Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation

2003 ◽  
Vol 99 (2) ◽  
pp. 275-282 ◽  
Author(s):  
Hussain Mulla ◽  
Peter McCormack ◽  
Graham Lawson ◽  
Richard K. Firmin ◽  
David Robert Upton
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Standard Error ◽  
Half Life ◽  
Volume Of Distribution ◽  
Metabolic Ratio ◽  
Critically Ill Children ◽  
Pharmacokinetic Analysis ◽  
Parameter Estimates ◽  
Membrane Oxygenation ◽  
Plasma Half Life

Background Although the pharmacokinetics of midazolam in critically ill children has been described, there are no such reports in extracorporeal membrane oxygenation. Methods The pharmacokinetics of midazolam and 1-hydroxy midazolam after continuous infusion (50-250 microg. kg(-1). h(-1)) were determined in 20 neonates undergoing extracorporeal membrane oxygenation. Patients were randomized into two groups: group 1 (n = 10) received midazolam extracorporeally (into the circuit), and group 2 received drug via central or peripheral access. Blood samples for determination of plasma concentrations were taken at baseline, 2, 4, 6, 12, 18, and 24 h, then every 12 h. Population pharmacokinetic analysis and model building was conducted using WinNonMix (Pharsight Corporation, Mountain View, CA). The 1-hydroxy midazolam/midazolam metabolic ratio was determined as a surrogate marker of cytochrome P450 3A activity. Results The parameter estimates (n = 19) were based on a one-compartment model with time-dependent change in volume of distribution. Volume (mean +/- standard error) expanded monoexponentially from the onset of extracorporeal membrane oxygenation to a maximum value, 0.8 l +/- 0.5 and 4.1 +/- 0.5 l/kg, respectively. Consequently, plasma half-life was substantially prolonged (median [range]) from onset to steady-state: 6.8 (2.2-39.8) and 33.3 (7.4-178) h, respectively. Total body clearance was determined as (mean +/- standard error) 1.4 +/- 0.15 ml. kg-1. min-1. The median metabolic ratio was 0.17 (0.03-0.9). No significant differences were observed between the two groups with respect to parameter estimates. Simulations of plasma concentration profiles revealed excess levels at conventional doses. Conclusions These results reveal significantly increased volume of distribution and plasma half-life in neonates receiving extracorporeal membrane oxygenation. Altered kinetics may reflect sequestration of midazolam by components of the extracorporeal membrane oxygenation circuit.

Procainamide pharmacokinetics during extracorporeal membrane oxygenation

Perfusion ◽  
2021 ◽  
pp. 026765912110506
Author(s):  
Nicholas J Vollmer ◽  
Erica D Wittwer ◽  
Andrew N Rosenbaum ◽  
Patrick M Wieruszewski
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Elevated Serum ◽  
Stable Condition ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Slow Acetylator ◽  
Membrane Oxygenation ◽  
Serum And Urine

Procainamide is a useful agent for management of ventricular arrhythmia, however its disposition and appropriate dosing during extracorporeal membrane oxygenation (ECMO) is unknown. We report experience with continuous procainamide infusion in a critically ill adult requiring venoarterial ECMO for incessant ventricular tachycardia. Pharmacokinetic analysis of procainamide and its metabolite, N-acetylprocainamide (NAPA), was performed using serum and urine specimens. Kidney function was preserved, and sequencing of the N-acetyltransferase 2 gene revealed the patient was a phenotypic slow acetylator. Procainamide volume of distribution and half-life were calculated and found to be similar to healthy individuals. However, despite elevated serum procainamide concentrations, NAPA concentrations remained far lower in the serum and urine. The magnitude of procainamide and NAPA discordance suggested alternative contributors to the deranged pharmacokinetic profile, and we hypothesized NAPA sequestration by the ECMO circuit. Ultimately, the patient received orthotopic cardiac transplantation and was discharged home in stable condition. Procainamide should be used cautiously during ECMO, with close therapeutic drug monitoring of serum procainamide and NAPA concentrations. The achievement of therapeutic NAPA concentrations while maintaining safe serum procainamide concentrations during ECMO support may be challenging.

Acetaminophen Developmental Pharmacokinetics in Premature Neonates and Infants

2002 ◽  
Vol 96 (6) ◽  
pp. 1336-1345 ◽  
Author(s):  
Brian J. Anderson ◽  
Richard A. van Lingen ◽  
Tom G. Hansen ◽  
Yuan-Chi Lin ◽  
Nicholas H. G. Holford
Keyword(s):  
Half Life ◽  
Lag Time ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Nonlinear Mixed Effects Models ◽  
Premature Neonates ◽  
First Order ◽  
Neonates And Infants

Background The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens. Methods A population pharmacokinetic analysis of acetaminophen time-concentration profiles in 283 children (124 aged < or = 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was 1 day (range, birth to 6 months), median postconception age was 40 weeks (range, 28-64 weeks), and median weight was 3.1 kg (range, 1.2-9.0 kg). Results Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 l (20%); clearance, 12.5 l/h (44%); standardized to a 70-kg person using allometric "1/4 power" models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 l x h(-1) x 70 kg(-1)) with a maturation half-life of 11.3 weeks to reach 10.8 l x h(-1) x 70 kg(-1) by 60 weeks. The absorption half-life for the oral elixir preparation was 0.21 h (120%) with a lag time of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66. Conclusions A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg x kg(-1) x d(-1) in premature neonates at 30 weeks' postconception, 45 mg x kg(-1) x d(-1) at 34 weeks' gestation, 60 mg x kg(-1) x d(-1) at term, and 90 mg x kg(-1) x d(-1) at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg. kg-1. d-1 in premature neonates at 30 weeks' gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg x kg(-1) x d(-1) at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2-3 days.

scholarly journals Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.

1996 ◽  
Vol 40 (5) ◽  
pp. 1139-1142 ◽  
Author(s):  
R D Amaker ◽  
J T DiPiro ◽  
J Bhatia
Keyword(s):  
Renal Impairment ◽  
Extracorporeal Membrane Oxygenation ◽  
Half Life ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Published Data ◽  
Term Infants ◽  
Circulating Blood Volume ◽  
Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a widely used therapy for neonates with respiratory failure. Because of sepsis, many of these infants require antibiotics like vancomycin during ECMO treatment. ECMO transiently alters renal function and increases the circulating blood volume by 75%. Initial vancomycin pharmacokinetics were determined in 12 infants undergoing ECMO to determine an adequate drug administration regimen. Vancomycin dosage was based on current recommendations for weight and gestational age. Pharmacokinetic parameters were determined by fitting the data to a two compartment model. This study yielded a mean steady-state volume of distribution of 1.1 +/- 0.5 (range, 0.6 to 2.1) liters/kg and a mean vancomycin clearance of 0.78 +/- 0.19 (range, 0.49 to 1.07) ml/min/kg. The mean vancomycin half-life was 16.9 +/- 9.5 (range, 8.8 to 42.9) h. Nomogram-calculated creatinine clearance was a significant predictor of vancomycin terminal rate constant and clearance. These data suggest alterations in the pharmacokinetics of vancomycin in infants on ECMO. With the goal of achieving vancomycin concentrations in serum above the MIC for the offending pathogen while using the least amount of the drug necessary, new administration guidelines for term infants without renal impairment undergoing ECMO should be 20 mg of vancomycin per kg at an interval of 24 h. With significant renal impairment, the interval should be extended on the basis of concentrations in serum. In comparison with previously published data, the neonates undergoing ECMO in our study demonstrated a much larger volume of distribution, a lower clearance, and consequently a longer vancomycin half-life.

Treatment of hyperammonemia using in-line renal replacement and hyperosmolar therapies within an extracorporeal membrane oxygenation circuit

Perfusion ◽  
2021 ◽  
pp. 026765912110359
Author(s):  
Alison Grazioli ◽  
Jamie E Podell ◽  
Aldo Iacono ◽  
Alexander Sasha Krupnik ◽  
Ronson J Madathil ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Cerebral Edema ◽  
Urea Cycle ◽  
Rare Complication ◽  
Volume Of Distribution ◽  
Intermittent Hemodialysis ◽  
Treatment Goals ◽  
Continuous Venovenous Hemofiltration ◽  
Small Molecular Weight ◽  
Membrane Oxygenation

After orthotopic lung transplantation, hyperammonemia can be a rare complication secondary to infection by organisms that produce urease or inhibit the urea cycle. This can cause neurotoxicity, cerebral edema, and seizures. Ammonia is unique in that it has a large volume of distribution. However, it is also readily dialyzable given its small molecular weight. As such, removal of ammonia requires renal replacement modalities that can both rapidly remove ammonia from the plasma space and allow for continuous removal to prevent rebound accumulation from intracellular stores. Prevention of iatrogenic osmotic lowering in this setting is required to prevent worsening of cerebral edema. Herein, we describe use of sequential in-line renal replacement therapy using both intermittent hemodialysis and continuous venovenous hemofiltration within an extracorporeal membrane oxygenation circuit in conjunction with higher sodium dialysate and 7.5% hypertonic saline to achieve these treatment goals.

Comparative metabolic clearance rate, volume of distribution and plasma half-life of human β-lipotropin and acth

Life Sciences ◽  
1978 ◽  
Vol 23 (23) ◽  
pp. 2323-2330 ◽  
Author(s):  
Anthony S. Liotta ◽  
Choh Hao Li ◽  
George C. Schussler ◽  
Dorothy T. Krieger
Keyword(s):  
Clearance Rate ◽  
Half Life ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Plasma Half Life

scholarly journals Pharmacokinetics of Once Daily Intraperitoneal Cefazolin in Continuous Ambulatory Peritoneal Dialysis Patients

2000 ◽  
Vol 11 (6) ◽  
pp. 1117-1121
Author(s):  
CHAI LUAN LOW ◽  
KAMANI GOPALAKRISHNA ◽  
WAI CHOONG LYE
Keyword(s):  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Half Life ◽  
Volume Of Distribution ◽  
Hplc Method ◽  
Dialysis Patients ◽  
Suitable Alternative ◽  
Once Daily ◽  
Cefazolin Sodium ◽  
Plasma Half Life

Abstract. This study determined the pharmacokinetic characteristics of once daily intraperitoneal (IP) cefazolin in continuous ambulatory peritoneal dialysis (CAPD) patients. Each of the 10 volunteer CAPD patients without active peritonitis received a single IP dose of 1 g of cefazolin sodium for a 6-h dwell. All patients underwent a fixed CAPD regimen comprising a first 6-h dwell followed by two 3-h dwells and a final 12-h overnight dwell. Blood and dialysate samples were collected at 0, 0.5, 1, 2, 3, 6 (end of first dwell), and 24 h after the administration of IP cefazolin. Any urine produced was collected over the 24-h study period. A validated HPLC method was used to analyze cefazolin in plasma, dialysate, and urine. The bioavailability was found to be 77.9 ± 3.1%, volume of distribution 0.20 ± 0.05 L/kg, and plasma half-life 39.9 ± 25.4 h. Mean total, renal, and peritoneal clearances were 4.5 ± 2.3, 1.4 ± 1.1, and 3.5 ± 1.8 ml/min, respectively. Mean plasma and dialysate concentrations at 24 h were 42.8 ± 14.3 and 31.8 ± 11.7 mcg/ml, respectively, well above the minimum inhibitory concentrations (MIC) of susceptible organisms. A once daily IP cefazolin dose of 500 mg/L gave desirable pharmacokinetic attributes for use as a suitable alternative to vancomycin for empiric treatment of CAPD-associated peritonitis.

Vancomycin volume of distribution estimation in adults with class III obesity

2019 ◽  
Author(s):  
Ryan D Dunn ◽  
Ryan L Crass ◽  
Joseph Hong ◽  
Manjunath P Pai ◽  
Lynne C Krop
Keyword(s):  
Body Weight ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Patient Specific ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Class Iii ◽  
Class Iii Obesity ◽  
Total Body

Abstract Purpose To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. Methods A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. Results Of 241 patients included in the study sample, 159 (66.0%) had a BMI of 40.0–49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0–49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) or use of 0.52 L/kg by total body weight yielded similar bias and error in this population. Conclusion Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate AUC, and improve the precision of vancomycin dosing in this patient population.

scholarly journals Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients

2017 ◽  
Vol 22 (5) ◽  
pp. 352-357 ◽  
Author(s):  
Nicholas O. Dillman ◽  
Mindl M. Messinger ◽  
Kimberly N. Dinh ◽  
Jennifer L. Placencia ◽  
Brady S. Moffett ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Extracorporeal Membrane Oxygenation ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Volume Of Distribution ◽  
Serum Concentrations ◽  
Inclusion Criteria ◽  
Lower Serum ◽  
Membrane Oxygenation ◽  
Dosing Strategies

OBJECTIVES Patients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations. METHODS A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. RESULTS Fourteen patients met inclusion criteria. The fos-PHT neonatal (20.1 vs 11.3 mg/kg/day, p = 0.044), PB composite (33.9 vs 21.6 mg/kg/day, p = 0.012), and PB neonatal (40.3 vs 20 mg/kg/day, p = 0.04) had larger 24-hour cumulative doses compared with non-ECMO patients. Lower serum concentrations were observed in the PB composite ECMO group (19.1 vs 35.4 mg/L, p &lt; 0.001) and the PB neonatal ECMO group (20.5 vs 27.8 mg/L, p = 0.01) compared with non-ECMO patients. CONCLUSION Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

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