Spinal Muscular Atrophy Type 1: Management and Outcomes
      by John R. Bach, MD

Reference: Bach JR, Baird JS, Plosky D, Nevado J, Weaver B. Spinal muscular atrophy type 1: management and outcomes.
Pediatr Pulmonol 2002 Jul;34(1):16-22

Departments of Physical Medicine and Rehabilitation and Pediatrics, UMDNJ-New Jersey Medical School, Newark, N.J.

Abbreviations

MI-E	mechanical insufflation-exsufflation
PIP+PEEP	positive inspiratory pressure plus positive end-expiratory pressure
SaO2	oxyhemoglobin saturation
SMA1	spinal muscular atrophy type 1
URI	upper respiratory tract infection

Summary

Objectives

To describe survival, hospitalization, speech, and respirator need outcomes for spinal muscular atrophy type 1 (SMA1) patients using noninvasive or tracheostomy ventilation.

Patient Selection

65 SMA patients referred to a clinic since 1996.

Methodology

The 56 SMA1 patients who developed respiratory failure before age 2 were studied. Either patients had tracheostomy tubes (Group A), or noninvasive ventilation, assisted coughing, and a previously reported extubation protocol (Group B) were used as needed.

Results

Sixteen patients underwent tracheotomy at 10.8 ±5.0 months of age, 33 were in Group B, and 7 others died when not receiving vital interventions. By comparison to Group B, the Group A patients had fewer hospitalizations until age 3 but more after age 5 and 15 of 16 lost all breathing tolerance post-tracheotomy and could not speak. One Group A patient died at 16 months of age and the others were 73.8 ±57 months of age (oldest 19 years old). Two of the Group B patients died at 6 and 13 months, respectively, whereas the other 31 were 41.8 ±26.0 months (up to 8.3 years) old. Three of 31 require high span positive inspiratory pressure plus positive end-expiratory pressure (PIP+PEEP) continuously with minimal breathing tolerance and 4 can not communicate verbally.

Conclusion

SMA type 1 children can survive beyond 2 years of age when offered tracheostomy or noninvasive respiratory aids. The latter is associated with fewer hospitalizations after age 5, freedom from daytime ventilator use, and facilitates speech.

Key Words

Spinal muscular atrophy; Mechanical ventilation; Respiratory insufficiency; Outcomes.

Introduction

The spinal muscular atrophies (SMAs) are inherited as autosomal recessive disorders of anterior horn cells with the genetic defect at chromosome 5q13. Gene deletions are detectable in 98% of patients. The incidence is about 1/5,000.¹ Severity is inversely proportional to the amount of Survival Motor Neuron (SMN) protein present in the anterior horn cells. They range from essentially total paralysis and need for ventilatory support from birth,² to relatively mild muscle weakness presenting in the young adult.

The SMAs have been arbitrarily separated into four types based on clinical severity and classified in 0.1 intervals from 1 to 4.9. Spinal muscular atrophy type 1 (SMA1) (Werdnig-Hoffmann disease) is defined by never attaining the ability to sit independently.³ The diagnosis of SMA1 has been reported to be uniformly fatal by 2 years of age with 50% mortality by 7 months and 90% mortality by 12 months of age.² Upper respiratory tract infections (URIs) or, occasionally, aspiration due to dysphagia or gastroesophageal reflux develop into pneumonia and respiratory failure largely because of an ineffective cough. Most physicians discourage endotracheal intubation and tracheotomy feeling that the prognosis for survival would not be significantly improved and quality of life is too poor to justify invasive interventions. Patients with SMA type 2 at least temporarily attain the ability to sit unsupported but usually also develop respiratory failure during childhood. Patients with SMA type 3 at least temporarily attain the ability to walk. Type 4 is adult onset.

When SMA patients are intubated, they are conventionally given oxygen supplementation that is continued following extubation. Extubation is done either without subsequent noninvasive ventilatory support (conventional extubation) or to the use of PIP+PEEP (conventional extubation plus PIP+PEEP). PIP+PEEP is usually delivered from BiPAP-STTM (Respironics Inc., Murrysville, PA) devices at inspiratory to expiratory pressure spans of less than 10 cm H₂O (low span).

In a previous publication we reported that, although intercurrent chest colds can necessitate intensive care and intubation, tracheotomy can be avoided for many SMA children by using a protocol in which, in addition to conventional medical, respiratory therapy, and nutritional support, mechanical insufflation-exsufflation (MI-E) (In-exsufflator™, J. H. Emerson Company, Cambridge, MA) is used via the translaryngeal tube and it along with high span nasal PIP+PEEP are used post-extubation.³ Care providers are trained and equipped with oximetry as feedback to use high span PIP+PEEP, MI-E, and manually assisted coughing to reverse decreases in SaO₂ below 95%. The purpose of this work is to report the long-term outcomes of tracheostomy, and extubation protocol/noninvasive approaches. There have been no previous long term studies of SMA1 patients and only one report of a SMA1 patient who survived to 3.7 years of age with a tracheostomy.⁴

Materials and Methods

The status of all 65 SMA1 patients who visited one Jerry Lewis Muscular Dystrophy Association Clinic from June 1996 until October 2001 was reviewed. This included contact by telephone in October 2001. SMA1 was diagnosed on the basis of DNA evidence of chromosome 5 exon 7 and 8 deletion in 56 of 65 children, affected siblings in 4 patients, and characteristic laboratory, muscle biopsy, and electromyography results in 5 children. Inclusion criteria included inability to roll or sit unsupported at any time. In addition, all patients had to develop respiratory failure and the respiratory failure had to occur before 2 years of age. All patients attaining 2 years of age had to have lost the ability to receive nutrition by mouth. By 18 months of age all of the patients had little more than residual finger, toe, and facial movements. Sixty-three of the 65 children had paradoxical chest wall movement, whereas for 2 children, the chest walls neither expanded nor retracted upon inspiration. One of these two, a 12 month old, has not been prescribed PIP+PEEP and has not been hospitalized for respiratory failure. In addition, 6 others have not yet developed respiratory failure; one other child had an equivocal diagnostic work-up; and one was lost to follow up after an initial visit at 8 months of age. These 9 SMA children were eliminated from further study. Of the remaining 56, 50 had initial episodes of respiratory failure before 1 year of age, 55 before 18 months of age, and all before the second birthday. Of the entire population of 56 patients, 43 had been intubated at least once for respiratory failure. These patients were intubated a total of 132 times.

The 56 patients in the study are considered in 3 groupings: 16 who underwent tracheotomy (Group A), 33 who did not but who used nocturnal high span PIP+PEEP and were intubated as needed during intercurrent respiratory infections (Group B), and 7 who died from respiratory failure when intubation and tracheotomy were rejected as options to treat respiratory failure (Group C).

All Group B patients were prescribed oximeters, MI-E, and high span PIP+PEEP at initial evaluation. PIP+PEEP was used for sleep and during URIs at spans of 13 to 17 cm H₂O with inspiratory positive airway pressures up to 20 cm H₂O. Since infants can not trigger BiPAP-STTM machines, are uncooperative, and will not initially breathe in synchrony with them, the nasal interface is placed and the PIP+PEEP is initiated during sleep. Ideally, back-up rates slightly higher than the child's spontaneous rate are used. As the deep insufflations increase tidal volumes, the child's spontaneous rate decreases and the PIP+PEEP rate is decreased accordingly. The goal is to see resolution of paradoxical chest wall movement and good chest expansion during the inspiratory positive airway pressure. After 3 to 7 days the children usually tolerated PIP+PEEP throughout sleep and even during waking hours. Most children 6 months and older used the Respironics Pediatric Petite Nasal Interface. Younger children had nasal interfaces adapted from infant "CPAP" circuits and small adult nasal prongs as previously described.³

Oximetry was used for spot checks and continuously during URIs or other periods of airway encomberment. At times it was also used as feedback to guide the daytime need for high span PIP+PEEP. MI-E was used via airway tubes when present. The positive pressure was also used daily via oro-nasal interfaces for children over 8 months of age to facilitate future cooperation with it. It was used aggressively during URIs for airway mucus expulsion at 35 to 40 cm H₂O to -35 to -40 cm H₂O pressures. The patients' parents were told to seek medical attention when the SaO₂ baseline could not be kept above 94% despite MI-E and PIP+PEEP.

Following episodes of respiratory failure, extubation was considered successful when re-intubation was not required during the current hospitalization.³ Extubations were considered conventional when PIP+PEEP was not used immediately post-extubation, conventional plus PIP+PEEP when supplemental oxygen was used along with low span PIP+PEEP post-extubation, or protocol extubations when patients were only extubated once oxyhemoglobin saturation (SaO₂) was normal in ambient air, MI-E was used at 35 to 40 cm H₂O to -35 to -40 cm H₂O pressures via the tube before and via oro-nasal interface after extubation, ventilator weaning was avoided at the expense of hypercapnia, and extubation was done irrespective of extent of ventilator dependence to high span PIP+PEEP with no ongoing post-extubation supplemental oxygen. Patients who underwent tracheotomy while intubated were not considered extubation failures. No non-protocol extubation attempts took place at our institution. Parents were questioned concerning whether their children had been extubated to PIP+PEEP at other institutions.

Avoided hospitalizations were defined as episodes of fever, respiratory tract infection, and ventilatory failure managed at home during which high span PIP+PEEP was used continuously with little or no autonomous breathing tolerance and MI-E use returned SaO₂ to over 94%. Possible avoided hospitalizations were defined by similar episodes during which MI-E re-normalized SaO₂ but continuous ventilatory support was not required. Statistical comparisons were made by two tailed, homoscedastic Student's T-test.

Results

A comparison of the 3 patient groupings is provided in Tables 1 and 2. Pneumonia and respiratory failure were noted to have resulted from otherwise benign URIs in 74 of 120 (60%) of the hospitalizations. The remainder were thought to have been caused by reflux or aspiration from dysphagia. In 2 cases, patients were admitted for gastrostomy tubes, were intubated, and developed respiratory complications. Hospitalizations per patient-year are noted in Table 3. From birth to the third birthday the Group B patients had a significantly higher hospitalization rate (p=0.039) than the Group A patients. From the third birthday on there was no significant difference in hospitalization rates (p=0.598) between the two groups. None of 8 Group B patients have been hospitalized after their fifth birthdays in 15 patient-years. The patients also had 72 hospitalizations avoided and many probable avoided hospitalizations. Many patients' parents reported that MI-E had to be used daily to reverse oxyhemoglobin desaturations associated with airway mucus encomberment due to difficulty controlling oral secretions. Thus, for many patients MI-E was needed more than for intercurrent URIs and so probable avoided hospitalizations could not be quantitated.

Considering the 16 Group A patients, 15 underwent tracheotomy at the mean age of 9.5 ±4.4 months. One patient used nocturnal noninvasive ventilation for 21 months following 2 hospitalizations for respiratory failure before undergoing tracheotomy at 30 months of age. Of the 5 children referred before tracheotomy, one underwent tracheotomy after 2 hospitalizations for 60 days, 6 intubations, and 4 conventional and one protocol extubation failures. Another patient underwent tracheotomy after 8 hospitalizations for 176 days, 10 intubations and 7 conventional extubation failures. A third patient underwent tracheotomy after 5 intubations including 3 conventional extubation failures during 6 hospitalizations for 55 days. This patient underwent tracheotomy for a persistent left lower lobe collapse. She was the only patient to die with a tube, dying suddenly at home 3 months following tracheotomy at 16 months of age. The fourth patient underwent elective tracheotomy without informing us. The fifth had severe bradycardias necessitating frequent cardiopulmonary resuscitation that were not diminished following tracheotomy. Nine of the other 11 patients who were referred to us with tracheostomy tubes underwent tracheotomy following failed conventional extubation attempts.

Seven, three, and six children underwent tracheotomy during their first, second, and subsequent hospitalizations at 2 to 30 months of age. One of the 16 tracheostomized patients has comprehendable speech. Fifteen of 16 lost all autonomous breathing tolerance immediately following tracheotomy whereas one patient weaned to nocturnal-only ventilatory assistance.

Of the 33 Group B patients, 2 died at home within 2 weeks of successful extubations. One 13 month old who had had 6 hospitalizations since 4 months of age became suddenly dyspneic one morning after nocturnal PIP+PEEP had been discontinued and died while her primary care provider was absent. Another 6 month old had a similar episode but also had a severe cleft palate and a single oro-nasal orifice that made PIP+PEEP delivery problematic. After an initial hospitalization for respiratory failure at 3 months of age she arrested at home in the morning after being discontinued from nocturnal PIP+PEEP at 6 months of age. She was hospitalized and intubated but the tube was withdrawn once brain death was diagnosed. Of the other 31 patients, 27 used high span PIP+PEEP only during sleep, three required it continuously with minimal breathing tolerance, and one required it over 16 hours per day and is hypercapnic when not using it. These latter 4 patients are averbal and several sleep-only PIP+PEEP users have severe dysarthria. Of the 26 successful protocol extubations in this group, in 12 cases the patient had no breathing tolerance post-extubation and weaned back to nocturnal-only PIP+PEEP up to 3 weeks post-extubation. Although 5 of 33 patients have not undergone gastrostomy, 2 of the 5 are under 1 year of age and 3 have received all nutrition via nasogastric tubes for 6, 5, and 4 years, respectively. One of the 31 patients has not been hospitalized for respiratory failure but has been 24 hour high span PIP+PEEP dependent since 5 months of age.

All seven Group C patients died when cared for conventionally. It was decided not to re-intubate one child who died at 12 months of age when 3 conventional extubations failed. Two children died at 5 and 13 months of age, respectively, receiving supplemental oxygen during URIs and intentionally not hospitalized. Two other Australian children died at 9 months of age in hospitals that did not offer intubation. Thus, these 7 patients died when not provided with vital support.

Of the 132 times that the patients were intubated, 26 of the 31 protocol extubations were successful, 14 of the 22 conventional extubations to PIP+PEEP were successful, and 3 of 47 conventional extubations without post-extubation PIP+PEEP were successful. Of the other 32 extubations, 16 were done following tracheotomy and 16 were brief intubations for placement of gastrostomy tubes.

Thirty-one of the patients including 24 in Group B were evaluated for gastroesophageal reflux, 22 diagnosed with reflux warranting intervention, and 18 including 13 of the 32 children using nocturnal PIP+PEEP underwent fundoplication. One child without apparent reflux began to regurgitate and vomit and underwent fundoplication 2 months after the initial evaluation.

Discussion

While in many neuromuscular disease centers, clinicians are increasingly using nocturnal low span PIP+PEEP and reporting statistically significant prolongations of survival by months,⁵ confining oneself to nocturnal-only aid will not prevent most episodes of respiratory failure. Indeed, the majority of such episodes occur during intercurrent URIs from an ineffective cough.⁶ Typically, since it is assumed that the prognosis is poor and, as we demonstrated here, conventional extubations fail over 90% of the time, families are convinced to refuse re-intubation and "let their children go".

We previously demonstrated that protocol extubations are significantly more likely to be successful than conventional extubations (p=0.006).³ Here we distinguished between conventional extubations with and without post-extubation PIP+PEEP. We found that although the 67% success rate of conventional extubations to PIP+PEEP was not as high as the 83% success rate of protocol extubations, it was much higher than the 6% success rate of conventional extubations (without PIP+PEEP). It is important to note, however, that all except one of the conventional extubations to PIP+PEEP were performed on patients who used PIP+PEEP nocturnally prior to acute illness. These children, therefore, were accustomed to it and more likely to cooperate with it post-extubation. Thus, extubation to full noninvasive ventilatory support via high span PIP+PEEP appears to be critical for successfully extubating these children. This is not surprising considering that at least 12 successful extubations were performed on patients with no ventilator-free breathing tolerance. Thus, ongoing nocturnal high span PIP+PEEP both facilitates its use post-extubation for ventilatory support and prevents or reverses pectus excavatum as previously reported.³

The children with tracheostomies were referred to us significantly later (41.8 ±54 months) and are significantly older than the other patients. Thus, these children might be thought to be atypical and to have milder disease, heightening the importance of avoiding tracheotomy to preserve autonomous breathing and speech. However, the patients with tracheostomies also lost the ability to take nutrition by mouth earlier. Indeed, 15 of 16 of these patients underwent tracheotomy (9.5 ±4.4 months) before the noninvasively managed patients first required intubation, before the deaths of the Group C infants, and their initial hospitalizations for respiratory failure occurred 2 months before those of the Group B and C children. All of these facts suggest that, if anything, the patients with tracheostomies were at least slightly more severely affected.

It should not be surprising that patients undergoing tracheotomy lose breathing tolerance whereas decanulated or extubated patients with no breathing tolerance often wean from continuous support to nocturnal-only noninvasive ventilation. This has been reported for patients with various diagnoses^7,8 and has been known since 1956.⁹ "If a patient is going to be left a respirator cripple with a very low VC, a tracheotomy may be a great disadvantage. It is very difficult to get rid of a tracheotomy tube when the VC is only 500 or 600 cc and there is no power of coughing, whereas, as we all know, a patient who has been treated in a respirator [iron lung] from the first can survive and get out of all mechanical devices with a VC of that figure."⁹ Loss of breathing tolerance post-tracheotomy can be explained by any combination of the following: tracheostomy ventilation is associated with lower pCO₂s (chronic hyperventilation);¹⁰ inspiratory muscle deconditioning;11 and ventilation-perfusion mismatching from airway encomberment due to secretions caused by the tube their clearance impaired by it.⁵

Besides avoiding continuous ventilatory dependence post-tracheotomy, this work suggests other advantages and disadvantages of noninvasive and invasive systems for a large group of SMA1 patients. One of the 2 deceased Group B patients died following an episode of respiratory failure when his primary care providers were not present. His death would have been less likely had he had a tracheostomy because it is easier to clear airway secretions and resuscitate infants with tubes, particularly for secondary care providers. On the other hand, immediately post-tracheotomy, 15 of 16 patients permanently lost all ability to breathe autonomously. Subsequently only 1 of 16 developed any ability to verbalize and tolerate cuff deflation whereas all patients extubated successfully to high span PIP+PEEP eventually weaned back to their pre-acute illness PIP+PEEP regimens and, thus far, all but 4 speak. Further, ventilatory support via tracheostomy has also been associated with abnormal electrocardiograms,⁴ autonomic dysfunction and cardiac arrhythmias,^12-14 trachiectasis, and sudden death from hemorrhage,¹⁵ mucus plugging,^16,17 accidental disconnections, and infection.

Besides possibly being more severely affected, the tracheostomy patients may also have been too permanently weakened by inadequate nourishment during the mean 74 day hospital stay during which tracheotomy was performed to recover autonomous breathing ability. SMA1 children have been described to have errors in fatty acid metabolism similar to those found in mitochondrial myopathies. Four hours or more of fasting results in ketoacidosis and respiratory muscle catabolism.¹⁸

The risk of gastroesophageal reflux is high in patients with neuromuscular disease, especially in those receiving noninvasive positive pressure ventilation and having gastrostomy tubes. Nissen fundoplication is being increasingly performed. However, no differences in hospitalization rates or mortality were apparent in patients as a function of having undergone this intervention. There was no increase in vomiting, regurgitation, or abdominal distension as a result of using high span PIP+PEEP.

In summary, while long-term survival is clearly possible with tracheostomy, many SMA1 patients without tubes can survive acute, life-threatening episodes until they are old enough to better cooperate with MI-E at which point their hospitalization rates decrease significantly and possibly to below those of patients with tracheostomies. Our oldest SMA type 1 patient with a tracheostomy, 19 years old, has been averbal and continuously ventilator dependent since 2 months of age but he graduated third in his high school class and is attending college. While the oldest noninvasively managed SMA1 child is only 8.3 years of age, we currently have 7 children over age 6. Since all are stable and none have been hospitalized since 4 years of age, we feel that survival into adulthood is likely.

References

1. Iannaccone ST. Spinal muscular atrophy. Semin Neurol 1998;18:19-26.

2. Dubowitz V. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. Europ J Paediatr Neurol 1999;3:49-51.

3. Bach JR, Niranjan V. Spinal muscular atrophy type 1: a noninvasive respiratory management approach. Chest 2000;117:1100-1105.

4. Iannaccone ST, Guilfoile T. Long-term mechanical ventilation in infants with neuromuscular disease. J Child Neurol 1988;3:30-32.

5. Bach JR. Conventional approaches to managing neuromuscular ventilatory failure. In: Bach JR, editor. Pulmonary Rehabilitation: The Obstructive and Paralytic Conditions. Philadelphia: Hanley & Belfus; 1996. p 285-301.

6. 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.

7. Gomez-Merino E, Bach JR, Blasco ML. Duchenne muscular dystrophy: prolongation of life by noninvasive respiratory muscle aids. Am J Phys Med Rehabil (in press).

8. Bach JR, Saporito LR. Criteria for extubation and tracheostomy tube removal for patients with ventilatory failure: a different approach to weaning. Chest 1996;110:1566-1571.

9. Hodes HL. Treatment of respiratory difficulty in poliomyelitis. In: Poliomyelitis: papers and discussions presented at the third international poliomyelitis conference. Philadelphia: Lippincott; 1955. p 91-113.

10. Bach JR, Haber II, Wang TG, Alba AS. Alveolar ventilation as a function of ventilatory support method. Eur J Phys Med Rehabil 1995;5:80-84.

11. Le Bourdelles G, Viires N, Boczkowski J, Seta N, Pavlovic D, Aubier M. Effects of mechanical ventilation on diaphragmatic contractile properties in rats. Am J Respir Crit Care Med 1994;149:1539-44.

12. Berk JL, Levy MN. Profound reflex bradycardia produced by transient hypoxia or hypercapnia in man. Eur Surg Res 1977;9:75-84.

13. Mathias CJ. Bradycardia and cardiac arrest during tracheal suction - mechanisms in tetraplegic patients. Europ J Intens Care Med 1976;2:147-56.

14. Welply NC, Mathias CJ, Frankel HL. Circulatory reflexes in tetraplegics during artificial ventilation and general anesthesia. Paraplegia 1975;13:172-82.

15. Moar JJ, Lello GE, Miller SD. Stomal sepsis and fatal haemorrhage following tracheostomy. Int J Oral Maxillofac Surg 1986;15:339-41.

16. Dee PM, Suratt PM, Bray ST, Rose CE. Mucous plugging simulating pulmonary embolism in patients with quadriplegia. Chest 1984;85:363-66.

17. de Groot REB, Dik H, Groot HGW, Bakker W. A nearly fatal tracheal obstruction resulting from a transtracheal oxygen catheter. Chest 1993;104:1634-35.

18. Crawford TO, Sladky JT, Hurko O, Besner-Johnston A, Kelley RI. Abnormal fatty acid metabolism in childhood spinal muscular atrophy. Ann Neurol 1999;45:337-343.

Table 1 -- SMA Type 1 Group Comparisons

Table 2 -- SMA Type 1 Group Comparison Statistics

Key for Tables 1 and 2 TT--tracheostomy All means are ±standard deviations

a--for hospitalizations not including when undergoing tracheotomy
b--for hospitalizations including tracheotomy
c--total hospitalizations without tracheostomy
d--total hospitalizations following the hospitalization when undergoing tracheostomy

* P derived from two tailed, homoscedastic Student's T-test

Table 3 -- Hospitalizations As A Function Of Year Of Age

a--one patient died after 3 months with a tracheostomy at age 16 months
b--one patient died at 6 months of age
c--one patient died at 13 months of age

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