Increased mortality after coronary artery bypass graft surgery is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release: results from the GUARDIAN trial.

OBJECTIVES: We sought to determine if elevated cardiac serum biomarkers after coronary artery bypass graft surgery (CABG) are associated with increased medium-term mortality and to identify patients that may benefit from better postoperative myocardial protection. BACKGROUND: The relationship between the magnitude of cardiac serum protein elevation and subsequent mortality after CABG is not well defined, partly because of the lack of large, prospectively studied patient cohorts in whom postoperative elevations of cardiac serum markers have been correlated to medium- and long-term mortality. METHODS: The GUARD during Ischemia Against Necrosis (GUARDIAN) study enrolled 2,918 patients assigned to the entry category of CABG and considered as high risk for myocardial necrosis. Creatine kinase-myocardial band (CK-MB) isoenzyme measurements were obtained at baseline and at 8, 12, 16 and 24 h after CABG. RESULTS: The unadjusted six-month mortality rates were 3.4%, 5.8%, 7.8% and 20.2% for patients with a postoperative peak CK-MB ratio (peak CK-MB value/upper limits of normal [ULN] for laboratory test) of < 5, > or = 5 to <10, > or =10 to < 20 and > or =20 ULN, respectively (p < 0.0001). The relationship remained statistically significant after adjustment for ejection fraction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, cardiac arrhythmias and the method of cardioplegia delivery. Receiver operating characteristic curve analysis revealed an area under the curve of 0.648 (p < 0.001); the optimal cut-point to predict six-month mortality ranged from 5 to 10 ULN. CONCLUSIONS: Progressive elevation of the CK-MB ratio in clinically high-risk patients is associated with significant elevations of medium-term mortality after CABG. Strategies to afford myocardial protection both during CABG and in the postoperative phase may serve to improve the clinical outcome.

Reactivation of coagulation after stopping infusions of recombinant hirudin and unfractionated heparin in unstable angina and myocardial infarction without ST elevation: results of a randomized trial. OASIS Pilot Study Investigators. Organization to Assess Strategies for Ischemic++ Syndromes.

AIMS: To compare effects of heparin and hirudin on biochemical markers of coagulation. METHODS AND RESULTS: Patients (n=395) with unstable angina or myocardial infarction without ST elevation were randomized to a 72-h infusion of one of three regimens: unfractionated heparin (bolus of 5000 IU followed by an infusion of 1200 IU. h(-1)), low-dose hirudin (HBW 023; 0.2 mg. kg(-1)bolus followed by 0.10 mg. kg(-1). h(-1)) or medium-dose hirudin (0.4 mg. kg(-1)bolus followed by 0.15 mg. kg(-1). h(-1)). Infusions were adjusted to maintain an activated partial thromboplastin time of between 60-100 s. Activated partial thromboplastin time, prothrombin fragment 1.2 (F1.2), thrombin antithrombin III complex and D-dimer were measured before, during and after the infusion. Median activated partial thromboplastin time was similar in the two groups early on, but was significantly lower in the heparin group than in the combined hirudin group 48 h after starting the infusion (53 s and 75 s, respectively;P<0.001), and 6 h after stopping (31 s and 46 s, respectively;P<0.001). Median F1.2 levels were not significantly different between the groups during the infusion. Median thrombin antithrombin III levels in the heparin and hirudin groups were 2.8 microg. l(-1)and 2.3 microg. l(-1), respectively, at 6 h (P<0.001), and 3.0 microg. l(-1)and 2.3 microg. l(-1), respectively, at 48 h (P<0.001). Median D-dimer levels were 320 ng. ml(-1)and 260 ng. ml(-1)48 h after starting the infusion in the heparin and hirudin groups, respectively (P<0.001), and 415 ng. ml(-1)and 280 ng. ml(-1), respectively (P<0.001) 6 h after stopping. D-dimer levels were significantly elevated above baseline values in both groups 24-48 h after stopping the infusions. CONCLUSIONS: The greater reduction of thrombin antithrombin III and D-dimer during the hirudin infusion supports the hypothesis that hirudin is a more potent antithrombin agent than heparin. Increased D-dimer levels after stopping heparin or hirudin suggest that there is an ongoing pro-coagulant state. These results point to the greater efficacy of hirudin in preventing early clinical events (death, myocardial infarction and refractory ischaemia) compared with heparin that have been observed in large randomized trials. Persistent activation of coagulation afterstopping infusions in our study suggests that a longer course of antithrombotic treatment may be needed to pacify the thrombus.

Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators.

BACKGROUND: The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis. METHODS AND RESULTS: A total of 11 590 patients with unstable angina or non-ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%, P=0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%, P=0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%, P=0.03), but the rate of non-Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%, P=0.005). There were no increases in clinically serious adverse events. CONCLUSIONS: No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk. The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.

Developmental correlates of school-age children with a history of benign congenital hypotonia.

In order to clarify the prognosis of benign congenital hypotonia (BCH), 25 children aged 6 to 8 years who had been diagnosed with BCH as infants were examined on a variety of sensory, perceptual-motor, and behavioural measures and compared with 26 control children. There were no significant differences between the two groups on any of the medical or neurological measures of the Touwen Neurological Examination (Touwen 1979), nor were there significant overall differences on any of the sensory or behavioural measures. However, the BCH group showed inferior gross motor performance on the Bruininks-Oseretsky Test of Motor Proficiency (Bruininks 1978). They scored significantly lower on the Gross Motor Composite, and performed worse on each of the four Gross Motor Subtests, reaching significance on two: Bilateral Coordination and Strength. The follow-up of children with BCH should continue even after the apparent resolution of the hypotonia, with particular attention to the gross motor aspects of performance.

HBW 023 (recombinant hirudin) for the acceleration of thrombolysis and prevention of coronary reocclusion in acute myocardial infarction: results of a dose-finding study (HIT-II) by the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte.

OBJECTIVE: To define an optimal dose of hirudin that would improve early coronary artery Thrombolysis in Myocardial Infarction grade 3 (TIMI 3) patency and prevent reocclusions in patients with acute myocardial infarction treated with front-loaded recombinant tissue-type plasminogen activator (rt-PA). METHODS: Recombinant hirudin (HBW 023) was tested in a sequential dose-escalating study as adjunct to front-loaded rt-PA in 143 patients with acute myocardial infarction. The sequential model was assigned two 'decision boundaries': it triggered an increase in dosage if the 60-min TIMI 3 flow rate in a dosage group was statistically not consistent with a target patency rate of 75%, or if the deterioration in coronary blood flow (of at least one TIMI grade, from TIMI 2 or 3, from one angiography to the next) exceeded 5%. RESULTS: The decision boundary for TIMI 3 flow grade at 60 min was crossed when 18 patients were treated with 0.1/0.06 mg/kg (bolus/infusion per hour over 48 h) r-hirudin (dosage group I), 42 patients treated with 0.2/0.1 mg/kg (dosage group II), and 83 patients with 0.4/0.15 mg/kg (dosage group III). TIMI 3 flow at 60 min was 50%, 58%, and 63% in dosage groups I-III, respectively (P = 0.15). Early, complete, and sustained patency (TIMI 3 flow at 60 min, 90 min and 48 h) were 44%, 55% and 64% (P = 0.07). Reocclusion between 90-min and 48-h angiograms or reinfarction occurred in 0 to 15, two of 36, and one of 72 patients, respectively (P = 0.5). Four patients (2.8%) died in hospital and 14 patients suffered a major bleeding event, but no intracranial bleeding was encountered. CONCLUSIONS: With increasing doses of hirudin, there was a trend towards greater early and complete patency, but no clear dose--response relationship was observed. A borderline significant effect was observed with respect to early, complete, and sustained patencies. In all groups, reocclusions or reinfarctions were rare. Neither clinical nor laboratory data predicted the imbalance in haemorrhagic events observed in a subsequent, prematurely terminated, phase III trial with hirudin and rt-PA.

Use of a computer simulator for training children with disabilities in the operation of a powered wheelchair.

OBJECTIVE: The purpose of this study was to evaluate the ability of a basic driving simulator program to evaluate and train children with disabilities in their ability to operate a powered wheelchair. METHOD: With a rating scale of skills considered essential for safe and efficient wheelchair operation, 22 children 7 to 22 years of age with either progressive muscular dystrophy or cerebral palsy were evaluated in their ability to drive a powered wheelchair through a driving course. They were divided into two groups: one without prior experience driving a powered wheelchair and the other with experience. After the driving assessment with an actual powered wheelchair, the inexperienced drivers were trained on a joystick-controlled computer game in which they navigated through labyrinths similar in layout to their own school environment. A test maze was administered before and after this training. Both groups were then evaluated on their ability to drive a powered wheelchair through the driving course. RESULTS: The inexperienced drivers significantly increased their simulator scores over the training period. Their wheelchair driving performance was significantly better after the simulator training, although their performance remained poorer than that of the experienced drivers. CONCLUSION: A simulator program can assist in the development and evaluation of the skills required to operate a powered wheelchair.

Virtual reality applications to work.

Virtual reality (VR) entails the use of advanced technologies, including computers and various multimedia peripherals, to produce a simulated (i.e. virtual) environment that users perceive as comparable to real world objects and events. With the aid of specially designed transducers and sensors, users interact with displayed images, moving and manipulating virtual objects, and performing other actions in a way that engenders a feeling of actual presence (immersion) in the simulated environment. The unique features and flexibility of VR give it extraordinary potential for use in work-related applications. It permits users to experience and interact with a life-like model or environment, in safety and at convenient times, while providing a degree of control over the simulation that is usually not possible in the real-life situation. The work-related applications that appear to be most promising are those that employ virtual reality for visualization and representation, distance communication and education, hands-on training, and orientation and navigation. This article presents an overview to the concepts of VR focusing on its applications in a variety of work settings. Issues related to potential difficulties in using VR including side effects and the transfer of skills learned in the virtual environment to the real world are also reviewed.

Recombinant hirudin as a periprocedural antithrombotic in coronary angioplasty for unstable angina pectoris.

Percutaneous transluminal coronary angioplasty is often complicated by thrombotic abrupt vessel closure in patients with unstable angina pectoris. The present multicentre trial was performed to determine the feasibility of two-dose regimens of recombinant hirudin (r-hirudin) compared to standard heparin in patients undergoing coronary angioplasty for unstable angina, and to investigate the effects of the different treatment regimen on markers of coagulation activation. At five participating centres, 61 patients were randomly enrolled in one of two sequential groups of r-hirudin (group 1: 0.3 mg.kg-1 i.v. bolus, 0.12 mg.kg-1.h-1 i.v. infusion; 21 patients; group 2: 0.5 mg.kg-1 i.v. bolus, 0.24 mg.kg-1.h-1 i.v. infusion; 19 patients) or in a heparin control group (150 IU.kg-1 i.v. bolus, 20 IU.kg-1.h-1 i.v. infusion; 21 patients). Antithrombotic therapy was started immediately before coronary angioplasty and continued for 24 h. This was followed by a low-dose anticoagulant infusion for another 24 h (r-hirudin: 0.04 mg . kg-1 . h-1; heparin: 7 IU . kg-1 . h-1). Activated partial thromboplastin time, r-hirudin plasma concentrations by both immunological and functional assay, thrombin-hirudin complex, thrombin-antithrombin III complex, soluble fibrin, and prothrombin fragment 1 + 2 were closely monitored. The median partial thromboplastin time prolongations at 24 h vs baseline were found to be 1.9-fold and 2.3-fold in r-hirudin group 1 and dose group 2, respectively, and 3.0-fold in the heparin group. There was a dose-dependent correlation between partial thromboplastin time and the r-hirudin plasma levels (r = 0.61). In five of 21 patients of dose group 1, three of 19 patients of dose group 2, and 10/21 patients of the heparin group, partial thromboplastin time values exceeding the predefined target range prompted an interruption of the infusion. One major bleeding complication occurred in dose group 2. The functional assay for the estimation of r-hirudin plasma concentrations showed excellent correlations to the immunological technique (r = 0.99). Differences between the thrombin-hirudin complex levels could not be observed. Increased concentrations of thrombin-antithrombin III complex, soluble fibrin, and prothrombin fragment 1 + 2 were seen 4-8 h after coronary angioplasty and after reduction of the high-dose therapy in dose group 1 when compared with dose group 2 and the heparin group, respectively. Based on coagulation tests the present study showed the feasibility of a periprocedural antithrombotic regimen with r-hirudin for patients undergoing coronary angioplasty for unstable angina. In addition to the partial thromboplastin time the determination of r-hirudin plasma levels by a chromogenic substrate assay considerably improves the monitoring of therapy. The lower dose r-hirudin regimen seems to be suboptimal as periprocedural anticoagulation in coronary angioplasty patients as indicated by markers of thrombin generation and thrombin activity.

Recombinant hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina.

OBJECTIVES: This study was performed to evaluate the efficacy of peri-interventional treatment with recombinant hirudin (r-hirudin [HBW 023]) compared with heparin in the prevention of troponin T release in patients with unstable angina. BACKGROUND: Percutaneous transluminal coronary angioplasty in patients with unstable angina is associated with a high risk of acute thrombotic complications. METHODS: Serial troponin T measurements were performed in 61 patients with unstable angina during the 48-h observation period after coronary angioplasty of the ischemia-related lesion. Patients were randomly assigned to peri-interventional intravenous treatment with either r-hirudin (dosage group I: 0.3-mg/kg body weight bolus, 0.12 mg/kg per h for 24 h; dosage group II: 0.5-mg/kg bolus, 0.24 mg/kg per h for 24 h) or heparin (150-IU/kg bolus, 20 IU/kg per h for 24 h). All patients received acetylsalicylic acid before coronary angiography. After 24 h, patients received a constant low dose infusion of either hirudin (0.04 mg/kg per h) or heparin (7 IU/kg per h) for another 24 h. The power of the study to detect a decrease in abnormal troponin T levels from 60% (heparin group) to 20% (combined r-hirudin groups) was 88%. RESULTS: Serial troponin T measurements revealed two peaks within the 48 h after coronary angioplasty in the heparin but not the hirudin groups. An elevated serum troponin T concentration (> 0.2 ng/ml) within 48 h of coronary angioplasty was found in 9 (24%) of 38 patients in the hirudin groups (5 [25%] of 20 in dosage group I; 4 [22%] of 18 in dosage group II) compared with 11 (58%) of 19 in the heparin group (p = 0.01). We observed major cardiac events (death, myocardial infarction, abrupt vessel closure) in 1 (4.8%) of 21 patients in dosage group I, 1 (5.3%) of 19 in dosage group II and 3 (14.3%) of 21 in the heparin group (p = 0.33). CONCLUSIONS: In this pilot trial, hirudin appears to be superior to heparin in preventing troponin T release after coronary angioplasty.

Recombinant hirudin and front-loaded alteplase in acute myocardial infarction: final results of a pilot study. HIT-I (hirudin for the improvement of thrombolysis).

Recombinant hirudin, a specific thrombin inhibitor, has been shown to accelerate thrombolysis and reduce reocclusions in experimental models. In a pilot trial recombinant hirudin (HBW 023) was used as an adjunctive therapy to thrombolysis with front-loaded tissue plasminogen activator (t-PA) (100 mg.90 min-1) in 40 patients with acute myocardial infarction whose duration of symptoms was less than 6 h. Patients received a bolus of r-hirudin of 0.07 mg.kg-1 b.w. followed by an infusion of 0.05 mg.kg-1.h-1 over 48 h. Complete patency (TIMI grade 3) of the infarct-related artery at 30, 60 and 90 min after the start of thrombolytic therapy was seen in 38.5%, 64.1% and 71.0% of patients, respectively. After 24-48 h, 80% of patients had a complete patent infarct vessel. A very early, complete and sustained patency (TIMI grade 3 at 60 and 90 min and at 24-48 h) was observed in 55% of patients. Reocclusions during the hirudin therapy appeared in six (16.1%) patients, two of whom had a PTCA at 90 min. The only reinfarction was seen after 6 h; this was successfully treated with additional thrombolysis. Major bleedings, mostly related to the invasive procedure, were observed in three patients. Spontaneous organ bleedings and intracerebral haemorrhages did not occur. There was one in-hospital death due to a late retroperitoneal bleeding. In was concluded that, with regard to safety and efficacy, the general feasibility of r-hirudin as adjunctive therapy to thrombolysis with front-loaded t-PA, has been demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models.

The specific thrombin inhibitor r-hirudin (HBW 023) has been demonstrated to be effective in preventing thrombosis in preclinical models. Up to now, no bleeding complications have been observed using therapeutically effective doses in animals studies. However, in case of inadvertent overdosing the occurrence of undesired impairment of coagulation cannot be excluded. As a potential antidote an activated prothrombin complex concentrate (APC) was tested on its ability to normalize blood coagulation. APC given s bolus injections 5 min and 3.0 mg/kg neutralized the r-hirudin-induced prolongation and 3.0 mg/kg neutralized the r-hirudin-induced prolongation of whole blood coagulation time in rabbits completely within 5 min without any clot formation in the blood vessels or capillaries of the heart, kidneys, or lungs. Furthermore, bleeding time prolongation induced by bolus application of 3.0 and 30.0 mg/kg r-hirudin was significantly inhibited by APC within 5 min. These results suggest that administration of APC may be an effective way to reverse the effects of r-hirudin in the coagulation system in case of inadvertent overdosing of r-hirudin.

Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK)

BACKGROUND: Adjunctive therapy for thrombolysis in acute myocardial infarction consists of platelet inhibition with aspirin and thrombin inhibition with heparin. Thrombin inhibition may be improved by the use of hirudin as indicated by experimental and phase II clinical studies. The randomized, double-blind phase III r-Hirudin for Improvement of Thrombolysis study (HIT III) compared a recombinant hirudin (HBW 023) with heparin. The primary end point was the incidence of death or reinfarction. METHODS AND RESULTS: Seven thousand patients with acute myocardial infarction and a duration of symptoms of less than 6 hours were to be randomized to receive intravenous heparin (70 IU/kg body wt bolus and 15 IU.kg-1.h-1) or hirudin (0.4 mg/kg body wt bolus and 0.15 mg.kg-1.h-1) infused over 48 to 72 hours and adjusted to an activated partial thromboplastin time of 2 to 3.5 times baseline values. In a pilot phase, 1000 patients receiving front-loaded alteplase for thrombolysis were to be recruited by 93 German centers. After enrollment of 302 patients, the trial was stopped after an increased rate of intracranial bleeding was observed in the hirudin group (5 of 148, 3.4%) compared with the heparin group (0 of 154). The overall stroke rate was 3.4% in the hirudin group and 1.3% in the heparin group. Other major bleeding occurred in five versus three patients and ventricular rupture occurred in three versus one patient in the hirudin and heparin groups, respectively. There were 19 in-hospital deaths, with 13 of them from the hirudin group. CONCLUSIONS: Although the number of patients was too small for a definite benefit-risk assessment, at the dosage tested, hirudin in combination with front-loaded alteplase and aspirin may be associated with an increased rate of intracranial hemorrhage. Our findings are consistent with the observations of the GUSTO-II and TIMI-9 trials, where higher doses of another recombinant hirudin were used. Therefore, the therapeutic range of hirudin as an adjunct to thrombolysis may be smaller than previously thought, and reappraisal of dose finding should be considered.

[Pulmonary siderosis in an arc welder]. / Lungensiderose eines Lichtbogenschweissers.

An arc welder of 32 years of age is presented with a random finding of miliar reticulonodular shadows in the plain film of the thorax. Subjectively and objectively the patient appears healthy. The presence of a pneumoconiosis is confirmed by biopsy. Differential diagnosis had to consider sarcoidosis and pulmonary siderosis in view of the known professional anamnesis. This case report underlines the reped demand to assess x-ray films of the thoracic organs only if the clinical findings and anamnesis are thoroughly known.

[Roentgenologic diagnosis and differential diagnosis of carcinomatous lymphangiosis of the lungs]. / Röntgenologische Diagnose und Differentialdiagnose der Lymphangiosis carcinomatosa der Lungen.

Generalised lymphatic carcinosis, also known as lymphangitis carcinomatosa, cannot be diagnosed by just one x-ray film of the thoracic organs. However, if an enhanced reticular striated pattern is seen, possibly associated with miliar stippling or hilar masses it is recommended to perform short-term follow-ups and comparisons with previous x-ray films. Lymphangitis carcinomatosa becomes probable if rapid progression of the findings or development of new lesions is seen besides the already existing ones and if this is associated with rapidly increasing dyspnoea. Pulmonary tomography will not yield highly significant results, but it can substantiate the diagnosis, the same applies to computed tomography of the thorax. CT is particularly important in differential diagnosis. Earliest possible diagnosis of lymphangitis carcinomatosa is of great importance for therapy, since it may be a first pointer towards an unknown metastasising primary tumor or haematogenous dissemination of already known tumours.

[High-dosage cotrimoxazole therapy of disseminated Nocardia brasiliensis infection]. / Hochdosierte Cotrimoxazol-Therapie einer disseminierten Nocardia-brasiliensis-Infektion.

After a scraping injury to the skin a 47-year-old man developed a generalized Nocardia brasiliensis infection with cutaneous, pulmonary and cerebral dissemination. There was no predisposing underlying illness. High-dosage cotrimoxazol and short-term intrathecal and systemic gentamycin administration achieved extensive healing. This form of treatment would thus seem capable of reversing the otherwise poor prognosis of generalized N. brasiliensis infection.