BACKGROUND: Sepsis is a clinical syndrome characterised by the systemic response to infection. It is a common problem in modern intensive care units and is associated with significant morbidity and mortality. Though the underlying cause of death is often multifactorial, refractory hypotension and cardiovascular collapse are frequently observed in the terminal phases of the condition. The aetiology of these cardiovascular abnormalities is complex but appears to be mediated by a circulating factor(s). The impact of sepsis upon left ventricular systolic function has been studied extensively. This may be because it is more readily assessed than diastolic function. Despite being increasingly appreciated as a contributor to morbidity and mortality in other clinical settings, there are scant data regarding the evaluation of left ventricular diastolic function in sepsis. Review of the haemodynamic monitoring literature reveals that many conventional measures of left ventricular filling, intravascular volume status and fluid responsiveness are influenced by ventricular diastolic (dys)function, such that interpretation can be challenging in critical care settings. In addition, many available techniques, such as pulmonary artery catheterisation, are invasive and potentially associated with risk to the patient. More robust and less invasive measures of left ventricular diastolic function and filling that can be applied within the intensive care unit (ICU) must be developed. The use of cardiac biomarkers, such as B-type natriuretic peptide (BNP), might represent a novel approach to evaluating left ventricular diastolic function and filling. BNP is released by the myocardium in response to wall stretch/tension. It has demonstrated value in the emergency department diagnosis of heart failure but interpretation of plasma BNP concentrations in critical care remains problematic. At least in part, this appears to relate to the significant number of potential confounders in patients with critical illness. Associations between BNP concentration and diastolic function have not previously been evaluated in severe sepsis and septic shock. The overall aim of this thesis is to investigate the usefulness of plasma BNP concentration in the evaluation of left ventricular diastolic function (including ventricular filling) in severe sepsis and septic shock. DIASTOLIC (DYS)FUNCTION IN SEPSIS: Review of the literature reveals that sepsis is associated with a spectrum of diastolic dysfunction. Characterisation of diastolic function in sepsis is challenging. In this regard, tissue Doppler imaging (TDI), offers promise. TDI is an echocardiographic technique that measures myocardial velocities, which are low frequency, high-amplitude signals filtered from conventional Doppler imaging. TDI has gained acceptance amongst cardiologists in the evaluation of diastolic function, particularly as a measure of ventricular relaxation and ventricular filling pressure; however, there are scant data regarding its use in critical care. We analysed echocardiographs from a large heterogeneous cohort of consecutive ICU patients (n=94) who had TDI as part of their clinically requested echocardiography. As well as supporting the feasibility of TDI in critically ill and mechanically ventilated patients, we demonstrated a wide range of TDI variables and a high prevalence of diastolic dysfunction using this modality. RODENT MODELS OF SEPSIS: We also sought to adapt, refine and evaluate rodent models of sepsis. Such models would allow control for a multitude of potential confounders commonly encountered in clinical sepsis. Two commonly employed rodent models of sepsis include caecal ligation and perforation (CLP) and endotoxin infusion. Comparison between CLP, sham and control groups demonstrated no difference in TDI or BNP. The observed changes in echocardiographic diastolic variables did not reflect those expected in sepsis and may be best explained by increases in heart rate rather than diastolic dysfunction per se. Endotoxaemia was associated with changes consistent with impaired myocardial relaxation (TDI) and reversible myocardial injury (histopathology), as expected in sepsis. BNP did not change significantly from baseline. This might be explained by the potential influence of fluid management upon BNP secretion. CLINICAL RESEARCH: The prediction of fluid responsiveness potentially prevents ineffective, excessive or deleterious intravenous fluid administration. Prospective evaluation of plasma BNP concentration in patients with septic shock found that it was not a predictor of a fluid responsive state. Furthermore, elevated BNP did not rule out a favourable response and therefore does not contraindicate a fluid challenge. Both impaired diastolic dysfunction, especially E/e’, and elevated BNP, have been associated with excess mortality in a range of cardiovascular diseases. These have not previously been compared in septic shock. In a cohort of patients with septic shock, E/e’ was a stronger predictor of mortality than cardiac biomarkers, including BNP. Fluid balance was an independent predictor of BNP in septic shock. OVERALL CONCLUSION: BNP appears not to be clinically useful in the evaluation of ventricular filling or diastolic function in sepsis. The association with fluid balance is a new finding and should be evaluated in a wider range of critically ill patients. In contrast to BNP, TDI appears to be a promising bedside tool in the evaluation of diastolic function and should be further evaluated in critical care.
| Identifer | oai:union.ndltd.org:ADTP/290227 |
| Creators | David Sturgess |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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