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Review of the Management of Traumatic Brain Injury in Horses
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The management of horses with acute traumatic brain injury begins with assessment, identification, and prompt treatment of systemic hypotension and hypoxemia to minimize secondary brain injury. Management guidelines used in human medicine can be applied to equine patients and may improve survival.
1. Introduction
Head trauma is common in horses, and a number of these cases will present with neurologic signs consistent with brain injury. The published information available to the equine practitioner regarding the diagnosis, management, and prognosis of horses with traumatic brain injury (TBI) is limited to a small number of case reports, review articles, and retrospective studies involving few cases [1-8] (less than five horses).
The management of horses with TBI is often based on recommendations from human and small animal medicine. Although the pathophysiology of TBI in horses may be considered similar to that in humans and other species, there are some aspects that may be unique to equine patients. In addition, the large size of equine patients limits the use of important diagnostic aids such as computed tomography and magnetic resonance imaging. Recently published guidelines for the management of TBI in humans targets therapeutic endpoints such as intracranial pressure and cerebral perfusion pressure parameters, neither of which is currently practical for routine monitoring in equine patients [9]. The management of recumbent, neurologic equine patients is particularly challenging and labor intensive, often limiting treatment options and duration. As a result, the management of severe brain injury in horses is anecdotally reputed to be intensive, expensive, and associated with a guarded to grave prognosis necessitating euthanasia [1,3,6].
This discussion will briefly review the unique anatomical aspects of the equine skull that relate to the types of injury observed in horses with head trauma, the pathophysiology of brain injury, and finally a more detailed discussion of current recommendations for management of TBI in humans that may be applicable to equine patients. The focus of this review is to discuss how we can manage and potentially improve the outcome of these challenging cases using more advanced monitoring tools and treatment options that are becoming more readily available and practical in equine practice and the prognostic indicators that may aid in the decision making process.
2. Type of Injury and Neurologic Signs
The type of brain injury resulting from head trauma in horses can be most simply described by the site of impact and is most commonly either poll injury or frontal injury.
Figure 1. Illustration of anatomical structures involved in poll injury and basilar bone fractures in horses. To view click on figure
Poll injury occurs when the horse rears up and flips over backward, which is not an unusual adverse reaction of young horses to restraint applied to the head such as during halter or trailer training, intravenous injection, cross-tying, etc. The biomechanics of this type of head trauma are well described and often result in the most severe brain injury in horses [2-5,10]. When the poll strikes the ground or other fixed object with force, the head and neck hyperextend, and the traction forces of the primary flexor muscles of the neck (rectus capitus ventralis) at their attachment to the basilar bones (basisphenoid, basioccipital) often result in avulsion fractures or separation of the bones at the suture site (Fig. 1). The characteristic clinical presentation of horses with poll injury is young age (≤12 mo), flipping over backward, and neurologic signs consistent with vestibular disease caused by brainstem injury (head tilt, nystagmus, depressed mentation, tetraparesis, ±facial nerve paralysis) and hemorrhage into the guttural pouches caused by disruption of important vessels in that area [3,6,11].
Frontal injury occurs as a result of blows to the dorsum of the head, such as when a horse runs head-on into a fixed object or is kicked. Impact and fracture involving the frontal or parietal bones can result in lacerations and contusions of the underlying cerebral cortex. Corresponding neurologic signs include contralateral cortical blindness (normal pupillary light response; PLR), depressed mentation, compulsive wandering, and generalized seizures.
Fracture of the petrous temporal bone often occurs as an acute, neurologic manifestation of chronic temporohyoid osteoarthropathy and subsequent ankylosis of the temporohyoid joint. Neurologic signs are most commonly associated with vestibular apparatus and cranial nerve VII damage. Hemorrhage or leakage of cerebral spinal fluid (CSF) from the external ear is supportive of fracture of the temporal bone.
3. Pathophysiology
The continuum of pathophysiologic events involved in neurologic dysfunction associated with acute traumatic brain injury can be conceptually divided into primary and secondary brain injury. Primary injury is the direct, mechanical injury to brain tissue occurring at the time of impact and the disruptive forces associated with local and diffuse neuronal depolarization. Primary neurologic injury is complete and non-reversible at the time of impact. Types of primary brain injury of increasing severity include the following: concussion, often manifest as a transient loss of consciousness after impact, but without structural damage to neuronal tissue; contusions, disruption of vascular and supporting structures without injury to cerebral architecture; lacerations, structural damage and loss of neuronal tissue architecture; edema; and intracranial hemorrhage. Because the brain comprises ≈80% of the space within the closed bony calvarium, which it shares with blood (10%) and CSF (10%), any increase in brain tissue volume caused by edema or hemorrhage rapidly overcomes compensatory decreases in blood flow and CSF and results in increased intracranial pressure (ICP) and the potential for lethal cerebral or cerebellar herniation [12].
Secondary brain injury encompasses the cascade of local, and then global, cellular and neurochemical alterations that occur in minutes to days after the initial injury and lead to progressive axonal degeneration and cell death. In contrast to primary injury, which the clinician has no or minimal control over, the deleterious effects of secondary injury may be attenuated with prompt and appropriate therapeutic intervention.
Secondary brain injury can be further discussed in terms of intracranial and extracranial factors. Intracranial factors include the biochemical events leading to neuronal tissue excitotoxicity and cell death. Normal brain function is dependent on a constant supply of glucose and oxygen through blood flow and is therefore particularly susceptible to ischemic injury. After brain injury, the tissue directly impacted by and adjacent to the site of impact have reduced blood flow caused by ischemia, vasogenic edema, and hemorrhage. Simultaneously, the metabolic rate of these poorly perfused areas is increased in an effort to re-establish normal cellular electrochemical gradients. Increased demand and reduced delivery of oxygen and glucose leads to rapid substrate (ATP) depletion and failure of ATP-dependent cell membrane pumps. Subsequent uncontrolled release and extracellular accumulation of the excitatory neurotransmitter glutamate, combined with unregulated influx of sodium and intracellular accumulation of calcium produces multiple cytotoxic effects, including activation of destructive enzyme systems, oxidative damage, cell swelling, and eventually cell death [12,13].
The other key concept in secondary injury is ICP dynamics. Cerebral perfusion pressure (CPP) is the primary determinant of blood flow, and hence, glucose and oxygen supply to the brain. Under normal circumstances, pressure autoregulation functions to maintain a constant blood flow to the brain through vascular reactivity, despite fluctuations in systemic mean arterial pressure (MAP). This important mechanism is functional within the MAP range of ≈50 - 150 mmHg according to the following equation:
CPP (mmHg) = MAP (mmHg) - ICP (mmHg)
In traumatic brain injury associated with increased ICP, there is loss of pressure autoregulation. As ICP increases, cerebral blood flow becomes linearly dependent on MAP alone. The additional mechanism of chemical autoregulation refers to the direct effect of the partial pressure of carbon dioxide in arterial blood (PaCO2) on global cerebral blood flow. Elevated PaCO2, as occurs with hypoventilation, results in vasodilation of cerebral vasculature, whereas decreased PaCO2 causes vasoconstriction.
The most important extracranial factors known to potentiate secondary brain injury are hypotension and hypoxemia. Both systemic states are significantly and independently correlated with a poor neurologic outcome in human patients with traumatic brain injury [13-15]. This finding emphasizes the importance of directing our diagnostic and therapeutic efforts toward the prompt recognition and aggressive treatment of hypoxemia and hypovolemia and/or hypotension in our equine patients. Additional systemic abnormalities that may contribute to secondary brain injury include hypo-and hyperglycemia, acidemia, and systemic inflammatory response syndrome (SIRS).
4. Diagnostics and Monitoring
The goal of management of traumatic brain injury is to minimize secondary injury; thus, it is essential that intracranial (elevated ICP) and extracranial (cardiovascular and respiratory) abnormalities are identified quickly. The presence of hypotension can be most practically determined with a thorough physical examination and assessment of perfusion parameters relating to both volume and hydration status. Many patients suffering traumatic brain injury will present in some degree of hypovolemic shock. A critical part of basic assessment is to evaluate carefully for ongoing causes of hypotension and hypoxemia. Initial diagnostic evaluation should include a minimum data base (complete blood count; CBC, biochemistry panel) and determination of systemic blood pressure and oxygenation with the use of blood lactate and arterial blood gas (pH, PaO2, PaCO2, HCO3-, SaO2), where SaO2 is the saturation of hemoglobin, which can also be readily determined by pulse oximetry (SpO2). Measurement of indirect MAP is an additional useful diagnostic tool if available. Values for MAP < 60 mmHg, PaO2 < 80 mmHg, and SaO2 < 96% confirm hypotension, hypoxemia, and reduced hemoglobin saturation, respectively, and indicate the need for immediate volume and oxygen support. Without the availability of these monitoring tools, the physical examination can be adequate for determining the need for blood volume and pressure support, less so for determining adequacy of oxygenation.
An initial complete, thorough neurologic examination with frequent re-evaluation is the most valuable diagnostic tool for detecting intracranial abnormalities in equine patients. In human brain-injured patients, monitoring ICP allows therapy to be goal-directed and titrated to definitive endpoints for CPP and ICP. The technical nature of monitoring ICP makes it currently impractical for use in horses outside of a clinical research setting; thus, the equine practitioner must rely on accurate neurologic assessment to indicate the need for specific therapy directed against elevations in ICP.
After evaluation and institution of support for systemic blood pressure and oxygenation, initial neurologic examination should focus on the horse’s level of consciousness; pupil size, symmetry, and pupillary light response; and respiratory pattern. Horses with elevated ICP and or brainstem injury (specifically midbrain) may have an abnormal breathing pattern of increased rate followed by periods of apnea, depressed mentation, pupil asymmetry, and loss of pupillary light response. Papillary edema and retinal detachment may also be evident on fundic examination. Care should be taken to interpret the initial neurologic examination in light of the cardiovascular and respiratory status, because level of consciousness will be depressed in hypovolemic patients. A more detailed neurologic examination and re-evaluation can be performed after systemic stabilization.
CSF analysis is unlikely to contribute useful information in head trauma patients and poses a risk in horses with impending cerebral herniation. CSF analysis can be important in horses with suspect bacterial meningitis secondary to open or petrous temporal bone fractures and in horses in which the cause of neurologic injury is uncertain.
Diagnostic imaging can be useful in determining the presence, type, and location of fractures, but is rarely a priority in the emergency setting. Skull radiography is not particularly sensitive for definitive diagnosis of fractures, particularly for basilar fractures in young horses in which the suture line (physis) between the basisphenoid/basioccipital bones is not fused, and fractures at this site are often non-displaced. Computed tomography (CT) is the imaging modality of choice for diagnosing bony fractures, acute hemorrhage, or edema. Although not routinely practical in equine head trauma patients, referral to a tertiary institution for CT of the head should be considered in cases with failure of significant clinical improvement in the first 3 - 5 days of treatment or deterioration of clinical signs at any time when prognosis for survival and particularly long-term athletic ability is important.
5. Management
Regardless of the cause of head trauma, initial diagnostic, and therapeutic management should be directed toward minimizing secondary brain injury. Because hypotension and hypoxemia are strongly correlated with increased mortality in humans, they should be addressed immediately. Blood pressure should be supported with IV fluids and supplemental oxygen provided through nasal insufflation until blood volume, pressure, and oxygen concentrations are known to be normalized and stable.
The following recommendations for equine brain-injured patients are based on available clinical evidence from human medicine and laboratory animal studies and are able to be instituted either by the equine practitioner as stabilization before referral and/or in referral practices or tertiary institutions.
Fluid Therapy
In contrast to previous beliefs, fluid therapy should never be restricted in head trauma patients. The goal should be to rapidly restore and maintain intravascular volume to optimize tissue perfusion and ultimately cerebral perfusion pressure. Human studies have not yet identified a single ideal type of fluid for treatment of head trauma patients [16,17]. However, there are some important guidelines applicable to equine patients. Isotonic crystalloid solutions, such as 0.9% sodium chloride, lactated Ringers, and Normasol-R are the current fluids of choice for rapid replacement and maintenance of blood volume [18]. Rates and volumes of fluid administered should be titrated to physical and laboratory parameters that indicate adequate intravascular volume and perfusion. Most cases will have some degree of hypovolemic shock, so initial fluid administration rates of 50 ml/kg/h (25-l bolus for 500-kg horse) may be needed. Intravascular volume may also be augmented with a combination of crystalloid and colloid solutions.
Synthetic colloids, such as hydroxyethyl starch, can be administered at maximal daily rates of 10 ml/kg. The benefits of colloid therapy include smaller volumes required for intravascular volume expansion and maintenance and longer duration of volume expansion. Potential adverse effects include cost, as well as dilutional coagulopathy and reduced platelet function that may exacerbate hemorrhage [19]. These risks are minimal to none at doses of hydroxyethyl starch <15 ml/kg/day or if plasma is the selected colloid.
Hypotonic crystalloid solutions, such as 5% dextrose in water (D5W) or 0.45% saline solutions, lower the plasma osmolarity and result in excess free water diffusion into the brain and cerebral edema formation. Hypotonic fluids should always be avoided for rapid volume replacement in patients with brain injury.
Hyperglycemia is believed to worsen neuronal injury and is associated with increased mortality and neurologic outcomes after TBI in humans [20]. Consequently, glucose supplementation during large volume fluid replacement should be avoided, unless the patient is hypoglycemic.
Hyperosmolar Therapy
If clinical evaluation of the equine patient with TBI suggests the patient has, or is at risk of developing, intracranial hypertension, osmotherapy is indicated. Such clinical signs might include obtunded mentation, progressive mydriasis, or any deterioration of neurologic status with treatment. Hyperosmolar solutions exert their effect on reducing ICP by creating an osmotic gradient across the blood-brain barrier (BBB) of at least 10 mOsm/l. Studies in humans suggest that the goal of increasing plasma osmolarity, without exceeding 320 mOsm/l, is probably a safe and effective approach [21]. It is advisable to measure plasma osmolarity in horses, at least before administration of hyperosmolar solutions, to avoid excessive increases in plasma osmotic pressure. Serum osmolality can be estimated by multiplying the horse’s sodium concentration by a factor of 2 [22].
The two most commonly used and available hyperosmolar solutions are mannitol (20%) and hypertonic (7.5%) saline. Both agents have been shown to be effective in lowering ICP in human TBI patients, and although there has been recent, renewed interest in hypertonic saline, studies comparing the effectiveness of the two agents have not yet shown a consistent benefit of one solution over the other [23-29].
Mannitol (20%)
The recommended dose is a 0.25 - 1.0 g/kg IV bolus administered over 20 - 30 min, every 6 - 8 h. Mannitol should only be administered after restoration of adequate intravascular volume. The ICP-reducing effects of hyperosmolar solutions are believed to be biphasic in nature. After bolus dose administration, there is an initial plasma expanding effect that reduces blood viscosity and hematocrit and improves rheologic properties of red blood cells. The osmotic diuretic effect is delayed but persists for longer. Mannitol should not be administered as a continuous infusion for the purpose of treating cerebral edema, because it loses its plasma-expanding effects and increases the likelihood of development of side effects [23,25].
The detrimental effects of mannitol are more likely to develop and become clinically significant with excessive or prolonged use (>1 - 2 days). Adverse effects include hypovolemia and hypotension caused by excessive diuresis, electrolyte disturbances (hyponatremia, hypochloremia, hypokalemia, hypocalcemia), acute renal failure, and a rebound increase in ICP associated with reversal of the osmotic gradient. There is insufficient evidence to support the dogma that mannitol is contraindicated in the presence of intracranial hemorrhage.
Hypertonic (7.5%) saline
Similar to mannitol, this effectively reduces ICP primarily through an immediate hemodynamic effect, followed by a delayed osmotic effect. Hypertonic saline may be the superior resuscitation fluid for traumatic brain injury because intravascular volume can be rapidly restored using small volumes (4 ml/kg or 2 l for a 500-kg horse). In addition, hypertonic saline is theoretically less likely to cross the BBB. Other additional benefits of hypertonic saline on the injured brain include Na-related stabilization of cell membrane gradients, anti-inflammatory properties, and reduced excitotoxicity and vasospasm [26-28]. Unlike mannitol, hypertonic saline can be used to augment intravascular volume and can be effective early in treatment before euvolemia has been attained by provision of isotonic crystalloid solutions.
Oxygen Therapy
If available, oxygen therapy should be provided through nasal insufflation at initial rates up to 15 l/min to maintain SpO2 > 96% or PaO2> 80 mmHg. If pulse oximetry or arterial blood gas cannot be monitored, oxygen supplementation should be provided if possible to avoid the effects of hypoxemia on potentiating secondary brain injury.
Anti-Inflammatory Therapy
The administration of non-steroidal anti-inflammatory drugs (NSAIDS) is indicated to reduce inflammation and provide analgesia in horses with head trauma.
High-dose glucocorticoid administration, once standard therapy in head trauma patients, is no longer recommended in human medicine. The evidence against the use of corticosteroids stems from large clinical trials in human patients that have not only failed to show a beneficial effect in traumatic brain injury but also found increased risk of mortality in patients administered traditional high-dose methylprednisolone therapy [30,31]. Proposed detrimental effects of corticosteroids relate mostly to hyperglycemia, but also immunosuppression, delayed wound healing, and increased catabolism. Hyperglycemia perpetuates secondary brain injury by providing additional substrate for anaerobic metabolism that leads to intracellular acidosis in environments of reduced oxygen delivery within the injured brain. Given the available data from human medicine, the use of corticosteroids in horses with head trauma should be judicious until further studied.
Antioxidant Therapy
Dimethyl sulfoxide (DMSO) is regarded as fairly standard therapy for neurologic disease in horses. Its reported free-radical scavenging and anti-inflammatory effects could be beneficial. There is some limited evidence in laboratory studies that it may reduce ICP in head injuries [32]. However, consistent evidence for the efficacy of DMSO is lacking, and the disadvantages should be considered when administering in equine patients; it is a hyperosmolar solution that may lead to diuresis and dehydration and can cause hemolysis at high concentrations. Vitamin E is an antioxidant that can be routinely administered to horses at a dose of 6000 IU orally once a day without detrimental effects.
Seizure Management
Prompt and effective anticonvulsant therapy with a benzodiazepine (diazepam or midazolam) or barbiturate (phenobarbital) is critical in the face of seizure activity. Barbiturates effectively reduce cerebral metabolic rate and thus reduce cerebral oxygen and ATP demands. Drugs that increase cerebral metabolic rate, such as ketamine, should be avoided.
If specific antiseizure drugs are not available, short-acting sedatives such as the alpha 2 adrenergic agent xylazine can facilitate initial handling and stabilization of the patient. Alpha 2 adrenergic agents have profound cardiorespiratory depressant effects and will contribute to hypotension and hypoxia and should be used judiciously.
Adjunctive Therapies
Thiamine (vitamin B1) plays a very important role in glucose metabolism and energy production, where it functions as a required co-factor for certain enzymes involved in glycolysis, the citric acid cycle, and the pentose phosphate pathway. Thiamine is also important in nerve and muscle function, where it plays a role in neurotransmission and excitation. Given the increased susceptibility of damaged neuronal tissue to inadequate energy production and supply, the practice of thiamine supplementation at a dose of 1 - 5 mg/kg IV in neurologic injury in horses appears justified.
Hypothermia to a moderate reduction in body temperature (32 - 33°C) reduces cerebral metabolic rate, suppresses inflammation and free-radical production, reduces ICP through vasoconstriction, and decreases glutamate release. Although impractical to induce hypothermia in the adult horse with brain injury, it may be reasonable to avoid active warming in hypothermic patients and to aggressively cool hyperthermic patients by way of alcohol baths and fans placed in the stall [2].
The effect of head position on ICP has some implications in equine patients. For the standing horse, the head should not be allowed to drop below the level of the shoulder, which should be taken into consideration when the horse is sedated. For the recumbent horse, slight head elevation of 10 - 30° will assist in lowering ICP. It is also important to avoid obstruction to jugular venous outflow, such as tight catheter wraps, thrombophlebitis, or a sharp head-neck angle with head elevation.
6. Prognosis
Horses with traumatic head and brain injury typically present in hypovolemic shock that may worsen the initial clinical assessment. The equine clinician is encouraged to re-evaluate physical and neurologic status after reasonable efforts at aggressive restoration of intravascular volume and oxygen deficits. Some patients with acute head trauma will have complete resolution of clinical signs over a period of days to weeks, and others with more severe injury may have residual neurologic deficits that may take months to resolve or may never fully resolve.
A recent retrospective study of 34 horses with traumatic brain injury at a tertiary institution found a 62% survival rate (survival to discharge). Factors found to be associated with a poor prognosis for survival included the presence of basilar, or skull base, fractures (odds ratio: 18) and recumbency beyond initial presentation (>4 h).
Survival rate in this study was higher than other previously reported studies in horses and widespread anecdotal belief, perhaps a reflection of the significant advances made in the equine veterinary profession through all levels from the general equine practitioner to critical care specialists and tertiary care.
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