Vol.18, No.
6 June 1996 V Small Animal Neurology
Continuing Education Article
FOCAL POINT
★ It is critical to initiate aggressive
and appropriate treatment within
hours after insult to prevent the
continued neuronal destruction
that follows acute spinal cord
trauma.
KEY FACTS
■ The use of high doses of
methylprednisolone seems to
be essential, but initiation of
treatment more than 8 hours
after injury is not only ineffective
but detrimental to the spinal cord.
■ Overdosage of glucocorticoids
as well as combined use with
nonsteroidal antiinflammatory
agents can result in severe
adverse effects.
■ Calcium channel blockers may be
beneficial in limiting secondary
injury and should be used in
conjunction with vasopressors.
■ The nonglucocorticoid
tirilazad mesylate seems to be
safer and more effective than
methylprednisolone and may
be available commercially in the
near future.
Pharmaceutic
Treatment of Acute
Spinal Cord Trauma
Louisiana State University
Elmarie Meintjes, BVSc, MS, MRCVS
Giselle Hosgood, BVSc, MS, FACVS
Joanna Daniloff, PhD
S pinal cord concussion or laceration as a result of vertebral fracture, luxa-
tion, or disk extrusion is one of the most frequent neurologic disorders
seen in small animal practice.1 The complex set of primary and secondary
pathologic changes that follow mammalian spinal cord injury have been exten-
sively described but are not yet completely understood,2–6 and much controver-
sy exists. Injury to the spinal cord, however, often results in relatively pre-
dictable pathology and pathophysiology.1,7,8
Ischemic, biochemical, and cellular changes following mechanical trauma are
believed to contribute to damage known as secondary injury.9–11 A possible
mechanism for the continued cellular destruction that is seen after injury may
involve vasogenic edema12 and a dramatic decrease in spinal cord blood flow in
segments cranial and caudal to the lesion.11,13 This progressive decline in spinal
cord blood flow is probably caused by an injury-initiated molecular cascade in-
volving a massive increase in intracellular calcium,1,14 liberation of vasoactive
prostanoids and thromboxane A2, and microvascular lipid peroxidative reac-
tions with release of excessive amounts of cytotoxic free radicals.1,5,15 The ulti-
mate consequence is continued neuronal cell death and loss of sensorimotor
function.
Control of the chemical and vascular changes that result in secondary injury
should limit the loss of function. Therefore, acute spinal cord injury is an
emergency, and early treatment is critical to limit the degeneration after in-
jury.9,16,17 Treatment should be directed at prevention of the spread of biochem-
ical neuronal destruction10 and at decompression of the spinal cord and/or sta-
bilization of the vertebral column. 18 In addition, adequate nursing and
supportive care for paraplegic or tetraplegic animals is vital for recovery and
should never be neglected.18–20
Numerous pharmacologic agents for the treatment of acute spinal cord injury
have been described, but there are many opposing views regarding the efficacy of
Small Animal
these agents (Table I). This
Problems Associated article assesses recent develop-
with the Use of ments in the use of drugs that
Dexamethasone specifically target the treat-
ment of secondary injury.
■ Uncertain efficacy
TREATMENT
■ Severe side effects
METHODOLOGIES
Gastrointestinal Glucocorticoids
hemorrhage Since the 1960s, glucocor-
Ulceration ticoids have been used exten-
Pancreatitis sively in the clinical treat-
Immunosuppression ment of spinal cord trauma,
mainly because of the theory
Colonic perforation
that they would reduce ede-
ma.21 The dose, timing, opti-
mum duration of treatment,
overall effectiveness, and mechanisms of action, howev-
er, remain controversial.17,22,23 Possible mechanisms of
action include suppression of edema, enhancement of
spinal cord blood flow, inhibition of the inflammatory
response that is associated with long-lasting vasospasm,
and protection from cytotoxic free radicals.7,15
Dexamethasone
Dexamethasone sodium phosphate at 2.2 mg/kg is
the drug most commonly used in the clinical treatment
of dogs with acute intervertebral disk herniation.24 The
use of repeated high doses of dexamethasone (4 mg/kg)
has also been reported, but such side effects as gastroin-
testinal hemorrhage, ulceration, pancreatitis, and im-
munosuppression are common complications. 19,25,26
One of the most catastrophic complications, colonic
perforation and death, occurred in dogs within 5 to 10
days after neurosurgery and the administration of dex-
amethasone sodium phosphate at 2.2 mg/kg.21,27
In addition, it is uncertain whether any beneficial ef-
fects are achieved from the use of dexamethasone. Cats
with a ventral compression injury at the second lumbar
vertebra (L2) were treated intravenously with 2.2
mg/kg of dexamethasone sodium phosphate twice daily
the first day, with a decreasing dose to 0.5 mg/kg twice
daily for 3 days after injury. In these animals, neurolog-
ic recovery scores (horizontal ladder walking) and elec-
trophysiologic responses (somatosensory-evoked poten-
tials) were the same as those for cats that received no
treatment.28 In summary, because of the frequency of
severe side effects in addition to the uncertain efficacy,
the use of dexamethasone for treating acute spinal cord
injuries is not recommended.
Methylprednisolone
Administration of a high-dose methylprednisolone
GLUCOCORTICOIDS ■ DEXAMETHASONE ■ METHYLPREDNISOLONE
The Compendium June 1996
sodium succinate regimen within 8 hours after trauma
has been reported to inhibit spinal tissue lipid peroxida-
tion. This mechanism of action is believed to be the ma-
jor reason for its therapeutic benefit.29,30 Methylpred-
nisolone also supports energy metabolism, reverses the
intracellular calcium accumulation, prevents progressive
ischemia, and increases electrophysiologic responses in
the spinal cord after injury.21,31,32 These beneficial effects
are achieved only with doses of methylprednisolone sodi-
um succinate that are higher (30 mg/kg) than antiinflam-
matory doses (0.25 mg/kg).30,32,33 Significant gastrointesti-
nal complications have not been reported when the high
dose is given over a short period (48 hours).34
In rats, a 30 mg/kg intravenous bolus of methylpred-
nisolone sodium succinate was given 1 hour after a
compression injury at the level of the first thoracic ver-
tebra (T1). This was followed by an intravenous dose
of 5.4 mg/kg/hour for 3 hours. The study reported that
somatosensory evoked potentials were preserved with
the use of this regimen.35
In cats with compression trauma at L2, treatment
was begun 30 minutes after injury with a 30 mg/kg in-
travenous bolus of methylprednisolone sodium succi-
nate; 6 hours later, an additional 15 mg/kg intravenous
bolus was given, followed by a continuous intravenous
infusion of 2.5 mg/kg/hour for 48 hours.36 Based on
evaluation of general mobility, running, and stair-
climbing, the treated cats scored significantly higher
than the placebo-treated cats at 4 weeks after injury.36
A single intravenous dose of methylprednisolone sodi-
um succinate (30 mg/kg) given as soon as possible after
injury, with a maintenance dose of 15 to 20 mg/kg in-
travenously every 2 to 3 hours, has also been reported
as the optimum dosage to inhibit spinal lipid peroxida-
tion and enhance motoneuron function in cats.30
In a report of 86 dogs with rear limb paresis or paral-
ysis (onset of 3 to 36 hours) due to intervertebral disk
herniation, 92% of the dogs recovered completely after
treatment with high-dose methylprednisolone sodium
succinate and decompressive surgery.37 Fifty-two dogs
had deep pain perception before surgery and 34 had no
deep pain perception. A 30 mg/kg intravenous bolus of
methylprednisolone sodium succinate was given before
surgery, with a continuous intravenous infusion of 5.4
mg/kg/hour for the next 23 hours. 37 Methylpred-
nisolone seemed to significantly increase the success
rate of decompressive surgery for intervertebral disk
herniation in dogs.37
Prednisolone
An initial intravenous dose of 20 mg/kg prednisolone
sodium phosphate followed 3 hours later by 10 mg/kg
intravenously and another 10 mg/kg intravenously 3
The Compendium June 1996 Small Animal

TABLE I
Compounds that May Ameliorate Secondary Injury after Experimental Mechanical Damage
(Contusion, Compression, Transection) to the Spinal Cord

Compound Species Dosage Mechanism of Action Reference

Available drugs

Methylprednisolone Cats 30 mg/kg IV within 8 hours Inhibits lipid 36

sodium succinate after injury; 15 mg/kg IV peroxidation
2 and 6 hours later; infusion
of 2.5 mg/kg/hr IV up to 48
hours after injury

Dogs 30 mg/kg IV bolus followed 37

by 5.4 mg/kg/hr IV
infusion for 23 hours

Prednisolone sodium Dogs 20 mg/kg IV; 10 mg/kg 3 and 6 May reduce edema 18
phosphate hours later; 9 hours later, infusion and inflammatory
of 2 mg/kg/hr IV for 24 hours response

Diltiazem Cats 100 µg/kg IV bolus with Prevents decrease in 11

5 µg/kg/min IV infusion spinal cord blood flow
for 4 hours (dissolve in because of reduction in
0.9% saline) intracellular Ca– influx

Nifedipine Cats 10 µg/kg IV bolus followed by Same as diltiazem 11

1 µg/kg/min IV infusion

Nimodipine Baboons 0.04 mg/kg/hr IV infusion for Same as diltiazem 41

7 days

Ibuprofen Cats 10 mg/kg IV bolus at time of Cyclooxygenase 11

injury with 5 mg/kg IV inhibitor that maintains
90 minutes later spinal cord blood flow
within normal limits

Experimental drug

Tirilazad mesylate Cats 0.3 to 30 mg/kg IV bolus 30 Nonglucocorticoid that 48

minutes after injury with 0.15 inhibits lipid peroxidation
to 15 mg/kg IV bolus at 21⁄ 2 and
6 hours after injury followed by
infusion of 1.6 to 160 mg/kg to
reach total dose within 48 hours

hours later has been suggested for dogs.18 Nine hours
after initiation of treatment, a continuous intravenous
infusion should be given at the rate of 2 mg/kg/hour
for 24 hours. The total dose should be approximately
90 mg/kg during a 30-hour treatment period.18 If the
animal’s neurologic status deteriorates after discontinu-
ation of glucocorticoid therapy, a continuous intra-
venous infusion should be reinstated, but not for more
than an additional 24 hours.18 Although side effects
were not seen with this regimen, no controlled studies
have been performed to establish its benefits.18
Additional Considerations on the
Use of Glucocorticoids
There is unequivocal evidence that methylpred-
nisolone beneficially modifies the course of events after

AVAILABLE DRUGS ■ EXPERIMENTAL DRUGS ■ PREDNISOLONE SODIUM PHOSPHATE

Small Animal
severe spinal cord injury21; however, several drawbacks
have been described. The effective dose range of
methylprednisolone is very narrow, with 60 mg/kg
causing loss of beneficial effect and 90 mg/kg promot-
ing lipid peroxidation.30 The potential for immunosup-
pression and gastrointestinal disturbances also exists
when the drug is administered over a longer period.17,23
Finally, the finding that initiating treatment after 8
hours may actually exacerbate neuronal necrosis and in-
hibit axonal sprouting has caused more controversy.17,38
In spinal cord injury models, several drugs (e.g., the
calcium-channel antagonist flunarizine 31) tested in
combination with methylprednisolone have produced
superior results.17 Combining some drugs with methyl-
prednisolone, however, can be deleterious.17 For exam-
ple, the combination of the narcotic antagonist nalox-
one and methylprednisolone does not reduce edema as
much as either drug alone and seems to be toxic by en-
hancing lipid peroxidation.39,40 In addition, the combi-
nation of glucocorticoids, particularly dexamethasone,24
with nonsteroidal antiinflammatory drugs (e.g,
phenylbutazone, ibuprofen, or flunixin meglumine)
may have serious and sometimes lethal side effects relat-
ed to gastrointestinal bleeding and perforation. One
must be aware of the sensitivity of dogs as well as cats
to nonsteroidal antiinflammatory drugs and to the
combination of nonsteroidal antiinflammatory drugs
and glucocorticoids—both impair normal defense
mechanisms of the bowel wall. No experimental data
exist to suggest that using such a combination is benefi-
cial.
Calcium-Channel Antagonists
Calcium-channel antagonists (e.g., nimodipine, dilti-
azem hydrochloride, nifedipine, and flunarizine hy-
drochloride) have recently been used with significant
success in experimental spinal cord injuries, possibly
because of the inhibitory effect of these drugs on cellu-
lar calcium entry. Nimodipine (0.04 mg/kg/hour, intra-
venous infusion for 7 days after insult) significantly in-
creased local spinal cord blood flow and improved
axonal function (as measured with somatosensory
evoked potentials) following a compression injury at L1
in baboons. 41 Pretreating cats with diltiazem (100
µg/kg intravenous bolus, followed by a 5 µg/kg/minute
intravenous infusion) or nifedipine (10 µg/kg intra-
venous bolus, followed by a 1 µg/kg/minute intra-
venous infusion) for 30 minutes before a contusion in-
jury (blunt impact) at L3 largely prevented the spinal
cord blood flow decrease after injury.11 Similar results
were not obtained, however, with verapamil.11
Flunarizine (0.1 mg/kg intravenously) was adminis-
tered 5 and 120 minutes after a contusion injury to the
DELETERIOUS COMBINATIONS ■ CALCIUM-CHANNEL ANTAGONISTS ■ NARCOTIC ANTAGONISTS
The Compendium June 1996
exposed spinal cord of cats, and somatosensory evoked
potentials were recorded 4 hours later. This treatment
resulted in a 52% recovery of the preinjury amplitude
versus a 17% recovery in cats without treatment.31 Fur-
thermore, when flunarizine and methylprednisolone
sodium succinate (30 mg/kg 5 minutes after injury)
were administered together, a significantly higher (62%)
recovery of preinjury amplitude was reported.31
Therefore, it is likely that treatment for acute spinal in-
juries will be enhanced by the inclusion of calcium-chan-
nel antagonists in conjunction with vasopressors (such as
high-dose dopamine at 10 µg/kg/min in dogs) to main-
tain systemic blood pressure.42 Experience in the clinical
use of these agents in both dogs and cats, however, is lim-
ited, and specific adverse effects are not well described.
Narcotic Antagonists
The potential use of the narcotic antagonist naloxone
has been tested because of its established ability to coun-
teract endorphin-mediated hypotension that follows
acute spinal injury.40,43 Although these studies resulted in
amelioration of neurologic deficits, another study could
not substantiate these effects.44 Furthermore, because
naloxone is expensive and inferior to methylpred-
nisolone, clinical use of the drug is precluded.38
Osmotic Diuretics
Although osmotic diuretics (e.g., mannitol, dextran,
and glycerol) are useful in reducing brain edema, there
is no evidence that these agents are effective in the
treatment of spinal cord injury. In fact, treatment with
osmotic diuretics can contribute to hemorrhage in the
gray matter18 and impede neurologic recovery.28 Such
treatment can also produce serious side effects that in-
clude hypokalemia, tissue dehydration, and rebound
increases in cerebrospinal fluid pressure.20 Despite the
fact that carbonic anhydrase inhibitors (e.g., furo-
semide) reduce cerebrospinal fluid pressure, they can
also induce hypokalemia.22
Dimethyl Sulfoxide
Electron microscopy indicated that dimethyl sulfox-
ide given 1 hour after contusion injury in dogs pro-
tected myelin sheaths and axons, reduced edema, and
accelerated return of motor function. 45 Dimethyl
sulfoxide may exert its effect by reducing thrombin-
stimulated serotonin release and acting as a hydroxyl
radical (released during lipid peroxidation) scav-
enger.5,20 Several side effects, however, have been re-
ported and include production of a destructive methyl
radical, fever, hemolysis, and renal toxicity.5,20
In cats, at 42 days after a compression injury at L2
and administration of decreasing doses (1.5, 1.5, 1.0,
Small Animal
0.7, and 0.5 g/kg, intravenously) of dimethyl sulfoxide
for 4 days, no therapeutic effect could be demonstrated
by somatosensory evoked potentials and horizontal
ladder walking.28 Many other studies on the effects of
dimethyl sulfoxide have been performed. Although
positive results have been reported, the majority are
negative; therefore, the use of dimethyl sulfoxide re-
mains controversial.
Miscellaneous Drugs
Numerous agents, such as superoxide dismutase,18
iron chelators (e.g., deferoxamine18), antioxidants (e.g.,
vitamin E and selenium11), nonsteroidal antiinflamma-
tory drugs (e.g., ibuprofen and flunixin11,15), and aspar-
tate-receptor antagonists (e.g., ketamine) have potential
value in the clinical treatment of spinal cord trauma.11,18
Deferoxamine inhibits the iron-catalyzed formation of
hydroxyl radicals by chelating iron, is well tolerated,
and has minimal toxicity.5 Allopurinol inhibits forma-
tion of superoxide radicals formed by the xanthine oxi-
dase pathway by inhibiting the xanthine oxidase. 5
Combined administration of deferoxamine (50
mg/kg/day) and allopurinol (50 mg/kg/day) for 3 days
before aortic crossclamping in pigs significantly re-
duced the incidence of paraplegia.46 Although used as a
pretreatment in this study, these two drugs may be clin-
ically useful after trauma to prevent the spread of sec-
ondary injury.
Nonsteroidal antiinflammatory drugs, such as
ibuprofen and flunixin, help prevent vasoconstriction
and platelet aggregation. 15 Cats were treated with
ibuprofen, a cyclooxygenase inhibitor at 10 mg/kg in-
travenously 30 minutes before a contusion injury at L2.
A 5-mg/kg intravenous bolus was also administered 1.5
hours after injury. The treated cats (in contrast to the
untreated controls) were reported to maintain spinal
cord blood flow within normal limits during the 4-
hour observation period after trauma.11 The effect of
anesthetics (e.g., nitrous oxide, isoflurane, fentanyl, and
ketamine) on neurologic outcome following spinal cord
injury in rats has been tested; no significant improve-
ment was demonstrated.47
Tirilazad Mesylate: The Future Drug of Choice?
The nonglucocorticoid tirilazad mesylate is currently
under investigation for its potential ability to limit
secondary injury. This agent is a potent inhibitor of
iron-dependent lipid peroxidation.48,49 It is a 21-amino-
steroid that lacks glucocorticoid or mineralocorticoid
activity; therefore it is especially useful for treatment of
central nervous system trauma.49,50
More than a 100-fold range of doses (1.6 to 160.0
mg/kg/48 hours, intravenously) promoted functional
DIMETHYL SULFOXIDE ■ NONSTEROIDAL ANTIINFLAMMATORY DRUGS ■ TIRILAZAD MESYLATE
The Compendium June 1996
recovery by 4 weeks in cats with a spinal cord compres-
sion injury at L2.48 Nearly 75% of normal neurologic
function was restored and no adverse effects were re-
ported. Furthermore, tirilazad mesylate (3 mg/kg intra-
venous bolus 4 hours after the insult) partially reversed
ischemia within 30 minutes in cats with a contusion in-
jury at L3, a result not seen with the 30 mg/kg intra-
venous methylprednisolone regimen.50,51
The preceding advantages should make the clinical
use of tirilazad mesylate more appealing than the gluco-
corticoid drugs currently available. Tirilazad mesylate is
already commercially available in Sweden and Den-
mark and is in phase 3 trials for FDA approval in the
United States. It is currently being administered within
8 hours following spinal cord injury in a human clini-
cal trial (NASCIS 3).38
DISCUSSION
The numerous studies that have used currently avail-
able drugs for the treatment of acute spinal cord injury
have provided controversial results. A successful treat-
ment protocol remains elusive as a result, in part, of the
lack of understanding of the complex set of events that
inhibit recovery and of the factors that support regener-
ation. Because effective treatment protocols for spinal
cord injury have not been established, the topic contin-
ues to be intensely investigated. Areas of study include
clarifying the pathophysiology of the acutely trauma-
tized spinal cord,1,8,16 developing experimental spinal
cord injury models for evaluating neurologic changes
that follow treatment,52–57 and describing therapeutic
interventions that limit secondary injury and stimulate
regeneration of axonal fibers.58–62
Supportive care of animals with spinal cord injuries is
essential. To limit the spread of secondary cellular de-
struction, however, treatment must be initiated within
hours after trauma. The faster and highly effective ac-
tion of methylprednisolone provides a distinct advantage
over the slower, more potent action of dexamethasone.
Methylprednisolone is therefore the drug of choice in
treating acute spinal cord injury.
Even methylprednisolone sodium succinate, however,
can be detrimental if treatment is initiated more than 8
hours after injury or if the dose is too high (more than
30 mg/kg initial intravenous dose). In animals in which
surgery (that may result in further spinal cord trauma)
is performed more than 8 hours after injury, it is un-
clear whether or not methylprednisolone should be ad-
ministered; no standard protocol can be defined.
A decision to administer methylprednisolone should
be made on an individual basis. It is probably necessary
to distinguish between the magnitude of damage
caused by the initial trauma and that of the surgical
The Compendium June 1996
procedure that will be performed. If neurologic signs
indicate that major trauma has already been inflicted,
treatment with methylprednisolone should be initiated
as soon as possible and continued only for the recom-
mended period, regardless of surgical intervention. Be-
cause of the strong indications that initiating treatment
more than 8 hours after acute trauma may actually ex-
acerbate neuronal necrosis and inhibit axonal sprout-
ing, it may be ill-advised to administer high-dose
methylprednisolone if a much longer period has
elapsed (despite the timing of surgical intervention). In
most cases, it is unlikely that the surgical trauma is of
significant magnitude in relation to the initial trauma.
The use of calcium-channel antagonists seems to be
beneficial and may potentiate the beneficial effects of
methylprednisolone. Clinical experience with the use of
these drugs, however, is limited. Calcium-channel an-
tagonists should be used in conjunction with vasopres-
sors (such as dopamine) to maintain systemic blood
pressure. Although clinical studies are lacking, this
treatment regimen could be introduced into current
veterinary protocols with minimal risk and possibly
considerable benefit.
Nonsteroidal antiinflammatory drugs may prevent
spinal cord ischemia after injury. When used in con-
junction with glucocorticoids, however, nonsteroidal
antiinflammatory drugs may have serious and even
lethal gastrointestinal complications.
All drugs currently available have limited beneficial
effects and several side effects. A promising drug that
should be available commercially in the near future is
tirilazad mesylate. This compound does not have glu-
cocorticoid activity, has a broad range of effective doses,
and lacks adverse side effects.
About the Authors
When this article was submitted, Drs. Meintjes and
Daniloff were affiliated with the Department of Veterinary
Anatomy and Fine Structure and Dr. Hosgood was affiliat-
ed with the Department of Veterinary Clinical Sciences,
School of Veterinary Medicine, Louisiana State Universi-
ty, Baton Rouge, Louisiana. Dr. Meintjes is currently in
practice at Parkway Animal Hospital in Cary, North Caroli-
na. Dr. Hosgood is a Diplomate of the American College
of Veterinary Surgeons.
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Duncan M, DACVC MS ori ing
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Frie M, MS ngi
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nisolone on functional recovery after experimental spinal in-
Lesley
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Karol
Ann Ma CC the An r Infections in 49
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Sheila
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D.H. Llo led Mu
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a Pow illard, E.J. Du n Study and D. Pankra
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DV

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