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Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

Sudden infant death syndrome (SIDS) is the devastating condition in which an infant suddenly and unexplainably passes away over the course of sleeping. This is an unfortunate situation that many new parents dread every night as they lay their newborns to rest. SIDS is the leading cause of death in infants aged from one month to one year, and the medical world still does not fully understand what causes it. However, the triple-risk theory is a new model that sets out to explain the pathology of this syndrome through the combination of genetic vulnerabilities, a critical time period, and external stressors. This thesis summarizes the current research in the realm of the central nervous system (specifically the cerebellum and brainstem) as a means of evaluating the validity of this new model. The analyzed literature concentrated on a few important topics, such as proven risk factors, evidence of homeostatic abnormalities, and significant associations with the occurrence of SIDS. It was found that there was central nervous system dysfunction on most levels, including: damaged Purkinje cells in the cerebellum, malformations of the human choroid plexus, decreased neuropeptide signaling (both orexin and brain-derived neurotrophic factors), malformations of the amino acid neurotransmitters (both excitatory glutamate and inhibitory GABA), and finally significant reductions in the receptor density and activity of the serotonin system. These irregularities were associated, in most studies, with either the prone sleeping position or known maternal nicotine use during pregnancy. In conclusion, the triple-risk model is currently the most accurate description of SIDS, given its reasonable three criteria and present-day research. This is because the studies, and real-life victims, were all concentrated within the critical time period of transition from intra-uterine to extra-uterine life, satisfying the first element of timing. The list of central nervous system dysfunctions found in SIDS cases was compelling enough to fulfill the second factor of inherent vulnerability. Finally, the associations between low oxygen rebreathing and the prone sleep position, or over-heating and tight swaddling displayed a strong relationship with the occurrence of SIDS and satisfied the third and final event, which was the induction of an exogenous stressor. These three factors of the triple-risk model allow for the variations in victim pathology, but still offers a compelling and coherent understanding of the sudden infant death syndrome.

Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01

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Chest physiotherapy is integral to the management of mechanically ventilated children and previous research has confirmed that chest wall vibrations are the manual techniques used most frequently by physiotherapists in this population. Chest wall vibrations involve the application of a compressive force to the chest during expiration, with the aim of removing accumulated secretions and improving lung aeration. However, these techniques are largely unquantified and may vary greatly between practitioners and clinical units, with any significance of such variability remaining unknown. In order to evaluate the effectiveness of any therapy it is important to have a means of quantifying the treatment. It is challenging to measure techniques which involve manual contact between the therapist and patient, and at the inception of this project no means existed of directly measuring the force applied through the hand during treatments. The effectiveness of chest physiotherapy in mechanically ventilated patients is likely to be influenced by the interactions between different treatment components, such as the magnitude and pattern of the chest wall vibrations and the accompanying lung inflations. It is therefore essential to assess both the forces applied during the vibrations with the simultaneous changes in air flow, recording the ventilatory pattern throughout the treatment. The study hypotheses were: 1. It is possible to create a technique to measure chest wall vibration forces during clinical treatments, and to relate such forces to simultaneous changes in respiratory flows, volumes and pressures 2. Maximum and mean force applied during chest wall vibrations increase with the size and age of the child 3. Manual lung hyperinflations with chest wall vibrations result in an increase in peak expiratory flow above that observed during baseline mechanical ventilation 4. After adjusting for inflation volume, application of chest wall vibrations result in an increase in peak expiratory flow above that obtained during manual lung inflations alone The primary objectives of this research were to: 1. Develop a method of quantifying chest wall vibration forces and a means of evaluating simultaneous changes in force with those of respiratory flow and pressure in ventilated infants and children of all ages 2. Estimate the variability over time, within and between individual physiotherapists when treating the same and different subjects with chest wall vibrations 3. Conduct a study to: i) Assess the feasibility of measuring force and respiration in a population of critically ill, mechanically ventilated children ii) Characterise the magnitude and pattern of forces applied during chest wall vibrations and evaluate the direct effects of these manoeuvres on flow and pressure changes in the lungs iii) Determine the relative contribution of manual lung inflations and chest wall vibrations to any observed increase in expiratory airflow A secondary objective was to explore the short term effects of chest physiotherapy, by recording changes in ventilation, respiratory system mechanics and blood gases following treatment. The thesis comprises four chapters: Chapter 1 contains a comprehensive literature review of published studies demonstrating the current knowledge base of the respiratory problems of mechanical ventilation in children, chest physiotherapy in intensive care and the relationship of chest physiotherapy to normal mechanisms of airway clearance. Chapter 2 describes the process of creating a dynamic force-sensing technique to characterise manual chest physiotherapy, detailing protocol and analysis refinement during pilot force and respiratory data collection. Assessment of the variability within and between physiotherapists is also assessed. Chapter 3 details a clinical study undertaken in intensive care units at Great Ormond Street Hospital for Children NHS Trust, London. The results are presented and interpreted. Chapter 4 discusses the findings of the thesis in relation to earlier research, highlights the strengths and limitations of the current study, interprets the clinical implications of the research and suggests future work.