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Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial

  • Zi-Meng Liu
  • Juan Chen
  • Qiuye Kou
  • Qinhan Lin
  • Xiaobo Huang
  • Zhanhong Tang
  • Yan Kang
  • Ke Li
  • Lixin Zhou
  • Qing Song
  • Tongwen Sun
  • Ling Zhao
  • Xue Wang
  • Xiandi He
  • Chunting Wang
  • Benquan Wu
  • Jiandong Lin
  • Shiying Yuan
  • Qin Gu
  • Kejian Qian
  • Xianqing Shi
  • Yongwen Feng
  • Aihua Lin
  • Xiaoshun He
  • Study Group of investigators
  • Xiang-Dong Guan
Original

Abstract

Purpose

Recent clinical data suggest that terlipressin, a vasopressin analogue, may be more beneficial in septic shock patients than catecholamines. However, terlipressin’s effect on mortality is unknown. We set out to ascertain the efficacy and safety of continuous terlipressin infusion compared with norepinephrine (NE) in patients with septic shock.

Methods

In this multicentre, randomised, double-blinded trial, patients with septic shock recruited from 21 intensive care units in 11 provinces of China were randomised (1:1) to receive either terlipressin (20–160 µg/h with maximum infusion rate of 4 mg/day) or NE (4–30 µg/min) before open-label vasopressors. The primary endpoint was mortality 28 days after the start of infusion. Primary efficacy endpoint analysis and safety analysis were performed on the data from a modified intention-to-treat population.

Results

Between 1 January 2013 and 28 February 2016, 617 patients were randomised (312 to the terlipressin group, 305 to the NE group). The modified intention-to-treat population comprised 526 (85.3%) patients (260 in the terlipressin group and 266 in the NE group). There was no significant difference in 28-day mortality rate between the terlipressin group (40%) and the NE group (38%) (odds ratio 0.93 [95% CI 0.55–1.56]; p = 0.80). Change in SOFA score on day 7 was similar between the two groups: − 7 (IQR − 11 to 3) in the terlipressin group and − 6 (IQR − 10 to 5) in the NE group. There was no difference between the groups in the number of days alive and free of vasopressors. Overall, serious adverse events were more common in the terlipressin group than in the NE group (30% vs 12%; p < 0.001).

Conclusions

In this multicentre, randomised, double-blinded trial, we observed no difference in mortality between terlipressin and NE infusion in patients with septic shock. Patients in the terlipressin group had a higher number of serious adverse events.

Trial registration

This trial is registered at ClinicalTrials.gov: ID NCT01697410.

Keywords

Terlipressin Norepinephrine Septic shock SOFA score 

Notes

Acknowledgments

We would like to thank all of the doctors, nurses, technicians and patients involved at the participating centres for their dedication to the study. We also thank Xuyu Zhang, Michael Quintel, Ström Christer, JL Teboul, Jianfeng Wu and Yao Nie for their kind help with the manuscript. This study was funded by Sun Yat-sen University Clinical Research Program 5010 (NO 2007015) and by Major Science and Technology Project (NO 2012A080204018) of Guangdong province, China.

Study Group of investigators

Xiang-Dong Guan, Zi-Meng Liu and Juan Chen (The First Affiliated Hospital of Sun Yatsen University); Aihua Lin, Jie Zeng and Yanlin Huang (School of Public Health, Sun Yat-sen University), Qiuye Kou and Enhe Liu (The Sixth Affiliated Hospital of Sun Yatsen University), Qinhan Lin and Jianling Liu (Qingyuan People's Hospital), Xiaobo Huang and Xiaoqin Zhang (Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital), Zhanhong Tang and Yaoping Pan (The First Affiliated Hospital, GuangXi Medical University), Yan Kang and Yao Chen (West China Hospital), Ke Li and Jiji Cheng (Chinese PLA 302 Hospital), Lixin Zhou and Xinhua Qiang (Foshan First Municipal People’s Hospital), Qing Song and Li Wang (Chinese PLA General Hospital), Tongwen Sun (The First Affiliated Hospital, Zhengzhou University), Ling Zhao and Jiwen Zhong (Zhuhai People's Hospital), Xue Wang and Hongli Chen (The First Affiliated Hospital, Xi,An JiaoTong University), Xiandi He and Qiang Wu (The First Affiliated Hospital, Bengbu Medical college), Chunting Wang and Juan Zeng(Shandong Provincial Hospital), Benquan Wu and Jinmei Luo (The Third Affiliated Hospital of Sun Yat-sen University), Jiandong Lin and Zhaohui Fu (Fujian Provincial Hospital), Shiying Yuan(Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology), Qin Gu and Ning Liu (The Affiliated Drum Tower hospital of Nanjing University Medical school), Kejian Qian (The First Affiliated Hospital, Nanchang University), Xianqing Shi(Guizhou Provincial Hospital), Yongwen Feng and Suiqing Gui (The Second People's Hospital of Shenzhen).

Author contributions

ZL and JC contributed eaqually to this work. ZL, JC and XG designed the research; QK, JC, QL, XH, ZT, YK, KL, LZ, QS, TS, LZ, XW, XH, CW, BW, JL, SY, QG, KQ, XS and YW performed the research and collected data; AL analysed the data; ZL wrote the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflicts of interest

We declare no competing interests.

Supplementary material

134_2018_5267_MOESM1_ESM.tif (492 kb)
Comparison of fluid intake between groups. Values are mean ± standard deviation. There were no statistically significant differences between the norepinephrine and terlipressin groups in fluid intake, P = 0.876. The p value for the interaction term (between group and time) was 0.523 (TIFF 492 kb)
134_2018_5267_MOESM2_ESM.tif (655 kb)
Kaplan–Meier estimate of the probability of 28-day survival. P values were calculated with the use of the log-rank test (TIFF 654 kb)
134_2018_5267_MOESM3_ESM.tif (496 kb)
Comparison of serum alanine transaminase (ALT) between groups. Values were presented as median and interquartile range. Between groups, the changes of serum ALT of each day were similar, P = 0.953. The p value for the interaction term (between group and time) was 0.659 (TIFF 496 kb)
134_2018_5267_MOESM4_ESM.tif (474 kb)
Comparison of serum total bilirubin between groups. Values were presented as median and interquartile range. Between groups, the serum bilirubin of each day was similar, P = 0.785. The p value for the interaction term (between group and time) was 0.497 (TIFF 474 kb)
134_2018_5267_MOESM5_ESM.tif (466 kb)
Comparison of serum creatinine between groups. Values were presented as mean ± standard deviation. The serum creatinine level significantly decreased compared to day 0 in both groups, p = 0.000. The reductions in serum creatinine level were more remarkable in the terlipressin group compared to the NE group, P = 0.035. Thevalue for the interaction term (between group and time) was 0.132 (TIFF 465 kb)
134_2018_5267_MOESM6_ESM.tif (455 kb)
Comparison of serum base excess between groups. Values were presented as median and interquartile range. Compared to baseline, the serum base excess increased significantly both in the norepinephrine and terlipressin groups, P = 0.025. Between groups, the serum base excess of each day was similar,= 0.892. The p value for the interaction term (between group and time) was 0.444 (TIFF 454 kb)
134_2018_5267_MOESM7_ESM.docx (290 kb)
Supplementary material 7 (DOCX 290 kb)
134_2018_5267_MOESM8_ESM.docx (118 kb)
Supplementary material 8 (DOCX 117 kb)
134_2018_5267_MOESM9_ESM.docx (717 kb)
Supplementary material 9 (DOCX 717 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature and ESICM 2018

Authors and Affiliations

  • Zi-Meng Liu
    • 1
  • Juan Chen
    • 1
  • Qiuye Kou
    • 2
  • Qinhan Lin
    • 3
  • Xiaobo Huang
    • 4
  • Zhanhong Tang
    • 5
  • Yan Kang
    • 6
  • Ke Li
    • 7
  • Lixin Zhou
    • 8
  • Qing Song
    • 9
  • Tongwen Sun
    • 10
  • Ling Zhao
    • 11
  • Xue Wang
    • 12
  • Xiandi He
    • 13
  • Chunting Wang
    • 14
  • Benquan Wu
    • 15
  • Jiandong Lin
    • 16
  • Shiying Yuan
    • 17
  • Qin Gu
    • 18
  • Kejian Qian
    • 19
  • Xianqing Shi
    • 20
  • Yongwen Feng
    • 21
  • Aihua Lin
    • 22
  • Xiaoshun He
    • 1
  • Study Group of investigators
  • Xiang-Dong Guan
    • 1
  1. 1.Department of Critical Care Medicine, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  2. 2.Department of Critical Care MedicineThe Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  3. 3.Department of Critical Care Medicine, Qingyuan People’s HospitalThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuanChina
  4. 4.Department of Critical Care MedicineSichuan Academy of Medical Sciences & Sichuan Provincial People’s HospitalChengduChina
  5. 5.Department of Critical Care MedicineThe First Affiliated Hospital, GuangXi Medical UniversityNanningChina
  6. 6.Department of Critical Care MedicineWest China Hospital, Sichuan UniversityChengduChina
  7. 7.Department of Critical Care MedicineChinese PLA 302 HospitalBeijingChina
  8. 8.Department of Critical Care MedicineFoshan First Municipal People’s HospitalFoshanChina
  9. 9.Department of Critical Care MedicineChinese PLA General HospitalBeijingChina
  10. 10.Department of Critical Care MedicineThe First Affiliated Hospital, Zhengzhou UniversityZhengzhouChina
  11. 11.Department of Critical Care MedicineZhuhai People’s HospitalZhuhaiChina
  12. 12.Department of Critical Care MedicineThe First Affiliated Hospital, Xi An JiaoTong UniversityXi anChina
  13. 13.Department of Critical Care Medicine, The First Affiliated HospitalBengbu Medical CollegeBengbuChina
  14. 14.Department of Critical Care MedicineShandong Provincial HospitalJinanChina
  15. 15.Department of Critical Care MedicineThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  16. 16.Department of Critical Care MedicineFujian Provincial HospitalFujianChina
  17. 17.Department of Critical Care Medicine, Wuhan Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyHubeiChina
  18. 18.Department of Critical Care MedicineThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
  19. 19.Department of Critical Care MedicineThe First Affiliated Hospital, Nanchang UniversityNanchangChina
  20. 20.Department of Critical Care MedicineGuizhou Provincial HospitalGuiyangChina
  21. 21.Department of Critical Care MedicineThe Second People’s Hospital of ShenzhenShenzhenChina
  22. 22.School of Public HealthSun Yat-sen UniversityGuangzhouChina

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