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。     

危重症患者替加环素的群体药动学

目的: 建立替加环素在危重症患者中的群体药动学模型,探究该类人群中影响替加环素药动学的因素。方法: 收集静脉使用替加环素的危重症患者的血样,使用高效液相色谱-质谱联用技术测定替加环素的血药浓度。利用NONMEM软件估算替加环素的药动学参数,通过向前纳入法和逆向剔除法建立替加环素群体药动学模型,并对该模型进行验证和评价。结果: 收集54名患者的143个血药浓度建立替加环素的群体药动学模型,静脉给药的一室模型较好地描述替加环素的药动学特征,替加环素的清除率(CL)、表观分布容积(V_d)的群体典型值分别为11.3 L·h^-1和105 L,患者的APACHE Ⅱ评分和年龄对模型有显著影响。结论: 建立的替加环素群体药动学模型预测性能稳定良好,APACHE Ⅱ评分影响替加环素CL,年龄影响替加环素V_d,可为临床替加环素在危重症患者中的个体化给药提供参考。     

The pharmacokinetics of ketobemidone in critically ill patients

AIMS: To study the pharmacokinetics of orally and intravenously administered ketobemidone in critically ill patients. METHODS: Seventeen patients were studied during their stay in the intensive care unit at Huddinge University Hospital. Nine patients received a single intravenous dose of ketobemidone (0.04 mg kg-1) and eight patients received a single oral dose of 5 mg. Plasma concentrations of ketobemidone were measured using liquid chromatography-mass spectrometry. The pharmacokinetic analysis was performed using WinNonlin trade mark software. RESULTS: There was a wide variation in the different pharmacokinetic parameters among patients. Mean clearance in patients treated intravenously was 74.5 (95% CI 43.2, 128.3) and mean Vd was 2.4 l kg-1 (95% CI 2.0, 2.8). t1/2,z also varied widely with a mean value of 4.41 h (95% CI 2.7, 7.0). The corresponding values for MRT were 5.4 and 3.3, 8.8. Mean oral clearance (CL/F) was 102 l h-1 (95% CI 82.7, 125.8), mean Vz/F was 11.2 l kg-1 (95% CI 9.7, 13.1) and mean t1/2,z was 6.0 (95% CI 4.9, 7.3) in orally treated patients. Cmax showed a mean of 38 nmol l-1 (95% CI of 31, 47). A significant correlation was observed between the glomerular filtration rate (GFR) and the half-life of ketobemidone (r = -0.72, P < 0.05). t1/2,z was generally longer and the variation larger in critically ill patients compared with healthy individuals. However, there was no correlation between the elimination of ketobemidone in critically ill patients and plasma C-reactive protein, white blood count or plasma albumin concentrations. CONCLUSIONS: The disposition of ketobemidone is highly variable in critically ill patients. In order to ensure sufficient analgesia and avoid toxicity, therapeutic monitoring should be employed when using ketobemidone in this group of patients.     

Altered aminoglycoside pharmacokinetics in critically ill patients with sepsis

The pharmacokinetic disposition of aminoglycosides in critically ill patients with sepsis was studied. In an open-label study of the disposition of gentamicin and tobramycin, individualized pharmacokinetic values of 100 critically ill patients in the surgical intensive-care unit were compared with those of a concurrently monitored group of 100 surgery patients who were not critically ill. The a priori computer-predicted dosage requirements of the critically ill patients were also compared with the dosages derived from their individualized pharmacokinetic values, and intrapatient variation in the critically ill patients was studied. Serum concentration-time data were analyzed using a one-compartment model and the DataMed Clinical Support Services system to provide individualized dosage requirements. Initial dosing guidelines were also generated for the critically ill patients using the a priori model of the DataMed Clinical Support Services program and patient demographic information. The critically ill patients were significantly older, had higher serum creatinine concentrations (SCr), and had lower elimination rate constants (k) and total body clearances (CL) than the surgery patients who were not critically ill. The volume of distribution (V) was not significantly different. The a priori computer predictions for the critically ill patients were significantly lower than the individualized values for V, CL, dose, and amount of drug per 24 hours. The dosing regimen from the a priori model was the same as the individualized regimen in only 2/100 patients. In the 76 critically ill patients who had a second pharmacokinetic analysis performed, there was a significant decrease in k and CL from the first analysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

ICU老年患者液体出入量对万古霉素药代动力学的影响

目的 研究液体出入量对ICU老年患者万古霉素药代动力学的影响.方法 完全随机选择8例ICU中应用万古霉素的老年患者,记录其每日液体出入量,并采集患者血液,利用高效液相色谱法测定万古霉素的血药浓度,计算药代动力学参数,对万古霉素药代动力学参数与患者每日出入量之间的关系给予统计学分析.结果 ICU老年患者年龄(71 ±11)岁,急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分(17.13±3.13)分,液体净出入量(375±123)ml,分布半衰期(t1/2α)(0.45±0.27)h,清除半衰期(t1/2β)(6.86±3.42)h,浓度时间曲线下面积(AUC)(137.9±19.9) mg/(h·L),峰值浓度(Cmax)(36.14±10.30) mg/L,清除率(61.56±29.11) ml/min,表观分布容积(0.28±0.14)L/kg.ICU老年患者与正常老年人相比,表观分布容积差别有统计学意义(P＜0.01).ICU老年患者APACHEⅡ评分与液体净出入量和万古霉素t1/2β均呈正相关(r=0.811,P=0.015;r =0.035,P=0.035);液体出入量与血AUC呈负相关,与血t1/2β呈负相关(r=- 0.786,P=0.021).结论 当ICU患者的出入量平衡增加时,其万古霉素的杀菌效果可能会降低,难以达到预期疗效.     

Intrapatient variation of aminoglycoside pharmacokinetics in critically ill surgery patients

Intrapatient variation in aminoglycoside pharmacokinetics was studied in 100 critically ill surgery patients, and the relationships between aminoglycoside pharmacokinetics and physiological variables were evaluated. A one-compartment model and the DataMed Clinical Support Service System were used to calculate pharmacokinetic values from serum concentration-time data and to provide individualized dosage regimens. A total of 323 pharmacokinetic analyses (2 to 9 per patient) were performed. There were significant intrapatient differences in clearance (CL) between analyses, and there was a downward trend in elimination rate constant (k) and an upward trend in half-life (t1/2) with time. There were no significant differences in mean volume of distribution (V) between analyses and no strong correlations of V, k, and CL between analyses. The total daily dosage necessary to provide the desired serum aminoglycoside concentration decreased with time, while the dosing interval increased. The mean absolute changes in t1/2, V, and CL between analyses were 3.2 hr, 7.1 L, and 15.7 mL/min, respectively. Dosing regimen changes were required in 90% of the patients, regardless of the time between analyses, including 75% (24/32) of the patients with analyses on consecutive days. There were weak correlations between changes in serum creatinine concentration and changes in dosing interval and between changes in weight and changes in V. Changes in calculated creatinine clearance, BUN, pulmonary capillary wedge pressure, central venous pressure, systemic vascular resistance, cardiac index, input minus output, and maximum temperature did not result in strong correlations with k, t1/2, V, and CL by univariate or multivariate regression analyses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration

AIMS: To investigate the pharmacokinetics of vancomycin in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF), a continuous renal replacement therapy (CRRT) and to see if routine measures approximate vancomycin clearance. METHODS: Pharmacokinetic profiles (15) of initial and steady-state doses of 750 mg twice daily intravenous vancomycin were obtained from blood and ultrafiltrate samples from 10 critically ill patients in the intensive care unit, with acute renal failure on CVVHDF (1 l h(-1) dialysate plus 2 l h(-1) filtration solution; 3 l h(-1) effluent; extracorporeal blood flow 200 ml min(-1)). RESULTS: CVVHDF clearance of vancomycin was 1.8 +/- 0.4 l h(-1) (30 +/- 6.7 ml min(-1)). This was 1.3-7.2 times that reported previously for vancomycin using other forms of CRRT. Total vancomycin body clearance was 2.5 +/- 0.7 l h(-1) (41.7 +/- 11.7 ml min(-1)). The clearance of vancomycin by CVVHDF was 76 +/- 16.5% of the total body clearance. CVVHDF removed approximately half the vancomycin dose during the 12-h period (A(CVVHDF) = 413 mg). The fraction eliminated by all routes was 60%. The sieving coefficient for vancomycin was 0.7 +/- 0.1 and for urea was 0.8 +/- 0.06. CONCLUSIONS: Vancomycin is cleared effectively by CVVHDF. Clearance was faster than other forms of CRRT, therefore doses need to be relatively high. Urea clearance slightly overestimates vancomycin clearance. The administered doses of 750 mg every 12 h were too high and accumulation occurred, as only approximately 60% of a dose was cleared over this period. The maintenance dose required to achieve a target average steady-state plasma concentration of 15 mg l(-1) can be calculated as 450 mg every 12 h.     

Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06–0.14) mg/L and 0.07 (0.05–0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10–7.26) mg/L and 1.81 (1.20–7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3–162.7) and 21.2 (18.4–109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.     

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.     

精细化护理在老年急危重症急救护理中的应用

目的 研究探讨精细化护理在急危重症老年患者中的应用效果.方法 将本院2014年3月至2015年3月收治的急危重症老年患者78例,按照统计学原理分为对照组和观察组,每组39例.对照组患者在急救护理的过程中展开常规化的护理措施,观察组患者在急救护理的时候实行精细化护理模式,比较两组患者各项急救措施所花时间与抢救成功率.结果 急救护理结果表明,观察组患者接诊时间、抢救室护理时间以及总急救时间都要短于对照组患者,差异有统计学意义(P＜ 0.05);与此同时,观察组患者基本生命支持5 min内完成率与抢救成功率分别为87.2％、92.3％,对照组患者基本生命支持5 min内完成率与抢救成功率为56.4％、71.8％,差异有统计学意义(P＜0.05).结论 在为急危重症老年患者实行急救护理的过程中,采用精细化护理模式,可以为患者迸一步抢救赢得时间,促使患者在最短的时间内恢复生命支持,提高抢救成功率,精细化护理在老年急危重症患者急救护理中具有重要的临床意义.     

Dopamine pharmacokinetics in critically ill newborn infants

Summary Dopamine is frequently used in critically ill newborn infants for treatment of shock and cardiac failure, but its pharmacokinetics has not been evaluated using a specific analytical method. Steady-state arterial plasma concentrations of dopamine were measured in 11 seriously ill infants receiving dopamine infusion, 5–20 g · kg^–1 · min^–1, for presumed or proven sepsis and hypotensive shock.Steady-state concentrations of dopamine ranged from 0.013–0.3 g/ml. Total body clearance averaged 115 ml · kg^–1 · min^–1. The apparent volume of distribution and elimination half life averaged 1.8 1 · kg^–1 and 6.9 min, respectively.No relationship was observed between dopamine pharmacokinetics and gestational age, postnatal age or birthweight. Substantial interindividual variation was seen in dopamine pharmacokinetics in seriously ill infants, and plasma concentrations could not be predicted accurately from its infusion rate.Marked variation in clearance explains in part, the wide dose requirements of dopamine needed to elicit clinical response in critically ill newborn infants.VBM was a Fellow at Ohio State University and Children's Hospital at the time of study and is now at the Department of Pharmacy Services and College of Pharmacy, University of Michigan, Ann Arbor, MI, USA     

Population pharmacokinetics of erythropoietin in critically ill subjects

The effects of various covariate factors on the pharmacokinetics of erythropoietin (EPO) in subjects who are critically ill and admitted to an intensive care unit were evaluated. Nonlinear mixed-effects modeling was used to analyze the data from 48 patients receiving subcutaneous doses of 40,000 IU/wk epoetin alfa enrolled in a randomized, double-blind, placebo-controlled, multicenter study. The pharmacokinetics of EPO follows a 1-compartment disposition model with first-order absorption and an endogenous input rate. For a patient weighing 70 kg, the typical apparent clearance (CL/F) and apparent volume of distribution (V/F) were estimated to be 1.86 L/h and 27.8 L. The interindividual variability in CL/F and V/F was estimated to be 57.2% and 83.8%. CL/F and V/F of EPO increased with body weight, as described by the following relation: CL/F = (CL/F)std*(W/W(std))0.75, and V/F = (V/F)std*(W/W(std))1.37, where W is individual weight, and W(std) is the median weight of the study population. There was a 46% drop in exposure of EPO from the first to the subsequent dosing events. The endogenous EPO production rate was found to decrease progressively with the course of the study. In addition, the modeled endogenous EPO production rate increased with body weight. The net effect of this increase on the endogenous plasma EPO levels may not be significant because EPO clearance was found to increase with body weight. All other factors investigated (eg, Sequential Organ Failure Assessment [SOFA] scores and APACHE II scores) had no significant effect on EPO pharmacokinetics. The typical population estimate of CL/F of EPO was close to previously reported values in healthy volunteers.     

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

AIMS

To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock.

METHODS

Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling.

RESULTS

The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h⁻¹ (49%), a mean half-life of 9.6 h (range 0.83–28.6 h) and a total volume of distribution of 19.5 l (range 6.48–35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low.

CONCLUSIONS

Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l⁻¹).     

The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients

The critically ill patient occupies an increasing amount of time and bed space in modern hospital practice, and also commands increasing expenditure. Drug therapy in these patients has, in the past, been based on data derived from healthy volunteers, fit anaesthetised patients undergoing minor operative procedures, or patients with single organ failure. Alterations in pharmacokinetics and pharmacodynamics have not been studied in depth in critically ill patients who often have multisystem failure. This paper reviews the currently available information on drugs in common usage in these patients. The studies that have been performed have usually shown delayed drug clearance, altered volumes of distribution and prolonged elimination half-lives. The sedative and analgesic drugs, in particular, have shown marked accumulation which may confuse the clinical picture, and prolonged periods of assisted ventilation may be required until the drugs are eliminated.     

The pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis

AIM

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis.

METHODS

Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg⁻¹. Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis.

RESULTS

Steady-state volume of distribution was determined to be 111 ± 71 ml kg⁻¹ and plasma clearance was 5.2 ± 1.8 ml min⁻¹ kg⁻¹ in these patients with greater inter-patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml⁻¹) was larger than previously described.

CONCLUSIONS

This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response.     

Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy

BACKGROUND AND OBJECTIVE: Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT. PATIENTS AND METHODS: A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CL(CR)), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied. RESULTS: The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CL(CR) was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CL(CR) on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 x CL(CR) for septic patients and CL = 6.63 + 0.72 x CL(CR) for polytraumatized patients). The volume of distribution of the central compartment (V(1)) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V(1) were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of > or =4 mg/L are isolated. Infections caused by pathogens with an MIC of > or =8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary. CONCLUSION: A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CL(CR) and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.     

低蛋白血症对重症患者抗菌药物药代动力学和药效学影响的研究进展

本文通过对合并低蛋白血症的重症患者使用高蛋白结合率抗菌药物后体内药代动力学与药效学的研究进行综述,为临床优化抗菌药物治疗、提高疗效、减少药品不良反应和住院时间及降低住院成本提供方案,为抗菌药物在合并低蛋白血症重症患者中的合理应用提供参考。     

Single-dose and steady-state pharmacokinetics of piroxicam in elderly vs young adults

Summary Age-dependent changes in pharmacokinetics are considered a possible factor contributing to a higher risk of side-effects from drug treatment in the elderly. However, very little is known about the kinetics and metabolism of most NSAI agents in geriatric subjects. In a prospective age-comparison study, the single dose and steady-state pharmacokinetics of piroxicam 20 mg once daily were determined in 44 subjects ranging in age from 30 to 80 years. Plasma concentrations, elimination half-life, AUC, and volume of distribution were not influenced by age or sex and were in agreement with previously reported results in young adults. Pharmacokinetic parameters in 18 patients with evidence of mild or moderate renal impairment at study entry were not different from those in patients without impairment. Based on this and other studies, elderly patients receiving the recommended dose of piroxicam are not exposed to undue risk related to pharmacokinetic considerations.