Oxygen demand and neuronal biomarker release during extracorporeal circulation

Extracorporeal circulation (ECC) has revolutionized open-heart surgery, but its application has also extended beyond cardiac procedures into other medical domains, including locoregional cancer treatment, where ECC is combined with chemotherapy. The overall aim of this thesis was to explore patient physiological response and alternative approaches in extracorporeal circulation to increase understanding of procedure related side effects. In Paper I, a randomized controlled non-inferiority trial, we investigated the possibility of replacing the current erythrocyte-based prime solution with a crystalloid-based one, while ensuring sufficient oxygen delivery for patients undergoing isolated limb perfusion (ILP). We found no significant benefits of continuing adding erythrocytes to the prime solution for ILP, a finding leading to practice and guideline changes. In Paper II the oxygen demand in an isolated extremity was measured and described for the first time. Based on the findings, recommendations for nadir oxygen delivery during ILP was provided. Patients treated with ILP can develop transient peripheral nerve damage, and in Paper III, we explored if this could be detected using novel neuronal biomarkers. We found the biomarkers measurable and significantly increased during ILP. However, in this small feasibility study, we found no correlation to clinical outcomes. In Paper IV, a randomized controlled trial, we investigated the release pattern for biomarkers associated with brain injury in patients undergoing open-heart surgery randomized to either a standard or a high ECC flow rate. We found several correlations between treatment characteristics and the levels of biomarkers, however, there was no reduction in biomarkers with the higher flow rate as we had hypothesized. In conclusion, the use of ECC has emerged as a crucial component in modern healthcare. While originally applied in heart surgery, ECC has also been integrated into novel cancer treatments. This thesis underscores the importance of continued research in ECC methodology and physiological reactions to enhance the technique and minimize associated side effects

Anaesthesia and Hypothermic Cardiopulmonary Bypass: Haemodynamic and Metabolic Variables

Despite extensive investigation, the effects of some aspects of cardiopulmonary bypass upon haemodynamic and metabolic variables remain unresolved. Also, there have been great changes in the practice of cardiopulmonary bypass over the years and the findings of early research may no longer be applicable to present day techniques. Three aspects of cardiopulmonary bypass were identified as requiring investigation regarding their haemodynamic and metabolic effects: low flow rates; flow character ie nonpulsatile or pulsatile perfusion; and acid-base management te pH or alpha-stat control. Anaesthesia during cardiopulmonary bypass has been found in the past to have important metabolic effects which could be used to improve patient wellbeing and hence, outcome. However, these agents have been largely superseded by modern drugs that are metabolically untested. Although the effects on haemodynamic variables of most modern anaesthetics have been extensively studied before and after cardiopulmonary bypass, their actions during the abnormal conditions of cardiopulmonary bypass have not been rigorously examined. It was hypothesised that cardiopulmonary bypass and anaesthetic techniques have important haemodynamic and metabolic effects. This thesis was undertaken to test this hypothesis. In all the studies, arterial and mixed venous blood samples were analysed for oxygen content, saturation and tension, pH, carbon dioxide tension, base excess and lactate concentration. Systemic oxygen uptake and delivery were calculated. Initially, a computerised system was developed to act as a data logger for haemodynamic, arterial pH and temperature measurements as well as to enhance thermostatic and acid-base control. This system was tested and found to function well both as a recording device and as a means of obtaining good thermostatic control. However, the system performed poorly with regard to arterial pH control. The haemodynamic and metabolic effects of flow rate, flow character and acid-base management during hypothermic cardiopulmonary bypass were studied in a factorial experiment. Of the three factors, only alternation of flow rate between 1.5 and 2.0 L. min-1.m-2 was found to have a significant effect on systemic oxygen uptake. Flow rate was also found to have a significant effect on mean arterial pressure and peripheral vascular resistance. Arterial pH and stage during cardiopulmonary bypass were found to significantly interact to influence mean arterial pressure but not peripheral vascular resistance. Alternation of flow character between pulsatile and nonpulsatile perfusion had no significant effect on haemodynamic variables. Over and above these effects, a progressive vasoconstriction throughout cardiopulmonary bypass was noted. Isoflurane's effects on haemodynamic and metabolic variables were examined during hypothermic cardiopulmonary bypass. Isoflurane was found to be a vasodilator during these abnormal haemodynamic conditions although no systemic metabolic effects were identified. Next, the haemodynamic and metabolic effects of atracurium during hypothermic cardiopulmonary bypass were studied. Neither haemodynamic nor metabolic effects were found from the use of atracurium. Finally, the haemodynamic and metabolic effects of alfentanil and it's antagonism with naloxone during hypothermic cardiopulmonary bypass were investigated. Neither alfentanil nor its antagonism with naloxone had any significant metabolic effect. However, administration of alfentanil prevented the expected increases in mean arterial pressure and peripheral vascular resistance that occur during the course of cardiopulmonary bypass. In contrast, antagonism of alfentanil with naloxone produced greater increases in mean arterial pressure and peripheral vascular resistance than would be predicted to occur simply as a result of stage. Flow rate proved to be an important determinant of haemodynamics and metabolism during hypothermic cardiopulmonary bypass. This finding makes questionable the practice of reducing the pump flow rate to low levels after induction of hypothermia. The lack of difference in haemodynamic and metabolic effects between nonpulsatile and pulsatile perfusion would add weight to the body of opinion which holds that flow character has no important actions during clinical cardiopulmonary bypass. Arterial pH interacted with stage during cardiopulmonary bypass to influence mean arterial pressure. However, the clinical importance of this finding is uncertain as the size of effect was small. This haemodynamic finding and the lack of any difference in metabolic effect add no weight to the use of either alpha or pH-stat acid-base management. The progressive vasoconstriction, found throughout these studies, is an important and well recognised phenomenon of cardiopulmonary bypass. (Abstract shortened by ProQuest.)

Recommendations for Haemodynamic and Neurological Monitoring in Repair of Acute Type A Aortic Dissection

During treatment of acute type A aortic dissection there is potential for both pre- and intra-operative malperfusion. There are a number of monitoring strategies that may allow for earlier detection of potentially catastrophic malperfusion (particularly cerebral malperfusion) phenomena available for the anaesthetist and surgeon. This review article sets out to discuss the benefits of the current standard monitoring techniques available as well as desirable/experimental techniques which may serve as adjuncts in the monitoring of these complex patients

Microvascular Responsiveness to Cardiopulmonary Bypass

Cardiopulmonary bypass can result in multiple organ failure due to mechanisms of ischemia reperfusion injury and the systemic inflammatory response syndrome. The primary objective of this thesis was to investigate and monitor the microvasculature in cardiac surgery patients using multiple methodologies and real-time monitoring techniques. The purpose of our first study was to determine whether pulsatile blood flow during bypass improves microvascular perfusion compared to non-pulsatile flow. We found that changes in sublingual mucosal microcirculation using orthogonal polarization spectral imaging correlate with indices of thenar muscle tissue oxygen saturation and its recovery during a vascular occlusion test using near-infrared spectroscopy in both groups. There were significantly fewer normally perfused vessels, along with impaired microvascular responsiveness and elevated levels of lactate in the non-pulsatile group. Although these technologies help to better understand the pathophysiology of acute circulatory failure, a need exists for improved monitors that can continuously track real-time changes in the microcirculation. Our subsequent studies involved the application of a custom broadband continuous wave near-infrared monitor to determine the feasibility of tracking microvascular hemoglobin content as a surrogate for red blood cell (RBC) flow in skeletal muscle during non-pulsatile bypass. We measure changes in optical density at the isosbestic wavelength as an index of change in hemoglobin over time. The changes in optical density relative to baseline values were continuously monitored throughout the procedure, and showed a positive correlation with various interventions during bypass and with potentially negative outcomes. In our third study we applied continuous wavelet transform analysis to the near-infrared data to reflect the dynamic variability in RBC distribution within the microvasculature as an indicator of autoregulation. We showed signal power composition varied within and between patients at all time points, and shifting of power distribution from high to low frequency ranges, and vice versa, in relation to specific events during the procedure. These studies support the potential for clinical devices that can be easily interpreted by a clinician in real-time to guide therapeutic targets and improve clinical outcomes. Our current research and related future work is an important first step and compelling pre-requisite for such a monitor

Evaluation of near-infrared spectroscopy in patients with acute coronary syndrome undergoing on and off-pump coronary artery bypass graft surgery

Thesis (M. Tech. (Clinical technology)) - Central University of technology, Free State, 2012The objective of this study was to investigate whether intra-operative regional cerebral tissue oxygen saturation (NIRS) and hemodynamic monitoring in patients with Acute Coronary syndrome (ACS) during coronary bypass graft surgery (CABG on-pump vs. off-pump) can predict clinical outcomes and complications. Data from 60 CABG patients (30 on-pump and 30 off-pump) were analyzed. The regional cerebral tissue oxygen saturation was monitored by using near-infrared spectroscopy (NIRS). The sensors were positioned in the middle of the patient's forehead and the cables were connected to the sensors and to the INVOS 5100C® Oximeter. According to NIRS values obtained, patients were subdivided into two groups. Patients in Group 1 had absolute NIRS values more than 50 or less than a 20% drop from the baseline value. Patients in Group 2 had absolute NIRS values of less than 50 or a drop of more than 20% from the baseline value. The lowest value recorded during the procedure was recorded for this purpose, irrespective of the time this value was obtained. Intra-operative hemodynamic monitoring was captured by a computer software program (Supplier Datex Ohmeda, South Africa). In order to describe surgical outcomes several parameters were analysed and compared. This included a Pre- and Post-operative Mini-Mental state examination that was performed to identify neurological outcomes or impairment. The NIRS values and trends in relation to renal function (U&E and creatinine, urine output, and urine electrolytes), as well as clinical outcomes were analyzed post-operatively for the different groups. Clinical outcomes were described using the Society of Thoracic Surgeons Database (STS database) data fields, and specifically the recording of complications. The overall clinical outcomes were analysed between the on-pump and off-pump groups as well as the NIRS results between the two groups. In order to elucidate the predictive role of NIRS the patients were divided into groups with either impaired /reduced NIRS values or acceptable NIRS values according to published results where a reduction of more than 20% from baseline or absolute values of less than 50 were associated with inferior outcomes. Finally, the predictive value of NIRS was evaluated within the on- and then the off-pump groups. In this analysis the outcomes of patients with reduced NIRS values was compared to those of patients with acceptable NIRS values. The study demonstrated that by far the majority of patients with reduced cerebral flow/oxygen delivery as reflected in cerebral NIRS, had on-pump CABG procedures (84% fell in risk group 2). It also showed that a NIRS reduction of more than 20 % from baseline and values of less than 50, has an impact on post–operative renal function. Monitoring of cerebral oximetry intra-operatively by using near-infrared spectroscopy during cardiac surgery (especially in on-pump cardiac surgery patients) allows the perfusionist and anaesthesiologist to detect cerebral desaturation and to intervene as necessary. This study also showed a tendency towards less renal function impairment in patients with absolute NIRS values > 50 or where there was < 20% drop from baseline. It is probably important to consider studying the time spend below 50 or a drop of more than 20% from baseline NIRS values, or the “area under the curve” as a specific factor contributing to the increased risk for post-operative complications applied on an increased study population. The study supports the routine use of NIRS as a non-invasive trend monitor of cerebral saturation and certainly initiated interventions by both anaesthetic and perfusion staff which contributed to excellent clinical outcomes in this research study

Tissue microvascular flow and oxygenation in critically ill patients

PhDThe use of fluid resuscitation and vasoactive agents to optimise global haemodynamics has been demonstrated to improve outcomes in patients undergoing major surgery and in early sepsis. Whether changes in global haemodynamics result in similar improvements in the microcirculation in critically ill patients remains unclear. The aim of this thesis was to investigate the changes in tissue microvascular flow and oxygenation that occur in patients undergoing major surgery and in those with sepsis, and specifically how haemodynamic therapies may affect these changes. The first part of this thesis investigates the treatment pathway of the high risk surgical patient. Analysis of two large health databases was performed and confirmed the existence of a high risk sub-population within the local surgical population. Only about a third of these high-risk patients were admitted to a critical care unit at any stage during their hospital admission. An observational trial was performed examining the relationship between global oxygen delivery, microvascular flow and tissue oxygenation in 25 surgical patients receiving usual care. Data including global haemodynamics, sublingual and cutaneous microvascular flow, and tissue oxygenation were collected before, and for eight hours after surgery. Abnormalities in sublingual microvascular flow were found to be associated with worse outcomes. 4 A randomised controlled study investigating the effects of two goal directed haemodynamic therapy (GDHT) algorithms on tissue microvascular flow and oxygenation compared to central venous pressure guided fluid therapy in 135 perioperative patients was performed. For eight hours after surgery, intravenous fluid therapy was guided by measurements of central venous pressure (CVP group) or stroke volume (SV group). In a third group stroke volume guided fluid therapy was combined with dopexamine (SV & DPX group). In the SV & DPX group, increased global oxygen delivery was associated with improved sublingual and cutaneous microvascular flow. Microvascular flow remained constant in the SV group but deteriorated in the CVP group. Cutaneous PtO2 improved only in the SV & DPX group. There were no differences in complication rates between groups. The importance of derangements in microvascular flow in patients with established sepsis is well recognized. However, little data is available to describe microvascular changes in early sepsis. Observational data were collected in 16 healthy volunteers and within six hours of presentation in 48 patients with sepsis and severe sepsis. Sublingual microvascular flow was impaired in patients with sepsis and severe sepsis compared to healthy volunteers. Greater alterations in flow were seen with increasing severity of illness. The dose-related effects of vasopressor therapy on microvascular flow and tissue oxygenation in sepsis have not been previously fully investigated. The effects of increasing doses of noradrenaline, targeted to achieve successively greater mean arterial pressures, on microvascular flow and tissue oxygenation in 16 patients with septic shock were investigated. Increasing doses of noradrenaline were associated with improvements in 5 global oxygen delivery, cutaneous PtO2 and cutaneous microvascular red blood cell flux. No changes in sublingual microvascular flow were identified. This thesis confirms the existence of a large sub-population of high risk surgical patients. It demonstrates that abnormal microvascular flow in the perioperative period may be associated with poor outcomes. The use of flow guided fluid therapy alongside low dose dopexamine infusion is shown to improve global haemodynamics, microvascular flow and tissue oxygenation in perioperative patients. Microvascular abnormalities are shown to occur in the earliest stages of sepsis with increasing severity of disease being associated with greater changes. Increasing doses of noradrenaline were found to improve global haemodynamics, cutaneous microvascular flow and cutaneous tissue oxygenation in septic shock. Further work is required to investigate the effects of haemodynamic therapies on microvascular flow and organ dysfunction in critically ill patients and the use of the microcirculation as a resuscitation endpoint