Effect of inhaled furosemide on air hunger induced in healthy humans

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Abstract

Recent evidence suggests that inhaled furosemide relieves dyspnoea in patients and in normal subjects made dyspnoeic by external resistive loads combined with added dead-space. Furosemide sensitises lung inflation receptors in rats, and lung inflation reduces air hunger in humans. We therefore hypothesised that inhaled furosemide acts on the air hunger component of dyspnoea. Ten subjects inhaled aerosolized furosemide (40 mg) or placebo in randomised, double blind, crossover experiments. Air hunger was induced by hypercapnia (50 ± 2 mmHg) during constrained ventilation (8 ± 0.9 L/min) before and after treatment, and rated by subjects using a 100 mm visual analogue scale. Subjects described a sensation of air hunger with little or no work/effort of breathing. Hypercapnia generated less air hunger in the first trial at 23 ± 3 min after start of furosemide treatment (58 ± 11% to 39 ± 14% full scale); the effect varied substantially among subjects. The mean treatment effect, accounting for placebo, was 13% of full scale (P = 0.052). We conclude that 40 mg of inhaled furosemide partially relieves air hunger within 1 h and is accompanied by substantial diuresis.

Introduction

Many patients suffer intractable dyspnoea during acute exacerbations of disease or during end-stage illness (Bruera et al., 2000, Webb et al., 2000). Dyspnoea overtakes suffering from pain as the most difficult problem as terminal illness progresses to the end stage (Mercadante et al., 2000, Webb et al., 2000). There is a lack of viable options for dyspnoea relief. Although opiate drugs reduce dyspnoea, adequate doses produce substantial sedation and other side effects that are frequently undesirable (Dudgeon and Rosenthal, 1996).

A case report showing that aerosolized inhaled furosemide relieved dyspnoea in a terminal cancer patient suggested a possible alternative to opiate sedation (Stone et al., 1994). Despite the potential usefulness, there has been little systematic study of this treatment. Furosemide, a chloride-channel blocking loop diuretic, is one of the most commonly prescribed drugs, but is usually given intravenously or orally. When inhaled as an aerosol, it provides modest protection against bronchoconstriction, inhibits the cough reflex, and potentially is absorbed systemically to produce diuresis, which may in turn reduce any existing pulmonary oedema. (Bianco et al., 1989, Stone et al., 1993); these actions, however, are not adequate to explain its effect on dyspnoea in patients with breathlessness due to factors other than congestive heart failure and asthma.

Inspired by this case report, Nishino and colleagues tested the effect of inhaled furosemide in controlled laboratory conditions. They reported that in healthy subjects furosemide substantially diminished respiratory discomfort induced by two manoeuvres: breathholding, and hypercapnia in the presence of a substantial inspiratory resistive load (Nishino et al., 2000). In healthy subjects this effect is very unlikely to result from either bronchoprotective or diuretic actions of the drug. The same group also provided data showing a possible mechanistic explanation for the action of inhaled furosemide on dyspnoea by showing that aerosol furosemide stimulates slowly adapting pulmonary stretch receptors (SARs) in animals (Sudo et al., 2000); we have previously provided evidence that increased pulmonary stretch receptor activity relieves air hunger in quadriplegic humans (Manning et al., 1992). These results shed new light on the neural mechanisms of dyspnoea, and suggest a means to develop a novel non-sedating treatment for dyspnoea.

We present here an experiment that adds information regarding furosemide relief of dyspnoea and helps to define further testable hypotheses. We used a stimulus that evoked air hunger alone, without a sense of respiratory work or effort. We also formally debriefed subjects to determine what they felt. Our experimental approach allowed us to relate dyspnoea to a steady-state level of stimulus intensity. In addition, we provided information on the diuretic “side effect” and followed the duration of the furosemide effect. At the same time, our study provides confirmation of the important finding of Nishino et al. (2000).

Section snippets

Subjects

Ten subjects (four female) were studied: height = 174 ± 6 cm; weight = 73 ± 8 kg; median age = 26 years (range 18–54 years). All subjects were blinded to timing and magnitude of interventions. Seven subjects were untrained in physiology and naive to hypothesis and procedures. Three were authors having extensive experience of laboratory air hunger (SM, RB, RS). All potential subjects were interviewed and examined by a physician; exclusion criteria included significant respiratory or cardiovascular disease

Effect of inhaled furosemide

Nine out of ten subjects rated less air hunger in the first trial after furosemide treatment compared to the period immediately before treatment; this reduction in air hunger varied greatly among subjects (Fig. 2; top left). The average reduction in air hunger from the pre-nebulizer trial to the first post-nebulizer trial was greater for furosemide inhalation (mean ± S.D.; 58 ± 11 to 39 ± 14 mm VAS) than for saline inhalation (66 ± 15 to 57 ± 22 mm VAS). There was, however, some positive placebo effect in

Discussion

The results of this study suggest that inhaled furosemide can partially relieve the air hunger associated with experimental hypercapnia and constrained ventilation. The magnitude of the effect varied greatly among subjects, however, nearly all subjects experienced a relief in breathlessness following inhaled furosemide.

These data support the observation of an earlier study by Nishino and coworkers who reported similar reductions in dyspnoea induced with a combination of resistive loads and

Acknowledgements

We thank Ms. Leslie Moser for technical assistance and Professor Abraham Guz for critical input. Dr. Takashi Nishino for providing additional details of published work from his laboratory and Mr. Mohammed Khan for statistical assistance. The study was supported by grants from; American Lung Association RG-240-N (SHM); Parker B. Francis Foundation (SHM is a Parker B Francis Fellow in Pulmonary Physiology); National Institute of Health HL46690 (RBB).

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