Beltrame 1998.

Study characteristics
Methods	Randomised, open‐label trial
Participants	87 consecutive patients with acute pulmonary oedema presenting to an ED of a University teaching hospital in Adelaide, Australia 69 patients enrolled (32 frusemide/morphine, 37 nitroglycerin/N‐acetylcysteine) presenting with: 1) Acute onset of dyspnoea within the preceding 6 hours 2) Clinical findings consistent with pulmonary oedema including tachypnoea, signs of increased respiratory work, gallop rhythm, widespread crepitations in the absence of a history of chest infection or aspiration 3) Radiological evidence of pulmonary oedema
Interventions	Intervention 1: Frusemide/morphine therapy: morphine by slow IV injection (1 to 2 mg/5 minutes) to a maximum dose of 10 mg + frusemide 40 mg IV bolus (or twice the patient's daily maintenance dose if appropriate) with a second bolus at 60 minutes if there was an inadequate response Intervention 2: Nitroglycerin/N‐acetylcysteine: N‐acetylcysteine 6.6 µg/minute as a continuous IV infusion over 24 hours + nitroglycerin 2.5 µg/minute as a continuous simultaneous infusion over 24 hours; if clinical response was considered inadequate and systolic BP was stable, the dose of the nitroglycerin infusion could be increased to 5 µg/minute after 15 minutes and/or 10 µg/minute after 60 minutes
Outcomes	Primary end point: change in the PaO2/FiO2 ratio over the first hour of therapy Secondary end points: Clinical status assessment by measuring: respiratory rate, pulse rate, blood pressure, Flammang dyspnoea score, pulmonary crepitation score, sweating score Rate of mechanical ventilatory assistance Duration of hospital admission
Notes	Clinical parameters improved significantly after 60 minutes of medical therapy although the PaO2/FiO2 ratio did not improve significantly until 3 hours
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "On arrival...patients were...if suitable, randomised to F/M or NTG/NAC therapy. Trial therapy was then instituted..." Comment: method of randomisation is not described
Allocation concealment (selection bias)	Unclear risk	Quote: "On arrival...patients were...if suitable, randomised to F/M or NTG/NAC therapy. Trial therapy was then instituted..." Comment: likely to have been done as baseline characteristics, including age, sex, history of heart disease, cardiovascular risk factors and drug therapy, are similar between both groups; however, there is no description of the randomisation process, with potential for selection bias
Blinding (performance bias and detection bias)	High risk	Comment: conducted as an open‐label study, with different administration protocols between the 2 types of drugs used
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of the 69 patients enrolled, 4 were subsequently shown not to have acute pulmonary oedema...However, all were included in the intention to treat analysis".
Selective reporting (reporting bias)	Low risk	Comment: likely, with data being analysed on an intention‐to‐treat basis
Other bias	Unclear risk	Comment: as this was an open‐label study with no description of the randomisation process there is a potential for selection bias