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Correspondence  |   February 2004
Delayed Postoperative Arousal following Remifentanil-based Anesthesia in a Myasthenic Patient Undergoing Thymectomy
Author Affiliations & Notes
  • Anis S. Baraka, M.D., F.R.C.A.
    *
  • *American University of Beirut, Beirut, Lebanon.
Article Information
Correspondence
Correspondence   |   February 2004
Delayed Postoperative Arousal following Remifentanil-based Anesthesia in a Myasthenic Patient Undergoing Thymectomy
Anesthesiology 2 2004, Vol.100, 460-461. doi:
Anesthesiology 2 2004, Vol.100, 460-461. doi:
To the Editor:—
Remifentanil (Ultiva; GlaxoSmithKline, Middlesex, UK) is an “ultra-short”–acting opioid that is rapidly hydrolyzed by circulating and tissue nonspecific esterases. Discontinuation of remifentanil infusion will be followed by a rapid recovery regardless of the duration of infusion. 1 The present report used the remifentanil-based technique of anesthesia, without the use of muscle relaxants, in a myasthenic gravis patient undergoing transternal thymectomy. However, the patient manifested unexpected delay of postoperative arousal for 12 h. This is the first case report about a significant delay of postoperative arousal following discontinuation of remifentanil infusion.
A 19-yr-old female patient (body weight, 57 kg) presented with myasthenia gravis (Osserman 2A) associated with a thymoma. Pyridostigmine, 60 mg, four times daily was administered for 2 months, to be followed by transternal thymectomy. The pyridostigmine regimen was maintained until the morning of surgery.
Premedication was limited to 0.2 mg intramuscular glycopyrrolate and1 mg intravenous midazolam. Anesthesia was induced with100 mg lidocaine and 2 mg/kg propofol intravenously, to be followed by 3.0 μg/kg remifentanil over 30 s, and tracheal intubation. Anesthesia was maintained by sevoflurane 1–2% in 100% oxygen, supplemented with remifentanil infusion (0.1–0.25 μg · kg−1· min−1). Neuromuscular transmission was monitored by electromyography using a Datex relaxograph (NMT-100–23–01; Datex-Ohmeda Division, Instrumentarium Corp, Helsinki, Finland), using the electromyographic response to ulnar nerve stimulation by the train-of-four. Intraoperatively, blood pressure ranged between 75/30 mmHg and 105/55 mmHg, heart rate ranged between 55 and 90 bpm, and electromyography showed normal T1/control and T4/T1 ratios. The duration of surgery was 2 h. Thirty minutes before the end of surgery, 5 mg intramuscular morphine was administered. Twenty minutes before the end of surgery, sevoflurane was turned off, and on completion of surgery remifentanil infusion was discontinued. The total dose of remifentanil administered throughout surgery amounted to about 2,000 μg.
Ten minutes after discontinuation of remifentanil, the patient started to breathe spontaneously, to respond to painful stimuli, and to buck on the tube. The trachea was extubated and the patient was transferred to the recovery room while receiving oxygen via  a facemask. In the recovery room, the patient exhibited sleepiness, pinpoint pupils, and sluggish response to light glabellar tap or loud auditory stimulus, but she responded to painful stimulus (Ramsay scale 5). Her blood pressure ranged between 70/40 mmHg and 90/60 mmHg; the heart rate ranged between 50 and 60 bpm. The patient maintained spontaneous breathing at a rate of 8–10 breaths per minute. Her oxygen saturation measured by pulse oximetry while breathing room air was 90%; arterial blood gases showed Po278 mmHg, Pco244 mmHg, and pH 7.32. Oxygen saturation increased to 97% with oxygen via  facemask. After 12 h, the patient started to respond to verbal stimuli and to have adequate spontaneous breathing, as evidenced by increased respiratory rate and by oxygen saturation of 95% while breathing room air.
Remifentanil is an esterase-metabolized opioid. 1 The esterase-based metabolism of remifentanil makes its pharmacokinetics independent of end organ failure 2,3 and results in a half-life of about 9–11 min. 4 
Our myasthenic patient had been receiving pyridostigmine for 2 months previous to the morning of surgery. Postoperatively, the patient remained somnolent for 12 h. This delayed postoperative arousal could not be attributed to the propofol, sevoflurane, or the small dose of morphine administered during surgery. Also, myasthenic respiratory depression was excluded because the T4/T1 ratio was greater than 0.9. The delayed arousal may be attributed to a possible inhibition of the nonspecific esterases hydrolyzing remifentanil by pyridostigmine.
Pyridostigmine is the traditional antiacetylcholinesterase that is used orally for the symptomatic management of myasthenia gravis. In addition to its antiacetylcholinesterase effect, Baraka et al.  showed that pyridostigmine inhibits the plasma pseudocholinesterase (butyrylcholinesterase) by about 70%, 5 which explains the low plasma cholinesterase activity and the prolonged neuromuscular block of succinylcholine in myasthenia gravis patients pretreated by pyridostigmine. 6 However, remifentanil does not appear to be a substrate for butyrylcholinesterases. 7,8 It is possible that pyridostigmine is a nonselective esterase inhibitor that may inhibit not only the acetylcholinesterase and butyrylcholinesterase enzymes, but also the nonspecific esterases that metabolize remifentanil with a subsequent delayed arousal.
Naloxone was not administered to confirm the diagnosis in our patient, and the blood concentrations of remifentanil were not measured. Therefore, the supposition that because pyridostigmine inhibits acetylcholinesterase and butyrylcholinesterase it might also inhibit the enzymes responsible for remifentanil’s metabolism is purely speculative. However, the present report calls to our attention that myasthenia gravis patients maintained on a pyridostigmine regimen up to the morning of surgery may be extremely sensitive to drugs metabolized by nonspecific esterases such as remifentanil.
References
Dershwitz M, Rosow CE: Remifentanil: A truly short-acting opioid. Semin Anesth 1996; 15( 1): 88–96Dershwitz, M Rosow, CE
Frank HJ, Shlugman D, Dershwitz M, Michalowski P, Malthouse-Dufore S, Connors PM, Martel D, Rosow CE, Muir KT, Rubin N, Glass P: Pharmacokinetics anesthesiologists, and phamacodynamics of remifentanil in persons with renal failure compared with healthy volunteers. Anesth Analg 1997; 87: 533–41Frank, HJ Shlugman, D Dershwitz, M Michalowski, P Malthouse-Dufore, S Connors, PM Martel, D Rosow, CE Muir, KT Rubin, N Glass, P
Dershwitz M, Hoke JF, Rosow CE, Michalowski P, Connors PM, Muir KT, Dienstag JL: Pharmacokinetics and phamacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesth Analg 1999; 84: 812–20Dershwitz, M Hoke, JF Rosow, CE Michalowski, P Connors, PM Muir, KT Dienstag, JL
Burkle H, Dunbar S, Van Aken H: Remifentanil: A novel, short-acting, mu-opioid. Anesth Analg. 1996; 83: 646–51Burkle, H Dunbar, S Van Aken, H
Baraka A, Wakid N, Mansour R, Haddad W: Effect of neostigmine and pyridostigmine on the plasma cholinesterase activity. Br J Anaesth 1981; 53: 849–51Baraka, A Wakid, N Mansour, R Haddad, W
Baraka A: Suxamethonium block in the myasthenic patient: Correlation with plasma cholinesterase. Anaesthesia 1992; 47: 217–9Baraka, A
Davis PJ, Stiller RL, Wilson AS, McGowan FX, Egan T, Muir KT: In vitro remifentanil metabolism: The effects of whole blood constituents and plasma butyrylcholinesterase. Anesth Analg 2002; 95: 1305–7Davis, PJ Stiller, RL Wilson, AS McGowan, FX Egan, T Muir, KT
Manullang J, Egan T: Remifentanil’s effect is not prolonged in a patient with pseudocholinesterase deficiency. Anesth Analg. 1999; 89: 529–30Manullang, J Egan, T