Treatment of postcatheterisation false aneurysms: ultrasound-guided compression vs ultrasound-guided thrombin injection.

OBJECTIVES: to compare the efficacy and cost-effectiveness of ultrasound-guided compression (UGC) with ultrasound-guided thrombin injection (UGTI) for treatment of postcatheterisation arterial false aneurysms (cFA). DESIGN: prospective clinical study using historical controls. MATERIALS AND METHODS: we prospectively collected data on 33 consecutive patients diagnosed with cFA larger than 1.5 cm in diameter. These were treated with UGTI. We performed a retrospective review of data on a former group of 33 consecutive historical control patients that were treated by UGC. RESULTS: the groups were similar in respect of demographic and clinical variables. Thirty patients were suitable for UGC and 33 patients were suitable for UGTI. The success rate for UGC was 26/30 (87%) compared to 33/33 (100%) for UGTI (p<0.05). Thrombosis was achieved during the first treatment session in 7/26 patients treated by UGC, compared to 26/33 in the UGTI group (p<0.0001). Four patients that failed UGC and two patients that were unsuitable for UGC required surgical repair. UGTI as compared to UGC was shorter in duration (25 vs 75 min) and required no sedation. No thromboembolic or systemic complications occurred in either group. Cost analysis revealed savings of $US 517 for each patient treated by UGTI as compared with UGC. CONCLUSIONS: in our study, UGTI is superior to UGC, and we suggest that UGTI should become the procedure of choice for the treatment of cFA.

Thromboembolic complications of central venous catheterization of the arm and neck veins.

For more than 30 years central venous catheterization has provided an important means of long-term vascular access and circulatory monitoring. Thrombosis of central veins is one of the serious complications of this procedure, The reported incidence of thrombosis varies and it is often underestimated clinicaIly due to the pau city of signs and symptoms. Symptomatic subelavian vein thrombosis is estimated to occur in up to 15% of patients with indwelling venous access devices.

Lateral venous ulcer and short saphenous vein insufficiency.

PURPOSE: The objective of this report is to emphasize the importance of saphenopopliteal junction (SPJ) reflux in the genesis of lateral leg ulcers and to suggest a proper diagnostic and therapeutic approach. METHODS: Twenty legs with isolated lateral perimalleolar ulcers from the basis for this report. None had medial ankle ulcers, and most showed no hyperpigmentation or lipodermatosclerosis. Fifteen had been treated with a nonvenous diagnosis. Reflux at the SPJ was detected by handheld continuous wave Doppler and was confirmed with duplex scans. No other abnormalities were found. Brief conservative treatment and duplex localization of the SPJ preceded its ligation and division. RESULTS: All ulcers healed within 12 weeks, but one in a radiated leg recurred at 9 months. Other complications included two hematomas and one each of ankle edema, superficial wound infection, and sural neuropathy. CONCLUSIONS: Even isolated lateral leg and ankle ulcers with minimal accessory venous stigmata can be of venous reflux origin. Detection with the continuous wave Doppler and confirmation of reflux and localization of the SPJ allow surgical correction to proceed swiftly with an expectation of satisfactory results.

Intraoperative urokinase as an alternative to heparin for patients with suspected heparin-induced thrombocytopenia requiring arterial reconstruction: report of a case and review of the literature.

Patients with heparin-induced thrombocytopenia (HIT) require an alternative antithrombotic treatment to heparin during arterial reconstruction. Ancrod and Iloprost have been employed but are not readily available and carry the risks of systemic side effects (depletion of fibrinogen, hypotension). A patient with HIT in whom intraoperative intraarterial urokinase (UK) was successfully utilized to enable safe arterial reconstruction is described. An 80 year old white female with diffuse arteriosclerotic cardiovascular disease and multiple vascular reconstructions had thrombotic complications following use for heparin during two of her prior operations associated with documented thrombocytopenia and anti-platelet antibodies. She presented with limb-threatening ischemia which was evaluated with angiography revealing severe stenosis of the proximal left superficial femoral artery, occlusion of both anterior tibial and peroneal arteries and several digital vessels, with intact posterior tibial runoff. A common femoral to mid-superficial femoral artery bypass was performed, utilizing contralateral reversed greater saphenous vein, while being treated with aspirin and a continuous intravenous infusion of low molecular weight dextran. During the procedure the clamped arteries were locally perfused with a high volume of dilute UK solution to prevent blood stasis, and enable local delivery of a thrombolytic agent. Although clot formation was observed in the operative field, none occurred within the clamped arteries. A total of 191,200 units of UK were employed with no bleeding complications. Following surgery the patient had a palpable pedal pulse and markedly improved perfusion of her toes. She was discharged on aspirin and coumadin on postoperative day five. It is concluded that for patients with HIT, systemic aspirin and dextran combined with local intraarterial UK are a simple and effective substitute for systemic anticoagulation with heparin during arterial reconstruction.

Pharmacological characterization of a new 4-amidinophenyl-alanine thrombin-inhibitor (CRC 220).

The new thrombin inhibitor CRC 220 was characterized in vivo for its antithrombotic effects. CRC 220 led to a dose-dependent prolongation of clotting parameters as determined in rats, rabbits, dogs, sheeps, pigs and monkeys. We evaluated the efficacy of CRC 220 to prevent thrombus formation in arteries and in the microcirculation in different animal models. In a rabbit model of tissue factor-induced coagulation activation, infusion of 0.5 mg/kg x h CRC 220 (3 hours) led to a significant prevention of fibrinogen decrease. In a rat model of lethal LPS-induced DIC CRC 220 significantly prevented the mortality rate after a 4h-infusion of 0.75 mg/kg x h. Thrombin-induced platelet aggregation in rat lungs could be prevented by the i.v. bolus injection of CRC 220. A dose of 0.3 mg/kg leads to a reduction of more than 80% of platelet deposition in the lung, significant inhibition was still observed 90 minutes after CRC 220 administration; at this time the inhibitor had already been cleared from plasma. Arterial thrombosis was induced in rabbits by squeezing and stenosis of the A. carotis. The i.v. bolus administration of CRC 220 dose-dependently prevented thrombus formation, an ED50 of 0.03 mg/kg was calculated. This dose was associated with only a minor prolongation of aPTT.

Perioperative myocardial ischemia in carotid endarterectomy under cervical plexus block and prophylactic nitroglycerin infusion.

Perioperative myocardial ischemia was evaluated in 36 consecutive carotid endarterectomy procedures carried out on patients with a high (72.2%) prevalence of ischemic heart disease. The procedures were performed under cervical plexus block plus a prophylactic intravenous nitroglycerin infusion. Findings of myocardial ischemia on perioperative (48 hours) continuous electrocardiogram recordings were correlated with preoperative cardiac status, perioperative continuous intra-arterial blood pressure measurements, and postoperative cardiac outcome. In two patients, ST segment analysis was un-interpretable because of bundle-branch blocks. Altogether, 64 episodes of significant ST segment depression were detected in 18 (52.9%) of the remaining procedures. In 8 (23.5%) procedures, ST segment depressions occurred either during carotid artery clamping at the time of the largest rise in blood pressure or within 2 hours of declamping, when blood pressure tended to decline. There were four (11.7%) postoperative cardiac events: three myocardial infarctions (one Q wave and two non-Q wave) and one episode of unstable angina pectoris. All four patients with cardiac events had early signs of myocardial ischemia either at the time of cross-clamping, or soon after declamping of the carotid artery. All myocardial infarctions developed following prolonged (> 10 hours) myocardial ischemia, starting with the first 20 hours after surgery. Thus, ST segment depression occurring during clamping or soon after carotid declamping was associated with cardiac complications (sensitivity 100% and specificity 86.6%) and suggests the possible usefulness of on-line ST segment trend monitoring.

Studies on the efficacy of mast cell growth factor (c-kit ligand) in vitro as well as in vivo.

We tested the ability of recombinant human (rhu) mast cell growth factor (MGF), also known as c-kit ligand, to stimulate the colony formation of human bone marrow cells in semisolid medium alone and in combination with rhu erythropoietin (EPO), rhu Interleukin 3 (IL-3), rhu granulocyte colony stimulating factor (G-CSF) and rhu granulocyte-macrophage colony stimulating factor (GM-CSF). The addition of MGF to cultures containing EPO or EPO + IL-3, GM-CSF and G-CSF, resp., resulted in macroscopic erythroid burst-forming units (BFU-E). Multipotential (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM]) progenitors were stimulated by MGF in the presence of EPO. Colony-forming unit granulocyte-macrophage (CFU-GM) were activated by MGF only in combination with GM-CSF. The combination of MGF with EPO was used for synergism studies in healthy cynomolgus monkeys. In the chosen concentration MGF alone had no effect on white blood cell (WBC) counts and on platelets, but a slight effect on reticulocytes. EPO by itself increased reticulocyte counts with no effects on WBC or platelets. The combination of both factors resulted in a significant increase of reticulocytes. No other effects were seen. These studies demonstrate the potent synergistic interaction of MGF and other hematopoietic growth factors.

Combined effects of granulocyte-macrophage colony stimulating factor with erythropoietin in subhuman primates.

Recently, we showed in a cynomolgus monkey model that the combination of interleukin-3 (IL-3) and granulocyte-macrophage colony stimulating factors (GM-CSF) demonstrates synergistic effects, if administered sequentially. Not only were progenitor cells of the myelocytic lineage stimulated cooperatively, but platelet release was also observed. These effects could not be found using these factors alone. In this study, GM-CSF was administered with erythropoietin (EPO) in a sequential manner. This treatment of GM-CSF and EPO resulted in a GM-CSF-stimulated increase in cells of myelomonocytic differentiation, and enhanced stimulation of erythroid and megakaryocytic lineages. The observed effects of growth factor combination were seen to the same extent with intravenous or subcutaneous administration. The results obtained may predict the potential usefulness of GM-CSF treatment together with EPO. This could improve the effectiveness of single growth factors in only limited indications, e.g., reduced need for transfusion (platelets, blood), correction of iatrogenic anemia, and recovery from myelosuppression due to chemo- and radiotherapeutic agents.

Purified chick-embryo-cell (PCEC) rabies vaccine: its potency performance in different test systems and in humans.

The potency of purified chick embryo cell rabies vaccine Rabipur was evaluated by four different in vivo test systems: (1) NIH test with homologous strain LEP challenge; (2) intramuscular challenge of vaccinated laboratory animals; (3) postexposure vaccine treatment trials in laboratory animals; and (4) antibody induction tests in laboratory animals. These different test systems were compared with the Standard NIH test and an in vitro test, the modified ABT. Each of the four in vivo methods chosen demonstrated potency values superior to that of the Standard NIH test in which challenge was with CVS strain. Potency relations were: Standard NIH test versus alternative methods versus modified ABT 1.0-2.2-1.85 respectively. There was good correlation between alternative in vivo methods and the ABT. In addition examples of antibody induction in man following administration of various postexposure treatment regimens are presented which lead to the conclusion that postexposure vaccination method and composition of the study group play a more important role in achieving optimum treatment results than vaccine potency, provided that it corresponds to WHO requirements (minimum 2.5 IU per dose).

Preclinical studies on synergistic effects of IL-1, IL-3, G-CSF and GM-CSF in cynomolgus monkeys.

The regulation of blood cell formation is mediated by a group of polypeptides classified as hematopoietic growth and differentiation factors. Overlapping as well as distinct functions have been described for three of these cytokines: interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Furthermore, interleukin 1 (IL-1) has been shown to promote hematopoietic regeneration after cytoreductive drug treatment. Evidence has been provided by in vitro studies that combinations of these factors exert a highly synergistic action on the proliferation and differentiation of committed hematopoietic progenitor cells. Additionally, these findings have been supported by studies of in vivo blood cell formation in nonhuman primates. We report here that IL-3 acts synergistically with GM-CSF or G-CSF on myelocytic cell development only if an administration time of eight days of IL-3 is followed by GM-CSF or G-CSF. Short-time IL-3 application of two and four days only resulted in platelet production. The reverse administration schedule did not show synergistically enhanced stimulation of myelocytic cells. However, G-CSF treatment followed by IL-3 did induce a two-fold increase in platelet numbers. This would appear to confirm previously reported in vitro findings that G-CSF shortens the G0 period of human hematopoietic stem cells, which subsequently proliferate in the presence of IL-3. The effects of IL-3 on myelocytic and megakaryocytic development seems to be differently regulated. Whereas, IL-1 failed to display synergistic activity with GM-CSF or G-CSF is sequentially applied. Only simultaneous application either in combination with GM-CSF or with G-CSF demonstrated enhanced efficacy.

Human recombinant derived IL-3 and GM-CSF in hematopoiesis of normal cynomolgus monkeys.

Recent progress in molecular cloning has provided access to several major human colony-stimulating factors - GM-CSF, IL-3, G-CSF and M-CSF. Now they are available highly purified from different expression systems (e.g. yeast, E. coli, CHO cells). These molecules, acting multifunctionally in the hematopoietic system, are responsible for proliferation and differentiation of bone marrow-derived progenitor cells in vitro. First clinical studies performed with colony-stimulating factors have shown that neutropenia caused by drug-induced immunosuppression in patients with refractory cancer or autologous bone marrow transplantation was reversed using rh GM-CSF or rh G-CSF. We have investigated the effect of the consecutive administration of rh IL-3 and GM-CSF on hematopoiesis in normal cynomolgus monkeys. Whereas administration of rh IL-3 alone did not result in an increase of WBC counts, the combination therapy of rh IL-3 followed by rh GM-CSF exhibited significant synergistic effects and raised WBC numbers. Furthermore, application of both factors resulted in a platelet rise not seen when one of the factors was used alone. The response was dose dependent and implicated that the therapeutical potential of rh GM-CSF could be expanded if used in combination with rh IL-3.

Potency testing of BCG vaccines on white mice: influence of variables on survival time, lung findings and vaccine assessment.

In protection tests on white mice vaccinated with BCG vaccine and challenged with a pathogenic strain of Mycobacterium bovis, the survival times are considerably altered by several variables. In the strains of mice used mainly in this study (NMRI and Albany), the median survival time of a group was roughly doubled in the sensitive range of the test system either by a twofold increase in the immunization period, a threefold decrease in the challenge dose or a 100-fold or less increase in the vaccine dose. The shape of the survival curve of an animal group depends on the median survival time achieved. The Gaussian distributions (sum curves) of the logarithms of the individual survival times are near linearity and parallelity in groups of animals which either survive for short or very long periods. In an intermediate range, however, the survival curves show a flatter and sometimes S-shaped course. This intermediate range of survival corresponds to the time at which the lung findings shift from acute to chronic. The occurrence of acute or chronic findings depends on the individual survival time after challenge. The autopsies show that both findings are equally frequent approximately equal to 35 days after challenge. Individual survival times should be evaluated by non-parametric methods due to their non-normal (bimodal) distribution. Evaluation of the gross lung findings supports these results but is, however, less efficient. The discriminating power of the test system can be altered by changes in any of the variables and is best when animal groups attaining less than 20 days median survival time are compared with groups attaining greater than 30 days. A twofold increase in the median survival time generally provides evidence of significance that may already be obtained 30 days after challenge. With a vaccination-challenge interval of 21 days or more, a 50 microliter vaccine dose generally induces a significant increase in the survival times of the vaccinated animals versus non-vaccinated controls. With increasing immunization periods (vaccination-challenge interval), however, a difference in the efficacy of several vaccines or vaccine doses will be evened out.

NIH test, a problematic method for testing potency of inactivated rabies vaccine.

A critical review of the NIH test is given. The results of four studies are presented which show that in the case of purified chick embryo cell inactivated rabies vaccine there is a profound difference between the result after heterologous intracerebral challenge with the prescribed CVS strain and homologous challenge with the LEP-C 26 strain. CVS strains from various laboratories produced relatively uniform results following intracerebral administration. Two in vitro tests, the single radial immunodiffusion test and the modified antibody binding test were employed in the studies. The results are discussed and alternative procedures to the NIH test are recommended for future consideration.

15-deoxyspergualin: from cytostasis to immunosuppression.

This article gives a survey on the pharmacological action of the new polyamine compound 15-Deoxyspergualin (15-DS). 15-DS is a derivative of the antitumor antibiotic spergualin which has been isolated by Prof. Umezawa's group in Japan. Besides its antitumor activity 15-DS was shown to possess immunosuppressive properties making the substance suitable for the application in organ transplantation and autoimmune disorders. Due to its immunopharmacological mode of action known hitherto 15-DS clearly differs from other immunosuppressants as e.g. Cyclosporin A.