Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16?g/24?h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean?±?standard deviation parameter estimates were 8.38?±?9.91?L/h for drug clearance and 25.54?±?3.65?L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90?mL/min/1.73?m², a high-dose continuous infusion of 24?g/24?h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT_{>4 x MIC}) against susceptible Pseudomonas aerginosa isolates (MIC ≤16?mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.     

基于治疗药物监测的重症患者哌拉西林他唑巴坦PK/PD研究

目的：探索临床使用哌拉西林他唑巴坦的重症感染患者首次治疗药物监测（TDM）后的峰谷浓度及PK/PD参数达标情况。方法：采用高效液相色谱法测定患者哌拉西林血药浓度,以本研究组建立的简易数学模拟法为基础,分别计算fT_>MIC ≥ 50%及100%的比例,并分析不同MIC值下各PK/PD目标值的达标情况。结果：58例患者的首次谷浓度为（31.68±44.33）μg·mL^-1,峰浓度为（206.59±101.37）μg·mL^-1,有5例（8.6%）患者首次谷浓度超过5 MIC,患者个体间变异较大;fT_>MIC ≥ 50%及100%的达标率分别为62.07%和36.21%。58例患者中7例确认为哌拉西林他唑巴坦耐药病原菌感染（MIC ≥ 128 μg·mL^-1）,当按耐药菌的最低MIC值（128 μg·mL^-1）计算时,其fT_>MIC ≥ 50%及100%的达标率仅为28.57%和0。结论：有必要在重症感染患者中开展基于TDM的哌拉西林他唑巴坦个体化给药方案设计。     

Clinical pharmacokinetic monitoring of midazolam in critically ill patients

Midazolam is a commonly used sedative in critically ill, mechanically ventilated patients in intensive care unit (ICU) settings worldwide. We used a nine-step decision-making algorithm to determine whether therapeutic monitoring of midazolam in the ICU is warranted. Midazolam has a higher clearance and shorter half-life than other benzodiazepines, and prolonged sedation is achieved with continuous infusion. There appears to be very good correlation between plasma concentrations of both midazolam and its active metabolite, alpha1-hydroxymidazolam, and the degree of sedation. However, due to high interpatient variability, it is not possible to predict the level of sedation in any given individual based on plasma concentration of midazolam or its metabolites. Moreover, no simple and practical assay is available to quantitate midazolam plasma concentrations in the acute ICU setting. Many scales are available to assess the sedative effects of midazolam. Because the plasma concentration of midazolam required to achieve a constant level of sedation is highly variable, it is usually more prudent for the clinician to monitor for sedation with a validated clinical scale than by plasma concentrations alone. Various physiologic parameters, including age-related effects, compromised renal function, and liver dysfunction affect the pharmacokinetics of midazolam and alpha1-hydroxymidazolam. Although routine drug monitoring for all critically ill patients receiving midazolam is not recommended, this practice is likely beneficial in patients with neurologic damage in whom sedation cannot be assessed and in patients who have renal failure with a prolonged time to awakening.     

Therapeutic drug monitoring of phenytoin in critically ill patients

Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and nontoxic levels. Hypoalbuminemia, renal failure, and interactions with other highly protein-bound drugs (e.g., valproic acid) alter protein binding of phenytoin. When these conditions are present, free serum concentrations, which represent the pharmacologically active entity, cannot be predicted from total serum concentrations. Besides general alterations in drug distribution and elimination, protein binding is often altered in critically ill patients. Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. Free drug measurements and theoretical equations to facilitate the interpretation of total phenytoin serum levels have been introduced. However, they are not widely implemented in clinical practice because evidence of improvements in patient outcomes is limited. Knowledge of the pharmacokinetic properties of phenytoin is indispensable for correct interpretation of total serum concentrations when protein binding is altered. Free serum concentrations should be measured, or theoretically calculated if measurements are unavailable, to avoid misinterpretation of total serum levels and consequent inappropriate adjustments in the dosage of phenytoin in critically ill patients.     

危重症感染患者血清中替考拉宁浓度测定

目的:建立高效液相色谱法快速测定人血清中替考拉宁浓度的方法,并用于危重症感染患者治疗药物监测。方法:色谱柱:Hypersil C18柱(250mm×4.6mm,5μm);流动相:0.01mol.L-1磷酸二氢钠-乙腈-甲醇(70∶25∶5,pH2.1),流速1.0mL.min-1。紫外检测波长为240nm,进样量20μL,柱温25℃。结果:替考拉宁在5.63~125.00mg.L-1内线性关系良好(r=0.999 5),最低定量限为5.63mg.L-1,提取回收率为95.13%,方法回收率为98.13%,日内、日间精密度的RSD分别为3.2%和6.8%。另外,所监测的8例肾功能不全患者中,有50%(4/8)患者替考拉宁质量浓度小于10mg.L-1。结论:HPLC简便、灵敏、快速、重复性好,可用于危重症感染患者替考拉宁的血药浓度监测;危重症感染患者应用替考拉宁后血药浓度变化较大,需要通过治疗药物监测的方法制定个体化给药方案。     

某三甲医院危重症病人万古霉素血药浓度监测与临床用药 87例分析

目的通过分析危重症病人万古霉素血药浓度监测结果,为临床合理用药提供参考。方法采用化学发光法( CIMA)测定万古霉素血药浓度,对 2016年 1月至 2018年 12月期间中国科学技术大学附属第一医院 87例病人共进行 190例次万古霉素血药浓度监测,对万古霉素的监测结果及用药信息进行统计分析。结果 87例病人共监测血药浓度 190次,血药浓度( 24.48± 18.65)μg/mL,在治疗窗的占 35.3%,其中首次监测浓度在治疗窗内的仅占 26.67%;18～60岁组、 60～75岁组以及＞ 75岁组病人血药浓度均值均超出治疗窗;肾功能下降组病人血药浓度［(21.84±19.86)μg/mL、(34.44±22.26)μg/mL、(36.14±20.33)μg/ mL］显著高于肾功能正常组［(13.04±8.09)μg/mL］差异有统计学意义( P＜0.05);用药前后,肾功能正常组的尿素氮［(7.42± 2.47)比( 11.16±9.44)μmol/L］和肾功能轻度下降组的肌,酐清除率［(75.98±6.72)比( 111.43±60.31)mL/min］的差异有统计学意义(P＜0.05)肾功能中度下降组和肾功能重度下降组肾功能指标均差异无统计学意义( P＞0.05);此外, 87例病人中急性肾损伤(AKI)的发生,率为 21.13%,肾功能亢进( ARC)的发生率为 18.31%。结论万古霉素药动学个体差异较大,临床应加强危重症病人万古霉素血药浓度的监测,结合病人个体情况,施行个体化用药;此外,在危重症病人中,应尽早识别 AKI及 ARC病人,根     

Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients

Since the bactericidal effects of beta-lactam antibiotics are time dependent, the optimum strategy for their administration could be continuous infusion. In this prospective, randomised controlled trial to evaluate the clinical efficacy of continuous infusion therapy, we evaluated the outcomes for 40 septic critically ill patients who received piperacillin either continuously (2 g intravenously (i.v.) over 0.5 h as a loading dose followed by 8 g i.v. daily over 24 h (n=20)) or as an intermittent infusion (3 g i.v. every 6h over 0.5 h (n=20)). Results from our study demonstrated that the clinical efficacy of piperacillin as a continuous infusion is superior to intermittent administration in critically ill patients. Change in APACHE II scores from baseline at the end of the second, third and fourth days, respectively, were 4.1, 5.1 and 5.2 for continuous infusion and 2.0, 2.6 and 2.8 for intermittent infusion (P< or =0.04). Considering minimum inhibitory concentrations (MICs) of 16 microg/mL and 32 microg/mL, the percentage of time for which piperacillin plasma concentrations were higher than the MIC (%T>MIC) was calculated for each patient in the two groups. For MICs of 16 microg/mL and 32 microg/mL, %T>MIC in the continuous infusion group was 100% and 65% of the dosing interval, respectively; in the intermittent infusion group, %T>MIC was only 62% and 39% of the dosing interval. There was a significant relationship between clinical results and laboratory data. It was shown that the superiority of the clinical efficacy of continuous infusion could be related to piperacillin pharmacodynamics. Continuous infusion significantly reduced the severity of illness as demonstrated by APACHE II scores during therapy.     

Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration

This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3–3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m². Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 samples were collected. Median peak plasma concentrations were 210.5 (interquartile range = 161.5–229.0) and 29.4 (27.9–32.0) mg/L and median trough plasma concentrations were 64.3 (49.0–68.9) and 12.3 (7.7–13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6–8.7) and 7.3 (4.6–11.8) h, volume of distribution 0.42 (0.29–0.49) and 0.32 (0.24–0.36) L/kg, total clearance 5.1 (4.2–6.2) and 3.8 (3.3–4.2) L/h and CVVHDF clearance 2.5 (2.3–3.1) and 2.5 (2.3–3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration–time curve of the unbound drug in ISF to plasma (unbound AUC_ISF/AUC_plasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5 g piperacillin/tazobactam administered evry 8 h resulted in piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.     

危重患者液体治疗

液体治疗是重症患者常用的治疗手段,其治疗方案的合理与否对患者预后起着决定性作用。本文对液体治疗的途径、液体种类的优缺点以及液体治疗的并发症及监测进行了论述。     

阿米卡星在严重败血症患者体内的药代动力学研究

目的：初步探讨25 mg·kg －1的阿米卡星在重症监护室（ICU）患者体内的药代动力学。方法纳入符合条件的30例革兰阴性（G －）败血症患者进行阿米卡星药物治疗研究,通过非房室模型计算每名患者的阿米卡星的药代动力学。结果阿米卡星在 G －败血症患者体内平均药物分布为（0．36±0．07）L·kg －1,平均血液清除率为（3．88±0．97）mL·min －1·kg －1。肌酐清除率与血清肌酸酐（SCr）相关性具有统计学意义。结论对 ICU 患者应用高剂量阿米卡星（≥25 mg·kg －1）需要考虑败血症对血液动力学的影响,需要密切监测败血症血液药物浓度变化,关键要考虑到重症患者体内药代动力学与普通人群是不同的。     

ICU危重患者无创脉搏血氧饱和度监测临床应用现状

无创脉搏血氧饱和度(SpO2)测量技术是一种克服了电化学法缺点的新型光学测量方法,具有无创、实时、连续等优点,被广泛用于ICU、手术室、急救病房、麻醉复苏室等临床工作中。本文从当前ICU危重患者常用的无创SpO2监测方法、原理和影响因素,对无创SpO2监测结果与动脉血氧分压、血氧饱和度的相关性进行综述,为更好地将无创SpO2监测技术应用于ICU危重患者的诊疗提供理论参考依据。     

连续性静脉-静脉血液滤过患者血清中利奈唑胺的浓度监测

目的:对连续性静脉-静脉血液滤过(continuous venovenous hemofiltration,CVVH)治疗的危重患者进行利奈唑胺血药浓度监测,为临床个体化治疗提供依据。方法:建立高效液相色谱法(以左氧氟沙星为内标),测定患者血清中利奈唑胺谷浓度。结果:利奈唑胺在0.31～20.00μg.mL-1内线性关系良好(r=0.999 5),定量限为0.31μg.mL-1。5例危重患者在治疗期间监测23次的利奈唑胺谷浓度变化明显,变化范围为1.53～17.10μg.mL-1。有2例患者谷浓度变化较大(相差近5倍)。结论:高效液相色谱法简单、快速、准确、灵敏、重复性好,可用于临床利奈唑胺的血药浓度监测。进行连续性静脉-静脉血液滤过治疗的患者,应用利奈唑胺时血药浓度变化较大,需要通过治疗药物监测的方法制定个体化给药方案。     

血清氯浓度与危重病患者急性肾损伤的关系

目的 探讨血清氯离子浓度与危重病患者急性肾损伤（AKI）的相关性。方法 回顾性分析合肥市第一人民医院2015年1月至2015年12月于ICU治疗的83例患者的临床资料,按照国际改善全球肾脏病预后组织（KDIGO）发表的AKI的定义,将入选患者分为AKI组（21例）和非AKI组（62例）。收集患者ICU治疗期间血清氯离子浓度数据。分别用Cl₀、Clmax、Clmin、Clmean表示收治ICU期间初始、最高、最低及平均血清氯离子浓度,分析血清氯离子浓度与急性肾损伤之间的关系。结果 83例患者中,21例发生AKI,占25.3%。两组患者Cl₀差异无统计学意义（P=0.410）;AKI组患者的Clmax、Clmean均高于非AKI组,Clmin低于非AKI组[（110.10±8.58）、（103.80±4.96）、（93.57±4.84）vs（105.61±3.64）、（100.67±5.21）、（96.26±4.71）],差异有统计学意义（P<0.05）。单因素logistic回归分析显示Clmax、Clmin、Clmean是AKI发生危险因素,随着Clmax、Clmean的升高,AKI发生的风险加大,而随着Clmin的上升,AKI发生的风险有下降的趋势。结论 过高或过低的血清氯离子浓度都可能与急性肾损伤发生相关,应注意及时干预。     

Nasogastric lansoprazole is effective in suppressing gastric acid secretion in critically ill patients

AIM: To evaluate the effect of nasogastric lansoprazole on acid suppression in critically ill patients. METHODS: Patients were eligible for the study if they had a nasogastric tube in place and had not received acid-suppressive agents for 3 days prior to enrolment into the study. Patients with active gastrointestinal bleeding or a baseline gastric pH > 4.0 were excluded. Patients served as their own controls during a 24 h lead-in period. Lansoprazole 30 mg was administered once daily with water through a nasogastric tube for 2 days. Intragastric pH was measured by continuous 24 h pH-metry for 3 days. RESULTS: Fifteen patients were enrolled into the study. The baseline median 24 h intragastric pH was 2.25 +/- 1.01, and increased to 6.70 +/- 0.82 (P= 0.001) after 2 days of lansoprazole. Mean percentage of time intragastric pH was > or = 4.0 was 25 +/- 13% at baseline, and increased to 84 +/- 14% (P=0. 001) after 2 days of lansoprazole. CONCLUSIONS: Nasogastric lansoprazole 30 mg daily is effective in suppressing gastric acid secretion in critically ill patients.     

Pharmacokinetics of linezolid in critically ill patients

Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion.

Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population.

Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.     

Infectious diseases in the critically ill patients

Infection is common in the critically ill and often results due to the severity of the patient's illness. Recent data suggest 51% of intensive care unit (ICU) patients are infected, and 71% receive antimicrobial therapy. Bacterial infection is the primary concern, although some fungal infections are opportunistic. Infection more than doubles the ICU mortality rate, and the costs associated with infection may be as high as 40% of total ICU expenditures. There are many contemporary antimicrobial resistance concerns that the critical care clinician must consider in managing the pharmacotherapy of infection. Methicillin resistance in Staphylococcus aureus, vancomycin resistance in Enterococci, beta-lactamase resistance in Enterobacteriaceae, multidrug resistance in Pseudomonas aeruginosa and Acinetobacter species, fluoroquinolone resistance in Escherichia coli, and fungal resistance are among the most common issues ICU clinician's must face in managing infection. Critical illness causes changes in pharmacokinetics that influence drug and dosing considerations. Absorption, distribution, metabolism, and excretion may all be affected by the various disease states that define critical illness. Several specific diseases are discussed, including ventilator-associated pneumonia, various fungal infections, gastrointestinal infections due to Clostridium difficile, urinary tract infections, and bloodstream infections. Within each disease section, discussion includes causes and prevention strategies, microbiology, evidence-based guidelines, and important caveats.     

Pharmacokinetics of cimetidine in critically ill patients

Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p<0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.