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(Chest. 2006;130:1834-1838.)
© 2006 American College of Chest Physicians

Effect of Home Mechanical Ventilation on Inspiratory Muscle Strength in COPD*

Bernd Schönhofer, MD, PhD, FCCP; Michael I. Polkey, MD, PhD; Stefan Suchi and Dieter Köhler, MD, PhD, FCCP

* From Krankenhaus Kloster Grafschaft (Drs. Schönhofer and Köhler, and Mr. Suchi), Zentrum für Pneumologie, Grafschaft, Germany; and Respiratory Muscle Laboratory (Dr. Polkey), Royal Brompton Hospital, London, UK.

Correspondence to: Bernd Schönhofer, MD, PhD, FCCP, Abteilung für Pneumologie und Internistische Intensivmedizin, Klinikum Region Hannover, Krankenhaus Oststadt-Heidehaus, Podbielskistrasse 380, 30659 Hannover, Germany; email: Bernd.Schoenhofer{at}t-online.de

Abstract

Background: The mechanism responsible for chronic hypercapnic respiratory failure (HRF) in patients with COPD remains unclear. In this study, we tested the hypothesis that chronic HRF in patients with COPD is associated with low-frequency fatigue (LFF) of the diaphragm.

Methods: To test this hypothesis, we measured the twitch transdiaphragmatic pressure (Tw Pdi) elicited by stimulation of the phrenic nerves in 25 patients with chronic HRF (mean [± SD] PaCO2, 55.2 ± 5.2 mm Hg) due to COPD before and 2 months after the initiation of noninvasive mechanical ventilation (NIV) [pressure-cycled ventilation with inspiratory positive airway pressure of 19.0 ± 2.5 cm H2O]. We reasoned that had LFF been present, Tw Pdi should rise after effective NIV.

Results: The treatment compliance with NIV was good (median of machine usage was 7.1 h per night). PaCO2 decreased from 55.2 ± 5.2 to 48.8 ± 5.9 mm Hg (p < 0.001), and PaO2 increased from 53.1 ± 5.9 to 57.7 ± 7.0 mm Hg (p = 0.007). Mean Tw Pdi at baseline was 11.1 ± 6.6 cm H2O and after treatment was 11.7 ± 7.2 cm H2O (not significant). Also, maximal static inspiratory mouth pressure did not change significantly (44.3 ± 15.9 cm H2O vs 46.5 ± 19.7 cm H2O).

Conclusion: LFF of the diaphragm does not accompany chronic HRF in patients with COPD.

Key Words: chronic hypercapnic respiratory failure • maximal inspiratory strength • noninvasive mechanical ventilation

Home noninvasive mechanical ventilation (NIV) is an established therapy in the treatment of chronic hypercapnic respiratory failure (HRF) due to restrictive lung and chest wall disorders.1 Similarly, in selected patients with severe COPD, the use of NIV can improve sleep quality and blood gases.2

One hypothesis for the mechanism underlying the beneficial effect of NIV postulates that the inspiratory muscles are in a condition of chronic fatigue and that the benefits of NIV are conferred by resting the inspiratory muscles and thus relieving fatigue.34 To date, the effect of NIV on inspiratory muscle strength has only been evaluated using maximal static inspiratory mouth pressure (PImax), and this method has yielded conflicting results.5678

PImax has two important limitations for testing the hypothesis that patients with untreated chronic HRF are in a state of chronic respiratory muscle fatigue. First, the PImax test is dependent on the subject’s aptitude and motivation; and second, the form of fatigue most likely to be implicated in chronic HRF is low-frequency fatigue (LFF), which is known to be long lasting.9 The PImax is a brief, high-intensity maneuver during which neural discharge is assumed to drive the muscle with high-frequency rather than low-frequency stimuli, and thus this method would have poor power to detect LFF. The most clinically appropriate test to detect LFF is measurement of twitch transdiaphragmatic pressure (Tw Pdi) elicited by a single bilateral phrenic nerve stimulus.1011 The current investigation was designed to test the hypothesis that LFF is associated with chronic HRF using the rationale that effective NIV would unload the muscles and reverse LFF.

Materials and Methods

Patients
Thirty-four consecutive patients with COPD and chronic HRF electively admitted for establishment of NIV were enrolled in this study. Nine patients, however, dropped out during the adaptation period because they could not tolerate NIV. Since the study was conceived to test physiologic rather than clinical outcomes, data from these subjects were not further analyzed. Thus, this report contains the data of the remaining 25 patients (14 men; mean [± SD] body mass index, 22.5 ± 4.7 kg/m2; age, 60.0 ± 10.4 years) who completed the study.

The inclusion criteria were chronic hypercapnic ventilatory failure (PaCO2 > 50 mm Hg) due to COPD despite maximal medical therapy supervised by a chest physician with no hospital admissions for at least 1 month prior to the study. Subjects were excluded if they had acute respiratory failure (requiring continuous mechanical ventilation) or severe acidosis (defined as pH < 7.30) in the month preceding enrollment in the study. Five patients with mild acidosis (pH between 7.30 and 7.35) were included.

All patients had a adaptation period of NIV of 5 days to determine the optimal ventilator settings. Pressure-cycled ventilation in controlled mode (BiPAP-ST; Respironics; Murrysville, PA) was used in all patients. The frequency of NIV was set slightly higher than spontaneous breathing frequency and adjusted until it was comfortable for the patient. The efficacy of NIV was established by the demonstration of a PaCO2 reduction to ≤ 45 mm Hg after having been on the ventilator during a 5-day hospital adaptation period. All patients received a positive expiratory pressure of 5 cm H2O. The maximal inspiratory pressure support was aggressively titrated upward to the highest level tolerated by the patient. All patients initially received ventilation using a conventional nose mask (Respironics; and ResMed; Sydney, Australia). If pressure sores developed or if the quality of ventilation deteriorated due to air leak, a custom-made nose or nose/mouth mask was made by a dental laboratory. The protocol was approved by the ethical review committee (Árztekammer Münster), and written informed consent was obtained from all participants.

Measurements
Spirometry and body plethysmography (Masterlab; Jäeger; Würzburg, Germany) was performed according the guidelines of the European Respiratory Society.12 Daytime blood gases were measured after 30 min of resting breathing room air.

PImax was measured from functional residual capacity (FRC) as previously described,1314 except that visual feedback was not available to the patient. Maximal expiratory pressure (PEmax) was measured from total lung capacity. Both maneuvers were performed five times, and maximal values were used for analysis.

Both hardware and software for registration of PImax and PEmax were designed and constructed in-house using a piezo-electric pressure sensor. The device uses a flanged mouthpiece connected to a two-way nonrebreathing valve and incorporates a small air leak but is without visual feedback for the patient. The inspiratory limb was occluded by the operator during expiration by an invisible, inaudible balloon without warning to the patient.

Transdiaphragmatic pressure was measured using esophageal pressure (Poes) and gastric balloon pressure (Pga) catheters (P.K. Morgan; Rainham, Kent, UK). The correct position of the esophageal balloon was checked using the occlusion technique.15 Pdi was obtained on-line so pressure tracings were visible to both subject and investigator.

The sniff maneuver was performed from FRC through unoccluded nostrils. Sniff Pdi and Poes were measured simultaneously, and the sniff giving the most negative Poes was chosen for analysis. To measure the cough Pga, patients performed maximal cough efforts from FRC until a plateau was reached. The cough giving the biggest Pga was used for analysis.

Bilateral cervical magnetic stimulation (CMS) was delivered from a 90-mm circular coil powered by a magnetic stimulator (Magstim 200; Magstim Company, Ltd; Whitland, Dyfed, UK). Magnetic stimulations were delivered with the subjects seated wearing a nose clip with the abdomen unbound, the trouser belt undone, and the neck flexed. To minimize twitch potentiation, subjects were required to breathe quietly for 20 min before stimulation.11 Single stimuli were delivered between the fifth and seventh cervical spines to find the best spot for stimulation. Once this area was determined, a minimum of five stimulations at maximal stimulator output were given while patients relaxed. Twitches were accepted for analysis if performed with the subject relaxed, as judged by Poes, and when baseline Pdi was similar to that recorded at end-expiration during resting breathing. The median value was used for analysis. Measurements were obtained on 2 consecutive days in the afternoon, before starting and after 2 months of NIV.

Statistics
Results are expressed as mean ± SD. The significance for matched pairs was determined by the t test for dependent samples in case of Gaussian distribution; otherwise, Wilcoxon signed-rank test was used. A p value < 0.05 was considered significant. Statistical analysis was performed using Statistica software (StatSoft; Tulsa, OK) except for power analysis, for which Gpower software (Department of Psychology, University of Bonn, Bonn, Germany) was used.

Results

Blood gas and lung function data are presented in Table 1 . All patients had chronic HRF with daytime hypercapnia and hypoxemia. Furthermore, vital capacity and FEV1 were reduced in keeping with the diagnosis of severe COPD. No change in FRC (measured as thoracic gas volume) was observed after NIV (Table 1).


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  		Table 1. Effect of NIV on Daytime Blood Gas Tensions and Lung Function Data*

 
Data from the hours counter on the machines used showed that the NIV patients had used the machines for a median of 7.1 h per night, reflecting good compliance. While by study design all patients were receiving 5 cm H2O expiratory positive airway pressure, the inspiratory positive airway pressure was 19.0 ± 2.5 cm H2O, which has been shown to result in reduced work of breathing.16

NIV resulted in a significant reduction in PaCO2 (p < 0.01) and increase of PaO2, although neither values returned to the normal range (Table 1). Consistent with the decreased PaCO2, the bicarbonate values decreased significantly. Spirometry and, critically, plethysmographically determined lung volumes did not change after 2 months of NIV.

The data showing the effect of NIV on strength are presented in Table 2 . Despite the improvement in daytime blood gases, there was no change in respiratory muscle strength as judged by Tw Pdi (Fig 1 ) or PImax. Moreover, sniff pressures and cough pressures did not change during the observation period (Table 2).


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  		Table 2. Effect of NIV on Respiratory Muscle Strength*

 

Figure 1
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  		Figure 1. Tw Pdi values at baseline (before NIV) and after 2 months of NIV, shown with box-whisker plot showing mean, SD, and minimum (Min)/maximum (Max) combined with case profiles.

 
A sample size calculation showed that our data could exclude an improvement in Tw Pdi of ≥ 20% (2.2 cm H2O) on a power level of 0.87 (one tailed). The data for PImax were similar: an effect of NIV on PImax of 15% improvement (6.65 cm H2O) on a power level of 0.97 (one tailed) was excluded.

Discussion

The main finding of this study is that in patients with chronic HRF due to severe COPD, successful application of NIV does not result in an increase in Tw Pdi. This suggests that low-frequency diaphragm fatigue is not present in such patients prior to therapy. Discussion of the significance of these data will follow a critique of the methods.

Critique of the Methods
The design of our study rests heavily on the belief that Tw Pdi would have risen if LFF had been present and if the muscles had been effectively unloaded. Strong data exist in healthy humans that low-frequency diaphragm fatigue is associated with a reduction in Tw Pdi,91718 although these data have been impossible to obtain for the diaphragm in many clinical scenarios.1019 Importantly, these studies have all shown that Tw Pdi rises after recovery from excessive loading. It is also reasonably established that NIV can unload the diaphragm,20 and indeed that NIV can reverse physiologic measures of excessive muscle loading.21 We did not confirm this directly using electromyography of the respiratory muscles or invasive techniques, and in fact it would have been impossible to do so over a 2-month period. However, we note that short-term muscle rest has been shown in laboratory studies2223 applying similar inspiratory pressures. Both the compliance and blood gas data suggest that the diaphragm was adequately unloaded in our patients. Therefore, we believe that our design would have captured low-frequency diaphragm fatigue had it existed prior to NIV.

Had our study not been large enough, a false-negative result could have been obtained. We conducted an interim sample size analysis and continued the study until this possibility could be excluded. The present data give an 87% chance of detecting a change of approximately 2 cm H2O; this change is of the order of magnitude that can occur due to cardiac contraction and therefore the smallest change that it is practicable to exclude

Inevitably, our study is weakened to some extent by the lack of a control group, and in fact some doubt exists as to whether NIV is beneficial in patients with COPD68; therefore, a randomized design would have been ethically justifiable (and indeed necessary) had we been investigating a clinical end point. However, the aim of the present investigation was to test a specific hypothesis in muscle physiology. Had we identified a rise in Tw Pdi after initiation of NIV, then a control group would also have been necessary to demonstrate that the observed rise was not simply a "regression to the mean" phenomenon. Since in fact we saw no change in Tw Pdi (and confirmed the robustness of this observation with a sample size calculation) we submit that a control group could have only modestly strengthened our conclusions

A rise in end-expiratory lung volume after NIV could, theoretically, have masked a true increase in Tw Pdi after NIV. However, in the present study this was confidently excluded by direct measurement of FRC using body plethysmography.

In order to improve patient recruitment and retention, we did not seek to demonstrate in this study that the stimuli were supramaximal, and indeed data suggest that it can be difficult to demonstrate a plateau in Tw Pdi24 or action potential25 elicited by CMS even in healthy subjects. However, the Tw Pdi elicited by CMS in our patients was similar to that previously found by us in a larger cohort of COPD patients who did not require ventilatory support,11 and to that elicited by bilateral supramaximal electrical stimulation2627 in patients with COPD. Therefore, we believe that the stimuli provided in the current study are close to, if not actually, supramaximal; certainly, the CMS-Tw Pdi is reproducible in patients with severe COPD,11 and we are confident that had the Tw Pdi increased in the NIV group we would have detected it, especially since we have previously shown that LFF can be detected with submaximal stimuli.28

Significance of the Findings
NIV is currently used for the treatment of patients with chronic HRF due to restrictive, chest wall, and neuromuscular disease. As previously noted, the value of NIV in patients with COPD remains more controversial68; however, in none of these three diagnostic categories is the mechanism of action understood. One possibility is that some other aspect of respiratory muscle function is improved by NIV; one example could, for example, be endurance properties. Traditional techniques for measuring respiratory muscle endurance are controversial, although a recently developed method developed by our group29 offers the potential to explore this theory.

There are other candidate mechanisms to explain the method of action of NIV: NIV causes resetting of central drive, or improvement in basal atelectasis reduces the work of breathing. We have recently shown that for patients with restrictive disease, the predominant mechanism is an increase in hypercapnic respiratory drive.30 Nevertheless, it is possible that differing mechanisms may make different contributions in other diagnostic groups, and those data could not be uncritically extended to COPD. In another study,31 the beneficial effects of NIV in stable hypercapnic COPD patients could be explained by a reduction in lung hyperinflation in terms of FRC and residual volume. Unfortunately, these parameters are not completely available in our study and therefore cannot be compared.

Although previous workers67 have found improvement in inspiratory muscle strength after NIV, chronic LFF was not found in hypercapnic patients with severe COPD. LFF is also not present in patients with respiratory failure requiring ventilatory support.32 This observation is in keeping with previous attempts to generate LFF acutely,1033 as well as the observation that, compared with normal subjects, type I fibers are overrepresented in the diaphragm in such patients.3435 Thus, an explanation other than LFF must be found to explain the clinical and physiologic improvements seen after NIV in patients with chronic HRF.

What implications do the current data have for clinical practice? The data show that clinical and blood gas improvement can occur without increase in respiratory muscle strength. This might imply that therapies whose rationale rests simply on increasing respiratory muscle strength (such as refeeding) may not be effective at relieving chronic HRF in isolation. Similarly, since successful therapy does not require relief of diaphragm fatigue, it could be that clinicians may be able to get satisfactory results from NIV with only partial unloading of the diaphragm; this could extend the range of patients potentially able to benefit from NIV. It is concluded that Tw Pdi measured before and after 2 months of NIV in patients with COPD does not increase and that LFF of the diaphragm does not accompany chronic HRF in COPD.

Footnotes

Abbreviations: CMS = cervical magnetic stimulation; FRC = functional residual capacity; HRF = hypercapnic respiratory failure; LFF = low-frequency fatigue; NIV = noninvasive mechanical ventilation; PEmax = maximal expiratory pressure; Pga = gastric balloon pressure; PImax = maximal static inspiratory mouth pressure; Poes = oesophageal pressure; Tw Pdi = twitch transdiaphragmatic pressure

The authors have no financial or other potential conflicts of interest to disclose.

Received for publication March 1, 2006. Accepted for publication June 4, 2006.

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