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Six healthy, consenting volunteer males received ketamine iv in five logarithmically scaled doses totaling 3 mg/kg on three occasions each. The sessions differed only in the initial injection of an unknown drug: placebo, morphine sulfate 0.2 mg/kg, or morphine sulfate 0.4 mg/kg. Initial and terminal steady-state ventilatory responses to CO2 (VERCO2) and isohypercapnic ventilation (end-tidal CO2 49.8 ± 2.4 mmHg) during drug administration assessed CO2-mediated ventilatory drive. Oxygen concentration of 40% ablated hypoxic drive contribution. Morphine caused a decrease of isohypercapnic ventilation (VE) of 8.2 ± 1.2 l/min after 0.2 mg/kg. Doubling the dose to 0.4 mg/kg gave a further depression of 6.6 ± 1.8 l/min. No subject lost consciousness after morphine. Over a dose range of 0.39 to 3.0 mg/kg ketamine caused log-linear dose-related depression of 1.6 ± 0.3 l/min for each doubling of dose, although the first significant depression of 4.9 ± 1.1 l/min did not occur until the third dose (1.1 mg/kg) in the absence of morphine. All subjects were unconscious after 1.8 mg/kg ketamine. Slopes of the VERCO2 did not differ from control, regardless of the pretreatment, placebo, or morphine in the two doses. Ketamine alone, 3.0 mg/kg, caused a displacement of VERCO2 of +2.0 ± 1.2 mmHg in CO2, while combination of ketamine and morphine in either dose caused a +10 mmHg displacement of VERCO2. Thus, ketamine appears qualitatively similar but less potent than premedicant doses of morphine in depressing respiration despite near equipotency in producing loss of consciousness.