Current Therapies for Brain Trauma

Anne E. Chauvet, DVM, DACVIM (Neurology)


Trauma causes about 150,000 deaths in the USA each year and about 1/2 are due to fatal head injury. 

Primary trauma:

  1. contusion
  2. laceration
  3. hemorrhage
  4. hematoma (extradural, subarachnoid, subdural, intracerebral). 

Damage depends on:

  • location, type of strain (compressive, tensile, sheer), tissue involved (brainstem compression = coma)
  • static forces/slow (>200 ms) (skull bending, focal brain damage) vs dynamic forces/fast (<200 ms) which are most common
  • impact or direct blow vs impulsive injury due to sudden head movement = secondary impact is elsewhere
  • neural vs vascular damage
    • secondary events = ischemia, edema, increase intracranial pressure
    • delayed events = deafferation and delayed cell death
Focal injury (40.4% mortality) produce a local mass effect and structural disruption and usually require surgical treatment.  Diffuse injury (23.9% mortality) cause primary axonal membrane defect, ionic shifts within the axons, axonal depolarization, altered transmission of neural networks and widespread neurologic dysfunction leading to primary coma.  The greater the acceleration force, the greater the axonal damage and electrolyte transport disturbances.  Diffuse injury requires medical therapy.

Secondary effects are due to acidosis.
  • cerebral metabolic rate of O2 is proportional to depth of coma
  • cerebral blood flow varies greatly in patients with same status
  • excess blood flow relative to metabolism can occur (hyperemia) = edema (PET scan helps diagnose perfusion status)
  • cerebral blood flow can be altered by changing arterial CO2 content

CHART 1: follow with chart for descriptions below

1.  Polyamines are ornithine derived molecules that promote cell proliferation and growth, calcium mobilization and membrane transport functions.  Seizures, excitatory conditions, ischemia, BBB breakdown activate ornithine decarboxilase (ODC) which is the rate controlling step for converting ornithine to putrescine.  Mechanical, thermal, chemical, metabolic injuries and axonotomy all lead to increased polyamine synthesis.  Excess putrescine leads to edema and delayed cell death.  ODC, a sensitive indicator of cell damage, increases in ipsilateral brain tissue within 8 hours of injury and normalizes at 24 hours.   Slight edema is seen as early as 4 hours post injury and is most significant 3 to 6 hours post injury. Post-traumatic inhibition of SAMdc may lead to putrescine increase and related decreases in spermidine and spermine which are potential mechanisms of delayed neuronal death.  Difluoromethylornithine (DFMO) inhibits ODC, decreasing putrescine amounts and mortality.  The increase in ODC mRNA suggests control at the transcriptional level which may correspond with the increase in ODC activity. DFMO also protects NMDA receptor mediated neurotoxicity.

2.  Brain injury leads to slow potassium release followed by massive efflux of K+ (1-2 minutes).  Increased extracellular K+ leads to loss of consciousness or ANS dysfunction, contributing to post trauma epilepsy.  Astrocytes take up the K+ and status spongiosus ensues due to rapid influx of Cl-, Na+ and water.  Neurotransmitter release is precipitated.  Anion exchange inhibitors such as ethacrynic acid, bindacrinone (MK-196), and L-644, 711 decrease mortality and improves neurologic signs in rats.

3.  Calcium channel antagonists such as nimodipine and dihydronaphthyridine Cl-951 improve cerebrovascular and metabolic status, and decrease edema secondary to ischemia.  (S)-emopamil therapy within 48 hours of traumatic brain injury (TBI) reduced focal brain edema, attenuated memory damage and motor dysfunction observed over 2 weeks post injury.  Calcium plays a role in the uncoupling of oxidative phosphorylation of mitochondria.  Controlled cortical impact injury perturbs the cellular Ca2+ homeostasis with an overloading of cytosolic Ca2+, resulting in an excessive amount of Ca2+ associated with mitochondrial membranes; consequently, the mitochondrial electron and energy transfer capacities are impaired.  Kynurenate, a glycine-site NMDA receptor antagonist, has been found to improve behavioral outcome and reduce the levels of lactate and FFA that are normally increased in the ipsilateral cortex following TBI.  These results suggest that the reduction of secondary injury factors may be involved in the observed improved behavioral outcome after brain injury.  Chronic post-injury administration of D-cycloserine an N-methyl-D-aspartate (NMDA) partial agonist, enhances cognitive recovery following TBI.

4.  Scopolamine (psychomimetic) reverts post-trauma injury only if administered within 156 minutes. Non competitive antagonists of EAA such as phencyclidine (PCP) and ifenprodil help decrease cell death due to influx of Cl- and Na+ (acute neuronal swelling) and Ca++ (delayed  damage).

5.  Deferoxamine mesylate is a potent iron chelator that crosses the BBB and cellular membranes,  and inhibits iron-dependent oxygen free radical-producing reactions by forming a chemically inert complex with iron and is excreted in urine.  Avoid using with phenothiazines. Success is best when used early in therapy.  There has been some thought in past about allopurinol which inhibits the enzyme xanthine oxidase which is important in reperfusion injury, a major pathway for oxygen free radical production after brain ischemia.

6.  Methylprednisolone sodium succinate is already used commonly for acute spinal cord and brain injury.  21-aminosteroids also called lazeroids inhibit iron induced lipid peroxidation and attenuate arachidonic acid metabolism.  U-74006F given 5 minutes after injury leads to 52% decrease in BBB breakdown and lipid peroxidation, and leads to early recovery after moderate injuries.  Higher doses may lyse cell membranes.  Tirilazad mesylate protects the brain concentration of vitamin C and E.  U74500A attenuates damage secondary to glucose deprivation.  However, the majority of available evidence indicates that glucocorticoids do not lower ICP nor improve outcome in severely head-injured patients.  Thus, the routine use of glucocorticoids is not recommended for these purposes.

7.  Thyroid releasing hormone antagonizes the many effects of endogenous opioid peptide (EOP) without altering analgesia. CG-3703 which may block endogenous opioid activity improves blood pressure and survival, leads to recovery in intracellular phosphocreatinine/inorganic phosphate ratio.

8.  The levels of leukotriene C4 were significantly elevated in the ipsilateral cortex and hippocampus at 10 minutes after injury and those elevations persisted as long as 2 hours suggesting that LTC4 may play a role in the BBB edema formation and neuronal cell loss associated with brain injury.  Modulators of the arachidonic acid pathway such as cyclooxygenase inhibitors and thromboxane synthetase inhibitors (U63447A) decrease white matter ischemia and cerebral edema.  Phenidone, a leukotriene synthetase inhibitor, decreased the BBB permeability and edema.  Alpha tocopherol works best pre treatment to decrease gliosis, edema, lipid peroxidation, and neuronal necrosis.  Superoxide dismutase decreases the BBB permeability but does not alter blood flow.  Newer free radical scavengers are ONO-3144 and MKI-186.

9.  Activated calpain is present after controlled cortical impact and could be responsible for necrosis at the site of injury.  The appearance of calpain mediated breakdown products at sites distal to the contusion site also suggest that calpain activation may precede or occur in the absence of overt necrosis.  Evolutionary temporal profiles of calpain activity in both the ipsilateral and contralateral cortex after TBI suggest that calpain activity is not exclusively a function of localized contusion and cell death, but may present a more global response to injury.

10.  DMSO reduces ICP, improving the outcome.  It also decreases oxygen and glucose requirements of brain tissue, scavenges oxygen free radicals, stabilizes lysosomal membranes, decreases brain edema by stabilizing capillary endothelium and acts as an antiinflammatory.  Cell death occurs with DMSO concentrations above 20%. 

11.  Neurons can produce platelet activating factors which increase the BBB permeability and lead to neurotoxicity/cytotoxicity.  Antagonists such as BN52021 help decrease motor injury when given prior to injury.

Gangliosides assist synaptic transmission and neuronal development and plasticity.  GM1 promotes neuronal sprouting.  AGF2, a derivative of GM1 has been found to decrease mortality and behavioral damage in rats.

The main determinants of survival are the adequacy of resuscitation and the early recognition of serious injuries.  Acknowledged negative influence of secondary insults such as hypotension and hypoxia on outcome from severe head injury establishes systemic resuscitation as the critical step to recovery.  Alternatively, signs of transtentorial herniation are strong evidence of intracranial hypertension and rapid treatment to lower ICP should be initiated. Maintenance of cerebral perfusion pressure > 70 mm Hg is a therapeutic option that may be associated with a substantial reduction in mortality and improvement in quality of survival, and is likely to enhance perfusion to ischemic regions of the brain following severe TBI. Systolic blood pressure of less than 90 mmHg or PaO2 < 60 mm Hg  are associated with increased mortality and morbidity.

Mannitol bolus produced a 32% reduction in ICP and the effect was seen for 60 minutes.  Tromethamine (THAM) was “at least as effective as mannitol”.  The response of ICP to mannitol is unpredictable in a given patient - both in extent and duration.  ICP monitoring and CSF drainage may be undertaken in patients with low Glascow Coma Scale (GCS) score and at high risk of increased ICP.  20-25 mmHg is the upper threshold above which treatment to lower ICP is generally accepted.  Serum osmolalities greater than 320 mOsm/l and hypovolemia should be avoided.  Bolus administration may be preferable to continuous infusion. Furosemide decreases CSF production, astroglial swelling, and ICP.  A combination of albumin and furosemide has been shown experimentally to have effect similar to mannitol and furosemide in reducing ICP.   Hypertonic maintenance fluid improves intracranial compliance by dehydrating uninjured cortex.  Cerebral blood flow (CBF) is improved and ICP is reduced, all reducing secondary brain injury after head trauma.

Hyperventilation has been recommended because respiratory depression superimposed on mechanical injury leads to severe metabolic derangement and acidosis due to glycolytic output exceeding the citric acid cycle.  Some research states that prophylactic sustained hyperventilation retards recovery from TBI.  The use of THAM overcomes the deleterious effects of this hyperventilation.  Aggressive hyperventilation (PaCO2 < 30 mm Hg) will reduce CBF values even further but will not consistently cause a reduction of ICP causing loss of autoregulation.  At 3 and 6 months after injury, patients with an initial GCS motor score of 4-5 had a significantly better outcome if not hyperventilated.  Chronic  prophylactic hyperventilation therapy should be avoided during the first five days after severe TBI especially the first 24 hours.

The effects of hypothermia, cerebral and systemic, on recovery from TBI are still controversial.  Decreased temperature suppresses high CSF levels of IL-1B (which attracts leukocytes) released with trauma.  Systemic temperatures lower than 320C are associated with ventricular arrythmias and bleeding complications.  The cooling rate should be 1.50C/hr.  Secondary hypokalemia is corrected by fluid therapy.  Hyperkalemia is not a complication of re-warming.

Sedation and anesthesia are commonly used to prevent sudden surges in BP and ICP.  There are no studies on  the effect of sedation on outcome from severe TBI.  The decision to sedate is the choice of the practitioner.  Neuromuscular blockade however has been shown to increase ICU stay, secondary complications and sepsis without improving outcome.  High doses of barbiturate therapy are efficacious in lowering ICP and decreasing mortality in the setting of uncontrollable ICP refractory to all other conventional medical and surgical treatments. Prophylactic barbiturate therapy is not indicated as it increases mortality and decreases outcome. Prophylactic anticonvulsants later than one week following head injury are not recommended for preventing late post-traumatic seizures.  Late onset of post-traumatic seizures should be dealt with as any other epilepsy case.

100%-140% replacement of resting metabolism expenditure with 15-20 % nitrogen calories reduces nitrogen loss.  30% weight loss is associated with increased mortality rate.  Therefore feed early with increased metabolic intake.  The best route of feeding is unknown but feeding must be initiated within the first week post TBI. Glucose administration would have the most adverse consequences for those head injured patients who suffer secondary insults, such as increase ICP, hypotension or hypoxia, during their hospital course.

Many consider head trauma requiring a surgical therapy.

How to treat a brain trauma patient in veterinary medicine?

1.       Intubate if comatose and ventilate if necessary to keep PaCO2 at 30 mmHg:

blood gases and blood pressure monitoring are important and advised.  If not equipped with ventilation and blood gas machines, ensure respiration is deep and not shallow and that it is regular at about 12-20 per minute. 

2.       IV maintainance fluid therapy

Consider hypertonic saline to decrease intracranial pressure if the patient is not in shock nor hypothermic.  Do not use hypertonic saline if you are going to use mannitol.  Keep the blood glucose in low normal range.

3.       Mannitol at 1 g/kg IV over 20 minutes; repeat every 4-12 hours.

An osmotic diuretic, it is useful to decrease intra-cranial pressure (ICP). Single bolus doses are better than slow infusions and will lead to a decrease in ICP over 5 minutes and the effects can last 60 to 120 minutes. The beneficial effects of mannitol administration have been attributed to a decrease in brain water content and also to an osmotic shift of water into the vascular space that leads to decrease in blood viscosity and increases cerebral blood flow and oxygen delivery.  Adequate hydration is crucial.

4.       Furosemide to follow mannitol at 2-4 mg/kg IV bolus, repeat every 6 hours or so.

Furosemide can decrease the CSF production (inhibits carbonic anhydrase activity). This does not affect ICP but furosemide however prolongs the effects of mannitol.

5.       DMSO at 1-2 g/kg IV over 45 minutes once (10-20% solution), every 8-12 hours but once preferred.

6.       Repeated use is not advised though as rebound increase in ICP is reported.

7.       Steroids are controversial but consider Solumedrol for shock and spine trauma: 30 mg/kg IV slow followed by 5.4 mg/kg/h CRI for 24 hours.  Alternatively, consider dexSP at 1-4 mg/kg IV.

8.       Supportive care:

eye lubrication, rotation, padding, seizure management. Keep the head above the heart slightly to decrease ICP.  Monitor the blood glucose every 2 to 4 hours.  Continue to assess the rest of the patient

9.       Assess neurologic status every 2-4 hours until stabilized.

Use the MGCS.  See Table 1.

10.   Nutrition (PPN or TPN or nasogastric feeding) is to be started by day 3 post trauma and at full nutritional need by day 7.  Patients lacking nutrition past 7 days have a grave prognosis.

11.   Scan (MRI or CT) as soon as possible to assess physical damage and determine if surgery is indicated.

12.   Sedation:

Avoid sedation unless the patient is too restless which could increase ICP. Patients placed on sedation tend to door more poorly. Do not place patients on anticonvulsants unless seizures are noted. Not all brain trauma cases develop seizures.  If you must sedate, consider acepromazine at 0.002 mg/kg IV.

13.   Analgesia:

Pain management should be considered. Butorphanol, morphine, oxymorphone are all useful but avoid overdosing. Do not confuse pain with dementia.

Table 1:  Modified Glascow Coma Scale: from Platt et al., JVIM 2001;15:581-584.


Motor Activity


  Normal gait, normal spinal reflexes


  Hemiparesis, tetraparesis or decerebrate activity


  Recumbent, intermittent extensor rigidity


  Recumbent, constant extensor rigidity


  Recumbent, constant extensor rigidity with opisthotonus


  Recumbent, hypotonia of muscles, depressed or absent spinal reflexes



Brain Stem Reflexes


  Normal PLR and oculocephalic reflexes


  Slow PLR and normal to reduced oculocephalic reflexes


  Bilateral unresponsive miosis with normal to reduced oculocephalic reflexes


  Pinpoint pupils with reduced to absent oculocephalic reflexes


  Unilateral, unresponsive mydriasis with reduced to absent oculocephalic reflexes


  Bilateral, unresponsive mydriasis with reduced to absent oculocephalic reflexes



Level of Consciousness


  Occasional periods of alertness and responsive to the environment


  Depression or delirium, capable of responding but response may be inappropriate


  Semicomatose, responsive to visual stimuli


  Semicomatose, responsive to auditory stimuli


  Semicomate, responsive only to repeated noxious stimuli


  Comatose, unresponsive to repeated noxious stimuli



Spinal trauma

l. Mechanism of injury


Fall in spinal cord blood flow is a hallmark of acute spinal cord trauma, acutely in the grey matter and delayed (2 hours or so) in the white matter.

Raised intraneuronal calcium

Activated phospholipases will disrupt cell membranes, releasing arachidonic acid from membrane phospholipids.  Calcium accumulation in organelles impair their function causing further disruption of the cell infrastructure.  Calcium also worsens free radical induced lipid peroxidation.  Membrane channels are either voltage-sensitive or agonist operated.  The voltage-senssitive calcium channels open at specific membrane potential  Lethal calcium entry can occur via certain agonist operated calcium channels.  N-methyul D-aspartate receptor is one of the subsets of the glutamate (excitatory neurotransmitter) receptor.  The binding of glutamate on the NMDA receptor leads to opening of ion channel allowing calcium ion entry.  Rapid removal of glutamate restores to the channel to resting stage.  In acute spinal injury, glutamate concentrations are elevated due to impaired uptake and increased release, leading to prolonged NMDA receptor opening.

 Lipid peroxidation

Damaged cell metabolism leads to production of oxygen free radicals, overwhelming natural defenses.  Membrane disruption occurs because the membrane phospholipid double bond is vulnerable to free radical attack.  Lipid peroxidation ensues.

How spinal cord damage demonstrates itself clinically:

  • paresis, ambulatory
  • paresis, non-ambulatory
  • plegic, superficial pain present
  • plegic, deep pain present
  • absence of deep pain – with trauma other than disc, this means grave prognosis.

See tables 2 and 3.

Spinal shock – hypotonia and hyporeflexia noted post trauma; can last a few hours (in humans, can last days). This phenomenon is not well understood but one should be careful not to give a prognosis too quickly after spinal trauma. I recommend waiting a few hours to reassess the neurological status.

II.  Working up spinal cord disease:

  •  Thoracic radiographs for metastasis check
  •  Survey spinal radiographs:  anesthesia is best
  •  Myelography and when applicable epidurography/discography
  •  Spinal fluid analysis: cell count, protein, cytology
  • MRI or CT scan 

Managing and treating spinal trauma:

1.       immobilize the patient’s spine: board, stretcher, straps. If you have to move the animal, place another board/hard surface over the patient.

2.        Steroids

  • Dexamethasone sodium phosphate
    0.25 mg/kg first dose then 0.1 mg/kg Q 6-12 hrs
    1-2 mg/kg for immunosuppression for 24 hours
  • Prednisone/olone
    0.5 mg/kg orally bid for x days, then sid for x days, then every other day for x Tx 1-2 mg/kg bid for immunosuppression for 2 weeks then taper
  • Solumedrol
    Solumedrol (methylprednisolone sodium succinate) has been shown to be effective in people with spinal injury when given within the first 8 hours after injury due to its inhibition of lipid peroxidation (Figure 4).
    30 mg/kg slow IV (10-20 min) for 1st dose.
    5.4 mg/kg/hr drip for 24 hours thereafter if the trauma was less than 4 hours prior to presentation and for 48 hours if the trauma was 4-8 hours prior to presentation.
  • Solu-Delta-Cortef (Prednisolone sodium succinate)
    Not the same as Solumedrol; requires 60 mg/kg for same effects. GI side effects.

3.  DMSO - Inhibition of platelet aggregation and preservation of microvascular blood flow are proposed mechanisms of action.
0.5-1 g/kg IV over 45 minutes once (10-20% solution)

4.  Surgery -

 When to operate

  • Non ambulatory or worse
  • Not responding to medical therapy
  • Worsening despite medical therapy          

Risks and benefits

  • Faster recovery.
  • Depends on diagnosis

5.  Others/Nursing care

            Bladder management is essential. Upper refers to injury to the spinal cord rostral to L4 and the lower motor neuron bladder to L4-S3. UMN bladder:  toned, difficult to manually express, empties by reflex .LMN bladder:  flaccid, easily emptied by abdominal pressure, leaking. Use pads under the dogs and express the bladder every few hours but best is to catheterize.

Table 2:  Upper motor neuron  vs  lower motor neuron


Upper Motor Neuron

Lower Motor Neuron

Anatomic location

descending tracts to arc

the reflex arc & neuron body


normal or increased

decreased or absent

Muscle mass

disuse atrophy = slow

EMG normal

neurogenic atrophy = rapid

EMG abnormal after 7-10 d

Muscle tone

normal to increased

spastic paresis/paralysis

decreased to absent

flaccid paresis/paralysis

Table 3: localization of UMN and LMN

Spinal segments

Thoracic limbs

Pelvic limbs





very mild lesions can present with only pelvic limb signs




large extradural space - thoracic limbs can look UMN




thoracic limbs can look UMN (Schiff-Scherington) due to cervicothoracic ventral horn cells from upper lumbar cord




L6-S3 can cause hyper patellar due to loss of flexor muscle function