This talk will incorporate epidemiology and risk factors, pathophysiology, diagnosis, risk stratification, treatment including anticoagulation, thrombolysis, and thrombolectomy, and recommendations for VTE prophylaxis. As part of the epidemiology, you'll see that VTE is the third most frequent cardiovascular disease. You can see the annual cases per 100,000 individuals there. This increases with age, and this can be a very expensive and morbid condition, not just in the United States, but around the world. I've tried to italicize those statements that may be important for your board exam. I have absolutely no role in creating board questions, but these seem to be important topics that may be asked. Risk factors for venous thromboembolism include multiple things, as you can see, including age, as well as the previous history of VTE, cancer, and recent surgery, as well as some of the other things that you are probably well aware of, including major trauma, pregnancy, certain types of medications, or hereditary diseases. In addition, it is associated with prolonged immobilization. So what about lower extremity deep vein thromboses? Many patients are asymptomatic, and it is often unilateral. The most common presenting signs and symptoms include swelling or edema, leg pain along the course of involved major veins, warmth, tenderness, and erythema, and often, not often, but you need to know about Hohmann's sign, but this can be unreliable, as often the patient will not demonstrate calf pain on passive dorsiflexion of the foot. One of the best ways to diagnose it is using the venous duplex ultrasound, and here are some examples you can see. Often there's a loss of compressibility, often associated with Doppler abnormalities, and this identifies DVT with a high degree of accuracy. Main reasons we worry about deep vein thromboses is the risk to potential pulmonary embolism. The pathophysiological response to PE can be due to the infarction, abnormal gas exchange that occurs that can lead to hypoxemia through VQ mismatch, intrapulmonary shunting, as well as hypercapnia and acidosis, unusual lessons of patient in shock. In addition, the patient can end up in cardiogenic shock and hypotension, which can be one of the most severe life-threatening issues from a pulmonary embolism. Pulmonary embolisms can be classified as low risk, which includes less than 1% mortality, intermediate risk or submassive, which has about a 3% to 15% mortality, and then a high-risk mass of PE, which has greater than a 15% mortality, and these have shock or persistent arterial hypotension. It's important to understand that RV failure is the primary cause of death in severe PE, and as you can see on the image here, it gives you an idea of how this happens, leading to increased RV afterload, which ends up eventually with death. Diagnostics. How can we diagnose it? Most patients have dyspnea, they're not intubated at the time, tachypnea. There can be pleuritic chest pain. You can find symptoms of DVT, but this is in less than 50% of patients. Sometimes patients will present with a cough or hemoptysis, but again, this is in less than half, and sometimes the patients, due to the symptoms, will have syncope. Chest radiographic findings can be normal up to about 25% of patients and can be very nonspecific. You can have anelectasis, or ankle opacities, an elevated hemidiaphragm, or what looks like a pleural effusion. That being said, there are certain things you can look for. Another example is Hampton's hump. And here you can see an example of Westermark sign with marked decreased vascularity. Importantly, the arterial blood gas can often have a normal O2 saturation. And interestingly enough, even though there can be BQ mismatch, there can be hypocapnia. So even though you would think the CO2 levels would go up due to BQ mismatch because of the hyperventilation, the patient can often present with a respiratory alkalosis. EKG findings are certainly something that could be asked on your boards or presented as part of a case presentation. The most common thing you will find is sinus tachycardia, but there can be nonspecific ST and T wave changes. A hypocapnia patient can have a new onset atrial arrhythmia and a new right bundle branch block. Of course, often we are tested on the BEGIN white sign, although this is infrequent with patients with a sign kind of like the Holman sign. It's there and it's true, but it's just not often seen. D-divers can also be very helpful. They've been known to have a high predictive value, so good for rule out, but a poor specificity. And part of the problem is it can be elevated in patients with cancer, pregnancy, advanced stage trauma, and recent surgery, which is frequently many of your patients in the ICU. Therefore, it really does have a better role in those patients that show up emergently in the emergency room who don't already necessarily have elevated levels of this sort of molecule. Our diagnostic modality of choice is CT pulmonary angiography, and here's an example of a massive PE that you can see on the right. What about sub-segmental PEs on CTA? It's still unclear what the clinical significance of these are. They can be present in 4.% of patients with pulmonary embolus imaged by single detector, and 0.4 with the more advanced scanners. Low predictive value and poor inter-observant agreement. Ventilation perfusion lung scans aren't used as much anymore, often frequently because the amount of time it takes to do in the patients, and often the caveat that it's not often diagnostic. That being said, you still need to know what they are. You know that a normal VQ scan essentially rules out a PE, but may only be diagnostic in 30% to 50% of cases. Echo findings can be somewhat helpful in a major PE. You might see a McConnell sign, which is RV dilatation and hypokinesis. You might see loss of inspiratory collapse in the IVC, pulmonary arterial dilatation, pericuspid regurgitation, right-sided thrombi, abnormal paroxysmal septum, or decreased left ventricular size with an increased RV to LV ratio. But to be clear, when you talk about the McConnell sign, if the patient isn't in shock, you need to sort of consider what you're seeing in relation to what the patient's symptoms are at the time. Here is an example of a normal right ventricle, and here's right ventricular dilatation on the right. And here again is another example that you might be able to find on Echo, as well as CT scan example. I won't go through this in detail, but here's an example of a diagnostic algorithm you can use for someone with suspected pulmonary embolism with shock or hypertension. And again, there are prognostic assessments. There's a Pulmonary Embolism Severity Index, known as SPESI. This includes giving points for a certain age, history of cancer, history of heart failure, chronic lung disease, significant tachycardia, lower blood pressure, systolic blood pressure, and desaturation. Other biomarkers that potentially can be used for QP include B-type natriuretic peptide or troponin IRT. But again, these can be quite nonspecific. They can be used to help predict mortality in some situations. What about management in the ICU? Of course, if the patient's in shock, you do your standard resuscitation. This would include use of fluid and vasoactive therapy to resolve the hypertension. Use of unfractionated heparin versus low molecular heparin as well can be used. In certain cases, empiric thrombolytic therapy would be involved. You can also use surgical or catheter-based thrombectomies. And in some situations, you will place an IVC filter. Again, here's another algorithm. This is for someone with a high-risk PE. Again, this includes hemodynamic support and considering fibrinolysis when necessary. So, what about initial therapy for pulmonary embolism? Consider anticoagulation therapy. So, for patients with objectively confirmed nonmassive PE, we recommend low moleculoid heparin, Fondoparanox, or IV unfiltered…unfractionated, excuse me, unfractionated heparin. And for patients with high clinical suspicion of PE, treat parentally while awaiting the outcome of a diagnostic test. So, for patients with sub-segmental PEs with no proximal leg DVT who have a low risk for recurrent VTE, clinical surveillance is considered over anticoagulation. And then, for patients with sub-segmental PEs and no proximal leg DVT with a high risk for recurrent VTE, anticoagulation is considered over clinical surveillance. What about…how do we do anticoagulation? Well, of course, there's unfractionated heparin where you level…you target a level of your PTT or your anti-10A levels. You can use therapeutic low-molecular weight heparins. Fondoparanox can also be used. And of course, direct thrombin inhibitors can be used as well as in the situation of heparin-induced thrombocytopenia. And then, of course, there's anticoagulation therapy for pulmonary embolism. And then, of course, there are oral anticoagulants. One of the complications of unfractionated heparin, bleeding can occur in 15 to 20 percent of patients, but it can be reversed with protamine. At least, unfractionated heparin can. And of course, there's heparin-induced thrombocytopenia, which can be an issue that goes beyond the scope of this talk. Just in general, though, for many ICU patients, when it is appropriate or safe, low-molecular weight heparin can be more cost-effective and induce less HIT in certain ICU populations than unfractionated heparin. But that is in regard to deep vein thrombosis prophylaxis and not specifically dealing with the risks and benefits of therapeutic low-molecular weight heparin versus unfractionated heparin for pulmonary embolism or anticoagulation for a DVT. Here's a list of the different types of low-molecular weight heparins. Your institution may use one or the other. And there can be some issues with low-molecular weight heparins that, if you can't get routine anti-factor XA levels, you may not be able to use it in certain situations when the patient is significantly obese or has renal failure. And it is a little bit harder to reverse with protamine. Again, here's a list of the direct oral anticoagulants that are on the market now. And how long do we do anticoagulation? Well, it depends. Three months for patients with a provoked pulmonary embolism or those with transient risk factors, such as major surgery or immobilization. Indefinite anticoagulation is recommended to those patients with an unprovoked pulmonary embolism or persistent risk factors. You can use a risk-assessment tube for venous thrombosis recurrence. That includes several scores, as you see there. And male sex in elevated D-dimer, either during or just after discontinuing therapeutic anticoagulation, is asserted with a higher risk of recurrent VTE, greater than 5% per year, and may necessitate ongoing treatment. Inferior vena cava filters, when we use them, when there's an absolute contraindication for or complication of anticoagulant therapy, recurrent pulmonary embolisms, despite adequate anticoagulation, and in almost all cases, retrievable is preferred over permanent IVC filters. Complications are not insignificant. This includes insertion site thrombosis, as well as recurrent DVTs or post-thrombotic syndrome. In addition, the filter can migrate or even potentially perforate the vein. In addition, there have been some studies. They've looked at the effect of retrievable and inferior vena cava filters, plus anticoagulation versus anticoagulation alone. They did not find a specific improvement in the primary outcome. However, their conclusions were that temporary placement of retrievable IVC filters should not routinely be performed, and IVC filters should generally be reserved for patients with contraindications to anticoagulation. What about when they look to see if IVC filters prevent pulmonary embolism? Going through a meta-analysis and a systematic review, the conclusions were they do reduce the risk of subsequent PE. They do increase the risk for DVT, but had no significant effect on overall mortality. So the ACCP recommendations for thrombolytic therapy, what we're looking at is a combination for thrombolytic therapy. What would those be? If you have an acute PE associated with hypotension and a low risk of bleeding, that would be a use. It is not recommended if the pulmonary embolism is not associated with hypotension, which again, if you're looking at a patient with your echo and you see a McConnell sign, please consider whether it's the appropriate situation for the patient being in shock and it makes sense from a clinical standpoint. More rapid resolution of radiographic and hemodynamic abnormalities than AC. Multiplase, you can use 100 milligrams, IV over two hours, and a half-dose TPA. A similar mortality and rates of major bleeding versus full dose, but with more treatment escalation required. Here's a study that can discuss the fibrinolysis for patients with intermediate risk PE. To be clear, this therapy prevented hemodynamic decompensation, but did increase the risk of major hemorrhage and stroke. So, one has to be careful before empirically giving thrombolytics. Here's an example that may show up on your boards. Again, phlegmasia serrala dolens. What about catheter-directed thrombolysis? This is used in patients with a risk of bleeding with systemic lysis, although the data on showing catheter-directed for systemic lysis isn't necessarily demonstrating improved results quite yet, although with improved technology, this may change. This can also be helpful with patients with massive iliofemoral DVT, or as you just saw, phlegmasia serrala dolens with symptoms for less than 14 days and good functional status. Patients with acute PE associated with hypotension and a high-bleeding-risk failed systemic thrombolysis or shock likely to cause death before systemic thrombolysis can take place, e.g. within hours, may be appropriate for catheter-directed thrombolysis. You also have to have the appropriate expertise and resources to be able to conduct this in patients. What about some of the trials for catheter-directed thrombolysis for PE? The ultimate trial showed at 24 hours, compared to conventional anticoagulation, there was a result in improved RV to LV ratios, suggesting a hemodynamic benefit, but at 90 days, there was no difference in mortality or major bleeding. And in the Seattle 2 trial, they had similar results using either method. What about using pharmacomechanical catheters? Studies have not, to this date, demonstrated improved results. And there have been studies that review ultrasound-accelerated catheter-directed thrombolysis in the treatment of DVTs. At this point, the data does not necessarily demonstrate that this can be recommended as therapy. So this is very important and could potentially be on a board exam. What are the major contraindications to thrombolysis? Known structural cerebrovascular lesion or neoplasm, previous intracranial hemorrhage, ischemic stroke within the last three months, active bleeding, recent brain or spine surgery, recent head trauma with fracture or brain injury, and a bleeding diaphysis. Relative contraindications can also include hypertension, so systolic blood pressure greater than 180 or diastolic blood pressure greater than 110, recent non-intracranial bleeding, recent surgery, recent invasive procedures, pregnancy, age greater than 75, or a patient on VKA therapy. People are trying, again, different percutaneous catheter approaches. These are patients with an absolute contraindication to thrombolysis. You can use different types of devices to try and work towards having the thrombectomy. What about surgical thrombectomy indications? You can still do it for massive PE, shock despite heparin resuscitation, and a failure of thrombolytic therapy or contraindication to its use. However, long-term outcomes and short-term outcomes from this procedure are still somewhat suboptimal. Somewhat suboptimal. What are the critical care recommendations for VTE prophylaxis? For ICU patients at high risk for bleeding, you should use mechanical prophylaxis or IPC at least until the bleeding risk decreases. When the high bleeding risk decreases, pharmacologic prophylaxis substituted or added to mechanical prophylaxis should occur. In the PREVENT trial, there's still some concern as to whether actual pneumatic, intermittent pneumatic compressing devices actually add any benefit to just chemical prophylaxis with either low-moleculoid heparin or unfractionated heparin, although there were some issues kind of with that study. Overall, going by the American Society of Hematology 2018 guidelines, if you compare low-moleculoid heparin versus unfractionated heparin, that when possible or safe for the patient, that low-moleculoid heparin or fondoparanox would be potentially superior to unfractionated heparin. What about with COVID-19? There was some initial buzz about using therapeutic dosing to help these patients with their pathology. However, that data has not turned out to be helpful or appropriate for patients. Therefore, at this time, for patients with COVID-19, empiric therapeutic-level anticoagulation or even intermediate intensity is not recommended over prophylactic intensity VTE prophylaxis. So again, to summarize for VTE, have a high suspicion of PE in patients with the risk factors and new or worse dyspnea, chest pain, or hypertension without an obvious cause, anticoagulation is appropriate for most patients in these situations. Thrombolytic therapy prevents hemodynamic decompensation and intermediate risk PE, but is associated with increased risk of major hemorrhage and stroke, and therefore that needs to be taken into consideration for delivering the dose. And again, IVC filter placements only when anticoagulation is contraindicated, catheter-based therapies may be promising in the future as the technology gets better, and VTE prophylaxis should be strongly considered in all ICU patients.

venous thromboembolism

risk factors

diagnosis

treatment options

prophylaxis

management strategies