Have We Neglected to Study Target-Site Drug Exposure in Children? A Systematic Review of the Literature.

BACKGROUND AND OBJECTIVE: Drug dosing should ideally be based on the drug concentrations at the target site, which, for most drugs, corresponds to the tissue. The exact influence of growth and development on drug tissue distribution is unclear. This systematic review compiles the current knowledge on the tissue distribution of systemically applied drugs in children, with the aim to identify priorities in tissue pharmacokinetic (PK) research in this population. METHODS: A systematic literature search was performed in the MEDLINE and Embase databases. RESULTS: Forty-two relevant articles were identified, of which 71% investigated antibiotics, while drug classes from the other studies were anticancer drugs, antifungals, anthelmintics, sedatives, thyreostatics, immunomodulators, antiarrhythmics, and exon skipping therapy. The majority of studies (83%) applied tissue biopsy as the sampling technique. Tonsil and/or adenoid tissue was most frequently examined (70% of all included patients). The majority of studies had a small sample size (median 9, range 1-93), did not include the youngest age categories (neonates and infants), and were of low reporting quality. Due to the heterogeneous data from different study compounds, dosing schedules, populations, and target tissues, the possibility for comparison of PK data between studies was limited. CONCLUSION: The influence of growth and development on drug tissue distribution continues to be a knowledge gap, due to the paucity of tissue PK data in children, especially in the younger age categories. Future research in this field should be encouraged as techniques to safely investigate drug tissue disposition in children are available.

Predictors of augmented renal clearance based on iohexol plasma clearance in critically ill children.

BACKGROUND: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). METHODS: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48-72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. RESULTS: Eighty-five patients were included; 57% were postoperative patients. Median CLiohexol1 was 122 mL/min/1.73 m2 (IQR 75-152). Forty patients (47%) expressed ARC on CLiohexol1. Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m2 and 140 mL/min/1.73 m2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CLiohexol2. CONCLUSIONS: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.

Microdialysis as a safe and feasible method to study target-site piperacillin-tazobactam disposition in septic piglets and children.

OBJECTIVES: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lacking. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project. METHODS: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability. RESULTS: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children. CONCLUSIONS: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.

Pharmacokinetics and Target Attainment of ß-lactam Antibiotics in Older People: A Systematic Review of Current Literature.

BACKGROUND AND OBJECTIVE: (Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard dosing regimens. This systematic review compiles the current knowledge on the PK and target attainment of ß-lactam antibiotics in older people, with the aim to identify priorities for dose optimization in this patient population. METHODS: A systematic literature search of the PubMed and EMBASE databases was conducted. Relevant articles published prior to 1 December 2021 were identified as eligible when they included data on the PK of ß-lactam antibiotics in adults ≥ 65 years of age. Extracted information included reported PK parameters (volume of distribution, clearance [CL], elimination rate constant, intercompartmental CL, elimination half-life, area under the concentration-time curve, maximum and trough concentration), covariates on PK parameters, target attainment rate, and dosing recommendations. RESULTS: Ninety-one relevant articles were included in this review. Four main ß-lactam subclasses were represented: 59.3% on cephalosporins + cephamycins, 25.3% on penicillins, 15.4% on carbapenems, and 3.3% on monobactams; 65.9% of articles involved intravenous administration, 16.5% mixed administration routes, 12.1% oral administration, and 5.5% intramuscular administration. The majority of studies had a small sample size, often did not include detailed information on the study population and methods, and were fairly old. CL was, on average, decreased, while elimination half-life was prolonged in aged subjects compared with young subjects. Volume of distribution was generally similar between age groups. Most studies identified renal function as the most important contributor to altered drug CL. In only 30.8% of the articles, target attainment was studied, and in 35.7% of these articles, target attainment was found to be suboptimal. Dosing recommendations were incorporated in 87.9% of articles. CONCLUSION: Studies frequently fail to provide an evidence-based dosing recommendation for this diverse patient population. Model-based PK studies that address both physiological and disease-related changes are urgently needed. This review identified gaps of knowledge to set priorities for further research.

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.

Suboptimal Beta-Lactam Therapy in Critically Ill Children: Risk Factors and Outcome.

OBJECTIVES: In critically ill children, severely altered pharmacokinetics may result in subtherapeutic ß-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for ß-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome. DESIGN: Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012-2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis. SETTING: The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital. PATIENTS: One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure. CONCLUSIONS: Subtherapeutic ß-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.

Foxglove poisoning: diagnostic and therapeutic differences with medicinal digitalis glycosides overdose.

We report a case of a 19-year-old woman who ingested Digitalis purpurea leaves as a suicide attempt. She developed gastro-intestinal symptoms, loss of colour vision, cardiac conduction disturbances as well as an elevated serum potassium. Treatment was initiated in analogy to medicinal digoxin poisoning by means of digoxin-specific Fab-fragments with a good effect. However during the further course we faced difficulties of prolonged intestinal absorption and inability to estimate the ingested dose or half-life of the vegetal cardiac glycoside compounds. To prevent further absorption and interrupt enterohepatic recycling, multi-dose activated charcoal was administered. Because of a relapse of cardiac conduction disturbances and hyperkalemia, two supplementary doses of Fab-fragments were given, up to a total dose of nineteen vials (one vial containing 40 mg). The important diagnostic and therapeutic differences of vegetal digitalis intoxication as compared to medicinal intoxication and the applicability of existing guidelines on medicinal digitalis intoxication in the light of these differences will be discussed here.

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.

The Development of a Juvenile Porcine Augmented Renal Clearance Model Through Continuous Infusion of Lipopolysaccharides: An Exploratory Study.

Augmented renal clearance (ARC) as observed in the critically ill (pediatric) population can have a major impact on the pharmacokinetics and posology of renally excreted drugs. Although sepsis has been described as a major trigger in the development of ARC in human critically ill patients, mechanistic insights on ARC are currently lacking. An appropriate ARC animal model could contribute to reveal these underlying mechanisms. In this exploratory study, a state of ARC was induced in 8-week-old piglets. Conscious piglets were continuously infused over 36 h with lipopolysaccharides (LPS) from Escherichia coli (O111:B4) to induce sepsis and subsequently trigger ARC. To study the dose-dependent effect of LPS on the renal function, three different doses (0.75, 2.0, 5.0 µg/kg/h) were administered (two ♂ piglets/dose, one sham piglet), in combination with fluid administration (0.9% NaCl) at 6 ml/kg/h. Single boluses of renal markers, i.e., creatinine [40 mg/kg body weight (BW)], iohexol (64.7 mg/kg BW), and para-aminohippuric acid (PAH, 10 mg/kg BW) were administered intravenously to evaluate the effect of LPS on the renal function. Clinical parameters were monitored periodically. Blood sampling was performed to determine the effect on hematology, neutrophil gelatinase-associated lipocalin, and prostaglandin E2 plasma levels. All piglets that were continuously infused with LPS displayed an elevated body temperature, heart rhythm, and respiratory rate ~1-3 h after start of the infusion. After infusion, considerably higher total body clearances of iohexol, creatinine, and PAH were observed, independent of the administration of LPS and/or its dose. Since also the sham piglet, receiving no LPS, demonstrated a comparable increase in renal function, the contribution of fluid administration to the development of ARC should be further evaluated.

Vancomycin dosing and therapeutic drug monitoring practices: guidelines versus real-life.

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1-Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved.

Volumetric absorptive microsampling as alternative sampling technique for renal function assessment in the paediatric population using iohexol.

The glomerular filtration rate (GFR) is considered the best overall index for the renal function. Currently, one of the most promising exogenous markers for GFR assessment is iohexol. In this study, the suitability of volumetric absorptive microsampling (VAMS) as alternative for the conventional blood sampling and quantification of iohexol in paediatric plasma was assessed. Therefore, a new, fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed. Subsequently, the clinical suitability was evaluated in 20 paediatric patients by comparing plasma iohexol concentrations and associated GFR values obtained by the VAMS method with those obtained by conventional blood sampling and quantification of iohexol in plasma. The developed, simple and cost-effective LC-MS/MS-method fulfilled all pre-set validation acceptance criteria. Iohexol could be accurately quantified within a haematocrit range of 20-60% and long-term stability of iohexol in VAMS was demonstrated up to 245 days under different storage temperatures. Both iohexol plasma concentrations (r = 0.98, mean bias: -4.20%) and derived GFR values (r = 0.99; mean bias: 1.31%), obtained by a conventional plasma and the VAMS method, demonstrated good correlation and acceptable bias. The agreement between the two methods was especially good for GFR values higher than 60 mL/min/1.73 m2. Nevertheless, for GFR values <60 mL/min/1.73 m2 the accuracy compared to the plasma method was lower. However, small adjustments to the sampling protocol could probably solve this problem.

An observational study of trampoline injuries admitted to a Belgian University emergency department between 2011 and 2016.

BACKGROUND: Trampoline injuries are a cause for concern and data from different countries indicate that these are increasing. The aim of this study was to collect data in a Belgian University Hospital emergency department. METHODS: Medical files of patients admitted with a trampoline-related injury between 1st July 2011 and 30th June 2016 were retrospectively analyzed. RESULTS: One hundred and sixty patients, aged between 2 and 64 years old and predominantly males (57%), were admitted most frequently during the months March until September. An increase was observed during the years 2013-2014. Most injuries (76%) occurred during activity on the trampoline. Fractures occurred in 40% of the patients with the extremities most frequently involved. An X-ray examination and a CT scan was performed in 82 and 3% of the cases, respectively. Surgery was carried out in 12% of the patients. 9% of the patients had to be admitted to hospital. CONCLUSIONS: Trampoline injuries are increasingly observed in the emergency department. These injuries are important and further research on the circumstances and causes for the accidents is needed. Preventive measures, as proposed in the literature, should be considered.

Implementation of a protocol using ketamine-propofol ('ketofol') in a 1 to 4 ratio for procedural sedation in adults at a university hospital emergency department - report on safety and effectiveness.

Objectives: To test the feasibility of an evidence-based protocol for procedural sedation in adults at our emergency department, using a mixture of ketamine and propofol ('ketofol') in a 1 to 4 ratio. We hypothesize that the protocol is safe and effective and can facilitate procedural sedation.Methods: During 14 months, adults in need of procedural sedation at our university hospital emergency department were included in a prospective convenience sample study. Patients with important comorbidity were discussed with the anaesthesiology department for feasibility of sedation in the emergency department setting. Outcome measures were procedural success, respiratory and hemodynamic events, vomiting, agitation or hallucinations, recall and physician's satisfaction.Results: Sixty-one patients between 18 and 89 years were included. All but one procedure were successful. Six respiratory events were registered in 6 patients (9.8%). These consisted of airway obstruction alleviated by airway repositioning and without influence on vital signs except for one brief episode of desaturation. Neither hemodynamic events nor vomiting were reported. Five patients (8.2%) experienced pleasant hallucinations and one patient (1.6%) became agitated upon awakening but recovered rapidly without medication. Three patients (4.9%) had recall and physician satisfaction rate was 93.4%.Conclusion: A feasibility trial of an implemented protocol for ketofol procedural sedation in adults showed only minor respiratory events, a low incidence of agitation or hallucinations, minimal recall and a high success and physician satisfaction rate. Despite a non-consecutive and limited sample used, ketofol in a 1 to 4 ratio appears safe and effective for use in the emergency department.

Impact of perceived inappropiate cardiopulmonary resuscitation on emergency clinicians' intention to leave the job: Results from a cross-sectional survey in 288 centres across 24 countries.

INTRODUCTION: Cardiopulmonary resuscitation (CPR) in patients with a poor prognosis increases the risk of perception of inappropriate care leading to moral distress in clinicians. We evaluated whether perception of inappropriate CPR is associated with intention to leave the job among emergency clinicians. METHODS: A cross-sectional multi-centre survey was conducted in 24 countries. Factors associated with intention to leave the job were analysed by conditional logistic regression models. Results are expressed as odds ratios with 95% confidence intervals. RESULTS: Of 5099 surveyed emergency clinicians, 1836 (36.0%) were physicians, 1313 (25.7%) nurses, 1950 (38.2%) emergency medical technicians. Intention to leave the job was expressed by 1721 (33.8%) clinicians, 3403 (66.7%) often wondered about the appropriateness of a resuscitation attempt, 2955 (58.0%) reported moral distress caused by inappropriate CPR. After adjustment for other covariates, the risk of intention to leave the job was higher in clinicians often wondering about the appropriateness of a resuscitation attempt (1.43 [1.23-1.67]), experiencing associated moral distress (1.44 [1.24-1.66]) and who were between 30-44 years old (1.53 [1.21-1.92] compared to <30 years). The risk was lower when the clinician felt valued by the team (0.53 [0.42-0.66]), when the team leader acknowledged the efforts delivered by the team (0.61 [0.49-0.75]) and in teams that took time for debriefing (0.70 [0.60-0.80]). CONCLUSION: Resuscitation attempts perceived as inappropriate by clinicians, and the accompanying moral distress, were associated with an increased likelihood of intention to leave the job. Interprofessional collaboration, teamwork, and regular interdisciplinary debriefing were associated with a lower risk of intention to leave the job. ClinicalTrials.gov; No.: NCT02356029.

Hospital referrals of patients with acute poisoning by the Belgian Poison Centre: analysis of characteristics, associated factors, compliance and costs.

OBJECTIVE: Aims were (1) to assess the characteristics, associated factors and compliance of patients with acute poisoning advised by the Belgian Poison Centre (BPC) to go (conditionally) to the hospital, (2) to assess the compliance and potential health-economic impact. METHODS: Three types of referrals to the hospital of patients who called the BPC between 1 January and 30 June 2018 were analysed: referrals in case of deterioration in the patient's condition (Hosp-watchful-wait), referrals (Hosp-referral) or urgent referrals (Hosp-urgent-referral). Factors associated with type of recommendation were registered. A survey was conducted on a second dataset of patients who called the BPC between 1 March and 15 May 2019 and referred (conditionally) to the hospital. RESULTS: 5476 referrals were included: 72.4% accidental poisoning, 25.3% intentional self-harm, 1.2% substance abuse and 1.1% unclear intentionality. There were 2368 (43.2%) Hosp-watchful-wait cases, 2677 (48.9%) Hosp-referrals and 431 (7.9%) Hosp-urgent-referrals. In Hosp-watchful-wait cases, soaps and detergents were represented most (20.5%). In Hosp-referrals and Hosp-urgent-referrals, benzodiazepines (12.7% and 15.1%, respectively) predominated. Factors associated with hospitalisation type were number of symptoms, intentionality, type of agent(s) involved and advising antidotes. The survey showed that 7.8% of Hosp-watchful-wait patients went to the hospital versus 57.3% of Hosp-referrals and 59.6% of Hosp-urgent-referrals. The mean cost for Hosp-watchful-wait patients, Hosp-referrals and Hosp-urgent-referrals was estimated at €127, €767 and €796, respectively. CONCLUSION: Only a small proportion of patients followed the advice of the BPC to go (conditionally) to the hospital. A systematic follow-up of cases is warranted to examine the appropriateness of referrals and the compliance of patients.

Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward.

OBJECTIVES: Disulfiram is an adjunct in the treatment of alcohol use disorders, but case reports indicate that disulfiram ethanol reactions are not always recognized in the emergency department. Our first aim is to remind of this risk with two case reports of life-threatening reactions not immediately considered by the emergency physician. The second aim is to estimate the probability that a disulfiram reaction goes unrecognized with the use of a retrospective study of patients admitted to the emergency department. METHODS: Clinical files of patients admitted between October 1, 2010 and September 30, 2014 to the emergency department were retrospectively screened for the key words "ethanol use" and "disulfiram". Their diagnoses were then scored by a panel regarding the probability of an interaction. RESULTS: Seventy-nine patients were included, and a disulfiram-ethanol reaction was scored as either 'highly likely', 'likely' or 'possible' in 54.4% and as 'doubtful' or 'certainly not present' in 45.6% of the patients. The interrater agreement was 0.71 (95% CI: 0.64-0.79). The diagnosis was not considered or only after a delay in 44.2% of the patients with a 'possible' to 'highly likely' disulfiram interaction. One patient with a disulfiram overdose died and was considered as a 'possible' interaction. DISCUSSION AND CONCLUSIONS: A disulfiram ethanol interaction can be life threatening and failure to consider the diagnosis in the emergency department seems frequent. Prospective studies with documentation of the intake of disulfiram and evaluation of the value of acetaldehyde as a biomarker are needed to determine the precise incidence. Improving knowledge of disulfiram interactions and adequate history taking of disulfiram intake may improve the care for patients.

Conventional Pig as Animal Model for Human Renal Drug Excretion Processes: Unravelling the Porcine Renal Function by Use of a Cocktail of Exogenous Markers.

Over recent years, pigs have been promoted as potential animal model due to their anatomical and physiological similarities with humans. However, information about the contribution of distinct renal elimination processes [glomerular filtration rate (GFR), effective renal plasma flow (ERPF), tubular secretion, and reabsorption] in pigs is currently limited. Therefore, a cocktail of renal markers, consisting of iohexol (GFR), para-aminohippuric acid (ERPF and net tubular anion secretion), pindolol (net tubular cation secretion), and fluconazole (net tubular reabsorption) was administered intravenously to 7-week-old male conventional pigs. Plasma and urinary concentrations were determined using validated analytical methods. The clearance of iohexol (GFR) was 97.87 ± 16.05 ml/min/m² (mean ± SD). The ERPF, calculated as the renal clearance of PAH, was 226.77 ± 62.45 ml/min/m², whereas the net tubular secretion of PAH was 130.28 ± 52.62 ml/min/m². The net tubular secretion of R-pindolol and S-pindolol was 13.53 ± 12.97 and 18.01 ± 39.23 ml/min/m², respectively. The net tubular reabsorption of fluconazole was 78.32 ± 13.52 ml/min/m². Overall, this cocktail of renal markers was considered to be safe for use in pigs since no adverse effects were observed. Iohexol, PAH and fluconazole were considered suitable renal marker to assess the porcine renal function. Pindolol seems less appropriate due to the high degree of nonrenal clearance in pigs. The values of GFR, ERPF, and anion secretion are within the same range for both human and pig. Regarding the tubular reabsorption of fluconazole, slightly higher values were obtained for pigs. Nevertheless, these results indicate the conventional pig could be an appropriate animal model to study renal drug elimination processes in humans.

Dried blood microsamples: Suitable as an alternative matrix for the quantification of paracetamol-protein adducts?

Paracetamol (acetaminophen, APAP) is the most frequently used analgesic drug worldwide. However, patients in several specific populations can have an increased exposure to toxic APAP metabolites. Therefore, APAP-protein adducts have been proposed as an alternative marker for the assessment of APAP intoxications and as an effective tool to study and steer APAP treatment in patients with an increased risk of APAP-induced liver damage. These adducts have been determined in plasma or serum as a matrix. Blood microsampling allows the determination of a variety of analytes, including protein adducts, in a drop of blood, facilitating convenient follow-up of patients in a home-sampling context, as well as repeated sampling of pediatric patients. We therefore evaluated the use of blood-based volumetric microsamples for the quantification of APAP-protein adducts. Quantitative methods for the determination of APAP-protein adducts in dried blood and dried plasma volumetric absorptive microsamples were developed and validated. Also a preliminary evaluation of pediatric patient dried blood microsamples was conducted. Method validation encompassed the evaluation of selectivity, carry over, calibration model, accuracy and precision, matrix effect, recovery and the effect of the hematocrit on the recovery, dilution integrity, and stability. All pre-set acceptance criteria were met, except for stability. Spiking of blank blood with APAP revealed a concentration-dependent ex vivo formation of APAP-protein adducts, resulting in a response for the measurand APAP-Cys, with an apparent role for the red blood cell fraction. Analysis of authentic samples, following intake of APAP at therapeutic dosing, revealed much higher APAP-Cys concentrations in dried blood vs. dried plasma samples, making interpretation of the results in the context of published intervals difficult. In addition, in contrast to what was observed during method validation, the data obtained for the patient samples showed a high and unacceptable variation. We conclude that, for a combination of reasons, dried blood is not a suitable matrix for the quantification of APAP-protein adducts via the measurement of the APAP-Cys digestion product. The collection of plasma or serum, either in the form of a liquid sample or a dried microsample for this purpose is advised.