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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).Observational prospective study.Tertiary-care-center PICU.All consecutive patients18 years who received ketamine for ≥12 h between January 2019 and July 2021.ketamine infusion for ≥12 h.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.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.

Objectives To investigate how life-sustaining treatment (LST) decisions are made and identify problematic ethical concerns confronted by physicians and nurses in pediatric intensive care within Italy. Methods An 88-question online survey was created, based on a previous qualitative study conducted by this team. The survey was designed to identify how LST decisions were managed; contrasting actual practices with what participants think practices should be. Replies from physicians and nurses were compared, to identify potential inter-professional ethical tensions. The study also identified participants’ principal ethical concerns. Moreover, open-ended questions elicited qualitative perspectives on participants’ views. The survey was pilot-tested and refined before initiation of the study. Results 31 physicians and 65 nurses participated in the study. Participants were recruited from pediatric intensive care units across five Italian cities; i.e., Florence, Milan, Padua, Rome, Verona. Statistically significant differences were identified for (a) virtually all questions contrasting actual practices with what participants think practices should be and (b) 14 questions contrasting physician replies with those of nurses. Physicians and nurses identified the absence of legislative standards for LST withdrawal as a highly problematic ethical concern. Physicians also identified bearing responsibility for LST decisions as a major concern. Qualitative descriptions further demonstrated that these Italian pediatric intensive care clinicians encounter significantly distressing ethical problems in their practice. Conclusions The results of this study highlight a need for the development of (a) strategies for improving team processes regarding LST decisions, so they can be better aligned with how clinicians think decisions should be made, and (b) Italian LST decision-making standards that can help ensure optimal ethical practices.

BackgroundCentral venous catheters (CVCs) represent one of the main risk factors for venous thrombotic events (VTEs) in children.MethodsWe studied the Italian Registry of Pediatric Thrombosis (RITI) with regard to systemic radiologically confirmed CVC-related VTEs (CVC-VTEs) occurred during 6.5 years in children aged 29 days to 18 years.ResultsA total of 78 CVC-VTEs were included, which occurred in 76 patients (40/76, 53% males). CVC-VTEs comprised 67 non-cardiac VTEs (86%) and 11 intracardiac thrombotic events (ICTEs) (14%); the median age at onset was 19 and 17 months, respectively. The most frequent reason for CVC insertion was supportive therapy. The catheters were placed percutaneously in 85% of cases (56/66) and surgically in the remaining 15% (10/66). Peripherally inserted central catheters (PICCs) were used in 47% (31/66) cases, partially implanted catheters in 42% (28/66), non-implantable catheters in 7% (5/66), and totally implanted catheters (Port) in 2% (1/66). CVC-VTEs were symptomatic in 77% of cases (60/78), while in the remaining 23%, they were incidentally detected on the imaging performed for the underlying condition. The median time between CVC insertion and the onset of symptoms was 10 days in non-cardiac VTEs and 39 days in ICTEs. Doppler ultrasound was the diagnostic technique most frequently used. The venous compartment most frequently affected was the veins of the lower extremities (52%, 43/73). Anti-thrombotic treatment was administered in 96% of CVC-VTEs (75/78). About 2.6% (2/76) of patients experienced a second thrombotic event. At discharge, post-thrombotic syndrome was reported in 13.5% (5/37) events with available data, CVC replacement in 10.8% (4/47), and ischemic necrosis with toe finger amputation in 2.7% (1/37). Three patients died due to an underlying condition; no CVC-VTE-related deaths were reported.ConclusionsWe have carried out a registry-based study on CVC-VTEs in the children in Italy, providing the data that may help improve the detection and management of this CVC-related complication.

Background Prolonged treatment with analgesic and sedative drugs in the pediatric intensive care unit (PICU) may lead to undesirable effects such as dependence and tolerance. Moreover, during analgosedation weaning, patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicate that dexmedetomidine, a selective α2-adrenoceptor agonist, may be useful to prevent WS, but no clear evidence supports these data. The aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during analgosedation weaning, and to clearly assess its safety. Methods We will perform an adaptive, multicenter, randomized, double-blind, placebo-controlled trial. Patients aged N = 154 patients). The study was approved by the Ethics Committee of the University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017. Discussion The present trial will allow us to clearly assess the efficacy of dexmedetomidine in reducing the occurrence of WS during weaning from analgosedation drugs. In addition, the study will provide a unique insight into the safety profile of dexmedetomidine. Trial registration ClinicalTrials.gov, NCT03645603. Registered on 24 August 2018. EudraCT, 2015–002114-80. Retrospectively registered on 2 January 2019.

The present work aims to identify the predictors of hemodynamic failure (HF) developed during pediatric intensive care unit (PICU) stay testing a set of machine learning techniques (MLTs), comparing their ability to predict the outcome of interest. The study involved patients admitted to PICUs between 2010 and 2020. Data were extracted from the Italian Network of Pediatric Intensive Care Units (TIPNet) registry. The algorithms considered were generalized linear model (GLM), recursive partition tree (RPART), random forest (RF), neural networks models, and extreme gradient boosting (XGB). Since the outcome is rare, upsampling and downsampling algorithms have been applied for imbalance control. For each approach, the main performance measures were reported. Among an overall sample of 29,494 subjects, only 399 developed HF during the PICU stay. The median age was about two years, and the male gender was the most prevalent. The XGB algorithm outperformed other MLTs in predicting HF development, with a median ROC measure of 0.780 (IQR 0.770–0.793). PIM 3, age, and base excess were found to be the strongest predictors of outcome. The present work provides insights for the prediction of HF development during PICU stay using machine-learning algorithms.

Background Limited mid-term durability of 12A/LX Mitroflow bioprosthesis has been reported. Aim of the study was to ascertain the pathologic substrates and possible mechanisms of structural valve deterioration in explants from animals and humans. Methods Nine aortic 12A/LX Mitroflow bioprostheses preserved in hypotonic solution and three aortic 12A/LX bioprostheses, preserved in isotonic solution, were explanted from juvenile sheep, mean time from implant 95.66 ± 36.04 days and 132.33 ± 28.88 days from implant respectively. One stented unimplanted 12A/LX Mitroflow preserved in isotonic colution before glutaraldeyde fixation served as control. Ten aortic 12A/LX Mitroflow bioprostheses were explanted from humans because of severe dysfunction: five children, (3 females and 2 males, mean age 14.19 ± 4.77 years, range 11-21), 26 ± 8.24 months from implant and 5 adults (4 females and 1 male, mean age 57.4 ± 19.85 years, range 31-72), 64.4 ± 26.94 months from implant. X-ray, histology, and transmission electron microscopy were carried out as well as spectroscopy for calcium (Ca++) and phosphorus (P) content in human explants. Results Explants, from both animals and humans, showed cusp folding and stiffness, with coarse calcific deposits at gross examination and X-ray. Severe collagen denaturation, plasma insudation and massive calcification, involving both collagen and cell debris, were observed microscopically. Mean Ca++ content of 183.27 ± 62.48 and P content of 94.35 ±33.76 mg/g dry weight was found in children and Ca++ content of 205.49 ± 2.23 and P content of 99.75 ± 0.11 mg/g dry weight in adults. Obstructive fibrous tissue overgrowth was detected in 6 human cases. Conclusions Collagen denaturation was observed in pericardial Mitroflow 12A/LX bioprosthesis with premature structural valve deterioration. Optimal collagen fixation and preservation as well as phospholipids reduction by removing cell debris, as employed in the novel CROWN PRT Mitroflow bioprosthesis, are expected to solve the flaw and achieve long-term durability.

Macrophage activation syndrome (MAS) is a rare, potentially life-threatening, condition triggered by infections or flares in rheumatologic and neoplastic diseases. The mainstay of treatment includes high dose corticosteroids, intravenous immunoglobulins and immunosuppressive drugs although, more recently, a more targeted approach, based on the use of selective cytokines inhibitors, has been reported. We present the case of a two-year-old boy with 1-month history of high degree fever associated with limping gait, cervical lymphadenopathy and skin rash. Laboratory tests showed elevation of inflammatory markers and ferritin. By exclusion criteria, systemic onset Juvenile Idiopathic Arthritis (sJIA) was diagnosed and steroid therapy started. A couple of weeks later, fever relapsed and laboratory tests were consistent with MAS. He was promptly treated with high doses intravenous methylprednisolone pulses and oral cyclosporin A. One day later, he developed an acute myocarditis and a systemic capillary leak syndrome needing intensive care. Intravenous Immunoglobulin and subcutaneous IL-1-antagonists Anakinra were added. On day 4, after an episode of cardiac arrest, venous-arterial extracorporeal membrane oxygenation (VA-ECMO) was started. Considering the severe refractory clinical picture, we tried high dose intravenous Anakinra (HDIV-ANA, 2 mg/Kg q6h). This treatment brought immediate benefit: serial echocardiography showed progressive resolution of myocarditis, VA-ECMO was gradually decreased and definitively weaned off in 6 days and MAS laboratory markers improved. Our case underscores the importance of an early aggressive treatment in refractory life-threatening sJIA-related MAS and adds evidence on safety and efficacy of HDIV-ANA particularly in acute myocarditis needing VA-ECMO support.

Objectives To evaluate the ability to predict central venous pressure by ultrasound measured inferior vena cava and aortic diameters in a PICU population and to assess interoperator concordance. Design Noninterventional observational study. Setting PICU of a tertiary-care academic center. Patients Eighty-eight pediatric patients (0-16 yr old) with a central venous catheter in place were studied. Sixty-nine percent of the patients received positive-pressure ventilation. Interventions None. Measurements and main results An experienced and a nonexperienced operator used ultrasound to measure the maximal diameter of inferior vena cava and minimal diameter of the inferior vena cava and the maximum diameter of the abdominal aorta from the subxiphoid window. The inferior vena cava collapsibility index and the ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta were then derived. The central venous pressure was measured using a central venous catheter and recorded. Twenty-three patients had low central venous pressure values (≤ 4 mm Hg), 35 patients a value in the range of 5-9 mm Hg, and 30 patients high values (≥ 10 mm Hg). Both inferior vena cava collapsibility index and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta were predictive of high (≥ 10 mm Hg) or low (≤ 4 mm Hg) central venous pressure. The test accuracy showed the best results in predicting low central venous pressure with an inferior vena cava collapsibility index greater than or equal to 35% and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta less than or equal to 0.8, and in predicting high central venous pressure with an inferior vena cava collapsibility index less than or equal to 20% and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta greater than or equal to 1.3. Inferior vena cava collapsibility index returned generally higher accuracy values than ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta. Lin's coefficient of concordance between the operators was 0.78 for inferior vena cava collapsibility index and 0.86 for ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta. Conclusions Inferior vena cava collapsibility index and ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta correlate well with central venous pressure measurements in this PICU population, and specific inferior vena cava collapsibility index or ratio of maximal diameter of inferior vena cava/maximum diameter of the abdominal aorta thresholds appear to be able to differentiate children with high or low central venous pressure. However, the actual clinical application of these statistically significant results remains limited, especially by the intrinsic flaws of the procedure.

Background Aortic stentless bioprosthetic valve (SLBPV), either porcine or pericardial, minimizes transvalvular gradient and favors regression of left ventricular hypertrophy. The drawback consists of longer time for suturing. While structural valve deterioration (SVD) in stented porcine and pericardial BPVs has been extensively investigated, less information is available on SLBPVs. Material and Methods We studied 82 SLBPVs explants, either porcine (Toronto SPV, [St. Jude Medical, MN, USA], CryolifeO'Brien Model 300 and CryoLife-O'Brien [Cryolife International, GA, USA], BioCor PVS [St. Jude Medical, MN, USA] Prima and Prima Plus [Edwards Lifesciences Corp. One Edwards Way, CA, formerly Baxter Inc, CA, USA]) or pericardial ([Pericarbon Freedom and Freedom Solo [Sorin-Biomedica, S.p.A., Saluggia, Italy]). Results By excluding cases with leak and endocarditis, we focused the investigation on 46 SLBPVs, which failed because of SVD. Gender was male in 29 (63%). Mean age of patients at time of implant was 59.8 years. Postoperative time of SVD was 115.0 months for porcine and 79.0 months for pericardial SLBPVs. Dysfunction requiring reoperation was mainly incompetence for porcine and stenosis for pericardial SLBPVs. Even pinpoint mineralization at the commissures resulted in sudden cusp tearing and incompetence. Cuspal atheromasia accounted for cusp tearing even in the absence of calcification. Mineralization showed progression with time in pericardial but not in porcine SLBPVs. Conclusions Tissue mineralization remains the nightmare also of SLBPVs, with the peculiar features of pinpoint calcific deposits at commissures, tearing and abrupt incompetence in porcine SLBPVs and of massive cuspal mineralization and stenosis in pericardial SLBPVs.

Background In numerous randomized controlled trials (RCTs) and systematic reviews such as those published by the Cochrane Collaboration, Pelargonium sidoides extract EPs® 7630 was shown to be effective in acute respiratory tract infections (aRTI) in all investigated age-groups. This narrative review focuses on recently published results from RCTs investigating the clinical efficacy and safety of EPs 7630 in children and adolescents with different manifestations of aRTI, in order to present a broader overview and to provide an update on the state of knowledge regarding the use of EPs 7630 in this age-group. Methods The Cochrane review on P. sidoides extract for aRTI published by the Cochrane Collaboration was searched for cited RCTs with EPs 7630 in children and adolescents suffering from aRTI. A PubMed and SCOPUS literature search was performed for publications issued before June 13, 2017 (search terms: children, Pelargonium sidoides, EPs 7630, respiratory). Reference lists of publications found were searched for relevant citations. Results Eight RCTs investigating the application of EPs 7630 in acute bronchitis, acute tonsil-lopharyngitis, and aRTI in the context of chronic preconditions were identified. Results showed a statistically significant improvement of aRTI symptom severity for EPs 7630 as compared to controls. The investigation of EPs 7630 in asthmatic children and adolescents with aRTI demonstrated a significant symptom-alleviating effect and a possibly associated reduction of asthma attacks. In immunocompromised children with acute upper RTI, an alleviating effect of EPs 7630 was shown. All RCTs reviewed reported good safety and tolerability of EPs 7630. Conclusion The P. sidoides extract EPs 7630 is effective and safe for those of pediatric age and may be regarded as an alternative option for the management of aRTI.

IntroductionSome evidence indicates that exogenous surfactant therapy may be effective in infants with acute viral bronchiolitis, even though more confirmatory data are needed. To date, no large multicentre trials have evaluated the effectiveness and safety of exogenous surfactant in severe cases of bronchiolitis requiring invasive mechanical ventilation (IMV).Methods and analysisThis is a multicentre randomised, placebo-controlled, double-blind study, performed in 19 Italian paediatric intensive care units (PICUs). Eligible participants are infants under the age of 12 months hospitalised in a PICU, suffering from severe acute hypoxaemic bronchiolitis, requiring IMV. We adopted a more restrictive definition of bronchiolitis, including only infants below 12 months of age, to maintain the population as much homogeneous as possible. The primary outcome is to evaluate whether exogenous surfactant therapy (Curosurf, Chiesi Pharmaceuticals, Italy) is effective compared with placebo (air) in reducing the duration of IMV in the first 14 days of hospitalisation, in infants suffering from acute hypoxaemic viral bronchiolitis. Secondary outcomes are duration of non-invasive mechanical ventilation in the post-extubation phase, number of cases requiring new intubation after previous extubation within 14 days from randomisation, PICU and hospital length of stay (LOS), duration of oxygen dependency, effects on oxygenation and ventilatory parameters during invasive mechanical respiratory support, need for repeating treatment within 24 hours of first treatment, use of other interventions (eg, high-frequency oscillatory ventilation, nitric oxide, extracorporeal membrane oxygenation), mortality within the first 14 days of PICU stay and before hospital discharge, side effects and serious adverse events.Ethics and disseminationThe trial design and protocol have received approval by the Italian National Agency for Drugs (AIFA) and by the Regional Ethical Committee of Verona University Hospital (1494CESC). Findings will be disseminated through publication in peer-reviewed journals, conference/meeting presentations and media.Trial registration numberClinicaltrials.gov, issue date 22 May 2019. NCT03959384.

Background: Prolonged treatment with analgesic and sedative drugs in Pediatric Intensive Care Unit (PICU) may lead to undesirable effects as dependence and tolerance. Moreover, during the analgosedation weaning patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicated that dexmedetomidine, a selective α2-adrenoceptors agonist, may be useful to prevent WS, but no clear evidences support this data. Aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during the analgosedation weaning, and to clearly assess its safety. Methods: We will perform an adaptive, multicenter, randomized, double-blind, placebo-controlled trial. Patients

Introduction: Children admitted to paediatric intensive care unit (PICU) are at risk of acute kidney injury (AKI). However, few paediatric studies have focused on the identification of factors potentially associated with the development of this condition. The aim of our study was to assess the incidence rate of AKI, identify risk factors, and evaluate clinical outcome in a large sample of critically ill children. Methods: This retrospective observational study was conducted including patients admitted to our PICU from January 2014 to December 2016. AKI was defined according to Kidney Disease: Improving Global Outcome criteria. Results: A total of 222 PICU patients out of 811 (27%) had AKI (stage I 39%, stage II 24%, stage III 37%). The most common PICU admission diagnoses in AKI cases were heart disease (38.6%), respiratory failure (16.8%) and postsurgical non-cardiac patients (11%). Hypoxic-ischaemic was the most frequent cause of AKI. Significant risk factors for AKI following multivariate analysis were age >2 months (OR 2.43; 95% CI 1.03–7.87; p = 0.05), serum creatinine at admission >44 µmol/L (OR 2.23; 95% CI 1.26–3.94; p = 0.006), presence of comorbidities (OR 1.84; 95% CI 1.03–3.30; p = 0.04), use of inotropes (OR 2.56; 95% CI 1.23–5.35; p= 0.012) and diuretics (OR 2.78; 95% CI 1.49–5.19; p = 0.001), exposure to nephrotoxic drugs (OR 1.66; 95% CI 1.01–2.91; p= 0.04), multiple organ dysfunction syndrome (OR 2.68; 95% CI 1.43–5.01; p = 0.002), and coagulopathy (OR 1.89; 95% CI 1.05–3.38, p = 0.03). AKI was associated with a significant longer PICU stay (median LOS of 8 days, interquartile range [IQR] 3–16, versus 4 days, IQR 2–8, in non-AKI patients; p < 0.001). The mortality rate resulted tenfold higher in AKI than non-AKI patients (12.6 vs. 1.2%; p < 0.001). Conclusions: The incidence of AKI in critically ill children is high, with an associated increased length of stay and risk of mortality. In the PICU setting, risk factors of AKI are multiple and mainly associated with illness severity.

Background: Prolonged treatment with analgesic and sedative drugs in Pediatric Intensive Care Unit (PICU) may lead to undesirable effects as dependence and tolerance. Moreover, during the analgosedation weaning patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicated that dexmedetomidine, a selective α2-adrenoceptors agonist, may be useful to prevent WS, but no clear evidences still support this data. Aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during the analgosedation weaning, to evaluate its safety, to identify its optimal dose-range and to quantify its ability in reducing time of weaning, time of mechanical ventilation and PICU-stay. Methods: We will perform a prospective, multicenter, randomized, double-blind, placebo-controlled study. Patients meeting the inclusion criteria will be randomly assigned to treatment A (dexmedetomidine) or treatment B (placebo). Treatments will be started 24 hours before the analgosedation-weaning and will be continued throughout the whole weaning time. Efficacy of treatments will be evaluated by monitoring the signs of WS using the withdrawal assessment tool version 1 score (WAT-1). If WAT-1 score is ≥3, dexmedetomidine/placebo-dose will be increased following a defined protocol. Thus, efficacy will be compared between treatment groups. Safety will be assessed collecting any potentially-related adverse event. Clinical or sedation characteristics will be analyzed to assess any significant association with outcome measures. The sample size assuring a power of 95% is 80 patients for each group (N total=160 patients). The study was approved by the Ethics Committee of the University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017. Discussion: The present trial will allow to clearly assess the efficacy of dexmedetomidine in reducing the occurrence of WS during the weaning of analgosedation drugs. In addition, the study will provide a unique insight into the safety profile of dexmedetomidine. Trial registration: ClinicalTrials.gov ID NCT03645603, registered on 24 August 2018, https://clinicaltrials.gov/ct2/show/NCT03645603. Retrospectively registered on EudraCT with ID 2015-002114-80, registered on 2 Jan 2019.