Mechanism of Cocaine-Induced Hyperthermia in Humans

Context The cause of hyperthermia in cocaine abuse is not well understood. Both excess heat generation and defective heat dissipation are potential causes of fatal hyperthermia. Contribution Nasal administration of cocaine causes greater increase in core body temperature, decrease in heat perception, and greater impairment of sweating and skin blood flow compared with nasal lidocaine administration. Implications Excessive heat production, impaired heat dissipation, and alteration of behavioral responses to increased body temperature may lead to fatal hyperthermia in cocaine abusers. The Editors Cocaine abuse is a major cause of life-threatening cardiovascular emergencies, including hypertensive crisis, acute myocardial infarction, and ventricular arrhythmias. The lethal effect of cocaine is unique among those of other illicit drugs because it is related not only to dose but also to cocaine's propensity to cause hyperthermia. Although fatal cocaine overdose typically is associated with high blood cocaine levels (3 to 6 mg/L) (1), cocaine-related deaths can also occur when hyperthermia is present at blood levels 10 to 20 times lower (2). The intrinsic thermogenic property of cocaine underlies recent epidemiologic data indicating that mortality rates for cocaine overdose increase substantially in hot weather (3). This temperature-dependent increase in mortality rates is specific to cocaine and is not seen with opiates or other illicit drugs. These clinical observations are bolstered by experiments in dogs demonstrating that cocaine-induced death can be eliminated by multiple strategies that prevent hyperthermia (4). In humans, however, the underlying mechanisms mediating cocaine-induced hyperthermia are poorly understood. The hyperthermic properties of cocaine have been attributed largely to a hypermetabolic state (agitation with increased locomotor activity) that increases heat production (5). Indeed, cocaine-induced hyperthermia has been likened to two other syndromes, neuroleptic malignant syndrome and malignant hyperthermia, that are characterized by hyperpyrexia, delirium, tachycardia, and elevated blood pressure (6, 7). In both of those syndromes, excessive heat production due to involuntary muscle contraction is sufficient to raise body temperature even in a cool environment (for example, an operating room). In contrast, cocaine-induced hyperthermia is seen primarily in the setting of high ambient temperatures. We therefore hypothesized that, in addition to increased heat production, impaired heat dissipation is another important mechanism contributing to the hyperthermic properties of cocaine. When body temperature increases above thermoregulatory set points, heat dissipation depends on both autonomic and behavioral adjustments. The major autonomic adjustments include activation of sympathetic cholinergic fibers that leads to sweating and cutaneous va sodilation (8). The behavioral adjustments are prompted by thermal discomfort and include heat avoidance and external cooling. In humans, these simple behavioral responses can be more important than autonomic adjustments in maintaining normal body temperature during heat stress (9). We sought to test the effect of cocaine on thermoregulatory adjustments in humans. Because cocaine has a profound influence on both cardiovascular and cognitive function, we conducted a randomized, placebo-controlled study to assess the effects of a low, noneuphoric dose of intranasal cocaine on autonomic and behavioral thermoregulation in healthy cocaine-naive volunteers. Methods Participants We studied 7 healthy male and female volunteers who ranged in age from 23 to 37 years. The Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas, Texas, approved the protocol, and all volunteers provided written informed consent. All participants were normotensive and had no history of cardiovascular disease, cocaine abuse, or other recreational drug use. No participant was taking prescription or nonprescription drugs with cardiovascular or autonomic effects. Participants refrained from smoking cigarettes or drinking alcohol- or caffeine-containing beverages for at least 12 hours before the experiment. Measurements Internal temperature was measured by using a thermistor placed in the esophagus at a depth equal to 25% of each participant's standing height, and skin temperature was measured from the weighted electrical average of six thermocouples attached to the skin. Each participant wore a tube-lined suit that controlled skin temperature by changing the temperature of the water perfusing the suit. The suit covered the entire body surface with the exception of the head, arms, and feet. We assessed skin blood flow from each participant's forearm during heat stress. The water-perfused suit did not cover the forearm where skin blood flow measurements were obtained; thus, any change in skin blood flow during heat stress was not directly related to mechanisms associated with local heating. Skin blood flow was measured by using multifiber laser Doppler flowmeter (Perimed, North Royalton, Ohio). Heart rate was obtained from the electrocardiogram by using a cardiotachometer (CWE, Inc., Ardmore, Pennsylvania), and blood pressure was obtained by using the oscillometric technique (Welch Allyn, Beaverton, Oregon). Mean arterial blood pressure was calculated as one third of the pulse pressure plus diastolic blood pressure. Cutaneous vascular conductance, which is the reciprocal of vascular resistance, was calculated from the ratio of the laser Doppler signal to mean arterial pressure. Forearm sweat rate was measured continuously with the ventilated capsule method, in which a capsule with a window of 2.8 cm2 is attached to the surface of the skin. Nitrogen gas is perfused through the capsule at a fixed rate, and as the person begins to sweat, the water on the skin evaporates through the window into the nitrogen gas. The humidity of the effluent nitrogen gas is quantified through a humidity detector downstream from the capsule. The sweat rate is then calculated from the humidity, temperature, and flow of the nitrogen gas. Throughout the heat stress, participants rated thermal sensation by using a standardized 9-point thermal comfort scale ranging from 4.0 (neutral) to 8.0 (unbearably hot) at increments of 0.5 (10). Experimental Protocol All experiments were conducted with the participants in a supine position. In a randomized, double-blind, crossover trial, each participant was exposed to whole-body heating after receiving intranasal cocaine hydrochloride (2 mg/kg of body weight, 10% solution) or lidocaine hydrochloride (2 mg/kg, 10% solution). Lidocaine was used as an internal control for the local anesthetic property of cocaine (11). The experiments were conducted on 2 separate days, at the same time of day, 3 to 6 days apart. The dose of cocaine administered is half the standard dose administered for rhinolaryngologic procedures (12). The heat stress test was performed by perfusing the tube-lined suit with water at 46 C. To assess maximal vasodilator responses, a heater surrounding the laser Doppler flow probe was used on completion of the heat stress to increase local skin temperature to 42 C for 30 minutes. Heating the skin at this temperature and duration elicits maximal cutaneous vasodilation (13). Skin blood flow during the final minutes of this 30-minute procedure was averaged, and maximal cutaneous vascular conductance was then calculated from the ratio of that value and mean arterial blood pressure. Values for cutaneous vascular conductance were then normalized to percentages of maximum for that site (13). Data Collection Temperatures, skin blood flow, and sweat rate data were sampled at 50 Hz (Biopac, Santa Barbara, California). The electrocardiogram was sampled by a cardiotachometer at 1000 Hz, using a multichannel digital data recorder (CWE, Inc.). These values were reduced to 20-second averages before statistical analysis. When cutaneous vascular conductance and sweat rate are plotted relative to esophageal temperature, two important variables can be identified to assess thermoregulatory function (14): the esophageal temperature threshold at which cutaneous vasodilation and sweating begin, and the slope of the line relating progressive elevations in cutaneous vascular conductance and sweating to increasing esophageal temperature. Esophageal temperature thresholds at which cutaneous vascular conductance and sweat rate began to increase were identified from individual plots of esophageal temperature versus cutaneous vascular conductance and esophageal temperature versus sweat rate. These points were selected as the internal temperatures at which pronounced and sustained increases in cutaneous vascular conductance and sweating were evident during the heating procedure. The investigator identifying these thresholds was blinded to the participants and to their experimental conditions (lidocaine or cocaine). Statistical Analysis Statistical comparisons of temperature thresholds and slopes during cocaine and lidocaine administration were performed by using the paired t-test. Differences in responses (internal temperature, skin temperature, cutaneous vascular conductance, and sweat rate) during cocaine and lidocaine administration throughout the heat stress were statistically analyzed by using two-way repeated-measures analysis of variance (SigmaStat 2.0, SPSS Science, Chicago, Illinois). Treatment order was also assessed in the models, and no effect of treatment order on any outcome variables was found. The effects of cocaine on thermal sensation were statistically analyzed by comparing the internal temperature at each perceived heating score between 5.0 and 7.5 using paired t-tests. All values are reported as the mean (SE), and the level for all statistical analyses was set at 0.05. Role of the Funding Sources The funding sources had no role in the design, a