1144 Tryptophan and Cysteine Mutations in M1 Helices of α1β3γ2L γ-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site
A number of clinically important general anesthetics positively modulate function of γ-aminobutyric acid type A (GABAA) receptors through allosteric interactions with their transmembrane domains. Most GABAA receptors consist of two α, two β, and one γ subunit arranged βαβαγ counterclockwise, creating four distinct types of subunit interfaces: α+-β–, α+-γ–, β+-γ–, and two β+-α–. Several intravenous anesthetics bind within intersubunit cavities as identified by anesthetic photolabeling with photoreactive anesthetics. Complementary structure-function studies involving site-directed mutagenesis of amino acid residues lining the five predicted intersubunit binding pockets in a typical GABAA receptor show that four intravenous anesthetics have distinct but overlapping patterns of interaction with the receptor. These findings validate previous anesthetic photolabeling findings and further define the properties of the distinct sites that mediate the potentiating effects of various intravenous anesthetics with GABAA receptors. See the accompanying Editorial View on page 1088.
1113 Effectiveness of an Electronic Alert for Hypotension and Low Bispectral Index on 90-day Postoperative Mortality: A Prospective, Randomized Trial
Two studies reported an association between the cumulative duration of a “triple low” of low mean arterial pressure (MAP), low bispectral index (BIS), and low end-tidal minimum alveolar concentration and mortality. The hypothesis that an automated intraoperative decision support alert for double low conditions, defined as MAP less than 75 mmHg and BIS less than 45, will reduce 90-day all-cause mortality was tested in 19,092 patients having noncardiac surgery who were randomized to receive either alerts for double low events or no alerts. Double low alerts prompted clinical intervention that decreased double low duration slightly, but did not decrease 90-day mortality. Advanced age, American Society of Anesthesiologists Physical Status of 3 or higher, and clinical comorbidities were all strong predictors of mortality. After controlling for patient and procedural risk factors, prolonged exposure to double low conditions was associated with increased 90-day mortality.
1121 Perioperative Aspirin for Prevention of Venous Thromboembolism: The PeriOperative ISchemia Evaluation-2 Trial and a Pooled Analysis of the Randomized Trials
The PeriOperative ISchemia Evaluation-2 (POISE-2) trial determined the effects of perioperative aspirin and clonidine on a broad range of cardiovascular outcomes in patients having noncardiac surgery. The present article reports the effects of aspirin on the occurrence of venous thromboembolism (VTE) in 10,010 POISE-2 patients randomly assigned to receive 200 mg aspirin or placebo 2 to 4 h before surgery followed by 100 mg aspirin daily or placebo for up to 30 days after surgery. VTE occurred in 53 patients (1.1%) allocated to aspirin and in 60 patients (1.2%) allocated to placebo (hazard ratio [HR] for the aspirin group = 0.89; 95% CI, 0.61–1.28). Major or life-threatening bleeding occurred in 312 patients (6.3%) allocated to aspirin and in 256 patients (5.1%) allocated to placebo (HR = 1.22; 95% CI, 1.04–1.44).
1103 Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance
The highly polymorphic cytochrome P4502B6 (CYP2B6) is the major enzyme catalyzing hepatic ketamine N-demethylation and overall ketamine metabolism at clinically relevant concentrations. The hypothesis that CYP2B6 variants (CYP2B6*6 heterozygotes or homozygotes) in vivo will have decreased ketamine metabolism and clearance was tested in 30 volunteers, 10 with each of the genotypes CYP2B6*1/*1 (wild-type), CYP2B6*1/*6, and CYP2B6*6/*6, who were administered a nonsedating oral dose of ketamine. There were no significant differences among subjects with the various genotypes in the N-demethylation of ketamine, assessed as either norketamine/ketamine area under the plasma concentration versus time curve ratio or norketamine formation clearance. There were also no differences in plasma concentrations of either enantiomer of ketamine, the primary metabolite norketamine, or the secondary metabolite dehydronorketamine. In vitro genetic differences may not have translated to in vivo differences because ketamine is a high hepatic extraction ratio drug. See the accompanying Editorial View on page 1085.
1136 Dose–response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man
The benzylisoquinolinium nondepolarizing neuromuscular blocking drug CW002 had an ED95 of 0.01 to 0.04 mg/kg in a variety of animal models and an intermediate duration of action. CW002 had minimal cardiopulmonary side effects and caused no histamine release in animal models until doses much larger than the ED95 were administered. A phase 1, first-in-man study was conducted to assess CW002 potency and neuromuscular blockade onset and recovery, along with dose-related effects on plasma histamine concentration, blood pressure, heart rate, and ventilation dynamics. The ED95 of CW002 in man was approximately 0.077 mg/kg. The clinical onset time of CW002 at a dose that was 1.8 times the ED95 was approximately 90 s and its mean clinical duration was 34 min. The ED95 of CW002 in man produced minimal cardiopulmonary side effects and no histamine release.
1221 Appropriateness of Language Used in Patient Educational Materials from 24 National Anesthesiology Associations
Patient education material produced by national anesthesiology associations is meant to help the public understand the contributions of anesthesiologists to perioperative care and may be used to facilitate patient informed consent. Material written for patients should use language between the sixth and eighth grade level. The linguistics of topically organized content from online patient educational materials generated by 24 anesthesiology associations in six English-speaking countries were evaluated using software that provides linguistic norms grouped into grade levels between kindergarten and twelfth grade. Two thirds of the anesthesiology associations examined provided educational materials, no passages of which had all linguistic measures at or below the eighth grade level. The language used was especially inappropriate for topics that are critical to promoting the discipline of anesthesiology and facilitating patient informed consent.
1159 Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity
Hippocampal dentate granule cells, which play important roles in cognition and behavior, are especially vulnerable to anesthesia-induced neurotoxicity in postnatal day 21 (P21, a brain maturational stage comparable to human infants) mice. Because granule cells are produced throughout life, the dentate could regenerate lost cells. A genetic fate-mapping approach was used to determine whether developmental anesthesia exposure leads to persistent deficits in granule cell numbers. Granule cell progenitors were genetically fate-mapped in P7 mice by inducing persistent green fluorescent protein (GFP) expression and animals were exposed to 6 h of 1.5% isoflurane on P21. Although isoflurane treatment produced a fivefold increase in apoptosis among GFP-labeled daughter cells immediately after anesthesia, GFP-labeled cell density in animals exposed to isoflurane was not different from that in control animals 60 days later, when animals were young adults. See the accompanying Editorial View on page 1090.
1229 Intensive Care Unit Delirium: A Review of Diagnosis, Prevention, and Treatment (Clinical Concepts and Commentary)
Delirium is a common and serious clinical manifestation of acute brain organ dysfunction associated with important adverse clinical outcomes. Recognition of this has led to routine screening for delirium and an increased interest in identifying and implementing effective prevention strategies. This Clinical Concepts and Commentary explores both predisposing and precipitating risk factors for intensive care unit (ICU) delirium, tools for its diagnosis such as the Confusion Assessment Method for the ICU and the Intensive Care Delirium Screening Checklist, preventative strategies including multidisciplinary ICU care bundles, and its potential pharmacologic treatments. This information can be used throughout the patient’s hospitalization, including in the perioperative environment, and can be practiced by anesthesiologists as well as intensivists to improve patient care.