Duchenne Muscular Dystrophy:
Prolongation of Life By Noninvasive Ventilation and Mechanically Assisted Coughing
      Elia Gomez-Merino, MD; John R. Bach, MD

Reference: Gomez-Merino E, Bach JR. Duchenne muscular dystrophy: prolongation of life by noninvasive respiratory muscle aids.
Am J Phys Med Rehabil 2002;81:411-415

Department of Physical Medicine and Rehabilitation, University Hospital, UMDNJ-The New Jersey Medical School.

This work was performed at University Hospital, Newark, N.J.

Abstract

Study objective

To quantitate prolongation of survival for Duchenne muscular dystrophy (DMD) patients with the use of noninvasive intermittent positive pressure ventilation (IPPV) with and without access to a home acute care protocol involving oximetry and the use of mechanically assisted coughing (MAC) to maintain normal oxyhemoglobin saturation (SaO2).

Design

A retrospective review of all DMD patients visiting a neuromuscular disease clinic.

Methods

Patients were trained to use mouth piece and nasal IPPV and MAC to maintain SaO2 greater than 94% (protocol). Survival was considered prolonged when noninvasive IPPV was required more than 16 hrs/day (full-time) indefinitely and with little breathing tolerance.

Results

Ninety-one of 125 patients used noninvasive IPPV 8 to 16 hrs/day (part-time) for 1.9 ±1.3 years, beginning at 19.1 ±3.3 years of age. They had a mean VC of 411 ±252 ml when beginning ongoing daily noninvasive IPPV. Survival was prolonged for 51 of these 91 patients as they used full-time IPPV for 6.3 ±4.6 (range = 6 months to 18) years. At least 17 of the 51 patients are still alive. Of the 31 noninvasive IPPV users who died without access to the protocol (oximetry and MAC), 20 died from respiratory causes. This included 6 noninvasive IPPV users who underwent tracheotomy and used ventilatory support for 9.2 ±7.1 years including 8.3 ±6.8 years of noninvasive IPPV. Seven of the 31 died from cardiac causes. Of the 91 patients, none of the 34 with access to home oximetry, MAC, and noninvasive IPPV underwent tracheotomy or died from respiratory complications over a 5.4 ±4.0 year period of full-time noninvasive IPPV whereas 3 of these patients died from heart failure. Five patients with no breathing tolerance were extubated/decanulated to continuous noninvasive IPPV and used MAC as needed to maintain normal SaO2 in ambient air post-extubation/decanulation.

Conclusions

Noninvasive respiratory aids can permit extubation/decanulation of patients with no breathing tolerance and can prolong survival for patients with DMD.

Introduction

Intermittent positive pressure ventilation (IPPV) can be delivered via a simple mouth piece for daytime ventilatory support, or a mouth piece with lipseal retention or a nasal interface for nocturnal support. The In-exsufflator™ (J. H. Emerson Company, Cambridge, MA) is a device that provides a maximal lung insufflation via an oronasal mask or invasive airway tube when present, immediately followed by a forced exsufflation to simulate a cough. It is used in conjunction with exsufflation-timed abdominal thrusts to further augment cough flows as part of mechanically assisted coughing (MAC).

It has been estimated that 55%1,2 to 90%3-5 of patients with Duchenne muscular dystrophy (DMD) die from pulmonary complications associated with respiratory muscle weakness between 16.2 and 19 years of age and uncommonly after age 25.4,6 Patients who undergo tracheotomy have been described to survive an additional 1 to 7 years using ventilatory support.7-9 Most patients who do not die from respiratory complications die from cardiomyopathy. Since there is no relationship between the extent of cardiomyopathy and age,10 some patients without respiratory dysfunction die from congestive heart failure (CHF) in their teen years whereas others can survive many years with ventilatory support.

In a recent study, it was found that 90% of episodes of pneumonia and respiratory failure occurred during otherwise benign upper respiratory tract infections (URIs) and were largely due to inability to cough effectively.11 In 1993 we introduced a protocol to avoid episodes of pneumonia and respiratory failure. It consisted of using oximetry as feedback to maintain normal oxyhemoglobin saturation (SaO2) by appropriately using noninvasive IPPV and MAC. In many cases our patients became continuously dependent on ventilatory support for years without ever requiring hospitalization.12 Although the use of nocturnal-only inspiratory aid can relieve symptoms and ameliorate hypercapnia early on, it does not necessarily prolong survival. The purpose of this report is to evaluate the effect on survival of the use of full-time noninvasive IPPV with and without access to this protocol.

Methods

A retrospective analysis was undertaken of 125 DMD patients referred to a University Hospital neuromuscular disease clinic since 1983. The diagnosis was established by absence of dystrophin on muscle biopsy or by DNA analysis. In addition, no patients who could walk beyond their 12th birthday were included. No patients had received glucocorticoid therapy. We considered life to be prolonged from the point at which patients required ongoing full-time ventilator use (without tracheostomy tubes) over 16 hrs/day and had limited ventilator-free breathing tolerance with respiratory distress and blood gas derangements forcing return to ventilatory support.

The etiology for death in DMD was considered to be cardiac when it occurred suddenly without evidence or history of recent URI or airway secretion management difficulties and with a left ventricular ejection fraction documented to be below 20%. Patients were noted to die from respiratory etiology when they died during intercurrent URIs, underwent tracheotomy for respiratory failure and subsequently died without meeting the criteria for cardiac death, or had decreases in SaO2 associated with airway mucus accumulation. Symptomatic, hypercapnic patients not receiving ventilatory assistance or who discontinued it and became unresponsive were noted to have died from ventilatory failure.

Before 1993 patients were provided with noninvasive IPPV for ventilatory support and manually assisted coughing but neither MAC nor oximeters for home use. Since 1993 patients have been provided with oximeters, manual resuscitators for deep insufflation therapy to facilitate manually assisted coughing, In-Exsufflators™, and access to portable volume ventilators when high risk for URI-associated acute respiratory failure was identified on the basis of maximum assisted peak cough flows being below 270 L/min.12 Since the patients' vital capacities (VCs) were also below 1000 ml at this point, they were prescribed daily air stacking of manual resuscitator delivered volumes to maximum insufflation capacities.13 They were instructed to monitor their SaO2 continuously during URIs in a protocol involving the use of noninvasive IPPV and MAC as needed to maintain normal SaO2. This assured effective alveolar ventilation. It also assured effective airway secretion elimination because any desaturations caused by airway mucus accumulation were promptly reversed and SaO2 base line returned to over 94% following MAC.

Statistical analysis was performed using the SPSS 8.0 for Windows.14 A nonparametric method (Mann-Whitney U test) was used in the basic descriptive statistical analysis because the variables measured did not approximate a normal distribution. The Kaplan-Meier survival analysis allowed for variable follow-up times. A P value less than 0.05 was used to establish statistical significance.

Results

A total of 125 DMD patients visited a neuromuscular disease clinic. Thirty-four patients, mean 14.9 ±6.0 years of age, had not yet experienced cardiac or respiratory distress and did not use ventilatory assistance or expiratory aids. The remaining 91 patients constituted our study population. These patients had become wheelchair dependent at 9.7 ±2.2 years of age. They began to use nocturnal noninvasive IPPV at 19.1- 3.3 years of age with a mean VC of 411 ±252 ml, used part-time noninvasive IPPV for 1.9 ±1.3 years, and were followed for a mean of 8.5 ±5.3 (range 1 to 18) years. Their mean age was 26.5 ±7.0 years at last evaluation, tracheotomy, or death. The probable reasons for death are listed in Table 1. For 11 of the 14 who died from respiratory failure without tracheostomy tubes, the failure was triggered by a URI. None of the 7 deaths for which autopsies were done were due to pulmonary emboli or non-cardiopulmonary causes.

We lost contact with 14 ventilator users. We considered them in this study from their first to last visits but we did not include them in the survival analysis. Three patients were already dependent on tracheostomy IPPV with no breathing tolerance at their initial visits.

Twelve patients with mean VC 265 ±104 ml and little or no breathing tolerance were able to use glossopharyngeal breathing to volumes of 1273 ±499 ml. This permitted them a mean of 5.3 ±4.8 hours of ventilator-free breathing tolerance.

Forty of the 91 patients either died from heart failure before requiring full-time noninvasive IPPV, required the use of noninvasive aids only during intercurrent URIs, or used only part-time noninvasive IPPV at the time of the study. Survival of the other 51 full-time users was prolonged for 6.3 ±4.6 (range = 6 months to 18) years with at least 17 patients still alive at last contact.

Eight of the 10 patients who died from CHF had had previous cardiac admissions and complaints of chest, abdomen, or back discomfort and abdominal distention before dying. They had long-standing clinical, radiographic, and laboratory evidence of CHF as well as left ventricular ejection fractions below 20%. Seven of the patients complained of dyspnea unrelieved by ventilator use.

Five patients with no breathing tolerance were referred to us intubated or using tracheostomy IPPV. We extubated/decanulated them to full-time noninvasive IPPV. Within days following extubation/decanulation all five patients developed breathing tolerance and weaned to nocturnal-only noninvasive IPPV for 1 to 3 years before requiring it full-time. They have now been using full-time noninvasive IPPV for 2, 6, 7, 8, and 9 years, respectively.

Fourteen of the 57 patients without access to oximetry and MAC eventually underwent tracheotomy and survived for an additional 4.1 ±4.5 years to 28.8 ±5.1 years of age. None of 34 patients with access to the oximetry protocol have been lost to follow-up, underwent tracheotomy, or died from respiratory complications over 1.6 ±1.6 years of using noninvasive IPPV part-time and subsequently 5.4 ±4.0 years of using noninvasive IPPV full-time. They have avoided episodes of respiratory failure and hospitalizations by using the protocol.12 The 3 who died all had left ventricular ejection fractions below 15%. Figure 1 illustrates the causes of death. The 14 patients lost to follow-up and 17 patients still alive were 25.7 ±4.5 years of age.

A P level of 0.6 was obtained by Mann-Whitney test comparing age of death of patients who died for cardiac reasons with or without protocol access. It was not possible to apply this test to patients who died from respiratory causes because no one using the protocol has died from respiratory causes. A Kaplan-Meier plot shows the survival distributions for protocol users (Figure 2). We applied the log rank statistical test for equality of survival distributions for protocol users and a statistic of 18.63 (P=0.0000) was obtained.

Discussion

This study demonstrates that DMD survival can be prolonged by using noninvasive IPPV and MAC as an alternative to tracheostomy for IPPV and airway suctioning. Since the availability of home oximetry and MAC with the use of SaO2 monitoring during URIs, we have had no respiratory mortality and only 3 cardiac deaths.

Even though life can also be prolonged by tracheotomy, noninvasive methods are associated with less pulmonary morbidity and fewer hospitalizations,11 and they are preferred over tracheostomy by patients and their care providers for safety, convenience, verbal communication, sleep, swallowing, appearance, comfort, and general acceptability.15 By avoiding hospitalizations, expense is also reduced.11,16 Thus, noninvasive approaches should be tried before resort to tracheostomy is considered.

A survey of neuromuscular disease clinics noted that the majority of clinics are offering nocturnal nasal ventilation to their patients.17 However, very few clinics are offering noninvasive IPPV for daytime support or MAC.17 Failure to do so inevitably results in patients developing pneumonia and acute respiratory failure during intercurrent URIs.11 Although prior to use of MAC guided by oximetry, life could be prolonged by full-time noninvasive IPPV, respiratory morbidity and mortality still occurred. Since the use of home oximetry and MAC it appears that respiratory mortality will be reduced, making cardiomyopathy a much more prevalent cause of death. It may, therefore, become particularly important to consider new medical approaches to improve the hemodynamic function of these patients.18

References

1. Brooke MH, Fenichel GM, Griggs RC, et al: Duchenne muscular dystrophy: patterns of clinical progression and effects of supportive therapy. Neurol 1989;39:475-80

2. Mukoyama M, Kondo K, Hizawa K, Nishitani H, and the DMDR Group: Life spans of Duchenne muscular dystrophy patients in the hospital care program in Japan. J Neurol Sci 1987;81:155-8

3. Inkley SR, Oldenburg FC, Vignos PJ Jr: Pulmonary function in Duchenne muscular dystrophy related to stage of disease. Am J Med 1974;56:297-306

4. Rideau Y, Gatin G, Bach J, Gines G: Prolongation of life in Duchenne muscular dystrophy. Acta Neurol 1983;5:118-24

5. Vignos PJ: Respiratory function and pulmonary infection in Duchenne muscular dystrophy. Isr J Med Sci 1977;13:207-14

6. Emery AEH: Duchenne muscular dystrophy: genetic aspects, carrier detection and antenatal diagnosis. Br Med Bull 1980;36:117-22

7. Baydur A, Gilgoff I, Prentice W, Carlson M, Fischer DA: Decline in respiratory function and experience with long-term assisted ventilation in advanced Duchenne's muscular dystrophy. Chest 1990;97;884-9

8. Fukunaga H, Okubo R, Moritoyo T, Kawashima N, Osame M: Long-term follow-up of patients with Duchenne muscular dystrophy receiving ventilatory support. Muscle Nerve 1993;16;554-8

9. Bach JR, O'Brien J, Krotenberg R, Alba A: Management of end stage respiratory failure in Duchenne muscular dystrophy. Muscle Nerve 1987;10:177-82

10. Stewart CA, Gilgoff I, Baydur A, Prentice W, Applebaum D: Gated radionuclide ventriculography in the evaluation of cardiac function in Duchenne's muscular dystrophy. Chest 1988;94:1245-8

11. Bach JR, Rajaraman R, Ballanger F, Tzeng AC, Ishikawa Y, Kulessa R, Bansal T: Neuromuscular ventilatory insufficiency: the effect of home mechanical ventilator use vs. oxygen therapy on pneumonia and hospitalization rates. Am J Phys Med Rehabil 1998;77:8-19

12. Bach JR, Ishikawa Y, Kim H: Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 1997;112:1024-8

13. Kang SW, Bach JR: Maximum insufflation capacity: the relationships with vital capacity and cough flows for patients with neuromuscular disease. Am J Phys Med Rehabil 2000;79:222-7

14. SPSS para Windows. Programacion y analisis estadistico

15. Bach JR: A comparison of long-term ventilatory support alternatives from the perspective of the patient and care giver. Chest 1993;104:1702-6

16. Bach JR, Intintola P, Alba AS, Holland I: The ventilator-assisted individual: cost analysis of institutionalization versus rehabilitation and in-home management. Chest 1992;101:26-30

17. Bach JR, Chaudhry SS: Management approaches in muscular dystrophy association clinics. Am J Phys Med Rehabil 2000;79:193-6

18. Ishikawa Y, Bach JR, Minami R: Cardioprotection for Duchenne's muscular dystrophy. Am Heart J 1999;137:895-902

Table 1 -- Duchenne Muscular Dystrophy Ventilator User Mortality


Noninvasive IPPV Use in Years
Reason*#<16hr/d>16hr/dtrach IPPVAge at Death
No Protocol Access
CHF20.9 ±0.12 20.5 ±3.5
CHF52.2 ±1.86.2 ±1.8 27.5 ±5.7
ARF10.5 14
ARF102.8 ±2.76.1 ±5.2 28.4 ±8.2
AVF**31.7 ±3.120.7 ±1.0 41.3 ±8.0
Other***12.513 34
Unknown32.5 ±2.37.7 ±6.4 29.0 ±8.2
post-trach61.9 ±1.46.4 ±6.80.9 ±1.829.1 ±7.1
With Protocol Access
CHF3without ventilator use16.0 ±1.0
ARF0with up to continuous noninvasive IPPV

* Reasons include congestive heart failure (CHF), acute respiratory failure (ARF), and acute ventilatory failure (AVF).
** The patients died while sleeping without putting on lipseal at age 29 after 15 years of ventilatory support, following trauma and loss of ventilator interface after 25 years of noninvasive ventilation support, and when using a rocking bed ventilator instead of noninvasive IPPV. His vital capacity was 30 ml and the rocking bed was ineffective for him.
*** Other deaths were due to: suicide at 34 years of age after 13 years of noninvasive ventilation.

Legends

Figure 1--Causes of Death in Relation to Access to Protocol

Figure 2--Survival Plot for Protocol and Non-Protocol Patients



Author: John R. Bach, MD

Web page: Rich Clingman

Updated: 04/10/03

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