Assessment and interpretation of aerobic exercise (dys)function in paediatric patients with cystic fibrosis

substantiates the potential of Ivacaftor to significantly improve V̇O2max in adults (18-65 y) with more severe CF (FEV1 21-110% predicted), in the absence of exercise training. Edgeworth et al. (2015, unpublished abstract) enrolled 20 adult patients with CF into a placebo-controlled crossover study of Ivacaftor over a 4 month period, with a further 3 month open-label extension. A stepwise increase in V̇O2max was observed, with a percentage increase from baseline of 8.0% at the end of the trial and 12.1% following the open label extension. Whilst this is within the TE determined in children with CF within the present thesis, further research is needed to confirm whether this is similar in adults with CF. Importantly, these improvements occurred independent of exercise training, changes in pulmonary function and sweat Cl, suggesting that these CFTR therapies are having their effect on the cardiovascular and/or muscular systems, as suggested by Chapter 7 of the present thesis. 9.3 Recommendations for future research As previously highlighted, there is now a need for further well-powered research directly comparing the accuracy of the Godfrey protocol, SRT, ramp testing and a combined ramp and Smax protocol to determine V̇O2max, in addition to the other key parameters of aerobic exercise function, in paediatric and adult patients with CF. Establishing this information will then enable us to explicitly provide a toolkit of CPET protocols, which are ranked on their accuracy and the comprehensive data that they can provide the user with. Confirming the findings regarding the utility of Smax 310 verification in adults with CF will also then allow us to further develop our understanding of how the progression of CF disease may further impair aspects of aerobic exercise function. There is also a need to employ additional investigative techniques to further document the impact of CF disease at both the central and peripheral level during exercise. Since NIRS only indicates the dynamic balance between O2 delivery and utilisation within the microvaculature of the skeletal muscle, there is a need for further research to investigate the influence of CF disease on the skeletal muscle metabolic, pH and blood oxygenation response to exercise of different intensities, demarcated by physiologically defined thresholds (i.e., the GET or its equivalent when using P-MRS; the intracellular threshold). It is a suggested that further utilisation of P-MRS imaging techniques will provide the necessary non-invasive window to monitor, in real time, the key variables involved in energy metabolism under both rest and exercise conditions. Specifically, in vivo interrogation of the muscle phosphates and pH during rest and exercise at a high sampling resolution will enable further investigation of any influence of CF disease upon muscle metabolism. Since recent data by Werkman et al. (2015) has further added to the debate regarding whether a skeletal muscle abnormality is present in individuals with mild CF, this work is warranted. Inclusion of a non-CF bronchiectatic respiratory disease control group, a limitation in the present thesis, would also enable any CFspecific abnormities to be further characterised. Furthermore, other non-invasive imaging techniques, such as blood oxygen level-dependent (BOLD) imaging could be used to detect any alteration in the muscle tissue temporal dynamics (i.e., perfusion and oxygenation) during exercise of different intensities.