Induction of a Prolonged Hypothermic State by Drug-induced Reduction in the Thermoregulatory Set-Point

Abstract

Background: The marked improvement in outcome following induction of hypothermia after cardiac arrest has spurred the search for better methods to induce cooling. A regulated decrease in core temperature mediated by a drug-induced reduction in the set point for thermoregulation may be an ideal means of inducing hypothermia. To this end, the exploratory drug HBN-1 was assessed as a means to induce mild and prolonged hypothermia. Methods: Free moving rats were infused i.v. for 12 hours with: a vehicle at room temperature (normothermia), a vehicle chilled to 4°C (forced hypothermia), or HBN-1 (mixture of ethanol, lidocaine, and vasopressin) at room temperature. Core (intra-abdominal) temperature (T c ) was measured telemetrically, tail skin temperature (T tail ) by infrared thermography, metabolic rate (MR) was estimated with indirect calorimetery, and shivering was scored visually. Results: HBN-1 elicited a reduction in T c from 37.5°C to 34°C within 80 minutes after initiation of the infusion; T c was maintained between 33°C and 34°C for more than 13 hours. HBN-1 infusion was associated with a reduction in MR ( p = 0.0006), a slight reduction in T tail , and no evidence of shivering ( p < 0.001). The forced hypothermia group displayed shivering ( p < 0.001), a significant increase in MR, and a decrease in T tail , indicative of peripheral vasoconstriction to reduce heat loss. Conclusion: HBN-1 infusion induced a mild and prolonged hypothermia in free moving, unanesthetized rats characterized by modulation of thermoeffectors to reduce heat gain and increase heat loss. HBN-1 thus appears to elicit regulated hypothermia and may provide a new method for achieving a prolonged state of therapeutic hypothermia.

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

“…Safer and more effective methods for producing TH are needed that are compatible with conscious subjects to make TH a viable treatment option for a broader patient population. Indeed, there has been renewed interest in a variety of pharmacological methods of promoting hypothermia without the need for sedation (19,45).…”

Effect of a pharmacologically induced decrease in core temperature in rats resuscitated from cardiac arrest

“…However, based on a rat’s behavioral and autonomic thermoregulatory responses, it is likely associated with stimulation of heat loss pathways and/or suppression of heat production/conservation pathways in CNS thermoregulatory centers of the pre-optic and anterior hypothalamus. 10, 22 Intravenous administration of a drug such as HBN-1 that lowers body temperature through a reset of a thermostat in the hypothalamus is a simple approach for inducing and maintaining therapeutic hypothermia. It has the potential to overcome perceived barriers to implementation of therapeutic hypothermia in a field or clinical setting.…”

“…10, 11 Regulated hypothermia is thought to be operative by lowering the body’s temperature set point in the hypothalamic regulatory center. 12 When the temperature set point is lowered, the body responds by reducing metabolic rate, blocks shivering, and increases heat loss through peripheral vasodilatation and sweating.…”

“…HBN-1 is a patented pharmaceutical preparation that combines ethanol, vasopressin and lidocaine. 10 It induces a rapid and prolonged hypothermia even at room temperature without the need for chemical paralysis, sedation, ancillary equipment, or mechanical ventilation. 10 The drug is administered intravenously so paramedics could use it in the field, thus minimizing delays in inducing hypothermia.…”

Pharmacological hypothermia: a potential for future stroke therapy?

“…35 There has been a recent surge of interest in the investigation of drug-induced hypothermia as a treatment option for ischemic stroke. 36,37 Several things must be kept in mind when assessing the final outcomes of a pharmacological agent under study. Firstly, a distinction must be made between hypothermic effects and hypothermia-like.…”