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Original article

Treatment of patients with severe sepsis using Ulinastatin and Thymosin α1: a prospective, randomized, controlled pilot study

CHEN, Hao; HE, Ming-yan; LI, Yu-min

Editor(s): HAO, Xiu-yuan

Author Information
doi: 10.3760/cma.j.issn.0366-6999.2009.08.001
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Abstract

Sepsis is defined as the systemic inflammatory response to infection, with its severe form associated with evidence of organ dysfunction.1,2 Although scientists have for many years researched the prevention and therapy of sepsis, it seems that the incidence of sepsis has not decreased but continues growing. The yearly incidence of sepsis is 50-95 cases per 100 000, and has been increasing by 9% each year.3 Estimates of sepsis indicate that the total of 750 000 cases in the U.S. every year with a mortality as high as 50% make sepsis the disease with the highest mortality of any major disease.4,5

In sepsis, the initiating stimuli are often bacterial components, which induce the secretion of pro-inflammatory cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) predominantly from cells of the immune system. High circulating concentrations of these cytokines sometimes indicate an increased risk of mortality6 but treatments antagonizing their activities have not improved patients' survival.7 Among the clinical trials, non-specific high-dose steroid treatments8 were tested in a series of disappointing studies.9,10 Specific therapies against TNF-α involving antibodies11,12-17 or soluble TNF-receptors18 were as unsuccessful as trials blocking IL-1 by IL-1-RA.19-22 These agents proved to be ineffective in improving outcome in sepsis. In addition, during sepsis bacterium often lead to a decrease in both number and function of circulating lymphocytes through the mechanism of cell apoptosis with resultant immunosuppression.

Ulinastatin (UTI) is one of the Kunitz-type protease inhibitors found in urine.23 UTI is synthesized from inter-trypsin inhibitor through proteolytic cleavage by neutrophil elastase at the site of inflammation. Various serine proteases such as trypsin, chymotrypsin, neutrophil elastase, and plasmin are inhibited by UTI. It was generally believed that UTI had the ability to control a series of proinflamatory mediators and cytokines. Thymosin α1 (Tα1) is a naturally occurring thymic peptide first described and characterized by Goldstein et al.24 In the form of a synthetic 28-amino acid peptide, the mechanism of action of the synthetic polypeptide is not completely understood, but it is thought to be related to its immunomodulating activities, centered primarily on the augmentation of T-cell function.

In the present study, the potential efficacy of UTI plus Tα1 in patients with severe sepsis was assessed in a randomized, placebo-controlled setting.

METHODS

Study design and treatment

The study consisted of three phases: screening, treatment, and follow-up. During the screening phase, patient eligibility was determined, informed consent was obtained, and patients were randomly assigned to receive either UTI (Guangdong Techpool Pharmaceutical Co., China) and Tα1 (Chengdu Diao Group, China), defined as Group A, or placebo, defined as Group B. During the treatment phase, all patients received an intravenous loading dose of 200 kU UTI three times a day plus a subcutaneous dose of 1.6 mg Tα1 twice a day for three days followed by a dose of 100 kU UTI thrice a day plus 1.6 mg Tα1 once a day for four continuous days or an equivalent amounts of placebo. Decisions regarding the use of antimicrobial agents, intravenous fluids, cardiovascular and respiratory support, and surgical intervention were made by each patient's attending physician. After completion of the 7-day treatment phase, patients were followed up for 28, 60 and 90 days.

Patient selection

Patients with a diagnosis of severe sepsis were enrolled if they fulfilled the criteria defined by the 2001 International Sepsis Definitions Conference.1 Patients were not eligible if they met any of the following criteria: (1) age under 18 or over 80 years; (2) incurable malignancies with documented metastases; (3) chronic treatment with high-dose immunosuppressive drugs or high dose nonsteroid anti-inflammatory drugs within the previous 2 days; (4) acute myocardial infarction; (5) chronic compensated organ dysfunction, such as chronic liver disease, dialysis-dependent renal failure, moderate to severe chronic heart failure. Informed consent for study participation was obtained from all patients prior to the performance of any study-related procedures.

Patient evaluation

Patients were followed throughout the 28, 60 and 90 days study period after receipt of study medication or until death, whichever occurred first. During screening, the patient's history was recorded and a physical evaluation was performed. Samples of blood and other body fluids and specimens from suspected sites of infection were obtained for culture. Vital signs were obtained and hematologic and biochemical tests were carried out at screening and on admission and on 3rd, 8th, and 28th day. These laboratory values and organ-specific parameters were also used to calculate the Acute Physiology and Chronic Health Evaluation II (APACHE II),25 multiple organ failure (MOF),26 Glasgow Coma Scores (GCS).27 Organ dysfunction was diagnosed according to the guideline.

Lymphocyte subset and cytokines detection

Lymphocyte subsets were counted by a Guava EasyCyte flow cytometer. Cytokine levels were determined by ELISA, using commercially available kits from Genzyme, Cambridge, MA, USA.

Statistical analysis

Numeric data on scores is represented as mean±standard deviation (SD). Welch's t test assessed differences in means for APACHE II, MOF and GCS scores. Student's t test was used to assess differences in lymphocyte subsets and inflammatory mediators. Survival rates over time were estimated by the Kaplan-Meier method. A log rank test was used to analyze the length of supportive ventilation using dopamine, the duration of stay in the ICU and length of antimicrobial therapy. Tests were indicated as significant if P was <0.05 with two-sided analysis. Statistical analyses were calculated using SPSS 13.0 software.

RESULTS

Characteristics of patients on admission

At screening, the following data were recorded: mean age, sex (M/F), body weight (kg), underlying diseases, mean APACHE II score, MOF scores and Glasgow score. This distribution, as well as the demographic characteristics and underlying diseases, the pathogens responsible for the septic episode, the severity of sepsis at study entry were well-balanced across the two treatment groups (P >0.05). During study, the mean length of supportive ventilation using dopamine, stay in the ICU and antimicrobial therapy was found significantly different between the two groups (P <0.01). Treatment with UTI plus Tα1 was found to be well-tolerated and safe without adverse events (Table 1).

Table 1
Table 1:
General characteristics of the two groups

Effects of UTI plus Tα1 in patients with severe sepsis

Differences in APACHE II, MOF and GCS between groups over time were found (P=0.041, 0.024 and 0.032, respectively). APACHE II and MOF were reduced significantly after therapy on the 3rd, 8th and 28th day in Group A (P=0.042, 0.000, 0.000 and 0.040, 0.000, 0.000 respectively), so did in Group B only after therapy on 28th day when compared with that on admission (P=0.036, 0.021, respectively). Glasgow score increases were found after therapy on the 8th and 28th in Group A (P=0.000), in Group B did the same merely after therapy on 28th day (P=0.039). There were significant differences in APACHE II, MOF, and Glasgow scores after therapy on the 8th day between Group A and Group B (P =0.012, 0.017 and 0.004, respectively) (Table 2).

Table 2
Table 2:
APACHE II, MOF, and Glasgow scores over treatment

Resolution of pre-existing organ dysfunction

Acute intestinal dysfunction: 33 patients already showed intestinal dysfunction on admission (Table 3). A reduction in the prevalence of intestinal dysfunction by 56% was recorded on day 8 in Group A. In Group B, the corresponding reduction was 24% (P=0.058).

Table 3
Table 3:
Resolution of pre-existing organ dysfunction

Acute neurological dysfunction: 21 patients already showed neurological dysfunction on admission. A reduction in the prevalence of central nervous system (CNS) dysfunction by 45% was recorded on day 8 in Group A. In the placebo group, the corresponding reduction was 20% (P =0.221).

Acute respiratory dysfunction: 39 patients were in respiratory failure on admission. A reduction in the prevalence of respiratory dysfunction by at least 53% was noted on day 8 in Group A. In Group B, the corresponding reduction was 20% (P=0.036).

Acute renal dysfunction: 35 patients had renal dysfunction on admission. A reduction in its prevalence by 63% was seen on day 8 in Group A. In Group B, the corresponding reduction was 25% (P=0.027).

Acute hepatic dysfunction: 30 patients had hepatic failure on admission. In Group A the prevalence of hepatic dysfunction was reduced by 62% on day 8. In Group B, the corresponding reduction was 21% (P=0.28).

Coagulation failure: 31 patients had coagulation failure on admission. A reduction in its prevalence by 27% was recorded on day 8 in Group A. In Group B, the corresponding reduction was 12% (P=0.146).

Survival analysis for Group A and Group B

The effect of UTI plus Tα1 treatment on the mortality of patients with sepsis was analyzed on an intention-to-treat basis (Figure 1). The cumulative survival (54.1%, 54.1% and 47.4% of Group A at days 28, 60, and 90) were increased respectively by 18.7%, 25.9%, and 27.4% compared with 35.4%, 28.2% and 20.0% of Group B (P=0.078, 0.045, and 0.033, respectively).

Figure 1.
Figure 1.:
Cumulative survival comparison between Group A and Group B at 28, 60 and 90 days. Cumulative survivals of Group A and Group B were 54.1% and 35.4% at 28 days, P=0.078; 54.1% and 28.2% at 60 days, P=0.045; 47.4% and 20.0% at 90 days, P=0.033.

Comparision of lymphocyte subsets and concentration of inflammatory mediators

There were significant differences in the CD4+/CD8+ ratio after therapy on the 8th, and 28th days between Group A and Group B (P=0.013, 0.039, respectively). In group A, TNF-α and IL-6 after therapy on the 8th and 28th days were reduced significantly when compared to those on admission (all P=0.000). In group B TNF-α and IL-6 after therapy on the 28th were decreased (P=0.012, 0.01 respectively) when compared to those on admission. The differences of TNF-α and IL-6 between Group A and Group B on the 8th after therapy were found (P=0.029, 0.039, respectively). The levels of IL-10 were heightened significantly after therapy on the 8th day in Group A when compared to that on admission (P=0.000), but not in the Group B (Figure 2).

Figure 2.
Figure 2.:
Comparison of lymphocyte subset and inflammatory mediators. Significant difference in CD4 +/CD8 + after therapy on the 8th and 28th day between two groups (P=0.013, 0.039 respectively). TNF-α, IL-6 were reduced significantly after therapy on the 8th and 28th day in Group A (all P=0.000), and were decreased after therapy on the 28th day in Group B (P=0.012, 0.01). The difference between Groups A and B in TNF-α, IL-6 were found on the 8th day after therapy (P=0.029, 0.039 respectively). The levels of IL-10 were heightened significantly after therapy on the 8th day in Group A (P=0.000), but not in the Group B.

DISCUSSION

Although treatment of sepsis with new therapies, including high dose corticosteroids28 and non-steroidal anti-inflammatory drugs29 and monoclonal antibodies targeting lipopolysaccharides30,31 and drugs for blocking one factor in the inflammatory cascade,32 have failed to improve survival, septic patients treated with UTI plus Tα1 did show a better performance. This study attempted to address the issue from three perspectives. First, we compared the differences in APACHE II, MOF and GCS between groups. Second, we followed the resolution of pre-existing organ dysfunction. Third, we analyzed the survival rate at 28, 60 and 90 days.

The results of this trial demonstrate a better performance of individual organ function in patients treated with the UTI plus Tα1 which was also reflected in overall organ failure scores. The trend for the improvement in APACHE II, MOF, and Glasgow scores started soon after initiation of treatment. APACHE II and MOF scores were reduced significantly after therapy on the 3rd, 8th and 28th day in Group A, but only on the 28th day in Group B. A GCS increase was found after therapy on the 8th and 28th in Group A, however only on the 28th day in Group B. Although both groups showed significant differences in APACHE II, MOF, and Glasgow scores over time, the Group A recovered sooner than the Group B. After therapy on the 8th and 28th days there was a significant difference in APACHE II, MOF, GCS between Group A and Group B.

In sepsis, the majority of patients have lung dysfunction associated with cardiovascular instability and deteriorating renal function and altered intestinal, liver, cerebral and coagulation function.5 In UTI plus Tα1-treated patients, there was a better resolution of these pre-existing organ failures. Especially on day 8 reductions in the prevalence of intestinal dysfunction by 56%, respiratory dysfunction by 45%, CNS dysfunction by 53%, renal dysfunction 63%, hepatic dysfunction by 62% and coagulation failure 27%, were noted in the Group A. In Group B, the corresponding reductions were 24%, 20%, 20%, 25%, 21% and 12%. There was a better clinical trend in Group A with respect to the intestinal, respiratory, renal, and liver systems and, especially, to the patients' cerebral and coagulation function. It remains open, however, as to whether the possible improvement in CNS and coagulation function is a direct benefit of the drug or rather an indirect consequence of the better performance of the patients' respiratory, kidney, and liver systems. However, recently it was reported that the PMNE concentration correlates with the activities of coagulation and fibrinolysis33 and Ulinastatin could inhibit coagulation and fibrinolysis by inhibiting PMNE activity.34

With UTI plus Tα1, the potential life-saving effect was embodied by the increased cumulative survival and the shorter length of supportive ventilation using dopamine, a shorter stay in the ICU and time on antimicrobial therapy. Lin et al35 found the mortality of patients with MODS who received treatment with UTI and Tα1 decreased from 38.32% to 25.14% (P = 0.0088), compared with a control group at 28 days. The survival benefit provided by treatment with UTI plus Tα1 appeared to occur middle-late in the septic process. It started within the second week after initiation of treatment and was most pronounced at the end of the second week. It was speculated that the time was related to reduction of inflammatory mediators by UTI and recovery of lymphocyte function by Tα1.

In the present study, the ratio of CD4+/CD8+ was corrected after treatment with UTI plus Tα1 and there was a significant difference in the CD4+/CD8+ ratio after therapy between the two groups. In Group B patients had higher levels of TNF-α and IL-6 and lower levels of IL-4 and IL-10 than did Group A patients. This difference was especially prominent the day after therapy was completed, Day 8, as were differences in APACHE II, MOF, GCS and resolution of pre-existing organ dysfunction.

It appears to be difficult to definitely unravel the mechanism by which the beneficial effect of UTI and Tα1 was brought about. According to the previous study, UTI is well known to suppress the production of TNF-α36 and IL-6 and IL-8.37 Tα1 can induce expression of various cytokines by peripheral blood lymphocytes, including interferon-γ, IL-2 and IL-7, and can stimulate maturation of thymocyte cells38 and up-regulates expression of Toll-like receptor (TLR) 2, 5, 8 and 9.39,40 In our study, it was found that the percent of different lymphocyte subset were corrected after Tα1 treatment. It was also observed that a proinflammatory response resulted in release of TNF-α and IL-6 which cause organ dysfunction to some extent. In the meanwhile anti-inflammatory cytokines such as IL-4, IL-10 are produced to protect from sepsis. The balance between these responses changes from minute to minute and determines the final outcome of the disease. From our other data, UTI plus Tα1 treatment achieves both control of the inflammatory reaction and activation of immunocompetence, and tends to quicken the balance between inflammatory injury and anti-inflammatory protection.

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Keywords:

Ulinastatin; Thymosinα1; severe sepsis; immunomodulatory therapy

© 2009 Chinese Medical Association