Anesthesia With and Without Nitrous Oxide and Long-term Cognitive Trajectories in Older Adults

Abstract

Background: We evaluated the hypothesis that the rate of postoperative decline in global cognition is greater in older adults exposed to general anesthesia with nitrous oxide (N2O) compared to general anesthesia without N2O.

Methods: Longitudinal measures of cognitive function were analyzed in nondemented adults, 70-91 years of age, enrolled in the Mayo Clinic Study of Aging. Linear mixed-effects models with time-varying covariates assessed the relationship between exposure to surgery with general anesthesia (surgery/GA) with or without N2O and the rate of long-term cognitive changes. Global cognition and domain-specific cognitive outcomes were defined using z scores, which measure how far an observation is, in standard deviations, from the unimpaired population mean.

Results: The analysis included 1819 participants: 280 exposed to GA without N2O following enrollment and before censoring during follow-up (median [interquartile range {IQR}] follow-up of 5.4 [3.9-7.9] years); 256 exposed to GA with N2O (follow-up 5.6 [4.0-7.9] years); and 1283 not exposed to surgery/GA (follow-up 4.1 [2.5-6.4] years). The slope of the global cognitive z score was significantly more negative following exposure to surgery/GA after enrollment (change in slope of -0.062 [95% confidence interval {CI}, -0.085 to -0.039] for GA without N2O, and -0.058 [95% CI, -0.080 to -0.035] for GA with N2O, both P < .001). The change in slope following exposure to surgery/GA did not differ between those exposed to anesthesia without versus with N2O (estimated difference -0.004 [95% CI, -0.035 to 0.026], P = .783).

Conclusions: Exposure to surgery/GA is associated with a small, but statistically significant decline in cognitive z scores. Cognitive decline did not differ between anesthetics with and without N2O. This finding provides evidence that the use of N2O in older adults does not need to be avoided because of concerns related to decline in cognition.

Figure 1.

Mayo Clinic Study of Aging (MCSA) participants according to exposures to general anesthesia (GA) with and without nitrous oxide after study enrollment. Abbreviations: CU, cognitively unimpaired; MCI, mild cognitive impairment; GA, general anesthesia. Of the 1,564 participants who were cognitively normal at baseline, 1,243 were in the original 2004 enrollment cohort and their baseline cognitive scores were included in the reference distribution used for calculating z-scores.

Figure 2.

Simulated trajectories for four hypothetical individuals under three scenarios (no post-enrollment exposure to anesthesia; a post-enrollment exposure to anesthesia with N₂O and without N₂O). The four hypothetical individuals were chosen to represent varying degrees of cognitive function at enrollment. The plot demonstrates statistically significant acceleration in decline of cognitive trajectories after exposure to surgery with general anesthesia. This acceleration was similar after anesthesia with vs. without N₂O. The clinical significance of the change of the acceleration decline of cognitive z-scores is relative to the level of cognitive reserve at the time of exposure. For individuals with above average cognitive function at the time of exposure (Individuals 1 and 2) there may be no clinical implications (i.e., development of mild impairment) until years following exposure, whereas individuals whose cognitive function is already below average (Individuals 3 and 4) clinical implications would be experienced sooner.