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 Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan

2021 ◽  
Vol 12 ◽  
Author(s):  
Muhammad Muaaz Munir ◽  
Huma Rasheed ◽  
Muhammad Imran Khokhar ◽  
Rizwan Rasul Khan ◽  
Hafiz Asad Saeed ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Goodness Of Fit ◽  
Volume Of Distribution ◽  
Surgical Patients ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Concentration Data ◽  
Population Pharmacokinetic Modeling

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan.Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration–time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks.Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively.Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

scholarly journals AB0739 MULTISYSTEM INFLAMMATORY SYNDROME ASSOCIATED WITH SARS-COV-2 INFECTION AND E.COLI SEPSIS: THE POTENTIAL ROLE OF PROCALCITONINE AS A RAPID DIAGNOSTIC BIOMARKER TO DISTINGUISH TWO DIFFERENT PHASES OF SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1399.1-1399
Author(s):  
M. Gilio ◽  
S. B. Morella ◽  
F. Picaro ◽  
C. Acierno ◽  
D. Palazzo ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Critically Ill ◽  
Systemic Inflammatory Response ◽  
Critically Ill Children ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Markers Of Inflammation ◽  
Inflammatory Syndrome

Background:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology.Objectives:We report a case of multisystem inflammatory syndrome in children (MIS-C) in patient with SARS-CoV-2 infection and Enteropathogenic Escherichia coli (EPEC) sepsis due to acute enteritis, observed at end of December 2020 to a tertiary-care center (San Carlo Hospital), in Basilicata region (Italy).Methods:This healthy 12-year- old male patient was tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Clinical presentations was characterized by fever, abdominal pain, gastrointestinal complaints and evanescent rash. Laboratory values were remarkable for high levels of procalcitonin, C-reactive protein (CRP), D-dimers, B-type natriuretic peptide (BNP), and troponin. He also had low albumin levels. Autoantibodies tests were negative. Chest tomography showed ground-glass opacities in less than 25% of the lungs, small bilateral pleural effusion and increased cardiac area; abdominal tomography showed enlargement of the lymphnodes and ascites. Evaluation for other infectious etiologies showed molecular test positivity on fecal samples for EPEC E. coli. He received broad spectrum intravenous antibiotics (macrolids and quinolones and then carbapenems). On the seventh day the enteritis resolved and procalcitonin normalized, however he continued to have lymphopenia, thrombocytopenia, hypoalbuminemia, elevated levels of CRP, D-dimers, ferritin, troponin, and increased BNP. On the ninth day he was feverish again and developed severe cardiac and respiratory failure requiring advanced respiratory support and admission to the intensive care unit. He received IVIG (intravenous immunoglobulin at 2 g/Kg, glucocorticoids (Methylprednisolone 1mg/kg) and enoxaparin.Results:The patient was discharged asymptomatic at home after 28 days of hospital stay.Conclusion:We observed multisystem inflammatory syndrome in children (MIS-C) in a previously healthy patient with SARS-CoV-2 infection and E.coli sepsis, who became critically ill with multisystem involvement. In this case viral and bacterial infections could be considered as a double hit for the etiopathogenesis of MIS-C. The trend of procalcitonin was better than C-reactive protein for differentiating bacterial from non-bacterial phase of systemic inflammatory response syndrome (SIRS) in this critically ill child. Although the accuracy of both tests is moderate. Diagnostic accuracy could be enhanced by combining these tests with bedside clinical judgment.References:[1]Consiglio CR, Cotugno N, Sardh et al. The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19. Cell. 2020 Nov 12;183(4):968-981.e7. doi: 10.1016/j.cell.2020.09.016. Epub 2020 Sep 6. PMID: 32966765; PMCID: PMC7474869.[2]Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children (Basel). 2020 Jul 1;7(7):69. doi: 10.3390/children7070069. PMID: 32630212; PMCID: PMC7401880.[3]Simon L, Saint-Louis P, Amre DK, Lacroix J, Gauvin F. Procalcitonin and C-reactive protein as markers of bacterial infection in critically ill children at onset of systemic inflammatory response syndrome. Pediatr Crit Care Med. 2008 Jul;9(4):407-13. PMID: 18496408.Disclosure of Interests:None declared

Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment

2021 ◽  
Author(s):  
Sonya Tang Girdwood ◽  
Min Dong ◽  
Peter Tang ◽  
Erin Stoneman ◽  
Rhonda Jones ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Pediatric Intensive Care ◽  
Compartment Model ◽  
The United States ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling ◽  
Dosing Regimens

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 hours of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg every 12 hours vs. 24 hours) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg and the peripheral volume is 19.6 L/70kg. For both models, we found that allometric weight scaling, post-menstrual age, creatinine clearance and daily highest temperature had significant effects on clearance. Presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 μg/mL for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 hours is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the minimum inhibitory concentrations (4 μg/mL).

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