All right, thank you for the opportunity to present today at this late-breaking session. I am here to present for our team, which is large, as it takes a village to perform a trial like this. And as Sapna said, we were published last week in Pediatric Critical Care Medicine. If you have any questions, you can refer to the article further. Our disclosures are the study was funded by the Gerber Foundation's National Research Grant and then also by Harvard Catalyst Clinical Research Center and the Institutional Centers for Clinical and Translational Research at Boston Children's Hospital. And below, you can see the individual author's support, although all are not necessarily relevant to the trial conduct. To start us off, as all of us know in this room, upper GI bleeding due to stress ulcer formation is a known complication of critical illness. When I think about critical illness, we think about increased catecholamines, low blood pressure, and hypovolemia that lead to low cardiac output. This can result in increased SVR and activation of our inflammatory cascade, which can lead to splint neck hypoperfusion and ischemia, which is often a complication we find in the pediatric cardiac ICU for our patients. The results of splint neck hypoperfusion and ischemia decreases bicarb secretion in the stomach, can decrease GI protective hormones, motility, decreases mucosal blood flow, and increases acidity, which increases the risk for stress ulcer formation. And as we know, those ulcers erode into gastric vessels and can result in upper GI bleeds. Upper GI bleeds have been associated with increased morbidity and mortality in critically ill patients, specifically in increased hospital resource utilization. As you can see on the right, there is an increase with ICU length of stay, and on the left, there's an increase in mortality when we look at adults that are critically ill. To try to combat from stress ulcers forming, since the early 1990s, the practice has generally been to ubiquitously prescribe stress ulcer prophylaxis. And this has eventually transitioned to the pediatric and neonatal ICUs as well. Stress ulcer prophylaxis is prescribed to prevent upper GI bleeds. And in this meta-analysis in 2018, you can see there's a trend towards benefit. But what we've known over, or what we've seen over the last 10 to 15 years, is that there's an increase in the adverse outcomes associated with stress ulcer prophylaxis, and specifically with hospital-acquired infections. The common adage is that pediatric patients are not small adults. And that is certainly true when we think about this as well. Risk factors for upper GI bleeds are unique for children that are critically ill. And that can include organ failure in high ventilator settings. And the adverse outcomes associated with stress ulcer prophylaxis are specifically unique as well. We do see ventilator-associated ammonias that have been previously described by some of the authors in our group. And in the neonatal ICU, they've published a number of studies also with hospital-acquired infections, but specifically necrotizing enterocolitis mortality that has led to a black box warning for most stress ulcer prophylaxis. Despite that, we still prescribe it to our patients. And I'll come back to this picture just to stress that our patients in the pediatric cardiac ICU are at risk for all of, from splint neck hyperperfusion and ischemia on. And specifically, in the pediatric cardiac ICU, there's some unique characteristics that put them at higher risk for stress ulcer formation. And specifically, that is most of our patients, somewhere between 70% to 80% are less than one year of age. We're mostly a surgical unit. We have lots of risk factors, including low cardiac output, use of mechanical ventilation both preoperatively and postoperatively, high incidence of end organ injury, fortunately temporary, and high-risk medication use. And that includes IV NSAIDs, high-dose aspirin, and anticoagulation drugs. And at times, steroids. And so our objectives were to investigate the feasibility of conducting the clinical trial, assessing the safety of withholding stress ulcer prophylaxis in infants with congenital heart disease in the cardiac ICU. We defined four a priori criteria for feasibility that included screen rate, consent rate, drug allocation, and protocol adherence. And our secondary outcome was to compare the rate of clinically significant upper GI bleeds, which I'll define in a minute for you, and hospital-associated infections in patients receiving stress ulcer prophylaxis versus placebo. This was a single-center, double-blinded, placebo-controlled pilot feasibility, randomized control trial. The inclusion criteria were infants that were less than 12 months of age. As previous papers have shown, that the incidence of upper GI bleeds in this patient population is quite low. And at our own institution, over an eight-year period, we only had four episodes of upper GI bleeds. We included patients who were diagnosed with anatomic, myopathic, or arrhythmic heart disease. And we required them to anticipate respiratory support for greater than 24 hours. Respiratory support was defined as either mechanical ventilation, non-invasive ventilation, or high-flow nasal cannula. And the reason we selected this as an inclusion criteria was to try to pick higher-risk patients. Exclusion criteria, some of them make sense. If you had received acid-suppressive therapy for greater than seven days in the last month, a lot of our patients have quote-unquote reflux and are on acid-suppressive therapy as a baseline medication when they come in for procedures. If they had received one dose of acid-suppressive therapy during the eligible admission, if they had an active GI bleed or active H. pylori infection, if they were on high-risk medications, as I alluded to previously, those included high-dose aspirin, some anticoagulation agents, specifically direct thrombin inhibitors in G2B3A because there are not reversal agents readily available for them in our patient population, and IV NSAIDs if they were planned to receive a course of that in their post-op care. We also excluded patients who had planned a recent GI surgery because most of the time general surgeons will prescribe reflux medications and were proximal to that, and then patients who required mechanical support. This is a schematic of our study. Randomization was by permeated block, and it was across two treatment groups, and we pre-identified two strata. One was medical-surgical, and one was neonates versus infants. The intervention was an H2 receptor antagonist or placebo. The nurses received individualized dose syringes that were blinded to both the nurse and family and provider were all blinded to them. We selected an H2 receptor antagonist because that was our institutional preference for stress ulcer prophylaxis prior, and also, if I have a minute at the end, I will share, we conducted a survey, and 75% of pediatric cardiac ICUs around the country use H2RAs as their stress ulcer prophylaxis agent of choice. Our outcomes were defined as feasibility, and that was screening rate of greater than 80%, consent rate of greater than 20% based on historical interventional trials in the critical care environment in children, drug allocation, meaning receiving the study drug within 48 hours, and we hope to achieve that 80% of the time, and protocol adherence of greater than 80%. The safety outcomes were incidence of clinically significant upper GI bleeds. We adopted the adult, previous adult definition for clinically significant upper GI bleeds, which was a new bleeding event with either a decrease in your hemoglobin by two, a decrease in your mean arterial blood pressure by 10, or increase in vasoactives, or an increase in heart rate by 20, which we also amended to make sure that it was in the absence of arrhythmias, which is a frequent thing we see after congenital heart surgery, if they had an unanticipated transfusion or an unanticipated GI procedure. We also identified hospital-associated infections or acquired infections and used the CDC guidelines for that. We also identified upper GI bleeds, which means they did not qualify under the definition of clinically significant upper GI bleeds in both medical and surgical NEC. In the results, we had 1,426 patients, of which we were able to screen 1,425. When we looked at ineligibility, the ones that stuck out the most were patients who did not require respiratory support for greater than 24 hours. We have a robust enhanced recovery after surgery program at Boston Children's Hospital, which dictates the amount of time we hope they are ventilated postoperatively. And we also had nearly 100 patients who planned to receive IV NSAIDs. That's one of our multimodal pain treatments for children that are over six months of age. On the 1,400-plus patients that were screened, we had 132 then that were eligible, and 70 were consented. Two patients were consented in their pre-op visit, but then did not require cardiac surgery and therefore did not go to the cardiac ICU. So we randomized 68 patients. In there, we had 34 in the placebo arm and 34 in the H2RA arm or study arm. We had 28 complete the study in the placebo arm. One came out because they got a direct thrombin inhibitor after having a BT shunt placed. And four received open-label acid suppressive therapy. And then we had 30 complete in the study arm, of which, again, one came out because they had direct thrombin inhibitor after a BTT shunt placed. And then three received open-label acid suppressive therapy after randomization. Real-world figure here in that we started the study in 2019. Some might recall in September of 2019, the FDA recalled ranitidine, which was our original H2RA of choice. And that was due to concerns about increased level of a carcinogenic agent. And so we took an eight-week pause to amend our protocol and switch to famotidine. And then, unfortunately, 2020 came. And we had an eight-month pause for all research at our institution. And so that was the effect of the COVID-19 pandemic. When you look at results, so our overall cohort and then our placebo and our study, you can see that they're equally distributed. Specifically, the strata that we were worried about was age and surgical admission. And they are statistically similar. We had a good mix of patients with both normal, meaning an arrhythmia or myopathy, isolated heart disease, complex by being single ventricle between the groups. A majority of our patients were surgically admitted. They had relatively high surgical complexity score with a stat score, median score of four. Their cardiopulmonary bypass times were similar. And their median time on study was similar as well. When we think about our feasibility outcomes, our screening rate was nearly 100%. Our consent rate was 53%, which, comparing to historical studies conducted by the Pediatric Heart Network, is within that realm. They range somewhere between 50% to 60%. Our drug allocation rate was 100% thanks to our investigational drug pharmacy. And our protocol adherence, which we're happiest about, was 85%, with equal number of open-label acid-suppressive therapy between groups. We did both an intention-to-treat and as-treated analysis for our statistics. But they were similar, so I'll only show you the intention-to-treat analysis here. None of the patients did we have a clinically significant upper GI bleed. We had one episode of tracheitis and CLABSI in the study arm, and we had one episode of mediastinitis in the placebo arm. So relatively similar distribution of hospital-associated infections. The minor GI bleeds were a little bit higher, although there were three events in one patient. And it still did not reach statistical significance in either the intention-to-treat or as-treated analysis. There was no medical NEC, and there was no surgical NEC. And so therefore, our conclusions were that a randomized controlled trial assessing the safety of withholding stress ulcer prophylaxis in infants with congenital heart disease is feasible. We had no episodes of significant upper GI bleeds in the trial, importantly. And our next step is to conduct a multicenter trial powered to detect the safety, meaning the incidence of upper GI bleeds and benefits, which hopefully is a decrease in hospital infections of withholding stress ulcer prophylaxis. And we're currently analyzing the gut microbiome profiles of these patients as potentially a mechanistic link between why we see an increase in hospital-associated infections. I think that there would probably be some questions about why we think we need a bigger trial. And so just as a carrot to get people excited, some of this is from a survey that we conducted that has not been published yet, and from a review of the PHIS database. So we often get the question, is there equipoise? Specifically, our head of cardiac surgery asked us, why are we doing this anymore? Just stop. And so when we surveyed across the countries, there's definitely equipoise about who is prescribing stress ulcer prophylaxis and for what indications. The perceived incidence of upper GI bleeds is actually quite high, somewhere around 5% compared to what is actually experienced. I think in our future trial, we would likely modify the inclusion criteria. I think we felt that being younger was protective. And in fact, the younger patients had an increased incidence of upper GI bleeds. So potentially, we would include older patients as well. In our analysis of the PHIS database, mechanical ventilation was actually not a risk factor, and IV NSAIDs were actually not a risk factor. So potentially, we would not include those as inclusion or exclusion criteria, which would definitely open up patients eligible for the study. People ask us, do upper GI bleeds actually impact outcomes? And again, looking at the PHIS database, it appears that from a resource utilization perspective, they do. They affect the duration of mechanical ventilation, ICU length of stay, hospital length of stay, mortality, and costs. And are there adverse outcomes associated with stress ulcer prophylaxis in our patients? And again, universally, there's an increased incidence for ventilator-associated pneumonia, CLABSI, UTIs, surgical site infections, neck, and thrombocytopenia. And so I think with all of that evidence, we're in a good position to advocate for a larger trial to see if this is an antiquated practice that we should be done with. So I will take questions after the session. And if anybody wants to partake in the larger study, we're looking for centers. And so please email us. Thank you.

stress ulcer prophylaxis

congenital heart disease

pediatric cardiac ICU

randomized controlled trial

hospital-acquired infections