Pharmacokinetics of piperacillin-tazobactam in anuric intensive care patients during continuous venovenous hemodialysis

The pharmacokinetics of piperacillin-tazobactam were investigated in eight anuric intensive care patients treated by continuous venovenous hemodialysis (CVVHD). The elimination half-life of piperacillin was 4.3 +/- 1.2 h, and that of tazobactam was 5.6 +/- 1.3 h. The contribution of CVVHD to the overall elimination was relevant (>25%) for both drugs.     

Low cefepime concentrations during high blood and dialysate flow continuous venovenous hemodialysis

Dosing of cefepime during high blood flow (Qb; 300 ml/min), high dialysate flow (Qd; 3 liter/h) continuous venovenous hemodialysis (CVVHD) is undefined. Six patients on CVVHD had serum and effluent cefepime concentrations measured at 0.5, 1, 2, 6, and 12 h after dosing. Three patients had cefepime concentrations less than the MIC for Pseudomonas aeruginosa. A dose of 2,000 mg every 12 h or 1,000 mg every 8 h may increase time at a therapeutic concentration.     

Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m(2) acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m(2) polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m(2) polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI(diffusion)) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17%+/-7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P<0.0001) were observed between CI(diffusion) of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.     

Online measurement of urea concentration in spent dialysate during hemodialysis

BACKGROUND: We describe online optical measurements of urea in the effluent dialysate line during regular hemodialysis treatment of several patients. Monitoring urea removal can provide valuable information about dialysis efficiency. METHODS: Spectral measurements were performed with a Fourier-transform infrared spectrometer equipped with a flow-through cell. Spectra were recorded across the 5000-4000 cm(-1) (2.0-2.5 microm) wavelength range at 1-min intervals. Savitzky-Golay filtering was used to remove baseline variations attributable to the temperature dependence of the water absorption spectrum. Urea concentrations were extracted from the filtered spectra by use of partial least-squares regression and the net analyte signal of urea. RESULTS: Urea concentrations predicted by partial least-squares regression matched concentrations obtained from standard chemical assays with a root mean square error of 0.30 mmol/L (0.84 mg/dL urea nitrogen) over an observed concentration range of 0-11 mmol/L. The root mean square error obtained with the net analyte signal of urea was 0.43 mmol/L with a calibration based only on a set of pure-component spectra. The error decreased to 0.23 mmol/L when a slope and offset correction were used. CONCLUSIONS: Urea concentrations can be continuously monitored during hemodialysis by near-infrared spectroscopy. Calibrations based on the net analyte signal of urea are particularly appealing because they do not require a training step, as do statistical multivariate calibration procedures such as partial least-squares regression.     

长期血液透析患者心理压力应对方式及其影响因素的调查研究

目的探索接受持续性血液透析的患者对压力的应对方式极其影响因素。方法研究采用描述性相关性设计 ,应对方式以Jalowiec应对方式量表 (JalowiecCopingScale)量度。结果乐观应对方式为本研究中最多患者采用的方式。年龄和并发症因素影响患者是否应用乐观应对 (P<0.01);年龄因素影响逃避应对的应用 (P<0.05):60岁以上的患者较中青年患者少应用此方法 (P<0.005);自助应对方式的应用受疾病的严重程度和患者的教育程度影响 (P<0.05);患者的职业影响其是否寻求帮助 (P<0.05) ;掩饰方式的采用受疾病的严重程度和医疗费用的支付方式影响 (P<0.05)。悲观应对为女性患者第二位最常用的方式。结论患者的应对方式呈多样性。年龄、性别、教育程度、职业、疾病的严重程度及医疗费用的支付方式显著影响应对方式。在探究持续性血液透析患者的应对方式时 ,医务人员有责任协助患者采用积极的应对方式应付这个压力源。对于女性患者 ,更应注意评估其应对方式 ,协助她们采取积极的应对方式 ,以提高长期透析患者的生存质量。     

环孢素A在肾移植后的应用及血药浓度监测分析

目的:通过分析不同免疫抑制剂在肾移植后的作用,评价环孢素A的应用价值及肾移植后环孢素A血药浓度与患者血常规因素的相关性.方法:以计算机检索方法在检索中国期刊全文数据库中(CNKI:2007/2009)检索关于环孢素A在肾移植后应用的临床研究相关文献并回顾分析辽宁省电力医院检验科收集的近年肾移植后应用环孢索A的患者资料.检索词为"肾移植、环孢素A、血药浓度监测",检索后对每项相关资料进行提取、分析.结果:收集9项与本院77例患者治疗过程相近的文献共纳入患者717例,6项使用不同免疫抑制剂的文献作为比较分析,昧唑立宾、西罗莫司、吗替麦考酚酯、赛尼哌、巴利昔单抗、布雷迪宁等免疫抑制刺在器官移植中起着极其重要的作用,但仍存在很多问题有待进一步探讨.通过对免疫抑制作用机制的深入分析和临床使用的发现,环孢素A的应用更适合普通临床患者的消费,而且综合来讲不良反应少与其他免疫抑制剂合用可更好的获得协同作用,减少毒副作用.结论:结合患者的临床表现作用全面分析,及时调整治疗方案,实现个体化用药,可使环孢素A在肾移植后的应用得到最佳治疗效果.同时,寻求高效低毒的药物最终实现特异性耐受是免疫抑制剂研究的最终目标.     

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.     

Therapeutic drug monitoring of amikacin in septic patients

Introduction

Use of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy.

Methods

Sixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (C_peak) and trough (C_min) concentrations. Target concentrations had to give a ratio of at least 8 between C_peak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A C_min >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality.

Results

The median AMK LD was 1500 (750 to 2400) mg, which resulted in a C_peak/MIC ≥8 in 40 (63%) patients. Increasing the dose in the 23 patients with a C_peak/MIC <8 resulted in optimal C_peak/MIC in 15 of these patients (79%). In 23 patients (37%), C_min was >5mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal C_peak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the C_peak/MIC increased (P = 0.006). Also, increased time to optimal C_peak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial C_peak/MIC ratios but lower C_min values compared to nonsurvivors.

Conclusions

TDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal C_peak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.     

Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation support

Background/purpose  Children receiving extracorporeal membrane oxygenation (ECMO) for respiratory failure can have significant fluid overload and renal insufficiency. Addition of inline continuous venovenous hemofiltration (CVVH) could provide additional benefits in fluid management compared to use of standard medical therapies with ECMO. Methods  Patients with pediatric respiratory failure receiving ECMO with CVVH were case-matched to similar patients receiving ECMO without CVVH to compare fluid balance, medication use, and clinical outcomes. Results  Twenty-six of eighty-six patients with pediatric respiratory failure on ECMO (30%) received CVVH for >24 h (median 7.5 days on CVVH). Survival was not significantly different between patients receiving CVVH and those who did not receive CVVH (P = 0.51). For ECMO survivors receiving CVVH, overall fluid balance was less than that in non-CVVH survivors (median 25.1 ml kg⁻¹ day⁻¹; range −40.2 to 71.2 vs. 40.2, 1.1 to 134.9; P = 0.028). Time to desired caloric intake was faster in patients receiving CVVH (1 day, 1–5) than in patients who did not receive CVVH (5 days; 1–11; P < 0.001). Patients receiving CVVH–ECMO also received less furosemide (0.67 vs. 2.11 mg kg⁻¹ day⁻¹; P = 0.009). Conclusions  Use of CVVH in ECMO was associated with improved fluid balance and caloric intake and less diuretics than in case-matched ECMO controls.     

Pharmacokinetics of moxifloxacin in patients undergoing continuous venovenous haemodiafiltration

OBJECTIVE: Moxifloxacin is an 8-methoxy quinolone with a broad range of activity against clinically important pathogens. Therefore it is frequently administered in severe respiratory tract infections. Continuous venovenous haemodiafiltration (CVVHDF) is an important extracorporeal renal replacement therapy for intensive care patients suffering from sepsis and multiple organ failure. The aim of this study was to investigate the pharmacokinetics of intravenous moxifloxacin in anuric critically ill patients undergoing CVVHDF. PATIENTS AND METHODS: Pharmacokinetic analysis was performed in nine intensive care patients with acute renal failure and suspected or proven infection sensitive to moxifloxacin, who received moxifloxacin 400 mg intravenously once daily. The concentration of moxifloxacin in serum and ultradiafiltrate was determined by HPLC. RESULTS: Peak and trough serum concentrations were 3.76 +/- 2.02 mg/L and 0.24 +/- 0.14 mg/L, respectively, at the arterial port after the first dose. The mean elimination half-life was 9.87 +/- 3.26 h, the volume of distribution 270 +/- 133 L and the calculated AUC0-24 18.41 +/- 8.46 mg.h/L. Total clearance was 19.09 +/- 8.22 L/h and the clearance of haemodiafiltration 1.63 +/- 0.33 L/h. CONCLUSIONS: The pharmacokinetics of moxifloxacin in critically ill patients with acute renal failure undergoing CVVHDF was comparable to healthy subjects and patients without renal impairment. We recommend 400 mg of intravenous moxifloxacin once per day in anuric patients during CVVHDF.     

Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration: using Monte Carlo simulations to predict doses for specified pharmacodynamic targets

Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CL(CVVHDF)) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CL(CVVHDF) decreased to 36.8% when filters were in use >48 h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent.     

Therapeutic drug monitoring of stiripentol

Stiripentol is a third generation antiepileptic, marketed since 2007 under the name of Diacomit(?). It is indicated, always in combination, in the treatment of severe myoclonic epilepsy in infancy or Dravet syndrome. Its pharmacokinetics is not linear. It is a potent inhibitor of CYP3A4, 1A2 and 2C19 and increases the plasma concentrations of many other antiepileptic drugs. Without this being considered as a validated therapeutic range, the trough plasma concentrations at steady-state, corresponding to the usual doses are between 10 and 15 mg/L. The concentration-efficacy relationship is not established, but there is some evidence for a concentration-related toxicity. However, because of its non-linear kinetics, stiripentol should be a good candidate for therapeutic drug monitoring (TDM). Nonetheless, the current level of evidence for the advantage of TDM is "remains to be estimated".     

Therapeutic drug monitoring of rufinamide

Rufinamide is a third-generation antiepileptic drug, available since early 2010 in France. It is indicated in combination therapy in the Lennox-Gastaut syndrome from the age of 4. It has orphan drug status. The bioavailability of rufinamide is high, but decreases with the dose and increases with food intake. Rufinamide is not metabolized by cytochromes but hydrolyzed by a carboxylesterase in an inactive carboxylic derivative. Elimination is mainly renal. The half-life varies from 6 to 10h. Although established from relatively few studies, exposure efficacy and exposure toxicity relationships are argued. A plasma concentration of 15 mg/L, obtained with a standard regimen, reduces the number of seizures of 25%. Few factors of intrinsic variability are described. There are few clinically significant pharmacokinetic interactions and they concern combinations with other antiepileptic drugs, especially valproate. Although there is no validated therapeutic range, the level of evidence for this therapeutic drug monitoring has been estimated at "possibly useful".     

北京市血液透析单位透析用水及透析液质量的持续性质量改进

目的了解近3年来北京市血液透析单位透析用水及透析液质量的状况.方法采用统一的透析登记表对在2002～2004年期间北京市各血液透析单位透析用水和透析液方面的管理状况进行调查,并对2003年和2004年度各单位透析用水的化学污染物的检测结果及2004年透析液的内毒素污染状况进行分析.结果2002年、2003年和2004年度分别有88家、115家和110家透析单位完成了透析登记工作.①透析用水的质量管理:3年来,北京市血液透析单位对透析用水的质量日趋重视,对透析用水硬度、电导度、游离氯以及透析液细菌培养进行检测频率的达标率均有明显的改进.②透析液的质量管理:所有透析单位均使用碳酸盐透析液.2004年直接使用A、B透析液原液的单位比2002年增加约1倍(35.7%vs 18.7%);98.2%单位都能够规范的配置透析液.此外越来越多的单位进行了透析液离子浓度处方个体化的调整.③对透析用水的化学污染物及透析液内毒素的检查及改进:2003年,19/99(18.6%)家透析单位透析用水的化学污染物不合格,主要的不合格项目为:钙、硝酸盐、铝和氯胺;2004年,4家(4%)单位透析用水的化学污染物不合格,主要不合格项目为钙和硝酸盐.经过对水处理设备进行检修及改进后,复检的结果均达标.2004年我们对透析单位进行了现场内毒素检测,其中28%的单位不合格;复检后仍有2家透析液内毒素水平超标.结论3年来,北京市血液透析单位提高了对透析用水和透析液重要性的认识,加强了管理.但是,仍要警惕透析用水的污染问题.为了保证患者透析治疗的安全,各透析单位应该对透析用水及透析液进行严格管理,定期进行检测.     

Therapeutic drug monitoring of lacosamide

Lacosamide is a third generation antiepileptic drug, available in France since 2008. It is indicated in combination therapy for the treatment of inadequately controlled focal seizures, from the age of 16. The bioavailability of lacosamide is 100% and is unaffected by food intake; protein binding is low; it is metabolized by CYP2C19 into inactive O-desmethyl lacosamide. It does not inhibit or induce cytochromes; the elimination is renal with a half-life of approximately 13h. The relationship between dose and plasma concentration is established, but there does not appear to be any clear relationship between concentration and efficacy. However, the main side effects are concentration dependent. The potential for drug-drug interaction of lacosamide is low and variability between individuals is minimal. Accordingly, the level of evidence for the therapeutic drug monitoring has been estimated at "probably of no use".