<p>Postoperative nausea and vomiting (PONV) is still a clinical problem and its incidence is unacceptably high. After the introduction of propofol as an agent for induction and maintenance of anesthesia, it was reported that the incidence of PONV was lower. It was also proposed that propofol possesses antiemetic effects. Dopamine, serotonin and opioids may contribute to PONV. Therefore the purpose of these investigations was to evaluate if propofol has dopamine, serotonin or opioid antagonistic effects and if a subhypnotic infusion of propofol decreases the incidence of PONV. </p><p>Nausea and vomiting were induced in volunteers by a dopamine agonist, apomorphine, and by ipecacuanha which releases serotonin from the enterochromaffin cells in the gut. The effects of propofol on gastric emptying and orocecal transit time were evaluated in volunteers with the paracetamol method and by measuring the endtidal hydrogen concentration after ingestion of the trisaccharide raffinose. The effects of morphine on gastric emptying and gastric tone were studied in patients before surgery with the paracetamol method and with an electronic barostat, respectively. The effects of low dose propofol for prophylaxis of PONV were studied in 172 patients undergoing breast and abdominal surgery. Propofol prophylaxis was compared with a multidrug regimen consisting of dexamethasone and three antiemetic drugs, ondansetron, droperidol and metoclopramide. </p><p>Propofol did not abolish apomorphine-induced vomiting but reduced the number of retchings induced by ipecacuanha. Propofol sedation did not influence gastric emptying of liquids but it slightly prolonged orocecal transit time. Gastric relaxation induced by morphine was abolished by propofol but propofol did not abolish morphine-induced delay of gastric emptying. Propofol in a low dose infusion reduced the incidence of PONV but nausea and especially vomiting increased significantly after termination of the infusion. Pro- phylaxis with the multidrug regimen was very effective in preventing PONV. </p><p>These studies have shown that propofol does not have any dopamine antagonistic effect but may have a weak serotonin antagonistic effect. Propofol cannot abolish morphine-induced delay of gastric emptying. Low dose propofol infusion was effective in preventing PONV as long as the infusion was ongoing but after termination of the infusion nausea and especially vomiting substantially increased. The multidrug regimen (dexamethasone, ondansetron, droperidol, metoclopramide) was very effective in preventing PONV and can be recommended as prophylaxis in patient groups with a known high risk for PONV. </p>

The present thesis addresses various means of reducing inflammatory responses associated with cardiopulmonary bypass (CPB) and retransfusion of pericardial suction blood (PSB) during cardiac surgery. Four (I-IV) prospective randomised controlled clinical trials comprising 475 patients were performed in the following areas: effects of heparin coating on measures of clinical outcome and memory function (I, II), inflammatory reactions in PSB and its systemic effects after retransfusion using cardiotomy suction or cell salvage (III) and effects of retransfusion of PSB on memory function and release patterns of protein S100B (IV). The use of heparin coated CPB-circuits was associated with a decrease of postoperative blood loss (I, II), transfusion requirements (II), shorter stay in hospital (I) decreased postoperative ventilator time (I), lower incidences of atrial fibrillation (II) and neurological deviations (I), reduction in releases of protein S100B (I, II) and lower postoperative creatinine elevation (I, II). PSB contained high concentrations of cytokines, complements, myeloperoxidase, free plasma haemoglobin and protein S100B (III, IV). Retransfusion using cardiotomy suction increased the systemic concentrations of free plasma haemoglobin and protein S100B, whereas retransfusion using cell salvage caused no detectable systemic effects (III, IV). CPB was associated with a small but significant release of protein S100B, despite elimination of PSB-contained protein S100B using cell salvage (IV). Subtle signs of impaired memory function were identified that were not associated with the use of heparin coated CPB-circuits (I, II) or retransfusion of PSB (IV). Key words: cardiopulmonary bypass, oxygenators, heparin, S100 proteins, blood loss, haemostasis, memory, outcome and process assessment.

Ischemic neuronal injury continues to be a major delimiting factor in achieving successful clinical outcomesafter resuscitation from cardiac arrest. In this thesis, a pig model of cardiopulmonary resuscitation (CPR) wasused to address the effects of different interventions on cerebral blood flow and oxygenation during CPR and theinitial postresuscitation period. A novel technique is presented to quantify the reperfusion oxidative injury. Maximization of cerebral blood flow during CPR by open-chest cardiac compression, continuous aortic balloon occlusion, and intra-aortic administration of hypertonic saline-dextran (HSD) did not ameliorate thepostresuscitation hypoperfusion or improve the cerebral oxygen extraction ratio or tissue pH. These findings disaffirm earlier studies suggesting that conserving brain viability after global ischemia is mostly a question ofmaintaining high perfusion pressure. Despite an increased cerebral perfusion pressure during CPR, intra-aortic administered epinephrineabove the aortic balloon occlusion did not further improve cerebral blood flow and oxygenation. This findingmay indicate adverse effects of epinephrine on cerebral vascular beds, possibly induced by a relatively highconcentration of epinephrine when administered above the site for aortic balloon occlusion. The IV administration of equipotent doses of epinephrine or vasopressin during CPR resulted incomparable hemodynamic changes. The peak increase in cerebral cortical blood flow, however, was reachedapproximately 30 sec later by vasopressin. Furthermore, the second bolus of vasopressin during CPR did notaugment cerebral perfusion, whereas epinephrine did. Consequently, reports suggesting that vasopressin issuperior to epinephrine with respect to its effects on central hemodynamics and vital organ blood flow may bebiased by the pharmacodynamic differences between the drugs, depending on the time point at which blood flowmeasurements are performed. In comparison with IV vasopressin, vasopressin administered above the aortic balloon occlusion resulted in a significant increase in cerebral perfusion pressure during CPR, but not after restoration of spontaneous circulation (ROSC). Cerebral cortical blood flow was, however, not improved during CPR, whereas a significant increase was recorded after ROSC. Relatively higher concentrations of vasopressin above the sitefor intra-aortic balloon occlusion may, therefore, predominantly induce cerebral cortical vasoconstriction duringCPR but induce vasodilatation after ROSC. Assessment of oxidative stress or inflammation have been extremely difficult to attain. In our pig model of resuscitation, an association wasobserved between the duration of cardiac arrest and jugular bulb levels of 8-iso-PGF2α, a major isoprostane and a novel index of oxidative injury. 8-iso-PGF2α, and the prostaglandin 15-K-DH-PGF2α, increased within 5 min after ROSC and remained so up to 2 h, indicating the interval of time during which cerebral reperfusion oxidative injury and inflammatory response may occur and are potentially preventable.

The purpose of this thesis was to develop novel ways to study tinnitus, to investigate the course of tinnitus, and to study the effects of cognitive-behaviour therapy on tinnitus related distress. Data from 377 tinnitus patients were collected. A group of 216 patients completed audiological measures and were assessed in a structured interview. The Klockhoff and Lindblom's grading system was used and its inter-rater reliability assessed in a subsample showing a high degree of correspondence. A discriminant analysis showed that a substantial proportion of patients could be correctly classified into grade II or III, by measures of pitch, minimal masking level of tinnitus, avoidance of situations because of tinnitus, and tolerance in relation to onset. Using tests developed in cognitive psychology, it was found that tinnitus patients had impaired performance. There was no evidence for an attentional bias towards tinnitus related words using a computerized emotional Stroop task, but masking sounds of an "on-and-off" character were more disruptive than constant masking when patients performed the digit-symbol test. It is suggested that tinnitus distress may be increased by the 'changing-state' character of the tinnitus signal, or alternatively by intermittent masking sounds. In a case-study a patient received an i.v. injection of lidocaine while Positron Emission Tomograpy was conducted. The brain activity associated with tinnitus included the left primary, secondary and integrative auditory brain areas, as well as right paralimbic areas related to negative feelings. The precuneus (Brodmann area 7) might be a brain area involved in the aversiveness associated with tinnitus. Using a tinnitus questionnaire as the dependent measure it was found that tinnitus maskability at admission predicted distress at follow-up for an average of five years following admission. Some improvement in tinnitus occurred over time, but this was more evident in patients who had received a cognitive-behavioural treatment program. The effect of an Internet based cognitive-behavioural self-help treatment program for tinnitus was investigated showing a high dropout rate, but with positive results in that the treated patients improved.

Hip fractures are the most serious consequence of osteoporosis, and are one important cause of morbidity and mortality among the elderly. Prophylactic treatment for hip fractures are now available. Early detection of individuals with increased risk for hip fractures is therefor of great interest. A subset of non-institutionalised patients with a first hip fracture (cases;n=l18) and controls (n=263), aged 65-85 years, underwent dual X-ray absorptiometry (DXA) of the femoral neck, quantitative ultrasound (QUS) of the heel and phalanges and radiographic absorptiometry (RA) of the phalanges. The entire cohort was followed for approximately four years or to death. In women, DXA of the proximal femur and QUS of the heel showed a high predictive value for an incident first hip fracture, adjusted odds ratio (OR) 3.6 (95% confidence interval (CI) 2.4-5.5) and 3.4 (95%CI 2.2-5.0) respectively. The association was even stronger in men, but only for DXA of the proximal femu,r with an adjusted OR of4.8 (95%CI 2.3-9.9). Bone densitometry at non-weight-bearing sites, QUS and RA of the phalanges did not discriminate female cases from controls, but proved capable of separating male cases from controls. The risk of death was higher in cases than in controls, with a multivariate rate ratio (RR) of 3.4 (95%CI 1.7-7.0). There was no significant association between bone density and mortality. Nursing home residents underwent QUS of the heel and phalanges. Almost all of the female residents and 51% of the male residents were, if the WHO-criterion for osteoporosis was applied, osteoporotic as assessed by heel and finger QUS. The QUS values were approximately 1.5 SD lower than expected for age and gender. In this randomised controlled intervention study we evaluated the effect of external hip protectors in nursing home residents; 302 residents were allocated to wear such protectors and 442 were controls. External hip protectors were found to be effective in preventing hip fractures in nursing home residents, with an adjusted relative risk for hip fracture of 0.33 (CI 0.11 - 1.00).

In two prospective, clinical studies the stability of implants and prosthetic constructions were evaluated after three years of loading. In the first study, the implant and the bridge stability of 39 patients with 1-stage bone grafts, were compared to a reference-group of 37 patients who did not need bone grafts. In the second study, 40 patients were randomised to have either 1-stage sinus inlay bloc grafts or 2-stage sinus inlay particulated grafts. Implant success in Paper 1, was 75.3% in the study group and 93.1% in the reference group. In Paper 2 implant survival in the 1-stage group was 77.7% and 86.5% in the 2-stage group. Bruxism and post-operative complications, such as unexpected pain, dehiscence and infection were found to be associated with the later loss of implants. The volumes of onlay block and inlay particulated bone grafts, after 6 months as evaluated by computed tomography showed the decrease of 49.5% and 47% respectively, although there was a wide range in both groups. Using of cutting torque measurements during the placement of implants in grafted and non-grafted jaw bone, showed a significant inverse correlation to the commonly used clinical estimation of jaw bone quality, acc. to Lekholm &amp; Zarb. Significantly lower torque values were recorded in grafted regions when compared to non-grafted. It was shown that autogenous bone grafts and implants to the edentulous maxilla, after early high failure rates, showed stable and predictable results after three years. Bruxism was found to be significantly associated with implant failures and initially reduced biomechanical properties was seen in the grafted bone.

Postoperative nausea and vomiting (PONV) is still a clinical problem and its incidence is unacceptably high. After the introduction of propofol as an agent for induction and maintenance of anesthesia, it was reported that the incidence of PONV was lower. It was also proposed that propofol possesses antiemetic effects. Dopamine, serotonin and opioids may contribute to PONV. Therefore the purpose of these investigations was to evaluate if propofol has dopamine, serotonin or opioid antagonistic effects and if a subhypnotic infusion of propofol decreases the incidence of PONV. Nausea and vomiting were induced in volunteers by a dopamine agonist, apomorphine, and by ipecacuanha which releases serotonin from the enterochromaffin cells in the gut. The effects of propofol on gastric emptying and orocecal transit time were evaluated in volunteers with the paracetamol method and by measuring the endtidal hydrogen concentration after ingestion of the trisaccharide raffinose. The effects of morphine on gastric emptying and gastric tone were studied in patients before surgery with the paracetamol method and with an electronic barostat, respectively. The effects of low dose propofol for prophylaxis of PONV were studied in 172 patients undergoing breast and abdominal surgery. Propofol prophylaxis was compared with a multidrug regimen consisting of dexamethasone and three antiemetic drugs, ondansetron, droperidol and metoclopramide. Propofol did not abolish apomorphine-induced vomiting but reduced the number of retchings induced by ipecacuanha. Propofol sedation did not influence gastric emptying of liquids but it slightly prolonged orocecal transit time. Gastric relaxation induced by morphine was abolished by propofol but propofol did not abolish morphine-induced delay of gastric emptying. Propofol in a low dose infusion reduced the incidence of PONV but nausea and especially vomiting increased significantly after termination of the infusion. Pro- phylaxis with the multidrug regimen was very effective in preventing PONV. These studies have shown that propofol does not have any dopamine antagonistic effect but may have a weak serotonin antagonistic effect. Propofol cannot abolish morphine-induced delay of gastric emptying. Low dose propofol infusion was effective in preventing PONV as long as the infusion was ongoing but after termination of the infusion nausea and especially vomiting substantially increased. The multidrug regimen (dexamethasone, ondansetron, droperidol, metoclopramide) was very effective in preventing PONV and can be recommended as prophylaxis in patient groups with a known high risk for PONV.

The extension of laparoscopic procedures into the chest may induce specific pathophysiologic effects. In pigs, we have demonstrated how devastating a combined thoraco-laparoscopic approach can be for gas exchange. Furthermore, the transmission of elevated pressure intra-cranially is a potential danger. The application of positive end-expiratory pressure (PEEP) was found to improve gas exchange and, more importantly, hypoxemia could be avoided. The application of PEEP did not increase intra-cranial pressure further; nor did it adversely affect cerebral circulation. Even before the introduction of the laparoscopic technique, there was a substantial increase in the annual number of antireflux procedures. Therefore, the threefold increase of the incidence of antireflux surgery recorded during the past decade cannot solely be explained by the introduction of minimal access surgery. However, a clear shift in the preferred methodology took place. This change was not scientifically supported at the time of the transition and, surprisingly, it is still not supported today. In comparison with open surgery, patients do not seem to derive significant long-term benefits from having the antireflux procedure done laparoscopically. As was demonstrated, laparoscopy might even be an inferior approach in some patients. Nevertheless, it is reasonable to assume that laparoscopy can yield equally good results as open surgery despite our failure to confirm that in our studies. Determination of the effectiveness of minimal access surgery in the treatment of GORD is critical, before minimal access techniques become the standard for antireflux surgery in the community.

From being a rare disease in the early 1900s, lung cancer is today the most common forms of cancer worldwide. This development is due to the gradual uptake of cigarette smoking in different populations and birth cohorts during the past 75 years. In spite of different modes of treatment, survival is still poor and surgery remains the prerequisite for cure. National data from the Swedish Cancer Register for the 35-year period 1958-1994 were analysed to estimate the effects of birth cohort, year of diagnosis (period) and age at diagnosis on the time trends in lung cancers. Early mortality, complications, major morbidity during the first 30 days, quality of life and long term survival after lung cancer surgery were assessed to estimate the significance of pre-surgical and tumour-related risk factors. Also, effects of delay in diagnosis and treatment among patients with non-small cell lung cancer were examined. The main results indicate that the overall age-adjusted incidence of lung cancer in Sweden has stabilised in men during the last two decades but has been increasing continuously in women. The fastest rate increase was noted among the youngest women and the incidence of adenocarcinoma is increasing in both sexes. Our results show low early mortality and morbidity after lung cancer surgery. Furthermore, quality of life was comparable with that of CABG patients postoperatively. However, patients with reduced lung capacity and those undergoing pneumonectomy should be treated with great care, as they run a considerable risk of major complications, impaired quality of life or death during the first 30 days postoperatively. Tumour stage (TNM) is the best prognostic indicator for long-term survival following radical surgery, underlying the importance of accurate surgical staging. Factors such as impaired preoperative lung function, older age, and major complications after surgery all negatively influence survival. Current smokers as a group run a significant risk of an adverse outcome (major complication or death), impaired mental health and shortened survival after lung cancer surgery. Waiting time for diagnosis and treatment of lung cancer was longer than recommended; especially among those surgically treated, but prolonged delay did not influence survival adversely.

There is very little data on physical and psychological long-term outcome after severe burn injury. The aim of the present thesis was to improve current instruments for assessment of these issues, to assess long-term outcome in a cohort of patients with burn injuries, and to explore the contribution of the individual factors of personality and coping on perceived outcome. Patients treated at the Burn Unit, Uppsala University Hospital, between 1980 and 1995 were included on a consecutive basis if they were 18 years of age or older at follow-up, had burn injuries of ten percent or more, or hospitalization times of seven days or more. A total of 350 patients fulfilled these inclusion criteria. A factor analytic approach was used to derive a 40-item instrument called the Burn Specific Health Scale-Brief (BSHS-B), resulting in nine well-defined domains. Most burn patients reported a very good perceived outcome but a subgroup reported problems years after injury. On a group level most problems were related to Heat Sensitivity, Work and Body Image. The depth of injury, gender, marital status and living conditions were all related to outcome. Neurotic personality traits were related to perceived health, and were not confined only to psychological aspects of life but also included physical aspects. A 33-item burn-specific coping scale, the Coping with Burns Questionnaire (CBQ), with six clearly separated domains with acceptable internal consistencies was developed. Coping strategies were strongly related to outcome in the subgroup of patients reporting most problems in perceived health, and coping contributed more to psychosocial than physical health. Avoidant coping and Emotional support seeking had independent effects on outcome. The observation that Neuroticism and Avoidant coping strategies are related to bad outcome after severe burn injury indicates that patients with such characteristics should be given special attention during rehabilitation.