TARGETED TISSUE PERFUSION VERSUS MACROCIRCULATORY-GUIDED STANDARD CARE IN PATIENTS WITH SEPTIC SHOCK (TARTARE-2S).

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1 Author s response to reviews Title: TARGETED TISSUE PERFUSION VERSUS MACROCIRCULATORY-GUIDED STANDARD CARE IN PATIENTS WITH SEPTIC SHOCK (TARTARE-2S): STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN FOR A RANDOMIZED CONTROLLED TRIAL. Authors: Ville Pettilä (ville.pettilae@insel.ch) Tobias Merz (tobias.merz@insel.ch) Erika Wilkman (erika.wilkman@hus.fi) Anders Perner (anders.perner@regionh.dk) Sari Karlsson (sari.karlsson@pshp.fi) Theis Lange (thlan@sund.ku.dk) Johanna Hästbacka (johanna.hastbacka@hus.fi) Peter Buhl Hjortrup (Peter.Buhl.Hjortrup@regionh.dk) Anne Kuitunen (anne.kuitunen@pshp.fi) Stephan M. Jakob (stephan.jakob@insel.ch) Jukka Takala (jukka.takala@insel.ch) Version: 1 Date: 06 Jun 2016 Author s response to reviews: RESPONSE TO REVIEWERS RE: TRLS-D TARGETED TISSUE PERFUSION VERSUS MACROCIRCULATORY-GUIDED STANDARD CARE IN PATIENTS WITH SEPTIC SHOCK (TARTARE-2S). We thank the reviewer for important remarks and constructive criticism. We would like to respond point-by-point as follows:

2 Reviewer #1: The protocol of the TARTARE study is well described and well written; I have however several questions/remarks: 1. The study appears to be ongoing (first enrollment planned on Jan 2016) so I won t argue on the design itself. RESPONSE: We have updated the status of institutional approvals and the study timelines to the manuscript. Due to delays in EC final approvals the first study patient was enrolled in April (Page 13) 2. I have however some concerns regarding the initiation of RRT. The Use of RRT appears to be encouraged if Serum potassium 6.0 mmol/l, however, it may be relevant to add "if AKI criteria are met'. Another criteria is : "Persistent severe AKI (serum creatinine remains > 50% the value recorded at randomization) for > 72 hours from randomization". Many patients with S-creat >50% from baseline do not require RRT. This may lead to unnecessary RRT initiation. RESPONSE: We appreciate the reviewer s view. However, there is no clear evidence or consensus when RRT should be started as highlighted in a recent systematic review [1]. We have considered this issue very carefully based on our propensity-matched analysis [2](MS ref 20), and thereafter decided to suggest the conventional criteria included also in the ongoing patient STARRT-AKI-trial (NCT )- the approach tested to be feasible in a pilot study [3]. We have added this reference [3] to our revised MS to further justify our approach as: (Page 5). Renal replacement therapy suggested criteria according to conventional standard criteria (MS ref No19,20), with proven feasibility [3] (MS ref No 21). Of note, our approach regarding RRT and other concomitant interventions is to suggest criteria in order to decrease the variability but not to strictly protocolize the co-interventions. Additionally, to ensure the comparability we plan to report the co-interventions in detail. 3. Regarding the targets, peripheral temperature should be targeted as "warm". This is however highly subjective. How will the author ensure homogenous interpretation of this parameter across centers. RESPONSE: We thank the reviewer for this comment. We partly agree with the reviewer - the agreement between different assessors is not perfect. However, as demonstrated by Lima and colleagues (MS ref No 15) the subjective measurement is congruent to measured skin temperature gradients [4] and, thus, reliable. In addition, we have planned a small additional observational study to evaluate/confirm the inter-assessor agreement among ICU nurses. Furthermore, we did not want to use absolute temperature measurements, because subjective assessment of peripheral temperature is part of the routine clinical practice, and thus, should part of the targeted tissue perfusion strategy, to be tested. We have added this agreement in the

3 background as : (Page 4, lines 3-4) Of note, subjectively assessed warmness of the peripheral skin had good agreement with the measured temperature differences [4] (MS ref No 15). 4. Indication and guidance of fluid loading is not addressed. RESPONSE: We agree that this point is extremely important. We have performed a systematic review comprising recent septic shock trials. Our findings indicate that total amount of fluids was reported in less than 35% and fluid balance in less than 15% of the septic shock trials. Therefore, we will record (to the best of our knowledge for the first time) the hemodynamic problems (assessed by the treating clinician) and the given amount and type of fluids (and hourly diuresis) over the first 72 hours. The reasoning behind choosing usual care decided by the clinicians for fluid management, instead of strictly protocolized care, is that the available guidelines [5] are based on low-quality data. The only exception is HES, which is mentioned in the full protocol to be avoided (1B). Furthermore, we have carefully chosen the participating study sites (all large university ICUs with previous experience in septic shock studies) to minimize the variability in current clinical practice regarding fluid management [6]. We have extended this point regarding fluids in the MS as: (Page 5).recommended (the hemodynamic problems to be registered and reported -Appendix 3). Fluids correction of hypovolemia (preferably crystalloids, starch not to be used) will be at the discretion of the treating clinician. 5. Septic shock is defined as: However, new definition suggest defining septic shock with need of vasopressors and serum lactate >2 mmol/l. The authors may adjust their inclusion criteria to avoid criticisms later on. RESPONSE: We appreciate this comment. In fact the study protocol was finalized before the recent definition. We have already considered broadening the study inclusion criteria according to the new definition [7]. Although we fully agree with the reviewer, that a septic shock patient group strictly according to sepsis-3 definition would be in many ways an optimal patient population, some arguments appear to be against this change. First, we have based our sample size calculations on the prospective FINNAKI-study data [8, 9], and carefully extracted the data on patients with admission lactate > 3 mmol/l and septic shock using their time off-vasopressors and time to normalization of lactate as basic assumptions for sample size calculations. Albeit we have included a possibility to adapt the sample size from 200 to 300, widening the inclusion criteria (to include patients with lactate >2 mmol/l) will require re-calculations regarding sample size. Second, including more severe patients will increase our chance to show the possible difference between the groups based on a recent simulation study showing the heterogeneity of treatment effect [10] an intervention might be neutral in less severe patient but beneficial in the more severe group, if a difference really exists. Third, our systematic review showed that none of the recently published septic shock trials has included a patient population in full agreement with the recent Sepsis-3 septic shock definition. Despite obvious criticism to be answered we would not like to change the inclusion criteria due to abovementioned reasons at this stage.

4 We have added references 7 and 10 to the MS (MS references no 28-29) with a more detailed reasoning of the study population as : (page 16). The targeted patient population fulfills the recent sepsis-3 septic shock definition [7] representing the most severe ill septic shock patients with plausibly the highest possible chance to show a difference between the intervention arms [10], if such a difference exists. We will also re-consider the excellent suggestion by the reviewer in August - September 2016 after analyzing the study enrollment rate and the lactate normalization data in less severe septic shock group. This will leave us an opportunity to add another less severe group (lactate 2-3 mmol/l) and add lactate as an additional variable for stratification to enable us to perform an additional severity of illness- treatment effect analysis. References 1. Wierstra BT, Kadri S, Alomar S, Burbano X, Barrisford GW, Kao RL: The impact of "early" versus "late" initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis. Crit Care 2016, 20(1): Vaara ST, Reinikainen M, Wald R, Bagshaw SM, Pettila V, Group FS: Timing of RRT based on the presence of conventional indications. Clin J Am Soc Nephrol 2014, 9(9): Wald R, Adhikari NK, Smith OM, Weir MA, Pope K, Cohen A, Thorpe K, McIntyre L, Lamontagne F, Soth M et al: Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury. Kidney Int 2015, 88(4): Lima A, Jansen TC, van Bommel J, Ince C, Bakker J: The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med 2009, 37(3): Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL et al: Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014, 40(12): Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, Della Rocca G, Aldecoa C, Artigas A, Jog S et al: Fluid challenges in intensive care: the FENICE study: A global inception cohort study. Intensive Care Med 2015, 41(9): Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM et al: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315(8): Nisula S, Kaukonen KM, Vaara ST, Korhonen AM, Poukkanen M, Karlsson S, Haapio M, Inkinen O, Parviainen I, Suojaranta-Ylinen R et al: Incidence, risk factors and 90-day

5 mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med 2013, 39(3): Poukkanen M, Vaara ST, Pettila V, Kaukonen KM, Korhonen AM, Hovilehto S, Inkinen O, Laru-Sompa R, Kaminski T, Reinikainen M et al: Acute kidney injury in patients with severe sepsis in Finnish Intensive Care Units. Acta Anaesthesiol Scand 2013, 57(7): Iwashyna TJ, Burke JF, Sussman JB, Prescott HC, Hayward RA, Angus DC: Implications of Heterogeneity of Treatment Effect for Reporting and Analysis of Randomized Trials in Critical Care. Am J Respir Crit Care Med 2015, 192(9):