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FOCAL POINT Treatment of Acute
★ It is critical to initiate aggressive
and appropriate treatment within
hours after insult to prevent the
Spinal Cord Trauma
continued neuronal destruction
that follows acute spinal cord
trauma. Louisiana State University
Elmarie Meintjes, BVSc, MS, MRCVS
KEY FACTS Giselle Hosgood, BVSc, MS, FACVS
■ The use of high doses of Joanna Daniloff, PhD
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. 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-
■ Overdosage of glucocorticoids
as well as combined use with sy exists. Injury to the spinal cord, however, often results in relatively pre-
nonsteroidal antiinflammatory dictable pathology and pathophysiology.1,7,8
agents can result in severe Ischemic, biochemical, and cellular changes following mechanical trauma are
adverse effects. 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
■ Calcium channel blockers may be involve vasogenic edema12 and a dramatic decrease in spinal cord blood flow in
beneficial in limiting secondary segments cranial and caudal to the lesion.11,13 This progressive decline in spinal
injury and should be used in cord blood flow is probably caused by an injury-initiated molecular cascade in-
conjunction with vasopressors. volving a massive increase in intracellular calcium,1,14 liberation of vasoactive
prostanoids and thromboxane A2, and microvascular lipid peroxidative reac-
■ The nonglucocorticoid tions with release of excessive amounts of cytotoxic free radicals.1,5,15 The ulti-
tirilazad mesylate seems to be mate consequence is continued neuronal cell death and loss of sensorimotor
safer and more effective than function.
methylprednisolone and may Control of the chemical and vascular changes that result in secondary injury
be available commercially in the should limit the loss of function. Therefore, acute spinal cord injury is an
near future. 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 The Compendium June 1996
these agents (Table I). This sodium succinate regimen within 8 hours after trauma
Problems Associated article assesses recent develop- has been reported to inhibit spinal tissue lipid peroxida-
with the Use of ments in the use of drugs that tion. This mechanism of action is believed to be the ma-
Dexamethasone specifically target the treat- jor reason for its therapeutic benefit.29,30 Methylpred-
ment of secondary injury. nisolone also supports energy metabolism, reverses the
■ Uncertain efficacy intracellular calcium accumulation, prevents progressive
TREATMENT ischemia, and increases electrophysiologic responses in
■ Severe side effects
METHODOLOGIES the spinal cord after injury.21,31,32 These beneficial effects
Gastrointestinal Glucocorticoids are achieved only with doses of methylprednisolone sodi-
hemorrhage Since the 1960s, glucocor- um succinate that are higher (30 mg/kg) than antiinflam-
Ulceration ticoids have been used exten- matory doses (0.25 mg/kg).30,32,33 Significant gastrointesti-
Pancreatitis sively in the clinical treat- nal complications have not been reported when the high
Immunosuppression ment of spinal cord trauma, dose is given over a short period (48 hours).34
mainly because of the theory In rats, a 30 mg/kg intravenous bolus of methylpred-
Colonic perforation
that they would reduce ede- nisolone sodium succinate was given 1 hour after a
ma.21 The dose, timing, opti- compression injury at the level of the first thoracic ver-
mum duration of treatment, tebra (T1). This was followed by an intravenous dose
overall effectiveness, and mechanisms of action, howev- of 5.4 mg/kg/hour for 3 hours. The study reported that
er, remain controversial.17,22,23 Possible mechanisms of somatosensory evoked potentials were preserved with
action include suppression of edema, enhancement of the use of this regimen.35
spinal cord blood flow, inhibition of the inflammatory In cats with compression trauma at L2, treatment
response that is associated with long-lasting vasospasm, was begun 30 minutes after injury with a 30 mg/kg in-
and protection from cytotoxic free radicals.7,15 travenous bolus of methylprednisolone sodium succi-
nate; 6 hours later, an additional 15 mg/kg intravenous
Dexamethasone bolus was given, followed by a continuous intravenous
Dexamethasone sodium phosphate at 2.2 mg/kg is infusion of 2.5 mg/kg/hour for 48 hours.36 Based on
the drug most commonly used in the clinical treatment evaluation of general mobility, running, and stair-
of dogs with acute intervertebral disk herniation.24 The climbing, the treated cats scored significantly higher
use of repeated high doses of dexamethasone (4 mg/kg) than the placebo-treated cats at 4 weeks after injury.36
has also been reported, but such side effects as gastroin- A single intravenous dose of methylprednisolone sodi-
testinal hemorrhage, ulceration, pancreatitis, and im- um succinate (30 mg/kg) given as soon as possible after
munosuppression are common complications. 19,25,26 injury, with a maintenance dose of 15 to 20 mg/kg in-
One of the most catastrophic complications, colonic travenously every 2 to 3 hours, has also been reported
perforation and death, occurred in dogs within 5 to 10 as the optimum dosage to inhibit spinal lipid peroxida-
days after neurosurgery and the administration of dex- tion and enhance motoneuron function in cats.30
amethasone sodium phosphate at 2.2 mg/kg.21,27 In a report of 86 dogs with rear limb paresis or paral-
In addition, it is uncertain whether any beneficial ef- ysis (onset of 3 to 36 hours) due to intervertebral disk
fects are achieved from the use of dexamethasone. Cats herniation, 92% of the dogs recovered completely after
with a ventral compression injury at the second lumbar treatment with high-dose methylprednisolone sodium
vertebra (L2) were treated intravenously with 2.2 succinate and decompressive surgery.37 Fifty-two dogs
mg/kg of dexamethasone sodium phosphate twice daily had deep pain perception before surgery and 34 had no
the first day, with a decreasing dose to 0.5 mg/kg twice deep pain perception. A 30 mg/kg intravenous bolus of
daily for 3 days after injury. In these animals, neurolog- methylprednisolone sodium succinate was given before
ic recovery scores (horizontal ladder walking) and elec- surgery, with a continuous intravenous infusion of 5.4
trophysiologic responses (somatosensory-evoked poten- mg/kg/hour for the next 23 hours. 37 Methylpred-
tials) were the same as those for cats that received no nisolone seemed to significantly increase the success
treatment.28 In summary, because of the frequency of rate of decompressive surgery for intervertebral disk
severe side effects in addition to the uncertain efficacy, herniation in dogs.37
the use of dexamethasone for treating acute spinal cord
injuries is not recommended. Prednisolone
An initial intravenous dose of 20 mg/kg prednisolone
Methylprednisolone sodium phosphate followed 3 hours later by 10 mg/kg
Administration of a high-dose methylprednisolone intravenously and another 10 mg/kg intravenously 3
TABLE I
Compounds that May Ameliorate Secondary Injury after Experimental Mechanical Damage
(Contusion, Compression, Transection) to the Spinal Cord
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
Experimental drug
hours later has been suggested for dogs.18 Nine hours than an additional 24 hours.18 Although side effects
after initiation of treatment, a continuous intravenous were not seen with this regimen, no controlled studies
infusion should be given at the rate of 2 mg/kg/hour have been performed to establish its benefits.18
for 24 hours. The total dose should be approximately
90 mg/kg during a 30-hour treatment period.18 If the Additional Considerations on the
animal’s neurologic status deteriorates after discontinu- Use of Glucocorticoids
ation of glucocorticoid therapy, a continuous intra- There is unequivocal evidence that methylpred-
venous infusion should be reinstated, but not for more nisolone beneficially modifies the course of events after
severe spinal cord injury21; however, several drawbacks exposed spinal cord of cats, and somatosensory evoked
have been described. The effective dose range of potentials were recorded 4 hours later. This treatment
methylprednisolone is very narrow, with 60 mg/kg resulted in a 52% recovery of the preinjury amplitude
causing loss of beneficial effect and 90 mg/kg promot- versus a 17% recovery in cats without treatment.31 Fur-
ing lipid peroxidation.30 The potential for immunosup- thermore, when flunarizine and methylprednisolone
pression and gastrointestinal disturbances also exists sodium succinate (30 mg/kg 5 minutes after injury)
when the drug is administered over a longer period.17,23 were administered together, a significantly higher (62%)
Finally, the finding that initiating treatment after 8 recovery of preinjury amplitude was reported.31
hours may actually exacerbate neuronal necrosis and in- Therefore, it is likely that treatment for acute spinal in-
hibit axonal sprouting has caused more controversy.17,38 juries will be enhanced by the inclusion of calcium-chan-
In spinal cord injury models, several drugs (e.g., the nel antagonists in conjunction with vasopressors (such as
calcium-channel antagonist flunarizine 31) tested in high-dose dopamine at 10 µg/kg/min in dogs) to main-
combination with methylprednisolone have produced tain systemic blood pressure.42 Experience in the clinical
superior results.17 Combining some drugs with methyl- use of these agents in both dogs and cats, however, is lim-
prednisolone, however, can be deleterious.17 For exam- ited, and specific adverse effects are not well described.
ple, the combination of the narcotic antagonist nalox-
one and methylprednisolone does not reduce edema as Narcotic Antagonists
much as either drug alone and seems to be toxic by en- The potential use of the narcotic antagonist naloxone
hancing lipid peroxidation.39,40 In addition, the combi- has been tested because of its established ability to coun-
nation of glucocorticoids, particularly dexamethasone,24 teract endorphin-mediated hypotension that follows
with nonsteroidal antiinflammatory drugs (e.g, acute spinal injury.40,43 Although these studies resulted in
phenylbutazone, ibuprofen, or flunixin meglumine) amelioration of neurologic deficits, another study could
may have serious and sometimes lethal side effects relat- not substantiate these effects.44 Furthermore, because
ed to gastrointestinal bleeding and perforation. One naloxone is expensive and inferior to methylpred-
must be aware of the sensitivity of dogs as well as cats nisolone, clinical use of the drug is precluded.38
to nonsteroidal antiinflammatory drugs and to the
combination of nonsteroidal antiinflammatory drugs Osmotic Diuretics
and glucocorticoids—both impair normal defense Although osmotic diuretics (e.g., mannitol, dextran,
mechanisms of the bowel wall. No experimental data and glycerol) are useful in reducing brain edema, there
exist to suggest that using such a combination is benefi- is no evidence that these agents are effective in the
cial. treatment of spinal cord injury. In fact, treatment with
osmotic diuretics can contribute to hemorrhage in the
Calcium-Channel Antagonists gray matter18 and impede neurologic recovery.28 Such
Calcium-channel antagonists (e.g., nimodipine, dilti- treatment can also produce serious side effects that in-
azem hydrochloride, nifedipine, and flunarizine hy- clude hypokalemia, tissue dehydration, and rebound
drochloride) have recently been used with significant increases in cerebrospinal fluid pressure.20 Despite the
success in experimental spinal cord injuries, possibly fact that carbonic anhydrase inhibitors (e.g., furo-
because of the inhibitory effect of these drugs on cellu- semide) reduce cerebrospinal fluid pressure, they can
lar calcium entry. Nimodipine (0.04 mg/kg/hour, intra- also induce hypokalemia.22
venous infusion for 7 days after insult) significantly in-
creased local spinal cord blood flow and improved Dimethyl Sulfoxide
axonal function (as measured with somatosensory Electron microscopy indicated that dimethyl sulfox-
evoked potentials) following a compression injury at L1 ide given 1 hour after contusion injury in dogs pro-
in baboons. 41 Pretreating cats with diltiazem (100 tected myelin sheaths and axons, reduced edema, and
µg/kg intravenous bolus, followed by a 5 µg/kg/minute accelerated return of motor function. 45 Dimethyl
intravenous infusion) or nifedipine (10 µg/kg intra- sulfoxide may exert its effect by reducing thrombin-
venous bolus, followed by a 1 µg/kg/minute intra- stimulated serotonin release and acting as a hydroxyl
venous infusion) for 30 minutes before a contusion in- radical (released during lipid peroxidation) scav-
jury (blunt impact) at L3 largely prevented the spinal enger.5,20 Several side effects, however, have been re-
cord blood flow decrease after injury.11 Similar results ported and include production of a destructive methyl
were not obtained, however, with verapamil.11 radical, fever, hemolysis, and renal toxicity.5,20
Flunarizine (0.1 mg/kg intravenously) was adminis- In cats, at 42 days after a compression injury at L2
tered 5 and 120 minutes after a contusion injury to the and administration of decreasing doses (1.5, 1.5, 1.0,
0.7, and 0.5 g/kg, intravenously) of dimethyl sulfoxide recovery by 4 weeks in cats with a spinal cord compres-
for 4 days, no therapeutic effect could be demonstrated sion injury at L2.48 Nearly 75% of normal neurologic
by somatosensory evoked potentials and horizontal function was restored and no adverse effects were re-
ladder walking.28 Many other studies on the effects of ported. Furthermore, tirilazad mesylate (3 mg/kg intra-
dimethyl sulfoxide have been performed. Although venous bolus 4 hours after the insult) partially reversed
positive results have been reported, the majority are ischemia within 30 minutes in cats with a contusion in-
negative; therefore, the use of dimethyl sulfoxide re- jury at L3, a result not seen with the 30 mg/kg intra-
mains controversial. venous methylprednisolone regimen.50,51
The preceding advantages should make the clinical
Miscellaneous Drugs use of tirilazad mesylate more appealing than the gluco-
Numerous agents, such as superoxide dismutase,18 corticoid drugs currently available. Tirilazad mesylate is
iron chelators (e.g., deferoxamine18), antioxidants (e.g., already commercially available in Sweden and Den-
vitamin E and selenium11), nonsteroidal antiinflamma- mark and is in phase 3 trials for FDA approval in the
tory drugs (e.g., ibuprofen and flunixin11,15), and aspar- United States. It is currently being administered within
tate-receptor antagonists (e.g., ketamine) have potential 8 hours following spinal cord injury in a human clini-
value in the clinical treatment of spinal cord trauma.11,18 cal trial (NASCIS 3).38
Deferoxamine inhibits the iron-catalyzed formation of
hydroxyl radicals by chelating iron, is well tolerated, DISCUSSION
and has minimal toxicity.5 Allopurinol inhibits forma- The numerous studies that have used currently avail-
tion of superoxide radicals formed by the xanthine oxi- able drugs for the treatment of acute spinal cord injury
dase pathway by inhibiting the xanthine oxidase. 5 have provided controversial results. A successful treat-
Combined administration of deferoxamine (50 ment protocol remains elusive as a result, in part, of the
mg/kg/day) and allopurinol (50 mg/kg/day) for 3 days lack of understanding of the complex set of events that
before aortic crossclamping in pigs significantly re- inhibit recovery and of the factors that support regener-
duced the incidence of paraplegia.46 Although used as a ation. Because effective treatment protocols for spinal
pretreatment in this study, these two drugs may be clin- cord injury have not been established, the topic contin-
ically useful after trauma to prevent the spread of sec- ues to be intensely investigated. Areas of study include
ondary injury. clarifying the pathophysiology of the acutely trauma-
Nonsteroidal antiinflammatory drugs, such as tized spinal cord,1,8,16 developing experimental spinal
ibuprofen and flunixin, help prevent vasoconstriction cord injury models for evaluating neurologic changes
and platelet aggregation. 15 Cats were treated with that follow treatment,52–57 and describing therapeutic
ibuprofen, a cyclooxygenase inhibitor at 10 mg/kg in- interventions that limit secondary injury and stimulate
travenously 30 minutes before a contusion injury at L2. regeneration of axonal fibers.58–62
A 5-mg/kg intravenous bolus was also administered 1.5 Supportive care of animals with spinal cord injuries is
hours after injury. The treated cats (in contrast to the essential. To limit the spread of secondary cellular de-
untreated controls) were reported to maintain spinal struction, however, treatment must be initiated within
cord blood flow within normal limits during the 4- hours after trauma. The faster and highly effective ac-
hour observation period after trauma.11 The effect of tion of methylprednisolone provides a distinct advantage
anesthetics (e.g., nitrous oxide, isoflurane, fentanyl, and over the slower, more potent action of dexamethasone.
ketamine) on neurologic outcome following spinal cord Methylprednisolone is therefore the drug of choice in
injury in rats has been tested; no significant improve- treating acute spinal cord injury.
ment was demonstrated.47 Even methylprednisolone sodium succinate, however,
can be detrimental if treatment is initiated more than 8
Tirilazad Mesylate: The Future Drug of Choice? hours after injury or if the dose is too high (more than
The nonglucocorticoid tirilazad mesylate is currently 30 mg/kg initial intravenous dose). In animals in which
under investigation for its potential ability to limit surgery (that may result in further spinal cord trauma)
secondary injury. This agent is a potent inhibitor of is performed more than 8 hours after injury, it is un-
iron-dependent lipid peroxidation.48,49 It is a 21-amino- clear whether or not methylprednisolone should be ad-
steroid that lacks glucocorticoid or mineralocorticoid ministered; no standard protocol can be defined.
activity; therefore it is especially useful for treatment of A decision to administer methylprednisolone should
central nervous system trauma.49,50 be made on an individual basis. It is probably necessary
More than a 100-fold range of doses (1.6 to 160.0 to distinguish between the magnitude of damage
mg/kg/48 hours, intravenously) promoted functional caused by the initial trauma and that of the surgical
The Rapid
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