Introduction: Nursing clinicians are primarily responsible for the monitoring and treatment of increased body temperature. The body temperature of patients during their acute care hospital stay is measured at regular repeated intervals. In the event a patient is assessed with an elevated temperature, a multitude of decisions are required. The action of instigating temperature reducing strategies is based upon the assumption that elevated temperature is harmful and that the strategy employed will have some beneficial effect. Background and Significance: The potential harmful effects of increased body temperature (fever, hyperthermia) following neurological insult are well recognised. Although few studies have investigated this phenomenon in the diagnostic population of non-traumatic subarachnoid haemorrhage, it has been demonstrated that increased body temperature occurs in 41 to 72% of patients with poor clinical outcome. However, in the Australian context the frequency, or other characteristics of increased body temperature, as well as the association between increased body temperature with poor clinical outcome has not been established. Design: This study used a correlational study design to: describe the frequency, duration and timing of increased body temperature; determine the association between increased body temperature and clinical outcome; and describe the clinical interventions used to manage increased body temperature in patients with non-traumatic subarachnoid haemorrhage. A retrospective clinical chart audit was conducted on 43 patients who met the inclusion criteria. Findings: The major findings of this study were: increased body temperature occurred frequently; persisted for a long time; and onset did not occur until 20 hours after primary insult; increased body temperature was associated with death or dependent outcome; and no intervention was recorded in many instances. Conclusion: This study has quantified in a non-traumatic subarachnoid haemorrhage patient population the characteristics of increased body temperature, established an association between increased body temperature with death or dependent outcome and described the current management of elevated temperatures in the Australian context to improve nursing practice, education and research.

Delayed control of haemorrhage or blood loss has been recognised as a major contributor to preventable trauma deaths, but early detection of internal bleeding is difficult due to unreliability of heart rate (HR) and blood pressure (BP) as markers of volume status. This thesis explores a novel method of early blood loss detection using a noninvasive finger photoplethysmographic (PPG) pulse oximetry waveform that is normally utilised in pulse oximeters for estimating arterial oxygen saturation. Graded head-up tilt (n = 13) and blood donation (n = 43) in human volunteers were selected as experimental models of mild to moderate blood loss. From the tilt study, a novel method for automatically detecting left ventricular ejection time (LVET) from the finger PPG waveform has been developed and verified by comparison with the LVET measured from aortic flow velocity. PPG waveform derived LVET (LVETp) and pulse transit time (PTT) were strongly correlated with aortic LVET and pre-ejection period respectively (median r = 0.954 and 0.964) and with the decrease in central blood volume indicated by the sine of the tilt angle (median r = -0.985 and 0.938), outperforming R-R interval (RRI) and BP in detecting mild central hypovolaemia. In the blood donation study, progressive blood loss was characterised by falling LVETp and rising PTT (p < 0.01). A new way of identifying haemorrhagic phases by monitoring changes and trends in LVETp, PTT and RRI has been proposed based on the results from the two studies. The utility of frequency spectrum analysis of PPG waveform variability (PPGV) in characterising blood loss has also been examined. A new technique of PPGV analysis by computing the coherence-weighted cross-spectrum has been proposed. It has been shown that the spectral measures of finger PPGV exhibited significant changes (p < 0.01) with blood donation and were mildly correlated with systemic vascular resistance in intensive care unit patients (r from 0.53 to 0.59, p < 0.0001), therefore may be useful for identification of different haemorrhagic phases. In conclusion, this thesis has established finger PPG waveform as a potentially useful noninvasive tool for early detection of blood loss.

Introduction: Coagulopathy in trauma increases the likelihood of death. Various approaches to correcting this coagulopathy are being investigated but the decision to use them is often haphazard. The guidelines on their use are limited. This project aims to produce a decision rule to rule in the need for massive transfusion in military trauma, and therefore to rule in the use of methods for treating the coagulopathy of trauma.Methods: A Delphi Study was performed to ascertain which variables a panel of experts felt were most predictive of the need for massive transfusion. This encompassed experts for the fields of emergency medicine, critical care, trauma surgery, pre-hospital care and haematology. Data from the British Defence Joint Theatre Trauma Registry, from January 2007 –July 2010 were obtained and divided into two groups to provide a derivation and validation dataset. Blood timings for people receiving 5 or more units were obtained from clinical records. Regression analysis of potential predictive factors either indicated by the Delphi panel or by literature review were analysed to confirm their value in prediction of Massive Blood Transfusion. A range of clinical prediction rules were produced using parameters deemed appropriate by the Delphi panel and shown to be predictive through regression analysis. Three of these models were then tested in the validation dataset.Results: Ethical approval has been found not to be required following decisions by the relevant military and civilian ethical boards. The Delphi panel was conducted over 3 rounds with a panel of 33 members. Response rates of 94%, 80% and 77% were achieved in rounds 1, 2, and 3 respectively. 195 statements were produced; agreement was achieved at the 80% level in 97 (49.7%) of statements.Regression analysis produced multiple factors that were highly predictive of Massive Blood Transfusion. These were formulated into 22 potential rules combining evidence of injury, clinical observations and pre-hospital care received to produce rules with high sensitivity and specificity. Overall 3 rules were deemed to provide the best balance of sensitivity and specificity, while remaining clinically valid. These were then validated, in a second dataset. The simplest of these rules has a sensitivity of 83.3% and a specificity of 85.5% with an AUROC of 0.907 in the derivation dataset. In the validation dataset sensitivity improved to 87.65% with a specificity of 80.45% with an AUROC curve of 0.91.Discussion: A clinical decision tool which ruled in the use of a massive transfusion protocol allowing early and aggressive resuscitation, and early provision of blood products, would result in better care for severely injured military trauma patients. Although several prediction models are available, they all require either weighted parameters or blood tests so limiting their utility. Further, sensitivity and specificity is poor. This project, through the use of expert opinion, and the production of a validated decision rule, has provided such a tool with improved sensitivity over the currently available prediction models. By using consensus from a Delphi panel, it is hoped that any tool will be acceptable to clinicians therefore improving quality of care. This rule now needs to be assessed prospectively for validity, ease of use and clinical acceptance.

Background: Prematurity is a major risk factor for intraventricular haemorrhage (IVH). Premature infants often require respiratory support. There is little information on neonates with IVH who require respiratory support in low and middle income countries. Objective: To describe the characteristics and short-term outcomes of very low birth weight (VLBW) infants with IVH who required respiratory support in a tertiary neonatal unit with resource limitations. Methods: This was a matched retrospective observational study. The population included VLBW infants with IVH, who received positive pressure respiratory support between January 2014 and December 2016. Outcomes of infants with severe IVH was compared to those with mild IVH. Outcomes were further analysed according to mode of ventilation. Results: 150 infants were included in the study, 56 (37%) received continuous positive airway pressure (CPAP) only and 94 (63%) mechanical ventilation. Severe IVH was associated with surfactant therapy across both ventilation groups (p=0.03). Oxygen requirement at 28 days was more frequent in infants with severe IVH compared to mild IVH (79% vs 38%, p=0.01) (OR 6.11 (95% CI 1.19-31.34), p=0.03). Severe IVH and the presence of coagulopathy were the strongest predictors of death in both ventilation groups (p <0.0001). Pulmonary haemorrhage was the commonest cause of death in those with severe IVH and blood culture confirmed sepsis in those with mild IVH. Periventricular leukomalacia (PVL) was associated with severe IVH in those receiving invasive ventilation (OR 6.67 (95% CI 1.11-40.17)). Conclusion: Mechanical ventilation, coagulopathy and pulmonary haemorrhage were strongly associated with death in VLBW infants with severe IVH in a resource-limited setting. These prognostic factors may have a role in end of life decisions.

Haemorrhage within the germinal matrix with extension into the ventricle is commonly seen in very low birth weight babies. Outcome following severe haemorrhage, in particular when associated with post haemorrhagic hydrocephalus and congestive venous infarction is poor, whilst outcome following moderate degrees of haemorrhage remains variable. The Neural Stem Progenitor Cells (NSPC) within the GM have been shown to be exquisitely sensitive to micro-environmental cues, as such, haemorrhage within the GM is postulated to impact on neurological outcome through aberration of normal NSPC behaviour. Here we have developed a stereotactic model of autologous blood injection which recapitulates key features of Papile grade II/III Germinal Matrix Haemorrhage / Intraventricular Haemorrhage (GMH/IVH). This model demonstrates that GMH/IVH causes an activation of the NSPC within the wall of the lateral ventricle and increases the number of transient amplifying cells within the transcallosal pathway. Further to this RNA extraction from the NSPC (selected using a CD133 MACS protocol) revealed that GMH/IVH causes a significant down regulation of the transmembrane receptor Notch, a finding that was validated using Hes5 in situ hybridisation (ISH). Using a battery of behavioural tests including assessment of developmental landmarks, neuromotor and reflex development we found that GMH/IVH causes subtle but significant impacts on early neonatal development. GMH/IVH in transgenic mice overexpressing the polycomb group gene Bmi1 in NSC (Nestin+ve) revealed increased self-renewal and resistance to oxidative stress (properties of Bmi1 overexpression) reduced the impact of GMH on the oligodendrocyte population, it also revealed a unique behavioural phenotype. We propose that GMH/IVH down regulates Notch in the NSPC causing a burst of precocious proliferation and depleting the NSPC pool, which impacts on neurological outcome due to altered cortical architecture. Further we suggest that modulation of NSPC properties may play role in determining outcome and should be further explored for its therapeutic potential.

The aim was to explore the possibility to diagnose retained placental tissue and other placental complications with 3D ultrasound and to investigate the impact of previous caesarean section on placentation in forthcoming pregnancies. 3D ultrasound was used to measure the volumes of the uterine body and cavity in 50 women with uncomplicated deliveries throughout the postpartum period. These volumes were then used as reference, to diagnose retained placental tissue in 25 women with secondary postpartum haemorrhage. All but three of the 25 women had retained placental tissue confirmed at histopathology. The volume of the uterine cavity in women with retained placental tissue was larger than the reference in most cases, but even cavities with no retained placental tissue were enlarged (Studies I and II). Women with their first and second birth, recorded in the Swedish medical birth register, were studied in order to find an association between previous caesarean section and retained placenta. The risk of retained placenta with heavy bleeding (&gt;1,000 mL) and normal bleeding (≤1,000 mL) was estimated for 19,459 women with first caesarean section delivery, using 239,150 women with first vaginal delivery as controls. There was an increased risk of retained placenta with heavy bleeding in women with previous caesarean section (adjusted OR 1.61; 95% CI 1.44-1.79). There was no increased risk of retained placenta with normal bleeding (Study III). Placental location, myometrial thickness and Vascularisation Index were recorded on 400 women previously delivered by caesarean section. The outcome was retained placenta and postpartum haemorrhage (≥1,000 mL). There was a trend towards increased risk of postpartum haemorrhage for women with anterior placentae. Women with placenta praevia had an increased risk of retained placenta and postpartum haemorrhage. Vascularisation Index and myometrial thickness did not associate (Study IV). In conclusion: 3D ultrasound can be used to measure the volume of the uterine body and cavity postpartum, but does not increase the diagnostic accuracy of retained placental tissue. Previous caesarean section increases the risk of retained placenta in subsequent pregnancy, and placenta praevia in women with previous caesarean section increases the risk for retained placenta and postpartum haemorrhage.

Background A cerebral cavernous malformation (CCM) is a small cluster of thin-walled, dilated blood vessels within the brain which is prone to bleed. Although the quantity of blood leaking tends to be small, even a small intracranial haemorrhage (ICH) can result in a clinically significant neurological deficit. Because some focal neurological deficits (FND) may in fact be haemorrhages that were undetected by imaging, FND were also included in the analysis wherever possible. In Scotland, between 2006 and 2010, the annual CCM detection rate was 0.8 per 100,000 people. Since estimates of prognosis inform decisions about whether to treat CCM, it is crucial that the untreated clinical course of the disease is fully understood. Aim The aims of this thesis are (i) to quantify the risk of ICH (or ICH or FND, referred to as ‘clinical event’) for an untreated adult within five years of CCM diagnosis, (ii) to identify prognostic factors for ICH (clinical event), and (iii) to create a model to predict, at the time of diagnosis, an individual’s risk of a subsequent ICH (clinical event). Methods Initially, a literature review was undertaken. Then data from adults diagnosed with CCM in the Scottish Intracranial Vascular Malformation Study (SIVMS) were analysed. SIVMS is a prospective, population-based cohort study: it includes all adults resident in Scotland at the time of diagnosis of a first-ever intracranial vascular malformation during the two five-year periods 1999–2003 and 2006–2010. Time-to-event methods were employed to compare the estimated risk of ICH (clinical event) for those who experienced a first ICH (clinical event) during untreated five-year follow-up with those who experienced a second ICH (clinical event). A statistical challenge when analysing clinical outcomes from patients with CCM is that the outcome event of ICH or FND is comparatively rare; therefore a larger cohort of CCM patients was required to identify more robustly potential predictors of ICH (clinical event) and to create a prognostic model to predict, at the time of diagnosis, an individual’s risk of a subsequent ICH (clinical event). Three research groups agreed to contribute their data to enable an individual patient data meta-analysis (IPDMA) to be undertaken. Results In the two SIVMS cohorts, 136 (1999–2003) and 165 adults (2006–2010) were diagnosed with CCM. In the earlier cohort, the estimated risk of a first ICH within five years of presentation (2.4%, 95% CI 0.0% to 5.7%) was significantly lower (p < 0.0001) than the risk of a recurrent ICH (31.9%, 95% CI 4.5% to 59.3%), but the annual risk of a recurrence declined over the five-year period. In the same cohort, women had an increased risk of a second clinical event (log-rank χ2(1) = 6.2, p = 0.01). The IPDMA was based on 988 adults, 62 of whom suffered a first ICH within five years of CCM diagnosis. When the data were pooled, the estimated adjusted hazard ratio for first ICH for clinical presentation (ICH/FND vs other presentation) was 4.5 (95% CI 1.5 to 13.4) and for brainstem location (brainstem vs other location) the adjusted hazard ratio was 3.3 (95% CI 1.5 to 7.2); age, sex and CCM multiplicity did not add any additional prognostic information. Conclusion In this thesis two risk factors have been identified that are independently associated with increased likelihood of experiencing an ICH (or clinical event) within five years of diagnosis. A prognostic model has been built and evaluated, based on these factors. Other areas to be explored in the future include external validation of the model and investigating the effects of (i) antithrombotic therapy and (ii) pregnancy on the progression of the disease.

Fungal contaminated buildings and related adverse human health implications have long been a topical issue throughout the world and concern is mounting with regards to the presence of more toxigenic fungi found in buildings and the associated health risks. These risks are compounded when homes are affected by water damage as a result of water intrusion problems, in particular flooding. With the ever changing climate and unpredictable weather conditions the frequency of flash flooding has increased in recent years and is set to increase and subsequently more homes will inevitably be effected by mould contamination. The present study initially aimed to determine the types of fungi commonly detected in buildings in the United Kingdom with varied levels of water intrusion problems via a small survey using various sampling techniques and particularly aimed to determine the conditions by which growth of the toxigenic fungi Stachybotrys chartarum could occur. Penicillium, Cladosporium and Aspergillus species were the most commonly detected fungi in buildings with relatively moderate levels of water intrusion problems; Stacybotrys chartarum was only detected in building with more severe water intrusion problems. Cont/d.

Magister Curationis - MCur / Background: Postpartum haemorrhage (PPH) is one of the most preventable causes of maternal death, yet it still ranks as one of the main conditions responsible for maternal mortality. PPH occurs at a stage when a mother is the least likely to receive care, and mothers often do not survive to be referred to a more specialised level of care. This is compounded by the patient not being able to warn healthcare providers timeously about their condition and healthcare providers lacking training resulting in a lack of accuracy in diagnosis, lack of resources, and differing methods of treatment. Due to the lack of consensus in available treatment options, and the paucity of research aimed at clinical interventions for midwives at the primary care level, this research report aimed to investigate the evidence in order to establish the best practices and evidence for clinical interventions to manage postpartum haemorrhage for midwives at the primary care level. This is to ensure that the continuing education for midwives in practice is based on evidence to keep their skill set current and expose practitioners to the latest evidence based care. Aim: To systematically review all available published evidence for the acute non-pharmaceutical, non-surgical, management of PPH for use by midwives at a primary maternity care setting.

Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ failure (MOF). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MOF are also not fully elucidated. As a result, successful therapies for trauma-related MOF are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through Toll-like receptor (TLR)-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. The first aim of this PhD thesis was to determine whether mtDNA released after trauma haemorrhage is sufficient for the development of MOF. Secondly, I then aimed to determine the extent of mtDNA release with varying degrees of tissue injury and haemorrhagic shock in a clinically relevant rodent model. My final aim was to determine whether neutralising mtDNA at a clinically relevant time point in vivo would reduce the severity of organ injury in this model.