Newly Published
Perioperative Medicine  |   July 2019
Genetic Analysis of Patients Who Experienced Awareness with Recall while under General Anesthesia
Author Notes
  • From Department of Anaesthesiology, Waikato Clinical Campus, University of Auckland, Hamilton, New Zealand (J.W.S.); Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia (K.L.); Centre for Integrated Critical Care (K.L.), Department of Pharmacology and Therapeutics (K.L.), Department of Paediatrics (A.J.D., D.J.A., P.J.L.), and Department of Medical Biology (M.B.), The University of Melbourne, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (K.L.); Department of Anaesthesia, Royal Children’s Hospital, Melbourne, Australia (A.J.D.); Murdoch Children’s Research Institute, Melbourne, Australia (A.J.D., D.J.A.); Royal Children’s Hospital, Melbourne, Australia (D.J.A.); Population Health and Immunity Division (P.D., M.B.) and Bioinformatics Division (V.L.), The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Melbourne, Australia (P.J.L.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication October 10, 2018. Accepted for publication June 4, 2019.
    Submitted for publication October 10, 2018. Accepted for publication June 4, 2019.×
  • Correspondence: Address correspondence to Dr. Sleigh: Department of Anaesthesiology, Waikato Clinical School, Hamilton, New Zealand. Jamie.sleigh@waikatodhb.health.nz. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Patient Safety / Pharmacology
Perioperative Medicine   |   July 2019
Genetic Analysis of Patients Who Experienced Awareness with Recall while under General Anesthesia
Anesthesiology Newly Published on July 15, 2019. doi:10.1097/ALN.0000000000002877
Anesthesiology Newly Published on July 15, 2019. doi:10.1097/ALN.0000000000002877
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • The incidence of explicit recall of intraoperative events, or awareness with recall, is less than 0.2%

  • Anesthetic dosing is apparently adequate in 10 to 25% of awareness with recall patients

  • The awareness with recall phenotype only reveals itself when patients are exposed to anesthesia

What This Article Tells Us That Is New:

  • A preliminary study sought to determine whether there is evidence that awareness with recall is caused by a few rare variants with high penetrance in 12 patients who had experienced awareness with recall in the presence of apparently adequate anesthesia

  • Whole exome sequencing was conducted and identified variants were filtered and prioritized to identify a candidate list that might be suitable for further investigation of causes of awareness with recall

  • No candidate gene(s) suggestive of a monogenic etiology were identified, possibly because of the application of a filtering strategy, the small sample size, or use of exome sequencing, which does not interrogate potentially important regulatory noncoding sequences

Background: Intraoperative awareness with recall while under apparently adequate general anesthesia is a rare, unexplained, and often very distressing phenomenon. It is possible that a relatively small number of genetic variants might underlie the failure of general anesthetic drugs to adequately suppress explicit memory formation and recall in the presence of apparently adequate anesthesia concentrations.

Methods: The authors recruited 12 adult patients who had experienced an episode of intraoperative awareness with recall (compared with 12 controls), performed whole exome sequencing, and applied filtering to obtain a set of genetic variants that might be associated with intraoperative awareness with recall. The criteria were that the variant (1) had a minor allele frequency less than 0.1% in population databases, (2) was within exonic or splicing regions, (3) caused a nonsynonymous change, (4) was predicted to be functionally damaging, (5) was expressed in the top 50% of genes expressed in the brain, and (6) was within genes in Kyoto Encyclopedia of Genes and Genomes pathways associated with general anesthesia, drug metabolism, arousal, and memory.

Results: The authors identified 29 rare genetic variants in 27 genes that were absent in controls and could plausibly be associated with this disorder. One variant in CACNA1A was identified in two patients and two different variants were identified in both CACNA1A and CACNA1S. Of interest was the relative overrepresentation of variants in genes encoding calcium channels and purinergic receptors.

Conclusions: Within the constraints of the filtering process used, the authors did not find any single gene variant or gene that was strongly associated with intraoperative awareness with recall. The authors report 27 candidate genes and associated pathways identified in this pilot project as targets of interest for future larger biologic and epidemiologic studies.