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Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients.

ABSTRACT: Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 ?g/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-? of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 ?g/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.ClinicalTrials.gov: NCT00747721.

SUBMITTER: Iirola T

PROVIDER: S-EPMC3334808 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients.

Iirola Timo T Aantaa Riku R Laitio Ruut R Kentala Erkki E Lahtinen Maria M Wighton Andrew A Garratt Chris C Ahtola-Sätilä Tuula T Olkkola Klaus T KT

Critical care (London, England) 20111026 5

<h4>Introduction</h4>Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.<h4>Methods</h4>Thirteen intensive care ...[more]

PMID: 22030215

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Project description:BackgroundIn critically ill patients, the use of high tigecycline dosages (HD TGC) (200 mg/day) has been recently increasing but few pharmacokinetic/pharmacodynamic (PK/PD) data are available. We designed a prospective observational study to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of HD TGC in a cohort of critically ill patients with severe infections.ResultsThis was a single centre, prospective, observational study that was conducted in the 20-bed mixed ICU of a 1500-bed teaching hospital in Rome, Italy. In all patients admitted to the ICU between 2015 and 2018, who received TGC (200 mg loading dose, then 100 mg q12) for the treatment of documented infections, serial blood samples were collected to measure steady-state TGC concentrations. Moreover, epithelial lining fluid (ELF) concentrations were determined in patients with nosocomial pneumonia. Amongst the 32 non-obese patients included, 11 had a treatment failure, whilst the other 21 subjects successfully eradicated the infection. There were no between-group differences in terms of demographic aspects and main comorbidities. In nosocomial pneumonia, for a target AUC0-24/MIC of 4.5, 75% of the patients would be successfully treated in presence of 0.5 mcg/mL MIC value and all the patients obtained the PK target with MIC ≤ 0.12 mcg/mL. In intra-abdominal infections (IAI), for a target AUC0-24/MIC of 6.96, at least 50% of the patients would be adequately treated against bacteria with MIC ≤ 0.5 mcg/mL. Finally, in skin and soft-tissue infections (SSTI), for a target AUC0-24/MIC of 17.9 only 25% of the patients obtained the PK target at MIC values of 0.5 mcg/mL and less than 10% were adequately treated against germs with MIC value ≥ 1 mcg/mL. HD TGC showed a relevant pulmonary penetration with a median and IQR ELF/plasma ratio (%) of 152.9 [73.5-386.8].ConclusionsThe use of HD TGC is associated with satisfactory plasmatic and pulmonary concentrations for the treatment of severe infections due to fully susceptible bacteria (MIC < 0.5 mcg/mL). Even higher dosages and combination strategies may be suggested in presence of difficult to treat pathogens, especially in case of SSTI and IAI.

Project description:Background and objectivesInfection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of β-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT.Design, setting, participants, & measurementsWe conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 μg/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate.ResultsSixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion.ConclusionsExtended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

Project description:BackgroundMeropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy.MethodsTwenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated.ResultsEleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05).ConclusionsThese findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.

Project description:In critically ill patients with neurologic disease, pupil examination abnormalities can signify evolving intracranial pathology. Analgesic and sedative medications (analgosedatives) target pupillary pathways, but it remains unknown how analgosedatives alter pupil findings in the clinical care setting. We assessed dexmedetomidine and other analgosedative associations with pupil reactivity and size in a heterogeneous cohort of critically ill patients with acute intracranial pathology.DesignRetrospective cohort study.SettingTwo neurologic ICUs between 2016 and 2018.PatientsCritically ill adult patients with pupil measurements within 60 minutes of analgosedative administration. Patients with a history of intrinsic retinal pathology, extracranial injury, inaccessible brain imaging, or no Glasgow Coma Scale (GCS) data were excluded.InterventionsNone.Measurements and main resultsWe used mixed-effects linear regression accounting for intrapatient correlations and adjusting for sex, age, GCS score, radiographic mass effect, medication confounders, and ambient light. We tested the association between an initiation or increased IV infusion of dexmedetomidine and pupil reactivity (Neurologic Pupil Index [NPi]) and resting pupil size (mm) obtained using NeurOptics NPi-200 (NeurOptics, Irvine, CA) pupillometer. Of our 221 patients with 9,897 pupil observations (median age, 60 [interquartile range, 50-68]; 59% male), 37 patients (166 pupil observations) were exposed to dexmedetomidine. Dexmedetomidine was associated with higher average NPi (β = 0.18 per 1 unit increase in rank-normalized NPi ± 0.04; p < 0.001) and smaller pupil size (β = -0.25 ± 0.05; p < 0.001). Exploratory analyses revealed that acetaminophen was associated with higher average NPi (β = 0.04 ± 0.02; p = 0.02) and that most IV infusion analgosedatives including propofol, fentanyl, and midazolam were associated with smaller pupil size.ConclusionsDexmedetomidine is associated with higher pupil reactivity (high NPi) and smaller pupil size in a cohort of critically ill patients with neurologic injury. Familiarity with expected pupil changes following analgosedative administration is important for accurate interpretation of pupil examination findings, facilitating optimal management of patients with acute intracranial pathology.

Dataset Information

Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients.

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Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients.

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