Gilbert Saissi

Training is required to improve the reliability of esophageal Doppler to measure cardiac output in critically ill patients

Objectives: Assessment of and effect of training on reliability of esophageal Doppler (ED) versus thermodilution (TD) for cardiac output (CO) measurement.Design: Prospective study.Setting: Intensive care unit of a university hospital.Patients: 64 consecutive critically ill patients requiring a pulmonary artery catheter, sedation, and mechanical ventilation.Interventions: Esophageal Doppler CO measurements were performed by the same operator, whereas TD CO measurements were carried out by other independent operators. A training period involving the first 12 patients made the operator self-confident. In the remaining patients, the reliability of ED was assessed (evaluation period), using correlation coefficients and the Bland and Altman diagram. Between training and evaluation periods, correlation coefficients, biases, and limits of agreement were compared.Measurements and results: During training and evaluation periods, 107 and 320 CO measurements were performed in 11 out of 12 patients and in 49 out of 52 patients, respectively. Continuous CO monitoring was achieved in 6 out of 11 patients and in 38 out of 49 patients during training and evaluation periods, respectively. Between the two periods, correlation coefficients increased from 0.53 to 0.89 (p < 0.001), bias decreased from 1.2 to 0.1 l.min−1 (p < 0.001), and limits of agreement decreased from 3.2 to 2.2 l.min−1 (p < 0.001).Conclusion: A period of training involving no more than 12 patients is probably required to ensure reliability of CO measurement by ED.

pulsed Doppler Ultrasonography Guidance for Catheterization of the Subclavian Vein : a Randomized Study

Background Catheterization of the subclavian vein may lead to severe complications. The current randomized study compared a technique of pulsed Doppler ultrasonography guidance and the standard method for subclavian vein catheterization. Methods Standard and Doppler ultrasonography guidance methods were performed by the same physician in 286 patients, 143 in each group. Primary end points were immediate complications (arterial puncture, pneumothorax, wrong position of catheter tip), failures, the number of subclavian vein catheterizations with immediate complication or failure, the number of skin punctures per catheterization, and the time to placement of the guide wire. The secondary end points were the determination of predicting factors of successful cannulation in each group. Results Both groups were similar according to morphologic parameters of the patients. A greater number of subclavian vein catheterizations were performed on the right side using Doppler guidance (105 vs. 73, P < 0.01). Doppler guidance decreased complications (5.6% vs. 16.8%, P < 0.01), largely because of a smaller number of catheters for which the tip was defined to be in incorrect position (0.7% vs. 7.7%, P < 0.01). The time to catheterization was longer with Doppler guidance (300 vs. 27 s, P < 0.001). Failures, catheterizations of the subclavian vein with immediate complications or failure, and the total number of skin punctures per catheterization were similar in both groups. Using Doppler guidance, the presence of a good Doppler signal (124 of 143) was predictive of successful catheterization (123 successful cannulations, P < 0.001). Conclusions Doppler guidance reduces the incidence of inappropriately positioned subclavian catheters.

Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability.

Pharmacokinetic studies on ceftazidime, an aminothiazole cephalosporin with a wide spectrum of antibacterial activity, including activity against Pseudomonas aeruginosa, were performed in patients with nosocomial pneumonia. The concentration-time profiles of ceftazidime in plasma, urine, and bronchial secretions of 12 patients were investigated after intravenous (i.v.) (n = 12), endotracheal (n = 10), and aerosol (n = 5) administrations. In all cases a 1-g dose was administered. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection. The elimination of the drug from the blood followed a biexponential (i.v. administration) or a monoexponential (endotracheal and aerosol administrations) decay, with an elimination half-life of 6 h and a total body clearance of 4.2 liters/h. The apparent volume of distribution was 0.36 liter/kg of body weight. Renal clearance of the drug accounted for 58% of the total clearance; 66% +/- 17.7%, 33.5% +/- 17.3%, and 6.59% +/- 3.45% of the administered dose were eliminated in urine as parent drug after i.v., endotracheal, and aerosol administrations, respectively. The absolute bioavailabilities were 0.47 and 0.08 for endotracheal and aerosol administrations, respectively. Very high concentrations were found in bronchial secretions after local administration. The MICs for 90% of the most important pathogens responsible for nosocomial infections were exceeded by concentrations in bronchial secretion for up to 12 h after i.v. infusion and for up to 24 h after endotracheal and aerosol administrations.

Cardiac output measurement in critically ill patients: comparison of continuous and conventional thermodilution techniques

The purpose of the study was to compare cardiac output (CO) measurement by continuous (CTD) with that by conventional thermodilution (TD) in critically ill patients. In 19 of 20 critically ill patients requiring a pulmonary artery catheterism, 105 paired CO measurements were performed by both CTD and TD. Regression analysis showed that: CTD CO = 1.18 TD CO − 0.47. Correlation coefficient was 0.96. Bias and limit of agreement were — 0.8 and 2.4 L · min−1, respectively. When a Bland and Altman diagram was constructed according to cardiac index ranges, biases were −0.2 and −0.3 and −0.8 L · min−1 · m−2 and limits of agreement were 0.3, 0.7 and 1.6 L · min−1 · m−2 for low (<2.5 L · min−1 · m−2), normal (between 2.5 and 4.5 L · min−1 · m−2) and high (> 4.5 L · min−1 · m−2) cardiac indexes, respectively. It is concluded that CTD, compared with TD, is a reliable method of measuring CO, especially when cardiac index is ≤4.5 L · min−1 · m−2.RésuméCette étude avait pour but de comparer les mesures du débit cardiaque réalisées par thermodilution continue (CTD) par rapport à la thermodilution classique (TD) chez des patients de réanimation. Cent cinq paires de mesures du débit cardiaque ont été comparées chez 19 des 20 patients de réanimation inclus dans l’étude. L’équation de la droite de régression est CTD CO = 1,18 TD CO − 0,47. Le coefficient de corrélation s’élève à 0,96. L’erreur moyenne et l’intervalle de confiance sont respectivement de −0,8 et 2,4 L · min−1. En réalisant un diagramme de Bland and Altman selon le niveau d’index cardiaque, les erreurs moyennes s’élèvent à −0,2, −0,3 et −0,8 L · min−1 · m−2 et les intervalles de confiance à 0,3, 0,7 et 1,6 L · min−1 · m−2, respectivement pour les index cardiaques bas (<2,5 L · min−1 · m−2), normaux (entre 2,5 et 4,5 L · min−1 · m−2) et hauts (> 4,5 L · min−1 · m−2). La thermodilution continue, comparée à la thermodilution classique, est une méthode fiable pour le monitorage du débit cardiaque surtout pour les index cardiaque ≤4,5 L · min−1 · m−2.

Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations

Low peak plasma concentrations (Cmax) of amikacin and gentamicin are reported in intensive care unit (ICU) patients after administration of the first dose. The present study aimed to describe the proportion of ICU patients in whom an adequate Cmax was achieved throughout the course of therapy. Septic ICU patients with an indication for intravenous amikacin or gentamicin were eligible for inclusion in this single-centre observational study. The first and subsequent doses and the corresponding Cmax values were recorded. The target Cmax was ≥60mg/L for amikacin and ≥30mg/L for gentamicin. Amikacin and gentamicin plasma concentrations were available in 66 and 24 patients, respectively (59±17 years; 79±19kg; height 169±12cm; SAPS II score 46±19). Pulmonary, abdominal and urinary tract infections were diagnosed in 64 patients. Culture-positive infection was confirmed in 65 patients (72%). A target first Cmax was achieved in 17/90 patients (19%). For amikacin, the target Cmax was achieved in 16/66 patients (24%) after the initial dose. In the 50 remaining patients, a change in dosing was performed in 14 patients, leading adequate peak plasma level in 2 patients. For gentamicin, the targeted Cmax was achieved in only 1/24 patient (4%) after the initial dose and was never achieved after the third dose. In conclusion, standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. Subtherapeutic Cmax were not significantly corrected after subsequent doses.

Multiple-dose pharmacokinetics of amikacin and ceftazidime in critically ill patients with septic multiple-organ failure during intermittent hemofiltration.

The pharmacokinetic parameters of amikacin and ceftazidime were assessed in four patients undergoing hemofiltration for septic shock. The parameters were assessed during hemofiltration and in the interim period. The concentration-time profiles of these two drugs in plasma, urine, and ultrafiltrate were investigated after intravenous perfusion (30 min). In all cases a 1-g dose of ceftazidime was administered; for amikacin, the dosage regimen was adjusted according to the patients amikacin levels (250 to 750 mg). Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection for ceftazidime and by enzyme multiplied immunoassay for amikacin. The elimination half-life (t1/2) and the total clearance of amikacin ranged from 31.1 to 138.2 h and from 5.4 to 8.9 ml/min, respectively, during the interhemofiltration period in anuric patients. Hemofiltration substantially decreased the t1/2 (3.5 +/- 0.49 h) and increased the total clearance (89.5 +/- 11.8 ml/min). The hemofiltration clearance of amikacin represented 71% of the total clearance, and the hemofiltration process removed, on average, 60% of the dose. During hemofiltration, the elimination t1/2 of ceftazidime (2.8 +/- 0.69 h) was greatly reduced and the total clearance increased (74.2 +/- 11.2 ml/min) compared with those in the interhemofiltration period (9 to 43.7 h and 7.4 to 16.8 ml/min, respectively). About 55% of the administered dose was recovered in the filtrate, and the hemofiltration clearance of ceftazidime was 46 +/- 14.3 ml/min. A redistribution phenomenon (rebound) in the amikacin and ceftazidime concentrations in plasma (35 and 28%, respectively) was reported after hemofiltration in two patients. The MICs for 90% of the most important pathogens were exceeded by the concentrations of the two drugs in plasma during the whole treatment of these patients.

Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration

OBJECTIVES Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). METHODS Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. RESULTS Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. CONCLUSIONS During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.

Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy

ABSTRACT The objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. Sixteen patients (9 undergoing CVVH, 11 undergoing CVVHDF) and 20 sampling intervals were analyzed. A two-compartment linear model best described the data. Patient weight was the only covariate that was associated with drug clearance. The mean ± standard deviation parameter estimates were 25.2 ± 17.3 liters for the central volume, 0.89 ± 1.17 h−1 for the rate constant for the drug distribution from the central to the peripheral compartment, 2.38 ± 6.60 h−1 for the rate constant for the drug distribution from the peripheral to the central compartment, 4.45 ± 2.35 liters/h for hemodiafiltration clearance, and 4.69 ± 2.42 liters/h for hemofiltration clearance. Dosing simulations for amikacin supported the use of high dosing regimens (≥25 mg/kg) and extended intervals (36 to 48 h) for most patients when considering PK/pharmacodynamic (PD) targets of a maximum concentration in plasma (Cmax)/MIC ratio of ≥8 and a minimal concentration of ≤2.5 mg/liter at the end of the dosing interval. The mean clearance of amikacin was 1.8 ± 1.3 liters/h by CVVHDF and 1.3 ± 1 liters/h by CVVH. On the basis of simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg every 48 h) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside treatment in critically ill patients receiving continuous renal replacement therapy (CRRT). (This study is a substudy of a trial registered at ClinicalTrials.gov under number NCT01403220.)

Multiple-Dose Pharmacokinetics of Pefloxacin in Patients with Hepatocellular Deficiency

SummaryMultiple-dose pharmacokinetics of pefloxacin were evaluated in 25 patients with hepatocellular insufficiency. The severity of liver disease was graded A, B or C according to the Child-Pugh classification. Pharmacokinetic parameters evaluated in patients on day 1 of treatment were compared with those computed in 11 healthy volunteers (the control group) after a single dose. Blood samples were taken at frequent intervals after drug administration and assayed by high performance liquid chromatography. The mean age of patients with liver impairment was slightly greater (59.5 years, range 33 to 81 years) than that of the control group (46.7 years, range 42 to 51 years).In the patients with liver disease, the mean (± SD) half-life of elimination, although highly variable, was significantly longer (46.3 ± 42.5 hours) than in the control group (11.3 ± 3.5 hours, p < 0.001). The total clearance was significantly decreased (1.76 ± 1.31 L/h vs 6.03 ± 2.99 L/h in the control group). In groups B and C of the Child-Pugh classification, total body clearance was about 30% of normal values. Elimination half-life increased by 200% in group B and 373% in group C compared with values in healthy volunteers. Intergroup differences (group B vs group C of the Child-Pugh classification) were not statistically significant.The minimum concentrations inhibiting 90% of Gram-negative strains (MIC90) were exceeded by plasma pefloxacin concentrations throughout treatment. For most patients, trough plasma concentrations were above 2 mg/L and peak plasma concentrations averaged 8.5 mg/L. Large inter- and intraindividual variations in the elimination half-life, total clearance and volume of distribution were observed. A practical index is proposed for estimating the most likely pharmacokinetic parameters for a given patient, taking into account the values of the Child-Pugh score or the prothrombin time.

CO assessment by suprasternal Doppler in critically ill patients: comparison with thermodilution

Objective: Comparison of suprasternal Doppler (SST) and thermodilution (TD) for the measurement of cardiac output (CO) in critically ill patients.¶Design: Prospective study.¶Setting: Intensive care unit of a university hospital.¶Patients and participants: 65 consecutive critically ill patients requiring a pulmonary artery catheter.¶Interventions: Paired CO measurements were made simultaneously using SST and TD by two independent operators. The time to obtain a CO value by SST was measured. Correlation coefficients and the linear regression equation were determined. A Bland and Altman diagram was plotted. A Bland and Altman diagram was also plotted for the level of cardiac index (CI) values (low: CI < 2.5 l min–1 m–2; normal: 2.5 ≤ CI ≤ 4.5 l min–1 m–2; high: CI > 4.5 l min–1 m–2).¶Measurements and results: In seven patients SST failed to measure CO. In the remaining 58 patients 314 paired CO measurements were performed. The mean time to measure CO by SST was 73 ± 45 s. The equation of linear regression was: SSTCO = 0.84 TDCO + 1.39. The correlation coefficient was 0.84. The bias between SST and TD was –0.2 ± 1.4 l min–1. Biases were –0.23 ± 0.50, –0.20 ± 0.68, and 0.25 ± 0.92 l min–1 m–2 for low, normal, and high levels of CI, respectively.¶Conclusion: SST does not accurately measure CO but allows a rapid assessment of CI level in critically ill patients.