B. Georges

Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches

The objective of this study was to evaluate the properties of ciprofloxacin in intensive care patients using a population approach. Seventy patients received ciprofloxacin. On Day 1, three to eight blood samples were taken over a 12-h period. Peak drug concentration (Cmax) and 24-h area under the concentration-time curve (AUC) were compared with the French breakpoint defining antibiotic susceptibility. A population pharmacokinetic modelling approach was then carried out. A two-compartment open model with a proportional error model best fitted the data. A relationship between the elimination constant rate and the Cockcroft creatinine clearance was found. Ciprofloxacin clearance was 13.6+/-5.8L/h, the volume of distribution was 62.0+/-10.7 L and the ciprofloxacin half-life was 3.7+/-1.8h. When the minimum inhibitory concentration (MIC) was equal to 1mg/L the inhibitory ratio (IR) was > or = 8 in only 10.8% of cases, and the AUC/MIC ratio (AUIC) was 42.0+/-36. In conclusion, this study highlights that the Cockcroft clearance significantly influences ciprofloxacin elimination. Target plasma concentrations for ciprofloxacin, the IR and AUIC were rarely reached with a standard dosing regimen. In critically ill patients, the observed pharmacokinetic variability is mainly responsible for the overly frequent low concentrations of ciprofloxacin, emphasising the need for therapeutic monitoring.

Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study.

IntroductionThe aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT).MethodsThis was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR .ResultsAmong the 106 patients with a CLCR above 120 mL minute-1 1.73 m-2, 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute-1 1.73 m-2 with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute-1. 1.73 m -2 were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute-1. 1.73 m -2. Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR.ConclusionsIn ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination.

Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations.

UNLABELLED WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? It is well known that tobramycin given as an once daily dose according to the usual recommendations needs therapeutic drug monitoring by measurement of peak and trough concentrations. In the literature, there are only few published studies on the population pharmacokinetics of once daily tobramycin in critically ill patients. Glomerular filtration rate and bodyweight were identified as covariates contributing to the inter-individual variability in the disposition of aminoglycosides. The study, by Peris-Marti et al. [24], only evaluated the pharmacodynamic effectiveness of a 4 mg kg(-1) dose of tobramycin given once daily in critically ill patients. The authors concluded with a simulation showing that for a theoretical MIC of 1 or 2 mg l(-1) , a 7 mg kg(-1) dose was required. WHAT THIS STUDY ADDS Our results confirm the high variability of tobramycin disposition in intensive care patients and consequently the possible lack of effectiveness. By using a population pharmacokinetic approach, two explicative covariates (height and Cockcroft creatinine clearance) added to a two-compartment model with proportional error, explained much of the inter-individual variability of tobramycin disposition in the critically ill patient population. In a median ICU patient, simulations were performed at various dosage regimens and peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Drug monitoring is required to manage efficacy and toxicity. AIM The aim of this study was to evaluate the disposition of tobramycin (TOB) in critically ill patients (ICU) by a population pharmacokinetic approach, to determine the covariates involved, and to simulate tobramycin dosage regimens. METHODS Forty-nine adult ICU patients received TOB (5 mg kg(-1) ) once daily. NonMem modelling was performed on 32 patients. The 17 other patients were used for the qualification process by normalized prediction distribution error. Then Monte Carlo simulations (MCS) were performed. RESULTS A two-compartment model with a proportional error best fitted the data. TOB total clearance (CL(TOB) ) was significantly correlated with Cockcroft creatinine clearance (COCK) and height. TOB clearance was 4.8 ± 1.9 l h(-1) (range 1.22-8.95), the volume of distribution of the central compartment was 24.7 ± 3.7 l (range 17.34-32.83) and that of the peripheral compartment and the inter-compartmental clearance were 30.6 l and 4.74 l h(-1) , respectively. Only 29% of the patients presented a target AUC between 80 and 125 mg l(-1) h and 61% were lower than 80 mg l(-1)  h. After considering COCK and height, MCS showed that only 50% of the population could achieve the target AUC for the 375 and 400 mg dosages. CONCLUSION Even after taking into account COCK and height, for strains with an MIC ≤ 1 mg l(-1) , MCS doses evidenced that peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Combination therapy in addition to drug monitoring are required to manage efficacy and toxicity.

Ceftazidime dosage regimen in intensive care unit patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The large variability in drug pharmacokinetic disposition has already been described in ICU patients leading to important variations in drugs concentrations. The usual recommended dosage of ceftazidime is not adapted for all ICU situations and ceftazidime should be monitored closely. New recommendations have to be given for some specific cases. WHAT THIS STUDY ADDS Our results propose individual therapeutic drug monitoring taking into account: For the patient: the reason of admission in the ICU, the mechanical ventilation status and the creatinine clearance calculated by the modified diet in renal disease (MDRD). • For the antibiotics: the lung distribution, the minimal inhibitory concentration (MIC) of the strain to eradicate and the potential toxicity. AIM To predict the ceftazidime dosage regimen as a function of the glomerular filtration rate expressed by the modification of the diet in renal disease (MDRD), reason for admission and mechanical ventilation in intensive care unit (ICU) patients to treat Pseudomonas aeruginosa pneumonia. METHOD A published and qualified population pharmacokinetic model was used to perform Monte Carlo simulations of ceftazidime concentrations. The serum target of 40-100 mg l(-1) was defined based on the minimal inhibitory concentration (MIC), the European break point (EBP), the pulmonary drug diffusion and toxicity. The recommended dosage regimens were based on the maximum percentile of the patients with simulated steady state concentrations reaching the target. RESULTS Steady-state was reached at 72 h whatever the MDRD. The simulations of serum concentrations generated higher percentiles of the population reaching the target after continuous administration. We recommend a 4 g continuous dose after the usual 2 g loading dose for patients with MDRD from 10 to 30 ml min(-1) , 6 g for MDRD between 40 and 80 ml min(-1) , 8 g for MDRD from 90 to 110 ml min(-1) , 10 g for MDRD from 120 to 190 ml min(-1) and 12 g day(-1) for patients with MDRD higher than 200 ml min(-1) . CONCLUSION Our study demonstrated that in ICU patients for a given MDRD, steady-state takes longer to reach in polytrauma patients than in patients with medical or post surgery reasons for admission. Continuous infusion ensures that a higher percentage of patients reaches the target than the same dose given by discontinuous administration and this only depends on MDRD.

Plasma free carnitine in severe trauma: Influence of the association with traumatic brain injury

BACKGROUND Metabolic response to severe trauma requires early nutritional resuscitation. Carnitine is essential for lipolysis, the energy source during this hypercatabolic phase. However l-carnitine is not present in nutritional replacement solutions. Furthermore, free carnitine depletion, defined as carnitine plasma level under 36μmol/L, was not adequately reported in adult patients with severe trauma. The aim of this study was to assess plasma free carnitine levels and factors of variation in severe trauma. METHOD Our observational study concerned 38 trauma patients including 18 with traumatic brain injury (TBI). On the third day after trauma, plasma free carnitine concentration was determined (by enzymatic method) while patients received artificial nutrition. RESULTS Low plasmatic free carnitine concentration was evidenced in 95% of the patients with a median value of 18μmol/L (11-47). Univariate analysis showed that mean arterial pressure, serum urea, CKD-EPI and patients with TBI were significantly associated with plasma free carnitine concentration less than 18μmol/L. Lower plasma free carnitine concentration was observed in the group of patients with TBI with 17.72μmol/L (11-36) versus 21.5μmol/L (11-47) for others patients (p=0.031). Logistic regression analysis showed that severe trauma with TBI and CKD-EPI above 94mL/min/1.73m2 appeared to be independent predictor of lower free carnitine plasmatic concentration (Goodness of fit=0.87 and AUC=0.89). CONCLUSION Our observations support hypotheses that plasma free carnitine concentration is lowered in severe injured patients especially for TBI patients and patients with estimated GFR above 94mL/min/1.73m2.

Predictors of desaturation during patient transport to the postoperative anesthesia care unit: an observational study ☆ ☆☆ ★

BACKGROUND The transport of postoperative patients to the postoperative anesthesia care unit (PACU) is a high-risk period for hypoxemia. The aim of this study was to determine risk factors for hypoxemia during transfers to the PACU. METHODS An observational, prospective, monocentric, and noninterventional study was conducted in the University Hospital of Toulouse in 2015 during a 5-week period. All patients who were transferred to PACU were included. Twenty-eight variables related to patient, surgery, and anesthesia were recorded. Hypoxemia during transfer was defined as Spo2 <90%. RESULTS Five hundred five patients were included. The incidence of hypoxemia during transfer was 13%. After logistic regression analysis, 3 risk factors for desaturation were identified: sedation score >2, Spo2 <96% before exiting the operating room (OR), and body mass index >30 kg/m2. The 72% of patients were transferred without oxygen. Most of the hypoxemia appears in these patients. CONCLUSION The development of hypoxemia during transfer from the OR to the PACU was greater in patients who were obese, were more sedated, or had lower oxygen saturations upon leaving the OR. The rates of hypoxemia were greater among patients in whom supplemental oxygen was not administered. Supplemental oxygen should be considered in higher risk patients.