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REVIEW

Refractory Asthma, Part 1: Epidemiology, Pathophysiology, Pharmacologic Interventions

From the Department of Emergency Medicine, Mount Sinai Medical Center, New York, New York*; the Department of Emergency Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania"; the Division of Critical Care, Department of Medicine, University o/Florida Health Sciences Center, Jacksonville, Florida'; and the Division of Pediatric Emergency Medicine, Department of Surgery, University of Florida Health Sciences Center, Jacksonville, Florida. J a

Received for publication March i3, i995. Revisions received February 27, April 15, and December 4, 1996. Accepted for publication December 9, I995.

Copyright © by the American College of Emergency Physicians.

Andy Jagoda, MD* Suzanne Moore Shepherd, MD* Antoinette Spevitz, MD § Madeline M Joseph, MD"

[Jagoda A, Shepherd SM, Spevitz A, Joseph MM: Refractory asthma, part 1: Epidemiology, pathophysiology, pharmacologic interventions. Ann Emerg Mefl February 1997;29:262-274.]

INTRODUCTION Reactive airway disease is estimated to affect 3% to 6% of the US population. However, this figure is almost certainly an underestimation; these prevalence data originate mainly from surveys rather than from large population studies. 1 Acute asthma attacks account for 1 to 2 million emergency department visits each year in the United States, more than 450,000 hospital admissions, and 5,000 deaths. >4 "Status asthmaticus" refers to those attacks in which the degree of bronchial obstruction is either severe from the onset or worsens and is not relieved by usual therapy in 30 to 60 minutes. 5 The term "refractory status asthmaticus" describes those cases in which the patient's condition continues to deteriorate despite aggressive pharmacologic interventions. The initial management of asthma has been extensively reviewed in the recent literature2,6-12; however, the management of refractory cases is less well defined, and clear guidelines are not readily available.

The incidence of reactive airway disease refractory to initial interventions is increasing, with a concomitant increase in morbidity and mortality. 3,13-2° The number of patients with refractory disease is very small compared with the large number of patients who are treated; however, management m these patients must involve rapid evaluation and considered action. Five to 10% of the asthmatic population is at risk for an episode of refractory status; of those patients in status asthmaticus who require intubation, 10% to 20% will die. 11, 21-23 In this review we focus on the pharmacologic and mechanical interventions available for the management of such cases.

EPIDEMIOLOGY Reports in the recent literature suggest an increasing number of deaths due to asthma. 3,4,>,15,24-26 Explanations for this growing incidence are varied and confounded by multiple

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REFRACTORY ASTHMA, PART 1 Jagoda et aI

factors. The reported increase in severity of disease is gen- erally accepted as real, but probably also represents a change in physician practices to admit asthmatic patients earlier in the course of their flare-ups, decreased access to outpatient care 14, and overreliance on [3-agonists at the expense of underuse of prophylactic antiinflammatory medications. 27 Other factors contributing to the increase in asthma-related morbidity and mortality include occupational and environmental exposures 19, inadequate perception or denial of the degree of lung disease 28-3°, and psychologic stress) 1,32 Evidence also suggests that use or abuse of [3-agonists may be an independent risk factor for severe disease, lr,33

Yunginger et a125 reported that a 55% increase from i964 to 1983 in the age- and sex-adjusted annual incidence of definite and probable asthma in children aged 1 to 14 years in a community with little significant change in population or in access to health care. 25 Weitzman et a127 found that the prevalence of childhood asthma increased from 3.1% in 1981 to 4.3% in 1988, nearly 40%. In a report covering the years 1977 to 1984, Robin reported that the prevalence of adult deaths per 100,000 population doubled to 1.12°, with most deaths occurring in patients with chronic disease, blacks, and older individuals. The Centers for Disease Control and Prevention reported that from 1982 to 1992 the annual age-adjusted death rate from asthma for persons aged 5 to 34 years increased by 40%, whereas the age- adjusted hospitalization discharge rate remained essentially the same)

Most severe asthma attacks evolve over days: delay in seeking care, caused by lack of resources or denial of degree of illness, is often cited as a contributing factor. On the other hand, the natural history of attacks resulting in prehospital death is probably much shorter; indeed, it is reported as being of Iess than 24 hours' duration in 70% of cases. 34 Sudden, out-of-hospital death resulting from asthma may identify a subset of patients at risk of a rapidly progressive crisis provoked by environmental factors. 35,36 O'Hallaren et a135 implicated exposure to the airborne spores of a com- mon mold as a significant risk factor for respiratory arrest in children and young adults with asthma. These authors reported that 91% of their patients, aged 11 to 25 years, who sustained sudden respiratory arrest had positive skin test findings, compared with 31% of asthmatic controls.

Individuals at greatest risk for status asthmaticus are those with recumng attacks, those in middle age or older, and those with a history of asthma dating back less than 10 years. These patients tend to have required systemic corticosteroids in the preceding year, to smoke, and to comply poorly with outpatient surveillance attempts. 11,15,22,36 Physical indicators of airway instability include short-lived

relief with the use of inhaled bronchodilators, wide variance in daily bronchodilator use, worsening of symptoms resulting from viral illness, nocturnal symptoms, and history of intubation. Kikuchi et aP ° compared patients who had experienced near-fatal asthma attacks with a control group. 3° They found that the patients who sustained near-fatal attacks had reduced hypoxic (but not hypercapnic) drive and a blunted perception of dyspnea; a positive correlation existed between the two.

History of near-fatal asthma attacks requiring mechanical ventilation appears to be the single strongest predictor of subsequent death from as thmas Marquette et a122 reported on 145 asthmatic patients who had been intubated for near-fatal attacks and found that 16.5% died in the hospital and that 23% died of asthma within 6 years, two thirds of whom died in the year after hospital discharge.

Asthmatic children who require intubation tend to be very young or teenagers, to have a history of multiple admissions, and to have previously been undertreated, i5 tn this report, 9 of 28 children who survived their first episode of intubation subsequently died of asthma, after a median interval of 1.6 years.

The influence of psychologic issues on the mortality of asthma is controversial, although the results of some studies suggest a significant role. 31,32 Strunk et aP 2 matched patients who died of asthma with controls with respect to age, sex, and disease severity; they found no physiologic differences between the groups but did note a prominence of psychologic risk factors in the children who died of asthma.

The authors of studies in the recent literature have focused on a possible association between [3-agonist use and asthma morbidity Spitzer et al xs reported an increased risk of death particularly associated with fenoterol (New Zealand study; drug not available in the United States) but also seen with albuterol; the odds ratios were increased by 5.4 and 2.4 per camster, respectively A subsequent study by the same authors examined the hypothesis that patients using [3-agonists had more severe disease as an explanation of increased inhaler use. lr The authors compared 129 patients with 655 control patients, accounting for clinical features associated with an increased risk of fatal and near- fatal asthma. They detected no significant reduction in the odds ratio for asthma death and near-death per metered- dose inhaler.

However, the authors of a metaanalysis of [3-agonist use and asthma death found only a very weak relationship between nebulized [3-agonist use and death and no association between metered-dose inhaler or oral [3-agonist use and death. 3s The discrepancy might be explained by the older

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REFRACTORY ASTHMA, PART 1 Jagoda et al

age of the patients in Spitzer's group, 32 years, compared with the mean age of the sample in the metaanalysis, 25.3 years. Whether 13-agonists are causally, indirectly, or spuri- ously related to asthma death continues to be debated. 39,4°

Clinically important tolerance, or tachyphylaxis, to the 13-agonist agents has not been documented; nor is it clear that worsening of disease despite 13-agonist use reflects pro- gression of disease or a drug-related effect. Although there is disagreement as to whether the use of ~-agonists them- selves increase mortality, physicians on both sides of the debate agree that 13-agonists are first-line therapy in the management of an acute exacerbation and that antiinflammatory medications serve as the focus of long-term therapy,

PATHOPHYSIOLOGY

Asthma is characterized by the triad of airway obstruction, airway hyperresponsiveness, and airway inflammation with edema. Although the three mechanisms all contribute to narrowing of the airway lumen, early hyper-responsive airway smooth muscle contraction and bronchial mucosal edema may occur within minutes of stimulus exposure. Whether the degree of genetic predisposition is more important than the acquired response producing the exaggerated bronchoconstrictor response to stimuli seen in asthmatic subjects remains a matter of controversy. Multiple mechanisms, in addition to being the key factor of inflammation, have been proposed to explain airway hyperresponsiveness, including alterations in intrinsic bronchial smooth muscle function and changes in autonomic neural control. 12 This early response is associated with decreased 1-second forced expiratory volume (FEV1), which responds readily to 13- agonist therapy.

The late-phase reaction to stimulus exposure, the result of significant bronchial wall inflammation with epithelial desquamation and infiltration of mononuclear ceils, occurs within 2 to 8 hours and persists for 24 to 48 hours. A stimulus, immunologic or nonimmunologic (eg, environmental irritants, viral respiratory infection, exercise, cold air) causes the degranulation of mast cells and the attraction and stimu- lation of macrophages, eosinophils, neutrophils, and other mediator-releasing inflammatory cells. These cells, through several complex interactions, release histamine, arachidonic acid metabolites, leukotrienes, and other inflammatory mediators that produce bronchial smooth muscle contraction, altered neural responses, epithelial injury, and increased permeability, mucosal edema, and fluid transudation, along with increased tenacious mucous production. 12,41-45 De- squamation of the respiratory epithelium yields an inflammatory mucoid exudate, which causes air-trapping and

infiltration of the bronchial wall by inflammatory ceils. +3,45-51 This explains why early treatment with bronchodilators may reverse bronchospasm, whereas the longer an acute attack persists the more inflammation takes place, the more hyper- reactive the airway becomes, and the more mucous phig- ging occurs, accounting for the difficulty encountered by physicians in controlling longer-standing flare-ups and the relatively minor stimulus necessary to produce a flare in symptoms. 6 Another decrease in FEV~ is seen during this phase, which may be prevented or ameliorated by steroid u s e .

Histopathologic studies of airways in patients who have died of asthma confirm the mucociliary abnormalities that result in airway obstruction. Hypertrophic mucous glands and goblet cells are present in increased numbers. Ciliated epithelium is lost, contributing to impairment of secretion clearance. Vascular permeability, cellular infiltration, and edema are increased.

Bronchospasm and mucous plugging obstruct both inspiratory and expiratory airflow, causing air-trapping and overinflation of the lungs. Airway obstruction, determined by the diameter of the airway lumen, is responsible for clinical manifestations of asthma such as dyspnea, cough, and wheezing. Airflow obstruction is not uniform, and mismatching of ventilation to perfusion occurs. This is the major cause of hypoxemia in asthma, although hypoxemia may also result from lobar collapse. Hypoxia is usual during episodes of acute asthma. Because this hypoxemia is caused mainly by ventilation/perfusion mismatch, even when airflow obstruction is severe it usually responds well to sup- plemental oxygen. 52,53

Mismatch increases minute ventilation, which increases the work of breathing. Bronchospasm interferes with effective expiration, causing hyperinflation and thereby increasing the lung's functional residual volume or capacity (FRV and FRC, respectively). These increases in FRV result in greater transpulmonary pressures, which combine with the increase in airway resistance to increase the work of breathing. Over time, as the patient becomes fatigued, failure of oxygenation and ventilation can occur. 5<55 Breathing from a high FRV requires a significant increase in inspiratory muscle force to overcome the elastic recoil of the lungs and thorax, necessitating the use of accessory muscles to effect inspiration. Clinically, the degree of sternocleidomastoid retraction has been correlated with the severity of an asthma attack. 2

Resistance to expiratory airflow results in positive alveolar pressures at the end of expiration, which is termed "intrinsic" or ~'autopositive end expiratory pressure" (auto-PEEP). 56 Carbon dioxide retention occurs when the respiratory


REFRACTORY A S T H M A , PART 1 .Iagoda et al

muscles can no longer maintain the lungs at a volume high enough to open the airways and can no longer maintain the respiratory rate and minute ventilation decreases. Over time, the hypocarbia that characterizes early status asthmaticus is replaced by relative normocarbia and then hyper- carbia. Ultimately, increased work with decreased oxygen supply results in anaerobic metabolism and the buildup of lactic acid: this lactic acidosis further compromises muscle function and serves as a marker for ventilatory failure. 5r

As one would expect from this pathophysiology, pulmonary function tests (PFTs) in the asthmatic show increased residual volume (RV), increased FRV,, and increased total lung capacity (TLC), with an increased ratio of RV to TLC. Vital capacity and FEV 1 are reduced. FEV 1 and its correlate, peak expiratory flow rate (PEFR), are the parameters best studied as predictors of outcome. An FEV 1 value less than 1 L, or 20% of the predicted value, is associated with poor response and the need for hospitalization. 5s Carbon dioxide retention begins when the FEV 1 is less than 25% of predicted, or about -/50 mL. 6

Patients in status asthmaticus are at risk for hypotension caused by compromised blood return and diastolic dys- function. In these patients, right ventricular filling is compromised during expiration, followed by increased filling during inspiration, which results in decreased stroke volume during inspiration versus expiration. The resulting differ- ential in systolic blood pressure between inspiration and expiration, termed "pulsus paradoxus," is significantly increased during severe asthma attacks. Positive-pressure ventilation can markedly accentuate cardiac underfilling. When such underfilling is combined with the relative de- hydration that accompanies many severe asthma attacks, the patient may become hypotensive. An excellent discus- sion of this eventuality is presented by Wiener 59 in a tragic case report describing a fatal cardiac arrest caused by intubation and mechanical ventilation.

BRONCHODILATOR AGENTS

~-Adreneroic agents [3-Adrenergic agents are effective in relieving asthma by stimulating sympathetic receptors in the respiratory tree, thereby effecting bronchodilatation; and in protecting patients against bronchoconstrictive stimuli. 6°,61 The evidence pertaining to their role in the late, inflammatory-mediated response in asthma is contra- dicto W. Historically, [3-agonists were not thought to have antiinflammatory properties; in fact, they have been implicated subsensitivity with down-regulation of [3-adrenergic receptors. 33,61

It remains undetermined whether ~-agonists used on a daily basis have a detrimental or beneficial effect on the pulmonary system's response to irritants. 62-64 The p-agents are the first-line therapy in the management of acute asthma attacks. Various [3-agonists are available, although ~2-selective agents are preferred and can be given by inhalation or intravenously, subcutaneously, or endotracheally.

Subcutaneous administration of j£agonists is less popular than in the past. In most cases, inhalation has been shown to be equally effective, lasts longer, and avoids the discom- fort of an injection. In certain circumstances when air flow is sufficiently poor, subcutaneous administration is an effective alternative, lo,6~ Both epinephrine and terbutaline can be given subcutaneously In one study the efficacy of .5 mg subcutaneous epinephrine was compared with that of an equivalent dose of terbutaline. 60 The authors of this study compared two groups of patients with severe asthma aged 18 to 64 years. Both drugs demonstrated effect within 5 minutes and produced the same amount of subjective and objective improvement in pulmonary function, with an increase in the PEFR of 20% and FEV 1 of 40%. The authors found no demonstrable difference in heart rate, blood pressure, or pulsus paradoxicus between the two groups at any time and noted no abnormalities on continuous electrocardiographic monitoring. These findings suggest that terbutaline given subcutaneously loses its [3-selectivity and confirm other reports of the safety of subcutaneous epinephrine m all age groups. Cydulka et al 6r administered subcutaneous epinephrine to 95 asthmatic patients aged 15 to 96 years and found no significant difference in the incidence of arrhythmias between those patients less than or older than 40 years. Blood pressure, respiratory rate, and pulse all decreased with treatment, suggesting that epinephrine is safe to use in an older population.

Inhaled [3-adrenergic agonists are considered the best first-fine drugs in the management of acute asthma exacerbations. Albuterol or salbutamol 2.5 to 5 rag, terbutaline 2 to 5 rag, and metaproterenol 10 to 15 mg are all acceptable and are repeated every 20 minutes as needed or until un- acceptable side effects are noted. 1° Continuous treatments are an alternative to intermittent nebulization treatments. 6s-r° Rudnitsky et a168 compared a regimen comprising four 2.5-mg albuterol treatments, one every 20 minutes, with one continuous treatment of l0 mg in 70 mL of saline solution over 2 hours. Results from this study showed that, in the subgroup of patients with PEFR less than 200 L/minute, continuous treatment resulted in greater improvement in PEFR at 60 and 120 minutes and that fewer patients were hospitalized in the continuous-nebulization group. Olshaker et al r° demonstrated the safety of continuous-nebulization

FEBRUARY 1997 29:2 ANNALS OF EMERGENCY MEDICINE 2 8 5


treatments, even in those patients with hypertension, coro- nary artery disease, or history of congestive heart failure. Seventy-six consecutive patients received 7.5 mg albuterol over 4-5 minutes without significant side effects: three had tremor, two had flushing, and one experienced palpitations. No patient exhibited significant cardiac toxicity.

Nebulized, air-driven delivery is the usual mode of [3- agonist administration, although metered-dose inhalation is acceptable if the patient can breathe slowly enough to coordinate breathing with the inhaler. Some evidence suggests that metered-dose inhalers are equally effective as nebulized treatments in mild to moderate attacks; more than 50% of the nebulized dose is lost during exhalation and as a result of precipitation on the tubing, rz,ra This degree of effectiveness depends on optimum conditions to ensure full delivery of the dose, however, and is therefore not applicable to severe attacks. Intermittent positive-pressure ventilation administration of ~-agonists has not been shown to be advantageous. 73

The use of continuous [3-agent nebulization has raised some concern about the potential of these agents to induce serum electrolyte alterations. Bodenhamer et al r4 investigated

the effect of intensive inhaled albuterol treatment on serum electrolyte concentrations. Twenty-three patients who presented to the ED with acute exacerbations of asthma received between two and five albuterol treatments. The average decrease in serum potassium concentration at 2 hours was .53 mEq/L. Potassium concentration decreased to less than 3.5 mmol/L in 57% of the patients at some point during treatment, confirming the findings of other investigators on the effect of [3-agonists on serum electrolytes.rS-rs Bodenhamer et al also found decreases in serum magnesium and phosphate levels. The mechanism for the electrolyte shifts is thought to be acid-base changes in combination with increases in serum glucose, hyperinsulinemia, and activation of sodium-potassium-ATPase, causing direct influx of potassium into cells. The clinical importance of the change in electrolyte concentrations remains undetermined, but ~-agonist-induced hypokalemia or cardiotoxi- city is not thought to play a significant role in the increased incidence of asthma-related mortality. 18,36

Most of the clinical experience involving IV [3-agents is in the pediatric population. Dales and Munt 21 reported on their experience with IV isoproterenol. They found that

Table. Medications for the treatment of acute asthma.

Route of Administration Adult Dose Pediatric Dose Onset

Subcutaneous Epinephrine .3-.5 mg, 1:1,000 aqueous solution .01 mg/kg; maximum dose, .03 mg 5 minutes Terbutaline .25-.5 mg .01 mg/kg 5 minutes Inhalation Albuterol (salbutamol) 2.5-5 rag, every 20 minutes; or 5-10 rag/hour, .05 mg/kg, every 20 minutes; or 5 minutes

continuous .1-.3 mg/kg/hour, continuous Terbutaline 2-5 mg 15 minutes Metaproterenol 10-15 mg 5-15 mg 5 minutes Atropine 2.5 mg every 3-4 hours .01-.03 mg/kg; maximum dose, 1.0 mg 15-20 minutes Ipratropium 500 pg every 3-4 hours 250 lag 20 minutes Glycopyrrolate .8-2 rag* 1 rag* 15-20 minutes IV Methylprednisolone Magnesium Aminophylline*

Isoproterenol Albuterol (salbutamol)

Terbutaline

Glycopyrrolate Ketamine

125 mg 2-4 g over 20 minutes 5 mg/kg* over 20 minutes, followed by infusion

at .6-.9 mg/kg/hour ~ .1-1.2 lag/minute infusion 200gg over 10 minutes, followed by infusion

of 3-12 lag/minute 250 gg over 10 minutes, followed by infusion

of 3-12 gg/minute .2 mg* .2-1.5 mg/kg, followed by infusion of

.3-2 mg/kg/hour *Not approved by the US Food and Drug Administration for use in asthma. tNo longer used as an ED intervention in acute, severe asthma. *Calculated on total body weight. ~Calculated on ideal body weight; decrease dose in older patients and in those with liver disease or heart failure.

2 mg/kg 30-70 mg/kg over 20 minutes 5 mg/kg over 20 minutes, followed by

infusion of 1 mg/kg/hour ~ .1-1.2 gg/kg/minute

10 gg/kg over 30 minutes, followed by infusion of .1 btg/kg/minute

.5-Z0 mg/kg every hour or as continuous infusion

4-6 hours 15-20 minutes



27 of 35 children judged to be candidates for intubation showed improvement with IV isoproterenol. No drug-related deaths have been attributed to the use of isoproterenol in the pediatric asthma population. One death, in an aduk asthmatic, has been attributed to IV isoproterenol use. 79

Bohn et al so studied the use of IV salbutamol in children with status asthmaticus. A loading dose of 1 gg/kg was administered over l0 minutes, followed by a .2-gg/kg/minute infusion. The authors reported that 69% of the patients demonstrated sustained reduction in Pa¢o2, whereas 31% showed no improvement and required mechanical ventilation. Comparing their results with those of other studies of IV isoproterenol, they reported that salbutamol produced less effect on heart rate, resulted in more lasting bronchodilatation, and did not demonstrate the tachyphylaxis seen with isoproterenol. Eor adult refractory asthma, the British Thoracic Society recommends IV salbutamol 200 ~tg or terbutaline 250 gg, administered over 10 minutes, followed by an infusion of 3 to 12 gg/minute. ~

In one case report, albuterol administered endotracheally produced improvement in respiratory function significant ~nough to permit extubation, sl In this case, a 67-year-old woman in status asthmaticus was given a 2.5-mg endotra- cheal bolus of albuterol in 2.5 mL of normal saline solution. A 5-rag dose was administered 25 minutes later, with subsequent improvement in ventilation, blood pressure, pulse, and respiratory rate. The authors argued that, as a result of poor airflow during status episodes, at most 20% of nebulized R-agent reach the site of action in the bronchial tree.

Antiehelinergie agents Airway smooth muscle tone is balanced between sympathetic and parasympathetic control. Bronchoconstriction can be accentuated by increased vagal tone; vagolytics have been used to treat bronchospasm, although their effect is less than that of sympathomimetics. Three vagolytics have been used in asthma: atropine, ipratropium bromide, and glycopyrrolate. Onset of action of atropine and ipratropium bromide tend to be slower than that of the Wagonists. The effect of these drugs, however, is suggested by several studies to be additive, s2-84 In addition, muscarinic receptors mediate submucosal gland secretion; secretion reduction may contribute in some cases to the opening of blocked airways.

Ipratropium bromide is an atropine derivative that is poorly absorbed and can therefore be described as a topi- cal anticholinergic. Bronchodilatation is produced within 20 minutes; however, maximum effect does not occur for 60 to 120 minutes, s5 Several studies have shown that the addition of ipratropium bromide to Wagonist therapy pro- vides additional bronchodilation 1 to 3 hours after therapy, suggesting that ipratropium bromide might not be of ben-

cfit during the first hour of treatment but might contribute to the longer-term treatment of patients in status asthmaticus, s,<sd,87

In a study by Owens and George ss, metaproterenol alone was compared with metaproterenol plus 2.5 mg of nebulized atropine. No difference was found in vital signs, spirometry findings, or side effects between the two groups at 0, 30, 60, and 120 minutes. It is possible that this study was pre- maturely terminated, however, and that delayed evaluation might have demonstrated an effect. Young and Freitas s9 studied patients who continued to wheeze after three doses of metaproterenol by comparing continued nebulized metaproterenol and 1.5 mg nebulized atropine. No significant improvement in the FEV> 60 minutes after treatment with atropine was found, whereas the metaproterenol-nebulization group demonstrated significant improvement. None of the patients receiving either of the drugs experienced significant side effects.

In one case report, the use of IV glycopyrrolate (.2 rag) is described in a 47-year-old man in status asthmaticus with an initial Pco 2 of 118 mm Hg. 9° Within 60 seconds of receiving the drug he began to demonstrate progressive improvement in air movement. Glycopyrrolate is an quater- nary ammonium compound that possesses the anticholinergic properties of atropine but produces no significant toxicity No peripheral or central manifestations of muscarinic blockade have been demonstrated in doses of 10 gg/kg. 91 Other investigators have examined nebulized glycopyrrolate both as a single agent and in conjunction with J3-agonists. 92-95 Nebulized glycopyrrolate has been found to cause bronchodilation equal to that of metaproterenol but with a significantly better side-effect profile. 94 No study has been published that supports a benefit of glycopyrrolate in addition to ~-agonist therapy 92

On the basis of an assessment of the current literature, anticholinergics are not recommended for routine use in asthma. They may be tried in combination with conventional therapy for the patient in status asthmaticus but are clearly not first-line therapy They appear to have a greater role in the management of chronic obstructive pulmonary disease (COPD).

Methylxanthines Aminophylline, once a mainstay in the acute management of severe asthma 9~, has not been found to offer added benefit to ~-agonist therapy in the emergency management of status asthmaticus. 97,9s Milgrom and Bender 99 showed that during the first hour of therapy, an increase in the serum theophylline level to a maximum therapeutic range resulted in 45% to 60% maximal reversi- bility, whereas [~-agonist use resulted in 80% to 90% improvement. Contrary to the findings of studies questioning

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I

the benefit of aminophylline in asthma exacerbation, its use has been supported in maintenance therapy in that patients given theophylline experience fewer symptoms than those receiving [3-agonists alone, loo-lo4 The roleof aminophylline in stabilizing the patient in refractory status asthmaticus is not clear. In one study of hospitalized patients with acute asthma exacerbations treated with steroids and isoproterenol, an additional benefit of IV theophylline was reported, lo5

Aminophylline's mechanisms of action include bronchodilation, enhancement of mucociliary clearance, decrement of microvascular permeability in the airway mucosa, increase in the level of circulating catecholamines, and enhancement of diaphragmatic contractility. 99 Its value in asthma may lie in modulation of the late phase of the disease, with con- tainment of inflammation and edema. Recently theophylline was also shown to significantly inhibit bronchoconstriction after allergen inhalation, to6,1o7 Theophylline has also been shown to increase the contractility and endurance of the diaphragm in patients with COPD, which may also prove helpful in the asthma patient with respiratory failure.

Fanta, Rossing, and McFadden 97 compared the use of aminophylline alone, sympathomimetics alone, and combination therapy and found that in the emergency management of asthma there was no advantage to the coadministration of aminophylline. Murphy et al 9s compared metaproterenol and steroids with the same regimen plus an aminophylline bolus followed by maintenance therapy (keeping the serum level between 12 and 15 mg/kg); at 5 hours PEFR had not improved significantly in the aminophylline group, yet significantly more side effects--such as nausea, vomiting, tremor, and nervousness--were noted. Both groups improved by approximately 225% (130 L/minute to 350 L/ minute).

Overall, the consensus in the literature is that theophylline has no role in the ED management of acute asthma. 11 In an often-cited paper, Littenberg l°s conducted a metaanalysis of 13 studies and found no good evidence for or against the use of aminophylline in the emergency management of asthma. The authors of 8 of the 13 reports compared aminophylline as a single drug with other drug regimens including IV or inhaled ~-agonists, and only 1 of the remaining 5 studies used an inhaled ~3-agent. Littenberg concluded that aminophylline as a single agent is less effective than a ~-agonist as a single agent in the emergency management of asthma; however, he could render no con- clusions regarding aminophylline as an adjunctive agent. More important, and still unaddressed, is the value of theophylline in the longer-term management of an acute episode; specifically, the question to be asked is whether patients who are started on aminophylline in the ED

have shorter hospital stays and longer periods between hospitalizations.

The bronchodilating effect of theophylline is correlated with increasing serum levels. When compared with lower dosing, use at the upper therapeutic range has been shown to significantly improve the FEV 1 measured 16 hours into therapy. 2 In a study by Carrier et al 1°9, IV and oral loading of theophylline were compared in patients with acute exacerbations of asthma. No correlation was found between serum theophylline levels during the first 3 hours of treatment and spirometric improvement; however, at 24 and 48 hours, during maintenance administration of oral theophylline, improvement in spirometry persisted and was attributed to the theophylline. In a study by Nassif et a111°, the use of theophylline was found to decrease the need for [~-agonists and steroids in the maintenance therapy of asthma.

The findings of one study suggest that theophylline used in the emergency management of asthma might decrease the need for hospitalization. Wrenn et al i l l compared the incidence of hospitalization in patients with acute bronchospasm treated with ]3-agonists, corticosteroids, and placebo or aminophylline. The investigators found no difference between the two groups in FEV1, FVC, or PEFR at baseline, 60, and 120 minutes; however, the aminophylline group had a threefold decrease in hospital admission rate. The authors conceded that they could not explain this reported decrease, but the impact on admissions is significant enough to warrant further study. Criticisms of Wrenn's study include poorly controlled admission criteria dependent on subjective variables, such as house staff assessment and patient self- appraisal, and the fact that the treatment protocol was not controlled for the use of inhaled [3-agents.

Aminophylline is not indicated in the management of acute exacerbation of asthma that responds to inhaled [3- agonists. It may be indicated in the management of status asthmaticus in patients with refractory disease. Aminophyl- line continues to be recommended in many management algorithms for hospitalized asthmatic patients, lo,23,sg,s s2 The benefit may reside in stabilization of airway function distinct from reversal of bronchospasm. The loading dose for aminophylline in adults is 5 to 6 mg/kg over 20 minutes, followed by a maintenance infusion of .6 to .9 mg/kg/ hour. 113 The maintenance dose is decreased by half in older patients and by two thirds in patients with congestive heart failure or liver disease. Obese subjects have an increased volume of distribution and a prolonged half-life of aminophylline; therefore their loading dose is calculated on total weight but maintenance dose is calculated on ideal body weight. Dosing is adjusted according to changes in pH and

26 8 ANNALS OF EMERGENCY MEDICINE 2£:2 FEBRUARY 1997


1,he concomitant use of cimetidine, erythromycin, and other drugs that alter the volume of distribution, change protein binding, or decrease rate of metabolism.

Cortieosteroids Recognition of the key role of inflammation in the pathogenesis of asthma has led to the liberal ase of steroids in emergency and long-term treatment. 114-116 The corticosteroid's primary mechanisms of action include !nterference with synthesis of leukotrienes, prostaglandins, arachidonic acid and other eicosanoids; prevention of ,directed migration and activation of inflammatory cells, such as eosinophils, and T-lymphocytes, reducing the inflamma- l:ory response; possible up-regulation of airway smooth :muscle cell receptors to ~-agonists. 12 It has also been pro- ~osed that corticosteroids promote vasoconstriction and ::educe capillary permeability, decreasing airway mucosal edema 1 is, and reduce mucus production. 117 At the molecular level these actions involve gene regulation and protein ~ynthesis; as such their clinical effect is not immediate but takes several hours to appear. H7

The onset of action of corticosteroids takes place within 4 to 8 hours of administration; however, it may take days or even weeks to reverse airway inflammation that has developed over a long period. The authors of several studies ]nave shown that the initiation of steroid administration in the ED and the continuation of steroids on a tapering dose after discharge decreases relapse rates. They also support the use of steroids early in the management of status asthmaticus. ~ >*, 119,12o-i23

Littenberg and Gluck 119 randomly assigned 97 acutely asthmatic patients to treatment with inhaled ~-agonists plus high-dose methylprednisolone or placebo. They found no difference in spirometry readings between the two groups at 4- hours but noted a significant decrease (from 47% to 19 %) in the incidence of hospitalization in steroid-treated patients compared with that in the placebo group. Schneider e,t a1121 reported similar success with the use of steroids. Fiel et a1122 found that an 8-day tapering dose of oral predni- solone reduced return ED visits at 10 days from 21% to 6%.

One study in the literature does not support steroid use. Stein and Cole 124 reported that IV glucocorticoids neither decreased the number of patients ultimately admitted to the hospital nor affected relapse. Criticisms of this study include the observation that not all patients discharged were prescribed steroids, that no information was provided con- cerning those patients treated with steroids on an outpatient basis, and that no documentation of medication compliance was made. All study patients were given a loading dose of aminophylline.

The initial recommended dose of methylprednisolone in status asthmaticus ranges from 60 to 125 mg intraven-

ously in adults, or 1 mg/kg in children, every 6 hours for the first 24 to 48 hours, followed by an oral taper. Alterna- tive regimens include hydrocortisone 2 mg/kg as an IV bolus, repeated every 4 hours, or hydrocortisone 2 mg/kg as an IV bolus followed by a .5-mg/kg/hour continuous infusion 12,M9,120,125

Magnesium Use of magnesium sulfate (MgSO 4) as an adjunct in the management of severe asthma has received considerable attention in the recent literature, but this use remains controversial. 126-128 Magnesium effects bronchodilation and smooth muscle relaxation by inhibiting cellular calcium uptake and inhibiting calcium release from vesicles in the sarcoplasmic reticulum. Magnesium has been shown to stabilize mast cell membranes, prevent the release of mediators, and block additional increases in calcium-ion flux. 129 Using an in vitro model, Spivey, Skobeloff, and Levin 129 showed that magnesium produces dose-dependent relaxation of bronchial smooth muscle both at rest and on stimu- lation with histamine, bethanechol, or electrical impulse. This finding supports the role of magnesium in relaxing smooth muscle and dilating bronchial rings.

Noppen et a113° studied six patients with severe asthma, defined as an FEV 1 less than 40% of that predicted, who were admitted to the hospital and treated with ~3-agonist nebulizations, steroids, and aminophylline. Each patient was given two trials of 3 g of MgSO 4 over 20 minutes and then underwent spirometry at the end of the infusion and 30 minutes after the infusion. The authors noted significant improvement in both FEV 1 and clinical signs after 10 of the 12 infusions, with a 12% to 132% improvement in FEV~. Magnesium infusion in combination with albuterol inhalation showed additional significant benefit.

In a placebo-controlled, double-blind trial of 38 patients with moderate to severe acute asthma, a significant increase in PEFR was demonstrated when MgSO 4 was added to the treatment regimen, and the number of patients requiring hospitalization was decreased. 131 Treatment consisted of 1.2 g of magnesium administered intravenously over 20 minutes to asthmatic patients who failed to respond to two nebulized [3-agonist treatments; response was determined by improvement in PEFR.

A recent small case series in the pediatric literature also supports a role for magnesium in status asthmaticus. Pabon, Moness, and Kissoon 132 reported four pediatric cases in which a 40-mg/kg infusion of MgSO 4 was associated with 20% to 90% improvement in PEER and 14% to 25% decrease in Paco 2.

The authors of several case reports note impressive response to magnesium in patients with refractory status. 127,128,131 In one case, a 4-months'-pregnant woman in

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status asthmaticus remained refractory to nebulized albuterol and IV methylprednisolone and was subsequently given 3 g of magnesium over 20 minutes. 133 Magnesium infusion was followed by significant subjective improvement, improvement in PEFR, and decreased respiratory rate, which permitted the patient to be discharged from the ED.

Not all studies have shown a benefit from magnesium infusion. Tiffany et a1134 studied 48 asthmatic patients with PEFR values less than 200 L/minute who failed to demonstrate improvement with nebulized albuterol, steroids, and aminophylline. None of the patients had a history of COPD. This study comprised three treatment groups: 12 patients were given 2 g magnesium over 20 minutes, followed by another 2 g/hour over 4 hours; 15 patients received the 2-g bolus but a placebo infusion; and 21 received placebo bolus and infusion. No clinical benefit was demonstrated in the magnesium-treated groups.

Green and Rothrock 135 studied 120 consecutive patients with acute asthma unresponsive to initial albuterol nebulization; the patients were given 2 g IV magnesium or no magnesium treatment. No difference was found between the two groups with respect to time in the ED, improvement in spirometry readings, or incidence of hospitalization. Chande and Skoner 136 studied the effect of nebulized magnesium on methacholine-induced bronchospasm in asthmatic patients and found no benefit of this therapy over nebulized saline solution.

Magnesium has been shown to be a relatively safe adjunct to other first-line therapies in asthma management. How- ever, its true benefit and role have yet to be clearly defined.

Anesthesia Inhalational and IV anesthetic agents have been used in the management of refractory status asthmaticus. Ketamine is an attractive agent because of its direct bronchodilator effects and its potential to be used without intubation and mechanical ventilation, but ketamine use in adult asthma has been limited by its potential to increase secretions and to cause emergence hallucinations. Halo- thane, isoflurane, enflurane, and ether are inhalational agents that cause bronchodilation, but their use in the ED is limited by the logistics of their administration and disposal.

Ketamine is an IV general anesthetic that has been recommended in the anesthesia literature as an effective bronchodilation agent in patients with asthmaJ 3r->° The mechanism of action is thought to be twofold: a direct effect on bronchial muscle and potentiation of catecholamines. Ketamine increases the levels of norepinephrine by way of blocking of reuptake and inhibition of vagal outflow. It exhibits minimal depressant effects on the myocardium and does not sensitize the myocardium to catecholamines, as seen with halothane, but ketamine does stimulate the cardiovas-

cular system and is therefore contraindicated in patients with hypertension and ischemic cardiac disease. Ketamine increases bronchial secretions; it is usually administered in conjunction with an anticholinergic such as atropine or glycopyrrolateJ 41 Ketamme's most controversial side effect is the induction of hallucinations, which are often un- pleasant and may recur. Concomitant sedation with benzo- diazepines has been reported to reduce this effect in pediatric patients and in adults. 141 EHommedieu and Arens >a described five pediatric patients (aged 4 to 15 years) m refractory status asthmaticus, treated with ketamine, who had consequent improvement in Pco2, acidosis, and pulmonary function. Three of the patients had been treated with isoproterenol drips (. 1 to 4.8 btg/kg/minute) without improvement. The initial dose of ketamine was 1.5 mg/kg, repeated at 2 mg/kg 20 minutes later when needed. Rock et a1143 administered a .5- to 1.0-mg/kg bolus of ketamine, followed by a 1- to 2.5-mg/kg/hour infusion, in two pediatric patients in refractory status asthmaticus. The regimens were continued for 1 and 2.5 days, respectively, with excellent results and no adverse sequelae.

Hemmmgsen, Kielsen, and Ordorico 144 used ketamine (1 mg/kg) in 14 intubated bronchospastic patients aged 50 to 100 years. They reported improvement in bronchospasm and in Pco 2. Patients were premedicated with midazolam; however, they did not discuss the incidence of postketamine hallucinations.

The inhalational anesthetics halothane, enflurane, and isoflurane are potent bronchodilators that have been success- fully used in status asthmaticus. 145-148 These agents possess direct bronchodilatory effects, decrease airway responsiveness, and attenuate histamine-induced bronchospasm. They do not stimulate respiratory secretions; nor do they produce laryngeal irritation. Side effects of halothane include myocardial depression and dysrhythmias, which are worsened by conditions of acidosis and hypoxia, limiting the use of this anesthetic. 149 Isoflurane and enflurane have not been associated with arrhythmias and may therefore be preferable to halothane. 147

Schwartz 146 reported the cases of two patients with severe asthma exacerbations who improved after halothane administration. O'Rourke and Crone 145 reported the case of an 11-month-old boy with refractory bronchospasm whose condition deteriorated despite the administration of subcutaneous terbutaline, IV aminophylline, and isoproterenol. This patient was intubated, but the Pco 2 increased to 67 mm Hg and the pH dropped to 7.1. Halothane 1% was started, and within 10 minutes clinical improvement was evident, with a repeat PCO 2 Of 47 mm Hg and a pH of 7.3.

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Halothane was discontinued after 75 minutes, and the child continued to improve.

The authors of one report discussed two cases of refractory status asth.maticus that did not respond to halothane 2%, but responded dramatically within ten minutes of diethyl ether inhalation, with inflation pressures dropping from greater than 80 cm H20 to 20 to 30 cm H20.15o The authors concluded that despite the risks of flammability and explosion, ether might have a role in the management of these cases.

Helium-oxygen mixture (60%-40%) was used success- fully in one study of seven ventilated asthmatic subjects with peak pressures in excess of 75 cm H20 , Paco 2 values of 62 to 110 mm Hg, and pH 6.87 to 7.1. ~51 Within minutes of use of the helium-oxygen mixture, airway pressures had decreased by 33 mm Hg and Paco 2 had decreased by 36 mm Hg. Gluck, Ornato, and Castriotta z51 reported good results with heliox use in six patients requiring mechanical ventilation for severe asthma; however, airway pressures and Paco 2 before and after heliox use were not reported. Manthous et a1152 documented a 35% increase in PEP and a significant decrease in pulsus paradoxus in patients breathing an 80:20 mixture of helium and oxygen compared with controls. Helium is an inert gas of low molecular weight, less dense than nitrogen, and is insoluble in human tissues under normal conditions. The kinematics of the helium- oxygen gas mixture permits laminar flow, which decreases airway resistance and allows greater oxygen delivery during inspiration and reduced work of breathing, resulting in decreased Paco 2. In all patients studied, the tidal volume and inspiratory flow rates were increased while they breathed the helium-oxygen mixture. No adverse effects were noted.

Experimental drugs Leukotrienes LTC,~, LTD,p and LTE,~ have been implicated in the pathophysiology of asthma. These agents promote bronchoconstriction, bronchial mucus secretion, and formation of airway mucosal edema. ~53,154 Leukotrienes, manufactured by the mast ceils, eosinophils, basophils, and macrophages, are released after challenge with inhaled antigens. 155 LTD,~ is 1,000 times more potent than histamine in causing bronchoconstriction. 156

Leukotriene-receptor blockade has been proposed as a potential mechanism for treating both acute bronchospasm and consequent inflammatory responses. 156-158 This has led to the development of investigational drugs such is MK-571 and MK-679, which have been studied in several clinical trials. 154,1~s,159 MK-571, infused intravenously, has been shown to be an effective bronchodilator when used as a single agent, producing 20% improvement in FEV> and to have an additive effect when used in conjunction

with nebulized albuterol. Results from human trials with MK-571 have also supported the speculation that LTD 4 receptor activation plays an important role in perpetuating dysfunctional airway tone in patients with active asthma. 154 Further testing should be conducted on the mechanism of action of leukotriene-receptor blockers, but they provide promise for future management of acute and chronic asthma.

REFERENCES 1. Mason R, Corsello P: Management of adult patients with chronic asthma. Semin Respir Med 1987;8:216-226.

2. Summer W: Status asthmaticus. Chest 1985;87(suppl}:87S-94S.

3. Centers for Disease Control. Asthma--United States 1982q 992. JAMA 1995;273:451-452.

4. Weiss K: Seasonal trends in U.S. asthma hospitalizations and mortality. JAMA 1990;263:2323- 2328.

5. Busey J, Fenger E, Hopper J, et al: Management of status asthmaticus. Am Rev Resp Dis 1968;97:735-736.

6. Fernandez E, Martin R: Treatment of acute, severe asthma. Semin Respir Med1987;8:227- 238.

7. Adams S, Martin H: The emergent approach to asthma. Chest1992;101 (suppl):422S-425S.

8. FitzGerald J, Hargreave F: Acute asthma: Emergency department management and prospective of outcome. Can MadAssoc J 1990;142:591-595.

9. British Thoracic Society: Guidelines for management of asthma in adults. II. Acute severe asthma. BMJ 1990;301:797-800.

10. Hargreave F, Dolovich J, Newhouse M: The assessment and treatment of asthma: A confer- ence report. J Allergy Ctin Immunol 1990;85:1098-1111.

11. Bone R, Calverley P, Chapman K, et al: The international clinical respiratory group: Special report. Chest 1992;101:1420-1424.

12. National Asthma Education Program: Executive Summary." Guidelines for the Diagnosis and Management ofAsthma. Bethesda, Maryland: National Institutes of Health, 1991: puNication no. 91-3042A.

13. Weiss K, Wagener D: Changing patterns of asthma mortality: Identifying target populations at high risk. JAMA 1990;264:1683-1687.

14. Buist A, Vollmer W: Reflections on the rise in asthma morbidity and mortality. JAMA 1990;264:1719-1720.

15. Seddon P, Heaf D: Long term outcome of ventilated asthmatics: Arch Dis Child1990;65:1324- 1327.

16. Benatar S: Fatat asthma. N Engl J Med 1986;314:423-428.

17. Ernst P, Habbick B, Suissa S, et al: Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity? Am Rev flespir Dis 1993;148:75-79.

18. Spitzer W, Suissa S, Ernst P, et ak The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-506.

19. Schenker M, Gold E, Lopez R, et ah Asthma mortality in California, 1960-1989. Am Rev Respir Dis 1993;147:1454-1460.

20. Robin E: Death from branchial asthma. Chest 1988;93:614-618.

21. Dales R, Munt P: Use of mechanical ventilation in adults with severe asthma. Can MedAssoc J 1984;130:391-394.

22. Marquette C, Saulnier F, Leroy O, et ah Long-term prognosis of near-fatal asthma. Am Rev flespir Dis 1992;146:76-81.

23. Mansel J, Stogner S, Petrini M, et ah Mechanical ventilation in patients with acute severe asthma. Am J Med! 990;89:42-48.

24. Sly R: Mortality from asthma in children: 1979-1984. J Allergy Clin Immunot1988;82:705- 717.

25. Yunginger J, Reed C, 0'gonnell J, et ah A community-based study of the epidemiology of asthma. Am Roy Respir Dis 1992;146:888-894.

FEBRUARY 1997 29:2 ANNALS OF EMERGENCY MEDICINE 2 7 I

R E F R A C T O R Y A S T H M A , P A R T 1

]agoda et aI

26. Gergen P, Weiss K: The increasing problem of asthma in the United States. Am Roy Respir Dis 1982;146:823-824.

27. Weitzman M, Gortmaker S, Sobol A, et al: Recent trends in the prevalence and severity of childhood asthma. JAMA 1992;268:2673-2677.

28. Burdow J, Juniper E, Killian K, et ah The perception of breathlessness in asthma. Am Rev Respir Dis 1982;126:825-828.

29. Brand P, Rijcken B, Schouten J, et al: Perception of airway obstruction in a random population sample. Am Roy Respir Dis 1992;146:396-401.

30. Kikuchi Y, Okabe S, Tamura G, et al: Ohemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994;330:1329-1334.

31. Strunk B, Mrazek [3, Wolfson F, et el: Physiologic and psychological characteristics associated with deaths due to asthma in childhood. JAMA 1985;254:1193-1198.

32. Miller B: Depression and asthma: A potentially lethal mixture. JAIlergyClin Immunol 1989;80:481-486.

33. Sears M, Taylor D, Print D, et al: Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;33:1391 -I 396.

34. British Thoracic Association: Death from asthma in two regions of England. BMJ 1982;285:1251-1255.

35. O'Hallaren M, Yunginger J, Offord K, et al: Exposure to an aeroallergen as a possible precipi- tating factor in respiratory arrest in young patients with asthma. N Engl J Med1991;324:359- 363.

36. Molfina N, Nannini L, Martelli A, et al: Respiratory arrest in near-fatal asthma. N Engl J Med 1991 ;324:285-288.

37. Rea HH, Scragg R, Jackson R, et al: A case control study of deaths from asthma. Thorax 1986;41:833-839.

38. Mullen M, Mullen B, Carey M: The association between beta-agonist use and death from asthma: A meta-analytic integration of case-control studies. JAMA 1993:270:1842-1845.

39. Zirnent I: Beta-adrenergio agonist toxicity: Less of a problem, more of a perception. Chest 1993;103:1591 -I 597.

4& Skorodin M: Beta-adrenergic agonists: A problem. Chest1993;103:1587-1590.

41. Liu M, Bleecker E, kichtenstein L, et ah Evidence for elevated levels of histamine, prostaglandin B, and other bronchocanstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Resp Dis 1990;142:126-132.

42. Bjukanovic R, Wilson J, Britten K, et ah Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immuno- histochemistry. Am Roy Respir Dis 1990;142:863-871.

43. Beasley R, Roche W, Roberts J, et al: Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989;139:806-817.

44. Busse WW: The role of inflammation in asthma: A new focus. JRespirDis 1989;10:72-80.

45. Wardlaw A J, Dunnette S, Gleich G J, at ah Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Am RevRespir Dis 1988;137:62-69.

46. Laitinen L, Heine M, Laitinen A, et ah Damage of the airway epithelium and bronchial reactiv- ity in patients with asthma. Am Rev Respir Dis 1985;131:599-606.

47. Bleecker ER: Cholinergic and neuragenic mechanisms in obstructive airways disease. Am J Med 1986;81:93-102.

48. Holgate ST, Beasley R, Twentyman [3P: The pathogenesis and significance of bronchial hyperresponsiveness in airway disease. Clio Sci1987;73:561-572.

49. Chang K: Bole of inflammation in the hyperactivity of the airways. Thorax 1986;41:657-662.

50. Kowalski M, Diddler A, Kaliner M: Neurogenic inflammation in the airways. Am Roy Respir Dis 1988;140:101-109.

51. O'Byrne P, Dolovich J, Hargreave F: Late asthmatic response. Am Roy Respir Dis 1987;136:704-751.

52. Roca J, Ramis L, Rodriguez-Roisin R, et ah Mechanisms of hypexemia in patient with status asthmaticus requiring mechanical ventilation. Am Roy Respir Dis 1989;139:732-739.

53. McFadden ER: Exertional dyspnea and cough as preludes to acute attacks of bronchial asthma. N Engl J Med 1975;292:555-559.

54. Waolcock A, Bead J: Lung volume in exacerbations of asthma. Am J Med 1966;41:259-264.

55. Calhoun W: Management of respiratory failure. Chest1992;101(suppl):410S-414S.

56. Appel D, Rubenstein R, Schrager K, et ah Lactic acidosis in severe asthma. Am J Med 1983;75:580-584.

57. Mountain R, Heffner J, Brackett N, et al: Acid-base disturbances in acute asthma. Chest 1990;98:651-655.

58. Nowak R, Tomlanovich M, Sarkar D, et ah Arterial blood gases and pulmonary function testing in acute bronchial asthm& JAMA 1983;249:2043-2046.

59. Wiener C: Ventilatory management of respiratory failure in asthma. JAMA 1993;269:2128- 2131.

60. Vathanen A, Knox A, Higgins B, et ah Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988;1:554-558.

61. Cockcroff D, Murdock K: Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. JAIlergy Clio Immunol 1987;79:734-740.

62. Howarth P, Durham S, Lee T, eL al: influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. Am Rev Reepir Dis 1985;132:986-992.

63. Twentyman O, Finnerty J, Holgate S: The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma. Am Rev Respir Dis 1991;144:782-787.

64. O'Connor B, Aikman S, Barnes P: Tolerance to the nonbronchodilator effects of inhaled beta 2- agonists in asthma. IV Engl J Med 1992;327:1204-1208.

65. Becker A, Nelson N, Simons F: Inhaled salbutamol vs injected epinephrine in the treatment of acute asthma in children. J Pediatr 1983;102:465-469.

66. Spiteri M, Millar A, Pavia D, et al: Subcutaneous adrenaline versus terbutaline in the treatment of acute severe asthma. Thorax 1988;43:19-23.

67. Cydulka R, [3avisan R, Grammer L, et al: The use of epinephrine in the treatment of older adult asthmatics. Ann Emerg Med 1988;17:322-326.

68. Rudnitsky G, Eberlein B, Schoffstall J, et al: Comparison of intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergency department. Ann Emerg Med 1993;22:1842-1846.

69. Lin R, Seuter [3, Newman T, et al: Continuous versus intermittent albuterel nebulization in the treatment of acute asthma. Ann Emerg Med 1993;22:1847-1883.

70. OIshaker J, Jerrard D, Barish B, et al: The efficacy and safety of a continuous albuterol protocol for the treatment of acute adult asthma attacks. Am J Emerg Med 1993;11:131-133.

71. Turner J, Corkery K Eekman B, et ah Equivalence of continuous flow nebulizer and metered dose inhaler with reservoir bag for treatment of acute airflow obstruction. Chest 1988;93:476- 481.

72, Hodder R, Culcutt L, Leech J: Metered-dose inhaler with spacer is superior to wet nebulization for emergency room treatment of acute, severe asthma. Chest1988;94 (suppl):529-58S.

73. Intermittent Positive Pressure Breathing Trial Group: Intermittent positive pressure breathing therapy of chronic obstructive pulmonary disease: A clinical trial. Ann intern Med 1983;99:612- 620.

74. Bodenhamer J, Bergstrom R, Drown D, et ah Frequently nebulized beta-agonists for asthma: Effects on serum electrolytes. Ann Emerg Med 1992;21:1337-1342.

75. Haalbaorn J, Beenstra M, Struyvenberg A: Hypokalemia induced by inhalation of fenoterol. Lancet 1985;1:1125-1127.

76. Whyte K, Reid C, Addis G, et ah Salbutamol induced hypokalamia: The effect of theophylline alone and in combination with adrenaline. BrJ Clio Pharmaco11988;25:571-578,

77. Kung M, White J, Burki N: The effect of subcutaneously administered terbutaline on serum potassium in asymptomatic adult asthmatics. Am Rev Respir Dis 1984;129:329-332.

78. Crane J, Burgess C, Graham A, et al: Hypokalemic and electrocardiographic effects of aminophylline and salbutamol in obstructive airways disease. NZMedJ 1987;100:309-311.

79. Kurland G, Williams J, Lewiston N: Fatal myocardial toxicity during continuous infusion intravenous isoproterenol during therapy of asthma. JAIlergy Clio Immuno11979;63:107-I 11.

80. Boho D, Kalloghlian A, Jenkins J, et ah Intravenous salbutamel in the treatment of status asthmaticus in children. Crit Care Med 1984;12:892-895.

2 7 2 ANNALS OF EMERGENCY MEDICtNE 29:2 FEBRUARY 1997

R E F R A C T O R Y A S T H M A , P A R T 1

Jagoda et al

81. Verbaek P, Gareau A, Rubes C: Treatment of asthmamelated respiratory arrest with endotra- cheal albutereh Ann Emerg Med1988;17:358~360.

82. Behuck A, Chapman K, Abboud R, et al: Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airway disease in the emergency room. Am J Mad 1987;82:59-64.

83. Ward M. Macfarlene J, Davies D: A place for ipratropium bremide in the treatment of severe acute asthma. Br J Dis Chest 1985;79:374-378.

84. Patrick D, Dales R, Stark R, et ah Severe exacerbations of COPD and asthma: Incremental benefit of adding ipratropium to usual therapy, Chest 1990;98:295-297.

85. Dates J, Wood A: Ipratropium bromide. N Engl J Mad 1988;319:486-493.

88. Beck R, Robertson C, Galdes-Sebaldt, et ah Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. J Pediatr 1985;107:605-608.

88. Owens M, George B: Nebulized atropine sulfate in the treatment of acute asthma. Chest 1991 ;99:1084-1087.

89. Young G, Freitas P: A randomized comparison of atropine and metaproterenol inhalational therapies for refractory status asthmaticus. Ann Emerg Mad 1991;20:513-519.

90. SIovis C, Baniels G, Wharton B: Intravenous use of glycopyrrolate in acute respiratory dis- tress due to bronchospastic pulmonary disease. Ann Emerg Mad 1987;16:898-900.

91. Green B, Briston A, Fisher S: Comparison of IV gtycopyrrelate and atropine in the prevention of bradycardia and arrhythmias following repeated doses of suxamethonium in children. Br J Anaasth 1984;56:981-985.

92. CyduIka R, Emerman C: Effects of combined treatment with glycopyrrolate and albuterol in acute exacerbation of asthma. Ann Emerg Med 1994;23:270-274.

93. Johnson B, Suratt P, Gal T, et el: Effect of inhaled glycopyrrolate and atropine in asthma. Chest 1984;85:325-328.

94. Gilman M, Meyer L, Carter J, et ah Comparison of aeroso[ized glycopyrrolate and metaproterenol in acute asthma. Chest 1990;98:1095-1098.

95. Walker F, Kaiser D, Kowal M, et ah Prolonged effect of inhaled glycopyrrolate in asthma. Chest 1987;91:51.

96. Schneider S: Effect of a treatment protocol on the efficiency of care of the adult acute asthmatic. Ann Emerg Mad 1988;15:703-706.

97. Fanta C, Rossing T, McFadden E: Treatment of acute asthma: Is combination therapy with sympathomimetics and methylxanthines indicated? Am J Mad 1986;80:5-10.

98. Murphy B, McDermott M, Rydman R, et ah Aminophylline in the treatment of acute asthma when betaz-adrenergics and steroids are provided. Arch Intern Mad1993;153:1784-1788.

99. Milgrem H, Bender B: Current issues in the use of theophylline. Am Rev RespirDis 1993;147 (suppl):S33-S39.

100. Nassif E, Weinberger M, Thomson R, et al: The value of maintenance theophylline in steroid-dependent asthma. N Eegl J Mad 1981;304:71-75.

101. Brenner M, Berkowitz R, Marshall N, et al: Need for theophylline in severe steroid-requiring asthmatics. Clio Allergy 1988;18:143-150.

102. Joad J, Ahrens R, Lfndgren S, et ah Relative efficacy of maintenance therapy with theephylline, inhated abutero!, and the combination for chronic asthma. JAgergy Clio Immortal 1987;79:78-85.

l O& Smith J, Weber R, Nawlson H: Theephytline and aeroselized terbutaline in the treatment of bronchial asthma. Chest 1980;78:816-818.

104. Rachetefsky G, Katz R, Mickey M, et ah Metaprotorenol and theophytline in asthmatic children. Ann Allergy 1980;46:207-212.

105. Pierson W, Bierman C, Stature S. et ah Double-blind trial of aminophylline in status asthmaticus. Pediatrics 1971;48:642-648.

106. Pauwels R: New aspects of the therapeutic potential of theophyJline in asthma. J Allergy Ch'n lmmunof 1989;83:548-553.

107. Pauwels R: The effects of theophylline on airway inflammation. Chest 1987;92:32-37.

108. Littenberg 8: Aminophylline treatment in severe, acute asthma. JAMA 1988;259:1678- 1684.

109. Carrier J, Shaw R, Porter B, et ah Comparison of intravenous and oral routes of theophyIline loading in acute asthma. Ann Emerg Mad 1985;14:1145-1151.

110. Nassif E, Weinberger M, Thompson B, et el: The value of maintenance theephylline in steroid-dependent asthma. N Eng/J Mad 1881 ;304:71-75.

111. Wrenn K, Sbvis C, Murphy F, et ah Aminophylline therapy far acute bronchospastic disease in the emergency room. Ann Intern Mad 1991;115:241-247.

112, Bramen S, Kaemmerien J: Intensive care of status asthmaticus. JAMA 1990;264:366-368.

113. Hendeles L, Weinberger M: Theophylline: A "state-of-art" review. Pharmacetherapy 1983;3:2-44.

114. McNamara R, Ruble P: Intramuscular methylprednisolone acetate for the prevention of relapse in acute asthma. Ann Emerg Mad1993;22:1829-1835.

115. Barnes P: New concepts in the pathegenesis of bronchial hyperrespoosiveeess and asthma. J Allergy Clio Immune/1989;83:1013-1026.

116. Larsen G: Asthma in chfldren. N Engl J Mad ~982;326:1540-1545.

t 17. Barnes N: Effects of corticosteroids in acute severe asthma. Thorax 1992;47:582-583.

11 & Ziment I: Steroids. Clio Chest Mad 1985;7:341-354.

119. Littenberg B, Gluck E: A controlled trial of methytprednisolone in the emergency treatment of acute asthma. N Engl J Mad 1986;314:150-152.

120. Haskell R, Wang B, Hansen J: A double-blind, randomized clinical trial of methylprednisolone in status asthmaticus. Arch Intern Mad1983;143:1324-1327.

121. Schneider S, Pipher A, Britton H, et ah High dose methylprednisolone as initial therapy in patients with acute bronchospasm. J Asthma 1988;25:189-193.

122. Eiel S, Swartz M, Glanz K, et el: Efficacy of short-term corticosteroid therapy in outpatient treatment of acute bronchial asthma. Am J Mad 1983;75:259-262.

123. Chapman K, Verbeek P, White J, et ah Effect of a short course of prednisone in the prevention of early relapse after the emergency room treatment of acute asthma. N Eegl J Mad 1991 ;324:788-794.

124. Stein L, Cole R: Early administration of corticesteroid in emergency room treatment of acute asthma. Ann Intern Med 1990;112:822-827.

125. Stein L, Cole R: Meta-analysis of steroid therapy in acute asthma. Am J Emerg Mad 1992;10:301-310.

126. McNamara R, Spivey W, Bkobeloff E, et al: Intravenous magnesium sulphate in the management of acute respiratory failure complicating asthma. Ann Emerg Mad 1989;18:197-199.

127. Leber M, Rao S: Magnesium sulfate used as an adjunct to beta-agonists in acute asthma: A case report. J Emerg Mad 1991;9:377.

128. Kuitert L, Kletchko S: Intravenous magnesium sulfate in acute, life4hreatening asthma. Ann Emerg Mad 1991;20:1243-1245.

129. Spivey W, Skobe[off E, Levin R: Effect of magnesium chloride in rabbit bronchial smooth muscle. Ann Emerg Mad 1990;19:1107-1112.

130. Noppen M, Vanmaale L, Nicole I, et el: Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma. Chest1890;97:373-375.

131. Skobeloff E, Spivey W, McNamara R, et ah Intravenous magnesium sulfate for the treatment of asthma in the emergency department. JAMA 1989;262:1210-1213.

132. Pabon H, Moness G, Kissoon N: Safety and efficacy of magnesium suifate infusion in children with status asthmaticus. PefliatrEmerg Care 1884;10:200-204.

133. Skobeloff E, Kim D, Spivey W: Magnesium sulfate for the treatment of bronchospasm complicating acute bronchitis in a four-months' pregnant woman. Ann Emorg Med1993;22:1365- 1367.

134. Tiffany B, Bark W, Todd K, et ah Magnesium bolus or infusion fails to improve spirometrie performance in acute asthma exacerbations [abstract]. Ann Emerg Mad 1992;21:648.

135. Green S, Bothrock S: Intravenous magnesium for acute asthma: Failure to decrease emergency treatment duration or need for hospitalization. Ann Emerg Mad 1992;21:280-265.

138. Chande V, Skener B: A trial of nebulized magnesium sulfate to reverse bronchespasm in asthmatic patients. Ann Ernerg Mad 1992:21;1111-1119.

137. Betts E, Parkin C: Use of ketamine in an asthmatic child. Anesth Anatg 1871;50:420-421.

138. Corseen G, Gutierrez J, Reeves J, et ah Ketamine in the anesthetic management of asthmatic patients. Anesth Analg 1972;51:588-896.

139. Fisher M: Ketamine for status asthmaticus. Anesthesia 1977;32:771-772.

140. Sarma V: Ketamine and asthma. Acta &and 1992;36:1867q 510.

FEBRUARY 1997 2£:2 ANNALS OF EMERGENCY MEDICINE 2 7 3

REFRACTORY A S T H M A , PART 1 Jagoda et al

141. Green S, Johnson N: Ketamine sedation for pediatric procedures. 2. Review and implica- tions. Ann Emerg Med 1990;19:1033-1046.

142. L'Hommedieu C, Arens J: The use of ketamine for the emergency intubation of patients with status asthmaticus. Ann Emerg Med 1987;16:568-571.

143. Rock M, De La Rocha R, L'Hommedieu C, et ah Use of ketamine in asthmatic children to treat respiratory failure refractory to conventional therapy. Crit Care Med 1986;14:514-516.

144. Hemmingsen C, Kielsen P, Ordorico J: Ketamine in the treatment of bronchospasm during mechanical ventilation. Am J Emerg Med 1994;12:417-420.

145. O'Rourke P, Crone R: Halothane in status asthmaticus. Crit Care Med1982;10:341-343.

146. Schwartz S J: Treatment of status asthmaticus with halethane. JAMA 1984;251:2888-2689.

147. Pamass S, FeN J, Chamberlin W, et ah Status asthmaticus treated with isoflurane and enflurane. Anesth Analg 1987;66:193-195.

148. Bierman M, Brown M, Muren O, et al: Prolonged isoflurane anesthesia in status asthmati- cos. Crit Care Med 1986;14:832-833.

149. Roizen M, Stevens W: Multiform ventricular tachycardia due to the interaction of aminophylline and halothane. AnesthAnalg 1978;57:738-741.

150. Robertson C, Steedman, Sinclair C, et al: Use of ether in life-threatening acute severe asthma. Lancet 1985;Jan 26:187-188.

151. Gluck E, Onarato B, Castriotta R: Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 1990;98:693-898.

152. Manthous CA, Hall JB, Me[reed A, et ah Heliox improves pulsus paradoxus and peak expiratory flow in non-intubated patients with severe asthma. Am J Respir Crit Care Med 1995;151:310-314.

153. Griffin M, Weiss W, Leitch A, et ah Effects of leukotriene B on the airways in asthma. N Engl J Med 1983;308:436-439.

154. Gaddy J, Margolskee D, Bush R, et ah Bronchodilation with a potent and selective leukotriene E} 4 (LTD 4) receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis 1992;146:358-363.

155. Busse W, Gaddy J: The role of [eukotdene antagonists and inhibitors in the treatment of airway disease. Am Rev Respir Dis 1991 ;143 (suppl):S103-$107.

156. Barnes N, Piper P, Costello J: Comparative effects of inhaled leukotriene C 4, leukotriene B 4, and histamine in normal human subjects. Thorax1984;39:500-504.

157. Jones T, Zamboni B, Belley M: Pharmacology of L-660,711 (MF-571): A novel potent and selective leukotriene D 4 receptor antagonist. Can J Physiol Pharmacol 1988;67:17-28.

158. Manning P, Watson R, Margolskee D, et al: Inhibition of exercise-induced branchocanstric- tion by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med 1990;323:1736-1739.

159. Impens N, Reiss T, Teahan J, eta]: Acute bronchodi[ation with an intravenously administered leukotfiene D 4 antagonist, mk-679. Am Rev Respir Dis 1993;147:1442-1446.

Reprint no. 47/1/79690

Address for reprints:

Andy Jagoda, MD

Box 1149

Mount Sinai Medical Center

One Gustave L Lew Place

New York, NY 10029

212-241-2987

Fax 212-423-1023


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