broncoespasmo durante induccion2011

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Bruno Riou, M.D., Ph.D., Editor

Case Scenario: Bronchospasm during Anesthetic Induction

Pascale Dewachter, M.D., Ph.D.,* Claudie Mouton-Faivre, M.D.,† Charles W. Emala, M.D.,‡Sadek Beloucif, M.D., Ph.D.§

This article has been selected for the ANESTHESIOLOGY CME Program. Learningobjectives and disclosure and ordering information can be found in the CMEsection at the front of this issue.

B RONCHOSPASM, the clinical feature of exacerbatedunderlying airway hyperreactivity, has the potential to

become an anesthetic disaster. During the perioperative pe-riod, bronchospasm usually arises during induction of anes-thesia but may also be detected at any stage of the anestheticcourse. Accordingly, prompt recognition and appropriatetreatment are crucial for an uneventful patient outcome.Perioperative bronchospasm (i.e., the clinical expression ofexacerbated underlying airway reactivity) may be associatedwith type E immunoglobulin (IgE)-mediated anaphylaxis ormay occur as an independent clinical entity, triggered byeither mechanical and/or pharmacologic factors. Whateverthe clinical circumstances, different triggers are identified inthe occurrence of perioperative bronchospasm with asthma,a chronic inflammatory disorder of the airways frequentlyinvolved. The purpose of this clinical scenario is to discussthe key points of perioperative bronchospasm.

Case Report

A 25-yr-old woman with morbid obesity (body mass index:54 kg/m2) and noninsulin-dependent diabetes was sched-uled for cochlear implant surgery. She had two previous sur-geries without incident during childhood. She denied anyhistory of atopy or drug allergy. Chest auscultation was nor-mal before anesthesia. She was premedicated with hy-droxyzine (100 mg orally) the day before and 1 h beforeanesthesia, which was induced with sufentanil (20 �g intra-venously) and propofol (350 mg intravenously). Trachealintubation (Cormack and Lehane grade I) was facilitatedwith succinylcholine (130 mg intravenously). After trachealintubation was performed, chest auscultation revealed acomplete absence of bilateral breath sounds. Initial concen-trations of end-tidal carbon dioxide (ETCO2) were low. Be-cause an esophageal intubation was suspected, the patientwas immediately extubated and mask ventilation attempted.Mask ventilation was difficult to perform because of dramat-ically decreased lung compliance, whereas ETCO2 demon-strated a marked prolonged expiratory upstroke of the cap-nogram. Therefore, bronchospasm was considered. Rapidarterial oxygen desaturation (oxygen saturation measured bypulse oximetry [SpO2], 55%) followed by arterial hypoten-sion (from 130/75 to 50/20 mmHg) associated with a mod-erate tachycardia (100 beats/min) occurred in less than 5 minafter the onset of bronchospasm. Concomitantly, titratedepinephrine (two intravenous boluses of 100 �g each) alongwith fluid therapy with crystalloids (lactated Ringer’s solu-tion, 1,000 ml) corrected the cardiovascular disturbances (ar-terial blood pressure, 110/50 mmHg; heart rate, 110 beats/min) while at the same time ventilation became easier toperform along with the return of audible wheezing over bothlung fields. As arterial blood pressure was restored, a localized(face and upper thorax) erythema occurred. Hydrocortisone(200 mg) was intravenously administered. A blood samplewas obtained to measure serum tryptase concentrations, 40and 90 min after the clinical reaction. Surgery was post-

* Staff Anesthesiologist, Service d’Anesthesie-Reanimation andSAMU de Paris, Universite Paris-Descartes, INSERM UMRS-970 andHopital Necker-Enfants Malades, Assistance Publique Hopitaux deParis, Paris, France; † Staff Internist and Allergologist, Poled’Anesthesie-Reanimation Chirurgicale, CHU Hopital Central,Nancy, France; ‡ Professor, Department of Anesthesiology, Collegeof Physicians and Surgeons, Columbia University, New York, NewYork; § Professor, Service d’Anesthesie-Reanimation, UniversiteParis 13 & Hopital Avicenne, Assistance Publique Hopitaux de Paris.

Received from the Universite Paris-Descartes, Paris, France. Sub-mitted for publication August 28, 2010. Accepted for publication Feb-ruary 11, 2011. Support was provided solely from institutional and/ordepartmental sources. Figures 1–3 in this article were prepared byAnnemarie B. Johnson, C.M.I., Medical Illustrator, Wake Forest Univer-sity School of Medicine Creative Communications, Wake Forest Uni-versity Medical Center, Winston-Salem, North Carolina.

Address correspondence to Dr. Dewachter: Serviced’Anesthesie-Reanimation & SAMU de Paris, Hopital Necker-Enfants Malades, 149 Rue de Sevres 75743 Paris Cedex 15,France. [email protected]. This article may be ac-cessed for personal use at no charge through the Journal Website, www.anesthesiology.org.

Copyright © 2011, the American Society of Anesthesiologists, Inc. LippincottWilliams & Wilkins. Anesthesiology 2011; 114:1200–10

Anesthesiology, V 114 • No 5 May 20111200

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poned, and the patient was transferred to the intensive careunit. No additional supportive vasopressor therapy was re-quired. Respiratory symptoms resolved within 2 h after in-haled �2-agonist (salbutamol; i.e., albuterol) and intravenouscorticoids (hydrocortisone, cumulative dose: 800 mg over24 h). Subsequent clinical outcome was uneventful, and thepatient was discharged home the following day and returned6 weeks later for allergologic assessment (see section III).

Discussion

I. Diagnosis and Differential Diagnosis of IntraoperativeWheezing/BronchospasmBronchospasm encountered during the perioperative periodand especially after induction/intubation may involve an im-mediate hypersensitivity reaction including IgE-mediatedanaphylaxis or a nonallergic mechanism triggered by factorssuch as mechanical (i.e., intubation-induced bronchospasm)or pharmacologic-induced (via histamine-releasing drugssuch as atracurium or mivacurium) bronchoconstriction inpatients with uncontrolled underlying airway hyperreactiv-ity.1,2 Chest auscultation should be done to confirm wheezing,whereas decreased or absent breath sounds suggest critically lowairflow.3 The differential diagnosis includes inadequate anesthe-sia, mucous plugging of the airway, esophageal intubation,kinked or obstructed tube/circuit, and pulmonary aspiration.3

Unilateral wheezing suggests endobronchial intubation or anobstructed tube by a foreign body (such as a tooth).3 If theclinical symptoms fail to resolve despite appropriate therapy,other etiologies such as pulmonary edema or pneumothoraxshould also be considered.

II. Diagnosis of a Perioperative Immediate ReactionImmediate hypersensitivity is a clinical entity evoking allergythat varies in severity1 and is subdivided into nonallergichypersensitivity (called anaphylactoid reaction by the Amer-ican Academy of Allergy Asthma and Immunology) where animmune mechanism is excluded, and allergic hypersensitivity(also called IgE-mediated anaphylaxis).4 By definition, im-mediate hypersensitivity occurs within 60 min after the in-jection/introduction of the culprit agent.1 The initial diag-nosis remains presumptive, whereas the etiologic diagnosis islinked to a triad including clinical features (the description ofthe clinical features according to the adapted Ring and Mess-mer� clinical severity scale); blood tests (tryptase level mea-surements, serum-specific IgEs); and postoperative skin testswith the suspected drugs or agents.1

III. Etiology of This Perioperative ImmediateHypersensitivity in the Current CaseThe sudden occurrence of bronchospasm after anesthetic in-duction, with cardiovascular disturbances and cutaneoussigns, clinically suggested a drug-induced anaphylactic reac-tion. Succinylcholine-induced anaphylaxis was the mostlikely etiology, because neuromuscular blocking agents arethe most frequent agents involved in perioperative anaphy-laxis in adults.1,5 Skin testing remained negative in responseto propofol, sufentanil, succinylcholine, and latex solutions(Allerbio, Varennes en Argonne, France and Stallergenes,Antony, France). Tryptase levels (ImmunoCAP, PhadiaSAS, Uppsala, Sweden) were unchanged (5.4 �g � l�1 and4.3 �g � l�1; N less than 13.5 �g � l�1) in blood samplesobtained 40 and 90 min, respectively, after the onset of thereaction. Serum-specific IgEs (ImmunoCAP) against succi-nylcholine and latex were not detectable. Specific serum IgEagainst quaternary ammonium was slightly increased (2.08kU/L, N less than 0.1). A basophil activation test was alsoperformed and analyzed using a FACSCanto II flow cytom-eter (Becton-Dickinson, Rungis, France). Succinylcholineinduced neither CD63 nor CD203c up-regulation.Clinical Considerations. The chronology of evolving clinicalfeatures is crucial to understand the pathophysiologic mech-anism of an immediate hypersensitivity reaction.

Cardiovascular disturbance is the hallmark of severe IgE-mediated anaphylaxis. In patients with neuromuscularblocking agent-induced perioperative anaphylaxis, cardio-vascular signs are usually the inaugural clinical event andoccur within minutes after the drug challenge. These cardio-vascular signs may be associated with or followed by bron-chospasm in 19–40% of patients, more likely in those withunderlying asthma or chronic obstructive pulmonary dis-ease.1 Drug-induced anaphylactic bronchospasm may occureither before or after instrumentation of the airway2 (fig. 1).

Latex-induced anaphylaxis typically occurs in patientswith a history of atopy.6 Because atopy is the strongest iden-tifiable predisposing factor for the development of asthma,7

severe clinical features occurring during latex-induced ana-phylaxis usually involve cardiovascular signs followed by orassociated with bronchospasm and cutaneous signs.8 As latexproteins are slowly absorbed, latex-induced anaphylaxis usu-ally occurs up to 30–60 min after the beginning of surgery(i.e., mucous membrane exposure).8

Acute increases in airway responsiveness may also occur inthe absence of an antigen challenge and result from irritationof the well-innervated upper airway by a foreign body (e.g.,endotracheal tube or suction catheter).2 Thus, nonallergicbronchospasm immediately follows nonspecific stimuli andusually is not associated with cardiovascular symptoms2 (fig. 1).Nevertheless, positive end-expiratory pressure with severe bron-chospasm may lead to a decrease in venous return and hence ofcardiac output. In addition, the association of hypoxia and re-spiratory failure from inadequate ventilation may lead tocardiovascular collapse.9

� Grade I: Erythema, urticaria with or without angioedema;grade II: cutaneous-mucous signs � hypotension � tachycardia �dyspnea � gastrointestinal disturbances; grade III: cardiovascularcollapse, tachycardia, or bradycardia � cardiac dysrythmia � broncho-spasm � cutaneous-mucous signs � gastrointestinal disturbances;grade IV: cardiac arrest.

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Anesthesiology 2011; 114:1200 –10 Dewachter et al.1201

IV. Distinguishing the Pathophysiologic Mechanism ofPerioperative Bronchospasm ClinicallyFour clinical variables were identified as independent predic-tors of allergic compared with nonallergic perioperativebronchospasm: the presence of any cutaneous symptoms;shock; episodes of desaturation; and the prolonged durationof clinical features (longer than 60 min).2 Compared withthat of patients who did not present with these “predictive”signs as part of the clinical syndrome, the occurrence of hy-potension or episodes of oxygen desaturation were 27 and 21times, respectively, more likely to be associated with IgE-mediated anaphylaxis. In addition, symptom duration lon-ger than 60 min or the presence of skin changes was two andseven times, respectively, more likely to be associated withIgE-mediated anaphylaxis.2 In the current case, inauguralsevere bronchospasm triggered by endotracheal tube inser-tion and followed by cardiovascular collapse, likely related tosubsequent hypoxemia after the patient’s extubation, yieldsclinical insight into the pathophysiologic mechanism of thereaction and suggests nonallergic bronchospasm. Cutaneoussigns, such as erythema, are not specific for IgE-mediatedanaphylaxis per se and may also be observed during nonaller-gic bronchospasm.2 The morbid obesity of the patient isof clinical interest and could also have been a precipitatingfactor of rapid arterial desaturation despite appropriatepreoxygenation.Allergologic Assessment: Blood Tests and Skin Testing. Atryptase increase is specific for mast cell activation such asthat occurring during IgE-mediated anaphylaxis.1 Increasedtryptase levels appear to distinguish clearly between allergicand nonallergic perioperative bronchospasm.2 Thus, Fisher2

suggested that an allergologic assessment is unnecessary in

patients with isolated bronchospasm occurring after airwayinstrumentation without an increase in tryptase. In the cur-rent case, allergic mast cell activation was ruled out becausetryptase levels measured within the recommended timeframe remained unchanged. Skin tests were negative in re-sponse to the medications received (i.e., propofol, sufentanil,and succinylcholine) as well as latex. These results were cor-roborated by basophil activation tests showing an absence ofCD63 and CD203c up-regulation with succinylcholine, rul-ing out basophil sensitization by specific IgE toward succi-nylcholine and undetectable specific serum IgEs against suc-cinylcholine. Serum IgEs against quaternary ammonium wasslightly increased (2.08 kU/L, N less than 0.1), but theseassays appear to be less sensitive than skin tests and do notprove that the drug/agent is responsible for the reaction.10

Succinylcholine-induced anaphylaxis was therefore ruledout according to clinical, biologic, and allergologic evidence.This is of particular importance because succinylcholine isthereby allowed to be used for future anesthetics in this pa-tient. In turn, uncontrolled asthma was suggested to be themain trigger of this nonallergic bronchospasm after endotra-cheal tube insertion. Wheezing induced by bronchial infec-tion during childhood or triggered by cold weather and ex-ercise in adulthood was elicited from the patient’s historyduring the postoperative evaluation.

V. Asthma Is a Frequently Underdiagnosed ConditionAsthma is one of the most common chronic airway diseasesworldwide, with a higher prevalence and incidence in theWestern world.11 The estimated annual death rate world-wide is 250,000.12 However, this condition frequently re-mains underdiagnosed. In 2008, the following definition for

Fig. 1. Pathophysiologic mechanisms involved during perioperative immediate hypersensitivity reaction according to the onsetof bronchospasm when compared with endotracheal tube insertion.

Bronchospasm during Anesthetic Induction


asthma was suggested: “Asthma is a chronic disorder of theairway in which many cells and cellular elements play a role. Thechronic inflammation is associated with airway responsivenessthat leads to recurrent episodes of wheezing, breathlessness, chesttightness and coughing, particularly at night or in the earlymorning. These episodes are usually associated with widespread,but variable airflow obstruction within the lung, that is oftenreversible either spontaneously or with treatment.”12 This pro-posal was ratified in the United States.7 Accordingly, a Eu-ropean and American Task Force issued by the correspond-ing Respiratory Societies suggested that the definition ofasthma includes two domains (symptoms and variable airwayobstruction) being assessed in clinical practice, with two ad-ditional domains (airway inflammation and hyperrespon-siveness) characterizing the underlying disease. An individualmay have features of any or all of these domains.13 Airwayhyperresponsiveness is induced by a variety of changes in theairway and sustained by underlying airway inflammation, thehallmark of asthma.

Recently, a crucial modification in the approach toasthma management was proposed with a classification bythe level of asthma control (controlled, partly controlled, oruncontrolled) rather than asthma severity per se while linkingthe classification of asthma control to asthma treatment.12

Two Main Phenotypes of Asthma Can be Distinguished.Two main phenotypes of asthma, allergic and nonallergic,are most commonly discussed; overlap may occur withinthese groups.14

Allergic Asthma. The largest overall phenotype in childrenand adults is allergic asthma. Although allergic asthma is achronic and often lifelong disease, its onset occurs primarilyin early childhood. However, more than 50% of asthma isallergic in adults.4 It results from immunologic reactions,mostly initiated by IgE antibodies, and is also called IgE-mediated allergic asthma. Genetic factors may promote thedevelopment of allergic asthma (inheritable component).Environmental factors such as tobacco smoke, air pollutants,and exposure to allergens including indoor (mites, animals,plant origin, e.g., ficus), outdoor (pollens, molds) or occupa-tional allergens may trigger asthma. Obesity, diet, and a hy-giene hypothesis may also trigger asthma.11 Thus, any poten-tial risk factor must eventually interact with an underlyinggenetically determined pathway to result in the manifesta-tion of disease (epigenetic component). However, atopy, thegenetic predisposition for the development of an IgE-medi-ated response to common aeroallergens, is the strongest iden-tifiable predisposing factor for developing asthma.7 Two ma-jor factors such as airborne allergens and viral respiratoryinfections seem to be the most important in the develop-ment, persistence, and possibly the severity of allergicasthma.7

Allergic Rhinitis and Allergic Asthma Belong to the SameAirway Disease. The effect of allergic rhinitis on asthmashould also be highlighted15 because the link of this distur-bance with asthma remains poorly understood. Rhinitis is

characterized by nasal symptoms including sneezing, nasalblockage, and/or itching of the nose; is either intermittent orpermanent; and is classified as mild, moderate, or severe.15

More than 80% of asthmatic individuals have rhinitis, and10–40% of patients with rhinitis have asthma. A combinedstrategy should ideally be used to treat the upper and lowerairway diseases (allergen avoidance is crucial but inhaled/intranasal corticosteroid is the most consistently effectivelong-term control therapy attenuating airway inflamma-tion). 7,15 Because the presence of asthma must be consideredin all patients with rhinitis, those with severe and/or persis-tent uncontrolled allergic rhinitis should be evaluated forasthma before surgery.Nonallergic Asthma: Aspirin-induced Asthma. The othermain variant of asthma in adults includes a widely underdi-agnosed phenotype not seen in childhood, such as aspirin-induced asthma. Aspirin-induced asthma is characterized byeosinophilic rhinosinusitis, nasal polyposis, aspirin or non-steroidal antiinflammatory drug sensitivity, and asthma.Asthma and sensitivity to aspirin usually appear approxi-mately 1–5 yr after the onset of rhinitis,16 whereas rhinor-rhea, nasal congestion, and anosmia are usually the first clin-ical features of aspirin-induced asthma. This phenotyperesults from the inhibition of cyclooxygenase enzymes byaspirin-like drugs in the airway of sensitive patients and is notsustained by an allergic mechanism.16

VI. Perioperative BronchospasmAsthma is considered to be more prevalent in westernizedcountries.11 Surprisingly, no academic society of anesthesi-ology issued from the European or the North American con-tinents has published recommendations concerning the peri-operative management of the asthmatic patient. Theliterature on this topic remains scarce.Epidemiology of Perioperative Bronchospasm. The occur-rence of perioperative bronchospasm has been reported in upto 9% of asthmatic patients given general anesthesia, mainlyafter endotracheal tube insertion.17 Smoking also representsa major risk. Compared with that of nonsmokers, the relativerisk of perioperative bronchospasm in smokers appearshigher in females and in young smokers (16–39 yrs old) andis higher in patients with chronic bronchitis than in asymp-tomatic patients.18

Why and When Does Perioperative Bronchospasm Occur?Of the 4,000 incidents reported in Australia, 103 reports ofperioperative bronchospasm (3%) showed that an allergicmechanism was less frequently involved (21%) than a non-allergic mechanism (79%).19 Among these nonallergic cases,44% occurred during the induction of anesthesia, 36% dur-ing the maintenance phase, and 20% during the emergence/recovery stage. During induction of anesthesia, broncho-spasm was mainly related to airway irritation (64%), whereasremaining causes were due to tube misplacement (17%),aspiration (11%), and other pulmonary edema or unknowncauses (8%). During the maintenance stage of anesthesia,

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allergy (34%), endotracheal tube malposition (23%), airwayirritation (11%), and aspiration with a laryngeal mask airway(9%) together accounted for almost 80% of the occurrencesof bronchospasm. During induction or maintenance of an-esthesia, bronchospasm caused by airway irritation occurredmore frequently in patients who had one or more predispos-ing factors such as asthma, heavy smoking, or bronchitis.Others showed that an allergic mechanism accounted for60% of the cases in patients experiencing bronchospasm dur-ing induction of anesthesia.2 A previous history of asthmawas present in 50% and 60% of patients with nonallergic andallergic bronchospasm, respectively. Thus, uncontrolledasthma/chronic obstructive pulmonary disease is frequentlyinvolved with either pathophysiologic mechanisms (allergicvs. nonallergic), regardless of the stage of anesthesia (induc-tion or maintenance).Morbidity and Mortality Rates. Respiratory events ac-counted for 28% of claims concerning anesthesia-relatedbrain damage and death in the United States.20 In this series,bronchospasm was included in the other categories and to-gether corresponded to 11% of total respiratory events. Inthe United Kingdom, respiratory and airway incidents ac-counted for 3% and 8%, respectively, of all claims includingsevere and fatal outcomes.21 Bronchospasm was not detailed.Nevertheless, airway incidents belong to the claims with thehighest overall cost and respiratory complications with thehighest mean cost per closed claim. Seven percent of anes-thesia-related deaths were attributed to bronchospasm inFrance.22

In conclusion, bronchospasm remains a serious life-threatening perioperative event. Its dramatic consequencesinvolving brain damage or death may be partly explained bysubstandard care and/or inadequate practice and system fail-ures.20,22 Optimal management of perioperative broncho-spasm should therefore be encouraged through teaching ap-plications such as an anesthesia simulator to compensate forthe low frequency with which the average practitioner wouldencounter severe bronchospasm during routine clinical care.Basic Science: Mechanisms of Reflex-induced Broncho-constriction. The mechanisms of asthmatic exacerbationsresulting in bronchoconstriction are complex and involveairway nerves, smooth muscle, epithelium, and inflamma-tory cells. However, reflex-induced bronchoconstriction in-duced by irritation of the upper airway by a foreign bodysuch as an endotracheal tube is modulated by synapse ofafferent sensory pathways in the nucleus of the solitary tract,which projects to the airway-related vagal preganglionic neu-rons. The excitatory neurotransmitter glutamate modulatesstimulation of the nucleus of the solitary tract and airway-related vagal preganglionic neurons, whereas inhibitorynerves releasing �-aminobutyric acid project from the nu-cleus of the solitary tract to the airway-related vagal pregan-glionic neurons.23 The excitatory outflow from the airway-related vagal preganglionic neurons back to the airway iscarried in the vagus nerve and results in acetylcholine release

onto airway structures, most prominently the M3 muscarinicreceptor on airway smooth muscle that induces airway con-striction.24 Thus, the initial airway irritant stimulus sends anafferent signal to the brainstem, resulting in an efferent signaltraveling in the vagus and releasing acetylcholine in the air-way (fig. 2). Because acetylcholine acting on M3 muscarinicreceptors on airway smooth muscle is a key mechanistic com-ponent of reflex-induced bronchoconstriction, the use of an-timuscarinic-inhaled medications (e.g., ipratropium ortiotropium) should be advantageous to prevent or treat thisphenomenon.25 In addition, nonadrenergic noncholinergicnerves releasing tachykinins, vasoactive intestinal peptide,and calcitonin gene-related peptide may participate in thisreflex arc and/or locally release the procontractile neurotrans-mitters via activation of interneurons in the airway.26 A re-cent study suggests that propofol preferentially relaxes tachy-kinin-induced airway constriction in airway smoothmuscle.27 It has long been clinically recognized that thedepth of anesthesia modulates the likelihood of eliciting re-flex-induced bronchoconstriction, but the pharmacologicmechanisms by which this occurs are unknown. Propofol28

and the volatile inhalational anesthetics (with the exceptionof desflurane) are known to be clinically effective at prevent-ing reflex-induced bronchoconstriction or attenuating intra-operative bronchoconstriction.29 These agents share activityat inhibitory �-aminobutyric acid-A chloride channels30;thus, it has been speculated that modulation of �-aminobu-tyric acid input to the airway-related vagal preganglionicneurons from the nucleus of the solitary tract and highercentral nervous system centers may be a mechanism by whichdeepening anesthesia prevents or relieves reflex-inducedbronchoconstriction. Moreover, both propofol and inhala-tional anesthetics have direct bronchodilatory effects at thelevel of airway smooth muscle itself31 acting via �-aminobu-tyric acid-A channels32 or modulating calcium sensitivity ofthe contractile proteins.33 However, despite these protectiveeffects of intravenous propofol and the adequate inductiondose used in the current case, reflex-induced bronchocon-striction developed in this patient who had previously unrec-ognized and untreated asthma.

VII. Obesity and Asthma: Is There Any Relationship?There is increasing evidence linking obesity, defined as abody mass index of at least 30 kg/m2, to asthma and airwayhyperreactivity in both children and adults.34 Both asthmaand obesity are systemic inflammatory states. Their develop-ment seems to be determined early in life, with this associa-tion not being mediated through atopy.34 In turn, potentialexplanations for the parallel increase of asthma and obesitymight involve genetic, mechanical, hormonal, and environ-mental factors. Accordingly, chromosomal regions with locicommon to obesity and asthma phenotypes have been iden-tified. Reduced functional residual capacity and decreasedtidal volume as a result of obesity result in greater contractileresponses of airway smooth muscle, causing potentially in-



creased airway reactivity.34–35 Although gastroesophageal re-flux resulting from obesity may potentially trigger a latentasthmatic condition,11 this condition was ruled out with anesophageal transit test.

Hormonal influences may also be involved as the effect ofobesity on asthma is stronger in females than males.35 Inaddition, the hormone leptin produced by adipocytes andthat acts in the hypothalamus to signal satiety35 has effects onimmune cell function and inflammation. Serum leptin levelsin adulthood were shown to be higher in women than menwith a higher prevalence of asthma.34 The association be-tween asthma and obesity may be of recent origin, suggestingthat recent changes in lifestyle and diet are now associatedwith both asthma and obesity.11 However, weight gain an-tedates asthma or asthma symptoms, ruling out the hypoth-esis that this association might be the result of reduced phys-ical activity by asthmatic patients leading to obesity.34

VIII. Sleep-disordered Breathing and AsthmaSleep-disordered breathing is more prevalent in asthmaticindividuals than in those without asthma, whereas sleep-disordered breathing and asthma share common risk factorssuch as obesity.35 The reasons for the association betweenboth conditions remain unknown.35 Asthma remains under-diagnosed in obese patients because respiratory symptomsare frequently attributed to being overweight, as was the casein our patient. In such patients, underlying airway hyperre-activity should be cautiously assessed during the preoperativeevaluation (see section IX).

In the current case and after the clinical postanestheticevaluation, borderline sleep-disordered breathing was alsodetected through polysomnography.

IX. Prevention of Perioperative BronchospasmThe controls of airway inflammation and corresponding asthmasymptoms are essential to optimize perioperative and postoper-ative care. The National Asthma Education and PreventionProgram Expert Panel Report 3 recommends that the level ofasthma control, medication use (especially oral systemic corti-costeroid within the past 6 months), and pulmonary functionbe reviewed before surgery.7 The Global Initiative for Asthmaguidelines suggest that perioperative and postoperative compli-cations rely on the severity of asthma at the time of surgery, thetype of surgery (thoracic and upper abdominal surgeries being atincreased risk), and modalities of anesthesia (general anesthesiawith tracheal intubation is at higher risk).12 Others suggest thatuncontrolled or poorly controlled asthma may be assessedthrough the degree of asthma control (increased use of inhaledshort-acting �2-agonists, previous/current use of inhaled corti-costeroids, recent use of oral/injected corticosteroids, recent ex-acerbations of asthma symptoms, emergency department orhospital visit within the last months) and potential risks or com-plication factors (recent infection of the respiratory tract, previ-ous bronchospasm after intubation, pulmonary complicationsduring/after previous surgical procedure, long-term use of a sys-temic corticosteroid for severe asthma, associated gastroesopha-geal reflux or smoking).36 The common key point of these rec-ommendations focuses on the level of asthma control before

Fig. 2. Schematic diagram of airway irritant reflex-induced bronchoconstriction by tracheal intubation. The upper airway is wellinnervated by afferent sensory pathways synapsing in the nucleus of the solitary tract (nTS), which projects excitatoryglutaminergic and inhibitory �-aminobutyric acid-A (GABA)-ergic neurons to the airway-related vagal preganglionic neurons(AVPN). Parasympathetic preganglionic efferents travel in the vagus nerve to release acetylcholine onto M3 muscarinicreceptors on airway smooth muscle inducing bronchoconstriction.

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surgery7,12,36 as uncontrolled asthma is considered to be themain risk factor for bronchoconstriction during surgery.36

Preoperative Clinical and Physical Examination. Carefulclinical and physical examinations are therefore crucial forpreoperative pulmonary risk assessment to identify findingssuggestive of unrecognized underlying airway hyperreactiv-ity. Decreased breath sounds as seen in markedly decreasedexpiratory airflow, sibilants, rhonchi, and prolonged expira-tory phase, as well as recent and/or frequent exacerbations ofrespiratory symptoms including wheezing, cough, exerciseintolerance, unexplained dyspnea, and gastroesophageal re-flux disease should raise concern during the preoperativeevaluation.3 Among these different findings, decreasedbreath sounds, dullness to percussion, wheezing, rhonchi,and a prolonged expiratory phase predict an increase in therisk of perioperative pulmonary complications.37 Thus, poorlycontrolled asthma usually favors perioperative pulmonary com-plications3,36,38 whereas airway instrumentation may inducelife-threatening bronchospasm, perioperative complications,and prolonged intensive care treatment.20 Conversely, con-trolled asthma does not promote additional risk.36,38

Corticosteroids Are the Key Point of Antiasthma Long-term Control Therapy. Long-term therapy is used daily toachieve and maintain asthma control. Asthma is an inflam-matory condition. Thus, inhaled glucocorticosteroids arecurrently the most effective antiinflammatory drug for thetreatment of persistent asthma.7,12 Glucocorticosteroids re-duce asthma symptoms, improve lung function, decrease air-way hyperreactivity, modulate airway inflammation, and re-duce asthma exacerbations and asthma mortality.12 Inhaledlong-acting �2-agonists (formoterol, salmeterol) shouldnever be used as single therapy because these �2-agonistsimprove lung function without antiinflammatory effects.12

Thus, significant clinical concerns regarding an increase inasthma-related deaths in patients on long-acting �2-ago-nists39 have led to revisions of product labels by the UnitedStates Food and Drug Administration stating that long-act-ing �2-agonists should never be used without concomitantinhaled corticosteroid therapy.40 Thus, �2-agonists are mostefficient when combined with glucocorticosteroids, when in-haled glucocorticosteroids alone fail to relieve asthma symp-toms.7,12 Corticosteroids increase the bronchodilatory effectof �2-agonists and increase the number of �2-adrenergic recep-tors and their response to �2-agonists.41 In turn, rapid-actinginhaled �2-agonists are used for quick relief of acute asthmaexacerbations.7,12 Additional studies are necessary to determinewhether tiotropium and possibly other long-acting anticholin-ergic agents are effective and safe alternatives to long-acting �2-agonists for the long-term treatment of asthma.42

Preoperative Pulmonary Evaluation. In the presence of ac-tive bronchospasm, elective surgery should be postponed.The cause and corresponding clinical symptoms should beactively treated until baseline status is achieved.3 Patientsshould be free of wheezing, cough, or dyspnea.38 Individualshaving symptoms suggestive of asthma, outside the contextof an emergency situation, should undergo preoperative as-sessment performed by pulmonologists to assess the degree ofairway reactivity and optimize preoperative treatment. Mea-surement of lung function to prove airflow limitation and thedemonstration of reversibility of lung function abnormalitiesenhance diagnostic confidence.12 Forced expiratory volumein 1 s (FEV1) or peak expiratory flow (PEF) are valid mea-sures of airway caliber and better indicators of the severity ofasthma exacerbation than clinical symptoms.7,12 FEV1 (nor-mal is approximately 80–100% of predicted) expressed as apercentage of the vital capacity is the standard index forassessing and quantifying airflow limitation. Reversibilitywith the use of a bronchodilator is defined as an increase inFEV1 of at least 12% or 200 ml. FEV1/forced vital capacity(normal is greater than 75%) appears to be a more sensitivemeasure of severity and control.7 In turn, a peak flow meter,which measures the highest expiratory flow rate in liters of airexpired per second or per min (normal is greater than 80% ofpredicted), is designed for monitoring due to the wide vari-ability in reference values.7,12 Before surgery, PEF or FEV1

greater than 80% of the predicted or personal best is recom-mended.38 If PEF or FEV1 is less than 80%, a brief course oforal corticosteroids should be considered to reduce airflowlimitation.12 Patients with asthma who are also smokers havepoorer control of asthma.36 Abstinence from smoking beforesurgery reduces perioperative pulmonary complicationsrates. At least 2 months of preoperative cessation is requiredto drastically reduce perioperative pulmonary complicationsrisk.38# A stepwise approach of either initiation or optimiza-tion of asthma treatment according to the level of asthma wasproposed into either five12 or six steps7 reflecting increasingintensity of treatment required to achieve asthma control(table 1). Combined with educational and environmentalmeasures, therapy for asthma is subdivided into two catego-ries (quick-relief and long-term control treatment). Briefly,rapidly acting �2-agonist should be prescribed as needed ateach step. The first step concerns patients with occasionaldaytime symptoms where rapid acting �2-agonist may besometimes requested. The second through fifth steps con-cern a pattern of features involving partly controlled to se-verely uncontrolled asthma where regular treatment is re-quested. Low-dose inhaled corticosteroid is recommendedfor the second step. The combination of a low-dose inhaledcorticosteroid with an inhaled long-acting �2-agonist or amedium- or high-dose inhaled corticosteroid with an inhaledlong-acting �2-agonist is recommended for the third andfourth steps, respectively. Oral corticosteroids may be usefulwhen added to other medications during the fifth step, whichconcerns patients with frequent exacerbations and daily lim-

# Association Francaise de Chirurgie & Societe Francaised’Anesthesie et de Reanimation & Office Francais de Prevention duTabagisme: Conference d’Experts. Tabagisme peri-operatoire, 2005.Available at: http://www.sfar.org/_docs/articles/151-Tabagisme%20p%C3%A9riop%C3%A9ratoire-recommandations.pdf. AccessedJanuary 12, 2011.



itation of activities.12 The recommendations proposed in theUnited States involve six steps but suggest a very similartherapeutic strategy (table 1). Therapy is increased as neces-sary and decreased when possible. In addition, some alterna-tive drugs are also proposed. 7,12

A specific approach adapted to the preoperative stage,including emergency and nonemergency conditions, wasproposed by a hospital-based working group.36 Thus, aninternational consensus promoted by the different corre-sponding anesthetic societies might be useful to define abetter approach to airway hyperreactivity during the periop-erative period.

In the current case, secondary pulmonary assessment con-firmed uncontrolled allergic asthma (dust mites, grass). Ini-tial spirometric evaluation showed a reduction of FEV1 andPEF at 67% and 70%, respectively, as well as an FEV1/forcedvitality capacity of 83% of predicted values. High doses ofinhaled therapy with fluticasone and salmeterol (1,000 �g,twice per day) along with educative measures were initiated.Three months later, a second spirometric evaluation showedbronchospasm reversibility of nearly 15%, with FEV1 at80%, PEF at 82%, and an FEV1/forced vitality capacity of97% of predicted values along with reduction of clinical signsnoted by the patient as wheezing disappeared. These signif-icant improvements have been noted at a constant bodyweight. Surgery was performed 6 months after the initialperioperative event. Anesthesia was conducted with propo-fol, sufentanil, and sevoflurane. Anesthesia and surgery aswell as the postoperative course remained uneventful.

X. Treating Perioperative BronchospasmThe aims of treatment are to relieve airflow obstruction andsubsequent hypoxemia as quickly as possible.General Measures. When isolated perioperative broncho-spasm occurs, oxygen concentration should be increased to100%, and manual bag ventilation immediately started toevaluate pulmonary compliance and to identify all causes ofhigh-circuit pressure.19 Increased concentration of a volatileanesthetic (sevoflurane, isoflurane) is often useful3 with theexception of desflurane because of its airway irritant effects,particularly in smokers.43 Deepening anesthesia with an in-travenous anesthetic (propofol) may be required because in-tubation-induced bronchospasm may be related to an inad-equate depth of anesthesia (fig. 3).Inhaled Short-acting �2-Selective Agents Belong to Im-mediate Therapy. Short-acting �2-selective agents (mainlyusing terbutaline and salbutamol) are key drugs for the fastrelief of bronchoconstriction. Their onset of action occurswithin 5 min, peak effect is within 60 min, and duration ofaction is 4–6 h. They should be immediately administeredvia a nebulizer (8–10 puffs to achieve appropriate therapeu-tic levels, may be repeated at 15- to 30-min intervals) or, ifavailable, with a metered-dose inhaler (5–10 mg/h) con-nected to the inspiratory limb of the ventilator circuit. Thereis no difference in efficacy between terbutaline and salbuta-mol.** Continuous rather than intermittent administrationof salbutamol results in greater improvement in PEF andFEV1. Moreover, nebulized epinephrine has no beneficialeffect compared with terbutaline or salbutamol.**Systemic Glucocorticosteroids Should Not be Omitted.Parenteral steroids also remain a key drug in the treatment ofbronchospasm because they speed resolution of exacerba-tions by decreasing airway inflammation. Systemic glucocor-

** British Thoracic Society & Scottish, Intercollegiate GuidelinesNetwork: British Guideline on the Management of Asthma: A Na-tional Clinical Guideline. May 2008. Revised June 2009. Available at:http://www.sign.ac.uk/pdf/sign101.pdf. Accessed January 12, 2011.

Table 1. Stepwise Approach for Asthma Treatment

Level of Asthma Control Step Levels Treatment

Global Initiative for Asthma �12� Five At each step, short-acting �2-agonist is recommendedas needed

Intermittent treatment 1 —Daily medication 2 Low-dose inhaled corticosteroid— 3 Low-dose inhaled corticosteroid combined with an

inhaled long-acting �2-agonist— 4 Medium- or high-dose inhaled glucocorticosteroid

with an inhaled long-acting �2-agonist— 5 Addition of oral glucocorticosteroid to other controllers

Expert Panel Report 3 �7� Six At each step, short-acting �2-agonist is recommendedas needed

Intermittent treatment 1 —Daily medication 2 Low-dose inhaled corticosteroid— 3 Medium-dose inhaled corticosteroid— 4 Medium-dose inhaled corticosteroid combined with

an inhaled long-acting �2-agonist— 5 High-dose inhaled corticosteroid combined with an

inhaled long-acting �2-agonist— 6 High-dose inhaled corticosteroid combined with an

inhaled long-acting �2-agonist and oral corticosteroids

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ticosteroids such as methylprednisone (1 mg � kg�1) are pre-ferred over cortisone because their antiinflammatory effect ismore potent. However, the antiinflammatory benefit is notimmediate.Alternative Agents. The use of an antimuscarinic inhaledmedication (e.g., ipratropium bromide) has been shown toattenuate reflex-induced bronchoconstriction with efficacysimilar to inhaled �2-agonists.25 Thus, combined nebulizedipratropium bromide (0.5 mg 4–6 times hourly) with a neb-ulized �2-agonist produces greater bronchodilatation than a�2-agonist alone and may be used to treat life-threateningbronchospasm or in those with a poor initial response to�2-agonist treatment.** Magnesium plays a beneficial role inthe treatment of asthma through bronchial smooth musclerelaxation, leading to the use of intravenous (single dose ofmagnesium sulfate: 2 g over 20 min) or inhaled preparations(doses from 110 mg to 1,100 mg) in patients with severebronchospasm that fails to be relieved with �2-agonists.12**Accordingly, salbutamol administered in isotonic magne-sium sulfate provides greater benefit when compared withthat diluted with saline.12 Intravenous aminophylline has no

indication in acute bronchospasm because its use does notresult in additional bronchodilatation, whereas adverse ef-fects such as arrhythmia and vomiting have been reportedwhen intravenous aminophylline was used.12**Therapeutic Rationale for Epinephrine. Epinephrine shouldbe used in cases of associated cardiovascular collapse sugges-tive of IgE-mediated anaphylaxis.1,12 During isolated bron-chospasm, its inhaled/systemic use is not recommended be-cause no study has proven its efficiency when compared with�2-agonists such as salbutamol or terbutaline12 and deleteri-ous adverse effects, including takotsubo cardiomyopathy,have been reported during asthma care.44 Others proposesystemic epinephrine but emphasize that no advantage hasbeen proven of systemic therapy over nebulization.7 Cur-rently, no recommendations regarding epinephrine can beproposed,45 except that its use would be reasonable as a rescuetherapy in patients with severe asthma complicated by hypoten-sion that is not secondary to dynamic hyperinflation.46 Electivesurgery should be postponed unless bronchospasm persists atbaseline despite maximal medical optimization of the patientand further care provided in a monitored setting.

Fig. 3. Stepwise approach to treatment of perioperative bronchospasm according to the clinical scenario. * May be used inlife-threatening bronchospasm or those with a poor initial response to �2-agonist; † may be used in cases of severebronchospasm that fails to relieve with �2-agonist; ‡ for further details, see Reference 1.



In our patient, extubation was performed because ofsuspected esophageal intubation. Verification of correctendotracheal tube position would have been the appropri-ate procedure. The patient’s extubation was associatedwith oxygen arterial desaturation and subsequent hemo-dynamic disturbances.

XI. Knowledge GapAlthough factors contributing to airway inflammation inasthma are multiple and not completely understood, factorstriggering perioperative bronchospasm are identified. Bothbasic science and clinical research efforts could improve theprevention and treatment of bronchospasm associated withanesthesia. Clinical research leading to the prevention ofbronchospasm will require a better identification of patientsat risk and then a better classification of the phenotypes,therapies, and level of control of asthma in patients duringthe preoperative period. Nevertheless, it should be ques-tioned whether perioperative bronchospasm is a clinical en-tity of its own occurring in predisposed patients (e.g., asth-matic patients and those with chronic obstructive pulmonarydisease or acute bronchitis) and triggered either by mechan-ical, pharmacologic, or inflammatory (i.e., anaphylaxis) fac-tors. Moreover, basic assumptions regarding the manage-ment of general anesthesia in patients at risk forbronchoconstriction have not been rigorously studied, spe-cifically the assumption that intubation of the trachea carriesa higher risk of morbidity in the perioperative period com-pared with airway devices such as the laryngeal mask airway.Basic science advances are needed in the understanding ofthe interaction between anesthetics, airway irritation, andthe role of tachykinins and other C fiber neurotransmitters inthe control of airway tone. Moreover, the mechanisms bywhich intravenous and inhaled anesthetics affect airwaynerves and directly modulate airway smooth muscle tonelikely involve modulation of plasma membrane ion channels,membrane potential, and intracellular calcium sensitivity butremain poorly understood.

An international consensus promoted by the differentcorresponding anesthetic societies might be useful to define abetter approach of airway hyperreactivity as well as providekey targeting questions to detect patients at risk during thepreoperative period (table 2) and propose clinical pathways.

The authors thank Sylvie Chollet-Martin, Pharm.D., Ph.D., United’Immunologie Auto-immunite & Hypersensibilites, Hopital Bichat-Claude Bernard, Assistance Publique Hopitaux de Paris & UniversiteParis-Sud 11, INSERM UMRS-996, Chatenay-Malabry, France, andPascale Nicaise-Roland, Pharm.D., Ph.D., Staff Biologist, United’Immunologie Auto-immunite & Hypersensibilites, Hopital Bichat-Claude Bernard, Paris, France, for performing biologic assessmentand Sylvie Bourdiau, M.D., Staff Anesthesiologist, Serviced’Anesthesie-Reanimation, Dominique Valeyre, M.D., Service dePneumologie, and Bruno Frachet, M.D., Service d’Oto-Rhino-Laryn-gologie, Hopital Avicenne, Assistance Publique Hopitaux de Paris,and Universite Paris 13, Bobigny, France, for clinical management.

References1. Dewachter P, Mouton-Faivre C, Emala CW: Anaphylaxis and

anesthesia: Controversies and new insights. ANESTHESIOLOGY

2009; 111:1141–50

2. Fisher MM, Ramakrishnan N, Doig G, Rose M, Baldo B: Theinvestigation of bronchospasm during induction of anaesthe-sia. Acta Anaesthesiol Scand 2009; 53:1006 –11

3. Woods BD, Sladen RN: Perioperative considerations for thepatient with asthma and bronchospasm. Br J Anaesth 2009;103(Suppl 1):i57– 65

4. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ,Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, RingJ, Thien F, Van Cauwenberge P, Williams HC: Revised no-menclature for allergy for global use: Report of the Nomen-clature Review Committee of the World Allergy Organiza-tion, October 2003. J Allergy Clin Immunol 2004; 113:832– 6

5. Hepner DL, Castells MC: Anaphylaxis during the periopera-tive period. Anesth Analg 2003; 97:1381–95

6. Sampathi V, Lerman J: Perioperative latex allergy in children.ANESTHESIOLOGY 2011; 114:673– 80

7. National Asthma Education and Prevention Program ExpertPanel Report 3 (EPR-3): Guidelines for the Diagnosis andManagement of Asthma-Summary Report 2007. J Allergy ClinImmunol 2007; 120:S94 –138

8. Hepner DL, Castells MC: Latex allergy: An update. AnesthAnalg 2003; 96:1219 –29

9. Hepner DL: Sudden bronchospasm on intubation: Latex ana-phylaxis? J Clin Anesth 2000; 12:162– 6

10. Harper NJ, Dixon T, Dugue P, Edgar DM, Fay A, Gooi HC,Herriot R, Hopkins P, Hunter JM, Mirakian R, Pumphrey RS,Seneviratne SL, Walls AF, Williams P, Wildsmith JA, Wood P,Nasser AS, Powell RK, Mirakhur R, Soar J: Working Party ofthe Association of Anaesthetists of Great Britain and Ireland:Suspected anaphylactic reactions associated with anaesthe-sia. Anaesthesia 2009; 64:199 –211

11. Eder W, Ege MJ, von Mutius E: The asthma epidemic. N EnglJ Med 2006; 355:2226 –35

12. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM,FitzGerald M, Gibson P, Ohta K, O’Byrne P, Pedersen SE,Pizzichini E, Sullivan SD, Wenzel SE, Zar HJ: Global strategyfor asthma management and prevention: GINA executivesummary. Eur Respir J 2008; 31:143–78

13. Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW,Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC,Kerstjens HA, Lazarus SC, Levy ML, O’Byrne PM, PartridgeMR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Szefler SJ,Sullivan SD, Thomas MD, Wenzel SE, Reddel HK: A newperspective on concepts of asthma severity and control. EurRespir J 2008; 32:545–54

Table 2. Example of Targeting Questions to IdentifyPatients at Risk with Undiagnosed Airway Hyperreactivity

Do you smoke?Do you have gastroesophageal reflux disease?Have you ever felt chest tightness or difficulty catching

your breath? If so, at rest or with physical effort?Have you ever been told that you have wheezing or

asthma?Have you ever used an inhaled medication for your

breathing?Have you ever visited an emergency department for

breathing problems?Have you ever had frequent bronchitis?Have you ever had rhinitis?Do you frequently cough?Do you have allergies to latex or tropical fruits (kiwi,

banana, papaya, avocado)?

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14. Wenzel SE: Asthma: Defining of the persistent adult pheno-types. Lancet 2006; 368:804 –13

15. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ,Togias A, Zuberbier T, Baena-Cagnani CE, Canonica GW, vanWeel C, Agache I, Ait-Khaled N, Bachert C, Blaiss MS, BoniniS, Boulet LP, Bousquet PJ, Camargos P, Carlsen KH, Chen Y,Custovic A, Dahl R, Demoly P, Douagui H, Durham SR, vanWijk RG, Kalayci O, Kaliner MA, Kim YY, Kowalski ML, KunaP, Le LT, Lemiere C, Li J, Lockey RF, Mavale-Manuel S,Meltzer EO, Mohammad Y, Mullol J, Naclerio R, O’Hehir RE,Ohta K, Ouedraogo S, Palkonen S, Papadopoulos N, Passal-acqua G, Pawankar R, Popov TA, Rabe KF, Rosado-Pinto J,Scadding GK, Simons FE, Toskala E, Valovirta E, van Cauwen-berge P, Wang DY, Wickman M, Yawn BP, Yorgancioglu A,Yusuf OM, Zar H, Annesi-Maesano I, Bateman ED, BenKheder A, Boakye DA, Bouchard J, Burney P, Busse WW,Chan-Yeung M, Chavannes NH, Chuchalin A, Dolen WK,Emuzyte R, Grouse L, Humbert M, Jackson C, Johnston SL,Keith PK, Kemp JP, Klossek JM, Larenas-Linnemann D, Lip-worth B, Malo JL, Marshall GD, Naspitz C, Nekam K, Nigge-mann B, Nizankowska-Mogilnicka E, Okamoto Y, Orru MP,Potter P, Price D, Stoloff SW, Vandenplas O, Viegi G, Wil-liams D: Allergic Rhinitis and its Impact on Asthma (ARIA)2008 update (in collaboration with the World Health Orga-nization, GA(2)LEN and AllerGen). Allergy 2008; 63(Suppl86):8 –160

16. Szczeklik A, Stevenson DD: Aspirin-induced asthma: Ad-vances in pathogenesis, diagnosis, and management. J Al-lergy Clin Immunol 2003; 111:913–21

17. Kumeta Y, Hattori A, Mimura M, Kishikawa K, Namiki A: Asurvey of perioperative bronchospasm in 105 patients withreactive airway disease. Masui 1995; 44:396 – 401

18. Schwilk B, Bothner U, Schraag S, Georgieff M: Perioperativerespiratory events in smokers and nonsmokers undergoinggeneral anaesthesia. Acta Anaesthesiol Scand 1997; 41:348 –55

19. Westhorpe RN, Ludbrook GL, Helps SC: Crisis managementduring anaesthesia: Bronchospasm. Qual Saf Health Care2005; 14:e7

20. Cheney FW, Posner KL, Lee LA, Caplan RA, Domino KB:Trends in anesthesia-related death and brain damage: Aclosed claims analysis. ANESTHESIOLOGY 2006; 105:1081– 6

21. Cook TM, Bland L, Mihai R, Scott S: Litigation related toanaesthesia: An analysis of claims against the NHS in England1995–2007. Anaesthesia 2009; 64:706 –18

22. Auroy Y, Benhamou D, Pequignot F, Bovet M, Jougla E,Lienhart A: Mortality related to anaesthesia in France: Anal-ysis of deaths related to airway complications. Anaesthesia2009; 64:366 –70

23. Haxhiu MA, Kc P, Moore CT, Acquah SS, Wilson CG, Zaidi SI,Massari VJ, Ferguson DG: Brain stem excitatory and inhibi-tory signaling pathways regulating bronchoconstrictive re-sponses. J Appl Physiol 2005; 98:1961– 82

24. Jooste EH, Sharma A, Zhang Y, Emala CW: Rapacuroniumaugments acetylcholine-induced bronchoconstriction viapositive allosteric interactions at the M3 muscarinic recep-tor. ANESTHESIOLOGY 2005; 103:1195–203

25. Kil HK, Rooke GA, Ryan-Dykes MA, Bishop MJ: Effect ofprophylactic bronchodilator treatment on lung resistanceafter tracheal intubation. ANESTHESIOLOGY 1994; 81:43– 8

26. Joos GF: The role of sensory neuropeptides in the pathogen-esis of bronchial asthma. Clin Exp Allergy 1989; 19(Suppl1):9 –13

27. Gleason NR, Gallos G, Zhang Y, Emala CW: Propofol prefer-entially relaxes neurokinin receptor-2-induced airwaysmooth muscle contraction in guinea pig trachea. ANESTHESI-OLOGY 2010; 112:1335– 44

28. Pizov R, Brown RH, Weiss YS, Baranov D, Hennes H, Baker S,Hirshman CA: Wheezing during induction of general anes-thesia in patients with and without asthma. A randomizedblinded trial ANESTHESIOLOGY 1995; 82:1111– 6

29. Brown RH: HRCT imaging of airway responsiveness: Effectsof anesthetics. J Clin Monit Comput 2000; 16:443–55

30. Belelli D, Pistis M, Peters JA, Lambert JJ: General anaestheticaction at transmitter-gated inhibitory amino acid receptors.Trends Pharmacol Sci 1999; 20:496 –502

31. Hirshman CA, Edelstein G, Peetz S, Wayne R, Downes H:Mechanism of action of inhalational anesthesia on airways.ANESTHESIOLOGY 1982; 56:107–11

32. Gallos G, Gleason NR, Virag L, Zhang Y, Mizuta K, Whitting-ton RA, Emala CW: Endogenous gamma-aminobutyric acidmodulates tonic guinea pig airway tone and propofol-in-duced airway smooth muscle relaxation. ANESTHESIOLOGY

2009; 110:748 –58

33. Akao M, Hirasaki A, Jones KA, Wong GY, Bremerich DH,Warner DO: Halothane reduces myofilament Ca2� sensitivityduring muscarinic receptor stimulation of airway smoothmuscle. Am J Physiol 1996; 271:L719 –25

34. Schaub B, von Mutius E: Obesity and asthma, what are thelinks? Curr Opin Allergy Clin Immunol 2005; 5:185–93

35. Weiss ST, Shore S: Obesity and asthma: Directions for re-search. Am J Respir Crit Care Med 2004; 169:963– 8

36. Liccardi G, Salzillo A, De Blasio F, D’Amato G: Control ofasthma for reducing the risk of bronchospasm in asthmaticsundergoing general anesthesia and/or intravascular adminis-tration of radiographic contrast media. Curr Med Res Opin2009; 25:1621–30

37. Smetana GW: Preoperative pulmonary evaluation. N EnglJ Med 1999; 340:937– 44

38. Sweitzer BJ, Smetana GW: Identification and evaluation ofthe patient with lung disease. Anesthesiol Clin 2009; 27:673– 86

39. Ortega VE, Peters SP: Beta-2 adrenergic agonists: Focus onsafety and benefits versus risks. Curr Opin Pharmacol 2010;10:246 –53

40. Kramer JM: Balancing the benefits and risks of inhaled long-acting agonists: The influence of values. N Engl J Med 2009;360:1592–5

41. Barnes PJ: Mechanisms of action of glucocorticoids inasthma. Am J Respir Crit Care Med 1996; 154:S21– 6; discus-sion S26 –7

42. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R,Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherni-ack RM, Craig T, Denlinger L, Engle LL, DiMango EA, Fahy JV,Israel E, Jarjour N, Kazani SD, Kraft M, Lazarus SC, LemanskeRF Jr, Lugogo N, Martin RJ, Meyers DA, Ramsdell J, SorknessCA, Sutherland ER, Szefler SJ, Wasserman SI, Walter MJ,Wechsler ME, Chinchilli VM, Bleecker ER: National Heart,Lung, and Blood Institute Asthma Clinical Research Network:Tiotropium bromide step-up therapy for adults with uncon-trolled asthma. N Engl J Med 2010; 363:1715–26

43. Goff MJ, Arain SR, Ficke DJ, Uhrich TD, Ebert TJ: Absence ofbronchodilation during desflurane anesthesia: A comparisonto sevoflurane and thiopental. ANESTHESIOLOGY 2000; 93:404 – 8

44. Osuorji I, Williams C, Hessney J, Patel T, Hsi D: Acute stresscardiomyopathy following treatment of status asthmaticus.South Med J 2009; 102:301–3

45. Green SM: Intravenous epinephrine in asthma? A word ofcaution. Ann Emerg Med 2003; 41:712–3

46. Holley DA, Boots RJ: Management of acute severe and near-fatal asthma. Emerg Med Australas 2009; 21:259 – 68



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