Doxapram Only Slightly Reduces the Shivering Threshold in Healthy Volunteers

Abstract

We determined the effects of doxapram on the major autonomic thermoregulatory responses in humans. Nine healthy volunteers were studied on two days: Control and Doxapram (intravenous infusion to a plasma concentration of 2.4 ±0.8 μg/mL, 2.5 ±0.9 μg/mL, and 2.6 ±1.1 μg/mL at the sweating, vasoconstriction, and shivering thresholds, respectively). Each day, skin and core temperatures were increased to provoke sweating, then reduced to elicit peripheral vasoconstriction and shivering. We determined the sweating, vasoconstriction, and shivering thresholds with compensation for changes in skin temperature. Data were analyzed with paired t tests and presented as means ± SDs; P < 0.05 was considered statistically significant. Doxapram did not change the sweating (Control: 37.5±0.4°C, Doxapram: 37.3±0.4°C, P=0.290) or the vasoconstriction threshold (36.8±0.7 vs. 36.4±0.5°C; P=0.110). However, it significantly reduced the shivering threshold from 36.2±0.5 to 35.7±0.7°C (P=0.012). No sedation or symptoms of panic were observed on either study day. The observed reduction in the shivering threshold explains the drug's efficacy for treatment of postoperative shivering; however, a reduction of only 0.5°C is unlikely to markedly facilitate induction of therapeutic hypothermia as a sole agent. Implications:The observed reduction of only 0.5°C in the shivering threshold explains the drug's efficacy for treatment of postoperative shivering. However, such a reduction is unlikely to markedly facilitate induction of therapeutic hypothermia as a sole agent.

A New Look at the Respiratory Stimulant Doxapram

“…Therefore, both doxapram and demerol were effective in the treatment of postoperative shivering, with demerol being perhaps slightly better. However, a more recent study has shown that doxapram's effect on shivering threshold is minor, lowering the shivering threshold in normal volunteers by only 0.5°C (28).…”

Thermoregulatory defense mechanisms

“…Ineffective drugs include ondansetron (a 5HT-3 antagonist used for prevention and treatment of nausea and vomiting), (70) magnesium sulfate, (71) and doxapram (effectively, a central dopamine agonist) (72). Dantrolene is a peripherally acting skeletal muscle relaxant primary used for treatment of malignant hyperthermia crises.…”

Optimal Management of Shivering During Therapeutic Hypothermia After Cardiac Arrest

“…Numerous pharmacological agents 7,10,[16][17][18][19][20][21][22][23][24][25] (Table 2) that reduce the vasoconstriction and shivering thresholds have been used to manage shivering during therapeutic hypothermia. According to the ILCOR, 3 sedative and hypnotic agents are often used to decrease metabolic demand and facilitate mechanical ventilation in comatose patients who lack signs of awakening within the first 5 to 10 minutes after return of spontaneous circulation.…”