Liberal versus restrictive transfusion strategies in subarachnoid hemorrhage: a secondary analysis of the TRAIN study

doi:10.1186/s13054-025-05270-5

Randomized Controlled Trial

. 2025 Feb 7;29(1):67.

doi: 10.1186/s13054-025-05270-5.

Liberal versus restrictive transfusion strategies in subarachnoid hemorrhage: a secondary analysis of the TRAIN study

Chahnez Taleb^#¹, Elisa Gouvea Bogossian^#², Carla Bittencour Rynkowski^{3

4}, Kirsten Møller^{5

6}, Piet Lormans⁷, Manuel Quintana Diaz⁸, Anselmo Caricato⁹, Luigi Zattera¹⁰, Pedro Kurtz^{11

12}, Geert Meyfroidt¹³, Herve Quintard¹⁴, Maria Celeste Dias¹⁵, Angelo Giacomucci¹⁶, Charlotte Castelain¹⁷, Russell Chabanne¹⁸, Pilar Marcos-Neira¹⁹, Stepani Bendel²⁰, Ahmed Subhy Alsheikhly²¹, Mohamed Elbahnasawy²², Samuel Gay²³, Maximilian D'Onofrio²⁴, Konstantin A Popugaev^{25

26}, Nikolaos Markou²⁷, Pierre Bouzat²⁸, Jean-Louis Vincent¹, Fabio Silvio Taccone¹; TRAIN Study Trial Group

Collaborators, Affiliations

Collaborators

TRAIN Study Trial Group:
Marco Antonio Cardoso Ferreira, Rafael Badenes, Christian Baastrup Sondergaard, Kirsten Colpaert, Leticia Petterson, Claudia Díaz, Andrés Saravia, Ahmad Bayrlee, Laura Nedolast, Hussam Elkambergy, Haamid Siddique, Jihad Mallat, Nahla AlJaberi, Samer Shoshan, Ayo Mandi, Bruno De Oliveira, Malligere Prasanna, Rehan Haque, Dnyaneshwar Munde, Sara Chaffee, Fatma Alawadhi, Jamil Dibu, Eija Junttila, Teemu Luoto, Simona Šteblaj, Jacques Creteur, Dominique Durand, Caroline Abbenhuijs, Nancy Itesa Matumikina, Filippo Annoni, Leda Nobile, Miguel Ulloa Bersatti, Igor Yovenko, Alexander Tsarev, Jasperina Dubois, Evy Voets, Luc Janssen, Luigi Zattera, Leire Pedrosa, Berta Monleon Lopez, Ainhoa Serrano, Nekane Romero-García, Xavier Wittebole, Antonio Maria Dell'Anna, Camilla Gelormini, Eleonora Stival, Pilar Marcos Neira, Regina Roig Pineda, Lara Bielsa Berrocal, Maite Misis Del Campo, Jorge H Mejía-Mantilla, Ángela Marulanda, Wojciech Dabrowski, Rune Damgaard Nielsen, Markus Harboe Olsen, Helene Ravnholt Jensen, Ida Møller Larsen, Roberta Tallarico, Umberto Lucangelo, Maria Isabel Gonzalez Perez, Carole Ichai, Karim Asenhoune, Karim Lakhal, Charlotte Fernandez-Canal, Samuel Gay, Marie Lebouc, David Bougon, Etienne Escudier, Michel Sirodot, Albrice Levrat, Alix Courouau, Jacques Duranteau, Aurore Rodrigues, Naima Makouche, Gilles Francony, Olivier Vincent, Perrine Boucheix, Clotilde Schilte, Marie Cecile Fevre, Thomas Mistral, Marion Richard, Samia Salah, Pierluigi Banco, Angelina Pollet, Anais Adolle, Thomas Gargadennec, Patricia Dias, Gwenaelle Desanglois, Alexia Meheut, Pauline Cam, Liese Mebis, Alexandra Hendrickx, Pieter Wouters, Sylvia Van Hulle, Alain D'Hondt, Marjorie Beumier, Marc Burgeois, Olivier Simonet, Frederic Vallot, Pablo Centeno, Matias Anchorena, Ximena Benavente, Nydia Funes, Antonio Barra de Oca, Gabriela Izzo, Charlotte Castelain, Filip Soetens, Mario Arias, Diego Morocho, Manuel Jabaja, Diego Tutillo, Elena Perez Solada, Pilar Justo, Amparo Lopez Gomez, Sara Alcantara, Francisco Chico, Maria Fernanda Garcia, Fabricio Picoita, Stela Velasco Eichler, Gabriela Nonticuri Bianchi, João Pedro Britz, Jaqueline Almeida Pimentel, Mário Sérgio Fernandes, Hedi Gharsallah, Zied Hajjej, Walid Samoud, Oleg Grebenchikov, Valery Likhvantsev, Elena Stroiteleva, Nikolaos Markou, Dimitra Bakali, Dionysia Koutrafouri, Sara Maccherani, Janneke Horn, Arezoo Ahmadi, Lien Decaesteker, Daphne Decruyenaere, Ruth Demeersseman, Yves Devriendt, Karen Embo, Ditty van Duijn, Patricia Ormskerk, Melanie Glasbergen-van Beijeren, Raphael Cinotti, Cassia Righy, Serena Silva, Catherine Vandewaeter, Daniel Lemke, Ata Mahmoodpoor, Aaron Blandino-Ortiz, Mathieu Van der Jagt, Walter Videtta

Affiliations

¹ Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.
² Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium. elisa.gouvea.bogossian@ulb.be.
³ Intensive Care Unit of Cristo Redentor Hospital, Porto Alegre, Brazil.
⁴ Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.
⁵ Department of Neuroanaesthesiology, Rigshospitalet - University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Clinical Medicine-Anesthesiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Intensive Care, AZ Delta, Roeselaere, Belgium.
⁸ Department of Intensive Care Medicine, Hospital Universitario de La Paz, Madrid, Spain.
⁹ Institute of Anesthesiology and Intensive Care, Catholic University School of Medicine, Rome, Italy.
¹⁰ Department of Anesthesiology and Intensive Care, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.
¹¹ Department of Intensive Care Medicine, DOr Institute of Research and Education, Rio de Janeiro, Brazil.
¹² Department of Neurointensive Care, Instituto Estadual do Cerebro Paulo Niemeyer, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
¹³ Department and Laboratory of Intensive Care Medicine, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
¹⁴ Division of Intensive Care Medicine, Department of Anesthesiology, Clinical Pharmacology, Intensive Care, and Emergency Medicine, Geneva University Hospital, Geneva, Switzerland.
¹⁵ Neurocritical Care Unit, Medical University Center (CUME), Porto, Portugal.
¹⁶ Anestesia and Intensive Care, Azienda Ospedaliera di Perugia, Perugia, Italy.
¹⁷ Department of Anesthesia and Intensive Care Medicine, AZ Groeninge, Kortrijk, Belgium.
¹⁸ Neurocritical Care Unit, Neurosurgical and Neurointerventional Anesthesiology Clinic, Division of Anesthesiology, Critical Care and Peri-Operative Medicine, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.
¹⁹ Department of Intensive Care Medicine, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
²⁰ Department of Intensive Care, Kuopio University Hospital, Kuopio, Finland.
²¹ Hamad Medical Corporation / Weill Cornell Medicine - Qatar, Doha, Qatar.
²² Tanta University Hospital, Tanta, El Gharbeya, Egypt.
²³ Intensive Care Unit, Centre Hospitalier Annecy-Genevois, Epagny Metz-Tessy, France.
²⁴ Artemidis Zatti Hospital, Viedma, Rio Negro, Argentina.
²⁵ Department of Intensive Care, Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department, Moscow, Russia.
²⁶ Department of Intensive Care, State Research Center, Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russia.
²⁷ General Hospital of Eleusis Thriasion, Magoula, Greece.
²⁸ Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France.

^# Contributed equally.

PMID: 39920710
PMCID: PMC11803982
DOI: 10.1186/s13054-025-05270-5

Randomized Controlled Trial

Liberal versus restrictive transfusion strategies in subarachnoid hemorrhage: a secondary analysis of the TRAIN study

Chahnez Taleb et al. Crit Care. 2025.

. 2025 Feb 7;29(1):67.

doi: 10.1186/s13054-025-05270-5.

Authors

Collaborators

TRAIN Study Trial Group:
Marco Antonio Cardoso Ferreira, Rafael Badenes, Christian Baastrup Sondergaard, Kirsten Colpaert, Leticia Petterson, Claudia Díaz, Andrés Saravia, Ahmad Bayrlee, Laura Nedolast, Hussam Elkambergy, Haamid Siddique, Jihad Mallat, Nahla AlJaberi, Samer Shoshan, Ayo Mandi, Bruno De Oliveira, Malligere Prasanna, Rehan Haque, Dnyaneshwar Munde, Sara Chaffee, Fatma Alawadhi, Jamil Dibu, Eija Junttila, Teemu Luoto, Simona Šteblaj, Jacques Creteur, Dominique Durand, Caroline Abbenhuijs, Nancy Itesa Matumikina, Filippo Annoni, Leda Nobile, Miguel Ulloa Bersatti, Igor Yovenko, Alexander Tsarev, Jasperina Dubois, Evy Voets, Luc Janssen, Luigi Zattera, Leire Pedrosa, Berta Monleon Lopez, Ainhoa Serrano, Nekane Romero-García, Xavier Wittebole, Antonio Maria Dell'Anna, Camilla Gelormini, Eleonora Stival, Pilar Marcos Neira, Regina Roig Pineda, Lara Bielsa Berrocal, Maite Misis Del Campo, Jorge H Mejía-Mantilla, Ángela Marulanda, Wojciech Dabrowski, Rune Damgaard Nielsen, Markus Harboe Olsen, Helene Ravnholt Jensen, Ida Møller Larsen, Roberta Tallarico, Umberto Lucangelo, Maria Isabel Gonzalez Perez, Carole Ichai, Karim Asenhoune, Karim Lakhal, Charlotte Fernandez-Canal, Samuel Gay, Marie Lebouc, David Bougon, Etienne Escudier, Michel Sirodot, Albrice Levrat, Alix Courouau, Jacques Duranteau, Aurore Rodrigues, Naima Makouche, Gilles Francony, Olivier Vincent, Perrine Boucheix, Clotilde Schilte, Marie Cecile Fevre, Thomas Mistral, Marion Richard, Samia Salah, Pierluigi Banco, Angelina Pollet, Anais Adolle, Thomas Gargadennec, Patricia Dias, Gwenaelle Desanglois, Alexia Meheut, Pauline Cam, Liese Mebis, Alexandra Hendrickx, Pieter Wouters, Sylvia Van Hulle, Alain D'Hondt, Marjorie Beumier, Marc Burgeois, Olivier Simonet, Frederic Vallot, Pablo Centeno, Matias Anchorena, Ximena Benavente, Nydia Funes, Antonio Barra de Oca, Gabriela Izzo, Charlotte Castelain, Filip Soetens, Mario Arias, Diego Morocho, Manuel Jabaja, Diego Tutillo, Elena Perez Solada, Pilar Justo, Amparo Lopez Gomez, Sara Alcantara, Francisco Chico, Maria Fernanda Garcia, Fabricio Picoita, Stela Velasco Eichler, Gabriela Nonticuri Bianchi, João Pedro Britz, Jaqueline Almeida Pimentel, Mário Sérgio Fernandes, Hedi Gharsallah, Zied Hajjej, Walid Samoud, Oleg Grebenchikov, Valery Likhvantsev, Elena Stroiteleva, Nikolaos Markou, Dimitra Bakali, Dionysia Koutrafouri, Sara Maccherani, Janneke Horn, Arezoo Ahmadi, Lien Decaesteker, Daphne Decruyenaere, Ruth Demeersseman, Yves Devriendt, Karen Embo, Ditty van Duijn, Patricia Ormskerk, Melanie Glasbergen-van Beijeren, Raphael Cinotti, Cassia Righy, Serena Silva, Catherine Vandewaeter, Daniel Lemke, Ata Mahmoodpoor, Aaron Blandino-Ortiz, Mathieu Van der Jagt, Walter Videtta

Affiliations

¹ Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.
² Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium. elisa.gouvea.bogossian@ulb.be.
³ Intensive Care Unit of Cristo Redentor Hospital, Porto Alegre, Brazil.
⁴ Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.
⁵ Department of Neuroanaesthesiology, Rigshospitalet - University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Clinical Medicine-Anesthesiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Intensive Care, AZ Delta, Roeselaere, Belgium.
⁸ Department of Intensive Care Medicine, Hospital Universitario de La Paz, Madrid, Spain.
⁹ Institute of Anesthesiology and Intensive Care, Catholic University School of Medicine, Rome, Italy.
¹⁰ Department of Anesthesiology and Intensive Care, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.
¹¹ Department of Intensive Care Medicine, DOr Institute of Research and Education, Rio de Janeiro, Brazil.
¹² Department of Neurointensive Care, Instituto Estadual do Cerebro Paulo Niemeyer, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
¹³ Department and Laboratory of Intensive Care Medicine, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
¹⁴ Division of Intensive Care Medicine, Department of Anesthesiology, Clinical Pharmacology, Intensive Care, and Emergency Medicine, Geneva University Hospital, Geneva, Switzerland.
¹⁵ Neurocritical Care Unit, Medical University Center (CUME), Porto, Portugal.
¹⁶ Anestesia and Intensive Care, Azienda Ospedaliera di Perugia, Perugia, Italy.
¹⁷ Department of Anesthesia and Intensive Care Medicine, AZ Groeninge, Kortrijk, Belgium.
¹⁸ Neurocritical Care Unit, Neurosurgical and Neurointerventional Anesthesiology Clinic, Division of Anesthesiology, Critical Care and Peri-Operative Medicine, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.
¹⁹ Department of Intensive Care Medicine, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
²⁰ Department of Intensive Care, Kuopio University Hospital, Kuopio, Finland.
²¹ Hamad Medical Corporation / Weill Cornell Medicine - Qatar, Doha, Qatar.
²² Tanta University Hospital, Tanta, El Gharbeya, Egypt.
²³ Intensive Care Unit, Centre Hospitalier Annecy-Genevois, Epagny Metz-Tessy, France.
²⁴ Artemidis Zatti Hospital, Viedma, Rio Negro, Argentina.
²⁵ Department of Intensive Care, Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department, Moscow, Russia.
²⁶ Department of Intensive Care, State Research Center, Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russia.
²⁷ General Hospital of Eleusis Thriasion, Magoula, Greece.
²⁸ Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France.

^# Contributed equally.

PMID: 39920710
PMCID: PMC11803982
DOI: 10.1186/s13054-025-05270-5

Abstract

Background: The optimal hemoglobin (Hb) threshold to trigger red blood cell transfusions (RBCT) in subarachnoid hemorrhage (SAH) patients is unclear. This study evaluated the impact of liberal versus restrictive transfusion strategies on neurological outcome in patients with SAH.

Methods: This is a pre-planned secondary analysis of the "TRansfusion Strategies in Acute brain INjured Patients" (TRAIN) study. We included all SAH patients from the original study that were randomized to receive RBCT when Hb levels dropped below 9 g/dL (liberal group) or 7 g/dL (restrictive group). The primary outcome was an unfavorable neurological outcome at 180 days, defined by a Glasgow Outcome Scale Extended score of 1-5.

Results: Of the 190 SAH patients in the trial, 188 (98.9%) had data available for the primary outcome, with 86 (45.3%) in the liberal group and 102 (53.6%) in the restrictive group. Patients in the liberal group were older than in the restrictive group, but otherwise had similar baseline characteristics. Patients in the liberal group received more RBCT and showed higher Hb levels over time. At 180 days, 57 (66.3%) patients in the liberal group and 78 (76.4%) in the restrictive group had unfavorable outcomes (risk ratio, RR 0.87; 95% confidence intervals, 95% CI 0.71-1.04). Patients in the liberal group had a significantly lower risk of cerebral ischemia (RR 0.63; 95% CI 0.41-0.97). In a multivariate analysis, randomization to the liberal group was associated with a lower risk of unfavorable outcome (RR 0.83, 95% CI 0.70-0.99).

Conclusions: A liberal transfusion strategy was not associated with a lower incidence of unfavorable outcome after SAH when compared to a restrictive strategy. However, in a multivariable analysis adjusted for confounders randomization to the liberal group was associated with lower risk of unfavorable outcome. The occurrence of cerebral ischemia was significantly lower in the liberal transfusion strategy group.

Trial registration: ClinicalTrials.gov number-NCT02968654 registered on November 16th, 2016.

Keywords: Acute brain injury; Anemia; Blood; Stroke.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: This is a secondary analysis of the TRAIN study. The TRAIN study was approved by the ethics committees in each hospital. The primary ethics committee, “Comite d’Ethique Erasme-ULB”, approved this multicentric study on the 14th of March 2016 (P2015/327). Written informed consent was obtained from a legal surrogate before enrollment. Whenever possible, deferred consent was also obtained from the patients who regained mental capacity. Consent for publication: Not applicable. Competing interests: Jean Louis Vincent is editor in chief of critical care. No other authors have reported competing interests.

Figures

**Fig. 1**
Median daily lowest hemoglobin concentration at baseline and after randomization in the two groups. Baseline values were the last blood hemoglobin level measured before randomization. Day 1 was defined as the day after randomization. Bars indicate the 25th and 75th percentiles

**Fig. 2**
Distribution of Glasgow Outcome Scale–Extended scores at 180 days after randomization in the restrictive and liberal group. Each cell corresponds to a score on the scale; the width of each cell represents the proportion of patients with equivalent scores. The vertical dashed line indicates the Glasgow Outcome Scale–Extended score used for dichotomization

**Fig. 3**
Time to Death. This figure shows the survival curves, with data censored at 28 days, in the two groups in the intention-to-treat population. Kaplan–Meier analysis showed that the survival time did not differ significantly between the two groups (log-rank P = 0.99 by Mantel-Cox analysis)

See this image and copyright information in PMC

References

1. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66. - PubMed
1. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D, Investigators ABC. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288(12):1499–507. - PubMed
1. Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ. The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States. Crit Care Med. 2004;32(1):39–52. - PubMed
1. Sampson TR, Dhar R, Diringer MN. Factors associated with the development of anemia after subarachnoid hemorrhage. Neurocrit Care. 2010;12(1):4–9. - PMC - PubMed
1. Kramer AH, Zygun DA, Bleck TP, Dumont AS, Kassell NF, Nathan B. Relationship between hemoglobin concentrations and outcomes across subgroups of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2009;10(2):157–65. - PubMed

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[1] Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66. - PubMed

[2] Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66. - PubMed

[3] Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D, Investigators ABC. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288(12):1499–507. - PubMed

[4] Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D, Investigators ABC. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288(12):1499–507. - PubMed

[5] Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ. The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States. Crit Care Med. 2004;32(1):39–52. - PubMed

[6] Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ. The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States. Crit Care Med. 2004;32(1):39–52. - PubMed

[7] Sampson TR, Dhar R, Diringer MN. Factors associated with the development of anemia after subarachnoid hemorrhage. Neurocrit Care. 2010;12(1):4–9. - PMC - PubMed

[8] Sampson TR, Dhar R, Diringer MN. Factors associated with the development of anemia after subarachnoid hemorrhage. Neurocrit Care. 2010;12(1):4–9. - PMC - PubMed

[9] Kramer AH, Zygun DA, Bleck TP, Dumont AS, Kassell NF, Nathan B. Relationship between hemoglobin concentrations and outcomes across subgroups of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2009;10(2):157–65. - PubMed

[10] Kramer AH, Zygun DA, Bleck TP, Dumont AS, Kassell NF, Nathan B. Relationship between hemoglobin concentrations and outcomes across subgroups of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2009;10(2):157–65. - PubMed

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Liberal versus restrictive transfusion strategies in subarachnoid hemorrhage: a secondary analysis of the TRAIN study

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Liberal versus restrictive transfusion strategies in subarachnoid hemorrhage: a secondary analysis of the TRAIN study

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