Editor’s Choice Articles for February

February 2024 of Pediatric Critical Care Medicine (PCCM) is yet another important issue of the Journal. First, read the Foreword about “fair use of augmented intelligence and artificial intelligence in the preparation and review of submissions” to all three Society of Critical Care Medicine (SCCM) journals (i.e., Critical Care Medicine, PCCM, and Critical Care Explorations) (1). For PCCM authors, readers, and reviewers, this position statement adds to PCCM’s 2023 recommendations for engaging with citation to references in the Chatbot Generative Pre-Trained Transformer era (2). After the Foreword, by way of celebrating this year’s SCCM annual conference, look at the three Late Breaker (i.e., not previously published ahead of print) items that serve as my Editor’s Choices (3–5). Taken together with the PCCM Connections section this month, all this material builds toward definitive answers to clinical questions; ultimately preparing for randomized controlled trials (RCT) or the equivalent form of clinical information. WHAT IS THE IMPACT OF REHABILITATION IN THE PICU ON SHORT- AND LONGER-TERM PATIENT OUTCOMES? Choong K, Fraser DD, Al-Farsi A, et al; Canadian Critical Care Trials Group: Early Rehabilitation in Critically Ill Children: A Two-Center Implementation Study (3). My first editor’s choice article is our first late breaker report for the SCCM meeting. Here, the authors from two centers in Canada (during 2018 to 2020) performed an implementation study of “bundled care” consisting of analgesia-first sedation, delirium monitoring and prevention, and early mobilization (3). In over 1,000 patients, representing over 4,000 patient days, the authors looked for relationships between the use of bundled care and the incidence of delirium, ventilator-free days, length-of-stay, and mortality. The accompanying editorial provides important insight and gives background to the use of an alternative to RCTs when evaluating effectiveness of a bundle of care; that is, what is now called a “hybrid implementation study” with type 2 design (6). The potential impacts of this work and editorial are, primarily, the addition of new information to the 2022 SCCM clinical practice guideline on “Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients with Consideration of the ICU Environment and Early Mobility” (7). The report also provides much needed detail about the ABCDEF (i.e., Assessing pain, Both spontaneous awakening and breathing trials, Choice of sedation, Delirium monitoring/management, Early exercise/mobility, and Family engagement/empowerment) approach in pediatric critical care (8,9). Last, the report should be seen as exemplary in its dealings with the complexities of Implementation Science, as recently outlined by the subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) network focused on Excellence in Pediatric Implementation Science (ECLIPSE) (10,11). WHAT IS THE SAFETY OF WITHHOLDING ROUTINE STRESS ULCER PROPHYLAXIS IN THE CARDIAC ICU POPULATION, AND IS A RANDOMIZED TRIAL FEASIBLE? Mills KI, Albert BD, Bechard LJ, et al: Stress Ulcer Prophylaxis Versus Placebo–A Blinded Randomized Controlled Pilot Trial to Evaluate the Safety of Two Strategies in Critically Ill Infants With Congenital Heart Disease (SUPPRESS-CHD) (2). My second editor’s choice and late breaker article is a report of a prospective pilot RCT in the cardiac intensive care unit (CICU) population carried out 2019-2022 (2). In the COVID-19 era, the authors were able to screen over 1,400 CICU admissions and recruited 58 patients to their pilot RCT about stress ulcer prophylaxis (i.e., histamine-2 receptor antagonist versus placebo) during CICU management in infants with congenital heart disease. The study adds to the catalogue of PCCM Trials content that I summarized in my end of 2023 review (12). Importantly, it follows an investigative approach using pragmatic trials to answer clinical questions in the CICU; for more information about pragmatic trials do review PCCM’s content on such studies (13,14). The next question is whether the authors can use their pilot-RCT experience to deliver a definitive RCT. The answer would be so useful to our practice, by either informing the decision to stop giving unnecessary treatment or encouraging the decision to continue with routine stress ulcer prophylaxis. WHAT IS THE SAFETY OF A SEPTIC SHOCK PROTOCOL COMPARING EARLY EPINEPHRINE INFUSION VERSUS STANDARD CARE, AND IS A RCT FEASIBLE? Harley A, George S, Phillips N, et al; Resuscitation in Paediatric Sepsis Randomized Controlled Pilot Platform Study in the Emergency Department (RESPOND ED) Study Group: Resuscitation With Early Adrenaline Infusion for Children With Septic Shock–A Randomized Pilot Trial (3). My third editor’s choice is another RCT feasibility study, which in this instance looks at a fluid-vasopressor algorithm in pediatric septic shock care (3). The question being asked is whether a protocol comparing early epinephrine infusion (i.e., started after a 20 mL/kg fluid bolus) versus standard care (i.e., 40−60 mL/kg fluid bolus followed by inotrope infusion) is safe and feasible in children with septic shock? Again, another pragmatic approach to answering a clinical question (see above and references 13, 14). Here, the investigators recruited 40 patients presenting to four pediatric emergency departments in Australia and concluded that a fluid-sparing algorithm, with early vasopressors, in septic shock is feasible and there is a rationale for performing a definitive RCT in children. Of note, the “fluid-sparing” algorithm is not a new concept in the Journal, since the evolution of this idea was covered at the time of publication of the post-FEAST (i.e., Fluid Expansion as Supportive Therapy) trial era data analysis from Uganda and Kenya (15,16). The next step for this algorithm should include broadening relevance to the international setting, as was highlighted in the recent Special Article on international sepsis diagnosis and care (17). Thought will also need to be given to the practicalities of early administration of peripheral vasoactive agents, as was covered in 2022 (18–20). So, enjoy the read, and follow closely the next iterations of this work. “PCCM CONNECTIONS” FOR READERS The pilot RCT about early vasopressors in septic shock (3) also provides us with an opportunity to focus on additional PCCM material about potential metabolic interventions in septic shock patients. Looking back to 2022, the Journal published a four-article Mini Symposium on the topic of vitamins in sepsis and critical illness. There was a single-center prospective study from Switzerland of patients with blood culture proven-sepsis that demonstrated the frequent finding of low and deficient vitamin C (ascorbic acid) and vitamin B1 (thiamine) levels (21). There was also a single-center study from the United States that showed vitamin C deficiency in a significant proportion of critically ill patients, compared with a control group (22). Last, there was a single-center study from Turkey that examined the prevalence and time course of thiamine deficiency in PICU patients (23). Then, to bring this information together, there was an accompanying editorial about metabolic resuscitation during sepsis using the combination of Hydrocortisone, Ascorbic acid, and Thiamine in so-called HAT-therapy (24). The conclusion being “…promising, but unproven therapeutic option for pediatric sepsis-associated organ dysfunction.” Now, in this February issue there are two new articles about vitamin C and vitamin B1 in children with suspected sepsis. First, a study from Australia showing that critically ill children evaluated for sepsis frequently have decreased levels of vitamin C, with lower levels in children with higher severity, but no similar associations were evident for thiamine (25). Second, a pilot RCT testing the feasibility of HAT-therapy in 60 children requiring vasopressors for septic shock; the authors from Australia and New Zealand concluded than a RCT was feasible, and it would require a sample size of 384 patients (26). Regarding the educational connection between the 2022 Mini Symposium (21−24) and the two new reports (25,26) on metabolic interventions in septic shock, it is worth spending time reviewing the contemporary PCCM data about hydrocortisone in pediatric septic shock from the United States. There is the 2013-−2017 life after pediatric sepsis evaluation (LAPSE) study that failed to identify an association between early corticosteroid therapy in children with septic shock and clinical and 1-month health-related quality of life outcomes (27,28). There is also the 2015−2018 sepsis biomarker model (PERSEVERE)-II risk stratification study of pediatric septic shock, which had an opposite result to the LAPSE data and showed that corticosteroid administration was associated with increased mortality in a subgroup of children with high PERSEVERE-II risk score (29,30). Hence, at present, we do not have a definitive answer about hydrocortisone. However, there is an ongoing RCT about Stress Hydrocortisone in Pediatric Septic Shock (SHIPSS, see ClinicalTrials.gov registration NCT03401398), which has now extended its recruitment to several international sites. Given the emerging international data on vitamin C and vitamin B1 levels in critically ill children with septic shock, the question is whether the metabolic dimension has more importance than previously thought?

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