Karpel 1990.

Methods	Design: CrOv Dates: N/S Location: US Assessment period: 90 min for each phase of crossover External validity: 3/5 COPD dx+ COPD bl‐ AECB dx+ AECB sev+ Tx duration‐ Internal validity: 5/5 r+, db+, dd
Participants	N = 32 Setting: ED and pulmonary clinic Inclusion (COPD): Chronic bronchitis or emphysema as defined by the ATS Committee on Diagnostic Standards for Nontuberculous Respiratory Disease (1962) Inclusion (AcEx): Increasing dyspnea and/or change in sputum production newly occurring in previous 24 hrs; FEV1 < 60% of predicted Exclusion: Asthma; baseline pulmonary function tests which failed to show persistent airway obstruction; any acute concomitant medical problem; respiratory acidosis with pH < 7.3; need for continuous oxygen therapy; need for medications other than those included in study protocol; use of inhaled b‐agonist or ipratropium in previous 6 hrs Smoking history: N/S Baseline stable FEV1: N/S FEV1 at admission: Ipratropium first: 0.62 ± 0.08 (SEM) L; metaproterenol first: 0.69 ± 0.06 L Age: 61.6 Sex: N/S Race: N/S
Interventions	Experimental: Ipratropium, single dose of 3 puffs (54 mg) administered by MDI Control: Metaproterenol, single dose of 3 puffs (1.95 mg) administered by MDI Co‐interventions: None Crossover design: Pts treated with one of the two study meds initially (phase 1), then crossed over to treatment with the other after 90 min (phase 2); no washout; no information on possible carry‐over effect
Outcomes	FEV1: Measured at entry and at 30, 60, and 90 min after administration of study med in both phases of crossover; investigators analyzed change in mean FEV1 from 0 to 90 min in phase 1 Blood gases: Recorded only for the first 20 pts randomized into the study; measured at entry and at 30, 60, and 90 min after administration of study med in phase 1 only; investigators analyzed mean changes in PaO2, PaCO2, and pH from 0‐30 min and 0‐90 min Percentage of pts admitted to hospital
Notes	RESULTS: In phase 1 of the trial, mean FEV1 (± SEM) improved significantly in both treatment groups from 0‐90 min. For ipratropium (n = 17), scores improved 25%, from 0.62 ± 0.08 to 0.88 ± 0.11 (p< 0.01). For metaproterenol (n = 15), the improvement was 18%, from 0.69 ± 0.06 to 0.92 ± 0.09 (p< 0.01). There was no significant difference between the two groups for this outcome (p > 0.05). For phase 2 of the trial, investigators reported only that there was no further improvement in FEV1 in either group. Blood gases: At 30 min, there was a significant (p < 0.05) rise in PaO2 with ipratropium (n = 10) (5.8 ± 3.0 [SEM]), and a significant (p < 0.05) decline in PaO2 with metaproterenol (n = 10) (‐6.2 ± 1.2). At 90 min, these changes were no longer significant. There were no other significant changes in PO2, PCO2, or pH during phase 1. Percentage of pts admitted to hospital: 3/17 pts (18%) from the ipratropium‐first group, 2/15 pts (13%) from the metaproterenol‐first group. Adverse events: Recorded for phase 1 only. Ipratropium: Nervousness (2 pts), tremors (2), dry mouth (1), palpitations (1), headache (1). Metaproterenol: Palpitations (3 pts), nervousness (3), tremors (2), dry mouth (1), headache (1). Dropouts: 0
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	Third party randomisation