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*Department of Anesthesiology, University of Washington, Seattle, Washington;
Department of Pharmacology, Rush Medical College, Chicago; and
Pharmaconsultant, Inc., Palatine, Illinois
Address correspondence and reprint requests to Michael J. Bishop, MD, Anesthesiology and Medicine (Adjunct), University of Washington School of Medicine, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108. Address e-mail to bish{at}u.washington.edu
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Abstract |
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IMPLICATIONS: Because of case reports of severe bronchospasm after the use of mivacurium, we used the Food and Drug Administration MedWatch database to determine the frequency of bronchospasm as an adverse event after the use of nondepolarizing muscle relaxants.
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Introduction |
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We requested and received, under the Freedom of Information Act, the FDA Adverse Event Reporting System compact disks for 2.25 yr of data from the fourth quarter of 1997 through the end of 1999. We searched for all AEs for the drugs mivacurium, pancuronium, vecuronium, rapacuronium, rocuronium, and atracurium and then searched specifically for the terms "bronchospasm/aggravated" and "asthma/aggravated." These terms are from the Medical Dictionary for Regulatory Activity (Northrop Grumman Mission Systems, Reston, VA) "Preferred Terms" for indexing adverse drug reactions. Searches were conducted using proprietary software created by Corel Corporation (Ottawa, Canada) for Pharmaconsultants, Inc. (Palatine, IL) to facilitate searching the FDA records. The proportion of all AEs that were bronchospasm or asthma were compared using a 
2 test for mivacurium versus each of the other muscle relaxants.
Two case reports from the FDA files are presented as well as a summary of the data received for 1997–1999. We were not involved in any of these cases and have no knowledge of them beyond the FDA files. These cases were chosen because the medico-legal consultation details are confidential and cannot be published.
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Case Reports |
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A 25-kg 6-yr-old boy with a history of albuterol use after respiratory infections was anesthetized for removal of tonsils and adenoids. The patient underwent an inhaled induction with halothane via a mask and then received 0.15 mg/kg IV mivacurium. The patient became extremely difficult to ventilate and developed hypoxemia. The patient was treated with atropine, diphenhydramine, and terbutaline as well as inhaled albuterol and isoetharine. Surgery was canceled because of persistent bronchospasm.
Within the FDA database, AEs for mivacurium disproportionately include bronchospasm or asthma when compared with either pancuronium or vecuronium (22.4% for mivacurium, 2.0% for pancuronium, 10.6% for vecuronium, and 7.6% for rocuronium) (P < 0.01 for mivacurium versus each of these drugs) or atracurium (13.5%, P = 0.06) using 2 analysis. The proportion of bronchospastic AEs for mivacurium was, however, far less than for rapacuronium—15 of 23 AEs reported during that period for rapacuronium were for bronchospasm. The calculated odds ratio for an adverse reaction attributed to bronchospasm is thus 11-fold for mivacurium compared with pancuronium and twofold compared with vecuronium. The raw numbers of reports for each drug are presented in Table 1. The market share for short/intermediate-acting muscle relaxants in the year 2000 was 53% for rocuronium, 24% for vecuronium, and 7% for mivacurium (IMS Health, Westport, CT).
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In 1996, a case report of anaphylaxis to mivacurium appeared in the literature (1) and in 1999, a study from France (2) found that muscle relaxants were the most common cause of anaphylactic reactions during anesthesia. Eighteen such cases were reported for mivacurium as compared with 41 for rocuronium, 107 for atracurium, and 130 for vecuronium. In 2001, the following information was added to the drug labeling: "From post marketing surveillance, Mivacron has been associated with reports of anaphylactic/anaphylactoid reactions. In some of these reports, sensitivity to Mivacron was confirmed using skin test procedures."
Because of the difficulty in developing a true incidence for a rare event, we studied the FDA database of adverse reactions and looked at the incidence of bronchospasm as compared with all AEs. This is similar to the technique used in analysis of the Closed Claims Project of the American Society of Anesthesiologists, in which factors associated with certain events are compared with the universe of all closed claims (3). One potential pitfall with this analysis is the possibility that mivacurium had an overall less frequent risk of nonbronchospasm AEs, which could have resulted in a relatively larger percentage of the AEs attributed to bronchospasm.
A small prospective study of mivacurium administration in children anesthetized with sevoflurane and propofol found that mivacurium caused a slight decrease in expiratory flows at small lung volume (4). The authors postulated that this was unrelated to histamine release because the patients had no cutaneous signs of a histamine reaction. The magnitude of the response was far less than for the comparison drug, rapacuronium.
Why might mivacurium be more likely to cause reported bronchospasm than atracurium or vecuronium? Rapidly infused intubating doses of mivacurium cause slightly larger histamine release than do comparable doses of atracurium, curare, vecuronium, or rocuronium (5). However, these differences alone do not seem sufficient to explain the apparent cases of severe bronchospasm with mivacurium. Drugs may release histamine by dissociating protein-bound histamine or they may lead to release via mast cell degranulation (6) A study of mast cell activation in human skin found that mivacurium was by an order of magnitude the most potent muscle relaxant in activation of mast cells when mast cell activation was considered as a function of the peak plasma concentration typically seen in plasma (7). Besides histamine, mast cells release other bronchoconstricting mediators such as leukotrienes. Some, but not all of the bronchoconstricting effects of large mivacurium doses in rabbits are abolished by antihistamines, further suggesting that other mediators besides histamine are involved in the reaction (8). Hence, potency for histamine release may not necessarily correlate with ability to induce bronchospasm. It may be that in asthmatics, or other patients who have larger numbers of mast cells present in the lungs, mivacurium may be the trigger for a severe reaction.
An alternative explanation for neuromuscular blocker-induced bronchospasm is blockade of M2 muscarinic receptors. Rapacuronium, in clinically achieved concentrations, inhibits M2 receptor binding (9). Because M2 receptor activation inhibits vagally induced bronchospasm, such blockade may facilitate bronchospasm. However, in in vitro studies, mivacurium has relatively low potency for the M2 muscarinic receptor and only at concentrations larger than those achieved with clinical use (10).
Given the infrequent incidence of severe bronchospasm during anesthesia (11), definitive data concerning the effect of a drug are difficult to identify. However, the anecdotal experience of the authors in medico-legal referral, combined with the FDA data analysis, suggests that extreme caution be exercised in the administration of mivacurium to patients at risk for bronchospasm (as suggested by the manufacturer) and that alternative drugs be considered for such patients.
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This article has been cited by other articles:
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  S. M. Katz and M. J. Bishop Mivacurium and Bronchospasm * Response Anesth. Analg., January 1, 2004; 98(1): 272 - 272. [Full Text] [PDF]
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