Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial.

BACKGROUND: To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0-3 years after cardiac surgery with cardiopulmonary bypass. METHODS: Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016-July 2020. Children aged 0-3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%. RESULTS: In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7-856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion - 3.1% (95% CI - 16.6-10.3%). CONCLUSIONS: In children aged 0-3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

A Strategy for Artificial Intelligence With Clinical Impact-Eyes on the Prize.

This Viewpoint describes a strategy for addressing major challenges in artificial intelligence in pediatrics to maximize clinical impact.

Continuous Data-Driven Monitoring in Critical Congenital Heart Disease: Clinical Deterioration Model Development.

BACKGROUND: Critical congenital heart disease (cCHD)-requiring cardiac intervention in the first year of life for survival-occurs globally in 2-3 of every 1000 live births. In the critical perioperative period, intensive multimodal monitoring at a pediatric intensive care unit (PICU) is warranted, as their organs-especially the brain-may be severely injured due to hemodynamic and respiratory events. These 24/7 clinical data streams yield large quantities of high-frequency data, which are challenging in terms of interpretation due to the varying and dynamic physiology innate to cCHD. Through advanced data science algorithms, these dynamic data can be condensed into comprehensible information, reducing the cognitive load on the medical team and providing data-driven monitoring support through automated detection of clinical deterioration, which may facilitate timely intervention. OBJECTIVE: This study aimed to develop a clinical deterioration detection algorithm for PICU patients with cCHD. METHODS: Retrospectively, synchronous per-second data of cerebral regional oxygen saturation (rSO2) and 4 vital parameters (respiratory rate, heart rate, oxygen saturation, and invasive mean blood pressure) in neonates with cCHD admitted to the University Medical Center Utrecht, the Netherlands, between 2002 and 2018 were extracted. Patients were stratified based on mean oxygen saturation during admission to account for physiological differences between acyanotic and cyanotic cCHD. Each subset was used to train our algorithm in classifying data as either stable, unstable, or sensor dysfunction. The algorithm was designed to detect combinations of parameters abnormal to the stratified subpopulation and significant deviations from the patient's unique baseline, which were further analyzed to distinguish clinical improvement from deterioration. Novel data were used for testing, visualized in detail, and internally validated by pediatric intensivists. RESULTS: A retrospective query yielded 4600 hours and 209 hours of per-second data in 78 and 10 neonates for, respectively, training and testing purposes. During testing, stable episodes occurred 153 times, of which 134 (88%) were correctly detected. Unstable episodes were correctly noted in 46 of 57 (81%) observed episodes. Twelve expert-confirmed unstable episodes were missed in testing. Time-percentual accuracy was 93% and 77% for, respectively, stable and unstable episodes. A total of 138 sensorial dysfunctions were detected, of which 130 (94%) were correct. CONCLUSIONS: In this proof-of-concept study, a clinical deterioration detection algorithm was developed and retrospectively evaluated to classify clinical stability and instability, achieving reasonable performance considering the heterogeneous population of neonates with cCHD. Combined analysis of baseline (ie, patient-specific) deviations and simultaneous parameter-shifting (ie, population-specific) proofs would be promising with respect to enhancing applicability to heterogeneous critically ill pediatric populations. After prospective validation, the current-and comparable-models may, in the future, be used in the automated detection of clinical deterioration and eventually provide data-driven monitoring support to the medical team, allowing for timely intervention.

Identifying the critically ill paediatric oncology patient: a study protocol for a prospective observational cohort study for validation of a modified Bedside Paediatric Early Warning System score in hospitalised paediatric oncology patients.

INTRODUCTION: Hospitalised paediatric oncology patients are at risk to develop acute complications. Early identification of clinical deterioration enabling adequate escalation of care remains challenging. Various Paediatric Early Warning Systems (PEWSs) have been evaluated, also in paediatric oncology patients but mostly in retrospective or case-control study designs. This study protocol encompasses the first prospective cohort with the aim of evaluating the predictive performance of a modified Bedside PEWS score for non-elective paediatric intensive care unit (PICU) admission or cardiopulmonary resuscitation in hospitalised paediatric oncology patients. METHODS AND ANALYSIS: A prospective cohort study will be conducted at the 80-bed Dutch paediatric oncology hospital, where all national paediatric oncology care has been centralised, directly connected to a shared 22-bed PICU. All patients between 1 February 2019 and 1 February 2021 admitted to the inpatient nursing wards, aged 0-18 years, with an International Classification of Diseases for Oncology (ICD-O) diagnosis of paediatric malignancy will be eligible. A Cox proportional hazard regression model will be used to estimate the association between the modified Bedside PEWS and time to non-elective PICU transfer or cardiopulmonary arrest. Predictive performance (discrimination and calibration) will be assessed internally using resampling validation. To account for multiple occurrences of the event of interest within each patient, the unit of study is a single uninterrupted ward admission (a clinical episode). ETHICS AND DISSEMINATION: The study protocol has been approved by the institutional ethical review board of our hospital (MEC protocol number 16-572/C). We adapted our enrolment procedure to General Data Protection Regulation compliance. Results will be disseminated at scientific conferences, regional educational sessions and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Netherlands Trial Registry (NL8957).

Reducing medical device alarms by an order of magnitude: A human factors approach.

The intensive care unit (ICU) is one of the most technically advanced environments in healthcare, using a multitude of medical devices for drug administration, mechanical ventilation and patient monitoring. However, these technologies currently come with disadvantages, namely noise pollution, information overload and alarm fatigue-all caused by too many alarms. Individual medical devices currently generate alarms independently, without any coordination or prioritisation with other devices, leading to a cacophony where important alarms can be lost amongst trivial ones, occasionally with serious or even fatal consequences for patients. We have called this approach to the design of medical devices the single-device paradigm, and believe it is obsolete in modern hospitals where patients are typically connected to several devices simultaneously. Alarm rates of one alarm every four minutes for only the physiological monitors (as recorded in the ICUs of two hospitals contributing to this paper) degrades the quality of the patient's healing environment and threatens patient safety by constantly distracting healthcare professionals. We outline a new approach to medical device design involving the application of human factors principles which have been successful in eliminating alarm fatigue in commercial aviation. Our approach comprises the networked-device paradigm, comprehensive alarms and humaniform information displays. Instead of each medical device alarming separately at the patient's bedside, our proposed approach will integrate, prioritise and optimise alarms across all devices attached to each patient, display information more intuitively and hence increase alarm quality while reducing the number of alarms by an order of magnitude below current levels.

Tidal Volume in Pediatric Ventilation: Do You Get What You See?

Mechanical ventilators are increasingly evolving into computer-driven devices. These technical advancements have impact on clinical decisions in pediatric intensive care units (PICUs). A good understanding of the design of mechanical ventilators can improve clinical care. Tidal volume (TV) is one of the corner stones of ventilation: multiple technical factors influence the TV and, thus, influence clinical decision making. Ventilator manufacturers make various design choices regarding the phase, site and conditions of TV measurement as well as algorithmic processing choices. Such choice may impact the measurement and subsequent display of TV. A software change of the TV measuring algorithm of the SERVO-i® (Getinge, Solna, Sweden) at the PICU of the University Medical Centre Utrecht was studied in a prospective cohort. It showed, as example, a clinically significant impact of 8% difference in reported TV. Design choices in both the hardware and software of mechanical ventilators can have a clinically relevant impact on the measurement of tidal volume. In our search for the optimal TV for lung-protective ventilation, such choices should be taken into account.

Misdiagnosis of CTX due to propofol: The interference of total intravenous propofol anaesthesia with bile acid profiling.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder, characterised by chronic diarrhoea, xanthomas, cataracts, and neurological deterioration. CTX is caused by CYP27A1 deficiency, which leads to abnormal cholesterol and bile acid metabolism. Urinary bile acid profiling (increased m/z 627: glucuronide-5ß-cholestane-pentol) serves as diagnostic screening for CTX. However, this led to a false positive CTX diagnosis in two patients, who had received total intravenous anaesthesia (TIVA) with propofol. METHODS: To determine the influence of propofol on bile acid profiling, 10 urinary samples and 2 blood samples were collected after TIVA with propofol Fresenius 7 to 10 mg/kg/h from 12 subjects undergoing scoliosis correction. Urinary bile acids were analysed using flow injection negative electrospray mass spectrometry. Propofol binding to recombinant CYP27A1, the effects of propofol on recombinant CYP27A1 activity, and CYP27A1 expression in liver organoids were investigated using spectral binding, enzyme activity assays, and qPCR, respectively. Accurate masses were determined with high-resolution mass spectrometry. RESULTS: Abnormal urinary profiles were identified in all subjects after TIVA, with a trend correlating propofol dose per kilogramme and m/z 627 peak intensity. Propofol only induced a weak CYP27A1 response in the spectral binding assay, minimally affected CYP27A1 activity and did not affect CYP27A1 expression. The accurate mass of m/z 627 induced by propofol differed >10 PPM from m/z 627 observed in CTX. CONCLUSIONS: TIVA with propofol invariably led to a urinary profile misleadingly suggestive of CTX, but not through CYP27A1 inhibition. To avoid further misdiagnoses, propofol administration should be considered when interpreting urinary bile acid profiles.

Intravenous morphine versus intravenous paracetamol after cardiac surgery in neonates and infants: a study protocol for a randomized controlled trial.

BACKGROUND: Morphine is worldwide the analgesic of first choice after cardiac surgery in children. Morphine has unwanted hemodynamic and respiratory side effects. Therefore, post-cardiac surgery patients may potentially benefit from a non-opioid drug for pain relief. A previous study has shown that intravenous (IV) paracetamol is effective and opioid-sparing in children after major non-cardiac surgery. The aim of the study is to test the hypothesis that intermittent IV paracetamol administration in children after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine requirement. METHODS: This is a prospective, multi-center, randomized controlled trial at four level-3 pediatric intensive care units (ICUs) in the Netherlands and Belgium. Children who are 0-36 months old will be randomly assigned to receive either intermittent IV paracetamol or continuous IV morphine up to 48 h post-operatively. Morphine will be available as rescue medication for both groups. Validated pain and sedation assessment tools will be used to monitor patients. The sample size (n = 208, 104 per arm) was calculated in order to detect a 30% reduction in morphine dose; two-sided significance level was 5% and power was 95%. DISCUSSION: This study will focus on the reduction, or replacement, of morphine by IV paracetamol in children (0-36 months old) after cardiac surgery. The results of this study will form the basis of a new pain management algorithm and will be implemented at the participating ICUs, resulting in an evidence-based guideline on post-operative pain after cardiac surgery in infants who are 0-36 months old. TRIAL REGISTRATION: Dutch Trial Registry ( www.trialregister.nl ): NTR5448 on September 1, 2015. Institutional review board approval (MEC2015-646), current protocol version: July 3, 2017.

Evaluation of a non-invasive bladder volume measurement in children.

OBJECTIVE: Postoperative urinary retention (PUR) is associated with overdistension of the bladder. The prevention of PUR by routine catheterization may increase the risk of urinary tract infection. Postoperative monitoring of the bladder volume by ultrasound to prevent PUR is reliable in adults, but has not been evaluated in children. MATERIAL AND METHODS: The BladderScan BVI 6200, an ultrasound device specifically designed for children, was assessed. Forty patients who required urinary catheter placement during surgery or during intensive care unit stay were entered into this blinded calibration study. An assessment of bladder urine volume by ultrasound was performed before and after catheterization in surgical patients. In these patients and intensive care patients 0, 2.5 or 5 ml/kg sterile normal NaCl was injected through the bladder catheter and the catheter was clamped. Volumes estimated with ultrasound were compared with measured catheter drainage or/and injected volume after the scan. RESULTS: The mean relative difference (bias) between the ultrasound estimate and the injected volume was -20% (95% confidence interval 140 to -180%). Precision, estimated using the Wilcoxon signed ranks test, showed a significant difference (Z = -3.25, p = 0.001) between the ultrasound-estimated volumes and the injected volumes. CONCLUSIONS: This study could not confirm good agreement between the ultrasound-estimated volumes and the injected volumes at volumes below 5 ml/kg. Bladder volumes were underestimated with a very broad 95% confidence interval. The ultrasound device should not replace current clinical assessment.

Jet ventilation for laryngotracheal surgery in an ex-premature infant.

A 4-month-old ex-premature infant with severe airway obstruction from subglottic cysts presented for surgical cyst removal. Laryngeal and tracheal surgical procedures in children may present difficulties for the anesthetist because the airway is shared with the surgeon. We report the use of high-frequency jet ventilation (HFJV) to maintain ventilation and provide adequate surgical access. Anesthesia was induced using sevoflurane in oxygen and was maintained with intravenous infusions of propofol 7.5 mg.kg(-1).h(-1) and remifentanil 0.4 microg.kg(-1).min(-1). The suction channel of the ENT laryngoscope was used to introduce an 8-FG ureteric drainage catheter into the larynx and this catheter was used to provide HFJV. Obstruction to expiratory flow was a major concern and was dependent on good positioning of the rigid laryngoscope. Complications such as barotrauma, pneumopericardium, CO2-retention, necrotizing tracheobronchitis, and gastric rupture dictate a fastidious technique.

Use of ultrasound bladder monitoring in children after caudal anaesthesia.

Urinary retention occurring after caudal anaesthesia in children has a low incidence. Most children will void within 12 h of surgery, although the incidence of retention is higher after hypospadias repair. However, overdistention causing bladder atony that is temporary, or may become permanent, is described in adults. Long-term effects of overdistention in children have not been described. Urine volume, used to describe overdistention, is traditionally measured after catheterization. We report two children suffering from urine retention after caudal anaesthesia (bupivacaine 0.25%) was used to supplement a general anaesthetic. Ultrasound bladder monitoring was used to assist with the clinical diagnosis of bladder distension in the postanaesthesia care unit (PACU) and subsequent management. In-out catheterization was required in a 1-year-old-girl with a bladder volume of 12 ml.kg-1 after external manual compression over the bladder was unable express urine. Spontaneous micturation occurred within the subsequent 8 h. A 10-year-old boy suffered distress in PACU with a bladder volume, measured by ultrasound, of 5 ml.kg-1. Catheterization relieved distress and spontaneous micturation returned 18 h after surgery. Measured urine volumes were similar to those estimated by ultrasound. Ultrasound bladder monitoring is a simple, noninvasive technique that can be used to assist with the diagnosis and management of urinary retention in children. It may replace catheterization as the prefered technique to measure urine volume. The correlation between measured bladder volumes and urine volume appears reasonable. A volume of approximately 10 mg.kg-1 may be considered as causing overdistension.