The Effect of Aerosol Saline on Laboratory-Induced Dyspnea

Abstract

Purpose In the ‘placebo arm’ of a recent study we found that aerosol saline (sham treatment) produced substantial relief of laboratory-induced dyspnea (Breathing Discomfort – BD) in nearly half the subjects. The sham intervention included a physiological change, and instructions to subjects could have produced expectation of dyspnea relief. In the present study we attempted to discover whether the response to sham aerosol was driven by behavioral or physiological aspects of the intervention. Methods Dyspnea (air hunger) was evoked by constraining tidal volume during graded hypercapnia. We measured Petco2 vs BD relationship before and after aerosol saline. To minimize subjects’ expectations of dyspnea relief, participants in were clearly instructed that we would only deliver saline aerosol. In Protocol 1, we delivered aerosol saline with a ventilator (mimicking our prior study); in Protocol 2, we delivered aerosol without a ventilator. Results Administration of aerosol saline had little effect on BD in this group of subjects with one exception: one subject experienced appreciable reduction in BD in Protocol 1. This treatment effect was less in Protocol 2. The two most likely explanations are a) that procedures surrounding ventilator administration of aerosol produced a psychological placebo treatment effect even though the subject knew a drug was not given, b) there were behavioral changes in breathing undetected by our measurements of respiratory flow and volume that altered the subjects comfort. Conclusion When the expectation of treatment effect is minimized, a significant reduction in dyspnea in response to saline placebo is uncommon but not impossible.

Inhaled furosemide for relief of air hunger versus sense of breathing effort: a randomized controlled trial

“…Some studies have shown a substantial relief of laboratory-induced dyspnoea with saline in over 30% of participants [ 22 , 23 ]. However, O’Donnell and colleagues found that overall the administration of aerosol saline had little effect on experimentally induced AH, provided the expectation of a treatment effect is minimized [ 34 ]. In the current study, the careful blinding procedures and instructions participants received ensured that they were unable to guess correctly when they had received the active or placebo substance.…”

Aerosol furosemide for dyspnea: High-dose controlled delivery does not improve effectiveness

“…Saline response was also a problem in interpreting the results of the first study in this series (Morelot-Panzini et al, 2017). In a study designed to examine the effect of expectation on response, we informed subjects that they would only receive saline placebo, and that it was not expected to improve their dyspnea – there was still one instance of a substantial treatment effect (O’Donnell et al, 2016). In the present study, we sought to reduce the opportunity for spurious saline response in several ways: 1) We attempted to minimize the prior expectations of the subjects and make drug administration less predictable; 2) we utilized a slightly different laboratory model of dyspnea that allows the subject less latitude to alter breathing pattern; 3) we tested the response to saline twice in each individual (due to FDA restrictions, we were unable to test furosemide twice); 4) we queried subjects about their expectations following the study, 5) we administered stimuli in both up and down steps to make the experience less predictable.…”

Measuring dyspnoea: new multidimensional instruments to match our 21st century understanding

“…The MDP has been used in a few studies both for validation and for discovery [29, 32–41]. A convenient graphical representation of results is shown in reference [41]…”