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Intensive Care Medicine

, Volume 40, Issue 8, pp 1164–1167 | Cite as

An exciting candidate therapy for sepsis: ulinastatin, a urinary protease inhibitor

  • Adam Linder
  • James A. Russell
Editorial

In a recent issue of Intensive Care Medicine (ICM), Karnad et al. [1] reported a randomized, double-blind, placebo-controlled multicenter trial (RCT) evaluating the efficacy of a urinary protease inhibitor (ulinastatin) compared to placebo in patients with severe sepsis. This RCT was conducted in the intensive care units (ICUs) of seven tertiary care hospitals in India including 114 patients. Patients received intravenous ulinastatin or placebo twice daily for 5 days. Ulinastatin was associated with significantly decreased mortality (7.3 vs. 20.3 %, P = 0.042), with 25 % of the deaths in the ulinastatin group judged related to ARDS compared to 42 % in the placebo group, lower frequency of new organ dysfunction, and shorter durations of mechanical ventilation and hospital stay compared to placebo. Furthermore, in stepwise multiple logistic regression (adjusted for age, gender, GCS, specific organ failures, number of organ failures, need for vasopressor, and mechanical ventilation), treatment with ulinastatin was associated with a statistically significant decrease in mortality.

This is an interesting trial with quite impressive results given the relatively small sample size, which raises these questions: what is ulinastatin and why might it be important in sepsis?

Ulinastatin (UTI) is a multifunctional Kunitz-type serine protease inhibitor found in human urine and blood. UTI (also known as ulinastatin, HI-30, ASPI, or bikunin) is produced by hepatocytes and belongs to a group of proteins known as the inter-α-inhibitor (IαI) family. During inflammation, ulinastatin is cleaved from IαI family proteins through proteolytic cleavage by neutrophil elastase in the peripheral circulation or at sites of inflammation. Ulinastatin inhibits various serine proteases that are important in the pathophysiology of sepsis including trypsin, thrombin, chymotrypsin, kallikrein, plasmin, elastase, cathepsin, and factors IXa, Xa, XIa, and XIIa. Ulinastatin also inhibits inflammation by suppressing the infiltration of neutrophils and release of elastase and inflammatory mediators from neutrophils. Ulinastatin also inhibits the production of TNF-α, IL-1, and IL-6 possibly through suppression of MAPK signalling pathway [2].

The RCT of Karnad and colleagues in ICM supports previous clinical trials of ulinastatin (Table 1). A recent systematic review and meta-analysis found 29 RCTs of ulinastatin in ARDS with more than 1,700 participants. Even though the authors concluded that most studies were of poor quality they found that ulinastatin decreased ICU mortality, improved oxygenation, and decreased duration of hospital stay [3]. Clinically ulinastatin is already in use, for instance in Japan, to treat acute pancreatitis (post-endoscopic retrograde cholangiopancreatography pancreatitis), in which proteases play a pathophysiological role. Other clinical conditions for which ulinastatin has been evaluated clinically are “systemic inflammatory response syndrome” conditions such as burns, post cardiac surgery, and ARDS (e.g., in China).
Table 1

Clinical studies of ulinastatin in septic patients

References

Journal (language)

Active drugs

Sample size (treatment/placebo)

Design

28-day mortality  % active drug(s) vs. placebo (P value)

Effect on inflammatory markersa

Other outcomes

Cooperative Group of Immunomodulatory Therapy of Sepsis and Lin [5]

Zhonghua (Chinese)

Ulinastatin + thymosin-α1

433 (210/223)

Prospective randomized double-blind multicenter trial

25.1 vs. 38.3 % (P = 0.009)

Significant drop in treatment group vs. placebo

 

Li et al. [6]

ICM (English)

Ulinastatin + thymosin-α1

56 (23/33)

Prospective randomized double-blind single center trial

22.7 vs. 39.3 % (P < 0.05)

Significant drop in treatment group vs. placebo

 

Chen et al. [7]

Chin Med J (English)

Ulinastatin + thymosin-α1

114 (59/55)

Prospective randomized double-blind single center trial

27.2 vs. 45.9 % (P = 0.08)

Significant drop in treatment group vs. placebo

Less organ failure

Su et al. [8]

Zhongguo (Chinese)

Ulinastatin + thymosin-α1

242 (128/114)

Prospective randomized double-blind single center trial

20.0 vs. 33.1 % (P < 0.05)

Significant drop in treatment group vs. placebo

More DAFb of mechanical ventilation

Subtotal of patients in RCTs with combination therapy

  

845 (420/425)

    

Shao et al. [9]

Zhongguo (Chinese)

Ulinastatin

60 (30/30)

Prospective randomized double-blind single center trial

3.3 vs. 20.0 % (P < 0.05)

Significant drop in treatment group vs. placebo

Less organ failure

Moon et al. [11]

J Kor Soc Em Med (Korean)

Ulinastatin

169 (43/126)

Prospective case control single center trial

18.6 vs. 27.1 % (P > 0.05)

Not done

Less organ failure. Significant lower predicted mortality

Wu et al. [10]

Zhonghua (Chinese)

Ulinastatin

60 (30/30)

Prospective randomized double-blind single center trial

18.2 vs. 20.1 (P > 0.05)

Significant drop in treatment group vs. placebo

 

Subtotal number of patients with monotherapy

  

289 (103/186)

    

Total number of patients in RCTs

  

1,134 (523/611)

    

aInflammatory markers investigated were TNF-α, IL-6, IL-10, IL-17, and C-reactive protein

bDAF = Days alive and free

Protease inhibitors are used to treat many different medical conditions, such as cancer and Alzheimer’s disease. In cancer treatment, there is still a widely held view that “broad spectrum” protease inhibitors will be needed to treat malignancies at particular stages [4].

This approach—using a more semi-selective antagonist—has not so far been widely adopted in treatment of sepsis. Ulinastatin has been evaluated as a sepsis therapeutic both as a single drug and in combination with the immunomodulatory agent thymosin-α1 (Table 1). We identified seven RCTs of ulinastatin in septic patients [5, 6, 7, 8, 9, 10, 11]. All these RCTs showed benefit of ulinastatin such as significant improvement in inflammatory markers and, to a lesser extent, in organ dysfunction. All studies showed lower 28-day mortality in the ulinastatin treatment arm. However, the majority of patients (more than 800) were treated with ulinastatin in combination with thymosin-α1 making interpretation of the independent therapeutic potency of ulinastatin difficult.

Ulinastatin and members of the IαI family are also considered as candidate biomarkers for diagnosis and prognosis of sepsis [12], but for some reason no clinical studies appear to have been done in Western countries to date. A clintrials.gov trial search revealed nine registered studies with ulinastatin, mainly focusing on cardiac surgery and ARDS, and none on sepsis treatment.

However, even if urinary protease inhibitors have biological plausibility for the treatment of sepsis, there are still a number of concerns of which many are highlighted by the comments from Saigal and Kapoor [13]. These include the high exclusion rate, young age, the higher presence of multidrug resistance in the control group, and the high mortality rate of the control group that mitigate the generalizability of the results to other countries. Also, the mean length of stay of 26.2 days for a 37-year-old man with one organ dysfunction (64 %) is strikingly high. Sample size calculation was performed assuming a 28-day all-cause mortality of 30 % in the control group and 10 % in the study group. A sample size of 59 completed patients in each group was required to attain a power of 80 % at significance level of 5 %. This is an extraordinarily high effect size and completely different from any prior RCT in severe sepsis. The trial cohort was very young (mean age, 37 years; mean age is about 55 years in most sepsis RCTs). The surprisingly low APACHE II could be well explained in part by young age. Still, we suggest that the mortality rate is high for severe sepsis in the control group given the mean age of 37 years, low rate of positive cultures (15/59), and predominance (65 %) of patients who had only one organ dysfunction. There is no clear explanation for this and thus there are concerns regarding the generalizability of this RCT, which highlights the need for further larger RCTs of ulinastatin in North America, Europe, and Australasia.

There are other “broad spectrum” protease inhibitors already available on the market, such as aprotinin (Trasylol), which have not been tested in the context of human sepsis treatment. It is not clear whether ulinastatin has advantages over such other available protease inhibitors.

What are the research and clinical implications of this publication? In conclusion, this is a provocative but not yet convincing RCT of ulinastatin in severe sepsis. It will be critical to see further preclinical evaluation of the mechanism(s) of action, comparison to other available protease inhibitors, and to see large well-conducted RCTs of ulinastatin in other countries.

Notes

Conflicts of interest

None.

References

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Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2014

Authors and Affiliations

  1. 1.Centre for Heart Lung Innovation, St. Paul’s HospitalUniversity of British ColumbiaVancouverCanada
  2. 2.Division of Critical Care Medicine, St. Paul’s HospitalUniversity of British ColumbiaVancouverCanada

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