Circadian Influences, Low-dose Isoflurane, and the Ventilatory Response to Hypoxia

Pandit et al.  1are to be congratulated on their study on the effects pain and audiovisual stimulation on depression of the acute hypoxic ventilatory response by low-dose halothane. Their results are in good correspondence with some of the key studies in this complex field of research.2–6As stated by the authors, there is now ample evidence for the existence of quantitative differences in the ability of low-dose inhalational anesthetics to depress the ventilatory response to acute hypoxia in humans. For example, 0.1% end-tidal halothane depresses the response by 50–60%, whereas the same concentration of isoflurane has much less of an effect (reduction 30–40%).1–6The authors discuss several explanations for the observed differences between halothane and isoflurane, such as differences in pharmacokinetics, differences in the production of reactive oxygen species, and differences in their interaction with sites in the central nervous system involved in behavioral control of breathing. Evenly important are issues related to methodology.7Often, very small differences in protocols may cause large differences in study outcomes. I would like to give an example of the latter. In three subjects, the ventilatory responses to hypoxia at three time points on one single day were measured: 8:00 am, noon, and 4:00 pm. At 9:00 am, one additional response during inhalation of 0.2% end-tidal isoflurane was obtained. The ventilation (Vi) response to five end-tidal Po²levels was analyzed using the following equation: Vi = G exp(−D Peto²) + y⁰(G is the hypoxic sensitivity, D is a shape parameter, and y⁰is ventilation at hyperoxia). Control and recovery responses varied considerably by 20–30% for parameter G and 30–40% for parameter y⁰(fig. 1). Consequently, the depression of the isoflurane response relative to the control and recovery responses was evenly variable and varied from 50 to 70%. The picture that emerges is that the circadian rhythm has important influences on the ventilatory response to hypoxia and consequently on the influences that low-dose anesthetics have on the response. How the behavioral control system interacts with circadian influences remains unknown. Although I realize that the study I present here is of small sample size, it points toward (1) an important and complex role for circadian influences on the interaction between anesthesia and behavioral and chemical control of breathing and (2) the need for identical protocols when comparing agents and studies on the influence of low-dose anesthetic agents on ventilatory control.

Leiden University Medical Center, Leiden, The Netherlands. a.dahan@lumc.nl