control of breathing in duchenne's muscular dystrophy

Control of Breathing in Duchenne’s Muscular Dystrophy

RAYMOND BfiGIN, M.D.’

MICHEL-A. BUREAU, M.D LUC LUPIEN. M.D. BERNARD I.EMIEUX, M.D.

Sherbrooke. Quebec. Canuda

Duchenne’s muscular dystrophy is a progressive degenerative muscular disease which leads to death fiwm respiratory insufficiency in over 80 percent of cases. Recent studies in neuroFuscular diseases have suggested that respiratory failure may he of central origin in some of the genetically transmitted neuromuscular diseases. We therefore evaluated the control of breathing in nine patients with advanced Duchenne’s muscular dystrophy and compared these patients to nine healthy controls matched on the basis of age, sex and arm span.

The purpose of the study was to assess the sensitivity of respiratory centers to hypercapnia, hypoxia and hyperoxia in nine patients with advanced Duchenne’s muscular dystrophy. We measured minute VentihtiOn#& tidal VOhUIU? VT), E9piratOry freqW?nCy(F), mean respiratory flow rate (VT:TJ and occlusion pressure (P& responses as indices of respiratory centers output during hypercapnia (Read’s methbd) and isocarbic hypoxia (Weil’s method). We also analysed irk during the transient hyperoxia test (Dejours’ method). The threshold and magnitude of responses to hypercapnia, hypoxia and hyperoxia were nearly similar in patients and in controls. Patients demonstrated subnormal response of ir,, VT:T~, VT. Occlusion pressures were nearly the same in normal subjects and in patients with severe muscle weakness. The patterns of responses to those stimuli were markedly different: patients demonstrated a tachypneic pattern of breathing whereas controls preferred to increase their tidal volume.

Our study establishes that in patients with advanced Duchenne’s muscular dystrophy, the integrity of the carbon dioxide (CO,] and oxygen (O&drive of breathing is well preserved. However in these patients, the pattern of ventilatory response is different from normal. There is a preferential increase in respiratory frequency to hypercapnia and hypoxia stimuli. This tachypnea could well he a clinical manifestation of inspiratory muscle fatigue which resulted in the subnormal ventilatory responses of our patients with Duchenne’s muscular dystrophy.

Respiratory failure is a common complication and a major cause of death in neuromuscular disease [l]. Respiratory muscle’weakness, chest wall deformities, repeated aspiration and chronic pulmonary infection are well recognized factors leading to respiratory insufficiency. However, in neuromuscular disease, respiratory failure is occasionally caused by an altered control of breathing [2-71. Recently, respiratory failure has been reported in two patients with mild congenital myopathy [8]. Both patients demonstrated an altered ventilatory response to hypercapnia, suggesting a functional impairment of the central respiratory chemoreceptors (81.

From the Unit6 de Recherche Pulmonaire. Fa- cult6 de Mkdecine. UniversitB de Sherbrooke. Sherbrooke. Quebec Canada. This study was supported by the Muscular Dystrophy Associa- tion of Canada and by Grant 5726 from the Medical Research Council of Canada. Requests for reprints should ba addressed to Dr. Raymond B&in. Unit6 de Recherche Pulmonaire, Facultb de MBdecine. Universitb de Sherbrooke. Sher- brooke. Quebec, Canada liH 5N4. Manuscript accepted tarmary 24. 1980. * Scholar of the Canadian Life Insurance Com- panics Association.

August 1990 The American Journal of Medicine Volume 69 227

CONTROL OF BREATHING IN DUCHENNE’S MUSCULAR DYSTROPHY-BEGIN ET AL.

In Duchenne’s muscular dystrophy. respiratory insufficiency is the cause of death in over 80 percent of cases [9] and analyses of such cases lead to the conclusion that respiratory failure in Duchenne’s muscular dystrophy is secondary to respiratory muscle weakness and pulmonary infection [9-131. However, in these patients, the possibility of a loss of chemosensitivity of the respiratory centers has not been assessed com- pletely. Indeed, only two studies pertain to that aspect: Vignos et al. [l4) noted that patients with Duchenne’s muscular dystrophy become easily hypercapneic during respiratory infections; later. Inkley et al. [9] reported that such patients do respond to CO2 inhalation by increasing ventilation but to a lower level than expected. This could be due to either insufficiency of the respiratory mechanical apparatus or a failure of the central chemical drive of breathing which results in a blunted CO2 sensitivity and a COZ retention tolerance.

The present study, therefore, evaluates the control of breathing in Duchenne’s muscular dystrophy; it was designed to assess the sensitivity of respiratory centers to hypercapnia, hypoxia and hyperoxia in patients with a well established advanced myopathy and a mild to moderate respiratory restrictive syndrome.

MATERIALS AND METHODS

Subjects. Nine patients with typical advanced Duchenne’s muscular dystrophy and nine normal subjects, used as controls, were voluntarily enrolled in this study. The disease of the nine patients was diagnosed based on the established criteria in all cases, many years prior to the study. The patients’ mean age was 13.4 with a standard error (SE) of 1.16 and a range of 10 to 20 years. Their functional capacity, according to the classifi- cation of Vignos et al. [9,14], was class 9 for seven patients, and class 7 and 3 for one patient each. The nine controls were normal volunteers selected from a pool of 30 normal subjects concomitantly tested. The selection of controls was based on age, sex and arm span to match the nine patients with Du- chenne’s muscular dystrophy. The mean age of these control subjects was 13.9 f 1.26 (SE) years. Al1 subjects and their parents were informed of the nature, benefits and potential risks of the study. and appropriate consent forms were signed. The investigation was approved by the committee on the use of human subjects in research of our university. Procedures. Within a month before the study, each patient underwent routine pulmonary function tests as part of his yearly evaluation. The assessment of the chemical drive of breathing was preceded, for each subject, by a brief orientation period during which he became acquainted with the apparatus and methods, and participated in trial runs. Thereafter. each subject had a control study while breathing room air (pre&udy) followed by, at random, the hypercapnia. hypoxia and the hyperoxia tests. Between each test a IS-minute rest period was allowed, at the end of which additional prestudy tests were obtained. During the entire respiratory centers study, each subject was tested with his eyes closed in the supine position, as previously suggested (I 51. Routine Pulmonary Function Tests. Lung volumes, expira-- tory flow rates. diffusion (DLco) and blood gas studies were

I

FIgwe 1. Schematic outline of the methods used to assess the resplratoty response to hypercapnia, isocapnlc hypoxia and hyperoxia. Details of the methods and equipment are presented in the tex-t under “Control of Breathing Appa- ratus.”

carried out according to methods previously described [16.17]. In addition, the mean of maximal inspiratory and expiratory mouth pressures (PM,J generated against an occlusion at residual volume (PIMJ and at total lung capacity (PEM,J was measured in all subjects [18,19]. All these routine pulmonary function tests were performed with the subjects sitting.

Control of Breathing Apparatus. To assess the response of the respiratory centers to hypercapnia, hypoxia and hyperoxia. we designed the apparatus schematically presented in Figure 1. The subject breathed with a mouth-piece through a Fleish No. 3 pneumotachograph attached to a Hewlett-Packard flow meter [H.-P. No. 47304A) and an integrator (H.-P. No. 8815). the signals of which were displayed on two of the four chan- nels of our recorder (H.-P. No. 7754A). Between the mouth- piece and the pneumotachograph. a pressure line was connected to a transducer (H.-P. No. 270) and was displayed on a channel of the recorder. The gas sampling line was connected to a CO2 infra-red analyzer (Beckman Lb-l) and an oxygen analyzer (AEM3A). and their outputs were displayed continuously on frontal readouts of the analyzers and regis- tered on the recorder when needed. The total flow rate of these analyzers. in series, was 5 ml/set. Calibrations and routine checks for accuracy were carried out repeatedly before and after each experiment according to methods previously de- tailed [16,17,20]. Above the pneumotachograph, a low resis- tance Koegel valve separated inspiratory and expiratory lines. On the inspiratory line, a five-way valve (Collins P-314) was inserted with selections for either occlusion, room air breathing or breathing gas mixtures of the hypercapnia. hypoxia and hyperoxia tests. Above that valve, the inspiratory and expiratory lines converged to a second five-way valve (Collins p-314) with selections for either the hypercapnia rebreathing, hypoxia or 100 percent 02 breathing tests. On the expiratory line above

228 August 1980 The American Journal of Medicine Volume 89

--~- -1 percent O:! breathing constitutes the prolonged 100 percent O2 breathing. During these tests of hyperoxia. end-tidal 02 and COZ were continuously monitored. Respiratory Centers Output Indices. During each of the tests of control of hreathing. ventilation (irk), tidal volume (VT) and

160

1 T

:r 2 P 0 :: g 4s

Y = Figure 2. The routlne pulmonary function studies of these patients included total lung capacity (TLC), vital capacity (VC), residual volume (RV), functional residual capacity by the helium method (FIX), maximum voluntary ventilation (MN). vital capacity expired in 1 second (VC,.O). maximal mid- expiratory flow rate (MMEF), diffusion for carbon monoxide by the steady state or single breath methods (DLco) and the maximal pressure generated at the mouth against a closed airway (PM,,). Results are presented as means f SEM. Pre- dictions for these analyses were obtained from Beaudry et al. [48] and Zepletal et al. [49]. PM predictions were obtained from the controls of this study.

_I I respiratory frequency (F] were measured. In addition, for the hypcrcapnia and hypoxia tests, two newer indices were measured: (1) the mean inspiratory flow rate (VT:Ti) where Ti is the mean inspiratory time, an index of inspiratory neural drive transformed into flow [ZS]. and (2) the occlusion pressure

d (P”.,], the mouth pressure generated at 0.1 second by the inspiratory muscles at functional residual capacity [27]. The latter parameter of respiratory centers output is not influenced by

& 2 the pulmonary mechanics [15]. In the present study, the oc-

0’ f clusion was performed as shown in Figure 1. according to the method of Lopata et al. 1281. Rricfly. with the subject having his eyes covered during the test, transient silent closure of the inspiratory circuit was performed randomly every 5 to 10 breaths during the hypercapnia and hypoxia tests. The occlusion lasted for between 0.2 and 0.3 second and the negative mouth pressure was measured at 0.1 second after the start of the inspiratory effort, at which time the subject had not yet realized that the inspiratory line was blocked (27.291. Analysis of the Data. During the hypercapnia test, we arbitrarily selected the following PAco, of 40.44.48.52 and 56 mm Hg as points of measurements for each index of the respiratory centers output (\j, VT. F. VT/Ti, PO.,). For each subject. data were collected as the mean values of three to five individual measurements at PAc.oz within 1 mm Hg of each selected PA(:o,. \j~ was derived from 3 to 5 consecutive breaths. During the hypoxia test, we also arbitrarily chose the PA<), of 95, 80, 70, 60 and 50 mm Hg as points of measurements. For each subject, collected data were also the means of three to five individual measurements at PAo, within 3 mm Hg of each selected PA(l,a \j~ was also derived from these 3 to 5 conscc- utive breaths. During the hyperoxia tests. only ir, was measured as presented herein.

the Koegel valve [Collins P-531) permitted either rebreathing or nonrebreathing of either gas mixture. Hypercapnia Test. For this test, we used the CO2 rebreathing method of Read (211. Briefly, a 6 liter bag filled with a 5 percent CO:! in O2 was connected to the breathing valve and each subject rebreathed in the bag until his alveolar CO2 (PAco,) as measured by the end tidal CO;! reached 60 mm Hg, at which point he was returned to room air breathing. Hypoxia Test. The hypoxia nonrebreathing method of Weil was used [22). In short, the subject breathed a gas mixture of room air to which was added an increasing volume of pure nitrogen (Ns) until the end-tidal O2 (PAo,) reached 50 mm Hg over a 15 to 20 minute period. PAo, was maintained at 50 mm Hg for 2 to 3 minutes. During the test, CO2 was added to the inspiratory line to maintain the PAco2 at 40 f 1 mm Hg. Each subject was monitored using a continuous electrocardiogram. The terminal PAo, of 50 mm Hg was selected for safety con- siderations in these patients known to have a cardiomyopathy

IlOl. Hyperoxia Test. The transient O2 100 percent test described by Dejours was used [23-251. First. each subject breathed room air for 5 minutes, during which period \j~ was measured over five breaths during the last minute of this prestudy period. Thereafter, the subject was switched to 100 percent 02 breathing and $‘E was again calculated from the first five breaths following the start of 100 percent 02 breathing. This initial change in 9~ from room air to loo percent O2 breathing constitutes the Dcjours’ transient 100 percent 02 test. Finally, after the patient was left breathing 100 percent O2 for an additional 15 minute period, ATE was again obtained at the end of that period. This final change in \j, from room air to 100

CONTROI. OF BREATHING IN DIJClIENKE’S MLISCLJI.AR DYSTROPHY-HtXIN 13‘ Al..

In the presentation of the results, mean values of the data of patients and of the data of controls are followed by the standard error of the mean (SEM) as an index of dispersion (“Results.” Figures 2 to 5). For statistical analysis searching differences hetwcen patients and controls. each subject’s response to hypcrcapnia and hypoxia was transformed into a linear regression equation. the classic fit for responses to hypercapnia and the best fit for our hypoxia data, when PAo, did not fall below 50 mm Hg. The mean slope of the response of patients versus controls was analyscd by a Student t test for unpaired values. For statistical analysis searching differences between sequential measurements on the same subjects, the data were tested by two-factor analysis of variance [a~]. Dif-

ferences with P <0.05 were considered significant.

RESULTS

Routine Pulmonary Function Tests. The results of lung volumes, expiratory flow rates, diffusion and ~~~~ of our patients are presented in Figure 2 as percents of their predicted values. Gas exchange study was also performed while the patients were resting and breathing room air. The patients’s arterial PO, was 87.6 T 4.1 mm Hg and P(;o, was 33.9 F 2.0 mm Hg. The highest arterial



A

00

l c

Figure 3. The respiratory centers output on progressive hypercapnia was assessed by looking at the minute ventilation (V,) in A, tidal volume (V,) in B, respiratory frequency (F) in C, mean inspiratory flow rate (VT/Ti) in D, and occlusion pressure (Po.,, in E. For each parameter, there was a significant increase as P&on increased in both normal controls (C) andpatients with Duchenne’s muscular dystrophy (D). Furthermore, the slope of the response of patients was slightly lower for VE (P >0.05), VT (Ti (P >0.05), Po.1 (P >0.05) but it was clearly different for VT (P CO.01) and F (P <O.Ol at the PAco2 of 56 mm Hg).

PCO, observed in these patients was 41.5 mm Hg. Their resting VE was 9.70 7 0.71 liters body temperature and pressure saturated (BTPS), F was 22.7 =F 1.9 breaths/min, VT was 0.42 =F 0.03 liter, VT:Ti was 0.33 =F 0.02 liter/set and Po.~ was 1.93 F 0.19 cm HzO. In controls, VE was 9.26 7 0.33 liters, F was 14.5 F 1.7 breaths/min, VT was 0.55 =F 0.03 liters, V$Ti was 0.38 =F 0.02 liters/set and Po.1 was 2.16 F 0.26 cm HzO. The difference between patients and controls was significant for F and VT only [P <O.Ol for both F and VT). Respiratory Centers Output to Hypercapnia. Figure 3 presents the responses of our patients and controls to progressive hypercapnia. The indices o.f respiratory centers output presented in A to E are VE (liter/min BTPS), VT (liter), F (breath/min], VT:Ti (liter/set) and P0.l (cm H20). As can be seen in this figure, both patients with Duchenne’s muscular dystrophy and normal

controls responded to a progressive increase in PAcoz by a significant increase in each index of respiratory centers output (P <O.Ol). Furthermore, the slope of the response was only slightly lower in patients than in controls for VE (P >0.05), VT:Ti (P >0.05) and P0.l (P >0.05), but VT was much lower (P <O.Ol] and F much higher in patients, particularly at the P&o, of 56 mm Hg (P <O.Ol). Respiratory Centers Output to Hypoxia. The response of our patients and controls to progressive isocarbic hypoxia is presented in Figure 4, the indices of the neural drive of breathing being similar to those of hypercapnia presented. In response to the progressive decrease in PAo2, both patients and controls had a significant increase (P <0.05) in 7j& VT, V$Ti and P0.l; changes in respiratory frequency however, did not reach significance (P >O.lO) for controls and reached the P


CONTROL OF BREATHING IN DUCHENNE’S MUSCULAR DYSTROPHY-BkGIN ET AL.

A a C

“T

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F

& A so-

gure 4. The respiratory centers output to isocarbic progressive hypoxia was assessed by looking at the same parameters as in Figure 2. For each parameter except F, there was a significant increase as PAo2 decreased in both controls (C) and patients with Duchenne’s muscular dystrophy (D). However, the slope of the response did not differ significantly between D and C for all parameters.

value of <O.lO for patients. Thus, in the response to progressive isocarbic hypoxia, patients differed from controls only in their pattern of breathing characterized by a smaller tidal volume (P <0.05) and a higher respiratory frequency (P <O.lO). Ventilatory Responses to Hyperoxia. The ventilatory responses (VE) to hyperoxia are presented in Figure 5. For both patients and controls, similar changes in Vz were observed. The transient Oz inhalation (Dejours’ test) caused a slight decrease in Vz and, after 15 minutes of 100 percent 02 breathing, Vz increased significantly above the prestudy levels in both groups (P <0.05).

COMMENTS

Over the last few years, some of the major advances realized in the field of regulation of respiration have included the standardization of simple and rapid tech- niques of selective stimulation of the chemical drive of breathing with the hypercapnia [21], isocarbic hypoxia [22] and hyperoxia [24] tests. Also, there has been an

increased awareness of the limitations of using only Va as the respiratory centers output index, particularly in disease [31,32]. Newer parameters such as VT:Ti and Pa.1 were introduced. Vr:Ti is thought of as a measure of the mean flow resulting from the inspiratory neural drive [26] and, therefore, should not be influenced by the expiratory events of respiration. Po.1 is said to be rela- tively unaffected by respiratory mechanic abnormalities (occurring at zero flow) and has the advantage of being a fast and easy parameter to measure 1151. P0.l should also reflect the output of respiratory centers in the ab- sence of any volume-related vagal modulation [33].

In the presence of neuromuscular disease, Po.1 could, in theory, reflect more accurately the output of respiratory centers, since the pressure, measured at 0.1 second after beginning of inspiration on an occluded airway, is only a small fraction of the total muscular pressure generated for the tidal volume and may be independent of the maximal inspiratory pressure limitation reached later in the inspiratory effort. Indeed, from the



data of our patients with advanced muscular dystrophy, it appears that PO., offers two characteristics needed for accurate assessment of the output of respiratory centers in the presence of abnormal mechanics of breathing. First, P0.1 is sensitive to small changes in PAcoz or PAo, (Figures 3 and 4). Secondly, Po.~ seems independent of respiratory mechanics inspite of marked differences in the respiratory mechanics between patients and controls [Figure 2). Po.1 was nearly identical at all points of the hypercapnia and hypoxia tests: the small differences at the extremes of hypercapnia and hypoxia tests were not statistically significant. However, it remains possible that, in presence of respiratory muscle weakness, “au- tomatic adjustments” in the central neural drive could have facilitated higher phrenic nerve activity and should have generated supranormal PO.1 values as observed in the presence of respiratory loads [34-361 and in milder neuromuscular disease [37]. In the presence of severe neuromuscular weakness, this higher central drive would be incompletely transmitted into the Po.~ of our patients with Duchenne’s muscular dystrophy. Thus P0.l should reflect accurately the neural drive of breathing at a point after the muscle output and before the drive is influenced by restrictions and limitations imposed by abnormalities of the respiratory apparatus.

VE and Vr:Ti are also sensitive to small changes in PAcoz or PAoz (Figures 3 and 4). but they clearly are dependent on the mechanics of the respiratory apparatus as seen in the significant differences [P <0.05) in controls in the hypercapnia and hypoxia tests.

Finally, VT and F, as indices of respiratory centers’ chemosensitivity, are clearly different from the other parameters: normal subjects respond to hypercapneic (Figure 3) or hypoxic (Figure 4) stimuli by increasing VT without changing F, whereas patients with Duchenne’s muscular dystrophy increased F without much change in VT. These parameters, VT and F, therefore, are not very good indicators of neural output of the respiratory centers and appear to reflect more accurately the final effective output of the total respiratory system. In conjunction with the other means of measurements of- chemosensitivity, VT and F reflect the modulation of the ventilatory response imposed by the mechanics of the respiratory apparatus and could be useful clinical indicators of respiratory muscle fatigue [38] and respiratory failure [39,40].

The Duchenne ventilatory response is reminiscent of the tachypneic response observed previously in mitral stenosis [41] and in pulmonary fibrosis [42]. In these interstitial lung diseases, the tachypnea is caused largely by the stimulation of the juxtacapillary receptors, the pulmonary stretch receptors and the irritant receptors of Widdicombe. These receptors would, upon stimulation, produce vagally-mediated reflexes to terminate inspiration and, thereby, control the respiratory frequency [41,43,45]. In our patients with Duchenne’s muscular dystrophy, an explanation of their tachypnea

OD

l C

I I I I 1 I

0 5 15

pre-study Time tmin)

02 21% 02 100% breathing

Figure 5. The ventilatory response to hyperoxia was measured as minute ventilation (Vs) at a prestudy point while subjects were breathing room air. Thereafter, the five first breaths immediately after the start of 100 percent 02 breathing were compiled as the second point, and the last point was obtained 15 minutes later ovar five breaths. In this figure, controls (C) and patients with Duchenne’s muscular dystrophy (D) did not differ significantly; however,. at 15 minutes after the start of 100 percent O2 breathing, Ve was significantly higher than at prestudy and at the beginning of 100 percent O2 breathing for both C and D (P cO.05).

related to a restrictive lung volume syndrome cannot apply since their functional residual capacity was 90 percent prediction and they had a normal lung roent- genogram, a normal resting PAoz and a normal diffusion (DL:VA) [43-451.

However, their respiratory muscle weakness was well established by a maximal voluntary ventilation of 55 percent prediction and by a ~~~~ of 25 percent prediction. This reduction of respiratory muscle strength and performance may well be a major factor in the genesis of tachypnea in Duchenne’s muscular dystrophy. Be- cause of muscle weakness, the neural drive of respiratory centers fails to be efficiently transformed into an increased VT, hence there is probably an early activa- tion of the inspiratory off switch mechanism, “affer- enting” from the respiratory mucles [46,47]. Therefore, it is likely that the tachypneic patterns of breathing of our myopathic patients was modulated by the weakly



contracting muscle fibers themselves: it may further be a clinical manifestation of inspiratory muscle fatigue.

During the hyperoxia tests, the only measured response of the respiratory centers (ir,] was also similar in patients and controls. The inhalation of z to 5 breaths of pure 02 causes a transient decrease in the output of the peripheral chemoreceptors and during such an “unload” of the respiratory apparatus, a very similar decrease in vj~ was observed in patients and controls. This is consistent with the O2 drive contribution to ventilation at room air breathing [18,32]. Although the early hyperoxia test is specific for the peripheral chemoreceptors sensitivity and decreases iTs, the prolonged hyperoxia test is multifactorial [18,32] and induces a small increase in \jc which was similar in patients and controls.

In this study, results of the early hyperoxia test, in conjunction with the data of the isocarbic hypoxia test, demonstrate the integrity of the peripheral 02 chemo-

receptor sensitivity in patients with Duchenne’s muscular dystrophy. The normal CO2 response and the late hyperoxia response of these patients demonstrate the adequacy of both peripheral and central COz sensitive chemoreceptors.

In conclusion, the present study establishes that, in moderately severe Duchenne’s muscular dystrophy, the respiratory peripheral and central chemoreceptors are adequately sensitive to hypercapnia, hypoxia and hyperoxia. The effective ventilatory response in Du- chenne’s muscular dystrophy, however, is subnormal and of a preferential increase in respiratory frequency at the expense of a larger tidal volume, thereby achieving a tachypneic pattern of breathing. The tachypnea appears to be caused by the weakness of inspiratory muscles and may well be a clinical manifestation of early inspiratory muscle fatigue in these myopathic patients.

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control of breathing in duchenne's muscular dystrophy

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