Respiratory comorbidities and treatments in Duchenne muscular dystrophy: impact on life expectancy and causes of death.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder with progressive decline of pulmonary function increasing the risk of early mortality. The aim of this study was to explore the respiratory-related comorbidities, and the effect of these comorbidities and treatments on life expectancy and causes of death. METHODS: All male patients living in Sweden with DMD, born and deceased 1970-2019, were included. Data regarding causes of death were collected from the Cause of Death Registry and cross-checked with the medical records along with diagnostics and relevant clinical features. RESULTS: Hundred and twenty nine patients were included with a median lifespan of 24.3 years. Acute respiratory failure accounted for 63.3% of respiratory-related causes of death. 70.1% suffered at least one pneumonia, with first episode at a median age of 17.8 years. Hypoventilation was found in 73.0% with onset at 18.1 years. 60.5% had their first pneumonia before established hypoventilation. Age at onset of hypoventilation showed a strong correlation with age at first pneumonia. First pneumonia and scoliosis non-treated with scoliosis surgery increased the risk of dying of respiratory-related causes. In 10% of the patients, first pneumonia resulted in acute tracheostomy or early death. Patients treated with assisted ventilation had higher life expectancy compared to untreated patients. CONCLUSIONS: Our results highlight the importance of identifying subclinical hypoventilation in a timely manner and the importance of an active treatment regime upon clinical signs of pneumonia.

Long-term survival following initiation of home non-invasive ventilation: a European study.

INTRODUCTION: Although home non-invasive ventilation (NIV) is increasingly used to manage patients with chronic ventilatory failure, there are limited data on the long-term outcome of these patients. Our aim was to report on home NIV populations and the long-term outcome from two European centres. METHODS: Cohort analysis including all patients established on home NIV from two European centres between 2008 and 2014. RESULTS: Home NIV was initiated in 1746 patients to treat chronic ventilatory failure caused by (1) obesity hypoventilation syndrome±obstructive sleep apnoea (OHS±OSA) (29.5%); (2) neuromuscular disease (NMD) (22.7%); and (3) obstructive airway diseases (OAD) (19.1%). Overall cohort median survival following NIV initiation was 6.6 years. Median survival varied by underlying aetiology of respiratory failure: rapidly progressive NMD 1.1 years, OAD 2.7 years, OHS±OSA >7 years and slowly progressive NMD >7 years. Multivariate analysis demonstrated higher mortality in patients with rapidly progressive NMD (HR 4.78, 95% CI 3.38 to 6.75), COPD (HR 2.25, 95% CI 1.64 to 3.10), age >60 years at initiation of home NIV (HR 2.41, 95% CI 1.92 to 3.02) and NIV initiation following an acute admission (HR 1.38, 95% CI 1.13 to 1.68). Factors associated with lower mortality were NIV adherence >4 hours per day (HR 0.64, 95% CI 0.51 to 0.79), OSA (HR 0.51, 95% CI 0.31 to 0.84) and female gender (HR 0.79, 95% CI 0.65 to 0.96). CONCLUSION: The mortality rate following initiation of home NIV is high but varies significantly according to underlying aetiology of respiratory failure. In patients with chronic respiratory failure, initiation of home NIV following an acute admission and low levels of NIV adherence are poor prognostic features and may be amenable to intervention.

Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders.

BACKGROUND: Chronic alveolar hypoventilation is a common complication of many neuromuscular and chest wall disorders. Long-term nocturnal mechanical ventilation is commonly used to treat it. This is a 2014 update of a review first published in 2000 and previously updated in 2007. OBJECTIVES: To examine the effects on mortality of nocturnal mechanical ventilation in people with neuromuscular or chest wall disorders. Subsidiary endpoints were to examine the effects of respiratory assistance on improvement of chronic hypoventilation, sleep quality, hospital admissions and quality of life. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE on 10 June 2014. We contacted authors of identified trials and other experts in the field. SELECTION CRITERIA: We searched for quasi-randomised or randomised controlled trials of participants of all ages with neuromuscular or chest wall disorder-related stable chronic hypoventilation of all degrees of severity, receiving any type and any mode of long-term nocturnal mechanical ventilation. The primary outcome measure was one-year mortality and secondary outcomes were unplanned hospital admission, short-term and long-term reversal of hypoventilation-related clinical symptoms and daytime hypercapnia, improvement of lung function and sleep breathing disorders. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology to select studies, extract data and assess the risk of bias in included studies. MAIN RESULTS: The 10 eligible trials included a total of 173 participants. Roughly half of the trials were at low risk of selection, attrition or reporting bias, and almost all were at high risk of performance and detection bias. Four trials reported mortality data in the long term. The pooled risk ratio (RR) of dying was 0.62 (95% confidence interval (CI) 0.42 to 0.91, P value = 0.01) in favour of nocturnal mechanical ventilation compared to spontaneous breathing. There was considerable and significant heterogeneity between the trials, possibly related to differences between the study populations. Information on unplanned hospitalisation was available from two studies. The corresponding pooled RR was 0.25 (95% CI 0.08 to 0.82, P value = 0.02) in favour of nocturnal mechanical ventilation. For most of the outcome measures there was no significant long-term difference between nocturnal mechanical ventilation and no ventilation. Most of the secondary outcomes were not assessed in the eligible trials. Three out of the 10 trials, accounting for 39 participants, two with a cross-over design and one with two parallel groups, compared volume- and pressure-cycled non-invasive mechanical ventilation in the short term. From the only trial (16 participants) on parallel groups, there was no difference in mortality (one death in each arm) between volume- and pressure-cycled mechanical ventilation. Data from the two cross-over trials suggested that compared with pressure-cycled ventilation, volume-cycled ventilation was associated with less sleep time spent with an arterial oxygen saturation below 90% (mean difference (MD) 6.83 minutes, 95% CI 4.68 to 8.98, P value = 0.00001) and a lower apnoea-hypopnoea (per sleep hour) index (MD -0.65, 95% CI -0.84 to -0.46, P value = 0.00001). We found no study that compared invasive and non-invasive mechanical ventilation or intermittent positive pressure versus negative pressure ventilation. AUTHORS' CONCLUSIONS: Current evidence about the therapeutic benefit of mechanical ventilation is of very low quality, but is consistent, suggesting alleviation of the symptoms of chronic hypoventilation in the short term. In four small studies, survival was prolonged and unplanned hospitalisation was reduced, mainly in participants with motor neuron diseases. With the exception of motor neuron disease and Duchenne muscular dystrophy, for which the natural history supports the survival benefit of mechanical ventilation against no ventilation, further larger randomised trials should assess the long-term benefit of different types and modes of nocturnal mechanical ventilation on quality of life, morbidity and mortality, and its cost-benefit ratio in neuromuscular and chest wall diseases.

SUDEP, suspected positional airway obstruction, and hypoventilation in postictal coma.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with chronic uncontrolled epilepsy. Despite intense interest in SUDEP from the medical and scientific communities in recent years, its etiologies are still largely unresolved. A 35-year-old woman had SUDEP after having a generalized seizure in the prone position. The cause of her death was likely asphyxia from the convergence of postictal coma and suspected positional airway obstruction and hypoventilation, rather than the commonly suspected periictal cardiac arrhythmia or central apnea. SUDEP may share a similar etiology with sudden infant death syndrome (SIDS) and is likely preventable, at least in a proportion of cases.

Hypoventilation in cystic fibrosis.

Cystic fibrosis (CF) is the most common life-shortening genetic disorder in Caucasians. With the improved treatments that have become available, the median survival for patients with this disorder has increased to 37.4 years of age. Unfortunately, the overwhelming majority of patients still die from respiratory failure. Hypoventilation, arising from a variety of etiologies, may occur as part of the disease process and causes increased morbidity and mortality. Although inspiratory muscles training, oxygen therapy, and noninvasive ventilation are used in the treatment of hypoventilation in CF, more data are needed to guide their optimal use.

PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is characterized by compromised chemoreflexes resulting in sleep hypoventilation. We report a Chinese family with paired-like homeobox 2B (PHOX2B) mutation-confirmed CCHS, with a clinical spectrum from newborn to adulthood, to increase awareness of its various manifestations. METHODS: After identifying central hypoventilation in an adult man (index case), clinical evaluation was performed on the complete family, which consisted of the parents, five siblings, and five offspring. Pulmonary function tests, overnight polysomnography, arterial blood gas measurements, hypercapnia ventilatory response, and PHOX2B gene mutation screening were performed on living family members. Brain MRI, 24-h Holter monitoring, and echocardiography were performed on members with clinically diagnosed central hypoventilation. RESULTS: The index patient and four offspring manifested clinical features of central hypoventilation. The index patients had hypoxia and hypercapnia while awake, polycythemia, and hematocrit levels of 70%. The first and fourth children had frequent cyanotic spells, and both died of respiratory failure. The second and third children remained asymptomatic until adulthood, when they experienced impaired hypercapnic ventilatory response. The third child had nocturnal hypoventilation with nadir pulse oximetric saturation of 59%. Adult-onset CCHS with PHOX2B gene mutation of the + 5 alanine expansions were confirmed in the index patient and the second and third children. The index patient and the third child received ventilator support system bilevel positive airway pressure treatment, which improved the hypoxemia, hypercapnia, and polycythemia without altering their chemosensitivity. CONCLUSIONS: Transmission of late-onset CCHS is autosomal-dominant. Genetic screening of family members of CCHS probands allows for early diagnosis and treatment.

Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death.

OBJECTIVE: Children with Congenital Central Hypoventilation Syndrome (CCHS) have cardiovascular symptoms consistent with the autonomic nervous system dysregulation/dysfunction (ANSD) phenotype. We hypothesized that children with CCHS would have a relationship between PHOX2B genotype and two clinically applicable cardiovascular measures of ANSD: duration of longest r-r interval and longest corrected QT interval (QTc). MATERIALS AND METHODS: We studied 501 days of Holter recordings from 39 individuals with PHOX2B mutation-confirmed CCHS, and analyzed longest r-r and QTc intervals with respect to PHOX2B genotype. RESULTS: We determined that longest r-r interval varied by genotype (P=0.001), with a positive correlation between repeat number and longest r-r interval duration (P=0.0007). Number of children with a longest r-r interval value>or=3 sec varied by genotype (P<0.0001): 0% with the 20/25 genotype, 19% with the 20/26 genotype, and 83% with the 20/27 genotype. Though longest QTc interval did not vary by genotype (P=0.09), all children with CCHS had at least one Holter with a QTc interval>450 msec, and percent of time with QTc>450 msec exceeded published values. The proportion of subjects who received a cardiac pacemaker due to prolonged r-r interval was greater for the children with the 20/27 genotype (67%) than the 20/25 (0%) or 20/26 genotype (25%) (P=0.01). Among three children who did not receive a cardiac pacemaker, but who had r-r intervals>or=3 sec, two died suddenly. CONCLUSIONS: These results confirm a disturbance of cardiac autonomic regulation in CCHS, indicate that PHOX2B genotype is related to the severity of dysregulation, predict the need for cardiac pacemaker, and offer the clinician the potential to avert sudden death.

Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature.

Symptoms of nocturnal hypoventilation may negatively influence the quality of life (QoL) of ALS patients long before respiratory failure ensues. Non-invasive mechanical ventilation (NIV) is considered a treatment option for nocturnal hypoventilation. The primary objective of NIV is improving quality of life (QoL). It may also prolong life by several months. A systematic review of the literature was performed to analyse what is known of the effect of NIV on survival, QoL and other outcome measures. A computerized literature search was performed to identify controlled clinical trials and observational studies of treatment of ALS-associated nocturnal hypoventilation from 1985 until May 2005. Twelve studies fulfilled the inclusion criteria. Four studies were retrospective, seven prospective and in one study randomization was used. All studies reported beneficial effects of NIV on all outcome measures. In seven studies NIV was associated with prolonged survival in patients tolerant for NIV, and five studies reported an improved QoL. In conclusion, studies on the use of NIV in ALS differ in study design and endpoint definitions. All studies suggest a beneficial effect on QoL and other outcome measures (Evidence level Class II-III). Well-designed randomized controlled trials comparing the effect on QoL and survival have not been performed.

Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome.

BACKGROUND: Severe obesity is associated with hypoventilation, a disorder that may adversely affect morbidity and mortality. We sought to determine the prevalence and effects of obesity-associated hypoventilation in hospitalized patients. METHODS: Consecutive admissions to internal medicine services were screened over a 6-month period. In all eligible subjects with severe obesity (body mass index > or =35 kg/m2), we administered a sleep questionnaire, and performed neuropsychological, arterial blood gas, and pulmonary function testing. Hospital course and mortality at 18 months was also determined. RESULTS: Of 4,332 admissions, 6% (n = 277) of patients were severely obese, of whom 150 were enrolled, 75 refused to participate, and 52 met the exclusion criteria. Hypoventilation (mean [+/- SD] arterial partial pressure of carbon dioxide [PaCO2], 52 +/- 7 mm Hg) was present in 31% (n = 47) of subjects who did not have other reasons for hypercapnia. Decreased objective attention/concentration and increased subjective sleepiness were present in patients with obesity-associated hypoventilation compared with in severely obese hospitalized patients without hypoventilation (simple obesity group; mean PaCO2, 37 +/- 6 mm Hg). There were higher rates of intensive care (P = 0.08), long-term care at discharge (P = 0.01), and mechanical ventilation (P = 0.01) among subjects with obesity-associated hypoventilation. Therapy for hypoventilation at discharge was initiated in only 6 (13%) of the patients with obesity-associated hypoventilation. At 18 months following hospital discharge, mortality was 23% in the obesity-associated hypoventilation group as compared with 9% in the simple obesity group (hazard ratio = 4.0; 95% confidence interval: 1.5 to 10.4]. CONCLUSION: Hypoventilation frequently complicates severe obesity among hospitalized adults and is associated with excess morbidity and mortality.

Use of heliox in patients with severe exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To assess whether patients with chronic obstructive pulmonary disease treated with heliox have a better prognosis than those treated with standard therapy. DESIGN: Retrospective analysis over 18 months. SETTING: Academic emergency department. PATIENTS: Eighty-one patients admitted with exacerbation of chronic obstructive pulmonary disease and respiratory acidosis. INTERVENTIONS: Use of helium-oxygen mixture as an adjunctive therapy. MEASUREMENTS AND MAIN RESULTS: The following data were collected: age, gender, medical history, vital signs, arterial blood gas at admission, emergency room treatment, requirement for intubation, admission in intensive care unit, length of stay, and evolution. Patients were classified into two groups according to whether heliox was used as a therapeutic agent (heliox group) or not (standard group). Chi-square test and Student's t-test were used for statistical analysis (significant at p <.05). In both groups, the following data were similar: age, gender, medical history, vital signs, initial arterial blood gas, and emergency room treatment. Significant decreases in intubation, and mortality rate were identified in the heliox group. Significant decreases in intensive care unit stay and in-hospital stay were observed for survivors in the heliox group. CONCLUSION: Use of heliox seems to improve prognosis in patients with severe acute exacerbation of chronic obstructive pulmonary disease. Prospective randomized studies are needed to confirm these results.

Consideraciones anestésicas en el paciente con traumatismo raquimedular / Anesthetic considerations in the patient with traumatic spinal injury

El traumatismo raquimedular involucra frecuentemente a individuos jóvenes; causado por accidentes de tránsito, actos de violencia o durante la práctica deportiva, produce significativa morbimortalidad y elevados costos durante la recuperación. Las medidas de transporte y soporte se basan en la inmovilización, el mantenimiento de la vía aérea y el control hemodinámico. La cirugía puede ser necesaria para remoción de fragmentos óseos, descompresión y estabilización o evacuación de hematomas. El cuadro clínico depende del nivel de lesión, por debajo del cual estará comprometido el funcionamiento de todos los órganos y la termorregulación, pudiendo existir falla respiratoria, secundaria a parálisis de los músculos de la respiración. Durante la anestesia debe asegurarse el flujo sanguíneo medular manteniéndose la presión de perfusión dentro de los límites de autorregulación (entre 60 y 120 mmHg de tensión arterial media); la hipotensión y la bradicardia deben corregirse mediante la expansión, seguida de la utilización de drogas inotrópicas, pudiendo ser necesario monitoreo hemodinámico invasivo (catéter en la arteria pulmonar). Se deben tomar medidas para evitar la aspiración del contenido gástrico y tratar el edema y el embolismo pulmonar. El tratamiento médico agresivo (resucitación y aumento de la presión de perfusión) y la cirugía de descompresión en las lesiones por dislocación, mejoran el pronóstico clínico neurológico.

Consideraciones anestésicas en el paciente con traumatismo raquimedular / Anesthetic considerations in the patient with traumatic spinal injury

El traumatismo raquimedular involucra frecuentemente a individuos jóvenes; causado por accidentes de tránsito, actos de violencia o durante la práctica deportiva, produce significativa morbimortalidad y elevados costos durante la recuperación. Las medidas de transporte y soporte se basan en la inmovilización, el mantenimiento de la vía aérea y el control hemodinámico. La cirugía puede ser necesaria para remoción de fragmentos óseos, descompresión y estabilización o evacuación de hematomas. El cuadro clínico depende del nivel de lesión, por debajo del cual estará comprometido el funcionamiento de todos los órganos y la termorregulación, pudiendo existir falla respiratoria, secundaria a parálisis de los músculos de la respiración. Durante la anestesia debe asegurarse el flujo sanguíneo medular manteniéndose la presión de perfusión dentro de los límites de autorregulación (entre 60 y 120 mmHg de tensión arterial media); la hipotensión y la bradicardia deben corregirse mediante la expansión, seguida de la utilización de drogas inotrópicas, pudiendo ser necesario monitoreo hemodinámico invasivo (catéter en la arteria pulmonar). Se deben tomar medidas para evitar la aspiración del contenido gástrico y tratar el edema y el embolismo pulmonar. El tratamiento médico agresivo (resucitación y aumento de la presión de perfusión) y la cirugía de descompresión en las lesiones por dislocación, mejoran el pronóstico clínico neurológico. (AU)

The role of hypoventilation in a sheep model of epileptic sudden death.

Unexpected sudden death is a common event in otherwise healthy epileptics, though its etiology has remained unclear. Many authors have suggested cardiac arrhythmias as the cause, and limited data in humans and animal studies have supported this. However, autopsy series in humans have shown pulmonary edema, a phenomenon not compatible with a sudden arrhythmic death, as a possible cause. We developed a model of status epilepticus in unanesthetized, chronically instrumented sheep in which sudden death and pulmonary edema occur. Catecholamine levels and seizure type and duration did not differ between animals dying suddenly and those surviving. Benign arrhythmias were generated in all animals; in no case did an arrhythmia account for the death of an animal. Striking hypoventilation was demonstrated in the sudden death group but not in the surviving animals. Differences in peak left atrial and pulmonary artery pressures, and in extravascular lung water were also demonstrated; pulmonary edema did not account for the demise of the sudden death animals. Thus, our model of epileptic sudden death supports a role of central hypoventilation in the etiology of sudden unexpected death and confirms the association with pulmonary edema. The importance of arrhythmia in its pathogenesis is not confirmed.

Anesthetic death.

Death due to anesthesia is a tragic paradox. The numbers about the frequency of anesthesia-related-death published in many reports have a relative value, as it is impossible to compare them one to another. A synoptic table of 20 important studies made on this subject, shows a great variation in figures concerning the incidence of death related to anesthesia. The most common causes of "anesthetic-death" are mentioned and some suggestions are made to decrease the frequency of death due to anesthesia.