Patient-ventilator synchrony in Neurally Adjusted Ventilatory Assist (NAVA) and Pressure Support Ventilation (PSV): a prospective observational study.

BACKGROUND: Weaning from mechanical ventilation is associated with the presence of asynchronies between the patient and the ventilator. The main objective of the present study was to demonstrate a decrease in the total number of patient-ventilator asynchronies in invasively ventilated patients for whom difficulty in weaning is expected by comparing neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV) ventilatory modes. METHODS: We performed a prospective, non-randomized, non-interventional, single-center study. Thirty patients were included in the study. Each patient included in the study benefited in an unpredictable way from both modes of ventilation, NAVA or PSV. Patients were successively ventilated for 23 h in NAVA or in PSV, and then they were ventilated for another 23 h in the other mode. Demographic, biological and ventilatory data were collected during this period. The two modes of ventilatory support were compared using the non-parametric Wilcoxon test after checking for normal distribution by the Kolmogorov-Smirnov test. The groups were compared using the chi-square test. RESULTS: The median level of support was 12.5 cmH2O (4-20 cmH2O) in PSV and 0.8 cmH2O/µvolts (0.2-3 cmH2O/µvolts) in NAVA. The total number of asynchronies per minute in NAVA was lower than that in PSV (0.46 vs 1, p < 0.001). The asynchrony index was also reduced in NAVA compared with PSV (1.73 vs 3.36, p < 0.001). In NAVA, the percentage of ineffective efforts (0.77 vs 0.94, p = 0.036) and the percentage of auto-triggering were lower compared with PSV (0.19 vs 0.71, p = 0.038). However, there was a higher percentage of double triggering in NAVA compared with PSV (0.76 vs 0.71, p = 0.046). CONCLUSION: The total number of asynchronies in NAVA is lower than that in PSV. This finding reflects improved patient-ventilator interaction in NAVA compared with the PSV mode, which is consistent with previous studies. Our study is the first to analyze patient-ventilator asynchronies in NAVA and PSV on such an important duration. The decrease in the number of asynchronies in NAVA is due to reduced ineffective efforts and auto-triggering.

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.

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.

Outcome of Critically Ill Patients With Influenza Infection: A Retrospective Study.

BACKGROUND: Influenza causes significant morbidity and mortality in adults, and numerous patients require intensive care unit (ICU) admission. Acute respiratory distress syndrome (ARDS) is clearly described in this context, but other clinical presentations exist that need to be assessed for incidence and outcome. The primary goal of this study was to describe the characteristics of patients admitted in ICU for influenza, their clinical presentation, and the 3-month mortality rate. The second objective was to search for 3-month mortality risk factors. METHODS: This is a retrospective study including all patients admitted to 3 ICUs due to influenza-related disease between October 2013 and June 2016, which assesses the 3-month mortality rate. We compared clinical presentation, biological data, and outcome at 3 months between survivors and non-survivors. We created a predicting 3-month mortality model with Classification and Regression Tree analysis. RESULTS: Sixty-nine patients were included, 50 patients (72.5%) for ARDS, 5 (7.2%) for myocarditis, and 14 (20.3%) for acute respiratory failure without ARDS criteria. Non-typed influenza A was found in 30 cases (43.5%), influenza A H1N1 in 18 (26.1%), H3N2 in 3 (4.3%), and influenza B in 18 cases (27.5%). The 3-month mortality rate was 29% (n = 20). Extracorporeal membrane oxygenation (ECMO) was implanted in 23 patients, without any significant increase in mortality (39% vs 24% without ECMO, P = .19). A creatinine serum superior to 96 µmol/L, an aspartate aminotransferase level superior to 68 UI/L, and a Pao2/Fio2 ration below 110 were associated with 3-month mortality in our predictive mortality model. CONCLUSION: Influenza in ICUs may have several clinical presentations. The mortality rate is high, but ECMO may be an effective rescue therapy.

Population pharmacokinetics of ceftazidime in intensive care unit patients: influence of glomerular filtration rate, mechanical ventilation, and reason for admission.

The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.

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.

Influence of renal function on trough serum concentrations of piperacillin in intensive care unit patients.

OBJECTIVE: To explore the effects of renal function estimated by measured creatinine clearance (Cl(CR)) on trough serum concentration (C(min)) of piperacillin given to critically ill patients. DESIGN: Prospective observational study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Seventy critically ill patients, including 22 with severe trauma. INTERVENTIONS: All subjects received an intravenous infusion of piperacillin 4 g three times (n = 61) or four times (n = 9) per day. Piperacillin C(min) values were determined 24 h after treatment started and compared to the French breakpoint defining antibiotic susceptibility against Enterobacteriaceae (8 mg/l) or Pseudomonas sp. (16 mg/l). RESULTS: Median (range) piperacillin C(min) was 11.9 (< 1-156.3) mg/l, with a great variability among patients. Although the median value was close to the breakpoints, sub-therapeutic plasma levels were frequently observed. Piperacillin C(min) was lower than the breakpoint for Enterobacteriaceae in 37% of patients, and lower than the breakpoint for P. aeruginosa in 67% of them. A strong relationship was observed between piperacillin C(min) and Cl(CR): the higher the Cl(CR,) the lower the piperacillin C(min )in serum. For patients with a Cl(CR) < 50 ml/min, enough piperacillin C(min) was achieved in most patients with 12 g piperacillin per day. For patients with higher Cl(CR) values, a piperacillin daily dose of 16 g or more may be warranted. CONCLUSIONS: In critically ill patients, therapeutic monitoring must be part of the routine, and knowledge of Cl(CR) value may be useful for the choice of adequate initial piperacillin dosing.

Pharmacodynamics of cisatracurium in the intensive care unit: an observational study.

BACKGROUND: Data from previous studies indicate that optimal conditions for intubation are met 120 seconds after administration of 0.15 mg.kg-1 cisatracurium (ED95 × 3) following the induction of anesthesia. The aim of this study was to compare the doses required for complete paralysis after induction of anesthesia in ICU patients with the dose used in patients undergoing elective surgery. METHODS: Seventeen ICU patients undergoing percutaneous tracheostomy and 17 patients undergoing an elective surgical procedure under muscle relaxation were included. In both groups, an initial intravenous bolus of cisatracurium besylate was given at a dose of 0.15 mg.kg-1 followed by repeated boluses of 0.03 mg.kg-1 every four minutes. The objective was to obtain no response to the train-of-four (TOF). The contractile response of the corrugator supercilii muscle was monitored every minute by observing the TOF in response to a peripheral nerve stimulator with a constant current set to 60 mA. RESULTS: After the initial dose of cisatracurium, none of ICU patients (0/17) versus 15/17 of the elective surgery patients were completely paralyzed (P < 0.0001). There was a delay in the onset of neuromuscular blockade among the ICU patients. The cumulative doses of cisatracurium were significantly higher in the ICU group with 38 ± 14 mg (that is, 10 ± 4.7 ED95) versus 11 ± 2 mg (that is, 3 ± 0.3 ED95) in the elective surgery group (P < 0.0001). CONCLUSION: The dosing of cisatracrurium for ICU patients, which is based on the dose recommended for elective anesthesia, is unsuitable because the onset is too slow. This phenomenon is probably caused by changes in the pharmacodynamics and pharmacokinetics. These data suggest that neuromuscular monitoring should be used in the ICU.

Risk of emergence of Pseudomonas aeruginosa resistance to beta-lactam antibiotics in intensive care units.

OBJECTIVE: The emergence of Pseudomonas aeruginosa resistance to antimicrobial drugs is frequent in intensive care units and may be correlated with the use of some specific drugs. The purpose of our study was to identify a relationship between the use of various beta-lactam antibiotics and the emergence of resistance and to characterize the mechanism of resistance involved. DESIGN: We conducted an open prospective study over a 3-yr period by including all patients in whom P. aeruginosa had been isolated from one or more specimens: bronchial aspiration, blood cultures, catheters, and urinary cultures. SETTING: General intensive care unit. PATIENTS: One hundred and thirty-two intensive care unit patients. INTERVENTIONS: The antibiotics studied were amoxiclav, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepim, and imipenem. The mechanisms of resistance studied were production of penicillinase or cephalosporinase, nonenzymatic mechanisms, and loss of porin OprD2. Analysis was performed using Cox proportional-hazard regression with time-dependant variables. MEASUREMENTS AND MAIN RESULTS: Forty-two strains became resistant, 30 to one antibiotic, nine to two, and three to three, leading to the study of 57 resistant strains. Imipenem (hazard ratio 7.8; 95% confidence interval, 3.4-18.1), piperacillin-tazobactam (hazard ratio 3.9; 95% confidence interval, 1.3-11.9), and cefotaxim (hazard ratio 9.3; 95% confidence interval, 2.9-30.2) were strongly linked to the emergence of resistance. The use of imipenem (p<.0001) was associated with the loss of porin OprD2. Thirty-six strains from nine patients, assayed by pulsed-field gel electrophoresis, showed that for any one patient, all the strains were genetically related. CONCLUSIONS: Our results show that there is a high risk of the emergence of drug resistance during treatment with cefotaxime, imipenem, and piperacillin-tazobactam. This has to be taken into account in the therapeutic choice and in the patient's surveillance.