Hi, this is Steve Pastoris from Memorial Sloan Kettering Cancer Center in New York City. And for this multi-professional critical care review course for adults, I'm going to talk about venous thromboembolism. My objectives are to describe the epidemiology and risk factors for VTE, understand the pathophysiology, diagnosis, and risk stratification of pulmonary embolism, and recognize the treatment approaches including anticoagulation, thrombolytic therapy, and catheter-directed therapies, and conclude with the importance of thromboprophylaxis in critically ill patients. Venous thromboembolism, which generally consists of deep venous thrombosis, DVT, or pulmonary embolism, PE, is the third most frequent acute cardiovascular syndrome. Approximately 370,000 symptomatic PE cases occur annually in the United States, associated with a mortality rate that ranges from 60 to 100,000 deaths per year. Treatment of VTE is expensive and has been estimated to be anywhere between $7 to $10 billion a year. There are many risk factors for VTE. Important ones include prior history of VTE, presence of cancer, recent surgery, the older populations are at high risk, those who have sustained major trauma, prolonged immobilization, who are in the ICU and prolonged mechanical ventilation, have central venous catheters, are sedated or paralyzed, and other patient populations that are high risk are those who are pregnant or postpartum, those receiving oral contraceptives, who have hereditary deficiencies of factor V Leiden or protrombin gene mutation, and those with comorbidities such as chronic lung or kidney disease, heart failure, and obesity. Lower extremity DVT is usually unilateral. Many patients are asymptomatic. Presenting signs most commonly are swelling or edema, leg pain along the course of the involved vein, warmth, tenderness, and erythema may be present. The presence of calf pain or passive dorsiflexion of the foot or the classic Holman sign is actually unreliable as a finding for lower extremity DVT. And one of the best ways to diagnose DVT is the use of venous duplex ultrasound. The loss of compressibility associated with Doppler abnormalities on venous duplex ultrasound usually identifies DVT with a very high degree of accuracy. Turning over to pulmonary embolism, this can be manifested by pulmonary infarction, abnormal gas exchange, so patients can be hypoxemic, usually from ventilation perfusion mismatch, and more severe cases from intrapulmonary shunting. Hypercapnia and acidosis are unusual unless the patients with PE are in shock. And of course, those who have cardiovascular compromise will manifest with hypotension. Right ventricular failure is the primary cause of death in patients with severe PE. PE is classified as low risk, intermediate risk, or high risk. Intermediate risk, previously known as submassive PE, can be associated with 3% to 15% mortality whereas high risk, previously known as massive PE, is commonly associated with mortality rates greater than 15%. These are patients who present with PE and shock or persistent arterial hypotension. PE diagnostics in terms of clinical manifestations from Biobed 2, dyspnea was present in 80% of patients, tachypnea, pleuritic chest pain as well. Legedema, erythema, tenderness at papal book cord, uncommon, less than 50%. Similarly, cough, hemoptysis, less than 50%. Syncope is an important clinical presentation or finding because it usually connotes a poor prognostic factor for pulmonary embolism. On chest X-ray, findings may be normal in up to 25% of cases. But when a finding is found on chest X-ray, it's usually either atelectasis, an isolated parenchymal opacity, or elevated hemidiaphragm, or pleural effusion. And then there are uncommon chest radiographic findings that are typically classic, such as the Hampton hump, which is a wedge-shaped opacity seen laterally. It's a rare sign of pulmonary infarction along the pleural surfaces. And the other uncommon sign is the Westermark sign, which is depicted by a sharp cutoff of the pulmonary vessel with distal hypoperfusion in a segment within the lung. On arterial blood gases, up to 40% of patients with PE will have a normal oxygen saturation. Patients are typically hyperventilating with respiratory alkalosis, and hypocapnea is common. On ECG, sinus tachycardia is the most common finding. You can also see nonspecific SD and T-wave changes, occasionally new arrhythmias such as atrial fibrillation or right bundle branch block may be present. An uncommon finding is the S1Q3D3 pattern on ECG, or the McGill-White sign as shown on the ECG on this slide. What about D-dimer? D-dimer has a very high negative predictive value. It's good to rule out pulmonary embolism or DVT. However, it has poor specificity in that it has a low positive predictive value. D-dimer is commonly elevated in patients with cancer, pregnancy, advanced age, those who sustain major trauma, or recent major surgery. What about the finding of subsegmental PE on CT angiography? Well, the clinical significance of isolated subsegmental PE has been questionable. You can see it in about 5% of patients with PE with single detector CTAs and up to nearly 10% in those with multi-phase CT scans. It has a low positive predictive value and a poor inter-observer agreement when you see this finding. A V-Q lung scan may be desirable in centers that do not have a multi-detector CT. Patients also with renal failure or contrast task allergy will be more suitable for V-Q lung scanning. A normal V-Q scan essentially rules out PE with a negative predictive value of 97%. A high probability scan, on the other hand, has a positive predictive value approaching 90%. The major caveat with V-Q lung scanning is that it is diagnostic in only 30% to 50% of patients. In echocardiography, we can find right ventricular dilatation or enlargement as shown on the slide here. There can be hypokinesis of the RV, loss of inspiratory collapse of the IVC, dilated pulmonary artery, significant tricuspid regurgitation. Even the presence of thrombi in the right atrium or right ventricle may be found. There's abnormal paradoxical motion of the septum, and there's a decrease in LV size and an increase in the RV-LV ratio. In terms of prognostic assessment, one of the more commonly used prognostic scoring is the PESI, pulmonary embolism severity index, where a point is assigned for each of the following, age over 80, history of cancer or history of heart failure or chronic lung disease, heart rate over 110 beats per minute, systolic blood pressure under 100, and an oxygen saturation of less than 90% on room air. What about biomarkers, such as B-natoric peptide and troponin I or T? These markers increase with RV dysfunction, and both BNP and troponins can be elevated and associated with high mortality, as has been shown in unselected patients as well as in hemodynamically stable patients. There have been at least three practice guidelines for VTE from the European Society of Cardiology, from the American Society of Hematology, and most recently, the antithrombotic therapy for VTE guideline from CHESS in 2021. Shown here is a risk-adjusted management strategy for acute PE, so in patients where PE has been diagnosed, you need to classify them into low-risk, intermediate-risk, or high-risk PE. For those with high-risk PE, immediate reperfusion therapy is indicated, and for those with intermediate-risk PE, they usually will require admission to the hospital, close monitoring of vital signs, and administration of anticoagulation therapy, such as with low molecular weight heparin. Inotropic support, in addition to fibrinitic therapy, is indicated for patients with high-risk PE. Caution on fluid expansion in these patients, if they have right ventricular dilatation or dysfunction on echocardiography. Patients that are hypotensive will require vasopressor therapy. Norepinephrine is commonly used, along with dobutamine, for inotropic support. You want to avoid intubation and mechanical ventilation, if possible, but if you're not able to avoid it, then you have to limit the tidal volume and plateau pressure, just like we do in patients with ARDS, and try to avoid adding PEEP, because it may increase the pulmonary pressures and increase the right ventricular afterload, which can be detrimental in patients that are already exhibiting right ventricular dysfunction or failure. In select situations with high-risk PE, there may be an indication to use VA ECMO. In terms of management, anticoagulation therapy is the mainstay. Importantly, for patients who have a high clinical suspicion for PE, you have to treat with anticoagulation while waiting for the outcome of your diagnostic testing. For those with objectively confirmed non-massive PE, direct oral anticoagulants, low molecular weight heparins, and fundoparanox are favored over unfractionated heparin in those with hemodynamically stable pulmonary embolism. However, in hemodynamically unstable PE, patients with severe renal failure with threatening clearance less than 30, morbidly obese patients, and those patients with PE and extensive clot burden in the lungs, unfractionated heparin is favored over low molecular weight heparin. What about those with subsegmental PE? For those with subsegmental PE with no evidence of proximal leg DVT on leg ultrasonography and have a low risk for recurrence of VTE, clinical surveillance is recommended over anticoagulation. However, for those with subsegmental PE and no proximal leg DVT who have a high risk for recurrence of VTE, anticoagulation is favored over clinical surveillance. In terms of anticoagulation therapy, if you're using unfractionated heparin, your goal is to achieve an anti-factor 10A level somewhere between 0.3 to 0.7 units per ml, or 1.5 to 2 times the APTT control level. There are many low molecular weight heparins that are available. Enoxaparin is the most commonly used. Zeparinox, which is an anti-factor 10A inhibitor, may also be used, as well as direct thrombin inhibitors like argatroban and dabigatran, and of course, Doax, your direct oral anticoagulants with rivaroxaban and epixaban most commonly used in the United States. Vitamin K antagonists are favored over direct oral anticoagulants in patients with advanced kidney or liver disease, as well as in patients with triple positive antiphospholipid syndrome and those with a history of arterial thrombosis. Both vitamin K antagonists like warfarin and direct oral anticoagulants are best avoided in pregnancy situations. Bleeding and heparin-induced thrombocytopenia are known complications of unfractionated heparin. Bleeding can occur in 5 to 20% of cases that correlates generally with the higher intensity of anticoagulation. Fortunately, there's protamine that can reverse unfractionated heparin. HIT, which can occur in up to 5% of patients receiving unfractionated heparin, puts them at risk for venous and arterial thrombosis. This is an IgG heparin-plated factor 4 immune complex syndrome, and the treatment in patients with HIT and thrombosis is, of course, to remove or discontinue all forms of heparin and administer a non-heparin anticoagulant like argatroban. In ICU patients, we try to use a lower infusion rate of 0.2 to 0.5 micrograms per kilogram per minute. Other agents that can be used for HIT include bivarioludin, fundoparanox, and Doex. In terms of low molecular weight heparins, the advantages are that they have greater anti-factor 10A activity and less factor 2A activity. Noxaparin, the dose of 1 mg per kilogram every 12 hours or 1.5 mg per kilogram once daily, is a very common regimen. There are issues with monitoring and dosing that you need to know about low molecular weight heparins. Routine anti-factor 10A levels are not indicated. You have to be cautious in those who are morbidly obese, in those with renal failure with creatinine clearance less than 30, where you need to avoid the use of low molecular weight heparin. Unlike unfractionated heparin, there is less protein reversal with low molecular weight heparins. In terms of duration of anticoagulation, three months is the most common duration of anticoagulation for patients with provoked PE or those with transient risk factors such as major surgery or immobilization. Beyond three months, or so-called extended phase anticoagulation, this is recommended in patients with unprovoked PE or provoked by a persistent risk factor. In these patients, a reduced dose of a DOAC, whether it's apixaban or rivaroxaban, is favored over full dose DOAC. There are risk assessment tools to determine which patients are going to be at higher risk for VTE recurrence, such as the HERDU, DASH, and Vienna prediction models. Interestingly, male and patients with elevated D-dimer, either during or just after discontinuation of therapeutic anticoagulation at three months, are associated with a higher risk of recurrent VTE, and these patients will require ongoing treatment. What about IVC filters? They are only indicated in those with absolute contraindication for, or have a complication following anticoagulant therapy. Patients with recurrent PE, despite adequate anticoagulation, may also be indicated for IVC filter placement. Nowadays, more retrievable rather than permanent IVC filters are placed that can be removed within three to five months after their insertion, once the reason for not being able to get anticoagulation has already been taken care of. Complications from IVC filters include thrombosis at the insertion site, and late complications can include recurrent DVT up to 20% and debilitating post-thrombotic syndrome, as well as migration or perforation of the filter. In a study looking at IVC filter plus anticoagulation versus anticoagulation alone, in almost 400 patients with acute PE and high risk of recurrence because of elderly age, active malignancy, or RV dysfunction, the investigators found no difference in the outcome of recurrent symptomatic PE at three months and at six months. They concluded from this trial that the temporary placement of a retrievable IVC filter should not be routinely performed, and they should only be reserved for patients who have a contraindication to anticoagulation therapy. In a systematic review and meta-analysis of 11 studies, including six RCTs and five observational studies, where the quality of the evidence for the RCTs was low to moderate, the authors found that IVC filters reduced the risk of subsequent PE. However, they did increase the risk for DVT and overall had no significant effect on mortality. What about thrombolytic therapy? Thrombolytic therapy is indicated for patients with acute PE associated with hypotension, i.e., systolic blood pressure less than 90, who have a low bleeding risk. Thrombolytic therapy is not recommended in patients with acute PE who are not hypotensive. Thrombolytic therapy is associated with more rapid resolution of radiographic and hemodynamic abnormalities than anticoagulation therapy. The most common regimen and agent is alteplase, given at 100 milligrams IV over two hours, or alteplase 0.6 milligram per kilogram, or single-dose weight-based enecteplase. Half-dose TPA, 50 milligrams, has also been shown in a fewer number of studies to have similar mortality and rates of major bleeding versus the full-dose TPA, but more treatment escalation, such as requiring four pressers or invasive mechanical inhalation, has been found when using half-dose TPA. An important study was the PITO study of pulmonary embolism thrombolysis, where about 1,000 patients were enrolled who had normal blood pressure and both right ventricular dilation and increased droponin. So, these were patients with intermediate risk PE. When they looked at the results, they found a 2.6 percent death or hemodynamic decompensation rate with tenecteplase versus 5.6 percent in placebo. So, lower mortality and lower hemodynamic decompensation with tenecteplase. However, the tradeoff was an increase in the risk of major hemorrhage, 6.3 with tenecteplase versus 1.2 without tenecteplase, as well as with stroke being at risk, 2.4 percent with tenecteplase versus 0.2 percent in the placebo group. More recently, catheter-directed thrombolysis have become in vogue. These are indicated for patients with high risk of bleeding with systemic lytic therapy, those with massive iliofemoral DVT, or blue leg syndrome, or plagmassia coerulea dolens, with symptoms for less than 14 days and who have otherwise good functional status. Patients with acute PE associated with hypotension and high bleeding risk fail systemic thrombolysis. Those in shock likely to cause death before systemic lytic therapy can take effect. And those centers with appropriate expertise and resources certainly are situations where catheter-directed thrombolysis should be strongly considered. There were two studies that looked at catheter-directed ultrasound-assisted lytic therapy for PE, a relatively small study. One, the Ultima had 59 patients, a Seattle 2 had 150 patients with acute massive or submassive PE, where they compared ultrasound-assisted thrombolytic therapy followed by IV heparin versus IV heparin alone. High-frequency ultrasound was combined with 10 to 20 milligrams of TPA that was infused over 15 hours. And both studies had similar results that indicated that in patients who receive ultrasound-assisted thrombolysis, in addition to heparin, had improved RV to LV ratio, suggesting hemodynamic benefit over the patients that just had anticoagulation therapy. But at 90 days, there was no difference in mortality or major bleeding between the two groups. An important study for catheter-directed thrombolysis was conducted in 2015 to 2017 in 692 patients with acute proximal DVT, where they compared anticoagulation alone versus anticoagulation plus pharmacomechanical thrombolysis, either catheter-mediated or device-mediated delivery of TPA and thrombus aspiration or maceration with or without stenting. Their primary outcome was looking at the development of post-thrombotic syndrome, which I mentioned is a very debilitating problem in patients with DVT. And they looked at the development of PTS between 6 and 24 months of follow-up. They showed in this study that the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of post-thrombotic syndrome, but carried a higher risk of major bleeding, 1.7% versus 0.3%, and that was clinically statistically significant. However, the severity of post-thrombotic syndrome was lower in the patients that were randomized to the catheter-directed thrombolytic therapy. In a systematic review of 16 studies of ultrasound-assisted catheter-directed thrombolysis, unfortunately, only one RCT was available. The use of ultrasound catheter-directed thrombolysis was performed 548 times in 512 patients. Substantial lysis over 50% was achieved in about 3 quarters to 100% of the patients. They concluded from the systematic review that ultrasound-assisted catheter-directed thrombolysis appeared to be safe with no reported procedure-related PE and only one procedure-related death. Bleeding events occurred in 14 of the 16 studies. About 4% were major bleeding. Post-thrombotic syndrome was observed in about 17%, and they concluded that the existing evidence is currently inadequate to make ultrasound catheter-directed therapy as the first choice for deep venous thrombosis treatment. We need to know the major contraindications to thrombolysis, including known structural cerebral vascular lesion or tumor, previous intracranial hemorrhage, ischemic stroke within the last three months, active bleeding, recent brain or spinal surgery, recent head trauma with fracture or brain injury, and, of course, bleeding diathesis patients. Relative contraindications may include systolic blood pressure over 180, recent bleeding that's not intracranial, recent surgery or invasive procedure, pregnancy, age over 75, and those on vitamin K antagonist therapy. What about percutaneous catheter-directed approaches? These are indicated for patients with absolute contraindication to thrombolysis. Options include fragmentation of the thrombus with a pigtail or balloon catheter, rheolytic thrombectomy with hydrodynamic catheter devices, as shown in the picture on the slide, suction thrombectomy with aspiration catheters, and rotational thrombectomy. Surgical thrombectomy may be indicated in those with massive PE, those who are in shock despite heparin and other resuscitative measures, those patients who have failed thrombolytic therapy or are contraindicated to receive thrombolytic therapy, and more recent experience appears to suggest that combining ECMO with surgical embolectomy, especially in those with high-risk PE, with or without need for cardiopulmonary resuscitation, has shown to be beneficial as well. Finally, for prophylaxis, for ICU patients at high risk of bleeding, mechanical compression devices such as compression stockings and or intermittent pneumatic compressions, at least until the bleeding risk decreases, is indicated. And when the high bleeding risk decreases, pharmacologic thromboprophylaxis should be used in place of mechanical prophylaxis or added to it if appropriate, and low molecular weight heparin or fundoparanox is favored for prophylaxis over unfractionated heparin. The PREVENT trial was a trial of about 2,000 critically ill patients, 80% of them were in medical ICUs, and they were looking at the addition of pneumatic compression devices for at least 18 hours per day added to unfractionated heparin or low molecular heparin. And what they found was that the addition of pneumatic compression did not reduce the rate of ultrasound-detected DVT or the symptomatic PE cases or death from any cause. However, the incidence of DTE was lower than expected in the control group, thereby reducing the power of the PREVENT trial to detect a real difference between the two groups. The ASH, the American Society of Hematology, guidelines for patients with COVID-19 suggest prophylactic intensity over intermediate dose or therapeutic dose anticoagulation for patients with COVID-19-related critical illness who do not have suspected or confirmed DTE. Similarly, they recommend prophylactic dose anticoagulation over intermediate or therapeutic dose anticoagulation for those with COVID-19 acute illness, not critically ill, who do not have suspected or confirmed DTE. Both of these recommendations were conditional. Finally, let's talk about pulmonary embolism response teams. These have been very popular over the last many years. In a recent systematic review and meta-analysis, the authors showed that with the involvement of a pulmonary embolism response team, there was a greater use of catheter-directed interventions, as well as systemic thrombolysis and use of IVC filters as compared to the control group where the PERT team was not available. In summary, a high suspicion for pulmonary embolism should be maintained in patients with risk factors for PE and new or worsening dyspnea, chest pain, or hypotension without obvious cause. In most patients, anticoagulation is appropriate. Thrombolytic therapy should be able to be used in patients with PE who are hypotensive. It does reduce hemodynamic decompensation in those with intermediate risk PE, but in these patients, thrombolytic therapy can be associated with an increased risk of major hemorrhage and stroke, and risk-benefit discussions, therefore, have to be undertaken with patients with PE that is in the submassive or intermediate risk category. IVC filter should only be placed when anticoagulation is contraindicated, and more recently, catheter-based therapies have excellent outcomes in high-risk and moderate-risk PE candidates. VTE prophylaxis should be strongly considered in all ICU patients, and the presence of multidisciplinary PERT teams can provide rapid, individualized, and expert-based care and potential benefit for patients suspected or who have documented PE. Thank you very much for your attention.

venous thromboembolism

pulmonary embolism

anticoagulation

thrombolysis

diagnostic techniques

risk factors

thromboprophylaxis