Myocardial injury after noncardiac surgery (MINS) is common in patients undergoing inpatient noncardiac surgery and has been shown to adversely impact short- and long-term patient prognosis. Most MINS events are asymptomatic and systematic troponin measurement early after surgery is of paramount importance to detect these events. The largest study to determine thresholds and prognostic importance of MINS used troponin T and high-sensitivity troponin T. There is limited information on how to diagnose MINS using high-sensitivity troponin I (hsTnI). How to predict who is at higher risk of MINS and would benefit the most from troponin monitoring, and how to manage patients who suffer a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps. Chapter 2 describes the result of a large prospective cohort of patients undergoing noncardiac surgery which determined the utility of preoperative N-Terminal pro-B type Natriuretic Peptide to predict 30-day MINS and vascular death, in addition to clinical evaluation. Chapter 3 uses data collected as part of a large prospective cohort with a nested biobank to determine thresholds of hsTnI that can predict major cardiovascular events in patients who underwent noncardiac surgery and be used to diagnosis MINS using hsTnI. Chapter 4 details the methods of an international, multicentre, randomized placebo-controlled trial (MANAGE Trial) determining the impact of dabigatran, a blood thinner, and using a partial factorial design, of omeprazole, a gastric acid reducing drug, on the occurrence of major vascular and upper gastrointestinal events in patients who suffered a MINS and are followed for up to 2 years. Chapter 5 presents the results of the omeprazole component of the MANAGE Trial. Chapter 6 discusses the key findings of the thesis and future research directions. / Thesis / Doctor of Philosophy (PhD) / Damage to the heart muscle occurring after a noncardiac surgery, called myocardial injury after noncardiac surgery (MINS), occurs frequently and negatively impacts patient’s short- and long-term health and survival. Most patients who suffer a MINS do not present symptoms suggestive of heart problems. Blood tests obtained after surgery measuring troponins, a marker of heart damage, is necessary to detect which patients are having MINS. Different troponin tests are available, including a test called high-sensitivity troponin I, for which there is limited information on how to diagnose MINS using this test. How to predict who is at higher risk of MINS and how to treat patients who suffered a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps.

BACKGROUND: Early postoperative cardiovascular complication rates are high and are associated with hemodynamic compromise. A large proportion of hypotensive episodes are missed with routine ward monitoring strategies due to low measurement frequency and nursing limitations. OBJECTIVES: The aim of this study was to determine the incidence of postoperative hypotension using a frequent monitoring strategy. Second, we looked at the relationship between postoperative hypotension and composite of mortality, non-fatal myocardial infarction, non-fatal stroke and new dialysis requirements. Finally, we sought to uncover significant predictors of postoperative hypotension. METHODS: Patients >45-years of age enrolled in the VISION Study were included in this sub-study. The COVIDIEN vital sign monitor was used to collect blinded hourly blood pressure measurements in patients post non-cardiac surgery until post-operative day three. RESULTS: 1248 patients were included in this analysis. The three-day incidence of hypotension in the compliant intensively monitored group was almost twice higher (31.4% - 81/258 patients) than in the routine monitoring group, and the average delay in identifying a drop in BP under 90mmHg was almost 1.5 hours (87.5min) (IQR 21.3-153.3min). Severe hypotension (SBP <80mmHg) in the first three postoperative days, had the strongest association amongst all perioperative factors with the composite outcome of death, MI, stroke and new requirement for dialysis after non-cardiac surgery at 30 days [adjusted OR of 2.83 (95%CI, 1.25-6.44)]. Significant predictors of postoperative hypotension include a history of dialysis [adjusted OR 3.1 (95%CI, 1.14-12.96)], open surgery [adjusted OR 2.39 (95%CI, 1.57-3.62)], abdominal surgery [adjusted OR 1.79 (95%CI, 1.25-2.57)], and orthopedic surgery [adjusted OR 1.72 (95%CI, 1.112.74)]. CONCLUSION: Early postoperative cardiovascular complication rates are high and are associated with hemodynamic compromise. A large proportion of hypotensive episodes are missed with routine ward monitoring strategies. / Thesis / Master of Science (MSc)

Background 200 million patients undergo noncardiac surgery every year. Overt stroke after noncardiac surgery is not common, but has a substantial impact on duration and quality of life. Covert stroke in the nonsurgical setting is much more common than overt stroke, and associated with an increased risk of cognitive decline and dementia. Little is known about covert stroke after noncardiac, noncarotid artery surgery. Methods We undertook a prospective cohort pilot study to inform the incidence of covert stroke after noncardiac, noncarotid artery surgery, and to determine the feasibility of a full prospective cohort study to characterize the epidemiology of perioperative covert stroke. Patients underwent a brain MRI study between postoperative days 3-10, and were followed up at 30 days after surgery. Results of the pilot study We enrolled a total of 100 patients from 6 centres in 4 countries, demonstrating excellent recruitment and no loss to follow-up at 30 days after surgery. The incidence of perioperative covert stroke was 10.0% (10/100 patients, 95% confidence interval 5.5% to 17.4%). Full study protocol We describe a proposal for a prospective cohort study of 1,500 patients. An MRI study of the brain will be performed between postoperative days 2 and 9. The primary outcome is cognitive function, measured 1 year after surgery using the Montreal Cognitive Assessment tool. We will perform multivariable logistic regression analysis where the dependent variable is the change in cognitive function 1 year after surgery, and the independent variables are incidence of perioperative covert stroke and other risk factors for cognitive decline. Conclusions This international multicentre pilot study suggests that 1 in 10 patients ≥65 years of age experiences a perioperative covert stroke. The proposed protocol describes a larger study which will determine the impact of perioperative covert stroke on patient-important outcomes. / Thesis / Master of Science (MSc) / This thesis describes a program of research to investigate silent stroke after surgery.

INTRODUCTION : Acute kidney injury (AKI) is a disorder that is defined by rising serum creatinine and reduced urine output. It occurs in approximately 1-7% of hospitalized patients and is a major predictor of morbidity and mortality. It increases the costs and duration of hospital stay. AKI has been extensively studied post cardiac surgery, but there has been little attention on AKI occurring after non cardiac surgery . There have been few studies on AKI from developing countries and a paucity of data of post non cardiac surgery AKI. OBJECTIVE : To identify which known risk factors for AKI are commonly encountered at Groote Schuur Hospital, to document 30 and 90 day mortality, length of hospital stay, recovery of renal function at 90 days and identify factors associated with outcome post non-cardiac surgery. DESIGN: Prospective observational study. SETTING: Surgical Wards and ICU. PARTICIPANTS: Patients with AKI post non-cardiac surgery admitted between July 2012 and July 2013, who were 18 years and above without underlying stage 5 chronic kidney disease. OUTCOME MEASURES: Mortality, identification of risk factors, length of hospital stay and recovery of renal function. RESULTS: Of 367 patients referred to renal unit with AKI, 60 patients met inclusion criteria. Patients had an average age of 52.8 years (standard deviation 16.6) and 70% (42/60) were male. 61.7% (37 /60) were Coloured, 20% (12/60) were White and 18.3% (11/60) were Black. These patients were exposed to the following risk factors: 80%(48/60) had emergency surgery, 66. 7%(40/60) had sepsis, 65%(39/60) had perioperative contrast exposure, 53.3%(32/60) had hypotension that required inotropic support in 50%(30/60). Mortality was 33.3% (20/60) at 30 days and 45% (27/60) at 90 days. Of the 33 patients who did not die, 81.8% (27 /33) recovered their renal function to normal baseline creatinine at 90 days. Of the 6 patients, whose renal function did not return to baseline, none required long term dialysis. Perioperative contrast exposure was associated with a longer median length of hospital stay compared to patients not exposed to contrast (21 vs 16 days respectively, p<0.05). Sepsis and age > 60 years was associated with poor recovery of renal function (p=0.005, p=0.01 respectively). No risk factor was identified to be associated with mortality. CONCLUSION: Risk factors for post non cardiac surgery AKI commonly encountered at Groote Schuur Hospital were emergency surgery, sepsis, hypotension, perioperative use of inotropes and perioperative contrast exposure. The latter was identified as a modifiable risk factor which significantly prolonged hospital stay. Sepsis and age > 60 years were associated with poorer recovery of renal function.

INTRODUCTION: Currently, patients diagnosed with Congenital Heart Disease (CHD) are living longer lifespans, leading to an increased number of these patients presenting for non-cardiac procedures/surgeries. Little research has been recently done analyzing intraoperative complications/risks for CHD patients undergoing non-cardiac surgeries. This study aims to identify common intraoperative events experienced by CHD patients undergoing non-cardiac surgeries using more recent data, while at the same time analyzing to see if there is any difference in frequency of intraoperative events experienced between different types of CHD diagnoses. METHODS: After receiving IRB approval, patients with CHD presenting for non-cardiac procedures/surgeries between the years 2008 and 2012 were pulled from Boston Children’s Hospital’s Electronic Medical records. 1,024 non-cardiac surgical encounters from 362 patients were analyzed to determine average age, average weight, patient gender, average ASA class, frequency of CHD diagnoses, ventricular function, type of non-cardiac procedure, premedication administration, type of induction and type and frequency of intraoperative events experienced. The 1,024 encounters were divided into two groups: those done in patients diagnosed with single ventricle physiology (n=79) and those done in patients diagnosed with non-single ventricle physiology (n=945). Unpaired Mann-Whitney tests were performed to determine if there was a significant difference in overall and specific intraoperative event occurrence between the single ventricle and non-single ventricle groups. RESULTS: Average age and weight at the time of these surgical encounters was 4.86 years and 20.57 Kg. A majority of the surgical encounters were done in males (59.2%). Atrial septal defect was the most common type of CHD, and most of the patients in these surgical encounters received an ASA class of 3. Intraoperative events occurred in 24.4% of the surgical encounters with cardiovascular events being the most common (44.82% of total events). Other events made up 30.49% of events experienced intraoperatively, with respiratory events making up the remaining 24.70%. There was a significant difference in the occurrence of overall events between the single ventricle and non-single ventricle group (P<0.0001). Additionally, there was a significant difference in the occurrence of cardiovascular events (P<0.0001) and Other events (P=0.0001) between the single ventricle and non-single ventricle groups. There was no significant difference in the occurrence of respiratory events between the two groups (P=0.648). DISCUSSION: The most common type of intraoperative event experienced by CHD patients during a non-cardiac surgery was cardiovascular events. Significantly more overall intraoperative events, including cardiovascular and other events, occurred in surgical encounters performed on CHD patients exhibiting single ventricle physiology than those encounters done on CHD patients with a non-single ventricle physiology. Results of this study suggest that it would be likely for CHD patients to have a cardiovascular event occur during non-cardiac surgery and that this may be more likely in patients with a single ventricle physiology. This study was subjected to the limitations of retrospective chart review, as well as missing and infrequent documentation. Future analysis will look to find correlations between the occurrence of intraoperative events, and demographic and procedure variables analyzed in this study. / 2017-06-16T00:00:00Z

Purpose: The purpose of this study was to investigate associations between postoperative delirium (POD) and unplanned perioperative hypothermia (UPH) among adults undergoing noncardiac surgery. Design: A retrospective, exploratory design was used. Methods: A retrospective, exploratory study was conducted using electronic medical record data abstracted from a purposive convenience sample of adult patients undergoing noncardiac surgery from January 2014 to June 2017. Findings: The analyzed data set included 22,548 surgeries, of which 9% experienced POD. Logistic regression indicated that American Society of Anesthesiologists (ASA) class was the strongest predictor of POD (χ2 = 1,207.11, df = 4, inclusive of all ASA class terms). A significant relationship between UPH and POD (χ2 = 54.94, df = 4, inclusive of all UPH terms) and a complex relationship among UPH, patient age, ASA class, and POD were also found. Conclusions: Results support a relationship between UPH and POD. Notably, there is also a complex relationship in the noncardiac surgery population among UPH, age, ASA class, and POD. Preliminary understanding of this relationship is based on the pathophysiological response to surgical stress. Further research is indicated.

ABSTRACT Atrial fibrillation (AF) is frequently detected in the setting of an acute physiologic stressor, such as medical illness or surgery. It is uncertain if AF detected in these settings (AFOTS: AF occurring transiently with stress) is secondary to a reversible trigger or is simply paroxysmal AF. This distinction is critical for clinicians and patients, as they must decide if AFOTS can be dismissed as a reversible phenomenon, or if it justifies the need for chronic therapy; in particular, anticoagulation to reduce the risk of disabling stroke. The uncertainty in the management of AFOTS is exacerbated by a poor understanding of its epidemiology. How frequently does AFOTS occur? Are there higher risk groups? What is the natural history of this condition? Across 8 chapters, this thesis systematically assesses previously published literature on this topic, focusing on patients who have an acute medical illness or have undergone noncardiac surgery, and addresses knowledge gaps therein. Chapter 1 is an introduction that outlines the justification of each of the studies in the thesis. Chapter 2 is a narrative review that defines AFOTS conceptually and outlines research priorities. Chapter 3 is a systematic review that explores the incidence and recurrence of AFOTS associated with acute medical illness. Chapter 4 is a systematic review and meta-analysis that explores the incidence and recurrence of AFOTS associated with acute noncardiac surgery. iii Chapter 5 examines the profiles of pacemaker-detected “subclinical” AF occurring before and after a hospitalization for medical illness or noncardiac surgery Chapter 6 reports the design, rationale and final results of a prospective study that aimed to provide a precise and accurate estimate of the incidence of AFOTS in critically ill patients. Chapter 7 reports the design and rationale of a matched prospective cohort study designed to estimate the rate of recurrence of AF following hospitalization with AFOTS and to compare it to similar patients who did not have AFOTS. Finally, Chapter 8 outlines the conclusions, discusses the limitations, and presents the implications of the research in this PhD thesis. / Thesis / Doctor of Philosophy (PhD) / Atrial fibrillation (AF) is the most common abnormal heart rhythm. AF is often diagnosed when a patient is hospitalized for an illness or after surgery. When AF is first found in this setting, it is unclear whether it has the same prognosis as other forms of the disease or is reversible. This thesis examines this problem and designs and executes studies to address it.

<p>Worldwide, more than 2 million patients die within 30 days after noncardiac surgery anually. Postoperative ischemic myocardial injury is frequent, however, no consensus exists about its definition.</p> <p><strong>Objective: </strong>to develop a term Myocardial Injury after Noncardiac Surgery (MINS) caused by myocardial ischemia, requiring at least, troponin T (TnT) elevation, and with prognostic relevance at 30 days after surgery.</p> <p><strong>Methods: </strong>we performed a prospective study including 15,167 patients ³45 years-old undergoing noncardiac surgery, who had fourth-generation TnT measurements during the first 3 postoperative days. We undertook Cox regression analyses with 30-day mortality after surgery as the dependent variable, using different TnT thresholds, clinical features and several perioperative variables. Non-ischemic etiologies were excluded. Furthermore, we developed a scoring system to predict risk in MINS patients.</p> <p><strong>Results:</strong> MINS was defined as TnT ≥0.03 ng/mL with or without clinical features, and it was an independent predictor of 30-day mortality (adjusted HR 3.82, CI 95% 2.84-5.10). We determined that MINS incidence was 8%, its population attributable risk 33.7%, and 30-days mortality rate 9.6%. Patients did not experience ischemic symptoms in 84% of MINS cases. Additionally, we developed a scoring system in patients suffering MINS with 3 independent predictors of death (age ≥75 years, new ST elevation or left bundle branch block, and anterior location of ECG changes),</p> <p><strong>Conclusion: </strong>Among patients undergoing noncardiac surgery, we defined MINS based on a TnT threshold ≥0.03 ng/mL. Mostly, MINS patients were asymptomatic. Therefore, this strongly suggests the importance of a troponin monitoring during the first few days after surgery.</p> / Master of Health Sciences (MSc)

<p>Introduction: Globally, more than 200 million patients undergo major non-cardiac surgery each year and more than 10 million patients will be exposed to postoperative myocardial ischemia, a condition strongly associated with 30-day mortality. The majority of these events go undetected without postoperative Troponin screening. Methods: We conducted a model-based cost-consequence analysis comparing a postoperative Troponin T screening vs. standard care in patients undergoing noncardiac surgery. In a first model, we evaluated the incremental number of detected perioperative myocardial infarctions and the incremental costs. A second model assessed the effect of the screening and consequent treatment on 1-year survival and the related cost. Model inputs based on the Vascular events In Non-cardiac Surgery patIents cOhort evaluatioN (VISION) Study, a large international cohort. We run probability sensitivity analyses with 5,000 iterations. We conducted extensive sensitivity analyses.</p> <p>Results: The cost to avoid missing an event amounted to CAD$ 5,184 for PMI and CAD$ 2,983 for isolated Troponin T. The cost-effectiveness of the postoperative Troponin screening was higher in patients’ subgroups at higher risk for PMI, e.g. patients undergoing urgent surgery. The incremental costs at 1 year of a postoperative PMI screening by 4 Troponin T measurements were CAD$ 169.20 per screened patient. The cost to prevent a death at 1 year amounted to CAD$ 96,314; however, there was relevant model uncertainty associated with the efficacy of the treatment in the 1-year model.</p> <p>Conclusion: Based on the estimated incremental cost per health gain, the implementation of a postoperative Troponin T screening after noncardiac surgery seems appealing, in particular in patients at high risk for perioperative myocardial infarction. However, decision-makers will have to consider it in terms of opportunity costs, i.e. in relation to the cost-effectiveness of other potential programs within the broader health care context.</p> / Master of Science (MSc)