To the Editor: 

In the March issue of ANESTHESIOLOGY, Istaphanous et al.  1compared the neurotoxic properties of isoflurane, sevoflurane, and desflurane in 7- to 8-day-old mice and found that all three agents cause a similar degree of neuronal cell death in the immature brain. This is at odds with other investigations reporting that sevoflurane has a more favorable neurotoxicity profile than, for example, isoflurane2,,4or propofol.5However, Istaphanous et al.  1recognized that comparative studies require equianalgesic dosing and attempted to establish such a dosing regimen. They administered 0.6 minimum alveolar concentrations (MAC), of each agent for 6 h. MAC was determined by tail clamping after an equilibration period of 15 min, after which the anesthetic concentration was adjusted according to prospectively defined criteria, and the response to tail clamping was reassessed after another 15-min equilibration period. A total of four tail clampings were performed per mouse. Using this methodology, the inspired anesthetic concentration, determined to be MAC for isoflurane, sevoflurane, and desflurane, was 2.7, 5.4, and 12.2, respectively.1As the authors pointed out, MAC is age-dependent, so it would have been inappropriate to simply use the published MAC for adult animals.

The authors1stated that MAC of isoflurane in 7- to 8-day-old mice agreed well with MAC of isoflurane in 7-day old rats, which had been found previously to be 2.75% atm (atmosphere).6We would like to point out that this is only a small part of the story, in that MAC was 2.75% atm only after 1 h of isoflurane anesthesia.6After 4 h of anesthesia, the inspired MAC of isoflurane had decreased to 1.21% atm, a 56% decrease.6In the same study,6the brain concentration of isoflurane after 1 h of isoflurane anesthesia was only 1.9%, indicating that equilibration between inspired and brain partial pressures of isoflurane had not yet occurred.6The same is true for the rather insoluble agent desflurane (data not shown), which may come as a surprise. Although we have not done the same experiment using sevoflurane, a central assumption underlying the methodology used by Istaphanous et al. , that equilibration between inspired and brain concentrations of volatile agents in immature rodents is complete within 15 min,1may not be correct.

After 4 h of anesthesia, the inspired and brain partial pressures of isoflurane had equilibrated and the brain isoflurane concentration at MAC was 1.27%, which is 33% less than at 1 h of anesthesia.6Therefore, both the inspired and the brain partial pressures that constitute MAC are moving targets in immature rats but not adult ones.6Administration of 1 MAC of a volatile agent to immature rats, and possibly also to mice, requires a continuous adjustment of the anesthetic concentration.6,Figure 1A shows the anesthetic depth of a 7-day-old rat anesthetized for 4 h with the isoflurane concentration determined to be MAC. Using this steady anesthetic concentration, the anesthetic depth initially would be less than 1 MAC, then exactly 1 MAC for a very brief period of time, followed by greater than 1 MAC for the remainder of the anesthetic period. Figure 1, B and C, show that a similar decrease of MAC occurs with increasing duration of sevoflurane and desflurane anesthesia in 7-day-old rats. Figure 1also suggests that the anesthetic concentrations used by Istaphanous et al.  1may or may not have been equipotent. Using isoflurane at a steady concentration of 0.6 MAC would result in an anesthetic depth of 1 MAC at approximately 2:30 h and exceed 1 MAC presumably for the remainder of the 6-h anesthetic period, although we cannot exclude the possibility that MAC increases between 4 and 6 h of anesthesia, however unlikely that seems. With sevoflurane, MAC is reached at approximately 1:45 h, and with desflurane, MAC is not reached until 3:15 h. Figure 2shows that the impression of lack of equipotency is confirmed when expressing the data as percentage of MAC given in figure 1. Using Simpson's method, we calculated the areas under the curves shown in figure 2, which are 328, 336, and 416 for isoflurane, desflurane, and sevoflurane, respectively. If MAC in 7-day-old mice decreases with increasing duration of anesthesia, as is the case for rats,6Istaphanous et al.  1would have used a relatively greater dose of sevoflurane than isoflurane and an even greater dose than that of desflurane. It might be prudent, for the time being, to keep an open mind regarding the relative neurotoxicity of the three volatile agents tested.

Fig. 1. Seven-day-old rats were anesthetized in groups of at least 10. Tail clamping was performed, and the anesthetic concentration was adjusted, as shown here in table 1. Minimum alveolar concentration (MAC) of isoflurane decreases with increasing duration of anesthesia (A ). MAC of desflurane decreases with increasing duration of anesthesia (B ). MAC of sevoflurane decreases with increasing duration of anesthesia (C ). atm = atmosphere.

Fig. 1. Seven-day-old rats were anesthetized in groups of at least 10. Tail clamping was performed, and the anesthetic concentration was adjusted, as shown here in table 1. Minimum alveolar concentration (MAC) of isoflurane decreases with increasing duration of anesthesia (A ). MAC of desflurane decreases with increasing duration of anesthesia (B ). MAC of sevoflurane decreases with increasing duration of anesthesia (C ). atm = atmosphere.

Table 1. Protocol for Adjusting Isoflurane, Sevoflurane, and Desflurane to 1 MAC in Postnatal Day 7 Rats

Table 1. Protocol for Adjusting Isoflurane, Sevoflurane, and Desflurane to 1 MAC in Postnatal Day 7 Rats
Table 1. Protocol for Adjusting Isoflurane, Sevoflurane, and Desflurane to 1 MAC in Postnatal Day 7 Rats

Fig. 2. Percentages of minimum alveolar concentrations (MAC) were calculated using the formula: (0.6 MAC from Istaphanous et al.  1/MAC from figure 1C × 100). The 0.6 MAC of Istaphanous et al.  1expressed as percent of MAC at 1.62% isoflurane from figure 1A (A ). The 0.6 MAC of Istaphanous et al.  1expressed as percent of MAC at 7.32% desflurane from figure 1B (B ). The 0.6 MAC of Istaphanous et al.  1expressed as percent of MAC at 3.24% sevoflurane from figure 1C (C ).

Fig. 2. Percentages of minimum alveolar concentrations (MAC) were calculated using the formula: (0.6 MAC from Istaphanous et al.  1/MAC from figure 1C × 100). The 0.6 MAC of Istaphanous et al.  1expressed as percent of MAC at 1.62% isoflurane from figure 1A (A ). The 0.6 MAC of Istaphanous et al.  1expressed as percent of MAC at 7.32% desflurane from figure 1B (B ). The 0.6 MAC of Istaphanous et al.  1expressed as percent of MAC at 3.24% sevoflurane from figure 1C (C ).

*University of California, San Francisco, San Francisco, California. stratman@anesthesia.ucsf.edu

References

1.
Istaphanous GK, Howard J, Nan X, Hughes EA, McCann JC, McAuliffe JJ, Danzer SC, Loepke AW: Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. ANESTHESIOLOGY 2011; 114:578–87
2.
Wei H, Kang B, Wei W, Liang G, Meng QC, Li Y, Eckenhoff RG: Isoflurane and sevoflurane affect cell survival and BCL-2/BAX ratio differently. Brain Res 2005; 1037:139–47
3.
Yang H, Liang G, Hawkins BJ, Madesh M, Pierwola A, Wei H: Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. ANESTHESIOLOGY 2008; 109:243–50
4.
Wang QJ, Li KZ, Yao SL, Li ZH, Liu SS: Different effects of isoflurane and sevoflurane on cytotoxicity. Chin Med J (Engl) 2008; 121:341–6
5.
Bercker S, Bert B, Bittigau P, Felderhoff-Müser U, Bührer C, Ikonomidou C, Weise M, Kaisers UX, Kerner T: Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia. Neurotox Res 2009; 16:140–7
6.
Stratmann G, Sall JW, Eger EI 2nd, Laster MJ, Bell JS, May LD, Eilers H, Krause M, Heusen F, Gonzalez HE: Increasing the duration of isoflurane anesthesia decreases the minimum alveolar anesthetic concentration in 7-day-old but not in 60-day-old rats. Anesth Analg 2009; 109:801–6