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Correspondence  |   July 2005
Circadian Influences, Low-dose Isoflurane, and the Ventilatory Response to Hypoxia
Author Notes
  • Leiden University Medical Center, Leiden, The Netherlands.
Article Information
Correspondence
Correspondence   |   July 2005
Circadian Influences, Low-dose Isoflurane, and the Ventilatory Response to Hypoxia
Anesthesiology 7 2005, Vol.103, 207-208. doi:
Anesthesiology 7 2005, Vol.103, 207-208. doi:
To the Editor:—
Pandit et al.  1 are 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.2–6 As 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%).1–6 The 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.7 Often, 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.
Fig. 1. Ventilatory response to hypoxia obtained at five oxygen levels in a 25-yr-old woman. Nondrug studies were performed at 8:00 am, noon, and 4:00 pm. At 9:00 am, the effect of 0.2% end-tidal isoflurane was measured. The  lines  through the data are curve fits to the data using the following equation: Vi = G exp(−D Peto2) + y0. The variability among control and recovery responses is apparent. Po2= partial pressure of oxygen. 
Fig. 1. Ventilatory response to hypoxia obtained at five oxygen levels in a 25-yr-old woman. Nondrug studies were performed at 8:00 am, noon, and 4:00 pm. At 9:00 am, the effect of 0.2% end-tidal isoflurane was measured. The  lines  through the data are curve fits to the data using the following equation: Vi = G exp(−D Peto2) + y0. The variability among control and recovery responses is apparent. Po2= partial pressure of oxygen. 
Fig. 1. Ventilatory response to hypoxia obtained at five oxygen levels in a 25-yr-old woman. Nondrug studies were performed at 8:00 am, noon, and 4:00 pm. At 9:00 am, the effect of 0.2% end-tidal isoflurane was measured. The  lines  through the data are curve fits to the data using the following equation: Vi = G exp(−D Peto2) + y0. The variability among control and recovery responses is apparent. Po2= partial pressure of oxygen. 
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Leiden University Medical Center, Leiden, The Netherlands.
References
Pandit JJ, Moreau B, Donoghue S, Robbins PA: Effect of pain and audiovisual stimulation on the acute hypoxic ventilatory responseby low dose halothane. Anesthesiology 2004; 101:1409–16Pandit, JJ Moreau, B Donoghue, S Robbins, PA
Knill RL, Gelb AW: Ventilatory response to hypoxia and hypercapnia during halothane sedation and anesthesia in man. Anesthesiology 1978; 49:244–51Knill, RL Gelb, AW
Knill RL, Kieraszewicz HT, Dodgson BG: Chemical regulation of ventilation during isoflurane sedation and anesthesia in humans. Can Anaesth Soc J 1983; 30:607–14Knill, RL Kieraszewicz, HT Dodgson, BG
Dahan A, van den Elsen MJLJ, Berkenbosch A, DeGoede J, van Kleef JW, Bovill JG: Effects of subanesthetic halothane on the ventilatory response to hypercapnia and acute hypoxia in healthy volunteers. Anesthesiology 1994; 80:727–38Dahan, A van den Elsen, MJLJ Berkenbosch, A DeGoede, J van Kleef, JW Bovill, JG
van den Elsen M, Dahan A, DeGoede J, Berkenbosch A, van Kleef J: Influences of subanesthetic isoflurane on ventilatory control in humans. Anesthesiology 1995; 83:478–90van den Elsen, M Dahan, A DeGoede, J Berkenbosch, A van Kleef, J
Sarton E, Dahan A, Teppema L, van den Elsen M, Olofsen E, Berkenbosch A, van Kleef J: Acute pain and central nervous system arousal do not restore impaired hypoxic ventilatory response during sevoflurane sedation. Anesthesiology 1996; 85:295–303Sarton, E Dahan, A Teppema, L van den Elsen, M Olofsen, E Berkenbosch, A van Kleef, J
Robotham JL: Do low-dose inhalational anesthetic agents alter ventilatory control? (editorial). Anesthesiology 1994; 80:723–6Robotham, JL
Fig. 1. Ventilatory response to hypoxia obtained at five oxygen levels in a 25-yr-old woman. Nondrug studies were performed at 8:00 am, noon, and 4:00 pm. At 9:00 am, the effect of 0.2% end-tidal isoflurane was measured. The  lines  through the data are curve fits to the data using the following equation: Vi = G exp(−D Peto2) + y0. The variability among control and recovery responses is apparent. Po2= partial pressure of oxygen. 
Fig. 1. Ventilatory response to hypoxia obtained at five oxygen levels in a 25-yr-old woman. Nondrug studies were performed at 8:00 am, noon, and 4:00 pm. At 9:00 am, the effect of 0.2% end-tidal isoflurane was measured. The  lines  through the data are curve fits to the data using the following equation: Vi = G exp(−D Peto2) + y0. The variability among control and recovery responses is apparent. Po2= partial pressure of oxygen. 
Fig. 1. Ventilatory response to hypoxia obtained at five oxygen levels in a 25-yr-old woman. Nondrug studies were performed at 8:00 am, noon, and 4:00 pm. At 9:00 am, the effect of 0.2% end-tidal isoflurane was measured. The  lines  through the data are curve fits to the data using the following equation: Vi = G exp(−D Peto2) + y0. The variability among control and recovery responses is apparent. Po2= partial pressure of oxygen. 
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