Amyotrophic lateral sclerosis : exercise and disease progression

Amyotrophic Lateral Sclerosis (ALS) belongs to a group of neurological disorders known as motor neuron diseases, which are caused by gradual degeneration and consequent death of motor neurons. In general, the disease begins in one of two fundamental ways: with involvement of the muscles of the bulbar region; or with loss of muscle strength of the upper or lower limbs - spinal form. Although other rare forms of manifestation are also cited in the literature, such as: respiratory (when respiratory muscles are initially affected); axial (initially affecting the cervical and paraspinal muscles) and the diffuse form (generalized onset of the disease). These forms of presentation determine the initial symptoms. Patients may initially develop muscle weakness in the limbs resulting in various clinical conditions with paresis, speech problems with dysarthria, dysphagia, and respiratory symptoms with dyspnea, and evolve to complete loss of body movements control. The degree of functional disability and dependence resulting from ALS lead the patient to gradually needing a caregiver for all their activities of daily life. The mean survival for ALS is around 3 - 5 years from first symptoms, and the fatal event usually occurs due to respiratory failure or infection. Although there is no effective treatment to halt disease progression, the clinical management has evolved positively in last years. The technological advance of medical interventions has contributed to a longer survival and higher quality of life. The monitoring of non-invasive ventilation has been very helpful for the clinical follow up and to decrease the anxiety experienced by caregivers. Unfortunately, the aerobic exercise is not a usual therapeutic option for ALS patients in the clinical management yet. Physical exercise has been suggested to promote growth factor delivery in experimental animal models of ALS. However, the aerobic exercise is understudied in ALS patients due the suspicious that the exercise could be harmful for this population. Meeting the recommendations from the last Cochrane review about Therapeutic exercise in ALS, we have analyzed the impact of aerobic exercise in the ALS progression. This thesis has 2 main contributions: 1 - To study the efficacy of moderated and accurate defined exercise program on the evolution and survival of ALS, and, 2 - to assess the feasibility to performing exercise monitored remotely from home in ALS patients. In addition, this thesis includes results from additional contributions, which are related to relevant issues always present during disease progression such as management of the respiratory failure (sub-chapters 5.2 and 5.3), the support for ALS caregivers (Chapter 6), and the potential impact of clinical management on disease progression in an environment with lack of resources (Chapter 7). In the sub-chapter 5.2 we present a work which describe the lack of consensus for the ideal timing to start NIV and about the use of alternative respiratory support. We address the impact of NIV and tracheostomy on family and / or informal caregivers, especially how it can affect quality of life. The importance of assessing the emotional, physical, social and psychological capacity of the caregiver is reinforced in order to cope with the increasing care needs of these patients. The sub-chapter 5.3 presents results on the importance of a careful management in the use and configuration of Non-Invasive Ventilation (NIV) parameters, in particular the role of ventilation and adherence adjustments in functional decline and survival of ventilated patients. A wide range of data recorded from the software used in ventilators, nocturnal pulse oximetry measurements and respiratory function tests were analyzed. Our results suggest that the variables that affect the respiratory comfort of the patient are relevant for adherence to NIV and positively affect survival in ALS. The Chapter 6 presents results of a feasibility study about a training program for caregivers. The uncertain progression of the disease and long-term care, as well as the insufficient number of skilled health professionals, determine that the admission of these patients to hospitals or to continuing care units is a complex option. Initiatives that allow better management of the disease at home can be an alternative solution. The functional disability of patients can promote significant financial constraints, and exposes their families to high levels of stress, which can compromise the provision of adequate health care, leading to the hospitalization of these patients. In this project, we identified an excellent level of participation as well as a good result in the evaluation of learning (above 70%). The main limiting factor for participation in the training program was the absence of a secondary caregiver. The Chapter 7 describes results from2 studies conducted with ALS patients in the African continent, which present data on disease progression in an environment with limited resources for clinical management. The Chapter 8 present a general discussion and conclusion of all works included in this Thesis. All the papers presented in this thesis aim to contribute to a broader view of the clinical management of ALS, where the role of exercise associated with more careful respiratory support, and the presence of a well-informed and trained caregiver, can together be an important contribution for the survival and quality of life of the patient with ALS. We hope our work presented in this thesis may contribute to a wider understanding on the clinical management of ALS. In particular demonstrating that controlled exercise associated with careful respiratory support, and the presence of a well-informed and trained caregiver, may be an added value in the survival and quality of life for ALS patient

Mechanical ventilation in patients with acute ischaemic stroke: From pathophysiology to clinical practice

Most patients with ischaemic stroke are managed on the ward or in specialty stroke units, but a significant number requires higher-acuity care and, consequently, admission to the intensive care unit. Mechanical ventilation is frequently performed in these patients due to swallowing dysfunction and airway or respiratory system compromise. Experimental studies have focused on stroke-induced immunosuppression and brain-lung crosstalk, leading to increased pulmonary damage and inflammation, as well as reduced alveolar macrophage phagocytic capability, which may increase the risk of infection. Pulmonary complications, such as respiratory failure, pneumonia, pleural effusions, acute respiratory distress syndrome, lung oedema, and pulmonary embolism from venous thromboembolism, are common and found to be among the major causes of death in this group of patients. Furthermore, over the past two decades, tracheostomy use has increased among stroke patients, who can have unique indications for this procedure - depending on the location and type of stroke - when compared to the general population. However, the optimal mechanical ventilator strategy remains unclear in this population. Although a high tidal volume (V T) strategy has been used for many years, the latest evidence suggests that a protective ventilatory strategy (V T = 6-8 mL/kg predicted body weight, positive end-expiratory pressure and rescue recruitment manoeuvres) may also have a role in brain-damaged patients, including those with stroke. The aim of this narrative review is to explore the pathophysiology of brain-lung interactions after acute ischaemic stroke and the management of mechanical ventilation in these patients

Substrats neurophysiologiques des interactions patient- ventilateur et des sensations respiratoires correspondantes

Ventilatory support must be tailored to the load capacity balance of the respiratory system to avoid patient-ventilator dysharmony as it may lead to patient-ventilator asynchronies and dyspnea. Minimizing this dysharmony is crucial. Neurally Ventilatory Assist Ventilation (NAVA) and Proportional Assist Ventilation (PAV) modes may improve patient-ventilator interaction. We showed in this work that PAV and NAVA both prevents overdistension, restores breath by breath variability of the breathing pattern and improves neuromechanical coupling and patient- ventilator asynchrony in fairly similar ways compared to pressure support ventilation. In addition the use of NAVA with non-invasive ventilation may also improve patient-ventilator interaction. We also demonstrated that dyspnea is a frequent issue in mechanically ventilated ICU patients and it can be difficult to assess when the patient is unable to report it. Surface electromyograms of extradiaphragmatic inspiratory muscles provides a simple, reliable and non-invasive indicator of respiratory muscle loading/unloading in mechanically ventilated patients. Because this EMG activity is strongly correlated to the intensity of dyspnea, it could be used as a surrogate of respiratory sensations in mechanically ventilated patients, and might, therefore, provide a monitoring tool in patients in whom detection and quantification of dyspnea is complex if not impossible. These data provide a better understanding of patient-ventilator dysharmony. Further studies are needed to evaluate the possible clinical benefits of NAVA and PAV on clinical outcomes and the impact of an early detection of dyspnea in mechanical ventilation.En ventilation assistée, l’inadéquation entre l’activité des muscles respiratoires du patient et l’assistance délivrée par le ventilateur se traduit par la survenue d’une dysharmonie patient-ventilateur potentiellement associée avec la survenue d’asynchronies patient-ventilateur et d’une dyspnée. Minimiser cette dysharmonie est un objectif majeur de la ventilation assistée. Le Neuro Asservissement de la Ventilation Assistée (NAVA) et la Ventilation Assistée Proportionnelle (PAV) sont deux nouveaux modes qui pourraient améliorer l’harmonie patient-ventilateur. Nous avons montré que, de façon similaire, le NAVA et la PAV diminuent le nombre d’asynchronie patient-ventilateur, préviennent la surdistension pulmonaire, restaurent la variabilité cycle à cycle du comportement ventilatoire et améliorent l’équilibre charge-capacité et le couplage neuromécanique. De plus, l’utilisation du mode NAVA en ventilation non invasive pourrait également permettre d’améliorer la synchronisation patient-ventilateur. Nous avons également montré aux cours de différents travaux sur la dyspnée en ventilation mécanique que celle ci était fréquente mais néanmoins difficile à identifier, en particulier chez les patients non communicants. L’EMG de surface des muscles inspiratoires extra-diaphragmatiques pourrait constituer un outil simple et objectif pouvant permettre au clinicien de diagnostiquer une dyspnée en ventilation mécanique et optimiser les réglages du ventilateur dans le but de minimiser la dysharmonie patient-ventilateur. Ces données permettent de progresser vers une meilleure connaissance de la dysharmonie patient- ventilateur. L’impact clinique de l’utilisation des modes proportionnels et d’une détection précoce de la dyspnée doit maintenant être évalué par des essais cliniques

Breathing pattern characterization in patients with respiratory and cardiac failure

El objetivo principal de la tesis es estudiar los patrones respiratorios de pacientes en proceso de extubación y pacientes con insuficiencia cardiaca crónica (CHF), a partirde la señal de flujo respiratorio. La información obtenida de este estudio puede contribuir a la comprensión de los procesos fisiológicos subyacentes,y ayudar en el diagnóstico de estos pacientes. Uno de los problemas más desafiantes en unidades de cuidados intensivos es elproceso de desconexión de pacientes asistidos mediante ventilación mecánica. Más del 10% de pacientes que se extuban tienen que ser reintubados antes de 48 horas. Una prueba fallida puede ocasionar distrés cardiopulmonar y una mayor tasa de mortalidad. Se caracterizó el patrón respiratorio y la interacción dinámica entre la frecuenciacardiaca y frecuencia respiratoria, para obtener índices no invasivos que proporcionen una mayor información en el proceso de destete y mejorar el éxito de la desconexión.Las señales de flujo respiratorio y electrocardiográfica utilizadas en este estudio fueron obtenidas durante 30 minutos aplicando la prueba de tubo en T. Se compararon94 pacientes que tuvieron éxito en el proceso de extubación (GE), 39 pacientes que fracasaron en la prueba al mantener la respiración espontánea (GF), y 21 pacientes quesuperaron la prueba con éxito y fueron extubados, pero antes de 48 horas tuvieron que ser reintubados (GR). El patrón respiratorio se caracterizó a partir de las series temporales. Se aplicó la dinámica simbólica conjunta a las series correspondientes a las frecuencias cardiaca y respiratoria, para describir las interacciones cardiorrespiratoria de estos pacientes. Técnicas de "clustering", ecualización del histograma, clasificación mediante máquinasde soporte vectorial (SVM) y técnicas de validación permitieron seleccionar el conjunto de características más relevantes. Se propuso una nueva métrica B (índice de equilibrio) para la optimización de la clasificación con muestras desbalanceadas. Basado en este nuevo índice, aplicando SVM, se seleccionaron las mejores características que mantenían el mejor equilibrio entre sensibilidad y especificidad en todas las clasificaciones. El mejor resultado se obtuvo considerando conjuntamente la precisión y el valor de B, con una clasificación del 80% entre los grupos GE y GF, con 6 características. Clasificando GE vs. el resto de los pacientes, el mejor resultado se obtuvo con 9 características, con 81%. Clasificando GR vs. GE y GR vs. el resto de pacientes la precisión fue del 83% y 81% con 9 y 10 características, respectivamente. La tasa de mortalidad en pacientes con CHF es alta y la estratificación de estospacientes en función del riesgo es uno de los principales retos de la cardiología contemporánea. Estos pacientes a menudo desarrollan patrones de respiraciónperiódica (PB) incluyendo la respiración de Cheyne-Stokes (CSR) y respiración periódica sin apnea. La respiración periódica en estos pacientes se ha asociadocon una mayor mortalidad, especialmente en pacientes con CSR. Por lo tanto, el estudio de estos patrones respiratorios podría servir como un marcador de riesgo y proporcionar una mayor información sobre el estado fisiopatológico de pacientes con CHF. Se pretende identificar la condición de los pacientes con CHFde forma no invasiva mediante la caracterización y clasificación de patrones respiratorios con PBy respiración no periódica (nPB), y patrón de sujetos sanos, a partir registros de 15minutos de la señal de flujo respiratorio. Se caracterizó el patrón respiratorio mediante un estudio tiempo-frecuencia estacionario y no estacionario, de la envolvente de la señal de flujo respiratorio. Parámetros relacionados con la potencia espectral de la envolvente de la señal presentaron losmejores resultados en la clasificación de sujetos sanos y pacientes con CHF con CSR, PB y nPB. Las curvas ROC validan los resultados obtenidos. Se aplicó la "correntropy" para una caracterización tiempo-frecuencia mas completa del patrón respiratorio de pacientes con CHF. La "corretronpy" considera los momentos estadísticos de orden superior, siendo más robusta frente a los "outliers". Con la densidad espectral de correntropy (CSD) tanto la frecuencia de modulación como la dela respiración se representan en su posición real en el eje frecuencial. Los pacientes con PB y nPB, presentan diferentesgrados de periodicidad en función de su condición, mientras que los sujetos sanos no tienen periodicidad marcada. Con único parámetro se obtuvieron resultados del 88.9% clasificando pacientes PB vs. nPB, 95.2% para CHF vs. sanos, 94.4% para nPB vs. sanos.The main objective of this thesis is to study andcharacterize breathing patterns through the respiratory flow signal applied to patients on weaning trials from mechanicalventilation and patients with chronic heart failure (CHF). The aim is to contribute to theunderstanding of the underlying physiological processes and to help in the diagnosis of these patients. One of the most challenging problems in intensive care units is still the process ofdiscontinuing mechanical ventilation, as over 10% of patients who undergo successfulT-tube trials have to be reintubated in less than 48 hours. A failed weaning trial mayinduce cardiopulmonary distress and carries a higher mortality rate. We characterize therespiratory pattern and the dynamic interaction between heart rate and breathing rate toobtain noninvasive indices that provide enhanced information about the weaningprocess and improve the weaning outcome. This is achieved through a comparison of 94 patients with successful trials (GS), 39patients who fail to maintain spontaneous breathing (GF), and 21 patients who successfully maintain spontaneous breathing and are extubated, but require thereinstitution of mechanical ventilation in less than 48 hours because they are unable tobreathe (GR). The ECG and the respiratory flow signals used in this study were acquired during T-tube tests and last 30 minute. The respiratory pattern was characterized by means of a number of respiratory timeseries. Joint symbolic dynamics applied to time series of heart rate and respiratoryfrequency was used to describe the cardiorespiratory interactions of patients during theweaning trial process. Clustering, histogram equalization, support vector machines-based classification (SVM) and validation techniques enabled the selection of the bestsubset of input features. We defined a new optimization metric for unbalanced classification problems, andestablished a new SVM feature selection method, based on this balance index B. The proposed B-based SVM feature selection provided a better balance between sensitivityand specificity in all classifications. The best classification result was obtained with SVM feature selection based on bothaccuracy and the balance index, which classified GS and GFwith an accuracy of 80%, considering 6 features. Classifying GS versus the rest of patients, the best result wasobtained with 9 features, 81%, and the accuracy classifying GR versus GS, and GR versus the rest of the patients was 83% and 81% with 9 and 10 features, respectively.The mortality rate in CHF patients remains high and risk stratification in these patients isstill one of the major challenges of contemporary cardiology. Patients with CHF oftendevelop periodic breathing patterns including Cheyne-Stokes respiration (CSR) and periodic breathing without apnea. Periodic breathing in CHF patients is associated withincreased mortality, especially in CSR patients. Therefore it could serve as a risk markerand can provide enhanced information about thepathophysiological condition of CHF patients. The main goal of this research was to identify CHF patients' condition noninvasively bycharacterizing and classifying respiratory flow patterns from patients with PB and nPBand healthy subjects by using 15-minute long respiratory flow signals. The respiratory pattern was characterized by a stationary and a nonstationary time-frequency study through the envelope of the respiratory flow signal. Power-related parameters achieved the best results in all of the classifications involving healthy subjects and CHF patients with CSR, PB and nPB and the ROC curves validated theresults obtained for the identification of different respiratory patterns. We investigated the use of correntropy for the spectral characterization of respiratory patterns in CHF patients. The correntropy function accounts for higher-order moments and is robust to outliers. Due to the former property, the respiratory and modulationfrequencies appear at their actual locations along the frequency axis in the correntropy spectral density (CSD). The best results were achieved with correntropy and CSD-related parameters that characterized the power in the modulation and respiration discriminant bands, definedas a frequency interval centred on the modulation and respiration frequency peaks,respectively. All patients, i.e. both PB and nPB, exhibit various degrees of periodicitydepending on their condition, whereas healthy subjects have no pronounced periodicity.This fact led to excellent results classifying PB and nPB patients 88.9%, CHF versushealthy 95.2%, and nPB versus healthy 94.4% with only one parameter.Postprint (published version

Effects of portable non-invasive ventilation on exercise tolerance in patients with COPD

Breathlessness is the dominant symptom that limits exercise tolerance in patients with COPD. Several ergogenic approaches have been employed to improve exercise tolerance in this population including bronchodilators, oxygen and heliox supplementation, intermittent exercise and non-invasive ventilation (NIV). Although application of NIV during exercise is beneficial for increasing exercise capacity in patients with COPD, there are several disadvantages that limit its wider application during exercise, including lack of compliance with the equipment, and the time required to set up and supervise the equipment in the setting of pulmonary rehabilitation. Recent advances in technology have facilitated the development of portable non-invasive ventilation (pNIV) devices aiming to alleviate breathlessness during activities of daily living. The VitaBreath (Philips, Respironics) was developed in 2016 as a portable, handheld, battery powered, bi-level, NIV device, providing fixed positive inspiratory and expiratory airway pressure support (IPAP:18 and EPAP: 8 cmH2O, respectively). Accordingly, this dissertation aimed to investigate the physiological effects of pNIV application during controlled laboratory exercise conditions and activities of daily living, in patients with advanced COPD. As the VitaBreath device is no longer commercially available, but similar devices may come to market, the present dissertation provides proof of concept on how pNIV can be applied intermittently during exercise in patients with COPD, and how to select patients most likely to respond to pNIV. This in turn may encourage the development of more suitable devices. Intermittent exercise was chosen to evaluate the effects of pNIV in comparison to the commonly adopted pursed lip breathing (PLB) technique, as this type of exercise allowed regular application of the pNIV device or the PLB technique during recovery periods. Patients retained the device for 3 months to investigate the acceptability, comfort and usability of the device during activities of daily living. Twenty-four COPD patients were randomised to perform two intermittent exercise protocols sustained at different work intensities (60% WRpeak for 6-min and 80% WRpeak for 2-min) alternated with 2-min rest periods. Within each intermittent exercise modality, patients performed two identical exercise tests using either pNIV or the PLB technique in a balanced order sequence, during the recovery phases of intermittent exercise. The findings of this study showed that with both intermittent protocols average endurance time was greater when pNIV was applied compared to PLB. Improvements in exercise tolerance were due to lower degrees of dynamic hyperinflation (DH) and breathlessness with pNIV compared to PLB. An important finding of the aforementioned study was that a subgroup of patients (8/24) failed to show a clinical important improvement in DH with pNIV compared to PLB and did not improve exercise tolerance. Analysis identified that these 8 patients experienced greater resting lung hyperinflation, greater exercise-induced DH and breathlessness, secondary to the adoption of a tachypnoeic breathing pattern with pNIV compared to PLB. Interestingly, these patients also reported less benefit from using the device at home, in terms of anxiety around breathlessness and recovery time from breathlessness. Considering the variation of response reported in the present thesis it is important that clinicians assess the response to pNIV on an individual basis. As with any new method, it was important to appreciate the physiological consequences of the acute application of pNIV on thoracoabdominal volume regulation and respiratory muscle recruitment (assessed by optoelectronic plethysmography), and central hemodynamic responses. Compared to PLB, acute application of pNIV was associated, in the majority of patients, with increased end-inspiratory and end-expiratory rib cage volumes and greater rib cage muscle recruitment, as well as decreased end-expiratory abdominal volumes reflecting reduced expiratory abdominal recruitment. Measurement of cardiac output revealed no adverse circulatory responses with the application of positive airway pressures provided by pNIV during the recovery periods. However, the pattern of thoracoabdominal volume regulation and respiratory muscle kinematics confirmed the findings of the original studies, thereby identifying responders and non-responders to pNIV. Interestingly, responders to pNIV exhibited greater recruitment of the expiratory abdominal muscles compared to non-responders, thereby facilitating them to combat end-expiratory rib cage dynamic hyperinflation effectively. When patients used the VitaBreath device during their daily physical activities, the majority of patients felt less anxious about becoming breathless and felt that their breathlessness recovered faster when using the device at home for 3 months. Moreover, almost all patients used the device at least weekly and all patients rated the ease of VitaBreath use to be between good and excellent. Additionally, most patients felt that using the device had benefited them and that they would recommend the device to other patients. The main disadvantage of the device was reported to be the high cost and its portability. The pNIV method provided fixed IPAP and EPAP. This represents a very important disadvantage of this particular pNIV device, which clearly mitigated the beneficial impact it had on some patients. Future research into pNIV devices should examine how best to identify patients who benefit from a pNIV method in everyday life. On-going development of auto-adjusted ventilators would facilitate a larger fraction of COPD patients to be physically active and experience a better quality of life

European Respiratory Society Statement on Thoracic Ultrasound

Thoracic ultrasound is increasingly considered to be an essential tool for the pulmonologist. It is used in diverse clinical scenarios, including as an adjunct to clinical decision making for diagnosis, a real-time guide to procedures, and a predictor or measurement of treatment response. The aim of this European Respiratory Society task force was to produce a statement on thoracic ultrasound for pulmonologists using thoracic ultrasound within the field of respiratory medicine. The multidisciplinary panel performed a review of the literature, addressing major areas of thoracic ultrasound practice and application. The selected major areas include equipment and technique, assessment of the chest wall, parietal pleura, pleural effusion, pneumothorax, interstitial syndrome, lung consolidation, diaphragm assessment, intervention guidance, training, and the patient perspective. Despite the growing evidence supporting the use of thoracic ultrasound, the published literature still contains a paucity of data in some important fields. Key research questions for each of the major areas were identified, which serve to facilitate future multi-centre collaborations and research to further consolidate an evidence-based use of thoracic ultrasound, for the benefit of the many patients being exposed to clinicians using thoracic ultrasound