Methods
The background to the CRASH-3 trial, the methods, baseline characteristics and main results were previously reported [
2,
6,
14]. Briefly, adults with TBI who were within 3 h of injury and had a Glasgow coma scale score (GCS) ≤ 12 or any intracranial bleeding on CT scan and no significant extra-cranial bleeding were eligible. The time window for eligibility was originally 8 h, but in 2016, the protocol was changed to limit recruitment to within 3 h of injury. Between July 2012 and January 2019, we randomly allocated 12,737 patients with TBI to receive tranexamic acid or placebo, of whom 9202 patients were treated within 3 h. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, care givers and those assessing outcomes were masked to treatment allocation.
Based on previous research on the mechanism of tranexamic acid in bleeding trauma patients, we hypothesised that tranexamic acid would have a greater effect on deaths soon after injury, since early bleeding-related deaths have the most potential to be reduced by tranexamic acid [
15]. We pre-specified this hypothesis in the statistical analysis plan that we published before un-blinding [
14]. We also anticipated that the treatment effect would be diluted by the inclusion of patients with a GCS score of 3 or unreactive pupils who have a very poor prognosis regardless of treatment [
14]. The trial results were consistent with both of these hypotheses [
2]. The pre-specified primary outcome in the CRASH-3 trial was death due to head injury within 28 days among patients treated within 3 h of injury. Although our scientific reasons for pre-specifying head injury death as the primary outcome were given in the statistical analysis plan and presented in detail elsewhere [
16], there has been strong interest in the effects of tranexamic acid on all-cause mortality. As such, this analysis focusses on early deaths from any cause, excluding patients with a GCS score of 3 or bilateral unreactive pupils. Analyses of head injury deaths and analyses including patients with a GCS score of 3 or bilateral unreactive pupils are presented in the Additional file
1 for comparison with the results presented below and for cross-reference with the main trial results.
We examine the temporal distribution of deaths from any cause in the CRASH-3 trial. We explore the effects of tranexamic acid on deaths due to any cause within 24 h of injury and on deaths due to any cause within 28 days, stratified by severity and country income level. We use the baseline GCS score to define severity—mild to moderate (GCS 9–15) and severe (GCS 3–8)—and World Bank definitions to determine country income level (LMIC vs HIC). Because a subgroup analysis demonstrated effect modification by severity, we explore this further. Because most patients were from LMICs, the generalisability of the results to HICs has been questioned and so we explore how the treatment effects vary by country income level. To check if the effect on early deaths could be explained by undiagnosed extra-cranial bleeding, we conducted a sensitivity analysis excluding patients with hypotension (SBP < 90 mmHg). We also examined the effects of tranexamic acid on vascular occlusive events (fatal and non-fatal) in all patients irrespective of time to treatment because theoretically the potential risk of vascular occlusive events would be greater with late treatment as there is a shift from a fibrinolytic to a coagulopathic state. We report risk ratios, 95% confidence intervals and heterogeneity p values. We excluded 98 patients with missing outcome data.
We prespecified an analysis setting the results of the CRASH-3 trial in the context of other evidence, including the CRASH-2 trial, in which 40% of deaths were due to head injury [
14]. The CRASH-3 trial essentially represents a subgroup of patients with isolated TBI who were excluded from the CRASH-2 trial. Here, to set our results in the context of tranexamic acid in polytrauma patients, we pooled the data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis using a Poisson regression model with sandwich variance estimation, adjusted for time to treatment. In the main CRASH-3 trial publication, we updated a systematic search for randomised trials of tranexamic acid in TBI. We searched PubMed, Science Citation Index, National Research Register, Zetoc, SIGLE, Global Health, LILACS, Current Controlled Trials, the Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE and EMBASE. We identified three trials in addition to the CRASH-3 trial including the CRASH-2 intracranial bleeding study, a randomised trial of 283 TBI patients sponsored by Khon Kaen University [
17] and a randomised trial of pre-hospital tranexamic acid in 967 TBI patients sponsored by the University of Washington (NCT01990768). The CRASH-2 intracranial bleeding study was omitted as this is already contained within the CRASH-2 trial dataset, and the small Thai study was omitted due to a lack of data on timing of death, cause of death and GCS score, and limitations in methodological quality including an unclear risk of selection bias from allocation concealment.
The model for the one-step meta-analysis was as follows:
$$ \log\ \pi ={\beta}_0+{\beta}_1\mathrm{trial}+{\beta}_2\mathrm{group}+{\beta}_3\mathrm{ttt} $$
where trial = 0 for CRASH-2 and 1 for CRASH-3, group = 0 for placebo and 1 for TXA, ttt is time to treatment and β2 is the summary effect estimate across both trials.
We also consider the CRASH-3 trial results in the context of the CRASH-2 trial and the trial of pre-hospital tranexamic acid (NCT01990768) using an aggregate data meta-analysis with fixed effects to assess the effect of tranexamic acid on death at 28 days excluding patients with a GCS score of 3 or bilateral unreactive pupils, and on vascular occlusive events in all patients. An aggregate data meta-analysis was used because we did not have access to the individual patient data for trial NCT01990768.
Acknowledgements
The CRASH-3 trial collaborators
Writing Committee—Prof Ian Roberts and Professor Haleema Shakur-Still (co-chairs), Amy Aeron-Thomas, Prof Antonio Belli, Amy Brenner, Prof Muhammad Anwar Chaudary, Prof Rizwana Chaudhri, Sabariah Faizah Bt Jamaluddin, Lauren Frimley, Kiran Javaid, Prof Rashid Jooma, Aasia Kayani, Caroline Leech, Prof Khalid Mahmood, Raoul Mansukhani, Julina Md Noor, Jorge Mejia-Mantilla, Phil Moss, Jason Pott, Prof Peter Sandercock, Prof Temitayo Shokunbi, and Liliana Vallecilla. Trial Steering Committee—Peter Sandercock (Chair), Henry Benjamin Hartzenberg, Manjul Joshipura (2011–2016), Amy Aeron-Thomas (patient representative [trial steering committee]; advocacy and justice manager, RoadPeace), Ian Roberts, Pablo Perel, and Haleema Shakur-Still. Data Monitoring and Ethics Committee—Michael J Clarke (chair), Samuel C Ohaegbulam, Anthony Rodgers, and Tony Brady (independent statistician). Protocol Committee—Ian Roberts, Haleema Shakur-Still, Yashbir Dewan, Phil Edwards, Edward O Komolafe, Jorge Mejia-Mantilla, and Pablo Perel. Clinical Trials Unit (CTU)—Monica Arribas (trial manager and research assistant), Emma Austin (assistant trial manager), Eni Balogun (trial manager), Lin Barneston (data manager 2011–2012), Collette Barrow (trial administrator), Danielle Beaumont (senior trial manager and research fellow), Myriam Benyahia (CTU administrator), Amy Brenner (research fellow), Imogen Brooks (trial assistant 2016–2018), Madeleine Cargill (data assistant), Laura Carrington (assistant trial administrator), Lisa Cook (assistant trial manager 2011), Beatrice Cornu-Hewitt (trial assistant), Phil Edwards (statistician 2011–2016), Lauren Frimley (trial manager and research assistant), Amber Geer (assistant data manager), Daniel Gilbert (data assistant 2012–2013), Catherine Gilliam (trial administrator), Julio Gil-Onandia (trial assistant), Daniel Hetherington (trial assistant 2012–2013), Courtenay Howe (CTU administrator 2015–2017), Carolyn Hughes (data assistant 2016–2017), David I’anson (assistant trial manager 2016–2017), Rob Jackson (data manager 2012–2014), Miland Joshi (statistician 2016–2017), Sneha Kansagra (assistant trial manager 2016–2018), Taemi Kawahara (senior trial manager 2011–2015), Katharine Ker (lecturer), Sergey Kostrov (systems officer), Abda Mahmood (PhD candidate), Raoul Mansukhani (medical statistician), Hakim Miah (IT systems manager), Bernard Ndungu (assistant trial manager 2016–2017), Kelly Needham (medical statistician), Cecilia Okusi (data assistant 2014), Aroudra Outtandy (trial assistant 2013–2015), Raul Pardinaz-Solis (assistant trial manager 2012–2013), Daniel Pearson (data assistant), Tracey Pepple (acting senior data manager), Claude Pisani (assistant trial manager 2013), Jason Pott (lead UK research nurse 2018), David Prieto-Merino (statistician 2012–2015), Danielle Prowse (assistant data manager), Nigel Quashi (data manager 2013–2016), Anna Quinn (data assistant 2013–2015), Maria Ramos (senior project administrator 2011–2015), Mia Reid (clerical assistant 2016–2018), Ian Roberts (chief investigator and CTU co-director), Chris Roukas (trial administrator 2013–2015), Giulia Scrapa (assistant trial manager 2018), Haleema Shakur-Still (project director and CTU co-director), Chelci Squires (trial assistant 2014–2016), Jemma Tanner (clinical trials associate 2013–2016), Andrew Thayne (data assistant), Lesley Vidaurre (assistant trial manager 2012), and Elizabeth Woods (assistant trial manager 2012–2015). Nigeria Coordinating Team—Bukola Fawole (coordinating centre director), Olusade Adetayo (assistant trial coordinator), Olujide Okunade (assistant trial coordinator), and Temitayo Shokunbi (clinical lead). Pakistan Coordinating Team—Rizwana Chaudhri (coordinating centre director), Kiran Javaid (assistant research coordinator), Rashid Jooma (clinical lead), and Aasia Kayani (research coordinator). National Coordinators—Rizwana Chaudhri (Pakistan), Rashid Jooma (Pakistan), Sabariah Faizah Bt Jamaluddin (Malaysia), Julina Md Noor (national coordinators assistant, Malaysia), Tamar Gogichaishvili (Georgia), Maria de los Angeles Munoz-Sanchez (Spain), Bukola Fawole (Nigeria), Temitayo Shokunbi (Nigeria), Jorge Mejia-Mantilla (Colombia), Liliana Vallecilla (Colombia), Fatos Olldashi (Albania), Satish Krishnan (United Arab Emirates), Vincent Djientcheu (Cameroon), Jorge Loria Castellanos (Mexico), Frank Rasulo (Italy), Qadamkhear Hama (Iraq), Yakub Mulla (Zambia), Prof Ioan Stefan Florian (Romania), Juan Tobar (El Salvador), Hussein Khamis (Egypt), Conor Deasy (Ireland), Bobby Wellsh (Papua New Guinea), Jean Williams-Johnson (Jamaica), Susilo Chandra (Indonesia), and Vincent Mutiso (Kenya).
CRASH trial sites and investigators (number of patients randomly assigned)
Pakistan (4567)—Lahore General Hospital Neurosurgery Unit I (1178): Rizwan Butt, Muhammad Hammad Nasir, Salman Ahmad, Farwah Aslam, Khurram Ishaque, Faheem Usmani, Shahrukh Rizvi, Farhad Ali, Omair Sajjad, and Ali Zunair; Jinnah Postgraduate Medical Centre (700): Lal Rehman, Raza Rizvi, Farrukh Javeed, Shakeel Ahmed, Asad Abbas, Ali Afzal, and Ali Mikdad; Lahore General Hospital Neurosurgery Unit III (648): Asif Bashir, Anwar Chaudary, Tariq Salahuddin, Bashir Ahemed, Shahrukh Rizvi, Faheem Usmani, and Amir Aziz; Jinnah Hospital Lahore (619): Naveed Ashraf, Shahzad Hussain, Usman Ahmad, Muhammad Asif, Muhammad Adil, and Adeel Rauf; Lahore General Hospital Neurosurgery Unit II (607): Khalid Mahmood, Rizwan Khan, Bilal Ahmad, Umair Afzal, Hassan Raza, and Quratul Ain; DHQ Hospital Narowal (303): Sajjad Yaqoob, Qaiser Waseem, Muffasser Nishat, Suneel Semvel, and Javed Iqbal; Services Hospital Lahore (226) Samra Majeed, Sana Zulfiqar, Madeeha Iqbal, Nazia Majeed, and Manzoor Ahmed; DHQ Rawalpindi (137): Nadeem Akhtar, Mohammad Malik, Yasir Shehzad, and Muhammad Yousaf; DHQ Hospital Khuzdar (65): Abdul Wahid, Abdul Samad, and Saifullah Shah; Lady Reading Hospital (31): Mumtaz Ali and Jehan Zeb; Shifa International Hospital (29): Abdus Salam Khan and Adeela Irfan; Liaquat National Hospital and Medical College (14): Salman Sharif; Liaquat University Hospital (7): Riaz Memon; Aga Khan University Hospital (3): Rashid Jooma. UK (3143)—Royal London Hospital (501): Ben Bloom, Tim Harris, Jason Pott, Imogen Skene, Geoffrey Bellhouse, and Olivia Boulton; University Hospital Coventry (312): Caroline Leech, Geraldine Ward, Catherine Jarvis, Carly Swann, and Sathananathan Ratnam; Queen Elizabeth Hospital Birmingham (302): Antonio Belli, Ronald Carrera, Kamal Yakoub, David Davies, and Emma Fellows; St George’s Hospital (280): Phil Moss, Heather Jarman, Sarah Rounding, Elizabeth Johnson, and Catherine Loughran; Salford Royal Hospital (176): Fiona Lecky, Kate Clayton, Angiy Michael, and Angela Coumbarides; Southmead Hospital (156): Jason Kendall, Beverley Faulkner, Ruth Worner, and Emma Gendall; King’s College Hospital (155): Philip Hopkins, Paul Riozzi, Hannah Cotton, and Raine Astin-Chamberlain; St Mary’s Hospital, London (117): Mark Wilson, Jan Bodnar, Rachel Williams, and Alberto Rigoni; Aintree University Hospital (108): Abdo Sattout, John Fletcher, Calum Edge, and Nina Maryanji; Addenbrooke’s Hospital (103): Adrian Boyle, Susie Hardwick, Ellen Nichols, and Catherine Hayhurst; Queen’s Medical Centre (100): Frank Coffey, Chris Gough, Philip Miller, and Lucy Ryan; John Radcliffe Hospital (76): Melanie Darwent, Alexis Espinosa, and Sally Beer; Royal Stoke University Hospital (71): Julie Norton, Holly Maguire, and Kay Finney; Derriford Hospital (67): Anthony Kehoe, Rosalyn Squire, and Alison Jeffery; Queen Alexandra Hospital (60): Christiane Vorwerk, Denise Foord, and Eliot Wilkinson; Northern General Hospital (57): Avril Kuhrt, Shammi Ramlakhan, and Stuart Reid; Royal Preston Hospital (41): Andy Curran and Sean McMullan; Leeds General Infirmary (39): Tajek Hassan and Stuart Nuttall; Great Western Hospital (32): Stephen Haig and Saif Al-Nahhas; Southampton General Hospital (31): Diederik Bulters and Ardalan Zolnourian; Dorset County Hospital (27): Tamsin Ribbons and Ian Mew; Gloucestershire Royal Hospital (27): Tanya de Weymarn and Victoria Hughes; Royal Liverpool Hospital (21): Jane McVicar; Queen Elizabeth University Hospital (20): Cieran McKiernan; Royal Berkshire Hospital (20): Liza Keating; Poole Hospital (17): Henrik Reschreiter; James Cook University Hospital (16): Judith Wright; Basingstoke and North Hampshire Hospital (13): Louisa Chan; Whiston Hospital (13): Himanshu Kataria; Glasgow Royal Infirmary (12): Alastair Ireland; Manchester Royal Infirmary (12): Richard Body; Royal Alexandra Hospital (12): Alasdair Corfield; Milton Keynes University Hospital (11): Shindo Francis; Hull Royal Infirmary (10): William Townend; Leicester Royal Infirmary (10): Timothy Coats; Musgrove Park Hospital (10): James Gagg; Wexham Park Hospital (10): Sarah Wilson; Royal Sussex County Hospital (8): Rowley Cottingham; Blackpool Victoria Hospital (7): Simon Tucker; Norfolk and Norwich University Hospital (7): Frank Sutherland; North Devon District Hospital (7): Louisa Mitchell; Whipps Cross University Hospital (7): Tim Harris; Whittington Hospital (7): Lucy Parker; Darlington Memorial Hospital (6): Ola Afolabi; Monklands Hospital (6): Fiona Hunter; Royal Cornwall Hospital (6): Mark Jadav; University Hospital of North Tees (6): Kayode Adeboye; Worthing Hospital (5): Mandy Grocutt; Royal Oldham Hospital (4): Gabrielle May; Royal United Hospitals Bath (4): David Watson; Arrowe Park Hospital (3): Andrea Wootten; Pinderfields General Hospital (3): Sarah Robertshaw; Birmingham Heartlands Hospital (2): Susan Dorrian; Gwynedd Hospital, Bangor (2): Rob Perry; Newham University Hospital (2): Tim Harris; University Hospital Lewisham (2): Hyun Choi; Western Infirmary (2): Claire McGroarty; Worcestershire Royal Hospital (1): Paul Shone; Yeovil District Hospital (1): David Maritz. Malaysia (1567)—Hospital Sungai Buloh (410): Sabariah Jamaluddin, Julina Noor, Norizan Rosli, Leonard Leong Sang Xian and Yong De Jun; Hospital Sultanah Bahiyah (241): Fatahul Mohamed, Cheng Hee Song, Arman Hawari, Leong Yuen Chin, and Hardawani Mohd Hussein; Hospital Sultanah Nur Zahirah (205): Mohd Lotfi, Hafiq Hamid, Nujaimin Udin, Peck Lian, and See Choo; Penang General Hospital (161): Kwanhathai Wong, Fathiyah Gani, Mardhiah Jusoh, and Darrsini Rajakumar; Miri General Hospital (111): Chia Boon Yang, Nur Shahidah Binti Dzulkiflee, Wong Chok Ky, and Muhaimin Azwan Bin Mohd Azman; Hospital Raja Permaisuri Bainun (101): Adi Bin Osman, Azma Haryaty Ahmad, Ramzuzaman Ismail, and Si Qi Lai; Hospital Sultanah Aminah (94): Mohd Amin Bin Mohidin, Norwani Binti Deraman, and Salliza Binti Selamat; Hospital Tuanku Fauziah (72): Ida Abidin, Nurkhairulnizam Halim, and Zuraini Bakar; Hospital Tengku Ampuan Afzan (41): Zainalabidin Mohamed Ismail, Badrul Hisham, and Ruhaida Kamal; Hospital Sultan Abdul Halim (36): Zainal Effendy and Mashitah Ismail; Hospital Seberang Jaya (30): Noor Azleen and Liu Yeo Seng; Universiti Sains Malaysia (26): Kamarul Aryffin Baharuddin and Regunath Kandasamy; Hospital Langkawi (13): Azlan Kamalludin; Hospital Kulim (8): Shamsul Asmee; Hospital Kemaman (7): Mohd Fadzil; Hospital Segamat (6): Ahmad Basitz; Hospital Pakar Sultanah Fatimah (5): Norhaya Abdullah. Georgia (771)— High Technology Medical Center, University Clinic (751): Tamar Gogichaishvili, Giorgi Ingorokva, Shota Ingorokva, Iamze Agdgomelashvili, Kote Mumladze, Ioseb Maisuradze, and Iulia Kugusheva; Archangel St Michael Multiprofile Clinical Hospital (18): Buba Shalamberidze; City Hospital 1 (2): Gia Tomadze. Spain (425)—Hospital Regional Universitario Carlos Haya (102): Juan Fernandez-Ortega, Raimundo Seara-Valero, Guillermo Ibañez-Botella, Victoria Garcia-Martinez; Hospital Alvaro Cunqueiro VIGO (82): Melida Garcia Martul, Santiago Freita Ramos, Guillermo Lago Preciado; Hospital Universitario Virgen del Rocio (77): Claudio Garcia-Alfaro, Angeles Munoz-Sanchez, Rafael Bellido-Alba; Hospital General Universitario de Ciudad Real (67): Carmen Corcobado, Ana Bueno, Alfonso Ambros; Complejo Hospitalario de Navarra (44): JuanTihista Jimenez, Jose Roldan Ramirez; Hospital Torrecardenas (21): José Martín; Hospital de Lucus Augusti (13): Laura Inés Rodríguez; Hospital Clinico de Barcelona (9): Jaime Fontanals; Hospital Universitario Puerta del Mar de Cadiz (9): José Manuel Jiménez-Moragas; Hospital General Universitario De Albacete (1): Joaquín Paya Berbegal. Nigeria (409)—National Hospital Abuja (64): Olaomi Oluwole, Raji Mahmud, and Nancy Ukwu; Lagos University Teaching Hospital (55): Femi Bankole, Abidemi Oseni, and Bamidele Adebayo; University College Hospital, Ibadan (53): Adefolarin Malomo, Liadi Tiamiyu, and Adefisayo Adekanmbi; Olabisi Onabanjo University Teaching Hospital (38): Lateef Thanni and Ayodeji Olubodun; Federal Medical Centre Abeokuta (36): Fidelis Ojeblenu and Michael Uwaezuoke; Obafemi Awolowo University Teaching Hospitals (31): Edward Komolafe and Oluwafemi Owagbemi; Lagos State Accident and Emergency Centre (22): Fatai Ishola; Bowen University Teaching Hospital Ogbomoso (17): Adewumi Durodola; Federal Medical Centre Lokoja (13): Ukpong Udoffa, Federal Medical Centre Bida (12): Adeniran James; Abubakar Tafawa Balewa University Teaching Hospital (11): Azeez Tella; Irrua Specialist Teaching Hospital (9): Andrew Dongo; Federal Medical Centre Umuahia (8): Uchechi Ekpemiro; Nnamdi Azikiwe University Teaching Hospital (8): Stanley Anyanwu; State Hospital, Ijaiye, Abeokuta (8): Nafiu Aigoro; University of Nigeria Teaching Hospital Enugu (7): Wilfred Mezue; Jos University Teaching Hospital (6): Danaan Shilong; University of Benin Teaching Hospital (6): Abiodun Azeez; Federal Medical Centre Ido-Ekiti (2): Olakunle Babalola; Federal Teaching Hospital, Gombe (2): Mohammed Ibrahim; University of Abuja Teaching Hospital (1): Joseph Obande. Colombia (335)—Hospital Pablo Tobon Uribe (127), Alfredo Constain Franco, Edwin Vasquez Salazar, Sebastian Betancur Londoño, and Viviana Medina Cardona; Hospital Universitario San Vicente Fundacion (112): Carlos Morales; Santiago Upegui; Santiago Naranjo; July Agudelo; Fundacion Valle del Lili (96): Jorge Mejia-Mantilla, Sandra Carvajal, and Yidhira Fajardo-Gaviria. Nepal (255)—Neuro Hospital (103): Yam Roka, Ushma Ghising, Narayani Roka, and Manzil Shrestha; National Institute of Neurological and Allied Sciences (64): Upendra Devkota, Bivek Vaidya, and Pankaj Nepal; Kathmandu Medical College Teaching Hospital (47): Amit Thapa and Bidur KC; Chitwan Medical College Teaching Hospital (24): Ajit Shrestha; Bir Hospital (11): Rajiv Jha; B & B Hospital Ltd. (6): Prabin Shrestha. Albania (214)—University Hospital of Trauma (214): Fatos Olldashi, Irgen Hodaj, Erion Spaho, Asllan Selaj, and Nirian Bendo. Japan (165)—Matsudo City Hospital (64): Tomohisa Shoko, Hideki Endo, and Atsushi Senda; Senshu Trauma and Critical Care Centre (61): Yasushi Hagihara, Takashi Fuse, and Naohisa Masunaga; Tokyo Medical and Dental University (28): Yasuhiro Otomo and Ryuichiro Egashira; Teikyo University Hospital (12): Takahiro Ohnuki. United Arab Emirates (126)—Al Qassimi Hospital (126): Satish Krishnan, Alya AlMazmi, Subrata Saha, and Alexander Suvarov. Myanmar (121)—1000 Bedded Nay Pyi Taw Hospital (121): Than Latt Aung, Kaung Myat Tun, Tint Tint Khaing, and Thinzar Maw. Cameroon (116)—Yaounde Central Hospital (38): Vincent Djientcheu and Orlane Ndome; Hopital General Douala (31): Mireille Moumi and André Mbida; Hopital Laquintinie de Douala (28): Joseph Fondop and N’Diaye; Yaounde General Hospital (19): Mba Sebastien. Afghanistan (87)—Nangarhar University Teaching Hospital (87): Abdul Azim, Jan Adil, and Zabiullah Amiry. Mexico (79)—Hospital Regional 25 IMSS (24): Jorge Loría-Castellanos; Hospital General Jose G Parres (21): Nancy Guevara Rubio; Hospital General de Uruapan, Pedro Daniel Martinez (11): Patricia Ortega Leon; Hospital General Regional No 1 (10): Francisco Estrada; Hospital General de Zona 197 (8): Erandy Montes de Oca-García; Hospital General Regional Bernardo Sepulveda (3): Hafid Sanchez; Hospital General La Perla (2): Angélica Soria. Italy (72)—Azienda Ospedaliera Universitaria Senese (35): Paola Bonucci and Federico Franchi; Fondazione Poliambulanza (19): Alan Girardini; Spedali Civili Di Brescia (18): Frank Rasulo. Iraq (55)—Rozhawa Emergency Hospital (51): Qadamkhear Hama, Himdad Hameed, and Muhammad Basim; Rojhelat Emergency Hospital (3): Qadamkhear Hama; Par Hospital (1): Qadamkhear Hama. Cambodia (45)—World Mate Emergency Hospital (45): Simon Stock and Eap Hourt. Zambia (44)—University Teaching Hospital Lusaka (40): Yakub Mulla and Ali Ilunga; Kitwe Central Hospital (4): Jonathan Mulenga. Romania (35)—Timisoara County Hospital (17): Horia Ples; Spitalul Sf Pantelimon Bucharest (11): Adam Danil; Bagdasar-Arseni Emergency Clinical Hospital (5): Mircea Gorgan; Cluj County Emergency Hospital (2): Ioan Florian. El Salvador (28)—Hospital Nacional Rosales (28): Juan Tobar, Fernandez. Egypt (20)—Mataria Teaching Hospital (20): Hussein Khamis. Slovenia (15)—University Medical Centre Ljubljana (15): Dusan Vlahovic. Ireland (12)—Cork University Hospital (12): Conor Deasy. Papua New Guinea (10)—Port Moresby General Hospital (10): Bobby Wellsh. Canada (7)—Saint John Regional Hospital (7): James French. Jamaica (7)—Cornwall Regional Hospital (5): Jeffrey East; University Hospital of the West Indies (2): Jean Williams-Johnson. Indonesia (6)—Rumah Sakit Sekar Kamulyan (6): Antonius Kurniawan. Kenya (1)—Kenyatta National Hospital, University of Nairobi (1): Julius Kiboi.