The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit.
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ABSTRACT: Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.
Project description:Interruption of enteral nutrition (EN) in the intensive care unit (ICU) occurs frequently for various reasons including feeding intolerance and the conduct of diagnostic and therapeutic procedures. However, few studies have investigated the details of EN interruption practices including reasons for and duration of interruptions. There is no standard protocol to minimize EN interruptions.This is a retrospective review of 100 patients in the ICU staying more than 72 h and receiving EN in a 12-bed, medical/surgical ICU in a tertiary care center in 2013. Data collected include total time designated for EN; the number of EN interruption episodes; reason for each interruption categorized as diagnostic study, therapeutic intervention, or gastrointestinal (GI) event, and their individual subcategories; duration of each interruption; and the presence of written orders for interruptions.One hundred patients staying in the ICU for at least 72 h and receiving EN were included. There were 567 episodes of EN interruption over a median ICU length of stay of 17.1 (interquartile range 8.0-22.0) days. There were a median of three EN interruption episodes per patient. EN interruption was performed for undetermined reasons (166 episodes, 29%), airway manipulation (103 episodes, 18%), GI events (78 episodes, 14%), and intermittent dialysis (71 episodes, 13%). Median duration of EN interruption in all patients was 5.5 (3.0-10.0) h. The cumulative interruption time corresponds to 19% of the total time designated for EN. Duration of EN interruption varied according to reason, including airway manipulation (9.0 [5.0-21.0] h), tracheostomy (9.5 [7.5-14.0] h), and GI events (6.5 [3.0-14.0] h). The average calorie deficits due to interruptions were 11.5% of daily target calories. Only 60 episodes (12%) had clear written orders for interruption.Based on this single-center retrospective chart review, interruption of EN in the ICU is frequent, reasons for and duration of interruption varied, and airway procedures are associated with a relatively longer duration of interruption. Documentation and orders were frequently missing. These results warrant development of a protocol for EN interruption.
Project description:BACKGROUND:Aminoglycosides have a concentration-dependent therapeutic effect when peak serum concentration (Cmax) reaches eight to tenfold the minimal inhibitory concentration (MIC). With an amikacin MIC of 8 mg/L, the Cmax should be 64-80 mg/L. This objective is based on clinical breakpoints and not on measured MIC. This study aimed to assess the proportion of patients achieving the pharmacokinetic/pharmacodynamic (PK/PD) target Cmax/MIC???8 using the measured MIC in critically ill patients treated for documented Gram-negative bacilli (GNB) infections. METHODS:Retrospective analysis from February 2016 to December 2017 of a prospective database conducted in 2 intensive care units (ICU). All patients with documented severe GNB infections treated with amikacin (single daily dose of 25 mg/kg of total body weight (TBW)) with both MIC and Cmax measurements at first day of treatment (D1) were included. Results are expressed in n (%) or median [min-max]. RESULTS:93 patients with 98 GNB-documented infections were included. The median Cmax was 55.2 mg/L [12.2-165.7] and the median MIC was 2 mg/L [0.19-16]. Cmax/MIC ratio???8 was achieved in 87 patients (88.8%) while a Cmax???64 mg/L was achieved in only 38 patients (38.7%). Overall probability of PK/PD target attainment was 93%. No correlation was found between Cmax/MIC ratio and clinical outcome at D8 and D28. CONCLUSION:According to PK/PD parameters observed in our study, single daily dose of amikacin 25 mg/kg of TBW appears to be sufficient in most critically ill patients treated for severe GNB infections.
Project description:ObjectiveTo study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.MethodsMicafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations.ResultsA two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016.ConclusionsThe licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.
Project description:Background: The present research aimed to evaluate the effect on outcomes of immunonutrition (IMN) enteral formulas during the intensive care unit (ICU) stay. Methods: A multicenter prospective observational study was performed. Patient characteristics, disease severity, nutritional status, type of nutritional therapy and outcomes, and laboratory parameters were collected in a database. Statistical differences were analyzed according to the administration of IMN or other types of enteral formulas. Results: In total, 406 patients were included in the analysis, of whom 15.02% (61) received IMN. Univariate analysis showed that patients treated with IMN formulas received higher mean caloric and protein intake, and better 28-day survival (85.2% vs. 73.3%; p = 0.014. Unadjusted Hazard Ratio (HR): 0.15; 95% CI (Confidence Interval): 0.06−0.36; p < 0.001). Once adjusted for confounding factors, multivariate analysis showed a lower need for vasopressor support (OR: 0.49; 95% CI: 0.26−0.91; p = 0.023) and continuous renal replacement therapies (OR: 0.13; 95% CI: 0.01−0.65; p = 0.049) in those patients who received IMN formulas, independently of the severity of the disease. IMN use was also associated with higher protein intake during the administration of nutritional therapy (OR: 6.23; 95% CI: 2.59−15.54; p < 0.001), regardless of the type of patient. No differences were found in the laboratory parameters, except for a trend toward lower triglyceride levels (HR: 0.97; 95% CI: 0.95−0.99; p = 0.045). Conclusion: The use of IMN formulas may be associated with better outcomes (i.e., lower need for vasopressors and continuous renal replacement), together with a trend toward higher protein enteral delivery during the ICU stay. These findings may ultimately be related to their modulating effect on the inflammatory response in the critically ill. NCT Registry: 03634943.
Project description:We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h-1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h-1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30-40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.
Project description:Critically ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decrease quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders associated with ICU-acquired muscle weakness. Although there are no available treatments for the ICU-acquired muscle weakness, it has been demonstrated that early mobilization can improve its prognosis and functional outcomes. This study aims at improving our understanding of the effects of passive mechanical loading on skeletal muscle structure and function by using a unique experimental rat ICU model allowing analyses of the temporal sequence of changes in mechanically ventilated and pharmacologically paralyzed animals at durations varying from 6 h to 14 days. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle structure and function is likely a consequence of a reduced oxidative stress, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle structure and function associated with mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients. This study aims to unravel the effects of passive mechanical loading on skeletal muscle structure and function in an experimental rat ICU model at duration varying between 6h and 14 days. A total of 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocking agent (NMBA) M-NM-1-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 8 days (n=4), and from 9 to 14 days (n=6). The left leg of the animal was activated for 6 hours at the shortest duration and 12 hours per day at durations 12 hours and longer throughout the experiment, using a mechanical lever arm that produced a continuous passive maximal ankle joint flexions-extensions at a speed of 13.3 cycles per minute. Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia, were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80M-BM-0C. RNA was extracted.