University of Vermont Larner College of Medicine, Burlington, VT, USA.
Queen's University, Kingston, ON, Canada.
Clin Nutr. 2020 Mar;39(3):958-965. doi: 10.1016/j.clnu.2019.03.040. Epub 2019 Apr 9.
Pharmacokinetics (PK) of pharmaceuticals and pharmaconutrients are poorly understood in critically ill patients, and dosing is often based on healthy subject data. This might be particularly problematic with enteral medications due to metabolic abnormalities and impaired gastrointestinal tract absorption common in critically ill patients. Utilizing enteral fish oil, this study was undertaken to better understand and define PK of enteral omega-3 fatty acids (eicospentaenoic acid [EPA] and docosahexaenoic acid [DHA]) in critically ill patients with severe sepsis.
Healthy volunteers (n = 15) and mechanically ventilated (MV) adults with severe sepsis (n = 10) were recruited and received 9.75 g EPA and 6.75 g DHA daily in two divided enteral doses of fish oil for 7 days. Volunteers continued their normal diet without other sources of fish oil, and sepsis patients received standard enteral feeding. Blood was collected at frequent intervals during the 14-day study period. Peripheral blood mononuclear cells (PMBCs) and neutrophils were isolated and analyzed for membrane fatty acid (FA) content. Mixed linear models and t-tests were used to analyze changes in FA levels over time and FA levels at individual time points, respectively. PK parameters were obtained based on single compartment models of EPA and DHA kinetics.
Healthy volunteers were 41.1 ± 10.3 years; 67% were women. In patients with severe sepsis (55.6 ± 13.4 years, 50% women), acute physiologic and chronic health evaluation (APACHE) II score was 27.2 ± 8.8 at ICU admission and median MV duration was 10.5 days. Serum EPA and DHA were significantly lower in sepsis vs. healthy subjects over time. PBMC EPA concentrations were generally not different between groups over time, while PBMC DHA was higher in sepsis patients. Neutrophil EPA and DHA concentrations were similar between groups. The half-life of EPA in serum and neutrophils was significantly shorter in sepsis patients, whereas other half-life parameters did not vary significantly between healthy volunteers and sepsis patients.
While incorporation of n-3 FAs into PBMC and neutrophil membranes was relatively similar between healthy volunteers and sepsis patients receiving identical high doses of fish oil for one week, serum EPA and DHA were significantly lower in sepsis patients. These findings imply that serum concentrations and EPA and DHA may not be the dominant driver of leukocyte membrane incorporation of EPA and DHA. Furthermore, lower serum EPA and DHA concentrations suggest that either these n-3 FAs were being metabolized rapidly in sepsis patients or that absorption of enteral medications and pharmaconutrients, including fish oil, may be impaired in sepsis patients. If enteral absorption is impaired, doses of enteral medications administered to critically ill patients may be suboptimal.
在重症患者中，药物和营养药物的药代动力学（PK）了解甚少，给药通常基于健康受试者的数据。由于代谢异常和胃肠道吸收受损在重症患者中很常见，因此肠内药物的给药可能会特别成问题。本研究利用肠内鱼油，旨在更好地了解和定义严重脓毒症的重症患者肠内 ω-3 脂肪酸（二十碳五烯酸[EPA]和二十二碳六烯酸[DHA]）的 PK。
招募了健康志愿者（n=15）和接受机械通气（MV）的严重脓毒症（MV）成年患者（n=10），并在 7 天内每天两次接受 9.75g EPA 和 6.75g DHA 的鱼油肠内剂量。志愿者继续正常饮食，不食用其他鱼油来源，脓毒症患者接受标准肠内喂养。在 14 天的研究期间，频繁采集血液样本。分离外周血单核细胞（PMBC）和中性粒细胞，并分析膜脂肪酸（FA）含量。使用混合线性模型和 t 检验分别分析 FA 水平随时间的变化和各时间点的 FA 水平。根据 EPA 和 DHA 动力学的单室模型获得 PK 参数。
健康志愿者的年龄为 41.1±10.3 岁；67%为女性。严重脓毒症患者（55.6±13.4 岁，50%为女性）的急性生理和慢性健康评估（APACHE）II 评分在 ICU 入院时为 27.2±8.8，中位 MV 持续时间为 10.5 天。血清 EPA 和 DHA 在脓毒症患者中随时间的推移明显低于健康受试者。PBMC EPA 浓度在组间随时间的变化无明显差异，而 PBMC DHA 在脓毒症患者中较高。中性粒细胞 EPA 和 DHA 浓度在组间相似。血清和中性粒细胞 EPA 的半衰期在脓毒症患者中明显短于健康志愿者，而其他半衰期参数在健康志愿者和脓毒症患者之间无明显差异。
虽然健康志愿者和接受相同高剂量鱼油治疗一周的严重脓毒症患者的 n-3 FA 掺入 PBMC 和中性粒细胞膜相对相似，但脓毒症患者的血清 EPA 和 DHA 明显较低。这些发现表明，血清浓度和 EPA 和 DHA 可能不是白细胞膜掺入 EPA 和 DHA 的主要驱动因素。此外，较低的血清 EPA 和 DHA 浓度表明，这些 n-3 FAs 在脓毒症患者中可能被快速代谢，或者包括鱼油在内的肠内药物和营养药物的吸收可能在脓毒症患者中受损。如果肠内吸收受损，给予重症患者的肠内药物剂量可能不理想。
