Dr. Susan Goobie - Advances in Patient Blood Management for the Pediatric Patient

Who'll be, uh, discussing advances in pediatric blood management of the pediatric patient. Um, briefly, uh, she, um, uh, has been at Boston Children's Hospital, um, uh, for part of her training and, um, as faculty. She started, um, uh, her training at Memorial University in Newfoundland, Canada, where she did her undergraduate and medical training, as well as her anesthesia residency. She did her fellowship here um at Boston Children's Hospital before returning for initially initial faculty positions um uh in Vancouver and then has been back at Boston Children's um since 2013. Um, she has, uh, uh, been productive in research in many fronts including, uh, Eotran ischemic acid, um, in pediatric patients and Um, uh, uh, perioperative, uh, management and most recently, um, been part of a, a, funded, um, research, um, study on the use of ran acid in trauma. Um, so, uh, please join me in welcoming Doctor Gubi. Thank you. Thank you for that nice introduction. It's really a pleasure to be here and um thank you for coming this morning. Um, so, I'd like to tell you about advances in, in patient blood management for the pediatric patient. Here are my uh conflict of interest statement and none of these influence my talk, and here are my objectives. In the next 45 minutes, I'll try to answer the following questions. Is a blood transfusion safe? What is pediatric, uh, patient blood management? Does anemia matter? Is there a role for TXA in your practice? And do we need a Boston Children's Hospital massive hemorrhage protocol? So this 2015 Nature editorial quoted Tim Goodenoff from Stanford. He published two really compelling papers in transfusion that year. One was restriction blood transfusion practices are associated with improved patient outcomes, and the second was improved blood utilization using real-time clinical decision support. And Tim Guenov in this editorial was quoted as saying, Save blood, save lives. Transfusions are one of the most overused treatments in modern medicine at a cost of billions of dollars, and researchers are working hard to cut back. The safest blood transfusion is one not given. And here's what they did at Stanford. They, uh, basically three main outcomes that they found by simply reminding doctors of the current guidelines and when they order blood in this California hospital, they were able to save money and lives. They reduced the blood transfusion rate by 24%, and as a result, save $1.6 million per year. They decreased the average length of stay per patient, uh, from 10 days to 6 days, but more importantly, the overall mortality among people who had a blood transfusion fell from 5% to 3%. So weaning doctors off their love affair with blood is going to be harder than we think, he said. Blood transfusion overuse, let's talk about that. Perioperative bleeding is one of the major indications for blood transfusions worldwide. But are we overprescribing blood to our patients? According to the American Medical Association and the Joint Commission September 2012 National Summit on Ouse, they identified blood transfusion as one of the most important healthcare-related overuse issues facing the world today. It was one of the top 5, and in that same category were antibiotics. So blood transfusion and antibiotics were identified as being one of the 5 most overprescribed and overused agents back in 2012. And therefore, the World Health Organization in its resolution at that same year, identified patient blood management strategies as one of the most important issues facing surgical patients worldwide. Children in our operating rooms are bleeding and being exposed on a daily basis to blood products. This article from Melbourne, Australia outlines one institution's practice, and this shows the percentage of episodes transfused by surgery type. And as you can see, the highest categories were liver transplant. Uh, neurosurgical procedures, some major, uh, GI procedures, uh, scoliosis, and cardiac. What does this look like for Boston Children's Hospital? I wish I could tell you. We don't seem to have good metrics on what our, um, blood transfusion use is, but I hope, uh, in maybe another 6 months, I'll be able to tell you that we're just starting a database, uh, to try to capture this information because I think it will be very informative to know where we are here. So let's try to answer the first question, is blood safe? Uh, this review article, Serious Hazards of Transfusion in Children, was published in 2011, and although, as you know, improvements in hemovigilance have significantly reduced the risk of transfusion-related infections. The reported incidence of serious hazards of transfusion has increased, particularly in infants, with respect to non-infectious transfusion associated complications as listed here. The three things I want to highlight from this article were that there were 2 pediatric deaths for 100,000 blood products transfused. There's a disproportionate number of adverse reactions in children. Um. 18 per 100,000 transfusions in children less than 18 years, and as high as 37 per 100,000 transfusions in those in, in, in less than a year. So this is particularly affecting our pediatric patients, uh, more so than our adults. 80% are due to incorrect blood component transfused and inappropriate or unnecessary transfusion. The most common cause of perioperative cardiac arrest, according to recent reports, is directly associated with a blood transfusion. 12% of all perioperative or cardiac arrests are in children undergoing non-cardiac surgery, and they're secondary to hypovolemia directly associated to blood loss or the consequences of a blood transfusion. So as I said, red blood cell transfusions and blood transfusions of other products are pretty safe with respect to infections. The risk for hepatitis, HIV, uh, and those listed here in this table have markedly decreased over the last 20 years. But with respect to transfusion, transmitted infections, there's two important concerns that we need to take into consideration. One is that testing for HIV, hep B, and C is performed in less than 45% of the members of the World Health Organization, uh, to date. And the other more concerning thing is, what about these unknown viruses? You probably remember when the Zika virus was uh going on. Well, our blood bank had no means initially to test for the Zika virus. What about all the other ones, and what will happen in the future? Finding other ways of decreasing our use of blood products, uh, might be a smart thing. So, uh, just to talk a little bit more, uh, in another couple of slides to present other hazards of transfusion, in this, uh, 2011 article by Jose La Vli from Montreal, Canada, uh, she outlined the major, uh, transfusion-related mortality by complication categories. And what I'd like to point out is that trolley, taco, and trim are, uh, three main considerations, uh, up to 15 to 30% in the US. Uh, these are responsible for, uh, reports of complications. What is trolley? Trolley is transfusion-related acute lung injury. Uh, recently, in the last 4 or 5 years, there's been a number of articles on trolley and children. Uh, we know that transfusion-related acute lung injury is the leading cause of transfusion-related death in the United States. But it's a diagnosis of exclusion. The clinical presentation ranges in severity. It's underestimated and underreported, even in this institution. You probably haven't even heard of a patient who you've given a blood product to who's had trolley or taco. And I would put it to you that they're probably more going on than you know. It certainly uh ranges in severity and can mimic a lot of other uh respiratory problems and therefore we have to have a high index of suspicion. The literature reports 5.6 per 100,000 transfusions in children, uh, have a trolley uh associated with them, and the incidence in our ICU patients is as great as 7%. The other hazard of transfusion is trim. This is very interesting. Transfusion-related immunomodulation. It refers to the transient depression of the immune system following the transfusion of blood products. Some research studies have shown that because this immune depression, blood transfusions may increase the risk of infections. In this JAMA article, healthcare associated infection after a red blood cell transfusion. The authors suggest that transfusion-related immunomodulation is the least understood, but potentially the most risk, or harmful risk of transfusion. Are we putting our patients at risk for infection by transfusing blood? The other concern is cancer patients. Uh, Trim is also implicated at promoting cancer reoccurrence, and it, as it can alter the immune system. So our cancer patients different and at higher risk when we give them blood transfusions for potential reoccurrence down the road. There's some suggestion in the literature that they are. And I actually just reviewed 4 articles for a Society for the Advancement of Blood Management meeting next year in New York, and those 4 articles were in cancer patients showing that there was an increased independent association of infection and cancer recurrence in patients who had um significant blood transfusion intraoperatively. Besides Trolley, Taco, and Trim, the authors of this study sought to identify complications associated with red blood cell transfusions in a single center, Saint Justine's in Montreal. They looked at over 1000 admissions to a PICU with a 17% transfusion rate over a one-year period. And the author was reported that there was an independent association of transfusion with multiple organ failure, systemic inflammatory response syndrome. There's the increased infection again and increased mortality. We looked, uh, by using the NISquip database at the relationship between transfusion volume and outcomes in children undergoing non-cardiac surgery, and this was over 7000 children in the transfusion group with matched cohorts of over 100,000 children in the control group, and we concluded that children who received red blood cell transfusions are at increased risk for 30-day mortality. Wound complications, pulmonary, neurologic, cardiac, septic, and prolonged hospital length of stay, and this was from the, uh, new script database in 2012 and 2013. And here's what it looks like in a table. Uh, what we're plotting here is the percentage of children with mortality at 30 days against the various amounts of blood transfusion. That they received, and as you can see, there's a stepwise increased uh incidence in the transfused patients in the dark black uh versus the match controls in the gray, and increased uh mortality with uh more blood in each category that the patient received. Match Everything, yes, Mach cohorts, the propensity matching. Mhm. And this is how it looks like, uh, with uh clotting, renal failure, infection, and wound complications. Again, in those three categories of blood transfusion. Most of our patients at least get 15 to 20 mLs per kilo, so probably are in the range here. Uh, and if you look at the adjusted odds ratio, and I've just circled infection. Uh, in the red. So with increasing volumes of blood transfused, there's an independent, uh, association between an increased risk of infection. I'm not talking cause and effect, I'm talking association. That's important to remember. I'll talk about that a little bit later. In our craniosynostosis, uh, patients, which have done a lot of work with this group, uh, we looked over a 10-year period, uh, from 2003 to 2013, uh, and we did a retrospective chart review and found that there was a 15% incidence of a major adverse event that would need an ICU stay. And when we looked at those independent predictors, um, besides body weight and the patient not receiving antifibrinolytics, the other two that popped up as being, uh, very, uh, important were, uh, red blood cell transfusion greater than 60 mL per kilo, and whether the patient got hemostatic, uh, blood products, that's FFP platelets, or cryo. So the risk of a clinically relative uh postoperative event in those two categories with blood and blood products uh increased over twofold. So here we go again. Blood transfusion kills patients. Um, that's not exactly what I'm saying. I'm saying that there's an increased association with, uh, adverse events in patients who've received a blood transfusion, but we also need to consider that actually bleeding may be the culprit, and that's something very important to keep in mind. So in this editorial, um, I posed the question to transfuse or not to transfuse and suggested that a blood transfusion can certainly save a child's life, as we all know and we all want to do in our operating rooms on a daily basis, but I would also remind you that it can threaten it. It can be clinically necessary for life and for maintaining vital organ perfusion. But the alternatives to a blood transfusion in our pediatric patients may be the safest choice, uh, relate to decrease adverse events. So what is patient blood management? Well, the World Health Organization recognized PBM as a means to promote the availability of transfusion alternatives. The Society for the Advancement of Blood Management, um, defined PBM as the timely application of evidence-based medical concepts designed to maintain hemoglobin concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient outcomes. And there are many hospitals around the nation that have well organized PBM programs in their hospitals. Our American Society of Anesthesiologists published in 2015, practical guidelines for uh PBM. And among all the different guidelines, evidence-based guidelines in this report, there were no specific recommendations from our, our American Society on Pediatrics. But luckily, uh, across the world, other, uh, Uh, guidelines have been published. The Australian government, uh, published in 2016 patient blood management guidelines. This is a really comprehensive 300 page document with evidence-based guidelines for neonatal and pediatrics and Around the world, children's hospitals are using this, uh, to help guide their, uh, their, uh, blood management programs. Um, it's something you can download. There are, you can put it on your iPhone, the, uh, the cards to, uh, to guide, uh, transfusion therapy. And on the bottom, the Society for the Advancement of Blood Management, which I'm a member, um, we recently wrote a standard 13, which were patient blood management guidelines for pediatric patients, and that's a, a national, uh, body. But here's my, um, way of summarizing PBM in this table with 3 pillars, and I'll highlight a few of these, uh, pillars in the next, uh, 20 minutes. Uh, I wanna talk about anemia. Uh, transfusion algorithms and anti-fibrin Linux, very specifically. But before we do that, we need to keep in mind what's the goal. Uh, the goal is not to transfuse the patient. The goal is not to let the patient bleed, but the goal is to really just have a fine balance of, uh, maintaining intraoperative hemostasis in children. And there's a balance between the patient factors, anesthesiologist factors, and the surgical factors. Um, as you surgeons all know, it's really just depends on the type of surgery, high versus low-risk surgery, uh, and whether there's a high incidence of hyperfibrinolysis associated with that surgery. Uh, and the anesthesiologists behind that curtain, we're all, we're trying to manage, uh, the, the blood loss as best we can. The fluid management strategy is very, very important. Avoiding hemodilution with aggressive volume, uh, replacement, I think is one thing that we, uh, should be doing as anesthesiologists and really strict. Hemodynamic control to avoid hypertension, which causes more bleeding, but hypotension, which would put the patient at risk for vital organ, uh, profusion, uh, troubles. So here, here are the goals in a nutshell, uh, to restore and maintain oxygen delivery to vital organs and tissues, maintain normal bulimia, avoid hypotension. Avoid a lethal triad with, with massive transfusion of acidosis, hypothermia, and coagulopathy, but at the same time, avoiding hemodilution, avoiding uh over-transfusion, and these goals can be met without giving uh blood and blood products in a lot of cases. So let's talk about anemia. The global prevalence of anemia is 42%. At least 1 in 4 preschool age children in industrialized countries are anemic. What does that mean for our patient population? Well, we looked nationally at craniofacial surgery. We looked at Boston Children's Hospital, at our craniofacial surgical patients, at the incidence of anemia. We did a six-month pilot studies here. And the results were the same nationally and also at this institution, that 20 to 25% of our patients are anemic preoperatively. And I'm sure if you looked at all of our sur pre-surgical patients across the board, that we would find a similar uh kind of number, that 20 to 25% of our patients are anemic preoperatively. When we looked at Boston Children's Hospital, we were able to conclude that there's a 60% higher odds ratio of a blood transfusion among children with a low preoperative crit. Um, and also among those with that low crit, among those anemic patients, there's a 28% risk of transfusion that's attributable directly to that anemia. Now, what does that matter, um, that they're anemic? Uh, well, up until a couple of years ago, we didn't have any good data in the pediatric population. We knew that adults coming for surgery, if they were anemic, they had a higher risk of morbidity and mortality, but we didn't know if that, uh, pertained to children. So we again utilize the new script database. We looked at the association of preoperative anemia with postoperative mortality and neonates, and this, uh, JAMA Pediatrics article caused quite a stir in the, uh, in the neonatal, in the NICUs, um, and, and even here at this institution. We were the first to report that neonates in US hospitals had a very high in-hospital mortality rate of 3.4%. But what I want to point out to you is that we reported. Um, by this multivariate analysis that, uh, hematocrit less than 40% had a 2.6 in odds ratio in neonates, uh, of, uh, higher hospital, hospital mortality, that's death, um, and so this seems to be a very high hematocrit, and we used a clever, um, statistical method to try to determine this, and because, uh, We don't really have good definitions for what anemia actually is in our neonates. It varies depending on gestation and, uh, age group. Uh, we used a, a rock analysis and we determined, uh, that a hematocrit of 40 put our patients, less than 40 put our patients at higher risk, uh, for, uh, in hospitals, uh, death. And here's uh what we found in older children, the same thing, that anemia caused an increased mortality in our uh children in hospital. My twofold. And when we look at it in a, in a figure, uh, this shows the incidence of inhospital mortality in children with and without preoperative anemia. Uh, so, No transfusion, transfusion in the red. Those patients who were anemic and got a blood transfusion, had an uh increased uh risk of inhospital mortality compared to the to the other groups. was It may have been. So that's the important to, to recognize that it's associated. So, uh, if you look at other factors that are associated with increased in hospital mortality, it certainly was patients ASA 3 or 4, those who were mechanically ventilated. This, the neonates were less than 2 kg, so the sicker group, uh, definitely also had a lower hematocrits. So it's an association, it's not a cause and effect. Uh, but the question is, that, given that preoperative anemia is a strong association with mortality and neonates in children, can we improve the outcome by timely diagnosis, prevention, and appropriate treatment? That's the question. And what can we do? We can diagnose it, which we aren't doing here in this hospital. There are many hospitals around the country, adults, in pediatric that have preoperative anemia clinics that any patient who's anemic preoperatively, they're canceled until they're optimized. We don't do that here. Um, so we can postpone and optimize. We can, uh, treat if iron deficiency anemia with PO or IV iron. We can consider erythropoietin, which is what our, uh, craniofacial group is, uh, starting to consider now, because if we bump that hematocrit up, um, then we, uh, potentially have, have a lot more wiggle room for blood loss. And just also really important is to prevent, um, Post-operative anemia or inhospital anemia by limiting blood draws. If any of you have gone to the intensive care unit and watched how many, uh, blood draws our patients get and how much blood is wasted, um, I think that's something that we could improve on here at this hospital. And that would be something a blood management program in a hospital will help, would help facilitate. So I'm gonna move on, uh, it's almost 7:30 to talk about antifibrinolytics, um, and, uh, give you a little bit of an insight and update on what's going on with the antifibrinolytics. So antifibrinolytics are inhibitants of inhibitors of, uh, fibrinolysis. So you've got the coagulation cascade that forms a clot, and then you've got the, uh, fibrinolytic cascade that's responsible for, uh, the clot breakdown, and in normal. No circumstances, uh, this is perfectly balanced between, uh, coagulation and fibrolysis so that we neither clot or bleed, uh, but in critical situations like surgery or trauma, that mechanism is disrupted. And so we have a number of uh inhibitors of fibrinolysis, uh, and one of them is tranexamic acid. It's a synthetic amino acid, uh, analog, and it works by inhibiting the plasminogen to plasmin. Uh, pathway and therefore it's antifibrolytic. It stops the, the clot breakdown, but it also has very potent anti-inflammatory action, which I think we'll hear more and more about in the literature. It inhibits plasmin and plasmin-induced platelet activation at higher doses, um. And the interesting thing, it's generic, it's cheap, it's effective, it's universally available, it's easy to administer, and it has a good safety profile, which I'll talk about. So here are the 1986 FDA guidelines for TXA. Still very old, so it's really just to treat patients with hemophilia. Uh, all other countries around the world, Europe, Canada, Australia, have, uh, updated their guidelines for, uh, uh, TXA injection, but we haven't done that yet. With the FDA. So more practically, here's the indications because most of the TXA has been used off-label, uh, in the United States for prophylactic treatment of trauma and surgery with major bleeding or hemorrhage expected, but also with mild to moderate bleeding. If there's a strong desire to avoid transfusion or blood is not an option for a patient. If there's preexisting anemia or coagulopathy, uh, a pre-existing hypofibrinogenemia, so if you have a bleeding patient and the fibrinogen is critical, less than 100, TXA may help, but just keep that fibrin clot. Um, stable, uh, given that you have hypofibrinoinemia, or if a patient might be difficult to cross-match due to antibodies, um, those are some indications. What about the contraindications? Here are the absolute ones. If there's a known hypersensitivity, if the patient has an active thromboembolic disorder, active DIC or consumptive coagulopathy, acute renal failure, or acute subarachnoid hemorrhage, which has been debated, and I can talk about that in a In the question session if you like. Um, the relative risks, and I, I want to point this out because I'm definitely biased. I do all my studies on TXA and um when people see me coming, they, they know that, um, I'm likely to give it the nod in a, a major surgery, but, uh, important to keep in mind that many trials exclude high-risk groups. Therefore, the safety is really, at this point, we're still teasing out in, in high-risk groups, those with renal dysfunction, seizure disorders, if there's a high risk of venous or arterial thrombus, like our liver transplant, um, Patients, if there's pre-existing coagulopathy, uh, or oral anticoagulants, these high-risk groups haven't really been represented well in, uh, our randomized trials. Uh, and so the adverse events are listed here. Most, uh, most concern is for thromboembolic events and, and, uh, convulsions. You need to know about three important trials in TXA. Uh, these are. Major, uh, multi-center trials, the CRAS 2 trial, which I'm sure you've all heard of, that was a large scale randomized trial, uh, where they, uh, randomized over 20,000 adult trauma patients, uh, with, uh, 1 g, uh, TXA loading and 1 g infusion, and there was an overall reduced cause morbidity and mortality. Uh, in these patients. The second trial you should know about is the woman trial, which was published in The Lancet last, last year. Along the lines of the CRS too, it was a very large scale randomized trial with over 20,000 patients with postpartum hemorrhage in women in 21 countries, and they also found that TXA, uh, significantly increased death from bleeding. Uh, and morbidity mortality in these, uh, women who had postpartum hemorrhage. And the third large multi-center trial is this, uh, uh, TXA trial in cardiac surgery, and again, the same results, decreased bleeding, transfusion, decreased death, decreased thromboembolic events, uh, but a slightly more seizures because they gave very, very high doses in that group. What do we know about children, um, The, the literature is uh scant, but there's more and more publications. Uh, the main two groups that have been mostly studied are the scoliosis group and the craniofacial surgical group. Uh, and in this, uh, review of the literature, we found that, uh, antifibbrics were effective and safe, and there was stronger evidence for TXA over the others. Um. We did a double-blind randomized trial and published in anesthesiology where we randomized children having craniofacial surgery to either placebo or TXA and we found a 55% reduction in blood loss, a 60% reduction in red blood cell transfusion, and um after this and other, other reports, uh, now TXA is standard of care in craniofacial surgery worldwide. Uh, we just finished this, uh, single-center study in our pediatric idiopathic scoliosis surgical population. It was a placebo-controlled randomized trial, um, and, uh, we're very fortunate to actually start that trial before I think TXA became the standard of care in this patient population. So we randomized 120 adolescents who are otherwise completely healthy, uh, to TXA or placebo, and overall we found a reduction in, in blood loss, uh, across the, across the board, and we were the first to report that, uh, the rate of blood loss over time is significantly different in the TXA group and the placebo group, and this has just been accepted to JBJS and should hopefully be coming out this year. So if you look at the rate of blood loss per hour over time, cumulative blood loss, the placebo group versus the TXA group, there's a significant reduction in blood cumulative blood loss by 27% in our idiopathic scoliosis patients, and the bleeding rate is significantly reduced in that patient population also. So, at national blood management meetings and, uh, major surgical meetings, TXA has been called the game changer, uh, and surgeons more and more asking for it, uh, intraoperatively. And when I talk to my anesthesiologist about it, uh, you know, they say, well, I was trying to get the surgeon to, to use it, but now they're starting to talk about it at all their meetings too, so I need to know more about it and, and what's the dose and what are the guidelines, um. We looked at uh TXA use in the United States Children's Hospital, and this was up until 2013, and mostly it was in cardiac surgery with 64% of uh uh cardiac surgical patients having TXA and lower in the other, in the other groups. Uh, so what was the reason for the, for the low incidence of administration? Uh, same thing in, uh, Canada. Hospitals shun cheap drug use to stop bleeding. Uh, one of the cheapest medical interventions to help stop bleeding is rarely used by Canadian hospitals, even though it could save hundreds of trauma patients per year. And mostly, uh, we're, we're concerned about the side effects, uh, and that's important not to overlook. In this report of TXA associated seizures, uh, it was found that it was likely related to very, very high doses and a multifactorial, um, etiology. We looked and wanted to really put that to rest, and we looked at our, uh, safety profile of giving. antifibroanalytics in over 4000 patients that we included in our pediatric craniofacial group. Uh, and when we looked at the incidence of, uh, seizures in our, uh, patients, there was no difference whether they had, uh, no antifibrolytics or TXA or immunocaproic acid, uh, in the incidence of seizures, and we also found no difference in thromboembolic events in this group. Um, I think this is a really important article because many of us take care of patients that have cancer and that may be at high risk for thromboembolic, uh, uh, events. Um, and this was a safety and efficacy of, uh, lysine analogs in cancer patients, a large, uh, review and meta-analysis where they included 11 randomized trials, over 1000 patients, and concluded that there was, uh, a significant efficacy but no increased risk of, uh, uh, thromboembolic events. So we have to remember that. The mechanism of action of TXA is that it's a clot stabilizer, not a clot promoter, and in all of those three large multi-center trials that I showed you, there was no increased incidence of thromboembolic events in any of those, uh, in any of those groups. And here we have a high-risk group of cancer patients where they also reported no increased risk of thromboembolic events. So we still have far to go. Uh, our pharmacokinetic lab here at Boston Children's Hospital is working on, uh, looking at, uh, pharmacokinetic data. We know it's efficacious. We know it's safe. Uh, we're trying to get dosing recommendations, and we've, we've just published some recommendations, uh, based on pharmacokinetics, but we still have a lot of, uh, information to tease out about TXA and that it has a high interpatient variability, um, but We're able to recommend, uh, specific guidelines, um, and we're the first to do this, and I think this is really important because giving very, very high doses is associated with more side effects. So from our, um, our lab and pharmacokinetic modeling and some prospective trials, we now recommend this dosage regime, um, and, and, uh, this is what, uh, the anesthesiologists in our department are, are told to use. So I have 2 or 3 more slides and then we're done. I want to introduce to you, uh, a little, uh, information about, uh, transfusion algorithms. Um, so, the, the Boston Children's Hospital massive transfusion protocol. Uh, is something that, uh, is available if you have a patient with massive bleeding. Massive blood loss is defined as that exceeding one blood volume in 24 hours, and in our operating room, um, the definition that we use mostly is greater than a 50% total blood volume loss in less than 3 hours, which we had yesterday in our operating room. So what is the goal of a massive transfusion protocol? Well, certainly studies in adult trauma patients have shown that a 1 to 1 to 1 ratio avoids giving, uh, just packed red blood cells, and it avoids coagulopathy as a consequence of platelet and clotting factor depletion, uh, secondary to just transfusion of, uh, red blood cells. Um, and here's our, uh, Uh, massive transfusion protocol for Boston Children's Hospital. Very simple, less than 5 kg, they get 1 to 1 to 1. You call the blood bank, you activate the massive transfusion protocol. This is available on our website. Um, and they immediately send, uh, red blood cells, FFP, and, uh, platelets, no cryo in this, uh, algorithm, which there probably should be, and I would mostly wanted to highlight that this is something we should activate, uh, routinely. I think it's only if all else fails, shit's hitting the fan, the patient's massively bleed. Bleeding and you just want to get all hands on deck, uh, activate the massive transfusion protocol, and the blood bank will send you, um, 1 to 1 to 1 ratio as fast as they can, but very, um, be aware that these, uh, may have a high potassium load, that they just send the quickest blood that they can get their hands on. Uh, crossmatched to the patient and therefore, there, it's not new blood, it's not washed blood. So you need to specifically ask, uh, for the blood bank to do that. Um, and I would propose that more goal-directed treatment, uh, would be, you know, the way we should go routinely. Um, if we look at all the reports of massive transfusion protocols in our pediatric patients, there's only a handful, and although we have good literature in the adult population, that doesn't necessarily, uh, trickle down to the pediatric population. And what they've shown is that really, um, it, it's not even feasible, let alone effective at treating um our massively bleeding pediatric patients. Um, so we need larger studies to determine whether MTPs will improve outcomes. Right now, we don't have that data in our pediatric population. So this is a very busy slide, and it's a draft of what uh I'm working on with the transfusion committee. I've presented this to uh the, the transfusion committee, to the, uh the, the ICUs, uh, I'll present it to the, um, I presented it to the trauma committee, to our, uh, anesthesia department, and, um, it's proposing maybe uh another approach to Uh, bleeding and massive hemorrhage in our pediatric patients. Uh, so this is a work in progress. Uh, it incorporates our massive transfusion, uh, protocol, but it also is, I think, a more mindful approach in an algorithm. Uh, that you can use when a patient is, is bleeding. Uh, and it's, it's a goal-directed therapy. So there's criteria for activation. There's goals to maintain, uh, hemoglobin, fibrinogen, INR, and platelets. There's There's, uh, suggestions on what your transfusion volume should be, uh, and there's also considerations for giving TXA, maintaining nothermia, how to treat hypomagnesmia, acidosis, hyperkalemia, and hypocalcemia. Uh, so this is a work in progress and you may see, uh, this, uh, being rolled out hopefully in the next, uh, year, and I would welcome your input into how to make this. Uh, user-friendly, but hopefully, it might be something we can pull up on the screen, uh, and so that we can get everybody on a protocol of how to approach these patients, um, more mindfully. So what's the take-home message? Uh, bleeding and blood transfusion is associated with increased mortality and morbidity in our children. A blood transfusion can be life saving or life-threatening. Uh, I would suggest that we use multimodal blood conservation strategies, uh, to, to keep the blood in the patient, which is your job as surgeons, and most of you do a very good job at doing that, so it's a pleasure to work with you everyday, um, to reduce blood transfusion and to reduce blood transfusion-related complications. Um, what we don't know is what are our metrics here at Boston Children's Hospital, and we don't know what your metrics are for blood transfusion in the operating room. Um, should we measure that? Are we interested in that? Could that help, uh, improve patient care? That's the question. Should we more mindfully diagnose and treat preoperative anemia in our patients? Should we have them, uh, when they're seen in the surgical office, sent for Uh, blood work? Should we screen them for iron deficiency anemia, given that probably 25% of our population are anemic? Um, right now, they come to the pre-op clinic the day before and we get the labs the day of. Should we use antifibrolytics? And would Boston Children's Hospital benefit for, from a patient blood management program? Can we improve patient care by decreasing transfusion? Thank you for your attention. Start at the first very compelling lecture and appreciate you giving it to us. I have two questions. One, I, I remain concerned that the neonate group, um, that the anemia may be a marker for more serious illness. In other words, the kids are getting multiple blood draws all of the time as compared with the neonate in the preemie in the bed next to them, that's not, that, that there may be, as you said, That the anemia may be a marker for some underlying morbidity that's really hard to, to tease out. The, the second question is, so what would you recommend are the um guidelines that we should be using in the operating room as far as when kids get transfusion? By age, and are there physiologic studies that show at what, what level a child with a decent heart and lungs are going to be affected by progressive anemia? Definitely, I have 4 or 5 slides on restrictive versus liberal transfusion strategy, and there's really good data. That's what we know best about is, is the red blood cell transfusion threshold, and we, the, the literature supports a restrictive transfusion, uh, strategy. So, uh, hematocrit of 7. In a critically stable patient, like a, a patient who's stable in our ICUs, 7, but in an actively bleeding patient in the operating room, 8. And if they have comorbidities, um, there's some thought that maybe pushing it a little higher, depending on what that comorbidity is. So if you want a number and, and you know, most uh experts recommend not treating a number, um, and treating the, the, the patient and the, uh, and the clinical situation. But if you want a number, uh, there's good literature, to support the TRIP ICU trial, um, specifically to, uh, to, uh, go with a, uh, restrictive transfusion strategy of 7 in a stable child, 8 in an actively bleeding child. But the thing we don't know about is what we should do for coagulopathy. Should we have a tolerance for a mild coagulopathy? Um, and, um, you know, the most, probably the most critical thing that we don't think about is the fibrinogen. The fibrinogen is really the thing that's gonna keep your patient bleeding if it's low. And so North American guidelines have been a fibrinogen of 100, but European and Australian, uh, and Canadian guidelines are 200. Uh, and we had a patient yesterday who had a fibrinogen of 65 at the end of the case who needed, who needed cryoprecipitate. So we have to keep in mind that it's really not the You know, maybe it's not the red blood cells, but maybe it's the coagulopathy that we need to be mindful about treating, and there's no good um data right now for numbers on what we should tolerate for coagulopathy, except that fibrinogen level. That But you're right about the neonates, and it's, it's definitely a marker of disease severity. It's one of many markers, anemia. So if they're anemic, if they get a blood transfusion, if they're mechanically ventilated, if their weight is less than 2 kg, if they're premature, those are all, you know, factors that increase morbidity and mortality. The question is, is can we Uh, decrease that mortality by treating the anemia, whether we treat it preoperatively with other measures, such as trying to bump the hematocrit up with EPO or IV iron, with, with, uh, some pediatric centers are using in their, uh, preoperative patients, or what a transfusion preoperatively. You know, decrease that risk of, of anemia. We don't know, we don't have the answers to those questions. Additional questions for Doctor Wilby. The front row is full of questions. Uh, a couple of questions. One would be the more use of, uh, tag or thromboelastogram or rotam or other measures to guide our administration of products, um. That'd be one thing. And the other would be there, I know there's some interest from military data and adult trauma data on the use of whole blood in an actively bleeding patient. Is there any interest in, in that in children? Those are excellent questions. Um, I've been struggling with thromboelastography and rotim, uh, for the last 5 to 10 years. Um, we have one rotin machine. It's up in the cardiac ICU. Uh, we managed to get it, um, I, I managed to get it in the COAG lab up there, and it's just for research purposes, um, and we had a patient yesterday who was, who bled half their blood volume, and I was waiting an hour for the coags and the fibrinogen to come back, and I could have had the answer in 1 minute with less than 5 minutes anyway, with Rote or tag, and it would have been able to guide me, goal directed therapy. Uh, for knowing that the fibrinogen was low just by using thromboelastography. So it's a dynamic, uh, look at the, at, at the, uh, at the blood clotting, and, uh, there, it hasn't caught on, uh, that much in, in the United States, but certainly in Europe, uh, and in other countries like Australia and in Canada, uh, rodents are set up in every operating room. Uh, and they have real-time feedback on, um, on bleeding. We're doing a pilot study now in our liver transplant patients. We're just screening and monitoring Rotem, uh, to see if we can look and if we would have predicted transfusion based on Rote different from what they got, uh, to try to see if that would have made a difference, uh, in, in that one patient population. First question. Second question is whole blood. Whole blood is really a hot topic at a lot of um national meetings. Blood bankers hate it. Uh, it's difficult to, uh, to get, it's difficult to store, and, um, but there are some hospitals that have whole blood programs. I know CHOP, uh, for craniofacial surgery, um, they bleed a lot more than our, our surgeons do, so they're giving massive transfusions in their craniofacial surgical patients, they just use whole blood. If you think about it, it makes sense because not only, it's like you're 1 to 1 to 1 in a, in a, in one bag, but you've got everything else in there. So it, it makes sense, um, and but then that's one extreme of, of treatment. I'm on the other side with, let's keep the blood in the patient. Let's use good patient blood management strategies, so we can avoid the need for having to go with the whole blood. But if you have a massively bleeding patient, greater than half of blood volume, and if I had the choice, I'd give whole blood, uh, in that situation. But if we can take it to the extreme where we're decreasing bleeding, And using all our other conservation strategies, and we don't need to give that. We don't have 50% of our blood volume loss. That means, that's a better way to go for our patients. And our hospital currently doesn't have that option, right? We don't, um, we have it. I mean, they can, we, we can get it if you ask Steve Sloan, um, I'm sure, you know, but they, they don't, um. Routinely support it because there's a lot of controversy about, about the benefits. Uh, thanks for a great talk. Just a question. The, the data on, um, immunomodulatory effects of red blood cells, red blood cell transfusion is pretty compelling. I was just wondering if there are, um, equivalent data on transfusion of other blood components, um, such as FFP platelets or cryo, particularly as you're talking about fibroanalysis. Um, whether there's any reason to worry about those, uh, and more so than, more so, so than packed red blood cells, there's a higher incidence of trim trolley taco, uh, with using FFP, uh, in particular, uh, uh, plasma, uh, compared to, uh, the others, and that, that's really the culprit, uh, and you know, most people who talk about blood and blood transfusions think about. Uh, a very narrow view and some of my talk was like that too, just talking about red blood cells. We seem to always hone in on red blood cells, but, uh, you know, the, the other. Uh, and that's what the literature is concentrated on in the last 10 years. I think we're gonna be seeing a shift to looking at, uh, the consequences of giving, um, you know, plasma and also treating coagulopathy more aggressively also. Um, so yes, there's a much higher incidence of those, uh, adverse, uh. Events with plasma. Uh, thanks very much for a great talk. Uh, every few years we seem to have an M&M where someone has a hyperkalemic arrest after massive transfusion. It would seem relatively easy to actually determine what the potassium content is of red blood cells. Why don't we have that? And why is this potentially avoidable complication, which is catastrophic, not a zero intolerable event? Yeah, in the last, I would say maybe 6 or 9 months, there's been probably about 8 to 10 cases of not hyperkalemia, but I just want to look more broadly. In our operating rooms, there's been a number of cases within the last 6 months to a year of adverse events, major morbidity mortality directly related to blood loss or blood transfusion. Uh, and, you know, part of that reason was why I wanted to develop this sort of protocol or algorithm or whatever just to give our fellows and residents and, uh, and faculty guidelines of treating. And when I looked into, um, one of them was a hyperkalemic cardiac arrest in a, in a patient who, uh, I think the MTP was activated and they got 1 to 1 to 1 and, and that's why I really want to, uh, you know, make sure everybody knows that when you activate that MTP they're gonna send you the only blood that they have, unless you ask them to wash it or ask for new blood. There is a way to measure potassium, number one, just, you could just take a, take it and send it to the blood gas. That that's one way. The other way is that if you do get that, yeah, but shouldn't, shouldn't the routine, shouldn't the people who give you the blood, it's if they know it's old blood, they'll say, you know, let me check the potassium on this because I'll give you an example. I was putting a patient on VA ECMO. This was quite a few years ago, and the patient. Just went into arrest. We did a, uh, it wasn't a, obviously we're on bypass, so no untoward consequences. However, we did the echo. Uh heart was frozen diastole. The potassium was over 8. We treated it. The patient did fine, but it seems totally unnecessary to have that event. Uh, why doesn't the blood bank test potassium in their blood? Um, because it's, it's, I mean, I, I wish Steve Sloan was here to answer that question, um. You know, I think that he would probably say, uh, that, you know, when you look at a number of units of, of blood in the blood bank, you know, they may randomly test for potassium, but that's not gonna really tell you anything because the patients who are at higher risk are those that are getting massively transfused. So it's not one unit, it's like the exposure to multiple units and the accumulation of potassium. In, in, you know, those units unless you have a small baby and then they're less than 5 kg and they get, uh, you know, 10 per kg which is only 50 cc's of blood, but if that has a high potassium concentration, um, Yeah, they could have a hyperkalemia cardiac arrest. That's why we shouldn't activate the massive transfusion protocol. That's why in our operating room, we have a policy if a patient's less than 10 kg or less than 12 months, they'll automatically get fresh blood or washed less than 10 days or washed blood, uh, which is a low potassium load. But if you have a patient who's, uh, 13 months old or 11 kg, you're not gonna get that. You specifically need to call the blood bank and say, This patient's at risk for, you know, massive blood loss. I want your new blood or washed blood for this patient, even though they don't meet that criteria. That's why the Wake Up Safe for the Pediatric Society of Anesthesiology recommended uh that, that patients less than 1 year or less than 12 months. Get, uh sorry, less than 10 kg, get fresh blood or washed blood because there was 12% incidence of cardiac arrest, and some of those cardiac arrests were because of hyperkalemia. So there's a, you know, a mandate by our society now that babies, small babies need to get fresh blood or washed blood unless you activate the MTP then you don't know what you're getting. Final question for Doctor Gobi. Oh, and the other thing I was gonna say is we have a cell saver in the operating room, so we can always wash the blood with the cell saver before giving it. That's another option that we have in our operating room is to take that pack of cells from and, and just wash it before we give it. Doctor Zurkowski. Well, I'd have to agree with Doctor Schamber. We're very informative talk and uh Very compelling. Multivariable, uh, multifactorial factors that go into not only the blood management, but things like screening for anemia, iron deficiency, and the best way based on CBCs to actually assess, um, anemia and the risk associated with anemia. But when you talk about unnecessary transfusion, Whether it's uh an orthopedic case, cranial facial case, a general surgical case that's very long, a prolonged case. Could you comment or emphasize the importance of AFs including TXA in particularly long cases? Yes, um, well, at least we've shown in our scoliosis population that the longer the surgical procedure, the increased risk of blood loss over time and the more independent effect of antifibrolytics at decreasing bleeding and blood loss. Uh, so, you know, uh, it, it. Mm it's up to the surgeon. If the surgeon has a quick surgery, then, uh, then that's good. If it's a long, bloody surgery, then, um, then higher risk of bleeding and, uh, we've shown that for those surgeons that have more complex cases, uh, you know, across the board, just say for the scoliosis cases, for those surgeons who take, who have longer operating room times, whatever, whatever the reason. And if they're more complex cases, more, uh, levels fused, uh, etc. then those cases that are over 4 hours, uh, you know, the difference in blood loss and bleeding in the antifibrinolytic group, uh, versus the placebo group is, is, is more, and so the more effective antifibrinolytics are over time. Is that what you meant? Yes, and, uh, particularly in terms of avoiding potential intraoperative or perioperative complication in a long case, as well as reducing the risk of transfusion. So it seems like the potential benefits of anti-fibroanalytics are potentiated with a very long case or a surgically complex case. Yeah, and I'll just leave everybody with one comment. You probably remember the coagulation cascade and the factors 1 through 13. Well, there's two other factors. There's factor 14 and factor 15, and they're probably the most important factors of all. And factor 14 is the surgeon, and factor 15 is the anesthesia. io log ist s So we work as a team to help, uh, take care of the patient, and there's nothing that the anesthesiologist can do if, if there's large volume blood loss from like a bleeding artery or something like that. And there's nothing the surgeon can do if the anesthesiologist is loading the patient up with fluid and not managing the hemodynamics. So, you know, we can talk about blood is bad, blood is good, you know, bleeding is bad, bleeding is good. Um, you know, the fact of the matter is, is we work with very, very complex patients, and, you know, every day we're in there working as a team to help, uh, make the operation as safe as possible for our patients. Susan, thanks so much for a great talk. I. Right. I