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dc.contributor.advisorWalsh, Timothy
dc.contributor.advisorLone, Nazir
dc.contributor.authorDocherty, Annemarie Beth
dc.date.accessioned2018-06-25T10:55:30Z
dc.date.available2018-06-25T10:55:30Z
dc.date.issued2018-06-30
dc.identifier.urihttp://hdl.handle.net/1842/31247
dc.description.abstractApproximately 30% of people admitted to ICU in the UK have co-existing cardiovascular disease (CVD), and this may rise as life-expectancy increases. Patients with CVD have impaired compensatory mechanisms to enable maximum oxygen delivery to the tissues in the event of critical illness, which itself increases global oxygen demand, further stressing the heart. This is exacerbated by tachycardia and hypotension, which may relatively reduce blood flow to the coronary arteries, and catecholamines which increase myocardial oxygen demand. The myocardium extracts 75% of the oxygen supplied by the coronary arteries at rest, and atheroma-related flow limitation further compromises myocardial oxygen delivery. However, the diagnosis of acute coronary syndrome in critical illness is not straightforward, due to patient inability to communicate symptoms, non-specific ECG changes, and poorly understood cardiac biomarker troponin elevation. My overall hypothesis is that patients with CVD benefit from increased oxygen delivery to the myocardium during critical illness. A focus is the importance of anaemia. The aims of the studies presented in this thesis are (i) to systematically review the literature regarding blood transfusion thresholds specifically in patients with CVD; (ii) to explore the association between Troponin I (TnI) within 24 hours of ICU admission and hospital mortality (iii) to describe and quantify the dynamics of TnI in patients with CVD during the first ten days after ICU admission; and (iv) to define myocardial infarction in the context of critical illness. I have performed a systematic review and meta-analysis of randomised controlled trials comparing a restrictive with liberal transfusion threshold and that included patients with CVD. In total, 11 trials enrolling patients with CVD (n=3033) were included for meta-analysis (restrictive n=1514, liberal=1519). The pooled risk ratio for the association between a restrictive transfusion threshold and 30 day mortality was 1.15 (95% CI 0.88 to 1.50, p=0.50, I2=14%). The risk of acute coronary syndrome in patients managed with restrictive compared with liberal transfusion was increased (nine trials, risk ratio 1.78, 95% CI 1.18 to 2.70, p=0.0, I2=0%). In contrast to broader literature supporting restrictive thresholds, our systematic review shows that a restrictive transfusion threshold of less than 80g/l may not be safe in patients with co-existing CVD, and highlights the variability in diagnostic definitions of ACS and the potential for ascertainment bias in transfusion trials. I undertook a retrospective cohort study in two independently collected cohorts of general ICU patients who had TnI measured within 24 hours of ICU admission. Importantly, the majority of TnI samples were collected routinely rather than for clinical indications. We used the Abbott ARCHITECT Stat assay (limit of detection 0.01mcg/l. We performed multivariable regression, adjusting for components of the APACHE II model. We derived the risk prediction score from the multivariable model with TnI. TnI was associated with all cause hospital mortality (OR per doubling TnI 1.16, 95% CI 1.13 to 1.20, p<0.001) which persisted after adjustment for APACHE II model components (OR TnI 1.05, 95% CI 1.01 to 1.09, p=0.003). TnI correlated highly with the Acute Physiological Score component of APACHE II (r=0.39), suggesting that TnI release may be largely explained by acute physiological stress. Addition of TnI to the APACHE II model did not improve the performance of the risk prediction model and we would not advocate the adoption of a routine single troponin sample at admission. I designed, set up, and recruited 279 patients to a prospective cohort study TROPonin I in Cardiovascular patients in CriticAL care (TROPICCAL, UKCRN 19253) in 11 UK centres. The aims were to (i) determine the incidence of Myocardial Injury and Infarction, defined by the Third Universal Definition of Myocardial Infarction; (ii) explore factors associated with Injury and Infarction from multivariable analyses; and (iii) explore the relationship between Injury/Infarction and outcome in unadjusted and adjusted analyses. We recorded baseline characteristics, and took daily hs-TnI for ten days after ICU admission, severity of illness measures and ECGs for 5 days. There was a wide range of peak TnI (med 114ng/l (min 3, Q1 27, Q3 412, max 58820ng/l)) and a high prevalence of myocardial injury on systematic screening: 71% of patients had peak TnI greater than the sex-specific diagnostic threshold (“Injury”), and 24% had peak TnI greater than the sex-specific diagnostic threshold and dynamic changes on ECG consistent with ischaemia (“Infarction”). TnI consistently showed a rise-and-fall pattern consistent with an acute myocardial ‘hit’ rather than persisting injury, which peaked early during ICU stay. Importantly, only 12 (4.4%) patients were diagnosed with MI by the clinicians looking after the patients. Independent predictors of peak TnI in the preceding 24 hours were SOFA score, dynamic ECG ischaemia, lactate, haemoglobin, and age. The lack of association with CRP (representing systemic inflammation), with stronger association with lactate (representing inadequate perfusion/oxygen supply), Hb and ECG ischaemia support the conjecture that injury results in part from an acute ischaemic hit in this population. Patients with Infarction had similar baseline demographics to patients with Injury, but had higher peak TnI concentrations, and higher hospital and six month mortality (Figure 2). This supports the importance of including systematic assessment of dynamic ECG changes in the myocardial injury ‘construct’ in ICU. My work has shown an increased risk of ACS in patients with CVD randomised to restrictive transfusion thresholds. TnI elevation is prevalent in general ICU patients, and is independently associated with hospital mortality. A systematic approach to the detection of myocardial injury in critically ill patients with co-existing CVD who are unable to communicate symptoms, can identify a high risk population who have poorer survival than patients with no injury. Markers of ischaemia are more associated with TnI rise than markers of inflammation, supporting the hypothesis that myocardial injury in this population is at least in part due to oxygen supply-demand imbalance “myocardial infarction”. From this work, I would recommend (i) a more liberal transfusion threshold of at least 80g/l in patients with coexisting CVD; (ii) systematic use of sequential ECGs in ICU to screen for myocardial injury in ‘at risk’ patients; and (iii) manipulation of physiological parameters such as anaemia, hypotension and tachycardia should be considered for patients with dynamic ECG changes plus troponin increase consistent with Infarction. Future research should include ‘precision medicine’ trials in the substantial cohort of ICU patients with co-existing CVD to explore whether interventions that increase myocardial oxygen supply and/or treat infarction alter outcomes.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionDocherty AB, Sim M, Oliveira J, Adlam M, Ostermann M, Walsh TS, Kinsella J, Lone NI. Early Troponin I in critical illness and its association with hospital mortality: a cohort study. Critical Care 2017; 21(1): 216.en
dc.relation.hasversionFisher SA, Docherty AB, Doree C, Hibbs SP, Murphy MF, Estcourt LJ. Protocol: Computerised decision support systems to promote appropriate use of blood products. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD012545. DOI: 10.1002/14651858.CD012545en
dc.relation.hasversionDocherty AB, O’Donnell R, Brunskill S, Trivella M, Doree C, Holst L, Parker M, Gregersen M, Almeida J, Walsh T, Stanworth S. The impact of restrictive versus liberal transfusion strategies on patient outcomes in patients with cardiovascular disease excluding those undergoing cardiac surgery: A Systematic Review and Meta-analysis. BMJ 2016;352:i1351en
dc.relation.hasversionDocherty AB, Walsh TS. Anaemia and blood transfusion in the critically ill patient with cardiovascular disease. Critical Care 2017; 21: 61 DOI: 10.1186/s13054-017-1638-9en
dc.relation.hasversionDocherty AB, Walsh TS. Anaemia and blood transfusion in the critically ill patient with cardiovascular disease. Annual Update in Intensive Care and Emergency Medicine 2017; 187-201.en
dc.relation.hasversionDocherty AB, Walsh TS. Should blood transfusion be individualised? We are not sure. Intensive Care Medicine 2015; 41(11): 1980-1982en
dc.relation.hasversionDocherty AB, Lone NI. Exploiting big data for critical care research. Current Opinion in Critical Care 2015; 21(5):467-72.en
dc.relation.hasversionDocherty AB, O’Donnell R, Brunskill S, Trivella M, Doree C, Holst L, Parker M, Gregersen M, Almeida J, Walsh T, Stanworth S. The impact of transfusion thresholds on mortality and cardiovascular events in patients with cardiovascular disease (non-cardiac surgery): a systematic review and meta-analysis (abstract). Critical Care 2016 20(Suppl 2):94 DOI: 10.1186/s13054-016-1208-6.en
dc.subjectcardiovascular diseaseen
dc.subjectTroponin Ien
dc.subjectTnIen
dc.subjectECGen
dc.subjectlower blood concentrationen
dc.subjectoxygen supply-demand imbalanceen
dc.titleMyocardial injury in critically ill patients with co-existing cardiovascular diseaseen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2019-06-30en
dcterms.accessRightsRestricted Accessen


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