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Abstract Background Management and monitoring of pain and sedation to reduce discomfort as well as side effects, such as over- and under-sedation, withdrawal syndrome and delirium, is an integral part of pediatric intensive care practice. However, the current state of management and monitoring of analgosedation across European pediatric intensive care units (PICUs) remains unknown. The aim of this survey was to describe current practices across European PICUs regarding the management and monitoring of pain and sedation. Methods An online survey was distributed among 357 European PICUs assessing demographic features, drug choices and dosing, as well as usage of instruments for monitoring pain and sedation. We also compared low- and high-volume PICUs practices. Responses were collected from January to April 2021. Results A total of 215 (60% response rate) PICUs from 27 European countries responded. Seventy-one percent of PICUs stated to use protocols for analgosedation management, more frequently in high-volume PICUs (77% vs 63%, p = 0.028). First-choice drug combination was an opioid with a benzodiazepine, namely fentanyl (51%) and midazolam (71%) being the preferred drugs. The starting doses differed between PICUs from 0.1 to 5 mcg/kg/h for fentanyl, and 0.01 to 0.5 mg/kg/h for midazolam. Daily assessment and documentation for pain (81%) and sedation (87%) was reported by most of the PICUs, using the preferred validated FLACC scale (54%) and the COMFORT Behavioural scale (48%), respectively. Both analgesia and sedation were mainly monitored by nurses (92% and 84%, respectively). Eighty-six percent of the responding PICUs stated to use neuromuscular blocking agents in some scenarios. Monitoring of paralysed patients was preferably done by observation of vital signs with electronic devices support. Conclusions This survey provides an overview of current analgosedation practices among European PICUs. Drugs of choice, dosing and assessment strategies were shown to differ widely. Further research and development of evidence-based guidelines for optimal drug dosing and analgosedation assessment are needed.

Background: Hypertensive crises in children represent critical medical situations characterized by severe hypertension and potential organ damage. Fenoldopam, a dopaminergic medication, offers a viable therapeutic option for managing such clinical scenarios. We aimed to evaluate efficacy and safety of fenoldopam in the management of hypertensive urgencies and emergencies., Methods: This retrospective analysis focused on pediatric patients affected by acute or chronic kidney disease, aged 1 month-18 years, admitted to the Pediatric Nephrology and the Pediatric Intensive Care Unit at University-Hospital of Padua, Italy, who presented with a hypertensive crisis treated with fenoldopam between March 2010 and December 2022., Results: The study included 74 patients with median age 10 years (interquartile range [IQR] 4-15 years) who received 102 fenoldopam infusions. Seventy-two percent were already receiving antihypertensive treatment before admission. In all cases, fenoldopam was associated with a reduction of blood pressure (BP) after 8 h of treatment, but in 87% of patients reduction of the initial mean arterial pressure (MAP) was higher than 25% of calculated drop pressure. MAP normalized in 26% of cases after 24 h and in 35% after 48 h. Occurrence of hypotension was 7%, while hypokalemia was observed in 13% of cases. Patients who presented a MAP reduction not exceeding 25% of calculated drop pressure received a lower median fenoldopam dose (0.2 mcg/kg/min; IQR 0.1-0.2) compared with patients having a MAP reduction > 25% of calculated drop pressure (0.4 mcg/kg/min; IQR 0.2-0.6; p = 0.002)., Conclusions: Fenoldopam seems effective and safe for the treatment of hypertensive crises in children with kidney disease, at a starting dose of 0.2 mcg/kg/min. Strict BP monitoring is required to identify possible excessive drop pressure in the first hours of infusion., (© 2024. The Author(s).)

Objective: Epidemiologic data on extracorporeal cardiopulmonary resuscitation (ECPR) use in children with cardiac disease after in-hospital cardiac arrest (IHCA) are lacking. We aimed to investigate trends in ECPR use over time in critically ill children with cardiac disease., Data Sources: We performed a secondary analysis of a recent systematic review (PROSPERO CRD42020156247) to investigate trends in ECPR use in children with cardiac disease. PubMed, Web of Science, Embase, and Cumulative Index to Nursing and Allied Health Literature were screened (inception to September 2021). For completeness of this secondary analysis, PubMed was also rescreened (September 2021 to March 2024)., Study Selection: Observational studies including epidemiologic data on ECPR use in children with cardiac disease admitted to an ICU., Data Extraction: Data were extracted by two independent investigators. The risk of bias was assessed using the National Heart Lung and Blood Institutes Quality Assessment Tools. Random-effects meta-analysis was used to compute a pooled proportion of subjects undergoing ECPR; meta-regression was used to assess trends in ECPR use over time., Data Synthesis: Of the 2664 studies identified, 9 (17,669 patients) included data on ECPR use in children with cardiac disease. Eight were cohort studies, 1 was a case-control, 8 were retrospective, 1 was prospective, 6 were single-center, and 3 were multicenter. Seven studies were included in the meta-analysis; all were judged of good quality. By meta-analysis, we found that a pooled proportion of 21% (95% CI, 15-29%) of pediatric patients with cardiac disease experiencing IHCA were supported with ECPR. By meta-regression adjusted for category of patients (surgical vs. general cardiac), we found that the use of ECPR in critically ill children with cardiac disease significantly increased over time (p = 0.026)., Conclusions: About one-fifth of critically ill pediatric cardiac patients experiencing IHCA were supported with ECPR, and its use significantly increased over time. This may partially explain the increased trends in survival demonstrated for this population., Competing Interests: Dr. Alexander is Treasurer and serves on the Board of Directors of the Extracorporeal Life Support Organization (ELSO); and the National Institute of Child Health and Human Development (R13HD104432). Drs. Alexander and Thiagarajan: their institution has received funding from the U.S. Department of Defense (Peer Reviewed Medical Research Program Clinical Trial Award Number W81XWH2210301). Dr. Thiagarajan received funding from the Society of Critical Care Medicine and the ELSO. Dr. Maschietto received funding from Edwards Lifesciences and Medtronic. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Hemodynamic support using vasoactive agents is a mainstay in the management of patients with pediatric Fluid-Refractory Septic Shock (FRSS). However, evidence supporting the appropriate choice of vasoactive agent is limited. This study aimed to perform a systematic review and meta-analysis on the effect of different first-line vasoactive strategies on mortality in pediatric FRSS., Methods: MEDLINE, EMBASE, Scopus, CINAHL, Web of Science, the Cochrane Library, ClinicalTrials.gov, and the ISRCTN registry were searched up until December 2023. Randomized controlled trials and observational cohort studies reporting vasoactive agent-specific outcomes of children with FRSS were included. Mortality was assessed as primary outcome in studies on patients receiving dopamine, epinephrine, or norepinephrine as first-line. Random-effects meta-analyses were conducted. Prevalence ratio (PR) estimates were calculated between two drugs when was available in the same study., Findings: Of the 26,284 identified articles, 13 were included, for a total of 997 children. Twelve studies included 748 patients receiving a single vasoactive agent. Of these, 361 received dopamine, 271 epinephrine, and 116 norepinephrine. Overall pooled mortality for patients receiving a single vasoactive was 12% (95% CI 6-21%) of which 11% (95% CI 3-36%) for patients receiving dopamine, 17% (95% CI 6-37%) for epinephrine, 7% (95% CI 1-48%) for norepinephrine. Four first-line dopamine (176 patients) and first-line epinephrine (142 patients): dopamine showed a tendency towards higher mortality (PR 1.38, 95% CI 0.81-2.38) and a significant higher need for mechanical ventilation (MV) (PR 1.12, 95% CI 1.02-1.22).InterpretationAmong children with FRSS receiving a single vasoactive agent, norepinephrine was associated with the lowest mortality rate. Comparing dopamine and epinephrine, patients receiving epinephrine needed less MV and showed a trend for lower mortality rate. Further research is needed to better delineate the first-line vasoactive agent in this population., (Copyright © 2024 by the Shock Society.)

Background: In a group of children admitted to the paediatric intensive care unit (PICU) receiving continuous kidney replacement therapy (CKRT), we aim to evaluate the data about their hemodynamic, ventilation and analgo-sedation profile in the first 24 h of treatment and possible associations with mortality., Methods: Retrospective cohort study of children admitted to the PICU of the University Hospital of Padova undergoing CKRT between January 2011 and March 2021. Data was collected at baseline (T 0 ), after 1 h (T 1 ) and 24 h (T 24 ) of CKRT treatment. The differences in outcome measures were compared between these time points, and between survivors and non-survivors., Results: Sixty-nine patients received CKRT, of whom 38 (55%) died during the PICU stay. Overall, the vasoactive inotropic score and the adrenaline dose increased at T 1 compared to T 0 (p = 0.012 and p = 0.022, respectively). Compared to T 0 , at T 24 patients showed an improvement in the following ventilatory parameters: Oxygenation Index (p = 0.005), Oxygenation Saturation Index (p = 0.013) PaO 2 /FiO 2 ratio (p = 0.005), SpO 2 /FiO 2 ratio (p = 0.002) and Mean Airway Pressure (p = 0.016). These improvements remained significant in survivors (p = 0.01, p = 0.027, p = 0.01 and p = 0.015, respectively) but not in non-survivors. No changes in analgo-sedative drugs have been described., Conclusions: CKRT showed a significant impact on hemodynamics and ventilation in the first 24 h of treatment. We observed a significant rise in the inotropic/vasoactive support required after 1 h of treatment in the overall population, and an improvement in the ventilation parameters at 24 h only in survivors., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Continuous renal replacement therapy (CRRT) is the preferred method for renal support in critically ill and hemodynamically unstable children in the pediatric intensive care unit (PICU) as it allows for gentle removal of fluids and solutes. The most frequent indications for CRRT include acute kidney injury (AKI) and fluid overload (FO) as well as non-renal indications such as removal of toxic metabolites in acute liver failure, inborn errors of metabolism, and intoxications and removal of inflammatory mediators in sepsis. AKI and/or FO are common in critically ill children and their presence is associated with worse outcomes. Therefore, early recognition of AKI and FO is important and timely transfer of patients who might require CRRT to a center with institutional expertise should be considered. Although CRRT has been increasingly used in the critical care setting, due to the lack of standardized recommendations, wide practice variations exist regarding the main aspects of CRRT application in critically ill children.     Conclusion: In this review, from the Critical Care Nephrology section of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC), we summarize the key aspects of CRRT delivery and highlight the importance of adequate follow up among AKI survivors which might be of relevance for the general pediatric community. What is Known: • CRRT is the preferred method of renal support in critically ill and hemodynamically unstable children in the PICU as it allows for gentle removal of fluids and solutes. • Although CRRT has become an important and integral part of modern pediatric critical care, wide practice variations exist in all aspects of CRRT. What is New: • Given the lack of literature on guidance for a general pediatrician on when to refer a child for CRRT, we recommend timely transfer to a center with institutional expertise in CRRT, as both worsening AKI and FO have been associated with increased mortality. • Adequate follow-up of PICU patients with AKI and CRRT is highlighted as recent findings demonstrate that these children are at increased risk for adverse long-term outcomes., (© 2023. The Author(s).)

Thoracic ultrasound (TUS) has become an essential procedure in respiratory medicine. Due to its intrinsic safety and versatility, it has been applied in patients affected by several respiratory diseases both in intensive care and outpatient settings. TUS can complement and often exceed stethoscope and radiological findings, especially in managing pleural diseases. We hereby aimed to describe the establishment, development, and optimization in a large, tertiary care hospital of a pleural clinic, which is dedicated to the evaluation and monitoring of patients with pleural diseases, including, among others, pleural effusion and/or thickening, pneumothorax and subpleural consolidation. The clinic was initially meant to follow outpatients undergoing medical thoracoscopy. In this scenario, TUS allowed rapid and regular assessment of these patients, promptly diagnosing recurrence of pleural effusion and other complications that could be appropriately managed. Over time, our clinic has rapidly expanded its initial indications thus becoming the place to handle more complex respiratory patients in collaboration with, among others, thoracic surgeons and oncologists. In this article, we critically describe the strengths and pitfalls of our "pleural clinic" and propose an organizational model that results from a synergy between respiratory physicians and other professionals. This model can inspire other healthcare professionals to develop a similar organization based on their local setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Tinè, Daverio, Semenzato, Cocconcelli, Bernardinello, Damin, Saetta, Spagnolo and Balestro.)

Introduction: Analgesia and sedation are essential for the care of children in the pediatric intensive care unit (PICU); however, when prolonged, they may be associated with iatrogenic withdrawal syndrome (IWS) and delirium. We sought to evaluate current practices on IWS and delirium assessment and management (including non-pharmacologic strategies as early mobilization) and to investigate associations between the presence of an analgosedation protocol and IWS and delirium monitoring, analgosedation weaning, and early mobilization., Methods: We conducted a multicenter cross-sectional survey-based study collecting data from one experienced physician or nurse per PICU in Europe from January to April 2021. We then investigated differences among PICUs that did or did not follow an analgosedation protocol., Results: Among 357 PICUs, 215 (60%) responded across 27 countries. IWS was systematically monitored with a validated scale in 62% of PICUs, mostly using the Withdrawal Assessment Tool-1 (53%). The main first-line treatment for IWS was a rescue bolus with interruption of weaning (41%). Delirium was systematically monitored in 58% of PICUs, mostly with the Cornell Assessment of Pediatric Delirium scale (48%) and the Sophia Observation Scale for Pediatric Delirium (34%). The main reported first-line treatment for delirium was dexmedetomidine (45%) or antipsychotic drugs (40%). Seventy-one percent of PICUs reported to follow an analgosedation protocol. Multivariate analyses adjusted for PICU characteristics showed that PICUs using a protocol were significantly more likely to systematically monitor IWS (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.01-3.67) and delirium (OR 2.00, 95% CI 1.07-3.72), use a protocol for analgosedation weaning (OR 6.38, 95% CI 3.20-12.71) and promote mobilization (OR 3.38, 95% CI 1.63-7.03)., Conclusions: Monitoring and management of IWS and delirium are highly variable among European PICUs. The use of an analgosedation protocol was associated with an increased likelihood of monitoring IWS and delirium, performing a structured analgosedation weaning and promoting mobilization. Education on this topic and interprofessional collaborations are highly needed to help reduce the burden of analgosedation-associated adverse outcomes., (© 2023 Pharmacotherapy Publications, Inc.)

Endobronchial Ultrasound (EBUS) has been widely used to stage lung tumors and to diagnose mediastinal diseases. In the last decade, this procedure has evolved in several technical aspects, with new tools available to optimize tissue sampling and to increase its diagnostic yield, like elastography, different types of needles and, most recently, miniforceps and cryobiopsy. Accordingly, the indications for the use of the EBUS scope into the airways to perform the Endobronchial Ultrasound-TransBronchial Needle Aspiration (EBUS-TBNA) has also extended beyond the endobronchial and thoracic boundaries to sample lesions from the liver, left adrenal gland and retroperitoneal lymph nodes via the gastroesophageal tract, performing the Endoscopic UltraSound with Bronchoscope-guided Fine Needle Aspiration (EUS-B-FNA). In this review, we summarize and critically discuss the main indication for the use of the EBUS scope, even the more uncommon, to underline its utility and versatility in clinical practice.

Study Objective: We aimed to evaluate the efficacy and safety of ketamine in ensuring comfort and sparing conventional drugs when used as an adjuvant for analgesia and sedation in the Pediatric Intensive Care Unit (PICU) as a continuous infusion (≥12 h)., Design: Observational prospective study., Setting: Tertiary-care-center PICU., Patients: All consecutive patients <18 years who received ketamine for ≥12 h between January 2019 and July 2021., Interventions: ketamine infusion for ≥12 h., Measurements and Main Results: Seventy-seven patients (median age 16 months, Interquartile Range (IQR) 7-43) were enrolled. Twenty-six percent of patients (n = 20) were paralyzed, while 74% (n = 57) were not. The median infusion duration was 90 h (IQR 39-193), with doses between 15 (IQR 15-20) and 30 μg/kg/min (IQR 20-50). At 24 h of ketamine infusion, values of COMFORT-B-Scale (CBS) were significantly lower compared with values pre-ketamine (p < 0.001). Simultaneously, doses/kg/h of opioids and benzodiazepines significantly decreased at 24 h (p < 0.001 and p = 0.002, respectively), while doses/kg/h of propofol (p = 0.500) and dexmedetomidine (p = 0.072) did not significantly change. Seventy-four percent of non-paralyzed patients (42/57) had a decrease in CBS ≥2 points with no increase of concomitant analgosedation drugs. Among paralyzed patients (n = 20), 13 (65%) had no increase of concomitant analgosedation within 24 h after ketamine initiation. Overall, 55/77 (71%) of patients responded to ketamine. The mean and maximum ketamine infusion dosages were significantly higher in the non-responders (p = 0.021 and 0.028, respectively). Eleven patients had adverse events potentially related to ketamine (hypersalivation, systemic hypertension, dystonia/dyskinesia, tachycardia, and agitation) and six patients required intervention (dose reduction, suspension, or pharmacologic therapy). None of the patients developed delirium during ketamine infusion., Conclusions: Ketamine used as a continuous infusion in the PICU might represent a valid strategy to ensure comfort and spare opioids and benzodiazepines in difficult-to-sedate PICU patients. Adverse events are minor and easily reversible. Future study will be needed to investigate long-term outcomes., (© 2022 Pharmacotherapy Publications, Inc.)

Objective: To compare the performance of several prognostic scores calculated in the first 24 hours of admission (day 1) in predicting mortality and morbidity among critically ill children with sepsis presenting to the pediatric emergency department (PED) and then admitted to the pediatric intensive care unit (PICU)., Methods: Single-center, retrospective cohort study in children with a diagnosis of sepsis visiting the PED and then admitted to the PICU from January 1, 2010 to December 31, 2019. Sepsis organ dysfunction scores-pediatric Sequential Organ Failure Assessment (pSOFA) (Schlapbach, Matics, Shime), quickSOFA, quickSOFA-L, Pediatric Logistic Organ Dysfunction (PELOD)-2, quickPELOD-2, and Pediatric Multiple Organ Dysfunction score-were calculated during the first 24 hours of admission (day 1) and their performance compared with systemic inflammatory response syndrome (SIRS) and severe sepsis-International Consensus Conference on Pediatric Sepsis(ICCPS)-derived criteria-using the area under the receiver operating characteristic curve. Primary outcome was PICU mortality. Secondary outcomes were: a composite of death and new disability (ie, change from baseline Pediatric Overall Performance Category score ≥1); prolonged PICU length of stay (>5 d); prolonged invasive mechanical ventilation (MV) (>3 d)., Results: Among 60 patients with sepsis, 4 (6.7%) died, 7 (11.7%) developed new disability, 26 (43.3%) experienced prolonged length of stay, and 21 (35%) prolonged invasive MV. The prognostic ability in mortality discrimination was significantly higher for organ dysfunction scores, with PELOD-2 showing the best performance (area under the receiver operating characteristic curve, 0.924; 95% confidence interval, 0.837-1.000), significantly better than SIRS 3 criteria (0.924 vs 0.509, P = 0.009), SIRS 4 criteria (0.924 vs 0.509, P < 0.001), and severe sepsis (0.924 vs 0.527, P < 0.001). Among secondary outcomes, PELOD-2 performed significantly better than SIRS criteria and severe sepsis to predict prolonged duration of invasive MV, whereas better than severe sepsis to predict "poor outcome" (mortality or new disability)., Conclusions: Day 1 organ dysfunction scores performed better in predicting mortality and morbidity outcomes than ICCPS-derived criteria. The PELOD-2 was the organ dysfunction score with the best performance for all outcomes., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: ExtraCorporeal Membrane Oxygenation (ECMO) in pediatric patients with COVID-19 has a survival rate similar to adults. Occasionally, patients may need to be cannulated by an ECMO team in a referring hospital and transported to an ECMO center. The ECMO transport of a COVID-19 patient has additional risks than normal pediatric ECMO transport for the possible COVID-19 transmissibility to the ECMO team and the reduction of the ECMO team performance due to the need of wearing full personal protective equipment. Since pediatric data on ECMO transport of COVID-19 patients are lacking, we explored the outcomes of the pediatric COVID-19 ECMO transports collected in the EuroECMO COVID&#95;Neo/Ped Survey., Methods: We reported five European consecutive ECMO transports of COVID-19 pediatric patients collected in the EuroECMO COVID&#95;Neo/Ped Survey including 52 European neonatal and/or pediatric ECMO centers and endorsed by the EuroELSO from March 2020 till September 2021., Results: The ECMO transports were performed for two indications, pediatric ARDS and myocarditis associated to the multisystem inflammatory syndrome related to COVID-19. Cannulation strategies differed among patients according to the age of the patients, transport distance varied between 8 and 390 km with a total transport duration between 5 to 15 h. In all five cases, the ECMO transports were successfully performed without major adverse events. One patient reported a harlequin syndrome and another patient a cannula displacement both without major clinical consequences. Hospital survival was 60% with one patient reporting neurological sequelae. No ECMO team member developed COVID-19 symptoms after the transport., Conclusion: Five transports of pediatric patients with COVID-19 supported with ECMO were reported in the EuroECMO COVID&#95;Neo/Ped Survey. All transports were performed by an experienced multidisciplinary ECMO team and were feasible and safe for both the patient and the ECMO team. Further experiences are needed to better characterize these transports and draw insightful conclusions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the last decades, the advancement of knowledge in analgesia and sedation for critically ill pediatric patients has been conspicuous and relevant. Many recommendations have changed to ensure patients' comfort during their intensive care unit (ICU) stay and prevent and treat sedation-related complications, as well as improve functional recovery and clinical outcomes. The key aspects of the analgosedation management in pediatrics have been recently reviewed in two consensus-based documents. However, there remains a lot to be researched and understood. With this narrative review and authors' point of view, we aimed to summarize the new insights presented in these two documents to facilitate their interpretation and application in clinical practice, as well as to outline research priorities in the field.    Conclusion: With this narrative review and authors' point of view, we aimed to summarize the new insights presented in these two documents to facilitate their interpretation and application in clinical practice, as well as to outline research priorities in the field. What is Known: • Critically ill pediatric patients receiving intensive care required analgesia and sedation to attenuate painful and stressful stimuli. •Optimal management of analgosedation is a challenge often burdened with complications such as tolerance, iatrogenic withdrawal syndrome, delirium, and possible adverse outcomes. What is New: •The new insights on the analgosedation treatment for critically ill pediatric patients delineated in the recent guidelines are summarized to identify strategies for changes in clinical practice. •Research gaps and potential for quality improvement projects are also highlighted., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The objective of this study is to describe the clinical features of young infants with apneas as a clinical sign of COVID-19. We reported the cases of 4 infants who needed respiratory support in our PICU for a severe course of COVID-19 complicated with recurrent apneas. Moreover, we conducted a review of the literature about COVID-19 and apneas in infants ≤ 2 months of corrected age. A total of 17 young infants were included. Overall, in most of the cases (88%), apnea was an initial symptom of COVID-19, and in two cases, it recurred after 3-4 weeks. Regarding neurological workup, most children underwent a cranial ultrasound, while a minority underwent electroencephalography registration, neuroimaging, and lumbar punctures. One child showed signs of encephalopathy on electroencephalogram, with further neurological workup resulting normal. SARS-CoV-2 was never found in the cerebrospinal fluid. Ten children required intensive care unit admission, with five of them needing intubation and three non-invasive ventilation. A less invasive respiratory support was sufficient for the remaining children. Eight children were treated with caffeine. All patients had a complete recovery.  Conclusion: Young infants with recurrent apneas during COVID-19 usually need respiratory support and undergo a wide clinical work-up. They usually show complete recovery even when admitted to the intensive care unit. Further studies are needed to better define diagnostic and therapeutic strategies for these patients. What is Known: • Although the course of COVID-19 in infants is usually mild, some of them may develop a more severe disease needing intensive care support. Apneas may be a clinical sign in COVID-19. What is New: • Infants with apneas during COVID-19 may require intensive care support, but they usually show a benign course of the disease and full recovery., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Since the beginning of the SARS-CoV-2 pandemic, over 550 million people have been infected worldwide. Despite these large numbers, the long-term pulmonary consequences of COVID-19 remain unclear., Aims: The aim of this single-center observational cohort study was to identify and characterize pulmonary sequelae of COVID-19 at 12 months from hospitalization and to reveal possible predictors for the persistence of long-term lung consequences., Methods: Based on the persistence or absence of radiological changes after 12 months from hospitalization, the whole population was categorized into NOT-RECOVERED (NOT-REC) and RECOVERED (REC) groups, respectively. Clinical and pulmonary function data tests and clinical data were also collected and compared in the two groups. In the NOT-REC group, high resolution computed tomography (HRCT) images were semiquantitatively scored analyzing ground-glass opacities (GGO), interstitial thickening (IT), consolidations (CO), linear and curvilinear band opacities, and bronchiectasis for each lung lobe. Logistic regression analyses served to detect the factors associated with 12-month radiological consequences., Results: Out of the 421 patients followed after hospitalization for SARS-CoV-2 pneumonia, 347 met inclusion and exclusion criteria and were enrolled in the study. The NOT-REC patients ( n = 24; 6.9%) were significantly older [67 (62-76) years vs. 63 (53-71) years; p = 0.02], more frequently current smokers [4 (17%) vs. 12 (4%); p = 0.02], and with more severe respiratory failure at the time of hospitalization [PaO 2 /FiO 2 at admission: 201 (101-314) vs. 295 (223-343); p = 0.01] compared to REC group ( n = 323; 93.1%). On multivariable analysis, being a current smoker resulted in an independent predictor for lung sequelae after 12 months from hospitalization [5.6 OR; 95% CI (1.41-22.12); p = 0.01]., Conclusion: After 12 months from hospital admission, a limited number of patients displayed persistent pulmonary sequelae with minimal extension. Being a current smoker at the time of SARS-CoV-2 infection is an independent predictive factor to lung consequences, regardless of the disease severity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bernardinello, Cocconcelli, Giraudo, Daverio, Castelli, Petrarulo, Bovo, Fichera, Cavinato, Cattelan, Saetta, Spagnolo and Balestro.)

Importance: Data on trends in incidence and mortality for in-hospital cardiac arrest (IHCA) in children with cardiac disease in the intensive care unit (ICU) are lacking. Additionally, there is limited information on factors associated with IHCA and mortality in this population., Objective: To investigate incidence, trends, and factors associated with IHCA and mortality in children with cardiac disease in the ICU., Data Sources: A systematic review was conducted using PubMed, Web of Science, EMBASE, and CINAHL, from inception to September 2021., Study Selection: Observational studies on IHCA in pediatric ICU patients with cardiac disease were selected (age cutoffs in studies varied from age ≤18 y to age ≤21 y)., Data Extraction and Synthesis: Quality of studies was assessed using the National Institutes of Health Quality Assessment Tools. Data on incidence, mortality, and factors associated with IHCA or mortality were extracted by 2 independent observers. Random-effects meta-analysis was used to compute pooled proportions and pooled ORs. Metaregression, adjusted for type of study and diagnostic category, was used to evaluate trends in incidence and mortality., Main Outcomes and Measures: Primary outcomes were incidence of IHCA and in-hospital mortality. Secondary outcomes were proportions of patients who underwent extracorporeal membrane oxygenation (ECMO) cardiopulmonary resuscitation (ECPR) and those who did not achieve return of spontaneous circulation (ROSC)., Results: Of the 2574 studies identified, 25 were included in the systematic review (131 724 patients) and 18 in the meta-analysis. Five percent (95% CI, 4%-6%) of children with cardiac disease in the ICU experienced IHCA. The pooled in-hospital mortality among children who experienced IHCA was 51% (95% CI, 42%-59%). Thirty-nine percent (95% CI, 29%-51%) did not achieve ROSC; in centers with ECMO, 22% (95% CI, 14%-33%) underwent ECPR, whereas 22% (95% CI, 12%-38%) were unable to be resuscitated. Both incidence of IHCA and associated in-hospital mortality decreased significantly in the last 20 years (both P for trend < .001), whereas the proportion of patients not achieving ROSC did not significantly change (P for trend = .90). Neonatal age, prematurity, comorbidities, univentricular physiology, arrhythmias, prearrest mechanical ventilation or ECMO, and higher surgical complexity were associated with increased incidence of IHCA and mortality odds., Conclusions and Relevance: This systematic review and meta-analysis found that 5% of children with cardiac disease in the ICU experienced IHCA. Decreasing trends in IHCA incidence and mortality suggest that education on preventive interventions, use of ECMO, and post-arrest care may have been effective; however, there remains a crucial need for developing resuscitation strategies specific to children with cardiac disease.

Importance: Continuous kidney replacement therapy (CKRT) is the preferred method of kidney support for children with critical illness in pediatric intensive care units (PICUs). However, there are no data on the current CKRT management practices in European PICUs., Objective: To describe current CKRT practices across European PICUs., Design, Setting, and Participants: This cross-sectional survey of PICUs in 20 European countries was conducted by the Critical Care Nephrology Section of the European Society of Pediatric and Neonatal Intensive Care from April 1, 2020, to May 31, 2022. Participants included intensivists and nurses working in European PICUs. The survey was developed in English and distributed using SurveyMonkey. One response from each PICU that provided CKRT was included in the analysis. Data were analyzed from June 1 to June 30, 2022., Main Outcome and Measures: Demographic characteristics of European PICUs along with organizational and delivery aspects of CKRT (including prescription, liberation from CKRT, and training and education) were assessed., Results: Of 283 survey responses received, 161 were included in the analysis (response rate, 76%). The attending PICU consultant (70%) and the PICU team (77%) were mainly responsible for CKRT prescription, whereas the PICU nurses were responsible for circuit setup (49%) and bedside machine running (67%). Sixty-one percent of permanent nurses received training to use CKRT, with no need for certification or recertification in 36% of PICUs. Continuous venovenous hemodiafiltration was the preferred dialytic modality (51%). Circuit priming was performed with normal saline (67%) and blood priming in children weighing less than 10 kg (56%). Median (IQR) CKRT dose was 35 (30-50) mL/kg/h in neonates and 30 (30-40) mL/kg/h in children aged 1 month to 18 years. Forty-one percent of PICUs used regional unfractionated heparin infusion, whereas 35% used citrate-based regional anticoagulation. Filters were changed for filter clotting (53%) and increased transmembrane pressure (47%). For routine circuit changes, 72 hours was the cutoff in 62% of PICUs. Some PICUs (34%) monitored fluid removal goals every 4 hours, with variation from 12 hours (17%) to 24 hours (13%). Fluid removal goals ranged from 1 to 3 mL/kg/h. Liberation from CKRT was performed with a diuretic bolus followed by an infusion (32%) or a diuretic bolus alone (19%)., Conclusions and Relevance: This survey study found a wide variation in current CKRT practice, including organizational aspects, education and training, prescription, and liberation from CKRT, in European PICUs. This finding calls for concerted efforts on the part of the pediatric critical care and nephrology communities to streamline CKRT education and training, research, and guidelines to reduce variation in practice.

Background and Importance: Pediatric cardiac arrest is a rare emergency with associated high mortality. Its management is challenging and deviations from guidelines can affect clinical outcomes., Objectives: To evaluate the adherence to guideline recommendations in the management of a pediatric cardiac arrest scenario by teams of pediatric residents. Secondarily, the association between the use of the Pediatric Advanced Life Support-2015 (PALS-2015) pocket card, and the teams' adherence to international guidelines, were explored., Design, Settings and Participants: Multicentre observational simulation-based study at three Italian University Hospitals in 2018, including PALS-2015 certified pediatric residents in their 3rd-5th year of residency program, divided in teams of three., Intervention or Exposure: Each team conducted a standard nonshockable pediatric cardiac arrest scenario and independently decided whether to use the PALS-2015 pocket card., Outcome Measure and Analysis: The primary outcome was the overall number and frequency of individual deviations from the PALS-2015 guidelines, measured by the novel c-DEV15plus score (range 0-15). Secondarily, the performance on the validated Clinical Performance Tool for asystole scenarios, the time to perform resuscitation tasks and cardiopulmonary resuscitation (CPR) quality metrics were compared between the teams that used and did not use the PALS-2015 pocket card., Main Results: Twenty-seven teams (81 residents) were included. Overall, the median number of deviations per scenario was 7 out of 15 [interquartile range (IQR), 6-8]. The most frequent deviations were delays in positioning of a CPR board (92.6%), calling for adrenaline (92.6%), calling for help (88.9%) and incorrect/delayed administration of adrenaline (88.9%). The median Clinical Performance Tool score was 9 out of 13 (IQR, 7-10). The comparison between teams that used ( n  = 13) and did not use ( n  = 14) the PALS-2015 pocket card showed only significantly higher Clinical Performance Tool scores in the former group [9 (IQR 9-10) vs. 7 (IQR 6-8); P  = 0.002]., Conclusions: Deviations from guidelines, although measured by means of a nonvalidated tool, were frequent in the management of a pediatric cardiac arrest scenario by pediatric residents. The use of the PALS-2015 pocket card was associated with better Clinical Performance Tool scores but was not associated with less deviations or shorter times to resuscitation tasks., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Delirium is an acute brain dysfunction associated with increased length of hospitalization, mortality, and high healthcare costs especially in patients admitted to the pediatric intensive care unit (PICU). The Cornell Assessment of Pediatric Delirium (CAPD) is a screening tool for evaluating delirium in pediatric patients. This tool has already been used and validated in other languages but not in Italian., Objectives: To test the reliability of the Italian version of the CAPD to screen PICU patients for delirium and to assess the agreement between CAPD score and PICU physician clinical evaluation of delirium., Methods: Prospective double-blinded observational cohort study of patients admitted to a tertiary academic center PICU for at least 48 h from January 2020 to August 2021. We evaluated intra- and inter-rater agreement using the Intraclass Correlation Coefficient (ICC). The ability of the scale to detect delirium was evaluated by comparing the nurses' CAPD assessments with the clinical evaluation of a PICU physician with expertise in analgosedation using the area under the ROC curve (AUC)., Measurements and Main Results: Seventy patients were included in the study. The prevalence of pediatric delirium was 54% (38/70) when reported by a positive CAPD score and 21% (15/70) when diagnosed by the PICU physician. The CAPD showed high agreement levels both for the intra-rater (ICC 1 0.98, 95% CI: 0.97-0.99) and the inter-rater (ICC 2 0.93, 95% CI: 0.89-0.96) assessments. In patients with suspected delirium according to the CAPD scale, the observed sensitivity and specificity of the scale were 0.93 (95% CI: 0.68-1.00) and 0.56 (95% CI: 0.42-0.70), respectively. The AUC observed was 0.75 (95% CI: 0.66-0.8490)., Conclusion: The Italian version of the CAPD seems a reliable tool for the identification of patients at high risk of developing delirium in pediatric critical care settings. Compared to the clinical evaluation of the PICU physician, the use of the CAPD scale avoids a possible underestimation of delirium in the pediatric population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fazio, Daverio, Masola, D’Angelo, Frison, Zaggia, Simeone, Pucciarelli, Gregori, Comoretto and Amigoni.)

Sucrose is effective in reducing pain during minor procedures in neonates. We evaluated whether a second dose of sucrose was more effective than a single dose during venipuncture. We performed a randomised, double-blind, controlled trial at the NICU of Padua Hospital (August 2016-October 2017). We randomised 72 preterm infants undergoing venipuncture for routine test to a control group, which received a single standard dose of sucrose 2' before the procedure and a placebo 30″ after the venipuncture, and an experimental group in which they received two doses of 24% sucrose 2' before and 30″ after the venipuncture. No difference in pain perception was found between the groups at 30″, 60″ and 120″. In conclusion, we do not recommend a second dose of sucrose during venipuncture in prematures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cavicchiolo, Daverio, Battajon, Frigo and Lago.)

Objectives: We aim to describe the use of continuous infusion of neuromuscular blocking agents in mechanically ventilated critically ill children and to test its association with in-hospital mortality., Design: Multicenter, registry-based, observational, two-cohort-comparison retrospective study using prospectively collected data from a web-based national registry., Setting: Seventeen PICUs in Italy., Patients: We included children less than 18 years who received mechanical ventilation and a neuromuscular blocking agent infusion from January 2010 to October 2017. A propensity score-weighted Cox regression analysis was used to assess the relationship between the use of neuromuscular blocking agents and in-hospital mortality., Interventions: None., Measurements and Main Results: Of the 23,227 patients admitted to the PICUs during the study period, 3,823 patients were included. Patients who received a continuous infusion of neuromuscular blocking agent were more likely to be younger (p < 0.001), ex-premature (p < 0.001), and presenting with less chronic respiratory insufficiency requiring home mechanical ventilation (p < 0.001). Reasons for mechanical ventilation significantly differed between patients who received a continuous infusion of neuromuscular blocking agent and patients who did not receive a continuous infusion of neuromuscular blocking agent, with a higher frequency of respiratory and cardiac diagnosis among patients who received neuromuscular blocking agents compared with other diagnoses (all p < 0.001). The covariates were well balanced in the propensity-weighted cohort. The mortality rate significantly differed among the two cohorts (patients who received a continuous infusion of neuromuscular blocking agent 21% vs patients who did not receive a continuous infusion of neuromuscular blocking agent 11%; p < 0.001 by weighted logistic regression). Patients who received a continuous infusion of neuromuscular blocking agent experienced longer mechanical ventilation and PICU stay (both p < 0.001 by weighted logistic regression). A weighted Cox regression analysis found the use of neuromuscular blocking agents to be a significant predictor of in-hospital mortality both in the unadjusted analysis (hazard ratio, 1.7; 95% CI, 1.3-2.2) and in the adjusted one (hazard ratio, 1.6; 95% CI, 1.2-2.1)., Conclusions: Thirteen percent of mechanically ventilated children in PICUs received neuromuscular blocking agents. When adjusting for selection bias with a propensity score approach, the use of neuromuscular blocking agent was found to be a significant predictor of in-hospital mortality., Competing Interests: Dr. Biban received funding from Getinge and Chiesi Pharmaceutical. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Study Objective: Withdrawal syndrome (WS) may be a critical drawback of opioid/benzodiazepine weaning in children. The most effective intervention to reduce WS prevalence is yet to be determined. Dexmedetomidine (DEX) was estimated to be effective in reducing WS-related symptoms, but no randomized trial has been conducted to prove its efficacy so far. We aimed to evaluate the efficacy and safety of DEX in reducing the occurrence of WS., Design and Setting: This was an adaptive randomized double-blind placebo-controlled trial conducted at three Italian Pediatric Intensive Care Units (PICUs)., Patients: It included children admitted to PICU, undergoing at least five days of opioids/benzodiazepines continuous infusion, and ready to start the analgosedation weaning., Intervention: Twenty-four hours before the start of weaning, an infusion of DEX/placebo was started. WS symptoms were monitored using the Withdrawal-Assessment-Tool-version-1 (WAT-1). In case of WS symptoms (WAT-1 ≥ 3) an opioid/benzodiazepine bolus was given and the DEX/placebo infusion-rate was increased., Measurements: The primary outcome measure was the prevalence of WS. Secondary outcomes were the trend of WAT-1 over time, number of rescue doses, length of weaning and PICU-stay, and onset of adverse events (AEs)., Main Results: Forty-five patients were enrolled, of whom 5 dropped-out and 40 entered the interim analysis. There were no significant baseline differences between groups. WS prevalence did not significantly differ between groups (77.8% DEX vs 90.9% placebo, p = 0.381). By generalized linear mixed modeling, the WAT-1 trend showed a significant increase per unit of time in the DEX arm (estimate 0.27, CI 0.07-0.47, p = 0.009) compared to placebo. Most frequent AEs were hemodynamic, and all of them happened in the DEX arm., Conclusions: A continuous infusion of DEX, started 24 h before the analgosedation weaning and increased based on WS signs, was not able to significantly modify the prevalence of WS in children who received at least five days of opioids/benzodiazepines treatment compared to placebo., (© 2021 Pharmacotherapy Publications, Inc.)

The Agouti gene (ASIP) is one of the most important genes for coat color determination in mammals. It has a complex structure with several promoters and alternative non-coding first exons that are transcribed into mRNAs with different 5'UTR. These mRNA isoforms regulate the temporal and spatial expression of the gene, producing diverse pigmentation patterns. Here, we studied ASIP transcriptional variants and their expression in the skin of llamas with different coat color phenotypes. We also described the ASIP locus, including promoter usage and the splicing events that originate each transcript variant. Using 5'RACE-PCR we isolated seven ASIP transcripts with alternative 5'UTR, where exons 1A, 1A', 1C, 1D, and a novel non-coding exon 1A" were identified. Additionally, new alternative spliced forms were found. The diversity of ASIP 5'UTRs is originated by a complex pattern of alternative promoter usage, multiple transcription start sites and splicing events that include exon skipping and alternative 3' splicing site selection. We found that ASIP was highly expressed in llamas with white and brown phenotypes while black animals presented very low expression. The main responsible for this difference was a fusion transcript between ASIP and NCOA6 genes, which was present in the skin of white and brown llamas but not in the black ones. The rest of ASIP transcripts presented very low expression in the skin, indicating that the main regulation point for ASIP gene expression is at the transcriptional level. Nevertheless, the characteristics of the 5'UTRs sequences suggest that alternative transcripts could be regulated differently at the protein synthesis level., (Copyright © 2021 Elsevier B.V. All rights reserved.)