Abstract：
OBJECTIVE: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lacking. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project.
METHODS: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability.
RESULTS: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children.
CONCLUSIONS: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.
METHODS: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability.
RESULTS: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children.
CONCLUSIONS: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.
摘要：
目的：关于哌拉西林-他唑巴坦在脓毒症儿童中的组织渗透的知识缺乏。在这项研究中,作为转化研究项目的一部分，在败血症仔猪和儿童中探索微透析实验的可行性和性能。
方法：对22只（其中11例为败血症）仔猪和6例败血症儿童的肌肉组织进行了多日微透析研究。在（预）临床试验之前进行了体外实验，以得出最佳的实验设置和校准技术。线性混合效应模型量化了脓毒症对相对恢复（RR）和导管间的影响，个体间,间歇,和残余变异性。
结果：仔猪和儿童体内微透析的耐受性良好，无重大不良事件。与体外实验（哌拉西林43.3％和他唑巴坦55.3％）相比，相同的实验设置导致健康和败血症仔猪的RR值较低（哌拉西林17.2-29.1％和他唑巴坦23.5％-29.1％的范围）和无法接受的低值在败血症儿童中（<10％）。因此,必须在儿科试验中进行方法学改变.得出仔猪和儿童的真实组织浓度-时间曲线。在仔猪中,脓毒症降低RR。RR变异性的最大贡献者是残差(>40%)和间期变异性(>30%)。在仔猪和儿童中，内标法是首选的校准技术。
结论：微透析是一种用于测量仔猪和儿童组织浓度的安全且适用的方法。此外，这项研究证明了实验设置的影响，脓毒症,和目标人群在个体RR上。
方法：对22只（其中11例为败血症）仔猪和6例败血症儿童的肌肉组织进行了多日微透析研究。在（预）临床试验之前进行了体外实验，以得出最佳的实验设置和校准技术。线性混合效应模型量化了脓毒症对相对恢复（RR）和导管间的影响，个体间,间歇,和残余变异性。
结果：仔猪和儿童体内微透析的耐受性良好，无重大不良事件。与体外实验（哌拉西林43.3％和他唑巴坦55.3％）相比，相同的实验设置导致健康和败血症仔猪的RR值较低（哌拉西林17.2-29.1％和他唑巴坦23.5％-29.1％的范围）和无法接受的低值在败血症儿童中（<10％）。因此,必须在儿科试验中进行方法学改变.得出仔猪和儿童的真实组织浓度-时间曲线。在仔猪中,脓毒症降低RR。RR变异性的最大贡献者是残差(>40%)和间期变异性(>30%)。在仔猪和儿童中，内标法是首选的校准技术。
结论：微透析是一种用于测量仔猪和儿童组织浓度的安全且适用的方法。此外，这项研究证明了实验设置的影响，脓毒症,和目标人群在个体RR上。
