Noninvasive Neuromonitoring of Hypothermic Circulatory Arrest in Aortic Surgery.

BACKGROUND AND AIMS: Circulatory arrest carries a high risk of neurological damage, but modern monitoring methods lack reliability, and is susceptible to the generalized effects of both anesthesia and hypothermia. The objective of this prospective, explorative study was to research promising, reliable, and noninvasive methods of neuromonitoring, capable of predicting neurological outcome after hypothermic circulatory arrest. MATERIALS AND METHODS: Thirty patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta were recruited in a single center and over the course of 4 years. Neuromonitoring was performed with a four-channel electroencephalogram montage and a near-infrared spectroscopy monitor. All data were tested off-line against primary neurological outcome, which was poor if the patient suffered a significant neurological complication (stroke, operative death). RESULTS: A poor primary neurological outcome seen in 10 (33%) patients. A majority (63%) of the cases were emergency surgery, and thus, no neurological baseline evaluation was possible. The frontal hemispheric asymmetry of electroencephalogram, as measured by the brain symmetry index, predicted primary neurological outcome with a sensitivity of 79 (interquartile range; 62%-88%) and specificity of 71 (interquartile range; 61%-84%) during the first 6 h after end of circulatory arrest. CONCLUSION: The hemispheric asymmetry of frontal electroencephalogram is inherently resistant to generalized dampening effects and is predictive of primary neurological outcome. The brain symmetry index provides an easy-to-use, noninvasive neuromonitoring method for surgery of the thoracic aorta and postoperative intensive care.

The impact of first year adherence to antiretroviral therapy on long-term clinical and immunological outcomes in the DART trial in Uganda and Zimbabwe.

OBJECTIVES: To describe associations between different summaries of adherence in the first year on antiretroviral therapy (ART) and the subsequent risk of mortality, to identify patients at high risk because of early adherence behaviour. METHODS: We previously described an approach where adherence behaviour at successive clinic visits during the first year on ART was seen as a Markov chain (MC), and the individually estimated transition probabilities between 'good', 'poor' and 'non-response' adherence states were used to classify HIV-infected adults in the DART trial into subgroups with similar behaviour. The impact of this classification and classifications based on traditional 'averaged' measures [mean drug possession ratio (DPR) and self-reported adherence] were compared in terms of their impact on longer-term mortality over the 2-5 years on ART using Cox proportional hazards models. RESULTS: Of 2960 participants in follow-up after 1 year on ART, 29% had never missed pills in the last month and 11% had 100% DPR throughout the first year. The poorest adherers by self-reported measures were more likely to have only none/primary education (P < 0.01). Being in the poorest adherence subgroup by MC and DPR was independently associated with increased mortality [HR = 1.57 (95% CI 1.02, 2.42); 1.82 (1.32, 2.51) respectively]. CONCLUSIONS: Classification based on dynamic adherence behaviour is associated with mortality independently of DPR. The classifications could be useful in understanding adherence, targeting focused interventions and improving longer-term adherence to therapy.

Responsiveness of the frontal EMG for monitoring the sedation state of critically ill patients.

BACKGROUND: Excessive sedation is associated with adverse patient outcomes during critical illness, and a validated monitoring technology could improve care. We developed a novel method, the responsiveness index (RI) of the frontal EMG. We compared RI data with Ramsay clinical sedation assessments in general and cardiac intensive care unit (ICU) patients. METHODS: We developed the algorithm by iterative analysis of detailed observational data in 30 medical-surgical ICU patients and described its performance in this cohort and 15 patients recovering from scheduled cardiac surgery. Continuous EMG data were collected via frontal electrodes and RI data compared with modified Ramsay sedation state assessments recorded regularly by a blinded trained observer. RI performance was compared with Entropy™ across Ramsay categories to assess validity. RESULTS: RI correlated well with the Ramsay category, especially for the cardiac surgery cohort (general ICU patients ρ=0.55; cardiac surgery patients ρ=0.85, both P<0.0001). Discrimination across all Ramsay categories was reasonable in the general ICU patient cohort [P(K)=0.74 (sem 0.02)] and excellent in the cardiac surgery cohort [P(K)=0.92 (0.02)]. Discrimination between 'lighter' vs 'deeper' (Ramsay 1-3 vs 4-6) was good for general ICU patients [P(K)=0.80 (0.02)] and excellent for cardiac surgery patients [P(K)=0.96 (0.02)]. Performance was significantly better than Entropy™. Examination of individual cases suggested good face validity. CONCLUSIONS: RI of the frontal EMG has promise as a continuous sedation state monitor in critically ill patients. Further investigation to determine its utility in ICU decision-making is warranted.

Estimation of population attributable fraction (PAF) for disease occurrence in a cohort study design.

The population attributable fraction (PAF) is a useful measure for describing the expected change in an outcome if its risk factors are modified. Cohort studies allow researchers to assess the predictive value of the risk factor modification on the incidence of the outcome during a certain follow-up. Estimation of PAF for both mortality and morbidity in cohort studies with censored survival data has been developed in the recent years. So far, however, censoring due to death in the estimation of PAF for morbidity has been ignored, resulting in estimation of a quantity which is not relevant in practice as some people are likely to die during the follow-up. The risk factors related to the disease incidence may also be related to mortality, and modification of these risk factors is likely to delay the occurrence of both events. Thus, censoring due to death and the impact of risk factor modification must be considered when estimating PAF for disease incidence. We consider both and introduce two measures of disease burden: PAF for the incidence of disease during lifetime and PAF for the prevalence of disease in the population at a certain time. We demonstrate how consideration of censoring due to death changes the estimated PAF for disease incidence and its confidence interval. This underlines the importance of choosing a correct PAF measure depending on the outcome of interest and the risk factors of interest to obtain accurate and interpretable results.

Serum alpha- and gamma-tocopherol concentrations and risk of advanced beta cell autoimmunity in children with HLA-conferred susceptibility to type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The aim of our study was to assess the associations of serum alpha- and gamma-tocopherol concentrations with the risk of advanced beta cell autoimmunity in children with HLA-conferred genetic susceptibility to type 1 diabetes mellitus. METHODS: A case-control study with 108 cases with advanced beta cell autoimmunity and 216 matched control participants nested within the birth cohort of the Type 1 Diabetes Prediction and Prevention Project. A serum sample for vitamin E analyses was collected from all the children in the cohort at the age of 1 year and thereafter at 12 month intervals. For each case-control group, all the repeated serum samples up to the age of seroconversion to autoantibody positivity in the case were analysed. A conditional logistic regression model was used to determine potential associations between seroconversion and serum tocopherol concentrations. RESULTS: Serum alpha- or gamma-tocopherol concentrations were not significantly associated with the risk of advanced beta cell autoimmunity. The odds ratio (95% CI) for micromol/l increase in serum concentration of the first-year sample was 0.97 (0.92-1.03) for alpha-tocopherol and 1.10 (0.70-1.74) for gamma-tocopherol. However, there was an interaction between high values of gamma-tocopherol at the age of 1 year and the time of seroconversion (p = 0.024). CONCLUSIONS/INTERPRETATION: It seems unlikely that high concentrations of alpha- or gamma-tocopherol protect against advanced beta cell autoimmunity in young children.

Assessment of surgical stress during general anaesthesia.

BACKGROUND: Inadequate analgesia during general anaesthesia may present as undesirable haemodynamic responses. No objective measures of the adequacy of analgesia exist. We aimed at developing a simple numerical measure of the level of surgical stress in an anaesthetized patient. METHODS: Sixty and 12 female patients were included in the development and validation data sets, respectively. All patients had elective surgery with propofol-remifentanil target controlled anaesthesia. Finger photoplethysmography and electrocardiography waveforms were recorded throughout anaesthesia and various waveform parameters were extracted off-line. Total surgical stress (TSS) for a patient was estimated based on stimulus intensity and remifentanil concentration. The surgical stress index (SSI) was developed to correlate with the TSS estimate in the development data set. The performance of SSI was validated within the validation data set during and before surgery, especially at skin incision and during changes of the predicted remifentanil effect-site concentration. RESULTS: SSI was computed as a combination of normalized heart beat interval (HBI(norm)) and plethysmographic pulse wave amplitude (PPGA(norm)): SSI = 100-(0.7*PPGA(norm)+0.3*HBI(norm)). SSI increased at skin incision and stayed higher during surgery than before surgery; SSI responded to remifentanil concentration changes and was higher at the lower concentrations of remifentanil. CONCLUSIONS: SSI reacts to surgical nociceptive stimuli and analgesic drug concentration changes during propofol-remifentanil anaesthesia. Further validation studies of SSI are needed to elucidate its usefulness during other anaesthetic and surgical conditions.

Correlation of EEG spectral entropy with regional cerebral blood flow during sevoflurane and propofol anaesthesia.

ENTROPY index monitoring, based on spectral entropy of the electroencephalogram, is a promising new method to measure the depth of anaesthesia. We examined the association between spectral entropy and regional cerebral blood flow in healthy subjects anaesthetised with 2%, 3% and 4% end-expiratory concentrations of sevoflurane and 7.6, 12.5 and 19.0 microg.ml(-1) plasma drug concentrations of propofol. Spectral entropy from the frequency band 0.8-32 Hz was calculated and cerebral blood flow assessed using positron emission tomography and [(15)O]-labelled water at baseline and at each anaesthesia level. Both drugs induced significant reductions in spectral entropy and cortical and global cerebral blood flow. Midfrontal-central spectral entropy was associated with individual frontal and whole brain blood flow values across all conditions, suggesting that this novel measure of anaesthetic depth can depict global changes in neuronal activity induced by the drugs. The cortical areas of the most significant associations were remarkably similar for both drugs.

Time-frequency balanced spectral entropy as a measure of anesthetic drug effect in central nervous system during sevoflurane, propofol, and thiopental anesthesia.

BACKGROUND: Time-frequency balanced spectral entropy of electroencephalogram (EEG) and frontal electromyogram (FEMG) is a novel measure of hypnosis during anesthesia. Two Entropy parameters are described: Response entropy (RE) is calculated from EEG and FEMG; and State Entropy (SE) is calculated mainly from EEG. This study was performed to validate their performance during transition from consciousness to unconsciousness under different anesthetic agents. METHODS: Response entropy, SE [S/5 Entropy Module, M-ENTROPY (later in text: Entropy), Datex-Ohmeda Division, Instrumentarium Corp., Helsinki, Finland] and BIS (BIS XP, A-2000, Aspect Medical Systems, Newton, MA) data were collected from 70 patients; 30 anesthetized with propofol 2 mg kg-1, 20 with sevoflurane inhalation, and 20 with thiopental 5 mg kg-1. Loss and regaining of consciousness (LOC, ROC) was tested every 10 s, and sensitivity, specificity, and prediction probability (Pk) were calculated. Behavior of the indices was studied. RESULTS: Sensitivity, specificity, and Pk values for consciousness were high and similar for all indices. During regaining of consciousness after propofol bolus, RE, SE, and BIS values recovered by 81 +/- 22%, 75 +/- 26%, and 59 +/- 18% (mean +/- SD), respectively, from the minimum relative to their baseline. After thiopental bolus, RE, SE, and BIS values recovered by 86+/-21%, 88 +/- 13%, and 63 +/- 14%, respectively. The relative rise was higher in RE and SE compared with BIS (P < 0.01). During deep levels of hypnosis, RE and SE decreased monotonously as a function of burst suppression ratio, while BIS showed biphasic behavior. On average, RE indicated emergence from anesthesia 11 s earlier than SE, and 12.4 s earlier than BIS. CONCLUSIONS: All indices, RE, SE, and BIS, distinguished excellently between conscious and unconscious states during propofol, sevoflurane, and thiopental anesthesia. During burst suppression, Entropy parameters RE and SE, but not BIS, behave monotonously. During regaining of consciousness after a thiopental or propofol bolus, RE and SE values recovered significantly closer to their baseline values than did BIS. Response entropy indicates emergence from anesthesia earlier than SE or BIS.

Positive experiences and the relationship between stress and asthma in children.

UNLABELLED: Ninety children aged 6 to 13 y and suffering from chronic asthma were included in a prospective follow-up study lasting 18 mo in order to assess whether life events involving substantial positive effects on the child can protect against the increased risk associated with stressful life events. The main outcome measures included positive life events, positive long-term experiences, severely negative life events, chronic psychosocial stress and new asthma exacerbation. The results showed that, provided they occurred in close proximity to severely negative life events, positive life events, generally related to the child's own achievements, afforded protection against the increased risk of a new asthma exacerbation precipitated by severe events in children whose lives were marked by low to medium levels of chronic stress. No such effect was found in children exposed to high chronic stress nor did long-term positive experiences, such as when the child has a rewarding hobby, affect the asthma risk. CONCLUSION: Life events with a definite positive effect can counteract the increased risk of an asthma exacerbation precipitated by a severely negative life event, provided the chronic stress is only of low to medium level. Because this protective influence does not apply where there is high chronic stress, reducing this condition must be seen as a priority in children suffering from asthma, as these children are also more vulnerable to negative life events precipitating asthma exacerbation.

Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 Birth Cohort.

Delayed childhood development may precede adult psychoses. We tested this hypothesis in a large, general population birth cohort (n=12058) followed to age 31 years. The ages at which individuals learned to stand, walk, speak, and became potty-trained (bowel control) and dry (bladder control), were recorded at a 1-year examination. Psychiatric outcome was ascertained through linkage to a national hospital discharge register. Cumulative incidence of DSM-III-R schizophrenia, other psychoses and non-psychotic disorders were stratified according to the timing of milestones and compared within the cohort using internal standardization. 100 cases of DSM-III-R schizophrenia, 55 other psychoses, and 315 non-psychotic disorders were identified. The ages at learning to stand, walk and become potty-trained were each related to subsequent incidence of schizophrenia and other psychoses. Compared with the whole cohort, earlier milestones reduced, and later milestones increased, the risk in a linear manner. These developmental effects were not seen for non-psychotic outcomes. The findings support hypotheses regarding psychosis as having a developmental dimension with precursors apparent in early life.

The role of acute and chronic stress in asthma attacks in children.

BACKGROUND: High levels of stress have been shown to predict the onset of asthma in children genetically at risk, and to correlate with higher asthma morbidity. Our study set out to examine whether stressful experiences actually provoke new exacerbations in children who already have asthma. METHODS: A group of child patients with verified chronic asthma were prospectively followed up for 18 months. We used continuous monitoring of asthma by the use of diaries and daily peak-flow values, accompanied by repeated interview assessments of life events and long-term psychosocial experiences. The key measures included asthma exacerbations, severely negative life events, and chronic stressors. FINDINGS: Severe events, both on their own and in conjunction with high chronic stress, significantly increased the risk of new asthma attacks. The effect of severe events without accompanying chronic stress involved a small delay; they had no effect within the first 2 weeks, but significantly increased the risk in the subsequent 4 weeks (odds ratio 1.71 [95% CI 1.04-2.82], p < or = 0.05 for weeks 2-4 and 2.17 [1.32-3.57], p < or = 0.01 for weeks 4-6). When severe events occurred against the backdrop of high chronic stress, the risk increased sharply and almost immediately within the first fortnight (2.98 [1.20-7.38], p < or = 0.05). The overall attack frequency was affected by several factors, some related to asthma and some to child characteristics. Female sex, higher baseline illness severity, three or more attacks within 6 months, autumn to winter season, and parental smoking were all related to increased risk of new exacerbations; social class and chronic stress were not. INTERPRETATION: Severely negative life events increase the risk of children's asthma attacks over the coming few weeks. This risk is magnified and brought forward in time if the child's life situation is also characterised by multiple chronic stressors.

Thought disorder index of Finnish adoptees and communication deviance of their adoptive parents.

BACKGROUND: Diverse forms of thought disorder, as measured by the Thought Disorder Index (TDI), are found in many conditions other than schizophrenia. Certain thought disorder categories are primarily manifest during psychotic schizophrenic episodes. The present study examined whether forms of thought disorder qualify as trait indicators of vulnerability to schizophrenia in persons who are not clinically ill, and whether these features could be linked to genetic or environmental risk or to genotype-environment interactions. The Finnish Adoptive Study of Schizophrenia provided an opportunity to disentangle these issues. METHODS: Rorschach records of Finnish adoptees at genetic high risk but without schizophrenia-related clinical diagnoses (N = 56) and control adoptees at low genetic risk (N = 95) were blindly and reliably scored for the Thought Disorder Index (TDI). Communication deviance (CD), a measure of the rearing environment, was independently obtained from the adoptive parents. RESULTS: The differences in total TDI between high-risk and control adoptees were not statistically significant. However, TDI subscales for Fluid Thinking and Idiosyncratic Verbalization were more frequent in high-risk adoptees. When Rorschach CD of the adoptive rearing parents was introduced as a continuous predictor variable, the odds ratio for the Idiosyncratic Verbalization component of the TDI of the high-risk adoptees was significantly higher than for the control adoptees. CONCLUSIONS: Specific categories of subsyndromal thought disorder appear to qualify as vulnerability indicators for schizophrenia. Genetic risk and rearing-parent communication patterns significantly interact as a joint effect that differentiates adopted-away offspring of schizophrenic mothers from control adopted-away offspring.

Aetiology and risk indicators of hearing impairments in a one-year birth cohort for 1985-86 in northern Finland.

The aetiology and risk indicators of hearing impairments of all types and degrees were studied in a 1-year birth cohort of 8713 children from northern Finland. The subjects (7 years of age) included in the clinical and audiometric examinations were recruited by standard clinical criteria, i.e. suspicion of parents according to a questionnaire, abnormal hearing screening result or a hearing impairment noted in hospital records (n = 541), and by random sampling from among the 8172 not suspected (n = 1009). One-hundred-and-one subjects in the group suspected of having hearing impairment and 27 subjects in the random sample eventually had hearing impairment. The aetiology could be defined in only 44.5% of the cases, ear infections being the most common. In this relatively small series, only a few risk indicators (congenital anomalies, meningitis and a history of ear discharge lasting for over 1 month) could be shown to be associated with impaired hearing in a logistic regression analysis.

Physiological fluctuations in nasal resistance may interfere with nasal monitoring in the nasal provocation test.

The physiological fluctuations in nasal flow and resistance in allergic subjects were studied by monitoring 12 subjects with perennial occupational allergic rhinitis with active anterior rhinomanometry (AAR) for 3 h at 15 min intervals. The subjects were then challenged bilaterally with the diluent solution for allergen extracts and the effect was monitored with AAR. In AAR. cellular rubber nose adapters were used. Many physiological fluctuations in nasal patency were observed. Reference intervals were calculated for the changes in flow and resistance at the gradient pressure of 150 pa. For example, a 100% increase in unilateral resistance was found to be significant at the risk level of 5-10% for the observation time of 30-60 min. The corresponding increase for bilateral resistance was close to 70%. Challenge with diluent solution had a negliglible effect on the resistance fluctuation, the reference intervals being close to those for baseline monitoring. In conclusion, rapid changes in nasal flow and resistance in allergic subjects were common, and caution is necessary when interpreting these changes as a positive nasal reaction in the nasal provocation test. In addition, the use of other objective parameters, such as the amount of nasal secretion is recommended.

Prevalence figures for mild hearing impairments cannot be based on clinical data.

The target population of the present study consisted of a 1-year (July 1985-June 1986) birth cohort from northern Finland. The prevalence of even slight hearing impairments (any threshold from 0.5 to 4 kHz > or = 25 db) at the age of 7 years was investigated among those 8,713 children still living in the area. The subjects for clinical audiometry were obtained in two ways. First, the standard clinical practice brought about 541 children, either with non-confirming results from their child welfare clinic screenings, suspected by their parents or already diagnosed as hearing impaired at a hospital. Secondly, in addition to this group, a random sample of 1,009 children, out of the 8,172 children not suspected, were also invited for audiometry. Of the clinical material, 101 children out of the 438 investigated were found to have impaired hearing according to the above criteria, and another 27 children out of the 789 investigated were obtained from the random sample. The estimated over-all prevalence of hearing impairments, even with the slight ones included, turned out to be 3.9% (95% confidence interval, CI, 2.7-5.7). Only 32% of the hearing impairments could be obtained according to the standard clinical policy! In conclusion, one cannot rely on clinical data when calculating prevalence figures for mild hearing impairments.

Gene-environment interaction in vulnerability to schizophrenia: findings from the Finnish Adoptive Family Study of Schizophrenia.

OBJECTIVE: This study assessed the interaction of genetic risk and rearing-family risk as a subsyndromal test measure of schizophrenic thought disorder in adoptees. METHOD: A group of 58 adoptees with schizophrenic biological mothers was compared with 96 comparison adoptees at ordinary genetic risk; putative adoptee vulnerability was assessed blindly and reliably by using the Rorschach Index of Primitive Thought. Environmental risk was measured by using frequency of communication deviance as a continuous variable, scored independently from Rorschach assessments of the adoptive parents. RESULTS: High genetic risk in itself was not associated with greater vulnerability to schizophrenic thought disorder in the adoptees, as indicated by the Index of Primitive Thought. Also, greater communication deviance in the adoptive parents was not associated with greater thought disorder in the comparison adoptees. However, there was a highly significant gene-environment interaction. Among the offspring of the adoptive parents with high levels of communication deviance, a higher proportion of high-risk than comparison adoptees showed evidence of thought disorder. In contrast, among the offspring of adoptive parents with low communication deviance, a lower proportion of high-risk than comparison adoptees showed evidence of thought disorder. The distribution of communication deviance scores did not differ significantly between the adoptive parents of high-risk offspring and the adoptive parents of comparison offspring. CONCLUSIONS: The findings are consistent with genetic control of sensitivity to the environment. There is no evidence that high genetic risk of schizophrenia among offspring is associated with high levels of communication problems in rearing parents.

Is a child's risk of early onset schizophrenia increased in the highest social class?

In a sample from the unselected, general population Northern Finland 1966 Birth Cohort, 11017 individuals alive at the age of 16 years were studied until the age of 27. The cumulative incidence of early onset schizophrenia until 23 years was higher (1.14%; 9/792) among young persons from the highest social class or class I (determined according to father's occupation) than among children from lower social classes (0.47%; 48/10225), the difference being statistically significant (p < 0.05). The incidence of schizophrenia in the highest social class was higher than expected among girls, firstborns, children of young mothers under 30 and urban residents (p < 0.05) compared with lower social classes. When cases from the highest and other social classes were compared, there was no clear difference in background factors or clinical course. Four alcoholics, one of them also schizophrenic, were found among nine social class I fathers. The results suggest that in some families in Northern Finland, a father's professional advancement, often linked to mental disorder, may be one determinant of an increased risk of schizophrenia in the child.

What is the natural history of recurrent acute otitis media in infancy?

BACKGROUND: Chemoprophylaxis or tympanostomy tubes are often recommended for recurrent acute otitis media because of the associated morbidity, temporary hearing loss, financial costs, and risks of middle-ear sequelae. The aim of this study was to study the natural course of recurrent acute otitis media in infancy without such prophylactic treatment. METHODS: Two hundred twenty-two children who had recurrent acute otitis media and received no prophylaxis were monitored for subsequent acute otitis media and the development of chronic otitis media with effusion. RESULTS: Only 4% of the 222 infants with recurrent acute otitis media developed chronic otitis media with effusion and an additional 12% continued having recurrent episodes. The most significant factor predicting an increased risk of recurrence was young age (< 16 months of age). Attending day care and having siblings had a less pronounced effect. CONCLUSIONS: Spontaneous recovery from recurrent acute otitis media is common with increasing age. Thus, until reliable causal evidence between recurrent otitis media and developmental disability is presented, chemoprophylaxis or tympanostomy tubes seem superfluous for most infants after the age of 16 months.