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      Amikacin Pharmacokinetics During Continuous Veno-Venous Hemodialysis

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          Abstract

          Introduction

          Little is known about the pharmacokinetics of amikacin during continuous renal replacement therapy.

          Methods

          This prospective observational study included patients admitted to an academic medical center who received amikacin therapy while on continuous veno-venous hemodialysis (CVVHD) and had at least two serum sample concentrations measured after first-dose administration. First-order pharmacokinetic parameters, patient characteristics, and CVVHD parameters were recorded.

          Results

          Fifteen patients were included in the analysis. The median (interquartile range) dose of amikacin and dialysate flow rate, based on adjusted body weight, were 14.1 mg/kg (11.7–17.3 mg/kg) and 23.9 mL/kg/h (19.0–29.5 mL/kg/h), respectively. This corresponded with a median C max of 28.5 μg/mL (20.9–39.0 μg/mL). There was a significant correlation between clearance and dialytic dose (for every 1 L/h increase in dialysate flow rate, clearance rate increased by 23.6 mL/min [95% confidence interval 1.7–45.4 mL/min; P = 0.037]).

          Conclusion

          The results of this study suggest that amikacin dose and interval should be individualized for each patient on CVVHD based on first-dose pharmacokinetic assessment.

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          Most cited references21

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          The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study.

          M Rangel-Frausto, D Pittet, M. Costigan … (1995)
          Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. Prospective cohort study with a follow-up of 28 days or until discharge if earlier. Three intensive care units and three general wards in a tertiary health care institution. Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count. Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death. During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857, 804, and 542 episodes per 1000 patient-days, respectively, and 671, 495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations. This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock.
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            Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock

            Fabio Taccone, Pierre-François Laterre, Herbert D. Spapen … (2010)
            Introduction It has been proposed that doses of amikacin of >15 mg/kg should be used in conditions associated with an increased volume of distribution (Vd), such as severe sepsis and septic shock. The primary aim of this study was to determine whether 25 mg/kg (total body weight) of amikacin is an adequate loading dose for these patients. Methods This was an open, prospective, multicenter study in four Belgian intensive care units (ICUs). All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom amikacin treatment was indicated, were included in the study. Results In 74 patients, serum samples were collected before (t = 0 h) and 1 hour (peak), 1 hour 30 minutes, 4 hours 30 minutes, 8 hours, and 24 hours after the first dose of amikacin. Blood amikacin levels were measured by using a validated fluorescence polarization immunoassay method, and an open two-compartment model with first-order elimination was fitted to concentrations-versus-time data for amikacin (WinNonlin). In 52 (70%) patients, peak serum concentrations were >64 μg/ml, which corresponds to 8 times the clinical minimal inhibitory concentration (MIC) breakpoints defined by EUCAST for Enterobacteriaceae and Pseudomonas aeruginosa (S 16 μg/ml). Vd was 0.41 (0.29 to 0.51) L/kg; elimination half-life, 4.6 (3.2 to 7.8) hours; and total clearance, 1.98 (1.28 to 3.54) ml/min/kg. No correlation was found between the amikacin peak and any clinical or hemodynamic variable. Conclusions As patients with severe sepsis and septic shock have an increased Vd, a first dose of ≥ 25 mg/kg (total body weight) of amikacin is required to reach therapeutic peak concentrations. However, even with this higher amikacin dose, the peak concentration remained below therapeutic target levels in about one third of these patients. Optimizing aminoglycoside therapy should be achieved by tight serum-concentration monitoring because of the wide interindividual variability of pharmacokinetic abnormalities.
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              Practice patterns in the management of acute renal failure in the critically ill patient: an international survey.

              Zaccaria Ricci, Claudio Ronco, Giuseppe D'Amico … (2006)
              Several controversies have developed over acute renal failure (ARF) definition and treatment: which approach to patient care is most desirable and which form of renal replacement therapy (RRT) should be applied is an everyday matter of debate. There is also disagreement on clinical practice for RRT including the best timing to start, vascular access, anti-coagulation, membranes, equipment and finally, if continuous or intermittent techniques should be preferred. In this lack of harmony, the epidemiology of ARF has recently displayed an outbreak of cases in the intensive care units and nephrologists and intensivists are now called to work together in the case of such a syndrome. We report on the responses of 560 contributors, mostly coming from Europe, to a questionnaire submitted during the third International Course on Critical Care Nephrology held in Vicenza, Italy in June 2004. The questionnaire was divided into several sections concerning demographic and medical information, definition of ARF, practice of RRT, current opinions about clinical advantages and problems related to different RRTs and modalities, and beliefs on alternative indications to extracorporeal treatments. More then 200 different definitions of ARF and about 90 RRT start criteria were reported. Oliguria and RIFLE (an acronym classifying ARF in different levels of severity: Risk of renal dysfunction; Injury to the kidney; Failure of kidney function; Loss of kidney function; End-stage kidney disease.) were the most frequent criteria used to define ARF. In 10% of centres all forms of renal replacement techniques are available, and in 70% of cases two or more different techniques are available: absolute analysis of different techniques showed that continuous renal replacement therapies are utilized by 511 specialists (91%), intermittent haemodialysis by 387 (69%) and sustained low efficiency dialysis by 136 (24%). Treatment prescription showed significant differences among specialists, 60% of intensivists being uncertain on RRT dose prescription compared to 40% of nephrologists (P = 0.002). The most frequently selected dosage was '35 ml/kg/h' for urea (25%) and creatinine targets (26%), and '2-3 l/h' for the septic dose (25%). Of the participants, 90% said that they used RRT for non-renal indications, 60% although responders admitted the lack of scientific evidence as a limiting factor to its use. New classifications such as RIFLE criteria might improve well-known uncertainty about ARF definition. Different RRT techniques are available in most centres, but a general lack of treatment dose standardization is noted by our survey. Non-renal indications to RRT still need to find a definitive role in routine practice.
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                Author and article information

                Contributors
                Simon W. Lam: lams@ccf.org
                Journal
                Journal ID (nlm-ta): Infect Dis Ther
                Journal ID (iso-abbrev): Infect Dis Ther
                Title: Infectious Diseases and Therapy
                Publisher: Springer Healthcare (Heidelberg )
                ISSN (Print): 2193-8229
                ISSN (Electronic): 2193-6382
                Publication date (Electronic): 16 August 2013
                Publication date PMC-release: 16 August 2013
                Publication date (Print): December 2013
                Volume: 2
                Issue: 2
                Pages: 217-226
                Affiliations
                Department of Pharmacy, Cleveland Clinic Health System, 9500 Euclid Avenue, Cleveland, OH 44195 USA
                Article
                Publisher ID: 12
                DOI: 10.1007/s40121-013-0012-8
                PMC ID: 4108101
                SO-VID: 2b7f0902-30f5-458c-95d9-03e2889812c3
                Copyright © © The Author(s) 2013
                History
                Date received : 13 May 2013
                Categories
                Subject: Original Research
                Custom metadata
                issue-copyright-statement © Springer Healthcare 2013

                Keywords: amikacin,continuous renal replacement therapy,pharmacokinetics
                Data availability:
                Keywords: amikacin, continuous renal replacement therapy, pharmacokinetics

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