Mortality despite new generation medications for pediatric neuromuscular diseases and how to prevent it

Abstract

With severe respiratory muscle weakness of pediatric patients with progressive neuromuscular disorders, progressive hypercapnic ventilatory failure can result in cor pulmonale but, even more often, otherwise benign upper respiratory tract infections result in pneumonia, supplemental oxygen administration, hypercapnic respiratory failure, coma, intubation, failure to ventilator wean, then the options of tracheotomy or terminal extubation with O₂ and morphine. While new medications for spinal muscular atrophy, Pompe disease, and Duchenne muscular dystrophy can slow deterioration, cough peak flows can become or remain ineffective to clear the airways to prevent those two options. This work reviewed publications that demonstrate that instead of weaning from ventilatory support to be extubated, it can be only by extubating or decannulating ventilator unweanable patients that permit them to wean back to any ventilator use regimens they used before hospitalization. Avoiding tracheostomies for mechanical ventilation can also result in over half a million dollars per year in cost savings as well as preserve quality of life.

Key Words: Noninvasive ventilation; Noninvasive ventilatory support; Neuromuscular diseases; Mechanical insufflation exsufflation; Spinal muscular atrophy; Muscular dystrophy; Extubation; Decannulation

Core Tip: New gene and RNA-based therapies slow progression of pediatric neuromuscular diseases but do not restore effective cough. When hypoxic episodes are treated with supplemental oxygen instead of noninvasive ventilatory support (NVS) and mechanical insufflation-exsufflation (MIE), CO₂ narcosis, intubation, and unnecessary tracheostomy or death often follow. Extubating ventilator-unweanable patients directly to continuous NVS and MIE, rather than pursuing prolonged weaning trials, allows most to return to their prior ventilator-use regimens without tracheostomy. This approach also saves over $500000 per patient annually in nursing and medical costs while preserving quality of life.

INTRODUCTION

Gene therapies[1-3] and other RNA[4-6], and survival motor neuron 2 modifying agents[7] are functionally converting infants with spinal muscular atrophy (SMA) type 1, who are treated in the first 6 weeks of life, into type 2 and type 3, permitting most to sit independently and eventually walk. Later onset of administration results in less, and eventually even no objective benefits. Gene[8,9] and exon skipping and splice modulation therapies are also benefiting children with Duchenne muscular dystrophy (DMD)[10-13], and are being developed for other neuromuscular diseases (NMDs) like myotonic, limb-girdle, and congenital muscular dystrophies, dysferlinopathies, and distal anterior compartment myopathies. Enzyme replacement therapies are also beneficial for Pompe disease, a glycogen storage disease[14-17], and the first truly effective medication for any NMD[16-18]. It, too, is clearly most effective with very early administration, even in utero[19]. There are also other “downstream”, non-DNA/RNA modulating therapies like those that promote muscle myotrophin[20] and corticosteroids that actually do slightly slow the progression of muscle weakening for muscular dystrophies as well[21,22]. However, despite an investment of $9.1 million in medical therapies for three children with SMA type 1, all three died before 4 years of age due to their physicians not maintaining their access to continuous noninvasive ventilatory support (CNVS) and mechanical in-exsufflation (MIE) to clear airway secretions[23]. Likewise, DMD patients have been reported to live 10 years longer using CNVS rather than continuous tracheostomy mechanical ventilation (CTMV) with, or without glucocorticoid therapy[24].

Untreated children with SMA type 1 have been reported to develop acute on chronic respiratory failure (ARF) 0.7 times per year to the third birthday, 0.3 per year from third to fifth birthdays, 4 per 100 years from ages 5 to 10 then 2 per 100 years subsequently[25]. Our center currently manages 23 with SMA 1 now between 20 and 32 years of age, most with 0 mL of vital capacity (VC) and only trace volitional eye movements. None have tracheostomy tubes[25]. Over 250 patients who left Iron Lungs in New York City in 1957 also survived using up to CNVS for over 60 years in many cases[26]. Thus, it appears that tracheostomy tubes may not be necessary for ventilatory support if the problem is only ventilatory pump failure (VPF) since CNVS and MIE can be used indefinitely even for patients with no ventilator free breathing autonomy (VFBA) at all. So, now that there are medications approved by the Food and Drug Administration that do not cure pediatric NMDs but have some statistically significant beneficial effects, the survival prognosis should not be worse with the drugs than without them.

Meanwhile, the new multi-million dollar medications for SMA and DMD can prolong survival, at least nominally for many cases, while unmedically treated SMA1 patients can live over 30 years with 2 per 100 year hospitalization rates after age 10[25]. Further, three DMD patients have died because of gene therapy and there is no evidence that DMD patients live significantly longer whether receiving gene therapy, RNA modifying agents, or corticosteroids, indeed few have been described to attain 40 years of age while 14 essentially unmedicated patients with DMD have been reported over age 50, and 57 over age 40 by using NVS and MIE to virtually eliminate respiratory morbidity and mortality and resort to tracheostomy tubes[26-30]. The most common causes of death for patients with NMDs are respiratory complications due to failure of physicians to both monitor and manage ineffective cough peak flows (CPF) and employ NVS and MIE instead of TMV that is responsible for the majority of morbidity[31-35], and of deaths in NMD patients with the tubes[36-40]. Medications can only be beneficial for patients alive to receive them. Progressively weakening of overworked respiratory muscles need not be considered lethal when physicians administer NVS and MIE[36,37].

Thus, ventilatory support can be provided via noninvasive, rather than invasive interfaces but few physicians have ever heard of CNVS via mouthpiece (Figure 1A), nasal, or oronasal interfaces using active circuits with exhalation valves even though this, and ventilation belts (Figure 1B), were all that was available for noninvasive management of patients leaving iron lungs. Besides permitting NVS, active circuits facilitate complimentary interventions like manually assisted coughing, lung volume recruitment, and glossopharyngeal breathing that can permit VFBA even for patients with no measurable VC[41,42].

Figure 1 Ventilatory support can be provided via noninvasive, rather than invasive interfaces. A: A currently 43-year-old with Becker muscular dystrophy using diurnal mouthpiece noninvasive ventilatory support (NVS), as well as sleep nasal NVS since 2005, in a regimen of continuous NVS with no significant ventilator free breathing ability since 2014. At age 31 he was spared from certain translaryngeal intubation, and tracheotomy or terminal extubation, by oxygen being discontinued in favor of continuous mouthpiece NVS in a local emergency room; B: Man with no measurable vital capacity, dependent on continuous noninvasive ventilatory support via mouthpiece during the day, and lip cover flange, seen here, for sleep for 49 years since age 15.

Most physicians are familiar with the typically prescribed noninvasive ventilation, or “NIV”, via passive circuits without exhalation valves. Bi-level NIV had become synonymous with continuous positive airway pressure (CPAP) and low pressure support bi-level positive airway pressure (PAP) since 1990[43]. It was initially prescribed to treat obstructive sleep apneas and cardiopulmonary diseases. However, with passive circuits the expiratory PAP (EPAP) prevents full expiration and can not be turned off. Crescimento et al[44] reported for bulbar amyotrophic lateral sclerosis (ALS) that the EPAP results in more air leaks, diminished N3 stage sleep and sleep quality, greater breathing effort, ventilator autotriggering, premature cycling, dyssynchronies, increased risk of aspiration and reflux, prolonged insufflations and reverse triggering, decreased heart rate variability and therefore increased sympathetic myocardial stimulation, and no benefit on oxyhemoglobin saturation (SpO₂), time spent with SpO₂ < 90%, or O₂ desaturation index (number of oxygen desaturations 4% per hour). Nor is there any evidence that EPAP improved symptoms or prognosis. Therefore, active circuits may be preferred for NVS[44], especially for daytime NVS, since deep lung volumes and air stacking for lung volume recruitment are not possible with any pressure limited ventilation.

For VPF patients, volume targeted bi-level, that is also open circuit NIV, can be used at NVS settings. However, inadequate maximum permitted pressures can diminish air delivery below targeted volumes. NVS settings used on volume preset portable ventilators, available since 1976, should generally be over a range of 600 mL to 1400 mL or pressure assist/control at 18 cm H₂O to 25 cm H₂O. Open systems of NVS rely on a central nervous system unsedated by supplemental oxygen (O₂) or sedatives[45-49]. NIV used at less than NVS settings does not optimally rest muscles, provide full NVS, nor permit extubation or tracheostomy tube decannulation when patients fail ventilator weaning for being too weak to breathe[45-47].

SYMPTOMS TO OXYGEN TO COMA TO INTUBATION TO TRACHEOSTOMY OR DEATH

Typically, people made feeble by advanced age and immobility, deconditioning, severe malnutrition, or neurological or myopathic conditions with weakening respiratory muscles, develop dyspnea, morning headaches, sleepiness, and fatigue as blood carbon dioxide (CO₂) levels rise during sleep. For mildly hypercapnic patients given supplemental O₂ instead of NVS, CO₂ levels often soar. In a recent study, 316 patients with NMDs became CO₂ narcotic and were intubated for ARF within minutes of being placed on supplemental O₂ instead of CNVS and MIE[48-51]. The supplemental O₂ did nothing to resolve, but only exacerbated the hypoventilation and airway secretions that had caused the hypoxia. All but two of these ventilator unweanable patients were successfully extubated to CNVS and MIE with the two undergoing tracheotomies for severe bronchiectasis and hypoxia. They all went back to their pre-hospitalization regimens of ventilator use if any at all. Even more often ARF occurs when intercurrent upper respiratory tract infections cause airway secretions that cannot be adequately cleared because of insufficient CPF and patients have no access to MIE[52].

Symptoms due to VPF prompt patients to seek emergency services/departments (EDs) that almost invariably administer O₂ rather than NVS and MIE, usually without knowledge of CO₂ levels[48-50]. The CO₂ levels soar to narcosis, coma, then intubation for invasive ventilatory support and airway suctioning, thus symptoms to O₂ to coma to intubation or SOCI. The airway tubes hamper ventilator weaning. When it seems impossible, only tracheotomy (SOCIT) for CTMV, or morphine and O₂ for terminal extubation to death (SOCID) are offered. Surviving using CTMV, patients lose financial resources to qualify for Medicaid for the expensive mandated nursing care for tracheal suctioning in the United States. Then, whether discharged to home nursing or permanent internment in a ventilator unit of a nursing institution the cost is over $440000 per year.

HOW TO AVOID SOCIT/D

In April 2014, a 31 year old man with Becker muscular dystrophy had his daytime end-tidal CO₂ decrease from 77 mmHg to 52 mmHg by using sleep nasal NVS but he would not use NVS during the day. At age 32 his end-tidal CO₂ was 57 mmHg and we advised him to use daytime mouthpiece NVS as well. Three days later he lost consciousness while toileting. ED delivered O₂ and he became comatose in a local ED with a blood pH 6.98, PaCO₂ 173 mm Hg, PaO₂ 143 on fiO₂ 100%, HCO₃ 40.8, and the ED physicians urged immediate intubation. His father refused this until the physicians called Dr. Bach who told his father to get his ventilator from the trunk of his car and apply it via an oronasal interface. Fifteen minutes later the patient was awake and alert with normal SpO₂ and CO₂ in ambient air. He returned home within 40 minutes but from that point on used NVS night and day. In an out-patient visit 1 month later his VC was 520 mL but end-tidal CO₂ and SpO₂ remained normal. Within 1 minute of ceasing NVS at that time his end-tidal CO₂ became 46 mmHg and SpO₂ 92 to 93% with dyspnea. Thus, he was spared SOCIT/D by using NVS to normalize his blood gases. In December 2025 at age 44 his VC was 280 mL and he had no VFBA but blood gases remain normal using CNVS (Figure 1) and MIE as needed.

AIRWAY TUBES AND FINANCES

Tracheotomies are the most frequent surgical procedure in intensive care units (ICUs). About 110000 are placed in the United States each year. This can be compared to 15000 annually in Great Britain. Forty-five to 62% of patients die within the first year following tracheotomy, with the highest risk of death within 90 days, even for those requiring TMV only for VPF. They die from both their primary lethal diseases but also from tube complications[40].

About 5% to 12% of all patients in our academic centers who are ventilator unweanable have only VPF from various disorders but not from lethal diseases like cancer, multiorgan, or brain disease. Those not extubated to CNVS and MIE but who undergo tracheotomies for mechanical ventilation (CTMV) may survive for years with each costing taxpayers over $500000. However, typical hospital bills of United States patients with VPF who undergo tracheotomies that include up to several months of futile ventilator weaning attempts in ICUs, are 1.5 to over 3.5 million dollars, of which medical insurance typically pays 13% to 20%. Subsequently, the nursing costs at $75/hour are typically for home nursing 16 hours per day, or over $1500/day for ventilator nursing units or over $500000 per year. CNVS costs a small fraction of that with many patients not entitled to nursing for lack of invasive tubes. There are estimates that 55% of Americans die in hospitals and nursing facilities, most often with invasive tubes into them rather than with dignity at home[53].

In 2025 Americans paid $5.6 trillion for the health care of 340 million people, six times more than for the United States military. Almost $1.5 trillion was for health care administration and over $1 trillion for interest on the federal debt of $38 trillion. The government only takes in about $2.4 trillion in income tax overall. The federal debt is now increasing by $1 trillion every 2 months to 3 months. Today, medical care costs every American an average $16471 per year. This is very different from the $84 per American for medical care in 1950. It comes to 19% of the American gross domestic product. Yet, Americans die younger than in 46 other countries, 6 years younger than in a country whose government pays 1.7% of GDP for medical care, guarantees it for all citizens, and is rated in the top seven rather than about 37^th as for the United States. The United States is rated last overall among 10 other high-income countries.

WHAT DOCTORS KNEW THEN BUT DON’T KNOW NOW

In 1955 physicians knew that tracheostomy tubes hamper and often make it impossible to wean from CTMV. Hodes[54] noted at an international consensus in 1955, “If a patient is going to be left a respirator cripple…a tracheotomy may be a great disadvantage. It is very difficult to get rid of a tracheotomy tube when the VC is only 500 cc 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”[54]. In a recent study of 486 DMD patients, all dependent on wheelchairs by age 12 and on NVS/CNVS, only three needed tracheostomy tubes for severe concomitant lung disease. The 14 over age 50 and 57 over age 40 with little to no VC[55], were successfully extubated 82 consecutive times without resort to tracheotomies for intercurrent episodes of pneumonia and ARF. All were unweanable both before and immediately after extubation to CNVS and MIE. They passed no ventilator weaning parameters or ventilator weaning trials but, instead of SOCIT/SOCID, CNVS and MIE were effective for all[45,46]. They all weaned back to the ventilator use regimens they used before being hospitalized, that is, sleep nasal NVS, CNVS, or nothing at all. With progressive weakening, 263 of the 486, who began sleep nasal NVS, extended it to CNVS without developing ARF or even being hospitalized. In fact, many CNVS users were never hospitalized for respiratory difficulties including some over age 50[55].

Thus, while alien to the macroscopic notions of virtually all physicians, the following are “take home” points for those who consider O₂ to always be harmless and use it instead of NVS and MIE at optimal settings for patients with VPF: (1) No one needs a tracheotomy tube for only being too weak to breathe[45-47,51]; (2) “NIV”, unless used at NVS pressure settings as noted above, does not provide long-term continuous support[45-47,51,52]; (3) O₂ does not resolve what causes hypoxia for VPF patients, NVS and MIE must be used to normalize blood gases; it is not a substitute for NVS and MIE[45-48,56]; (4) When patients with VPF develop O₂ desaturation below 95% it should be renormalized by NVS and/or using MIE at 60 cm H₂O[45-47]; (5) Patients with severe upper motor neuron diseases that render MIE-exsufflation flows ineffective (below 140 L/m to 170 L/m) can require tracheostomy tubes to survive[45,46]; (6) EPAP is not beneficial and is occasionally harmful for patients with VPF[44]; (7) Symptoms, spirometry in sitting and supine positions, CPF, CO₂, and oximetry are needed to evaluate for VPF. Positive end-expiratory pressure, polysomnographies, and conventional pulmonary function studies are unnecessary[51]; (8) The home administration of O₂ can cause CO₂ narcosis and SOCIT or SOCID and must always be avoided for patients with only VPF[51]; (9) Since, in the 1970s at Goldwater Memorial Hospital in New York City, personal care attendants were trained and certified to suction tracheostomy tubes with no subsequent tort litigation, they can be trained and certified to perform this at less than one-third the cost of nursing[57]; (10) Active ventilator circuits and volume preset NVS permit lung volume recruitment, assisted coughing, and the elimination of EPAP for patients with glottis function who can air stack[42,51]; (11) Patients who are CTMV dependent due to strokes, traumatic brain injury, and cerebral palsy can wean from CTMV by discontinuing supplemental O₂ and removing the tube to CNVS and using MIE via the tubes to clear the airways and maintain normal O₂ saturation in ambient air[58]; (12) Closed systems of ventilatory support include CTMV with an inflated cuff and oronasal CNVS[58,59]; and (13) Open systems of ventilatory support include CTMV with cuffless tubes or cuff deflation, and nasal CNVS[60].

Limitations to the generalization of this information include that: (1) This requires specialized knowledge and training of intensivists and respiratory therapists so expert centers, of which there are very few and only one that has published this approach in the United States, is currently available[45-47]; (2) Candidates for CNVS and extubation and decannulation to CNVS and MIE must satisfy specific criteria including being cognitively intact, alert, have only VPF and otherwise be healthy with no severe lung or other organ disease[45-47]; (3) It is a limitation to not compare assist control inspiratory support via volume and pressure modes with and without EPAP/PEEP. However, the question of ubiquitous need for EPAP/PEEP is inconsistent with the fact that severely hypercapnic morbidly obese patients’ blood gases were normalized by NVS delivered via pressure and volume modes without EPAP/PEEP using active ventilator circuits with positive inspiratory pressures as high as 55 cm H₂O[60]. These pressures have not been reported to be administered via passive circuits. No less than 35 cm H₂O to 55 cm H₂O inspiratory pressures could normalize CO₂ and O₂ saturation levels in ambient air without PEEP[60]; and (4) The PIPs decreased over a few days due to the improved pulmonary compliance by receiving increased (normal) tidal volumes. No EPAP/PEEP was needed to normalize PaCO₂ levels as high as 82 mmHg. For patients for whom CPAP levels approaching 30 cm H₂O keep the airways open during sleep, higher PIPs deliver adequate lung volumes without EPAP/PEEP with exhalations being passive[60].

CONCLUSION

Invasive ventilatory support can prolong life but also cause morbidity and mortality and hinder ventilator weaning. However, it can be required for many lethal diseases. New medications for pediatric neuromuscular diseases can benefit survival and function, particularly when administered from infancy, but despite millions of dollars of expense for many, patients, without access to noninvasive ventilatory and cough support can die unnecessarily from respiratory causes anyway. So, since patients with little to no VC or any other than volitional eye movements can survive decades without tracheostomy tubes, trach tubes should not be needed for ONLY being too weak to breathe. Ventilator unweanable patients can be routinely extubated and decannulated and only then can many patients be able to wean from continuous ventilatory support. Avoiding tracheostomies for mechanical ventilation can result in half a million dollars per year in cost savings for nursing alone.