G Model
YPRRV-959; No. of Pages 5 Paediatric Respiratory Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Review
Determinants of respiratory pump function in patients with cystic fibrosis Theodore Dassios * Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0SW, UK
EDUCATIONAL AIMS
To To To To
review the role of respiratory pump dysfunction in the pathophysiology of respiratory failure in Cystic Fibrosis (CF). describe the determinants of respiratory pump failure in CF. outline new methodological approaches to respiratory pump assessment in CF. discuss potential therapeutic interventions based on the pathophysiology of respiratory pump impairment in CF.
A R T I C L E I N F O
S U M M A R Y
Keywords: Cystic Fibrosis CF Respiratory muscles Respiratory failure
Respiratory failure constitutes the major cause of morbidity and mortality in patients with Cystic Fibrosis (CF). Respiratory failure could either be due to lung parenchyma damage or to insufficiency of the respiratory pump which consists of the respiratory muscles, the rib cage and the neuromuscular transmission pathways. Airway obstruction, hyperinflation and malnutrition have been historically recognised as the major determinants of respiratory pump dysfunction in CF. Recent research has identified chronic infection, genetic predisposition, dietary and pharmaceutical interventions as possible additional determinants of this impairment. Furthermore, new methodological approaches in assessing respiratory pump function have led to a better understanding of the pathogenesis of respiratory pump failure in CF. Finally, respiratory muscle function could be partially preserved in CF patients with structured interventions such as aerobic exercise, inspiratory muscle training and noninvasive ventilation and CF patients could consequently be relatively protected from respiratory fatigue and respiratory failure. ß 2014 Elsevier Ltd. All rights reserved.
INTRODUCTION
function have been utilised [2,3] and new determinants of respiratory pump function have been identified [4,5].
Respiratory failure in patients with Cystic Fibrosis (CF) is due to lung parenchyma or to respiratory pump failure. In CF there is dynamic interrelation of these two components, as progressive lung parenchyma destruction results in hypoxia and hypercarbia which affect respiratory pump function, while concurrently the evolving respiratory pump dysfunction impacts on gas exchange. The respiratory pump comprises the respiratory muscles, the thoracic cage and the neural and neuromuscular transmission pathways [1]. A number of studies have recently addressed the respiratory pump involvement in the pathophysiology of respiratory failure in CF. New indices assessing respiratory muscle
* Tel.: +44 7908210948; fax: +44 1223 256 044. E-mail address: [email protected].
THE LOAD/CAPACITY BALANCE The integrity of the respiratory pump is a prerequisite for sustained normal breathing: the respiratory muscles must be capable of generating sufficient force to overcome the elastance of the lungs and the chest wall (which constitute the elastic load), as well as the airway and tissue resistance (conjointly forming the resistive load) [1]. Normal breathing is maintained as long as the balance between inspiratory load and neuromuscular competence is polarized in favor of the latter [1]. Hence, the respiratory muscles must generate sufficient strength to overcome the elastic and resistive loads, while adequate neural output, neuromuscular transmission and intact chest wall geometry are also required [1,6]. In CF all compartments of this model are affected.
1526-0542/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2014.01.001
Please cite this article in press as: Dassios T. Determinants of respiratory pump function in patients with cystic fibrosis. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.01.001
G Model
YPRRV-959; No. of Pages 5 2
T. Dassios / Paediatric Respiratory Reviews xxx (2014) xxx–xxx
RESPIRATORY MUSCLE STRENGTH Conflicting conclusions have been reached regarding maximal inspiratory (Pimax) and maximal expiratory (Pemax) pressures in CF [7]. Some studies have reported decreased maximal respiratory pressures. Szeinberg et al reported decreased Pimax, Pemax and skeletal muscular indices in severely hyperinflated, malnourished adult CF patients [8]. Mier et al studied 25 young adult CF patients with a mean Forced Expiratory Volume in 1 s (FEV1) 46% predicted and described a modest decrease (64% predicted) in Pimax and Pemax, while quadriceps strength was diminished within the same range (68% predicted) [9]. Lands et al compared 22 CF patients to controls and concluded that maximal pressures were significantly diminished in CF [10]. Pradal et al invasively recorded transdiaphragmatic pressure in 15 CF patients with a mean FEV1 59% predicted and concluded that diaphragmatic strength decreases with disease progression, worsening hyperinflation and nutritional status [11]. Hayot et al reported diminished Pimax in 16 CF patients with mean FEV1 81% predicted and Functional Residual Capacity/ Total Lung Capacity ratio 54% predicted as well as a significant correlation of Pimax to lean body mass (LBM) [12]. Ionescu et al studied 49 CF patients and reported a significant association between low LBM, impaired inspiratory muscle function, and reduced somatic force, suggesting a general reduction in skeletalmuscle strength, rather than a condition limited purely to the inspiratory muscles [13]. Pinet et al reported lower twitch transdiaphragmatic pressure in 18 stable CF patients [mean FEV1 39% predicted, mean Residual Volume (RV) 221% predicted] compared to controls. The CF patients had decreased LBM and somatic muscular indices but diaphragm mass and abdominal muscle thickness were preserved [14]. Recently, Hahn et al reported significantly lower Pimax in 47 CF patients with a median FEV1 59% predicted and median RV 166% predicted [15] while in a lungmilder cohort of 140 CF patients with a median FEV1 100.3% predicted, Dassios et al reported lower maximal respiratory pressures which correlated significantly to somatic muscular indices [16]. Conversely, some studies have advocated that the increased respiratory load in CF has led, through a training effect, to preservation/augmentation of respiratory muscle strength. O’Neill et al reported normal or supra-normal maximal pressures despite chronic hyperinflation and malnutrition in 23 CF patients (mean FEV1 35% predicted, mean RV 255% predicted, mean body mass percentile 78% predicted) [17]. Bradley et al compared 14 CF patients with a mean FEV1/FVC ratio 0.49 and normal anthropometry to controls and reported normal maximal pressures in the CF group [18]. Marks et al studied 25 CF patients with significant malnutrition (mean body mass percentile 78% predicted) and reported above-normal inspiratory muscle strength [19]. Lands et al studied 14 stable CF patients with increased mean RV/TLC ratio (0.38) and decreased mean weight (94% of ideal) and concluded that maximal pressures were preserved while Pemax correlated with LBM [20]. Similarly, Hart et al reported relatively well-preserved twitch trans-diaphragmatic pressure in 20 adolescent CF patients with mean FEV1 45% predicted [21]. Recently, Ziegler et al reported normal maximal respiratory pressures regardless of nutritional state in 39 CF patients with mean FEV1 5055% predicted [22]. Furthermore, Dunnink et al reported significantly higher Pimax in 27 stable adolescent and adult CF patients compared to reference values [23]. Chronic pulmonary inflammation might be an additional factor causing respiratory muscle weakness via ‘‘spill-over’’ of inflammatory mediators or direct vicinity to the diaphragm [5]. Animalmodel data have supported this hypothesis [5,24,25] while adults with CF mounted more intense systemic inflammatory response to exercise compared to controls [26]. Furthermore, Pimax was
significantly decreased in CF patients who were chronically infected with Pseudomonas aeruginosa. [27] Genetic parameters might predispose CF patients to a generalized myopathy. Divangahi et al described that lack of the CF trans-membrane conductance regulator (CFTR) plays an intrinsic role in skeletal muscle atrophy and dysfunction. After pulmonary infection with P.aeruginosa was induced in mice, the diaphragmatic forcegenerating capacity was noted to be selectively reduced in CFTR-deficient mice compared to non CFTR-deficient ones [4]. Oral magnesium supplementation resulted in significant rise of Pimax and Pemax in 44 children with CF, suggesting that specific nutrient deficiencies might play a role in respiratory muscle weakness [28]. Conversely, corticosteroid therapy has been shown to attenuate respiratory muscle strength [29]. Of note, androgen levels did not correlate with maximal respiratory pressures in 15 adult male CF patients, indicating that androgen deficiency is probably not a significant contributor to muscle dysfunction in this population [30]. Assessment of respiratory muscle strength in CF has also been undertaken by Sniff Nasal Inspiratory Pressure (SNIP) in a study which reported lower SNIP values in CF children [31] although SNIP might underestimate esophageal pressure in CF children, probably secondary to the increased time-constant of the CF lung and the ensuing dampening of pressure changes [32]. To conclude, respiratory muscle strength is affected by airway obstruction, hyperinflation and malnutrition to which chronic infection, dietary insufficiencies and genetic predisposition could be added. ENDURANCE AND FUNCTION OF THE RESPIRATORY MUSCLES Regarding respiratory muscle endurance in CF, similarly, two conflicting schools of thought have emerged advocating diminished or preserved endurance in CF, depending on whether the chronically increased work of breathing exerts a conditioning/ training effect on the respiratory muscles. Keens et al concluded that in 55 CF patients the highest level of sustained-normocapnichyperpnoea was higher than controls, reflecting the chronic training effect of breathing against increased respiratory loads [33]. Orenstein et al reported a wide variation of sustainednormocapnic-hyperpnoea scores in 35 CF patients with mean FEV1 63% predicted [34]. Hanning et al investigated 16 children with CF and mild lung disease (mean FEV1 95% predicted) and concluded that endurance assessed by repeated maximal static efforts was similar in CF patients compared to healthy children [35]. Lands et al, in their aforementioned study, concluded that endurance evaluated by repeated static efforts was not different in CF patients compared to healthy controls owing to the selective training stimulus [20]. Contrarily, Ionescu et al supported that loss of LBM in CF was associated with marked decrease in sustained-Pimax, while they documented decreased handgrip-force [13]. Leroy et al applied incremental threshold-loading in 18 stable CF adults (mean FEV1 44% predicted) and concluded that inspiratory muscle endurance was associated with the degree of exercise dyspnea [36]. Recently, Reilly et al measured twitch trans-diaphragmatic and twitch abdominal pressures after exhaustive exercise and concluded that overt low-frequency fatigue of the respiratory muscles did not develop [37]. Maximal relaxation rate of the respiratory muscles during a maximal maneuver was prolonged in 123 CF patients (mean FEV1 100.3% predicted) compared to healthy controls indicating increased danger of respiratory muscle fatigue. Maximal relaxation rate was significantly related to FEV1 and somatic muscular indices [2] The pressure-time index of the respiratory muscles (PTImus) incorporates values of Pimax, occlusion pressure generated 0.1s after the onset of inspiration (P0.1), inspiratory time and total
Please cite this article in press as: Dassios T. Determinants of respiratory pump function in patients with cystic fibrosis. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.01.001
G Model
YPRRV-959; No. of Pages 5 T. Dassios / Paediatric Respiratory Reviews xxx (2014) xxx–xxx
respiratory time, and thus quantifies the tendency of the muscles to resist fatigue under conditions of increased work. In concept, the higher the percentage of the maximal pressure needed for normal inspiration and the longer the respiratory muscles contract over the total respiratory cycle, the more likely they are to succumb to fatigue. Lower values of PTImus describe more efficient respiratory muscle function and decreased risk of respiratory muscle fatigue [38] Hayot et al measured PTImus in 16 CF children (mean FEV1 81% predicted, FRC 133% predicted) and concluded that PTImus was significantly increased in CF children compared to healthy controls, while the major determinants of PTImus were LBM and FRC [12] Hahn et al studied 47 CF patients with mean FEV1 59% predicted and mean FRC 119% predicted, and similarly concluded that median PTImus was significantly increased in CF patients with severely abnormal pulmonary function compared to both healthy controls and CF patients with mild/moderate respiratory disease and that PTImus in CF patients was significantly related to airway resistance, FEV1 and FRC [15]. Dassios et al studied a cohort of 140 CF patients with mild lung disease (mean FEV1 100.3% predicted) and likewise concluded that median PTImus was significantly higher in CF patients compared to healthy controls. In the subgroup of CF patients with abnormal lung function, PTImus was increased mainly due to increased P0.1 values, while in malnourished patients, PTImus abnormalities were primarily caused by decreased Pimax [16]. RESPIRATORY DRIVE AND BREATHING PATTERN Respiratory rate (RR), P0.1 and Tv/Ti describe the respiratory drive, which in CF is increased, reflecting increased airway resistance and airway obstruction. Bureau et al reported normal P0.1 response to hypercapnic challenge in 10 non-severely obstructed children with CF which was independent of airway obstruction. Furthermore, while controls in response to hypercapnic challenge tended to primarily increase tidal volume, CF patients primarily tended to increase respiratory rate [39]. Coates et al evaluated the respiratory drive in 14 children with CF by measuring P0.1 and TV/Ti in response to induced hypercapnia. They concluded that the P0.1 response was normal in CF children, whereas no correlation was demonstrated between P0.1 and the degree of airway obstruction [40]. Cerny et al studied 7 CF patients with severe lung dysfunction (FEV1 18%-51% predicted) and described that while healthy controls responded to additional expiratory loads by increasing minute ventilation and decreasing end-tidal CO2, CF patients failed to respond in a similar fashion. Furthermore, their resting tidal volume and respiratory rate was higher than those of healthy controls at rest and corresponded to those of controls breathing against resistive loads of 5-10 cmH2O [41]. Hart et al, studied 32 severely obstructed CF patients with FEV1
YPRRV-959; No. of Pages 5 Paediatric Respiratory Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Review
Determinants of respiratory pump function in patients with cystic fibrosis Theodore Dassios * Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0SW, UK
EDUCATIONAL AIMS
To To To To
review the role of respiratory pump dysfunction in the pathophysiology of respiratory failure in Cystic Fibrosis (CF). describe the determinants of respiratory pump failure in CF. outline new methodological approaches to respiratory pump assessment in CF. discuss potential therapeutic interventions based on the pathophysiology of respiratory pump impairment in CF.
A R T I C L E I N F O
S U M M A R Y
Keywords: Cystic Fibrosis CF Respiratory muscles Respiratory failure
Respiratory failure constitutes the major cause of morbidity and mortality in patients with Cystic Fibrosis (CF). Respiratory failure could either be due to lung parenchyma damage or to insufficiency of the respiratory pump which consists of the respiratory muscles, the rib cage and the neuromuscular transmission pathways. Airway obstruction, hyperinflation and malnutrition have been historically recognised as the major determinants of respiratory pump dysfunction in CF. Recent research has identified chronic infection, genetic predisposition, dietary and pharmaceutical interventions as possible additional determinants of this impairment. Furthermore, new methodological approaches in assessing respiratory pump function have led to a better understanding of the pathogenesis of respiratory pump failure in CF. Finally, respiratory muscle function could be partially preserved in CF patients with structured interventions such as aerobic exercise, inspiratory muscle training and noninvasive ventilation and CF patients could consequently be relatively protected from respiratory fatigue and respiratory failure. ß 2014 Elsevier Ltd. All rights reserved.
INTRODUCTION
function have been utilised [2,3] and new determinants of respiratory pump function have been identified [4,5].
Respiratory failure in patients with Cystic Fibrosis (CF) is due to lung parenchyma or to respiratory pump failure. In CF there is dynamic interrelation of these two components, as progressive lung parenchyma destruction results in hypoxia and hypercarbia which affect respiratory pump function, while concurrently the evolving respiratory pump dysfunction impacts on gas exchange. The respiratory pump comprises the respiratory muscles, the thoracic cage and the neural and neuromuscular transmission pathways [1]. A number of studies have recently addressed the respiratory pump involvement in the pathophysiology of respiratory failure in CF. New indices assessing respiratory muscle
* Tel.: +44 7908210948; fax: +44 1223 256 044. E-mail address: [email protected].
THE LOAD/CAPACITY BALANCE The integrity of the respiratory pump is a prerequisite for sustained normal breathing: the respiratory muscles must be capable of generating sufficient force to overcome the elastance of the lungs and the chest wall (which constitute the elastic load), as well as the airway and tissue resistance (conjointly forming the resistive load) [1]. Normal breathing is maintained as long as the balance between inspiratory load and neuromuscular competence is polarized in favor of the latter [1]. Hence, the respiratory muscles must generate sufficient strength to overcome the elastic and resistive loads, while adequate neural output, neuromuscular transmission and intact chest wall geometry are also required [1,6]. In CF all compartments of this model are affected.
1526-0542/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2014.01.001
Please cite this article in press as: Dassios T. Determinants of respiratory pump function in patients with cystic fibrosis. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.01.001
G Model
YPRRV-959; No. of Pages 5 2
T. Dassios / Paediatric Respiratory Reviews xxx (2014) xxx–xxx
RESPIRATORY MUSCLE STRENGTH Conflicting conclusions have been reached regarding maximal inspiratory (Pimax) and maximal expiratory (Pemax) pressures in CF [7]. Some studies have reported decreased maximal respiratory pressures. Szeinberg et al reported decreased Pimax, Pemax and skeletal muscular indices in severely hyperinflated, malnourished adult CF patients [8]. Mier et al studied 25 young adult CF patients with a mean Forced Expiratory Volume in 1 s (FEV1) 46% predicted and described a modest decrease (64% predicted) in Pimax and Pemax, while quadriceps strength was diminished within the same range (68% predicted) [9]. Lands et al compared 22 CF patients to controls and concluded that maximal pressures were significantly diminished in CF [10]. Pradal et al invasively recorded transdiaphragmatic pressure in 15 CF patients with a mean FEV1 59% predicted and concluded that diaphragmatic strength decreases with disease progression, worsening hyperinflation and nutritional status [11]. Hayot et al reported diminished Pimax in 16 CF patients with mean FEV1 81% predicted and Functional Residual Capacity/ Total Lung Capacity ratio 54% predicted as well as a significant correlation of Pimax to lean body mass (LBM) [12]. Ionescu et al studied 49 CF patients and reported a significant association between low LBM, impaired inspiratory muscle function, and reduced somatic force, suggesting a general reduction in skeletalmuscle strength, rather than a condition limited purely to the inspiratory muscles [13]. Pinet et al reported lower twitch transdiaphragmatic pressure in 18 stable CF patients [mean FEV1 39% predicted, mean Residual Volume (RV) 221% predicted] compared to controls. The CF patients had decreased LBM and somatic muscular indices but diaphragm mass and abdominal muscle thickness were preserved [14]. Recently, Hahn et al reported significantly lower Pimax in 47 CF patients with a median FEV1 59% predicted and median RV 166% predicted [15] while in a lungmilder cohort of 140 CF patients with a median FEV1 100.3% predicted, Dassios et al reported lower maximal respiratory pressures which correlated significantly to somatic muscular indices [16]. Conversely, some studies have advocated that the increased respiratory load in CF has led, through a training effect, to preservation/augmentation of respiratory muscle strength. O’Neill et al reported normal or supra-normal maximal pressures despite chronic hyperinflation and malnutrition in 23 CF patients (mean FEV1 35% predicted, mean RV 255% predicted, mean body mass percentile 78% predicted) [17]. Bradley et al compared 14 CF patients with a mean FEV1/FVC ratio 0.49 and normal anthropometry to controls and reported normal maximal pressures in the CF group [18]. Marks et al studied 25 CF patients with significant malnutrition (mean body mass percentile 78% predicted) and reported above-normal inspiratory muscle strength [19]. Lands et al studied 14 stable CF patients with increased mean RV/TLC ratio (0.38) and decreased mean weight (94% of ideal) and concluded that maximal pressures were preserved while Pemax correlated with LBM [20]. Similarly, Hart et al reported relatively well-preserved twitch trans-diaphragmatic pressure in 20 adolescent CF patients with mean FEV1 45% predicted [21]. Recently, Ziegler et al reported normal maximal respiratory pressures regardless of nutritional state in 39 CF patients with mean FEV1 5055% predicted [22]. Furthermore, Dunnink et al reported significantly higher Pimax in 27 stable adolescent and adult CF patients compared to reference values [23]. Chronic pulmonary inflammation might be an additional factor causing respiratory muscle weakness via ‘‘spill-over’’ of inflammatory mediators or direct vicinity to the diaphragm [5]. Animalmodel data have supported this hypothesis [5,24,25] while adults with CF mounted more intense systemic inflammatory response to exercise compared to controls [26]. Furthermore, Pimax was
significantly decreased in CF patients who were chronically infected with Pseudomonas aeruginosa. [27] Genetic parameters might predispose CF patients to a generalized myopathy. Divangahi et al described that lack of the CF trans-membrane conductance regulator (CFTR) plays an intrinsic role in skeletal muscle atrophy and dysfunction. After pulmonary infection with P.aeruginosa was induced in mice, the diaphragmatic forcegenerating capacity was noted to be selectively reduced in CFTR-deficient mice compared to non CFTR-deficient ones [4]. Oral magnesium supplementation resulted in significant rise of Pimax and Pemax in 44 children with CF, suggesting that specific nutrient deficiencies might play a role in respiratory muscle weakness [28]. Conversely, corticosteroid therapy has been shown to attenuate respiratory muscle strength [29]. Of note, androgen levels did not correlate with maximal respiratory pressures in 15 adult male CF patients, indicating that androgen deficiency is probably not a significant contributor to muscle dysfunction in this population [30]. Assessment of respiratory muscle strength in CF has also been undertaken by Sniff Nasal Inspiratory Pressure (SNIP) in a study which reported lower SNIP values in CF children [31] although SNIP might underestimate esophageal pressure in CF children, probably secondary to the increased time-constant of the CF lung and the ensuing dampening of pressure changes [32]. To conclude, respiratory muscle strength is affected by airway obstruction, hyperinflation and malnutrition to which chronic infection, dietary insufficiencies and genetic predisposition could be added. ENDURANCE AND FUNCTION OF THE RESPIRATORY MUSCLES Regarding respiratory muscle endurance in CF, similarly, two conflicting schools of thought have emerged advocating diminished or preserved endurance in CF, depending on whether the chronically increased work of breathing exerts a conditioning/ training effect on the respiratory muscles. Keens et al concluded that in 55 CF patients the highest level of sustained-normocapnichyperpnoea was higher than controls, reflecting the chronic training effect of breathing against increased respiratory loads [33]. Orenstein et al reported a wide variation of sustainednormocapnic-hyperpnoea scores in 35 CF patients with mean FEV1 63% predicted [34]. Hanning et al investigated 16 children with CF and mild lung disease (mean FEV1 95% predicted) and concluded that endurance assessed by repeated maximal static efforts was similar in CF patients compared to healthy children [35]. Lands et al, in their aforementioned study, concluded that endurance evaluated by repeated static efforts was not different in CF patients compared to healthy controls owing to the selective training stimulus [20]. Contrarily, Ionescu et al supported that loss of LBM in CF was associated with marked decrease in sustained-Pimax, while they documented decreased handgrip-force [13]. Leroy et al applied incremental threshold-loading in 18 stable CF adults (mean FEV1 44% predicted) and concluded that inspiratory muscle endurance was associated with the degree of exercise dyspnea [36]. Recently, Reilly et al measured twitch trans-diaphragmatic and twitch abdominal pressures after exhaustive exercise and concluded that overt low-frequency fatigue of the respiratory muscles did not develop [37]. Maximal relaxation rate of the respiratory muscles during a maximal maneuver was prolonged in 123 CF patients (mean FEV1 100.3% predicted) compared to healthy controls indicating increased danger of respiratory muscle fatigue. Maximal relaxation rate was significantly related to FEV1 and somatic muscular indices [2] The pressure-time index of the respiratory muscles (PTImus) incorporates values of Pimax, occlusion pressure generated 0.1s after the onset of inspiration (P0.1), inspiratory time and total
Please cite this article in press as: Dassios T. Determinants of respiratory pump function in patients with cystic fibrosis. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.01.001
G Model
YPRRV-959; No. of Pages 5 T. Dassios / Paediatric Respiratory Reviews xxx (2014) xxx–xxx
respiratory time, and thus quantifies the tendency of the muscles to resist fatigue under conditions of increased work. In concept, the higher the percentage of the maximal pressure needed for normal inspiration and the longer the respiratory muscles contract over the total respiratory cycle, the more likely they are to succumb to fatigue. Lower values of PTImus describe more efficient respiratory muscle function and decreased risk of respiratory muscle fatigue [38] Hayot et al measured PTImus in 16 CF children (mean FEV1 81% predicted, FRC 133% predicted) and concluded that PTImus was significantly increased in CF children compared to healthy controls, while the major determinants of PTImus were LBM and FRC [12] Hahn et al studied 47 CF patients with mean FEV1 59% predicted and mean FRC 119% predicted, and similarly concluded that median PTImus was significantly increased in CF patients with severely abnormal pulmonary function compared to both healthy controls and CF patients with mild/moderate respiratory disease and that PTImus in CF patients was significantly related to airway resistance, FEV1 and FRC [15]. Dassios et al studied a cohort of 140 CF patients with mild lung disease (mean FEV1 100.3% predicted) and likewise concluded that median PTImus was significantly higher in CF patients compared to healthy controls. In the subgroup of CF patients with abnormal lung function, PTImus was increased mainly due to increased P0.1 values, while in malnourished patients, PTImus abnormalities were primarily caused by decreased Pimax [16]. RESPIRATORY DRIVE AND BREATHING PATTERN Respiratory rate (RR), P0.1 and Tv/Ti describe the respiratory drive, which in CF is increased, reflecting increased airway resistance and airway obstruction. Bureau et al reported normal P0.1 response to hypercapnic challenge in 10 non-severely obstructed children with CF which was independent of airway obstruction. Furthermore, while controls in response to hypercapnic challenge tended to primarily increase tidal volume, CF patients primarily tended to increase respiratory rate [39]. Coates et al evaluated the respiratory drive in 14 children with CF by measuring P0.1 and TV/Ti in response to induced hypercapnia. They concluded that the P0.1 response was normal in CF children, whereas no correlation was demonstrated between P0.1 and the degree of airway obstruction [40]. Cerny et al studied 7 CF patients with severe lung dysfunction (FEV1 18%-51% predicted) and described that while healthy controls responded to additional expiratory loads by increasing minute ventilation and decreasing end-tidal CO2, CF patients failed to respond in a similar fashion. Furthermore, their resting tidal volume and respiratory rate was higher than those of healthy controls at rest and corresponded to those of controls breathing against resistive loads of 5-10 cmH2O [41]. Hart et al, studied 32 severely obstructed CF patients with FEV1
