Gastrointestinal injury following cardiopulmonary bypass

The gastrointestinal (GI) tract may be the source of a number of bacterial and non-bacterial mediators, which may contribute to the development of morbidity and mortality following episodes of gut hypoperfusion/ ischaemia. The aim of this thesis has been to identify the changes in gut blood flow, oxygenation and function following cardiopulmonary bypass (CPB) and their relationship to the development of post-CPB morbidity. The findings are summarised below: The retrospective study identified age (>65 yr) and CPB time as risk factors for the development of post-CPB intra-abdominal complications . Tonometrically determined values for intramucosal pH (pHi) need temperature correction to avoid calculation of erroneously high values during hypothermic CPB. Considerable hypoperfusion occurs during hypothermic CPB, with laser Doppler flowmetry (LDF) falling to approximately 45% of pre-CPB values. The gastric and colonic pHi becomes acidotic (<7.35) during the re-warming and immediate post-CPB period. Intramucosal acidosis occurs at a time when mucosal LDF blood flow is normal or supranormal. CPB increases gut permeability and reduces the absorption of the monosaccharides, 3-O-m-D-glucose, D-xylose & L-rhamnose. Post-CPB gut permeability has a temporal relationship with the CPB time. Pulsatile flow attenuates the increase in post-CPB gut permeability. Endotoxaemia occurs during CPB but is not associated with the production of TNFα; pulsatile flow attenuates this endotoxaemia. When examining perfusion and patient factors, the best predictor for a protracted ventilation & ICU stay for patients was a low gastric pHi (<7.35). A canine model of CPB supported the clinical findings, but also found that: (a) changes in large vessel blood flow do not indicate more dynamic alterations in small vessel blood flow (b) blood flow is prioritised to the mucosa at the expense of the serosal aspects of the bowel wall (c) in the re-warming phase of hypothermic CPB & the immediate post-CPB period, when intramucosal acidosis occurs, there is a disparity between gut oxygen consumption & delivery (b) increased expression of vasoactive intestinal peptide was found in the neural plexus of the submucosa post-CPB, which may indicate a role in preserving mucosal blood flow during periods of hypoperfusion

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.)

VALIDATION OF COMPUTATIONAL FLUID DYNAMIC SIMULATIONS OF MEMBRANE ARTIFICIAL LUNGS WITH X-RAY IMAGING

The functional performance of membrane oxygenators is directly related to the perfusion dynamics of blood flow through the fiber bundle. Non-uniform flow and design characteristics can limit gas exchange efficiency and influence susceptibility of thrombus development in the fiber membrane. Computational fluid dynamics (CFD) is a powerful tool for predicting properties of the flow field based on prescribed geometrical domains and boundary conditions. Validation of numerical results in membrane oxygenators has been predominantly based on experimental pressure measurements with little emphasis placed on confirmation of the velocity fields due to opacity of the fiber membrane and limitations of optical velocimetric methods. A novel approach was developed using biplane X-ray digital subtraction angiography to visualize flow through a commercial membrane artificial lung at 1–4.5 L/min. Permeability based on the coefficients of the Ergun equation, α and β, were experimentally determined to be 180 and 2.4, respectively, and the equivalent spherical diameter was shown to be approximately equal to the outer fiber diameter. For all flow rates tested, biplane image projections revealed non-uniform radial perfusion through the annular fiber bundle, yet without flow bias due to the axisymmetric position of the outlet. At 1 L/min, approximately 78.2% of the outward velocity component was in the radial (horizontal) plane verses 92.0% at 4.5 L/min. The CFD studies were unable to predict the non-radial component of the outward perfusion. Two-dimensional velocity fields were generated from the radiographs using a cross-correlation tracking algorithm and compared with analogous image planes from the CFD simulations. Velocities in the non-porous regions differed by an average of 11% versus the experimental values, but simulated velocities in the fiber bundle were on average 44% lower than experimental. A corrective factor reduced the average error differences in the porous medium to 6%. Finally, biplane image pairs were reconstructed to show 3-D transient perfusion through the device. The methods developed from this research provide tools for more accurate assessments of fluid flow through membrane oxygenators. By identifying non-invasive techniques to allow direct analysis of numerical and experimental velocity fields, researchers can better evaluate device performance of new prototype designs

End organ effects of paediatric cardiopulmonary bypass

Despite the scientific, technological and surgical improvements of the past 50 years organ dysfunction following elective paediatric cardiac surgery utilising cardiopulmonary bypass continues to account for increased complications, often leading to a protracted course in hospital with a longer stay in intensive care and the potential for irreversible organ damage long term. Furthermore, paediatric cardiac surgeons are routinely undertaking more complex operations with a shift from palliation to early correction. This has resulted in younger children being subjected to longer periods on the bypass machine with increased effects on vital organs. This thesis describes two clinical studies designed to further assess and characterise peri-operative cardiac, renal and pulmonary function in children undergoing elective cardiac repair at a tertiary referral centre in Scotland, UK. In the first instance a prospective, observational study was undertaken in forty-five children to examine the use of tissue Doppler imaging in the assessment of peri-operative cardiac function, its relationship to myocardial injury and clinical outcome. Tissue Doppler parameters were obtained using a Vivid 7 ultrasound scanner with a 7-MHz probe pre-operatively, on admission to paediatric intensive care and on day one. Myocardial injury was assessed using Troponin-I on the first post-operative day by a commercially available chemiluminescent immunoassay. In twenty children within this group peri-operative renal function was also investigated using standard estimates of glomerular filtration rate, namely creatinine clearance measured by the kinetic Jaffe method during the first and second twelve hour post-operative periods, in comparison to serum creatinine and the novel biomarker cystatin C. Routine plasma retained pre-operatively and on days 0, 1, 2 and 3 post-operatively was used to measure serum cystatin C and creatinine using a particle-enhanced nephelometric immunoassay and the Roche Creatinine Plus enzymatic assay respectively. The association between cystatin C and recorded perfusion parameters including bypass duration, pump flow, haematocrit, oxygen delivery and Troponin-I was investigated. Peri-operative pulmonary function was evaluated through a phase IV, randomised, double-blind, placebo controlled trial. In total, twenty four children were randomised to receive oral sildenafil or equivalent volume placebo four times the day before surgery. Blood samples were collected peri-operatively to measure serum cyclic guanosine monophosphate with a commercially available competitive enzyme immunoassay. Haemodynamic data and echocardiography were acquired at two and twenty four hours post-operatively including pulmonary vascular resistance index and bi-ventricular contractility. Post-operative oxygenation was also determined at the same time by oxygen delivery and oxygenation index. In Chapter 2, peri-operative cardiac function as assessed by tissue Doppler imaging was examined. The results of this study demonstrated that pre-operatively, bi-ventricular systolic function in the study group was reduced compared with normal controls, displaying a significant step-wise decrease with increasing complexity of lesion. This picture persisted post-operatively predominantly in the right ventricle and was significantly associated with the extent of myocardial injury. Impaired peri-operative left ventricular function correlated with clinical outcomes. In Chapter 3, peri-operative renal function as assessed by cystatin C and its association with parameters of perfusion was examined. The results of this study demonstrated that in comparison to serum creatinine, cystatin C had a superior correlation with glomerular filtration rate in the early post-operative period. An elevated level of this biomarker was significantly associated with bypass duration, minimum pump flow and post-operative myocardial injury. Haematocrit was not directly linked to renal dysfunction in this study although evidence of a critical dysoxic threshold within the kidney was suggested indirectly through oxygen delivery calculations. In Chapter 4, peri-operative pulmonary function and vascular reactivity in association with the pre-operative administration of oral sildenafil (0.5mg/kg, six hourly) was examined. The results of this trial demonstrated that compared to placebo, pre-operative sildenafil resulted in modest elevations of serum cyclic guanosine monophosphate, limited effects on pulmonary vascular resistance index, significant reductions in peri-operative bi-ventricular contractility, significant reductions in post-operative oxygen delivery and a trend for increasing ventilatory support. In summary, the current thesis has demonstrated that in children undergoing corrective cardiac surgery peri-operative bi-ventricular function can be accurately assessed by tissue Doppler imaging which to date has had limited use in this patient group. With regards to renal function, cystatin C was shown to be a better estimate of glomerular filtration rate and a more sensitive marker of early renal dysfunction in children after surgery. Furthermore, cystatin C identified a transient post-operative renal impairment, the magnitude of which was associated with duration of bypass, pump flow and myocardial injury. In relation to pulmonary function, this research identified that pre-operative administration of oral sildenafil to children undergoing cardiac surgery produced limited effects on pulmonary vascular resistance but was associated with reduced ventricular contractility and post-operative oxygenation raising significant concerns over its routine clinical use

Capacitive Air-Bubbles Detector for Extracorporeal Blood Circulation

Extracorporeal blood circuits, or ECBC, have been used in hemodialysis, hemofiltration, plasmaphersis, and for assisted blood circulation during open-heart surgery for many years. ECBC devices consist of numerous individual parts which, dependent upon their operating characteristics, are potential generators of embolism or air bubbles in the blood. The purpose of this study is to construct a capacitive device capable of detecting these embolisms in an ECBC, and to investigate the relation between the size of air bubbles and change in capacitance and output voltage at various applied frequencies. Theoretical analysis of the system and simulation using Multisim2001 software were obtained and compared with experimental results. Results showed that the device was capable of detecting air bubbles with diameters 620 µm and over using Dextran70 and 730 µm using human blood. The capacitance of the capacitor was found to decrease as air bubble diameter increased whereas output voltage increased as air bubble diameter increased. The output voltage was found to increase when the frequency decreased, as theoretically predicted. The main finding was that air bubble, with diameters from 620 µm to 4.21 mm in Dextran70 solution and human blood, produced significant changes in the capacitance of the test cell device. In addition, experimental results were in good agreement with simulation and theoretical analysis. The sensitivity of the device for the Dextran70 was found to be 16.8 mV/nF obtained at 40 Hz and for human blood it was 16.4 mV/nF at 30 Hz

Aspects of circulatory failure in respiratory extracorporeal membrane oxygenation

Extracorporeal Membrane Oxygenation (ECMO) was developed in the seventies for the intended use of supporting respiratory failure. Today ECMO has become a well-established treatment for patients with both respiratory and circulatory failure where conventional intensive care is inadequate. The conventional way of treating adults with respiratory failure has been venovenous ECMO (VV ECMO) and for cardiogenic failure venoarterial (VA ECMO). However, since the respiratory system is an intrinsic part of the cardiocirculatory system and these systems exist in conjunction with each other, a respiratory failure may also inflict impairment on the circulation. Furthermore, a distributive shock differs from a cardiogenic shock. Therefore, it also remains to be clarified if, and to what extent vasoplegic (distributive) circulatory failure in conjunction with respiratory failure benefits from ECMO support, and which mode (VV or VA) should be preferred. Furthermore, if VA ECMO is instituted in a patient with a respiratory failure there are several issues that needs to be addressed that differ from the VA patient with single organ cardiogenic failure. AIMS The first aim of this thesis was to describe if ECMO and more specifically VA ECMO has a positive effect on survival in adult patients with septic shock (Study 1). In Study 2 we investigated the incidence, indication and outcome in patients who were converted from VV to VA ECMO to clarify whether conversion has an impact on mortality. Furthermore, since patients on peripheral VA ECMO will have parallel circulations with ensuing differential hypoxemia (DH), we went on with investigating patients with signs of DH. Thus, in Study 3 we investigated the impact on oxygen saturation in the upper body by change of drainage position from the inferior vena cava (IVC) to the superior vena cava (SVC). Since septic shock on ECMO can lead to prolonged ECMO with significant lung parenchymal damage we continued in study 4 to investigate if pulmonary blood flow (PBF) measured with echocardiography may assist in assessment of the extent of pulmonary damage, and if echocardiography and CT findings were associated with patient outcome. METHODS All studies are retrospective, originating from a high-volume ECMO centre. Patients who were not treated at our unit during the whole ECMO run, and patients with ongoing cardiopulmonary resuscitation (CPR) at the time of ECMO initiation were excluded in all studies. In Study 1 all patients treated for septic shock between 2012 and 2017 with an age >18 years, fulfilling septic shock criteria according to Sepsis-3, and a vasoactive- inotropic support equivalent to a Vasoactive inotropic score (VIS) >50 to reach a mean arterial pressure >65 mmHg despite adequate fluid resuscitation, were included. In Study 2 all patients >18 years old who were commenced on VV ECMO between 2005 and 2018 were included. Patients who were converted to VA ECMO within the first six hours after ECMO treatment was commenced were excluded. In Study 3 all patients from the age of 15 years between 2009 and 2020 identified with differential hypoxemia were included. Patients were included if there had been a state of fulminant differential hypoxemia (FDH) leading to a repositioning or change of the drainage cannula. FDH was defined as a higher saturation in the lower part of the body compared to the upper part of the body or a saturation of the upper body below or equal to 60%. In Study 4, all patients from the age of 15 between 2011 and 2017 were screened. Patients with septic shock (according to Sepsis 2) originating from pneumonia and treated for >28 days were eligible for inclusion. RESULTS In Study 1, thirty-seven patients were included. Twenty-seven patients were submitted to VA and 10 patients to VV ECMO. Hospital survival was 90% in septic shock with left ventricular failure, and 65% in patients with distributive vasoplegic shock. In Study 2, 219 VV ECMO patients were evaluated, 21% (n=46) were converted to VA ECMO. The two main reasons for conversion were right ventricular failure (RVF) or cardiogenic shock. In the converted patients, there was a significant increase in Sequential Organ Failure Assessment (SOFA) scores between admission 12 (IQR 9-13) and conversion 15 (IQR 13-17), p<0.001. The converted patients had a higher mortality rate compared to the non-converted patients (62 vs. 16%, p<0.001). These patients also scored lower at admission on the Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score (2 (0–4) versus −2.5 (−4–1), p<0.001). Mortality among RVF patients was 67% compared to 50% in converted patients with circulatory shock. In Study 3, 472 patients were screened and seven were identified with FDH. The mean peripheral capillary saturation increased from 54(±6.6) to 86(±6.6) %, (p=<0.001) after repositioning of the cannula from the IVC to the SVC. Pre-oxygenator saturation increased from 62(±8.9) % to 74(±3.7) %, (p=0.016) after repositioning. In Study 4, CT failed to indicate any differences in viable lung parenchyma between survivors and non-survivors at any time over the course of ECMO treatment. A mixed effects model with time, survivors and non-survivors and the interaction between time and the two groups as independent variables, showed that the interaction was significant (p=0.004) with different coefficient slopes between the two groups regarding PBF. CONCLUSIONS Study 1 supported the use of VA ECMO for distributive septic shock. Study 2 indicated that VA ECMO should be considered as the first mode of choice in patients with respiratory failure combined with a compromised circulation. Study 3 elucidated DH in a clinical patient setting which has never been presented previously, showing that moving the drainage zone into the upper part of the body had a marked positive effect on upper body saturation. Finally in Study 4 we presented results demonstrating that CT was supported as a prognostic tool in prolonged respiratory ECMO. However, we found that PBF may possibly assist in the prediction of pulmonary recovery