The first and most serious problem is their assertion that arousal of subjects (by visual or auditory stimulation) prevents the depression of the hypercapnic response to anaesthesia. They quote four studies to support this.25 It is unfortunate that none of the studies quoted examined the interaction of subject arousal and hypercapnic ventilatory response. Indeed, two of these studies did not even measure the hypercapnic ventilatory response.4 5 The interaction of arousal and the hypercapnic ventilatory response is an area that still remains to be studied and, so far as we are aware, our recently completed, unpublished study is the first attempt to examine possible interactions.
The authors are confused by the papers reporting possible interactions of arousal with the hypoxic ventilatory response.4 6 However, even where the hypoxic response is concerned, there is doubt that arousal has an important influence.6 7 For example, we have recently reported7 that arousal does not reverse the action of halothane on the hypoxic response (an observation which is in contrast to the reported effects of arousal on the effect of isoflurane).4
The authors claim that humans preferentially increase tidal volume rather than ventilatory frequency in response to hypercapnia. However, data from our previous paper shows that sustained hypercapnia in humans causes a significant increase in both tidal volume and ventilatory frequency.8 This study also shows that low dose sevoflurane does not affect the ventilatory response to hypercapnia,8 in contrast to the result of Groeben and colleagues in mice.1
The final concern relates to the extent to which the mice used in their study can be properly described as having a blunted hypercapnic response. The authors' data suggest that the minute ventilation of the mice quadrupled in response to the carbon dioxide challenge.1 This would seem to be a reasonable response. Of course, it is possible that this is not quite as strong a response as compared with other mice,9 but since the authors seek to use these mice as a model for humans with blunted responses, it might be less suitable than is claimed. We also do not know whether the effect of the three anaesthetics tested is similar in other mice with even more vigorous hypercapnic responses (i.e. there is no control group). The authors have previously reported strain differences for isoflurane with respect to the recovery process,9 but these observations cannot be extrapolated to other anaesthetic agents without further experiment. If the effects are similar with these other agents, then the anaesthetic effect is a general one, and the initial (baseline) degree of blunting of the hypercapnic response is irrelevant.
Oxford, UK
However, we cited the references that explicitly write about hypercapnic and hypoxic respiratory responses. Undoubtedly, these references refer to studies on these responses. As Dr Pandit clearly describes, the number of studies looking at hypercapnic responses and the effect on arousal is very small, and we are looking forward to the results of his forthcoming study. Because of the shortage of available data on this topic, we referred in the discussion of our results to these studies as references for central nervous effects on respiratory drive, but we did not differentiate the mode of stimulation. We accept this approach is inaccurate and we apologize for this simplified generalization. Unfortunately, as yet we have not been able to read the article cited as in press by Dr Pandit in Pubmed or other online services.
Second, Dr Pandit comments on the statement that humans preferentially respond with an increase in tidal volume rather than an increase in ventilatory frequency under a hypercapnic challenge and the influence of anaesthesia. Dr Pandit believes that both increase significantly and cites one of his articles to prove this.8 There is no doubt that tidal volume as well as ventilatory frequency can increase significantly in response to hypercapnia. However, Sollevi and colleagues10 demonstrated that under the influence of isoflurane, this mixed response to hypercapnia at baseline turns into a purely tidal-volume response. Looking at a large number of studies, it was our impression that humans respond more with an increase in ventilatory frequency than an increase in tidal volume.
Overall, this point demonstrates, as described in Dr Pandit's article from 2002,6 that the results of studies in humans are affected by sometimes only slight differences in study design and more importantly by a wide variation of the individual responses, which can make it difficult to detect small differences. This is also the most likely explanation why Dr Pandit did not find a significant effect of sevoflurane on the hypercapnic response in eight adult volunteers,8 while we did find significant differences using 11 inbred mice.1
Finally, Dr Pandit raises concern about the validity of our mouse model of a blunted respiratory drive. Without doubt, any animal model leaves concerns about how many of the conclusions can be transferred to human physiology and pathophysiology. However, studies on respiratory drive in patients or human volunteers suffer from the wide interindividual differences in hypercapnic and hypoxic responses, discussed in our article. Therefore, we used inbred mice to minimize these individual (genetic) differences. Moreover, as Dr Pandit points out, the mice we used were not without a response to a hypercapnic challenge. They were not Pickwickian mice. They were at the lower end of the normal responses from a variety of mice strains. It was one of our main interests to see how individuals with a low but not obviously pathological response behaved. In human terms, these might be the individuals most at risk, in contrast to well monitored patients with a known impairment of their respiratory drive.
We thank Dr Pandit for writing to express his concerns and for pointing out how much is still unclear in this field of research.
Essen, Germany
References
1 Groeben H, Meier S, Tankersely CG, Mitzner W, Brown RH. Influence of volatile anaesthetics on hypercapnoeic ventilatory responses in mice with blunted respiratory drive. Br J Anaesth 2004; 92: 697703
2 van den Elsen M, Sarton E, Teppema L, Berkenbosch A, Dahan A. Influence of 0.1 minimum alveolar concentration of sevoflurane, desflurane and isoflurane on dynamic ventilatory response to hypercapnia in humans. Br J Anaesth 1998; 80: 17482[CrossRef][ISI][Medline]
3 Dahan A, Sarton E, van den Elsen M, van Kleef J, Teppema L, Berkenbosch A. Ventilatory responses to hypoxia in humans. Influences of subanaesthetic desflurane. Anesthesiology 1996; 85: 608[ISI][Medline]
4 van den Elsen M, Dahan A, Berkenbosch A, DeGoede J, van Kleef JW, Olievier ICW. Does subanesthetic isoflurane affect the ventilatory response to acute isocapnic hypoxia in healthy volunteers? Anesthesiology 1994; 81: 8607[ISI][Medline]
5 Temp JA, Henson LC, Ward DS. Effects of subanesthetic minimum alveolar concentration of isoflurane on two tests of the hypoxic ventilatory response. Anesthesiology 1994; 80: 73950[ISI][Medline]
6 Pandit JJ. The variable effect of low-dose volatile anaesthetics on the acute ventilatory response to hypoxia in humans: a quantitative review. Anaesthesia 2002; 57: 63243[CrossRef][ISI][Medline]
7 Pandit JJ, Moreau B, Robbins PA. Interaction of arousal states with depression of acute hypoxic ventilatory response by 0.1 MAC halothane. Adv Exp Med Biol 2004; in press
8 Pandit JJ, Manning-Fox J, Dorrington KL, Robbins PA. Effects of subanaesthetic sevoflurane on ventilation. 1: Response to acute and sustained hypercapnia in humans. Br J Anaesth 1999; 83: 2049
9 Groeben H, Meier S, Tankersley CG, Mitzner W, Brown RH. Heritable differences in respiratory drive and breathing pattern in mice during anaesthesia and emergence. Br J Anaesth 2003; 91: 5415
10 Sollevi A, Lindahl SGE. Hypoxic and hypecapnic ventilatory responses during isoflurane sedation and anaesthesia in women. Acta Anaesthesiol Scand 1995; 39: 9318[ISI][Medline]