[Medicolegal aspects of driving ability and discussion of study methods]. / Medicolegale Aspekte der Fahrsicherheit und Methodendiskussion.

Medicolegal aspects of driving ability primarily concern patients themselves, because they are responsible when driving in traffic while under drug treatment. Pain patients taking analgesic medication prescribed by a doctor do not commit an offence, insofar as they are able to drive. A doctor's main duty consists of informing the patient about the way a given disease or drug intake affects driving ability. Patients have the duty to inform themselves about the drug they are taking and to assess their driving ability each time before they drive a car.

[Influence of changes to daily dose of opioids on aspects of cognitive and psychomotor performance involved in driving]. / Einfluss von Anderungen der Opioidtagesdosis auf fahrrelevante kognitive und psychomotorische Leistungen.

INTRODUCTION: It has been shown that long-term treatment with opioids does not necessarily impair driving ability in patients suffering from chronic pain. However, few studies are so far available on how increases in daily opioid dosage affect driving ability. METHODS: A prospective trial was conducted in patients suffering from chronic noncancer pain, to examine the effects of the daily dose of opioids on psychomotor and cognitive functions. A computerized test system was administered to patients before and 7 days after alteration of their opioid therapy, to determine performance affecting driving ability at each time point. The test design was based on both international and national recommendations for the examination of driving safety. RESULTS: Raising the daily dose of opioids and/or changing to an opioid at a higher WHO level had no effect on the functions relevant to driving ability in the group context. Pain intensity and serum concentrations of morphine influenced only few items in the test battery. CONCLUSION: Seven days after an increase in the daily dose of an opioid or after the initiation of opioid therapy there was no general deterioration in patients' driving ability at group level.

Recombinant hirudin for cardiopulmonary bypass anticoagulation: a randomized, prospective, and heparin-controlled pilot study.

BACKGROUND: Lepirudin, a recombinant hirudin, is a direct acting thrombin inhibitor that has been used as a heparin alternative in patients with heparin-induced thrombocytopenia requiring on-pump cardiac surgery. To evaluate the efficacy, safety, and clinical utility of lepirudin as a cardiopulmonary bypass (CPB) anticoagulant, we compared lepirudin with heparin in a routine CPB setting. METHODS: Twenty patients were randomly assigned to receive lepirudin (0.25 mg/kg b. w. bolus and 0.2 mg/kg b. w. added to the CPB priming) or heparin (400 U/kg b. w. bolus) with protamine reversal. Lepirudin and heparin anticoagulation during CPB was monitored using the ecarin clotting time or ACT, respectively and additional lepirudin (5 mg) or heparin (5000 U) boluses were administered. RESULTS: The CPB circuit was performed in both groups without thromboembolic complications. Median blood loss during the first 36 hours was statistically higher ( P = 0.007) in the lepirudin group (1.226 +/- 316 ml) compared to the heparin group (869 +/- 189 ml). One patient of the lepirudin group developed pulmonary embolism 24 hours after surgery. This patient was tested homozygous for the FV-Leiden mutation. CONCLUSION: Lepirudin provides effective CPB anticoagulation but induces a higher postoperative blood loss than heparin. Lepirudin should be restricted to patients undergoing CPB who cannot be exposed to heparin.

Meta-analyses in research in forensic medicine: Alcohol, drugs, diseases and traffic safety.

The meta-analytic approach is one of the most informative methods to structure and combine findings of different studies. Hence, even in forensic sciences meta-analyses were used to arrange knowledge. At most this technique was applied to summarize results of experimental and epidemiological studies on alcohol, illegal drugs, medicines, diseases and driving or skills related to driving. The article demonstrates the method used and the results obtained.

Demands on scientific studies in different fields of forensic medicine and forensic sciences. Traffic medicine--impaired driver: alcohol, drugs, diseases.

Since human performance is a key factor in crash causation detailed knowledge of the involvement of alcohol, drugs and diseases is of fundamental interest for road safety. To better understand the effect of these influencing factors it is important to use a combination of witness observations and a range of experimental and epidemiological studies. Epidemiological approaches to research such as road-side-surveys, case-control-studies, culpability analysis, pharmaco-epidemiological studies are usually seen as being able to provide the best answers. This article discusses the relative merits of experimental and epidemiological approaches.

Trapidil decreases the aggregation of platelets from heart transplant recipients ex vivo.

Heart transplant recipients show platelet hyperaggregability, which may be related to the incidence of graft vasculopathy. We investigated whether trapidil can inhibit the aggregation of platelets from these patients. Platelet count, mean platelet volume (MPV), and adenosine diphosphate (ADP)-induced platelet aggregation were determined in 18 heart transplant recipients and 12 healthy subjects. Additionally, platelet-rich plasma from the patients was incubated with trapidil or with saline, prior to measuring ADP-induced aggregation. The MPV was significantly greater in patients compared to controls (9.4+/-1.1 vs 8.5+/-0.7 fL; P=.01), and ADP-induced platelet aggregation was significantly increased in patients compared to controls (81.2%+/-13.1% vs 69.6%+/-16.2%; P=.04, respectively). The trapidil-treated samples showed significantly decreased platelet aggregation compared to the control samples (24.2%+/-12.6% vs 66.7%+/-11.7%; P<.001). Platelets from heart transplant recipients showed an increased MPV and increased ADP-induced aggregation. Trapidil effectively reduced the ADP-induced aggregation ex vivo.

Atrial fibrillation at discharge from the hospital in patients undergoing mitral valve repair.

BACKGROUND: Patients undergoing mitral valve repair (MVRr) are often discharged on oral anticoagulation with warfarin. Because the decision about oral anticoagulation is made at discharge from the hospital and because atrial fibrillation (AF) represents the only well-documented indication for oral anticoagulation in these patients, we studied the frequency of AF at discharge after MVRr. METHODS: We reviewed the records of 245 patients who underwent MVRr over the past 5 years and assessed the frequency of AF at discharge from the hospital and the factors that were associated with an increased risk for arrhythmia. RESULTS: The group comprised 95 women and 150 men with a mean age of 62.1 +/- 14 years. Seventy-three (30 %) patients were in and/or had a history of AF on admission. Sixty-five (27 %) patients had AF at discharge. Factors that were associated with AF at discharge were: AF on admission (odds ratio [OR] 57.1; confidence interval [CI] 20.8 - 157.3; p < 0.0001), enlarged left atrium (OR 3.2; CI 1.2 - 8.7; p = 0.025) and intake of ACE inhibitors (OR 3.9; CI 1.2 - 12.3; p = 0.022). The OR for AF at discharge in patients with none of the above risk factors was 0.02 (95 % CI 0.02 - 0.13; p < 0.0001). CONCLUSION: Only a relatively small proportion of the studied patients, especially patients with AF on admission, with larger atria and with a history of ACE inhibitors intake, were in AF at discharge after MVRr. Patients with none of these risk factors were at low risk for AF at discharge after MVRr and the optimal oral anticoagulation regimen for these low-risk patients needs to be determined.

Dose related risk of motor vehicle crashes after cannabis use.

The role of Delta(9)-tetrahydrocannabinol (THC) in driver impairment and motor vehicle crashes has traditionally been established in experimental and epidemiological studies. Experimental studies have repeatedly shown that THC impairs cognition, psychomotor function and actual driving performance in a dose related manner. The degree of performance impairment observed in experimental studies after doses up to 300 microg/kg THC were equivalent to the impairing effect of an alcohol dose producing a blood alcohol concentration (BAC) >/=0.05 g/dl, the legal limit for driving under the influence in most European countries. Higher doses of THC, i.e. >300 microg/kg THC have not been systematically studied but can be predicted to produce even larger impairment. Detrimental effects of THC were more prominent in certain driving tasks than others. Highly automated behaviors, such as road tracking control, were more affected by THC as compared to more complex driving tasks requiring conscious control. Epidemiological findings on the role of THC in vehicle crashes have sometimes contrasted findings from experimental research. Case-control studies generally confirmed experimental data, but culpability surveys showed little evidence that crashed drivers who only used cannabis are more likely to cause accidents than drug free drivers. However, most culpability surveys have established cannabis use among crashed drivers by determining the presence of an inactive metabolite of THC in blood or urine that can be detected for days after smoking and can only be taken as evidence for past use of cannabis. Surveys that established recent use of cannabis by directly measuring THC in blood showed that THC positives, particularly at higher doses, are about three to seven times more likely to be responsible for their crash as compared to drivers that had not used drugs or alcohol. Together these epidemiological data suggests that recent use of cannabis may increase crash risk, whereas past use of cannabis does not. Experimental and epidemiological research provided similar findings concerning the combined use of THC and alcohol in traffic. Combined use of THC and alcohol produced severe impairment of cognitive, psychomotor, and actual driving performance in experimental studies and sharply increased the crash risk in epidemiological analyses.

Sildenafil (Viagra): is there an influence on psychological performance?

BACKGROUND: Sildenafil (Viagra) is a well-introduced medicine for erectile dysfunction; many studies about effects and side effects are published. Beside these aspects of treatment the influence of sildenafil on psychophysical performance is of interest. cGMP is one of the most important second messengers in the central nervous system (CNS), so even very small changes of the intracellular cGMP-level caused by phosphodiesterases inhibition may be relevant for CNS-function. We wanted to verify the hypothesis whether sildenfail influences human psychomotor performance, especially under the aspect of traffic safety, or not. METHODS: Designed as a pilot study we tested 6 male healthy volunteers using a test battery of 7 different psychophysical performances tests. Each individual did the test battery twice, once without drug and once after a single oral dose of 100-mg sildenafil. 3 persons did the first and 3 others did the second experiment under the influence of drug (UID). All results (37 parameters) were analysed by t-test for paired samples using a confidence interval of 95%. RESULTS: Only two parameters of 2 different tests showed significant differences. In the simple choice reaction test (DR2) the mean reaction time got better in the group with sildenafil; in the multiple choice reaction test with stress induction (RST3) the amount of wrong answers indicated a weak influence of performance without statistical significance, six parameters (dominantly in the speed anticipation test (DEST)) represented an increase and one other (RST3 second part) showed a decrease UID. The uppermost parameters (76% of all items) stayed on equal levels for both groups. CONCLUSION: Sildenafil showed no important impairment of psychophysical performance, no strong improvement was found as well. With a look at the therapeutically indication of sildenafil the improvement in sexual activity may indicate no incapacity in traffic and other psychomotoric/psychophysical functions.

Lipid reductions by low-density lipoprotein apheresis: a comparison of three systems.

There are currently three established low-density lipoprotein (LDL) apheresis systems: immunoadsorption, heparin-induced extracorporeal LDL precipitation (HELP), and dextran sulfate. We treated the same patient with all three systems and compared the lipid reductions achieved. A total of 135 consecutive treatments were studied, 57 with immunoadsorption, followed by 30 with HELP and 48 with dextran sulfate adsorption. The mean plasma volume (mean +/- SD) treated was 4.9 +/- 0.05, 3.08 +/- 0.091, and 3.39 +/- 0.71 L, respectively. The LDL-cholesterol (LDL-C) reduction was 75.5% +/- 7.4%, 61.6% +/- 5.1%, and 57.1% +/- 12.4%, respectively (P < .001 for immunoadsorption vHELP and dextran sulfate). The mean removal efficiency (mass removed/plasma volume treated) for LDL-C was 1.0 +/- 0.12, 1.42 +/- 0.25, and 1.15 +/- 0.21 g/L, respectively (P < .001 for HELP v immunoadsorption and dextran sulfate). The mean LDL-C plasma concentration before apheresis was 199 +/- 23.9, 201 +/- 25.7, and 186 +/- 28 mg/dL, respectively (P < .001 for dextran sulfate adsorption v immunoadsorption and HELP). Among the three LDL apheresis systems, immunoadsorption caused the greatest percent reduction in LDL-C, while HELP eliminated LDL-C from the plasma most efficiently. Dextran sulfate was similar to HELP in terms of LDL-C reduction, and its removal efficiency was similar to immunoadsorption. Dextran sulfate was also associated with the lowest pretreatment plasma LDL-C concentration.

Analysis of the long-term efficacy and selectivity of immunoadsorption columns for low density lipoprotein apheresis.

Immunoadsorption low density lipoprotein (LDL) apheresis is performed with reusable columns containing anti-apolipoprotein B(ApoB) antibodies. We analyzed their long-term efficacy and selectivity. Performance over 60 treatment sessions of six pairs of immunoadsorption LDL apheresis columns was evaluated by analysis of variance using the removal of total cholesterol and ApoB to assess efficacy and the ratio of total cholesterol/high density cholesterol removed to assess selectivity. The removal of cholesterol did not vary significantly with treatment number. The mass of ApoB removed increased significantly (p = 0.002), and the mass of ApoB removed per volume unit of processed plasma showed a trend (p = 0.065) toward an increase with treatment number. Both parameters correlated with the serum ApoB concentration before treatment, which also increased significantly (p = 0.0007) with treatment number. No significant variation of selectivity was found. The efficacy of the LDL apheresis immunoadsorption columns did not decrease after 60 treatment sessions. The columns' selectivity also remained unchanged.

Changes in blood coagulation and fibrinolysis associated with maximal exercise and physical conditioning in women taking low dose oral contraceptives.

Blood coagulation parameters (thromboplastin time. PT; activated partial thromboplastin time, aPTT; fibrinogen; antithrombin III, ATIII; von Willebrand factor-concentration, vWF; factor VIII-activity, FVIII) and fibrinolytic parameters (plasminogen; (alpha-antiplasmin; euglobulin-lysis-time, Elt; tissue plasminogenactivator-antigen, tPA-antigen; plasminogenactivator-1-antigen, PAI-1-antigen) were evaluated in 34 women on low-dose oral contraceptives (OC) twice at intervals of 12 weeks each time before and after maximal exercise. During the 12 weeks, 24 women took part in an aerobic conditioning program and 10 women were requested to avoid any kind of sports activity for this period. Blood samples were taken before training and before and after maximal treadmill exercise. This procedure was repeated after the training program. After maximal exercise we found a significant reduction of aPTT and PT (increase in %), a decrease in ATIII, vWF, fibrinogen, plasminogen and alpha2-antiplasmin but an increase in fibrinolytic activity (all p<0.05). Maximal exercise is associated with an increase in blood coagulation and fibrinolysis also in women taking OC. After the physical conditioning program an increase in fibrinolytic activity at rest was noted in the training group. Opposed to that the fibrinolytic activity at rest decreased in the control group after abstinence of sports activity over this period (p<0.05, MANOVA).

The 536C-->T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis.

Tissue factor pathway inhibitor (TFPI) is an important regulator in the extrinsic blood coagulation pathway. Although the regulatory biochemical role of TFPI is evident, the clinical significance of this proteinase inhibitor remains to be elucidated. The definition of a clinical TFPI deficiency seems to be more complex than that of other coagulation inhibitors because the activity and concentration of circulating TFPI can not be considered a true measure of in vivo levels. Its determination in plasma samples by immunological methods or functional assays has been shown to be inadequate in the detection of a clinical deficiency. Therefore, we screened genomic DNA samples of blood donors and thrombotic patients for alterations in the TFPI gene to assess the influence of a modified TFPI in venous thromboembolic diseases. We detected a single nucleotide substitution in exon 7 (536C-->T) leading to a proline to leucine exchange at amino acid position 151 of the protein ([P151L]TFPI) and found the prevalence of heterozygous carriers in German unrelated blood donors to be 0.2% (n = 5120). Four unrelated persons out of 14 probands carrying the genetic variation could be linked to venous thrombosis. For calculation of a potential risk for venous thrombosis for carriers of the mutation we investigated healthy blood donors about thrombotic events. 7 out of 308 blood donors were found to have a history of venous thrombosis, one of them carried the TFPI mutation. Statistical calculation showed a significant relative risk for venous thrombosis for individuals with the trait (odds ratio, 9.3; confidence interval, 1.8-48.6; p <0.01).

State-of-the-art patient self-management for control of oral anticoagulation.

Currently, in Germany, there is a successful program where patients monitor their own coagulation status through self-testing. The advent of a new generation of coagulometers has allowed more and more patients to use self-testing to monitor their coagulation status. The development of a structured training program by the Association of Self-Management of Anticoagulation (ASA), and the effective cost reimbursement system by health insurance companies has furthered the success of this program. The reliability of the coagulometers is quite important to the success of this program, and has been extensively evaluated. These systems are characterized by high accuracy and precision, and low intra-/interassay variation. They also exhibit excellent recovery of the therapeutic range. Several clinical studies have shown that patients performing self-management remain in the therapeutic range a greater percentage of the time when compared to conventional testing, and tended to have less incidences of bleeding or thromboembolic complications. It is estimated that about 50 to 60% of all patients on anticoagulant therapy in Germany are suitable candidates for self-management.

Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40.

CD40 is a type I member of the tumour necrosis factor (TNF) receptor superfamily of proteins, and is present on a wide variety of cells including vascular endothelial cells. Ligation of this receptor on endothelial cells is known to increase expression of inflammatory adhesion molecules. We have recently demonstrated that platelets express the ligand of CD40 (CD154) within seconds of exposure to agonist, and interact with endothelial cells to participate directly in the induction of an inflammatory response. Here we show that activated platelets induce tissue factor (TF) expression on endothelial cells in a CD40/CD154-dependent manner, and that the magnitude of this response can equal that induced by TNFe. Moreover, CD40 ligation on endothelial cells downregulates the expression of thrombomodulin. We also show that CD40-mediated TF expression is less sensitive to inhibition with the oxidative radical scavenger pyrrolidine dithiocarbamate than is that mediated by TNFalpha, indicating that CD40 has a distinct signalling pathway. Tissue factor is a cell membrane protein which functions as the main trigger of the extrinsic pathway of blood coagulation, and its expression on endothelial cells is implicated in wound healing and angiogenesis. Since platelets are among the first cells involved in haemostasis following tissue injury, our data showing that ligation of CD40 by CD154 induces a procoagulant phenotype on vascular endothelial cells suggests that platelets may play an important role in the induction of wound healing.