An investigation into the effects of commencing haemodialysis in the critically ill

<b>Introduction:</b> We have aimed to describe haemodynamic changes when haemodialysis is instituted in the critically ill. 3 hypotheses are tested: 1)The initial session is associated with cardiovascular instability, 2)The initial session is associated with more cardiovascular instability compared to subsequent sessions, and 3)Looking at unstable sessions alone, there will be a greater proportion of potentially harmful changes in the initial sessions compared to subsequent ones. <b>Methods:</b> Data was collected for 209 patients, identifying 1605 dialysis sessions. Analysis was performed on hourly records, classifying sessions as stable/unstable by a cutoff of >+/-20% change in baseline physiology (HR/MAP). Data from 3 hours prior, and 4 hours after dialysis was included, and average and minimum values derived. 3 time comparisons were made (pre-HD:during, during HD:post, pre-HD:post). Initial sessions were analysed separately from subsequent sessions to derive 2 groups. If a session was identified as being unstable, then the nature of instability was examined by recording whether changes crossed defined physiological ranges. The changes seen in unstable sessions could be described as to their effects: being harmful/potentially harmful, or beneficial/potentially beneficial. <b>Results:</b> Discarding incomplete data, 181 initial and 1382 subsequent sessions were analysed. A session was deemed to be stable if there was no significant change (>+/-20%) in the time-averaged or minimum MAP/HR across time comparisons. By this definition 85/181 initial sessions were unstable (47%, 95% CI SEM 39.8-54.2). Therefore Hypothesis 1 is accepted. This compares to 44% of subsequent sessions (95% CI 41.1-46.3). Comparing these proportions and their respective CI gives a 95% CI for the standard error of the difference of -4% to 10%. Therefore Hypothesis 2 is rejected. In initial sessions there were 92/1020 harmful changes. This gives a proportion of 9.0% (95% CI SEM 7.4-10.9). In the subsequent sessions there were 712/7248 harmful changes. This gives a proportion of 9.8% (95% CI SEM 9.1-10.5). Comparing the two unpaired proportions gives a difference of -0.08% with a 95% CI of the SE of the difference of -2.5 to +1.2. Hypothesis 3 is rejected. Fisher’s exact test gives a result of p=0.68, reinforcing the lack of significant variance. <b>Conclusions:</b> Our results reject the claims that using haemodialysis is an inherently unstable choice of therapy. Although proportionally more of the initial sessions are classed as unstable, the majority of MAP and HR changes are beneficial in nature

Improving Outcome After Cardiac Arrest: New Pharmacological And Electrophysiological Approaches During Cardiopulmonary Resuscitation

Cardiac arrest (CA) represents a leading cause of death in the western world. CA is a dramatic clinical event that can occur suddenly and often without premonitory signs. This condition is characterized by sudden loss of consciousness caused by the lack of cerebral blood flow, which occurs when the heart ceases to pump. Chest compressions (CCs) and early defibrillation (DF) are the cornerstones of cardiopulmonary resuscitation (CPR) in CA, while the only definitive treatment for ventricular fibrillation (VF) remains prompt DF. The present thesis includes both experimental and clinical studies directed to evaluate new pharmacological and electrophysiological approaches that have a potential benefit in the outcome of patients affected from CA. In order to achieve such aims, we performed two separate studies concurrently. The first study was directed to investigate experimentally the role of β1-blockade during CPR, while the second series of study evaluated prospectively the feasibility of a real time VF waveform analysis, in particular Amplitude Spectrum Area (AMSA), to guide interventions during resuscitation and to potentially diagnose underlying cardiac ischemia. Both the studies therefore concurred to the same goal of identify new tools to improve the outcome of CA and are presented together in this thesis as a single study with an introduction, methods, results, and discussion section. Nevertheless, in order to help the readers going throughout the work, each section is divided into sub-sections presenting separately the studies

Glucometer accuracy and implications for clinical studies

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Mannose binding lectin deficiency attenuates neurobehavioral deficits following experimental traumatic brain injury

Introduction: Mannose binding lectin (MBL) is the activator of the lectin complement pathway. After cerebral ischemia it has been shown that MBL could be a mediator of secondary brain damage, in contrast after traumatic brain injury (TBI) there are data suggesting that it could be linked to neuroprotection. We tested the hypothesis that MBL is involved in the pathophysiology of TBI. We 1) characterized the temporal activation of MBL and 2) the effects of its inhibition in a model of experimental TBI. Methods: 1) Male C57/Bl6 mice were subjected to intraperitoneal anesthesia (Pentobarbital, 65 mg/kg) followed by the controlled cortical impact brain injury model of experimental TBI (injury parameters: velocity of 5 meter/second and 1 mm depth of deformation). MBL immunostaining was evaluated at various time points after TBI: 30 minutes, 1, 6, 12, 24, 48, 96 hours and 1 week using anti MBL-A and MBL-C antibodies (n=3). 2) The effects of MBL inhibition were evaluated by comparing functional and histologic outcomes in C57/Bl6 mice (WT) and in MBL knock-out (-/-) mice. Functional outcome was tested using the Composite Neuroscore and Beam Walk test weekly up to 4 weeks postinjury (n = 11). Histologic outcome was evaluated by calculating the contusion volume at 4 weeks postinjury (n = 6). Sham-operated mice received identical anesthesia without brain injury. Results: We observed a robust MBL positive immunostaining in the injured cerebral cortex starting at 30 minutes postinjury and up to 1 week, suggestive of an activation of this pathway following TBI. MBL was observed both at endothelial and tissue level. Consistently, injured WT and MBL (-/-) mice showed neurological motor deficits up to 4 weeks postinjury when compared to their sham controls. Notably, MBL (-/-) mice showed attenuated behavioral deficits when compared to their WT counterpart at 2-4 weeks postinjury (p < 0.01 for both Neuroscore and Beam Walk test). In contrast we observed similar contusion volumes at 4 weeks postinjury (WT = 15.6 \ub1 3.2 cm3 and MBL KO = 13.9 \ub1 3.2 cm3, p = 0.3). Conclusions: We observed that 1) MBL deposition and/or synthesis is increased following TBI; 2) MBL deficiency is associated with functional neuroprotection, suggesting that MBL modulation might be a potential therapeutic target after TBI