Bronchodilator Reversal of Bronchospasm and Symptoms Incurred During Methacholine Bronchoprovocation Challenge

Bronchodilator Reversal of Bronchospasm and Symptoms Incurred During Methacholine Bronchoprovocation Challenge* Documentation of Safety and nme Course

Melvin R. Pratter; M.D .• F.C.C.P.; 'I7uuidew C. Bartter, M.D .• F.C.C.P.; and }ames Dubois, M.H.A.. R.R.T. We undertook a prospective study of broochoprovocation challenge (BPC) to Ioolt at issues ol safety and revenibiJity ol broochospasm and symptoms iDducecl by BPC. Over a 14-IDOIIth interval, we documented 6! coasecutive cases o( bronchial hypenespomiveness. During BPC, there was a statistically signi&c:ant but clinically modest iocrease in both cough and clyspoea. Both bronebospasm and symptoms were readily reversed with a simple protocol o( iDhaled albuterol usiag a metered-dose inhaler with a spacer. Routine protocol was effective in every case; there was

Bronchoprovocation challenge (BPC) is an important

tool for the diagnosis of asthma: BPC demonstrating bronchial hyperresponsiveness (BHR) can help to confirm a diagnosis of asthma; BPC has allowed us to understand and diagnose cough-variant asthma and to evaluate the role of BHR in chronic cough; and BPC plays an important role in the evaluation of dyspnea. 1-3 The absence ofBHR can also be very useful clinically, as it makes a diagnosis of asthma very unlikely, even For editorial comment see page 1323

in the patient with classic asthma-like symptoms. 1 Despite its documented clinical utility, l-4 BPC is not

used as widely as it could be, leaving many clinicians with the task of diagnosing asthma on clinical grounds alone. 5 One reason for the underutilization of BPC has been a fear that the test is unsafe. 8 In more than 10 years of clinical experience with BPC involving several thousand tests, we have come to believe that BPC is actually very safe and that concerns about safety are unfounded. 1 In the literature, we have found reviews describing large numbers of challenges without adverse effects but have not found formal prospective documentation of this belie£ 1•7 '\\e therefore wished to establish a formal protocol and to document prospectively how and in what time span the clinical *From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Robert Wood Johnson School of Medicine, Cooper Hospital/University Medk81 Center, Camden, NJ. Manuscript received December 8, 1992; revision accepted Marc:b 10, 1993. Reprint requem: Dr. Fratter, Ste 312, 3 Cooper l'ftwJ, Cmnden, N}

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never a need for individualized physician intervention. Our prospective data document the safety ofBPC; we could 6od no reasoo why BPC would need to be coa6ned to the hospital. We conclude that BPC is a valuable dinical test which merits wider disseminatioo and use. (C"-' 1993; 104:134J-4S)

BHR • brooehial hyperrespoosiveoeu; BHR + • presence of BHR; BHR- •uo BHR; BPC• broochopnMICIII:ioa dWieap; PCIO•pl'0¥0CIIIive CODCieDtntioo c:ausiDi 10 pen:ent drop in FEV,

and spirometric effects of methacholine can be reversed. MATERIALS AND METHODS

Every BPC completed by our laboratory from June 8, 1990 until Aug 27, 1991 was included in the study. Data collection began with a two-page questionnaire filled out by the patient describing his or ber symptoms or disease. After the patient bad filled out the questionnaire, the technician performing the BPC recorded demographics for each patient. Most spirometric values were obtained with a Sensormedics 2100 spirometer. A few studies were performed on Sensormedics 2130, Sensormedics 2200, and Sensormedics 6200 spirometen. Computer software was unifOrm for all systems. Tbe test solutions were aerosolized using a nebulizer (DeVilbiss 646) with compressed air at 8 Umin. Tbe measured outputs of the ten nebulizen in our laboratory range from 0.26 to 0.28 mllmin, with a mean of0.27 mll min. Tbe methacholine BPC was performed acrording to the tidal volume method of Hargreave et al ...,. After the inhalation of plain physiologic saline solution (NaCI) to establish the baseline FEV, tOr the BPC, dilutions of methacholine in NaCI were deli'W!red in sequentially higher concentrations (0.125 mglml, 0.25 mglml, 0.5 mglml, 1 mglml, 2 mglml, 4 mglml, and 8 mglml). Each concentration was inhaled fOr 2 min, with spirometry obtained 1 min after the end of that dose. Tbe BPC was terminated when a drop of at least 00 percent in FEV, bad OCCUI'J'ed or after the highest concentration bad been administered. If methacholine did induce a drop in FEY, ofOO percent or more, the extrapolated concentration at which a 2o percent drop in FEV, bad occurred was calculated and termed the PCOO. Patients with a PCm o£8 mglml or less were considered to have increased bronchial hyperresponsiveness (BHR + ) .Patients with less than a 00 percent drop in FEV, after methacholine at 8 mglml were considered not to have clinically relevant bronchial hyperresponsiveness (BHR- ). Our protocol is that all patients proven to be BHR + are immediately given 2 inhalations of albuterol, 1 min apart, using a metered-dose inhaler with a spacer (Aerochamber). Spirometry is performed 5 min after the second inhalation. If the FEV, has not

·x

Borg Ratings for Dyspnea and Cough During BPC 10 9

8 7

8 5 4

3 2 1

0 1. Borg ratings for mean levels of cough and dyspnea at baseline and maximal values during BPC and at time of discharge. FIGURE

BASEUNE

returned to within 10 percent of baseline by that time, a single third inhalation of albuterol is administered. No further albuterol is administered; spirometry is performed every 5 min until the FEV, has returned to within 10 percent of the baseline before methacholine, at which time the FEV, is deemed "acceptable" for discharge from the laboratory. If after 30 min the FEV, is not within 10 percent of the baseline before BPC, the pulmonologist covering the pulmonary function laboratory is to be called for further instructions. In addition to spirometric data, cough and dyspnea were monitored. Levels were recorded on a Borg visual analog scale (0 to 10; O=none; 10=near maximal)." Cough and dyspnea were documented before the first spirometric test, after every dose of methacholine, and after albuterol. For BHR + patients the time from the last dose of methacholine until the patient was ready for discharge was recorded. Data were entered into a computerized database (Statistical Package lOr the Social Sciences [SPSS], version 4.1). Data were analyzed using two-tailed Student's paired t tests. RESULTS

Our laboratory performed 114 methacholine BPCs during the period of study. All patients had been referred to the pulmonary function laboratory because of dyspnea, cough, or other symptoms consistent with asthma. Six patients were excluded from analysis because of inadequate data collection, leaving 108 cases. No patient was tested twice; each study represents a separate individual. Of the 108 patients, 62 (57 percent) were BHR +, and 46 (43 percent) were BHR- . The BHR + group was the basis for this study. The BHR + patients had a mean age of 42.2 years, with a range of 12 to 72 years. There were 14 men and 48 women. The mean baseline FEV 1 was 2.60 L or 93 ± 13 percent of predicted ( ± SD) (range, 71 to 124 percent). The values for PC20 ranged from 0.06 to 6.35 mglml (mean, 2.13±2.01 mglml). The maximal drop in the FEV 1 during establishment of a PC20 in the BHR + group ranged from 20 to 45 percent (mean, 27 ± 6 percent).

BPC -DYSPNEA

DISCHARGE

B

COUGH

Symptoms Induced by BPC

The mean baseline level of dyspnea before BPC using the Borg scale ofO to 10 was 1.06± 1.39 (range, 0 to 7) (Fig 1). The mean maximal level of dyspnea incurred during BPC was 3.29± 1.85 (range, 0 to 7) (Fig 1). When each patient's baseline dyspnea was compared with his or her maximal dyspnea during BPC using a paired Students t test, there was a significant increase in dyspnea during BPC (p<0.001). The mean cough level before BPC (using the Borg scale) was 1.14± 1.47 (range, 0 to 5) (Fig 1). The maximal mean level of cough incurred during BPC was 2.69 ± 1.8 (range, 0 to 7) (Fig 1). When each patients cough before BPC was compared with his or her maximal cough during BPC using a paired Students t test, there was a significant increase in cough during BPC (p<0.001). Reversal of Methacholine-Induced Bronchoconstriction

Data review revealed that in 2 cases the technician had inadvertently discharged the patient 12 min after the last dose of methacholine with values for FEV 1 of 11 percent (28 ml below protocol threshold for discharge) and 13 percent (67 ml below protocol threshold for discharge) below baseline (technician errors). While the differences are not clinically meaningful, the two did not complete standard protocol and are eliminated from the ensuing reversal data. For the cases treated appropriately with the standard albuterol protocol (n = 60), the FEV 1 returned to within 10 percent of the baseline after NaCI in all cases (100 percent). At the time of discharge, the mean FEV1 was 1.5 ±6.2 percent less than baseline (range, -10 to + 15 percent). The mean time from the first inhalation of albuterol to reversal of methacholineCHEST I 104 I 5 I NOVEMBER, 1993

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100~ 80~

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Minutes to Reversal induced bronchospasm was 7.42±3.48 min (range, 6 to 22 min). For 82 percent (49) of the patients, values for FEV1 were within 10 percent of baseline (acceptable) following 2 puffs of albuterol. Eighteen percent (11) of the patients received a total of 3 puffs of albuterol. A cumulative 82 percent of the values for FEV1were acceptable within 6 min, 92 percent within 12 min, 98 percent within 17 min, and 100 percent within 22 min (Fig 2). No patient experienced significant side effects from P-adrenergic agonists; there was never a need to withhold doses or to contact a physician.

Rever8al of Symptoms Final symptom scoring was performed after pulmonary function had returned to within 10 percent of baseline and prior to discharge. At discharge the mean level of dyspnea was 1.4, and the mean level of cough was 1.6 (Fig 1). Each patients baseline .cough and dyspnea were compared with cough and dyspnea before discharge using paired Students t testing to see if there were differences between baseline and levels before discharge. There was no significant difference for either symptom (p = 0.13 for dyspnea and 0.17 for cough). DISCUSSION

Specific data about treatment to reverse symptoms and bronchospasm incurred during BPC are rare; for example, these aspects were not even mentioned in a recent review of BPC.ll Our data, which were collected prospectively, demonstrate that BHR + patients do experience increases in cough and dyspnea which reach statistical significance, although the mean levels (3.29 for dyspnea and 2.67 for cough) are still within the moderate range (level 3 ="moderate" on the Borg scale). More importantly, both bronchospasm and symptoms incurred during BPC are readily reversed within a maximum of 22 min using a maximum of 3 inhalations of albuterol. As stated, our protocol requires that a pulmonologist be contacted if the FEV1 1344

22 minutes

Ftcuu: 2. nme from lut cballeuge until revenal ~ methacholine-induced symptoms and bronchospasm for BHR + patients.

is not acceptable for discharge within 30 min of the initial inhalation of albuterol. This never occurred over the 14-month interval of the study.

Bronchoprovocation challenge is an extremely useful diagnostic test, and we believe that despite its clinical utility, it is underused. 13 One of the reasons for underutilization is a concern for safety.• Our prospective data are consonant with our prior clinical experience and with the retrospective recollections of others.l,7,14 ~ would posit that as long as the guidelines for methacholine BPC include the absence of significant airflow obstruction at the outset of BPC and a low starting dose of methacholine, the study is safe enough to be performed in any pulmonary function laboratory, be it hospital-based or office-based, which would perform BPC on a routine basis. There is no aspect of the study which requires the hospital environment. First, there is no need for a pharmacy; methacholine is stable in physiologic saline solution at room temperature for at least 4 months. 15 Secondly, BPC is reasonably easy to perform. Thirdly, in contrast to' allergen challenge, which may involve late-phase reactions and for which prolonged monitoring of pulmonary function is advised, 14 we are unaware of any reports of late-phase reactions to methacholine or histamine. Finally, all bronchospasm and symptoms induced during BPC with methacholine are readily reversed, such that a physician would not need to be in attendance. Although our data were generated with methacholine using a tidal volume inbalational technique, we see no reason why they could not be extrapolated to the Chai technique and to histamine BPC. In summary, we have demonstrated prospectively that the airflow obstruction and symptoms elicited in BHR + patients during BPC can be reversed rapidly and effectively with a p-adrenergic agonist administered via metered-dose inhaler with a spacer. Bronchoprovocation challenge is both simple and safe. ~ hope that these data will encourage wider dissemination and use of this valuable clinical tool.

REFERENCES

1 Irwin RS, Pratter MR. The chnical value of pharmacologic bronchoproYOCal:ion cballenp. In: Dosman JA, Cocb:roft DW, eds. Obstructiw IUDI ~. Med Clin North Am 199o; 74:7frf78 2 DePuo WJ, Wintmbauer RH, Luslc JA, Dnris DF, Springmeyer SC. Chrome dyspnea UDelplained by history, physical eumination, chest roentgenogram, and spirometry. Chest 1991; 100: 1293-99 3 Pratter MR, Curley FJ, DuBois J, Irwin RS. Cause and

evaluatioo of chroDic dyspnea In a pulmonary disNse clinic. An:h Intern Med 1989; 149-.2277-82 4 Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough In the adult: the spectrum and frequency ofcauses and successful

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outcome oE speclflc therapy. Am Rev 8espir Dis 1981; 123:41317 Pratter MR, Hlnpton DM, Irwin RS. Diapolis oE broncbial asthma by chnical evaluatioo. Chest 1983; 84:42-7 Methacholine Cor dJapom of asthma. Med Letter 1987; 29:60 'lbwnley RC, Bewtra R, Nair NM. Methacholine cballenge Inhalation studies. J Allergy Clin lmmuDOI1979; 64:589-74 Cocb:roft DW, Killian DN, Mellon JJA, Hargreaye FE. Bron-

cbial reKtivity to lnhaJed histamine: a method and chnical suney. Clln Allergy 19'71; 7:235-t:J 9 JUniper EF, Frith PA, Dunnett C, Cocb:roft DW, Hargreaye FE. Reproductbi]ity and comparison oE responses to inhaled histamine and methacholine. Thorax 1978; 33:7015-10 10 llargreaYe FE, Ryan C, Thomson NC, O'Byrne PM, Latimer 1:, Juniper EF, et al. Broachial respoDiiYeness to histamine or metbacbollne In asthma: measurement and chnical sjgniflcaooe. J Allergy Clin Immunol1981; 68:347-55 11 Borg CAV. Psychophysical hues oE perceived exertion. Med Sci Sport1 Exercise 1970; 14:377-81 12 Scott CC, Braun SR. A IUI'Ye)' oE the current use and methods of analysis ofbrooc:hoproyoca cballeuges. Chest 1991; 100: 322-28 13 Pratter MR, Hartter T. Dyspoea: time to &ncl the facts. Chest 1991; 100:1187 14 1bwnley RJ, Hopp RJ. Inhalation methods Cor the study oE airway respoosMnell. J Allergy Clin Immunol1987; 80:111-24 15 Pratter MR, \\bodman TF, Irwin RS, ]obnsoo B. StabiJity oE stored metbacboline cbloride solutions. Am Rev 8espir Dis 1982; li6:717-19

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