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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.

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.

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.

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 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.

Background Propranolol has become the first-line treatment for complicated Infantile Hemangioma (IH), showing so far a good risk-benefit profile. Case presentation We report the case of a toddler, on propranolol, who suffered cardiac arrest during an acute viral infection. She had a neurally-mediated syncope that progressed to asystole, probably because of concurrent factors as dehydration, beta-blocking and probably individual susceptibility to vaso-vagal phenomena. In fact a significant history of breath-holding spells was consistent with vagal hyperactivity. Conclusions The number of patients treated with propranolol for IHs will increase and sharing experience will help to better define the safety profile of this drug.

To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P = .030) and second or third HSCT (P = .018). Characteristics significantly associated with mortality were mismatched HSCT (P = .011), relapse of underlying disease before PICU admission (P .001), acute respiratory distress syndrome at admission (P = .012), hepatic failure at admission (P = .021), and need for invasive ventilation during PICU course (P .001). Our data indicate which patients have a high risk for PICU admission after HSCT and for dismal outcomes after PICU stay. These findings may provide support for the clinical decision-making process on the opportunity of PICU admission for severely compromised patients after HSCT.

There is a lack of definitive data on the effective management of acute respiratory distress syndrome (ARDS) in infants and children. The development and validation of the Berlin definition (BD) for ARDS and the Pediatric Acute Lung Injury Consensus Conference (PALICC) recommendations in children represented a major advance in optimizing research and treatment, mainly due to the introduction of a severe ARDS category. Proposed reasons for the lack of consistent results with surfactants in children and infants compared with neonates include different causes, type of lung damage (direct or indirect), timing and mode of administration as well as the type of surfactant used. Secretory phospholipase A2 plays an important role in inflammation and possible dysfunction of surfactants in ARDS. Bronchoalveolar lavage (BAL) with normal saline and surfactant allows the removal of inhaled material, the recruitment of non-ventilating areas and the maintenance of the surfactant pool size. BAL with diluted surfactant allows rapid absorption of the surfactant at the air/liquid interface, which blocks the progression of pathological lung disease and in turn disrupts the inflammatory cycle. Importantly, it is now recognized that the type of surfactant, the time of administration and the method of administration could all play an important role in the management of ARDS, and there is evidence that surfactant is effective and well tolerated in children and infants with ARDS.

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.

To evaluate the health-related quality of life on a very long-term follow-up in patients treated with extracorporeal membrane oxygenation (ECMO) during neonatal and pediatric age. Prospective follow-up study. Pediatric Intensive Care Unit of a tertiary-care University-Hospital. Out of 20 neonates and 21 children treated with ECMO in our center, 24 patients underwent short-term neurological follow-up. Twenty of them underwent long-term neurological follow-up. Short-term follow-up was performed at 18 months and consisted in clinical evaluation, electroencephalography, and neuroimaging. Long-term follow-up was performed in 2017, at the mean period 19.72 years from ECMO (median 20.75, range 11.50–24.08) and consisted in a standardized questionnaires self-evaluation (PedsQL 4.0 Generic Core Scale) of health-related quality of life and an interviewed about the presence of organ morbidity, school level, or work position. Sixty-one percent (25/41) of the patients survived within 30 days after ECMO treatment. Short-term follow-up was performed in 24 patients (1 patient but died before the evaluation): 21 patients (87%) showed a normal neurological status, and 3 developed severe disability. Long-term follow-up was performed in 20 long-term survivors (3 patients were not possible to be contacted and considered lost to follow-up): mean age of patients at long-term follow-up was 21.23 (median 20.96, range 13.33–35.58) years; 90% (18/20) of them have no disability with a complete normal quality of life and 95% have no cognitive impairment. ECMO represents a life-saving treatment for infants and children with respiratory and/or heart failure; survivors show a good quality of life comparable to healthy peers.

PurposeThe emergence of antimicrobial resistance has led to increasing efforts to reduce unnecessary use of antibiotics in primary care, but potential hazards from bacterial infection continue to cause concern. This study investigated how primary care prescribers evaluate the risks of reduced antibiotic prescribing.MethodsQualitative study using semi-structured interviews conducted with primary care prescribers from 10 general practices in an urban area and a shire town in England. A thematic analysis was conducted.ResultsThirty participants were recruited, including 23 general practitioners, 5 nurses and 2 pharmacists. Three main themes were identified: risk assessment; balancing treatment risks; and negotiating decisions and risks. Respondents indicated that their decisions were grounded in clinical risk assessment, but this was informed by different approaches to antibiotic use, with most leaning towards reduced prescribing. Prescribers’ perceptions of risk included the consequences of both inappropriate prescribing and inappropriate withholding of antibiotics. Sepsis was viewed as the most concerning potential outcome of non-prescribing, leading to possible patient harm and potential litigation. Risks of antibiotic prescribing included antibiotic resistant and C. difficile infections, as well as side effects, such as rashes, that might lead to possible mislabelling as antibiotic allergy. Prescribers elicited patient preferences for use or avoidance of antibiotics to inform management strategies, which included educational advice, advice on self-management including warning signs, use of delayed prescriptions, and safety netting.ConclusionsAttitudes towards antibiotic prescribing are evolving, with reduced antibiotic prescribing now being approached more systematically. The safety trade-offs associated with either use or non-use of antibiotics present difficulties especially when prescribing decisions are inconsistent with patients’ expectations.Strengths and limitations of this studyThe study provides an investigation of primary care prescribers’ perceptions, emphasising safety perspectives in the context of antimicrobial stewardship.The main themes identified may inform the basis for future improvement and antimicrobial stewardship programs.The study is based on interviews with prescribers and may be susceptible to the limitations associated with qualitative interview studiesThe diverse sample of participants provide a good spread of opinions that are of a high validity and rigorously analysed.The study may lack generalisability beyond high-income countries.

Supplemental Digital Content is available in the text., Objectives: Extracorporeal membrane oxygenation has been used to support children who fail to wean from cardiopulmonary bypass after pediatric cardiac surgery, but little is known about outcomes. We aimed to describe epidemiology and extracorporeal membrane oxygenation factors associated with inhospital mortality in these patients. Design: Retrospective multicenter registry-based cohort study. Setting: International pediatric extracorporeal membrane oxygenation centers. Patients: Children less than 18 years old supported with extracorporeal membrane oxygenation for failure to wean from cardiopulmonary bypass after cardiac surgery during 2000–2016 and reported to Extracorporeal Life Support Organization’s registry. Intervention: None. Measurements and Main Results: The primary outcome measure was inhospital mortality. Cardiac surgical procedural complexity was assigned using risk adjustment in congenital heart surgery-1. Multivariable logistic regression was used to identify factors independently associated with the primary outcome. We included 2,322 patients, with a median age of 26 days (interquartile range, 7–159); 47% underwent complex surgical procedures (risk adjustment in congenital heart surgery 4–6 categories). Inhospital mortality was 55%. The multivariable model evaluating associations with inhospital mortality showed noncardiac congenital anomalies (odds ratio, 1.78; CI, 1.36–2.32), comorbidities (odds ratio, 1.59; CI, 1.30–1.94), preoperative cardiac arrest (odds ratio, 1.67; CI, 1.20–2.34), preoperative mechanical ventilation greater than 24 hours (odds ratio, 1.49; CI, 1.21–1.84), preoperative bicarbonate administration (odds ratio, 1.42; CI, 1.08–1.86), longer cardiopulmonary bypass time (> 251 min; odds ratio, 1.50; CI, 1.13–1.99), complex surgical procedures (odds ratio, 1.43; CI, 1.13–1.81), longer extracorporeal membrane oxygenation duration (> 104 hr, odds ratio, 1.54; CI, 1.17–2.02), and extracorporeal membrane oxygenation complications increased the odds of inhospital mortality. Age greater than 26 days (odds ratio, 0.56; CI, 0.42–0.75) reduced the odds of mortality. Conclusions: Children supported with extracorporeal membrane oxygenation for failure to wean from cardiopulmonary bypass after cardiac surgery are at high risk of mortality (55%). Younger patients, those with congenital abnormalities and comorbidities, undergoing complex procedures, requiring longer cardiopulmonary bypass, and experiencing extracorporeal membrane oxygenation complications and longer extracorporeal membrane oxygenation duration have higher mortality risk. These data can help assessing prognosis in this high-risk population.

SummaryBackground Errors in are estimated to occur with an incidence of 3.7–16.6% in hospitalized patients. The application of systems for detection of adverse events is becoming a widespread reality in healthcare. Incident reporting (IR) and failure mode and effective analysis (FMEA) are strategies widely used to detect errors, but no studies have combined them in the setting of a pediatric intensive care unit (PICU). Aim The aim of our study was to describe the trend of IR in a PICU and evaluate the effect of FMEA application on the number and severity of the errors detected. Methods With this prospective observational study, we evaluated the frequency IR documented in standard IR forms completed from January 2009 to December 2012 in the PICU of Woman's and Child's Health Department of Padova. On the basis of their severity, errors were classified as: without outcome (55%), with minor outcome (16%), with moderate outcome (10%), and with major outcome (3%); 16% of reported incidents were ‘near misses’. We compared the data before and after the introduction of FMEA. Results Sixty-nine errors were registered, 59 (86%) concerning drug therapy (83% during prescription). Compared to 2009–2010, in 2011–2012, we noted an increase of reported errors (43 vs 26) with a reduction of their severity (21% vs 8% ‘near misses’ and 65% vs 38% errors with no outcome). Conclusion With the introduction of FMEA, we obtained an increased awareness in error reporting. Application of these systems will improve the quality of healthcare services.

Background and aims The use of CAM (Complementary and Alternative Medicine) in paediatrics is high, although a variability of usage frequency between countries is reported, depending on data collection methods and type of CAM. The aim of this survey was to look into physicians’ approaches towards paediatric use of natural medicines, by a consistent study approach in a multi-country survey. Methods On-line survey involving 582 general paediatricians and general practioners treating paediatric patients in 6 countries. The study was sponsored by DHU-Arzneimittel GmbH and Co. KG. Results 99% of respondents recommended natural medicines (Phytotherapy or vitamins/minerals/supplements, VSM) in the previous year. Natural medicines were used as a complement to conventional treatment in most of patients. The most frequently treated conditions were: upper respiratory tract infections (51%), allergies (22%), acute abdominal problems (22%), recurrent infections (22%), earache (17%) and infant colic (15%). Here we give summarised data about the trends in natural remedies prescriptions by paediatricians. In the case of a 2 month old infant with recurrent colic 80% of physicians advised dietary changes. Conventional drugs were as frequently recommended as phytotherapy or homeopathy. The therapy of choice was probiotics. For a 2 year old child with teething problems, homeopathy was advised by 30% of physicians, while only 25% recommended conventional drugs. For a 5 year old child with recurrent upper respiratory tract infections the most frequent recommendations were conventional drugs, dietary advice and vitamins. Personal use of natural medicines corresponded to physicians´ predisposition to recommend natural treatments for their paediatric patients. Nearly half of the physicians were extremely interested in phytotherapy for paediatric conditions. Conclusions This survey confirms that physicians have a high interest in using natural medicines in paediatrics. Natural medicines were most often prescribed alongside conventional drugs. There is evidence of a variable level of knowledge about natural medicine options. There were significant country differences showing a cultural influence on physicians’ decisions.

There is a lack of definitive data on the effective management of acute respiratory distress syndrome (ARDS) in infants and children. The development and validation of the Berlin definition (BD) for ARDS and the Pediatric Acute Lung Injury Consensus Conference (PALICC) recommendations in children represented a major advance in optimizing research and treatment, mainly due to the introduction of a severe ARDS category. Proposed reasons for the lack of consistent results with surfactants in children and infants compared with neonates include different causes, type of lung damage (direct or indirect), timing and mode of administration as well as the type of surfactant used. Secretory phospholipase A2 plays an important role in inflammation and possible dysfunction of surfactants in ARDS. Bronchoalveolar lavage (BAL) with normal saline and surfactant allows the removal of inhaled material, the recruitment of non-ventilating areas and the maintenance of the surfactant pool size. BAL with diluted surfactant allows rapid absorption of the surfactant at the air/liquid interface, which blocks the progression of pathological lung disease and in turn disrupts the inflammatory cycle. Importantly, it is now recognized that the type of surfactant, the time of administration and the method of administration could all play an important role in the management of ARDS, and there is evidence that surfactant is effective and well tolerated in children and infants with ARDS.

BACKGROUND Pediatric oncohematologic patients are a high-risk population for clinical deterioration that might require pediatric intensive care unit (PICU) admission. Several studies have described outcomes and mortality predictors for patients post hematopoietic stem cell transplantation (HSCT), but fewer data exist regarding the category of non-HSCT patients. PROCEDURE All oncohematologic non-HSCT patients ≤18 years requiring PICU admission from 1998 to 2015 in our tertiary-care academic hospital were retrospectively evaluated by means of the pediatric hematology-oncology unit database and the Italian PICUs data network database. We assessed the relation between demographic and clinical characteristics and 90-day mortality after PICU admission. RESULTS Of 3750 hospitalized oncohematologic patients, 3238 were non-HSCT and 63 (2%) of them were admitted to the PICU. Patients were mainly affected by hematological malignancies (70%) and mostly were in the induction-therapy phase. The main reasons for admission were respiratory failure (40%), sepsis (25%), and seizures (16%). The median PICU stay was 5 days (range 1-107). The mortality rate at PICU discharge was 30%, and at 90 days it was 35%. Fifty-five percent of deaths happened in the first 2 days of the PICU stay. Cardiac arrest (P = .007), presence of disseminated intravascular coagulation (DIC, P = .007), and acute kidney injury (AKI) at PICU admission (P

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare, but potentially lethal, pediatric disorder. To date, nearly 80 patients have been reported in the literature; however, the etiopathogenesis is still unclear and debated. Both genetic and paraneoplastic or immune-mediated causes have been supposed to be involved in this syndrome. Nonetheless, at this time, a diagnostic biomarker is not available and diagnosis is based exclusively on clinical criteria. Aiming to establish the immune-mediated pathogenesis, we report 2 children with a clinical picture consistent with ROHHADS and whose cerebrospinal fluid analysis disclosed an intrathecal synthesis of oligoclonal bands. Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.

Chiari malformation type 2 is characterized by hindbrain protrusion and a constellation of supratentorial malformations. Chiari malformation type 2 is thought to be causally related to myelomeningocele due to intrauterine cerebrospinal fluid overdrainage. This relationship is so strong that it has become a rule. A 14-year-old girl affected by mental retardation, spastic triparesis, and epilepsy is presented. Brain magnetic resonance imaging disclosed a severe Chiari malformation type 2, whereas spine magnetic resonance imaging was unremarkable. The authors discuss previous literature describing rare cases of Chiari malformation type 2 without open spinal dysraphism and the relevance of concomitant, sometimes overlooked, neuroimaging findings, underlying how exceptions might be hurdles but might also eventually strengthen the rules.

In order to better understand the global approach and country differences in physicians’ usage, knowledge, and attitudes towards natural remedies and homeopathy in pediatric practice, an online survey involving 582 general pediatricians and general practitioners treating pediatric diseases was conducted in 6 countries. Overall, 17% of the pediatric prescriptions refer to phytotherapy and 15% refer to homeopathic preparations. Natural remedies and homeopathic preparations are more frequently used in upper respiratory tract infections, infant colic, sleep disturbances, and recurrent infections. In the majority of cases, they are used together with chemical drugs. Both treatment options are typically used if parents are concerned about side effects of conventional drugs or prefer natural remedies for themselves. Physicians express high interest in natural remedies and homeopathy; however, their knowledge is variable. Lack of proven efficacy, knowledge on mechanism of action, and information on indications are main factors that limit their usage.

Background Urea cycle disorders (UCD) have a poor prognosis despite dietary and pharmacologic therapy, especially if the onset of the disease is within the neonatal period. They are promising target diseases for liver cell transplantation (LCT), which may be a less invasive alternative or supplementation to orthotopic liver transplantation. Methods Cryopreserved hepatocytes were isolated under good manufacturing practice conditions. Four children with severe neonatal UCD (age 1 day-3 years) received multiple intraportal infusions of cryopreserved hepatocytes from that same donor, a 9-day old neonate. Portal vein access was achieved surgically in two children, whereas the umbilical vein was suitable for interventional catheter placement in two neonates. Cell applications were carefully monitored by means of Doppler ultrasound and portal vein pressure. Results LCT was feasible in all children. No signs of portal vein thrombosis or extrahepatic shunting were observed. All children showed metabolic stabilization during observation periods of 4 to 13 months. One child with prenatally diagnosed ornithine transcarbamylase deficiency died after 4 months from a fatal metabolic decompensation. Conclusions Given the poor prognosis of UCD with conservative therapy, LCT caused considerable beneficial effects. Periods of hyperammonemia and clinically relevant crises could be reduced during an observation period of up to 13 months. Though cell therapy is not a permanent therapeutic option, bridging to liver transplantation may be substantially improved.

Juvenile dermatomyositis (JDM) is a multisystemic disease of children that affects primarily muscle and skin. The prevalence of pulmonary involvement is not well known but seems to be rarer than in adult patients with dermatomyositis/polymyositis (DM/PM) [1–3]. A wide spectrum of clinical presentations have been described, ranging from asymptomatic patients with merely abnormal pulmonary function tests [4] to severe, potentially fatal cases refractory to immunosuppressive and supportive therapy [5-9]. Here we present the case of a child with JDM and severe interstitial lung disease (ILD) successfully treated with immunosuppressive drugs and extracorporeal membrane oxygenation (ECMO).

Amiodarone (AMI) is a potent antiarrhythmic agent; however, its clinical use is limited due to numerous side effects. In order to investigate the structure--cytotoxicity relationship, AMI analogues were synthesized, and then, using rabbit alveolar macrophages, were tested for viability and for the ability to interfere with the degradation of surfactant protein A (SP-A) and with the accumulation of an acidotropic dye. Our data revealed that modification of the diethylamino-beta-ethoxy group of the AMI molecule may affect viability, the ability to degrade SP-A and vacuolation differently. In particular, PIPAM (2d), an analogue with a piperidyl moiety, acts toward the cells in a similar manner to AMI, but is less toxic. Thus, it would be possible to reduce the cytotoxicity of AMI by modifying its chemical structure.

Objective To assess how clinical practice of noninvasive ventilation has evolved in the Italian PICUs. Design National, multicentre, retrospective, observational cohort. Setting Thirteen Italian medical/surgical PICUs that participated in the Italian PICU Network. Patients Seven thousand one-hundred eleven admissions of children with 0-16 years old admitted from January 1, 2011, to December 31, 2012. Interventions None. Measurements and main results Cause of respiratory failure, length and mode of noninvasive ventilation, type of interfaces, incidence of treatment failure, and outcome were recorded. Data were compared with an historical cohort of children enrolled along 6 months from November 1, 2006, to April 30, 2007, over the viral respiratory season. Seven thousand one-hundred eleven PICU admissions were analyzed, and an overall noninvasive ventilation use of 8.8% (n = 630) was observed. Among children who were admitted in the PICU without mechanical ventilation (n = 3,819), noninvasive ventilation was used in 585 patients (15.3%) with a significant increment among the three study years (from 11.6% in 2006 to 18.2% in 2012). In the endotracheally intubated group, 17.2% children received noninvasive ventilation at the end of the weaning process to avoid reintubation: 11.9% in 2006, 15.3% in 2011, and 21.6% in 2012. Noninvasive ventilation failure rate raised from 10% in 2006 to 16.1% in 2012. Conclusions Noninvasive ventilation is increasingly and successfully used as first respiratory approach in several, but not all, Italian PICUs. The current study shows that noninvasive ventilation represents a feasible and safe technique of ventilatory assistance for the treatment of mild acute respiratory failure. Noninvasive ventilation was used as primary mode of ventilation in children with low respiratory tract infection (mainly in bronchiolitis and pneumonia), in acute on chronic respiratory failure or to prevent reintubation.

Summary We present a dramatic case of a patient presenting with disseminated intravascular coagulation related to meningococcal sepsis who developed heparin-induced thrombocytopenia following heparin administration during continuous renal replacement therapy. Association of these two prothrombotic conditions led to severe limbs ischemia and finally to bilateral legs amputation. We stress the importance of suspect heparin-induced thrombocytopenia in intensive care unit patients, especially when an improvement of other coagulation parameters is observed, and heparin therapy was started.

Amiodarone may induce lung damage by direct toxicity or indirectly through inflammation. To clarify the mechanism of direct toxicity, we briefly exposed rabbit alveolar macrophages to amiodarone and analyzed their morphology, synthesis, and degradation of dipalmitoylphosphatidylcholine (DPPC); distribution of lysosomal enzymes; and uptake of diphtheria toxin and surfactant protein (SP) A used as tracers of the endocytic pathway. Furthermore, in newborn rabbits, we studied the clearance of DPPC and SP-A instilled into the trachea together with increasing amounts of amiodarone. We found that in vitro amiodarone decreases the surface density of mitochondria and lysosomes while increasing the surface density of inclusion bodies, increases the incorporation of choline into DPPC, modifies the distribution of lysosomal enzymes, and does not affect the uptake and processing of diphtheria toxin but inhibits the degradation of SP-A. In vivo amiodarone inhibits the degradation of SP-A but not of DPPC. We conclude that the acute exposure to amiodarone perturbs the endocytic pathway acting after the early endosomes, alters the traffic of lysosomal enzymes, and interferes with the turnover of SP-A.

Before being considered for a cystic fibrosis (CF) gene therapy trial, any gene delivery agent must be able to show that it produces low levels of toxicity as well as being able to protect the DNA from nuclease degradation. Here we show that complexes of linear polyethylenimine (L-PEI) and DNA can repeatedly be administered to animals (up to 21 consecutive days) without eliciting an immune response against PEI/DNA particles or inducing toxic side effects due to accumulation of PEI in the lungs. However, the host response to the exogenous protein resulted in some decrease of expression. PEI-mediated transfection was unaffected by treatment of the complexes with DNase (frequently used to reduce the viscosity of lung secretions in CF patients). Taken together, these properties make L-PEI a valuable vector for gene therapy of CF.

Near-infrared spectroscopy (NIRS) is a non-invasive technique designed to study regional oxygenation (rSO(2)) by measuring the absorption of chromophores. This study investigated the role of NIRS in the real-time monitoring of kidney graft perfusion for 72 h post-transplantation.Consecutive children undergoing living related donor (LRD) or deceased donor (DD) kidney transplantation (KTP) were prospectively enrolled between April 2010 and August 2011. Renal rSO(2) values were registered continuously for 3 days and correlated with hourly urine output, serum creatinine, and urinary neutrophil gelatinase-associated lipocalin (u-NGAL).Twenty-four children were included, 6 underwent LRD and 18 DD KTP. Median age was 12.5 years (interquartile range [IQR] 3.5-16.6) and median body weight was 37 kg (IQR 13-49.7). Four patients experienced delayed graft function (DGF). Renal Doppler ultrasound showed normal vascularization patterns in all children. Median basal renal rSO(2) value was 68.8 % (IQR 59.3-76.2), significantly lower than the end-of-period result (83.6 %; IQR 79.2-90.4; p 0.0001). Renal rSO(2) values showed significant correlation with serum creatinine (rs = -0.62; p 0.05) and estimated glomerular filtration rate (eGFR) (rs = 0.64; p 0.05). No correlation was shown between rSO(2) and diuresis. Increased rSO(2) was also found in patients who experienced DGF. u-NGAL exhibited a trend toward a decrease from baseline in both DD and LRD KTPs, with a strong negative correlation with rSO(2).rSO(2) assessed by NIRS strongly correlates with common markers of kidney graft function and perfusion, allowing continuous real-time monitoring of blood flow in renal grafts.

High-flow nasal cannula (HFNC) is a widely used ventilatory support in children with bronchiolitis in the intensive care setting. No data is available on HFNC use in the general pediatric ward. The aim of this study was to evaluate the feasibility of HFNC oxygen therapy in infants hospitalized in a pediatric ward for moderate–severe bronchiolitis and to assess the changes in ventilatory parameters before and after starting HFNC support. This prospective observational pilot study was carried out during the bronchiolitis season 2011–2012 in a pediatric tertiary care academic center in Italy. Interruptions of HFNC therapy and possible side effects or escalation to other forms of respiratory support were recorded. Oxygen saturation (SpO2), end-tidal carbon dioxide (ETCO2), and respiratory rate (RR), measured for a baseline period of 1 h before and at specific time intervals in 48 h after the start of HFNC were recorded. Twenty-seven infants were included (median age 1.3 months; absolute range 0.3–8.5). No adverse events, no premature HFNC therapy termination, and no escalation to other forms of respiratory support were recorded. Median SpO2 significantly increased by 1–2 points after changing from standard oxygen to HFNC (p

Objective To evaluate clinical data and associated risk conditions of noncerebral systemic venous thromboembolism (VT), arterial thromboembolism (AT), and intracardiac thromboembolism (ICT) in neonates. Study design Data analysis of first systemic thromboembolism occurring in 75 live neonates (0-28 days), enrolled in the Italian Registry of Pediatric Thrombosis from neonatology centers between January 2007 and July 2013. Results Among 75 events, 41 (55%) were VT, 22 (29%) AT, and 12 (16%) ICT; males represented 65%, and 71% were preterm. In 19 (25%), thromboembolism was diagnosed on the first day of life. In this "early onset" group, prenatal-associated risk conditions (maternal/placental disease) were reported in 70% and inherited thrombophilia in 33%. Postnatal risk factors were present in 73%; infections and central vascular catheters in 56% and 54% VT, respectively, and in 67% ICT vs 27% AT ( Conclusions This report from the Registro Italiano Trombosi Infantili, although limited by representing an uncontrolled case series, can be used to develop future clinical trials on appropriate management and prevention of neonatal thrombosis, focusing on obstetrical surveillance and monitoring of critically ill neonates with vascular access. A thrombosis risk prediction rule specific for the neonatal population should be developed through prospective controlled studies.

Graphical abstract Amiodarone, having basic pKa and high water solubility at acidic pH, accumulates within late endocytic compartments, blocking fluid-phase endocytosis, proteolysis and lipid trafficking and inducing a Niemann-Pick C-like phenotype., Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control.

Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear. Our objective was to study amiodarone uptake, clarify the origin of vacuoles, and investigate the effect of amiodarone on the life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of (125)I-amiodarone and (125)I-B2, an analog lacking the lateral group diethylamino-beta-ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus. We found that (1) amiodarone associates with different cell membranes and accumulates in acidic organelles; (2) the diethylamino-beta-ethoxy group is an important determinant of uptake; (3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes; (4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and (5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS coronavirus infection by acting after the transit of the virus through endosomes.