The effects of ultra-selective beta1-antagonism on the metabolic and cytokine profile in septic shock patients receiving noradrenaline: a sub-investigation from the STRESS-L Randomised Study
Authors: Thomas Jarrod L. , McGee Kirsty C. , Hossain Anower , Perkins Gavin D. , Gordon Anthony C. , Young Duncan , McAuley Danny , Singer Mervyn , Lall Ranjit , Kramaric Tina , Lord Janet M. , Whitehouse Tony , Mur Luis A. J. ,   for the STRESS-L. collaborators, Veenith Tonny , Patel Jaimin , Murphy Nick , Bangash Mansoor , Torlinski Tomasz , Talbot Nicholas , Snelson Catherine , Parekh Dhruv , Desai Amisha , Kotada Mary , Chin Yin May , 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 , Goundry Stephanie , Smith Hazel , Mason Tracy , Dooley Natalie , Clark Amy , Yeung Joyce , Gresty Jo , Melody Teresa , Reeves Ellie , Smith Rachel , Sampson Julia ,   ACCP Team BHH Criticla Care Unit, Nutt Chris , Mcnamee James , Mcauley Danny , Boyle Andren , 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 , Arias Sonia Sousa , Rojo Roceld , de Pinedo Artaraz Ziortza Fernandez , Coghlan Phoebe , Templeton Maie , ElHaddad Ahmed , Loko Zohonon Sabine , Barker Gareth , MacCallum Niall , Brealey David , 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 , Clark Amy , Morris Lucy , Sampson Julia , Woodford Claudia , Hodgkinson Sally , Finucane Sonya , Camporota Luigi , Shankar-Hari Manu , Ostermann Marlies , Bociek Aneta , Lim Rosario , GrauNovellas Neus , Palmer Natalie , Cape Angela , Kelly Andrea , 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 Andrew , 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 , Roman Jaime Fernandez , Hall Alison , Martinez Maria Lopez , Hamilton David Oliver , 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 , Depante Maria Therese , 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 , 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 , Drage Stephen , Porter John , Harrison Alex , Evans Lynn , de Gordoa Lousie Ortiz-Ruiz , Wlazly Dominika , Andrews Tomas , West Jess , Attwood Ben , Jefferson Paul , Parsons Penny , Mason Sophie , Campbell Bridget , Jones Julia , Webb Kathryn , Spicer Karen , Day Angela , Stagg Camilla , Shah Noor Ayesha , Purcell Ian , Shafiq Lucy , Carle Coralie , Chilvers Rebecca , MacColl Heather , Pope Alan , Holder Andrew , 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 Andrew , 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 , Morris Andrew Conway , 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 Andrea , 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 , Hughes Sophie , Henderson Steven , McLeash Kirsty , Gratrix Andrew , Martinson Victoria , Foster Louise , Stones Elizabeth , Lowthorpe Vicki , Crawley Daniel , Leaver Susannah , Ward Sarah Farnell , Saluzzio Romina Pepermans , Robinson Frances , Delgado Carlos , Gray Geraldine , Kanu Rebecca , Oakley Robert 
Published: January 2025

Abstract

Purpose
The landiolol and organ failure in patients with septic shock (STRESS-L study) included a pre-planned sub-study to assess the effect of landiolol treatment on inflammatory and metabolomic markers.

Methods
Samples collected from 91 patients randomised to STRESS-L were profiled for immune and metabolomic markers. A panel of pro- and anti-inflammatory cytokines were measured through commercially acquired multiplex Luminex assays and statistically analysed by individual and cluster-level analysis (patient). Metabolite fingerprinting was carried out by flow infusion electrospray ionisation high-resolution mass spectrometry and metabolomic data were analysed using the R-based platform MetaboAnalyst. The metabolites were identified using DIMEdb (dimedb.ibers.aber.ac.uk) from their mass/charge ratios. These metabolomic data were also re-analysed using individual and cluster-level analysis. The individual-level models were adjusted for confounders, such as age, sex, noradrenaline dosage and patient (random effect).

Results
Analysis was undertaken at cluster- and individual-level. There were no significant differences in cytokine concentration level between trial arms nor survivors and non-survivors over the duration of the observations from day 1 to day 4. Metabolomic analysis showed some separation in the levels of ceramides and cardiolipins between those who survived and those who died. Following adjusted analysis for confounders, plasma metabolite concentrations remained statistically different between landiolol and standard care arms for succinic acid, l-tryptophan, l-alanine, 2,2,2-trichloroethanol, lactic acid and d-glucose.

Conclusions
In a study of ICU patients with established septic shock and a tachycardia, landiolol treatment used to reduce the heart rate from above 95 to a range between 80 and 94 beats per minute did not induce significant cytokine changes. d-Glucose, lactic acid, succinic acid, l-alanine, l-tryptophan and trichloroethanol were pathways that may merit further investigation.

Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001785-14/GB); ISRCTN registry Identifier: ISRCTN12600919 (https://www.isrctn.com/ISRCTN12600919).