 1 Newborn Emergency Transport Service of Western Australia, Child and Adolescent Health Service, Perth Children’s Hospital, Nedlands, Western Australia, Australia. 2 Neonatology, Child and Adolescent Health Service, King Edward and Perth Children’s Hospital, Perth, Western Australia, Australia. 3 School of Medicine, University of Western Australia, Monash Avenue, Nedlands, Western Australia. 4 The Kids Research Institute, Perth Children’s Hospital, Hospital Avenue, Nedlands, Western Australia, Australia References https://www.cahs.health.wa.gov.au/~/media/HSPs/CAHS/Documents/Health-Professionals/NETS/Hypoxic-Ischaemic-Encephalopathy-HIE-Asphyxia.pdf. 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03:19:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6407483/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6407483/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-09111-2","type":"published","date":"2025-09-29T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87214734,"identity":"5203353b-eef6-4481-a8eb-77a2aebeec62","added_by":"auto","created_at":"2025-07-21 15:16:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222234,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eCriticool mini-mounted as part of a neonatal transport system.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6407483/v1/c76340e2409297c516c03319.png"},{"id":87213829,"identity":"30bf33d1-c3bb-45c8-a305-86bf39333437","added_by":"auto","created_at":"2025-07-21 15:08:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":191908,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eThe battery servo-controlled device used was a Criticool Mini and Infant wrap (Infant wrap, Belmont Medical \u003c/em\u003eTechnologies\u003cem\u003e, MA, USA). The infant in the photo is from Belmont Medical Technologie promotional material.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6407483/v1/d1d8c0ade47d776e3b4fb0e6.png"},{"id":87213837,"identity":"89158a92-016e-4c79-b7da-de14c4fabcdd","added_by":"auto","created_at":"2025-07-21 15:08:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":93236,"visible":true,"origin":"","legend":"\u003cp\u003eThe schedule of enrolment, interventions, and assessments: Patient timeline from birth to 2 years of age, including enrolment, interventions, assessments, and data collection. X indicates discrete events, and arrows represent continuous processes. Modified from On the Spirit 2013 (diagram) (26).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6407483/v1/eede494118e33c0f4f55b70b.png"},{"id":92884408,"identity":"ff42a1bc-2336-4af3-bc90-18c23398191d","added_by":"auto","created_at":"2025-10-06 16:12:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2144060,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6407483/v1/b4269314-c2a2-4bc6-a3fa-ac75924df19f.pdf"},{"id":87213831,"identity":"8abf3cc6-3534-4084-b439-d22d9dab727e","added_by":"auto","created_at":"2025-07-21 15:08:49","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":30206,"visible":true,"origin":"","legend":"","description":"","filename":"completedSPIRITchecklistheathcoteetal.docx","url":"https://assets-eu.researchsquare.com/files/rs-6407483/v1/2af1bdbe1787691ae97665b6.docx"},{"id":87213908,"identity":"ca95a0fb-9602-4809-9576-68a41fc95a16","added_by":"auto","created_at":"2025-07-21 15:08:51","extension":"eml","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":97482,"visible":true,"origin":"","legend":"","description":"","filename":"FWYourACTRNregistrationnumber.eml","url":"https://assets-eu.researchsquare.com/files/rs-6407483/v1/91af5818b75f6c82a0d86641.eml"}],"financialInterests":"","formattedTitle":"\u003cp\u003eCoolCot Study: Active methods of therapeutic hypothermia for newborns with hypoxic ischaemic encephalopathy (HIE) during neonatal transport: a study protocol for a randomised controlled trial comparing battery enabled servo-controlled cooling blankets and ice-gel pack methods\u003c/p\u003e","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (1).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eCOOLCOT Study: Active methods of therapeutic hypothermia for newborns with hypoxic ischaemic encephalopathy (HIE) during neonatal transport: a study protocol for a randomised controlled trial comparing battery servo-controlled cooling blankets and ice-gel pack methods.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eWHO ICTRP Registry/Australian New Zealand Clinical Trials Registry: ACTRN12623001298606p. Date or registration \u0026ndash; 13 Dec 202\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eProtocol version 4.1, June 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eFunding provided to cover consumables for the study, statistical support, publication of protocol, dissemination of results, personnel FTE to coordinate the running of the trial.\u003c/p\u003e\n \u003cp\u003eFunding provided by the Perth Children\u0026rsquo;s Hospital Foundation (PCHF). Indemnity and insurance provided by Child and Adolescent Health Service (CAHS) governance.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eDr Adam Heathcote\u003csup\u003e1,2\u003c/sup\u003e, Dr Kate Hooper\u003csup\u003e1,2\u003c/sup\u003e, Sebastian Lee\u003csup\u003e2\u003c/sup\u003e, Fan Tang\u003csup\u003e2\u003c/sup\u003e, Dr Matt Cooper\u003csup\u003e4\u003c/sup\u003e, Dr Vamsi Batta\u003csup\u003e1,2\u003c/sup\u003e, Dr Saumil Desai\u003csup\u003e1,2,3\u003c/sup\u003e, Dr Jacqueline Gardiner \u003csup\u003e1,2\u003c/sup\u003e, Alex Wilson\u003csup\u003e1,2,3\u003c/sup\u003e Tess Watson\u003csup\u003e1,2\u003c/sup\u003e, Kylie McDonald\u003csup\u003e1,2\u003c/sup\u003e Alysha Timoney\u003csup\u003e2\u003c/sup\u003e, Dr Jonathan Davis\u003csup\u003e1,2,3,4\u003c/sup\u003e\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003eNewborn Emergency Transport Service of Western Australia, Perth\u003c/li\u003e\n \u003cli\u003eNeonatology, Child and Adolescent Health Service, Perth, Western Australia\u003c/li\u003e\n \u003cli\u003eSchool of Medicine, University of Western Australia, Monash Avenue, Nedlands, Western Australia, Australia.\u003c/li\u003e\n \u003cli\u003eThe Kids Research Institute Australia, Perth, Western Australia, Australia.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eA/Prof Jonathan Davis, Newborn Emergency Transport Service, Perth Children\u0026apos;s Hospital, 15 Hospital Avenue, Nedlands WA 6009 Australia, +61 0864565392, [email protected]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eThe trial Sponsor is responsible for the initiation, management and controlling the financing of the trial and carries the medicolegal responsibility associated with its conduct\u003c/p\u003e\n \u003cp\u003eThe Sponsor is also responsible for ensuring that appropriate approvals are obtained prior to the commencement of the clinical trial, that conditions of any approvals are adhered to during the course of the clinical trial and ensuring that the ethics principles of research merit and integrity, justice, beneficence and respect are applied to the conduct of clinical trials. The Sponsor also ensures that the trial is appropriately monitored for compliance with the protocol\u003c/p\u003e\n \u003cp\u003eThe Trial Steering Committee, chaired by JD, is responsible for the study design, management and analysis of data, and decision to\u0026nbsp;publish the results.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Background and rationale {6a}","content":"\u003cp\u003eHypoxic ischemic encephalopathy (HIE) results from a lack of cerebral blood flow or oxygen delivery around the time of birth. It is a leading cause of death and neurodevelopmental impairment in term and near-term infants (2). Therapeutic hypothermia (TH) is the only proven treatment for moderate to severe HIE (3). TH involves whole-body cooling to a target temperature of 33–34°C for 72 hours, followed by 12 hours of rewarming. Infants with moderate to severe HIE who undergo TH within 6 hours of life demonstrate improved survival and reduced neurodevelopmental impairment (4).\u003c/p\u003e\n\u003cp\u003eIn Western Australia, there are approximately 30,000 births each year, and 30-60 infants are born annually with HIE who require TH (incidence is 1-2 per 1,000 births). Most of these infants (50 to 85%) are born in hospitals that do not provide TH and need to be transported by NETS WA to one of two tertiary centres. A large UK study reported that 50% of patients with moderate to severe HIE are born outside centers capable of providing TH (5). As the benefits of TH are greatest when treatment is initiated early (6), NETS WA begins active cooling (using ice‒gel packs) upon arrival and continues during transport.\u003c/p\u003e\n\u003cp\u003eGenerally, TH is achieved via one of three methods: passive cooling, active cooling with ice-gel packs, or a servo-controlled cooling blanket (7, 8). \u003cem\u003ePassive cooling\u003c/em\u003e removes clothing and any external heat source from the infant and allows the temperature to fall without active intervention. The temperature is monitored with a continuous rectal thermometer or intermittent axillary measurements.\u0026nbsp;\u003cem\u003eIce-gel packs were\u0026nbsp;\u003c/em\u003estoredin the refrigerator, carried with the transport team on the outbound journey to the patient and kept cool\u0026nbsp;in a portable insulated picnic cooler. These packs are applied to the baby’s body to induce TH. A treatment algorithm guides the number and distribution of cold packs applied, and the core temperature is continuously monitored via an indwelling rectal thermometer\u0026nbsp;(9). \u003cem\u003eA servo-controlled cooling blanket\u003c/em\u003e actively functions via a cooling/heating pump, which circulates water to regulate the temperature. A control unit constantly monitors the patient’s core temperature through skin and rectal probes and uses a temperature control algorithm at very short intervals, and the optimum water temperature is delivered to reach the desired setpoint temperature. The cooling/heating pump brings the water to the required temperature and circulates it through a wrap or blanket.\u003c/p\u003e\n\u003cp\u003eTH has been reported to be most effective in moderate to severe HIE when the target temperature is reached earlier (6, 10). Accurate temperature maintenance within the desired range is necessary to avoid the adverse effects associated with lower temperatures (\u0026lt;33°C) (11). Reports have described the superiority of active TH in neonatal transport (8, 12-16). The impact of active TH during transport has not been assessed in terms of long-term neurodevelopmental outcomes (7). Ice-gel packs are the standard active TH method used during neonatal transport in Australia (17), and maintaining the temperature in the therapeutic range with ice-gel packs is challenging (17, 18). No prospective studies have compared active methods of TH during neonatal transport. We hypothesise that infants receiving servo-controlled TH will reach the target temperature sooner, spend more between 33 and 34°C and arrive at the TH centre with temperatures in the target range in greater proportions than infants receiving the current standard of care (ice‒gel packs). We also hypothesise that long-term neurodevelopmental outcomes will be improved by the use of servo-controlled methods compared with ice‒gel packs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe aim to compare the effectiveness of two active TH methods: a battery-enabled servo-controlled TH device (Criticool Mini, Belmont Medical Technologies, MA, USA) with the current standard ice‒gel packs for providing TH during transport to newborns with HIE.\u003c/p\u003e\n\u003cp\u003eAims\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eTo determine whether battery-enabled servo-control or standard care with ice gel packs achieves the target TH temperature (33–34°C) upon arrival at the receiving or destination unit.\u003c/li\u003e\n \u003cli\u003eTo determine whether servo-controlled management achieves the target temperature faster than current stand care does with ice gel packs.\u003c/li\u003e\n \u003cli\u003eMonitoring the duration of time spent within the target temperature range during the transport journey.\u003c/li\u003e\n \u003cli\u003eTo compare the number of safety events between methods of active TH during neonatal transport.\u003c/li\u003e\n \u003cli\u003eTo assess the long-term impact of active TH in transport and compare differences among methods via 2-year Bayley IV developmental assessment.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSingle-centre (service) randomised controlled superiority trials of TH management with a battery-enabled servo-controlled system (Criticool Mini, Belmont Medical Technologies MA, USA) or ice‒gel packs (standard care) during neonatal transport of infants with HIE. The null hypothesis is that there is no difference between modalities of active TH in the described outcomes below.\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The study will be conducted in Western Australia (WA) during the transportation of infants by the Newborn Emergency Transport Service of WA (NETS WA). The newborn emergency transport infrastructure in Western Australia has been described previously (19).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe eligibility criteria for the study will follow the institutional criteria for TH in the Child and Adolescent Health Service based at King Edward Memorial and Perth Children\u0026rsquo;s Hospital in Perth Western Australia (20). In short, infants born at \u0026gt; 35 weeks gestation with moderate or severe HIE who are referred to NETS WA for transport for TH will be eligible for screening.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ei.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Moderate to severe HIE was defined according to institutional guidelines.\u003c/p\u003e\n\u003cp\u003eii.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Require transport for TH\u003c/p\u003e\n\u003cp\u003eiii.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Informed parental consent.\u003c/p\u003e\n\u003cp\u003eEvidence of asphyxia was defined as the presence of at least two of the following four criteria (20):\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Any acute perinatal event that may result in HIE (e.g., abruption of the placenta, cord prolapse, severe fetal heart rate abnormality).\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Patients with an Apgar score \u0026lt; 6 at 10 minutes or who continued to need resuscitation with positive pressure ventilation +/- chest compressions at 10 minutes of age.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;A pH \u0026lt; 7.0 or a base deficit of 12 or more was used.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;If cord pH is not available, pH \u0026lt; 7.0 or BE \u0026gt; 12 mmol/L should be used within 60 minutes of birth on postnatal blood gas.\u003c/p\u003e\n\u003cp\u003eModerate or severe encephalopathy was defined by at least one of the following 3 criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;\u0026ge;3 criteria in the moderate/severe category on the basis of the modified Sarnat classification (21) (see Table 1 below).\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; Seizures\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; Abnormal aEEG (Hellstr\u0026ouml;m‒Westas classification (22); discontinuous normal voltage, burst suppression, low voltage, flat trace seizures).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 1. Clinical features of moderate to severe (stages 2 to 3) HIE based on the Sarnat Classification\u0026nbsp;\u003c/em\u003e\u003cem\u003e(21)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cimg src=\"https://myfiles.space/user_files/95224_ce634422aaf2e7a6/95224_custom_files/img1752650560.png\"\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Major congenital abnormalities that require urgent surgery in the first 72 hours of life\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Gastrointestinal abnormality in which a rectal probe cannot be inserted\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Active bleeding and coagulopathy, which TH is likely to exacerbate\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; Infants who appear moribund and whose treatment is likely futile\u003c/p\u003e\n\u003cp\u003e5. \u0026nbsp; Refusal of consent\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will provide informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent is obtained in a two-stage process. The parent(s) of infants who meet the criteria will be approached by the trial-trained NETS team (doctor or nurse), who will explain the proposed management and introduce the CoolCot study. At the start of the transfer process, when the transport team arrives at the referring hospital, parent(s) will receive a description of the study and will be given an explanatory leaflet. They will be asked to provide verbal consent. Following this, the study team will use a REDcap randomisation module to assign the therapeutic group. If parents decline to give consent, the baby will receive standard care, with an ice‒gel pack delivering TH. Following admission and within 72 hours of life, parents will be given the detailed Participant Information and Consent Form (PICF) before being asked for written consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for the collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable \u0026ndash; There are no current plans to use data for ancillary studies, although the data will be stored and may be used for separate studies in the future.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eActive cooling using ice-gel (current standard care)\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eThis is the standard of care for neonatal transport teams across Australia (and other parts of the world).\u003c/em\u003e It is inexpensive and easy to use and requires very little additional equipment. One study reported that it is inferior in providing target thermoregulation, but there was no difference in long-term neurodevelopmental outcomes compared with servo-controlled devices in the NICU (23). It is embedded as a standard of care, and staff are very accustomed to its practice.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eActive cooling using a battery-enabled servo-controlled device (Criticool Mini, Belmont Medical Technologies, MA, USA).\u003c/em\u003e Devices similar to this have provided proven, safe and effective TH to infants with HIE who are inpatients in the NICU and during transport (24). This device was chosen owing to the portable (battery) power supply. Most servo-controlled devices are connected to a \u0026lsquo;mains\u0026rsquo; supply by the bedside and in the vehicle during neonatal transport. A \u0026lsquo;mains\u0026rsquo; power supply is unavailable during transit between these settings. The Criticool Mini is battery-enabled and allows maintenance of the cold chain throughout transport. The infant will receive active TH from initiating the device until arriving at the receiving TH centre. The only other prospective RCT of TH in transport used a device that would only operate if connected to \u0026lsquo;mains\u0026rsquo; power (25). Our study is the first to investigate continuous, uninterrupted TH throughout the transport process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NETS team will be dispatched with the capacity to provide both active methods: standard ice‒gel packs and servo-controlled TH. The decision to commence TH will be made before the arrival of the transport team. Before the arrival of NETS, the referring team is advised to commence \u003cem\u003epassive TH.\u0026nbsp;\u003c/em\u003eThis is performed by undressing the infant on a radiant warmer switched off (e.g., GE Panda\u0026trade;️ Warmer) and undressing to the nappy (23). The infant will then have 15-minute axillary temperatures to monitor before the transport team\u0026rsquo;s arrival.\u003c/p\u003e\n\u003cp\u003eThe treating team cannot be blinded to the study intervention. Following consent and group allocation (randomisation), the intervention will be applied from arrival at the referring healthcare facility until admission to the NICU at one of the tertiary TH centres in Perth, the state capital of Western Australia. All infants in the study will be transported in a portable incubator and neonatal transport system (Mansell, Toowoomba, QLD) with a mounted Criticool mini (Belmont Technologies MA, USA), as shown in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1. Ice-gel packs (current standard care)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe transport incubator was switched off, and the infants were placed inside for transport. Ice gel packs are applied to the infant depending on the recorded internal temperature (rectal temperature probe) per the institutional treatment algorithm (9) (Table 2). They are placed into cotton bags to avoid direct contact with the skin and to avoid adverse reactions, e.g., cold burns. The infant\u0026rsquo;s temperature will be monitored continuously via an in-dwelling rectal thermometer read every 15 minutes via the Criticool mini set to standby mode (no thermoregulation provided). This allows continuous temperature data to be recorded via the internal Criticool recording system (Clinilogger, Belmont Medical Technologies, MA, USA). If the rectal temperature falls \u0026lt; 33.0\u0026deg;C, the transport incubator warmer (on manual) is switched on and gradually adjusted to maintain the rectal temperature at 33.0\u0026ndash;34.0\u0026deg;C. The incubator heater was turned off once the temperature reached 33.5\u0026deg;C. The infant will receive this method of TH until admission to the receiving unit, and the final admission temperature will be recorded.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 2. Ice gel pack treatment algorithm for active TH based on institutional guidelines\u0026nbsp;\u003c/em\u003e\u003cem\u003e(9)\u003c/em\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"560\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eTemperature algorithm (Celsius)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eNumber of cool packs to be applied\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAreas to apply\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026gt;37.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eHead, shoulders, neck, trunk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e36.1 \u0026ndash; 37.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eShoulders, neck, trunk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e35.1 \u0026ndash; 36.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eShoulders, neck\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e34.1 \u0026ndash; 36.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eShoulders, trunk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e33.0 \u0026ndash; 34.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eNil\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2. \u003cem\u003eBattery-enabled servo-controlled mattress\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe infants will be placed in the switched-off transport incubator, and their temperature will be managed via a battery-enabled servo-controlled Criticool mini and infant wrap (Curewrap, Belmont Medical Technologies, MA, USA; Figure 2). The device uses a rectal and skin thermometer, which is read by the neonatal transport staff every 15 minutes. It weighs 11 kg and has a 60-minute battery life if disconnected from the \u0026lsquo;mains\u0026rsquo; supply. The temperature was set at 33.5\u0026deg;C in the targeted \u003cem\u003etemperature management mode\u003c/em\u003e on the device. The infant will be wrapped in infant wrap (Curewrap, Belmont Medical Technologies, MA, USA), a single-use, one-piece, body-shaped, flexible garment that is easy to wrap around and secure for the patient. A pressure relief algorithm periodically drains the water from the wrap for slight repositioning of the infant. Specially designed channels within the garment distribute pressure. The infant will receive this method of TH until admission to the receiving unit, and the final admission temperature will be recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiscontinuation of the allocated intervention will only occur in circumstances where there is catastrophic failure of the battery-enabled servo control system, if there is risk of extreme harm to the infant using the intervention, or if ice‒gel packs completely thaw. As clinical care may be compromised in this situation, an alternate TH method will be used instead. Nonadherence to the study protocol will be declared and described in any published manuscript of results, and analysis will be by intention to treat.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntervention packs have been created as \u0026lsquo;grab bags\u0026rsquo;. These will include patient recruitment materials, consent forms, temperature probes, infant wrap (Curewrap, Belmont Medical Technologies, MA, USA) and action cards for a step-by-step guide for TH via both methods and data collection. The battery-enabled servo-controlled device is mounted on a transport system and is taken on each transport for HIE. Staff training is recurrent and cyclical, and recruitment remains a regular educational focus. Staff are regularly trained on the use of the device.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePassive cooling and supportive care can be utilised before the transport team arrives. Active cooling prior to NETS WA\u0026rsquo;s arrival and any additional cooling methods beyond the designated intervention are not allowed during this trial.\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Provisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants will receive standard institutional care for HIE following transport by NETS. Acute care includes 72 hours of TH, 12 hours of rewarming, and all necessary supportive care. As part of routine management, all infants will receive an MRI scan on day 5 of life. The same standard post-discharge follow-up included developmental assessments at 4, 8, and 12 months and a BSID-IV at 2 years. The latter will be the study\u0026apos;s secondary outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe outcomes will be reported as primary (immediate arrival) or secondary (short-term: transport, safety, inpatient; long-term: 2-year developmental assessment). They will be stratified by means of transport: road versus air transport.\u003c/p\u003e\n\u003cp\u003ePrimary outcome:\u003c/p\u003e\n\u003cp\u003eThe proportion of infants whose temperature was within the target thermal range (33\u0026ndash; 34\u0026deg;C) upon admission to the receiving NICU.\u003c/p\u003e\n\u003cp\u003eSecondary outcomes:\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eShort-term\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003ea)\u0026nbsp; \u0026nbsp;The proportion of time spent in the target thermal range\u003c/p\u003e\n\u003cp\u003eb)\u0026nbsp; \u0026nbsp;The length of time taken to reach the target thermal range\u003c/p\u003e\n\u003cp\u003ec) \u0026nbsp; The highest and lowest recorded temperatures of the baby during transport\u003c/p\u003e\n\u003cp\u003ed) \u0026nbsp; Comparison of MRI brain findings on days 5-10 (routine care)\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSafety assessments\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events from active TH methods during transport will be recorded. The risks of using the Criticool mini and infant wrap (Curewrap, Belmont Medical Technologies, MA, USA\u003cem\u003e)\u003c/em\u003e devices are associated with the cooling process and may involve the presence of ice packs. These risks include skin complications (fat necrosis), increased bleeding, and discomfort.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eLong-term\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eComparison of 2-year cognitive and motor scores based on the BSID-IV assessment performed at the 2-year follow-up (part of routine care).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on local data from 2018-2022 of the 130 infants who met the criteria and were transported for cooling by NETS WA, 64 (49.2%) arrived at temperatures outside the desired range. To detect a reduction from 50% (in the control arm) to 10% (in the intervention arm), with over 85% power and a 0.05 alpha, 23 participants would be required in each arm (based on a test of two independent proportions); 26 participants would be recruited per arm to accommodate up to 10% data loss. Recruitment should occur within 12 to 18 months at current operating rates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll suspected cases of HIE in Western Australia (born outside the sole tertiary perinatal centre) are referred through NETS WA for TH assessment and transferred to Perth Children\u0026rsquo;s Hospital. Both written and verbal information is provided, and consent is obtained verbally at the reference site. Written consent will be confirmed within 72 hours of arrival at the tertiary TH centre. This phased two-step approach has previously been used in clinical research within NETS WA (27), and similar processes in neonatal clinical trials have been reported successfully().\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions and allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe infants will be randomly assigned to a battery-enabled, servo-controlled system (intervention arm) or standard care (ice-gel pack or control arm) at a 1:1 ratio, according to a computer-generated, block-randomised sequence produced by the Redcap randomisation module(29). The randomised block sizes range from 4--6. Multiple births will be randomised as individuals since they are transferred independently.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt is not possible to conceal the intervention from the treating team. The interventions use different external equipment. To minimise bias, the team will travel with the capacity to provide THs via both active methods. Randomisation occurs after the transport team arrives. Deidentified data will only be extracted from the database for analysis by the study team and biostatistician.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne of five authorised and trial-trained neonatal transport consultants will allocate and randomise infants through the Redcap randomisation module. The study team can access only deidentified data. Data reidentification is only possible for a tiny group of authorised team members and would only be necessary for rare safety, risk, or open disclosure purposes. Description of allocation, interventions and assessments are described in the Spirit diagram (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo blinding of the intervention will occur to the treating clinical team. Blinding is not possible owing to the physical nature of the intervention. The statistician conducting the analysis will be blinded to the group allocations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo blinding of the intervention will occur.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the end of each transport of every infant in WA, a REDcap form is used to collect a standard set of transport data. In addition to this standard form, a trial case report will be completed simultaneously. Data will be collected from the electronic transport database, patient medical records, and trial database. Copies of consent forms and case report forms will be saved in a dedicated password-protected trial file on a secure government server in Western Australia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participants will remain within the health service for two years for follow-up as standard care. This includes routine appointments with a neonatologist at 4, 8, and 12 months of age and correspondence to promote regular communication. The infants will be reviewed for formal developmental assessments at 2 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA study database will be established on the WA Health Instance of REDCap. This database is password-protected and accessible from a WA Health-registered iPad, tablet, computer, or laptop. Study-approved members of the NETS Team will have access to the database. Data can be entered directly into the REDCap database for the duration of transport.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDemographic, outcome, and other trial data will be collected via a mixed method. The transport service routinely gathers all required baseline, treatment, and observational data through a standard REDcap data entry form. An individualised REDCap data collection form captures specific trial data, including aspects related to HIE diagnosis (maternal, delivery, and infant), detailed TH information (passive and active), and temperature data, encompassing the primary and secondary outcome components.\u003c/p\u003e\n\u003cp\u003eContinuous temperature data are recorded via skin and rectal probes and stored by the Clinilogger (Belmont Medical Technologies, v1.6.3, MA, USA) module attached to the servo-controlled device via the Criticool mini. The clinilogger is removed from the Criticool mini, and data are extracted once the cot has returned to the base and the patient has been handed over. The continuous data are extracted as a CSV file.\u003c/p\u003e\n\u003cp\u003eBaseline data from standard transport collection will be \u0026lsquo;cross-piped\u0026rsquo; with trial data to form a composite trial database. Clinical staff transporting trial infants will enter the data, which the NETS transport research nurse will check to ensure quality and consistency. Information from (days 5\u0026ndash;10) MRI will be scored via a current best practice scoring system, e.g., Weeke (30), Barkovitch (31), or other future published scoring systems.\u003c/p\u003e\n\u003cp\u003eNeurodevelopmental impairment will be assessed via the BSID IV at a 2-year appointment. Severe NDI will be defined by a BSID-IV cognitive score below 70 at age 2. Severity will be assigned using the worst cognitive or motor outcome. The BSID-IV cognitive outcome is defined as normal (\u0026ge;90), mild (85-89), or moderate (70-84) (32).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData security and confidentiality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData in the REDCap database contain patient identifiers. REDCap automatically assigns a study ID number. Only deidentified data will be extracted from the REDCap database for analysis by the study team and biostatistician. Reidentification is only possible by study team members with authorised access to the REDCap database. Any hard copies of source documents will be filed in a locked cabinet. The study team and study biostatistician will perform the data analysis and reporting.\u003c/p\u003e\n\u003cp\u003eThe data will be archived and stored for 25 years at the end of the trial, as detailed in the Western Australian Sector Disposal Authority, Section 12.4.4. 8 Data will be destroyed per the CAHS policy, documented and listed with the disposal authority to retain and dispose of research records. Physical files are shredded and disposed of in confidential waste. At the end of the archive period, the digital records will be erased.\u003c/p\u003e\n\u003cp\u003eThe study team collecting data will consist of individuals, including associate investigators, the project nurse, the medical team, and assigned medical students. During regular study meetings, the project coordinator will oversee the data collection and source documents. Once a month, the project coordinator will verify the information gathered in the study database and address any missing data or errors in data entry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data in the REDCap database contain patient identifiers. REDCap automatically assigns a study ID number. Only deidentified data will be extracted from the REDCap database for analysis by the study team and biostatistician. Reidentification is only possible by study team members with authorised access to the REDCap database. Any hard copies of source documents will be filed in a locked cabinet. The study team and study biostatistician will perform the data analysis and reporting.\u003c/p\u003e\n\u003cp\u003eDisposal Authority, Section 12.4.4. 8 Data will be destroyed in accordance with the CAHS policy, documented and listed with the disposal authority to retain and dispose of research records. Physical files are shredded and disposed of in confidential waste. The digital records will be erased.\u003c/p\u003e\n\u003cp\u003eThe study team collecting data will consist of team members, including associate investigators, project nurses, and the medical team. During regular study meetings, the project coordinator will oversee the data collection and source documents. Once a month, the project coordinator will verify the information collected in the study database and check for any missing data or errors in data entry. All the data are stored on the WA Health REDCap system and are accessible only to the study team under WA Health security access protocols. No identifiable data will be used in the analysis or reporting of outcomes. No participant will be identified in any form of reporting or analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable, no biological specimens were collected as part of this trial\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive statistics will be reported by group, including counts (and percentages) for dichotomous and categorical data and either medians (and interquartile ranges) or means (and standard deviations) for continuous data. The primary outcome will be analysed via logistic regression, where the odds ratio (OR) and 95% confidence interval for the group effect (intervention group relative to the control group) will be reported, alongside the proportion of infants whose temperature is in the range of each group. An unadjusted OR will be reported, in addition to an adjusted OR from a model that includes adjustment for potential confounders, including gestational age (weeks), birth weight, duration of transfer (hours), temperature prior to transfer, and month of year.\u003c/p\u003e\n\u003cp\u003eAnalysis of secondary and additional outcomes, where dichotomous, will follow the same framework as outlined above. Continuous outcomes (for example, the length of time taken to reach the target thermal range) will be analysed via linear regression (assuming that model assumptions are met), where the unadjusted and adjusted (based on the potential confounders listed above) between-group mean differences (and 95% confidence intervals) will be reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be accessible only to the study team in accordance with WA health security access protocols. Interim analysis of the primary outcome and adverse events will conducted for the data monitoring and safety committee at 26 recruits (50%). The study will only be terminated if there is substantial, consistent, and identifiable life or limb-threatening harm to the infant as a direct result of the use of the battery-enabled servo-controlled cooling system. This decision may be communicated by the CAHS Human Research Ethics Committee at any point during the study or by the coordinating principal investigator.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g., subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssuming that sufficient data within each group are available, both primary and secondary outcomes will be analysed stratified by mode of transport (air or land-based transport). Further exploratory analysis may look to understand the impact of \u0026lsquo;mission critical events\u0026rsquo;, related to transport or required emergency interventions that directly impact TH, on study outcomes. However, it is acknowledged that the study is not powered for these events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary analysis will be based on an intention-to-treat population of all randomised infants. Imputation (via multiple-chained equations) for missing data will be considered and carried out if missing data are problematic and if the method assumptions are satisfactorily met; otherwise, complete case analysis will be utilised.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant-level data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe entire protocol will be shared for publication. Participant-level data and statistical code will not be shared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is coordinated by the Newborn Emergency Transport Service Western Australia (NETS WA), which is part of the neonatology division of the Child and Adolescent Health Service (CAHS; WA Health) and is based at Perth Children\u0026rsquo;s Hospital in Perth, the state capital of WA. The trial steering committee, which includes the CPI, PI, AI, senior medical and nursing staff, and a dedicated trial nurse, meets monthly. The trial is discussed weekly with the operational team, and feedback is obtained from the CPI and trial nurse.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data safety and monitoring committee is external and independent of the trial team and includes neonatal experts in TH and HIE and an independent statistician. The committee is made up of three individuals. The DSMC meets six months and prepares a report for the CPI. The CPI provides 12 monthly submissions to the Human Research Ethics Committee of the Child and Adolescent Health Service and reports on the safety of the device, ethics of recruitment, and results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSafety reporting from the CoolCot Trial will adhere to standards from the 2016 recommendations of the National Health and Medical Research Council (NHMRC), Australia (33). Any potential or realised adverse events will be documented in REDCap. Newborns in neonatal intensive care are at a greater risk of clinical incidents than are patients in other areas. Any adverse event (AE) identified while the infant is an inpatient will be recorded accordingly in the trial documentation. In infants receiving intensive care, several AEs may occur that are not ultimately related to the trial intervention. This study will maintain a low threshold for reporting and documenting AEs, and the responsibility for identification will rest with the CPI and PIs in conjunction with the treating NICU team.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial will be reviewed every six months in conjunction with the DMSC review. The consent procedure, data entry, and temperature management processes will be reviewed specifically to ensure consistency and quality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA single service conducts the trial. Protocol changes will be a last resort and avoided as much as possible. If necessary, they will be amended and approved through the Child and Adolescent Human Ethics Amendment process. The team will be informed of these changes through regular education communication and sessions. The trial registry will be updated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe intend to publish the protocol and project results in a peer-reviewed journal. We hope that selected data will be submitted and presented nationally and internationally at appropriate scientific meetings through the neonatal network in Western Australia and, more widely, through the Perinatal Society of Australia and New Zealand. Importantly, we will share through regular updates of consumer groups that were consulted to support the funding and ethics applications. Acquittal reports and outcomes will be prepared for the funding organisation, the Perth Children\u0026rsquo;s Hospital Foundation, and associated partners.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTH has been established as an effective treatment for moderate to severe HIE (24). Many infants are born in hospitals without neonatal intensive care or access to TH; the neonatal transport team plays a key role in establishing and maintaining TH during transfer to larger treatment centres (34). Rapid access to active TH is necessary to reach the target temperature and improve outcomes (35). Methods of active TH have not been prospectively compared, nor has the long-term impact of TH during neonatal transport (7).\u003c/p\u003e\n\u003cp\u003eThe trial is powered to detect differences in arrival temperature, demonstrating the direct efficacy of servo-controlled methods. This study will address gaps in the evidence concerning active methods of thermoregulation in infants with HIE who require neonatal transport. The trial is embedded in clinical practice and pragmatic in its design, simplifying the approach to patient care and the intervention.\u003c/p\u003e\n\u003cp\u003eAn important secondary outcome is longer-term development, assessed by the BSID-IV. Assessment of surviving infants at 2 years of age will provide evidence of the long-term efficacy and safety of active TH in transport.\u003c/p\u003e\n\u003cp\u003eOwing to the complexity of the clinical environment, randomised controlled trials in neonatal emergency transport are rarely conducted. In approximately 50% of cases, infants with HIE are not born in centres equipped to provide necessary TH(5). This study aims to demonstrate the feasibility of such acute care trials in this setting and address a treatment gap for infants in these circumstances. Data from this trial should inform other trials both nationally and internationally.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis published protocol is Version 4.1 as of 7\u003csup\u003eth\u003c/sup\u003e June 2025. Recruitment began on 1st July 2023 and is ongoing; it is expected to be complete by 30\u003csup\u003eth\u003c/sup\u003e June 2027.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHIE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypoxic ischaemic encephalopathy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTherapeutic Hypothermia\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePCH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePerth Children\u0026rsquo;s Hospital\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNETS WA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNewborn Emergency Transport Service\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNICU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNeonatal intensive care unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTGA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTherapeutic Goods Administration\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCAHS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChild and Adolescent Health Service\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBSID\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIV\u0026ndash;Bayley Scales of Infant and Toddler Development, 4th Edition\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePICF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eParticipant Information and Consent Form\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the parents of the infants enrolled in this trial. We appreciate the trust you place in NETS WA. The authors wish to acknowledge the hard work and dedication of the nurses and doctors from the Newborn Emergency Transport Service Western Australia for their commitment to identifying and consenting patients and collecting the data. The authors also wish to thank Ms. Jennifer Mountain for her support in preparing the manuscript and for helping to bring the project to life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJD, the chief investigator, conceived the study, led the proposal and protocol development, partially wrote, and approved the final manuscript. AH and KH wrote and developed the protocol and supervised SL and FT in the protocol manuscript. AH and KH submitted the protocol for ethics and governance with the support of JM. VB, JG, SD, AW, AT, and KM are members of the trial steering committee and provided input on developing the protocol and the important practical aspects of the trial and its execution. TW was the trial nurse and supervised data collection and quality control. MC is the trial statistician and is advised on all aspects of data collection, randomisation, group allocation, and analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Perth Children\u0026rsquo;s Foundation generously provided funds to conduct the trial, including support for staffing and publication. They had no role in the design, collection, analysis, interpretation or writing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CPI and trial statisticians will have access to the completed trial database. There are no contractual agreements in place. The complete deidentified CoolCot trial database will be available 6 months after the publication of the primary outcome. The study protocol and documentation have been submitted for publication in a journal. An application to obtain data may be made to the CPI ([email protected]). The final decision to share data will be made by the trial steering committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Human Ethics Research Committee of the Child and Adolescent Health Service, Perth Western Australia, provided granted trial approval. RGS000006472.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CoolCot trial steering committee is willing to provide a model consent form on written request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNewborn Emergency Transport Service of Western Australia, Child and Adolescent Health Service, Perth Children\u0026rsquo;s Hospital, Nedlands, Western Australia, Australia.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eNeonatology, Child and Adolescent Health Service, King Edward and Perth Children\u0026rsquo;s Hospital, Perth, Western Australia, Australia.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u0026nbsp;\u003c/sup\u003eSchool of Medicine, University of Western Australia, Monash Avenue, Nedlands, Western Australia.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u0026nbsp;\u003c/sup\u003eThe Kids Research Institute, Perth Children\u0026rsquo;s Hospital, Hospital Avenue, Nedlands, Western Australia, Australia\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ehttps://www.cahs.health.wa.gov.au/~/media/HSPs/CAHS/Documents/Health-Professionals/NETS/Hypoxic-Ischaemic-Encephalopathy-HIE-Asphyxia.pdf.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"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":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hypoxic ischaemic encephalopathy, Therapeutic hypothermia, Servo-controlled cooling, Neonatal transport, Randomised control trial","lastPublishedDoi":"10.21203/rs.3.rs-6407483/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6407483/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e. Impaired oxygen delivery or blood flow to the brain around the time of birth can cause injury. Hypoxic ischaemic encephalopathy (HIE) is a leading cause of death and disability in term and near-term infants. Therapeutic hypothermia (TH) (reducing body temperature to 33–34°C for 72 hours after birth) is the only intervention available for infants with moderate-to-severe encephalopathy. TH should be initiated within 6 hours of birth for maximum benefit. Many infants worldwide are not born in a centre where TH is possible, and transport is required for active TH. In Australia, the current method of active TH during transport involves ice‒gel packs. There have been no prospective studies comparing active methods of TH in neonatal transport reporting short- and long-term outcomes. We aim to compare two active TH modalities: a battery servo-controlled cooling blanket (Criticool mini (Belmont Medical Technologies, MA, USA)) and standard care (ice‒gel packs) for TH during the transport of newborns with HIE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e. The CoolCot study will be conducted in the Newborn Emergency Transport Service of Western Australia (NETS WA), a single state-wide transport service. Eligible infants with confirmed or suspected HIE will be referred to NETS WA from healthcare facilities without tertiary health (TH) capacity in Western Australia. Following the arrival of the transport team, infants with informed consent will be randomly assigned to battery-enabled servo-controlled TH or standard care (ice‒gel packs). The primary outcome will be the proportion of patients with a temperature in the range of 33.0°C–34.0°C on arrival at the receiving unit. The secondary outcomes include the time to achieve the therapeutic temperature, the time spent out of the temperature range, the degree of temperature fluctuation, and safety. Long-term measures: MRI brain findings (days 5-10 of life) and Bayley Scales of Infant Development assessment at 2 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e: The CoolCot study is the first RCT to prospectively compare the effectiveness of active cooling methods in neonatal emergency transport. Reducing the time needed to achieve the target temperature is crucial in optimising neurodevelopmental outcomes. A key feature of this study is the neurodevelopmental assessment conducted at age two.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: WHO ICTRP Registry/Australian New Zealand Clinical Trials Registry: ACTRN12623001298606p. 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