Evaluation of an aPTT guided versus a multimodal heparin monitoring approach in patients on extra corporeal membrane oxygenation: A retrospective cohort study.

INTRODUCTION: Bleeding and thrombotic complications are common in extracorporeal membrane oxygenation (ECMO) patients and are associated with increased mortality and morbidity. The optimal anticoagulation monitoring protocol in these patients is unknown. This study aims to compare the incidence of thrombotic and hemorrhagic complications before and after a protocol change. In addition, the association between hemostatic complications, coagulation tests and risk factors is evaluated. METHODS: This is a retrospective single center cohort study of adult ECMO patients. We collected demographics, ECMO parameters and coagulation test results. Outcomes of the aPTT guided and multimodal protocol, including aPTT, anti-Xa assay and rotational thromboelastometry were compared and the association between coagulation tests, risk factors and hemostatic complications was determined using a logistic regression analysis for repeated measurements. RESULTS: In total, 250 patients were included, 138 in the aPTT protocol and 112 in the multimodal protocol. The incidence of thrombosis (aPTT: 14%; multimodal: 12%) and bleeding (aPTT: 36%; multimodal: 40%), did not significantly differ between protocols. In the aPTT guided protocol, the aPTT was associated with thrombosis (Odds Ratio [OR] 1.015; 95% confidence interval [CI] 1.004-1.027). In both protocols, surgical interventions were risk factors for bleeding and thrombotic complications (aPTT: OR 93.2, CI 39.9-217.6; multimodal OR 17.5, CI 6.5-46.9). DISCUSSION: The incidence of hemostatic complications was similar between both protocols and surgical interventions were a risk factor for hemostatic complications. Results from this study help to elucidate the role of coagulation tests and risk factors in predicting hemostatic complications in patients undergoing ECMO support.

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.

Pro-opiomelanocortin and ACTH-cortisol dissociation during pediatric cardiac surgery.

In critically ill adults, high plasma cortisol in face of low ACTH coincides with high pro-opiomelanocortin (POMC) levels. Glucocorticoids further lower ACTH without affecting POMC. We hypothesized that in pediatric cardiac surgery-induced critical illness, plasma POMC is elevated, plasma ACTH transiently rises intraoperatively but becomes suppressed post-operatively, and glucocorticoid administration amplifies this phenotype. From 53 patients (0-36 months), plasma was obtained pre-operatively, intraoperatively and on post-operative day 1 and 2. Plasma was also collected from 24 healthy children. In patients, POMC was supra-normal pre-operatively (p<0.0001) but no longer thereafter (p<0.05). ACTH was never high in patients. While in glucocorticoid-naive patients ACTH became suppressed by post-operative day 1 (p<0.0001), glucocorticoid-treated patients had suppressed ACTH already intraoperatively (p≤0.0001). Pre-operatively high POMC, not accompanied by increased plasma ACTH, suggests a centrally-activated HPA-axis with reduced pituitary processing of POMC into ACTH. Increasing systemic glucocorticoid availability with glucocorticoid treatment accelerated the suppression of plasma ACTH.

Acquired von Willebrand disease in children undergoing extracorporeal membrane oxygenation: a prospective observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support for children with severe cardiac and/or pulmonary failure. The incidence of bleeding complications during ECMO support is high. Acquired von Willebrand disease (AVWD) might contribute to the development of bleeding complications. OBJECTIVE: To study the incidence and longitudinal profile of AVWD during the first 14 days of ECMO support in children and to investigate the association between AVWD and bleeding complications. METHODS: This prospective observational study included pediatric patients (0-17 years) receiving ECMO. Blood was sampled prior to and after ECMO start, daily and 12 to 24 hours after stopping ECMO. von Willebrand factor (VWF) parameters and multimer patterns were determined. Clinical data were collected for each patient. AVWD was defined as loss of high-molecular weight multimers (ie, decreased compared with baseline) or a VWF:collagen binding/VWF: antigen (Ag) ratio or VWF:activity/VWF:Ag ratio below 0.7. RESULTS: All of 50 (100%) patients developed AVWD during ECMO. The VWF:collagen binding /VWF:Ag ratio, VWF:activity/VWF:Ag ratio, and high-molecular weight multimers decreased during the initial days and recovered to baseline level within 24 hours after stopping ECMO. The incidence and longitudinal profile of AVWD were similar in patients with and without major bleeding complications. CONCLUSION: Children receiving ECMO support commonly develop AVWD. AVWD develops rapidly after ECMO initiation and recovers quickly after ECMO cessation. Importantly, AVWD appears to be independent of major bleeding.

Bacteria in Extracorporeal Membrane Oxygenation Circuit Clots of a Patient With Persistent Bacteremia: A Case Report.

A neonate with pulmonary hypertension was supported with extracorporeal membrane oxygenation (ECMO). During ECMO support, the patient developed Enterococcus faecalis bacteremia, treated with targeted antibiotics. Despite the maximum dose of antibiotics, routine blood cultures remained positive throughout the ECMO treatment. A circuit change was performed due to buildup of thrombotic material and disseminated intravascular coagulation (DIC) inside the circuit. Thrombus formation was more extensive in the first than the second circuit. Gram-positive diplococci were present in all initial circuit clots and gram-positive masses surrounded by fibrin were found inside thrombi of the second circuit. Scanning electron microscopy (SEM) revealed a dense fibrin network with embedded red blood cells and bacteria in the first circuit. In the second circuit, SEM analysis revealed scattered micro thrombi. Polymerase chain reaction for identification of bacteria in the thrombus of the first circuit showed the same bacteria as found in blood cultures and did not achieve a sufficient signal in the second circuit. This case report shows that bacteria can nestle in thrombi of an ECMO circuit and that there is a rationale for a circuit change in a patient with persistent positive blood cultures and DIC.

A Population Pharmacokinetic Model of Pentobarbital for Children with Status Epilepticus and Severe Traumatic Brain Injury.

BACKGROUND: Pentobarbital pharmacokinetics (PK) remain elusive and the therapeutic windows narrow. Administration is frequent in critically ill children with refractory status epilepticus (SE) and severe traumatic brain injury (sTBI). OBJECTIVES: To investigate pentobarbital PK in SE and sTBI patients admitted to the paediatric intensive care unit (PICU) with population-based PK (PopPK) modelling and dosing simulations. METHODS: Develop a PopPK model with non-linear mixed-effects modelling (NONMEM®) with retrospective data (n = 36; median age 1.3 years; median weight 10 kg; 178 blood samples) treated with continuous intravenous pentobarbital. An independent dataset was used for external validation (n = 9). Dosing simulations with the validated model evaluated dosing regimens. RESULTS: A one-compartment PK model with allometrically scaled weight on clearance (CL; 0.75) and volume of distribution (Vd; 1) captured data well. Typical CL and Vd values were 3.59 L/70 kg/h and 142 L/70 kg, respectively. Elevated creatinine and C-reactive protein (CRP) levels significantly correlated to decreased CL, explaining 84% of inter-patient variability, and were incorporated in the final model. External validation using stratified visual predictive checks showed good results. Simulations demonstrated patients with elevated serum creatinine and CRP failed to achieve steady state yet progressed to toxic levels with current dosing regimens. CONCLUSIONS: The one-compartment PK model of intravenous pentobarbital described data well whereby serum creatinine and CRP significantly correlated with pentobarbital CL. Dosing simulations formulated adjusted dosing advice in patients with elevated creatinine and/or CRP. Prospective PK studies with pharmacodynamic endpoints, are imperative to optimise pentobarbital dosing in terms of safety and clinical efficacy in critically ill children.

Withdrawal of Life-Sustaining Therapies in Children With Severe Traumatic Brain Injury.

Neuroprognostication in severe traumatic brain injury (sTBI) is challenging and occurs in critical care settings to determine withdrawal of life-sustaining therapies (WLST). However, formal pediatric sTBI neuroprognostication guidelines are lacking, brain death criteria vary, and dilemmas regarding WLST persist, which lead to institutional differences. We studied WLST practice and outcome in pediatric sTBI to provide insight into WLST-associated factors and survivor recovery trajectory ≥1 year post-sTBI. This retrospective, single center observational study included patients <18 years admitted to the pediatric intensive care unit (PICU) of Erasmus MC-Sophia (a tertiary university hospital) between 2012 and 2020 with sTBI defined as a Glasgow Coma Scale (GCS) ≤8 and requiring intracranial pressure (ICP) monitoring. Clinical, neuroimaging, and electroencephalogram data were reviewed. Multi-disciplinary follow-up included the Pediatric Cerebral Performance Category (PCPC) score, educational level, and commonly cited complaints. Seventy-eight children with sTBI were included (median age 10.5 years; interquartile range [IQR] 5.0-14.1; 56% male; 67% traffic-related accidents). Median ICP monitoring was 5 days (IQR 3-8), 19 (24%) underwent decompressive craniectomy. PICU mortality was 21% (16/78): clinical brain death (5/16), WLST due to poor neurological prognosis (WLST_neuro, 11/16). Significant differences (p < 0.001) between survivors and non-survivors: first GCS score, first pupillary reaction and first lactate, Injury Severity Score, pre-hospital cardiopulmonary resuscitation, and Rotterdam CT (computed tomography) score. WLST_neuro decision timing ranged from 0 to 31 days (median 2 days, IQR 0-5). WLST_neuro decision (n = 11) was based on neurologic examination (100%), brain imaging (100%) and refractory intracranial hypertension (5/11; 45%). WLST discussions were multi-disciplinary with 100% agreement. Immediate agreement between medical team and caregivers was 81%. The majority (42/62, 68%) of survivors were poor outcome (PCPC score 3 to 5) at PICU discharge, of which 12 (19%) in a vegetative state. One year post-injury, no patients were in a vegetative state and the median PCPC score had improved to 2 (IQR 2-3). No patients died after PICU discharge. Twenty percent of survivors could not attend school 2 years post-injury. Survivors requiring an adjusted educational level increased to 45% within this timeframe. Chronic complaints were headache, behavioral problems, and sleeping problems. In conclusion, two-thirds of sTBI PICU mortality was secondary to WLST_neuro and occurred early post-injury. Median survivor PCPC score improved from 4 to 2 with no vegetative patients 1 year post-sTBI. Our findings show the WLST decision process was multi-disciplinary and guided by specific clinical features at presentation, clinical course, and (serial) neurological diagnostic modalities, of which the testing combination was determined by case-to-case variation. This stresses the need for international guidelines to provide accurate neuroprognostication within an appropriate timeframe whereby overall survivor outcome data provides valuable context and guidance in the acute phase decision process.

Factors XI and XII in extracorporeal membrane oxygenation: longitudinal profile in children.

Background: Extracorporeal membrane oxygenation (ECMO) is used in children with cardiopulmonary failure. While the majority of ECMO centers use unfractionated heparin, other anticoagulants, including factor XI and factor XII inhibitors are emerging, which may prove suitable for ECMO patients. However, before these anticoagulants can be applied in these patients, baseline data of FXI and FXII changes need to be acquired. Objectives: This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children. Methods: This is a prospective observational study in neonatal and pediatric patients with ECMO (<18 years). All patients with venoarterial ECMO and with sufficient plasma volume collected before ECMO, on day 1 and day 3, and 24 hours postdecannulation were included. Antigenic levels and functional activity of FXI and FXII were determined in these samples. Longitudinal profiles of these values were created using a linear mixed model. Results: Sixteen patients were included in this study. Mean FXI and FXII antigenic levels (U/mL) changed from 7.9 and 53.2 before ECMO to 6.0 and 34.5 on day 3 and they recovered to 8.8 and 39.4, respectively, after stopping ECMO. Function (%) of FXI and FXII decreased from 59.1 and 59.0 to 49.0 and 50.7 on day 3 and recovered to 66.0 and 54.4, respectively. Conclusion: This study provides the first insights into changes of the contact pathway in children undergoing ECMO. FXI and FXII antigen and function change during ECMO. Results from this study can be used as starting point for future contact pathway anticoagulant studies in pediatric patients with ECMO.

Coagulation in pediatric extracorporeal membrane oxygenation: A systematic review of studies shows lack of standardized reporting.

Objectives: Extracorporeal membrane oxygenation (ECMO) involves complex coagulation management and frequent hemostatic complications. ECMO practice between centers is variable. To compare results between coagulation studies, standardized definitions and clear documentation of ECMO practice is essential. We assessed how study population, outcome definitions, and ECMO-, coagulation-, and transfusion-related parameters were described in pediatric ECMO studies. Data sources: Embase, Medline, Web of Science, Cochrane Library and Google Scholar. Study selection: English original studies of pediatric ECMO patients describing hemostatic tests or outcome. Data extraction: Eligibility was assessed following PRISMA guidelines. Study population, outcome and ECMO-, coagulation, and transfusion parameters were summarized. Data synthesis: A total of 107 of 1312 records were included. Study population parameters most frequently included (gestational) age (79%), gender (60%), and (birth) weight (59%). Outcomes, including definitions of bleeding (29%), thrombosis (15%), and survival (43%), were described using various definitions. Description of pump type, oxygenator and cannulation mode occurred in 49%, 45%, and 36% of studies, respectively. The main coagulation test (53%), its reference ranges (49%), and frequency of testing (24%) were the most prevalent reported coagulation parameters. The transfusion thresholds for platelets, red blood cells, and fibrinogen were described in 27%, 18%, and 18% of studies, respectively. Conclusions: This systematic review demonstrates a widespread lack of detail or standardization of several parameters in coagulation research of pediatric ECMO patients. We suggest several parameters that might be included in future coagulation studies. We encourage the ECMO community to adopt and refine this list of parameters and to use standardized definitions in future research.

Role of extracorporeal membrane oxygenation in pediatric cancer patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in pediatric patients with underlying malignancies remains controversial. However, in an era in which the survival rates for children with malignancies have increased significantly and several recent reports have demonstrated effective ECMO use in children with cancer, we aimed to estimate the outcome and complications of ECMO treatment in these children. METHODS: We searched MEDLINE, Embase and CINAHL databases for studies on the use ECMO in pediatric patients with an underlying malignancy from inception to September 2020. This review was conducted in adherence to Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Study eligibility was independently assessed by two authors and disagreements resolved by a third author. Included studies were evaluated for quality using the Newcastle-Ottawa Scale (NOS). Random effects meta-analyses (DerSimonian and Laird) were performed. The primary outcomes were mortality during ECMO or hospital mortality. RESULTS: Thirteen retrospective, observational cohort studies were included, most of moderate quality (625 patients). The commonest indication for ECMO was severe respiratory failure (92%). Pooled mortality during ECMO was 55% (95% confidence interval [CI], 47-63%) and pooled hospital mortality was 60% (95% CI 54-67%). Although heterogeneity among the included studies was low, confidence intervals were large. In addition, the majority of the data were derived from registries with overlapping patients which were excluded for the meta-analyses to prevent resampling of the same participants across the included studies. Finally, there was a lack of consistent complications reporting among the studies. CONCLUSION: Significantly higher mortalities than in general PICU patients was reported with the use of ECMO in children with malignancies. Although these results need to be interpreted with caution due to the lack of granular data, they suggest that ECMO appears to represents a viable rescue option for selected patients with underlying malignancies. There is an urgent need for additional data to define patients for whom ECMO may provide benefit or harm.

Review of Scavenged Sampling for Sustainable Therapeutic Drug Monitoring: Do More With Less.

PURPOSE: Innovative and sustainable sampling strategies for bioanalytical quantification of drugs and metabolites have gained considerable interest. Scavenging can be stratified as a sustainable sampling strategy using residual material because it aligns with the green principles of waste reduction and sampling optimization. Scavenged sampling includes all biological fluids' (eg, blood, liquor, and urine) leftover from standard clinical care. This review elaborates on the past and current landscape of sustainable sampling within therapeutic drug monitoring, with a focus on scavenged sampling. METHODS: In February 2021, 4 databases were searched to assess the literature on the clinical use of innovative and sustainable sampling techniques without applying publication date restrictions. Studies reporting the clinical use of scavenged blood sampling and bridging studies of scavenged sampling and normal blood sampling were eligible for inclusion. RESULTS: Overall, 19 eligible studies concerning scavenged sampling were identified from 1441 records. Scavenged sampling is mainly applied in the pediatric population, although other patient groups may benefit from this strategy. The infrastructure required for scavenged sampling encounters several challenges, including logistic hurdles, storage and handling conditions, and documentation errors. A workflow is proposed with identified opportunities that guide the implementation of scavenged sampling. CONCLUSIONS: This review presents current evidence on the clinical use of scavenged sampling strategies. Scavenged sampling can be a suitable approach for drug quantification to improve dosage regimens, perform pharmacokinetic studies, and explore the value of therapeutic drug monitoring without additional sample collection.

The Pharmacokinetics of Beta-Lactam Antibiotics Using Scavenged Samples in Pediatric Intensive Care Patients: The EXPAT Kids Study Protocol.

Background: Emerging evidence supports the importance of optimized antibiotic exposure in pediatric intensive care unit (PICU) patients. Traditional antibiotic dosing is not designed for PICU patients, as the extreme pharmacokinetic (PK) behavior of drugs threatens the achievement of optimal antibiotic treatment outcomes. Scavenged sampling is a sampling strategy which may have positive implications for routine TDM and PK research, as well as monitoring other biomarkers. EXPAT Kids study was designed to analyze whether current empiric dosing regimens of frequently used beta-lactam antibiotics achieve defined therapeutic target concentrations in PICU patients. Methods: A mono-centre, exploratory pharmacokinetic and pharmacodynamic study was designed to assess target attainment of beta-lactam antibiotics. One hundred forty patients will be included within 24 months after start of inclusion. At various time points serum concentration of the study antibiotic (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, and meropenem) are determined. In parallel with these sampling moments, residual material is collected to validate the use of blood of scavenged heparinized astrup syringes for the quantification of antibiotic exposure. The primary outcome is the time that the free (unbound) concentration of the study antibiotic remains above one to four the minimal inhibitory concentration during a dosing interval (100%ƒT > MIC and 100%ƒT>4xMIC). Other included outcomes are disease severity, safety, length of stay, and inflammatory biomarkers. Discussion: Potentially, scavenged sampling may enrich the EXPAT Kids dataset, and reduce additional blood sampling and workload for clinical personnel. The findings from the EXPAT Kids study will lead to new insights in the PK parameters of beta-lactams and consecutive effects on target attainment and clinical outcomes. Is there a need for more precision in dosing? Netherlands Trial Register Number: Trial NL9326.

Use of rotational thromboelastometry to predict hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation: A retrospective cohort study.

BACKGROUND: The incidence of hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) is high. The optimal anticoagulation strategy in children undergoing ECMO is unknown. OBJECTIVES: To study the association between hemostatic complications, coagulation tests, and clinical parameters in pediatric patients undergoing ECMO and their effect on survival. METHODS: We performed a retrospective cohort study of pediatric patients undergoing centrifugal pump ECMO. Collected data included patient characteristics, risk factors, and coagulation test results. Statistical analysis was done using logistic regression analysis for repeated measurements. Dependent variables were thrombosis and bleeding, independent variables were rotational thromboelastometry (ROTEM), activated partial thromboplastin time (aPTT) and antifactor-Xa assay (aXa) results, ECMO duration, age <29 days, sepsis and surgery. RESULTS: Seventy-three patients with 623 ECMO days were included. Cumulative incidences of thrombosis and bleeding were 43.5% (95% confidence interval [CI], 26.0%-59.8%) and 25.4% (95% CI, 13.4%-39.3%), respectively. A lower maximum clot firmness of intrinsic ROTEM (INTEM; odds ratio [OR], 0.946; 95% CI, 0.920-0.969), extrinsic ROTEM (OR, 0.945; 95% CI, 0.912-0.973), and INTEM with heparinase (OR, 0.936; 95% CI, 0.896-0.968); higher activated partial thromboplastin time aPTT; OR, 1.020; 95% CI, 1.006-1.024) and age <29 days (OR, 2.900; 95% CI, 1.282-6.694); surgery (OR, 4.426; 95% CI, 1.543-12.694); and longer ECMO duration (OR, 1.149; 95% CI, 1.022-1.292) significantly increased thrombotic risk. Surgery (OR, 2.698; 95% CI, 1.543-12.694) and age <29 days (OR 2.242, 95% CI 1.282-6.694) were significantly associated with major bleeding. Patients with hemostatic complications had significantly decreased survival to hospital discharge (P = .009). CONCLUSION: The results of this study help elucidate the role of ROTEM, aPTT, anti-factor Xa, and clinical risk factors in predicting hemostatic complications in pediatric patients undergoing ECMO.

Effectiveness and Safety of Nadroparin Therapy in Preterm and Term Neonates with Venous Thromboembolism.

INTRODUCTION: Optimal neonatal nadroparin dosages to treat venous thromboembolism (VTE) are unknown. OBJECTIVE: To evaluate therapeutic nadroparin dosages to reach therapeutic target ranges (TTR: 0.5-1.0 International Unit (IU)/mL) and the effectiveness and safety of nadroparin in neonatal VTE. METHODS: Retrospective study including neonates with VTE on nadroparin in a tertiary center between 2007 and 2018. Two groups were distinguished: neonates before (group 1) and after (group 2) switch to higher starting dosages in 2014. RESULTS: Sixty-one neonates (44 preterm, 17 term) with 64 VTEs were included. TTR was reached in 32/64 (50%) VTEs (group 1: 35.7%; group 2: 61.1%). Median nadroparin dosage to reach TTR was 197 (97.9-330.3) IU/kg/12 h. No therapy-related deaths occurred. Recurrent VTE developed in 6 (9.8%) neonates. Complete clot resolution was observed in 31/41 (75.6%) VTEs. TTR was reached in 58.1% VTEs with complete clot resolution. No major bleeding occurred. Non-major clinically relevant bleedings occurred in 3/64 (4.7%) VTEs, consisting of large hematomas due to the use of subcutaneous catheters. CONCLUSIONS: High nadroparin dosages are needed to reach TTR in neonates, which seem to be safe. Clot resolution may occur without reaching TTR. Subcutaneous catheters may cause important bleeding complications.

Model-Informed Precision Dosing of Antibiotics in Pediatric Patients: A Narrative Review.

Optimal pharmacotherapy in pediatric patients with suspected infections requires understanding and integration of relevant data on the antibiotic, bacterial pathogen, and patient characteristics. Because of age-related physiological maturation and non-maturational covariates (e.g., disease state, inflammation, organ failure, co-morbidity, co-medication and extracorporeal systems), antibiotic pharmacokinetics is highly variable in pediatric patients and difficult to predict without using population pharmacokinetics models. The intra- and inter-individual variability can result in under- or overexposure in a significant proportion of patients. Therapeutic drug monitoring typically covers assessment of pharmacokinetics and pharmacodynamics, and concurrent dose adaptation after initial standard dosing and drug concentration analysis. Model-informed precision dosing (MIPD) captures drug, disease, and patient characteristics in modeling approaches and can be used to perform Bayesian forecasting and dose optimization. Incorporating MIPD in the electronic patient record system brings pharmacometrics to the bedside of the patient, with the aim of a consisted and optimal drug exposure. In this narrative review, we evaluated studies assessing optimization of antibiotic pharmacotherapy using MIPD in pediatric populations. Four eligible studies involving amikacin and vancomycin were identified from 418 records. Key articles, independent of year of publication, were also selected to highlight important attributes of MIPD. Although very little research has been conducted until this moment, the available data on vancomycin indicate that MIPD is superior compared to conventional dosing strategies with respect to target attainment. The utility of MIPD in pediatrics needs to be further confirmed in frequently used antibiotic classes, particularly aminoglycosides and beta-lactams.

Development of entrustable professional activities for paediatric intensive care fellows: A national modified Delphi study.

Entrustable professional activities (EPAs), as a focus of learner assessment, are supported by validity evidence. An EPA is a unit of professional practice requiring proficiency in multiple competencies simultaneously, that can be entrusted to a sufficiently competent learner. Taken collectively, a set of EPAs define and inform the curriculum of a specialty training. The goal of this study was to develop a set of EPAs for Dutch PICU fellows. A multistage methodology was employed incorporating sequential input from task force members, a medical education expert, PICU fellowship program directors, and PICU physicians and fellows via a modified three-round Delphi study. In the first modified Delphi round, experts rated indispensability and clarity of preliminary EPAs. In the subsequent rounds, aggregated scores for each EPA and group comments were provided. In round two, respondents rated indispensability and clarity of revised EPAs. Round three was used to gain explicit confirmation of suitability to implement these EPAs. Based on median ratings and content validity index (CVI) analysis for indispensability in the first two rounds, all nine preliminary EPAs covered activities that were deemed essential to the clinical practice of PICU physicians. Based on median ratings and CVI analysis for clarity however, four EPAs needed revision. With an agreement percentage of 93-100% for all individual EPAs as well as the set as a whole, a high degree of consensus among experts was reached in the third round. The resulting nine PICU EPAs provide a succinct overview of the core tasks of Dutch PICU physicians. These EPAs were created as an essential first step towards developing an assessment system for PICU fellows, grounded in core professional activities. The robust methodology used, may have broad applicability for other (sub)specialty training programs aiming to develop specialty specific EPAs.

Coagulation complications after conversion from roller to centrifugal pump in neonatal and pediatric extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Coagulation complications are frequent, unwanted occurrences in extracorporeal membrane oxygenation (ECMO) treatment, possibly influenced by the pump in the ECMO-circuit. We hypothesized that fewer complications would occur with a smaller, heparin-coated ECMO system with a centrifugal pump (CP) than with one with a roller pump (RP) and that after conversion, complication rates would decrease over time. METHODS: This single-center, retrospective chart study included all first neonatal and pediatric ECMO runs between 2009 and 2015. Differences between groups were assessed with Mann-Whitney U tests and Kruskal-Wallis tests. Determinants of complication rates were evaluated through Poisson regression models. The CP group was divided into three consecutive groups to assess whether complication rates decreased over time. RESULTS: The RP group comprised 90 ECMO runs and the CP group 82. Hemorrhagic complication rates were significantly higher with the CP than with the RP, without serious therapeutic consequences, while thrombotic complications rates were unaffected. Intracranial hemorrhage rates and coagulation-related mortality rates were similar. Gained experience with the CP did not improve complication rates or survival over time. CONCLUSIONS: Although the CP seems safe, it does not seem beneficial over the RP. Further research is warranted on how pump type affects coagulation, taking into account the severity and implications of coagulation complications. LEVEL OF EVIDENCE: Level III.

Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: An in vitro Study.

Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve ® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung ® petite kits, two iLA-ActivveMiniLung ® kits, two iLA-ActivveiLA ® kits, and two iLA-Activve X-lung ® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.

Hyperoxia in pediatric severe traumatic brain injury (TBI): a comparison of patient classification by cutoff versus cumulative (area-under-the-curve) analysis.

OBJECTIVE: Hyperoxia is associated with adverse outcome in severe traumatic brain injury (TBI). This study explored differences in patient classification of oxygen exposure by PaO2 cutoff and cumulative area-under-the-curve (AUC) analysis. METHODS: Retrospective, explorative study including children (<18 years) with accidental severe TBI (2002-2015). Oxygen exposure analysis used three PaO2 cutoff values and four PaO2 AUC categories during the first 24 hours of Pediatric Intensive Care Unit (PICU) admission. RESULTS: Seventy-one patients were included (median age 8.9 years [IQR 4.6-12.9]), mortality 18.3% (n = 13). Patient hyperoxia classification differed depending on PaO2 cutoff vs AUC analysis: 52% vs. 26%, respectively, were classified in the highest hyperoxia category. Eleven patients (17%) classified as 'intermediate oxygen exposure' based on cumulative PaO2 analysis whereby they did not exceed the 200 mmHg PaO2 cutoff threshold. Patient classification variability was reflected by Pearson correlation coefficient of 0.40 (p-value 0.001). CONCLUSIONS: Hyperoxia classification in pediatric severe TBI during the first 24 hours of PICU admission differed depending on PaO2 cutoff or cumulative AUC analysis. We consider PaO2 cumulative (AUC) better approximates (patho-)physiological circumstances due to its time- and dose-dependent approach. Prospective studies exploring the association between cumulative PaO2, physiological parameters (e.g. ICP, PbtO2) and outcome are warranted as different patient classifications of oxygen exposure influences how its relationship to outcome is interpreted.

A Systematic Review of Neuromonitoring Modalities in Children Beyond Neonatal Period After Cardiac Arrest.

OBJECTIVES: Postresuscitation care in children focuses on preventing secondary neurologic injury and attempts to provide (precise) prognostication for both caregivers and the medical team. This systematic review provides an overview of neuromonitoring modalities and their potential role in neuroprognostication in postcardiac arrest children. DATA RESOURCES: Databases EMBASE, Web of Science, Cochrane, MEDLINE Ovid, Google Scholar, and PsycINFO Ovid were searched in February 2019. STUDY SELECTION: Enrollment of children after in- and out-of-hospital cardiac arrest between 1 month and 18 years and presence of a neuromonitoring method obtained within the first 2 weeks post cardiac arrest. Two reviewers independently selected appropriate studies based on the citations. DATA EXTRACTION: Data collected included study characteristics and methodologic quality, populations enrolled, neuromonitoring modalities, outcome, and limitations. Evidence tables per neuromonitoring method were constructed using a standardized data extraction form. Each included study was graded according to the Oxford Evidence-Based Medicine scoring system. DATA SYNTHESIS: Of 1,195 citations, 27 studies met the inclusion criteria. There were 16 retrospective studies, nine observational prospective studies, one observational exploratory study, and one pilot randomized controlled trial. Neuromonitoring methods included neurologic examination, routine electroencephalography and continuous electroencephalography, transcranial Doppler, MRI, head CT, plasma biomarkers, somatosensory evoked potentials, and brainstem auditory evoked potential. All evidence was graded 2B-2C. CONCLUSIONS: The appropriate application and precise interpretation of available modalities still need to be determined in relation to the individual patient. International collaboration in standardized data collection during the (acute) clinical course together with detailed long-term outcome measurements (including functional outcome, neuropsychologic assessment, and health-related quality of life) are the first steps toward more precise, patient-specific neuroprognostication after pediatric cardiac arrest.