Hypercapnic Respiratory Failure due to L-Tryptophan-lnduced Eosinophilic Polymyositis*

After completing this article, readers should be able to: Chest wall mechanics of neonates and infants play an essential role in ventilation that frequently is underappreciated. Dysfunction of the respiratory muscles can cause both a disease process and an inability of the patient to compensate for it. As an example, respiratory muscle failure may be the underlying cause in about 50% of preterm infants who have ventilatory failure. (1) In this article, we detail the current understanding of the physiology of the respiratory muscles in neonates and discuss a number of tests designed to assess their function.Mechanically, the respiratory system can be thought of as being composed of two components. The first includes the respiratory muscles, the rib cage, and the anterior abdominal wall, which together make up the “pump,” whose function is to move air in and out of the lungs. The second includes the airways and lung parenchyma through which gas exchange occurs and can be referred to as the “load” on which the pump must act. For ventilation to occur, the respiratory pump must overcome both the frictional (eg, airway resistance) and tissue elastic forces (eg, lung and chest wall compliance) that create the load. The balance between the capabilities of the pump and the magnitude of the load can influence whether respiratory “success” or “failure” occurs.The chest wall, which contains muscles and skeletal structures, undergoes dramatic maturational changes over the first several years of life. In addition to changing its geometry to augment the thoracic contribution to tidal volume (Figs. 1 and 2), the rib cage becomes stiffer, thereby making the chest wall less compliant. Along with these changes, the role of the intercostal muscles changes from that of supporting the chest wall and minimizing its distortion in infancy to that of increasing tidal volume in childhood. In the neonate, therefore, the principal muscle to produce a tidal volume is the diaphragm, while the function of the intercostals is to defend the thoracic volume against chest wall distortion.Deformation of the highly compliant neonatal chest wall can be seen during forceful breathing or airway occlusions in term infants (2) and even during normal breathing in preterm infants (3) and represents nonproductive work on the part of the respiratory muscles that can lead to greater energy expenditure and promote respiratory failure. Also, other accessory muscles of respiration must generate force to stiffen the chest wall and resist the inward deformation on inspiration, even during quiet breathing. This also increases the metabolic cost of breathing and the amount of work that certain respiratory muscles must perform.The passive properties of the immature chest wall also result in the need for infants to maintain end-expiratory volume (functional residual capacity [FRC]) actively above the level determined by the balance between the outward recoil of the chest wall and the inward recoil of the lungs. Any process that interferes with the ability of the chest wall or laryngeal muscles to maintain the elevated FRC predisposes to premature airway closure and atelectasis. This, in turn, increases the load on the ventilatory pump and can result in respiratory failure.A number of neonatal conditions can have deleterious effects on the normal function of the respiratory muscles. These can be categorized broadly into conditions that increase the magnitude of the “load” and those that decrease the strength of the “pump,” each of which has congenital, acquired, and iatrogenic causes.Conditions that increase the load include those that decrease lung compliance (eg, surfactant deficiency, congenital diaphragmatic hernia, atelectasis, and pulmonary edema or overcirculation), those that hinder chest movement (eg, rib cage deformities, omphalocele), those that obstruct air flow (eg, bronchospasm, tracheomalacia, subglottic stenosis, midfacial hypoplasia), and those that bypass the normal laryngeal braking mechanism (eg, tracheostomy placement).A number of conditions lead to respiratory muscle weakness in neonates. Although mechanical ventilation sometimes is needed to keep neonates alive, it can lead to respiratory muscle atrophy. Infants who died after receiving more than 12 days of ventilation were found to have decreased diaphragmatic muscle mass compared with those who died after receiving fewer than 8 days of ventilation. (4) Also, a number of studies using rats and rabbits have shown that even a few days (≤4 d) of mechanical ventilation produced diaphragmatic remodeling and decreased strength. Neonates who have gastrointestinal complications, such as necrotizing enterocolitis or short gut syndrome, are prone to malnutrition that subsequently can lead to generalized muscle atrophy, including the respiratory muscles. A number of experiments using animal models of malnutrition have shown decreased diaphragm mass, changes in the diaphragm muscle fiber isoforms, and possibly a greater tendency for the muscle to become fatigued. (5)(6)(7)(8) Malformations of the chest wall (eg, absent or fused ribs) and diaphragm (eg, congenital diaphragmatic hernia) can place the respiratory muscles at a mechanical disadvantage that leads to decreased force production and predisposes to muscle fatigue. Congenital neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy type 1) can lead directly to weakness of the respiratory muscles. Functional denervation of the diaphragm can cause varying degrees of weakness and even paralysis. Such diaphragms may stay in a fixed position or can increase the workload of the functioning contralateral hemidiaphragm by moving paradoxically. Possible causes include damaged upper motor neurons (eg, due to stroke, infection, or respiratory center compression associated with Arnold-Chiari type 2 malformations) and lower motor neuron injury (eg, spinal injury and phrenic nerve injury related to birth trauma or surgery). Dysfunction of the neuromuscular junction can be caused by some medications, such as nucleoside analogs, neuromuscular blockers, and aminoglycosides. (9) Finally, congenital heart disease can cause respiratory muscle weakness if the cardiac output is unable to provide sufficient blood flow to meet energy demands of the muscles.It is worthwhile to consider the effects of hyperinflation on the respiratory system because it highlights a number of important physiologic phenomena. Hyperinflation can be seen with any obstructive lung disease, such as bronchopulmonary dysplasia, where the respiratory time constant is longer than the time available for exhalation. Hyperinflation is believed to cause respiratory muscle weakness by several mechanisms. As with all skeletal muscles, the diaphragm has a length-tension relationship, so when it is shortened by hyperinflation, its maximal force production is decreased. Hyperinflation also reduces the effectiveness of the rib cage muscles by causing the ribs to assume a more horizontal position, which hinders further rib cage expansion. (9)Finally, a few causes of respiratory muscle weakness that have been described in adults have yet to be studied in the neonatal age group. Myopathy from systemic corticosteroid use (10)(11) can result from muscle catabolism that can be severe (with rhabdomyolysis and myoglobinuria); can be acute or chronic; can take weeks to months for recovery; and can be potentiated by the simultaneous use of neuromuscular blockade. Also, “critically ill polyneuropathy” (in which electromyographic readings are consistent with denervation) has been described as an entity occurring in association with sepsis and other serious illness. (12)Knowledge relating to the strength of the respiratory muscles can be useful in various clinical situations encountered in neonatal intensive care units. It may aid in decisions regarding if and when a patient should be weaned or liberated from mechanical ventilation; in assessing recovery from sepsis, other acute illnesses, and surgeries; and in gauging the effects of thoracotomies and other chest wall procedures (eg, placements of titanium ribs) on the function of these muscles.The maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) are simple, noninvasive clinical measures of the strength of all of the respiratory muscles. Children who are old enough to cooperate are told to place the mouth around a mouthpiece that is connected to a pressure transducer and either exhale (to measure MEP) or inhale (to measure MIP) as forcefully as they can. Typically, MEP is measured from total lung capacity (TLC), and MIP is measured from residual volume (RV). The opening to the mouthpiece then is closed to obstruct airflow, allowing the mouth pressure to equilibrate with alveolar pressure. When measured in this manner, the MIP and MEP represent the combined forces of all of the muscles of inspiration or exhalation.One also can measure specifically the pressure generated by the diaphragm alone, the transdiaphragmatic pressure (Pdi). This is accomplished by the transnasal insertion of gastric and esophageal pressure transducers and measuring the difference between esophageal and gastric pressures during the same maximal effort maneuvers. Because of the invasive nature of this measurement, it rarely is used other than for research purposes.The patient’s effort must be taken into account when performing and interpreting MIP and MEP maneuvers because attaining the intended starting lung volume and performing a maximally forceful breath are both effort-dependent maneuvers. There also is a “learning curve” to the performance of these tests, in which higher pressures may be achieved with serial maneuvers during a testing session. To account for these effects, some clinicians advocate having patients perform a minimum of 20 maneuvers; (13) others stop once there is less than 5% variability in the results.Studies in healthy children show that the MIPs and MEPs are related strongly to the patient age, gender, and the lung volume at which they are measured. Some of these trends can be seen in Tables 1 and 2, which summarize most of the available literature on these measures in healthy individuals. Both MIP and MEP increase with age and tend to be somewhat higher in males than in females (not shown). MIPs are higher when measured from lower lung volumes (approaching RV); MEPs are higher at higher lung volumes (approaching TLC). Because of these factors, there is great variability in values between the various studies, as can be seen in the Tables. Thus, measurement considerations must be kept in mind when such values are used as normative data in the assessment of clinical situations.One aspect that is unique to neonates and toddlers is their inability to cooperate with the testing, which has led to important differences in how MIP and MEP measurements are conducted in this age group. The pressure transducer is connected to a mask that covers and forms an airtight seal around the infant’s mouth and nose. Alternatively, the pressure transducer can be connected to endotracheal or tracheostomy tubes, although any air leak around the tube must be eliminated for accurate measurements. The size of the mask, tubing, and pressure transducer should be as small as possible to minimize dead space. During measurements, the airway opening can be temporarily occluded manually or with the use of a balloon (Fig. 3) or a two-way valve connected distal to the pressure transducer.There are two widely used methods for eliciting a maximal breathing effort in infants. Both rely on involuntary responses on the part of the patient, so in some respects, effort/motivation variability does not play as much of a role as in older patients. Also, timing the occlusion in the respiratory cycle allows a choice of the lung volume (eg, FRC, RV, or TLC) at which the test is conducted. The first method, as described by Shardonofsky and associates, (14) makes use of the infant’s reflexive cry when the mask is applied to the face, with the assumption that crying represents maximal respiratory efforts. The airway opening is occluded at the end of a crying effort, when lung volume approaches RV, to measure MIP and at the beginning of a crying effort, when lung volume approaches TLC, to measure MEP. Each maneuver is repeated several times. As originally described, MEP was chosen as the highest expiratory pressure that was sustained for 1 second, and MIP was the highest peak inspiratory pressure from a series of five measurements. (14) The second method, as described by Dimitriou and colleagues, (15) makes use of the fact that when the airway opening is occluded, the infant reflexively produces progressively higher respiratory efforts to overcome the obstruction. These researchers performed at least three occlusions at the ends of both inspiration and exhalation. Each of the occlusions was sustained for a period of five respiratory efforts, using the same criteria as described previously for choosing MIP and MEP. We have used the latter technique successfully with an occlusion time of 10 seconds in many infants who had various respiratory disorders and interfaces (mask, tracheostomy, and endotracheal tubes) (Fig. 4). The question of how many times the measurement needs to be repeated before it truly represents the maximal effort has not been addressed in neonates. In older children who performed up to 20 maneuvers, however, higher MIPs could be obtained if defined as the average of the three highest values with ≤5% variability from all recorded maneuvers, rather than just the first three values with ≤5% variability. (13)Measurements of strength reflect the function of muscle at a specific point in time, but they do not indicate how well the muscle will function under a given load over a prolonged time. Thus, although MIP and MEP tests convey information about the strength of the respiratory muscles, they do not reflect their endurance or predisposition to fatigue. Unlike other skeletal muscles, the respiratory muscles must function continually without the opportunity for rest, similarly to cardiac muscles. The different information reflected in strength versus endurance measurements is highlighted by a number of studies showing that MIP or MEP assessments were not useful discriminators between patients who were able or unable to tolerate weaning or discontinuation of mechanical ventilation.The tension time index of the diaphragm (TTdi) was introduced initially (16) as a measure that correlated closely with the time elapsed until a target pressure no longer could be sustained by the contracting diaphragm, suggesting fatigue. Fatigue occurs when a muscle no longer can generate its maximal force despite being stimulated maximally. The development of respiratory muscle fatigue is linked closely to both the force and the duration of muscle contraction. (16) In other words, fatigue occurs more quickly as the force a muscle must generate repeatedly increases toward maximal tension or as it must sustain the contraction for longer periods of time. Thus, the TTdi is the dimensionless product of: 1) the ratio of mean inspiratory Pdi to maximal Pdi (Pdimax) and 2) the ratio of the inspiratory time (Ti) to the total respiratory cycle time (Ttot) [TTdi=(Pdi/Pdimax)×(Ti/Ttot)]. Of note, the measurements needed to calculate the TTdi require the placement of pressure-measuring catheters in the esophagus and stomach to measure Pdi (Fig. 3). Furthermore, because only the Pdi is measured, TTdi does not reflect the force generated by respiratory muscles other than the diaphragm.A completely noninvasive method, the tension time index of all the respiratory muscles (TTmus), for measuring respiratory muscle fatigue in adults and subsequently in children was described later, which also has the advantage of including all of the inspiratory muscles, not just the diaphragm. (17) Rather than using only measurements of transdiaphragmatic pressures (Pdi and Pdimax), this technique uses the mean and maximal inspiratory pressures measured at the mouth (Pimean and MIP, respectively) while the patient breathes against an occlusion. Thus, TTmus=(Pimean /MIP)×(Ti/Ttot), where Pimean is estimated by measuring mouth pressure 100 msec after the beginning of inspiration (P100) and extrapolating it to end inspiration (Pimean=P100×5×Ti). To date, TTmus has been validated in school-age children, but neither TTdi nor TTmus has been validated in infants. There are also questions to be answered regarding the appropriate uses (who, when, how often) of these tests in various diseases seen in neonates.The respiratory muscles play an important part in neonatal medicine. Good methods of measuring their strength and endurance could enhance the care of neonates. Although much progress has been made in this area, there is still a great deal of opportunity for future research. How various therapies used to treat parenchymal and airway disease affect respiratory muscle strength is not known. Determinants of chronic respiratory failure, or conversely, the ability of an infant to be liberated from chronic mechanical ventilation might involve changes in the ability of the respiratory pump to take over the role of breathing from the mechanical ventilator. The role of respiratory pump failure or fatigue should be considered in any neonate who has hypercapnic respiratory failure.

Mouth occlusion pressure 0.1 s after onset of inspiration (P0.1) reflects central respiratory drive (CRD), but its dependence on respiratory muscle strength is unknown. To clarify this relationship, we produced progressive levels of respiratory muscle weakness by infusion of d-tubocurarine in eight supine spontaneously breathing normal subjects. Hypercapnic ventilatory response (HCVR) was measured before curarization and at mild (mean inspiratory effort 62 +/- 3% of control), moderate (42 +/- 3%), and severe (23 +/- 1%) weakness. At the severe level of weakness 1) supine functional residual capacity was not significantly changed from base line, 2) the percent of base-line slope of delta P0.1/delta PCO2 (122 +/- 27%) was significantly greater (P less than 0.01) than that for change in expired minute ventilation (delta VE)/delta PCO2 (39 +/- 10%), 3) the percent of base-line delta P0.1/delta VE (381 +/- 46%) during HCVR was significantly increased (P less than 0.01), 4) the P0.1 response was significantly increased from base line at two out of three specific levels of PCO2 while the VE was unchanged or significantly decreased, and 5) peak inspiratory resistance did not significantly change. Thus P0.1, unlike VE, did not decrease with even severe respiratory muscle weakness. Indeed, P0.1 increased at two out of three levels of PCO2 under circumstances when higher CRD is expected. One potential explanation for the results is that P0.1 may at least qualitatively reflect CRD up to the level of severe respiratory muscle weakness attained in this study.

SUMMARYRespiratory muscle dysfunction frequently occurs in patients with neuromuscular disorders, cardiopulmonary diseases and in patients in intensive care units. Respiratory muscle weakness and/or fatigue is responsible for dyspnoea, reduced exercise tolerance, nocturnal 'desaturation, and prolonged weaning from mechanical ventilation. Chronic respiratory muscle weakness may also be associated with poor quality of life and increased mortality. Patients with severe respiratory muscle weakness are at increased risk of respiratory failure due to respiratory infections, electrolyte imbalance, sedation or uncontrolled inspired oxygen therapy. Although respiratory muscle weakness is often seen in clinical practice, the consequences and the precise point at which respiratory muscle fatigue occurs remain elusive. This article reviews the pathophysiology of respiratory muscle weakness and fatigue, and therapeutic interventions for enhancing respiratory muscle function in patients with neuromuscular and cardiopulmonary diseases.

The aim of the present study was to determine whether lung volume recruitment (LVR) acutely increases respiratory system compliance (Crs) in individuals with severe respiratory muscle weakness (RMW).Individuals with RMW resulting from neuromuscular disease or quadriplegia (n=12) and healthy controls (n=12) underwent pulmonary function testing and the measurement of Crs at baseline, immediately after, 1 h after and 2 h after a single standardised session of LVR. The LVR session involved 10 consecutive supramaximal lung inflations with a manual resuscitation bag to the highest tolerable mouth pressure or a maximum of 50 cmH2O. Each LVR inflation was followed by brief breath-hold and a maximal expiration to residual volume.At baseline, individuals with RMW had lower Crs than controls (37±5 cmH2O versus 109±10 mL·cmH2O−1, p<0.001). Immediately after LVR, Crs increased by 39.5±9.8% to 50±7 mL·cmH2O−1 in individuals with RMW (p<0.05), while no significant change occurred in controls (p=0.23). At 1 h and 2 h post-treatment, there were no within-group differences in Crs compared to baseline (all p>0.05). LVR had no significant effect on measures of pulmonary function at any time point in either group (all p>0.05). During inflations, mean arterial pressure decreased significantly relative to baseline by 10.4±2.8 mmHg and 17.3±3.0 mmHg in individuals with RMW and controls, respectively (both p<0.05).LVR acutely increases Crs in individuals with RMW. However, the high airway pressures during inflations cause reductions in mean arterial pressure that should be considered when applying this technique.

Diseases that affect the neuromuscular junction (NMJ) interfere with normal nerve transmission and cause weakness of voluntary muscles. The two most commonly encountered are acquired myasthenia gravis (MG) and the Lambert–Eaton myasthenic syndrome (LEMS). Acquired MG is an autoimmune disease in which antibodies are directed towards receptors at the NMJ. In 85% of patients, IgG antibodies against the postsynaptic acetylcholine receptor (AChR) are found (seropositive MG). The thymus gland appears to be involved in the production of these which cause an increase rate of degradation of AChR resulting in a decreased receptor density resulting in a reduced postsynaptic end-plate potential following motor nerve stimulation and leading to muscle weakness. Although all voluntary muscles can be affected, ocular, bulbar, respiratory, and proximal limb weakness predominates. In the majority of seronegative patients, an antibody directed towards a NMJ protein called muscle specific tyrosine kinase (MUSK) is found. Anti-MUSK MG is characterized by severe bulbar and respiratory muscle weakness. Diagnosis of MG requires a high degree of clinical suspicion coupled with pharmacological and electrophysiological testing, and detection of the various causative antibodies. Treatment of MG involves enhancing neuromuscular transmission with long-acting anticholinesterase agents and immunosuppression. Acute exacerbations are treated with either plasma exchange or intravenous immunoglobulin. Myasthenic crisis is associated with severe muscle weakness that necessitates tracheal intubation and mechanical ventilation. LEMS is an autoimmune disease in which IgG antibodies are directed towards the pre-synaptic voltage-gated calcium channels at the NMJ. It is often associated with malignant disease (usually small cell carcinoma of the lung). Autonomic dysfunction is prominent and patients show abnormal responses to neuromuscular blocking drugs.

Background:Respiratory muscle weakness in patients with Duchenne muscular dystrophy (DMD) leads to respiratory failure for which non-invasive positive pressure ventilation (NIPPV) is an effective treatment. This is used initially at...

We report the cases of eight children with histologic findings in the muscle of congenital fiber-type disproportion myopathy. Five had severe muscle weakness at birth; three of them died at 6 months, 18 months, and 6.5 years of age, respectively, and the other two are ventilator dependent and need total care at 2.5 and 4 years of age. The five children with severe weakness at birth had profound respiratory muscle weakness and needed assisted ventilation since early infancy. They also had severe facial and bulbar muscle weakness that required tube feeding, and four had gastrostomy. Ptosis and marked external ophthalmoparesis were also noted. Our study shows that the presence of the above constellation of signs at birth or in early infancy is a predictor of a high rate of mortality in infancy and poor developmental outcome in the survivors.

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder, characterized by severe and progressive skeletal muscle weakness, which extends to the respiratory muscles. We have determined that peak inspiratory pressure-generating capacity is preserved in early dystrophic disease in the mdx mouse model of muscular dystrophy, but this early compensation is lost as disease progressesa. We sought to examine the structure-function relationship of obligatory and accessory respiratory muscles in early (4-month) and advanced (16-month) disease. Ex vivo muscle function of obligatory (diaphragm and parasternal) and accessory (sternomastoid, cleidomastoid and scalene) respiratory muscles was assessed in wild-type and mdx mice in early dystrophic disease (n = 8-15 per group). Diaphragm and scalene ex vivo muscle function was assessed in advanced dystrophic disease (n = 10-14 per group). Histology (sirius red, and haematoxylin and eosin) and immunofluorescence (laminin) were used to assess the form of obligatory (diaphragm, parasternal and intercostal) and accessory (sternomastoid, cleidomastoid, scalene and trapezius) respiratory muscles (n=6 per group). Pro-inflammatory cytokine concentrations were examined in muscle homogenates of obligatory and accessory respiratory muscles of wild-type and mdx mice in early and advanced dystrophic disease (n=10 per group). Our study revealed obligatory (diaphragm and parasternal) and accessory (sternomastoid and cleidomastoid) muscle weakness evident in early dystrophic disease. Scalene muscle function is preserved in mdx mice in early disease but is weak in mdx mice in advanced dystrophic disease. Structural remodelling by way of increased collagen deposition (fibrosis), increased central nucleation, increased area of inflammatory cell infiltrate and reduced mean minimal Feret’s diameter (relative atrophy) was evident in obligatory and accessory respiratory muscles in early dystrophic disease. The relative area of collagen deposition in obligatory and accessory respiratory muscles increased with disease progression, but interestingly the increase was most pronounced in the diaphragm muscle. Increased concentration of pro-inflammatory cytokines (IFN-γ, IL-1β, IL-6, KC/GRO, TNF-α, MCP-1, IL-33, MIP-1α, IP-10, MIP-2) was observed in mdx obligatory and accessory muscle homogenates compared to wild-type in early and advanced dystrophic disease. These data widen characterisation of the respiratory control system in mdx mice, potentially revealing novel therapeutic targets. References a O'Halloran KD, Maxwell MN, Marullo AL, Hamilton CP, Ó Murchú SC, Burns DP, Mahony CM, Slyne AD, Drummond SE (2023). Loss of compensation afforded by accessory muscles of breathing leads to respiratory system compromise in the mdx mouse model of Duchenne muscular dystrophy. J Physiol. 601(19):4441-4467. Eli Lilly &amp; Science Foundation Ireland (19/FFP/6628). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Eosinophilic infiltration into skeletal muscles has been rarely reported in a variety of conditions such as parasite infection, sarcoidosis, rheumatoid arthritis, eosinophilia-myalgia syndrome, and idiopathic hypereosinophilic syndrome. Eosinophilic myositis (EM) is one of idiopathic inflammatory muscle diseases associated with muscle and/or blood eosiophilia. The case of EM complicated with hypercapnic respiratory failure has been extremely rarely reported. A 61-year-old woman was admitted with sudden-onset pain in both calves. She had elevated serum muscle enzymes and peripheral eosinophil count. Findings of electromyography were consistent with inflammatory myopathy. MRI showed diffuse hyperintensity of calf muscles on T2-weighted and enhanced T1 images. Muscle biopsy showed eosinophils' infiltration in the endomysium and perivascular area. During the diagnostic work-up, she presented with hypercapnic respiratory failure. She was successfully treated with mechanical ventilation and high doses of prednisolone. This case suggests EM can cause respiratory failure secondary to respiratory muscle involvement.

Measurement of respiratory muscle strength is useful in order to detect respiratory muscle weakness and to quantify its severity. Apropos of a patient with bilateral diaphragmatic paralysis, we review the clinical manifestations and methods for assessing the strength of the respiratory muscles. In patients with severe respiratory muscle weakness, vital capacity and total lung capacity are reduced but are a non-specific and relatively insensitive measure. Conventionally, inspiratory and expiratory muscle strength has been assessed by maximal inspiratory and expiratory mouth pressures sustained for one second (PIMax and PEMax). The sniffmanoeuvre is natural and probably easier to perform. Sniff pressures are more reproducible and useful measure of diaphragmatic strength. However, the PIMax-PEMax and sniff manoeuvres are volition dependent, and submaximal efforts are most likely to occur in patients who are ill or breathless. Non-volitional tests include measurements of twitch esophageal, gastric and transdiaphragmatic pressure during bilateral electrical and magnetic phrenic nerve stimulation. Electrical phrenic nerve stimulation is technically difficult and is also uncomfortable and painful. Magnetic phrenic nerve stimulation is less painful and transdiaphragmatic pressure is reproducible in normal subjects. Systematic clinical evaluation and additional laboratory tests allow the diagnosis in most patients with respiratory muscle weakness.

Respiratory management of children with spinal muscular atrophy (SMA)

Reversible respiratory muscle weakness in hypothyroidism

The term amyotrophic lateral sclerosis (ALS) comprises a group of motor neuron diseases which are characterized by rapid disease progression and poor prognosis which is mostly due to severe respiratory muscle weakness and its sequelae. Since causative treatment options are limited it is crucial to offer comprehensive symptomatic therapies to affect patients. Symptoms of respiratory muscle weakness, sleep-disordered breathing and, subsequently, chronic hypercapnic respiratory failure are known to severely affect health-related quality of life and social functioning of patients with ALS. This review article delineates the clinical presentation of respiratory muscle weakness, diagnostic procedures to assess diaphragmatic function, and practical aspects of both mechanical ventilation and cough assistance, respectively. Various technical and electrophysiological methods allow for detection of diaphragmatic weakness and nocturnal hypoventilation. These include spiro-manometric tests of respiratory muscle strength, cardiorespiratory polygraphy and polysomnography, transcutaneous capnography, and blood gas analysis. Once the diagnosis of respiratory muscle weakness is established, non-invasive ventilation, tracheostomy-invasive ventilation (if the patient agrees to it), and management of secretions all become increasingly important in the course of the disease.

A patient with scleroderma presented with hypercapnic respiratory failure. Evaluation of pulmonary mechanics revealed severe restriction caused in part by respiratory muscle weakness. Treatment with prednisone corrected hypoventilation, improved symptoms, increased lung volumes, returned respiratory muscle strength to normal range, but did not change the degree of lung stiffness. This case demonstrates that restrictive patterns in scleroderma can be due to either lung or chest wall disease and that the latter may be reversible. If respiratory muscle weakness is present with restrictive ventilatory patterns in patients with scleroderma, a therapeutic trial of corticosteroid is warranted.

Breathlessness appears to be closely related to the perception of the outgoing motor command to breathe and should be increased in the presence of muscle weakness. However, breathlessness is not a common symptom in patients with chronic muscle disease who have weak respiratory muscles. The factors that determine the perception of respiratory effort in such patients have not been examined. The inspiratory effort sensation during resting breathing and progressive hypercapnia was investigated in 12 patients with dystrophia myotonica with weak respiratory muscles (nine men and three women of mean (SD) age 41.1 (10.5) years; maximum inspiratory pressure 43.1 (17.2) cm H2O) and an age and sex matched control group of normal subjects of mean age 39.6 (10.6) years and a maximum inspiratory pressure of 123 (15.2) cm H2O. During resting breathing with a mouthpiece no differences were seen in inspiratory effort sensation, mouth occlusion pressure, or tidal volume, but inspiratory time and cycle duration were significantly shorter in the patients with dystrophia. Minute ventilation (VE) was significantly higher in the patients (15.8 (4.0) l/min v 12.5 (2.6) l/min), while resting breathing was no more variable in the patients than in controls. The ventilatory response to carbon dioxide (VE/PCO2) was not significantly lower in the patients (14.9 (6.9) l/min/kPa) than in the controls (17.4 (4.3) l/min/kPa). Effort sensation responses to carbon dioxide driven breathing were similar in the control subjects and the patients. With regression analysis of pooled data neither maximum inspiratory pressure nor disease state contributed to perceived inspiratory effort during hypercapnia. Moderately severe global respiratory muscle weakness does not appear to influence the ventilatory response to rising carbon dioxide tension or the perception of inspiratory effort in patients with dystrophia myotonica.