严重脓毒症免疫炎症反应紊乱及双向免疫调节的前瞻性随机对照研究

目的 分析严重脓毒症患者的免疫炎症反应紊乱状态,探讨连续血液净化、α1胸腺肽以及两者联用对免疫炎症反应紊乱及预后的影响.方法 年龄18岁、Marshall评分>5分的严重脓毒症患者91例,监测血清白细胞介素(IL)-6、IL-10、TNFα水平和单核细胞人白细胞DR抗原(HLA-DR)、T淋巴细胞计数的动态变化;并随机分为血液净化组、胸腺肽组、联合组和对照组.血液净化组连续3 d应用连续性肾脏替代治疗(cRRT)或分子吸附再循环系统(MARS)治疗,同时给予经典SSC治疗;胸腺肽组皮下注射α1胸腺肽1.6 mg/d,连续7 d,同时给予经典SSC治疗;联合组:联合应用血液净化组和胸腺肽组治疗方案;对照组给予经典SSC治疗.观察患者治疗前及治疗后3、7 d以上免疫炎症指标及临床预后.结果 与健康对照组比较,严重脓毒症患者血清IL-6、IL-10、IL-6/IL-10和TNFα明显升高,HLA-DR、CD+3、CD+4;和CD+8T淋巴细胞明显降低(P<0.05或P<0.01),与存活者比较,死亡患者血清IL-6、IL-6/IL-10、TNFα、HLA-DR、CD+4、CD+4和CD+8;变化更明显(P<0.05或P<0.01).与对照组同期比较,胸腺肽组治疗后7d CD+3;明显升高(P<0.05),血液净化组和联合组治疗后7 d IL-6、IL-6/IL-10和TNFα均明显下降,HLA-DR、CD+3、CD+4和CD+8均明显增高,且联合组治疗后3 d TNFα已有明显下降,CD+3和CD+4就已明显升高(P<0.05或P<0.01);与胸腺肽组同期比较,血液净化组和联合组所有指标均有改善,但仅联合组治疗后3 d CD+3;明显升高,治疗后7 dIL-6/IL-10明显下降(P<0.05);3个治疗组28 d内机械通气时间、ICU停留时间均有缩短,28 d病死率和90 d病死率均有下降,其中血液净化组ICU停留时间、联合组28 d内机械通气时间和ICU停留时间明显缩短(P<0.05).结论 严重脓毒症患者全身炎症反应和免疫抑制同时存在;α1胸腺肽具有免疫增强的作用,连续血液净化具有抗炎和免疫增强双向调节作用;两者均可改善患者临床预后,且联用后效果更好.

Immune and inflammation confusion in severe sepsis and effects of bi-immunomodulation therapy:a prospective, randomized, controlled clinical trial

Objective To investigate the immune and inflammation confusion state in severe sepsis and the effects of two way immunomodulation therapy with continuous blood purification (CBP), thymosin α1, and combined therapy of CBP and thymosin α1. Methods 91 Patients with severe sepsis aged 18,with Marshall score >5. Were randomly divided into 4 groups: CBP Group (n =22) undergoing continuous renal replacement therapy (CRRT) or molecular adsorbents recirculating system (MARS) therapy once a day for 3 days in addition to classical Surviving Sepisis Campaign (SSC) therapy, Thymosin α1 Group (n =23) undergoing subcutaneous injection of thymosin α1 1.6 mg once a day for 7 days in addition to SSC therapy, Combined Therapy Group (n = 22) undergoing CBP combined with thymosin α1 treatment in addition to SSC therapy, and SSC Group (treatment control group, n = 24) undergoing SSC therapy only. Peripheral blood samples were collected before treatment, and 3 and 7 days after the beginning of treatment (days 4 and 8) to detect the serum interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α. The levels of CD+ 14 monocyte human leucocyte antigen (HLA)-DR and T lymphocytes were monitored. The mechanical ventilation time, ICU stay length, and mortality within 28 d and mortality within 90 d were observed. Ten healthy persons were used as healthy control group. Results Thirty-four of the 91 patients died within 28 d with a mortality of 77.4% (Death Group) and other 57 patients were put in Survival Group. The levels of serum IL-6, IL-10, and TNFα, and IL-6/IL-10 at different time points of both Death and Survival Groups were all significantly higher, and the HLA-DR level, and CD+3, CD+4, and CD+8 T lymphocyte numbers at different time points of both Death and Survival Groups were all significantly lower than those of the healthy controls (P <0.05 or <0.01). The levels of serum IL-6, IL-6/IL-10,TNFα,HLA-DR, and CD+4, CD+4 and CD+8 T lymphocyte at different time points of Death Group were all significantly higher than those of Survival Group (P <0.05 or <0.01). The CD+3 T lymphocyte number on day 8 of Thymosin Group was significantly higher than that of SSC Group (all P < 0.05). The serum IL-6and TNFα and IL-6/IL-10 were decreased, and HLA-DR, and CD+3, CD+4, and CD+8 were increased significantly on day 8 in CBP and Combined Therapy Groups. The level of TNFot decreased, and the numbers of CD+3 and CD+4 T lymphocytes increased significantly on day 4 in Combined Therapy Group(P <0.05 or P <0.01). Compared with Thymosin Group, almost all the indexes of CBP and Combined Therapy Groups were improved, only the CD+3 T lymphocyte level on day 4 increased and the IL-6/IL-10 ratio on day 8 was decreased significantly in Combined Therapy Group (both P < 0.05). Compared with those of SSC Group, the mechanical ventilation time, length of ICU stay within 28 days, and 28 days mortality and 90 days mortality of the 3 treatment groups were all decreased, and there were statistical differences in the length of ICU stay of CBP Group and in the mechanical ventilation time and length of ICU stay within 28 days of Combined Therapy Group (both P < 0.05) . Conclusion Systemic inflammatory response and immunodeprossion exist simultaneously in severe sepsis. Thymosin α1 increases the cellular immunity, and CBP hi-modulates the immune turbulence, reduces the inflammatory mediators, and meliorates the immune homeostasis. These 2 therapies also improve the clinical prognosis and the combination of both would be more effective.