Spinal Muscular Atrophy (SMA) Mortality Despite Novel Medications: Case Reports.

ABSTRACT: Despite new effective medications, patients with SMA types 1-3 can continue to have inadequate cough flows to prevent episodes of acute respiratory failure. Ventilator unweanable intubated patients are thought to require tracheostomy tubes. As a result, potentially beneficial medications may be discontinued and patients die despite receiving these medications. Three cases are presented of medically treated, physically strengthening children, with SMA type 1. All three subsequently died or underwent tracheotomy. However, there is no evidence of extubation attempts to noninvasive ventilatory support settings or optimal mechanical insufflation-exsufflation despite this option being described to be over 98% successful for extubating unweanable medically untreated children with SMA1.

Percutaneous Endoscopic Gastrostomy Placement under NIV in Amyotrophic Lateral Sclerosis with Severe Ventilatory Dysfunction: A Safe and Effective Procedure.

Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with an inexorably progressive course which leads to a progressive neuromuscular weakness. Weight loss is one of the major bad prognostic factors in ALS. The placement of percutaneous endoscopic gastrostomy (PEG) is of paramount importance in patients with dysphagia to improve the disease outcomes, although some fear exists regarding the possible ventilatory complications during the procedure. The aim of this study was to evaluate the safety and effectiveness of PEG tube insertion under non-invasive ventilation (NIV) in patients with ALS and severe ventilatory impairment. Methods: A retrospective study of all consecutive PEGs placed in our department from May 2011 to January 2018 in patients with ALS was performed. The procedure was performed under non-invasive positive-pressure ventilation for ventilatory support. Results: We included 59 patients with ALS with severe ventilatory impairment, 58% were female, with a mean age of 67.2 ± 10.1 years and a median follow-up of 6 [2-15] months. The main indication for PEG placement was dysphagia (98%). The median time for PEG tube insertion since the established diagnosis of ALS was 12 [6-25] months and 4 [2-18] months since the beginning of bulbar symptoms. The majority of the patients had placed a 20-Fr PEG (63%) and under mild sedation with midazolam (80%), all under NIV. There were no immediate complications during and after the procedure (no episodes of aspiration or orotracheal intubation) and mortality. Conclusion: The placement of PEG is a very important procedure in patients with ALS and severe ventilatory impairment. The interdisciplinary department collaboration permitted the placement of PEG under NIV, in a safe and effective procedure in this special population.

Introdução: A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa com um curso inexorável que leva a fraqueza neuromuscular progressiva. A perda de peso é um dos principais fatores de mau prognóstico na ELA. Apesar do receio de complicações ventilatórias durante o procedimento, a colocação de gastrostomia percutânea endoscópica em doentes com disfagia é extremamente importante para melhorar o prognóstico. O objetivo deste estudo é avaliar a segurança e eficácia da colocação de gastrostomia percutânea endoscópica (GEP) sob ventilação não invasiva (VNI) em doentes com ELA e disfunção ventilatória grave. Métodos: Estudo retrospetivo de todas as gastrostomias percutâneas endoscópicas colocadas em doentes com ELA no nosso departamento entre Maio 2011 e Janeiro 2018. O procedimento foi realizado sob VNI para suporte ventilatório. Resultados: Foram incluídos 59 doentes com ELA e disfunção ventilatória grave, 58% do sexo feminino, com uma idade média de 67.2 ± 10.1 anos e um follow-up mediano de 6 [2­15] meses. A principal indicação para colocação de gastrostomia percutânea endoscópica foi disfagia (98%). O tempo mediano para a colocação de GEP desde o diagnóstico de ELA foi 12 [6­25] meses e 4 [2­18] meses desde o início dos sintomas bulbares. A maioria dos doentes colocaram uma GEP de 20 Fr (63%) e sob sedação com midazolam (80%), todos sob VNI. Não se verificaram complicações imediatas durante e após o procedimento (sem episódios de aspiração ou entubação orotraqueal) e mortalidade. Conclusão: A colocação de GEP é um procedimento muito importante em doentes com ELA e disfunção ventilatória grave. A colaboração interdisciplinar permitiu a colocação de GEP sob ventilação não invasiva, tornando-o um procedimento seguro e eficaz nesta população especial.

Mouthpiece ventilation in neuromuscular disorders: Narrative review of technical issues important for clinical success.

In neuromuscular disorders (NMDs), nocturnal non-invasive ventilation (NIV) via a nasal mask is offered when hypercapnic respiratory failure occurs. With disease progression, nocturnal NIV needs to be extended into the daytime. Mouthpiece ventilation (MPV) is an option for daytime NIV. MPV represents a difficult task for home ventilators due to rapidly changing load conditions resulting from intermittent connections and disconnections from MPV circuit. The 252nd ENMC International Expert Workshop, held March 6th to 8th 2020 in Amsterdam, reported general guidelines for management of daytime MPV in NMDs. This report could not present all the detail regarding the technical issues important for clinical success of MPV. Based on the expert workshop discussions and the evidence from existing studies, the current narrative review aims to identify the technical issues of MPV and offers guidance via a decisional algorithm and educational figures providing relevant information that is important for successful implementation of MPV.

Home Mechanical Ventilation Practices in Spain and Portugal.

Introduction: Home mechanical ventilation (HMV) practice has changed with publication of new evidence and introduction of new technologies, and varies between countries. This study investigated current HMV use and practices in Spain and Portugal. Methods: 94 healthcare professionals identified as regularly performing HMV-related activities were sent an e-mail link to an online questionnaire. The questionnaire included 40 items relating to responder demographics, non-invasive ventilation (NIV) care structure, ventilated patient profile, work habits, and potential future practice improvements. Results: 66 questionnaires (70%) were returned (Spain, 36; Portugal, 30). The majority of respondents were physicians (Spain, 95%; Portugal, 63%). Overall, 83% of hospitals had a dedicated NIV unit (Spain, 100%; Portugal, 63%). The most common indication for HMV was neuromuscular disorders in Spain and obstructive diseases in Portugal. Homecare providers (HCPs) and pulmonologists were usually responsible for managing HMV; HCPs were involved more often in Portugal. Choice of ventilator was most often based on usage hours/day; the most important device features were 'ease of use' (Spain) and 'adjustment range' (Portugal). HMV monitoring practices varied between countries. Telemonitoring was used more often in Portugal (20%; vs. Spain, 3%). Follow-up frequency and practices also differed markedly between Spain and Portugal. Respondents highlighted identification of new patient groups and patient phenotyping to optimize treatment and personalize therapy as future HMV strategies. Conclusions: Important differences in the management of HMV were observed between two similar European countries. Better understanding of clinical practices can facilitate targeted education and training to ensure optimal management of patients using HMV.

Introducción: El manejo de la ventilación mecánica domiciliaria (VMD) ha cambiado tras la publicación de información nueva y la introducción de nuevas tecnologías, y varía entre países. Este estudio investigó el uso y el manejo actuales de la VMD en España y Portugal. Métodos: Noventa y cuatro profesionales de la salud que realizaban actividades relacionadas con la VMD con regularidad recibieron un enlace mediante correo electrónico a un cuestionario en línea. El cuestionario incluyó 40 ítems relacionados con la demografía de los encuestados, la estructura de cuidados de la ventilación no invasiva (VNI), el perfil del paciente ventilado, los hábitos de trabajo y las posibles mejoras en el futuro manejo de la VMD. Resultados: Se respondieron 66 cuestionarios (70%) (España, 36; Portugal, 30). La mayoría de los encuestados eran médicos (España, 95%; Portugal, 63%). En total, el 83% de los hospitales tenían una unidad dedicada a la VNI (España, 100%; Portugal, 63%). La indicación más frecuente de VMD fueron los trastornos neuromusculares en España y las enfermedades obstructivas en Portugal. Los prestadores de servicios médicos domiciliarios (SMD) y los neumólogos generalmente fueron los responsables del manejo de la VMD. Los SMD participaron con mayor frecuencia en Portugal. La elección del ventilador se basó con mayor frecuencia en las horas de uso/día; las características más importantes del dispositivo fueron «facilidad de uso¼ (en España) y «rango de ajuste¼ (en Portugal). El manejo del seguimiento de la VMD varió entre países. La telemonitorización se utilizó con mayor frecuencia en Portugal (20%; frente a España, 3%). La frecuencia y la forma de seguimiento también difirieron notablemente entre España y Portugal. Los encuestados destacaron la identificación de nuevos grupos de pacientes y el fenotipado de los pacientes para optimizar el tratamiento y personalizar la terapia como estrategias futuras en la VMD. Conclusiones: Se observaron diferencias importantes en el manejo de la VMD entre dos países europeos similares. Una mejor comprensión de las prácticas clínicas puede facilitar la educación y la formación específicas para garantizar un manejo óptimo de los pacientes que utilizan VMD.

Ventilatory Support via Mouthpiece to Facilitate Ambulation.

OBJECTIVE: The aim of the study was to evaluate the efficacy of noninvasive ventilatory assistance/support via mouthpiece to improve performance in 6-min walk tests for individuals with severe restrictive ventilatory disorders. DESIGN: Each subject performed the 6-min walk test breathing spontaneously and again while using mouthpiece noninvasive ventilatory assistance/support at full ventilatory support. Oxyhemoglobin saturation (O2 sat), heart rate, Borg scale, distance walked, and ambulation duration were recorded. RESULTS: Eighteen patients using nocturnal nasal noninvasive ventilatory assistance/support, median (interquartile range) age of 58.5 (20) yrs, were studied. Their median baseline forced vital capacity and PaCO2 were 940 (385) ml and 54.1 (6) mm Hg, respectively. All used noninvasive ventilatory assistance/support for at least overnight hours for 36 (111) mos. Because of the progression of ventilatory impairment and hypercapnia, daytime mouthpiece noninvasive ventilatory assistance/support was initiated. All the 6-min walk test parameters improved significantly by using noninvasive ventilatory assistance/support. Both initial and final values of O2 saturation significantly increased (92% [6] vs 96% [2], P < 0.001) and (80% [19] vs 85.50% [13], P = 0.001), respectively. The median distance walked increased by 43% with noninvasive ventilatory assistance/support (175 [218] m vs 250 [113] m, P = 0.017), and the total ambulation time also increased with noninvasive ventilatory assistance/support (5.45 [3] mins vs. 6 [0] mins, P = 0.008). CONCLUSIONS: The exercise tolerance of patients with severe ventilatory impairment can improve by using noninvasive ventilatory support.

Airway clearance techniques in neuromuscular disorders: A state of the art review.

This is a unique state of the art review written by a group of 21 international recognized experts in the field that gathered during a meeting organized by the European Neuromuscular Centre (ENMC) in Naarden, March 2017. It systematically reports the entire evidence base for airway clearance techniques (ACTs) in both adults and children with neuromuscular disorders (NMD). We not only report randomised controlled trials, which in other systematic reviews conclude that there is a lack of evidence base to give an opinion, but also include case series and retrospective reviews of practice. For this review, we have classified ACTs as either proximal (cough augmentation) or peripheral (secretion mobilization). The review presents descriptions; standard definitions; the supporting evidence for and limitations of proximal and peripheral ACTs that are used in patients with NMD; as well as providing recommendations for objective measurements of efficacy, specifically for proximal ACTs. This state of the art review also highlights how ACTs may be adapted or modified for specific contexts (e.g. in people with bulbar insufficiency; children and infants) and recommends when and how each technique should be applied.

Investigating Low-Velocity Fluid Flow in Tumors with Convection-MRI.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers.Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859-72. ©2018 AACR.

Decomposition of spontaneous fluctuations in tumour oxygenation using BOLD MRI and independent component analysis.

BACKGROUND: Solid tumours can undergo cycles of hypoxia, followed by reoxygenation, which can have significant implications for the success of anticancer therapies. A need therefore exists to develop methods to aid its detection and to further characterise its biological basis. We present here a novel method for decomposing systemic and tumour-specific contributions to fluctuations in tumour deoxyhaemoglobin concentration, based on magnetic resonance imaging measurements. METHODS: Fluctuations in deoxyhaemoglobin concentration in two tumour xenograft models of colorectal carcinoma were decomposed into distinct contributions using independent component analysis. These components were then correlated with systemic pulse oximetry measurements to assess the influence of systemic variations in blood oxygenation in tumours, compared with those that arise within the tumour itself (tumour-specific). Immunohistochemical staining was used to assess the physiological basis of each source of fluctuation. RESULTS: Systemic fluctuations in blood oxygenation were found to contribute to cycling hypoxia in tumours, but tumour-specific fluctuations were also evident. Moreover, the size of the tumours was found to influence the degree of systemic, but not tumour-specific, oscillations. The degree of vessel maturation was related to the amplitude of tumour-specific, but not systemic, oscillations. CONCLUSIONS: Our results provide further insights into the complexity of spontaneous fluctuations in tumour oxygenation and its relationship with tumour pathophysiology. These observations could be used to develop improved drug delivery strategies.

Cuff deflation: rehabilitation in critical care.

This is a case series of rehabilitation failures that resulted in severe reactive depression from patients unnecessarily bereft of verbal communication by being left to breathe or be ventilated via tracheostomy tubes, with or without inflated cuffs, for months to years.

Alternatives to mouthpiece noninvasive ventilatory support to permit dental care.

Patients who are dependent on continuous noninvasive intermittent positive pressure ventilation for ventilatory support via angled mouthpiece interfaces during daytime hours often need dental interventions that are prevented by the presence of the mouthpiece. To permit dental interventions, however, the noninvasive intermittent positive pressure ventilation can most conveniently and safely be delivered via nasal interface using oximetry monitoring as long as both sedation and supplemental oxygen are avoided. Three mouthpiece continuous noninvasive intermittent positive pressure ventilation users are described who were switched to nasal noninvasive intermittent positive pressure ventilation to permit dental care. The most common mistake is to fail to cover the nasal interface exhalation portals when switching from ventilatory assistance by bilevel positive airway pressure devices with passive ventilator circuits to portable ventilators with active ventilator circuits and exhalation valves.

Genetics correlates with lung function and nocturnal ventilation in myotonic dystrophy.

BACKGROUND: Dystrophia myotonica (DM) is the most frequent adult-onset muscular dystrophy. Type 1 is caused by the cytosine-thymine-guanine (CTG) repeat expansion in the DM protein kinase gene. Respiratory muscle weakness and altered central ventilatory control lead to hypercapnia and lung volume restriction. PURPOSE: This study aims to review the respiratory involvement in DM patients and study its relation with genetics. METHODS: Retrospective study of patients with DM referred for respiratory assessment was made. Noninvasive ventilation (NIV) was considered to daytime hypercapnia or symptoms of nocturnal hypoventilation. RESULTS: Forty-two consecutive patients (37.9 ± 13.6 years) were evaluated. Mean CTG length was 642.8 ± 439.2 repeats. In the first evaluation, mean forced vital capacity (FVC) was 74.4 ± 20.2 %, maximal expiratory pressure (MEP) 35 ± 16 %, maximal inspiratory pressure 52 ± 23 %, peak cough flow (PCF) 327.3 ± 97.7 L/min, arterial pressure of oxygen 79.7 ± 11.3 mmHg, arterial pressure of carbon dioxide 45.5 ± 6.2 mmHg, overnight minimal peripheral oxygen saturation (SpO2) 79.6 ± 11.6 %, and apnea-hypopnea index 13.9 ± 9.9. CTG length was found to be related with MEP (r = -0.67; p = 0.001) and SpO2 (r = -0.37; p = 0.039). NIV was started in 25 patients. Ventilated patients had lower FVC (2.19 to 3.21 L; p < 0.001) and PCF (285.3 to 388.5 L/min; p = 0.003) and more CTG repeats (826.6 to 388.5 repeats; p = 0.02). NIV compliance was poor in seven patients (28 %) and related with hypercapnia (r = 0.87; p = 0.002) and inspiratory positive airway pressure setting (r = 0.65; p = 0.009). Ventilation improved symptoms and nocturnal hypoventilation. Comparing the first and last evaluations, only PCF was significantly lower (275.0 to 310.8 L/min; p = 0.019). CONCLUSIONS: Ventilatory insufficiency is very common in patients with DM and CTG length may be useful to predict it. Prolonged NIV improves symptoms, nocturnal hypoventilation and maintains daily blood gases. Routine evaluation of PCF should not be forgotten and assisted coughing training provided.

Changing trends in the management of end-stage neuromuscular respiratory muscle failure: recommendations of an international consensus.

OBJECTIVE: Respiratory management of patients with end-stage respiratory muscle failure of neuromuscular disease has evolved from no treatment and inevitable respiratory failure to the use of up to continuous noninvasive intermittent positive pressure ventilatory support (CNVS) to avert respiratory failure and to permit the extubation of "unweanable" patients without tracheostomy. An international panel experienced in CNVS was charged by the 69th Congress of the Mexican Society of Pulmonologists and Thoracic Surgeons to analyze changing respiratory management trends and to make recommendations. DESIGN: Neuromuscular disease respiratory consensuses and reviews were identified from PubMed. Individual respiratory interventions were identified; their importance was established by assessing the quality of evidence-based literature for each one and their patterns of use over time. The panel then determined the evidence-based strength for the efficacy of each intervention and made recommendations for achieving prolonged survival by CNVS. RESULTS: Fifty publications since 1993 were identified. Continuous positive airway pressure, oxygen therapy, bilevel positive airway pressure used at both low and high spans, "air stacking," manually assisted coughing, low pressure (<35 cm H2O) and high pressure (≥40 cm H2O) mechanically assisted coughing, noninvasive positive pressure ventilation part time (<23 hrs per day) and full time (>23 hrs per day; CNVS), extubation and decannulation of ventilator-dependent patients to CNVS, and oximetry feedback for noninvasive positive pressure ventilation and mechanically assisted coughing were identified. All noted interventions are being used with increasing frequency and were unanimously recommended to achieve prolonged survival by CNVS, with the exception of supplemental oxygen and continuous positive airway pressure, which are being used less and were not recommended for this population. CONCLUSIONS: CNVS and extubation of unweanable patients to CNVS are increasingly being used to prolong life while avoiding invasive interfaces.

Effects of mechanical insufflation-exsufflation in preventing respiratory failure after extubation: a randomized controlled trial.

INTRODUCTION: Weaning protocols that include noninvasive ventilation (NIV) decrease re-intubation rates and ICU length of stay. However, impaired airway clearance is associated with NIV failure. Mechanical insufflation-exsufflation (MI-E) has been proven to be very effective in patients receiving NIV. We aimed to assess the efficacy of MI-E as part of an extubation protocol. METHOD: Patients with mechanical ventilation (MV) for more than 48 hours with specific inclusion criteria, who successfully tolerated a spontaneous breathing trial (SBT), were randomly allocated before extubation, either for (A) a conventional extubation protocol (control group), or (B) the MI-E extubation protocol (study group). During the postextubation period (48 hours), group A patients received standard medical treatment (SMT), including NIV in case of specific indications, whereas group B received the same postextubation approach plus three daily sessions of mechanical in-exsufflation (MI-E). Reintubation rates, ICU length of stay, and NIV failure rates were analyzed. RESULTS: Seventy-five patients (26 women) with a mean age of 61.8 ± 17.3 years were randomized to a control group (n = 40; mean SAPS II, 47.8 ± 17.7) and to a study group (n = 35; mean SAPS II, 45.0 ± 15.0). MV time before enrollment was 9.4 ± 4.8 and 10.5 ± 4.1 days for the control and the study group, respectively. In the 48 hours after extubation, 20 control patients (50%) and 14 study patients (40%) used NIV. Study group patients had a significant lower reintubation rate than did controls; six patients (17%) versus 19 patients (48%), P < 0.05; respectively, and a significantly lower time under MV; 17.8 ± 6.4 versus 11.7 ± 3.5 days; P < 0.05; respectively. Considering only the subgroup of patients that used NIV, the reintubation rates related to NIV failure were significantly lower in the study group when compared with controls; two patients (6%) versus 13 (33%); P < 0.05, respectively. Mean ICU length of stay after extubation was significantly lower in the study group when compared with controls (3.1 ± 2.5 versus 9.8 ± 6.7 days; P < 0.05). No differences were found in the total ICU length of stay. CONCLUSION: Inclusion of MI-E may reduce reintubation rates with consequent reduction in postextubation ICU length of stay. This technique seems to be efficient in improving the efficacy of NIV in this patient population.

Continuous noninvasive ventilation delivered by a novel total face mask: a case series report.

Noninvasive ventilation (NIV) has been widely used to decrease the complications associated with tracheal intubation in mechanically ventilated patients. However, nasal ulcerations may occur when conventional masks are used for continuous ventilation. A total face mask, which has no contact with the more sensitive areas of the face, is a possible option. We describe 3 patients with acute respiratory failure due to amyotrophic lateral sclerosis, who developed nasal bridge skin necrosis during continuous NIV, and one patient with post-extubation respiratory failure due to a high spinal cord injury, who had facial trauma with contraindication for conventional mask use. The total face mask was very well tolerated by all the patients, and permitted safe and efficient continuous NIV for several days until the acute respiratory failure episode resolved. None of the patients required endotracheal intubation during the acute episode.

At home and on demand mechanical cough assistance program for patients with amyotrophic lateral sclerosis.

OBJECTIVE: To establish a cost-effective telephone-accessed consultation and mechanical in-exsufflation (MI-E) and manually assisted coughing, oximetry feedback program for 39 patients with amyotrophic lateral sclerosis. DESIGN: Rapid access to healthcare consultation and to MI-E was provided to treat episodes of distress as a result of secretion encumbrance not reversed by suctioning and associated with a decrease in oxyhemoglobin saturation (SpO(2)) baseline. Avoided hospitalizations, defined by relief of respiratory distress and return of SpO(2) baseline to >or=95% by continuous ventilator use and assisted coughing, were recorded. Patient satisfaction was queried at 6 mos, and a cost analysis was performed of continuous vs. on demand MI-E use. RESULTS: Thirty-nine patients made a total of 1661 calls in 7.46 +/- 5.8 mos of follow-up. Twenty-seven patients had 66 home care visits by a respiratory therapist for a total time commitment of 89.7 +/- 99.3 min/patient/mo. Twelve patients, all ventilator users, were also brought mechanical in-exsufflators for mechanically assisted coughing for 47 respiratory episodes. Thirty hospitalizations were avoided. Seventy-five percent of the patients were extremely satisfied. Mean monthly cost per patient for on-demand telephone consultation, professional home healthcare visits, and MI-E as deemed necessary was euro403 +/- euro420 or 59% less than for continuous MI-E rental. Hospitalization costs were also spared. CONCLUSIONS: An on-demand consult and MI-E access program can avoid hospitalizations for patients with amyotrophic lateral sclerosis with significant cost savings.