HBN-1

A feasibility study was performed to compare an investigational drug, HBN-1, to forced cooling to induce hypothermia after resuscitation in a translation model of asphyxial cardiac arrest in swine. Serum and cerebral spinal fluid neuron-specific enolase activity (sNSE and csfNSE) were measured after cardiac arrest as surrogate markers of brain injury. In a block design, swine resuscitated from 10 minutes of asphyxial cardiac arrest were infused intravenously with HBN-1 or iced saline vehicle (forced hypothermia [FH]) 5 to 45 minutes after return of spontaneous circulation (ROSC). External cooling in both groups was added 45 minutes after ROSC until hypothermia (T=4°C below baseline) was attained. Esophageal (core) temperature, shivering, cardiopulmonary parameters, and time to hypothermia after ROSC were monitored. sNSE and csfNSE were measured 180 minutes after ROSC. HBN-1 induced hypothermia significantly lowered temperature compared to FH 5-45 minutes after ROSC (p<0.0001). Time to hypothermia was reduced by HBN-1 (93±6 minutes) compared to FH (177±10 minutes) (p<0.0001). HBN-1 sNSE (0.7±1.9 ng/mL) and csfNSE (17.3±1.9 ng/mL) were lower compared to FH (6±1.6 ng/mL) and (49.7±32.0 ng/mL) (p<0.0001, p=0.022, respectively). There was no shivering with HBN-1 cooling while all FH cooled swine shivered (p<0.0001). The time to reach target hypothermia after cardiac arrest was reduced by nearly 50% with HBN-1 compared to the FH method of inducing hypothermia. Moreover, surrogate biomarkers of brain injury were significantly reduced with HBN-1 as compared to FH. While HBN-1-induced hypothermia shows promise for being neuroprotective, survival studies are needed to confirm these preliminary findings.

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.

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 (Tc) was measured telemetrically, tail skin temperature (Ttail) by infrared thermography, metabolic rate (MR) was estimated with indirect calorimetery, and shivering was scored visually.

HBN-1 elicited a reduction in Tc from 37.5°C to 34°C within 80 minutes after initiation of the infusion; Tc 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 Ttail, 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 Ttail, indicative of peripheral vasoconstriction to reduce heat loss.

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.