Abstract: ß-Agonists, administered by metered-dose inhaleror nebulizer, are still the mainstay of therapy for asthma exacerbations.A trial of a subcutaneous ß-agonist should beconsidered in patients who fail to respond to inhaled medications.Levalbuterol may play a role in managing refractoryasthma, particularly in patients with ischemic heart disease orsevere tachycardia. Systemic corticosteroids should be administeredto all patients presenting to the hospital withasthma unless their peak expiratory flow rate (PEFR) orforced expiratory volume in 1 second (FEV1) is at least 80% ofpredicted after 1 hour of treatment; this therapy should be institutedwithin 1 hour of presentation. For patients with severeobstruction, the combined use of an anticholinergic and aß-agonist improves PEFR and FEV1 more than ß-agonistsalone and significantly decreases the risk of hospital admission.(J Respir Dis. 2005;26(6):238-249)
Asthma remains a significant causeof morbidity and mortality throughoutthe world. Patients presentingwith near-fatal asthma provide aunique population in which tostudy the variables that contributeto asthma-related mortality. Byidentifying high-risk patients, usingobjective and subjective measuresto detect severe exacerbations, andinitiating early medical intervention,the morbidity and mortality ofasthma can be reduced.
In the May 2005 issue of TheJournal of Respiratory Diseases, wereviewed the risk factors associatedwith life-threatening asthma. Inthis article, we will focus on managementstrategies.
Standard therapies for severe asthmainclude ß-agonists, oxygen, andcorticosteroids (Table). ß-Agonistsremain first-line therapy for patientswith exacerbations of any degreeof severity (Figure 1).1 Theseagents, with the exception of thelong-acting agents, induce bronchodilationwith a rapid onset ofaction. Patients with life-threateningasthma may have significantbronchoconstriction, airway edema,and inflammation, and may requirehigh doses or repeated dosesof ß-agonists before showing a sufficientresponse.
Numerous studies have indicatedthat administration of ß-agonistsvia metered-dose inhaler withspacer is as effective as nebulizedtreatments.2,3 Reports in the litera-ture suggest that continuous nebulizationmay be beneficial in themost severe asthma exacerbations.4Levalbuterol, an isomer of racemicalbuterol, may play a role inmanaging refractory asthma,5 particularlyin patients with ischemicheart disease or severe tachycardia.Levalbuterol is reported to havefewer side effects, since the bronchodilatoryeffects of albuterol resultfrom activity of the R-isomer,while the side effects may resultfrom the S-isomer.5 In a subset ofpatients with severe asthma, adose-dependent relationship existedwhen higher doses of levalbuterolwere used.6
Nebulized doses of levalbuterolrange from 0.63 to 1.25 mg inadults, but a dose of 2.5 mg shouldbe considered in those with severeasthma. One study demonstrated adose-response curve with dosesranging from 0.31 to 2.5 mg in childrenwith severe exacerbations.6
Intravenous ß-agonists have notbeen shown to be of more benefitthan inhaled ß-agonists in Europeanstudies.7,8 Although mostpatients respond to inhaled ß-agonists,some may benefit from systemictreatment. Appel and associates9performed a randomizedcontrolled trial of patients withacute asthma. In this double-blindcross-over study, patients with apeak expiratory flow rate (PEFR) ofless than 150 L/min received inhaledmetaproterenol or subcutaneousepinephrine. At 120 minutes,61% of those who received metaproterenolhad improved PEFR,compared with 89% of those whoreceived epinephrine. Patients inwhom initial therapy failed hadsymptoms for a significantly longerduration before presentation, suggestingthat marked inflammationand mucous plugging may result ina suboptimal response to inhaledmedications.9 The results of thisstudy do not clearly define the roleof systemic ß-agonists in the treatmentof life-threatening asthma,but they suggest that a trial of subcutaneousß-agonists should beconsidered in patients who fail torespond to inhaled medications.
Epinephrine can be administeredsubcutaneously as 0.3 to 0.5mg of a 1:1000 solution every 20minutes to a maximum of 3 doses.Terbutaline, 0.25 to 0.5 mg, shouldbe used in pregnant patients requiringsubcutaneous ß-agonist treatment.Although there is some concernabout using systemic ß-agonistsin older patients, Cydulka andassociates10 showed that patientsolder than 40 years had minimalrisk of side effects from subcutaneousepinephrine if they hadno active angina and no history ofmyocardial infarction in the previous6 months.
Corticosteroids should be administeredto all patients presenting tothe hospital with asthma unlessPEFR or forced expiratory volumein 1 second (FEV1) is at least 80% ofpredicted after 1 hour of treatment(Figure 2). Systemic corticosteroidsdecrease inflammation, increasethe number and sensitivity ofß-receptors, and inhibit the migrationand function of eosinophilsand neutrophils.11
A meta-analysis of 700 articleswith 30 randomized, controlled trialsdemonstrated that corticosteroidadministration in the emergencydepartment (ED) reduced admissionrates and decreased relapse rates at 7 to 10 days.12 Oral therapywas equivalent to intravenous therapy.Corticosteroids were most effectivein patients with severe asthmawho were not receiving longtermcorticosteroid therapy.
Because the maximum effect ofcorticosteroids is not seen until 4 to6 hours after administration, thistherapy should be instituted early(within 1 hour of presentation).The optimal dose remains controversial.Haskell and associates13randomized patients with severeasthma to receive 125, 40, or 15 mgof methylprednisolone every 6hours. Medium and high dosescaused more significant improvementthan did low doses. The highdosegroup had a more rapid improvementin the first 24 to 36hours of therapy.
We prefer using 125 mg ofmethylprednisolone every 6 hoursfor the first 24 to 48 hours in patientsadmitted to the ICU. Thepractice guidelines published bythe NIH recommend prednisone,120 to 180 mg/d in 3 or 4 divideddoses (or the equivalent) for 48hours, then 60 to 80 mg/d untilPEFR reaches 70% of predicted orpersonal best.13 The guidelines alsostate that no advantage has beenidentified for higher doses or intravenousadministration if GI absorptionis normal.14
If patients have improvement onthis regimen, they may be switchedto oral prednisone, 60 to 80 mg (1mg/kg) per day. Treatment shouldbe continued for 3 to 10 days, then discontinued without a taperif the patient is receiving inhaledcorticosteroid therapy. Inhaledcorticosteroids should becontinued during systemic treatmentto avoid rebound bronchoconstrictionwith discontinuationof systemic therapy.
Ipratropium has been shown to bebeneficial in managing acute bronchospasminduced by ß-blockersand monoamine oxidase inhibitors.15 Patients with severe airwayobstruction (FEV1 of less than 50%of predicted) also benefit from ipratropiumin combination with ßagonists.In such patients, the combineduse of anticholinergics and ß-agonistsimproves PEFR and FEV1more than ß-agonists alone and significantlydecreases the risk of hospitaladmission.16
The onset of action of anticholinergicsin patients with acute exacerbationsof asthma is short, occurringwithin 1 minute, with peakeffects within 20 minutes.15 Benefitsmay persist for up to 48 hours.16Anticholinergic therapy should becontinued until the patient stabilizesbut should not be added to thepatient's long-term asthma managementregimen.
This has not been shown to be beneficialin the ED management ofacute asthma in adults.17 In additionto bronchodilation, theophyllinemay provide benefits such asdecreased airway inflammation.15This drug has a narrow therapeutic-to-toxic window, however, andsignificant side effects, such as GIupset and tachycardia, can occur.
Studies of the use of theophyllinein the ED have not demonstrateda significant advantage intime to recovery or reduction inhospital admission rates. Huangand associates18 found an improvementin FEV1 at 3 to 48 hours whentheophylline was administeredwith albuterol and corticosteroidsto adults with asthma. In addition,numerous pediatric studies havedemonstrated a benefit with the additionof theophylline in the treatmentof status asthmaticus.
Two studies suggest that theophyllinemay have a role in thetreatment of children with impendingrespiratory failure in whom aggressivetherapy with inhaled bronchodilatorshas failed.19 Ream andassociates20 published results of arandomized controlled trial ofaminophylline given with ß-agonists,systemic corticosteroids, andanticholinergics in children admittedto the pediatric ICU because ofasthma. Patients receiving theophyllinehad a more rapid improvementin their clinical asthma scoresthan those receiving placebo.
We recommend the addition oftheophylline in patients with pooror incomplete responses to therapywith ß-agonists, oxygen, and intravenouscorticosteroids with orwithout anticholinergics. Patientsreceiving long-term theophyllineshould have a baseline bloodtheophylline level measured beforeinitiation of therapy. These patientsmay not require bolus dosing orintravenous administration of theophyllinein the hospital.
Magnesium sulfate inhibits calciumchannel-mediated smoothmuscle activity and reduces acetylcholinerelease. One to 2 g maybe administered intravenously over30 minutes. A Cochrane meta-analysisshowed no improvement inPEFR or FEV1 after administrationof magnesium.21 A subgroup analysissuggested that patients with anFEV1 of less than 30% at admissionor less than 60% after 1 hour of treatment might benefit from 1 to 2g of magnesium. Overall, the availabledata did not support the routineuse of magnesium in statusasthmaticus.
Heliox is a combination of heliumand oxygen at typical ratios of60:40 or 70:30, which provides aless dense, more viscous mediumthan air. This gas decreases turbulentflow through constricted airways.Case reports suggest that helioxmight increase distal airway deliveryof ß-agonists, decrease pulsusparadoxus and work of breathing,and decrease peak airway pressuresand PaCO2 in intubated patients.17
Four randomized controlled trialshave failed to show improvementin pulmonary function orhospital admissions with use of heliox.One study, however, showedthat using a helium-to-oxygen ratioof 80:20 delivered via non-rebreathermask led to significant improvementsin pulmonary functionover the first 3 hours of treatment.22
The role of inhaled corticosteroidsin the treatment of severeasthma remains under investigation.Although inhaled corticosteroidshave been shown to be of benefitwhen added to ß-agonist therapyfor acute asthma, the additivebenefit in combination with systemiccorticosteroids remains unproven.4 Current data support thecontinued use of inhaled corticosteroidsafter hospital discharge,23but no clear evidence exists thatinhaled corticosteroids are safefor use without systemic therapyfor life-threatening asthma.
Leukotriene antagonists and leukotrienesynthesis inhibitors mayplay a role in the managementof acute, life-threatening asthma.5These agents may complement theanti-inflammatory effects of systemiccorticosteroids in patientswith severe asthma exacerbations.5A randomized controlled clinical trial published in 1999 demonstrateda decrease in the need for hospitaladmission among patients withacute asthma treated with zafirlukast.24 Further studies are neededto confirm the role of leukotrieneantagonists in near-fatal asthma.
Arterial blood gas values aloneshould not be used to determinethe need for mechanical ventilation.The overall clinical status ofthe patient and rate of decline orimprovement in dyspnea, tachypnea,tachycardia, and objectivemeasures of airflow are the mostimportant determinants of theneed for artificial ventilatory support.Maffei and colleagues25 foundthat the need for early initiation ofmechanical ventilation was a markerfor near-fatal asthma and did notnecessarily represent a simple failureof preintubation asthma management.Thus, physicians shouldassess the patient's clinical conditionand, if ventilatory support isindicated, institute this therapyearly and under elective conditionsin the appropriate clinical setting.
If mechanical ventilation is required,nasal intubation should beavoided because of the increasedincidence of sinusitis and nasalpolyps in patients with asthma.26Permissive hypercapnia is a ventilatorystrategy often favored in patientswith asthma. This strategyminimizes lung hyperinflation byproviding adequate time to exhalealveolar gas while allowing PaCO2to rise if necessary to achieve thisgoal.26 In general, hypercapnia canbe tolerated as long as PaCO2 doesnot rise above 90 mm Hg and doesnot change acutely.26
Studies have shown that noninvasivemechanical ventilation hassome benefit in preventing progressionof respiratory failure in asubset of asthmatic patients whohad rapid progression, althoughthe studies are small.26 For example,in a comparison of 11 asthmaticpatients who were placed onmechanical ventilation and 22 whowere treated with noninvasive ventilation,only 3 of the latter requiredintubation.27 In responders, PaCO2tends to decrease quickly after institutionof therapy.26
Thus, noninvasive mechanicalventilation can be considered in patientswith severe asthma exacerbationsif respiratory failure is notthought to be imminent but there isconcern that mechanical ventilationmay eventually be required.Close monitoring and a low thresholdfor intubation are warranted insuch patients.
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