Clinical and Genetic Factors Associated with Intraoperative Minimum Alveolar Concentration Ratio: A Single-center Retrospective Cohort and Genome-wide Association Study.

Background: Minimum alveolar concentration (MAC) is a standard dosing metric for general anesthesia. Although influences of MAC have been identified in controlled studies, the determinants of clinical delivery of MAC ratio are largely unknown. To address this knowledge gap, the authors performed this single-center retrospective study. The primary objective was to understand factors associated with MAC ratio, as indexed by the end-tidal volatile anesthetic concentration, for a given case. It was hypothesized that mean arterial pressure (MAP) was strongly associated with anesthetic delivery; a secondary objective was to perform a genome-wide association study to identify genetic variants associated with MAC ratio in clinical practice.

Methods: The primary outcome was mean age-adjusted MAC ratio during the maintenance phase of anesthesia. The primary exposure variable was mean MAP during the same time window. The correlation between the outcome, exposure, and a variety of demographic, laboratory, procedural, and anesthetic covariates was assessed in adjusted multivariable linear regressions. Next, the authors performed two genome-wide association studies of clinically delivered MAC ratio.

Results: Of the 30,125 cases included in the final dataset, mean ± SD age-adjusted MAC ratio was 1.066 ± 0.173, and mean MAP was 82 ± 10 mmHg. MAP was associated with MAC ratio in the overall model (β = 0.0028; 95% CI, 0.0024 to 0.0032; P < 0.0001). A variety of demographic ( e.g. , female sex: β = -0.0182; 95% CI, -0.0219 to -0.0144; P < 0.0001), laboratory, surgical, and anesthetic factors were also associated with anesthetic agent concentration. Eight variants located near six genes ( DPH6 , CPM , EEFSEC , SGSM1 , CDH9 , and DISC1 ) reached the lower suggestive threshold ( P < 1 × 10 -6 ) in one but not both models; none exceed the threshold for genome-wide significance ( P < 5 × 10 -8 ).

Conclusions: The hypothesis was verified that MAP was associated with clinical delivery of MAC ratio. The authors also characterized practice patterns of inhalational anesthetic management and identified numerous covariates that need to be accounted for when modeling anesthetic requirements. Female patients received lower doses of anesthetic, despite evidence that they have a higher requirement. While genome-wide association studies failed to identify novel variants at the level of genome-wide significance ( P < 5 × 10 -8 ), multiple mechanistically plausible genes were suggested. Notably, the DISC1 gene has been shown to impact resting-state brain activations under general anesthesia with isoflurane and has been linked to abnormal sleep/wake patterns.