Management of venous thromboembolism in the ICU

In the ICU patient both deep vein thrombosis and pulmonary embolism are likely to be silent and may therefore go unrecognized. Clinical suspicion of venous thromboembolism merits urgent consideration of therapeutic anticoagulation with intravenous heparin. Objective testing for thromboembolic disease, although necessary, may be logistically problematic and therefore restricted, limiting precise definition of the incidence of thromboembolic events. Prior to the commencement of anticoagulation, a careful risk assessment with consideration of the relative contraindications for full therapeutic anticoagulation must be undertaken.

Heparin acts by binding to and potentiating the action of antithrombin, which inhibits activated factor X and the action of thrombin. A standard regimen is an initial 5000-IU intravenous bolus of unfractionated heparin followed by a continuous intravenous infusion of 25 000 to 35 000 units over 24 h to ensure rapid achievement of full therapeutic anticoagulation. The activated partial thromboplastin time is measured at 4 h, aiming to maintain a ratio of 1.5 to 2.5. Dosage adjustments are followed by monitoring activated partial thromboplastin time every 4 h until stable anticoagulation is achieved, and then every 12 to 24 h. Omission of the bolus dose and reduction of the initial infusion rate, with the aim of maintaining the activated partial thromboplastin time ratio at 1.5, is advisable in patients with platelet counts of less than 50 * 109/l, within 24 h of surgery, or with a recent cerebrovascular event or gastrointestinal bleed. Bleeding associated with heparin over-anticoagulation can be reversed by protamine sulfate. The platelet count should be monitored daily to allow early detection of heparin-induced thrombocytopenia. Intravenous unfractionated heparin is the mainstay of treatment, but thrombolysis, surgical intervention, and inferior vena caval filters may be required. Oral anticoagulation with warfarin should be deferred until the patient is stable and able to take oral medication, usually after discharge from the ICU. Warfarin should be started using a standard protocol which has been agreed locally. The international normalized ratio (INR) is measured daily, aiming for a therapeutic range of 2.0 to 3.0. The heparin infusion is stopped once the INR exceeds 2.0. The coumarins are vitamin K antagonists which act by inhibiting g-carboxylation of factors II, VII, IX, and X. The duration of oral anticoagulant therapy is usually 3 to 6 months for a deep vein thrombosis or pulmonary embolus. Longer-term anticoagulation is considered for recurrent events and in patients with an ongoing risk factor.

Thrombolysis

Thrombolytic therapy should be considered in patients with massive pulmonary embolism, and in young patients with extensive thrombosis compromising the vascular function of the affected limb. Thrombolysis improves radiographic resolution, right ventricular function, and pulmonary perfusion in small randomized trials. In addition, it may reduce recurrence rates and subsequent pulmonary hypertension. The currently available agents for thrombolysis are streptokinase, anisolated plasminogen streptokinase activator complex, recombinant tissue plasminogen activator, and urokinase. These agents have been widely used in the treatment of myocardial infarction. Recombinant tissue plasminogen activator is given as 100 mg over 2 h (10 mg over 1 to 2 min followed by 90 mg over 2 h). A continuous intravenous infusion of unfractionated heparin is subsequently administered when the activated partial thromboplastin time ratio is less than 2.0, and the heparin dose is then titrated to maintain an activated partial thromboplastin time ratio of 1.5 to 2.5. Streptokinase is given as a 30-min infusion of 600 000 units followed by 100 000 IU/h for 24 to 72 h. The thrombin time is monitored to maintain a value two to five times that of the control. The quoted risk of major bleeding varies from 3 to 5 per cent, depending on patient selection and the thrombolytic regimen used. The mortality rate is approximately 1.6 per cent. Bleeding associated with thrombolytic therapy requires treatment with fresh frozen plasma and cryoprecipitate. Consideration should be given to the use of aprotinin and other antifibrinolytic agents. Contraindications for thrombolysis include recent major surgery or trauma, organ biopsy, risk of gastrointestinal or genitourinary bleeding, pregnancy, hemostatic disorders, aortic dissection, pericarditis, severe hypertension, recent intracranial events or surgery, puncture of a non-compressible vessel, and cardiopulmonary resuscitation for over 10 min.

Indications for inferior vena caval filters

The insertion of percutaneous inferior vena caval filters should be considered in patients with thromboembolic disease in whom full anticoagulation is contraindicated, when thrombus extension or further pulmonary emboli occur despite adequate therapeutic anticoagulation, or in the presence of large free-floating thrombi of the iliac vein or inferior vena cava. Filters are effective in preventing fatal pulmonary embolus and are associated with few serious side-effects. Permanent filters have high long-term patency rates of up to 96 per cent at 12 years.

Massive pulmonary embolism

This condition is likely to be seen either as an indication for admission to the ICU or occurring in an existing patient. Sudden changes in hemodynamic variables, such as a rise in pulmonary artery pressure and reduction in cardiac index, may indicate the occurrence of a large pulmonary embolus. Severe right heart failure, hypoxemia, and death may occur quickly, with an estimated mortality rate of 43 to 80 per cent in the first 2 h. Diagnostic measures may necessarily be limited. Pulmonary angiography is the gold standard test, but echocardiography may be useful and more readily performed. Oxygen, inotropic agents, thrombolysis, surgical embolectomy, and ventilatory support may all be required. The placement of an inferior vena caval filter should be considered once the patient is stable.

Predisposition to thromboembolic disease

Consideration should be given to the identification of potential underlying conditions that may lead to venous thromboembolism. These include medical disorders

(Table 1) which may require specific treatment. In individuals who develop thromboembolism at a relatively young age, i.e. under 45 years, an underlying hemostatic defect (thrombophilia) should be sought (Tib.l§...2.). This may be particularly relevant where there is extension of venous thromboembolism despite adequate treatment, as replacement therapy with specific factor concentrates may be indicated. The prevalence of thrombophilic defects in individuals with a history of venous thromboembolism depends on selection criteria; the overall prevalence of antithrombin, protein C deficiency, and protein S deficiency varies between 6.5 and 26 per cent. Activated protein C resistance is by far the most common heritable thrombophilic defect with a reported prevalence of between 21 and 64 per cent in patients with deep vein thrombosis. The newly recognized prothrombin gene mutation, with a G to A transition at position 20210, occurs in 18 per cent of selected cases ( Poort eia/ 1996). Congenital dysfibrinogenemia is very rare. However, it is important to be aware of these defects in the ICU setting as they may present with venous thromboses in unusual sites or arterial thrombosis.

Table 1 Medical conditions predisposing to venous thrombosis kfrdfibS prtuwi t «wain' V laJefl mouton ftdfroribri gftflfrtUlMft QQQ10Q

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Table 2 Hemostatic defects predisposing to venous thrombosis

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