scholarly journals O33 Towards personalised weaning of sedatives and analgesics using mechanism-based modelling of iatrogenic withdrawal in critically ill children

2019 ◽  
Vol 104 (6) ◽  
pp. e14.3-e15
Author(s):  
S Goulooze ◽  
E Krekels ◽  
M van Dijk ◽  
T Hankemeier ◽  
D Tibboel ◽  
...  
Keyword(s):  
Critically Ill ◽  
Rating Scale ◽  
Numerical Rating Scale ◽  
Statistical Significance ◽  
Prolonged Treatment ◽  
Morphine Dependence ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Over Time

BackgroundProlonged treatment with analgesics and sedatives can result in iatrogenic withdrawal syndrome (IWS) in children being weaned from these drugs.1Personalized weaning strategies might lower the incidence of IWS, but this requires a quantitative understanding of withdrawal over time in individual patients.MethodsData from 81 children (aged 1 month to 17 years) collected during an observational clinical study on IWS2 were used, including a total of 1782 withdrawal assessments performed by PICU nurses, on a numerical rating scale (NRSwithdrawal) from 0 (no withdrawal) to 10 (worst withdrawal possible). Population pharmacokinetic models from literature were used to generate concentration-time profiles in each patient of all key analgesics and sedatives: morphine, fentanyl, methadone, midazolam, lorazepam, propofol, esketamine and clonidine. A mechanism-based withdrawal model was developed using NONMEM 7.3 to quantify IWS over time. The final model was used to perform simulations in which different weaning strategies were compared.ResultsA novel mechanism-based withdrawal model structure was developed with a hypothetical compartment, which equilibrates with the central pharmacokinetic compartment, and which characterizes the development and disappearance of drug dependence over time. With this model and available data, withdrawal dynamics could be established with statistical significance for fentanyl (p< 10-6), morphine (p=0.043) and esketamine (p=0.002), and not for any of the other drugs. Compared with fentanyl, development and disappearance of esketamine and morphine dependence is slower.ConclusionsGiven the patient‘s use of fentanyl, morphine and esketamine, the developed model can dynamically predict IWS from these substances under different weaning strategies. The results show that the optimal strategy for weaning of drug dependent children depends on both the type of drug and the drug levels prior to weaning. In this study, there was insufficient information to characterise midazolam withdrawal dynamics, potentially because of slow midazolam weaning with insufficiently high NRSwithdrawal scores.ReferencesBest KM, Boullata JI, Curley MAQ. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: A Systematic Review and Conceptual Model. Pediatr Crit Care Med ( 2015) 16(2): 175–183.Ista E, de Hoog M, Tibboel D, Duivenvoorden HJ, van Dijk M. Psychometric evaluation of the sophia observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med ( 2013).14(8): 761–769.Disclosure(s)Nothing to disclose

scholarly journals P103 Target attainment of amikacin therapy in critically ill children

2019 ◽  
Vol 104 (6) ◽  
pp. e60.2-e61
Author(s):  
J Verbruggen ◽  
K Jakipbayeva ◽  
T Van Der Heggen ◽  
E Dhont ◽  
L Dhondt ◽  
...  
Keyword(s):  
Steady State ◽  
Pilot Study ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Clinical Pharmacokinetics

BackgroundResearch regarding the optimal amikacin (AMI) dosing regimen in critically ill children is scarce.1 Optimal AMI efficacy has been observed with plasma peak over minimal inhibitory concentration of the suspected pathogen (peak/MIC) ratios of 8 to 10. Plasma trough levels (Cmin) >5mcg/ml are related to its toxicity.The objectives of this pilot study were to: (1) evaluate target attainment rate and occurrence of supratherapeutic concentrations in early and assumed steady-state dose conditions, and (2) investigate the correlation between AMI clearance and estimated glomerular filtration (eGFR).MethodsChildren admitted to the ICU receiving intravenous AMI (20 mg/kg once daily) were included. Serial blood samples were obtained from early (1st/2nd) and assumed steady-state (SS) doses. The evaluated target peak concentration range was 54–64 mcg/ml, assuming a Pseudomonas aeruginosa infection with Eucast MIC breakpoint of 8 mg/L, and a Cmin threshold of 5 mcg/L. eGFR was estimated using the modified Schwartz formula. AMI clearance was calculated using noncompartmental PK analysis. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (r).ResultsTwenty-one patients (median age1,5 years; range:0,5 months-14 year, median eGFR 162 ml/min/1,73m2 (range:107–475 ml/min/1,73m2) were included. In early dose conditions, 69% of patients had therapeutic peak concentrations (median: 60 mcg/ml; range:26–73 mcg/ml). In SS conditions, 60% of patients had therapeutic peak concentrations (median: 59 mcg/ml; range:35–83 mcg/ml). Only one supratherapeutic Cmin was observed. AMI clearance (median 0.08L/h/kg; range: 0.05–0.91 L/h/kg) was comparable to what has been previously reported but showed no correlation with eGFR (r=0.1; p=0,66) [1].ConclusionThis pilot study suggest that the current AMI dosing regimen may lead to subtherapeutic concentrations in patients infected with less susceptible pathogens. Supratherapeutic Cmin were far less of a concern. Dose adjustments of renally cleared drugs based on eGFR may not be reliable in this patient population.ReferencesIllamola SM, Sherwin CM, van Hasselt JGC. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive review of Population Pharmacokinetic Analysis. Clin Pharmacokinet ( 2018) 57:1217.Disclosure(s)Nothing to disclose

The Bacterial Populations of the Gut, Mouth, and Skin are Unstable Over Time in Critically Ill Children

2014 ◽  
Vol 186 (2) ◽  
pp. 590-591
Author(s):  
R. Brower-Sinning ◽  
M. Shi ◽  
B. Firek ◽  
B. Long ◽  
T. Pasek ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Children ◽  
Bacterial Populations ◽  
Over Time

Nebulized morphine for analgesia in an emergency setting

2018 ◽  
Vol 5 (1) ◽  
pp. 23 ◽  
Author(s):  
Vincent Bounes, MD ◽  
Jean Louis Ducassé, MD ◽  
Annie Momo Bona, MD ◽  
Florent Battefort, MD ◽  
Charles-Henri Houze-Cerfon, MD ◽  
...  
Keyword(s):  
Pain Relief ◽  
Acute Pain ◽  
Rating Scale ◽  
Numerical Rating Scale ◽  
Statistical Significance ◽  
A Priori ◽  
Primary Outcome Measure ◽  
Point Estimate ◽  
Emergency Setting ◽  
Significant Difference

Objective: To evaluate the efficacy and safety of inhaled morphine delivered in patients experiencing severe acute pain in an emergency setting.Patients and Methods: Patients were eligible for inclusion if they were aged 18 years or older, with a severe acute pain defined by a numerical rating scale (NRS) score of 60/100 or higher. The intervention involved administering a single dose of 0.2 mg/kg morphine nebulized using a Misty-Neb nebulizer system. NRSs were recorded and were repeated at 1, 3, 5, and 10 minute after the end of inhalation (T10). The protocol-defined primary outcome measure was pain relief (defined by an NRS score of 30/100 or lower) at T10. Secondary outcomes included differences between pain scores at baseline and at T10 and incidence of adverse events.Results: A total of 28 patients were included in this study. No patient experienced pain relief 10 minutes after the end of inhalation, and no adverse effects were recorded. Respective initial and final median NRS scores were 80 (70-90) and 70 (60-80), p < 0.0001. Despite achieving statistical significance, the value of this point estimate is less than the 14 NRS difference that was defined a priori as representing a minimum clinically significant difference in pain severity.Conclusion: 0.2 mg/kg nebulized morphine is not effective in managing acute pain in an emergency setting. In spite of the potential advantages of the pulmonary route of administration, opioids should be intravenous prescribed at short fixed intervals to control severe acute pain in an emergency setting.

ORGAN FAILURE AND C-REACTIVE PROTEIN BOTH AFFECT MIDAZOLAM CLEARANCE IN CRITICALLY ILL CHILDREN: A POPULATION PK MODEL

2015 ◽  
Vol 101 (1) ◽  
pp. e1.8-e1
Author(s):  
Nienke J Vet ◽  
Janneke M Brussee ◽  
Matthijs de Hoog ◽  
Miriam G Mooij ◽  
Carin WM Verlaat ◽  
...  
Keyword(s):  
Body Weight ◽  
Organ Failure ◽  
Critically Ill ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
C Reactive Protein ◽  
Population Pharmacokinetic Modeling ◽  
Reactive Protein ◽  
Organ Failures

ObjectivesTo study the effect of organ failure and inflammation on midazolam clearance in critically ill children, using population pharmacokinetic modeling.MethodsA total of 83 critically ill children (median age 5 months (range 1 day-17 years), n=523 samples) receiving intravenous midazolam for continuous sedation during mechanical ventilation were included. Disease severity was described using the validated and clinically used scores PELOD, PIM2 and PRISM II. Cytokines (IL-1, IL-2, IL-6, TNF-a) and C-reactive protein (CRP) were used as markers for inflammation. A population pharmacokinetic model for midazolam was developed using NONMEM 7.3. Body weight, age, severity of organ failure and inflammatory markers were considered as potential covariates.ResultsIn a two-compartmental PK model, body weight was found as most significant covariate for clearance and volume of distribution. Moreover, both severity of organ failure (PELOD) and inflammation (IL6 and CRP) were significant determinants of clearance (p<0.01), and either of these factors improved the model significantly. With increasing number of organ failures, midazolam clearance significantly reduced. CRP was linearly correlated with clearance (slope −0.095), with higher CRP levels resulting in lower clearances. Either one of the covariates could explain part of the variability in clearance.ConclusionFor midazolam clearance, apart from body weight, we found organ failure reflected by the PELOD score, and inflammation reflected by IL6 and CRP, as significant covariates. Most likely this effect is due to reduced activity of CYP3A in critically ill mechanically ventilated children. Both CRP concentration and organ failure should be considered when dosing midazolam and potentially other CYP3A substrates in critically ill children.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

2015 ◽  
Vol 60 (1) ◽  
pp. 522-531 ◽  
Author(s):  
Kristen Nichols ◽  
Eun Kyoung Chung ◽  
Chad A. Knoderer ◽  
Lauren E. Buenger ◽  
Daniel P. Healy ◽  
...  
Keyword(s):  
Steady State ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Study Objective ◽  
Population Pharmacokinetics And Pharmacodynamics ◽  
Extended Infusion

ABSTRACTThe study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

scholarly journals Antibiotics in critically ill children—a narrative review on different aspects of a rational approach

2021 ◽  
Author(s):  
Nora Bruns ◽  
Christian Dohna-Schwake
Keyword(s):  
Antibiotic Therapy ◽  
Critically Ill ◽  
Antibiotic Treatment ◽  
Antibiotic Stewardship ◽  
Narrative Review ◽  
Rational Approach ◽  
Critically Ill Children ◽  
Resistant Bacteria ◽  
Therapeutic Drug ◽  
List Type

Abstract Especially critically ill children are exposed to antibiotic overtreatment, mainly caused by the fear of missing out a severe bacterial infection. Potential adverse effects and selection of multi-drug resistant bacteria play minor roles in decision making. This narrative review first describes harm from antibiotics and second focuses on different aspects that could help to reduce antibiotic overtreatment without harming the patient: harm from antibiotic treatment, diagnostic approaches, role of biomarkers, timing of antibiotic therapy, empiric therapy, targeted therapy, and therapeutic drug monitoring. Wherever possible, we linked the described evidence to the current Surviving Sepsis Campaign guidelines. Antibiotic stewardship programs should help guiding antibiotic therapy for critically ill children. Impact Critically ill children can be harmed by inadequate or overuse of antibiotics. Hemodynamically unstable children with a suspicion of infection should be immediately treated with broad-spectrum antibiotics. In contrast, in hemodynamically stable children with sepsis and organ dysfunction, a time frame of 3 h for proper diagnostics may be adequate before starting antibiotics if necessary. Less and more targeted antibiotic treatment can be achieved via antibiotic stewardship programs.

scholarly journals Bayesian forecasting for intravenous tobramycin dosing in adults with Cystic Fibrosis using one versus two serum concentrations in a dosing interval

2021 ◽  
Author(s):  
Philip G. Drennan ◽  
Yann Thoma ◽  
Lucinda Barry ◽  
Johan Matthey ◽  
Sheila Sivam ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Sampling Strategy ◽  
Prolonged Treatment ◽  
Accurate Estimation ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Bayesian Forecasting ◽  
Concentration Data ◽  
Dosing Interval ◽  
Post Infusion

AbstractBackgroundIntravenous tobramycin requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of Cystic Fibrosis (CF). The 24 hour area under the concentration time curve (AUC24) is widely used to guide dosing, however there remains variability in practice around methods for its estimation.ObjectivesTo determine the potential for a sparse sampling strategy using a single post-infusion tobramycin concentration and Bayesian forecasting, to assess the AUC24 in routine practice.MethodsAdults with CF receiving once daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) following end of infusion as routine monitoring. We estimated AUC24 exposures using Tucuxi, a Bayesian forecasting application incorporating a validated population pharmacokinetic model. We performed simulations to estimate AUC24 using the full dataset using c1 and c2, compared to estimates using depleted datasets (c1 or c2 only), with and without concentration data from earlier in the course. We assessed agreement between each simulation condition and the reference graphically, and numerically using median difference (Δ) AUC24, and (relative) root mean square error (rRMSE) as measures of bias and accuracy respectively.Results55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ΔAUC24 <2 mg.h.l-1 and rRMSE of <15% for sequential c1 and c2 conditions.ConclusionsBayesian forecasting, using single post-infusion concentrations taken 2-6 hours following tobramycin administration can adequately estimate true exposure in this patient group and are suitable for routine TDM practice.Key Points-In stable adult patients with Cystic fibrosis without significant renal impairment, Bayesian forecasting allows accurate estimation of tobramycin AUC24 using a single blood sample taken 2-6 hours post-infusion with acceptable accuracy, especially when including prior measured concentrations.-A single sample approach with Bayesian forecasting is logistically less complicated than a two-sample approach, and could facilitate best-practice TDM in the outpatient setting.-A more intensive sampling strategy with Bayesian forecasting using two tobramycin concentrations in a dosing interval should be considered in unstable patients, or where observed concentrations deviate significantly from model predictions.

scholarly journals Longitudinal clusters of pain and stiffness in polymyalgia rheumatica: 2-year results from the PMR Cohort Study

Rheumatology ◽  
2019 ◽  
Vol 59 (8) ◽  
pp. 1906-1915
Author(s):  
Sara Muller ◽  
Rebecca Whittle ◽  
Samantha L Hider ◽  
John Belcher ◽  
Toby Helliwell ◽  
...  
Keyword(s):  
Latent Class ◽  
Rating Scale ◽  
Numerical Rating Scale ◽  
Postal Questionnaire ◽  
The Other ◽  
Future Research ◽  
Partial Recovery ◽  
Numerical Rating ◽  
Sustained Recovery ◽  
Over Time

Abstract Objectives To investigate potential subgroups of primary care–diagnosed patients with PMR based on self-reported pain and stiffness severity over time. Methods A total of 652 people with an incident PMR diagnosis were recruited from English general practices and completed a baseline postal questionnaire. They were followed up with a further six questionnaires over a 2 year period. A total of 446 people completed the 2 year follow-up. Pain and stiffness were reported on a 0–10 numerical rating scale. Latent class growth analysis was used to estimate the joint trajectories of pain and stiffness over time. A combination of statistical and clinical considerations was used to choose the number of clusters. Characteristics of the classes were described. Results Five clusters were identified. One cluster represented the profile of ‘classical’ PMR symptoms and one represented sustained symptoms that may not be PMR. The other three clusters displayed a partial recovery, a recovery followed by worsening and a slow, but sustained recovery. Those displaying classical PMR symptoms were in better overall health at diagnosis than the other groups. Conclusion PMR is a heterogeneous condition, with a number of phenotypes. The spectrum of presentation, as well as varying responses to treatment, may be related to underlying health status at diagnosis. Future research should seek to stratify patients at diagnosis to identify those likely to have a poor recovery and in need of an alternative treatment pathway. Clinicians should be aware of the different experiences of patients and monitor symptoms closely, even where there is initial improvement.

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