Corticosteroid Randomisation After Significant Head Injury

In 1990, road traffic crashes caused 5,563,000 intracranial injuries worldwide Murray CJL, Lopez AD. Global health statistics. Boston: Harvard University Press, 1996 Global Health Statistics

Aggregate mortality from 13 randomised trials of corticosteroids in head injury 39% DEAD 422 out of % DEAD 396 out of % 35% 40% SteroidControl Alderson P, Roberts I. BMJ 1997;314:1855-9

0% 5% 10% 15% 20% Study size (number randomised) Smallest absolute risk reduction detectable Smallest absolute risk reduction detectable in study of given size* (*baseline risk = 0.2, power = 80%) ,2802,5605,12010,24020,480

0% 5% 10% 15% 20% Study size (number randomised) Smallest absolute risk reduction detectable Smallest absolute risk reduction detectable in study of given size* (*baseline risk = 0.2, power = 80%) ,2802,5605,12010,24020, trials

A large simple placebo controlled trial, among adults with head injury and impaired consciousness, of the effects of a 48-hour infusion of corticosteroids on death and neurological disability

To determine reliably the effects of high dose corticosteroid infusion on: death and disability after head injury risk of infection and gastrointestinal bleeding Aim

Randomisation Take next numbered treatment pack Fax entry form to Co-ordinating Centre - Pack number - Patient details - Hours since injury - GCS - Pupil reactiveness

Treatment 1 hour loading infusion of 100mL (2g steroid/placebo) 48 hour infusion of 20mL/hr or until discharge, if sooner (0.4g/hr steroid/placebo)

Adverse events Serious and unexpected adverse events suspected to be related to trial medicine  Telephone UK randomisation service and ask for “adverse events”

Unblinding If care depends importantly on knowing whether patient received steroid or not  Telephone UK randomisation service and ask for “unblinding”

Follow-up No extra tests Single-sided outcome form completed at discharge, death in hospital, or 14 days Short interview or postal questionnaire sent at six months

Started - April 1999 Estimated end - March 2005 Target - 20,000 patients Recruitment to date - 2,420 patients Trial progress

Projections

Who’s taking part? 105 hospitals in 31 countries

Recruitment by country HospitalsPatients Argentina1181 Australia1 Belgium3241 Brazil17 Colombia577 Cuba4 Czech Republic6370 Egypt289 Eire176 Germany28 Ghana12 Greece3 Italy11 Malaysia168 Mexico1 New Zealand19 HospitalsPatients Nigeria113 Paraguay14 Romania296 Singapore19 Slovakia438 South Africa1174 Spain558 Sri Lanka199 Switzerland374 Tunisia1 Turkey1 Uganda116 UK36807 USA2 Venezuela3

Recruitment rates HospitalCountry Patients/month Research Institute for Special Surgery and Trauma Czech Republic9.6 Centre Hospitalier Regional de NamurBelgium8.2 Spitalul Clinic de Urgenta BucurestiRomania7.7 Tygerberg Academic HospitalSouth Africa7.3 Makerere Medical SchoolUganda5.5 Mataria Teaching HospitalEgypt4.4 Hospital University Science MalaysiaMalaysia3.9 Hope HospitalUK3.9 University Hospital of ZurichSwitzerland3.2 Clinica Las AmericasColombia3.2 St James's University HospitalEire3.0 Birmingham Heartlands HospitalUK2.8 Hospital Universitario Virgen del RocioSpain2.8 Suez Canal UniversityEgypt2.8 Hospital San BernardoArgentina2.4 Batticaloa General Hospital, TeachingSri Lanka2.3 NsP PopradSlovakia2.2

Pilot phase 13/4/1999 to 21/12/2000 1,000 patients enrolled Early outcome (14 days) 99 % complete Six month outcome 93 % complete Some results

Age and sex Age group n % 16 – 24259(26) 25 – 34227(23) (51) Sex Male781(78) Female219(22)

GCS n % Severe (3-8)381(38) Moderate (9-12)289(29) Mild (13-14)330(33) Glasgow Coma Scale

Hours Time from injury

16% 22% Mortality by sex

Age group Mortality by age 8% 35% 14% 23%

Mortality by GCS GCS 31% 11% 6%

n % Admitted to ICU – 3 days days or more Seizure Haematemesis or melaena 4 0 Wound infection 31 3 Pneumonia treated by antibiotics 90 9 Other treatment with antibiotics Neurosurgical operation Major extracranial injury Management/Complications

The MRC CRASH Trial is working well in both university and general hospitals The assumed mortality rate is appropriate Large numbers can be successfully followed-up Conclusions to date

CRASH Co-ordinating Centre Bedford Square, London WC1B 3DP Tel: +44 (0) Fax: +44 (0)