Unfractionated Heparin (UFH)
Heparin has long been the mainstay of therapy for PE, although its pre-eminent role in treating thromboembolic disease has lately been challenged by newer medications. Unfractionated heparin is a mixture of acidic glycosaminoglycans typically extracted from porcine intestinal mucosa, with a variable molecular weight of between 5000 and 30,000 da, depending on its clinical preparation.70,71 Along with a coumarin derivative, it was the first anticoagulant to be prospectively shown to decrease mortality and recurrent PE, decreasing mortality by 25%.72 While it has proven effective, it requires monitoring of coagulation parameters as well as dose adjustment due to unpredictable plasma levels even within individuals. Although a recent study has shown that UFH given subcutaneously is as effective and safe as fixed dose nadroparin,73 UFH is generally given by continuous intravenous infusion and we expect this practice to continue. These limitations functionally restrict the use of heparin to the hospital setting. Heparin essentially catalyzes the effect of antithrombin to rapidly inhibit several of the factors from the intrinsic and common coagulation pathways, factors Xa, IXa, XIa, and XIIa.70 It also inhibits the activation of factors V and VIII by thrombin.71 Heparin is cleared rapidly from the plasma by binding to cell surface receptors on endothelial cells and reticuloendothelial elements,70 and its clearance is not affected by renal or hepatic insufficiency.
In dosing heparin, a singular concept emerges: one must give enough heparin to surpass a minimal level of anticoagulation in order to prevent further thromboembolism. This threshold level appears to be doses at which the activated partial thromboplastin time (aPTT) is at least 1.5 times control74 (or alternatively at which a heparin level of 0.2 to 0.4 U/mL by the protamine sulfate assay or 0.3 to 0.6 IU/mL by amidolytic anti-Xa study is reached), and it should be reached as quickly as possible. When continuous intravenous heparin was compared with intermittent subcutaneous heparin in the treatment of proximal deep vein thrombosis, only 1 of 61 patients who achieved an aPTT of greater than 1.5 times control suffered recurrent venous thromboembolism (VTE). In contrast, 13 of 53 patients whose aPTT was below 1.5 times control for 24 hours had recurrence, independent of the method of administration of heparin (relative risk = 15:1).74 Rapid, adequate anticoagulation is facilitated by a weight-based nomogram.73,75 Heparin is typically initiated with a bolus of 80 U/kg followed by a continuous infusion of 18 U/kg per hour. For most patients, oral anticoagulation (coumadin) is begun within 3 days of initiating heparin.
While the evidence supporting a lower therapeutic limit for heparin of 1.5 times control as judged by the aPTT is quite strong, the conventional upper limit (2.5 times control) is arbitrary. For years it had been assumed that the risk of hemorrhage was significantly related to the level of the aPTT, but one trial has cast doubt on this assumption.76 In this study, hemorrhagic complications were related to underlying predisposing factors (eg, recent surgery, ulcer disease, or cancer) rather than to supratherapeutic levels of the aPTT. Patients were initially treated with heparin plus warfarin or with heparin alone. Of 99 patients in the combined treatment group, 69 (69%) had aPTT levels greater than 2.5 times control for more than 24 hours. In contrast, in the heparin only group, 24 of 100 patients (24%) had supratherapeutic aPTT levels. Bleeding complications were similar in the two groups (combined therapy, 9.1%; heparin alone, 12.0%). In addition, bleeding complications were seen in only 8 of 93 patients with supratherapeutic aPTT regardless of therapeutic arm, compared with 13 of 106 patients without such elevation. These findings refute an association between modestly elevated aPTT and hemorrhage, and combined with the importance of prompt, adequate anticoagulation, suggest the value of an approach that aims to assure enough heparin in the first hours of treatment, rather than to avoid too much.
Complications of heparin, in addition to hemorrhage, include heparin-induced thrombocytopenia (HIT), osteoporosis, hypersensitivity, and (rarely) hyperkalemia. The most important complication of heparin is bleeding. In a pooled analysis of its use in deep venous thrombosis, major bleeding (bleeding greater than 1 L, bleeding requiring blood transfusion, or intracerebral bleeding) was reported in 2 of 59 patients (3%).77 In a group of 121 patients given heparin for all indications, 8% developed major hemorrhage (fatal, life-threatening, potentially life-threatening, or bleeding leading to reoperation or requiring at least three units of blood).78 When heparin dosing is guided by nomogram as described above, the risk of hemorrhage was 9% to 12%.76 Hemorrhage typically occurs from the gastrointestinal or urinary tract, or from surgical incisions. Less common sites of serious bleeding include the retroperitoneum, adrenal glands, soft tissues, nose, and pleural space. Intracranial hemorrhage is uncommon in patients anticoagulated with heparin.
The approach to treatment of the patient who bleeds on heparin depends on the severity of bleeding. When bleeding is minor, simply stopping the heparin may be sufficient. Bleeding related to needlesticks may respond to sustained direct pressure. When hemorrhage endangers life or organ function, a more aggressive approach is mandatory. Transfusion of fresh frozen plasma is usually ineffective since circulating heparin inhibits the function of transfused factors. Protamine sulfate is an antidote to heparin. The dose of protamine depends on heparin levels, and is therefore related to dose, route of administration, and time since the last dose. When hemorrhage immediately follows a bolus of heparin, sufficient protamine to completely neutralize the heparin (1 mg protamine per 100 U heparin) should be administered. In the more usual situation in which heparin therapy is ongoing, the dose of protamine should be based on the approximate half-life of heparin (90 minutes). Since protamine is also an anticoagulant, the dose should be calculated to only half-correct the estimated circulating heparin. Protamine has been known to cause hypotension, shock, dyspnea, and pulmonary hypertension upon intravenous injection. The incidence is reduced by giving the drug very slowly (no more than 50 mg in 10 minutes). When protamine is administered, a physician should be present in case of an anaphylactoid reaction. Alternatives for the treatment of underlying conditions should be considered once heparin is stopped. For example, the patient with pulmonary embolization should have vena caval interruption with a percutaneous filter (see below).
Thrombocytopenia is a relatively common complication of heparin administration, typically occurring after several days of therapy. In large series, roughly 1% to 3% of patients given full-dose intravenous heparin have developed thrombocytopenia.79 Interestingly, in our experience at a tertiary care center where many of our patients are repeatedly exposed to heparin, the incidence of heparin-induced thrombocytopenia seems to be much higher. The mechanism in most patients is thought to be related to specific IgG directed against heparin. Thrombocytopenia is less commonly seen with highly purified low-molecular-weight heparins, suggesting that higher-molecular-weight components may be responsible. It is also rare in patients given prophylactic, minidose heparin, occurring in only one of 348 patients.80 The onset of thrombocytopenia is usually on the third to fifteenth day (mean = day 10), but it can occur after several hours in patients previously sensitized. The severity of thrombocytopenia is variable (commonly to 50,000/mm3), but can be severe (<5000/mm3). Most patients remain asymptomatic, but some suffer major arterial or venous thrombosis, or life-threatening hemorrhage. Rarely, this syndrome is associated with skin bullae that progress to necrosis (“heparin necrosis”). These may occur at sites of injection or at distant sites. Any time heparin is given, it is prudent to measure platelet counts on a daily basis. An otherwise unexplained drop in platelet count of 30% has been suggested as the threshold that should prompt discontinuation of heparin,80 although there are few data upon which to base this. Heparin-dependent IgG should be sought in the patient's serum, since a positive result may simplify management decisions. None of the available assays are fully sensitive, so a negative test is no guarantee against recurrent thrombocytopenia or thrombosis if the patient is rechallenged with heparin.
Low Molecular Weight Heparin
The promise of low molecular weight heparins (LMWHs) is a simple, once or twice daily therapy for venous thromboembolism that does not require monitoring of anticoagulant effect. As a class, the LMWHs encompass a number of fragments of unfractionated heparin which are on average 5000 da in molecular weight. The different LMWHs have been depolymerized by various means, and thus differ in their pharmacokinetic and pharmacodynamic properties.70 One LMWH may not be interchangeable with another. LMWHs achieve excellent bioavailability when given subcutaneously (about 90% of that achieved with an equal intravenous dose), have a long half-life (2 to 4.4 hours), correlate well between anticoagulant response and body weight, and have equal or better antithrombotic effects than unfractionated heparin. There have now been numerous trials comparing LMWHs (subcutaneously or intravenously) with unfractionated heparin in both DVT and PE.81–85 In an early meta-analysis pooling the results of over 2000 patients, LMWHs appeared superior with regard to venographic score improvement, recurrence rate of VTE, and hemorrhage. There is also a trend towards an all-cause mortality benefit for LMWHs.81 Similarly, a recent meta-analysis of LMWH compared to unfractionated heparin for the treatment of PE found non–statistically-significant decreases in recurrent symptomatic VTE, PE, and bleeding complications.86 With such data, groups such as the American College of Chest Physicians now recommend that clinicians use LMW heparin over unfractionated heparin.71
Aspects of caring for critically ill patients may limit the full implementation of such recommendations in the ICU. Many patients with critical illness have coincident renal failure, bleeding diatheses, or need for ongoing invasive procedures, all of which make unfractionated heparin, which can be quickly discontinued and rapidly cleared from the body, preferable. Conversely, certain situations appear to be ideally suited to the use of LMWH, such as in the long-term treatment of cancer patients with venous thromboembolism.87,88 As stated, the incidence of HIT is lower with LMWH than with unfractionated heparin, although in many trials of LMWH for DVT or PE, the incidence of HIT was sufficiently low in both arms to preclude a statistical comparison. In orthopedic and surgical studies as well as the initial industry-sponsored trials of various LMWHs, the incidence of HIT varied between 0% and 0.8% of patients, compared with approximately 3% of patients treated with unfractionated heparin.89 However, antibodies from patients with previous HIT cross-react with every commercially available LMWH, therefore LMWHs cannot be safely used in a patient known to have HIT.89
Neither heparin nor low molecular weight heparin can be used in patients with HIT; furthermore, no safe dosing regimen has been approved for LMWH in the presence of renal failure. Current alternatives to heparin include selective factor Xa inhibitors, direct thrombin inhibitors, and oral anticoagulants.
Direct thrombin inhibitors include the hirudin family, first isolated from leeches, and the argatroban family of active-site inhibitors. The advantage of such agents over unfractionated heparin is their ability to inhibit fibrin-bound thrombin with a predictable dose response, and their inability to produce HIT.70 Hirudin and its derivatives, especially lepirudin and bivalirudin, are potent anticoagulants which have been proven more effective than enoxaparin, a LMWH, in DVT prophylaxis of patients undergoing hip replacement.90 The risk of life-threatening bleeds appears to be equal between hirudin and heparin,90,91 although an increased risk of moderate bleeding was observed with hirudin.91 aPTT must be monitored with hirudin agents (goal aPTT = 1.5 to 2.5 times control). Dosages must be adjusted for renal insufficiency. The agents are approved for use in patients with HIT, but they have not been extensively studied in prospective comparison to heparin or LMWH in treatment of pulmonary embolism.
Additional direct thrombin inhibitors are the class represented by argatroban, melagatran, and the new oral agent ximelagatran. Argatroban is an effective anticoagulant in patients with HIT, and has been licensed for use in this capacity.70 Like the hirudins, argatroban has not been studied in any randomized trials in PE, but it appears to be as safe or safer than heparin when given to patients with myocardial infarcation.92 It is cleared principally by the biliary system and the dose needs no adjustment for renal failure. Monitoring of both the aPTT and the prothrombin time (PT) is recommended. Ximelagatran, an oral prodrug converted to melagatran, does not require monitoring. Having been proved favorable in preventing DVT following total knee replacement compared to both coumadin93 and enoxaparin,94 ximelagatran was tested for secondary prevention of DVT. In this study, the oral drug was compared to warfarin therapy for patients who had already received 6 months of oral anticoagulation with coumadin.95 Recurrent thromboembolism was significantly reduced in the ximelagatran group (2.8% vs. 12.6% in the warfarin group, p <0.001), with similar rates of major bleeding. Three cases of fatal pulmonary embolism were diagnosed in the warfarin group, compared to none in the ximelagatran group, though overall mortality was equivalent between groups. Ximelagatran has been shown to cause elevated liver aminotransferases, especially in the first 4 months of therapy; in this study, all cases of elevated alanine aminotransferase were transient, and no case (out of 600) progressed to hepatic failure.95
Among the newest of antithrombotic agents approved for the prophylaxis of DVT and pulmonary embolus is fondaparinux, a novel synthetic drug inhibiting factor Xa. By binding to antithrombin with tight affinity and inducing a conformational change, fondaparinux facilitates the binding of antithrombin with factor Xa, thus blocking the common pathway of coagulation.70 It has been approved by the FDA as a subcutaneous injection of 2.5 mg once daily for use in DVT and PE prophylaxis in patients undergoing orthopedic surgery for hip fracture, hip replacement, or knee replacement, after several randomized controlled trials found superior reduction of DVT for fondaparinux compared to enoxaparin.96 A study comparing fondaparinux and heparin for pulmonary embolism found the new agent to be as effective and safe as heparin, with a nonsignificant trend toward fewer recurrences of VTE in the fondaparinux group.97 Bleeding events were similar, and no difference in mortality was detected. HIT has not been observed with fondaparinux use. A number of additional anti–factor Xa agents are in development, but they have not yet been widely tested in humans. While fondaparinux shows promise in the acute treatment of PE, more studies are necessary before recommending that factor Xa inhibition replace our traditional anticoagulant strategies.
Warfarin anticoagulation should be instituted in the first few days (5 mg PO qhs for the first 2 days, then adjust the dose to achieve an International Normalized Ratio [INR] between 2.0 and 3.0) and continued to overlap with heparin therapy for at least 5 days. If the patient is clinically unstable or likely to require ongoing invasive procedures, heparin or a rapidly adjustable agent such as lepirudin or argatroban should be used preferentially, to facilitate rapid adjustment of anticoagulation if necessary.
Occasionally patients have compelling reasons that preclude anticoagulation, or continue to embolize despite adequate anticoagulation. As most thromboemboli originate in the legs, pelvis, or inferior vena cava (IVC),98 inferior vena caval interruption (VCI) has the potential to prevent subsequent embolization. Conventional indications for the use of VCI in patients with venous thromboembolism have included contraindications to anticoagulation, hemorrhage following anticoagulation, failure of anticoagulation to prevent recurrent embolization, and prophylaxis of extremely high-risk patients. Only one randomized prospective trial has evaluated using VCI to prevent PE.99 This trial randomized 400 patients with proximal DVT who were at risk for PE to receive a vena caval filter or standard anticoagulation. Over the first 12 days, the vena caval filter group had significantly fewer cases of PE (1.1% vs. 4.8%, p <0.03). However, over the subsequent 2 years, during which all patients were anticoagulated for at least 3 months, the rates of PE, major bleeding, and death were similar in both groups. Moreover, the vena caval filter group actually had a significantly higher rate of recurrent DVT, with a nearly twofold increase in odds ratio for DVT compared to the no-filter group. Thus VCI appeared to be a successful short-term strategy to prevent PE, but came at the expense of increased long-term DVT and a trend toward increased thromboembolic disease. This landmark study prompted widespread discussion on two fronts: whether anticoagulation should be considered for all patients receiving a vena caval filter, and whether a temporary or retrievable filter might be more successful.100 Unfortunately, no prospective trial evaluates either question. Progress has been made in the technology of retrievable filters, and small case series of several different types of temporary filters have been published.101,102 Whereas initially, temporary filters had to be removed within a 2-week period in order to minimize the risk of endothelialization, newer filters have been retrieved after up to 134 days without complication.101
As VCI devices have evolved, they have become smaller and more easily placed. As physicians have become more experienced with them, they have become safer as well, although published complication rates have varied widely, from 2% to 19%.101 Proposed indications for VCI continue to expand as the technology improves,100 yet caval filters are probably underutilized in the sickest patients. Those with critical cardiopulmonary compromise may be least able to tolerate the admittedly low risk of heparin failure. Patients who survive sublethal embolism but remain hemodynamically compromised may benefit from VCI since recurrent embolism, while unlikely, will be fatal. In addition, some patients have such a predictably high risk of venous thromboembolism that VCI may be indicated even before any thrombosis is detected. For example, we have placed caval filters prophylactically in patients with severe COPD and proximal venous thrombosis and in a woman with Crohn's disease complicated by toxic megacolon and ARDS on her way to the operating room. Additional potential indications include extensive free-floating vena caval thrombus (since the efficacy of heparin in this setting is controversial), pre–pulmonary embolectomy, and as primary treatment in patients with malignancy (since anticoagulants seem less effective and less safe in this setting). The advent of safe, effective retrievable filters may greatly expand our use of VCI.
Complications include filter fracture (occasionally with embolization of fragments), improper placement of the filter, venous thrombosis at the insertion site (seen in 8% to 25%103), caval occlusion (which is now far less common than when the Mobin-Uddin “umbrella” filters were in use), inadvertent dislodgment by guidewires during central venous catheterization, and erosion or perforation of the caval wall and other viscera. A final point about VCI is that while it prevents most recurrent emboli, it does not treat the (presumed) leg source. Therefore, when these devices are used, concomitant anticoagulation is necessary (unless the indication for VCI is contraindication to anticoagulation). The significance of upper extremity sources of thromboemboli in ICU patients, who often have central catheters, is unknown but probably small. Nevertheless, inferior VCI would clearly be ineffective so that when the clinical presentation suggests an upper source, due consideration should precede placement of this device. Filters have been placed in the superior vena cava and in the suprarenal IVC with apparent safety, but the experience is limited.
It has been clear for more than three decades that thrombolytic therapy more rapidly lyses pulmonary emboli and improves hemodynamics.104 However, 7 days after therapy, patients given thrombolytic therapy cannot be distinguished from those treated only with heparin on the basis of clinical findings or lung perfusion.105 Combined with the clearly increased risk and cost of thrombolytic agents, this has led to a general skepticism about the value of thrombolytic therapy for the treatment of PE. In a survey of pulmonary physicians, only 11% would give thrombolytic therapy for a large PE without hypotension, severe hypoxemia, or right ventricular strain.106 However, nearly all would give thrombolytics to a patient with shock due to PE, and there is now convincing data to support this approach. For example, when patients with massive PE were given alteplase (1 mg/kg over 1 hour) in an uncontrolled trial, there was significant clinical improvement in 11 of 15 with shock.107
In another study comparing alteplase (100 mg over 2 hours) and heparin, right ventricular function assessed echocardiographically improved more rapidly in patients given alteplase.108 This more rapid hemodynamic improvement could translate into improved survival in critically compromised patients. Furthermore, of the 55 patients treated with heparin alone, 5 suffered recurrence (2 fatal) within 14 days, whereas none of 46 patients given alteplase recurred. Finally, one very small (eight patients) randomized clinical trial comparing thrombolysis (streptokinase, 1,500,000 U over 1 hour) with heparin in patients with massive embolism and hypoperfusion showed a mortality benefit for thrombolytic therapy; all four patients receiving heparin alone died, while there were no deaths in the streptokinase group.109
Recently, the debate over thrombolytic therapy has moved from discussion of massive PE to that of submassive PE: PE which has not yet provoked hypotension, but for which the risk for death is high. Data from echocardiographic studies show an indisputably higher mortality in patients with moderate RV dysfunction.30 The utility of echocardiography in prognostication has led to great interest as to whether echocardiographic criteria should be used routinely to guide the use of thrombolytic therapy.110,111 Two studies address this question. In a retrospective cohort study of patients with radiographically large emboli and right ventricular dilation (but without hypotension or shock), those who received thrombolytic therapy had better pulmonary perfusion on day one, but this advantage disappeared by day seven.112 Mortality was 6% in the thrombolytic group compared to no deaths in the heparin group, and severe bleeding in the thrombolytic group approached 10%, with intracranial bleeds in 4% of patients. In a second, prospective study, patients with acute PE and right ventricular dysfunction (but without shock) were randomized to heparin plus alteplase or heparin plus placebo.113 While there was no difference in mortality between groups, the alteplase group had a significantly lower rate of treatment escalation, mostly consisting of secondary thrombolysis for worsened symptoms. No significant difference in bleeding was found between groups, which was surprising, as previous studies have never failed to show an increased risk of major hemorrhage with thrombolytic therapy compared to heparin. In a large prospective registry of over 2400 patients with PE, the rate of major hemorrhage in patients receiving thrombolytics was almost 22%, and intracranial bleeds were noted in 3%.114 The retrospective, nonrandomized nature of the first study raises concerns for its validity, but the latter has also been cited as potentially flawed in its design, both in its definition of “right heart dysfunction” and its use of secondary thrombolysis based on vague clinical criteria.115 As no mortality benefit has yet been established for patients with submassive PE who receive thrombolysis, we advocate restricting thrombolytic therapy for those patients with clinically apparent shock.
The optimal regimen for thrombolytic therapy has not been established. A number of approaches are listed in Table 27-6.104,107,109,116–118 There has been a general trend towards bolus, as opposed to long-duration, infusion, based on both animal studies and human trials in patients with myocardial infarction showing increased efficacy and reduced hemorrhage. Yet the increasing benefits of front-loaded regimens has a limit as demonstrated in a comparison of alteplase, 0.6 mg/kg (maximum dose = 50 mg) over 15 minutes versus 100 mg over 2 hours, in which there was no significant difference in efficacy or rate of hemorrhage.119–121 The particular thrombolytic agent is probably not of much importance. In a head-to-head comparison of alteplase (100 mg over 2 hours) and urokinase (1,000,000 U over 10 minutes followed by 2,000,000 over 110 minutes), the two regimens yielded similar efficacy and safety.122 A powerful case can be made that streptokinase is the agent of choice since it is the one agent for which a mortality benefit has been shown,109 and it is fourfold cheaper than any of the current alternatives. Careful attention should be given to selecting patients appropriately to reduce the rate of hemorrhagic complications (Table 27-7). Especially important is a concerted effort to avoid invasive procedures, including arterial blood gases, arterial catheters, central venous punctures, and pulmonary angiograms, where possible.123
Table 27–6. Alternative Thrombolytic Strategies in Acute Massive Pulmonary Embolism ||Download (.pdf)
Table 27–6. Alternative Thrombolytic Strategies in Acute Massive Pulmonary Embolism
Urokinase, 4400 U/kg bolus, followed by 4400 U/kg per hour for 24 hours104|
Urokinase, 1,000,000 U bolus over 10 minutes, followed by 2,000,000 U over 110 minutes116|
Urokinase, 15,000 U/kg bolus over 10 minutes117|
|rt-PA, 0.6 mg/kg bolus over 2–15 minutes118|
|rt-PA, 1 mg/kg over 10 minutes107|
|art-PA, 100 mg over 2 hours116|
Streptokinase, 1,500,000 U over 1 hour109|
Streptokinase, 250,000 U over 30 minutes, followed by 100,000 U/h for 24 hours|
Table 27–7. Contraindications to Thrombolytic Therapy ||Download (.pdf)
Table 27–7. Contraindications to Thrombolytic Therapy
- Recent puncture in a noncompressible site
- Active or recent internal bleeding
- Hemorrhagic diathesis
- Recent central nervous system surgery or active intracranial lesion
- Uncontrolled hypertension (BP >180/110 mm Hg)
- Known hypersensitivity, or for streptokinase, use of streptokinase within 6 months
- Diabetic hemorrhagic retinopathy
- Acute pericarditis
- Recent obstetric delivery
- History of stroke
- Trauma (including cardiopulmonary resuscitation) or major surgery within 10 days
- High likelihood of left heart thrombus
- Advanced age
- Liver disease
Various measures of the lytic state correlate poorly with both efficacy and incidence of bleeding, so that outside of clinical research protocols, routine monitoring is not indicated. When streptokinase is given, the manufacturer recommends that the thrombin time be assayed at 4 hours to ensure that a lytic state is achieved. An adequate lytic state can be assumed if the thrombin time is prolonged above the normal limits of the laboratory, or if the fibrinogen level is reduced. Clinical monitoring should include serial neurologic examinations to detect central nervous system hemorrhage and frequent vital signs to detect gastrointestinal or retroperitoneal hemorrhage. Patients who have undergone catheterization should have the groin puncture examined, and preferably have repeated measurements of thigh girth. Huge volumes of blood can be lost into the thigh and groin, especially in obese patients, with little external evidence of bleeding.
After the thrombolytic agent is discontinued, heparin is typically begun (without a bolus) when the thrombin time or the aPTT falls to less than 2 times control. Heparin is begun as an intravenous infusion at 1300 U/h and titrated to a PTT of 1.5 to 2.5 times control.
No advantage to infusing the thrombolytic agent directly into the pulmonary artery has been shown in controlled trials despite claims of benefit in small case series.124 Investigational approaches include pharmacomechanical thrombolysis125 and augmentation of cardiac output to enhance thrombolysis.126
Thrombolytic Therapy Following Surgery
Although recent surgery is generally included among the absolute contraindications to thrombolytic therapy, there is an evolving literature supporting its use. For example, 13 patients with angiographically confirmed embolism within 2 weeks of major surgery (mean = 9.6 days) were given a modified regimen of urokinase (2200 U/kg directly into the clot, followed by 2200 U/kg per hour for up to 24 hours).127 Complete lysis was achieved in all and there were no deaths or bleeding complications. In another report, two patients in shock due to PE were given bolus regimens of urokinase (1,200,000 U) or alteplase (40 mg, followed by another 40 mg over 1 hour) only 2 days after lung resection.128 There was prompt clinical improvement, although one patient had delayed hemorrhage. Finally, nine patients were treated with urokinase (1,000,000 U over 10 minutes, followed by 2,000,000 U over 110 minutes) following neurosurgery (mean = 19 days following surgery).129 All of the patients survived their acute episode of PE and no intracranial hemorrhage occurred, although one patient developed a subgaleal hematoma. These reports suggest that recent surgery is a relative, not an absolute, contraindication, and that the risks and benefits should be considered on an individual basis.
The greatest limitation of the thrombolytic drugs, and the factor which has limited their acceptance for the treatment of venous thromboembolism, is the consequential incidence of bleeding. In patients treated for pulmonary embolism the risk of major hemorrhage is reported to be around 15%,107 but these data were gathered in an era of frequent pulmonary angiography. As mentioned, intracranial bleeds have been observed in as many as 4.7% of patients,112 although larger series report a 3% incidence.114 When serious bleeding occurs, the lytic agent should be immediately discontinued, and reliable, multiple, large-bore catheters secured. Direct compression of bleeding vessels may stop or slow ongoing blood loss. If heparin has been given, it too should be stopped and consideration given to reversing heparinization with protamine. Most patients will be adequately managed without the transfusion of clotting factors. If it becomes necessary to reverse the lytic state, cryoprecipitate, which contains fibrinogen and factor VIII (both of which are consumed by plasmin) is the preferred blood product.130 The initial dose is 10 units, after which the fibrinogen level should be assayed. Fresh frozen plasma (as a source of factors V and VIII), platelets, and fibrinolytic drugs (e.g., epsilon aminocaproic acid 5 g over 30 minutes) all may play a role in the critically bleeding patient.
Allergic reactions, including skin rashes, fever, and hypotension are rare except with streptokinase. Mild reactions can be treated with antihistamines and acetaminophen. More severe reactions should prompt the addition of hydrocortisone. Hypotension usually responds to volume administration.
Fluid, Vasoactive Drugs, and Nitric Oxide
Volume administration with saline or colloid has generally been advocated in patients with PE and shock on the grounds that it will increase filling pressures and thereby augment Q̇t. However, in a patient with elevated right heart pressures and a grossly distended right ventricle, it is possible that further distention of the right ventricle during volume administration will increase myocardial oxygen consumption, yet fail to increase Q̇t and oxygen supply. In addition, to the extent that fluids increase right ventricular end-diastolic volume, the interventricular septum will bulge further to the left, impede left heart filling, and further compromise Q̇t. Experimental studies to determine the effect of fluids have shown a detrimental effect on hemodynamics.131 Therefore, volume administration should not be routine therapy unless the patient is clearly hypovolemic. When fluids are given, central venous catheterization (to measure venous oxyhemoglobin saturation and changes in right atrial pressure) and echocardiography may provide useful guidance. These issues are further discussed in Chapter 26.
There is also controversy regarding the use of vasoactive drugs to treat the hypoperfusion caused by PE. Successful use of vasoconstrictors, inotropes, and vasodilators has been reported. Since no controlled studies in patients have been performed, it is hard to give firm recommendations. However, the pathophysiology of this form of shock, the results of some animal experiments, and limited human data (all discussed in Chapter 26) provide some guidance. When any of these drugs are used, serial assessment of the effect of the intervention is mandatory. Any drug which does not result in the intended salutary effect should be discontinued promptly.
The vasoactive drug of choice, based on the largest published experience in patients, is dobutamine.132 Dobutamine is infused beginning at 5 μg/kg per minute and increased to effect. If dobutamine is ineffective or incompletely effective, norepinephrine should be tried. The rationale for the use of this vasoconstrictor is based on the assumption that right ventricular ischemia is the fundamental problem leading to shock. A vasoconstrictor that increases systemic arteriolar tone could raise aortic pressure and augment coronary blood flow, without increasing right ventricular load. In animal models of sublethal PE, norepinephrine was shown to be superior to no therapy, to volume administration, and to isoproterenol in the maintenance of cardiac output as well as in survival time.133 Infusion is initiated at 2 μg/min and adjusted (up to 30 μg/min) based on the hemodynamic response. In the clinical setting, hypoperfusion may have additional contributors such as left ventricular dysfunction or ischemic heart disease, so that a vasoconstrictor might be less beneficial than in controlled animal experiments. If dobutamine and norepinephrine fail to improve cardiac output, epinephrine may succeed.134 Finally, nitric oxide, which can lower the pulmonary artery pressure, boost cardiac output, and improve oxygenation, can be tried if available.135,136
Embolectomy and Mechanical Therapies
Surgical embolectomy is a major procedure rarely resorted to in most institutions. In part, this is related to the availability of other, more benign, therapies such as heparin and thrombolysis. Additionally, it takes time to organize a surgical team, operating room, cardiopulmonary bypass and so on, by which time the patient is often hemodynamically improved or moribund. Yet embolectomy has its advocates, who maintain that thrombolytic therapy is often contraindicated in patients who could benefit from it, the operative mortality for embolectomy is now acceptable, and chronic cor pulmonale can be averted.
In one institution's review of 87 patients with PE, 34 were treated with heparin, 28 with streptokinase, and 25 with embolectomy.137 Pretreatment embolic scores were most severe in the embolectomy group. Hospital mortality in the heparin, streptokinase, and surgery groups was 6%, 21%, and 20%, respectively. However, cumulative survival at 5 years was 68%, 64%, and 80%, a trend favoring embolectomy. However, most late deaths were due to malignancy, not recurrent PE or chronic pulmonary hypertension. Although the authors recommended surgical embolectomy for all patients with emboli in the main pulmonary arteries based on their results, regardless of the hemodynamic impact, this study was not randomized and the possibility seems large that the long-term benefit for embolectomy was related to selection of patients. A more recent trial showed that surgical embolectomy was comparable to thrombolytic therapy in patients with massive PE.138
Mortality due to embolectomy appears to be in the range of 30% to 40%, but may be as low as 8% in those who have not sustained cardiac arrest preoperatively.139,140 Even if this lower number reflects improvements in anesthetic or operative technique, this mortality is still comparable to that of patients with massive embolism treated less invasively.141 The argument that embolectomy might reduce the long-term consequences of chronic pulmonary hypertension lacks force, even though this complication is more common than previously thought.142 Thus it has never been demonstrated in a well-performed trial that embolectomy confers any advantage over thrombolytic therapy, or for that matter heparin. The population of patients who might benefit from embolectomy appears to be those who meet the following criteria: those with a hemodynamically significant embolism, in whom thrombolytic therapy is contraindicated; and in a center with a rapidly responding cardiopulmonary bypass team and a surgeon experienced in the technique of embolectomy.
Several new devices have been tested which aim to remove pulmonary emboli less invasively than the direct surgical approach. For example, a 10F suction catheter, inserted through a jugular or femoral venotomy and advanced into the pulmonary artery has been used to extract clot.143 Eleven of eighteen patients improved immediately. Suction embolectomy was more likely to be successful in patients treated promptly after hemodynamic deterioration. More recently, patients with shock underwent mechanical fragmentation of their massive PE with a rotational pigtail catheter, followed by thrombolytic therapy.144 Nine of ten patients survived, and 6 of the survivors achieved hemodynamic stability within 48 hours of the procedure. Alternative methods to re-establish pulmonary artery patency include endovascular stents,145 but experience with all of these techniques is limited.