䡵 CASE REPORT

Anesthesiology 2005; 102:473–5 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Severe Bronchospasm after Parenteral Parecoxib:

IN a subset of patients with asthma, nonsteroidal antiin- and after a short period of ventilation in the operating room, she was
flammatory drugs (NSAIDs) that inhibit both cyclooxy- allowed to wake up and was extubated. She was transferred to the
postanesthesia care unit, where she received nebulized ipratropium bro-
genase 1 (COX-1) and cyclooxygenase 2 (COX-2) can mide and salbutamol, and her bronchospasm resolved within 30 min. A
precipitate dangerous asthmatic attacks. It has been pro- chest x-ray film showed normal lung fields with no evidence of pneumo-
posed that in these patients, the attacks are triggered by thorax. Arterial blood gas measurement was normal. The patient was
inhibition of COX-1 and not COX-2, and that the use of returned to the ward after a few hours in the postanesthesia care unit,
highly selective COX-2 inhibitors may be safe in asth- with no lasting adverse effects. Her case was reviewed by the respiratory
physicians, who commenced her on a short course of oral steroids. She
matic patients, even those with sensitivity to NSAIDs.1 was discharged home the next day.
We describe two cases of acute, life-threatening bron-
chospasm after administration of parecoxib, a parenteral
COX-2 inhibitor, in patients with a history of asthma but Case 2
no previous history of aspirin or other NSAID sensitivity.
A 70-yr-old man presented for urgent laparotomy for large bowel
obstruction. He had a history of ischemic heart disease and had under-
gone coronary artery bypass grafting 10 yr previously; he had atrial
Case 1 fibrillation for which he was anticoagulated with warfarin, non–insulin-
dependent diabetes mellitus, and chronic obstructive airway disease.
A 26-yr-old woman was admitted for arthroscopy of her left knee. She
He used inhaled ipratropium bromide four times a day. He had no
reported a history of mild asthma, which was well controlled with inhaled
known drug allergies. On examination, he had mild bilateral wheezing.
salbutamol and beclomethasone. She had no known drug allergies. Anes-
A rapid sequence induction was performed, and anesthesia was
thesia was induced with fentanyl and propofol, and a laryngeal mask
maintained with sevoflurane in oxygen and nitrous oxide. Muscle
airway was inserted. Anesthesia was maintained with sevoflurane in oxy-
relaxation was achieved with vecuronium, and morphine was given for
gen and nitrous oxide. Surgery proceeded uneventfully, and toward the
analgesia. The patient was ventilated for a few hours in the intensive
end of the case, 40 mg parecoxib sodium was administered intravenously.
care unit postoperatively. He underwent extubation the next morning
Within 10 min after administration, the patient began to desaturate, and
and was later transferred to the ward on a morphine patient-controlled
her peak airway pressures increased acutely to the extent that she became
analgesia pump.
extremely difficult to ventilate. The laryngeal mask airway was removed
The next day, the patient was allowed to sit out of bed and contin-
on suspicion that it had become displaced. However, the patient contin-
ued his preoperative ipratropium bromide regimen. He received rou-
ued to desaturate despite the application of positive end-expiratory pres-
tine chest physiotherapy and was noted to have a moderately effective
sure via a facemask. The patient underwent immediate intubation with a
cough with little sputum and no wheezing on auscultation. He later
clear view of the endotracheal tube going through the glottic opening.
reported breakthrough pain and was given an intramuscular injection
After intubation, the patient continued to desaturate, and there was
of 40 mg parecoxib sodium. During the next 2 h, the patient became
minimal chest movement with hand ventilation. No end-tidal carbon
increasingly dyspneic, wheezy, and hypoxic. He required reintubation
dioxide was detected, and there was no air entry heard on auscultation.
and transfer back to the intensive care unit, where he was treated with
The patient became bradycardic and required one dose of 0.6 mg atropine
nebulized bronchodilators and intravenous steroids. He underwent
and a brief period of chest compressions. During this time, salbutamol was
extubation 3 days later and was discharged back to the ward, where he
administered via a metered dose inhaler through the endotracheal tube.
made a full recovery.
An end-tidal carbon dioxide trace appeared on the monitor, and the chest
began to move more easily with hand ventilation. On auscultation, there
was diffuse bilateral wheezing. The patient’s saturations recovered to 98%,
Discussion

This article is featured in “This Month in Anesthesiology.” Nonsteroidal antiinflammatory drugs are now widely
䉫 Please see this issue of ANESTHESIOLOGY, page 5A. used for the management of postoperative pain. However,
these drugs are associated with a number of adverse ef-
fects, including gastrointestinal damage, deterioration in
* Specialist Registrar, † Consultant Anaesthetist. renal function, impaired platelet aggregation, and broncho-
Received from the Department of Anaesthesia and Intensive Care, Beaumont spasm. In some asthmatic individuals, aspirin and other
Hospital, Dublin, Ireland. Submitted for publication July 4, 2004. Accepted for NSAIDs exacerbate the condition. This may sometimes
publication September 27, 2004. Support was provided solely from institutional
and/or departmental sources. Presented at the joint meeting of the Canadian take the form of a distinct clinical syndrome called aspirin-
Anesthesiologists’ Society and the College of Anaesthetists, Royal College of induced asthma or aspirin-sensitive respiratory disease
Surgeons in Ireland, in conjunction with the South of Ireland Association of
Anaesthetists, Killarney, Co., Kerry, Ireland, September, 27, 2003. and is characterized by an eosinophilic rhinosinusitis, nasal
Address reprint requests to Dr. Looney: Department of Anaesthesia and Inten- polyposis, aspirin sensitivity, and asthma. The incidence of
sive Care, Beaumont Hospital, Dublin 9, Ireland. Address electronic mail to:
ymlooney@[Link]. Individual article reprints may be purchased through the
NSAID sensitivity in asthmatic adults is thought to be 3–5%
Journal Web site, [Link]. based on patients’ histories alone but may be as high as 15%

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when adult asthmatic patients are prospectively challenged known as coxibs, are well tolerated and can be safely
with an NSAID.2 However, because asthmatic patients may used in these patients.1,8 –11
deliberately avoid NSAIDs or may not recognize mild These highly selective inhibitors of COX-2, namely
NSAID-induced reactions, aspirin-sensitive respiratory dis- celecoxib, rofecoxib, and parecoxib, theoretically
ease remains widely underdiagnosed in this particular pop- should not cause airway mucosal inflammation because
ulation. The asthmatic attacks that ensue are often severe of the preservation of constitutive prostaglandin E2.
and, in many cases, may be life threatening, requiring emer- Therefore, it is thought that selective COX-2 inhibitors
gency mechanical ventilation.3 should be safe in patients with NSAID sensitivity.
The clinical presentation of an NSAID-related attack is Parecoxib sodium is an injectable prodrug of valde-
usually that of an acute asthma attack developing within coxib, which is a potent and selective inhibitor of
3 h after ingestion of the drug. This can be accompanied COX-2. It is the first parenteral COX-2–selective inhibitor
by profuse rhinorrhea, conjunctival injection, sometimes to be developed for the management of pain. Various
a scarlet flushing of the head and neck, and occasionally studies have demonstrated the tolerance of selective
periorbital edema, abdominal pain, and minor degrees of COX-2 inhibitors in patients with NSAID-sensitive respi-
urticaria. Definitive diagnosis can be established only by ratory disease. Martin-Garcia et al.8 showed that all 40 of
provocation tests using increasing doses of aspirin. More their study patients, who had previously experienced
recently, provocation tests have been accompanied by asthma induced by at least two different NSAIDs, toler-
measurement of urinary leukotriene E4, which increases ated a 25-mg dosage of rofecoxib well, without any signs
proportionally with the increasing severity of the respi- of immediate or delayed reactions, and concluded that
ratory reaction.4 rofecoxib is a suitable NSAID for treatment of patients
The mechanism of this extreme sensitivity to NSAIDs with aspirin- and other NSAID-induced asthma. Similarly,
remains unclear. We know that cyclooxygenase enzymes the same investigators showed that celecoxib at a dose
exist in at least two isoforms, which are encoded by dis- of 200 mg was well tolerated by all 33 participants in a
tinct genes. Both isoforms constitute the central core of a study of patients with the same condition.9 Stevenson
coenzyme called prostaglandin H2 synthase, which in and Simon1 showed that none of 60 patients with aspi-
turn is responsible for the formation of oxygen radicals, rin-induced asthma reacted to rofecoxib after oral inges-
prostacyclin, prostaglandin F2␣, and prostaglandin E2 from tion and concluded that cross-reactivity between aspirin
arachidonic acid. COX-1 is the constitutive form and is and rofecoxib does not occur in these patients. Dahlen
found in most cells in the body. It is the main source of et al.10 examined 27 patients with aspirin intolerance for
prostaglandin E2 in all organ systems. COX-2 is induced bronchospasm after the administration of celecoxib and
during inflammation and enhances the synthesis of inflam- found that it did not induce any adverse reaction. In a
matory prostanoids. Much evidence suggests that prosta- recent double-blind, randomized, crossover, increasing-
glandin E2 may have an important part to play in maintain- dose challenge study with placebo or celecoxib, inves-
ing bronchial patency.5 Prostaglandin E2 partially inhibits tigators looked for biochemical and clinical evidence
5-lipooxygenase, which is involved in the production of that COX-2 inhibitors are well tolerated in aspirin-intol-
leukotrienes. These provoke constriction of smooth mus- erant asthmatic patients, and the study showed no sig-
cle and stimulation of airway mucus production, a hallmark nificant differences in pulmonary function, nasal symp-
of allergic and inflammatory reactions. Prostaglandin E2 tom scores, extrapulmonary responses (such as dermal
also has a role in stabilizing mast cells, thus preventing flush, urticaria, and gastrointestinal symptoms) or uri-
discharge of preformed mediators, histamine and tryptase. nary leukotriene E4 concentrations after oral celecoxib
The reduction of prostaglandin E2 by COX-1 inhibitors in 33 subjects with aspirin-intolerant asthma.11 How-
seems to contribute to the pathogenesis of NSAID-induced ever, all of these studies involved limited numbers of
respiratory reactions. When concentrations of prostaglan- patients, and the patients were desensitized by receiving
din E2 decrease, their inhibitory effect on mast cells and progressively larger oral doses of the COX-2 inhibitor for
eosinophils declines and then disappears. 5-Lipooxygenase a few days before receiving a therapeutic dose.
activity remains unchecked and hastens the synthesis of In both of our cases, severe, life-threatening broncho-
new leukotrienes. At the same time, mast cells discharge spasm occurred within a short period after administra-
their contents. The upper respiratory reaction is thought to tion of parenteral parecoxib. On questioning after the
be predominantly caused by histamine.6 It has been found event, the patient in case 1 confirmed that she had taken
that in patients with NSAID-induced asthma, bronchial oral COX-2 inhibitors infrequently in the past without
prostaglandin E2 is already deficient, thus making them noticing any ill effects. The patient in case 2 had avoided
more susceptible to cyclooxygenase inhibition.7 NSAIDs because he was taking warfarin. All of the stud-
Recent clinical studies indicate that it is the inhibition ies in the literature to date involved gradually exposing
of COX-1 and not COX-2 that precipitates asthmatic subjects to therapeutic doses of oral COX-2 inhibitors
attacks, and there is a growing body of evidence indicat- over a period of days. Both of our patients received the
ing that the new, highly specific COX-2 inhibitors, recommended dosage of parecoxib (40 mg) by the par-

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