Landiolol and Organ Failure in Patients With Septic Shock
Authors: Whitehouse Tony , Hossain Anower , Perkins Gavin D. , Gordon Anthony C. , Bion Julian , Young Duncan , McAuley Danny , Singer Mervyn , Lord Janet , Gates Simon , Veenith Tonny , MacCallum Niall S. , Yeung Joyce , Innes Richard , Welters Ingeborg , Boota Nafisa , Skilton Emma , Ghuman Belinder , Hill Maddy , Regan Scott E. , Mistry Dipesh , Lall Ranjit ,   STRESS-L Collaborators, Veenith Tonny , Patel Jaimin , Murphy Nick , Bangash Mansoor , Torlinski Tomasz , Talbot Nicholas , Snelson Catherine , Parekh Dhruv , Desai Amisha , Kotada Mary , May Chin Yin , Holden Sophie , Neal Aoife , Ventura Maximina , Pope Martin , Harkett Samantha , McGhee Christopher , Fellows Emma , Bamford Amy , Carrera Ronald , Ellis Karen , Spruce Elaine , Despy Liesl , Porter Stephanie , Bergin Colin , Gouny Stephanie , Smith Hazel , Mason Tracy , Dooley Natalie , Clark Amy , Yeung Joyce , Gresty Jo , Melody Teresa , Reeves Ellie , Smith Rachel , Sampson Julia , Team BHH Critical Care Unit ACCP , Nutt Chris , Mcnamee James , Mcauley Danny , Boyle Anen , McGinley Loren , Wright Chris , Ward Kathryn , Macartney Lauren , Mccann Justine , Wells Brian , Mills Janette , Bannon Leona , O’Neill Aisling , Finn Stephanie , Gordon Anthony , Antcliffe David , Brett Stephen , Banach Dorota , Cabreros Leilani , Curran Laura , Sousa Arias Sonia , Rojo Roceld , Fernandez de Pinedo Artaraz Ziortza , Coghlan Phoebe , Templeton Maie , ElHaddad Ahmed , Sabine Loko Zohonon , Barker Gareth , MacCallum Niall , Brealey David , Singer Mervyn , Warnes Kristian , Bason Nina , Filipowicz Dorota , Bercades Georgia , Hass Ingrid , Ryu Jung , Smyth Deborah , Ilano Dorothy , Harvey Dan , Conner Louise , Ryan Lucy , Peters Cecilia , Meredith Megan , Mcaulay Megan , Whitman Zoe , Morris Lucy , Woodford Claudia , Hodgkinson Sally , Finucane Sonya , Camporota Luigi , Shankar-Hari Manu , Ostermann Marlies , Bociek Aneta , Lim Rosario , GrauNovellas Neus , Palmer Natalie , Cape Angela , Kelly Anea , Arbane Gill , Campos Sarah , Singh Michael , Yoo Jinny , Innes Richard , Dempsey Fiona , Doble Patricia , Purnell Rebecca , Tait Moira , Hutter Jo , Pawley Corinne , Rowe Joy , Wane Catherine , Burgess Richard , Thomas Ashly , Paul Pulak , White Brenda , Lovegrove Wayne , Gill Mandy , Wade Lynne , Brear Tracy , Dhokia Vishal , Jackson Debbie , Shelton Sarah , Kirk Jill , Boulton Anew , Roy Alistair , Rostron Anthony , Elcioglu Zeynep , Woods Lindsey , Cornell Sarah , Betts Rebecca , Holden Jill , Laybourne Stephen , Rogerson Kimberley , Bewley Jeremy , Johnson Rebekah , Chillingworth Anna , Gumbrill Bethany , Galvin Hilary , Wright Kim , Efford Georgia , Corcoran Kathleen , Cole Libby , Sweet Katie , Webster Denise , Grimmer Lisa , Paris Gemma , Searles Chloe , Garland Zoe , Gibson Charly , Hutchings Melanie , Walters Fiona , Kelly Sinead , Scaife Lorraine , Littlewood Kelly , Leavy James , Todd Shirley , Gordon Elizabeth , Heddon Sadie , Mariano Victor , Gupwell Karin , Appelboam Rebecca , Keenan Samantha , Brady Cassie , Mew Ian , Chambler Duncan , Williams Sarah , Ashcroft Pauline , Williams Patricia , Rees James , Wiseman Sophie , Horton Sarah , Shortland Mark , Dukes Stephanie , Ball Andy , Spivey Michael , Stephens Jennie , Bean Sarah , Burt Karen , Chapman Rachel , Richards Carol , Moore Lorraine , Allsop Linda , Wynn Amber , Latty Louise , Waddy Sam , Spencer Kayleigh , Stowe Bethan , Cox Georgina , McMillan Helen , Lankester Liana , Wells Colin , Squire Rosalyn , Marner Mike , Jackson Robert , Nikitas Nikitas , Dickson Stuart , Reschreiter Henrik , Bromilow James , Keegan James , Loew Chris , Power Ken , Briggs Spike , Camsooksai Julie , Patch Sarah , Jenkins Sarah , Power Sharon , Woodward Elizabeth , Pogson David , Daly Zoe , Rose Steve , Collins Aimi , Phelps Amy , Claridge Helen , Minnis Christine , Inglis Sarah , Brimfield Lutece , Wong Charlotte , Welters Ingeborg , Williams Karen , Waugh Victoria , Patrick-Heselton Julie , Johnson Emily , Shaw David , Johnston Brian , Crews Maryam , Waite Alicia , Sankar Vinoth , Walker Jonathan , Turton Peter , Wenstone Richard , Fernandez Roman Jaime , Hall Alison , Lopez Martinez Maria , Oliver Hamilton David , Coey David , Shelley Philip , Goulding Martin , Kavanagh Karen , Marron Ann , Allsop Hannah , Hopkins Phil , Smith John , Noble Harriet , Pappa Evita , Finney Clare , Heyler Sinead , Clarey Emma , Cockrell Maeve , Therese Depante Maria , O'Reilly Kevin , Waterhouse Christopher , Chu Vicky , Gordon Joanne , Marchant Greg , Chandler Stuart , Haile Senait , Flanagan Joanna , Notcheva Gaynor , Jimenez Dom , Gill Dilbagh , Jamadarkhana Sunil , Gohil Sunita , Dabbagh Sura , Chick Katy-Jane , Cruz Carina , Anumakonda Vikram , Moore Vanessa , Stanton Lisa , Westwood Sharon , Smith Jacqueline , Reid Karen , Gidda Ranjit , Anastasescu Elena , Salem Karim , Mooradun Mohamed , Reay Michael , Ekbal Nasirul , McNeil Margaret , Filipe Helder , Nandani Aarti , Pakou Glykeria , de Neef Mark , Mingo Sara , Maharajh Amitaa , Nandhabalan Prashanth , Billyard Thomas , Wild Laura , Bremmer Pamela , Ward Geraldine , McGurk Fiona , Deol Rajbinder , Morgan Catherine , Pachoo Kirandeep , Phillips Barbara , Boyd Owen , Phillips Claire , Hindocha Rakhee , Age Stephen , Porter John , Harrison Alex , Evans Lynn , Ortiz-Ruiz de Gordoa Louise , Wlazly Dominika , Anews Tomas , West Jess , Attwood Ben , Jefferson Paul , Parsons Penny , Mason Sophie , Campbell Bridget , Jones Julia , Webb Kathryn , Spicer Karen , Day Angela , Stagg Camilla , Ayesha Shah Noor , Purcell Ian , Shafiq Lucy , Carle Coralie , Chilvers Rebecca , MacColl Heather , Pope Alan , Holder Anew , Butterworth-Cowin Nicola , Davies Matthew , Wilmer Louise , Ismail Nadeem , Gurung Sneha , Murphy Piers , Elkington Toby , Camilleri Matthew , Charnock Rob , Shevlin Claire , McGregor Emma , Clarke Chris , Hinds Judith , Hughes Sophie , McKee Raymond , McFarland Denise , McNulty Roisin , Breen Andy , Wilby Elizabeth , Youngs Nora , French Richard , Colquhoun Suzie , Posnett Claire , Howcroft Clare , Taylor Anew , Whiteley Simon , Ogg Bethan , Long Kate , Tomkinson Alicia , Clement Ian , Shrestha Tara , Dunn Leigh , Calder Verity , Babio-Galan Maite , Zwiggelaar Kimberley , Mitchell Anne , Stephenson Julie , Rigden Lesley , Davison Jude , Carter Joseph , Howard Kate , Cahill Hazel , Grainger Lia , Cottrell-Howe Poppy , Rowbotham Abigail , Jeffery Laura , Waterman Emily , Fletcher Arran , Guy Zoe , Birkinshaw Isabel , Ingham Jo , Scott Zoe , Stead Samantha , West Raha , Shanmugasundaram Pradeep , Abrams Judith , Hambrook Geraldine , Manso Katarina , Scott Sally , Husain Iram , Chan Evelyn , Gettings Siobhan , Hormis Anil , Walker Rachel , Collier Dawn , Graham Cheryl , Murray Victoria , Curtis Katy , Widdop Charlotte , Kimpton Sarah , Oakley Susan , Afzal Zirlish , Varley James , Polgarova Petra , Johnston Andrew , Whitehead Lynne , Conway Morris Andrew , Mahroof Razeen , Teixeira Sofia , Ali Nazrudeen , Wilkinson Jonny , Lyon Alex , Mills Charlotte , Hall Kathryn , Grantham Gayna , Campey Lorraine , Cronshaw Helen , Malanjum Livia , Dudgeon Lucy , Hinchley Clare , Langhon Stephen , Hosea Jane , Hillyer Anea , Kontogonis Rachel , Ndefo Oninye , Robinson Laura , Kaye Callum , Sim Kevin , Scott Ian , Scott Teresa , Anderson Felicity , Mitchell Wendy , Cooper Patricia , MacBrayne James , Willox Fiona , Richmond Kate , Colleron Rebecca , Trumper Erin , Was Bartosz , Christie Michael , Johnson Amber , Price Gillian , Sim Malcolm , Docking Robert , McQueen Scott , Kennedy-Kay Sophie , Abel Lynn , Henderson Steven , McLeash Kirsty , Gratrix Anew , Martinson Victoria , Foster Louise , Stones Elizabeth , Lowthorpe Vicki , Crawley Daniel , Leaver Susannah , Farnell Ward Sarah , Pepermans Saluzzio Romina , Robinson Frances , Delgado Carlos , Gray Geraldine , Kanu Rebecca , Oakley Robert , Keates Karen M. , Walsh Tim 
Published: October 2023

Importance

Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality.

Objectives

To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (&amp;gt;24 hours) vasopressor support.

Design, Setting, and Participants

An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm.

Intervention

Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion.

Main Outcomes and Measures

The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group.

Results

The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event.

Conclusion and Relevance

Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock.

Trial Registration

EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919