Measurement and Assessment of Work of Breathing in Neonates During Nasal Continuous Positive Airway Pressure Therapy

Introduction: Nasal continuous positive airway pressure (nCPAP) is a widely used form of non-invasive respiratory support in neonates. The general aim of nCPAP therapy is to improve lung volume, oxygenation and decrease work of breathing. There is little data to guide clinicians on how to adjust the pressure and what parameter nCPAP should be titrated against. This is due to the lack of commercially available equipment to measure lung mechanics in patients receiving non-invasive respiratory support. In mechanically ventilated patients, measurements of work of breathing have been found to be useful in optimising ventilation strategies. An indicator of work of breathing or estimate of the metabolic and oxygen cost of breathing is the pressure time product (PTP). Objectives: To develop a monitoring system for the measurement of work of breathing in neonates on nCPAP, to investigate the effects of different nCPAP levels on PTP and to identify non-invasively determined predictors of PTP. Methods: PTP’s (PTPoe=oesophageal, PTPga=gastric and PTPdi=diaphragmatic pressure time product) derived by oesophageal gastric pressure transducer was compared with parameters derived by respiratory inductance plethysmography. Subjects were randomised to receive nCPAP level sequences of 2, 4, 6 and 8 cmH2O. Main results 37 of 57 subjects were analysed. Median gestational age 30 ± 4.9 weeks, median birth weight 1234 ± 443 g, chronological age ≤ 24 hours 24 subjects (64.9%) and baseline FiO2 ≤ 0.35. PTP’s decreased with increasing nCPAP level (p < 0.05). “Optimal” nCPAP as determined by the lowest PTPoe and PTPdi occurred between 6-8 cmH2O for 56% of the subjects. “Optimal” nCPAP as defined by the lowest PTPga occurred between 6-8 cmH2O for 39% of the subjects. Respiratory rate, abdominal excursion decreased, Te increased and heart rate remained unchanged with increased nCPAP level. PTPoe correlated best out of all three PTP’s with selected variables derived by non-invasive techniques. Respiratory rate explained 36.7% of the variance of PTPoe and abdominal excursion explained 45.5% of the variance of PTPoe. Best fitted prediction model for PTPoe included respiratory rate, phase angle, abdominal excursion, birth weight, gestational age and applied nCPAP level and explained 65.8% of the variance of PTPoe. One suspected pneumothorax was reported (1.7%). Conclusion: Respiratory muscle work load is affected by changes in nCPAP levels and can be predicted more accurately by a model consisting of respiratory rate, phase angle, abdominal excursion, gestational age and birth weight than by clinical parameters alone

The role of real-time ultrasound in the assessment and management of preterm labour

In this thesis the use of real-time ultrasound in the assessment and management of preterm labour has been studied, with particular reference to the observation of fetal breathing movements, gross fetal body movements and the state of the uterine cervix. In addition, a longitudinal analysis of the trends in preterm labour in the John Radcliffe Hospital in Oxford between 1973 and 1981 has been performed. Finally, an attempt has been made to clarify the relationship between prostaglandin E2 and fetal breathing movements. The analysis of the trends in preterm labour in Oxford has shown that the incidence of preterm delivery remains unaltered. Of these patients, however, those eligible for tocolytic therapy (unexplained spontaneous preterm labour) form a small proportion. The incidence of extreme prematurity in this group is very low and the neonatal outcome is good. The presence or absence of Fetal Breathing Movements (FBM) by defined criteria is shown to be a highly sensitive index of whether the preterm labour is going to progress to delivery or not in singleton pregnancies with intact membranes. Its significance is lost when the membranes are ruptured and in multiple pregnancies. In pregnancies complicated by antepartum haemorrhage the presence or absence of Fetal Breathing Movements does not predict further haemorrhage leading to delivery. Fetal Breathing Movement status on admission bears no relationship to neonatal outcome and gives no indication of the presence of intrauterine infection. Silent chorioamnionitis has been highlighted as an important cause of "unexplained" preterm labour. Gross Fetal Body Movements (FM) are shown to give no early indication of impending preterm delivery. Evidence is presented to suggest that significant diminution in Fetal Movements is related to poor neonatal outcome. Ultrasonic measurement of the uterine cervix has been found to be technically feasible but of no benefit in the diagnosis of ongoing preterm labour. The relationship between prostaglandin E2 (PGE2) and the cessation of fetal breathing movement has been approached by elucidating the maternal absorption of PGE2 from a vaginal pessary. This then enabled me to sample fetal blood at the time of maximal maternal concentrations (the time we expect the fetal concentration to be greatest). This was performed by fetoscopy and demonstrated that a significant rise in fetal bicycleprostaglandin-E-metabolite (bicyclo-PGEM) occurs following maternal vaginal administration of PGE2. Using this information FBM has been assessed two and a half hours following the vaginal administration of PGE2. Although inconclusive, no reduction in FBM was demonstrated. as the bicyclo-PGE metabolite is used to assess PGE levels, this evidence decreases the probability that PGE mediates the reduction in FBM with the onset of labour

An Interdisciplinary Investigation of Infant Sleep: How We Study It, What It Means for Other Areas of Development, and Where Methodological Creativity Can Take Us

The present dissertation is broken into six chapters. Chapters 2 through 5 comprise four research projects that build upon each other and in both theoretical and methodological ways. The bookends – my introduction and conclusion – are written for an interdisciplinary, even lay audience. In its entirety, the text is centered on infant sleep. First, I describe the functional role of sleep and liken it to a barista working in a coffee shop. Then, I lay out researcher choices – of design and measurement – when incorporating sleep as a facet of a research paradigm. After comparing three measurement techniques (parent report, actigraphy, and Nanit videosomnography), I apply one (Nanit) to the study of sleep and motor development. Intensive longitudinal data collections allowed for more precision in documenting when and how sleep is disrupted around motor skill onset. To see if changes in the ultradian cycle were underlying these results, I manually analyze the Nanit video data, state scoring nightly videos for total time spent in REM and NREM around onset. Finally, I offer another methodological adaptation to record infant sleep and state code, using both actigraphy and wireless cardiorespiratory sensors. Future interdisciplinary research on infant sleep and development can benefit from instances of methodological creativity, as I have shown here. Doing so will also resolve some of the barriers that prevent potential participants and researchers from engaging in the field

Impedance Pneumography for the Nocturnal Assessment of Lower Airway Obstruction

Tidal breathing analysis is a lung function technique suggested for infants and children who are unable to cooperate with forced spirometry. This technique aims to quantify lower airway obstruction from average changes in the shape or the breath-to-breath variations of the tidal breathing flow-volume loop (TBFV) profiles. If tidal airflow is recorded with a mouth pneumotachograph (PNT), tidal breathing analysis finds the same limitations as other alternatives to spirometry. These are typically the need for sedation and the assessment of lung function only for sort times at the hospital. Recent improvements in impedance pneumography (IP) enable for the first time the continuous non-invasive monitoring of respiratory airflow overnight. This can improve the analysis of tidal breathing by capturing circadian and nocturnal worsening in lower airway obstruction. However, due to the lack of previous methods recording nocturnal airflow, little is known about how the interaction of sleep physiology and lower airway obstruction is reflected in the shape and variability of tidal breathing. This thesis reviews the literature regarding shape and variability analysis of tidal breathing during lower airway obstruction, sleep, or maturation. The thesis also extends this knowledge by presenting four original publications. The first publication describes a technical improvement in the IP method. The other three study the nocturnal TBFV’s shape in wheezing infants and children, and the nocturnal TBFV’s variability in healthy children. Both the literature and the results agree that for the TBFVs’ shape, increasing lower air- way obstruction advances the peak of expired flow and turns the middle part from convex to concave. However, these changes occur at a different degree of obstruction for differ- ent subjects depending on the compensation strategy that they have chosen. In infants, changes putatively occur at a higher degree of obstruction because most of the expiration is controlled by the respiratory musculature. During rapid eye movement (REM) sleep, changes putatively occur at a lower degree of obstruction because muscle atony limits the compensation strategies. For the variability of TBFVs, increasing lower airway obstruction decreases the variability in the early part of expiration in the long term (the whole night). However, the short-term variability is dominated by the stage-dependent variations in the respiratory drive. The thesis concludes that, at the present, tidal breathing analysis can estimate lower airway obstruction but cannot quantify its degree with accuracy. However, nocturnal IP recordings are easy to conduct and can serve as a first-line diagnosis or for the monitoring of disease progression. Nonetheless, future improvements in signal processing and the understanding of the tidal airflow signal can easily increase the accuracy and find new applications

The effects of mild hypoxaemia on hypoglossal motoneurone activity in neonates

Introduction: Apneic episodes and consequent hypoxaemia are common features of breathing in high- risk neonates. Apneas of central origin (no respiratory effort) usually terminate with an obstructive component due to collapse of the upper airway. The genioglossus muscle, the main protruder muscle of the tongue, plays a crucial role in maintaining upper airway patency by opposing the negative intra-airway pressure generated during contraction of the diaphragm and by preventing the tongue blocking the oropharyngeal opening. In adults, the respiratory-related activity of the hypoglossal nerve (the motoneurone of the genioglossus) increases during hypoxaemia in order to maintain upper airway patency. However, in neonates it has been shown that the genioglossus muscle during hypoxia is age-related and this increased activity is not sustained. In neonates, little is known about how the hypoglossal motoneurones respond to hypoxaemia and the role of hypoglossal motoneurones during hypoxia in the maintenance of upper airway patency. Aim: The aim of this study was to determine the effects of hypoxaemia on hypoglossal motoneurones in neonates. Methods: Extracellular and intracellular recordings were made from hypoglossal motoneurones in vagotomized and vagi-intact neonatal kittens during normoxia and hypoxia. Results: The results showed: (1) the majority of hypoglossal motoneurones either decreased their discharge frequency or had only a transient increase during hypoxia. (2) During intracellular recordings, the membrane potential showed a sustained depolarisation during hypoxaemia in most cases and respiratory-related rhythmic EPSP activity was reduced in amplitude. The membrane impedance of these motoneurones increased and the excitability was reduced. (3) During upper airway stimulation, the amplitude of the laryngeal-evoked potentials was reduced during hypoxia. Conclusions: My results demonstrate that, in neonates, hypoglossal motoneurone activity is inhibited during hypoxia and the hypoglossal-upper airway reflexes are also inhibited. The probable consequence of such inhibition, for the newborn human infant, would be the failure of the maintenance of upper airway patency, thus leading to obstructive apnea. The mechanisms mediating the inhibition of hypoglossal motoneurones during hypoxia remain to be determined

Methodological Challenges and Clinical Applications of Hair Cortisol Analysis

This thesis examines methodological and clinical aspects of hair cortisol analysis. The methodological study examines the role of sweat as a contributor to hair cortisol concentrations. Hair cortisol analysis is an effective measure of chronic stress. Cortisol is assumed to enter the hair via blood, sebum, and sweat, however the extent to which sweat contributes to hair cortisol content was unknown. This study concluded that human sweat contains cortisol that likely contributes to hair cortisol content. Subjects with prolonged sweating at the time of hair collection may have increased hair cortisol concentrations that cannot be decreased with conventional laboratory washing procedures. Clinically, hair cortisol analysis is explored as a tool to determine if obstructive sleep apnea (OSA) is associated with increased stress. OSA is a common sleep disorder with serious cardiovascular and metabolic co-morbidities that may be mediated by increased cortisol secretion. Recent studies have focused on the ability of continuous positive airway pressure (CPAP) to reduce cortisol secretion in OSA patients, but the results have been mixed and only point measures of cortisol measurement have been used. Hair cortisol analysis presents a means of non-invasively and retrospectively examining cortisol production in these patients. This study examined whether hair cortisol concentrations are increased in OSA patients. Further, the effect of CPAP on hair cortisol concentrations was examined. It was concluded that cortisol secretion may be up-regulated in severe cases of OSA. The psychological stress of OSA may be reduced with CPAP, however physiological stress may remain unchanged after 3 months of treatment

Noninvasive autonomic nervous system assessment in respiratory disorders and sport sciences applications

La presente tesis está centrada en el análisis no invasivo de señales cardíacas y respiratorias, con el objetivo de evaluar la actividad del sistema nervioso autónomo (ANS) en diferentes escenarios, tanto clínicos como no clínicos. El documento está estructurado en tres partes principales. La primera parte consiste en una introducción a los aspectos fisiológicos y metodológicos que serán cubiertos en el resto de la tesis. En la segunda parte, se analiza la variabilidad del ritmo cardiaco (HRV) en el contexto de enfermedades respiratorias, concretamente asma (tanto en niños como en adultos) y apnea del sueño. En la tercera parte, se estudian algunas aplicaciones novedosas del análisis de señales cardiorespiratorias en el campo de las ciencias del deporte. La primera parte está compuesta por los capítulos 1 y 2. El capítulo 1 consiste en una extensa introducción al funcionamiento del sistema nervioso autónomo y las características de las bioseñales analizadas a lo largo de la tesis. Por otro lado, se aborda la patofisiología del asma y la apnea del sueño, su relación con el funcionamiento del ANS y las estrategias de diagnóstico y tratamiento de lasmismas. El capítulo concluye con una introducción a la fisiología del ejercicio, así como al interés en la estimación del volumen tidal y del umbral anaeróbico en el campo de las ciencias del deporte.En cuanto al capítulo 2, se presenta un marco de trabajo para el análisis contextualizado de la HRV. Después de una descripción de las técnicas de evaluación y acondicionamiento de la señal de HRV, el capítulo se centra en el efecto de los latidos ectópicos, la arritmia sinusal respiratoria y la frecuencia respiratoria en el análisis de la HRV.Además, se discute el uso de un índice para la evaluación de la distribución de la potencia en los espectros de HRV, así como diferentes medidas de acoplo cardiorespiratorio.La segunda parte está compuesta por los capítulos 3, 4 y 5, todos ellos relacionados con el análisis de la HRV en enfermedades respiratorias. Mientras que los capítulos 3 y 4 están centrados en asma infantil y en adultos respectivamente, el capítulo 5 aborda la apnea del sueño. El asma es una enfermedad respiratoria crónica que aparece habitualmente acompañada por una inflamación de las vías respiratorias. Aunque afecta a personas detodas las edades, normalmente se inicia en edades tempranas, y ha llegado a constituir una de las enfermedades crónicasmás comunes durante la infancia. Sin embargo, todavía no existe un método adecuado para el diagnóstico de asma en niños pequeños. Por otro lado, el rol fundamental que desempeña el sistema nervioso parasimpático en el control del tono bronco-motor y la bronco-dilatación sugiere que la rama parasimpática del ANS podría estar implicada en la patogénesis del asma. De estemodo, en el capítulo 3 se evalúa el ANS mediante el análisis de la HRV en dos bases de datos diferentes, compuestas por niños en edad pre-escolar clasificados en función de su riesgo de desarrollar asma, o de su condición asmática actual. Los resultados del análisis revelaron un balance simpáticovagal reducido y una componente espectral de alta frecuencia más picuda en aquellos niños con un mayor riesgo de desarrollar asma. Además, la actividad parasimpática y el acoplo cardiorespiratorio se redujeron en un grupo de niños con bajo riesgo de asma al finalizar un tratamiento para bronquitis obstructiva, mientras que estos permanecieron inalterados en aquellos niños con una peor prógnosis.A diferencia de los niños pequeños, en el caso de adultos el diagnóstico de asma se realiza a través de una rutina clínica bien definida. Sin embargo, la estratificación de los pacientes en función de su grado de control de los síntomas se basa generalmente en el uso de cuestionarios auto-aplicados, que pueden tener un carácter subjetivo. Por otro lado, la evaluación de la severidad del asma requiere de una visita hospitalaria y de incómodas pruebas, que no pueden aplicarse de una forma continua en el tiempo. De este modo, en el capítulo 4 se estudia el valor de la evaluación del ANS para la estratificación de adultos asmáticos. Para ello, se emplearon diferentes características extraídas de la HRV y la respiración, junto con varios parámetros clínicos, para entrenar un conjunto de algoritmos de clasificación. La inclusión de características relacionadas con el ANS para clasificar los sujetos atendiendo a la severidad del asma derivó en resultados similares al caso de utilizar únicamente parámetros clínicos, superando el desempeño de estos últimos en algunos casos. Por lo tanto, la evaluación del ANS podría representar un potencial complemento para la mejora de la monitorización de sujetos asmáticos.En el capítulo 5, se analiza la HRV en sujetos que padecen el síndrome de apnea del sueño (SAS) y comorbididades cardíacas asociadas. El SAS se ha relacionado con un incremento de 5 veces en el riesgo de desarrollar enfermedades cardiovasculares (CVD), que podría aumentar hasta 11 veces si no se trata convenientemente. Por otro lado, una HRV alterada se ha relacionado independientemente con el SAS y con numerosos factores de riesgo para el desarrollo de CVD. De este modo, este capítulo se centra en evaluar si una actividad autónoma desbalanceada podría estar relacionada con el desarrollo de CVD en pacientes de SAS. Los resultados del análisis revelaron una dominancia simpática reducida en aquellos sujetos que padecían SAS y CVD, en comparación con aquellos sin CVD. Además, un análisis retrospectivo en una base de datos de sujetos con SAS que desarollarán CVD en el futuro también reveló una actividad simpática reducida, sugiriendo que un ANS desbalanceado podría constituir un factor de riesgo adicional para el desarrollo de CVD en pacientes de SAS.La tercera parte está formada por los capítulos 6 y 7, y está centrada en diferentes aplicaciones del análisis de señales cardiorespiratorias en el campo de las ciencias del deporte. El capítulo 6 aborda la estimación del volumen tidal (TV) a partir del electrocardiograma (ECG). A pesar de que una correcta monitorización de la actividad respiratoria es de gran interés en ciertas enfermedades respiratorias y en ciencias del deporte, la mayor parte de la actividad investigadora se ha centrado en la estimación de la frecuencia respiratoria, con sólo unos pocos estudios centrados en el TV, la mayoría de los cuales se basan en técnicas no relacionadas con el ECG. En este capítulo se propone un marco de trabajo para la estimación del TV en reposo y durante una prueba de esfuerzo en tapiz rodante utilizando únicamente parámetros derivados del ECG. Errores de estimación del 14% en la mayoría de los casos y del 6% en algunos sugieren que el TV puede estimarse a partir del ECG, incluso en condiciones no estacionarias.Por último, en el capítulo 7 se propone una metodología novedosa para la estimación del umbral anaeróbico (AT) a partir del análisis de las dinámicas de repolarización ventricular. El AT representa la frontera a partir de la cual el sistema cardiovascular limita la actividad física de resistencia, y aunque fue inicialmente concebido para la evaluación de la capacidad física de pacientes con CVD, también resulta de gran interés en el campo de las ciencias del deporte, permitiendo diseñar mejores rutinas de entrenamiento o para prevenir el sobre-entrenamiento. Sin embargo, la evaluación del AT requiere de técnicas invasivas o de dispositivos incómodos. En este capítulo, el AT fue estimado a partir del análisis de las variaciones de las dinámicas de repolarización ventricular durante una prueba de esfuerzo en cicloergómetro. Errores de estimación de 25 W, correspondientesa 1 minuto en este estudio, en un 63% de los sujetos (y menores que 50 W en un 74% de ellos) sugieren que el AT puede estimarse de manera no invasiva, utilizando únicamente registros de ECG.<br /

A reversal of fate : unravelling the role of central 5-HT in cardiorespiratory control in neonatal and adult rodents

We seek to address the extent to which a specific loss of 5-hydroxytryptamine (5-HT) affects the control of respiration, arterial blood pressure (ABP) and heart rate (HR) across vigilance-states based on existing evidence suggesting that 5-HT defects increase the risk for Sudden Infant Death Syndrome (SIDS) and neurogenic hypertension. SIDS is the leading cause of infant mortality between 1 month and 1 year of age, occurs during sleep, and up to 70% of all SIDS cases have at least one 5-HT system abnormality. Neonatal rodents lacking central 5-HT exhibit severe apneas, and a reduced ABP and HR. Central 5-HT has been implicated in the etiology of neurogenic hypertension, presumably due to projections of 5-HT neurons within the midline raphe to vagal and presympathetic regions of the brain. However, data from studies examining the specific role of central 5-HT function is conflicting or inconclusive. Neurogenic hypertension accounts for more than 90% of all hypertensive cases and the normal fall in ABP that occurs during non-rapid eye movement sleep is absent in some patients with hypertension. Understanding the mechanisms associated with the development of hypertension is critical not only to lower blood pressure, but to lower its associated cardiovascular events. The purpose of this dissertation is to examine the role of central 5-HT in the control of ABP during sleep and reveal, mechanistically, the physiological role of 5-HT in the autonomic control of ABP in neonatal and adult rodents. The overarching hypothesis for this dissertation is that central 5-HT is required for the maintenance of ABP and autonomic tone at rest in both neonatal and adult rodents.Includes bibliographical reference