Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

2022 ◽  
Author(s):  
Seyedeh Sana Khezrnia ◽  
Bita Shahrami ◽  
Mohammad Reza Rouini ◽  
Atabak Najafi ◽  
Hamid Reza Sharifnia ◽  
...  
Keyword(s):  
Brain Injury ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Normal Population ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Uv Detector ◽  
Therapeutic Goals ◽  
The Impact

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

scholarly journals Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Eline W. Muilwijk ◽  
Dylan W. de Lange ◽  
Jeroen A. Schouten ◽  
Roeland E. Wasmann ◽  
Rob ter Heine ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Open Label ◽  
Time Curve ◽  
Icu Patients ◽  
Unbound Fraction ◽  
Multicenter Observational Study ◽  
The Impact

ABSTRACT Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.)

scholarly journals Individualization of Piperacillin Dosing for Critically Ill Patients: Dosing Software To Optimize Antimicrobial Therapy

2014 ◽  
Vol 58 (7) ◽  
pp. 4094-4102 ◽  
Author(s):  
T. W. Felton ◽  
J. A. Roberts ◽  
T. P. Lodise ◽  
M. Van Guilder ◽  
E. Boselli ◽  
...  
Keyword(s):  
Linear Regression ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Volume Of Distribution ◽  
Drug Clearance ◽  
Dose Optimization ◽  
Optimization Software ◽  
The Impact

ABSTRACTPiperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated anr2of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.

scholarly journals Extensive Therapeutic Drug Monitoring of Colistin in Critically Ill Patients Reveals Undetected Risks

2020 ◽  
Vol 8 (3) ◽  
pp. 415 ◽  
Author(s):  
Stefan Felix Ehrentraut ◽  
Stefan Muenster ◽  
Stefan Kreyer ◽  
Nils Ulrich Theuerkauf ◽  
Christian Bode ◽  
...  
Keyword(s):  
Renal Function ◽  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Plasma Levels ◽  
Therapeutic Drug ◽  
The Right ◽  
The Impact ◽  
Current Guidelines

(1) Background: With the rise of multi-/pan-drug resistant (MDR/PDR) pathogens, the less utilized antibiotic Colistin has made a comeback. Colistin fell out of favor due to its small therapeutic range and high potential for toxicity. Today, it is used again as a last resort substance in treating MDR/PDR pathogens. Although new guidelines with detailed recommendations for Colistin dosing are available, finding the right dose in critically ill patients with renal failure remains difficult. Here, we evaluate the efficiency of the current guidelines’ recommendations by using high resolution therapeutic drug monitoring of Colistin. (2) Methods: We analyzed plasma levels of Colistin and its prodrug colisthimethate sodium (CMS) in 779 samples, drawn from eight PDR-infected ICU patients, using a HPLC-MS/MS approach. The impact of renal function on proper Colistin target levels was assessed. (3) Results: CMS levels did not correlate with Colistin levels. Over-/Underdosing occurred regardless of renal function and mode of renal replacement therapy. Colistin elimination half-time appeared to be longer than previously reported. (4) Conclusion: Following dose recommendations from the most current guidelines does not necessarily lead to adequate Colistin plasma levels. Use of Colistin without therapeutic drug monitoring might be unsafe and guideline adherence does not warrant efficient target levels in critically ill patients.

scholarly journals Evaluation of Amikacin Pharmacokinetics in Critically Ill Patients with Intra-abdominal Sepsis

2019 ◽  
Vol 10 (1) ◽  
pp. 114-118
Author(s):  
Bita Shahrami ◽  
Farhad Najmeddin ◽  
Mohammad Reza Rouini ◽  
Atabak Najafi ◽  
Kourosh Sadeghi ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Half Life ◽  
Abdominal Sepsis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Significant Difference ◽  
Group 2 ◽  
Intraabdominal Sepsis ◽  
Group 1

Purpose: Although the current widespread use of amikacin is in intra-abdominal sepsis treatment, its pharmacokinetic changes in the present setting are not yet well known. This study was aimed to evaluate the amikacin pharmacokinetic profile in critically ill patients with intraabdominal sepsis compared to pneumosepsis. Methods: Adult septic patients received amikacin therapy were studied. Patients with intraabdominal sepsis were enrolled in group 1 (n=16), and patients with pneumosepsis were enrolled in group 2 (n=13). The amikacin serum concentrations were evaluated in the first, second, fourth and sixth hours after initiating 30-minute infusion. The pharmacokinetic parameters were calculated for each patient. Results: There was no significant difference in the volume of distribution between the two groups (0.33±0.08 vs. 0.28±0.10 L/kg, P=0.193). The amikacin clearance was significantly lower in group 1 compared to group 2 (58.5±21.7 vs. 83.9±37.0 mL/min, P=0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (P=0.206). The half-life was significantly longer in group 1 compared to group 2 (5.3±2.8 vs. 3.4±3.2 hours, P=0.015). Conclusion: Pathophysiologic changes following intra-abdominal sepsis can affect amikacin pharmacokinetics behavior. The clearance and half-life may change, but the alteration of the volume of distribution is not significantly different in comparison with pneumosepsis. Further studies are required to evaluate the pharmacokinetic variables of amikacin in critically ill patients with intra-abdominal sepsis.

scholarly journals A Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed Meninges

2020 ◽  
Vol 65 (1) ◽  
pp. e01998-20
Author(s):  
Nilesh Kumta ◽  
Jason A. Roberts ◽  
Jeffrey Lipman ◽  
Wai Tat Wong ◽  
Gavin M. Joynt ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Pharmacokinetic Data ◽  
Significant Heterogeneity ◽  
Related Factors ◽  
Meningeal Inflammation

ABSTRACTVentriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically appraise studies with reported antibiotic concentrations or pharmacokinetic data in cerebrospinal fluid of critically ill patients without meningeal inflammation. We systematically reviewed the literature to identify published reports and studies describing antibiotic concentrations, pharmacokinetics, and pharmacokinetics/pharmacodynamics in cerebrospinal fluid of critically ill patients with uninflamed meninges. Fifty-eight articles met the inclusion criteria. There was significant heterogeneity in methodologies and results. When available, antibiotic pharmacokinetic parameters displayed large intersubject variability. Intraventricular dosing achieved substantially higher antibiotic concentrations in cerebrospinal fluid than did intravenous doses. Few studies conducted a robust pharmacokinetic analysis and described relevant clinical pharmacokinetic/pharmacodynamic indices and exposure targets in cerebrospinal fluid. Robust and clinically relevant antibiotic pharmacokinetic data describing antibiotic disposition in cerebrospinal fluid are necessary. Such studies should use a standardized approach to accurately describe pharmacokinetic variability. These data should ideally be tied to clinical outcomes whereby therapeutic targets in the cerebrospinal fluid can be better defined. Altered dosing strategies, in conjunction with exploring the utility of therapeutic drug monitoring, can then be developed to optimize antibiotic exposure with the goal of improving outcomes in this difficult-to-treat patient group.

scholarly journals Achievement of Vancomycin Therapeutic Goals in Critically Ill Patients: Early Individualization May Be Beneficial

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Bita Shahrami ◽  
Farhad Najmeddin ◽  
Sarah Mousavi ◽  
Arezoo Ahmadi ◽  
Mohammad Reza Rouini ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Pharmacokinetic Parameters ◽  
Serum Concentrations ◽  
Therapeutic Goals ◽  
Dose Monitoring ◽  
Trough Serum ◽  
Group 2 ◽  
Group 1

Objective.The aim of our study was to assess and validate the effectiveness of early dose adjustment of vancomycin based on first dose monitoring in achieving target recommended goal in critically ill patients.Methods.Twenty critically ill patients with sepsis received loading dose of 25 mg/kg of vancomycin and then were randomly assigned to 2 groups. Group 1 received maximum empirical doses of vancomycin of 15 mg/kg every 8 hrs. In group 2, the doses were individualized based on serum concentrations of vancomycin. First dose nonsteady state sampling was used to calculate pharmacokinetic parameters of the patients within 24 hours.Results.Steady state trough serum concentrations were significantly higher in group 2 in comparison with group 1 (19.4 ± 4.4 mg/L versus 14.4 ± 4.3 mg/L) (P=0.03). Steady state AUCs were significantly higher in group 2 compared with group 1 (665.9 ± 136.5 mg·hr/L versus 490.7 ± 101.1 mg·hr/L) (P=0.008).Conclusions.With early individualized dosing regimen, significantly more patients achieved peak and trough steady state concentrations. In the context of pharmacokinetic/pharmacodynamic goal of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) ≥400 and also to obtain trough serum concentration of vancomycin of ≥15 mg/L, it is necessary to individualize doses of vancomycin in critically ill patients.

scholarly journals Case Report: Monitoring Vancomycin Concentrations and Pharmacokinetic Parameters in Continuous Veno-Venous Hemofiltration Patients to Guide Individualized Dosage Regimens: A Case Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jihui Chen ◽  
Xiaohui Huang ◽  
Zhiyan Lin ◽  
Chao Li ◽  
Haoshu Ding ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Dynamic Change ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Blood Concentrations ◽  
Dosage Regimens ◽  
Drug Concentrations

There are limited pharmacokinetic (PK) studies on vancomycin in patients treated with continuous renal replacement therapy (CRRT), and the results have been inconsistent. Because of individual differences, proposing a definite recommendation for the clinical regimen is not possible. Rapidly reaching target vancomycin concentrations will facilitate effective treatment for critically ill patients treated with CRRT. In this study, to understand the dynamic change in drug clearance rates in vivo, analyze the effect of PK changes on drug concentrations, and recommend loading and maintenance dosage regimens, we monitored the blood concentrations of vancomycin and calculated the area under the curve in two critically ill patients treated with vancomycin and continuous veno-venous hemofiltration (CVVH). On the basis of real-time therapeutic drug monitoring results and PK parameters, an individualized vancomycin regimen was developed for patients with CVVH. Good clinical efficacy was achieved, which provided support and reference for empirical vancomycin therapy in these patients.

scholarly journals Association between voriconazole exposure and Sequential Organ Failure Assessment (SOFA) score in critically ill patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260656
Author(s):  
Anne-Lise Bienvenu ◽  
Pierre Pradat ◽  
Alexandra Plesa ◽  
Vincent Leclerc ◽  
Vincent Piriou ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Critically Ill ◽  
Sofa Score ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Therapeutic Drug ◽  
Multicenter Cohort Study ◽  
Large Variability ◽  
Optimal Drug ◽  
The Impact

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.

scholarly journals Optimizing Antimicrobial Drug Dosing in Critically Ill Patients

2021 ◽  
Vol 9 (7) ◽  
pp. 1401
Author(s):  
Pedro Póvoa ◽  
Patrícia Moniz ◽  
João Gonçalves Pereira ◽  
Luís Coelho
Keyword(s):  
Critically Ill ◽  
Antimicrobial Therapy ◽  
Critically Ill Patients ◽  
Pathogen Resistance ◽  
Volume Of Distribution ◽  
Drug Clearance ◽  
Therapeutic Drug ◽  
Drug Dosing ◽  
Sepsis And Septic Shock ◽  
Drug Pharmacokinetics

A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.

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