Study into the reversal of septic shock with landiolol (beta blockade): STRESS-L Study protocol for a randomised trial

Introduction In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p<0.001). Beta blockers are one of the most studied groups of drugs but their effect in septic shock is poorly understood; proposed mechanisms include not only the modulation of cardiac function but also immunomodulation. Methods and analysis STRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines. Ethics and dissemination This trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368). The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration. Registration The trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registered ISRCTN12600919 and EudraCT: 2017-001785-14.

Background -Page 7, lines 30-3: please add the reference to the recent work by Stolk et al. who report improved immune competence in septic shock patients on beta-blockers. -Page 7, lines 36-40: This statement appears to reflect actual data, but the authors refer to a review. -Page 8, lines 6-7: "baseline cardiovascular" should be changed to "baseline hemodynamic situation" Methods -Why are patients included in which noradrenaline has been stopped (<12 hours), this seems to not correspond with the inclusion criteria (i.e. requiring vasopressors)? -The study will include patients admitted well into 2020. Will patients suffering from COVID-19 who fulfill the inclusion criteria also be included?  has been demonstrated to have specific inflammatory properties unlike other infections/sepsis causes, which might confound results. Specific statements on this should be made in the manuscript. -Will vasopressors other than noradrenaline be used in the patients included during this trial?
Outcome measures -Use of beta-blockers was associated with an enhanced TNF/IL-10 ratio in septic shock patients in the aforementioned recent study by Stolk et al. Therefore, I would advise to add this specific ratio to the outcome measures. Furthermore, noradrenaline inhibited production of CXCL-10 and MCP-1 in humans in vivo in this study. Therefore, I would advise to add these chemokines to the list of inflammatory markers of interest. -It would be nice to add secondary ICU-acquired infections as an outcome measure.
-If possible, measurements of monocytic HLA-DR expression could be added (in a subset of patients).
Statistical analysis -Heart rate is not part of the SOFA score and SOFA therefore represents a nicely chosen primary outcome -Will the detailed statistical plan be published before study inclusion is complete? Could the SAP be published as a supplement?

REVIEWER
Lex van Loon Australian National University, Canberra, Australia REVIEW RETURNED 09-Oct-2020 Please be more specific when mentioning "the efficacy". One can think of many.... Reducing SOFA, HR, other? in which timeframe? I see you later explained it, but it is better to be specific from the beginning -Secondary objective. Please change "improves" with "reduces". It is more appropriate for mortality and LOS -Regarding the "second bullet" of secondary objectives. It is better to specify if you have an hypothesis on that, explaining what exactly you suppose to find on metabolism, inflammation and cardiac samage -Study setting. I would explain readers why you are publishing a study protocol after 2 and half years.

GENERAL COMMENTS
-Outcome measures. Please explain how will you handle (statistically) the SOFA score for deceased or discharged patients -Please explain why you have not considered echocardiographic evaluation as part of the study objectives. The evaluation of cardiac performance is of utmost importance when considering beta-blockade, though the identification of beta-blocker responders (non-compensatory tachycardia) and non-responders (compensatory for 'fixed' stroke volume [SV]) is challenging. Echocardiography may be particularly helpful in understanding the effects of beta-blockers in septic shock patients. Even if not performing echocardiography, other measures may be very interesting. Recently Prof Morelli in a post-hoc analysis tested the ability of the difference between systolic and dicrotic pressure (SDPdifference), which reflects the coupling between myocardial contractility and a given afterload, in discriminating the origin of tachycardia. The authors found that a decrease in SDPdifference could discriminate between compensatory and non-compensatory tachycardia, revealing a covert loss of myocardial contractility not detected by conventional echocardiographic parameters and deteriorating after HR reduction with esmolol. Comments to the Author With interest I read the manuscript "Study into the Reversal of Septic Shock with landiolol (Beta Blockade): Study Protocol for the STRESS-L Randomised Trial". It is a study protocol for the investigation of the use of landiolol in septic shock patients. As the drawbacks of catecholamine use are becoming more apparent and better characterized, the use of beta blockers in sepsis patients is an important research topic. This study is timely and well described. I do have some comments.
Background -Page 7, lines 30-3: please add the reference to the recent work by Stolk et al. who report improved immune competence in septic shock patients on beta-blockers. We have included the reference although note that the paper was published after original submission of the paper to BMJOpen. -Page 7, lines 36-40: This statement appears to reflect actual data, but the authors refer to a review. The statement is a composite of many factors that are referenced in the preceding paragraph and nicely summarised in the review. We have altered the wording of the text -Page 8, lines 6-7: "baseline cardiovascular" should be changed to "baseline hemodynamic situation" This has been placed in the Track Changes

Methods
-Why are patients included in which noradrenaline has been stopped (<12 hours), this seems to not correspond with the inclusion criteria (i.e. requiring vasopressors)? This only applies to patients who have previously been treated with noradrenaline and then recently stopped as there is a high risk that the noradrenaline will need to be restartedwe have made minor phrase changes to the paper to clarify this.
-The study will include patients admitted well into 2020. Will patients suffering from COVID-19 who fulfill the inclusion criteria also be included? COVID-19 has been demonstrated to have specific inflammatory properties unlike other infections/sepsis causes, which might confound results. Specific statements on this should be made in the manuscript. As the study was started in 2018 we had no plans to recruit patients for COVID 19. We have subsequently made an amendment to include COVID 19 patients but this was after the submission to BMJOpen -Will vasopressors other than noradrenaline be used in the patients included during this trial? Yes, this is a pragmatic, real world study. The concomitant use of vasopressin is assumed. Although this does risk reducing the dose of noradrenaline and potentially reducing the number of patient eligible for the study, our hypothesis is about beta blocker immunomodulation and protection of the adverse effects of noradrenaline Outcome measures -Use of beta-blockers was associated with an enhanced TNF/IL-10 ratio in septic shock patients in the aforementioned recent study by Stolk et al. Therefore, I would advise to add this specific ratio to the outcome measures. Furthermore, noradrenaline inhibited production of CXCL-10 and MCP-1 in humans in vivo in this study. Therefore, I would advise to add these chemokines to the list of inflammatory markers of interest.
-It would be nice to add secondary ICU-acquired infections as an outcome measure.
-If possible, measurements of monocytic HLA-DR expression could be added (in a subset of patients). Thank you for these excellent suggestionswe will include them in the secondary measures of our parallel mechanistic study. We are slightly constrained by our ability to make wholesale changes (for example to the Outcomes) as this study has already been recruiting since March 2018 but have done what we can to accommodate the reviewers' suggestions. The outcomes have already gone through funding, regulatory and ethical approval. We will, however, seek appropriate regulatory approval to add these to our mechanism study. We will be publishing a lab investigation protocol Statistical analysis -Heart rate is not part of the SOFA score and SOFA therefore represents a nicely chosen primary outcome. Please be more specific when mentioning "the efficacy". One can think of many.... Reducing SOFA, HR, other? in which timeframe? I see you later explained it, but it is better to be specific from the beginning. We are more specific in our Primary Outcome section. The Objectives of the trial remain the same as these are a composite of the things that the reviewer mention. A clinical trial is harder to run and to analyse with a composite outcome or with multiple outcomes.
-Secondary objective. Please change "improves" with "reduces". It is more appropriate for mortality and LOS. Please see above -Regarding the "second bullet" of secondary objectives. It is better to specify if you have an hypothesis on that, explaining what exactly you suppose to find on metabolism, inflammation and cardiac samage Please see above -Study setting. I would explain readers why you are publishing a study protocol after 2 and half years.
-Outcome measures. Please explain how will you handle (statistically) the SOFA score for deceased or discharged patients We plan to publish a SAP separately -Please explain why you have not considered echocardiographic evaluation as part of the study objectives. The evaluation of cardiac performance is of utmost importance when considering betablockade, though the identification of beta-blocker responders (non-compensatory tachycardia) and non-responders (compensatory for 'fixed' stroke volume [SV]) is challenging. Echocardiography may be particularly helpful in understanding the effects of beta-blockers in septic shock patients. Even if not performing echocardiography, other measures may be very interesting. Recently Prof Morelli in a post-hoc analysis tested the ability of the difference between systolic and dicrotic pressure (SDPdifference), which reflects the coupling between myocardial contractility and a given afterload, in discriminating the origin of tachycardia. The authors found that a decrease in SDPdifference could discriminate between compensatory and non-compensatory tachycardia, revealing a covert loss of myocardial contractility not detected by conventional echocardiographic parameters and deteriorating after HR reduction with esmolol. Link: https://pubmed.ncbi.nlm.nih.gov/32690246/ Performing ECHO is easy in a single centre setting but validating training and unifying ECHO techniques and interpretation across 40 centres whilst minimising inter-and intra-user variability would involve