Studies on the assessment of the adequacy of anesthesia

Several hypnosis monitoring systems based on the processed electroencephalogram (EEG) have been developed for use during general anesthesia. The assessment of the analgesic component (antinociception) of general anesthesia is an emerging field of research. This study investigated the interaction of hypnosis and antinociception, the association of several physiological variables with the degree of intraoperative nociception, and aspects of EEG Bispectral Index Scale (BIS) monitoring during general anesthesia. In addition, EEG features and heart rate (HR) responses during desflurane and sevoflurane anesthesia were compared. A propofol bolus of 0.7 mg/kg was more effective than an alfentanil bolus of 0.5 mg in preventing the recurrence of movement responses during uterine dilatation and curettage (D C) after a propofol-alfentanil induction, combined with nitrous oxide (N2O). HR and several HR variability-, frontal electromyography (fEMG)-, pulse plethysmography (PPG)-, and EEG-derived variables were associated with surgery-induced movement responses. Movers were discriminated from non-movers mostly by the post-stimulus values per se or normalized with respect to the pre-stimulus values. In logistic regression analysis, the best classification performance was achieved with the combination of normalized fEMG power and HR during D C (overall accuracy 81%, sensitivity 53%, specificity 95%), and with the combination of normalized fEMG-related response entropy, electrocardiography (ECG) R-to-R interval (RRI), and PPG dicrotic notch amplitude during sevoflurane anesthesia (overall accuracy 96%, sensitivity 90%, specificity 100%). ECG electrode impedances after alcohol swab skin pretreatment alone were higher than impedances of designated EEG electrodes. The BIS values registered with ECG electrodes were higher than those registered simultaneously with EEG electrodes. No significant difference in the time to home-readiness after isoflurane-N2O or sevoflurane-N2O anesthesia was found, when the administration of the volatile agent was guided by BIS monitoring. All other early and intermediate recovery parameters were also similar. Transient epileptiform EEG activity was detected in eight of 15 sevoflurane patients during a rapid increase in the inspired volatile concentration, and in none of the 16 desflurane patients. The observed transient EEG changes did not adversely affect the recovery of the patients. Following the rapid increase in the inhaled desflurane concentration, HR increased transiently, reaching its maximum in two minutes. In the sevoflurane group, the increase was slower and more subtle. In conclusion, desflurane may be a safer volatile agent than sevoflurane in patients with a lowered seizure threshold. The tachycardia induced by a rapid increase in the inspired desflurane concentration may present a risk for patients with heart disease. Designated EEG electrodes may be superior to ECG electrodes in EEG BIS monitoring. When the administration of isoflurane or sevoflurane is adjusted to maintain BIS values at 50-60 in healthy ambulatory surgery patients, the speed and quality of recovery are similar after both isoflurane-N2O and sevoflurane-N2O anesthesia. When anesthesia is maintained by the inhalation of N2O and bolus doses of propofol and alfentanil in healthy unparalyzed patients, movement responses may be best avoided by ensuring a relatively deep hypnotic level with propofol. HR/RRI, fEMG, and PPG dicrotic notch amplitude are potential indicators of nociception during anesthesia, but their performance needs to be validated in future studies. Combining information from different sources may improve the discrimination of the level of nociception.

Preoperative visual acuity of cataract patients. Repeatability of visual acuity and refractive error measurements in clinical settings

Visual acuities at the time of referral and on the day before surgery were compared in 124 patients operated on for cataract in Vaasa Central Hospital, Finland. Preoperative visual acuity and the occurrence of ocular and general disease were compared in samples of consecutive cataract extractions performed in 1982, 1985, 1990, 1995 and 2000 in two hospitals in the Vaasa region in Finland. The repeatability and standard deviation of random measurement error in visual acuity and refractive error determination in a clinical environment in cataractous, pseudophakic and healthy eyes were estimated by re-examining visual acuity and refractive error of patients referred to cataract surgery or consultation by ophthalmic professionals. Altogether 99 eyes of 99 persons (41 cataractous, 36 pseudophakic and 22 healthy eyes) with a visual acuity range of Snellen 0.3 to 1.3 (0.52 to -0.11 logMAR) were examined. During an average waiting time of 13 months, visual acuity in the study eye decreased from 0.68 logMAR to 0.96 logMAR (from 0.2 to 0.1 in Snellen decimal values). The average decrease in vision was 0.27 logMAR per year. In the fastest quartile, visual acuity change per year was 0.75 logMAR, and in the second fastest 0.29 logMAR, the third and fourth quartiles were virtually unaffected. From 1982 to 2000, the incidence of cataract surgery increased from 1.0 to 7.2 operations per 1000 inhabitants per year in the Vaasa region. The average preoperative visual acuity in the operated eye increased by 0.85 logMAR (in decimal values from 0.03to 0.2) and in the better eye 0.27 logMAR (in decimal values from 0.23 to 0.43) over this period. The proportion of patients profoundly visually handicapped (VA in the better eye <0.1) before the operation fell from 15% to 4%, and that of patients less profoundly visually handicapped (VA in the better eye 0.1 to <0.3) from 47% to 15%. The repeatability visual acuity measurement estimated as a coefficient of repeatability for all 99 eyes was ±0.18 logMAR, and the standard deviation of measurement error was 0.06 logMAR. Eyes with the lowest visual acuity (0.3-0.45) had the largest variability, the coefficient of repeatability values being ±0.24 logMAR and eyes with a visual acuity of 0.7 or better had the smallest, ±0.12 logMAR. The repeatability of refractive error measurement was studied in the same patient material as the repeatability of visual acuity. Differences between measurements 1 and 2 were calculated as three-dimensional vector values and spherical equivalents and expressed by coefficients of repeatability. Coefficients of repeatability for all eyes for vertical, torsional and horisontal vectors were ±0.74D, ±0.34D and ±0.93D, respectively, and for spherical equivalent for all eyes ±0.74D. Eyes with lower visual acuity (0.3-0.45) had larger variability in vector and spherical equivalent values (±1.14), but the difference between visual acuity groups was not statistically significant. The difference in the mean defocus equivalent between measurements 1 and 2 was, however, significantly greater in the lower visual acuity group. If a change of ±0.5D (measured in defocus equivalents) is accepted as a basis for change of spectacles for eyes with good vision, the basis for eyes in the visual acuity range of 0.3 - 0.65 would be ±1D. Differences in repeated visual acuity measurements are partly explained by errors in refractive error measurements.

Randomised Evaluation of New Technologies within the Population‐Based Cervical Cancer Screening Programme in Finland: Cross‐Sectional Performance and Validity

A randomised and population-based screening design with new technologies has been applied to the organised cervical cancer screening programme in Finland. In this experiment the women invited to routine five-yearly screening are individually randomised to be screened with automation-assisted cytology, human papillomavirus (HPV) test or conventional cytology. By using the randomised design, the ultimate aim is to assess and compare the long-term outcomes of the different screening regimens. The primary aim of the current study was to evaluate, based on the material collected during the implementation phase of the Finnish randomised screening experiment, the cross-sectional performance and validity of automation-assisted cytology (Papnet system) and primary HPV DNA testing (Hybrid Capture II assay for 13 oncogenic HPV types) within service screening, in comparison to conventional cytology. The parameters of interest were test positivity rate, histological detection rate, relative sensitivity, relative specificity and positive predictive value. Also, the effect of variation in performance by screening laboratory on age-adjusted cervical cancer incidence was assessed. Based on the cross-sectional results, almost no differences were observed in the performance of conventional and automation-assisted screening. Instead, primary HPV screening found 58% (95% confidence interval 19-109%) more cervical lesions than conventional screening. However, this was mainly due to overrepresentation of mild- and moderate-grade lesions and, thus, is likely to result in overtreatment since a great deal of these lesions would never progress to invasive cancer. Primary screening with an HPV DNA test alone caused substantial loss in specificity in comparison to cytological screening. With the use of cytology triage test, the specificity of HPV screening improved close to the level of conventional cytology. The specificity of primary HPV screening was also increased by increasing the test positivity cutoff from the level recommended for clinical use, but the increase was more modest than the one gained with the use of cytology triage. The performance of the cervical cancer screening programme varied widely between the screening laboratories, but the variation in overall programme effectiveness between respective populations was more marginal from the very beginning of the organised screening activity. Thus, conclusive interpretations on the quality or success of screening should not be based on performance parameters only. In the evaluation of cervical cancer screening the outcome should be selected as closely as possible to the true measure of programme effectiveness, which is the number of invasive cervical cancers and subsequent deaths prevented in the target population. The evaluation of benefits and adverse effects of each new suggested screening technology should be performed before the technology becomes an accepted routine in the existing screening programme. At best, the evaluation is performed randomised, within the population and screening programme in question, which makes the results directly applicable to routine use.

Children and adolescents in full-time special education : an epidemiological and magnetic resonance imaging study

The need for special education (SE) is increasing. The majority of those whose problems are due to neurodevelopmental disorders have no specific aetiology. The aim of this study was to evaluate the contribution of prenatal and perinatal factors and factors associated with growth and development to later need for full-time SE and to assess joint structural and volumetric brain alterations among subjects with unexplained, familial need for SE. A random sample of 900 subjects in full-time SE allocated into three levels of neurodevelopmental problems and 301 controls in mainstream education (ME) provided data on socioeconomic factors, pregnancy, delivery, growth, and development. Of those, 119 subjects belonging to a sibling-pair in full-time SE with unexplained aetiology and 43 controls in ME underwent brain magnetic resonance imaging (MRI). Analyses of structural brain alterations and midsagittal area and diameter measurements were made. Voxel-based morphometry (VBM) analysis provided detailed information on regional grey matter, white matter, and cerebrospinal fluid (CSF) volume differences. Father’s age ≥ 40 years, low birth weight, male sex, and lower socio-economic status all increased the probability of SE placement. At age 1 year, one standard deviation score decrease in height raised the probability of SE placement by 40% and in head circumference by 28%. At infancy, the gross motor milestones differentiated the children. From age 18 months, the fine motor milestones and those related to speech and social skills became more important. Brain MRI revealed no specific aetiology for subjects in SE. However, they had more often ≥ 3 abnormal findings in MRIs (thin corpus callosum and enlarged cerebral and cerebellar CSF spaces). In VBM, subjects in full-time SE had smaller global white matter, CSF, and total brain volumes than controls. Compared with controls, subjects with intellectual disabilities had regional volume alterations (greater grey matter volumes in the anterior cingulate cortex bilaterally, smaller grey matter volume in left thalamus and left cerebellar hemisphere, greater white matter volume in the left fronto-parietal region, and smaller white matter volumes bilaterally in the posterior limbs of the internal capsules). In conclusion, the epidemiological studies emphasized several factors that increased the probability of SE placement, useful as a framework for interventional studies. The global and regional brain MRI findings provide an interesting basis for future investigations of learning-related brain structures in young subjects with cognitive impairments or intellectual disabilities of unexplained, familial aetiology.

Depression, Anxiety, Psychiatric Comorbidity and Dimensions of Temperament and Personality

This study is part of the Mood Disorders Project conducted by the Department of Mental Health and Alcohol Research, National Public Health Institute, and consists of a general population survey sample and a major depressive disorder (MDD) patient cohort from Vantaa Depression Study (VDS). The general population survey study was conducted in 2003 in the cities of Espoo and Vantaa. The VDS is a collaborative depression research project between the Department of Mental Health and Alcohol Research of the National Public Health Institute and the Department of Psychiatry of the Peijas Medical Care District (PMCD) beginning in 1997. It is a prospective, naturalistic cohort study of 269 secondary-level care psychiatric out- and inpatients with a new episode of Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) MDD. In the general population survey study, a total of 900 participants (300 from Espoo, 600 from Vantaa) aged 20 70 years were randomly drawn from the Population Register Centre in Finland. A self-report booklet, including the Eysenck Personality Inventory (EPI), the Temperament and Character Inventory Revised (TCI-R), the Beck Depression Inventory and the Beck Anxiety Inventory was mailed to all subjects. Altogether 441 participants responded (94 returned only the shortened version without TCI-R) and gave their informed consent. VDS involved screening all patients aged 20-60 years (n=806) in the PMCD for a possible new episode of DSM-IV MDD. 542 consenting patients were interviewed with a semi-structured interview (the WHO Schedules for Clinical Assessment in Neuropsychiatry, version 2.0). 269 patients with a current DSM-IV MDD were included in the study and further interviewed with semi-structured interviews to assess all other axis I and II psychiatric diagnoses. Exclusion criteria were DSM-IV bipolar I and II, schizoaffective disorder, schizophrenia or another psychosis, organic and substance-induced mood disorders. In the present study are included those 193 (139 females, 54 males) individuals who could be followed up at both 6 and 18 months, and their depression had remained unipolar. Personality was investigated with the EPI. Personality dimensions associated not only to the symptoms of depression, but also to the symptoms of anxiety among general population and in depressive patients, as well as to comorbid disorders in MDD patients, supporting the dimensional view of depression and anxiety. Among the general population High Harm Avoidance and low Self-Directedness associated moderately, whereas low extraversion and high neuroticism strongly with the depressive and anxiety symptoms. The personality dimensions, especially high Harm Avoidance, low Self-Directedness and high neuroticism were also somewhat predictive of self-reported use of health care services for psychiatric reasons, and lifetime mental disorder. Moreover, high Harm Avoidance associated with a family history of mental disorder. In depressive patients, neuroticism scores were found to decline markedly and extraversion scores to increase somewhat with recovery. The predictive value of the changes in symptoms of depression and anxiety in explaining follow-up neuroticism was about 1/3 of that of baseline neuroticism. In contrast to neuroticism, the scores of extraversion showed no dependence on the symptoms of anxiety, and the change in the symptoms of depression explained only 1/20 of the follow-up extraversion compared with baseline extraversion. No evidence was found of the scar effect during a one-year follow-up period. Finally, even after controlling for symptoms of both depression and anxiety, depressive patients had a somewhat higher level of neuroticism (odds ratio 1.11, p=0.001) and a slightly lower level of extraversion (odds ratio 0.92, p=0.003) than subjects in the general population. Among MDD patients, a positive dose-exposure relationship appeared to exist between neuroticism and prevalence and number of comorbid axis I and II disorders. A negative relationship existed between level of extraversion and prevalence of comorbid social phobia and cluster C personality disorders. Personality dimensions are associated with the symptoms of depression and anxiety. Futhermore these findings support the hypothesis that high neuroticism and somewhat low extraversion might be vulnerability factors for MDD, and that high neuroticism and low extraversion predispose to comorbid axis I and II disorders among patients with MDD.

The Impact of Lifestyle and Cardiovascular Risk Factors in Midlife on the Health-Related Quality of Life among Old Men

Prevention of cardiovascular diseases is known to postpone death, but in an aging society it is important to ensure that those who live longer are neither disabled nor suffering an inferior quality of life. It is essential both from the point of view of the aging individual as well as that of society that any individual should enjoy a good physical, mental and social quality of life during these additional years. The studies presented in this thesis investigated the impact of modifiable risk factors, all of which affect cardiovascular health in the long term, on mortality and health-related quality of life (HRQoL). The data is based on the all male cohort of the Helsinki Businessmen Study. This cohort, originally of 3.490 men born between 1919 and 1934 has been followed since the 1960s. The socioeconomic status of the participants is similar, since all the men were working in leading positions. Extensive baseline examinations were conducted among 2.375 of the men in 1974 when their mean age was 48 and at this time the health, medication and cardiovascular risk factors of the participants were observed. In 2000, at the mean age of 73, the HRQoL of the survivors of the original cohort was examined using the RAND-36 mailed questionnaire (n=1.864). RAND-36, along with the equivalent SF-36, is the world s most widely used means of assessing generic health. The response rate was generally over 90%. Mortality was retrieved from national registers in 2000 and 2002. For the six substudies of this thesis, the impact of four different modifiable cardiovascular risk factors (weight gain, cholesterol, alcohol and smoking) on the HRQoL in old age was studied both independently and in combination. The follow-up time for these studies varies from 26 up to 39 years. Mortality is reported separately or included in the RAND-36 scores for HRQoL. Elevated levels of all the risk factors examined among the participants in midlife led to a diminished life expectancy. Among survivors, lower weight gain in midlife was associated with better HRQoL, both physically and mentally. Higher levels of serum cholesterol in middle age indicated both an earlier mortality and a decline in the physical component of HRQoL in a dose-response manner during the 39-year follow-up. Mortality was significantly higher in the highest baseline category of reported mean alcohol consumption (≥ 5 drinks/day), but fairly comparable in abstainers and moderate drinkers during the 29-year follow-up. When HRQoL in old age was accounted for mortality, the men with the highest alcohol consumption in midlife clearly had poorer physical and mental health in old age, but the HRQoL of abstainers and those who drank alcohol in moderation were comparatively similar. The amount of cigarette smoking in midlife was shown to have had a dose-response effect on both mortality and HRQoL in old age during the 26 year follow-up. The men smoking over 20 cigarettes daily in middle age lost about 10 years of their life-expectancy. Meanwhile, the physical functioning of surviving heavy smokers in old age was similar to men 10 years older in the general population. The impact of clustered cardiovascular risk factors was examined by comparing two subcohorts of men who were healthy in 1974, but with different baseline risk factor status. The men with low risk had a 50 % lower mortality during the 29-years follow-up. Their RAND-36 scores for the physical quality of life in old age were significantly better, and the 2002 questionnaire examining psychological well-being indicated also significantly better mental health among the low-risk group. The results indicate that different risk factor levels in midlife have a meaningful impact on life-expectancy and the quality of these extra years. Leading a healthy lifestyle improves both survival and the quality of life.

Cutaneous porphyrias : Clinical and histopathological study

The prevalence of variegate porphyria (VP) (2.1:100 000, in 2006 n=108) was higher in Finland than elsewhere in European countries due to a founder effect (R152C). The incidence of VP was estimated at 0.2:1 000 000 based on the number of new symptomatic patients yearly. The prevalence of porphyria cutanea tarda (PCT) was 1.2:100 000 (in 2006 n=63), which is only one fourth of the numbers reported from other European countries. The estimated incidence of PCT was 0.5:1 000 000. Based on measurements of the uroporphyrinogen decarboxylase activity in erythrocytes, the proportion of familial PCT was 49% of the cases. The prevalence of erythropoietic protoporphyria (EPP) was at 0.8:100 000 (in 2006 n=39) including asymptomatic carriers of a mutation in the ferrochelatase (FECH) gene. The incidence of EPP was estimated at 0.1:1 000 000. After 1980 the penetrance was 37% among patients with VP. Of the mutation carriers (n=57) 30% manifested with skin symptoms. Frequency of skin symptom as only clinical sign was stable before or after 1980 (22% vs. 21%), but acute attacks became infrequent (29% vs. 7%). Of the symptomatic patients 30% had both acute attacks and skin symptoms and 80% had skin symptoms. Fragility (95%) and blistering (46%) of the skin in the backs of the hands were the most common skin symptoms. Transient correction of porphyrin metabolism using eight haem arginate infusions within five weeks had no effect on the skin symptoms in three of four patients with VP. In one case skin symptoms disappeared transiently. One patient with homozygous VP had severe photosensitivity since birth. Sensory polyneuropathy, glaucoma and renal failure developed during the 25-year follow-up without the presence of acute attacks. The I12T mutation was detected in both of his alleles in the protoporphyrinogen oxidase gene. Lack of skin symptoms and infrequency of acute attacks (1/9) in the patients with I12T mutation at the heterozygous stage indicate a mild phenotype (the penetrance 11%). Four mutations (751delGAGAA, 1122delT, C286T, C343T) in the FECH gene were characterised in four of 15 families with EPP. Burning pain (96%) and swelling (92%) of the sun-exposed skin were the major skin symptoms. Hepatopathy appeared in one of 25 symptomatic patients (4%). Clinical manifestations and associated factors of PCT were similar in the sporadic and familial types of PCT. The majority of the patients with PCT had one to three precipitating factors: alcohol intake (78%), mutations in hemochromatosis associated gene (50%), use of oestrogen (25% of women) and hepatitis B or C infections (25 %). Fatty liver disease (67%) and siderosis (67%) were commonly found in their liver biopsies. The major histopathological change of the sun-exposed skin in the patients with VP (n=20), EPP (n=8) and PCT (n=5) was thickening of the vessel walls of the upper dermis suggesting that the vessel wall is the primary site of the phototoxic reaction in each type of porphyria. The fine structure of the vessel walls was similar in VP, EPP and PCT consisting of the multilayered basement membrane and excess of finely granular substance between the layers which were surrounded by the band of homogenous material. EPP was characterised by amorphous perivascular deposits extending also to the extravascular space. In direct immunofluorescence study homogenous IgG deposits in the vessel walls of the upper dermis of the sun-exposed skin were demonstrated in each type of porphyria. In EPP the excess material around vessel walls consisted of other proteins such as serum amyloid protein, and kappa and lambda light chains in addition to the basement membrane constituents such as collagen IV and laminin. These results suggest that the alterations of the vessel walls are a consequence of the repeated damage and the repairing process in the vessel wall. The microscopic alterations could be demonstrated even in the normal looking but sun-exposed skin of the patients with EPP during the symptom-free phase suggesting that vascular change can be chronic. The stability of vascular changes in the patients with PCT after treatment indicates that circulating porphyrins are not important for the maintenance of the changes.

Inflammatory and coagulation disturbances in acute pancreatitis

Acute pancreatitis (AP), a common cause of acute abdominal pain, is usually a mild, self-limited disease. However, some 20-30% of patients develop a severe disease manifested by pancreatic necrosis, abscesses or pseudocysts, and/or extrapancreatic complications, such as vital organ failure (OF). Patients with AP develop systemic inflammation, which is considered to play a role in the pathogenesis of multiple organ failure (MOF). OF mimics the condition seen in patients with sepsis, which is characterized by an overwhelming production of inflammatory mediators, activation of the complement system and systemic activation of coagulation, as well as the development of disseminated intravascular coagulation (DIC) syndrome. Vital OF is the major cause of mortality in AP, along with infectious complications. About half of the deaths occur within the first week of hospitalization and thus, early identification of patients likely to develop OF is important. The aim of the present study was to investigate inflammatory and coagulation disturbances in AP and to find inflammatory and coagulation markers for predicting severe AP, and development of OF and fatal outcome. This clinical study consists of four parts. All of patients studied had AP when admitted to Helsinki University Central Hospital. In the first study, 31 patients with severe AP were investigated. Their plasma levels of protein C (PC) and activated protein C (APC), and monocyte HLA-DR expression were studied during the treatment period in the intensive care unit; 13 of these patients developed OF. In the second study, the serum levels of complement regulator protein CD59 were studied in 39 patients during the first week of hospitalization; 12 of them developed OF. In the third study, 165 patients were investigated; their plasma levels of soluble form of the receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) protein were studied during the first 12 days of hos-pitalization; 38 developed OF. In the fourth study, 33 patients were studied on admission to hospital for plasma levels of prothrombin fragment F1+2 and tissue factor pathway inhibitor (TFPI), and thrombin formation capacity by calibrated automated thrombogram (CAT); 9 of them developed OF. Our results showed significant PC deficiency and decreased APC generation in patients with severe AP. The PC pathway defects seemed to be associated with the development of OF. In patients who developed OF, the levels of serum CD59 and plasma sRAGE, but not of HMGB1, were significantly higher than in patients who recovered without OF. The high CD59 levels on admission to the hospital seemed to be predictive for severe AP and OF. The median of the highest sRAGE levels was significantly higher in non-survivors than in survivors. No significant difference between the patient groups was found in the F1+2 levels. The thrombograms of all patients were disturbed in their shape, and in 11 patients the exogenous tissue factor did not trigger thrombin generation at all ( flat curve ). All of the patients that died displayed a flat curve. Free TFPI levels and free/total TFPI ratios were significantly higher in patients with a flat curve than in the others, and these levels were also significantly higher in non-survivors than in survivors. The flat curve in combination with free TFPI seemed to be predictive for a fatal outcome in AP.