A fixed-dose combination of low molecular weight heparin with dihydroergotamine versus adjusted-dose unfractionated heparin in the prevention of deep-vein thrombosis after total hip replacement.

The low dose heparin regimen (LDH) is not appropriate for prevention of intra- and postoperative thromboembolic complications in high risk patients, especially those undergoing elective hip replacement. Despite LDH prophylaxis, the incidence of deep-vein thrombosis (DVT) remains in a range of 20 to 35%. Adjusted-dose unfractionated heparin prophylaxis is thought to be one of the most effective regimens for thrombosis prophylaxis in this indication, but it requires two or three daily injections as well as precise monitoring of the activated partial thromboplastin time (aPTT). As an attractive alternative, we investigated the efficacy and safety of the low molecular weight heparin (LMWH) certoparin combined with dihydroergotamine (DHE) given once daily. In a randomised, open clinical trial, a total number of 305 patients undergoing total elective hip replacement were enrolled and divided into two groups, either receiving a fixed-dose combination of LMWH (3,000 IU) and DHE (0.5 mg) subcutaneously once daily, or adjusted-dose unfractionated heparin (UFH) subcutaneously every 8 h. The UFH dosage was adjusted daily to keep an aPTT of about 50 s. The aPTT was determined 3 h after the morning injection. During the study, the starting dose (15,000 IU/day) was increased to a plateau value of 28,800 +/- 7,150 IU/day (mean +/- SD) to maintain the aPTT in the prescribed range. The plateau value was achieved after 8 postoperative days. For analysis of efficacy 289 patients were evaluable. The occurrence of deep vein thrombosis was determined by bilateral ascending venography, which was performed on the same day in patients with clinical signs suggesting DVT; and in all remaining patients at the end of the prophylaxis period. Deep vein thrombosis was diagnosed in 17 of 142 patients (12.0%) treated with LMWH/DHE and in 13 of 147 patients (8.8%) treated with adjusted-dose UFH. Combined distalproximal thrombosis was more frequently in patients receiving UFH (n = 5; 3.4%) compared to the LMWH/DHE group (n = 2; 1.4%). These differences are statistically not significant. In the UFH group one case of non-fatal pulmonary embolism occurred. Both prophylaxis regimens were well tolerated; wound bleeding was observed in 8 (5.3%) patients in the LMWH group and in 6 (4.0%) patients in the UFH group. Intraoperative blood-loss volume (mean +/- SD) was 751 +/- 339 mL (LMWH/DHE) and 736 +/- 380 mL (UFH), whereas postoperative drain-loss volume (mean +/- SD) was found to be 523 +/- 333 mL (LMWH/DHE) and 581 +/- 404 mL (UFH). Whole blood transfusion volumes (mean +/- SD) were 570 +/- 202 mL (LMWH/DHE) and 748 +/- 455 mL (UFH). Additionally, red cell replacement volumes (mean +/- SD) were 804 +/- 435 mL (LMWH/DHE) and 720 +/- 328 mL (UHF). Revision of wound or additional drainage were necessary in 3 LMWH/DHE and 7 UFH patients. One patient needed reoperation due to bleeding, 3 (2.0%) had petechia and 1 exhibited an allergic exanthema, all of them in the UFH group. A slight erythema at the injection site was observed in 6 (3.9%) patients receiving LMWH/DHE. During the course of prophylaxis, injection hematomas were documented in 57.9% (LMWH/DHE) and in 61.4% (UFH) of the patients. All differences were statistically not significant. Single daily subcutaneous injections of LMWH/DHE appeared to be safe and efficacious compared to adjusted-dose UFH for prophylaxis of DVT in high-risk patients.

Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb.

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

Determination of erythrocyte-bound acetylcholinesterase activity for monitoring pyridostigmine therapy in myasthenia gravis.

Monitoring of pyridostigmine therapy in patients with myasthenia gravis is not routinely performed, since the daily pyridostigmine doses are adjusted to the patient's actual clinical status rather than to pyridostigmine plasma concentrations (PPC). Moreover, PPC determination is time-consuming and needs much technical equipment. Since pyridostigmine reversible blocks acetylcholinesterase (AChE) at the neuromuscular junction, we studied the correlation between the enzyme's blood activity (erythrocyte-bound AChE) and PPC, on the one hand, and between blood AChE activity and the clinical status of the individual patient, on the other. In five previously untreated patients with myasthenia gravis blood AChE activity decreased in accordance with the actual PPC after a single oral dose of 60 mg pyridostigmine (group A). Amelioration of the clinical status corresponded to the decrease of AChE activity in the same way. In another five patients, who were on stable pyridostigmine medication for at least 1 week, AChE activity and PPC were constant during the day (group B). Since it is easier to perform than PPC, our results suggest that the determination of AChE activity may be superior to measuring PPC for monitoring cholinesterase inhibitor therapy in selected cases.

Anticoagulant effects and tissue factor pathway inhibitor after intrapulmonary low-molecular-weight heparin.

The present study was designed to investigate the anticoagulant action of inhaled low-molecular-weight (LMW) heparin on the release of tissue factor pathway inhibitor (TFPI) and on antifactor Xa activity, Heptest, activated partial thromboplastin time (APTT) and thrombin clotting time (TCT) in healthy volunteers. 3000 IU (group 1), 9000 IU (group 2), 27,000 IU (group 3) or 54,000 IU (group 4) LMW-heparin were given to 20 healthy volunteers each at 4 weeks intervals by inhalation. For safety reasons a dose escalating design was chosen. APTT and TCT did not change after inhalation of any dose of LMW-heparin as well as all parameters in group 1. In group 2, Heptest coagulation times were prolonged from 18.7 +/- 2.0 s before to 26.1 +/- 5.2 s 6 h and 20.5 +/- 1.9 s 24 h after inhalation and the other parameters remained uneffected. In group 3, S2222 method and the protamine assay increased from 0.01 to about 0.1 IU/ml 6 h after inhalation and returned to normal values after 24 h. TFPI antigen increased from 74.1 +/- 13.9 to 80.5 +/- 14.2 ng/ml 3 h after inhalation. TFPI activity remained unchanged. Heptest coagulation values were prolonged to 42 +/- 7.6 s after 6 h and returned to normal within 72 h after inhalation. In group 4, the following changes were observed: antifactor Xa activity increased to 0.343 +/- 0.196 U/ml after 6 h and normalized after 72 h. The protamine assay detected 0.2 +/- 0.18 U LMWH/ml after 6 h, TFPI antigen increased to 103 +/- 17.9 ng/ml and TFPI activity to 1.14 +/- 0.23 U 3 h after inhalation. All tests were normal after 24 h. Heptest coagulation values increased to 77.5 +/- 11.8 s 6 h after inhalation and normalized after 144 h. The area under the activity time curve of the S2222 method and of the Heptest assay increased with increasing doses (r = 0.677 and r = 0.571), respectively. The calculated elimination half-life of the aXa-effect was 7.5 h using S2222-, Heptest- and protamine assays. The data demonstrate a resorption of LMW-heparin by intrapulmonary route in man. The dose to produce antifactor Xa levels, prolongations of Heptest coagulation values and in releasing TFPI is about ten-fold higher than after subcutaneous administration.

Comparison of 3,000 IU aXa of the low molecular weight heparin certoparin with 5,000 IU aXa in prevention of deep vein thrombosis after total hip replacement. German Thrombosis Study Group.

BACKGROUND: The aim of this randomized, double-blind and prospective clinical trial was to investigate whether an increase of the conventional daily dosage (3,000 IU aXa) of the low molecular weight heparin certoparin up to 5,000 IU aXa/day might lower the incidence of deep vein thrombosis (DVT) in patients undergoing elective hip surgery. METHODS: The main criterium of this trial was the incidence of DVT diagnosed by bilateral ascending venography, which was performed either if DVT was clinically suspected or in each remaining patient between the 12th and the 14th postoperative day. A total number of 172 patients were enrolled to receive the conventional dosage of 3,000 IU aXa (Mono-Embolex NM) and 169 patients to receive the high dosage form (5,000 IU aXa) once daily. The mean age (+/-SD) was 69.6+/-9.5 and 67+/-11.7 years. RESULTS: No relevant differences were found concerning predisposing risk factors. The duration of surgery was 93+/-25.2 and 88+/-21.4 min (mean+/-SD). Surgical type and approach were not different between the groups. Deep vein thrombosis was detected in 17 patients (9.9%) in the conventional dose group and in 16 patients (9.5%) in the high dose group (intent-to-treat analysis; n.s.). The rate of bleeding complications was not significantly different except the cell saver volumes (770+/-136 vs 475+/-186 ml; p<0.001). No significant difference was found in the serious adverse event reporting along the lines of EC-GCP (10 vs 8 events; p=0.65). CONCLUSIONS: This clinical trial confirmed that the conventional dosage (3,000 IU aXa/day) of certoparin ensures maximal antithrombotic activity.

[Quantitative determination of total urinary protein utilizing the principle of Coomassie Brilliant Blue G250 binding to protein (author's transl)]. / Quantitative Proteinbestimmung im Harn mit dem Proteinbindungsfarbstoff Coomassie Brilliant Blau G250.

Coomassie Brilliant Blue G250 was used for the determination of total urinary protein and compared with the biuret-procedure. In the Coomassie Brilliant Blue G250-assay 0.10 ml urine are added to 5.0 ml Coomassie Brilliant Blue G250 reagent and the sample is read against the reagent blank. The Coomassie Brilliant Blue G250 method seems to be superior to the biuret-procedure because of better reproducibility, higher sensitivity and simpler handling. The upper limit or urinary protein excretion in 49 healthy subjects was 120 mg/24 h. To evaluate the clinical significance of the Coomassie Brilliant Blue G250 method the urinary protein concentration of 134 patients with metabolic, systemic and organ diseases was compared with the biuret-procedure. The regression line was y = 0.827 X + 8.713 mg/l with a correlation coefficient of r = 0.966. The type of proteinuria (mixed, glomerular, tubular) had no influence on the protein value measured with the Coomassie Brilliant Blue G250 method. However in selective proteinuria, like Bence-Jones protein excretion, there is no correlation between the two methods, because the concentration of Bence-Jones protein is underestimated. Lower protein values were also frequently obtained for patients with diabetes mellitus. Some specimens from patients with chronic renal failure treated by haemodialysis showed elevated values. In spite of these limitations the Coomassie Brilliant Blue G250 method might become the method of choice for the determination of total urinary protein.

Rhabdomyolysis after suicidal ingestion of an overdose of caffeine, acetaminophen and phenazone as a fixed-dose combination (Spalt N).

Rhabdomyolysis without renal failure was noted after suicidal ingestion of 29 tablets of Spalt N containing 7.25 g of acetaminophen, 7.25 g of phenazone and 1.45 g of caffeine by a 29 year-old weighing 73 kg. The maximum serum creatine kinase was 1920 U/L, serum myoglobins were 49 to 167 ng/mL. Acetaminophen, phenazone and caffeine were quantified and identified in serum by gas chromatography and gas chromatography/mass spectrometry. It is suggested that rhabdomyolysis might have been caused by caffeine.

Sensitive determination of piritramide in human plasma by gas chromatography.

A selective and sensitive method for the determination of piritramide in human plasma is described. A 1-ml aliquot of plasma was extracted with 10 ml of hexane-isoamyl alcohol (99.5:0.5, v/v) (extraction efficiency 86%) after addition of 50 microliters of 2 M ammonia and 20 microliters of aqueous strychnine solution (100 ng per 10 microliters) as internal standard. Gas chromatography was performed with J&W DB-1, 30 m x 0.53 mm I.D. separation column, film thickness 1.5 microns, using an nitrogen-phosphorus-sensitive detector. The assay was linear in the concentration range 3.75-2250 ng/ml (r = 0.999), with a lower limit of detection of 1-2 ng/ml. The precision was determined using spiked plasma samples (10 and 50 ng/ml), with coefficients of variation of 3.5 and 3.1% (intra-day; n = 5) and 4.6 and 4.1% (inter-day; n = 4). In the range 3.75-150 ng/ml, the accuracy of the assay was 3.36%. The method was used for the determination of piritramide plasma concentrations in patients receiving intra- or post-operative analgesia.

[Extreme duration of action of diazepam as a cause of respiratory insufficiency in a female geriatric patient]. / Extreme Wirkungsdauer von Diazepam als Ursache einer Ateminsuffizienz bei einer geriatrischen Patientin.

A 77-year-old woman who had undergone surgery of a non-malignant extracerebral retro-orbital tumor suffered postoperatively from respiratory failure due to impaired respiratory drive and unconsciousness of unknown origin and required artificial ventilation for 14 days. After cerebral and endocrinological causes had been excluded, the residual effects of diazepam were taken into consideration, since the patient had received this substance for premedication and during 3 days postoperatively (total 165 mg). After the application of flumazenil (Anexate), a specific benzodiazepine receptor antagonist, she awoke immediately and was extubated with sufficient spontaneous breathing. The hypothesis that diazepam was the causative agent for the respiratory failure and impaired consciousness was supported by the detection of high serum concentrations of diazepam and its active metabolite desmethyldiazepam. During the following 3 days repetitive injections of flumazenil were necessary to counteract recurring depression of respiration and vigilance. Thereafter further application of flumazenil was not necessary.

Acetonitrile serum concentrations and cyanide blood levels in a case of suicidal oral acetonitrile ingestion.

Acute acetonitrile toxicity is mainly dependent on the release of cyanide via hepatic metabolism. Although evaluated in animals, few data are available concerning the toxicokinetic parameters of acetonitrile and acetonitrile-liberated cyanide in human. This paper reports a case of suicidal oral acetonitrile ingestion of about 5 mL without severe symptoms of intoxication in a previously healthy adult male with a body weight of 60 kg. Acetonitrile serum concentrations as well as cyanide blood levels were determined over the whole hospitalization. The elimination half-lives calculated from these data were 32 h for acetonitrile and 15 h for cyanide. After sodium thiosulfate bolus application, the cyanide blood level rapidly decreased to 10% of the initial value, indicating that sodium thiosulfate sufficiently detoxifies acetonitrile-liberated cyanide. Since cyanide levels again increased to maximal values about 4.5 h after sodium thiosulfate application, continued thiosulfate therapy is required as predicted by the long elimination half-lives of acetonitrile and acetonitrile-liberated cyanide. Determination of cyanide and acetonitrile concentrations is recommended for the estimation of optimal individual sodium thiosulfate dosage.

Determination of 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 3'-fluoro-3'-deoxythymidine and 2',3'-dideoxyinosine in biological samples by high-performance liquid chromatography.

A simple and fast high-performance liquid chromatographic assay for the determination of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 3'-fluoro-3'-deoxythymidine (FT) and 2',3'-dideoxy-inosine (ddI) in complex biological matrices is described. The method allows rapid nucleoside determination using a phenyl column within extra- as well as intracellular media without further sample pretreatment and extraction procedures. The lower limit of detection is ca. 0.05 micrograms/ml for each nucleoside, and the separation can easily be optimized for AZT, ddC, FT and ddI by variation of the methanolic part of the mobile phase and the detector wavelengths.