Late results after paediatric cardiac surgery

Background: Congenital heart defects include a wide range of inborn malformations. Depending on the defect, the life expectancy of a newborn with cardiac anomaly varies from a few days to a normal life span. In most instances surgery, is the only treatment available. The late results of surgery have not been comprehensively investigated. Aims: Mortality, morbidity and the life situation of all Finnish patients who had been operated on for congenital heart defect during childhood were investigated. Methods: Patient and surgical data were gathered from all hospitals that had performed heart surgeries on children. Late mortality and survival data were obtained from the population registry, and the causes of deaths from Statistics Finland. Morbidity of patients operated on during 1953-1989 was assessed by the usage of medicines. The pharmacotherapy data of patients and controls were obtained from the Social Insurance Institute. The life situation of patients was surveyed by mailed questionnaire. Survival, causes of deaths and life situation of patients were compared with those of the general population. Results: A total of 7240 cardiac operations were performed on 6461 children during the first 37 years of cardiac surgery (1953-1989). The number of procedures constantly rose during this period, and the increase continued in later years. The patient material varied over time, as more defects became surgically treatable. During 1953-1989 the operative mortality (death within 30 days of surgery) was 6.9%. In the 1990s a slight rise occurred in early mortality, as increasingly complicated patients were surgically treated. During 2000-2003 practically no defects were beyond the operative range. Thus, the operative mortality of 4.4% was excellent, decreasing even further to 2.0% in 2004-2007. The overall 45-year survival of patients operated on in 1953-1989 was 78%, and the corresponding figure for the general population was 93%. Survival depended on the defect, being worst among patients with univentricular heart. Late survival was also better during the 1990s and at the beginning of the 21st century. Of the 6028 early survivors, 592 died late (>30 days) after surgery. A total of 397 deaths (67%) were related and 185 (31%) unrelated to congenital heart defect. The cause of death was unknown in 10 cases. Of those 5774 patients who survived their first operation and had complete follow-up, 16% were operated on several times. Seventeen percent of patients used medicines for cardiac symptoms (heart failure, arrhythmia, hypertension and coronary disease). Patients risk of using cardiac medicines was 2.16 (Cl 1.97-2.37) times higher than that of controls. Patients also had more genetic syndromes and mental retardation and more often used medicines for asthma and epilepsy. Adult patients who had been operated on as children had coped surprisingly well with their defects. Their level of education was similar and their employment level even higher than expected, and they were living in a steady relationship as often as the general population. Conclusions: Cardiac surgery developed rapidly, and nowadays practically all defects can be treated. The overall survival of all operated patients was 78%, 16% less than that of the general population. However, it was significantly better than the anticipated natural survival. However, many patients had health problems; 16% needed reoperations and 17% cardiac medicines to maintain their condition. Most of the patients assessed their general health as good and lived a normal life.

Molecular mechanisms of hypertension-induced heart failure : Experimental studies with special emphasis on local renin-angiotensin system, cardiac metabolism and levosimendan

Hypertension is a major risk factor for stroke, ischaemic heart disease, and the development of heart failure. Hypertension-induced heart failure is usually preceded by the development of left ventricular hypertrophy (LVH), which represents an adaptive and compensatory response to the increased cardiac workload. Biomechanical stress and neurohumoral activation are the most important triggers of pathologic hypertrophy and the transition of cardiac hypertrophy to heart failure. Non-clinical and clinical studies have also revealed derangements of energy metabolism in hypertensive heart failure. The goal of this study was to investigate in experimental models the molecular mechanisms and signalling pathways involved in hypertension-induced heart failure with special emphasis on local renin-angiotensin-aldosterone system (RAAS), cardiac metabolism, and calcium sensitizers, a novel class of inotropic agents used currently in the treatment of acute decompensated heart failure. Two different animal models of hypertensive heart failure were used in the present study, i.e. hypertensive and salt-sensitive Dahl/Rapp rats on a high salt diet (a salt-sensitive model of hypertensive heart failure) and double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes (a transgenic model of hypertensive heart failure with increased local RAAS activity). The influence of angiotensin II (Ang II) on cardiac substrate utilization and cardiac metabolomic profile was investigated by using gas chromatography coupled to time-of-flight mass spectrometry to detect 247 intermediary metabolites. It was found that Ang II could alter cardiac metabolomics both in normotensive and hypertensive rats in an Ang II receptor type 1 (AT1)-dependent manner. A distinct substrate use from fatty acid oxidation towards glycolysis was found in dTGR. Altered cardiac substrate utilization in dTGR was associated with mitochondrial dysfunction. Cardiac expression of the redox-sensitive metabolic sensor sirtuin1 (SIRT1) was increased in dTGR. Resveratrol supplementation prevented cardiovascular mortality and ameliorated Ang II-induced cardiac remodeling in dTGR via blood pressure-dependent pathways and mechanisms linked to increased mitochondrial biogenesis. Resveratrol dose-dependently increased SIRT1 activity in vitro. Oral levosimendan treatment was also found to improve survival and systolic function in dTGR via blood pressure-independent mechanisms, and ameliorate Ang II-induced coronary and cardiomyocyte damage. Finally, using Dahl/Rapp rats it was demonstrated that oral levosimendan as well as the AT1 receptor antagonist valsartan improved survival and prevented cardiac remodeling. The beneficial effects of levosimendan were associated with improved diastolic function without significantly improved systolic changes. These positive effects were potentiated when the drug combination was administered. In conclusion, the present study points to an important role for local RAAS in the pathophysiology of hypertension-induced heart failure as well as its involvement as a regulator of cardiac substrate utilization and mitochondrial function. Our findings suggest a therapeutic role for natural polyphenol resveratrol and calcium sensitizer, levosimendan, and the novel drug combination of valsartan and levosimendan, in prevention of hypertension-induced heart failure. The present study also provides a better understanding of the pathophysiology of hypertension-induced heart failure, and may help identify potential targets for novel therapeutic interventions.

Pain measurement and management in elderly patients : Clinical studies in long term hospital care and after cardiac surgery

The proportion of patients over 75 years of age, receiving all different types of healthcare, is constantly increasing. The elderly undergo surgery and anaesthetic procedures more often than middle-aged patients. Poor pain management in the elderly is still an issue. Although the elderly consumes the greatest proportion of prescribed medicines in Western Europe, most clinical pharmacological studies have been performed in healthy volunteers or middle-aged patients. The aim of this study was to investigate pain measurement and management in cognitively impaired patients in long term hospital care and in cognitively normal elderly patients after cardiac surgery. This thesis incorporated 366 patients, including 86 home-dwelling or hospitalized elderly with chronic pain and 280 patients undergoing cardiac surgery with acute pain. The mean age of patients was 77 (SD ± 8) years and approximately 8400 pain measurements were performed with four pain scales: Verbal Rating Scale (VRS), the Visual Analogue Scale (VAS), the Red Wedge Scale (RWS), and the Facial Pain Scale (FPS). Cognitive function, depression, functional ability in daily life, postoperative sedation and postoperative confusion were assessed with MMSE, GDS, Barthel Index, RASS, and CAM-ICU, respectively. The effects and plasma concentrations of fentanyl and oxycodone were measured in elderly (≥ 75 years) and middle-aged patients (≤ 60 years) and the opioid-sparing effect of pregabalin was studied after cardiac surgery. The VRS pain scores after movement correlated with the Barthel Index. The VRS was most successful in the groups of demented patients (MMSE 17-23, 11-16 and ≤ 10) and in elderly patients on the first day after cardiac surgery. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients. The plasma concentrations of oxycodone were comparable between the groups. Pain intensity on the VRS was lower and the sedation scores were higher in the elderly. Total oxycodone consumption during five postoperative days was reduced by 48% and the CAM-ICU scores were higher on the first postoperative day in the pregabalin group. The incidence of postoperative pain during movement was lower in the pregabalin group three months after surgery. This investigation demonstrates that chronic pain did not seem to impair daily activities in home-dwelling Finnish elderly. The VRS appeared to be applicable for elderly patients with clear cognitive dysfunction (MMSE ≤17) and it was the most feasible pain scale for the early postoperative period after cardiac surgery. After cardiac surgery, plasma concentrations of fentanyl in elderly were elevated, although oxycodone concentrations were at similar level compared to middle-aged patients. The elderly had less pain and were more sedated after doses of oxycodone. Therefore, particular attention must be given to individual dosing of the opioids in elderly surgical patients, who often need a smaller amount for adequate analgesia than middle-aged patients. The administration of pregabalin reduced postoperative oxycodone consumption after cardiac surgery. Pregabalin-treated patients had less confusion, and additionally to less postoperative pain on the first postoperative day and during movement at three months post-surgery. Pregabalin might be a new alternative as analgesic for acute postoperative and chronic pain management in the elderly. Its clinical role and safety remains to be verified in large-scale randomized and controlled studies. In the future, many clinical trials in the older category of patients will be needed to facilitate improvements in health care methods.