Section 7: Spinal muscular atrophy and home ventilation

This article is related to:

Pediatric home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline executive summary

Introduction

Spinal muscular trophy (SMA) is a recessively inherited neurodegenerative disorder of the anterior horn cells of the spine¹; the incidence of SMA is 1/5000 live births.² The International Spinal Muscular Atrophy Consortium (ISMAC) in 1992 established the presence of 3 types of SMA characterized by varying clinical severity.⁴ Type I (Werdnig-Hoffman disease) is diagnosed between birth and 6 months of age and the majority of patients have a life expectancy <2 years.⁵ The onset of SMA Type 2 is before 18 months of age; death generally occurs prematurely, typically, after the age of 2.⁴ Type 3 is the mildest form of the disease with onset after 18 months of age; death occurs in adulthood.⁴

Ventilatory failure is an inevitable manifestation of the progressive muscle weakness in this disease and the pediatric literature consequently is focused on the management of children with Type 1 and Type 2 SMA. Ventilatory interventions include noninvasive positive pressure ventilation (NIV), invasive ventilation via a tracheostomy and negative pressure ventilation. These can be used from birth onwards, during an acute presentation of illness and/or chronically for respiratory support due to progressive muscle weakness.

Survival of SMA Type 1 has increased in the last few decades based on the ISMAC data. Median survival has increased to 24.0 months for those born in 1995–2006 versus 7.5 months for those born in 1980–1994, due to a combination of ventilation, airway clearance techniques and supplementary feeding.⁶ However, there continues to be significant debate regarding the ethics of prolonging survival in these patients. The debate is going to become increasingly complex as newer therapies aimed at correcting the underlying defect, currently in Phase III and Phase IV clinical trials, change the natural history of the disease. There is a lack of consensus worldwide as to the type and timing of ventilation that should be offered for the 3 different disease phenotypes.

Literature review: Methodology

Searches were conducted looking for publications on spinal muscular atrophy and modes of ventilation (including invasive and noninvasive ventilation). We aimed at identifying all studies published in English and French. We searched Cochrane and MEDLINE databases (1966–August 24, 2015), as well as hand searching reference lists from identified publications to add any missed studies. We also searched the web sites of large associations of physicians and health professionals in the fields of respiratory medicine, intensive care, nursing and respiratory therapy for reviews, consensus statements and clinical practice guidelines. We obtained the full publication of all relevant studies identified.

Results

We retrieved 297 publications that were relevant to our inclusion criteria and dealing with home mechanical ventilation in children, in the English language. Editorials and opinions, general reviews, publications with clinical practice guidelines and publications on the type of equipment used were eliminated, as were publications dealing solely with adult populations. We were then left with 29 publications dealing specifically with SMA and ventilation.

Discussion

There are no randomized controlled trials of ventilatory management for children with SMA in the pediatric literature. The following is based on prospective or retrospective case control and cohort studies with the majority of the evidence focusing on various aspects of NIV.

NIV

There is insufficient evidence to make any recommendations with respect to the type of interface or the ideal pressures that should be used for NIV at the present time.

Benefits of NIV

The goals of NIV include improved quality of life (QoL) for patients and families, adequate inspiratory chest wall expansion, normalization of nocturnal and diurnal gas exchange, prevention of respiratory infection, reductions in hospitalization and improvement of overall survival.^6–17 There have been 5 studies assessing the efficacy of NIV for the treatment of sleep-disordered breathing in children with SMA.^7–11 The benefit of NIV has been demonstrated for both subjective and objective outcomes (Table 1). Improvements in the respiratory disturbance index and sleep architecture has been reported in patients. Symptomatic benefits in sleep quality, headaches, daytime sleepiness, appetite, concentration and sweating have also been noted.⁷ NIV has also been shown to reduce hospital as well as intensive care unit (ICU) stays.⁹ There were 85% fewer days in hospital and 68% fewer ICU days in the year following NIV initiation, as compared to the preceding year, in a mixed population of 15 children with neuromuscular conditions, some of whom had SMA. Although children with SMA Type 1 on NIV required multiple admissions during infancy, they had fewer admissions with increased age.^10,12,13 A review of SMA registry data indicates that ventilation (invasive or noninvasive) for more than 16 hours per day, in addition to use of the mechanical insufflation-exsufflation (MI-E) device, and gastrostomy tube feeds, are the 3 factors that significantly improve survival after controlling for demographic and clinical care variables.⁶ The majority of NIV, based on registry data, was from mask NIV.⁶ In the group of patients with later presentation, improved survival on NIV is seen. Thus, in some cases, NIV can ameliorate symptoms as well as extend life.^5,10,12,13 Earlier data suggested that NIV appeared to improve survival only in children with SMA Type 1 presenting after the age of 3 months.^5,10,14 However, a more recent study by Gregoretti et al. showed that NIV and MI-E still improved long-term survival outcomes despite including a subset of children with SMA Type 1 who had onset of clinical symptoms prior to 3 months of age.¹⁷

The use of NIV in SMA is generally considered safe, and, when used with adequate pressures and correct mask placement, appears to have no deleterious effects on hemodynamics.¹⁵ However, potential limitations to NIV include difficulty identifying a well-fitting interface, particularly for infants, and the possible complications of applying the interface for prolonged periods of time (skin irritation and/or breakdown as well as midface hypoplasia). In addition, gastric distension and emesis are recognized risks, which can subsequently lead to aspiration pneumonia and even death.¹⁸

NIV during acute illness

During acute respiratory illness, patients experience an added ventilatory load, increased muscle weakness and ineffective secretion clearance leading to ventilatory decompensation,¹ as well as difficulties in oxygenation secondary to secretions and mucus plugging. Therefore, the use of NIV plus supplemental oxygen to bridge periods of respiratory illness may be helpful (Table 2). If nocturnal NIV is already in place, then a transition to continuous use may be needed; short-term daytime NIV may further help augment the effectiveness of chest physiotherapy. Given the progressive nature of the disease, it is not uncommon that acute illness may lead to intubation, tracheostomy or death, especially for children with SMA Type 1. However, in a retrospective study, Bach et al. reported a noninvasive respiratory management approach for respiratory failure in children with SMA Type 1.¹³ Using a protocol that consists of achieving room air oxygen saturations greater than 94% prior to extubation attempts, using the MI-E during and post-extubation and using NIV and airway clearance rather than supplemental oxygen alone when oxygen saturations dropped to less than 94% post-extubation, only 1 of 11 patients required a tracheostomy following unsuccessful extubation attempts; another patient underwent tracheostomy 3 months later.¹³ This protocol has been adopted in the United Kingdom and Chatwin et al. published improvements in outcome of children with SMA Type 1 when using a combination of NIV and this extubation protocol.¹⁰

NIV for palliative care

NIV can also be used as a palliative care adjunct to facilitate discharge to home from hospital or to reduce the work of breathing. Birnkrant et al. published the first case series of 4 children with SMA Type 1 for whom NIV was initiated with a palliative indication after the development of aspiration pneumonia.²⁰ Although duration of survival was only 1–3 months after the initiation of NIV, it facilitated the ability to care for these children at home.²⁰ Two cohort studies, 1 prospective and 1 retrospective, have since reported on the palliative application of NIV.^15,21 These studies suggested that the use of NIV in the subset of children with SMA and severe neuromuscular weakness plus evidence of bulbar dysfunction may transiently improve QoL for patients and their families and facilitate transfer home.

NIV for prophylactic use

Although NIV is not routinely used as a prophylactic measure in other neuromuscular diseases, there is some interest in using NIV this way in infants with SMA Type 1. It has been suggested based on case reports of infants with SMA Type 1 who demonstrate paradoxical breathing that “high-span” NIV (pressure support ≥10 cm H₂0) has the potential to reduce the pectus excavatum deformity, improve chest wall development³ and normalize inspiratory muscle synchrony.¹¹ A recent retrospective review of long-term ventilation in children from Portugal suggests this practice may also now be gaining in use for infants with other types of SMA. A 10-year analysis within a pediatric tertiary care hospital identified 3 children with SMA Type 2 who were initiated on prophylactic NIV in the first 2 years of life with the goals of improving quality of life and prolonging life expectancy.²²

NIV post scoliosis surgery

Please see Section 9 on kyphoscoliosis for further details.

Tracheostomy and invasive ventilation

There are no randomized controlled trials evaluating the outcomes of children with SMA managed with invasive ventilation, but cohort studies demonstrate that long-term survival is possible for children with SMA who are invasively ventilated (Table 3).^1,6

Invasive ventilation offers the advantage of providing a secure airway, access for airway clearance through a tracheostomy and support of ventilation, particularly if high ventilator settings are required. However, the burden of care for families is tremendous as the majority of patients are discharged to the home environment.

One potential complication of a trachesotomy for SMA patients is the loss of speech. It has been described that the tracheostomy process may lead to weakness of the bulbar muscles resulting in an inability to phonate or make sounds and therefore an inability to verbally communicate despite average or above average intelligence.¹⁰ Bach et al. reported only 1 of 16 patients retained comprehensible speech after tracheostomy insertion and similarly, only 1 maintained the ability to spontaneously breathe.¹³ However, more recent reviews suggest that speech can be retained in some children after tracheostomy insertion.^37,38 In addition, tracheostomy limits socialization and attendance at school without the appropriate resources. The use of NIV has allowed many children with SMA to have their tracheostomies reversed.

Ethics

Despite the clear survival benefit of ventilatory support, the approach to ventilation for SMA is an area of significant controversy. This is further complicated by the fact that patients are usually unable to participate in the decision-making process because of their young age. The management of children with SMA currently varies between countries, with mechanical ventilation being offered in some cases to children in countries such as Canada, US, France and Japan, but not in Australasia.^23–25 Hardart et al. reported that the majority of physicians (70%) would recommend and offer NIV to patients with SMA, in contrast to only 27% who would recommend tracheostomy plus ventilation.²³ These practice differences may be founded on the differing physician perceptions of QoL for children with SMA on ventilatory support as well as by national cultures.²⁶ Overall, physician perceptions of QoL for patients with SMA maintained on ventilation are reported to be much lower than the perceptions of parents or healthcare professionals working with such patients.²⁹ Children with SMA Type 2 and 3 were found to report a good QoL, irrespective of their functional status.²⁷ This discrepancy can lead to physicians making recommendations regarding provision of ventilation with which the family may not agree.^23,28–30

It is the responsibility of the physician and the healthcare team to disclose all available treatment options to the patient and family along with the values attached to each treatment; these include the advantages and disadvantages, as well as the likely outcomes.^31–36 Therefore, early and repeated discussions with patients and families are critical to ensure informed decision making. In addition, the decision to initiate NIV or ventilation through a tracheostomy may also be influenced by regional differences in financial and home support resources available to families.

Conclusion

In summary, there has been a significant improvement in survival in recent years for children with SMA due to the introduction of ventilatory support as well as MI-E and aggressive nutritional management. In particular, there has been an increase in the number of patients being maintained on NIV. However, despite improved survival, the ability to prolong life must always be tempered by an appreciation for quality of life. Special considerations when counseling families about ventilation for their children with SMA include the type of SMA (1, 2 or 3) as well as the age of diagnosis, as these two factors have been shown to affect outcomes. In addition, these factors must be considered in combination with the advantages and disadvantages of the different ventilation modalities. Ultimately, the role of the treating physician is to present all of the therapeutic options, offer recommendations and support the family through the decision-making process. In practice, the parent’s authority is recognized when there is more than 1 option for treatment.

Research questions

1. What are the specific indications and optimal timing for initiation of NIV?

2. What are the specific indications and optimal timing for initiation of tracheostomy and invasive ventilation?

3. What are the optimal targets used to titrate ventilator support settings?

4. What aspects of QoL for both the patient and family are affected when using NIV or invasive ventilation?

Recommendations for long-term mechanical ventilation at home in spinal muscular atrophy

1. Children with SMA whose parents would like a respiratory opinion should be referred to an experienced center to discuss the treatment options. (Grade 1C)

2. The option of invasive and noninvasive HMV support as well as the differences between therapeutic and palliative NIV should be presented to all parents of children with SMA. (Grade 1C)

3. Assessment for sleep-disordered breathing (ideally with a polysomnogram conducted as per the American Academy of Sleep Medicine standards) should be considered for children with SMA if this is in accordance with the child's and family’s goals of care. (Grade 1C)

4. The decision to recommend or not recommend ventilatory support to children with Type 1 and Type 2 SMA by the treating physician should be made on a case-by-case basis after discussion with family and other caregiver and a careful assessment of medical benefits as well as the effect on quality of life. (Grade 1C).

5. Airway clearance is an important adjunct to ventilator management in children with SMA. See Section 5 recommendations. (Grade 1C)

6. If children are intubated, a protocol-led extubation, including the use of a mechanical in-exsufflation device and NIV, is recommended. (Grade 1C)

7. The decision as to when and how to augment ventilatory support during acute illnesses should be made on a case-by-case basis for each patient by the treating physician, as there is no validated protocol at present. (Grade 1C)

Table 1. Benefits of NIV.

Author (Year)	Study type	Sample size	Outcome: Sleep	Outcome: Hospitalizations	Outcome: Survival
Oskoui (2007)^6	Retrospective patient registry	143	N/A	N/A	-ventilation for >16 hours/day ↓ risk of death Hazard ratio =0.3 (0.1–0.6); p value =0.002
Mellies (2004)^7	Retrospective cohort	15	Eliminated sleep-disordered breathing: Improved respiratory disturbance index (p < 0.005) and nocturnal saturations (p < 0.05) Normalized sleep architecture: higher sleep efficiency (p < 0.005), more deep sleep (p < 0.05), less electro-encephalograph arousals (p < 0.005) Improved symptoms: sleep disturbance, nocturnal sweating, morning headaches, nausea/lack of appetite/feeding difficulties, and impaired concentration (p < 0.005 for all)	N/A	N/A
Mellies (2003)^8	Retrospective cohort	30 NMD = (11 SMA)	Improved nocturnal gas exchange and heart rate (p < 0.01), respiratory disturbance index (p < 0.001), arousals from sleep (p < 0.001) and sleep architecture (p < 0.05)	N/A	N/A
Katz (2004)^9	Retrospective cohort (patients served as own controls)	15	Improved nocturnal desaturations with a 92% decrease in the number of events (p < 0.039) and transcutaneous CO2 levels (p <0.05)	Spent 85% fewer days in hospital (p < 0.01 Spent 68% less days in intensive care (p < 0.05)	N/A
Chatwin (2011)^10	Retrospective descriptive cohort	13	6 patients were using NIV to successfully control sleep-disordered breathing	In 6 long-term survivors, hospitalizations decreased after age of 3 years (from 7.6/yr to 0.2/yr)	N/A
Petrone (2007)^11	Prospective cohort	9	Improved oxygen desaturation index (p < 0.010), mean transcutaneous CO2 (p < 0.001), and thoracoabdominal coordination as measured by phase angle (p < 0.001) using NIV compared to baseline sleep study	N/A	N/A
Bach (2002)^13	Retrospective cohort	56 (33 NIV)	N/A	More hospitalizations compared to those with tracheostomies from 0–3 years of age (p = 0.039) but after 3 years and on there was no difference (p = 0.598) No hospitalizations noted after their 5^th birthday in 15 patient-years	Average age was 41.8 ± 26 months (up to 8.3 years) 2 died at 6 and 13 months
Lemoine (2012)^16	Retrospective cohort	49	N/A	More likely to be hospitalized for respiratory insufficiency compared to patients receiving supportive care (83% vs 46%; p = 0.21)	Longer survival compared to just supportive care when using Kaplan-Meier survival curves (log rank 0.047)
Gregoretti (2013)^17	Retrospective chart review	194	N/A	N/A	Based on Kaplan-Meier survival curves, higher survival probability compared to just supportive care – Lower survival than invasive ventilation at ages 24 months (p < 0.001) and 48 months (p < 0.001)

Table 2. NIV during acute illness.

Author (Year)	Study type	Sample size	Protocol	Outcome
Chatwin (2011)^10	Retrospective descriptive çohort	13	Maintain normal oxygen saturation and carbon dioxide levels while ventilated in room air; MI-E during (if required) and post extubation; post-extubation NIV; post-extubation clapping and nasopharyngeal suctioning	17 intubations for respiratory infections with 9 successful extubations using the protocol versus 3 non-protocol-led approach
Bach (2000)^12	Retrospective cohort	11	Oxygen saturation >94% prior to extubation; MI-E during and post-extubation; post-extubation NIV	More successful extubations using protocol (23 of 28 times) versus no protocol (2 of 10 times) p < 0.001 7 of 11 patients required nocturnal NIV 2 of 11 patients required continuous NIV
Ottonello (2011)^19	Retrospective chart review	16	Continuous NIV at home with increased pressures and backup rate to maintain oxygen saturations ≥95%; MI-E, postural drainage and deep airway suctioning; broad spectrum antibiotics	43 of 49 acute episodes avoided hospitalization: 6 episodes required hospitalization (0.15/patient per year) 4 of 6 episodes required endotracheal intubation (0.01/patient per year), with 3 of the 4 successfully extubated to full NIV support

Table 3. Invasive ventilation via tracheostomy for SMA.

Author (Year)	Study type	Sample size	Outcomes after tracheostomy insertion	Survival
Oskoui (2007)^6	Retrospective patient registry	143		39 of 143 patients had tracheostomies: 17 alive at time of data censorship Ventilation for >16 hours/day ↓ risk of death Hazard ratio =0.3 (0.1–0.6); p value =0.002
Bach (2002)^13	Retrospective cohort	56 (16 invasively ventilated)	1 of 16 had comprehensible speech post tracheostomy 1 of 16 maintained the ability to spontaneously breathe post tracheostomy	Mean age 73.8 ± 57 months (oldest patient was 19 years old) 1 death 3 months after tracheostomy insertion at 16 months of age
Ioos (2004)^14	Retrospective cohort	180	N/A	11 SMA true type 1 with tracheostomies: 6 living (mean age 19 ± 20 months) 20 SMA intermediate type 1 with tracheostomies (mean age 5 ± 4 years) 15 SMA type 2 with tracheostomies (mean age 12.5 ± 3.5 years 0 SMA type 3 with tracheostomies
Gregoretti (2013)^17	Retrospective chart review	194	Choice of tracheostomy and invasive ventilation by families decreased from 50% (1992–1998) to 12.7% (2005–2010) p = 0.0002	Higher survival probability in patients with tracheostomies and invasive ventilation compared to those using NIV or just supportive care at ages 24 and 48 months (p < 0.001 for both)