So welcome to this last late-breaking session. We've got four fascinating presentations today that will all affect patient outcomes. So my name is Emma Granger, and I'm editor-in-chief of the Lancet Respiratory Medicine, and I'm one of your co-moderators today. I'm delighted to be joined by my co-moderator, Ravi Thiragujaran, who's at the Boston Children's Hospital sitting on my right. So we're hoping today that there'll be lots of questions, but there won't be time for questions probably at the end of the session in the room. But if you did want to talk to any of the speakers, please go outside, turn left, and there's kind of an area where you can congregate. Thank you very much. So over to you, Ravi. Thanks, Emma, and good morning, everybody. Our first speaker is Dr. Lars Palmowski from the University Hospital in Bochum, Germany. And his topic is going to be Timely Cessation of Proton Pump Inhibitors in Critically Ill Patients Impacts Mobility and Mortality, a Propensity Score Matched Cohort Study. And this was published in Critical Care Medicine. Dr. Palmowski. Good morning, everyone. Thank you to the SSCM for being here, for the opportunity. Our study is titled Timely Cessation of Proton Pump Inhibitors in Critically Ill Patients Impacts Morbidity and Mortality, a Propensity Score Matched Cohort Study. And all authors declare no conflicts of interest and no funding was received. So let us examine proton pump inhibitors. The major representative of the drug class of proton pump inhibitors are pentopretzol, omepretzol, and esomepretzol. And the mechanism of action is an irreversible inhibition of the proton pump in the stomach. And we're facing the following situation. Proton pump inhibitors are among the most commonly prescribed medications worldwide. And they're ranked third among the most prescribed medications nationwide in Germany in 2021. And approximately 40% of all patients over the age of 17 regularly use proton pump inhibitors. So let's take a look at the diverse spectrum of indications. And for an intensivist, the term gastrointestinal bleeding will catch attention. A major focus of PPI therapy on the ICU resolves around stress ulcer prophylaxis. Depending on the study, up to 90% of patients on the ICU are treated with proton pump inhibitors. And currently, it's up to debate which patients actually benefit from SUP. But what's not up to debate is that SUP is only a temporary indication. And therefore, timely cessation is essential. However, PPI therapy initiated in the ICU is at risk of being continued throughout the patient's hospital course and even beyond discharge. So let's take a look at the potential side effects of PPI therapy. And it gets evident that potential side effects are pre-described in the literature in a diverse way. And it would be particularly tragic if patients suffer from side effects of PPI therapy, although they do not require PPI therapy anymore. And here our work begins. We tested the hypothesis that continuation of PPI therapy without an indication beyond hospital discharge is associated with an increased incident of adverse effects, an increased re-hospitalization rate, or an increased mortality. And a retrospective analysis of data from a large German health insurer. Our aim was to form a cohort of patients who received an ICU treatment who were critically ill and exhibited the following additional characteristics. Not receiving PPI therapy before hospital admission. A newly initiated PPI treatment during the ICU stay. And no coded indication for PPI therapy beyond eight weeks after hospital discharge. Our study cohorts composition and certification were as follows. 11,576 ICU patients were included who received proton pump inhibitor therapy for the first time during the ICU stay. And no one of them had an indication for its continuation. Patients in group A did not receive further proton pump inhibitor therapy beyond hospital discharge as they had no indication. In contrast, patients in group B had their PPI therapy initially at the ICU, continued after hospital discharge, and as just described, without an appropriate indication. And to test our hypothesis, we established the following three endpoints. The incidence of pre-described adverse events associated with PPI therapy, the re-hospitalization rate within one year, and the mortality rate in two years. And for good comparability of the groups, we conducted propensity score matching, including a total of 12 variables. So let's move on to the results. Here you see the baseline characteristics of our matched cohort. And it becomes immediately evident that 4,825 patients out of the total cohort of over 11,000 patients received PPI therapy beyond hospital discharge. This correspondence to a proportion of 41.7% of former ICU patients who were discharged from the hospital was ongoing, unnecessary PPI therapy. Now I'd like to draw your attention back to the baseline characteristics. Through propensity score matching, we achieved a proper comparability. And in particular, some concomitant medications were of interest, like anticoagulants, antiplatelet medications, NSAIDs, or glucocorticoids. We also aimed for matching by the comorbid conditions. And here you see a balance ratio except for chronic kidney disease, diabetes, and hypertension, but with a trend towards a higher disease severity in the non-PPI group. Other variables we aimed for comparability were the primary ICU conditions within 10 categories, and also some relevant secondary diagnosis acquired during ICU stay, like acute kidney injury or sepsis. Here you see the re-hospitalization rate and a selection of pre-described adverse events in association with PPI therapy. First, let's take a look at the re-hospitalization rate. And it becomes evident that continuation of PPI therapy without an appropriate indication is associated with a 35% increased risk of re-hospitalization within the first year. Considering gastrointestinal and renal diseases, there were more frequent diagnosis of clostridium difficile infections and chronic kidney disease in association with PPI therapy. Patients suffered more frequently from cardiopulmonary diseases. There was an increase of 17% of the risk of cardiovascular events, and 27% increased risk for pneumonia. There were increased incidences of malignant diseases like esophageal cancer, colorectal cancer, and pancreatic cancer in association of prolonged PPI therapy without an indication. And finally, when examining malabsorption disorders like vitamin B12 deficiency, hypomagnesemia, and hypercalcemia, there was an increased risk in association with PPI therapy. And now let's take a look at the mortality. Here you see a Kaplan-Meier curve. On the x-axis, you see the days after hospital discharge. And on the y-axis, you see the percentage survival of our cohort. And when examining the timeline, you see that during the first year, there's no significant difference in the mortality rate. But when examining the second year, it becomes evident that there is a 17% increase of mortality risk in association with prolonged PPI therapy without an indication. So summarizing our findings, the proportion of patients with continued PPI therapy without an objectifiable indication was 41.7%, or in absolute numbers, 4,825 out of over 11,000 patients. And continuation of this PPI therapy post-hospital discharge is associated with increased morbidity, a 35% increased risk for rehospitalization within the first year, and 17% increased mortality risk observed over a period of two years, which leads me to my final slide. We identified an excessive overtreatment with PPI in prior critical patients after hospital discharge. And this unnecessary continuation of PPI therapy has implications for both morbidity and mortality. And finally, our data necessitate more attention from ICU physicians regarding communication and interventions to ensure the time discontinuation of an only temporary indicated PPI therapy. Thank you very much. Thank you very much, Dr. Palmarski. So we're moving on to our second speaker now. So our second speaker is Dr. Gayan Kayaster, and he is going to talk today about reducing antibiotic treatment duration for ventilation-associated pneumonia. And it's a multicenter, individually randomized, open-label non-inferiority trial, the RIGAV-BAP trial. And this is hot off the press, so it was published yesterday in the Lancet Respiratory Medicine. So over to you, Gayan. Thank you. Thank you, Ma'am. Thank you, everybody. So RIGAV-BAP, reducing antibiotic treatment duration for ventilator-associated pneumonia. I have nothing to disclose, and this involves six hospitals, one in Nepal, two in Singapore, and three in Thailand. And Oxford University is the study sponsor, as well as Moroo, and the funding is from Medical Research Council, UK, and National Medical Research Council, Singapore. So a lot of good people are involved in this research. Moin is the research fellow and infectious disease specialist who put all these things together. So I'll try to cover a little bit about background research, methodology, results, discussion, and conclusion, introduction. So VAP, ventilator-associated pneumonia, is very common in ICU, and it's one of the main drivers of antibiotic prescription. So quite often, we start with clinical suspicions, and you see clinical diagnosis is overly sensitive, poorly specific, and costly. Sources are not identified initially, and quite often, it's wrongly diagnosed. Microbiology is very important, but it's time-consuming, and quite often, we cannot differentiate between colonizers versus pathogens. And so empiric antibiotics, broad-spectrum antibiotics we tend to use. Antibiotic stewardship is important, but usually it is not available in developing countries. And it is important in the sense of reducing inappropriate antibiotic choice use and inappropriate durations. So what do we know? This is the most recent study, systemic review and meta-analysis of randomized control trials in comparing short- versus long-course antibiotic therapy in ventilator-associated pneumonia. This was done by Dangmuri et al., and published in eClinical Medicine in April 2023. They looked at five different studies after screening for more than 300 trial studies, and three of them are from France, one from United States, and one from Tunisia. So in this meta-analysis, there is no significant differences between primary outcome and secondary outcome. Primary outcome, in the sense, recurrence and relapse of pneumonia. Secondary outcome, ventilated mortality, ICU stay, and ventilator days. So in these studies, actually, there's no mortality difference. You can see arbitrary durations, not catered to clinical response, and there's a small trend towards increased recurrence in non-fermenting gram-negatives. And it is exclusively done in high-income settings, and there is no inclusion of culture-negative map. And you can see here, in this forest plot, all these studies cross one at 95% confidence interval. Even in VAP, due to non-fermenting bacillus and gram-negatives, there's no difference. So our methodology regarding VAP is a pragmatic, multi-center, non-inferior, individually-randomized controlled trial. So it starts with screening, and we take consent mainly from the patient's relatives. And once the patient is fit for antibiotic stopping criteria, very simple criteria, no fever for 48 hours or more, and patient is hemodynamically stable without any use of inotrops or vasopressors. And we randomize the patient, and we stop antibiotic as early as three days if it's culture-negative, and in culture-positive cases, as early as five days in short-course antibiotic therapy. But as in long course, we give at least eight days. So we try to give culturally-directed antibiotic choice, and individualized duration in terms of short or long course, and primary outcome, 60-day mortality of pneumonia, 60-day mortality or pneumonia recurrence. Secondary outcome, length of hospital stay, ICU stay. Similarly, these carbapenem resistant cases. And this is spread on 39 ICUs in six hospitals, two in Nepal, two ICUs, and eight in Singapore in two hospitals, and rest in Thailand in three hospitals. So enrollment started May 25, 2018 to December 16, 2022. So we screened about 11,000 patients, and about 10,000 patients are excluded, and most of them didn't meet the criteria. About 2,200, 22 made exclusion criteria. Out of that, about 1,000 had concurrent infections. Some of them had SOPA score more than 11, and 403 patients were immunocompromised, and 203 had already received antibiotics. So a lot of patients didn't meet the criteria. And out of that, 461 patients were randomly assigned in short-term, 232, and long-term, 229. So one patient was excluded from short-term, altogether 231 in short course, and 229 in usual care group. So baseline characteristics, you can see, age is 64 years average, and 42% female. Not that much difference between the two groups. Most of the patients are referred from other hospitals, and most of the patients are from surgical ICU. And duration of intubation prior to VAP is about 15 days in short-term and 14 days in long-term. And SARS-CoV-2 score is also not that different between the two groups. And reason for intubation, mostly respiratory cause, and second most common is neurological cause. And infection severity on enrollment, like SOPA score, mean heart rate, and SbO2, FiO2 ratio is not that different. So isolated bacteria for index episodes of VAP. It's very interesting. 94% are gram-negative, and only 4% gram-positive, and 2% others. Out of gram-negatives, 53% are non-fermenters, and 41% are inter-bacterials. And then you see there's 28% carapenem resistance, and this in non-fermenters and about 4% in enterobacterials. So altogether there are 51% resistant, 34% carbapenem, and 17% cephalosporin. Duration of antibiotic received, you see in short-term, it's six days average into quarter range, five to seven days. In long-term, 14 days. And dotted line represents the average this thing, duration of antibiotic therapy. And primary outcome, 60-day mortality or recurrence. In both groups, comparing short course versus long course, there is no difference in this Kaplan-Meier curve. So primary outcome, if you see combined mortality recurrence in both intention to treat and per-protocol analysis, it's similar. And there's a 3% difference, you can see. Minus 3% as I said and minus 2% in both analysis. So it favors short course at absolute risk difference of 12%. You can see here. And this M2, or at 95% confidence ratio, this is less than 12% absolute risk difference, favoring short course. And it did not satisfy superiority because although point estimate is less than zero, but it causes the confidence interval of one. So secondary outcome is very interesting. You can see median duration of antibiotic is significantly different, minus 5.2 days. Similarly, side effects is 30% difference. 8% in short arm and usually cure long arm is 38%. And both are statistically highly significant. And mean duration of mechanical ventilation during admission, mean duration of intensive care unit admission. Similarly, secondary outcomes, mean duration of hospital stay, readmission rate, pneumonia recurrence, and bloodstream infection as well as carotene resistance bacteria. Not that different between the two. So among the secondary income, sorry, secondary outcome, AKI is the most common, most common side effect. You see 35% in usually cure long arm, long course group. So the antibiotic side effect in terms of liver injuries, diarrhea, allergies, not that different. But AKI is significantly different. And both are statistically significant. Discussion. So individualized short course antibiotic duration for ventilator-associated pneumonia based on simple clinical criteria is non-inferior to usual care. This can be used in developing country setting, low income setting as well. So the strength of this study is first to, to our knowledge, is first to use clinical response to determine antibiotic duration in high-stake patient population, predominantly in low-middle income setting. And there is no increased recurrence of subgroup analysis of 218 episodes of non-fermenting gram-negatives. And it is generalizable given the diverse research setting. And the limitation is usually care duration is longer than recommended guidelines. The CDC recommends only seven to eight days. But in practice, it's usually 14, 15 days or more. And majority of patients enrolled are 81% are from Thailand. So in conclusion, it's the first RCT conducted in hospital across low-middle income countries. Carbapenem resistant gram-negative bacilli constitute 34%. And it's a major driver of antibiotics. And most commonly used antibiotics, polystyrene, polymyxin, beta-lactam, including carbapenem, aminoglycosides. And they are the cause of frequent AKI. It's non-inferior at less than 12% absolute risk. However, there is no difference in outcome. But short course has less side effects, less antibiotics used, definitely low cost. And the risk of antimicrobial resistance is also lower. So this is the article published just yesterday in Lancet Respiratory. Individualized short course antibiotic treatment versus usual long course treatment for ventilator-associated pneumonia. We got back our trademark. So a multicenter, individually randomized, open-level, non-inferiority trial. So just yesterday, it came out in Lancet Respiratory Medicine. Thank you all. And thanks also goes to all the investigators from hospitals across Nepal, Thailand, and Singapore, especially to Ben Cooper from Oxford University. And thank you all from regard by our family to all of you. Thank you. Thank you. Thank you very much, Dr. Kayesta. I think the first two presentations really illustrate the importance of rationalizing treatment for patient morbidity and to reduce side effects. So without further ado, we're going to move on to our third speaker today. So Dr. Nazima Pathan, who's at the Annenberg's Hospital at the University of Cambridge. And she's going to talk about methylprednisone, IV immunoglobulin, tozolizumab, or Ankara for children with pediatric inflammatory multisystem syndrome, temporarily associated with SARS-CoV-2. And this is a report from a randomized, controlled, open-label platform trial. And again, this is a content that's hot off the press, published yesterday in the Lancet Child and Adolescent Health. So over to you, Nazima, please. Thank you very much. I'm presenting this on behalf of the working group, and I have no disclosures. So in terms of background for COVID-19 in children and the recovery trial, the problem that the Royal College of Pediatrics identified early in 2020 was that children were being given experimental therapies without being part of any formal clinical trials, because the focus naturally was on the larger numbers of adult cases. And the National Institute for Health Research approached two of the large platform trials, of which recovery was the one that took on pediatric. And we established a working group to consider interventions and develop guidance to both diagnose and to treat and add treatments as appropriate over the course of the pandemic. It was a pragmatic trial in order to ensure maximal enrollment without a burden on the frontline health care staff. So it was low risk from a clinical trials perspective, because initially repurposed drugs were used. There was no requirement for GCP for patients, for staff recruiting at the sites, and support at a national level to gather data. In terms of the pre-PIMS TS enrollment of children into recovery, of course, this was initially focused on the acute respiratory presentations, which were relatively low in numbers. But dose adjustments were made in order to randomize children to therapy. That's not what I'm going to report here, because these were smaller numbers. And what obviously became apparent later on was the inflammatory multi-system inflammatory syndrome associated with SARS-CoV-2 called PIMS TS or MISC in a small proportion of children, most of whom would improve, but some of whom became quite unwell because of their multi-organ failure requiring intensive care and immune modulation. In order to have a pathway from diagnosis through to appropriate treatment, a Delphi process was undertaken to establish diagnostic criteria and assess the equipoise for clinical trials interventions. The rationale for how recovery approached PIMS TS was that initial observational data suggested that symptoms resolved after treatment with IVIG and corticosteroids, but that some children were receiving supportive care and recovered, but some of them continued to have refractory inflammation and required intensive care, so were being treated with biologics targeting key pro-inflammatory cytokines, such as interleukin 1, TNF, and IL-6. The primary question from clinicians across the country was whether children and young people given corticosteroids had worse outcomes than those given intravenous immunoglobulin. So the aims for recovery were twofold, to address both the larger number of children requiring first-stage therapy and to assess in children and young people admitted to hospital with mild to moderate PIMS TS, how does IVIG or corticosteroids compare with usual care on the length of hospital stay? And in children with more severe disease, or those who had ongoing symptoms after having received first-stage randomization, or in those where they were enrolled after having received the drugs included in stage 1, how did tocilizumab and anakinra, the first anti-IL-6, the second, and IL-1 receptor antagonists, compare with usual care on length of hospital stay? Children were enrolled if they were under 18 and had a fulfilled criteria for PIMS TS. Exclusions included if Kawasaki disease were thought likely and if patients had either hypersensitivity to immunoglobulin, human immunoglobulin, or IgA deficiency, they were excluded from the IVIG treatment arm. And for those patients under a year, tocilizumab was not allowed, and for those under, sorry, anakinra was not allowed, and for those under 10 kilos, tocilizumab. The first-stage interventions were compared in a one-to-one-to-one randomization of standard care, no additional treatment over what they'd already had, if anything, at randomization, and then IVIG and methylpregnizolone. In the second-stage randomization, to ensure, to encourage enrollment, the randomization was adjusted at one-to-two-to-two, so children enrolled had an 80% chance of receiving an active therapy, and these were tocilizumab and anakinra compared to no additional treatment. As I mentioned earlier, it was a pragmatic trial, so investigators were free to use no treatment IVIG or steroids as standard care, if deemed clinically necessary. And through the analysis, the effects of each of these treatments were compared against no initial additional treatments in the presence and absence of the other drug. There was obviously a wide spectrum of disease, because it went from children admitted to the ward to those requiring critical care because of multi-organ failure, and the baseline levels of any drug use at second randomization was collected. The analysis was undertaken on an intention-to-treat basis, using a Bayesian analysis to look at, in a similar way to the adult recovery trial, to look at the effects of the interventions, both individually and despite the fact that patients had different treatments. I'm not a statistician, but the main point from this slide is to say that the statistical approach was to look at what's called the posterior distribution difference between the outcome of the active treatment and the outcome of usual care. And the posterior probability was a figure that was calculated to look at the difference in outcome, and the higher the number, the more likely a signal of benefit. So a posterior probability of 95% signified a very strong signal of benefit, and similarly 70% to 80% and 80% to 95% signaled moderate to strong signals. And on the inverse, a lower score below 50 suggested a possibility of harm, a probability of harm of the intervention. The outcome measures, the primary outcome was duration of hospital stay. Secondary outcomes included the use of inotropes and inflammation as measured by baseline-adjusted CRP at day 3. You can scan the QR code directly into the paper, which has just come out, as you've heard. This is the first sort of global RCT, and alongside Lauren Schlappbach's trial in children in Switzerland, we looked at COVID-19. It's the largest one for PIMS-DS, recruiting from May 2020 to January 22. 51 hospitals recruited children to the first randomization, and then 25 recruited into R2, second-level randomization. So looking at the total numbers, the number of children considered as having a diagnosis of PIMS-DS was 244, of which some entered second randomization directly, 23 of them. And 214 were randomized to either usual care, methylpred or IVIG. And then in the second randomization, there were 70 children, and as I mentioned earlier, it was a 1 to 2 to 2 randomization to usual care, tocilizumab, or anakinra. The reason for the low number of anakinra is because it was introduced later on during the course of the pandemic, and therefore, obviously, there were smaller numbers of children enrolled to the trial at that point. In terms of baseline characteristics, the average age of children involved in first-line randomization was at around nine years of age. They presented to hospital around six to seven days of symptom onset, and within the first day or so of hospitalization, they were randomized and all had a relatively strong inflammatory response as measured by their CRP. Second-stage randomization, similar age distribution of about nine years of age, and it was interesting to see a higher proportion of black and Asian minority ethnic children in the tocilizumab arm, but that's just an observation. Otherwise, the presentation occurred that these children were randomized at about two days post-hospitalization. Now, this slide looks at the treatment given, and as I mentioned earlier, because it was a trial that allowed clinicians the freedom to treat as they felt clinically necessary at the time, but in order to maximize enrollment to the study, what we did see was a high level of treatment given in patients who had been randomized to usual care. As you can see here, for IVIG, 35% of patients randomized to usual care received IVIG, and similarly for methylprednisolone, 50% of children randomized to usual care received the steroids regardless. At second-stage randomization, numbers were much better. Certainly for tocilizumab, only those randomized to active treatment received it compared to the usual care arm for that comparison, and for anakin, a small number did receive it, but otherwise the majority did not. When we look at the Bayesian analysis for the first randomization, what this shows, so on the left are the numbers, the raw numbers, and on the right, you can see the posterior probability. So what we found was that both of IVIG and methylprednisolone reduced the numbers of days in hospital, particularly methylprednisolone, which you can see has an 87% posterior probability of benefit. In terms of inflammation, methylprednisolone, again, had a reduction that was highly beneficial, 97% posterior probability of reduction in baseline-adjusted CRP at day three. When we looked at second randomization, again, both anakinra and tocilizumab did reduce the number of days in hospital, as you can see here, from 9.9 to 6.6 and 8.5, respectively, but tocilizumab particularly had a very strong beneficial effect of over 99%, anakinra too, although, as you remember, it was a very small group of patients, only 14 patients, so we can say with less certainty that there was some benefit with anakinra. Interestingly, although both of these drugs are anti-inflammatory, we did observe a higher use of inotropes and an increase in the number of days on inotropes for both these, so you can see at the bottom that patients in usual care had 0.2 days on inotropes compared to 0.6 and 1.1 for tosylizumab and anakinra, respectively. So, an evidence of posterior probability of harm in terms of that particular outcome. Nevertheless, as expected, CRP was reduced with a moderate effect with tosylizumab. In terms of safety outcomes, there were two deaths which were not as appeared to be any associated with any particular intervention. The main outcome, as you all know, is the risk of cardiovascular sequelae from PEMS-TS, and there wasn't any association with any of the interventions. So, in summary, methylprednisolone, there was a strong signal for benefit with a reduction in the duration of hospital stay with 87% probability that the number of days in hospital was shorter and a 97% probability of benefit for inflammatory response as measured by baseline-adjusted CRP. IVIG was interesting because of the modest, slightly less strong reduction in terms of outcomes. So, steroid was clearly superior. In terms of the immunomodulation in randomization 2, tosylizumab had a very high confidence of reduction in hospital stay of over 99%, but the baseline-adjusted CRP was improved, but the inotrope use increased with a posterior probability of harm of 96%. In terms of anakinra, again, a reduced length of stay, but more time on inotropes. And no, not as good an anti-inflammatory response. So, in terms of our final remarks and limitations, clearly, in order to expedite setup in a pandemic setting, this trial had to be pragmatic and adapted as time went on and new therapies came on board, which is why anakinra was a smaller group. The sample size and trial size and the substantial use of study treatments in usual care group did reduce the ability to detect plausible effects of treatment. But despite this, what we observed was a clear benefit of steroids over standard of care, but no clear benefit of IVIG over standard of care for the initial treatment of PIMS-TS. And tosylizumab was an effective second-line treatment. The anakinra arm was too small to be confident that it's of benefit. It's a huge group of work and led by Peter Horby and Martin Landry, who are the co-chief investigators of the overall recovery trial, and Saul Faust, who, my colleague at Southampton, is the chair of the Pediatric Recovery Working Group, of which I'm part. Work is funded by NIHR. Thank you very much for listening. Thank you. The last presentation is from Dr. Loren Schlappach, who's professor at the University Children's Hospital in Zurich. And he's going to present on resuscitation with vitamin C, hydrocortisone, and thiamine in children with septic shock, a multi-syndrome randomized pilot study. And he's also going to present information on a corresponding paper that also appeared in Pediatric Critical Care Medicine as an observational study on serum vitamin C and thiamine levels in children suspected with sepsis. Thank you, Ravi. Good morning. Thank you so much for the opportunity to present the results of this pilot trial, which was conducted on behalf of many, many colleagues and investigators representing the ENZX Pediatric Study Group. These are the disclosures in relation to funding received for this trial, and as well a full trial, which is currently on the way. And I will briefly comment on this towards the end. When we started the SCCM conference, we've had a wonderful ceremony from a local leader. And I would like to acknowledge, as well, the country based on which this trial was performed, the Jogir and the Tarbul people, which are the traditional owners of the land. And it's important that we pay respect to the elders and the past of the communities which own the land on which this study was conducted. As Ravi briefly mentioned, the presentation today relates to three papers which have come out together this week in Pediatric Critical Care Medicine. And we're mainly going to focus on two of these here. So two papers report on findings of a pilot study, which is conducted within a platform, set up one investigating early use of inotropes in children with septic shock, primarily needy, and the second one actually using metabolic recitation using vitamin C, thiamine, and hydrocortisone. And there's the middle paper here, which actually now in an observational design in another cohort of patients not enrolled in the trial actually looked at serum levels of vitamin C and thiamine. So we'll go briefly through the backgrounds of the current evidence gap in terms of adjunctive strategies, which can potentially improve outcomes for children with septic shock. We'll then show you the data on levels of vitamin C and thiamine in children with infection across a range of severities, go briefly through the design of this RESPOND platform trial, and then mainly focus on the results of the RESPOND PICU study, which focused on the metabolic intervention. And finally, as well, I'll try and give you a brief lessons learned and outlook from this work. So if you consider the surviving sepsis campaign guidelines for children, what's very important is depending on what setting you work in or what type of population you're exposed to, there is a funnel in terms of epidemiology, but a reverse funnel in terms of actually the mortality these patients have. And so our colleagues in ED, they're confronted with large numbers of patients with mild degrees of disease, where the mortality is very low. But even in high-income countries, mortality of a child in ICU on inotropes actually may be as high as 13%. And the strategies we have for children that are in ICU on inotropes, refractory to conventional interventions, actually these strategies are very limited. Sorry, somehow it's jumping. Let me just go back. If you compare previous guidelines in relation to steroids, and Michael Agus, you know, who's here in the audience, you know, can tell you more about this. Actually, we've had for the last 20 years actually a little bit of, you know, forth and back in relation to hydrocortisone. And the last guidelines very clearly state that actually we do not know there's potential for benefits as well, potential for harm, which is why a large trial, the SHIPS trial, is currently being conducted. When it comes to other adjunctive therapies, we actually have very, very few options. And in adults, since pretty much a hype started in 2016 on potential benefits of high-dose vitamin C was started, there's been a wealth of trials, some of which you can see here. So based on essentially a pre-post study, a single-center study, properly designed RCTs were conducted across different continents, different types of populations, which have enrolled, you know, several thousand patients in total together. And the hypothesis between these trials was that vitamin C, you know, which is a very, which is strong antioxidant, which our body cannot synthesize, and that's relevant because as we're going to see in a moment actually, sick patients actually have a quick decrease in levels of vitamin C. So the question is whether the supplementation of vitamin C may potentially now protect or even restore functions of various cells or organs, in particular on the endothelial cell, with potential benefits as well for glucocorticoid receptor function. And it's been postulated as well that vitamin C may have potentially immunomodulative effects in addition to hydrocortisone. Thiamine itself has been tested in RCTs in adults, and there's a small case here from CHOP in children as well, and seemed to indicate that potentially the administration of thiamine may support cellular metabolism, mitochondrial metabolism in patients with sepsis, you know, potentially, you know, resulting benefits. And so there's been a suggestion that essentially cocktail combining these three or as well sometimes label metabolic intervention or head therapy may potentially lead to benefits. But none of the RCTs conducted actually of these initial findings could actually support such. And the most recent one, the LOVIT trial, in fact actually suggested potential for harm, in particular for 90-day mortality. At the same time, they are encouraging ovine models, one which you can see on the bottom left, you know, which indicate that potentially at least in an animal model that high dose vitamin C may reverse vasoplegia and brain dysfunction. And so the current state of evidence is that most units actually have stopped using it, in particular based on the LOVIT trial results. The meta-analysis is somewhat conflicting because it indicates benefits for 30-day mortality but potential harm for 90-day mortality. But all of these are adult patients. And at this stage, actually, there's a number of units around the world that still use vitamin C in pediatric sepsis. But we do not have RCT-based data on this group. The only data we have on the use of high dose vitamin C and thiamine together with hydrocortisone in children is based on a propensity match study conducted by Eric Wald from Chicago, which actually showed a relatively impressive effect on mortality as the primary outcome, as you can see on the graph on the left. We've conducted a systematic review published in PCCM just over two years ago, which looked at actually which studies actually have tested the administration of high dose vitamin C to establish actually sort of a safety range. And there were a total of near 200 patients, you know, with a median dose of 260 milligrams per kilo per day of vitamin C, providing actually some rationale as well to conduct that type of studies in children. Before engaging in a trial, what we wanted to do is actually measure vitamin C and thiamine levels in a range of children evaluated for sepsis. So this is a range of children, mostly, most of them presenting to ED. Most of them not having organ dysfunction. As you can see, actually, there are patients with single organ dysfunction. There was about a third of patients with multi-organ dysfunction. And we assessed organ dysfunction both at time of presentation as well as 25 hours later. And so what we observed, and this is consistent with some smaller previous studies, is that the sicker the patients, actually there's a negative inverse, sorry, there's an inverse correlation between the PSOFA score measuring degree of organ dysfunction and the degree of deficiency of vitamin C. With low vitamin C levels upon presentation being associated with an adjusted increased odds ratio for MOTS 24 hours after presentation. And we could not find a clear association with thiamine deficiency. So these data are presented in one of the papers. And so based on this, actually, we've designed the RESPOND platform pilot study. The intention was that along the continuum of severity of a patient with sepsis, which is, in fact, as well, a continuum of care from ED to the ICU, that we wanted to enroll patients that actually had just received the first fluid bolus in ED to the RESPOND ED study, which I'm not going to go into detail here, where essentially they received adrenaline infusion already after 20 mils per kilo of fluid as compared to SSC-based resuscitation with 40 to 60 mils per kilo fluid before starting adrenaline. Then for patients that either were shock persisted and needed to go on inotropes, but as well for many patients that actually come to ICU through retrievals, for example, sorry, they became eligible for the RESPOND PICU study. So this was an investigator-initiated multicenter open-label trial applying a one-to-one randomization. So children less than 18 years that were admitted to ICU and where clinicians had started inotropes already with the suspicion of septic shock were eligible if inotropes were used for at least two hours, but less than 24 hours. An intervention received vitamin C given as sodium ascorbate, thiamine, and hydrocortisone for a maximum of seven days or until resolution shock, death, or discharge from ICU, whichever occurred earlier. And the standard care were children that essentially were not treated with this combination of therapies. However, in a very pragmatic design, we did allow the use of hydrocortisone at the discretion of the treating clinician. We looked at the number of outcomes because it was a feasibility pilot study. Actually, feasibility was key. And the primary clinical outcome for which the study was not powered for was survival free of organ dysfunction and survival free of inotrope support at seven day as sort of the main secondary outcome. The patients then underwent follow-up at 28 days and as well at six months to look at health-related quality of life. And we're currently analyzing actually as well the gene expression and number of biomarkers in the cohort here. I won't go much into detail here, but I would like to express the thanks for the DSMB. And in terms of sample size, this was really based on what we expected the full trial to look like and sample size that gave us confidence that we could answer that relevant feasibility question. So 44 respond ED, 64 respond PICU. And the studies were conducted from mid-2019 and completed, you know, roughly two years later. Respond PICU was primarily conducted at one site. And in the last months of the study as well, an additional five PICUs in Australia and New Zealand participate in it. If you're interested in the details of the design, you find the published protocol which lists as well the link to GitHub which shows you the exact analysis code used actually submitted before the completion of these pilot trials there. So let's now talk about the enrollment. So as you can see here for respond PICU, we assessed just over 100 children for eligibility of which 77 patients were eligible. And most patients were missed because actually of clinicians, not because of parental considerations. And you can see on the right side of baseline characteristics. So overall, there was a very strong interest of families with a high rate of consent provided over 90%. But what we've noticed as well, and I think this is an important feasibility aspect, it was that roughly one in four patients had already been given steroids by treating clinicians before meeting eligibility criteria. In terms of the feasibility outcomes, what you can see here actually is that we succeeded a very quick moment from screening to randomization and as well from randomization to delivering the interventions of less than one hour actually for most patients. You can see as well that most patients were recruited within the first few hours of ICU admission. This includes patients that initially were not on inotropes so which had not met eligibility criteria. But what you can see as well on the fourth line there is that the standard care arm about one in four received, you know, steroids at clinician's discretion. When assessing primary and secondary clinical outcomes, again, you know, this was a pilot study so we're not powered for this. As you can see here, actually the survival free of organ dysfunction, sentence at 28 days was between 20 and 21. And survival free of inotrope support, you know, was around the six days. Then what we noticed was that the time to shock reversal which was defined as the time by which clinicians stopped inotropes and the patient did not have to go back was 35 hours in the intervention arm as opposed to 47 hours. We did not record any major drug-related side effects. So in terms of evaluating this trial, what we saw as strength was a very pragmatic design of starting with clinician-based sepsis. We had a standardized study education package which we could actually deploy across both trials. And we tried to have the fidelity of how the trial was conducted, the analysis were conducted, similar to a full-size trials so that all of this was published actually before. Weaknesses, of course, this was open label. As shown, actually there's a severity bias in the way that steroids were used in the standard arm. And we did not perform any dose finding or dosing studies. What we've noticed as well actually were issues with six-month follow-up compliance by the parents. So in terms of lessons learned, and these are some of the conclusions here, our experience showed that we can do platform-type trials in children with septic shock, but only about one in six patients progressed from respond ED to respond PICU. We were able to show as well that actually parents want this, which is important as well for the use of, you know, consent to continue type approaches. And I think as well this trial illustrates some of the difficulties, you know, where do you, where is the sweet spot between precision and pragmatism when you think about conducting trials? And an important feasibility aspect is as well that, and I did not go into detail here because of time, but was that because patients with sepsis are not usually owns, let's say, by one groups, you know, compared to cardiac patients for example, we really need to think about better follow-up strategies because most of these parents, they're not aware that there is follow-up and that may actually impact the rates of follow-up. Based on this pilot study, actually, the pediatric study group is conducting a full trial powered for clinical endpounds, which now is a three-arm trial. So there's a hydrocortisone alone arm, which is recruiting and is almost halfway through, and we expect to have results in about two years for you. And with this, I would like to thank you, and in particular thank the many, many collaborators, in particular Kristen Gibbons and Sai Rahman at the University of Queensland. Thank you for your attention. So that concludes the session today. Thank you so much to all the speakers for their excellent presentations, and thank you to my co-moderator. As I mentioned at the start of the session, if you do have questions for any of the speakers, they will be around for the next 10 minutes or so. But because there's another session in here soon, if you could go out and turn left, that's where they'll be waiting. So thank you very much for attending. Thank you.

critical care

patient outcomes

proton pump inhibitors

ventilator-associated pneumonia

antibiotic duration

PIMS-TS

metabolic resuscitation

COVID-19

pediatric trials