Steroids
for Spinal Cord Injury
Following this review, members of
the trauma-list are signing
a letter to present to the American College of Surgeons
ATLS subcommittee asking them to revise the ATLS position
on the use of steroids in spinal cord injury. If you agree
with the evidence review below, please take a moment to
read and add your name to the letter in the TraumaWiki:
Steroids
for SCI open letter.
Table of Contents
1
Overview
2 Summary of Relevant Studies
2.1 Prospective, Randomized
Controlled Trials
2.2 Retrospective Studies
Overview
1. There is no evidence
to support the use of steroids in the management of spinal
cord injury.
2. Administration of high dose
steroids to trauma patients can have significant adverse
effects on patient outcome.
3. There is evidence to suggest
a worse outcome in patients with penetrating injury who
receive steroids.
4. There
are no studies of the use of steroid therapy in the paediatric
population.
Summary of Relevant Studies
Study |
Design |
Outcome |
NASCIS 1
USA, 1984 |
Prospective, randomized, double-blind.
Methylprednisolone, 2 dose regimens.
|
Negative. |
NASCIS 2 USA,
1990 |
Prospective, randomized, double-blind.
Methylprednisolone, Naloxone, Placebo
|
Negative. |
Otani Japan,
1994 |
Prospective, randomized*, un-blinded.
Methylprednisolone vs ?Placebo
|
Negative. |
NASCIS 3 USA,
1997 |
Prospective, randomized, double-blind.
Methylprednisolone, Tirilizad |
Negative. |
Petitjean, Pointillart
France, 1998, 2000
| Prospective, randomized, single-blind.
Methylprednisolone, Nimodipine,
Placebo
| Negative.
|
Retrospective Studies
Study |
Design |
Outcome |
Prendergast
USA, 1994 |
Retrospective |
Negative |
Gerhart USA,
1995 |
Retrospective |
Negative |
George USA,
1995 |
Retrospective |
Negative |
Gerndt USA,
1995 |
Retrospective |
N/A (looked at adverse events)
|
Poynton Ireland,
1997 |
Retrospective |
Negative |
Prospective, Randomized Studies
NASCIS 1, USA 1984
Design: Multicentre,
prospective, randomized, double-blind trial.
Patients: 330 patients
with acute spinal cord injury. 179 6-month follow-up.
Randomization:
- Treatment 1: 100mg bolus methylprednisolone,
then 25mg every 6 hours for 10 days.
- Treatment 2: 1000mg bolus methylprednisolone,
then 250mg every 6 hours for 10 days.
Neurologic outcome:
No significant differences in neurologic outcome between
the two groups.
Safety & Adverse events:
Statistically significant increase in wound infections
in high dose group (9.3% vs 2.6%, p=0.01) Non-significant
trend towards increased incidence of sepsis, pulmonary
embolism and death in the high-dose group.
Comments Animal studies
subsequently determined that dose of methylprednisolone
used in NASCIS 1 was below the therapeutic threshold to
observe any potential beneficial effect. Subsequent trials
used higher dosing regimens. Nevertheless, NASCIS I demonstrated
an increased incidence of adverse events even at these
dose levels.
NASCIS 2, USA 1990
Design Multicentre,
prospective, randomized, double-blind trial.
Patients: 487 patients
with acute spinal cord injury. Follow-up of 427 patients
(95%) at 1 year (deaths excluded).
Exclusions: Injuries
below L1 Children
Randomization:
- Treatment 1: Methyprednisolone 30
mg/kg bolus, then 5.4 mg/kg/hr for 23 hours
- Treatment 2: Naloxone 5.4 mg/kg
bolus, then 4.5 mg/kg/hr for 23 hours
- Treatment 3: Placebo
Neurologic outcome:
Patients were examined at admission, 6 weeks, 6 months
and 1 year. Motor strength was measured using the American
Spine Injury Association (ASIA) 0-5 scale in 14 muscle
groups, giving a maximum possible score of 70. Pin prick
& touch sensation were assessed in 29 dermatomes.
Maximum sensory score was 58. Analysis only used scores
from the right side of the body. There was no mention
of left-sided scores, although both sides were examined.
There was no difference in motor score
between treatment groups at any time point. There was
a statistically significant improvement in pinprick (3.4/58)
and light touch (3.8/58) scores at 6 months which was
lost at 1 year.
Safety & Adverse events:
Wound infection and pulmonary embolus were doubled in
the steroid group (non-significant, study not sufficiently
powered).
Post-hoc analyses All
the reported positive results from the NASCIS 2 trial
are from post-hox subgroup analysis.
When patients were stratified by time
to treatment, patients receiving steroids within 8 hours
had a statistically significant improvement of 5 points
on the motor score at 6 months and 1 year (p=0.03). Patients
treated with steroids more than 8 hours after injury had
a worse neurological outcome, but this did not achieve
significance.
Comments:
Statistical significance:
NASCIS 2 was a negative study. The Level
1 evidence from this data is that there is no difference
between methylprednisolone and placebo in the outcome
of spinal cord injury. Data from post-hoc analyses cannot
be classed as Level 1 or 2 evidence (or even level 3).
The 8-hour cut-off point for the post-hoc
analysis appears completely arbitrary. This splits the
patients into 183 (38%) that randomized before 8 hours
and 304 after. Control patients in the pre-8 hour administration
category had significantly worse outcomes than those in
the post-8 hour category, a difference which could entirely
account for the statistically significant improvement
seen in the steroid group.
NASCIS 2 allows for 78 potential discrete
post-hoc subgroup analyses based on time of administration.
By chance, 1 in 20 of these would be expected to be statistically
significant at a p of 0.05. Furthermore, the NASCIS 2
statistical analysis includes over 60 t-tests for comparing
neurological outcomes. There are no corrections for multiple
comparisons, and no analysis of variance or multivariate
statistical techniques were employed. Additionally, much
of the data is thought to be non-parametric, and hence
the t-test is not appropriate. It is unlikely that any
statistical significance would be observed if correct
statistical methodology was used.
Clinical significance:
The post-hoc analysis identified a statistically
significant improvement of 5 motor points improvement
at 1 year. Is this clinically significant? An improvement
of 5 motor points in one muscle group is unlikely - but
even so would not confer any increased functionality on
a spinal cord injured patient. Similarly, and increase
of 1 motor point across 5 different muscle groups will
also have little impact on functional ability and independence.
The mean motor and sensory scores between steroid and
placebo groups in NASCIS 2 are shown below:
Otani, Japan 1994
Design Multicentre,
prospective, randomized*, un-blinded trial.
Patients: 158 patients.
116 of 117 patients wiere available for 6-month follow-up.
Exclusions: Patients
<15 or >65.
Randomization:
- Treatment 1: Methyprednisolone 30
mg/kg bolus then 5.4 mg/kg/hr for 23 hours
- Treatment 2: Routine medical management.
This included in some patients, steroid therapy, subsequently
excluding 29 patients.
Neurologic outcome:
Neurological assessment was almost identical to the NASCIS
2 study.
There was no significant difference
in outcome between treatment groups.
Safety & Adverse events:
There was a trend towards an increase in septic complications
in the methylprednisolone group (66% vs. 45%) although
this did not achieve statistical significance.
Post-hoc Analyses:
Post-hoc subgroup analyses identified a statistically
significant increase in the number of patients who experienced
an improvement in sensation for those patients who received
steroids (68% vs 32%).
Comments: 41 Exclusions
after randomization (primarily for protocol violations)
make it impossible to clearly assess this study as Level
1 evidence.
Admission characteristics between the
two groups were different in terms of severity of spinal
cord injury (Frankel grade) and neurologic scores for
motor and pinprick.
If the post-hoc analyses identified
more patients in the steroid arm experienced a sensory
improvement, then more patients in the control arm must
have experienced a motor improvement, as overall neurological
outcome was unchanged between the two groups.
NASCIS 3, USA 1997
Design Multicentre,
prospective, randomized, double-blind trial. No placebo
arm.
Patients: 499 patients
with acute spinal cord injury. Follow-up of 459 patients
(92%) at 1 year (439 / 88% including deaths). Treatment
initialized within 8 hours. All patients received a bolus
of 20-40 mg/kg methylprednisolone.
Exclusions: Children
Randomization:
- Treatment 1: Methyprednisolone 5.4
mg/kg/hr for 24 hours
- Treatment 2: Methyprednisolone 5.4
mg/kg/hr for 48 hours
- Treatment 3: Tirilizad 2.5 mg/kg
every 6 hours for 48 hours
Neurologic outcome:
Patients were examined at admission, 6 weeks, 6 months
and 1 year. Motor strength was measured using (ASIA) 0-5
scale in 15 muscle groups, although the extra group was
subsequently excluded, giving a maximum possible score
of 70. Pin prick & touch sensation were assessed in
29 dermatomes. Maximum sensory score was 58. Disability
was scored using the Functional Independence Measure (FIM)
to try to interpret the functional significance of any
improvement in motor score. Only right sided deep pain
& pressure, left sided light touch & motor scores
used in analyses, despite both being examined.
There was no significant difference
in motor score between treatment groups at any time point.
Safety & Adverse events:
Mortality due to respiratory complications was 6 times
higher in the 48-hour group (p=0.056). There was a 2x
increase in the incidence of severe pneumonia and a 4x
increase in severe sepsis in the 48-hour group compared
to the 24-hour group. This was not statistically significant
but the study was underpowered for this analysis.
Post-hoc analyses All
the reported positive results from the NASCIS 3 trial
are from post-hox subgroup analysis.
Patients were stratified by time to
treatment into those treated less than 3 hours from injury
and 3-8 hours from injury. There was no difference in
outcome for those patients receiving steroids within 3
hours of injury. Only for patients treated between 3 and
8 hours of injury was there a 5-point improvement in motor
scores at 1 year (p=0.053). There was no difference in
sensory outcome. Disability as measured by FIM was also
unchanged at 1 year (there was a statistically significant
improvement in sphincter control of 1/14 points at 6 months
which was lost at 1 year).
Comments:
Statistical significance:
NASCIS 3 was a negative study. As with
NASCIS 2, The Level 1 evidence from this data is that
there is no difference between methylprednisolone and
placebo in the outcome of spinal cord injury. Data from
post-hoc analyses cannot be classed as Level 1 or 2 evidence
(or even level 3).
The post-hoc analysis of subgroups receiving
steroids in 0-3 hours or 3-8 hours is completely arbitrary.
Patients who received steroids early did not gain any
benefit from steroids (70% of the study population). Ensuing
statistically significant results are almost certainly
due to random events.
NASCIS 3 allows for 36 potential discrete
post-hoc subgroup analyses based on time of administration.
By chance, 1 in 20 of these would be expected to be statistically
significant at a p of 0.05. Again, as with NASCIS 2, NASCIS
3 statistical analysis includes over 100 t-tests for comparing
neurological outcomes. There are no corrections for multiple
comparisons, and no analysis of variance or multivariate
statistical techniques were employed. Additionally, much
of the data is thought to be non-parametric, and hence
the t-test is not appropriate. It is unlikely that any
statistical significance would be observed if correct
statistical methodology was used.
Clinical significance:
The post-hoc analysis identified a statistically
significant improvement of 5 motor points improvement
at 1 year. As with the NASCIS 2 results, the clinical
significance of this improvement is doubtful. Indeed,
the FIM measurements showed no difference in the level
of disability. The mean motor and sensory scores between
steroid and placebo groups in NASCIS 3 are shown below:
Petitjean, Pointillard, France 1998,
2000
Design Single centre,
prospective, randomized, double-blind trial.
Patients: 106 patients,
hospitalised within 8 hours of injury. 100 patients available
for follow-up at one year. Policy of early surgery. 76%
operated on within 24 hours, 46% within 8 hours of injury.
Exclusions: Patients
<15 or >65.
Randomization:
- Treatment 1: Methyprednisolone 30
mg/kg bolus then 5.4 mg/kg/hr for 23 hours
- Treatment 2: Nimodipine 0.5 mg/kg/hr
for 2 hours then 0.03 mg/kg/hr for 7 days
- Treatment 3: Methylprednisolone
& Nimodipine
- Treatment 4: Placebo
Neurologic outcome:
Patients were examined at admission and 1 year by a trained
neurologist blinded to the treatment..
There was no significant difference
in ASIA score between treatment groups at one year. There
was also no significant difference overall in those patients
who received steroids (54) and those who did not (52).
Two-way ANOVA showed no evidence of interaction between
methylprednisolone and nimodipine.
Safety & Adverse events:
There was a trend towards an increase in septic complications
in the methylprednisolone group (66% vs. 45%) although
this did not achieve statistical significance.
Comments: Not only
was there no significant difference in outcome in this
study, but not even a trend to improved outcome in this
study.
Retrospective Studies
Prendergast, USA 1994
Design: Retrospective
review
Patients: 54 patients
with acute spinal cord injury. 31 patients with penetrating
injury 29 patients received steroid therapy
Neurologic 'Outcome:' Neurologic
assessments were performed at 4 days and 1, 2, 4 &
8 weeks.
There was no difference in neurologic
improvement in blunt trauma patients.
Patients with penetrating trauma who
received steroids had a significantly worse outcome within
the first week of injury which persisted throughout the
study (p<0.05).
Gerhart, USA 1995
Design: Retrospective,
population-based study
Patients: 363 spinal
cord injury survivors from two time periods, pre- and
post- NASCIS 2. 188 with NASCIS protocol, 90 no steroids.
Neurologic Outcome:
Frankel grade was assessed by neurological documentation
at admission and at the end of rehabilitation or discharge
home.
There was no significant difference
in Frankel grade between those patients who received steroids
and those who did not.
George, USA 1995
Design: Retrospective
review
Patients: 130 patients
with acute spinal cord injury. 9 patients with penetrating
injury. 75 patients received steroid therapy. The steroid
group was younger and has lower Injury Severity scores
Neurologic Outcome:
There was no difference in disability outcome between
those patients who received steroids and those who did
not.
Safety & Adverse events:
There was a trend towards an increase in infectious complications
in the methylprednisolone group although this did not
achieve statistical significance.
Comments: There was
equivalent outcome in steroid and no-steroid groups, despite
the control group being older and more severely injured.
Poynton, Ireland 1995
Design: Retrospective
review
Patients: 71 consecutive
patients with acute spinal cord injury. 63 patients available
for follow-up, mean 30 months. Patients admitted more
than 8 hours following injury were not given steroids
and were used as controls.
Neurologic Outcome:
Patients were assessed with ASIA scores on admission,
on transfer to rehabilitation and at follow-up.
There was no difference in disability
outcome between those patients who received steroids and
those who did not.
Safety & Adverse events:
There was a trend towards an increase in infectious complications
in the methylprednisolone group although this did not
achieve statistical significance.
Comments: There was
equivalent outcome in steroid and no-steroid groups, despite
the control group being older and more severely injured.
Levy, USA 1996
Design: Retrospective
review of penetrating injury patients.
Patients: 252 patients
with single penetrating spinal cord injury. 71 received
steroid therapy, 55 NASCIS protocol.
Neurologic Outcome:
Frankel Scores at admissionm & discharge from rehabilitation.
Discharge assessment conducted at mean of 174 days. No
difference in neurological outcome.
Gerndt, USA 1997
Design: Retrospective
review. Study was aimed towards idntifying adverse events
from steroid therapy
Patients: 231 acute
blunt spinal cord injured patients. 91 received steroid
therapy.
Neurologic Outcome:
Not detailed
Safety & Adverse events:
There was significant increase in the incidence of pneumonia
and in the duration of ventilation and ICU stay in the
methylprednisolone group.
Comments: There was
equivalent outcome in steroid and no-steroid groups, despite
the control group being older and more severely injured.
Heary, USA 1997
Design: Retrospective
review of penetrating trauma patients (gunshot wounds).
Patients: 254 patients
with gunshot wounds to the spine or spinal cord. 61 received
steroid therapy (methylprednisolone or dexamethason).
Neurologic Outcome:
ASIA grade & Frankel scores. Mean follow-up was 53
months. No statistically significant difference in neurologic
outcome at any stage.
Safety & Adverse events:
There was significant increase in the incidence of infections
in the steroid group. The dexamethasone group had a statistically
significant increase in the number of gastrointestinal
complications, and the methylprednisolone group had a
statistically significant increase in the incidence of
pancreatitis.
Safety and Adverse Effects of Steroids
Potential adverse effects of high-dose
steroid administration in trauma patients include:
- Increased incidence of infectious
and septic complications
- Increased incidence & severity
of respiratory complications
- Increased incidence of pulmonary
embolism
- Worsening of head injury outcome
- Increased incidence of gastrointestinal
haemorrhage
- Increased incidence of pancreatitis
- Possibility of missed hollow viscus
injury due to 'masking' of abdominal signs
References
Prospective, randomized studies
Bracken MB, Shepard MJ, Hellenbrand
KG et al. 'Methylprednisolone and neurological function
1 year after spinal cord injury. Results of the National
Acute Spinal Cord Injury Study.' J Neurosurg. 1985;63:704-13.
Pubmed
Bracken MB, Shepard MJ, Collins WF et
al. 'A randomized, controlled trial of methylprednisolone
or naloxone in the treatment of acute spinal-cord injury.
Results of the Second National Acute Spinal Cord Injury
Study.' N Engl J Med. 1990;322:1405-11 Pubmed
Bracken MB, Shepard MJ, Collins WF Jr
et al. 'Methylprednisolone or naloxone treatment after
acute spinal cord injury: 1-year follow-up data. Results
of the second National Acute Spinal Cord Injury Study.'
J Neurosurg. 1992;76:23-31 Pubmed
Otani K et al. 'Beneficial effect of
methylprednisolone sodium succinate in the treatment of
acute spinal cord injury.' Sekitsui Sekizui 1994;7:633-647
[no Pubmed listing]
Bracken MB, Shepard MJ, Holford TR e
al. 'Administration of methylprednisolone for 24 or 48
hours or tirilazad mesylate for 48 hours in the treatment
of acute spinal cord injury. Results of the Third National
Acute Spinal Cord Injury Randomized Controlled Trial.
National Acute Spinal Cord Injury Study. JAMA. 1997;277:1597-604
Pubmed
Petitjean ME, Pointillart V, Dixmerias
F et al. 'Medical treatment of spinal cord injury in the
acute stage.' (French) Ann Fr Anesth Reanim. 1998;17:114-22
Pubmed
Pointillart V, Petitjean ME, Wiart L
et al. 'Pharmacological therapy of spinal cord injury
during the acute phase.' (English) Spinal Cord. 2000;38:71-6
Pubmed
Retrospective or case-control studies
Prendergast MR, Saxe JM, Ledgerwood
AM et al. 'Massive steroids do not reduce the zone of
injury after penetrating spinal cord injury.' J Trauma.
1994;37:576-9 Pubmed
George ER, Scholten DJ, Buechler CM
et al. 'Failure of methylprednisolone to improve the outcome
of spinal cord injuries.' Am Surg. 1995;61:659-63 Pubmed
Gerhart KA, Johnson RL, Menconi J et
al. 'Utilization and effectiveness of methylprednisolone
in a population-based sample of spinal cord injured persons.'
Paraplegia. 1995;33:316-21 Pubmed
George ER, Scholten DJ, Buechler CM
et al. 'Failure of methylprednisolone to improve the outcome
of spinal cord injuries.' Am Surg. 1995;61:659-63 Pubmed
Levy ML, Gans W, Wijesinghe HS et al.
'Use of methylprednisolone as an adjunct in the management
of patients with penetrating spinal cord injury: outcome
analysis.' Neurosurgery 1996;39:1141-8 Pubmed
Gerndt SJ, Rodriguez JL, Pawlik JW et
al. 'Consequences of high-dose steroid therapy for acute
spinal cord injury.' J Trauma. 1997;42:279-84 Pubmed
Heary RF, Vaccaro AR, Mesa JJ et al.
'Steroids and gunshot wounds to the spine.' Neurosurgery.
1997;41:576-83 Pubmed
Poynton AR, O'Farrell DA, Shannon F
et al. 'An evaluation of the factors affecting neurological
recovery following spinal cord injury.' Injury. 1997;28:545-8
Pubmed
Reviews, Re- or Meta-analyses
Nesathurai S. 'Steroids and spinal cord
injury: revisiting the NASCIS 2 and NASCIS 3 trials.'
J Trauma. 1998;45:1088-93 Pubmed
Short DJ, El Masry WS, Jones PW 'High
dose methylprednisolone in the management of acute spinal
cord injury - a systematic review from a clinical perspective.'
Spinal Cord. 2000;38:273-86 Pubmed
Coleman WP, Benzel D, Cahill DW et al.
'A critical appraisal of the reporting of the National
Acute Spinal Cord Injury Studies (II and III) of methylprednisolone
in acute spinal cord injury.' J Spinal Disord. 2000;13:185-99
Pubmed
Hurlbert RJ. 'The role of steroids in
acute spinal cord injury: an evidence-based analysis.'
Spine. 2001;26(24 Suppl):S39-46 Pubmed
Authors & Contributors
Karim Brohi |