Modeling and Estimation of Cardiorespiratory Function, with Application to Mechanical Ventilation

Evidence-based medicine is at the heart of current medical practice where clinical decisions are driven by research data. However, most current therapy recommendations follow generalized protocols and guidelines that are based on epidemiological (population) studies and thus not suited for the individual patient's demands. Patient-tailored therapies are considered, hence, an unmet clinical need. We believe that mathematical models of the physiology can attend to such a clinical need, because they can be tuned to the individual patient. Such models provide a sound mathematical framework for personalized clinical decisions. In particular, physiological models in medicine can serve the following two purposes: 1) They can be an efficient tool to quantify cardiopulmonary dynamics, conduct virtual clinical/physiological experiments, and investigate the effects of specific treatments. 2) Model-based estimation techniques can assess physiological parameters or variables, which are otherwise impractical or dangerous to measure; they can effectively tune a generic model to become patient-specific, able to mimic the behavior of a particular patient. In this thesis, we propose a series of modifications to a previously developed cardiopulmonary model (CP Model) in order to better replicate heart-lung interaction phenomena that are typically observed under mechanical ventilation, hence allowing for a more accurate analysis of ventilation-induced changes in cardiac function. The response of this modified model is validated with experimental data collected during mechanical ventilation conditions. Further, as an industrial application of mathematical models, we present a patient emulator system that comprises the modified CP Model, a physical ventilator, and a piston-cylinder arrangement that serves as an electrical-to-hydraulic transducer. The modified CP Model then serves as the virtual patient that is being ventilated, where disease conditions can be instilled. Such a system is designed to offer a well-controlled experimental environment for ventilator manufacturers to efficaciously test and compare ventilation modalities and therapies, thereby enhancing their verification and validation manufacturing processes. Finally, we develop a model-based approach to estimate (noninvasively) the function of the cardiovascular system, in terms of cardiac performance (i.e., cardiac output) and the dynamics of the systemic arterial tree (i.e., time constant). With this technique, we envision to provide continuous and real-time bedside monitoring of changes in cardiovascular function, such as those induced by changes in ventilator settings

Web applications for teaching the respiratory system: content validation

The subject of respiratory mechanics has complex characteristics, functions, and interactions that can be difficult to understand in training and medical education contexts. As such, education strategies based on computational simulations comprise useful tools, but their application in the medical area requires stricter validation processes. This paper shows a statistical and a Delphi validation for two modules of a web application used for respiratory system learning: (I) “Anatomy and Physiology” and (II) “Work of Breathing Indexes”. For statistical validation, population and individual analyses were made using a database of healthy men to compare experimental and model-predicted data. For both modules, the predicted values followed the trend marked by the experimental data in the population analysis, while in the individual analysis, the predicted errors were 9.54% and 25.38% for maximal tidal volume and airflow, respectively, and 6.55%, 9.33%, and 11.77% for rapid shallow breathing index, work of breathing, and maximal inspiratory pressure, respectively. For the Delphi validation, an average higher than 4 was obtained after health professionals evaluated both modules from 1 to 5. In conclusion, both modules are good tools for respiratory system learning processes. The studied parameters behaved consistently with the expressions that describe ventilatory dynamics and were correlated with experimental data; furthermore, they had great acceptance by specialists.Peer ReviewedPostprint (published version

Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndrome

Paediatric acute respiratory distress syndrome (PARDS) is a heterogeneous clinical syndrome that is associated with high rates of mortality and long-term morbidity. Factors that distinguish PARDS from adult acute respiratory distress syndrome (ARDS) include changes in developmental stage and lung maturation with age, precipitating factors, and comorbidities. No specific treatment is available for PARDS and management is largely supportive, but methods to identify patients who would benefit from specific ventilation strategies or ancillary treatments, such as prone positioning, are needed. Understanding of the clinical and biological heterogeneity of PARDS, and of differences in clinical features and clinical course, pathobiology, response to treatment, and outcomes between PARDS and adult ARDS, will be key to the development of novel preventive and therapeutic strategies and a precision medicine approach to care. Studies in which clinical, biomarker, and transcriptomic data, as well as informatics, are used to unpack the biological and phenotypic heterogeneity of PARDS, and implementation of methods to better identify patients with PARDS, including methods to rapidly identify subphenotypes and endotypes at the point of care, will drive progress on the path to precision medicine.</p

The preterm infant : evaluating and developing non-invasive respiratory strategies to avoid mechanical ventilation

Avoiding mechanical ventilation of preterm infants is important to prevent morbidity and mortality. Non-invasive ventilation and CPAP has been shown to be superior to intubation and mechanical ventilation in preventing chronic lung disease in very preterm infants.1 . CPAP for infants was first used in the early 70’s. Since then, several different CPAP devices have been developed. Some of them are designed to give long term respiratory support while others are designed for initial support, with the possibility to give positive pressure ventilation (PPV) if needed. Some are expensive and complicated with several add on features while other are cheap, with simple mechanisms and easy to use. The goal for CPAP treatment is to give continuous airway pressure to the infants in order to minimize the work of breathing and improve gas exchange. But are all CPAP systems the same? Do all CPAP systems deliver stable airway pressure which helps the infants with their work of breathing? The overall aim of this thesis was to evaluate existing and newly developed devices for noninvasive respiratory support used in neonates in the DR and the NICU. The focus was on device resistance, pressure stability, imposed work of breathing and interfaces used. The aim of Paper I was to examine the in vitro performance of a new system (rPAP) and to perform a clinical feasibility trial, comparing a T-piece system with face mask, and the new system with face mask or nasal prongs, for initial stabilization of preterm infants. The new device was shown in a mechanical lung model to be pressure stable and have low imposed work of breathing compared to the T-piece. The feasibility trial comparing these devices revealed no safety issues when stabilizing preterm infants with the new device. The aim of Paper II was to examine the in vitro performance of the Medijet CPAP reusable and disposable generators and compare them to other CPAP systems. The main mechanism of CPAP generation for the disposable Medijet generator was shown to be resistance. The Medijet systems shows increasing resistance to breathing with each design generation. Our results suggest that the disposable Medijet should be used cautiously in patients where lowresistance and pressure-stable CPAP is believed to be clinically important. The aim of Paper III was to compare the revised Pumani CPAP system with two traditional bubble CPAP systems, focusing on in-vitro performance and safety. The revised Pumani system had high resistance, high imposed work of breathing and submersion depth had almost no impact on the delivered pressure which is the main CPAP generating mechanism of true bubble CPAP systems. The aim of Paper IV was to evaluate if using the new system (rPAP) with nasal prongs as interface, could reduce the need for intubation of extremely preterm infants in the DR compared to using the standard T-piece system with face mask. The CORSAD randomized controlled trial showed that using the new system decreased delivery room intubations in extremely preterm infants and creates thereby a possibility to avoid mechanical ventilation

Physiotherapy Care of Patients with Coronavirus Disease 2019 (COVID-19) - A Brazilian Experience

Some patients with coronavirus disease (COVID-19) present with severe acute respiratory syndrome, which causes multiple organ dysfunction, besides dysfunction of the respiratory system, that requires invasive procedures. On the basis of the opinions of front-line experts and a review of the relevant literature on several topics, we proposed clinical practice recommendations on the following aspects for physiotherapists facing challenges in treating patients and containing virus spread: 1. personal protective equipment, 2. conventional chest physiotherapy, 3. exercise and early mobilization, 4. oxygen therapy, 5. nebulizer treatment, 6. noninvasive ventilation and high-flow nasal oxygen, 7. endotracheal intubation, 8. protective mechanical ventilation, 9. management of mechanical ventilation in severe and refractory cases of hypoxemia, 10. prone positioning, 11. cuff pressure, 12. tube and nasotracheal suction, 13. humidifier use for ventilated patients, 14. methods of weaning ventilated patients and extubation, and 15. equipment and hand hygiene. These recommendations can serve as clinical practice guidelines for physiotherapists. This article details the development of guidelines on these aspects for physiotherapy of patients with COVID-19

Towards respiratory muscle-protective mechanical ventilation in the critically ill: technology to monitor and assist physiology

Inadequate delivery of ventilatory assist and unphysiological respiratory drive may severely worsen respiratory muscle function in mechanically ventilated critically ill patients. Diaphragm weakness in these patients is exceedingly common (>60% of patients) and associated with poor clinical outcomes, including difficult ventilator liberation, increased risks of intensive care unit (ICU) and hospital readmission, and mortality. The underlying mechanisms of diaphragm dysfunction were extensively discussed in this thesis. Pathways primarily include the development of diaphragm disuse atrophy due to muscle inactivity or low respiratory drive (strong clinical evidence), and diaphragm injury as a result of excessive breathing effort due to insufficient ventilator assist or excessive respiratory drive (moderate evidence, mostly from experimental work). Excessive breathing effort may also worsen lung injury through pathways that include high lung stress and strain, pendelluft, increased lung perfusion, and patient-ventilator dyssynchrony. Relatively little attention has been paid to the effects of critical illness and mechanical ventilation on the expiratory muscles; however, dysfunction of these muscles has been linked to inadequate central airway clearance and extubation failure. The motivation for performing the work presented in this thesis was the hypothesis that maintaining physiological levels of respiratory muscle activity under mechanical ventilation could prevent or attenuate the development respiratory muscle weakness, and hence, improve patient outcomes. This strategy, integrated with lung-protective ventilation, was recently proposed by international experts from different professional societies (this thesis), and is referred to as a combined lung and diaphragm-protective ventilation approach. Today, an important barrier for implementing and evaluating such an approach is the lack of feasible, reliable and well-understood modalities to assess breathing effort at the bedside, as well as strategies for assisting and restoring respiratory muscle function during mechanical ventilation. Furthermore, monitoring breathing effort is crucial to identify potential relationships between patient management and detrimental respiratory (muscle) function that can be targeted to improve clinical outcomes. In this thesis we identified and improved monitoring modalities for the diaphragm (Part I), we investigated the impact of mechanical ventilation on the respiratory pump, especially the diaphragm (Part II), and we evaluated a novel strategy for maintaining expiratory muscle activity under mechanical ventilation (Part III)

Association of intensity of ventilation with 28-day mortality in COVID-19 patients with acute respiratory failure:insights from the PRoVENT-COVID study

BACKGROUND: The intensity of ventilation, reflected by driving pressure (ΔP) and mechanical power (MP), has an association with outcome in invasively ventilated patients with or without acute respiratory distress syndrome (ARDS). It is uncertain if a similar association exists in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure.METHODS: We aimed to investigate the impact of intensity of ventilation on patient outcome. The PRoVENT-COVID study is a national multicenter observational study in COVID-19 patients receiving invasive ventilation. Ventilator parameters were collected a fixed time points on the first calendar day of invasive ventilation. Mean dynamic ΔP and MP were calculated for individual patients at time points without evidence of spontaneous breathing. A Cox proportional hazard model, and a double stratification analysis adjusted for confounders were used to estimate the independent associations of ΔP and MP with outcome. The primary endpoint was 28-day mortality.RESULTS: In 825 patients included in this analysis, 28-day mortality was 27.5%. ΔP was not independently associated with mortality (HR 1.02 [95% confidence interval 0.88-1.18]; P = 0.750). MP, however, was independently associated with 28-day mortality (HR 1.17 [95% CI 1.01-1.36]; P = 0.031), and increasing quartiles of MP, stratified on comparable levels of ΔP, had higher risks of 28-day mortality (HR 1.15 [95% CI 1.01-1.30]; P = 0.028).CONCLUSIONS: In this cohort of critically ill invasively ventilated COVID-19 patients with acute respiratory failure, we show an independent association of MP, but not ΔP with 28-day mortality. MP could serve as one prognostic biomarker in addition to ΔP in these patients. Efforts aiming at limiting both ΔP and MP could translate in a better outcome. Trial registration Clinicaltrials.gov (study identifier NCT04346342).</p