Prevention and treatment of adverse effects of corticosteroids in systemic lupus erythematosus

The therapy of deep venous thrombosis consists of several elements and depends on the localization, the age and the extent of the thrombus. This article discusses various types of initial therapy and long-term treatment of venous thromboembolism and also reviews future perspectives of pharmacological treatment. The initial treatment regimens comprise thrombolysis, thrombectomy, inferior vena cava filters and the anticoagulation with either unfractionated heparin or low molecular weight heparins. Various thrombin-inhibitors have been tested for initial treatment of thrombosis, however, further investigations of their efficacy, safety and cost-effectiveness will have to provide firm evidence on their superiority when compared to unfractionated or low molecular weight heparins.     

Low molecular weight heparins: a valuable tool in the treatment of acute coronary syndromes

Standard heparin, low molecular weight heparin and aspirin are at present the only antithrombotic agents of proven value in the initial treatment of patients with an acute coronary syndrome. The combined use of aspirin and one of the heparins for at least 6 days should be considered for all such patients. With their high bio-availability after subcutaneous injection and prolonged half-life, low molecular weight heparins simplify short-term treatment in the acute phase and enable long-term therapy to be maintained on an outpatient basis without the need for repeated laboratory monitoring of anticoagulant effects. Such long-term therapy would appear to be beneficial, at least in high-risk patients, in the light of increasing evidence that the underlying lesion in acute coronary syndromes resolves over a period of weeks or months.     

Ultrafast freezing of the embryos of outbred and inbred mouse strains

Prophylaxis of postoperative thromboembolism is widely used because it has been shown to save lives and money. However, some surgeons are still reluctant to use general prophylaxis in high-risk orthopedic surgery. In total hip and total knee replacement the best method of prophylaxis is currently low molecular weight heparin started preoperatively and continued for 7 to 14 days or until the patient is fully ambulatory. A shorter prophylaxis period failed to be effective in an English study. At present there is an ongoing debate on the length of the period of risk, and whether there is a need for prophylaxis after discharge. Oral anticoagulation has been used for extended prophylaxis, but studies show that anticoagulant levels need to be monitored by repeated measurements by international normalized ratio. An alternative method would be to continue low molecular weight heparin injections for 4 to 5 weeks after surgery. No studies so far have evaluated the efficacy and safety of prolonged prophylaxis with low molecular weight heparin after discharge.     

Assessing colposcopic skills: the instructor''s handbook

As part of the National Study of Primary Hip Replacement Outcome, 402 consultant orthopaedic surgeons from three regions were contacted by postal questionnaire which covered all aspects of total hip replacement (THR). There was a 70% response rate of which 71 did not perform hip surgery, a further 33 refused to take part, leaving 181 valid responses. Preoperative assessment clinics were used by 89% of surgeons, but anaesthetists and rehabilitation services were rarely involved at this stage. Of respondents, 99% used routine thromboprophylaxis, with 79% using a combination of mechanical and chemical methods. Of surgeons, 84% routinely used stockings, whereas 95.5% used chemical prophylaxis, 63% employed low molecular weight heparins. Theatre facilities were shared with other surgical specialties by 6% of surgeons and 18% regularly used body exhaust suits for THR. Antibiotic loaded cement was used by 69% of surgeons, the majority (65%) used a single brand of normal viscosity cement with 9% using reduced viscosity formulations. Modern cementing techniques were commonly used at least in part, 87% used a cement gun and 94% a cement restrictor for femoral cementing. On the acetabulum, 47% pressurised the cement. In all, 36 different femoral stems and 35 acetabular cups were in routine use, but the majority of surgeons (55%) used Charnley type prostheses. Of the surgeons, 57% performed only cemented THR, while 3% exclusively used uncemented THR. Of consultants, 21% followed up their patients to 5 years, the majority discharge patients within the first year. Of concern is a large proportion of surgeons using low molecular weight heparins despite a lack of evidence with regard to reducing fatal pulmonary embolism, and also the small number of surgeons using prostheses of unproven value. Third generation cementing techniques have yet to be fully adopted. The introduction of a national hip register could help to resolve some of these issues.     

Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin

Low molecular weight heparins are used extensively for thromboprophylaxis. The aim of this study was to compare the activity of the low molecular weight heparin, enoxaparin, 20 mg and 40 mg, given once per day with unfractionated heparin, 7500iu given twice per day, in terms of their anti-Xa activity in puerperal women following caesarean section and with an additional risk factor for venous thromboembolism. Seventeen women were randomised to receive one of the three treatments. The anti-Xa activity associated with each treatment was measured prior to treatment and at 2, 4, 6, 12 and 24 hours. The mean anti-Xa values of the groups receiving enoxaparin, 20 mg and 40 mg, were significantly higher than those of the group receiving unfractionated heparin. There was no difference between the two enoxaparin groups in terms of the anti-Xa activity profiles. This study suggests that the use of enoxaparin is superior to unfractionated heparin in terms of anti-Xa activity.     

Efficacy and safety of low molecular weight heparin in renal transplantation

BACKGROUND: Deep venous thrombosis (DVT) is a common problem with potentially devastating results in patients undergoing major surgical procedures. Certain renal transplant recipients are particularly at risk for allograft loss as a consequence of renal vein and artery thrombosis. Over the past few years, low molecular weight heparin has been well established as an accepted modality of treatment and prophylaxis of DVT. The efficacy and safety of low molecular weight heparin in the prophylaxis of DVT following renal transplantation in adults has not previously been reported. METHODS: Dalteparin was administered to 120 adult renal transplant recipients postoperatively at the Oregon Health Sciences University. RESULTS: No patient developed allograft arterial or venous thrombosis. One patient developed subclavian vein thrombosis. No bleeding complications were encountered, and side effects were very minimal. CONCLUSION: Prophylaxis with dalteparin is an effective and safe modality for the prevention of thrombosis in adult patients undergoing renal transplantation.     

Peptide vaccination with an anchor-replaced CTL epitope protects against human papillomavirus type 16-induced tumors expressing the wild-type epitope

PURPOSE: Upper-extremity thrombosis appears to be more frequent today, comprising about 2% of all deep venous limb thrombosis. Its severity depends on the type of possible complications, i.e., pulmonary embolism and post-thrombotic sequelae. In this retrospective series, we investigated both the predisposing factors and the evolution of upper-extremity deep venous thrombosis. METHODS: Forty-nine consecutive patients (24 men and 25 women, mean age 50.2 years) with upper extremity deep venous thrombosis documented by color Doppler ultrasonography (n = 47) or phlebography (n = 2) were included in the study. RESULTS: Clinical manifestations were mainly pain (81.6%) and edema (93.9%). Mean time between the onset of clinical signs and diagnosis was 7.2 days. Thrombosis involved humeral (26.5%), axillary (46.9%), subclavian (73.5%) and jugular (24.5%) veins. Causative factors were malignancies (32.7%), venous catheters (22.4%), deep venous thrombosis related to effort or thoracic outlet syndrome (22.5%) and thrombophilic states (8.2%). During the 6-month follow-up, six patients developed symptomatic pulmonary embolism (12.2%); one recurrence (2.2%) and 19 post-thrombotic sequelae such as residual edema (36.7%) were also observed. Initial therapy included heparin administration, principally subcutaneous low molecular weight heparins (n = 36/49). CONCLUSION: This series highlights the fact that upper-extremity deep venous thrombosis is mainly secondary to either malignancies or catheterization. Moreover, it confirms that color Doppler ultrasonography may be useful in the diagnosis of the disease and also underlines the high frequency of severe complications, i.e., pulmonary embolism and post-thrombotic sequelae. Finally, this study also demonstrates that low molecular weight heparins should be considered as the initial treatment of choice.     

Heparin therapy in pediatric patients

Advances in tertiary care pediatrics have resulted in heparin being one of the most frequently prescribed drugs in children's hospitals. Heparin is essential for cardiopulmonary bypass, extracorporeal membrane oxygenation, renal dialyses, maintenance of patency of venous and arterial catheters, and treatment of thromboembolic events. Currently, protocols validated in adults are used for children. However, optimal use of heparin in pediatric patients will likely differ from adults because of age-dependent physiologic and pathologic differences in hemostasis that influence the activities of heparin. The following review summarizes the influence of age on heparin anticoagulant activities, and pharmacokinetics. The indications, monitoring, therapeutic range, factors influencing dose-response relationships, and side effects of heparin therapy in pediatric patients are discussed. Finally the current and future indications for low-molecular-weight heparins in pediatric patients are summarized. Multi-centered, international clinical trials are urgently needed to assess and optimize the use of heparin in pediatric patients in a variety of clinical settings. Until these studies are completed, recommendations for adults provide guidelines for children.     

Prophylaxis for venous thromboembolism in head and neck surgery: the practice of otolaryngologists

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are an important cause of morbidity and mortality in the surgical patient. The first guideline produced by the Scottish Intercollegiate Guidelines Network was for the prophylaxis of venous thromboembolism. Patients undergoing major head and neck cancer surgery commonly exhibit risk factors for venous thromboembolism. Currently, however, there are no data on its incidence in these patients. A questionnaire survey was performed to assess the current practice of consultant otolaryngologists regarding DVT prophylaxis in patients undergoing head and neck cancer surgery. Of those respondents who managed these patients, 57 per cent did not use routine DVT prophylaxis while 43 per cent did. A wide variety of techniques were employed among those practising DVT prophylaxis. A consensus is needed concerning the use of thromboembolism prophylaxis in head and neck surgery patients.     

Self-blame and peer victimization in middle school: an attributional analysis

Intravenous heparin followed by warfarin has been the classical anticoagulant therapy of acute venous thromboembolism for the past 30 years. In recent years a number of low-molecular-weight heparins have become available for clinical trials. These agents have a number of advantages over unfractionated heparin and are now being used internationally for the prevention and treatment of venous thromboembolism. Low-molecular-weight heparin will undoubtedly replace intravenous unfractionated heparin not only in the treatment of venous thromboembolism but in other conditions where heparin therapy is indicated. Whether or not the low-molecular-weight heparins can decrease or eliminate some of the complications of unfractionated heparin will depend on the outcome of future clinical trials.     

Comparative effects of L-NOARG and L-NAME on basal blood flow and ACh-induced vasodilatation in rat diaphragmatic microcirculation

Anticoagulants are widely used in the prevention of thromboembolic disease (particularly during the postoperative period) and in the curative treatment of deep vein thromboses. Two classes of anticoagulants are currently available: heparins (standard heparin, low molecular weight heparin) and coumarin anticoagulants. The choice of anticoagulant must take into account the clinical context (preventive or curative treatment), as well as the pharmacological and pharmacokinetic properties of the anticoagulant. This treatment requires laboratory monitoring adopted to the anticoagulant selected.     

Interactions between antinociception induced by cholecystokinin antagonists and GABA agonists in the tail-flick test

BACKGROUND: Total joint replacements are high-risk procedures for development of deep venous thrombosis (DVT) and pulmonary embolism (PE), therefore, routine pharmacological prophylaxis should be instituted in all cases. Cost-containment has become an important factor with the present changes in health care. This report presents an economic model for DVT prophylaxis after total hip and total knee arthroplasty (THA & TKA) that approximates closely to the current standards in orthopedic practice, and encourages the balance of clinical and economic considerations in patient care management. METHODS: A simplified cost-effectiveness (cost-minimization) analysis, from the consumer's perspective, between Warfarin and Enoxaparin for DVT prophylaxis after THA and TKA, for a total of 15 days, in both inpatient and outpatient settings was used. The costs of drugs, laboratory, and home care services were evaluated through surveying three different providers in each category and obtaining the mean value for each of the services supplied. All providers were located within the Louisville, KY, metropolitan area. Data collection took place in October 1996. RESULTS: The main outcome measure was the difference in cost between the two drugs when all factors associated with therapy were considered. The overall cost of DVT prophylaxis with Enoxaparin was somewhat less expensive ($925.38) when compared to Warfarin ($971.77). CONCLUSIONS: Within the limitations of this study Enoxaparin was slightly more cost-effective than Warfarin for venous thromboembolism prophylaxis after total hip and knee arthroplasty.     

Pharmacokinetic optimisation of the treatment of deep vein thrombosis

The current treatment for deep vein thrombosis is a 5- to 10-day course of heparin followed by 3 to 6 months of oral anticoagulants. Both heparin and oral anticoagulants present a high inter- and intra-individual variability and require individualisation and monitoring of their dosage. The pharmacokinetic properties of heparin have been difficult to assess through the radiolabelling procedures typically used for many other drugs. This is partially a result of the heterogeneous nature of heparin. Thus, the pharmacokinetics of heparin are expressed in terms of its pharmacodynamic activity. Improved coagulation test methodology coupled with the incorporation of patient factors such as bodyweight, height, baseline coagulation status, pretreatment heparin sensitivity and heparin concentrations, can be used to improve the accuracy of heparin dosage determination. Computer-based systems are now available to assist clinicians in quantitating dosage requirements, estimating bleeding risks, and storing patient dose-response relationships for future therapy monitoring. Low molecular weight heparin products might improve our ability to control anticoagulant therapy because drug concentration, as well as the effect on the clotting system, will be more predictable in patients receiving these products. In addition, low molecular weight heparins produce a more consistent, predictable anticoagulant response, and clinicians have a new pharmacological tool which may readily lend itself to patient-controlled, home-based anticoagulant pharmacotherapy. Where pharmacokinetics and pharmacodynamics could contribute to the optimisation of warfarin treatment is in the initiation of treatment, the estimation of the dosage required, the methods for drug monitoring, the assessment of unusual responses and the avoidance of drug interactions. Traditional pharmaco kinetic methods have limited applicability to the optimisation of warfarin therapy because there is no direct relationship between drug concentration and therapeutic effect. However, a variety of simple or sophisticated computer-assisted methods have been developed to help clinicians in individualising and monitoring warfarin treatment. New therapeutic approaches, such as direct thrombin inhibitors and thrombolytic agents, could overcome some limitations of the standard heparin plus oral anticoagulation therapy.     

Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting

BACKGROUND: Venous thromboembolism is a common complication of surgery. Although surveys of physician self-reported practices have suggested near universal support for routine use of measures to prevent venous thromboembolism, medical record auditing has demonstrated underuse. OBJECTIVE: To assess physician practices of venous thromboembolism prophylaxis in the community hospital setting. METHODS: Retrospective review of the medical records from 20 hospitals in Oklahoma of 419 Medicare patients aged 65 years or older undergoing major abdominothoracic surgery between April 1 and December 31, 1995. Utilization rates of prophylaxis stratified according to patient risk for venous thromboembolism were measured. RESULTS: Prophylaxis measures were implemented for only 160 (38%) of 419 patients studied (95% confidence interval, 33%-43%). There was little variation in the use of prophylaxis based on the risk for venous thromboembolism. Only 97 (39%) of 250 patients (95% confidence interval, 33%-45%) at very high risk received any form of prophylaxis and of these 97, only 64 patients (66%) received appropriate measures (95% confidence interval, 56%-75%). CONCLUSIONS: Despite widely disseminated, evidence-based recommendations, venous thromboembolism prophylaxis is underused in Medicare patients undergoing major abdominothoracic surgery in community hospitals in Oklahoma.     

New antithrombotic agents

The wide range of compounds currently being developed is the result of the continuing need for validated new antithrombotic agents. The prevention and treatment of venous thrombosis is predominated by anticoagulants: low molecular weight heparins, and potentially new antithrombin agents including hirudin. The effectiveness of new antiplatelet agents, and particularly c7E3 and integrelin, confirms the hypothesis concerning the role played by platelets in thrombogenesis in coronary arteries. But, due to the proaggregating effect of thrombin, anticoagulants could also have an important role in preventing arterial clots, either when given alone or in combination. Finally, the development of antithrombin and anti-platelet-glycoprotein IIb IIIa given orally is one of the major objectives of current research. Until the ideal antithrombotic agent is discovered, multiple-drug regimens combining anticoagulants and/or antiplatelet agents could be proposed in patients with a very high risk of thrombosis. Such regimens must taken into account the increased risk of bleeding and be adapted on the basis of careful laboratory surveillance.     

Low molecular weight heparins in special populations

Low molecular weight heparins (LMWH) are replacing unfractionated heparin (UH) as safe and effective agents for the prevention and treatment of thromboembolism. Although LMWH offer many advantages over UH, usage is less clearly defined in certain special populations, including renal dysfunction, obesity and pregnancy. This article will briefly review the pharmacology of LMWH and discuss usage in these special populations.     

A PIL for every ill? Patient information leaflets (PILs): a review of past, present and future use

PURPOSE: The necessity of effective prevention of DVT is generally accepted. However, attitudes and beliefs concerning prophylaxis vary greatly in terms of the risk groups receiving prophylaxis and the prophylactic methodology. This paper reviews current research on the subject and seeks to provide recommendations. RESULTS: Known clinical risk factors allow the classification of patients according to high, medium and low risk of developing thromboembolism. Basic forms of prophylaxis are physiotherapy and early mobilisation. However, there are no data on the safety and efficacy of these methods. Mechanical devices used include external intermittent pneumatic compression and graduated compression stockings. Used in isolation, these methods reduce the incidence of deep vein thrombosis in low and moderate risk patients by one half or one third. There is no distinction between mechanical and pharmacological methods in terms of safety and efficacy. Furthermore, secondary effects are extremely rare. Moderate and high risk category patients should receive combined modes of mechanical and pharmacological treatment. A direct comparison of safety in moderate risk patients fixed doses of standard heparin vs. low molecular weight heparin revealed no significant differences. In the case of high risk patients, adjusted dose heparin administered subcutaneously or fixed dose low molecular heparin is recommended. A severe secondary effect of heparin-prophylaxis is heparin-induced thrombocytopenie. The optimum duration of pharmacological prophylaxis is not yet clear. CONCLUSION: The methods and duration of prophylaxis remain subject to an individual medical assessment of the clinically significant benefits in relation to the risk secondary effects of the treatment. On major questions there are significant variations in the specialist literature. This means that standards cannot be formulated, although recommendations can be given.     

Danaparoid in the prevention of thromboembolic complications

OBJECTIVE: To review the therapies used to prevent postoperative thromboembolic complications with a focus on the role of danaparoid, a new low-molecular-weight glycosaminoglycan. DATA SOURCES: A MEDLINE search was performed to identify pertinent English-language literature including studies, abstracts, and review articles. Key search terms included danaparoid, heparinoid, lomoparin, heparin, prophylaxis, thrombosis, embolism, thromboembolism, and thromboembolic and postoperative complications. The manufacturer of danaparoid was contracted for additional information related to this compound. STUDY SELECTION AND DATA EXTRACTION: All identified articles were reviewed for possible inclusion in this review. Comparisons primarily focused on data obtained from prospective, randomized, controlled, blind clinical trials. Another important consideration was the use of venography to determine the presence of deep venous thrombosis. DATA SYNTHESIS: Various therapies are available for the prevention of postoperative thromboembolic complications. Effective pharmacologic treatments currently available include adjusted-dose heparin, warfarin, aspirin, dextran, and low-molecular-weight heparins (LMWHs). Until recently, warfarin was considered the drug of choice for thromboprophylaxis in high-risk patients, including patients undergoing orthopedic surgical procedures. Because of their comparable efficacy and greater ease of use, LMWHs are gaining favor over warfarin in this patient population. In well-designed clinical trials involving patients undergoing elective total hip replacement or fractured hip surgery, danaparoid has demonstrated greater efficacy than other active treatments, including warfarin, dextran, aspirin, and heparin plus dihydroergotamine. While studies comparing danaparoid with LMWHs have not yet been published, danaparoid may be more useful in patients with heparin-associated thrombocytopenia. CONCLUSIONS: Danaparoid is an antithrombotic agent with characteristics that distinguish it from heparin and LMWHs. Based on the efficacy and safety data reviewed, danaparoid should be considered one of the drugs of choice for the prevention of thromboembolic complications in patients undergoing orthopedic hip procedures and the drug of choice for the management of any patient with heparin-induced thrombocytopenia who requires anticoagulant therapy.     

Central venous catheter use in low-risk coronary artery bypass grafting

BACKGROUND: To assess the impact of central venous pressure catheter monitoring in low-risk coronary artery bypass grafting (CABG), we compared the hospital course of patients undergoing CABG with central venous pressure catheter monitoring with that of similar patients undergoing CABG with pulmonary artery catheter monitoring. METHODS: All isolated primary CABG procedures (n = 312) performed between April 22 and October 31, 1996, were evaluated, and 194 patients meeting six central venous pressure catheter use criteria were identified. Of these 194 patients, 133 (68%) underwent CABG with central venous pressure catheter monitoring, and 61 (32%) had pulmonary artery catheter monitoring owing to surgeon or anesthesiologist preference. RESULTS: In-hospital mortality was similar. A trend toward increased overall complications was seen in the pulmonary artery catheter group. The total volume infused in the first 12 hours, the 24-hour weight gain, and the intubation time were significantly greater in the pulmonary artery catheter group. Increases in intensive care unit length of stay and in total hospital charges trended toward statistical significance in the pulmonary artery catheter group. CONCLUSIONS: Pulmonary artery catheter use in low-risk patients undergoing CABG was associated with greater weight gain and longer intubation time and may be associated with increased morbidity and utilization of hospital resources.     

Increased kidney xanthine oxidoreductase activity in salt-induced experimental hypertension

OBJECTIVES: To assess the efficacy and safety of low molecular weight heparin (LMWH) as deep venous thrombosis (DVT) prophylaxis following total knee arthroplasty. DATA SOURCES: Medline 1986 to June 1997, Embase, and manufacturers were used to identify randomized controlled trials. REVIEW METHODS: Trials included were randomized studies of LMWH with routine radiological screening for DVT. Placebo or active controls were included. Two reviewers independently screened trials for inclusion, and assessed their quality. Pooled relative risk estimates of DVT and proximal DVT rates were calculated using a DerSimonian and Laird random effects model. Sensitivity of the results to the type of control used and the quality of the trial was assessed. RESULTS: The relative risk of DVT for a patient given LMWH is 0.73 (95% CI 0.66 to 0.80) when compared with patients treated with adjusted dose heparin or warfarin controls. The relative risk for proximal DVT is 0.58 (95% CI 0.38 to 0.90). The relative risk of pulmonary emboli in the LMWH group was 0.55 (95% C.I. 0.20 to 1.57). No excess of bleeding was recorded in the LMWH group. CONCLUSIONS: Low molecular weight heparin is more efficacious than either adjusted dose heparin or adjusted dose warfarin, when used to prevent DVT and proximal DVT following total knee arthroplasty.