Side lying during nebulisation can significantly improve apical deposition in healthy adults and adults with mild cystic fibrosis lung disease: a randomised crossover trial

The distribution of deposition of inhaled drugs is influenced by airflow. In sitting, tidal ventilation is preferentially to basal regions [1]. Nebulisation in sitting may under-dose the apical regions [2]. It has been hypothesised that inhalation in alternate side lying will improve homogeneity of drug deposition by dosing each lung (including its apex) when it is dependent [3]. Additionally, many people with Cystic Fibrosis (CF) prefer to nebulise in side lying due to comfort and convenience [4]. A recent study confirmed that the use of an alternate side-lying positioning strategy during inhalation therapy does not prolong nebulisation time [5].

There are however potential disadvantages of a side-lying strategy. Gravitational and biomechanical changes reduce lung volumes and compliance in side lying [6, 7]. Closing volume of the small airways equals or exceeds functional residual capacity as early as 44 years of age, in recumbent positions [8, 9]. Side lying can also decrease alertness [10], negatively impacting inspiratory flows and nebuliser technique. Finally, oropharyngeal pooling may increase the proportion of the loaded drug dose being swallowed in side lying compared to upright sitting. Thus any potential benefits of the side-lying strategy may be outweighed if less drug is deposited in the lungs. Investigation of the strategy’s effect on the pattern of drug deposition is therefore needed to guide clinical practice.

Progression of CF lung disease reduces both lung elasticity and airflow [11]. Therefore, it is possible that the effect of the side-lying strategy would be different in people with mild versus advanced lung disease. Accordingly the research questions were:

A randomised crossover trial was undertaken to compare two positioning strategies during nebulised delivery of a radioaerosol on 2 days within 1 week, separated by at least one washout day. Adults with CF were recruited from the CF Clinic at Royal Prince Alfred Hospital, Sydney, Australia. Potential participants were excluded if they: had received a lung transplant, were colonised with Burkholderia cepacia complex, were not clinically stable; were pregnant; or had hepatomegaly, hepatosplenomegaly, current intestinal obstruction, or significant malignant, neurological or musculoskeletal comorbidities. Adults with CF were recruited in two strata: mild and advanced CF. Mild CF was defined as stable normal lung function with an FEV₁ and FVC greater than 80% predicted and a normal FEV₁:FVC ratio, plus minimal upper lobe damage evident on chest radiograph or, if available, on computerised tomographic (CT) scan of the lungs. Advanced CF was defined as stable abnormal (moderate to severe) lung function defined as FEV₁ less than 80% predicted, with evidence of upper lobe damage on chest radiograph or, if available, on CT scan of the lungs. A third group of healthy adults with an FEV₁ greater than 80% predicted were recruited from the staff of the hospital.

Testing appointments were scheduled at least 4 h after standard CF morning medications, and not within 1 h of a meal. On both days, participants performed spirometry¹ in standing according to American Thoracic Society criteria [12]. Healthy participants and participants with mild CF lung disease were required to demonstrate an FEV₁ greater than 80% predicted that day. Participants with CF were required to have maintained their FEV₁ within 10% of their best value recorded as an outpatient within the preceding 6 months that day. Participants were then randomised, by flipping a coin, to one of two positioning regimens for their first day: upright sitting, which was maintained throughout the nebulisation period of 20 min; or alternate side lying, with alternation between left and right sides every 2 minutes during the nebulisation period of 20 min.

In an earlier study by our group [5], the two-minute turning regimen and the 20-min total inhalation period were shown to be appropriate to completely nebulise the loaded dose and to ensure equal total nebuliser output while in each side lying position. During the study inhalation periods, all participants were requested to adopt their allocated position and inhale slowly, with a slightly greater volume than at rest, maintaining a lip seal throughout. Inhalation breathing pattern was minimally coached to reflect the spontaneous nebulisation that occurs during unsupervised self-management. When participants returned for their second study day, they adopted the other positioning regimen. Participants with CF were requested to keep their medication regimen, chest physiotherapy and exercise constant during their entire study participation period.

The percentage of the loaded nebuliser dose that deposited in the lungs was low for all participants, 11 to 16% are consistent with previous and current studies of jet nebulisers [2, 19, 20]. Healthy participants had significantly lower lung deposition than participants with mild CF in both positioning regimens. Participants with CF were very familiar with nebulised therapies in comparison to healthy naive participants who reported that 20 min of inhalation on a nebuliser was more challenging than they expected. The distribution of drug deposition to lung, orophranyx and stomach was unaltered by side-lying strategy.

In sitting, adults with advanced CF had almost twice as much variability in lung drug deposition compared to healthy adults of similar age. With increasing lung disease there is increasing variability in lung deposition of a nebulised drug. This finding is consistent with previous work involving deposition scanning in this patient population [3, 4, 21‐23]. The variability of deposition was not substantially altered by side lying in either group. Participants with advanced CF demonstrated the greatest response with a MD in the variability index of 337 (95% CI, − 186 to 860). This equates to a 7% change, which is half that of our proposed minimum clinically worthwhile difference of 15%; nevertheless, the positive trend provides further reassurance that taking a nebuliser in side lying does not substantially compromise drug deposition.

Statistically the side-lying positioning strategy can improve apical deposition. Our best estimate of the effect is a positive one in all three participant groups (Healthy: 13% better (95%CI: 7 to 19) Mild CF: 4% better (95%CI: 1 to 7) Advanced CF: 4% better (95%CI: − 2 to 9). It is difficult to estimate the clinical impact of this small shift of 4 % towards greater apical deposition in CF participants over the course of multiple nebulised drug doses. Permitting people with CF to have the flexibility to nebulise in side lying may improve treatment adherence in patients who prefer this regimen. The effect of regular use of this positioning regimen could be further examined in a longitudinal trial.

The side-lying strategy was only effective at reversing the deficiency in apical deposition in the subgroups of participants who had well preserved lung function. This suggests that the side-lying strategy may be more helpful in children with CF, or in respiratory conditions where lung function is well preserved, such as pneumocystis pneumonia [24].Additionally, the delivery rate of inhaled medications should be further investigated in mesh and adaptive delivery nebulisers and with drugs of greater viscosity.

There is no negative impact on lung deposition if adults with CF nebulise in alternate side lying. Adults with CF have almost twice as much variability in the density of nebulised drug deposition across the lung fields compared to healthy adults, which is unaltered with inhalation in side lying. Positioning in side lying can improve apical deposition in healthy lungs and to a lesser extent in mild CF lung disease. Given many patients prefer to nebulise in side lying due to comfort and convenience, permitting nebulisation in side lying may improve treatment adherence without adversely affecting deposition, provided side lying on each side is given equal time.