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Unwarranted Administration of Acetylcholinesterase Inhibitors Can Anesthesiology 2007; 107:621–9 Copyright © 2007, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Unwarranted Administration of Acetylcholinesterase Inhibitors Can Impair Genioglossus and Diaphragm Muscle Function Matthias Eikermann, M.D., Ph.D.,* Philipp Fassbender,† Atul Malhotra, M.D.,‡ Masaya Takahashi, Ph.D.,§ Shigeto Kubo, M.D.,࿣ Amy S. Jordan, Ph.D.,# Shiva Gautam, Ph.D.,** David P. White, M.D.,†† Nancy L. Chamberlin, Ph.D.§ Background: It is standard practice to administer a cholines- tromyogram effects were the same when neostigmine was given terase inhibitor (e.g., neostigmine) at the end of a surgical case with no previous NB. Neostigmine caused a decrease in upper to reverse suspected effects of neuromuscular blocking agents airway volume to 83 ؎ 3% of control, whereas end-expiratory lung regardless of whether such residual effects are present. The volume remained constant. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/621/364870/0000542-200710000-00018.pdf by guest on 02 October 2021 authors hypothesized that cholinesterase inhibition when Conclusions: The cholinesterase inhibitor neostigmine mark- given the in absence of neuromuscular blockade (NB) would edly impairs upper airway dilator volume, genioglossus muscle decrease upper airway dilatory muscle activity and conse- function, diaphragmatic function, and breathing when given quently upper airway volume. after recovery from vecuronium-induced neuromuscular block. Methods: The authors measured genioglossus and diaphragm electromyograms during spontaneous ventilation in anesthe- PARTIAL neuromuscular transmission failure (train-of- tized, tracheostomized rats before and after administration of four [TOF] ratio at the adductor pollicis muscle: 0.5–0.9) neostigmine (0.03, 0.06, or 0.12 mg/kg), after recovery of the evokes dysphagia,1 aspiration,1 and a decrease in the rate train-of-four ratio (quadriceps femoris muscle) to unity after NB 2,3 -of maximum airflow during inspiration by partial in ؍ (n 18). For comparison, the authors made the same measure- 4 In intact spiratory upper airway obstruction. These signs and .(27 ؍ ments in rats that had no previous NB (n 1–4 5 anesthetized rats, the authors measured upper airway volume symptoms can be difficult to detect because they and end-expiratory lung volume by magnetic resonance imag- may be present even with a magnitude of muscle weak- ness insufficient to evoke dyspnea or a decrease in vital .(9 ؍ ing before and after 0.12 mg/kg neostigmine (n Results: Neostigmine treatment in rats that had fully recovered capacity,3–5 respiratory drive,4,6 or lung volume,4 sug- from NB based on the train-of-four ratio caused dose-dependent gesting that upper airway muscles are more vulnerable ؎ ؎ decreases in genioglossus electromyogram (to 70.3 7.6, 49.2 4 .and 39.7 ؎ 2.3% of control, respectively), decreases in dia- to NB than the respiratory “pump” muscles ,3.2 phragm electromyogram (to 103.1 ؎ 6.5, 83.1 ؎ 4.7, and 68.7 ؎ Cholinesterase inhibitors (ChEIs; e.g., neostigmine) are 7.3% of control), and decreases in minute ventilation to a nadir clinically useful to improve skeletal muscle function value of 79.6 ؎ 6% of preneostigmine baseline. Genioglossus elec- when receptors are partially blocked due to lingering effects of neuromuscular blocking agents.7,8 Therefore, Additional material related to this article can be found on the it is recommended to reverse effects of neuromuscular ANESTHESIOLOGY Web site. Go to http://www.anesthesiology blocking agents at the end of a surgical procedure by .org, click on Enhancements Index, and then scroll down to find ChEI administration.7,8 This approach increases skeletal the appropriate article and link. Supplementary material can also muscle force reliably in patients presenting with residual be accessed on the Web by clicking on the “ArticlePlus” link either in the Table of Contents or at the top of the Abstract or neuromuscular blockade (NB) from short- or intermedi- 9 HTML version of the article. ate-acting neuromuscular blocking drugs. One possible drawback to this treatment practice is that ChEI-based reversal agents, in high doses having been applied to 7,10 * Assistant Professor, Brigham and Women’s Hospital and Harvard Medical humans by some anesthesiologists, can cause neuro- School; Universita¨tsklinikum Essen, Klinik fuer Ana¨sthesie und Intensivmedizin, muscular transmission failure when administered to pa- Essen, Germany. † Research Associate, Brigham and Women’s Hospital and 11–14 Harvard Medical School; Beth Israel Deaconess Medical Center and Harvard tients who have already recovered from NB. ChEIs Medical School, Boston, Massachusetts. ‡ Assistant Professor, # Instructor, may cause neuromuscular transmission failure by desen- †† Gerald E. Mc Ginness Professor of Sleep Medicine, Brigham and Women’s 13 Hospital and Harvard Medical School. § Assistant Professor, ࿣ Research Fellow, sitization of acetylcholine receptors, depolarization ** Associate Professor, Beth Israel Deaconess Medical Center and Harvard Medical block of neuromuscular transmisssion,12 or open chan- School, Boston, Massachusetts. nel block.15 Neuromuscular transmission impairment of Received from the Division of Sleep Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Submitted for publication respiratory muscles could increase the risk of developing February 21, 2007. Accepted for publication July 6, 2007. Supported by grants respiratory complications. from the National Institute of Health (Beeson Award K23 AG024837-01), Nos. P50 HL 60292 and RO1-HL73146 (National Institutes of Health, Bethesda, Mary- The objective for this preclinical study in rats was to land); and Organon International Inc., Roseland, New Jersey. Organon did not study the dose–response relation of ChEIs on genioglos- participate in generation of the protocol, data analysis and interpretation, or writing. sus muscle and diaphragmatic activity to maintain nor- 16 Address correspondence to Dr. Eikermann: Department of Anesthesia and mal upper airway dimensions. We hypothesized that Critical Care, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114-2696. [email protected]. Informa- neostigmine, when given after recovery from NB (based tion on purchasing reprints may be found at www.anesthesiology.org or on the on TOF ratio), would decrease upper airway dilatory 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 muscle activity and consequently upper airway volume. date of the issue. We further aimed to explore whether giving neostig- Anesthesiology, V 107, No 4, Oct 2007 621 622 EIKERMANN ET AL. mine to rats that had recovered from NB would be as integrated on a moving-time-average basis with a time detrimental as giving neostigmine to rats that had re- constant of 100 ms. Tonic genioglossus activity was ceived no previous NB treatment. defined as nadir (expiratory) genioglossus activity during expiration minus genioglossus activity measured after euthanasia of the rat. This approach was used to discrim- Materials and Methods inate between electrical noise and the small tonic genio- glossus signal. Phasic genioglossus activity was defined Fifty-seven adult male Sprague-Dawley rats (300–400 as peak inspiratory genioglossus activity minus nadir g, Harlan Sprague-Dawley; Indianapolis, IN) were used in expiratory activity of the same respiratory cycle. Tra- these experiments. All procedures were approved by cheal airflow was recorded by using a pneumotacho- local animal care and use committees (Harvard Medical graph (Fleisch 00; Gould Medical Ltd., Lutterworth, School, Boston, MA), and every effort was made to min- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/621/364870/0000542-200710000-00018.pdf by guest on 02 October 2021 United Kingdom) and differential pressure transducer imize the numbers of rats used and their suffering. (PT5; Grass Instruments) attached to the tracheostomy cannula. We also measured continuously end-tidal car- Experimental Preparation bon dioxide with an infrared carbon dioxide analyzer. Electromyographic recording electrodes were inserted All signals were digitized and analyzed off-line with during isoflurane (Baxter Healthcare Corporation, Deer- Axotape and Clampfit software (Molecular Devices, field, IL) anesthesia into the diaphragm and the genio- Sunnyvale, CA). glossus (one on each side of the midline by open sur- gery). The trachea was carefully transected (protocols 1 Protocols and 2 only) and cannulated proximally, and a femoral Pilot Study. In a pilot study (n ϭ 6 rats), we admin- artery and vein were cannulated for measurement of istered 0.06 mg/kg neostigmine (Sicor Pharmaceuticals arterial blood pressure and administration of drugs and Inc., Irvine, CA) and glycopyrrolate (American regent fluid, respectively.17 To assess the degree of NB, the Inc., Shirley, NY) during pancuronium (Bexter, Deer- femoral nerve was stimulated and the evoked muscular field, IL)–evoked NB (target NB ϭ TOF ratio 0.2–0.5) to response was measured by accelerometry of the quadri- determine whether the typical mg/kg dose used in hu- ceps femoris muscle (TOF-Watch SX Monitor; Organon mans would be appropriate in rats. International, Oss, The Netherlands; as depicted in fig- Protocol 1. Neuromuscular blocking drugs were not ures E1 and E2 on the ANESTHESIOLOGY
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