SCCM Resource Library-Current and Future Practice in Pediatric Thrombosis

Video Transcription

Good morning, or afternoon, as the case may be. I want to welcome you to the session on the current and future practice in pediatric thrombosis.  I'm Bob Parker, Professor Emeritus of Pediatric Hematology from the Renaissance School of Medicine at SUNY Stony Brook, and I will be your moderator.  Critically ill children have been well recognized to have an increased risk of hemostatic imbalance manifest by excessive bleeding, unwanted thrombosis, or at times both.  However, there is no consensus on how to identify those children at risk, how to intervene, or even how to define what constitutes a clinically relevant event.  This session will focus on some of the important aspects of these questions. Today we have three excellent and experienced speakers who have been active investigators in this arena.  Vince Faustino from Yale will speak on clinical trials in pediatric hemostasis. Marianne Ellis from Cornell will present information regarding the assessment and management of  bleeding in critically ill children, and Sheila Hansen from the Medical College of Wisconsin will speak on the assessment, measurement, and treatment of thrombosis in pediatrics.  I look forward to an educational session with a lively Q&A to follow our last talk. I will ask Vince to start off the morning. Thank you. Thanks, everyone.  I would like to first and foremost thank the organizers for inviting me to talk about clinical  trials in pediatric hemostasis and anticoagulation, how they apply trial results in my practice. I have a couple of disclosures which funded my ongoing research work.  I have two learning objectives for today. The first is to review and interpret data from recent pediatric clinical trials in anticoagulation  and apply it to current pediatric ICU and pediatric cardiac ICU care. Towards the end, I will briefly discuss the data and potential future uses of direct oral  anticoagulants in children. It's been almost a decade now since Dr. Raffini from CHOP presented this data on the incidence of VTE or venous thromboembolism in hospitalized children.  In her study, she showed that in the early 2000s that the risk of VTE or the rate of VTE increased by 70% over almost a decade.  Since then, the Solutions for Patient Safety have incorporated the prevention of VTE as one of their key projects.  As you can see on the figure on the right, the rate of VTE has been stagnant. It's basically the same for the past number of years.  The risk of VTE in this pediatric population has increased or stabilized over the last two decades.  There are a number of reviews, including ours, that looked into the epidemiology of pediatric venous thromboembolism.  For the purpose of this presentation, I'm only going to focus on the presence of central venous catheter, critical illness, and infants.  CVC and critical illness each double the risk of DVT. More than 85% of DVT in children are from central venous catheters, and nearly all DVT-related  deaths occur in the presence of a central venous catheter.  The risk of VTE in children is bimodal. It's highest in infants and in the adolescent age group, but the risk in infants can be as high as 72%.  Because of the risk of VTE in the presence of central venous catheter, most of the prior trials have focused on catheter-associated DVT or CADVT.  In a systematic review we performed a couple of years ago, we showed that none of these trials showed an improvement or a reduction in the risk of catheter-associated DVT.  Some of the interventions that have been tested were heparin-bonded central venous catheter and fractionated heparin and low molecular weight heparin and antithrombin.  We identified two major reasons for failure to demonstrate efficacy. First is a delay in starting intervention, and second is we don't know the correct dose of anticoagulation.  So to address these two issues, we recently completed a pre-trial. But before I discuss the pre-trial, I just want to go over this sort of complex slide.  So this is a Kaplan-Meier graph showing the risk of DVT or catheter-associated DVT at different days after its insertion.  As the graph shows, by day 4 after insertion of the central line, most of the DVT would have already occurred.  However, within the first 24 hours after insertion of the catheter, the risk is pretty low and less than 2.5%.  In a prior trial of using Reviparin, which is a low molecular weight heparin, they failed to show benefit against catheter-associated DVT with a risk ratio of 1.17.  It has to be noted that the anti-TAN-A level that they reached was only 0.1 international units per mL.  In the pre-trial, we used prophylactic dosing of enoxaparin, targeting it at 0.2 to 0.5 IU per mL.  What we've shown is that if you start prophylactic dosing within the first 24 hours after insertion of the central line, then potentially you can reduce the risk of CA-DVT to 0.55.  However, it's a small randomized clinical trial, thus the credible interval is wide and included who won. So this was very exciting data that we got from this initial trial.  However, when we separated infants, meaning less than 1 year old, and older children more than 1 year old, what we saw was that the risk of DVT with prophylaxis was completely  different. So what do I mean? If you look at the distribution of the risk distribution with prophylaxis, for infants the risk ratio is 1, meaning there's no effect.  However, for older children, the risk of DVT with prophylaxis was 0.24. So there's around 75% reduction in the risk of DVT. So the question we ask is, why was this so?  So we looked at pharmacokinetics. So what we've shown that the start of prophylaxis was almost exactly the same for infants and  older children, as shown in the Kaplan-Meier graph here.  Then we achieved an anti-TNA level of more than 0.2, almost at similar time between infants and children. So we don't think it's the kinetics that's the problem.  We looked at the relationship between the size of the central venous catheter and the veins. So a number of groups have advocated using a CVC to vein ratio of less than 0.5.  But what we've shown is that there's no difference in the CVC to vein ratio between infants and older children, as shown in the figure on the right upper figure.  There may be some difference in the difference, the absolute difference in the size of the CVC compared with the vein, such that the difference is smaller in infants.  So that means the central venous catheter occupies a bigger part of the central vein. So there's some statistical significance there.  So maybe that's one of the factors affecting it. But we found other interesting stuff. So we looked at different markers of thrombin generation.  So we included endogenous thrombin potential, which is measured from a thrombin generation assay. We looked at factor VIII activity, and then we looked at D-dimer.  So for all these markers of thrombin generation, we noted that the levels were lower in infants compared to the older children.  So that's sort of counter-intuitive. I mean, they have lower thrombin generation, and yet at the same time, they have a higher risk of DVT with prophylaxis.  It was the other way around for platelets. The platelet counts for infants were higher than older children.  So when we looked at the association with prophylaxis with enoxaparin between thrombin generation as measured by factor VIII activity and platelet count, what we showed is if your  factor VIII activity is low, then the risk of DVT with prophylaxis is 1 or 10 to the 0. So that means there's no effect.  However, as your factor VIII activity increases, then the risk of DVT decreases. So that means it's more effective when there's higher thrombin generation.  So that sort of explains the finding that we were seeing from the CRIT trial. So there's less thrombin generation in infants, and therefore prophylaxis is less effective.  But we found the opposite finding for platelets. So if your platelets are high, then enoxaparin has less effect, and again this is consistent with what we've seen in infants.  So the question now is can you use a higher dose of enoxaparin, and this may probably be true because in cardiac patients who are mostly less than 1 year old, they use therapeutic  enoxaparin as prophylaxis and they've shown a hazard ratio of 0.5, meaning a 50% reduction in the risk of VTE. So another trial which is outside of the ICU is a thrombotect trial.  So they enrolled patients with acute leukemia and then provided either enoxaparin or antithrombin before start of asperaginase.  So what they've shown is compared to placebo, which is the blue line, the risk of VTE is much lower with enoxaparin, which is the red line, which is consistent with what we saw  with the CRIT trial. But the other interesting thing is if you just replace their antithrombin levels, then the risk of VTE is actually much lower.  So now the question is can we use antithrombin replacement to prevent VTE in children? So that's one thing that we're looking into right now.  I will be remiss in this lecture if I don't mention that daltaparin was recently approved by the FDA for the treatment of VTE in children.  It's sort of disappointing that the approval was based on just 34 children and the metric that they used to approve it is the time to therapeutic anti-TNA level.  But nevertheless, daltaparin is now approved for the treatment of VTE in children, but that's only for those older than 8 weeks.  Another study that's using daltaparin is the KIDS.trial, but this trial does not answer the question of whether daltaparin is superior or non-inferior to standard treatment.  Because the main question for this trial is whether 6 weeks is better than 12 weeks in terms of recurrence of VTE or post-thrombotic syndrome.  So in their pilot study, they actually included around half of the patients had catheter-associated DVT.  So at least we'll have information on that with regards to how long we should treat these patients.  The figure on the right is just a constant diagram of how they plan to do the study. So basically they randomized the patients after receiving 6 weeks of daltaparin.  Either they stop it at that point or proceed with another 6 weeks and then follow them up to look for recurrence of VTE or post-thrombotic syndrome. So moving on to DOACs.  DOACs are direct acting oral anticoagulants. You may have seen them in commercials. So they are the rivaroxaban, edoxaban, and apixaban.  So they are those with XA in their names, which is because they act directly on XA. So just this year, the pediatric trial on the use of rivaroxaban for the treatment of  VTE was published. The intent was to do a non-inferiority trial comparing rivaroxaban to standard treatment.  Unfortunately, it didn't happen that way because of the low risk of recurrent VTE in children.  Nevertheless, they did a 2-to-1 trial and there's no significant difference in the risk of recurrent VTE with rivaroxaban compared to standard treatment.  They also have a pre-hoc analysis plan for CVC-associated DVT and again they showed basically the same findings as in the parent trial.  So the recurrence of VTE was similar with rivaroxaban or standard anticoagulation. So that's a quick look in clinicaltrials.gov and we have at least four other studies looking  at DOACs in children. So the first two are using apixaban and the last two in this list are using edoxaban.  It's important to note that two of these are for treatment and two of them are prophylaxis. And then one of the prophylactic studies is in cardiac patients.  So while this may be an interesting option for prophylaxis in children, for those who are critically ill because we want to start them within the first 24 hours after insertion  of a central line, its use for prophylaxis may be limited because a lot of these children are NPO initially.  So in summary, so hopefully I've convinced you that venous thromboembolism is probably preventable in critically ill older children.  I think it's the timing that's likely, it has to be started as soon as possible. For critically ill infants who are defined as less than one year old, prophylactic dosing  of enoxaparin may not work so therefore we probably should be looking for alternatives. And this is an important consideration for post-op cardiacs who most of them are infants  who are less than one year old. DOAC, while it's still not FDA approved for children, the study is already out there.  I'm assuming that FDA approval is in process, but eventually they may be used for the treatment of VTH in children and we may be seeing them in the ICU.  However, its use as prophylaxis may be limited because most of these kids are initially NPO. That's when we need to start prophylaxis. So thank you very much.  If you have questions, I'll be more than happy to answer them. At the same time, I have my email address for you to shoot me your questions. Again, thank you very much and good day.  Hello, as previously mentioned, my name is Marianne Mellis. I'm a pediatric intensivist at Weill Cornell Medicine in New York City, and today I'll  be discussing the approach to bleeding in the critically ill child. A few disclosures to start, I do have some funding for the work that I'll be discussing  and I'll be very briefly discussing the off-label usage of factor concentrates and antifibrinolytics in critically ill children.  Today, we're going to review the definitions of bleeding in critically ill children, we'll describe the epidemiology of bleeding in the PICU, and then lastly and very briefly, we'll  discuss some treatment options for hemostasis in the critically ill child. To start, I'd like to discuss the initial approach, which is how to define bleeding in children.  So as you all probably know, there are many different perspectives on bleeding. For my 10-year-old son, bleeding like this from his finger he feels might be life-threatening  is very disturbing, whereas you and I as pediatric intensivists are probably very used to this  type of bleeding, where a child is cannulated to ECMO and there's a bleeding around the cannula.  It's very important that you and I are able to describe bleeding in the same way, so that  when we sign out to one another, we're describing the same type of bleeding, or when we're trying  to do studies to understand bleeding and its interventions, we're enrolling the same types of children. Also very important is we encounter bleeding in a variety of settings.  For example, you might have a child who's had a recent G-tube placed with bleeding from the G-tube, a child who's had cardiac surgery and comes back with bleeding from the chest  tube, or a child who's intubated and might have blood coming from the NG-tube or from the ET-tube with suctioning.  And it's really important for us to understand what bleeding is clinically relevant in our patients, because even though bleeding can be very disturbing to parents, to families,  to patients, and to providers, it may not be always clinically relevant and we may not need to intervene on that bleeding if it's not going to affect the patient clinically.  So with this in mind, we started our investigation of bleeding definitions with a systematic  review, and we wanted to understand the bleeding scales that existed and how they may or may not be applicable to critically ill children.  And in our systematic review, we found that very few bleeding scores or scales involved  bleeding that's relevant to critically ill children in sites that are relevant and in ways that are relevant to critically ill children.  And so our next step was to conduct a survey. And so we surveyed over 200 intensivists, all pediatric intensivists, from many countries  and a variety of levels of experience, to ask what types of bleeding that they felt were clinically relevant in their patients, and also what types of bleeding were clinically  irrelevant, meaning it had no impact on the outcome of their patients.  And based on those findings, we then presented a variety of definitions or elements of definitions to a large group of experts.  These experts we wanted to draw from a diverse group of people who had published on hemostasis in critically ill children.  And so not only did we include pediatric intensivists, but we included pediatric cardiac intensivists, pediatric hematologists, pediatric transfusion medicine specialists, pediatric  surgeons, and pediatric anesthesiologists.  And we went through a modified Delphi process. And over the period of about six months, this group of experts developed what is now known  as BASIC, or the Bleeding Assessment Scale in Critically Ill Children. And I'd like to spend some time going through that definition.  So first, the experts defined what they believed to be severe bleeding by any one of the following criteria.  And so they felt that severe bleeding was quantifiable bleeding, which they defined as more than five cc's per kilo per hour for more than one hour in patients that had a  means to measure or quantify their bleeding. So patients with a chest tube or surgical drain.  Next, bleeding that led to at least one organ dysfunction using the PILOD2 score within 24 hours of the previous assessment.  And here's where some subjectivity comes into the definition, because as we all know, there are a variety of reasons that a critically ill child might develop organ dysfunction  during their course of critical illness. And bleeding might only be a part of that.  And so in order to qualify for severe bleeding, a patient would need to adopt organ dysfunction solely because of bleeding and in absence of other causes.  Next, bleeding is severe if it leads to hemodynamic instability, defined as an increase in heart rate by 20% from baseline or decrease in blood pressure by the same amount.  Again, in absence of other causes really caused by bleeding alone.  Severe bleeding is that which leads to a drop in hemoglobin of more than 20% in 24 hours, again, because of bleeding.  And lastly, the experts felt like there were three sites of bleeding in which a patient could bleed, but the PILOD score would not be affected.  And so therefore, they specifically indicated intraspinal bleeding, leading to loss of neurologic function, non-traumatic interarticular bleeding, leading to a decreased range of  motion, or intraocular bleeding, leading to impaired vision.  Next, the experts defined moderate bleeding. All of the criteria must be present to qualify as moderate bleeding.  That would be more than minimal, but not meeting the criteria for severe bleeding, quantifiable bleeding more than one cc per kilobrower, but less than five cc's per kilobrower,  bleeding not leading to organ dysfunction, bleeding not leading to hemodynamic instability, or bleeding that leads to a drop in hemoglobin of less than 20%.  And then lastly, the experts defined minimal bleeding, which they felt was clinically irrelevant as any of the following elements.  So streaks of blood present in the intratradial tube or during section only, streaks of blood in the NG tube, macroscopic hematuria, or less than or equal to one plus red cells,  subcutaneous bleeding of a certain size, quantifiable bleeding less than one cc per kilobrower, or in patients who might be oozing from central lines  in which there are bloody dressings, they need to be changed no more than every six hours, or no more frequently than every six hours.  And if they're being weighed, which is pretty uncommon, but weighing no more than one cc per kilo.  And so there are many benefits of this basic definition. The first is it's a physician-driven definition. It relies on both the opinion from the clinical providers  obtained through the survey and experts of various backgrounds, and relies on a strong methodology. Secondly, it includes physiologic variables that are appropriate for children,  as most of the previous definitions relied upon vital signs that were really only applicable for adults. It includes sites of bleeding,  such as endotracheal tubes or urinary catheters that are particular to critically ill patients. Probably most importantly, it's untied to interventions that are physician-dependent,  such as transfusion, that are subjective and highly variable. So most previous definitions define severe bleeding by the receipt of Lourette cell transfusion.  And lastly, we believe the definition can be applied to critically ill children or adults by simply inserting the SOFA score in place of the PVOT score.  We did do a very small validation study in the publication of the original definition with 40 children from a single center, finding that there was good intra-  and inter-rater reliability. But we are currently in the process of enrolling 400 to 500 critically ill bleeding children from a variety of settings,  not all of which are primarily English-speaking, to be able to really describe the reliability of the definition.  Next, I'd like to discuss some of the epidemiology of bleeding in the PICU. So first, in a recent study by Vince Faustino and colleagues, they enrolled children,  or they screened children at Yale in the PICU to look for those children who were bleeding according to a variety of definitions. And so this graph represents the basic definition  where clinically relevant bleeding were those who qualified for moderate or severe bleeding according to that definition. The solid line represents their current study,  and they compared the frequency of bleeding to what the frequency would be if other bleeding definitions were applied. And they found they were relatively similar  with a frequency of approximately 10% in the 400 children that they screened, approximately 40 had bleeding.  We currently are conducting some local studies in populations of children that are particularly prone to bleed. So the first is in cohort of children  with underlying oncologic diagnoses at Memorial Sloan Kettering Cancer Center.  Giuliano Romano has studied retrospectively those children,  and retrospectively, you can really only look at children with severe bleeding according to basic definition. And it's found that 14% of those children who are critically ill  with an underlying oncologic diagnosis have at least one episode of severe bleeding. And then Joy Levasseur is doing a prospective study following those same children,  but prospectively over a year, and looking at the occurrence of bleeding in that population. Similarly, Ramsey Sheik has looked at children following cardiopulmonary bypass  and has found that approximately 9% of them have at least one episode of severe bleeding.  We've also looked at bleeding in children supported by ECMO, certainly a patient population that's very prone to bleed, as previously mentioned. And in a recent publication,  we found that nearly half of those children have chest tube bleeding, irrespective of the day of ECMO. And this is using the BATE dataset from the Capcorn group.  So a little over 500 children from eight ECMO centers.  Also looking at this dataset, we found that the amount of bleeding was independently associated with the odds of mortality in almost a dose-dependent manner.  And this was adjusted for a variety of factors listed here that would affect mortality in this patient population. And so again, this is not a direct application  of the basic definition, but I attempt to understand if those numbers that were added to the basic definition of quantifiable bleeding are applicable across patient settings.  As I mentioned, I wanted to give a whirlwind tour of the hemostatic agents that one could consider giving in critically ill children who are bleeding.  And it's really important to mention there are many options possible, but there's very little evidence for any of these in critically ill children.  The studies just haven't been done. Though we hope that with the basic definition, that there can be some studies done. So I think probably first,  especially for patients who have maybe oozing around, oozing around lines, topical treatments such as topical thrombin can be used. There are a variety of blood components  that have been historically used to control bleeding. Whether or not these actually help with bleeding is unclear, but historically, platelets, plasma,  and cryoprecipitate have been used. There has been a lot of work looking at fibrinogen concentrate in a variety of patients' populations,  mostly surgical patient populations in the past year. There are pro-thrombin complex concentrates consisting of factors two, seven, nine, and 10 is often used in medical bleeding.  And then recombinant factor 7A that's often used in life-threatening bleeding. In addition, there's been a lot of use in, especially in the recent years of antifibrinolytics,  aminopropoic acid and more common, more in use now, transexamic acid. And both of these have been used a lot in post-surgical patients in the operating room. And for the most part,  have not been linked to the increased risk of clots.  In smaller studies, DDADP has been used to control bleeding. And then there are some, what I call newer therapies, although they've been used historically in the past.  And that being the use of whole blood transfusions, especially in massively bleeding patients and cold stored platelets, which is now being studied in children  on cardiopulmonary bypass surgery. And so I think both of those products you'll see used much more commonly.  And hopefully we'll be having some guidelines soon to help to guide pediatric intensivists for plasma and platelet transfusions in critically ill children.  So I've been very fortunate to lead what's known as Taxi-CAB or the second stage of the Taxi process with Bob Parker, Stacey Valentine, Oliver Caron, and Scott Bateman.  And we've been leading a large group of experts through a systematic review and the development of guidelines in this area. And hopefully in the next six months,  you'll be seeing these published in Pediatric Critical Care Medicine, and there'll be a little more guidance for providers based on the evidence that does exist.  I'd like to thank you for your attention. Hi, I'm Sheila Hansen, and I'm very happy to talk with you today about thrombosis in the pediatric ICU.  I have no financial disclosures. I will be discussing some off-label use of TPA and other anticoagulation.  We'll review the epidemiology and management of thrombosis in the pediatric ICU, and I'm gonna focus on DVT, pulmonary embolus, and acute ischemic stroke.  ICU admission as a surrogate for critical illness is associated with higher incidence of DVT, about 1% in prospective studies. Certain populations,  such as children with central venous catheters, cardiac disease, or after trauma have an even higher incidence. Risk factors include adolescence, central venous catheters,  surgery, single ventricle palliation, and other markers of illness severity are associated with increased odds of DVT. And this includes mechanical ventilation,  red blood cell transfusion,  and a Glasgow coma scale of less than nine. And in other studies, inotropic use or neuromuscular blockade use have also been associated with increased odds of DVT.  The American Society of Hematology, ASH, put out guidelines in 2018 regarding the management of pediatric DVT.  It's recommended that symptomatic DVT be treated  with provoked clots being treated for six weeks to three months rather than longer after the risk factor has resolved. For unprovoked DVT,  it's suggested that they be treated for six to 12 months rather than longer.  For asymptomatic DVT, it's suggested treating or not treating based upon individual patient factors. Routine screening for DVT is not recommended.  And I wanna point out that determining symptoms in DVT can be difficult in critically ill children who are sedated, in bed, on a ventilator,  or who may not express pain or the sites of pain due to their developmental status. And so some asymptomatic DVT may really have been symptomatic at some level,  and this may impact the decision to treat.  For CVC-associated DVT, if the line's not needed or not functioning, it's recommended to remove it. ASH recommends delaying the removal of the central line  for after a few days of anticoagulation to avoid paradoxical emboli when it's pulled.  If the CVC is functioning and still needed, it suggests not to remove it and treat through.  If the symptoms progress after starting anticoagulation, then remove or not remove the line based upon individual patient factors.  Now switching to acute pulmonary embolus, this is a relatively rare diagnosis in pediatrics. It's highest in infants and toddlers with the second peak in adolescence, the DVT peaks.  You need to have a high index of suspicion, given its rarity. In pediatrics, this diagnosis can be delayed often up to seven days.  High-risk symptoms include dyspnea, chest pain, hypoxia, hypotension, without another etiology to explain it.  Patients with sudden onset of symptoms, those with a recent VTE or at risk of VTE are at higher risk of PE.  Diagnosis is most commonly by use of CT angiogram. It's quick, it's available at every hospital, and it can be used to assess other pulmonary etiologies. It does have radiation  and it can miss some small peripheral emboli of unclear clinical significance. MRI, MRA, VQ scans and angiography have all been used,  but these require sedation or cooperation in children.  There's really no cure for CVC. There's really no evidence for treatment of PE in children. Management has been extrapolated from adult evidence.  The recent 2019 European Society of Cardiology and the 2020 guidelines from ASH will be summarized in the next few slides.  The PE risk category, which predicts how likely the PE is gonna lead to a poor prognosis, determines the level of therapy recommended for intervention.  Those at high risk, a massive PE, are hemodynamically unstable, they're on vasopressor support or hypotensive.  These patients are recommended to have urgent reperfusion therapy, fibrinolysis or mechanical thrombectomy and anticoagulation.  Those with intermediate risk are normotensive, but they show evidence of right heart strain. These could be stratified by ancillary studies  such as EKG, echocardiogram and troponin levels. Those with elevated troponin would be intermediate high risk and those with normal troponins would be intermediate low risk.  And the decision to have reperfusion therapy can be based on these adjunctive tests and comorbidities.  Otherwise, the patient can be monitored with anticoagulation and then rescued with TPA if they decompensate.  Patients at low risk have symptomatic, but their absence of any of the preceding features. And for these patients, anticoagulation solely is recommended.  The main complication of fibrinolysis is bleeding and the contraindications pertain to bleeding, particularly in critical areas such as the brain.  Remember, however, that in some patients, the critical nature, the life-threatening nature of the PE may necessitate treatment despite these contraindications.  Tissue plasminogen activator or TPA is the most common fibrinolytic in the US. Thrombolysis restores pulmonary blood flow and improves PA pressures and RV dysfunction.  We know it's efficacious in adults. It decreases mortality in high-risk PE with a relative risk of 0.68.  It has the greatest efficacy when used within 48 hours of symptoms. As discussed, there is a risk of major bleeding with a relative risk of 1.89. And this is higher for those  with catheter-directed fibrinolysis with a relative risk of 3.77. A 3.77, though this may be mostly related to the population selected.  The dose for adult-sized children greater than 50 kilos is 10 milligrams bolus of TPA once and then 90 milligrams over two hours. For smaller patients less than 50 kilos,  it's an infusion typically at 0.75 mgs per kg per hour over two hours.  Mechanical and surgical reperfusion therapies can be used for high-risk PE where thrombolysis is either contraindicated or it has failed. Percutaneous catheter-directed embolectomy  is a combination of mechanical aspiration with site-directed low-dose thrombolysis, typically limited to children greater than four years of age  due to the size of the cannulas needed.  Surgical embolectomy is often used in children  with underlying congenital heart defects as well as other patients. It typically requires cardiopulmonary bypass and is often used with ECMO post-operatively.  Management of acute PE as well as fibrinolysis involves treating the RV failure and trying to prevent further decompensation. So volume optimization with very cautious volume load  is indicated, however, oftentimes vasopressors  and inotropes are needed given the already distended right ventricle.  Inhaled nitric oxide may have some benefit. There's very limited evidence that it can decrease pulmonary vascular resistance and improve pulmonary blood flow.  And mechanical circulatory support may be needed as well. Supplemental oxygen should be used to keep the oxygen sats greater than 92%. And consider intubation  if there's a high vasopressor requirement or refractory hypoxemia, remembering though that this is a high-risk intubation given the severe RV dysfunction  and intubation can result in peri-intubation arrest.  Anticoagulation is the mainstay of therapy. Typically, unfractionated heparin is preferred if reperfusion therapies are planned and then transition to low-molecular weight heparin  when more stable.  Acute ischemic stroke is also a rare diagnosis in children with an incidence about one to two per 100,000. It's highest in infants and children less than five years of age.  Black and Asian children have a higher incidence than white children. And some of this is accounted for by sickle cell disease which increases the stroke risk greater than 200-fold.  There are many stroke mimickers in pediatrics including migraines, top paralysis, and encephalitis as well as the relative rarity. And so the extrapolation of adult diagnosis  and management for acute ischemic stroke cannot be generalized to peds. Certain diseases place a child at greater risk for stroke. This includes arteriopathies, both inflammatory,  infectious, as well as Moyamoya disease,  cardiac disorders, infection, trauma, or thrombophilias.  Child AIS resulting from cardiac disease is the most common and infants with congenital heart defects make up about 25% of the pediatric stroke population.  Brain MRI is the most common imaging modality to diagnose ischemic stroke. It's helpful in assessing for some of the stroke mimics as well.  However, there can be delays in obtaining MR which impacts the delivery of hyperacute therapies, particularly nights and weekends. And there's also often a need for anesthesia  in children who are not able to cooperate.  Head CT with reflex CTA is used at some institutions including my own to emergently diagnose AIS.  The head CT rules out hemorrhagic component as well as other etiologies for the symptoms such as hydrocephalus or brain tumor. The CTA will then confirm a large vessel occlusion.  It will miss some strokes, however, it's fast and readily available.  Hyperacute therapies including fibrinolysis are effective in adults. It improves the 90 day survival without disability. However, there's little evidence in children.  There's no RCTs. The one well-designed fibrinolysis in pediatric stroke, the TIPS trial was suspended for poor enrollment in 2013. There's not likely to be any in the near future.  So guidelines and recommendations have been extrapolated from adult studies, incorporating a few pediatric studies as well as expert opinion.  Previous recommendations by the American College of Chest Physicians and American Heart Association, AHA,  used to say TPA is generally not recommended for children with arterial ischemic stroke outside of a clinical trial. But despite this, database studies show  that about 1.2% of pediatric strokes receive TPA with the rates increasing. So two recent documents, one by the AHA in 2019  and one by Australian Clinical Consensus Guidelines in 2017 have been published with guidelines for stroke management.  These newer guidelines recommend or say to at least consider fibrinolysis for a very exclusive population. To recognize the difference, first of all,  the different risk-benefit ratio in peds versus adults. In children, we found that there's no functional deficits in one-third to one-half of children  with acute ischemic stroke, even without intervention.  So the new guidelines recommended  considering hyperacute therapy for a very limited population and adhering to this group will optimize the benefits of TPA while limiting the bleeding risk.  So the patient has to have a persistent disabling neurologic deficit, a PEDS NIS score greater than four, has to be less than 4.5 hours from known symptom onset,  must have radiographically confirmed imaging showing a large artery occlusion, age greater than two, the treatment should be made in conjunction with a pediatric stroke neurologist,  and any intervention should be done by an endovascular surgeon with both PEDS and adult experience. The major complication is bleeding, and the exclusion criteria is the same  as what was for acute PE with some additions such as severe hypertension.  For children outside the window for TPA or don't meet the indications for hyperacute therapy, acute stabilization consists of optimizing cerebral oxygen delivery.  Clinical seizures are common as well as subclinical seizures, 20% for both, and should be treated aggressively.  Hyperoxia may not be beneficial, it can increase the formation of oxygen-free radicals and induce cerebral vasoconstriction, so it's recommended to supplement with oxygen  only if hypoxic.  Fever, hyperglycemia, and hypertension are markers of stroke severity and associated with worse outcomes. Though it's unclear if correcting these improves outcomes,  so we typically aim for normal values. Be particularly cautious in lowering the blood pressure and make sure to maintain cerebral perfusion pressure.  Anticoagulation is beneficial  compared to aspirin or no treatment. Recurrent strokes are most likely within the first 48 to 72 hours if it's a result of dissection or embolus,  and so it's recommended to anticoagulate at least until those diagnoses have been ruled out.  There's a strong recommendation for early neurosurgical consult for increased ICP monitoring, increased ICP, which may require monitoring. About one to 12% of acute ischemic strokes  develop malignant middle cerebral artery infarction and raised ICP. Infra-tentorial strokes can also develop raised ICP.  And so consideration for decompressive praniectomy is recommended.  I know I went through a lot of material, but the punchline is a DVT is not uncommon in the PCICU. Acute PE and acute ischemic stroke are rare,  and hyperacute therapies can improve outcomes in selected children.  Thank you for your time. Please put any questions in the chat or email and I'll be happy to answer. Thank you.

Video Summary

The video transcript is a summary of a session on the current and future practice in pediatric thrombosis. The session covers three main topics: clinical trials in pediatric hemostasis, assessment and management of bleeding in critically ill children, and assessment, measurement, and treatment of thrombosis in pediatrics. <br /><br />The first speaker discusses clinical trials in pediatric hemostasis and anticoagulation. They highlight the increase in venous thromboembolism (VTE) in hospitalized children and the lack of effective interventions. They present the results of a pre-trial on prophylactic dosing of enoxaparin and its potential benefits in reducing the risk of catheter-associated DVT in older children. They also mention the use of direct oral anticoagulants (DOACs) in the treatment of VTE in children, although DOACs are not yet approved for pediatric use.<br /><br />The second speaker focuses on the assessment and management of bleeding in critically ill children. They introduce the Bleeding Assessment Scale in Critically Ill Children (BASIC), which was developed by experts through a modified Delphi process. The scale provides definitions for severe, moderate, and minimal bleeding in critically ill children. The speaker also mentions various hemostatic agents that can be used to control bleeding in critically ill children, although there is limited evidence for their effectiveness.<br /><br />The third speaker discusses the epidemiology and management of thrombosis in the pediatric ICU, specifically focusing on DVT, pulmonary embolism (PE), and acute ischemic stroke. They highlight the higher incidence of DVT in critically ill children, particularly those with central venous catheters, cardiac disease, or after trauma. They discuss the current guidelines for the management of pediatric DVT, including the use of anticoagulation and the removal of central venous catheters. They also mention the recommendations for the management of acute PE and acute ischemic stroke, which involve hyperacute therapies such as fibrinolysis and mechanical thrombectomy in selected cases.<br /><br />Overall, the session provides an overview of the current knowledge and practices in pediatric thrombosis, highlighting the challenges and potential interventions in the field.

Asset Subtitle

Pediatrics, Hematology, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Analyze and interpret the current guidelines for managing bleeding and thrombosis in pediatric extracorporeal life support
Assess the existing data and current recommendations for use of tissue plasminogen activator in children for acute stroke and submassive pulmonary embolism
Review and interpret data from recent pediatric clinical trials on anticoagulation and apply it to current pediatric ICU and pediatric cardiac ICU care
Discuss data and potential future uses of direct oral anticoagulants in children

Clinical Trials in Pediatric Hemostasis and Anticoagulation: How Do I Apply Trial Results in My Practice?
E. Vincent Faustino

Hemostatis: Assessment, Measurement, and Bleeding Risks
Marianne Nellis

Thrombosis: Assessment, Measurement, and Treatment
Sheila J. Hanson

Meta Tag

Content Type Presentation

Knowledge Area Pediatrics

Knowledge Area Hematology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Anticoagulation

Tag Hemorrhage

Year 2021

Keywords

pediatric thrombosis

clinical trials

pediatric hemostasis

bleeding assessment

critically ill children

thrombosis management

venous thromboembolism

anticoagulation

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.