The Effect of Active External Rewarming on Rewarming Rate in Simulated Prehospital Accidental Hypothermia

Accidental hypothermia is defined as an involuntary drop in core body temperature below 35°C. Hypothermia is a risk factor for cardiac arrythmia, pulmonary oedema, coagulopathy and neurological pathology. Isolated accidental hypothermia is potentially lethal on its own, and it is also an independent risk factor for increased mortality in patients with traumatic injury.

When core temperature drops, the body will automatically activate compensatory mechanisms in order to both increase thermic production and minimize heat loss in order to restore normal temperature. The mechanisms for thermal homeostasis are complex, strictly regulated and effective.

Until quite recently, active external rewarming was considered to be harmful and dangerous for patients with accidental hypothermia. A fear of fatal complications such as increased afterdrop and "rearming syndrome" leading to dangerous arrythmias and a drop in blood pressure which in a worst case scenario could lead to circulatory collapse, shock and potentially death.

Given the potentially detrimental consequences of being cold, any advice to abstain from warming patients should be well-documented, and the adverse effects of warming should outweigh those of being hypothermic. The lack of evidence for this claim that active external rewarming is dangerous along with many reports of successful external rewarming is leading to a change in most guidelines where active external rewarming is now an advisable treatment option.

A variety of different technological devices exist for the purpose of rewarming, but there is no established standard which is proven superior to others. Several trials have compared different rewarming methods, but evidence is limited. There is particularly deficient evidence regarding the amount of heat available for transfer from different methods and also the required amount of heat transfer for the rewarming to have a significant clinical impact.

Given the relatively short time in which active external rewarming has been advised, we suspect there is still a huge amount of room for improvement of care and technological innovation.

There is however reason to be cautious with active external rewarming of hypothermic patients. In a normothermic patient with normal circulatory function, thermal energy will be absorbed by the blood which flows back into central circulation distributing the heat evenly into a large volume. In a hypothermic patient there will be less cutaneous blood flow and less heat will be transferred to systemic circulation. This means that heat will accumulate on the skin surface and increase the risk of cutaneous injury, and there are several reported cases of this.

Hypothermia research with volunteer research participants is a complicated matter for many reasons. One complicating factor is shivering, which is an autonomic defense mechanism in which the muscles contract rapidly producing heat. It is the most effective method for the body to increase the metabolic heat production and re-establish normothermia. The shivering response is complicated in a research setting because there is a large interindividual variation in temperature threshold for initiation of shivering and in shivering intensity. This means that if you cool research participants down they will start to shiver at different core temperatures and with different intensities. Standardization of data is therefore impossible, and the researcher will be measuring the interindividual shivering abilities of the different research participants instead of the effect of the intervention. Shivering must therefore be inhibited in order to achieve reliable data.

Participants are eligible to be included in the study only if all of the following criteria apply:

Age

• Participant must be over 18 and under 40 years of age at the time of signing the informed consent.

Type of Participant and Disease Characteristics

• Participants who are overtly healthy as determined by their medical history. The participants will be asked to fill out a health-report stating to be healthy, using no relevant medication, and having no relevant allergies or hypersensitivity to the active substances or to any of the excipients of the medications used.

Weight

• BMI under 30 kg/m2 Sex and Contraceptive/Barrier Requirements 4. Both male and female participants can be included. Female participants of childbearing potential will be asked to take a pregnancy test to confirm the absence of pregnancy prior to study drug administration on both visit 1 and 2.

Informed Consent 5. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria

Ahead of trial the participants will be contacted by a medical physician in the research group who will go through a medical questionnaire mainly based on the SmPC of Meperidine, Buspirone and Sodium chloride in "Felleskatalogen" with the following exclusion criteria.

• Drugs: Concomitant use of sedatives, MAO-inhibitors, SSRI, ritonavir, cimetidine, chlorpromazine, phenytoin, erythromycin, itraconazole, platelet inhibitors, Apomorphine, alcohol (during the trial period) or other opioids or opioid antagonists (during the trial period). History of drug dependency.
• Recent head injury (last. 12 months), known increased ICP, seizures or epilepsy
• Other: Known reduced liver- or kidney function, reduced respiratory drive, known supraventricular tachycardia or prolonged QTc, hypertrophy of the prostate or urinary constriction, ongoing pregnancy or breastfeeding. Known acute glaucoma, myasthenia gravis. Previous abdominal surgery. History of cold injuries or frostbites.
• Planned MRI the next two days after ingestion of temperature capsule.