Optimized Treatment of Pulmonary Edema or Congestion

IV-loop diuretics are a central part of acute treatment of pulmonary edema and is recommended in guidelines (Class 1 recommendation) with a higher recommendation as compared to vasodilation, which was downgraded from Ia to IIb in the 2021 guidelines for heart failure. However, the effects of loop-diuretics alone or in combination with nitrates compared to nitrates alone is unknown and should be investigated in adequately powered prospective trials to optimize acute treatment of these patients.

Trial objective The primary objective is to determine the superior strategy of urgent treatment (starting within 3 hours after hospital-admission) of pulmonary edema. Strategies are: 1. Diuretics (Furosemide), 2. Vasodilation (nitrates), 3. A combination of both furosemide and nitrates. Patient-outcome will be evaluated through the primary endpoint as described elsewhere.

Hypothesis:

Iv nitrates in combination with iv furosemide are superior compared to iv furosemide alone or iv nitrates alone during initial (first 6 hours) in-hospital treatment of pulmonary edema. "Superior" is defined as a significant benefit on the primary outcome.

Study design The study is an investigator-initiated, randomized, placebo-controlled, double-blinded, multicenter, interventional, clinical trial. Following successful completion of screening procedures, patients will be randomized in a 1:1:1 fashion to receive either of the 3 treatments-strategies.

Since patients are in cardio-respiratory and mental stress, informed consent prior to the intervention will be impossible. Instead, a legal guardian will be contacted and asked for consent in addition to next of kind and patients regaining mental ability.

Inclusion criteria

• Age ≥ 18 years
• Acute (within minutes to days) onset or worsening of subjective dyspnea*
• Systolic blood pressure ≥100 mmHg
• Oxygen saturation <94% or need of oxygen
• Signs or suspicion of congestion (peripheral edema, rales, and/or clinical suspicion of congestion) *

• by the best assessment from a medical doctor. Inclusion must not wait on x-ray or other measures: patients suspected of pulmonary congestion should be included immediately.

Exclusion criteria

• More than 40 mg IV furosemide within the last three hours before randomization including prehospital treatment.
• More than 3 hours from hospital-admission to randomization
• Ongoing ventricular taky- or brady-arrythmias or supraventricular arrhythmias with HR > 180 or < 40 bpm.
• Suspected severe infection or sepsis.

Exclusion criteria

are purposely liberal, so patients can be included in accordance with everyday clinical practice. However, a safety criterion will be implemented:

If blood pressure drops below 90 mmHg in 2 measurements with 5 minutes apart and/or if urine production is below 50 ml after 1 hour, the intervention will be stopped, and patients can receive furosemide and nitrates freely.

We purposely chose not to exclude patients with aortic stenosis, since observational studies did not find excess risk of given nitrates to patients with pulmonary edema and aortic stenosis