Dyspnea is a major problem in many classes of patients including ICU patients, patients with chronic lung and heart disease, and patients nearing the end of life from most causes. The armamentarium for treatment of intractable dyspnea is very limited. The only drugs proven effective in reducing dyspnea when treatment of the underlying disease has not brought relief are systemic opiates. Opiates carry many disadvantages including depression of respiration, confusion, nausea and constipation. Inhaled furosemide aerosol has shown promise in relieving dyspnea with none of these side effects. Both controlled laboratory studies and small clinical studies have produced encouraging but very variable results. Evidence suggests that furosemide works locally in the lung by sensitizing slowly adapting pulmonary stretch receptors, giving the sensory 'illusion'of larger breaths;we have previously shown that stimulation of pulmonary stretch receptors with larger ventilator- delivered breaths relieves dyspnea;the bigger the breath, the greater the relief. Two placebo-controlled laboratory human studies of aerosol furosemide (one from our lab) have shown that the response in individual subjects ranges from profound relief of air hunger to no response. Importantly, no subjects experienced worsening of air hunger, showing that the positive effect observed in many subjects is not merely measurement variability. This variation of response among subjects has resulted in experimental results that are encouraging if inconclusive. Given this variation of response in laboratory conditions, it is not surprising that overall outcomes of the few small clinical trials have varied greatly;the majority of trials have been encouraging but none has been conclusive. We hypothesize that treatment failures have been due to two factors: 1) inconsistent aerosol drug delivery and 2) failure to adjust drug dose according to individual phenotypic sensitivity to the drug. Before undertaking a large clinical trial of this promising therapy, it is necessary to discover how to make the treatment more uniformly effective. Our aim is to show that this can be achieved by: a) controlling aerosol inhalation characteristics such as aerosol particle size, inspiratory volume and flow rate, and residence time (i.e., inspiratory pause);a large body of aerosol science research demonstrates that these factors have profound effects on drug deposition. b) determining the effect of higher dose on treatment efficacy. We will perform definitive laboratory studies to determine aerosol administration protocols and dose regimens that give consistent dyspnea relief. Having optimized aerosol delivery and dose, we will perform studies aimed at translating laboratory findings into clinical practice. These studies in hospitalized patients requiring palliation for dyspnea will lead to larger scale clinical effectiveness trials. We believe this integration of laboratory and clinical studies within one grant will optimize translation of results from laboratory to patient. PUBLIC HEALTH RELEVANCE: Severe shortness of breath is a disabling symptom afflicting millions of ageing Americans with heart and lung disease, cancer, and other diseases, and is a common source of suffering near the end of life. The best treatment available, morphine, has serious side effects such as impairment of consciousness and dangerous suppression of breathing. The drug furosemide (used safely for other conditions) has shown promise of relieving dyspnea without these side effects when it is breathed as an aerosol mist, but its effect on shortness of breath has been inconsistent. We will study improved methods of furosemide delivery and dose that we believe will provide much more consistent treatment effectiveness. If this treatment can be made to work consistently, it will have a profound effect on palliative care of patients with severe shortness of breath.