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.

Chest pain is one of the most common symptoms responsible for emergency department and primary care office visits in the United States. Chest pain can be noncardiac and may be attributed to multiple causes. Esophageal disorders including reflux, motility and functional conditions, affect a large proportion of patients with NCCP and lead to significant morbidity. The use of HRM has changed the diagnostic approach to esophageal motility disorders. It is the most specific and sensitive test for diagnosing motor disorders and a promising procedure in detecting dysmotility disorders in patients with NCCP. Despite the increased sensitivity of HRM, the main indications for esophageal manometry exclude NCCP. This study assessed the percentage of undiagnosed esophageal motility disorders in patients with NCCP referred for high resolution manometry. Differences in HRM findings in patients with NCCP versus patients meeting AGA recommendations for the clinical use of esophageal manometry were also compared. A retrospective descriptive design was utilized. Two hundred-nineteen patient charts were reviewed. One hundred sixty-eight (77%) patients underwent HRM and met AGA recommendations for esophageal manometry; 51 (23%) patients underwent the procedure after receiving a NCCP diagnosis. Findings showed that 116 (69%) patients in the AGA group had abnormal findings while 52 (31%) did not. In the NCCP group 34 (67%) had abnormal findings compared to 17 (33%) who did not. To compare normal and abnormal HRM findings in patients with NCCP versus those meeting AGA criteria, Chi-Square analysis was performed between the groups. The results were not statistically significant (p = 0.10). iv There were no significant differences in the results of HRM in both groups indicating the findings on HRM are the same despite the indication for the procedure. The findings support the use of HRM as a diagnostic tool in patients with chest pain after cardiac workup and endoscopic evaluation. This indicates a possible need to update the AGA indications for esophageal manometry and increase the awareness among healthcare providers regarding the use of HRM in patients with chest pain. Implication for future research is also discussed.

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.

Introduction Postoperative medical complications are often preceded by a period with hypotension. Postoperative hypotension is poorly described in the literature. Data are needed to determine the incidence and risk factors for the development of postoperative clinically important hypotension after noncardiac surgery. Methods The incidence of postoperative clinically important hypotension was examined in a cohort of 40,004 patients enrolled in the VISION (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation) Study. Eligible patients were ≥45 years of age, underwent an in-patient noncardiac surgery procedure, and required a general or regional anesthetic. I undertook a multivariable logistic regression model to determine the predictors for postoperative clinically important hypotension. Model validation was performed using calibration and discrimination. Results Of the 40,004 patients included, 20,442 patients were selected for the derivation cohort, and 19,562 patients were selected for the validation cohort. The incidence of clinically important hypotension in the entire cohort was 12.4% (4,959 patients) [95% confidence interval 12.1-12.8]. Using 41 variables related to baseline characteristics, preoperative hemodynamics, laboratory characteristics, and type of surgery, I developed a model to predict the risk of clinically important postoperative hypotension (bias-corrected C-statistics: 0.73) The prediction model was slightly improved by adding intraoperative variables (bias-corrected C-statistics: 0.75). A simplified prediction model using the following variables: high-risk surgery, preoperative systolic blood pressure <130 mm Hg, preoperative heart rate >100 beats per minute, and open surgery, also predicted clinically important hypotension, albeit with less accuracy (bias-corrected C-statistics 0.68). Conclusion Our clinical prediction model can accurately predict patients’ risk of postoperative clinically important hypotension after noncardiac surgery. This model can help identify which patients should have enhanced monitoring after surgery and patients to include in clinical trials evaluating interventions to prevent postoperative clinically important hypotension. / Thesis / Master of Science (MSc) / In patients undergoing noncardiac surgery, numerous patients will develop postoperative clinically important hypotension. This may lead to complications including death, stroke, and myocardial infarction. I performed a large observational study to examine which risk factors would predict clinically important postoperative hypotension. Once we have identified these risk factors, we will use them to conduct randomized trials in patients at risk of clinically important hypotension to determine if we can prevent major postoperative complications.

Background: Postoperative cognitive dysfunction (POCD) is a deterioration in cognitive function that occurs after surgery as measured by neuropsychological tests. The purpose of this study was to determine the incidence and risk factors for POCD in older adults three months after major noncardiac surgery. Methods: This is a prospective study of patients aged 65 years and older who underwent major noncardiac surgery. Patients’ cognitive function was assessed before and three months after surgery using a computerized neurocognitive battery. Blood samples were withdrawn from patients before surgery to identify patients with high level of C-reactive protein (CRP), and patients who had the apolipoprotein-E4 (ApoE4) allele, as potential inflammatory and genetic biomarkers for POCD, respectively. A nonsurgical control group, that is similar to patients in age, education level, and computer familiarity, was recruited to adjust for learning effects from repeated administration of neurocognitive tests. Patients were classified as having POCD if they had less than -1.96 in the individual Z-scores of two or more tests or in the composite Z-score. Results: A total of 69 patients and 54 controls completed the study. The mean age for patients was 71 ± 5.4 (65–88) years old and 66.7% of them were females. The majority of patients (78.3%) had above high school education. There was no difference between the surgical and nonsurgical groups in demographics except for age which was marginally higher in the nonsurgical group [73 ± 6.3 (65-92)]. The incidence of POCD was 15.9% three months after surgery. Multivariable logistic regression showed that carrying the ApoE4 allele (OR = 4.74, 95% CI = 1.09 – 22.19), using one or more highly anticholinergic or sedative-hypnotic drugs at home prior to surgery (OR = 5.64, 95% CI = 1.35 – 30.22), and receiving sevoflurane for anesthesia (OR = 6.43, 95% CI = 1.49 – 34.66) were risk factors for POCD. Conclusion: The incidence of POCD in older adults is 15.9% three months after major noncardiac surgery. Risk factors for POCD were carrying the ApoE4 allele, using one or more highly anticholinergic or sedative-hypnotic drugs at home prior to surgery, and receiving sevoflurane for anesthesia.