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Intervention Review

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Steroids for acute spinal cord injury

  1. Michael B Bracken*

Editorial Group: Cochrane Injuries Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 19 SEP 2007

DOI: 10.1002/14651858.CD001046

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Bracken MB. Steroids for acute spinal cord injury. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD001046. DOI: 10.1002/14651858.CD001046.

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  1. Yale University Medical School, Department of Epidemiology & Public Health, New Haven, CT, USA

*Michael B Bracken, Department of Epidemiology & Public Health, Yale University Medical School, Box 20834, 60 College Street, New Haven, CT, 06520-8034, USA. michael.bracken@yale.edu.

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  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

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Characteristics of included studies [ordered by study ID]
Bracken 1984/85
MethodsMulti-center (n=9) double-blind randomized trial. After ascertaining eligibility a 24-hour telephone number called to learn which uniquely numbered drug packet (already delivered to the hospital) should be used. Each hospital given block of 6 (3 patients in each treatment arm). Double dummy technique used to mask study drugs.
ParticipantsIn all, 330 patients randomized within 48h of injury (165 to each treatment), 24 patients excluded from analysis for specified reasons (table 2). In this review morbidity and mortality use all randomized patients in denominator but conclusions remain unchanged. This review delineates those patients treated within 8h of injury.
InterventionsTreatment arm 1: (n=165) Immediately after randomization a loading dose of 100 mg MPPS and 25 mg every six hours thereafter for 10 days.

Treatment arm 2: (n=165) As above but 1000 mg LD and 250 mg thereafter. LD administered over 10 minutes.
Maintenance doses administered using fluid administration set, either directly or through IV.
OutcomesNeurological examinations and clinical status examined six weeks, six months and one year after injury. Neuroexam included motor function and pinprick and light touch sensation, all measured categorically and as continuous scales. All outcomes assessed blind.

Clinical outcomes included: urinary tract infection, pneumonia, decubitus, gastrointestinal hemorrhage, wound infection, sepsis, arrythmia, thrombophlebitis, pulmonary embolus, paralytic ileus, congestive heart failure, myocardial infarction, angina pectoris and death < 14 days, 15-28 days and at 1 year.
NotesHistorical note: This may be the first randomized controlled trial of any treatment modality for acute spinal cord injury. This trial is often referred to as NASCIS 1 (The first National Acute Spinal Cord Injury Study).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Bracken 1990/93
MethodsMulti-center (n=10) double-blind randomized trial. Three treatment arms in blocks of 9 (3 each arm) per center. Randomized by central telephone. Double-dummy technique used to mask study drugs which were given by separate IV sites using flow rates and concentrations according to each patient's body mass.
ParticipantsEligible patients had a diagnosed spinal cord injury, gave consent, were randomized within 12 hours of injury, 13 years or older, and met other specified clinical and study criteria. In all 487 patients randomized to three arms and analysis followed intention-to-treat principle.
InterventionsTreatment arm 1: (n=162) Methylprednisolone bolus of 30 mg/kg body weight followed by 5.4 mg/kg per hour for 23 hours.
Treatment arm 2: (n=154) Naloxone bolus of 5.4 mg/kg of body weight followed by 4.0 mg/kg per hour for 23 hours.
Treatment arm 3: (n=171) Placebo given by bolus and infusion using double-dummy technique.
OutcomesNeurological function examined six weeks, six months and one year after injury using categorical and continuous scales to assess motor function, pin and light touch sensation.
Morbidity evaluated at same times and included all outcomes studied in earlier (1984) NASCIS trial. Mortality assessed to 1 year after injury. All outcomes assessed blind.
NotesThis trial is often referred to as NASCIS 2 (The second National Acute Spinal Cord Injury Study).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Bracken 1997/98
MethodsMulti-center (n=16) double-blind randomized trial. After ascertaining eligibility a 24-hour telephone number called to randomize. Three treatment arms in blocks of 9 (3 each arm per center). Double-dummy techniques used to mask study drug which were given by IV using infusion rates and dose schedules according to each patient's body mass.
ParticipantsEligible patients had diagnosed spinal cord injury, gave consent, were randomized within 6 hours of injury to begin treatment within 8 hours, were 13 years or older, and met other specified clinical and study criteria. In all 499 patients were randomized (485 planned) to three arms and analysis used intent-to-treat and compliers (N=461) groups.
InterventionsAll patients received an IV bolus of methylprednisolone (30 mg/kg) before randomization. Patients in 24h regimen (N=166) received methylprednisolone infusion of 5.4 mg/kg/h for 24h, those in the 48h methylprednisolone group (n=167) received an infusion of 5.4 mg/kg/h for 48h, and those in a third group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6h for 48h.
OutcomesMotor function change between initial presentation and at 6 weeks and 6 months after injury, and functional independence measure (FIM) assessed at 6 weeks and six months and one year. Morbidity evaluated at six weeks and six months and included all outcomes assessed in earlier (1984 and 1990) NASCIS trials. Mortality assessed at six months and at one year post injury. All outcomes assessed blind.
NotesThis trial is often referred to as NASCIS 3 (the third National Acute Spinal Cord Injury Study). Methylprednisolone is the sodium succinate preparation.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Glasser 1993
MethodsRandomized single (patient) blind trial. Method of randomization not specified.
ParticipantsPatients undergoing lumbar discetomy presenting with radicular symptoms and radiographically confirmed herniated nucleus pulposus.
Interventions1) 160 mg IM Depo-Medrol and 250 mg MPPS at start of procedure. Macerated fat graft soaked in 80 mg Depo-Medrol placed over affected nerve root after discetomy. 30 ml 0.25% bupivacaine infiltrated to paraspinal muscles during closure (N=12).
2) Bupivacaine procedure only (N=10).
3) No corticoids or bupivacaine (N=10).
OutcomesLength of hospital stay; postpartum narcotic analgesia; back and radicular pain on post-op day 1.
NotesDepo-Medrol is methylprednisolone acetate.
MPPS is methylprednisolone sodium succinate.
This study may largely be assessing nerve roots rather than acute spinal cord injuty.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Matsumoto 2001
MethodsSingle center randomized double blind trial. Method of randomization not specified.
ParticipantsIn all 46 patients with cervical spine injury. Exclusions were only nerve root injuries, cauda equina and gunshot victims.
InterventionsTreatment arm 1: (n=23) MPSS given according to NASCIS 2 protocol.
Treatment arm 2: (n=23) placebo (no details of placebo provided).
OutcomesEfficacy not studied. Complications assessed 8 weeks after injury.
NotesSome evidence for MPSS group to be more severely injured.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate




Otani 1994
MethodsPatients allocated "by envelope method" and so assumed to be randomized. Blinding is not assumed since no placebo group.
ParticipantsMulticenter trial in Japan including 15 neurosurgery, 27 orthopedic and 11 emergency centers. Inclusion criteria: diagnosis of loss of motor or sensory function from spinal cord injury; could receive treatment within 8 hours of injury; 16-25 years of age; obtained informed consent; available for 6 month follow-up.
Excluded: root involvement or cauda equina only; serious co-morbidity; corticosteroid use > 100 mg MPSS or equivalent before randomization; other prespecified clinical criteria. In all 158 patients randomized (82 MPSS, 76 control) of which 81 and 70, and 70 and 47 entered the safety and efficacy analyses respectively.
Reasons for drop-out are tabulated. It appears as if largest exclusions were for control patients. Baseline differentials suggest this occurred most frequently in severely injured controls.
Interventions1. Treated group: MPSS as bolus of 30 mg/kg for 15 mins by infusion, 45 mins pause then 23 hr maintenance infusion by 5.4 mg/kg. (NB this is an exact replication of the NASCIS 2 MPSS protocol, see Bracken et al 1990). No other corticosteroid therapy.
2. Control group: standard treatment without any corticosteroid therapy. No placebo given.
NB surgery appears to have been given as necessary but this is not entirely clear from text.
OutcomesNeurological follow-up was at 24 and 48 hrs, one and six weeks, three and six months.
Motor function, pin and light touch sensation were assessed using NASCIS 2 criteria and Frankel's classification (at 6 months).
Urinary function and sphincter control were evaluated. A global improvement assessment was also used. A large number of laboratory values and vital signs were measured.
NotesA translation of this paper from the original Japanese has been provided by Pharmacia Upjohn Inc. Copies of the English translation are available from the editor of this review.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Petitjean 1998
MethodsSingle center trial. Randomization methods: two numbers given each treatment and followed "table de permutation au hasard" and balanced every eight patients. Administration of intervention not masked.
ParticipantsEligible patients had a diagnosed spinal cord injury, gave consent, were hospitalized within 8h of injury, were aged 16 to 64, and met other clinical criteria.
Interventions1) Methylprednisolone bolus of 30mg/kg over 1h followed by 5.4mg/kg/h for 23h (N=27).
2) Nimodipine 0.015mg/kg/h over 2h followed by 0.03mg/kg/h for 7days if MABP > 60mgHg (N=27).
3) Both of the above treatments given concurrently (N=27).
4) No pharmacologic treatment (N=25).
OutcomesNeurological examination using ASIA criteria at admission and 1year after injury. Outcome assessed blind.
NotesA translation of this paper from the original French is available from the Cochrane Injuries review Group.
ASIA and NASCIS neurological examinations are identical except for one additional segment measured in NASCIS. Additional information obtained from author but N's slightly larger in published report.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear




Pettersson 1998
MethodsRandomized double blind trial. Method of randomization not specified.
ParticipantsMen and women with whiplash injury Grade 2 and 3 by Quebec criteria and enrolled within 8 hours of injury.
Interventions(1) Methylprednisolone bolus of 30 mg/kg for 15 min, wait 45 min, then 5.4 mg/kg/h for 23h (N=20).
(2) Placebo (N=20).
OutcomesRepeated neurological examinations, VAS-scales and pain sketch form at baseline, 2 and 6 weeks and 6 months after injury. Number of sick days. Outcomes assessed blind.
Notes
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate


 
Characteristics of excluded studies [ordered by study ID]
StudyReason for exclusion
Kiwerski 1992Patients not randomized to treatment.
Pointillart 2000Duplicate publication of Petitjean 1998. Translated into English, very minor changes to table 3 (numbers instead of per cent), and no reference in this paper to original French version. Change in first authorship.
Yokota 1995Patients not randomized to treatment. An English translation of this study is available from the Cochrane Injuries Group.


 
Comparison 1. Moderate vs low-dose MPSS, 10-day regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Motor function at six weeks, six months and one year: all patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    1.1 Motor function at six weeks
1258Mean Difference (IV, Fixed, 95% CI)-0.60 [-4.44, 3.24]
    1.2 Motor function at six months
1179Mean Difference (IV, Fixed, 95% CI)-0.90 [-5.38, 3.58]
    1.3 Motor function at one year
1223Mean Difference (IV, Fixed, 95% CI)0.46 [-3.11, 4.03]
 2 Motor function at six weeks, six months and one year: <8 hours to treatment1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    2.1 Motor function at six weeks
1129Mean Difference (IV, Fixed, 95% CI)1.70 [-2.46, 5.86]
    2.2 Motor function at six months
1103Mean Difference (IV, Fixed, 95% CI)5.0 [-0.21, 10.21]
    2.3 Motor function at one year
1112Mean Difference (IV, Fixed, 95% CI)3.80 [-2.06, 9.66]
 3 Pinprick sensation at six weeks, six months and one year: all patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    3.1 Pinprick sensation at six weeks
1258Mean Difference (IV, Fixed, 95% CI)0.90 [-3.28, 5.08]
    3.2 Pinprick sensation at six months
1179Mean Difference (IV, Fixed, 95% CI)-0.5 [-4.79, 3.79]
    3.3 Pinprick sensation at one year
1223Mean Difference (IV, Fixed, 95% CI)-1.67 [-4.76, 1.42]
 4 Pinprick sensation at six weeks, six months and one year: <8 hours to treatment1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    4.1 Pinprick sensation at six weeks
1129Mean Difference (IV, Fixed, 95% CI)2.7 [-1.27, 6.67]
    4.2 Pinprick sensation at six months
1103Mean Difference (IV, Fixed, 95% CI)2.40 [-1.71, 6.51]
    4.3 Pinprick sensation at one year
1112Mean Difference (IV, Fixed, 95% CI)3.10 [-1.11, 7.31]
 5 Touch sensation at six weeks, six months and one year: all patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    5.1 Touch sensation at six weeks
1258Mean Difference (IV, Fixed, 95% CI)0.40 [-3.43, 4.23]
    5.2 Touch sensation at six months
1179Mean Difference (IV, Fixed, 95% CI)Not estimable
    5.3 Touch sensation at one year
1221Mean Difference (IV, Fixed, 95% CI)0.25 [-2.68, 3.18]
 6 Touch sensation at six weeks, six months and one year: <8 hours to treatment1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    6.1 Touch sensation at six weeks
1129Mean Difference (IV, Fixed, 95% CI)3.3 [-0.52, 7.12]
    6.2 Touch sensation at six months
1102Mean Difference (IV, Fixed, 95% CI)4.1 [-0.06, 8.26]
    6.3 Touch sensation at one year
1111Mean Difference (IV, Fixed, 95% CI)3.5 [-0.61, 7.61]
 7 All-cause mortality, <210 days1330Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.75, 2.86]
 8 Wound infection at six weeks1330Risk Ratio (M-H, Fixed, 95% CI)3.5 [1.18, 10.41]
 9 GI haemorrhage at six weeks1330Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.57, 2.35]
 10 Sepsis at six weeks1330Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.43, 1.76]
 
Comparison 2. High-dose MPSS vs none, 24-hour regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Motor function at six weeks, six months and one year: all patients3Mean Difference (IV, Fixed, 95% CI)Subtotals only
    1.1 Motor function at six weeks
1306Mean Difference (IV, Fixed, 95% CI)1.23 [-1.08, 3.54]
    1.2 Motor function at six months
2414Mean Difference (IV, Fixed, 95% CI)0.85 [-1.79, 3.49]
    1.3 Motor function at one year
2335Mean Difference (IV, Fixed, 95% CI)-1.17 [-4.80, 2.47]
 2 Motor function at six weeks, six months, and one year: <8 hours to treatment3Mean Difference (IV, Fixed, 95% CI)Subtotals only
    2.1 Motor function at six weeks
1136Mean Difference (IV, Fixed, 95% CI)3.47 [0.02, 6.92]
    2.2 Motor function at six months
2250Mean Difference (IV, Fixed, 95% CI)4.44 [0.96, 7.93]
    2.3 Motor function at one year
2177Mean Difference (IV, Fixed, 95% CI)4.17 [-0.27, 8.61]
    2.4 Motor function at final (six-month or one-year) outcome
3294Mean Difference (IV, Fixed, 95% CI)4.06 [0.58, 7.55]
 3 Pinprick sensation at six weeks, six months and one year: all patients2Mean Difference (IV, Fixed, 95% CI)Subtotals only
    3.1 Pinprick sensation at six weeks
1301Mean Difference (IV, Fixed, 95% CI)1.88 [-0.23, 3.99]
    3.2 Pinprick sensation at six months
1295Mean Difference (IV, Fixed, 95% CI)3.37 [0.74, 6.00]
    3.3 Pinprick sensation at one year
2334Mean Difference (IV, Fixed, 95% CI)0.18 [-2.66, 3.02]
 4 Pinprick sensation at six weeks, six months and one year: <8 hours to treatment2Mean Difference (IV, Fixed, 95% CI)Subtotals only
    4.1 Pinprick at Six Weeks
1136Mean Difference (IV, Fixed, 95% CI)3.02 [-0.14, 6.18]
    4.2 Pinprick at Six Months
1133Mean Difference (IV, Fixed, 95% CI)4.82 [0.91, 8.73]
    4.3 Pinprick at One Year
2177Mean Difference (IV, Fixed, 95% CI)2.32 [-1.73, 6.37]
 5 Touch sensation at six weeks, six months and one year: All patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    5.1 Touch Sensation at Six Weeks
1300Mean Difference (IV, Fixed, 95% CI)2.17 [-0.17, 4.51]
    5.2 Touch Sensation at Six Months
1294Mean Difference (IV, Fixed, 95% CI)2.88 [0.10, 5.66]
    5.3 Touch Sensation at One Year
1282Mean Difference (IV, Fixed, 95% CI)0.69 [-2.21, 3.59]
 6 Touch sensation at six weeks, six months and one year: <8 hours to treatment2Mean Difference (IV, Fixed, 95% CI)Subtotals only
    6.1 Touch Sensation at Six Weeks
1136Mean Difference (IV, Fixed, 95% CI)3.79 [0.28, 7.30]
    6.2 Touch Sensation at Six Months
1133Mean Difference (IV, Fixed, 95% CI)4.59 [0.43, 8.75]
    6.3 Touch Sensation at One Year
2177Mean Difference (IV, Fixed, 95% CI)3.35 [-0.82, 7.53]
 7 All-cause mortality <180 days3530Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.24, 1.25]
 8 Wound infection at 6 weeks1333Risk Ratio (M-H, Fixed, 95% CI)2.11 [0.81, 5.49]
 9 GI haemorrhage at 6 weeks2379Risk Ratio (M-H, Fixed, 95% CI)2.18 [0.80, 5.93]
 
Comparison 3. High-dose MPSS for 48 hours vs 24 hours
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Motor function at six weeks, six months and one year: all patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    1.1 Motor function at six weeks
1305Mean Difference (IV, Fixed, 95% CI)2.81 [-0.62, 6.24]
    1.2 Motor function at six months
1291Mean Difference (IV, Fixed, 95% CI)3.37 [-0.54, 7.28]
    1.3 Motor function at one year
1286Mean Difference (IV, Fixed, 95% CI)2.35 [-1.75, 6.45]
 2 Motor function at six weeks, six months and one year: 3-8 hours to treatment1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    2.1 Motor function at six weeks
1174Mean Difference (IV, Fixed, 95% CI)4.90 [0.51, 9.29]
    2.2 Motor function at six months
1165Mean Difference (IV, Fixed, 95% CI)6.46 [1.41, 11.51]
    2.3 Motor function at one year
1159Mean Difference (IV, Fixed, 95% CI)5.28 [-0.00, 10.56]
 3 Pinprick sensation at six weeks, six months and one year: all patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    3.1 Pinprick sensation at six weeks
1305Mean Difference (IV, Fixed, 95% CI)1.39 [-1.55, 4.33]
    3.2 Pinprick sensation at six months
1291Mean Difference (IV, Fixed, 95% CI)0.42 [-2.57, 3.41]
    3.3 Pinprick sensation at one year
1286Mean Difference (IV, Fixed, 95% CI)0.40 [-2.70, 3.50]
 4 Pinprick sensation at six weeks, six months and one year: 3-8 hours to treatment1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    4.1 Pinprick sensation at six weeks
1174Mean Difference (IV, Fixed, 95% CI)3.03 [-1.01, 7.07]
    4.2 Pinprick sensation at six months
1165Mean Difference (IV, Fixed, 95% CI)1.67 [-2.53, 5.87]
    4.3 Pinprick sensation at one year
1159Mean Difference (IV, Fixed, 95% CI)1.40 [-2.73, 5.53]
 5 Touch sensation at six weeks, six months and one year: all patients1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    5.1 Touch sensation at six weeks
1305Mean Difference (IV, Fixed, 95% CI)1.72 [-1.26, 4.70]
    5.2 Touch sensation at six months
1291Mean Difference (IV, Fixed, 95% CI)0.89 [-2.23, 4.01]
    5.3 Touch sensation at one year
1286Mean Difference (IV, Fixed, 95% CI)1.0 [-2.10, 4.10]
 6 Touch sensation at six weeks, six months and one year: 3-8 hours to treatment1Mean Difference (IV, Fixed, 95% CI)Subtotals only
    6.1 Touch sensation at six weeks
1170Mean Difference (IV, Fixed, 95% CI)2.28 [-2.12, 6.68]
    6.2 Touch sensation at six months
1165Mean Difference (IV, Fixed, 95% CI)0.25 [-4.01, 4.51]
    6.3 Touch sensation at one year
1159Mean Difference (IV, Fixed, 95% CI)-0.70 [-4.94, 3.54]
 7 Severe pneumonia at 6 weeks1308Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.71, 7.15]
 8 Severe sepsis at 6 weeks1308Risk Ratio (M-H, Fixed, 95% CI)4.0 [0.45, 35.38]
 9 Mortality at 1 year1332Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.46, 2.66]
 
Comparison 4. Methylprednisolone for 23 hours and nimodipine for 7 days
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 One-year motor function improvement score149Mean Difference (IV, Fixed, 95% CI)-8.1 [-23.28, 7.08]
 2 One-year pinprick sensation improvement score149Mean Difference (IV, Fixed, 95% CI)-1.0 [-21.98, 19.98]
 3 One-year touch sensation improvement score149Mean Difference (IV, Fixed, 95% CI)-1.80 [-21.04, 17.44]
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