In a canine model of combined carbon monoxide (CO) and cyanide (CN) poisoning, cardiac output (QT) and oxygen consumption (Vo2) decreased but recovered to baseline values by 15 min after toxic exposure; elevated blood CN and lactic acidosis persisted for at least another 10 min. Given the rapid spontaneous recovery after cessation of toxic exposure, we questioned the efficacy of usual treatment with oxygen (O2) and sodium thiosulfate (Na2S2O3) for CN poisoning. Accordingly, in seven dogs (26 +/- 3 kg, chloralose and urethane anesthesia), we sequentially administered CO by closed circuit inhalation (231 +/- 42 ml) and potassium CN by intravenous infusion (0.072 mg.kg-1.min-1 for 17 +/- 3 min). Fifteen minutes after toxic exposure, O2 breathing began and Na2S2O3 (150 mg/kg) was infused. Measurements were repeated 10 and 45 min after treatment. At the end of the CN infusion, QT decreased by 43% and Vo2 decreased by 51%, compared to baseline values. Both variables recovered to baseline by 15 min after stopping toxic exposure. Significant lactic (4.8 +/- 2.9 mM) acidosis (7.14 +/- 0.10) persisted for at least another 10 min. Treatment with oxygen and Na2S2O3 did not hasten the recovery of this lactic acidosis or decrease blood cyanide levels compared to nontreated dogs. However, after treatment, plasma thiocyanate significantly increased from 16.3 +/- 12.5 to 94.4 +/- 72.2 microM, as Na2S2O3 participated in the increased metabolism of cyanide to thiocyanate. We conclude that O2 and Na2S2O3 therapy should be continued during combined CO and HCN poisoning. Oxygen increases CO elimination and can enhance anti-CN treatment. After infusion or inhalation of CN, when most CN has already penetrated the intracellular compartment, postexposure sodium thiosulfate increased the metabolism of CN.