Neuromuscular Blocker Use in Critically Ill Children: Assessing Mortality Risk by Propensity Score-Weighted Analysis.

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.

Perioperative management of children with neuromuscular disorders based on a common protocol: A prospective, national study in Italy.

BACKGROUND: Children with neuromuscular diseases (NMDs) often display respiratory muscle weakness which increases the risk of postoperative pulmonary complications (PPCs) after general anaesthesia. Non-invasive ventilation (NIV) associated with mechanical insufflation-exsufflation (MI-E) can reduce the incidence and severity of PPCs. The aim of this study was to report our experience with a shared perioperative protocol that consists in using NIV combined with MI-E to improve the postoperative outcome of NMD children (IT-NEUMA-Ped). METHOD: We conducted a multicentre, observational study on 167 consecutive paediatric patients with NMDs undergoing anaesthesia from December 2015 to December 2018 in a network of 13 Italian hospitals. RESULTS: We found that 89% of the 167 children (mean age 8 years old) were at high risk of PPCs, due to the presence of at least one respiratory risk factor. In particular, 51% of them had preoperative ventilatory support dependence. Only 14 (8%) patients developed PPCs, and only two patients needed tracheostomy. Average hospital length of stay (LOS) was 6 (2-14) days. The study population was stratified according to preoperative respiratory devices dependency and invasiveness of the procedure. Patients with preoperative ventilatory support dependence showed significantly higher intensive care unit (ICU) admission rate and longer hospital LOS. CONCLUSION: Disease severity seems to be more related to the outcome of this population than invasiveness of procedures. NIV combined with MI-E can help in preventing and resolve PPCs.

Efficacy and safety of exogenous surfactant therapy in patients under 12 months of age invasively ventilated for severe bronchiolitis (SURFABRON): protocol for a multicentre, randomised, double-blind, controlled, non-profit trial.

INTRODUCTION: Some 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 ANALYSIS: This 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 DISSEMINATION: The 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 NUMBER: Clinicaltrials.gov, issue date 22 May 2019. NCT03959384.

A shared protocol for porcine surfactant use in pediatric acute respiratory distress syndrome: a feasibility study.

BACKGROUND: Pediatric ARDS still represents a difficult challenge in Pediatric Intensive Care Units (PICU). Among different treatments proposed, exogenous surfactant showed conflicting results. Aim of this multicenter retrospective observational study was to evaluate whether poractant alfa use in pediatric ARDS might improve gas exchange in children less than 2 years old, according to a shared protocol. METHODS: The study was carried out in fourteen Italian PICUs after dissemination of a standardized protocol for surfactant administration within the Italian PICU network. The protocol provides the administration of surfactant (50 mg/kg) divided in two doses: the first dose is used as a bronchoalveolar lavage while the second as supplementation. Blood gas exchange variations before and after surfactant use were recorded. RESULTS: Sixty-nine children, age 0-24 months, affected by Acute Respiratory Distress Syndrome treated with exogenous porcine surfactant were enrolled. Data collection consisted of patient demographics, respiratory variables and arterial blood gas analysis. The most frequent reasons for PICU admission were acute respiratory failure, mainly bronchiolitis and pneumonia, and septic shock. Fifty-four children (78.3%) had severe ARDS (define by oxygen arterial pressure and inspired oxygen fraction ratio (P/F) < 100), 15 (21.7%) had moderate ARDS (100 < P/F < 200). PO2, P/F, Oxygenation Index (OI) and pH showed a significant improvement after surfactant use with respect to baseline (p < 0.001 at each included time-point for each parameter). No significant difference in blood gas variations were observed among four different subgroups of diseases (bronchiolitis, pneumonia, septic shock and others). Overall, 11 children died (15.9%) and among these, 10 (90.9%) had complex chronic conditions. Two children (18.2%) died while being treated with Extracorporeal Membrane Oxygenation (ECMO). Mortality for severe pARDS was 20.4%. CONCLUSION: The use of porcine Surfactant improves oxygenation, P/F ratio, OI and pH in a population of children with moderate or severe pARDS caused by multiple diseases. A shared protocol seems to be a good option to obtain the same criteria of enrollment among different PICUs and define a unique way of use and administration of the drug for future studies.

Prolonged sedation in critically ill children: is dexmedetomidine a safe option for younger age? An off-label experience.

BACKGROUND: Dexmedetomidine (DEX) is an alpha-2-adrenergic agonist, recently approved by Italian-Medicines-Agency for difficult sedation in pediatrics, but few data exist regarding prolonged infusions in critically-ill children, especially in younger ages. Aim of our study was to evaluate DEX use and safety for prolonged sedation in Pediatric Intensive Care Units (PICUs). METHODS: Patients receiving DEX for ≥24 hours were retrospectively evaluated to analyze DEX indications, dosages, use of analgesics or sedatives, adverse events (AEs), withdrawal syndrome or delirium. RESULTS: Forty-seven patients (median 0.7years) from nine PICUs were enrolled. Main indications were adjuvant for drugs sparing (59.6%) and for analgosedation weaning (36.2%). Median infusion duration was 82.0 hours (IQR 62.2-126.0), with dosages between 0.4 (IQR 0.2-0.5) and 0.8 mcg/kg/h (IQR 0.6-1.2). Fifty-nine-percent of patients received other sedatives, 83% other analgesics. Twenty-one-percent presented withdrawal syndrome, 4.2% delirium, none of them DEX-related. Forty-six-percent experienced a potentially-DEX-related AE. AEs were all hemodynamic, 14.9% requiring intervention but none DEX interruption. The median minimum and maximum dosages were significantly higher in patients with AEs (0.5 vs. 0.3,P=0.001; 1.0 vs. 0.7,P<0.001), without correlations with the infusion duration. AEs rate was higher in patients receiving benzodiazepines (P=0.020) or more than one analgesic (P=0.003) and in those presenting withdrawal syndrome (P<0.001). CONCLUSIONS: DEX was confirmed as useful and relatively safe drug for prolonged sedation in critically-ill children, particularly in younger ages. Main AEs were cardiovascular, reversible, related with higher doses, with the concomitant use of benzodiazepines or multiple sedation drugs and with the presence of withdrawal syndrome.

Withdrawal Assessment Tool-1 Monitoring in PICU: A Multicenter Study on Iatrogenic Withdrawal Syndrome.

OBJECTIVES: Withdrawal syndrome is an adverse reaction of analgesic and sedative therapy, with a reported occurrence rate between 17% and 57% in critically ill children. Although some factors related to the development of withdrawal syndrome have been identified, there is weak evidence for the effectiveness of preventive and therapeutic strategies. The main aim of this study was to evaluate the frequency of withdrawal syndrome in Italian PICUs, using a validated instrument. We also analyzed differences in patient characteristics, analgesic and sedative treatment, and patients' outcome between patients with and without withdrawal syndrome. DESIGN: Observational multicenter prospective study. SETTING: Eight Italian PICUs belonging to the national PICU network Italian PICU network. PATIENTS: One hundred thirteen patients, less than 18 years old, mechanically ventilated and treated with analgesic and sedative therapy for five or more days. They were admitted in PICU from November 2012 to May 2014. INTERVENTIONS: Symptoms of withdrawal syndrome were monitored with Withdrawal Assessment Tool-1 scale. MEASUREMENTS AND MAIN RESULTS: The occurrence rate of withdrawal syndrome was 64.6%. The following variables were significantly different between the patients who developed withdrawal syndrome and those who did not: type, duration, and cumulative dose of analgesic therapy; duration and cumulative dose of sedative therapy; clinical team judgment about analgesia and sedation's difficulty; and duration of analgesic weaning, mechanical ventilation, and PICU stay. Multivariate logistic regression analysis revealed that patients receiving morphine as their primary analgesic were 83% less likely to develop withdrawal syndrome than those receiving fentanyl or remifentanil. CONCLUSIONS: Withdrawal syndrome was frequent in PICU patients, and patients with withdrawal syndrome had prolonged hospital treatment. We suggest adopting the lowest effective dose of analgesic and sedative drugs and frequent reevaluation of the need for continued use. Further studies are necessary to define common preventive and therapeutic strategies.

The Importance of Mortality Risk Assessment: Validation of the Pediatric Index of Mortality 3 Score.

OBJECTIVE: To evaluate the performance of the newest version of the Pediatric Index of Mortality 3 score and compare it with the Pediatric Index of Mortality 2 in a multicenter national cohort of children admitted to PICU. DESIGN: Retrospective, prospective cohort study. SETTING: Seventeen Italian PICUs. PATIENTS: All children 0 to 15 years old admitted in PICU from January 2010 to October 2014. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Eleven thousand one hundred nine children were enrolled in the study. The mean Pediatric Index of Mortality 2 and 3 values of 4.9 and 3.9, respectively, differed significantly (p < 0.05). Overall mortality rate was 3.9%, and the standardized mortality ratio was 0.80 for Pediatric Index of Mortality 2 and 0.98 for Pediatric Index of Mortality 3 (p < 0.05). The area under the curve of the receiver operating characteristic curves was similar for Pediatric Index of Mortality 2 and Pediatric Index of Mortality 3. The Hosmer-Lemeshow test was not significant for Pediatric Index of Mortality 3 (p = 0.21) but was highly significant for Pediatric Index of Mortality 2 (p < 0.001), which overestimated death mainly in high-risk categories. CONCLUSIONS: Mortality indices require validation in each country where it is used. The new Pediatric Index of Mortality 3 score performed well in an Italian population. Both calibration and discrimination were appropriate, and the score more accurately predicted the mortality risk than Pediatric Index of Mortality 2.

Comparison of three sites to check the pulse and count heart rate in hypotensive infants.

BACKGROUND: Current international guidelines state that heart rate counted at the brachial pulse must be absent or <60 b x min(-1) to diagnose cardiac arrest. Some data suggest that this site may not be the best to check cardiac activity. Hypotension is a likely real scenario of the need for chest compressions in infants. We compared the performance of three sites of pulse palpation (brachial, carotid, and femoral) for detecting and counting heartbeat in hypotensive infants. METHODS: In an operating theater of a pediatric teaching hospital in Italy, we studied 40 anesthetized hypotensive infants just prior to surgery, checked by two doctors and two nurses by a cross-sectional, repeated-measures study design. Each examiner, blind to the monitoring data of the patient, was asked to find the infant's arterial pulse within 10 s and count heart rate for 15 s. During each examination, the order of the three sites was randomized. RESULTS: Among successful detections, femoral pulse palpation resulted as the most successful, rapid, and accurate site to detect and count heart rate in hypotensive infants. CONCLUSIONS: Femoral palpation proved to be the best site for detecting heartbeat and counting heart rate in hypotensive infants. These findings challenge the current guidelines. More data are needed, but the current standard of brachial pulse assessment is debatable.

Heartbeat assessment in infants: a comparison of four clinical methods.

OBJECTIVE: To compare the performance of four clinical methods (apex ear auscultation; brachial, carotid, and femoral pulse palpation) for detecting and counting heart beat in infants. DESIGN: Cross-sectional, repeated-measures study design. Prospective data collection. SETTING: A postanesthesia care unit of a pediatric teaching hospital in Italy. PATIENTS: Fifty-six normotensive sedated infants, aged 1-12 mos, were evaluated by 14 pediatric basic life support (PBLS)-qualified health professionals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The proportion of successful heartbeat detections ranged from 60% with carotid pulse palpation to 98% with apex auscultation. Among successful detections, apex auscultation proved to be the most rapid way to detect heart rate (median, 4 secs) and the most accurate with a median discrepancy of 8 beats/min (vs. 12 with the other methods) from the electrocardiographic results. Differences between apex auscultation and pulse palpation were statistically significant (p < .0001). In contrast, no significant differences were found among the three methods of pulse checking. CONCLUSIONS: Apex listening is the most successful, rapid, and accurate method to detect and count the heartbeat by PBLS-certified professionals in normotensive infants without instruments. Pulse checking remains important for assessing the effectiveness of circulation. Palpating the brachial, carotid, or femoral pulse is equally effective.