The Efficacy and Immunomodulatory Effects of Ulinastatin and Thymosin α1 for Sepsis: A Systematic Review and Meta-Analysis.

Objective. To systematically review the efficacy and potential immunomodulatory effect of ulinastatin combined with thymosin α1 (UTI) for sepsis. Design. A systematic review and meta-analysis of randomized controlled trials (RCTs). Data Sources. The following databases: PubMed, Embase, and Cochrane Central were searched to identify related clinical trials. The search terms were "ulinastatin", "thymosin", and "sepsis". Results. Six RCTs, 944 septic patients in total, were included in this meta-analysis. The result shows UTI increased the 28-day survival rate of septic patients, odds ratio (OR) = 2.01, 95% CI [1.53, 2.64]. After the treatment with UTI, the APACHE II score (four studies) dropped 4.72 further, mean = -4.72, 95% CI [-6.54, -2.91] (p < 0.00001). The mean time of ICU stay (four studies) in UTI group decreased 3.03 days further, mean = -3.03 [-6.99, 0.95] (p = 0.14), and mechanical ventilation time (four studies) decreased 2.05 days, mean = -1.81 [-2.96, -0.66] (p = 0.002). With the treatment of UTI, CD4+T cells raised 5.13%, mean = 5.13, 95% CI [2.75, 7.50] (p < 0.0001); there was no significant change in CD8+T cells, mean = -0.74 [-2.93, 1.45] (p = 0.51). Conclusion. According to this meta-analysis, with the treatment of UTI, the short-term survival rate of septic patients was increased and the illness severity was alleviated. ICU stay and mechanical ventilation time were effectively shortened. The beneficial effect of UTI might be due to the potential immunomodulatory effects of these two drugs.

Prognosis Risk of Urosepsis in Critical Care Medicine: A Prospective Observational Study.

This study aimed to investigate the clinical features of urosepsis and to raise awareness of this problem. Of the 112 sepsis patients enrolled, 36 were identified as having urosepsis. The bacteria involved in the infection leading to urosepsis included Escherichia coli, Proteus species, Enterococcus species, Klebsiella species, other Gram-positive cocci, and Pseudomonas aeruginosa. Although the organ/system dysfunction appeared earlier in the urosepsis patients than in the other sepsis patients (4.7 ± 2.4 versus 7.2 ± 4.5 hours, P < 0.001), the urosepsis patients presented with a better prognosis and lower 28-day mortality rate than the others (6% versus 37%). In the multivariate analysis, the type of sepsis (urosepsis, OR = 0.019, 95% CI = 0.001, 0.335, P = 0.007) and SOFA score (OR = 1.896, 95% CI = 1.012, 3.554, P = 0.046) remained significantly associated with the survival. The time of admission to the intensive care unit of 17 patients transferred from the Department of Urinary Surgery was significantly prolonged compared with those transferred from other departments (11.6 ± 7.3 versus 7.2 ± 4.9 hours, P < 0.05). In conclusion, urosepsis suggested a better prognosis, but attention needs to be paid in clinical practice, especially in urinary surgery.

[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 alpha1, and combined therapy of CBP and thymosin alpha(1). 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 Sepsis Campaign (SSC) therapy, Thymosin alpha(1) Group (n = 23) undergoing subcutaneous injection of thymosin alpha(1) 1.6 mg once a day for 7 days in addition to SSC therapy, Combined Therapy Group (n = 22) undergoing CBP combined with thymosin alpha(1) 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)-alpha. 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 TNFalpha, 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, TNFalpha, HLA-DR, and CD(3)(+), 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-6 and TNFalpha 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 TNFalpha 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 immunodepression exist simultaneously in severe sepsis. Thymosin alpha(1) increases the cellular immunity, and CBP bi-modulates the immune turbulence, reduces the inflammatory mediators, and ameliorates the immune homeostasis. These 2 therapies also improve the clinical prognosis and the combination of both would be more effective.

[Effect of continuous blood purification and thymosin alpha1 on the cellular immunity in patients with severe sepsis: a prospective, randomized, controlled clinical trial].

OBJECTIVE: To discuss the effect of continuous blood purification (CBP), thymosin alpha1 and combined therapy on cellular immunity in patients with severe sepsis. METHODS: Ninety-one patients, age over 18 years, suffering from severe sepsis with Marshall score over 5, admitted to the intensive care unit (ICU) from June, 2004 to October, 2007, were randomly divided into four groups. The patients in control group (24 cases) were treated with classical Surviving Sepsis Campaign (SSC) therapy, those in CBP group (22 cases) were treated with continuous renal replacement therapy (CRRT) or molecular adsorbent recirculating system (MARS) in the first 3 days. The group of thymosin alpha1 (23 cases) were treated with thymosin alpha1, in a dose of 1.6 mg subcutaneous injection per day for 7 days. The patients in the group of combined therapy (22 cases) were treated with CBP and thymosin alpha1. All three treatment groups were treated with classical SSC therapy at the same time. Acute physiology and chronic health evaluation II (APACHE II) score and Marshall score were evaluated. CD14(+) monocyte human leucocyte antigen DR (HLA-DR) levels and the count of T lymphocyte were measured before treatment and 3 days and 7 days after the treatment. RESULTS: All 91 patients were included in the study. Compared with the control group, the 28-day mechanical ventilation (MV) time, length of ICU stay, 28-day mortality of three treatment groups were decreased. There was statistically significant difference in the length of ICU stay of the CBP group, and also the 28-day MV time, length of ICU stay of the group of combined therapy group (all P<0.05). Compared with the variables before treatment, Marshall scores were decreased significantly and levels of HLA-DR, CD3(+), CD4(+), CD8(+)T lymphocytes were increased significantly after 7-day treatment with thymosin alpha1 group (all P<0.05) . The above indexes and APACHE II scores were changed significantly as early as 3 days after treatment in CBP group and combined therapy group (P<0.05 or P<0.01). Compared with the variables at the same period in the control group, only CD3(+) T lymphocytes were increased significantly after 7-day treatment in thymosin alpha1 group (P<0.05), APACHE II scores and Marshall scores were decreased significantly , levels of HLA-DR and CD3(+), CD4(+), CD8(+) T lymphocytes were increased significantly after 7-day treatment in CBP group (all P<0.05). The above indexes were already changed significantly after 3-day treatment in the combined therapy group (P<0.05 or P<0.01). Compared with thymosin alpha1 group, all the indexes were improved but only level of CD3(+) T lymphocytes after 3-day treatment in the combined therapy group increased significantly (P<0.05). CONCLUSION: CBP and thymosin alpha1 could increase cellular immunity in patients with severe sepsis, promote recovery of organ function and improve prognosis. The effect of CBP appears earlier and more pronounced. Combined treatment can be more effective.