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Response to: Understanding the null hypothesis (H0) in non-inferiority trials

We thank Dr. Mallat for their interest in our study of stepwise lactate kinetics-oriented hemodynamic therapy and for putting forward a statistical problem [1]. Central venous oxygen saturation (ScvO2)-targeted therapy was recommended by the Surviving Sepsis Campaign (SCC) guidelines in 2012 [2] and we initially envisaged that the stepwise lactate kinetics strategy was, at least, not inferior to the ScvO2 target strategy. Therefore, the design of non-inferiority analysis was adopted at the beginning of the trial.

We rechecked and recalculated the data by non-inferiority and superiority test. The lactate kinetics group mortality rate (P1) was 18.3% and the Scvo2 group mortality rate (P2) was 27.9%. The standard error for the mortality difference between the two groups was 0.0441, and thus the mortality difference was –0.0944 (95% confidence interval –0.1809 to –0.0080). The upper limit of the interval is less than 0, and thus the superiority conclusion is established. At this point, regardless of the non-inferior value (0.15 or 0.10), non-inferior conclusions must be established.

Additionally, the non-inferiority threshold of 10% is indeed more reasonable according to a previous study [3].Therefore, regardless of whether the non-inferiority threshold is set at 10% or 15%, no effect on the final conclusion was seen in this study.

Last, but not the least, the latest sepsis guidelines released by the SCC in 2016 have weakened early goal-directed therapy (EGDT) and highlighted the importance of normalization of lactate [4], which also supports the conclusion we draw that stepwise lactate kinetics-oriented hemodynamic therapy can reduce mortality in patients with sepsis-associated hyperlactatemia compared with ScvO2-oriented therapy.



Early goal-directed therapy


Surviving Sepsis Campaign


Central venous oxygen saturation


  1. 1.

    Mallat J. Understanding the null hypothesis (H0) in non-inferiority trials. Crit Care. 2017;21(1):101.

  2. 2.

    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228.

  3. 3.

    Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739–46.

  4. 4.

    Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–77.

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We thank Prof. Guangliang Shan and Dr. Biao Zhang from the Department of Epidemiology and Biostatistics, Institute of Basic Medicine Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College for helping us to check and perform the statistical analysis.


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XZ, LS, and DL drafted the manuscript. All authors read and approved the final manuscript.

Correspondence to Dawei Liu.

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See related Letter by Mallat,

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Zhou, X., Liu, D. & Su, L. Response to: Understanding the null hypothesis (H0) in non-inferiority trials. Crit Care 21, 201 (2017).

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