A systematic review of duloxetine and venlafaxine in major depression, including unpublished data.

OBJECTIVE: To determine the short-term antidepressant efficacy and tolerability of duloxetine and venlafaxine vs. each other, placebo, selective serotonin reuptake inhibitors (SSRIs), and tri- and tetracyclic antidepressants (TCAs) in adults with major depression. METHOD: Meta-analysis of randomised controlled trials identified through bibliographical databases and other sources, including unpublished manufacturer reports. RESULTS: Fifty-four studies including venlafaxine arms (n = 12,816), 14 including duloxetine arms (n = 4,528), and two direct comparisons (n = 836) were analysed. Twenty-three studies were previously unpublished. In the meta-analysis, both duloxetine and venlafaxine showed superior efficacy (higher remission and response rates) and inferior tolerability (higher discontinuation rates due to adverse events) to placebo. Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs (OR = 1.20, 95% CI 1.07-1.35 and 1.38, 95% CI 1.15-1.66, respectively), and no differences in efficacy and tolerability to TCAs. Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine (OR = 1.53, 95% CI 1.10-2.13 and OR 1.79, 95% CI 1.16-2.78, respectively). CONCLUSION: Rather than being a first-line option, venlafaxine appears to be a valid alternative in patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be indicated as a first-line treatment.

[EEG-adjusted target-controlled infusion : Propofol target concentration with different doses of remifentanil]. / EEG-adaptierte "target-controlled infusion" : Propofolzielkonzentration bei unterschiedlichen Remifentanildosierungen.

BACKGROUND: The aim of this study was to examine to what extent the use of electroencephalography (EEG) monitoring leads to an adaptation of the target-controlled infusion (TCI) concentration of propofol during propofol anaesthesia with different doses of remifentanil. PATIENTS AND METHODS: With ethics committee approval 60 patients (27-69 years old) with American Society of Anesthesiologists classification (ASA) I-III received anaesthestics with propofol (TCI, Diprifusor, AstraZeneca, Wedel, Deutschland) and 0.2, 0.4, or 0.6 microg/kg body weight remifentanil, respectively (groups 1-3). Anaesthesia was maintained at a level of deep hypnosis (EEG stages D(2)/E(0), EEG monitor: Narcotrend, version 2.0/5.0, manufacturer: MT MonitorTechnik, Bad Bramstedt, Germany). RESULTS: During the steady state the propofol concentration in groups 1-3 was 3.02+/-0.86, 1.93+/-0.53 and 1.60+/-0.55 microg/ml, respectively (p<0.001). Women had a higher propofol consumption than men (p<0.05). Dreams during anaesthesia were more often reported by women than by men (p<0.05). The need for postoperative analgesia decreased with an increasing intraoperative remifentanil dose (p<0.05). CONCLUSIONS: The study demonstrates that remifentanil has both analgetic and hypnotic effects. With increasing remifentanil dose the propofol requirement decreased and in this context EEG monitoring is useful to adapt the target concentrations of propofol to the patients' age and gender.

Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study.

AIMS/HYPOTHESIS: The aim of this cohort study was to investigate the risk of malignant neoplasms and mortality in patients with diabetes treated either with human insulin or with one of three insulin analogues. METHODS: Data were provided by the largest German statutory health insurance fund (time-frame: January 1998 to June 2005 inclusive), on patients without known malignant disease who had received first-time therapy for diabetes mellitus exclusively with human insulin, aspart, lispro or glargine. The primary outcome was the diagnosis of a malignant neoplasm. Data were analysed by multiple Cox regression models adjusting for potential confounders. RESULTS: A total of 127,031 patients were included, with a mean follow-up time of 1.63 (median 1.41, maximum 4.41) years. A positive association between cancer incidence and insulin dose was found for all insulin types. Because patients receiving combined therapy with insulin analogues and human insulin were excluded, the mean daily dose was much lower for glargine than for human insulin, and a slightly lower cancer incidence in the glargine group was found. After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p < 0.0001): the adjusted HR was 1.09 (95% CI 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU, and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. No increased risk was found for aspart (p = 0.30) or lispro (p = 0.96) compared with human insulin. CONCLUSIONS/INTERPRETATION: Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin. Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. Prospective long-term studies are needed to further evaluate the safety of insulin analogues, especially glargine.

Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review.

OBJECTIVE: To systematically review the evidence for the medium to long term benefits and risks of montelukast as add-on therapy to inhaled corticosteroids (ICS) in comparison with placebo and active controls in mild to moderate asthma. DATA SOURCES: Medline, Embase, Cochrane Register of Controlled Trials, reference lists of retrieved articles, clinical trial registries and study results databases. REVIEW METHODS: Systematic review of randomised controlled trials (duration > or = 12 weeks) in adolescents and adults comparing montelukast/ICS versus ICS monotherapy or montelukast/ICS versus active control/ICS. Meta-analyses were conducted where feasible. The main focus was on clinical outcomes (eg, exacerbations). Adverse events were also assessed. RESULTS: 13 studies meeting all of the inclusion criteria were identified: 7 studies, including constant or tapered doses of ICS, compared montelukast/ICS with ICS monotherapy. Six studies compared add-on montelukast with an add-on active control (salmeterol). Overall, the data indicated that montelukast/ICS was clinically more effective than ICS monotherapy. The ICS sparing potential of montelukast was clearly demonstrated in one study. Montelukast/ICS and ICS monotherapy showed similar safety profiles. In the active controlled studies, montelukast/ICS was clinically less effective than salmeterol/ICS in the 12 week trials (pooled proportion of patients with > or = 1 exacerbation: p = 0.006). However, separate analysis of active controlled 48 week trials showed comparable proportions for patients with > or = 1 exacerbation in both groups. CONCLUSIONS: Montelukast as add-on therapy to ICS improves control of mild to moderate asthma compared with ICS monotherapy. Although the addition of salmeterol to ICS is clinically as effective as or even more effective than the addition of montelukast, montelukast may have a better long term safety profile and offer a treatment alternative for asthma patients.

[Is it possible to calculate minimum provider volumes for total knee replacement using routine data? Results of a threshold value analysis of German quality assurance data for inpatient treatment]. / Können Mindestmengen für Knieprothesen anhand von Routinedaten errechnet werden? Ergebnisse einer Schwellenwertanalyse mit Daten der externen stationären Qualitätssicherung.

AIM OF THE STUDY: The aim of this study was to calculate, for the first time, minimum provider volumes in total knee replacement using routine German data. MATERIALS AND METHODS: In patients with primary total knee replacement (TKR), the relationship between hospital volume per year and risk of "insufficient mobility" (primary quality indicator) and "wound infection" (secondary quality indicator) was calculated by means of logistic regression models. RESULTS: For both indicators, a statistically significant relationship between hospital volume and outcome could be demonstrated. Other risk factors such as age and ASA status also had a significant influence, but did not appear as important confounders. The risk for the secondary quality indicator "infection" decreased constantly with increasing hospital volume, thus the curve was very flat. This supports the hypothesis that high volume hospitals have a higher quality level than low volume hospitals. A threshold value could be calculated. However, the explanation value for hospital volume was too low to derive a threshold level that clearly discriminates between good and bad quality of care. The relationship between the primary quality indicator "insufficient mobility" and hospital volume unexpectedly showed a U-shaped distribution. This questions the concept of a minimum provider volume regulation for primary total knee replacement for the quality indicator "insufficient mobility". Therefore, in this case no quantitative threshold values were calculated. CONCLUSION: This analysis supports the hypothesis of a volume-outcome relationship in primary total knee replacement. However, a minimum provider volume that clearly discriminates between good and bad quality of care could not be calculated on the basis of these German quality assurance data.

[Aspects of sample size determination and power calculation illustrated on examples from rehabilitation research]. / Aspekte der Fallzahlkalkulation und Powerberechnung anhand von Beispielen aus der rehabilitationswissenschaftlichen Forschung.

Often it is reported in medical studies that an expected effect could not be detected. This may be the case if the sample size had been too small to detect an effect which actually exists. This often is due to the fact that sound sample size estimation had been omitted prior to the study outset. As a result, it is not known how many persons should have been involved in the study to detect this effect if present. On the other hand, if sample size estimation has not been realized, more persons than needed might be included in the study. This is problematic for economic and in particular for ethical reasons. The aim of this paper is to point out the principles of sample size estimation as well as to emphasize its importance not only in general but also in medical rehabilitation research.

The Narcotrend Index: classification algorithm, correlation with propofol effect-site concentrations, and comparison with spectral parameters.

A reliable assessment of the depth of hypnosis during sedation and general anaesthesia using the EEG is a subject of current interest. The Narcotrend Index implemented in the latest version 4.0 of the EEG monitor Narcotrend provides an automatic classification of the EEG on a scale ranging from 100 (awake) to 0 (very deep hypnosis, EEG suppression). The classification algorithms implemented in the EEG monitor Narcotrend are described. In a study the correlation of the propofol effect-site concentration with the Narcotrend Index and with the traditional spectral parameters total power, relative power in the standard frequency bands delta, theta, alpha, and beta, median frequency, 95% spectral edge frequency, burst-compensated spectral edge frequency, and spectral entropy was investigated. The Narcotrend Index had the highest average correlation with the propofol effect-site concentration and the smallest variability of the individual correlation values. Moreover, the Narcotrend Index was the only parameter which showed a monophasic trend over the whole investigated time period. The Narcotrend monitor can make a significant contribution to the improvement of the quality of anaesthesia by adjusting the dosage of hypnotics to individual patient needs.

Age-related effects in the EEG during propofol anaesthesia.

BACKGROUND: Age-related differences in the spectral composition of the EEG in induction and emergence times, and in drug consumption during propofol anaesthesia were investigated. METHODS: The EEGs of 60 female patients between 22 and 85 years of age were monitored continuously during standardized induction of anaesthesia with 2 mg of propofol kg(-1)60 s(-1). The EEGs were visually assessed in 20-s epochs according to a scale from A (awake) to F (very deep hypnosis). Visual EEG classifications, spectral parameters, and induction times were compared between different age groups. Additionally, data of 546 patients included in a multicentre study with 4630 patients (EEG monitor Narcotrend, MT MonitorTechnik, Bad Bramstedt, Germany) were analyzed with regard to age-dependent changes of propofol consumption using target-controlled infusion (TCI). RESULTS: During induction, patients older than 70 years reached significantly deeper EEG stages than younger patients, needed a longer time to reach the deepest EEG stage, and needed more time until a light EEG stage was regained. In patients aged 70 years and older, the total power, mainly in deep EEG stages, was significantly smaller due to a distinctly smaller absolute power of the delta frequency band. No single spectral parameter was able to reliably distinguish all EEG stages. During the steady state of anaesthesia, older patients needed less propofol for the maintenance of a defined stage of hypnosis than younger patients. CONCLUSION: Older patients differ from younger ones regarding the hypnotic effect of propofol and the spectral patterns in the EEG. For an efficient automatic assessment of the EEG during anaesthesia a multivariable approach accounting for age-effects is indispensable.

[The Narcotrend monitor. Development and interpretation algorithms]. / Der Narcotrend((R))-MonitorEntwicklung und Interpretationsalgorithmus.

The Narcotrend performs an automatic interpretation of the electroencephalogram (EEG) during anaesthesia. The classification algorithms have been developed on the basis of visually classified EEG epochs. The classification scheme which was used for these visual assessments has its origin in sleep analysis and was adapted for the EEG during anaesthesia. From the awake state to very deep anaesthesia, 15 stages (A, B(0-2), C(0-2), D(0-2), E(0-2), F(0-1)) are distinguished. The transformation of these stages into a numerical scale from 100 to 0 is a further refinement for a differentiated presentation of EEG effects. For the automatic classification multivariate discriminant functions are used. Age-related changes of the EEG were incorporated. The device contains functions for the identification of artifacts. The EEG can be recorded from a frontal channel using standard ECG electrodes, other electrode positions and types can be chosen. The device has been clinically and scientifically validated.

Influence of EEG monitoring on intraoperative stapedius reflex threshold values in cochlear implantation in children.

BACKGROUND: Cochlear implantation is a widely used means of treating deafness and severe hearing disorders. The surgical procedure includes inserting the cochlear implant electrode array into the cochlea and embedding the corresponding signal receiver in the mastoid bone behind the ear. Postoperative fitting of the externally worn speech processor is very important for successful use of the cochlear implant. For this purpose, electrically elicited stapedius reflex threshold values can be used. However, stapedius reflex threshold values measured intraoperatively are influenced by anaesthetics. The goal of this retrospective study was to find out whether electroencephalogram (EEG) control of anaesthesia produces more reliable reflex threshold values as a basis for the fitting of the speech processor. METHODS: Three groups of children, after surgery for cochlear implantation, were analysed with regard to the magnitude of intraoperative electrically elicited stapedius reflex threshold values and their deviations from postoperatively determined maximum comfortable levels (group 1: methohexital/remifentanil with EEG monitoring, n = 10; group 2: isoflurane/fentanyl with EEG monitoring, n = 9; group 3: isoflurane/fentanyl without EEG monitoring, n = 11). RESULTS: Children with EEG monitoring had significantly lower electrically elicited stapedius reflex threshold values and also significantly lower differences between intraoperative stapedius reflex threshold values and postoperatively determined maximum comfortable levels. CONCLUSIONS: Electroencephalogram monitoring in cochlear implantation is of considerable value in controlling anaesthesia and improving speech processor fitting based on more reliable intraoperative neurophysiological data.

Cortical activity assessed by Narcotrend in relation to haemodynamic responses to tracheal intubation at different stages of cortical suppression and reflex control.

BACKGROUND AND OBJECTIVE: Many anaesthesiologists still interpret haemodynamic responses as signs of insufficient cortical suppression. The aim was to illustrate how haemodynamics may only poorly reflect the level of cortical suppression and that electroencephalographic monitoring could indicate different relationships between cortical effects and haemodynamics. METHODS: Anaesthesia was induced with thiopental (7 mg kg(-1)), and fentanyl (2 microg kg(-1)) with succinylcholine (1.5 mg kg(-1)) for neuromuscular blockade in the 11 patients of Group 1. In Group 2 (n = 15), thiopental (7 mg kg(-1)) and succinylcholine (1.5 mg kg(-1)) were given. In Group 3, the patients (n = 13) received thiopental (7 mg kg(-1)), fentanyl (2 microg kg(-1)) and cisatracurium (0.1 mg kg(-1)), and they were intubated 3 min later than the patients in Groups 1 and 2. We determined conventional electroencephalographic (EEG) variables and classified 14 EEG stages in real-time ranging from A (= 1), indicating full wakefulness, to F1 (= 14), at profound cortical suppression. RESULTS: All groups had profound cortical suppression 45 s after thiopental administration, which rapidly decreased (EEG stage, 11 (6-13) versus 7 (2-13) at 4 min, P < 0.0001). Decreasing EEG stages were associated with increasing SEF 95, relative alpha and beta power and decreasing relative delta power. During tracheal intubation, profound cortical suppression remained unchanged in Groups 1 and 2. In Group 3, cortical suppression had decreased before laryngoscopy (P < 0.005). In Group 2, 11 patients had heart rate responses to tracheal intubation, whereas only two responded in Group 1 (P = 0.015) and three in Group 3 (P = 0.02). Thirteen patients in Group 2 had arterial pressure responses, and five in Group 1 (P = 0.038). Circulatory responses did not differ between Groups 1 and 3. CONCLUSIONS: Electroencephalographic monitoring was suitable to indicate in real-time that haemodynamics only poorly reflect rapidly changing levels of cortical suppression, and how haemodynamics and cortical activity depend on the applied combination of hypnotic and analgesic drugs during anaesthesia induction with thiopental.

Automatic classification algorithms of the EEG monitor Narcotrend for routinely recorded EEG data from general anaesthesia: a validation study.

Impacts of hypnotic drugs on brain function are reflected in the EEG. The EEG monitor Narcotrend performs an automatic classification of the EEG using a scale which was proposed by Kugler for visual evaluation of the EEG. In this article the results of a validation study of the automatic classification algorithms implemented in the EEG monitor Narcotrend are presented. Visual and automatic classification of EEG data recorded in routine clinical practice were compared. The correlation between visual and automatic assessment was high (Spearman rank correlation r = 0.90, prediction probability Pk = 0.90) and a sufficient agreement between visual and automatic assessment was achieved for 92% of the analysed EEG epochs. The results of the study suggest that the automatic classification algorithms implemented in the EEG monitor Narcotrend yield a reliable assessment of the depth of hypnosis.

Sharp transients in the EEGs of non-epileptic adult patients receiving sevoflurane.

OBJECTIVE: In this article unexpected EEG findings are described which were observed during EEG monitoring under sevoflurane anesthesia. METHOD: In seven non-epileptic adult patients sevoflurane was administered as inhalation anesthetic during routinely performed surgical operations. The EEG was recorded continuously as part of the standard monitoring process and served mainly as a dosage guide for anesthetics/narcotics. MAIN OUTCOME MEASURE: Occurrence of sharp transients in the EEG resembling distinctive waves which can be seen in epileptic disorders. RESULTS: In six of the seven patients under 8.0% sevoflurane, sharp transients were observed which appeared in very deep EEG stages, mostly with endtidal sevoflurane concentrations of 4.8-5.9%. The findings are in accordance with observations in non-epileptic children from our clinic. CONCLUSIONS: The clinical significance of the observed EEG pattern under sevoflurane anesthesia is still unclear. Taking into consideration that convulsive and nonconvulsive status epilepticus can be followed by signs of brain damage, it would appear to be important to further investigate the phenomenon.

[Value of EEG monitoring in intensive care patients in plastic surgery--indications and experiences]. / EEG-Monitoring bei Intensivpatienten in der Plastischen Chirurgie--Indikationen und Erfahrungen.

EEG monitoring can be performed at the patients' bedside and it is a valuable support in therapeutic decision making providing unique information about the functional state of the brain. Due to newer technical developments, EEG monitoring can be conducted rather easily. In this article, indications for EEG monitoring in plastic surgical patients are presented: controlling the level of sedation, use in states of increased intracranial pressure, screening the cerebral state in comatose patients, diagnosis and therapy of epileptic seizures, and the search for circumscribed cerebral abnormalities. Furthermore, practical experience with the use of the new EEG monitor Narcotrend, which is provided with an automatic EEG classification, is described.

[Epileptoform EEG activity: occurrence under sevoflurane and not during propofol application]. / Epilepsietypische EEG-Aktivität: Auftreten bei Sevofluran-anflutung und nicht unter Propofolapplikation.

In a 62-year-old female patient without a history of epileptic seizures EEG monitoring (EEG monitor: Narcotrend) was routinely performed during propofol/remifentanil and during sevoflurane/remifentanil/nitrous oxide anaesthesia. In the first course of anaesthesia after a bolus of propofol 1% a continuous EEG slowing was followed by a burst suppression pattern without occurrence of epileptiform activity throughout this sequence. During the second course of anaesthesia the sevoflurane concentration was increased from 2 to 8 % by volume. After 5 min epileptiform activity appeared in the EEG at an endtidal concentration of 5.9% by volume.