Effect of remote ischaemic preconditioning in cardiac dysfunction and end-organ injury following cardiac surgery with cardiopulmonary bypass in children: A translational approach investigating clinical outcome and myocardial molecular biology

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.

Creating a modern home: homeowners in post-war suburban Glasgow, 1945-1975

This thesis examines how married couples bought and created a modern home for their families in suburban Glasgow between 1945-1975. New homeowners were on the cusp of the middle-classes, buying in a climate of renters. As they progressed through the family lifecycle women’s return to work meant they became more comfortably ensconced within the middle-classes. Engaged with a process of homemaking through consumption and labour, couples transformed their houses into homes that reflected themselves and their social status. The interior of the home was focused on as a site of social relations. Marriage in the suburbs was one of collaboration as each partner performed distinct gender roles. The idea of a shared home was investigated and the story of ‘we’ rather than ‘I’ emerged from both testimony and contemporary literature. This thesis considers decision-making, labour and leisure to show the ways in which experiences of home were gendered. What emerged was that women’s work as everyday and mundane was overlooked and undervalued while husband’s extraordinary contributions in the form of DIY came to the fore. The impact of wider culture intruded upon the ‘private’ home as we see they ways in which the position of women in society influences their relationship to the home and their family. In the suburbs of post-war Glasgow women largely left the workforce to stay at home with their children. Mothers popped in and out of each other houses for tea and a blether, creating a homosocial network that was sociable and supportive unique to this time in their lives and to this historical context. Daily life was negotiated within the walls of the modern home. The inter-war suburbs of Glasgow needed modernising to post-war standards of modern living. ‘Modern’ was both an aesthetic and an engagement with new technologies within the house. Both middle and working-class practices for room use were found through the keeping of a ‘good’ or best room and the determination of couples to eat in their small kitchenettes. As couples updated their kitchen, the fitted kitchen revealed contemporary notions of modern décor, as kitchens became bright yellow with blue Formica worktops. The modern home was the evolution of existing ideas of modern combined with new standards of living. As Glasgow homeowners constructed their modern home what became evident was that this was a shared process and as a couple they placed their children central to all aspects of their lives to create not only a modern home, but that this was first and foremost a family home