Abstract
REM-related oxygen desaturation occurs in advanced Duchenne muscular dystrophy (DMD) and might be an independent predictor of disease progression. We have followed 18 patients for 10 yr after an initial respiratory sleep study or until death or onset of nasal ventilation. We measured baseline spirometry, blood gas tensions, maximal respiratory pressures, and body mass index. In 11 cases, VC was recorded serially. Median survival was 50 (range, 13 to 89) mo from initial study and unrelated to age at time of study, BMI, or mouth pressures but correlated with PaCO2 (r = − 0.72, p < 0.005, n = 17), minimal nocturnal SaO2 (r = 0.62, p < 0.007, n = 18) and VC (r = 0.65, p < 0.005, n = 17). Cox regression analysis showed a VC of less than 1 L at the time of study to be the best single predictor of subsequent survival. The only measure associated with age of death was the age at which the VC fell below 1 L (r = 0.79, p < 0.004). These data suggest measurement of PaCO2 or serial assessment of VC should be studied further as valid methods of assessing prognosis in DMD.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscular weakness that ultimately involves all the respiratory muscles leading to substantial morbidity and mortality (1-3). Death usually occurs between 15 and 25 yr of age, commonly from respiratory or cardiac failure (4-6). The VC depends on the strength of both the inspiratory and expiratory muscles and is lower in patients with more advanced disease (6). Likewise, older patients exhibit alveolar hypoventilation and resting hypercapnia (1, 7). However, these associations have been established in cross-sectional studies and there are little data about the prognostic implications of any of these measurements in an individual patient. Previously we reported that some older boys (older than 14 yr of age) with DMD exhibited episodic nocturnal desaturations, predominantly in REM sleep (8). These resulted from recurrent apparently central apneic events, which may represent an inability of the weakened diaphragm to overcome the physiologic increase in upper airway resistance occurring during sleep (8-10). There was an inverse relationship between the rib cage contribution to breathing in non-REM sleep and the number of REM desaturations (10). Thus the presence of apnea might be a noninvasive surrogate marker of impaired musculature during sleep in these weakened patients. Moreover, the accompanying desaturations have been associated with cardiac rhythm disturbances, which could predispose to early mortality (11).
To address whether these sleep-related problems are predictors of mortality we have conducted a prospective study of all patients undergoing respiratory sleep studies in a 3-yr period with follow-up until the patient's death or the institution of nighttime nasal positive pressure ventilation. We hypothesized that those patients showing most sleep-disordered breathing (SDB) would die soonest and that this would be a more informative investigation than reliance on daytime spirometry or assessment of the arterial CO2 tension, which is itself invasive. In addition, in a subset of our population, we obtained serial spirometric data to determine whether the rate of deterioration in lung function was of clinical predictive value.
Nineteen male patients attending two regional muscle outpatient clinics were studied. They were selected solely on the basis of their age (older than 14 yr of age) and willingness to take part in the studies. Fourteen participated in the study of Smith and colleagues (8) and five additional patients were taken from the study of Carroll and colleagues (11). None had symptoms of daytime hypersomnolence, morning headache, or evidence of respiratory infection at the time of study. DMD had been diagnosed on the clinical and muscle biopsy criteria in use at that time. Subsequent analysis of muscle from one patient showed the presence of dystrophin: he is thought to have an autosomal recessive muscular dystrophy and has been omitted from subsequent analysis. An approximation of body mass index (BMI) was derived from weight/span2 as height was difficult to measure accurately. In 14 patients BMI was taken from data at the time of the study, for the rest from data within 6 mo of the study date. The median age at which patients had stopped walking was 10.0 yr (range, 7 to 14 yr), and their median age at time of sleep study was 17.8 yr (range, 14 to 24 yr). Twelve patients had had Luque spinal instrumentation. There were abnormalities in resting ECG in all 12 patients who had an ECG taken within 6 mo of the sleep study. Six further patients did not have an ECG within that time limit. Abnormalities noted were T wave inversion (4), partial right bundle branch block (6), abnormal Q waves (2) and abnormal ST segment (2). Some patients had more than one abnormality. Echocardiograms were performed only if there was a clinical suspicion of a symptomatic cardiomyopathy. Three patients had transthoracic echocardiograms: two were normal, one showed mild global hypokinesis.
FVC was recorded in the study by Carroll and colleagues and VC in the study by Smith and colleagues, both using a dry bellows spirometer (Vitalograph, Beckenham, Kent, UK). FVC and VC were considered to be equivalent in analysis of results as these patients had no clinical or radiographic evidence of intrinsic pulmonary disease. A flanged soft plastic mouthpiece (Morgan Medical, Gillingham, Kent, UK) was used for the respiratory measurements. Both tests were recorded in a sitting position, the procedure being repeated at least three times until the highest two values were within 100 ml of each other. Maximal inspiratory (Pimax) and expiratory (Pemax) static mouth pressures were measured using the method of Black and Hyatt (12). Arterial blood gas tensions were measured by radial artery puncture with the patient seated breathing air. Fourteen patients had full polysomnography (PSG) in hospital for two consecutive nights. The mother would turn and position the patients as at home, and data from the second night only were considered, the first night being used to acclimatize them to the equipment. Overnight recordings were made onto an eight-channel EEG pen recorder (SLE 100T). These recordings were: electroencephalogram (EEG); electrooculogram (EOG), and submental electromyogram (EMG) using Ag/AgCl electrodes placed at standard positions for sleep staging; chest and abdominal wall movement using respiratory inductance plethysmography (RIP) (Respitrace; Ambulatory Monitoring, Ardsley, NY) onto three channels; and oronasal airflow using a thermistor secured below the nares. Oxygen saturation (SaO2 ) was measured continuously using an ear oximeter (Biox Mk3; Ohmeda, Boulder, CO) and also recorded on a separate slow-running chart recorder. Five patients were studied at home and in these, oxygen saturation and pulse rate were measured using a pulse oximeter (Ohmeda Biox 3700) and a slow-running pen recorder system (Model R-03; Rikadenki).
The maximal arterial oxygen saturation reached during sleep (minSaO2 ) and presence or absence of desaturation (fall in the SaO2 by > 4% of awake value) were derived from the oxygen saturation results. Hypopneas were recognized in the PSG studies as a reduction in the derived sum signal of the RIP to < 50% of the preceding stable level for more than a 10-s duration. Their association with sleep stage was noted and they were expressed as hypopneas per hour and as a percentage of sleep time for both REM sleep and total EEG confirmed sleep. In the polysomnograms the amount of sleep with an SaO2 < 90% was calculated, but this proved difficult to estimate where only oximetry data were available.
The date of death or date of initiation of noninvasive nocturnal ventilation was recorded during follow-up and “survival,” calculated as the length of time in months from sleep study until death or initiation of nocturnal ventilation. The decision to institute ventilatory support was based on symptoms and careful discussion of the implications of this treatment with patients and carers. The clinicians undertaking the patients' follow-up were unaware of the results of the respiratory sleep investigations. Maximal follow-up was 120 mo. The first patient died at 13 mo.
In a subgroup of 11 cases serial measurements of VC from twice yearly clinic attendances were available. The age at which the VC fell below 1 L was recorded as a method of assessing disease progression, as has been used elsewhere (13). The age was estimated to the nearest half year, and taken as the patient's age when the FVC was recorded as < 1 L having been > 1 L on the previous visit. If the FVC had varied around the 1 L mark for a while it was taken as the oldest age at which this occurred.
Data were analyzed using SPSS for Windows, version 6.1.2. Results are expressed as median (range). Correlations between variables were assessed by scatterplots and Spearman's rank correlation coefficients, the latter because most variables were nonparametric. Ten variables were considered by this method, and so the Bonferroni correction was applied to give a p value of 0.005 as significant. In the publication of Smith and colleagues (8) patients were split into those who had experienced oxygen desaturation of at least 4% during sleep (desaturators) and those who had not (nondesaturators). In this larger study there were 11 desaturators and seven nondesaturators. Age at sleep study, age off legs, BMI, VC, PaO2 , PaCO2 , Pimax, Pemax, percentage of hypopnea/apnea in REM sleep, and minSaO2 during sleep were compared between these two groups using Mann-Whitney U tests.
Survival to 3 yr was studied by Kaplan Meier analysis and Cox regression analysis (14). Kaplan Meier analysis was used to compare PaCO2 > 38 mm Hg with PaCO2 < 38 mm Hg, minSaO2 ⩽ 90% with minSaO2 > 90%, presence of arterial oxygen desaturation > 4%, with none, VC > 1 L with VC < 1 L, over a 3-yr survival period, and the significance of the difference in survival between groups was calculated using the log-rank test. A stepwise Cox regression analysis of factors that were correlated with survival was used.
Median VC was 1.2 L (0.55 to 1.95 L, n = 17). One patient was unable to produce an adequate mouthpiece seal, giving invalid results for VC measurements. Median Pimax was 30 cm H2O (10 to 60 cm H2O, n = 18) and Pemax 25 cm H2O (13 to 70 cm H2O, n = 18). Median PaCO2 was 40 mm Hg (33.6 to 73.7 mm Hg, n = 17) and PaO2 105.6 mm Hg (60.8 to 143.6 mm Hg, n = 18), the sample obtained from one patient being technically unsatisfactory. The reason for the abnormally high PaO2 was thought to be due to patients breathing oxygen-enriched air during measurement of FRC, which took place 20 to 30 min before arterial blood gas sampling. All three patients with a high PaO2 had a normal PaCO2 . Median awake arterial oxygen saturation was 96% (90 to 97.5%, n = 18).
The median minimal arterial oxygen saturation recorded during sleep was 87.8% (53 to 97%, n = 18). The median percentage of time occupied by hypopnea and/or apnea in REM sleep was 28.6% (8.5 to 51.5%, n = 13), and in total sleep it was 6.5% (1.7 to 17.5%, n = 13). The median time and percentage of time below an SaO2 of 90% was 0 min, but with a wide range of 0 to 620 min.
Sixteen patients died during the 10-yr follow-up period from time of sleep study, mean age of death being 22 yr (95% confidence interval, 21 to 23 yr). The two survivors had commenced domiciliary nocturnal ventilation 47 and 49 mo after the sleep studies, and they continue with this treatment.
The median survival postsleep study was 50 mo (range 13 to 89 mo). Values of age at time of sleep study, VC, percentage of time desaturated at night, PaCO2 , minSaO2 , and survival for each patient are given in Table 1.
| Patient No. | Age at Time of Sleep Study (yr) | Vital Capacity (L) | MinSaO2 (%) | Monitoring Time below 90% | PaCO2 (mm Hg) | Survival*(mo) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 21.0 | 1.21 | 84.0 | — | 39.1 | 113 Ventilated 47 mo | ||||||
| 2 | 16.5 | 1.6 | 87.5 | — | 39.3 | 87 | ||||||
| 3 | 15.5 | 1.45 | 94.0 | 0 | 36.5 | 58 | ||||||
| 4 | 17.5 | 0.80 | 90.0 | — | 40.3 | 27 | ||||||
| 5 | 18.25 | 0.70 | 79.0 | — | 44.8 | 13 | ||||||
| 6 | 24.0 | — | 53.0 | 86% | 73.7 | 15 | ||||||
| 7 | 19.25 | 0.77 | 79.0 | — | 46.0 | 32 | ||||||
| 8 | 16.5 | 1.00 | 58.0 | — | 41.0 | 32 | ||||||
| 9 | 17.5 | 1.9 | 67.0 | — | 34.7 | 64 | ||||||
| 10 | 16.5 | 1.4 | 88.0 | 4% | — | 38 | ||||||
| 11 | 23.0 | 0.55 | 68.0 | — | 40.0 | 28 | ||||||
| 12 | 15.5 | 1.35 | 94.0 | 0 | 33.6 | 73 | ||||||
| 13 | 19.0 | 1.2 | 92.0 | 0 | 35.7 | 89 | ||||||
| 14 | 15.5 | 1.15 | 93.0 | 0 | 42.9 | 47 | ||||||
| 15 | 14.0 | 1.95 | 97.0 | 0 | 34.2 | 87 | ||||||
| 16 | 18.0 | 1.85 | 92.0 | 0 | 33.8 | 82 | ||||||
| 17 | 15.5 | 0.60 | 93.0 | 0 | 43.5 | 121 Ventilated 49 mo | ||||||
| 18 | 20.5 | 1.30 | 79.0 | — | 40.1 | 26 | ||||||
| Median | 17.5 | 1.2 | 87.75 | 0 | 40.0 | 47 |
Age at going off legs, BMI at time of sleep study, minSaO2 , awake PaCO2 , VC, and age at which VC fell below 1 L were compared with age at death using Spearman's rank correlation coefficients. Only the age at which VC fell below 1 L showed a significant association (r = 0.79, p < 0.004, n = 11).
Age at time of sleep study, BMI, awake PaCO2 , Pimax, Pemax, VC, minSaO2 , percentage of hypopneas in total sleep, and percentage of hypopneas in REM sleep were compared with survival using Spearman's rank correlation coefficients. Of these, only PaCO2 (r = −0.72, p < 0.005, n = 17), minSaO2 (r = 0.62, p < 0.007, n = 18), and VC (r = 0.65, p < 0.005, n = 17) showed a significant association (Figure 1). These indices were also related to each other, with the strongest relationship being between PaCO2 and VC (r = −0.74, p < 0.001, n = 16). There was a weaker correlation (r = −0.73, p < 0.03, n = 9) for the smaller number of patients on whom we had data concerning the length of time for which they desaturated below 90%.
Fig. 1. Graphs of awake PaCO2 , minimal arterial oxygen saturation, and vital capacity against survival. Spearman's rank correlation coefficients are −0.72 (p < 0.005), 0.62 (< 0.007), and 0.65 (p < 0.005), respectively.
[More] [Minimize]Differences in 3-yr survival between the groups, as described in Methods, were compared and the results are shown in Table 2. The greatest discrimination between groups was seen when VC < 1 L or > 1 L was used, log rank statistic 8.9, p < 0.003 (Figure 2).
| Patients (n) | Criteria for Group 1 | Fraction Surviving < 3 Years | Log Rank Statistic | p Value | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Group 1 | Group 2 | |||||||||||
| MinSaO2 | 18 | O2 saturation | 6/10 | 1/8 | 3.75 | 0.05 | ||||||
| ⩽ 90% | ||||||||||||
| Desaturation | 18 | Desaturation | 7/11 | 0/7 | 6.4 | 0.01 | ||||||
| at night | > 4% | |||||||||||
| Vital capacity | 17 | VC ⩽ 11 | 5/6 | 1/11 | 8.9 | 0.003 | ||||||
| PaCO2 | 17 | PaCO2 > 38 | 7/11 | 0/6 | 7.4 | 0.007 | ||||||
| mm Hg | ||||||||||||
Fig. 2. Survival curves comparing those with an initial vital capacity of ⩽ 11 and those with an initial vital capacity of > 11.
[More] [Minimize]When the 11 desaturators were compared with the seven nondesaturators they were similar in age at sleep study, age off legs, VC, PaCO2 , Pemax, and Pimax, but varied in BMI, minSaO2 during sleep, and percentage of hypopnea/apnea in REM sleep at the 0.05% level. There was a significant difference in survival between the groups (p < 0. 008) (Table 3).
| Desaturators (n = 11) | Nondesaturators (n = 7) | p Value* | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Median | Range | Median | Range | |||||||
| Age, yr | 18 | 16.5–24 | 15.5 | 14–19.5 | — | |||||
| Age off legs, yr | 10 | 7–12 | 11.0 | 7–14 | — | |||||
| BMI, kg−2 | 19.9 | 18.4–26.4 | 17.5 | 13.1–23.5 | 0.04 | |||||
| Survival, mo | 32.0 | 13–87 | 73.0 | 47–89 | 0.008 | |||||
| Vital capacity, L | 1.1 | 0.55–1.9 | 1.35 | 0.6–1.95 | — | |||||
| PaCO2 , mm Hg | 40.3 | 34.7–73.7 | 35.7 | 33.6–43.5 | — | |||||
| MinSaO2 , % | 79 | 53–90 | 93.0 | 92–97 | 0.0005 | |||||
| Pimax, cm H2O | 30 | 10–45 | 34.0 | 20–65 | — | |||||
| Pemax, cm H2O | 20 | 15–50 | 38.5 | 13–70 | — | |||||
| Hypopnea in | ||||||||||
| REM sleep, % | 40.3 | 20–51.5 | 14.5 | 8.5–33 | 0.03 | |||||
Vital capacity, VC > 1 L or < 1 L, PaCO2 , PaCO2 > 38 mm Hg or < 38 mm Hg, minimal arterial oxygen saturation during sleep, desaturation episodes > 4% or episodes < 4%, age at time of sleep study were allowed to compete in a stepwise Cox regression analysis to see which indices could be used to predict survival. In this analysis survival to 3 yr from time of sleep study was considered. The only variable to be included in the equation was VC, taken as either ⩽ 1 L or > 1 L (χ2 = 7.7, R = 0.30, p < 0.03).
Cardiorespiratory causes are acknowledged as the major reason for death in advanced neuromuscular disease where simple measures of pulmonary function such as vital capacity are seen to decline with increasing disease severity (6). These observations are generally based on mixed groups of patients with neuromuscular disease and, given the difficulties of conducting follow-up pulmonary function studies, data about their relationship to an individual's survival are lacking. Although the number of patients described here is modest, it is still one of the larger reports in a single type of neuromuscular disease and the only one to relate a number of different types of pulmonary function assessment to outcome. Our previous observations about SDB in DMD raised the possibility that this might be an important independent mechanism causing patient deterioration, early detection of which could improve prognosis. The present study does not support this view, but instead confirms the relationship between reproducible tests of respiratory mechanics and alveolar hypoventilation to the eventual outcome.
The study has a number of limitations apart from the size of the population. It was restricted to patients agreeing to some form of overnight investigation. Both patients and carers expressed concern about the prospect of overnight polysomnography and we completed our recruitment protocol by including a number of other patients monitored only by pulse oximetry. These patients were not significantly worse than those in the PSG group and our principal end-point remained the number and severity of episodes of oxygen desaturation. Oximetry is particularly sensitive to SDB in patients whose relative immobility reduces saturation trace artefacts and whose reduced pulmonary oxygen stores means that even small changes in total ventilation result in detectable desaturations.
The incidence and severity of SDB was broadly spread across the study population. Inclusion of a larger number of subjects to those in our first report (8) confirmed that age at the time of study did not differ between those desaturating and those not doing so (Table 3), and it was not surprising to see more hypopneas in REM sleep in those exhibiting desaturations as this was the sleep stage where the earliest and most frequent changes in oxygen saturation occurred. Although the age distribution of the population was similar the BMI was higher in those patients who desaturated during sleep. This difference is likely to reflect a higher fat deposition around the neck of those patients who desaturated, and this is in keeping with the pseudo-obstructive nature of the events (8, 9). Regrettably no data about the neck circumference were available. Although there was a clear survival difference between the group that desaturated during sleep and those who did not, this may reflect higher arterial CO2 tensions in the desaturators, and no additional explanatory power was found in the Cox regression analysis even when desaturation was considered as a binary variable. Possible reasons for this include the transient nature of the desaturations, which resolve within a few minutes, and the variable amount of REM sleep experienced on a given night. In the restricted data set where information was available about the time spent below 90% saturation, a correlation was seen with survival, but similar considerations to those noted for minimal arterial oxygen desaturation apply and more patients would need to be studied before an independent effect of this variable could be established.
By contrast, vital capacity is a relatively simple test to perform with a known reproducibility within and between patients and standard criteria for assessing the best results (15). It showed the best correlation with overall survival and, even when this was restricted to 3 yr, showed the widest dispersion between those likely to survive or die. The results emphasize the highly interrelated nature of differing indices of respiratory function, and it is possible that small changes in the number of patients in the study may have changed this relationship to one dependent on PaCO2 . The association of VC with desaturations is relatively weak, but more desaturation would be likely to occur when VC is reduced as this may reflect greater diaphragm weakness and relatively smaller oxygen stores. Maximal inspiratory and expiratory pressures measured seated were not of predictive value, possibly because the reproducibility is poorer. Although no better than vital capacity, PaCO2 was also related to the duration of illness. However, values normally considered to lie in the normal range (as great as 45 mm Hg) were associated with adverse survival (Table 1 and Figure 1). In fact, only two values exceeded the conventional normal range of PaCO2 . We have no data to directly explain this, but reduction in the muscle mass may be associated with a lower metabolic CO2 production so that alveolar ventilation would have to fall disproportionately below normal levels before CO2 retention could occur (3). Thus, CO2 tension may remain relatively normal at a time when muscle weakness is progressing. This is in keeping with earlier data in neuromuscular disease where arterial CO2 was found to be in the low normal range in most subjects (16), and observations in amyotrophic lateral sclerosis where significant loss of VC occurred in adults without necessarily producing hypercapnia (17).
The serial measurement of VC demonstrates that individual rates of decline vary, the age at which VC fell below 1 L ranging from 16.0 to 22.3 yr. A VC of less than 1 L proved to be the best single predictor of survival in a 3-yr period. We do not know how much this was influenced by the time of onset of disease and subsequent pulmonary growth, but the age at which the patients became chair-bound was not a predictor of survival, suggesting that variations in decline of lung function were more important.
Clinically, this study has a number of implications. Although on in the VC below an arbitrary value (18) or increase in PaCO2 above 45 mm Hg (19) have been used to select patients for assisted ventilation, the rate of decline of pulmonary function may also be an indicator of end-stage disease. This has implications for the interpretations of the results of earlier trials of treatment (18, 20-22). Secondly, data from either the absolute VC or arterial CO2 tension may provide valid prognostic information; whether this can be used in the place of data concerning nocturnal oxygen desaturation in asymptomatic cases needs to be studied further. The implications of these findings for other disorders such as motor neurone disease, post-poliomyelitis syndrome, and kyphoscoliosis (23-25) where similar transient REM-related desaturations occur should be considered.
Supported in part by the Muscular Dystrophy Group of Great Britain and Northern Ireland.
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