BackgroundThe implementation of the approved respiratory syncytial virus (RSV) preventive interventions in immunisation programmes is advancing rapidly. Insight into healthcare costs of RSV-related paediatric intensive care unit (PICU) admissions is lacking, but of great importance to evaluate the impact of implementation. Therefore, this study aimed to determine the total annual RSV-related paediatric intensive care healthcare costs in the Netherlands.MethodsA nationwide prospective, observational, multicenter study was performed from September 2021 until June 2023. The total annual RSV-related healthcare costs on PICUs in the Netherlands were calculated using RSV-related costs (subgroup I) and consequential costs (subgroup II and III). Subgroup I comprised all PICU admitted infants ≤12 months of age with laboratory-confirmed RSV infection. Subgroup II and III consisted of postponed elective PICU admissions and refused acute PICU admissions due to RSV-related lack of PICU capacity.FindingsA total of 424 infants with RSV-related PICU admission were included. Median age at PICU admission was 46 days (IQR 25–89). The median length of PICU admission was 5 days (IQR 3–8). The total RSV-related PICU costs are € 3,826,386 in 2021–2022, and € 3,183,888 in 2022–2023. Potential costs averted by RSV preventive interventions is € 1.9 to € 2.6 million depending on season, and the duration of protection.InterpretationRSV-related PICU admissions cost €3.1 to €3.8 million in the Netherlands during one season. The introduction of new RSV preventive interventions into the Dutch immunisation programme will generate significant cost-savings on PICUs and decreases the admission burden of PICUs.FundingNone.

In critically ill adults, high plasma cortisol in the face of low ACTH coincides with high pro-opiomelanocortin (POMC) levels. Glucocorticoids further lower ACTH without affecting POMC. We hypothesized that in pediatric cardiac surgery-induced critical illness, plasma POMC is elevated, plasma ACTH transiently rises intraoperatively but becomes suppressed post-operatively, and glucocorticoid administration amplifies this phenotype. From 53 patients (0–36 months), plasma was obtained pre-operatively, intraoperatively, and on post-operative days 1 and 2. Plasma was also collected from 24 healthy children. In patients, POMC was supra-normal pre-operatively (P < 0.0001) but no longer thereafter (P > 0.05). ACTH was never high in patients. While in glucocorticoid-naive patients ACTH became suppressed by post-operative day 1 (P < 0.0001), glucocorticoid-treated patients had already suppressed ACTH intraoperatively (P ≤ 0.0001). Pre-operatively high POMC, not accompanied by increased plasma ACTH, suggests a centrally activated HPA axis with reduced pituitary processing of POMC into ACTH. Increasing systemic glucocorticoid availability with glucocorticoid treatment accelerated the suppression of plasma ACTH. Significance statement Glucocorticoids are often administered during pediatric cardiac surgery. In critically ill children, endogenous systemic glucocorticoid availability is elevated already upon ICU admission while ACTH levels are normal. This hormonal constellation suggests the presence of active feedback inhibition of ACTH. In this study, we have documented that intraoperative administration of glucocorticoids accelerates the suppression of ACTH, resulting in low plasma ACTH already upon ICU admission. Pre-operative plasma POMC, the ACTH precursor, but not ACTH, was increased. This is compatible with a centrally activated HPA axis prior to surgery in young children but reduced processing of POMC into ACTH within the pituitary. These findings suggest that glucocorticoid treatment in the context of pediatric cardiac surgery may amplify pre-existing impaired pituitary processing of the prohormone POMC.

To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0–3 years after cardiac surgery with cardiopulmonary bypass. Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016–July 2020. Children aged 0–3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20

OBJECTIVES:To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission. DESIGN:National prospective cohort study March 2020 to November 2021. SETTING:Seven PICUs in the Netherlands. PATIENTS:Children with MIS-C (0-17 yr) admitted to a PICU. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found. CONCLUSIONS:Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated.

Abstract Introduction In critically ill adults, high plasma free cortisol in face of suppressed plasma ACTH coincides with high plasma pro-opiomelanocortin (POMC), the ACTH precursor (1). Further augmenting the systemic glucocorticoid availability with hydrocortisone treatment further lowered plasma ACTH, while plasma POMC remained unaffected (2). The dynamics of POMC in relation to ACTH and free cortisol prior to intensive care unit (ICU) admission are unknown, as well as the impact hereon of glucocorticoid treatment. Also, elevated plasma POMC concentrations have not yet been confirmed in pediatric ICU (PICU) patients. In pediatric cardiac surgery-induced critical illness, we hypothesized that plasma POMC is elevated and that plasma ACTH transiently rises per-operatively and becomes suppressed once free cortisol has risen on PICU day 1 and 2. In addition, we hypothesized that in patients receiving glucocorticoids per-operatively, plasma ACTH is further suppressed while plasma POMC is unaffected. Methods From 53 children aged 0-36 months, who underwent cardiac surgery and were admitted to the PICU, blood samples were taken prior to surgery (pre-operatively, available samples N=51), during surgery (per-operatively, N=47), on the following morning (PICU day 1, N=40) and the day hereafter (PICU day 2, N=24). Blood samples were also collected from 24 age- and gender-matched healthy children. To investigate the impact of synthetic glucocorticoid treatment on the endogenous plasma hormone concentrations, patients were categorized into steroid-naive (total N=38) and steroid-treated patients (total N=15). Plasma hormone concentrations were quantified with highly-specific ELISA (POMC), RIA (ACTH, cortisol, CBG) or colorimetric assays (albumin). Cross reactivity with synthetic glucocorticoids within the used cortisol RIA is minimal (<0.27% for methylprednisolone, <0.1% for dexamethasone). Free cortisol was estimated with the adapted Coolens’ formula. Results Plasma POMC was increased pre-operatively (p<0.0001) but no longer thereafter (p>0.05), irrespective of steroid treatment. Plasma ACTH in patients was never higher than in healthy children. While in steroid-naive patients, plasma ACTH became suppressed only by PICU day 1 (p<0.0001), steroid-treated patients had already suppressed plasma ACTH per-operatively (p≤0.0001). In steroid-naive patients, plasma free cortisol was increased from per-operatively onwards (p≤0.002), while in steroid-treated patients, plasma free cortisol (endogenous) concentrations always remained comparable to those of healthy children (p>0.05). Conclusion Pre-operatively high plasma POMC, not followed by increased ACTH, suggests a centrally-activated HPA-axis already prior to surgery and an immature pituitary processing of POMC into ACTH. Systemic glucocorticoid availability is elevated from surgery onwards, likely driven by ACTH-independent mechanisms. Further increasing systemic glucocorticoid availability exogenously with glucocorticoid administration accelerates the suppression of plasma ACTH. The long-term impact of early glucocorticoid treatment in critically ill children remains to be investigated. References (1) Téblick A. et al. Critical Care 2021. (2) Téblick A. et al. Endocrinology 2022. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m.

Morphine is worldwide the analgesic of first choice after cardiac surgery in children. Morphine has unwanted hemodynamic and respiratory side effects. Therefore, post–cardiac surgery patients may potentially benefit from a non-opioid drug for pain relief. A previous study has shown that intravenous (IV) paracetamol is effective and opioid-sparing in children after major non-cardiac surgery. The aim of the study is to test the hypothesis that intermittent IV paracetamol administration in children after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine requirement.