Reliability of glomerular filtration rate estimating formulas compared to iohexol plasma clearance in critically ill children.

Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CLiohexol) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CLiohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland-Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CLiohexol was measured in 98 patients. Mean CLiohexol (± SD) was 115 ± 54 ml/min/1.73m2. Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC- and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of - 18 ± 51% (95% confidence interval (CI) - 29; - 9), poor precision with 95% LoA from - 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58). CONCLUSION: In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings. CLINICALTRIALS: gov NCT05179564, registered retrospectively on January 5, 2022. WHAT IS KNOWN: • Both acute kidney injury and augmented renal clearance may be present in PICU patients and warrant adaptation of therapy, including drug dosing. • Biomarker-based eGFR formulas are widely used for GFR assessment in critically ill children, although endogenous filtration biomarkers have important limitations in PICU patients and eGFR formulas have never been validated against measured GFR in this population. WHAT IS NEW: • eGFR formulas were found to be largely inaccurate in the PICU population when compared to measured GFR by iohexol clearance. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. • Iohexol plasma clearance could be considered an alternative for accurate GFR assessment in PICU patients.

Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3.

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CLR post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.

Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients?

Many critically ill patients display a supraphysiological renal function with enhanced renal perfusion and glomerular hyperfiltration. This phenomenon described as augmented renal clearance (ARC) may result in enhanced drug elimination through renal excretion mechanisms. Augmented renal clearance seems to be triggered by systemic inflammation and therapeutic interventions in intensive care. There is growing evidence that ARC is not restricted to the adult intensive care population, but is also prevalent in critically ill children. Augmented renal clearance is often overlooked due to the lack of reliable methods to assess renal function in critically ill children. Standard equations to calculate glomerular filtration rate (GFR) are developed for patients who have a steady-state creatinine production and a stable renal function. Those formulas are not reliable in critically ill patients with acutely changing GFR and tend to underestimate true GFR in patients with ARC. Tools for real-time, continuous, and non-invasive measurement of fluctuating GFR are most needed to identify changes in kidney function during critical illness and therapeutic interventions. Such devices are currently being validated and hold a strong potential to become the standard of practice. In the meantime, urinary creatinine clearance is considered the most reliable method to detect ARC in critically ill patients. Augmented renal clearance is clearly associated with subtherapeutic antimicrobial concentrations and subsequent therapeutic failure. This warrants the need for adjusted dosing regimens to optimize pharmacokinetic and pharmacodynamic target attainment. This review aims to summarize current knowledge on ARC in critically ill children, to give insight into its possible pathophysiological mechanism, to evaluate screening methods for ARC in the pediatric intensive care population, and to illustrate the effect of ARC on drug exposure, therapeutic efficacy, and clinical outcome.

Impact of a VAP bundle in Belgian intensive care units.

BACKGROUND: In order to decrease the incidence of ventilator-associated pneumonia (VAP) in Belgium, a national campaign for implementing a VAP bundle involving assessment of sedation, cuff pressure control, oral care with chlorhexidine and semirecumbent position, was launched in 2011-2012. This report will document the impact of this campaign. METHODS: On 1 day, once a year from 2010 till 2016, except in 2012, Belgian ICUs were questioned about their ventilated patients. For each of these, data about the application of the bundle and the possible treatment for VAP were recorded. RESULTS: Between 36.6 and 54.8% of the 120 Belgian ICUs participated in the successive surveys. While the characteristics of ventilated patients remained similar throughout the years, the percentage of ventilated patients and especially the duration of ventilation significantly decreased before and after the national VAP bundle campaign. Ventilator care also profoundly changed: Controlling cuff pressure, head positioning above 30° were obtained in more than 90% of cases. Oral care was more frequently performed within a day, using more concentrated solutions of chlorhexidine. Subglottic suctioning also was used but in only 24.7% of the cases in the last years. Regarding the prevalence of VAP, it significantly decreased from 28% of ventilated patients in 2010 to 10.1% in 2016 (p ≤ 0.0001). CONCLUSION: Although a causal relationship cannot be inferred from these data, the successive surveys revealed a potential impact of the VAP bundle campaign on both the respiratory care of ventilated patients and the prevalence of VAP in Belgian ICUs encouraging them to follow the guidelines.

Dose optimization of piperacillin/tazobactam in critically ill children.

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen. Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L). Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

Impact of vancomycin protein binding on target attainment in critically ill children: back to the drawing board?

Objectives: The objectives of this observational study were to investigate plasma protein binding and to evaluate target attainment rates of vancomycin therapy in critically ill children. Patients and methods: Paediatric ICU patients, in whom intravenous intermittent dosing (ID) or continuous dosing (CD) with vancomycin was indicated, were included. Covariates on unbound vancomycin fraction and concentration were tested using a linear mixed model analysis and attainment of currently used pharmacokinetic/pharmacodynamic (PK/PD) targets was evaluated. Clinicaltrials.gov: NCT02456974. Results: One hundred and eighty-eight plasma samples were collected from 32 patients. The unbound vancomycin fraction (median = 71.1%; IQR = 65.4%-79.7%) was highly variable within and between patients and significantly correlated with total protein and albumin concentration, which were both decreased in our population. Total trough concentration (ID) and total concentration (CD) were within the aimed target concentrations in 8% of patients. The targets of AUC/MIC ≥400 and f AUC/MIC ≥200 were achieved in 54% and 83% of patients, respectively. Unbound vancomycin concentrations were adequately predicted using the following equation: unbound vancomycin concentration (mg/L) = 5.38 + [0.71 × total vancomycin concentration (mg/L)] - [0.085 × total protein concentration (g/L)]. This final model was externally validated using 51 samples from another six patients. Conclusions: The protein binding of vancomycin in our paediatric population was lower than reported in non-critically ill adults and exhibited large variability. Higher target attainment rates were achieved when using PK/PD indices based on unbound concentrations, when compared with total concentrations. These results highlight the need for protein binding assessment in future vancomycin PK/PD research.

Therapeutic plasma exchange in children with acute autoimmune central nervous system disorders.

BACKGROUND: There is a growing evidence for autoimmunity in acute central nervous system (CNS) disorders and treatment with therapeutic plasma exchange (TPE) may be considered. The aim was to share our experience on the clinical application of TPE in these disorders and to present a reproducible protocol which can be used even in small children. METHODS: We present a series of 8 children aged 2-12 years with transverse myelitis, Bickerstaff's brainstem encephalitis, neuromyelitis optica, and acute paraneoplastic or unspecified encephalitis in whom TPE was used as a second-line or rescue treatment. RESULTS: A total of 104 TPE sessions were performed where 80-110 ml/kg of plasma was exchanged using 4% albumin solution and fresh frozen plasma. Six episodes of TPE-related adverse events were documented. Fibrinogen concentrations decreased after the first TPE, whereas platelets decreased gradually. One patient died in the course of the acute illness. Three children achieved a complete resolution of symptoms, 2 children have mild sequelae; whereas 2 children remain paraplegic after a follow-up of 3 to 17 months. CONCLUSIONS: We report 8 children with presumably autoimmune-mediated, acute CNS disorders treated with TPE as a rescue therapy. Although the effect of TPE can only be inferred, 5 children had a good clinical outcome. TPE is feasible even in small children with acute autoimmune CNS disorders.

Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].).

Possible pathogenic mechanism of propofol infusion syndrome involves coenzyme q.

BACKGROUND: Propofol is a short-acting intravenous anesthetic agent. In rare conditions, a life-threatening complication known as propofol infusion syndrome can occur. The pathophysiologic mechanism is still unknown. Some studies suggested that propofol acts as uncoupling agent, others suggested that it inhibits complex I or complex IV, or causes increased oxidation of cytochrome c and cytochrome aa3, or inhibits mitochondrial fatty acid metabolism. Although the exact site of interaction is not known, most hypotheses point to the direction of the mitochondria. METHODS: Eight rats were ventilated and sedated with propofol up to 20 h. Sequential biopsy specimens were taken from liver and skeletal muscle and used for determination of respiratory chain activities and propofol concentration. Activities were also measured in skeletal muscle from a patient who died of propofol infusion syndrome. RESULTS: In rats, authors detected a decrease in complex II+III activity starting at low tissue concentration of propofol (20 to 25 µM), further declining at higher concentrations. Before starting anesthesia, the complex II+III/citrate synthase activity ratio in liver was 0.46 (0.25) and in skeletal muscle 0.23 (0.05) (mean [SD]). After 20 h of anesthesia, the ratios declined to 0.17 (0.03) and 0.12 (0.02), respectively. When measured individually, the activities of complexes II and III remained normal. Skeletal muscle from one patient taken in the acute phase of propofol infusion syndrome also shows a selective decrease in complex II+III activity (z-score: -2.96). CONCLUSION: Propofol impedes the electron flow through the respiratory chain and coenzyme Q is the main site of interaction with propofol.

The long-term outcome after severe trauma of children in Flanders (Belgium): a population-based cohort study using the International Classification of Functioning--related outcome score.

Important long-term health problems have been described after severe paediatric trauma. The International Classification of Functioning (ICF) was developed as a universal framework to describe that health. We evaluated outcome in children after 'severe' trauma (defined as: hospitalised >48 h) by means of a questionnaire based on this ICF construct (IROS). Questionnaires were sent to children; one year after this trauma and to 'control' children without any previous 'severe' trauma. We created propensity score-matched pairs (n = 133) and evaluated differences in health perception. IROS characteristics were investigated by means of Item Response Theory models. We then estimated the health state of each individual based on his/her response pattern (factor score z01) and investigated the effect of selected covariates with simple linear regression. Significant odds ratios for differences between matched groups (p < 0.05) were observed for among others emotional problems, mobility, societal life and family burden, but not for chronic pain. Children in the trauma group showed, e.g. significant more physician (estimated relative risk R' 1.7) and psychologist (R' 3.5) visits. IROS primarily provides information from medium to high health burden levels and factor scores ranged from 0.41 (lowest) to 0.967 (highest burden). A significant impact on health burden could only be proven for the 'state at discharge' (p = 0.015), although there was a tendency towards worse factor scores for children that were older, had a higher Injury Severity Score or after traffic injury. In conclusion, we showed that the burden of health problems for children and families after severe trauma is still high and physical, as well as psychosocial in nature. The health state at discharge seems to predict long-term outcome, which might be of importance in view of, e.g. trajectory assistance. IROS may provide an improved scoring system to evaluate outcome after (paediatric) injury or critical illness.

Vagus nerve stimulation for refractory status epilepticus.

We report on the long-term follow-up of a patient with refractory non-convulsive SE who was successfully treated with VNS. A 7-year old girl with a medical history of thrombosis in the right internal cerebral vein and right thalamic bleeding 8 days after birth, developed epilepsy at the age of 13 months. At the age of 6 she presented with a refractory non-convulsive SE. A vagus nerve stimulator was placed after 11 days of thiopental-induced coma. Three days after VNS implantation, the thiopental-induced coma was successfully withdrawn and electroencephalography showed normalization one week after start of VNS. After a follow-up of 13 months she remains seizure-free and AEDs have been partially tapered. This case illustrates a potential acute abortive effect with sustained long-term seizure reduction of VNS in a 7-year old girl who presented with refractory non-convulsive SE.

Closing the knowledge-performance gap: an audit of medical management for severe paediatric trauma in Flanders (Belgium).

AIMS: Considerable variability in (paediatric) trauma care has been reported. We wanted to audit current practice in Flanders (Belgium). METHODS: The PENTA network prospectively collected data on paediatric trauma patients in a representative sample of Flemish hospitals during 2005. All cases with an ISS>or=13 and sufficient data availability were withheld for panel evaluation (n=92). Two trained experts reviewed the medical care provided in the first hours after trauma, based on available evidence and existing universal guidelines. 'Defaults' were only withheld as such if there was 100% consensus. At random, about 25% of cases were also reviewed by two other experts in order to assess interobserver variability. RESULTS: In the 92 cases, 264 defaults were recognised. 25.4% of all defaults were thought to have a direct impact on the individual patient's outcome. Specific difficulties were observed with, e.g. cervical spine management (18/82 relevant cases), pCO2 and global respiratory management (38/92), fluid management (29/92) and analgesia (27/89). The agreement between the two panels was good for defaults identified (crude agreement 74.8%), yet only fair for the presumed impact on outcome (crude agreement 58.3%). CONCLUSIONS: We audited paediatric trauma care in Flanders and identified several problem areas (often in basic areas of paediatric life support). The inherent degree of interobserver variability does not diminish the importance of these findings. More performance-based teaching and timely recertification may have a positive impact on the quality of the care delivered.

Paediatric trauma and trauma care in Flanders (Belgium). Methodology and first descriptive results of the PENTA registry.

Paediatric injury surveillance and prevention are definite priorities for the European, Belgian, and Flemish authorities. Current available data for Flanders (Belgium) are fragmentary and out-of-date. The PENTA registry (PaEdiatric Network around TraumA) was therefore set up to obtain recent population-based data on trauma and trauma care in children and youngsters in Flanders. Data were collected prospectively in a representative sample (n = 18) of Flemish emergency departments (ED). All children (age 0-17 years) who presented at the ED in 2005 or died prehospital due to trauma were included. The registry was split into two levels. The basic A registry ('all' trauma) consisted of 30 variables, and the more exhaustive B registry ('severe trauma', defined as length of hospitalisation >48 hours, including all nonsurvivors) collected data on 291 variables. The incidence for paediatric trauma presenting at Flemish ED was approximately 119/1000/year. Further data were collected in a random sample of 7,879 cases (21.9% of 35,900 eligible patients). Of all cases, 0.8% were considered 'severe' and included in the B registry. In conclusion, the 'burden' of injury in Flanders is still enormous. PENTA provides the first population-based data about the circumstances and the extent of injury in children and youngsters for the Flemish region. In this article we present in detail the surplus value of the methods used, the difficulties encountered, and the most relevant epidemiological findings from the registry.

Assessing the level of consciousness in children: a plea for the Glasgow Coma Motor subscore.

AIM: The Glasgow Coma Scale (GCS) is not always easy to score and its reliability has been questioned. In adults the GCS Motor score has proven a valuable alternative, as it is easier to assess yet shows similar predictive capacity for outcome. We wanted to test the non-inferiority of the Glasgow Coma Motor score GCS-M versus the Total score GCS-T for predicting outcome in children. MATERIALS AND METHODS: As part of the Flemish paediatric trauma registry (PENTA) we collected data on 96 consecutive children (0-18 years) with moderate to severe traumatic brain injury. Outcome was evaluated using a three level ordinal scale: [normal to mild disability, moderate to severe disability and death]. A number of proportional odds models were fitted for various choices of predictive variables (GCS-T, GCS-M, age, sex, and injury severity score ISS). For each model we calculated Somers'D(xy) rank correlation and NagelKerke's R(2)N index, both measures of the predictive performance of the model. RESULTS: All children had an injury to the brain that resulted in a hospital stay of more than 48h. Half of them had a "best" initial GCS of 15; 60%, a Motor score of 6. The median Injury Severity Score ISS was 16. Outcome was 'normal to mild' in 79 children, 'moderate to severe' in 7, and 'death' in 10. D(xy) values were 0.983 for the model with the Motor score and 0.972 for that with the total GCS, indicating excellent predictive performance for both. R(2)N indices were 0.862 and 0.813, respectively. Overall the difference between all models was small. CONCLUSION: The GCS Motor subscore was shown to have at least the same predictive ability for outcome as the total GCS. It is our opinion that the total GCS is unnecessarily complicated (especially in children). Using the Motor score alone will improve scoring compliance and statistical performance. We do not believe that the reduction in number of potential scores from 13 to 6 would decrease the descriptive capacity significantly, since clinical algorithms typically group values of the total GCS into five or fewer ranges.