Optimal Determination of Respiratory Airflow Patterns Using a Nonlinear Multicompartment Model for a Lung Mechanics System

We develop optimal respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. Specifically, we use classical calculus of variations minimization techniques to derive an optimal airflow pattern for inspiratory and expiratory breathing cycles. The physiological interpretation of the optimality criteria used involves the minimization of work of breathing and lung volume acceleration for the inspiratory phase, and the minimization of the elastic potential energy and rapid airflow rate changes for the expiratory phase. Finally, we numerically integrate the resulting nonlinear two-point boundary value problems to determine the optimal airflow patterns over the inspiratory and expiratory breathing cycles

Infant populations exposed to prolonged sedation: are they at risk for long-term sequelae?

OBJECTIVE: Opioids are considered standard of care for pain treatment for infants undergoing painful procedures. In addition, prolonged opioid administration is used for sedation during non-surgical treatment (e.g. infants that require intubation and prolonged ventilation). Intubated infants often receive sedative drugs for a prolonged period of time, which leads to opioid dependence and tolerance. The long-term sequelae of such treatment involving the prolonged administration of opioids are unknown. There is evidence in cell cultures and animal models that prolonged opioid exposure is associated with increased neuronal apoptosis (neuronal cell death). In addition, human studies in premature children have suggested that prolonged opioid treatment is associated with decreased visual intelligence, social skills, and memory function. The goal of this study was to identify the population of the youngest patients (less than one year old) that requires prolonged administration of opioids for pain and sedation management. Our overarching hypothesis is that a select group of patients might be at risk for long-term neurologic sequelae from prolonged opioid treatment. METHODS: A retrospective chart review for admission cases over a period of one year was conducted to identify infants that received prolonged administration of opioids and/or benzodiazepines for their treatment. Infants were included if they were less than one year old, full-term (born 37-42 weeks of gestational age), and received prolonged treatment with opioids (e.g. fentanyl, morphine, hydromorphone) and/or benzodiazepines (e.g. midazolam, diazepam, lorazepam). Data on their diagnoses and sedation management at Boston Children's Hospital, including total dose of drugs received and if they developed dependence, was collected. RESULTS: Out of the 221 charts reviewed, only 46 infants were exposed to prolonged sedation and were full-term. Of these 46 infants, the largest proportion (35%; 16/46) was diagnosed with congenital anomalies. The other diagnoses included respiratory diseases (24%; 11/46), neurological diseases (13%; 6/46), and the remaining infants had a combination of two to three of these diagnoses (28%; 13/46). Infants with congenital diseases had a longer duration of sedation management (59.3 days ± 31.3 days) than infants with respiratory distress/infection (5.9 days ± 3.4 days). Those receiving the longest opioid treatments also exhibited signs of withdrawal when drugs were discontinued, which suggested the development of opioid dependence and required weaning treatment. Patients with sedation for 4 days or less did not show withdrawal symptoms, while those with sedation of 6 days or more required an opioid and benzodiazepine weaning regimen. CONCLUSION: The chart review was valuable from several perspectives. Sedation management at Boston Children's Hospital included prolonged administration not only of opioids, but also benzodiazepines. Such treatment is considered the standard of care. Even otherwise healthy, full-term children that received such sedation for the management of an acute illness (e.g. pneumonia) were at risk for opioid and benzodiazepine dependence if they required intubation and sedation for longer than 4 days. However, the majority of full-term children at risk for potential long-term sequelae of prolonged sedation presented with other confounding factors (e.g. congenital diseases, surgeries, exposure to anesthetic agents). In summary, future research on potential long-term sequelae of prolonged opioid administration should include infants with complex medical diseases as they were exposed to such treatment the longest

Adaptive Inverse Dynamics Control Scheme of Two-Compartment Lung System

University of Minnesota M.S.E.E. thesis. March 2017. Major: Electrical Engineering. Advisor: Jiann Shiou Yang. 1 computer file (PDF); iv, 55 pages.A study of using an adaptive inverse dynamics control technique to a two-compartment modeled respiratory system. Based on the nonlinear respiratory model and desired respiratory volumes, the adaptive inverse dynamics control scheme consisting of a control law and an adaptation law is then applied. The control law has the structure of the two-compartment inverse dynamical model but uses estimates of the dynamics parameters in the computation of pressure applied to the lungs. The adaptation law uses the tracking error to compute the parameter estimates for the control law. The preliminary results indicate that the tracking errors can be improved if the parameter values associated with the adaptation law are properly chosen, and the performance is also robust despite relatively large deviations in the initial estimates of the system parameter

Reduced Cardiorespiratory Fitness after Stroke: Biological Consequences and Exercise-Induced Adaptations

Evidence from several studies consistently shows decline in cardiorespiratory (CR) fitness and physical function after disabling stroke. The broader implications of such a decline to general health may be partially understood through negative poststroke physiologic adaptations such as unilateral muscle fiber type shifts, impaired hemodynamic function, and decrements in systemic metabolic status. These physiologic changes also interrelate with reductions in activities of daily living (ADLs), community ambulation, and exercise tolerance, causing a perpetual cycle of worsening disability and deteriorating health. Fortunately, initial evidence suggests that stroke participants retain the capacity to adapt physiologically to an exercise training stimulus. However, despite this evidence, exercise as a therapeutic intervention continues to be clinically underutilized in the general stroke population. Far more research is needed to fully comprehend the consequences of and remedies for CR fitness impairments after stroke. The purpose of this brief review is to describe some of what is currently known about the physiological consequences of CR fitness decline after stroke. Additionally, there is an overview of the evidence supporting exercise interventions for improving CR fitness, and associated aspects of general health in this population

Pathophysiology of Spinal Cord Injury (SCI)

Spinal cord injury (SCI) leads to paralysis, sensory, and autonomic nervous system dysfunctions. However, the pathophysiology of SCI is complex, and not limited to the nervous system. Indeed, several other organs and tissue are also affected by the injury, directly or not, acutely or chronically, which induces numerous health complications. Although a lot of research has been performed to repair motor and sensory functions, SCI-induced health issues are less studied, although they represent a major concern among patients. There is a gap of knowledge in pre-clinical models studying these SCI-induced health complications that limits translational applications in humans. This reprint describes several aspects of the pathophysiology of spinal cord injuries. This includes, but is not limited to, the impact of SCI on cardiovascular and respiratory functions, bladder and bowel function, autonomic dysreflexia, liver pathology, metabolic syndrome, bones and muscles loss, and cognitive functions

Investigating Risk Factors for Pediatric Opioid Morbidity and Mortality

Young children are sometimes prescribed opioids and may be exposed to opioids in utero and through breast milk. Clinical and genetic factors create large inter- individual variability in opioid response and have been associated with life threatening and often fatal adverse drug reactions in young children. Genetic factors have been studied in adults but there is little clinical evidence in young children. The focus of this thesis is on three commonly prescribed opioids: codeine, morphine and methadone. The objective of this work was to investigate risk factors associated with opioid related morbidity and mortality in young children. Risk factors were examined in three populations of children including neonates exposed to opioids in utero, infants exposed to codeine in breast milk as well as young children receiving codeine and morphine for post-surgical pain relief. We hypothesize that genetics and clinical factors will affect opioid response in young children. As the prevalence of opioid use increases it is important to investigate clinical and genetic risk factors as well as cost-effective treatment options. Neonates exposed to opioids in utero do not show an increased risk for mortality. Genetics may play a role in the development of neonatal withdrawal symptoms following in utero methadone exposure. Further work is necessary in order to corroborate the role of genetic and clinical factors in predicting neonatal abstinence syndrome. Codeine use during lactation has been shown to result in a significant neonatal sedation, much of which was associated with maternal genotype and dose. Guidelines based on predetermined clinical risk factors were able to mitigate the previously identified increased genetic risk. Several fatalities have been reported following codeine use in children post-tonsillectomy. In a randomized clinical trial we found that standard morphine doses (0.2-0.5mg/kg) may not be a safe alternative in children with obstructive sleep apnea. The safety and effectiveness of lower morphine doses should be investigated. Genetic variability in drug metabolizing enzymes, drug transporters and receptors, influence opioid response and create risks for adverse effects in young children. Standard doses of opioids are not safe in all children, and should be dosed on an individual basis

Proceeding: 3rd Java International Nursing Conference 2015 “Harmony of Caring and Healing Inquiry for Holistic Nursing Practice; Enhancing Quality of Care”, Semarang, 20-21 August 2015

This is the proceeding of the 3rd Java International Nursing Conference 2015 organized by School of Nursing, Faculty of Medicine, Diponegoro University, in collaboration with STIKES Kendal. The conference was held on 20-21 August 2015 in Semarang, Indonesia. The conference aims to enable educators, students, practitioners and researchers from nursing, medicine, midwifery and other health sciences to disseminate and discuss evidence of nursing education, research, and practices to improve the quality of care. This conference also provides participants opportunities to develop their professional networks, learn from other colleagues and meet leading personalities in nursing and health sciences. The 3rd JINC 2015 was comprised of keynote lectures and concurrent submitted oral presentations and poster sessions. The following themes have been chosen to be the focus of the conference: (a) Multicenter Science: Physiology, Biology, Chemistry, etc. in Holistic Nursing Practice, (b) Complementary Therapy in Nursing and Complementary, Alternative Medicine: Alternative Medicine (Herbal Medicine), Complementary Therapy (Cupping, Acupuncture, Yoga, Aromatherapy, Music Therapy, etc.), (c) Application of Inter-professional Collaboration and Education: Education Development in Holistic Nursing, Competencies of Holistic Nursing, Learning Methods and Assessments, and (d) Application of Holistic Nursing: Leadership & Management, Entrepreneurship in Holistic Nursing, Application of Holistic Nursing in Clinical and Community Settings

Automatic Control of General Anesthesia: New Developments and Clinical Experiments

L’anestesia generale è uno stato di coma farmacologicamente indotto, temporaneo e reversibile. Il suo obiettivo consiste nel provocare la perdita totale della coscienza e nel sopprimere la percezione del dolore. Essa costituisce un aspetto fondamentale per la medicina moderna in quanto consente di praticare interventi chirurgici invasivi senza causare ansia e dolore al paziente. Nella pratica clinica dell’anestesia totalmente endovenosa questi effetti vengono generalmente ottenuti mediante la somministrazione simultanea del farmaco ipnotico propofol e del farmaco analgesico remifentanil. Il dosaggio di questi farmaci viene gestito dal medico anestesista basandosi su linee guida farmacologiche e monitorando la risposta clinica del paziente. Recenti sviluppi nelle tecniche di elaborazione dei segnali fisiologici hanno consentito di ottenere degli indicatori quantitativi dello stato anestetico del paziente. Tali indicatori possono essere utilizzati come segnali di retroazione per sistemi di controllo automatico dell'anestesia. Lo sviluppo di questi sistemi ha come obiettivo quello di fornire uno strumento di supporto per l'anestesista. Il lavoro presentato in questa tesi è stato svolto nell'ambito del progetto di ricerca riguardante il controllo automatico dell'anestesia attivo presso l'Università degli Studi di Brescia. Esso è denominato ACTIVA (Automatic Control of Total IntraVenous Anesthesia) ed è il risultato della collaborazione tra il Gruppo di Ricerca sui Sistemi di Controllo dell’Università degli Studi di Brescia e l’Unità Operativa Anestesia e Rianimazione 2 degli Spedali Civili di Brescia. L’obiettivo del progetto ACTIVA consiste nello sviluppo teorico, nell’implementazione e nella validazione clinica di strategie di controllo innovative per il controllo automatico dell’anestesia totalmente endovenosa. Nel dettaglio, in questa tesi vengono inizialmente presentati i risultati sperimentali ottenuti con strutture di controllo basate sull'algoritmo PID e PID ad eventi per la somministrazione di propofol e remifentanil. Viene poi presentato lo sviluppo teorico e la validazione clinica di strutture di controllo predittivo basate su modello. Successivamente vengono presentati i risultati di uno studio in simulazione riguardante una soluzione di controllo innovativa che consente all'anestesista di regolare esplicitamente il bilanciamento tra propofol e remifentanil. Infine, vengono presentati gli sviluppi teorici ed i relativi studi in simulazione riguardanti soluzioni di controllo personalizzate per le fasi di induzione e mantenimento dell'anestesia.General anesthesia is a state of pharmacologically induced, temporary and reversible coma. Its goal is to cause total loss of consciousness and suppress the perception of pain. It constitutes a fundamental aspect of modern medicine as it allows invasive surgical procedures to be performed without causing anxiety and pain to the patient. In the clinical practice of total intravenous anesthesia, these effects are generally obtained by the simultaneous administration of the hypnotic drug propofol and of the analgesic drug remifentanil. The dosing of these drugs is managed by the anesthesiologist on the basis of pharmacological guidelines and by monitoring the patient's clinical response. Recent developments in physiological signal processing techniques have introduced the possibility to obtain quantitative indicators of the patient's anesthetic state. These indicators can be used as feedback signals for automatic anesthesia control systems. The development of these systems aims to provide a support tool for the anesthesiologist. The work presented in this thesis has been carried out in the framework of the research project concerning the automatic control anesthesia at the University of Brescia. The project is called ACTIVA (Automatic Control of Total IntraVenous Anesthesia) and is the result of the collaboration between the Research Group on Control Systems of the University of Brescia and the Anesthesia and Intensive Care Unit 2 of the Spedali Civili di Brescia. The objective of the ACTIVA project consists in the theoretical development, implementation, and clinical validation of innovative control strategies for the automatic control of total intravenous anesthesia. In detail, in this thesis the experimental results obtained with control structures based on the PID and on event-based PID controllers for the administration of propofol and remifentanil are initially presented. The theoretical development and clinical validation of model predictive control strategies is then proposed. Next, the results of a simulation study regarding an innovative control solution that allows the anesthesiologist to explicitly adjust the balance between propofol and remifentanil are given. Finally, the theoretical developments and the relative simulation studies concerning personalized control solutions for induction and maintenance phases of anesthesia are explained

Probing brain function with pharmacological MRI

Lo sviluppo di tecniche di risonanza magnetica funzionale (fMRI) ha rivoluzionato le ricerca neuroscientifica clinica, determinando la possibilit\ue0 di investigare le dinamiche spazio-temporali dell\u2019attivit\ue0 cerebrale in maniera non invasiva e con grande accuratezza. Sebbene la tecnica sia stata originariamente sviluppata in ambito clinico, essa ha il potenziale di poter essere utilizzata in ambito preclinico come efficace strumento investigativo e traslazionale. Tuttavia, l\u2019implementazione preclinica di questi metodi \ue8 complicata da una serie di costrizioni sperimentali, in primis l\u2019utilizzo di anestetici, che minano fortemente il potenziale traslazionale di queste tecniche. Il recente sviluppo di tecniche di "MRI farmacologico" (phMRI) offre la possibilit\ue0 di superare alcune delle limitazioni sperimentali correlate all\u2019implementazione di approcci fMRI classici in animali da laboratorio. La tecnica si basa sull'utilizzo di metodi fMRI per mappare alterazioni di attivit\ue0 cerebrale prodotte dalla somministrazione di sostanze psicoattive. Studi preliminari hanno evidenziato la capacit\ue0 di generare robusti e specifici segnali phMRI anche in condizioni di anestesia, ed ha dimostrato la possibilit\ue0 di stimolare selettivamente diversi sistemi di neurotrasmettitori. Sfruttando la conservazione di circuiti cerebrali tra specie, tecniche phMRI offrono quindi l\u2019opportunit\ue0 di ampliare in maniera significativa il repertorio di stimolazione neuronale a disposizione in ambito preclinico, consentendo di indagare selettivamente specifici aspetti della funzione cerebrale in diversi stati di precondizionamento neuronale. In tale contesto, le attivit\ue0 di ricerca di questa tesi sono state finalizzate ad ampliare il campo di applicazione di metodi phMRI preclinici in due diversi ambiti sperimentali: a) come modalit\ue0 di indagine traslazionale, qualora applicata a modelli di malattia clinicamente rilevanti, b) pi\uf9 in generale come piattaforma investigativa per l'indagine della funzione cerebrale e della sua topologia funzionale in contesti sperimentali diversi. In un primo gruppo di studi, tecniche phMRI sono state impiegate per mappare i circuiti neuronali attivati da antagonisti del recettore del glutammato NMDA nel cervello del ratto (Sezione 4.1). Tali composti, grazie alle loro propriet\ue0 psicotogeniche, sono ampiamente sfruttati come modelli sperimentali di schizofrenia in animali ed in volontari allo scopo di valutare e validare nuovi trattamenti per la malattia. I risultati di questa ricerca hanno evidenziato uno specifico circuito corticolimbo- talamico che risulta essere attivato da antagonisti NMDAR sia nell'uomo che in Riassunto XII specie precliniche, e che \ue8 risultato essere modulabile da meccanismi antipsicotici diversi (Sezione 4.2). Il potenziale traslazionale dei metodi phMRI \ue8 stato ulteriormente avvalorato da un secondo gruppo di studi, in cui un approccio multi-parametrico \u201cphMRI-based\u201d \ue8 stato impiegato per indagare molteplici aspetti della funzione cerebrale in un modello murino di dipendenza da cocaina. Questa linea di investigazione ha evidenziato multiple alterazioni della funzione cerebrale basale e reattiva nel cervello di roditori esposti alla cocaina strettamente connesse a quelle osservate in analoghi studi di imaging su pazienti cocaina-dipendenti (Sezione 4.2). In una terza linea d\u2019 investigazione, l'uso combinato di avanzate strategie di targeting neuro-genetico (pharmaco-genetic silencing) e phMRI si \ue8 dimostrato efficace nello stabilire correlazioni dirette tra cellule, circuito e comportamento in linee di topo geneticamente modificate. Questi studi hanno portato all\u2019identificazione di una nuova e circoscritta popolazione neuroni nell'amigdala, in grado di controllare qualitativamente la risposta comportamentale alla paura attraverso il reclutamento di circuiti colinergici corticali (Sezione 4.3) Infine, l'approccio phMRI si \ue8 dimostrato uno strumento potente e versatile per l\u2019implementazione di misure di connettivit\ue0 funzionale nel cervello di roditori. Questo aspetto ha permesso l\u2019esplorazione di nuovi approcci statistici per l\u2019analisi della topologia funzionale del cervello basati sulla rappresentazione di misure di connettivit\ue0 in termini di reti complesse (Sezione 4.4). Complessivamente, i risultati di questo lavoro avvalorano il potenziale traslazionale di metodi phMRI nell\u2019ambito di diverse aree delle neuroscienze e della psicofarmacologia. La combinazione di phMRI e tecniche di manipolazione genetica avanzate definisce una nuova, potente piattaforma tecnologica per lo studio delle basi circuitali del comportamento in animali da laboratorio.The development of functional Magnetic Resonance Imaging (fMRI) has heralded a revolution in neuroscience, providing clinicians with a method to non-invasively investigate the spatio-temporal patterns of neuro-functional activity. Although primarily developed for human investigations, there exists significant scope for the application of fMRI in pre-clinical species as a translational and investigational platform across different areas of neuroscience and psychiatry research. However, the realization of this potential is hampered by a number of experimental constraints which make the application of fMRI methods to animal models less than straightforward. As a result, most fMRI research in laboratory species has been reduced to the employment of basic somato-sensory stimulation paradigms, thus greatly limiting the translational potential of the technique. An interesting approach to overcome some of these limitations has been dubbed \u201cpharmacological MRI\u201d (phMRI) and relies on the use of fMRI to map patterns of brain activity induced by psychoactive drugs. The approach has demonstrated the ability to elicit reliable fMRI signals even under anaesthesia, and to enable selective stimulation of different neurotransmitter systems. Building upon the homology between brain circuits in humans and laboratory animals, phMRI techniques thus offer the opportunity of significantly expanding the stimulation repertoire available to preclinical fMRI research, by allowing to selectively probe specific aspects of brain function under different preconditioning states. Within this framework, the research presented herein was aimed to broaden the scope of application of preclinical phMRI both as a translational technique, when applied to clinically-relevant disease models, and more generally as a versatile platform for the pre-clinical investigation of brain activity and its functional topology as a function of behavioural, pharmacological or genetic preconditioning. In a first group of studies, we developed a phMRI assay to map the circuitry activated by NMDAR antagonists in the rat brain. These psychotogenic compounds are widely exploited to model schizophrenia symptoms and to provide experimental models that may prove useful in the development of novel treatments for the disorder. The results of this research highlighted a conserved cortico-limbo-thalamic circuit that is activated by NMDAR antagonists both in humans and preclinical species, which can be modulated by existing and novel antipsychotic drugs (Section 4.1). The translational potential of phMRI measurements was further corroborated by a second group of studies, where a multi-parametric phMRI-based approach was applied to investigate multiple facets of brain function in a rodent cocaine selfSummary X administration model, a behavioural paradigm of established construct-validity for research of drug addiction. This line of investigation revealed specific basal and reactive functional alterations in the brain of cocaine-exposed rodents closely related to those observed in analogous neuroimaging studies in humans (Section 4.2). In a third line of investigation, the combined use of advanced neuro-genetic targeting strategies (i.e. pharmacogenetic silencing) and phMRI has proven successful in establishing direct correlations between cells, circuit and complex behaviours in genetically engineered mouse lines. These studies (Section 4.3) have led to the identification of a novel cell population in the amygdala that controls the behavioural response to fear through the recruitment of cholinergic circuits. Finally, the phMRI approach has proven a powerful tool to explore functional connectivity in rodents, and to map a variety of different neurotransmitter pathways by performing measures of correlated responses in spatially remote brain areas. This has provided a useful playground to explore novel statistical methods of analysis of functional connectivity represented in terms of complex networks (Section 4.4). Collectively, the results of this work strongly corroborate the translational use of phMRI approaches, and pave the way to the integrated implementation of phMRI and advance genetic manipulation as a novel powerful platform for basic neurobiological research