Effect of dichloroacetate on ventilatory response to sustained hypoxia in normal adults

In adult humans, the ventilatory response to acute sustained hypoxia is biphasic, characterized by an initial brisk increase followed by a decline to an intermediate plateau. Recently, it has been shown that hypoxic lactate formation in the brain depresses ventilation in peripherally chemodenervated animals, and postulated that this formation might mediate the hypoxic ventilatory decline observed in adult humans. To investigate this hypothesis, the ventilatory response to 25 min of acute isocapnic hypoxia (SaO2 = 80%) was evaluated in adult humans after pretreatment with intravenous dichloroacetate (DCA), a drug that crosses the blood-brain barrier and reduces lactate formation. Ten subjects were pretreated with DCA (50 mg.kg-1.h-1) or normal saline infusion on two days in a double blind manner. The infusion started 35 min before the institution of hypoxia and continued throughout the experiment. Independent of pretreatment, the ventilatory response to acute sustained hypoxia was biphasic; an increase followed by a decline. Ventilation during hypoxia declined significantly and the magnitude of the decline did not differ between the DCA and placebo pretreatments, averaging 3.32 +/- 0.45 and 3.17 +/- 0.58 L/min, respectively (mean +/- SE). With and without DCA infusion the hypoxic ventilatory decline was due to significant decrease in tidal volume and mean inspiratory flow without changes in breathing frequency. We conclude that brain lactic acidosis is unlikely to be involved in the ventilatory response to sustained hypoxia of adult humans, at least in the range of hypoxia studied.