The leading cause of SE in humans is inappropriate low concentrations, with noncompliance with prescribed medications among the most common reasons. Accordingly, the application of the principles of pharmacology to anticonvulsant therapy should facilitate effective control and the avoidance of SE. A number of proepileptic drugs are also cited as causes for SE (discussed later).223
Early therapeutic intervention is more important than drug choice; in humans intervention within the first 30 minutes was associated with an 80% response to first-choice drugs, whereas 60% of patients in SE for more than 2 hours did not respond to first-line therapy. Physiologic responses of concern include fever, cardiac arrhythmias, changes in systemic (initially hypertension and later hypotension) and pulmonary blood pressures, and altered blood chemistries.223
In humans223 the traditional definition of SE as continuous or repetitive seizures lasting 20 minutes or more has been challenged; therapy for SE is recommended for two or more generalized convulsions without full recovery of consciousness between seizures, or continuous convulsive activity lasting more than 10 minutes. However, recommendations have been reduced to 5 minutes because few seizures last this long.
Benzodiazepines tend to be more effective early but not later, whereas NMDA receptor antagonists (e.g., ketamine) tend to be effective later but not early. In humans, drugs of choice vary with the duration of SE. The suggested approach is 6 to 10 minutes: intravenous lorazepam, followed by diazepam or midazolam (intranasally, or intramuscularly); 10 to 20 minutes: fospheyntoin for 10 to 60 min followed by midazolam by CRI or phenobarbital IV if no response,propofol by CRI or valproate if no response, and finally, the addition or alternative of pentobarbital or midazolam if no response. For seizures greater than 60 minutes in duration, pentobarbital is indicated. Despite ketamine’s potential efficacy as an anticonvulsant drug, antagonism of NMDA may result in severe neurotoxicity, and its use in SE should be reserved until scientific data support its efficacy.
In dogs or cats, treatment for more than one seizure per hour is a medical emergency.49 The use of drugs for acute management of seizures is addressed in detail with individual drugs. In general, however, acute therapy of seizures (e.g., SE) is preferentially implemented with diazepam (intravenous bolus to effect). Diazepam has a short half-life, and it may be necessary to repeat the dose once or twice during the first 2 hours to stabilize the dog.49 To terminate the seizures, various methods of administration have been recommended. Diazepam is recommended in an intravenous dose of 5 to 20 mg. Frey and Löscher42 recommended an intravenous dose of 0.5 to 1 mg/kg. Control by diazepam can be prolonged by continued administration as a CRI (2 to 5 mg/hr of 5% dextrose; the infusion line should first be flushed with the diazepam solution to allow diazepam binding to the polyvinyl), or co-administration of phenobarbital (2 to 6 mg/kg intramuscularly to avoid respiratory or cardiac depression). Clonazepam (0.05 to 0.2 mg/kg intravenously) may provide antiepileptic efficacy that lasts longer (but is not necessarily any more efficacious) than that of diazepam. Unfortunately, an intravenous preparation is not available in the United States.Alternatively, phenobarbital can be administered as the first choice (intravenous bolus to effect, as a loading dose). Note that for each 3 mg/kg of phenobarbital given intravenously, serum concentration increases approximately 5 μg/mL. For a patient not receiving phenobarbital at the time that therapy is begun, up to 18-mg/kg total dose (given in 3- to 6-mg/kg increments at 15- to 30-minute intervals) may be necessary to achieve the midtherapeutic range (30 μg/mL). Drug distribution of phenobarbital into the CNS may take 15 to 30 minutes. Failure to control seizures may indicate the need for pentobarbital.As such, the risk of cardiovascular or respiratory depression is great. An advantage to the use of pentobarbital, however, is its protective effects on the brain during periods of hypoxia induced by the seizure.
KEY POINT 27-28
Although diazepam is very effective, its short duration of action may require alternative drugs or methods of administration.
Alternative routes of anticonvulsant therapy might be considered for clients attempting to control life-threatening seizures without immediate access to veterinary medical assistance. Phenobarbital (5 mg/kg), diazepam, and bromide are partially to completely bioavailable after rectal administration.94,95 The risk of potassium overload can be minimized by administration of the loading dose over a 12- to 24-hour period in 5- to 15-mL increments.
A small number (20) of human patients with refractory epilepsy were treated with either propofol (14) or midazolam (6) in a retrospective study. For each drug seizures were eradicated in about 65% of patients. However, overall mortality, although not statistically significant, was higher with propofol (57%) compared with midazolam (17%).224
General gas anesthesia generally is not recommended in the patient with SE because of the risk of hepatotoxicity induced by the anesthetic that may occur with prolonged therapy. If the clinician decides that general gas anesthesia is necessary, anesthetics that are minimally hepatotoxic are preferable. Discontinuation of therapy should be undertaken cautiously to minimize the risk of seizures. Propofol and etomidate are two chemical restraining agents that, are characterized by anticonvulsant effects, although these drugs are expensive. Of the two, etomidate (a human drug only) may be characterized by CNS-protective effects. These drugs can be administered as intravenous infusions to effect (see later discussion regarding brain trauma).
Diazepam can be used in the cat to control acute epileptic disorders regardless of etiology Generally, an intravenous dose (5 to 10 mg) is given to effect. A dose as high as 20 mg may be necessary; if high dosages are used, they must be injected slowly. The procedure commonly followed is to administer 2 to 10 mg intravenously and then wait 10 minutes. If seizures persist, phenobarbital sodium can be administered (5 to 60 mg). Caution must be taken not to oversedate or depress the animal when these drugs are administered in close succession. Should the animal manifest refractoriness to diazepam and phenobarbital, as in SE, pentobarbital anesthesia is then carefully administered to effect.
SE may require management of cerebral edema (see later discussion of brain trauma and injury).
Use of selected antiepileptic drugs to control seizures has been discussed with regard to individual drugs. What constitutes successful anticonvulsant therapy will vary among clinicians and may be defined by client satisfaction. Eradication of seizures may be an unachievable goal; decreased frequency, severity, or duration of the seizure episode may be considered a success for many animals. Indeed, close counseling of clients and reorientation to what constitutes successful control may be important techniques to successfully treating an epileptic dog. Chronic control of epilepsy is likely to be a balancing act for many patients: controlling seizures without putting the patient’s health at excessive risk. Because patients are likely to need drug therapy for the rest of their lives, establishing a minimum effective dose for any anticonvulsant drug is prudent. Monitoring is important to prevent toxic concentrations, or to confirm ineffectiveness at high concentrations, even for newer, safer drugs. Monitoring should be used to determine the minimum effective dose for each patient. In the case of breakthrough seizures, monitoring can help the clinician determine whether the seizures reflect a decrease in drug concentrations (which should lead the clinician to confirm owner compliance, addressing potential drug or diet interactions, and so forth) or a change in the underlying pathophysiology (leading to further diagnostics and potential treatment).
KEY POINT 27-29
Ideally, long-term control of therapy should begin with a single drug, with combination therapy initiated only after the first drug fails. Failure should be assumed only as drug concentrations approach the maximum end of the therapeutic range.
If manipulation of a dosing regimen is the focus of successful control, a chosen therapeutic regimen should not be abandoned until steady-state plasma drug concentrations have been reached. Thus an animal should not be considered refractory to a drug simply because it is receiving more than the recommended dose or its serum concentrations are within the therapeutic range. A drug should not be abandoned until serum concentrations in the maximum therapeutic range (and, in some circumstances, exceeding it if the drug is sufficiently safe) have been documented or unacceptable adverse side effects occur. Regardless of the anticonvulsant used, therapy should never be stopped suddenly, and drug concentrations should not be allowed to drop precipitously during a dosing interval. SE may occur. Cautious exceptions might be made for drugs with a very long half-life (e.g., bromide) that naturally gradually decline (as long as chloride content in the animal has not increased).
The thyroid and liver status of patients should be determined before initiation of therapy. Anticonvulsant-induced liver disease should be distinguished from hepatic induction for several anticonvulsant drugs; unnecessary discontinuation of a drug that is controlling seizures might thus be avoided. Moderate elevations in the serum transaminases and SAP activity and abnormalities (more than 50 mmol/L) in fasting bile acids and serum albumin are indicative of hepatic pathology. The incidence of serious liver toxicity can be reduced by avoiding combination therapy with more than one drug metabolized by the liver; using therapeutic drug monitoring225 (see Chapter 5) to achieve adequate serum concentrations at the smallest dose possible; and evaluating hepatic function every 6 months or more, depending on the magnitude of phenobarbital serum concentrations. The higher the plasma drug concentration, the more important hepatic monitoring becomes. Seizure-induced hypoxia can result in liver damage; thus evaluation of the liver should not occur in association with a seizure episode. Hepatotoxicity induced by anticonvulsants is often reversible if the drug dose is sufficiently decreased before cirrhotic changes occur.
Phenobarbital has remained the first-choice anticonvulsant for chronic control of seizures in both dogs and cats because of its efficacy and, as long as drug concentrations do not approach the maximum therapeutic concentration, safety. However, increasingly evidence is emerging that other anticonvulsants may be effective. Therapeutic drug monitoring should be used to ensure that adequate serum drug concentrations have been achieved before the patient is considered refractory. As concentrations of phenobarbital approach the maximum end of the therapeutic range, an alternative regimen should be considered. The addition of a second anticonvulsant is the most likely next step.
Use of combination therapy appears to be popular in veterinary medicine, on the basis of therapeutic drug monitoring information in the author’s laboratory. Although combination therapy is a reasonable approach for control of seizures in patients that fail to reasonably respond to first-choice anticonvulsants (e.g., plasma drug concentrations approach or enter the high end of the therapeutic range, or unacceptable side effects emerge), many of these patients are on two or more drugs, each of which is in the subtherapeutic to low-therapeutic range. The American Epilepsy Society notes that most human patients can be controlled with single-drug therapy and that higher concentrations of a single drug are preferred to lower concentrations of multiple drugs. Single-drug therapy should be considered prudent for several reasons. The most obvious is avoidance of side effects (the combined side effects of a drug might, like efficacy, be worse than either drug by itself), fewer drug interactions, better owner compliance, and reduced cost (because multiple drugs require more than one prescription and additional monitoring). Other reasons to limit combination therapy to patients with proven need are likely to be less obvious. However, no drug therapy is likely to be innocuous. Drugs that affect the CNS may be problematic because of the sophisticated mechanisms that exist to minimize the effects of CNS drugs. These include efflux proteins, receptor downregulation, and desensitization. In the author’s opinion, because the CNS does not want drugs in the CNS, an attempt should be made to respect the body’s attempt to limit exposure of the brain to drugs. Accordingly, the author recommends that single-drug therapy be targeted and combination therapy be instituted only in patients that have failed initial therapy.
Bromide increasingly is recommended as a first-choice antiepileptic drug. Although Boothe and Dewey28 demonstrated that it is not as efficacious as phenobarbital for control of seizures in dogs, its lack of drug interactions and improved safety compared with phenobarbital warrant consideration as first choice, particularly in older dogs for which the risk of drug interactions and liver disease might be decreased.
Bromide also has been recommended as the first combination drug of choice for dogs should phenobarbital therapy fail. However, as newer predominantly renally excreted drugs become available in generic preparations, their use should be considered so as to avoid the gastrointestinal side effects of bromide. Bromide increasingly is being used as the sole anticonvulsant, although a severe seizure history may warrant using a more accepted and predictable first-choice drug (e.g., phenobarbital).
Controlling refractory seizures with any anticonvulsant drug might be facilitated using a stair-step approach. Using bromide as an example, increase concentrations in 0.5-mg/mL increments. If the patient develops seizures at one concentration, the concentration is increased to the next level. This is continued until the patient is acceptably controlled or sedation becomes untenable. In the latter case, decreasing phenobarbital concentrations by 25% may help resolve grogginess. If the goal of bromide therapy is to wean the patient off an anticonvulsant (using phenobarbital as an example), concentrations should be confirmed before implementing a stair-step decrease. For example, bromide concentrations ideally are at least 1.5 mg/mL before phenobarbital is decreased by 25%. Every time the dose of an anticonvulsant is changed, at least 3 drug half-lives, plus one seizure interval (to assure the patient is challenged by a seizure at the new concentration), must lapse before the impact of the dose change can be fully assessed. For phenobarbital, at least 2 to 4 weeks should lapse before a second decrease is implemented. Ideally, the anticonvulsant is monitored at each decrease in dosage so that a target has been identified, should seizures return. Deciding what concentration to target with the second anticonvulsant can be difficult. If the goal is to simply add a second anticonvulsant, targeting in the lower therapeutic range of the new drug is reasonable. If the goal is to reduce the first anticonvulsant, the target of the second drug might be a little higher. If the goal is to eradicate the original anticonvulsant, at the very least, the second drug concentration should be at the same level of the therapeutic range (if not higher) than the first. For example, if a patient’s phenobarbital dose is 25 μg/mL (midtherapeutic range), bromide should be at least 2 mg/mL before a decrease is considered. Some animals will require higher concentrations: for example, for bromide, higher than 2.5 mg/mL before phenobarbital can be lowered to less than 20 μg/mL (the standard goal). It may not be possible to decrease the first anticonvulsant in some patients, despite the addition of a second drug at concentrations that are in the high therapeutic range. On the other hand, some patients can be completely weaned off the first anticonvulsant (e.g., phenobarbital).
Diazepam has been the second drug of choice for chronic control of seizures in cats. However, its use may be limited by the concern for hepatic disease. In the author’s monitoring laboratory, either zonisamide or levetiracetam appear to be well tolerated and effective, with gabapentin a third viable alternative.
Whether anticonvulsant therapy facilitates remission of spontaneous seizures is not clear, although a tendency for contemporary anticonvulsant therapy to be associated with epileptic cure has been described in humans.226 In human medicine, antiepileptic drugs can be withdrawn in 60% of patients that remain seizure free for 2 to 4 years. A similar statistic is not available in veterinary medicine. The likelihood of success can be somewhat correlated with the underlying cause or type of seizure, with the best chance occurring in the nonjuvenile patient with idiopathic generalized epilepsy. Such patients should have a normal neurologic exam, and the absence of a structural brain lesions. The author recommends that therapy might be discontinued in those patients whose drug concentrations are substantially below the recommended therapeutic range. Should the decision be made to discontinue therapy, concentrations might first be monitored (to provide a target to which concentrations can be returned if the patient has a seizure) and then the antiepileptic drug be slowly discontinued over several months (e.g., 25% each month). Note that with each decrease, the response should be assessed after the drug has reached steady state plus one seizure interval (i.e., ensure, to the extent possible, that the patient is challenged by a seizure before the next decrease is implemented).
Melatonin is described as having demonstrated anticonvulsant activity in many animal models.225 A study in gerbils demonstrated greater survival in animals treated with melatonin (25 μg subcutaneously daily). Anticonvulsant activity of melatonin may reflect antioxidant activity and subsequent free radical scavenging.228 In an open, uncontrolled study in epileptic children refractory to standard therapy, melatonin (3 mg at bedtime), seizure activity decreased and sleep improved in five of six patients.228
Deprenyl was associated with reduction in experimentally induced seizures in a rat kindling seizure model after multiple intraperitoneal dosing.229 L-Deprenyl (and to a lesser degree, D-deprenyl) was effective in controlling electroshock-induced seizures in mice when administered at 1 to 40 mg/kg intraperitoneally, with the highest reduction (44%) occurring at the highest dose. Although less potent, D-deprenyl also reduced seizures but was toxic at doses higher than 10 mg/kg. Pentylenetetrazol nduced clonic and myoclonic, but not tonic, seizures. Seizures also were decreased by L-deprenyl at 5 mg/kg intraperitoneally (but not subcutaneously); 10 mg/kg did not provide further control. The spectrum of anticonvulsant activity was described as comparable to that of phenobarbital (and levetiracetam), including breadth of seizure type controlled. A proposed mechanism is inhibition of norepinephrine and dopamine metabolism. Other proposed mechanisms include modulation of NMDA receptor activity and stimulation of melatonin synthesis in the pineal gland. In his review, Löscher229 notes that tricyclic antidepressants provide some anticonvulsant effects through inhibition of norepinephrine uptake.
The role of phenothiazines, and acepromazine in particular, in epileptic dogs is controversial. Although phenothiazines are connected with seizures in humans,230 the contraindication for phenothiazines, and specifically acepromazine, in epileptic animals is less clear. The author has personally induced seizures in a dog suffering from lead poisoning that developed acute respiratory distress syndrome. Treatment with acepromazine was immediately followed by severe seizures. However, Tobias and coworkers231 retrospectively studied the use of acepromazine in epileptic dogs (n = 47; 15 with idiopathic epilepsy) with seizures that received acepromazine for diagnostic testing, anesthetic premedication, to facilitate postoperative recovery, or to decrease excitatory behavior; acepromazine was given with the intent of reducing seizures in 11 of the dogs. Acepromazine also was administered to 11 of the 47 dogs in order to decrease seizure activity, with either seizures stopping for 1.5 to 8 hours (n = 8) or not recurring (n = 2). Chlorpromazine has been used (2 to 4 mg/kg orally every 8 to 12 hours) to treat SE, with 9 of 10 dogs responding (as reviewed by Tobias and coworkers).231 McConnell and coworkers232 also retrospectively studied the medical records of 31 dogs experiencing no seizures (n = 3) or a history of acute or chronic seizures, including SE (n = 3) or cluster seizures (n = 22). Fifteen of 22 dogs with a history of seizures were receiving AED medication. Dogs were treated with a median of 2 but up to 5 doses of acepromazine during hospitalization; the intravenous dose ranged from 0.008 to 0.057 mg/kg. Seizures (n = 23) occurred in 11 of 31 dogs during hospitalization; 15 before and 8 (n = 4 dogs) after treatment with acepromazine. The dose of acepromazine in dogs that experienced seizures after administration ranged from 0.019 to 0.036 mg/kg, with seizures occurring at 18 minutes to 10 hours after administration. It is the author’s opinion that these retrospective studies support the potential use of acepromazine in epileptic dogs as adjuvant therapy—and potentially as anticonvulsant therapy, but only after well-designed placebo or other controlled randomized clinical trials in epileptic patients have determined the impact in epileptic dogs or cats.
A number of medications are associated with decreased seizure threshold and an increased risk of SE in humans (Table 27-6). Several anticonvulsant drugs may be proepileptic at suprapharmacologic doses (e.g., phenytoin).223 The impact of phenothiazines was discussed with alternative drugs. Drugs inducing seizures in selected patients include fluorinated quinolones, lidocaine, and possibly metoclopramide. Seizures induced by lidocaine should be treated with a benzodiazepine (e.g., diazepam).233 Morphine sulfate and related compounds as well as CNS stimulants such as the methylxanthines and behavior-modifying drugs should be avoided. Chloramphenicol also activates the CNS and should not be used in dogs known to have epileptiform seizures. Glucocorticoids may also decrease seizure threshold, although they stabilize neuronal membranes. Long-term effects on the neuronal membrane, however, may reflect downregulation of glucocorticoid receptors and thus loss of the stabilizing effect. Long-term use of glucocorticoids might be minimized for epileptic patients. Behavior-modifying drugs are CNS stimulants and, accordingly, might be associated with an increased risk of seizures. Cocaine acts on monoamine transporters to block the reuptake of dopamine, norepinephrine and serotonin from synapses following their release. Activity at dopamine, adrenergic and serotonin receptors will increase, although the major effects of cocaine are thought to be reflect actions on dopaminergic systems. Cocaine will also increase motor activity by increasing dopamine in the striatum, and at high doses can cause psychosis. Finally, cocaine also acts as a sympathomimetic, increasing activity of the sympathetic nervous system, due to its action on norepinephrine transport.
Table 27-6 Potentially Proconvulsant Drugs10,223
| Drug Class | Drug |
|---|---|
| Analgesics | fentanyl |
| meperidine | |
| tramadol | |
| Antiarrhythmics | digoxin |
| lidocaine | |
| mexiletine | |
| Antibiotics | cefazolin |
| imipenem | |
| fluoroquinolones | |
| metronidazole | |
| Anticonvulsants at Supraphysiologic Doses | |
| Immunomodulators | chlorambucil |
| cyclosporine | |
| interferons | |
| tacrolimus | |
| Tranquilizers | butyrophenones |
| phenothiazines (see text) | |
| Others | baclofen |
| reserpine | |
| theophylline | |
| Behavior-modifying drugs | amitriptyline |
| clomipramine | |
| nortriptyline | |
| imipramine | |
| doxepin | |
| bupropion | |
Drugs associated with seizures in nonhuman animal models have included but are not limited to the tricyclic antidepressants, bupropion, and doxepin. However, increased concentration of serotonin or norepinephrine by transport inhibitors are likely to be associated with anticonvulsant rather than proconvulsant effects in epileptic patients, despite the fact that overdose may be associated with seizures.10 Finally, drugs for which CNS derangements or seizures are a listed side effect generally should be avoided in epileptic animals.
After head trauma, secondary injury occurs in both contused and adjacent tissues.234 A cascade of events begins with massive depolarization and ion fluxes that initiate increased energy expenditure by the sodium/potassium adenosine triphosphatase (ATPase) pump, the main regulator of cell volume and electrochemical gradient. Systemic hypotension and disrupted cerebral blood flow exacerbate ATP depletion. Brain tissue is extremely sensitive to decreased oxygenation. Glutamate, an excitatory neurotransmitter that allows calcium influx into the neuron, appears to play an important role in the early stages of secondary brain injury caused by head trauma. Normal intracellular concentrations are approximately 1500-fold greater than extracellular concentrations. Well-developed energy-requiring mechanisms exist to maintain very low extracellular glutamate concentrations; this system becomes overwhelmed as a result of the combined effects of efflux of intracellular glutamate and decreased energy. As a result, calcium influx causes uncontrolled release of intracellular calcium and subsequent cytotoxic events, including uncoupling of oxidative phosphorylation necessary for ATP. Enzyme systems activated included protein kinase C, the phospholipases (and thus arachidonic acid cascades and platelet-activating factor), and nitric oxide synthase. Oxygen radicals are released, leading to irreversible cell injury and death.234
Blood flow to the CNS is well autoregulated through a combination of metabolic, vascular pressure, and oxygen-related mechanisms. Cerebral vasculature and intracranial pressure (ICP) must, however, be functioning normally. Metabolic demands of the brain appear to affect regional blood flow through the effects of pH and adenosine on vascular tone. Increased metabolic activity decreases vascular tone, causing vasodilation. Arterial Pco2 has global control of the brain such that increases result in increased cerebral blood flow (and increased ICP), whereas decreases cause decreased cerebral flow. The potential exists for these reflex responses to exceed (in the case of increase) or to be insufficient (in the case of decrease) for the metabolic needs. Response to Pco2 is regional, complicating the use of hyperventilation as a treatment for increased ICP.234 Local nitric oxide synthesis plays a role in regional blood flow and can contribute to secondary brain injury.
The cerebral ischemic response is global and depends on an intact vasomotor center. It occurs relatively late in response to poor perfusion. Increased ICP decreases cerebral perfusion. Increased Pco2 causes the vasomotor center to increase heart rate and intense systemic vasoconstriction in an attempt to support cerebral blood flow. Clinically, the increase in systemic blood pressure may cause a decrease in heart rate, an indicator that increased ICP is limiting cerebral blood flow. The lack of the ischemic response does not, however, indicate that ICP increase is not severe; rather, it may reflect vasomotor damage.
Primary brain injury occurs as a result of direct brain trauma.234-236 Secondary brain injury reflects damage to the brain as a result of increased metabolic demands, inadequate cerebral blood flow, or both. Epilepsy causes the former by increasing metabolic demands (oxygen and glucose). Hyperthermia increases ICP (several millimeters of increase for each degree of increase in body temperature) by increasing metabolic demands. Head trauma tends to cause the latter by increasing ICP. Systemic hypotension also can cause secondary brain injury. Because the patient with severe head injury is less tolerant of derangements in metabolism, both hyperglycemia and hypoglycemia can contribute to secondary damage. Hypoglycemia contributes to decreased ATP production, whereas hyperglycemia can lead to anaerobic glycolysis and cellular acidosis in cells with impaired mitochondrial function.
Cerebral edema can be categorized into a number of forms, each of which can occur after head trauma.237 Vasogenic edema reflects increased permeability of the blood–brain barrier and may be exemplified by focal cerebral contusion and hemorrhage. Water, sodium, and protein increase in the interstitial space. In addition to trauma, causes of vasogenic edema include loss of the tight endothelial junctions (as might occur during infusion of hyperosmotic solutions), tumors, hyperthermia, and epileptic seizures. Mediators associated with vasogenic edema include bradykinin, serotonin, histamine, and the eicosanoids (especially leukotrienes), as well as free oxygen radicals. Drugs that increase cerebral blood flow will increase the rate of cerebral edema. White matter has more compliance, and most of the edema accumulates there.
Cytotoxic edema occurs intracellularly when membrane sodium/potassium ATPase pump mechanisms fail because of a lack of energy. Energy loss can reflect decreased cerebral blood flow (i.e., ischemia). Potassium accumulation occurs in the extracellular space. Calcium influx initiates a cascade of events that are lethal to astrocytes. The remaining types of edema might be considered a variation of either vasogenic or cytotoxic edema. Hydrostatic edema reflects accumulation of protein-free fluid in the interstitial tissues. Hydrostatic edema probably results from an abrupt increase in the hydrostatic pressure gradient between the intravascular and extravascular spaces. Osmotic brain edema occurs as serum osmolality (generally caused by hyponatremia) declines below a critical threshold. The use of 5% dextrose can contribute to osmotic brain edema. Interstitial edema is exemplified by high-pressure hydrocephalus associated with increased hydrostatic pressure in the ventricular CSF. Water infiltrates into the periventricular tissues. This type of edema occurs rarely after CNS trauma.
At the cellular level, traumatic brain injury is associated with loss of the axonal cytoskeleton and subsequent irreversible of axonal division with 12 hours. This damage is associated with very high concentrations of glutamate.238 Traumatic depolarization, characterized by a massive influx of ions at the moment of injury, may reflect excitatory neurotransmitters and is among the most important mechanisms of cellular injury leading to cerebral edema and increased ICP. Cerebral edema and axonal swelling are sequelae; these may respond to interventions intended to block oxidative or nitrosative stresses.238 The blood–brain barrier also is disrupted with severe injuries, perhaps in response to vascular endothelial growth factor and subsequent release of nitric oxide. Secondary neuronal damages reflect the neuroinflammatory response, resulting in production of reactive oxygen species and inflammatory cytokines. Cyclophilin (targeted by cyclosporine) appears to be among the mediators contributing to postinjury inflammation.238
Treatment of traumatic brain injury focuses on control of brain edema and ICP. This includes reversal of the underlying cause, medical management, and surgical decompression.
The control of increased ICP is paramount in the treatment of head trauma. In humans approximately 40% of those losing consciousness after a traumatic episode will develop intracranial hypertension, and mortality will parallel increases in ICP. Indeed, ICP is a strong predictor of outcome, and monitoring ICP in human medicine has become a safe and effective tool for monitoring both the need for and efficacy of treatment.
Early and aggressive treatment has been shown to improve outcome.235,236 The pressure at which ICP is maintained is not clear, but humans maintained at 15 mm Hg (normal being 20 mm Hg) had an improved outcome compared with those managed at 25 mm Hg. This may reflect the fact that herniation after lesions in some areas can occur despite ICP being normal (20 mm Hg). Recommendations in human medicine are to treat ICP when increased above 20 mm Hg for more than 15 minutes. Hypotension (systolic blood pressure <90 mm Hg) and hypoxia (Pao2 <60 mm Hg) also commonly occur in patients with head trauma and can contribute to increased ICP. Of the two, however, hypotension is more devastating and is predictive of a poorer outcome of severe head injury. Thus hypotension should be prevented and immediately treated when present.
Surgical removal of brain volume is the easiest method (in humans) of lowering ICP. Removal of CSF is another method.239 Medical management is facilitated by discriminating the cause of ICP. Omeprazole may be useful for long-term management of increased CSF production. Although the mechanism is not clear, in an experimental rabbit model, 0.2 mg/kg reduced production by 35%.239a
Because little information is known regarding the direct treatment of damaged neuronal tissue, treatment focuses on maintaining as normal an environment as possible to support neuronal regeneration. Supportive management focuses on maintaining normal physiologic homeostasis. Blood pressure, arterial oxygenation (pulse oximetry and arterial blood gases), body temperature, and fluid and electrolyte balance should be maintained. Electrocardiographic monitoring also is indicated. Hypotension in particular must be avoided in the patient with increased ICP; the hyperdynamic state (physiologic responses compensating for hypovolemia) will complicate control of ICP. Hyperglycemia can increase metabolism and should be avoided and aggressively managed in the patient with head trauma. Fluids containing dextrose should be avoided in such patients.
Elevation of the head 30 degrees above heart level appears to be beneficial in decreasing ICP.235,236,240 Hypercapnia must be avoided in patients with head trauma; this includes hypercapnia that may be iatrogenically induced during procedures intended to support the respiratory system. Hyperventilation to maintain a Paco2 of 27 to 30 mm Hg can decrease cerebral blood flow and help lower ICP. It is, however, dependent on intact autoregulation. Hyperventilation can decrease the metabolic activities of the brain and induce or potentiate cerebral ischemia. Its effectiveness in diminishing cerebral blood volume decreases with time (at 72 to 96 hours), and a rebound effect with restoration to normocapnia may potentially increase ICP.
Hypocarbia is easy to induce. Its use in the management of increased ICP might be reserved for the initial stages. Later use should be accompanied by strict monitoring of ICP, especially as hyperventilation is discontinued. Profound hyperventilation should be avoided. Hypothermia currently is being investigated for use in the prevention of CNS ischemia associated with severe head injuries.239 It has been used experimentally in dogs. Mild degrees of hypothermia (between 31° and 35°C) are recommended to prevent cardiovascular instability.240
Osmotic diuretics are commonly used to treat intracranial hypertension.235,236,239,241 Both mannitol and urea have been used, although mannitol has largely replaced urea. Mannitol is a 6-carbon sugar, similar in structure to glucose, but it is not able to cross the normal blood–brain barrier.239 Thus it remains in the extracellular and intravascular spaces of the brain, where it will cause an osmotic draw toward the extravascular tissues, and intracranial fluid will move into the vascular space. The effect of mannitol on increased ICP are severalfold. Reversal of the blood–brain osmotic gradient decreases extracellular fluid volume in both the normal and damaged brain. This effect is delayed for 15 to 30 minutes but can continue for up to 6 hours. Blood viscosity is lowered, causing reflex vasoconstriction and lowered ICP. This effect, however, requires that mannitol be administered as a bolus, not slowly.235,236,239
Doses of 0.25 mg/kg appear to be as effective as larger doses (1 mg/kg) in lowering ICP. Repeated administration of mannitol can induce hyperosmolar states, rendering it ineffective and subjecting the patient to the risk of renal failure. Additionally, continuous administration of mannitol can lead to increased penetration of the blood–brain barrier in the injured brain, resulting in a rebound ICP increase. For these reasons, serum osmolality should not be allowed to increase above 320 mOsm/L. Additionally, this effect is more likely if mannitol is give as a CRI rather than as a rapid bolus.239
A Cochrane Review has addressed the efficacy of mannitol for treatment of acute brain injury in humans.242 Four clinical trials were eligible for review. Among these, mannitol (1 g/kg generally over 5 minutes) was compared with standard care, with pentobarbital (10 mg/kg intravenous bolus followed by CRI of 0.5 to 3 mg/kg such that ICP remained less than 20 torr), with hypertonic saline (2.5 mL/kg of a 7.5% solution over 20 minutes) and with placebo (5 mL/kg 0.9% saline), with treatment occurring before hospitalization. Treatment consisted of 5 mL/kg of a 20% (1 g/kg) mannitol solution; placebo groups were given saline. The review concluded that no evidence existed to support prehospitalization treatment, evidence showed that mannitol might be preferred to pentobarbital but hypertonic saline might be preferred to mannitol. The overall conclusion of the review is that reliable evidence on which recommendations might be made for the use of mannitol in patients with traumatic brain injury was lacking. The review further concluded that randomized clinical trials were clearly indicated.
Benefits of nonosmotic diuretics in the treatment of increased ICP are less clear. Furosemide is not as effective as mannitol, but it may prolong its effects.237 It may interact synergistically with mannitol to decrease ICP.235,236 However, it also may exacerbate the dehydrating effects of mannitol and complicate the maintenance of normovolemia.
Jain238 reviewed neuroprotection associated with traumatic brain injury. Drugs that may be relevant include immunomodulators and antiinflammatory compounds. The observation that cyclophilin (an inducer of micochondrial permeability) concentrations increase and appear to contribute to secondary neurodegeneration after traumatic brain injury provides a basis for use of cyclosporine.238 Cyclosporine is available or being developed in a neuroprotective formula for military personnel subjected to brain injury or gas poisoning. Erythropoietin has demonstrated several potential mechanisms of neuroprotection. This includes inhibition of apoptosis, reduction of cerebral edema, and possibly reduction of glutamate concentrations. A variety of neurotrophic factors are under investigation.238 Phase II or III clinical trials examining the effect of darbepoietin or human recombinant erythropoietin are currently under way. Other pharmacologic approaches have included NMDA or AMPA-receptor antagonists; a phase II clinical trial examining the effects of ketamine is under way in children. Several antiepileptic drugs also have demonstrated oxygen radical scavenging or other neuroprotectant effects.
Naturally occurring neurosteroids allosterically modulate the GABA(A) receptors, protecting against NMDA overactivation and ischemia associated with injury. Endogenous examples include progesterone and its metabolite, alloprenanolone. Interestingly, progesterone appears to facilitate repair of the blood–brain barrier, as well as decreasing edema and muting the inflammatory response.238 A phase II clinical trial involving progesterone is apparently under way in human medicine.238 In contrast to endogenous neurosteroids, the role of glucocorticoids in traumatic brain injury is less clear. Kamano243 reviewed the earlier evidence supporting their use, and particularly megadose of methylprednisolone in human patients with severe brain injury. Although such dosing may be appropriate for acute spinal cord injury, the same is not true for acute head injury.
The use of steroids to treat increased ICP is generally ineffective, with the possible exception of increases associated with tumors.239 The potential beneficial effects support consideration of their use in patients with increased ICP. Damaged vascular permeability might be restored in areas of damage, rendering them particularly useful for vasogenic edema (e.g., such as that caused by tumors). Decreased CSF production has been documented in dogs.239,244 Oxygen-mediated free radical lipid peroxidation can be reduced by glucocorticoids, particularly methylprednisolone.245Despite these potential therapeutic effects, however, clinical studies have failed to show a therapeutic benefit of glucocorticoids for patients with head trauma.239 Jain238 notes that a phase III corticoisteroid clinical trial in humans failed to show efficacy. However, a phase II clinical trial (in humans) involving prednisone showed some efficacy .
The use of glucocorticoids may increase the risk of a poor outcome in patients with traumatic brain injury.235,236 Their effects on metabolism (increasing peripheral glucose and cerebral glutamate) and immunosuppression contribute to their potential detrimental effects. Among the glucocorticoids, methylprednisolone appears to have the greatest radical-scavenging ability and, should glucocorticoids be used in CNS trauma, would be preferred to others. If there is to be a positive benefit, it will be realized only with early administration. Steroids that have no glucocorticoid activity, such as the lazaroids, provide oxygen radical–scavenging effects without many of the detrimental effects of glucocorticoids. These products are not yet commercially available.
Although their use is very labor intensive (and thus reserved for critical care environments), barbiturates (pentobarbital, human dose 10 mg/kg over 30 minutes, followed by 1 to 1.5 mg/kg per hour) have been shown to be beneficial for human patients with severe head injury who have not responded to other therapies. Thus barbiturates may be indicated for patients with sustained, refractory intracranial hypertension. Barbiturates decrease cerebral metabolism, alter vascular tone, and inhibit lipid peroxidation mediated by free radicals.239 Lowered metabolism decreases the cerebral ischemia threshold, allowing lower cerebral oxygenation and thus cerebral blood flow (without ischemic damage).239 Barbiturates also may decrease intracellular calcium.240 Although they appear to rapidly lower ICP, barbiturates place the patient in a coma and thus can cause complications resulting from hypotension, hypothermia, and hypercapnia.
In human medicine the use of barbiturates is accomplished in conjunction with intubation and ventilation, fluid administration, and monitoring of arterial blood pressure (pulmonary artery catheter) and temperature. In human patients support of the pulmonary system is rigorous to prevent pneumonia or atelectasis. Electroencephalographic monitoring accompanies barbiturate therapy in order to document a dose sufficient for burst suppression. Serum barbiturate concentrations are measured (ideally maintained between 30 and 50 mg per day). The efficacy of the barbiturates in lowering ICP are less likely in patients with cardiovascular complications (e.g., hypotension). Once ICP control has been satisfactory for 24 to 48 hours, the drug can be gradually tapered (e.g., 50% per day) to prevent uncontrolled rebound hypertension. Mannitol may be helpful during this period to control ICP. Prophylactic control with barbiturates appears to offer no therapeutic advantage.239
Crystalloids, colloids, and blood may be indicated for treatment of brain trauma or injury. Physiologic crystalloids containing saline or saline and glucose, with or without the addition of potassium, generally can be administered as necessary to prevent hypovelemic shock. Whereas glucose is essential as an energy substrate, under anaerobic conditions it can be converted to lactate, contributing to neurotoxic acidosis.241 Albumin and other colloids are indicated for acute volume expansion, although subsequent metabolism to smaller molecules can contribute to disruption of ion balance. Blood remains the best resuscitative fluid in patients that are hypovolemic and hypotensive.241 Infusion of plasma protein (50 to 100 mL) after mannitol administration also has been recommended to prevent hypovolemia.235 Colloidal products such as hetastarch or Oxyglobin may be similarly effective.
Prophylactic use of anticonvulsants has been recommended for patients with head trauma to minimize the risk of posttraumatic seizure disorders. Seizures increase ICP and may be masked by unconsciousness. Indeed, electroencephalography is recommended for patients with unexplained autonomic dysfunction or increased ICP to detect possible SE. Seizures are more likely when treating for intracranial hypertension. Because the risk of seizures is high, neurologists frequently recommend anticonvulsant therapy for their human patients.
Pain or agitation will exacerbate ICP hypertension, and analgesia is recommended. Human patients (even those subjected to pharmacologic paralysis) are often routinely treated with a reversible opioid analgesic (e.g., morphine). Pharmacologic paralysis is a therapeutic modality that is more applicable to human patients or veterinary patients in a critical care environment. Paralysis is used to prevent muscle activity (particularly in intubated patients, such as those on ventilators), which can contribute to increased ICP. Paralysis is often, however, combined with sedation; the latter can preclude effective neurologic evaluation.235,236 The impact of phenothiazine tranquilizers was previously discussed with regard to epilepsy.
Armitage-Chan and coworkers have reviewed the use of anesthetic agents in canine patients with traumatic brain injuries.246 A number of anesthetic agents have been cited for protective effects in patients with head trauma. Althesin is a rapidly acting steroidal anesthetic that, during CRI, can decrease ICP while maintaining cerebral perfusion pressure. Its tendency to cause anaphylaxis in human patients led to its removal from the market in the United States.239 Propofol can provide protective effects when used at a rate of infusion that induces coma.241 Etomidate is an imidazole anesthetic agent somewhat similar to barbiturates in action. It causes electroencephalography burst suppression, decreased cerebral blood flow, and decreased ICP in human patients with severe head injury.235,236,239 Etomidate may provide some cytoprotective effects induced by hypoxia. Finally, it appears to have antiseizural effects induced through gabaminergic actions (see earlier discussion of anticonvulsants). For humans, however, a single report of interference with the adrencortical axis and stress response after CRI led to its exclusion as recommended therapy for increased ICP. Controlled clinical studies regarding the efficacy of etomidate for the patient with increased ICP have yet to be performed.
Lidocaine decreases CNS synaptic transmission (either directly or as a result of the blockade of sodium channels) and may cause vasoconstriction. The net result is a decrease in cerebral oxygen and glucose consumption. Lidocaine appears to be effective in minimizing increased ICP caused by intubation and surgical stimulation and, in dogs, decreases hypertension after acute cerebral ischemia. Risks associated with lidocaine include myocardial depression and lowering of the seizure threshold. Thus it is generally recognized to be ineffective in treating patients with increased ICP.
Chondrodystrophoid breeds of dogs are predisposed to disk extrusion. The intervertebral disks of these breeds contain more collagen, fewer proteoglycans, and hence less water in the nucleus pulposus. Poor biomechanics of the degenerating disk result in disruption of the annulus fibrosus and the eventual eruption of calcified disk material into the spinal cord. Demyelination and necrosis of the spinal cord develop as a result of the secondary injury mechanisms. These include decreased spinal cord flow, increased intraneuronal calcium, and increased free radical formation. Despite predilection for the chondrodystrophoid breeds, acute disk extrusion can occur in a large number of nonchondrodystrophoid breeds as well. The clinical manifestations vary with the severity of extrusion. Medical management is indicated for animals with grades 1 and 2 thoracolumbar disk protrusion. This includes animals with spinal hyperesthesia and ataxia that is mild enough to allow weight bearing.247 Surgical intervention is indicated for animals that cannot ambulate, regardless of the perception of pain. The loss of deep pain sensation for more that 24 hours is, however, associated with a poor prognosis.247 Smith and Jeffery248 described spinal shock as a component of severe spinal injury. A common manifestation in humans, the pathophysiology may be sufficiently different in dogs that it is often overlooked. However, unexplained neurologic abnormalities caudal to the anatomic localization may support the diagnosis. Further research may be warranted to identify differential therapies targeting the pathophysiology in animals that endure spinal shock.
Nonpharmacologic therapy of thoracolumbar disk extrusion is appropriate for mild to moderate cases of prolapse and focuses on strict immobilization (i.e., cage or crate) for at least 3 weeks.249,250 This time is intended to allow resolution of spinal cord inflammation, reabsorption of extruded disk material, and fibrosis of the ruptured annulus fibrosus. Physical therapy with both passive and active exercises is indicated. Urinary catheterization may be necessary for some dogs. Pharmacologic therapy should focus on control of the inflammatory response to the extruded disk material. Muscle relaxants (e.g., methocarbamol; see Chapter 25) may be helpful. For thoracolumbar disk protrusion, the success rate in ambulatory dogs treated with medical management ranges from 82% to 100%; the success rate in nonambulatory dogs ranges from 43% to 51%.249 Because the intervertebral disk function depends on glycosaminoglycans, compounds used as disease-modifying agents (e.g., glucosamine, chondroitin sulfates) might be considered for long-term prevention or treatment.
KEY POINT 27-33
Pharmacologic therapy of disk protrusion focuses on control of accompanying inflammation.
Among the drugs to control inflammation are glucorticoids and nonsteroidal antiinflammatory drugs (NSAIDs). Mann and coworkers251 reviewed some of the advantages and disadvantages of each. Low doses of corticosteroids (0.5 mg/kg prednisolone or prednisone orally twice daily) are intended to control spinal cord edema, inflammation, and pain and improve spinal cord blood flow. Methylprednisolone at high doses (30 mg/kg intravenously, repeated at 2 and 6 hours at 15 mg/kg intravenously, if indicated) presumably provides the additional advantage of free radical scavenging generated by lipid peroxidation (see Chapter 29). However, some drugs may impair healing of the annulus fibrosus. Both glucocorticoids and newer NSAIDs are more potent toward cyclooxygenase-2, the cyclooxygenase isoform more consistently associated with promotion of healing. Thus both classes of drugs might be associated with a adverse effect. However, an advantage to glucocorticoids might be inhibition of collagen contraction, which has been demonstrated for dexamethasone and hydrocortisone. Timing of drug therapy is important, with neurologic recovery greater in humans for which methylprednisolone was initiated within 8 to 12 hours of recovery. However, this and other recommendations in human medicine are complicated by limitations in supportive study designs.251a
A number of prospective or retrospective studies have addressed the role of glucocorticoids in the treatment of intervertebral disk disease. Bush and coworkers252 prospectively studied the functional outcome of 51 nonambulatory dogs weighing less than 15 kg. Dogs had undergone hemilaminectomy. By 10 days after the operation, 90% were ambulatory, 98% pain free, and 82% continent. The numbers improved to 100%, 94%, and 86% by 6 weeks based on phone interviews. All dogs had received a myelogram as part of their presurgical diagnostics. Levine and coworkers253 demonstrated that 20% of dogs receiving no glucocorticoid and 69% receiving dexamethasone developed urinary tract infection (UTI) in association with hospitalization and surgical correction of disk prolapse. Factors other than immunosuppression that may have contributed to UTI were not addressed. The incidence associated with long-term management is less clear. Wyndaele254 and Igawa and coworkers255 reviewed the role of catheterization in the cause or prevention of UTI in humans with spinal injuries; much of the information may be relevant to dogs. In humans UTI is among the complications associated with long-term intermittent catheterization.254 Identifying the need for antibacterial treatment is difficult in humans because of differences in evaluation, prophylactic antibiotics, and other methods. However, asymptomatic bacteriuria is not necessarily an indication for treatment. The incidence of bacteriuria in human ranges from 11% to 25% asymptomatic to 53% symptomatic (3% with major symptoms). Indwelling catheters increased the risk of infection both during acute and chronic phases of treatment and increase the risk of sepsis. Trauma associated with catheterization (which is not unusual, particularly if someone other than the patient is catheterizing) does not appear to lead to long-term complications. Prophylaxis is helpful and does not necessarily include antibiotics. Indeed, antimicrobials should be reserved for symptomatic patients: Use of ciprofloxacin eradicated susceptible organisms from the urinary tract in humans, only to be replaced shortly thereafter by resistant gram-positive isolates.
Controversy exists regarding the best methods of UTI prevention. Urine can be kept sterile for 15 to 20 days during acute stages of spinal cord injury without prophylaxis and up to 55 days if prophylaxis is implemented. Predictive factors for infection in humans include gender (female), age (young), and neurogenic bladder dysfunction; in male patients low frequency of catheterization was a risk factor. Prostatitis may also be present and increases the risk of recurrent infections. Increased residual volume also is a risk factor; the incidence of infections increased in humans when the frequency of catheterization was reduced from sixfold to threefold. Bacteriuria was a risk factor for clinical infection. Use of dipsticks to detect bacturia other than pyuria alone is recommended to detect bacturia. E. coli is the predominant infecting organisms. Technique and materials, but particularly education of the catheter team, were the most important factors associated with prevention of complications. The use of hydrophilic catheters has been proposed to lower the risk of urinary strictures or false passages (more likely if urethra bleeding has occurred), complications associated with intermittent catheterization. Instillation of colistin–kanamycin at the end of catheterization decreased the incidence of bacteriuria by 50% in humans. Alternatives to standard antimicrobial use also include intravesicular administration of kanamycin–colistin coupled with low-dose nitrofurantoin therapy. The role of adjuvant therapies, including vitamin C, cranberry juice, and polysulfated glycosaminoglycans, are not supported by convincing evidence but warrant consideration in lieu of or in addition to antimicrobial therapy.
KEY POINT 27-34
Glucocorticoid therapy (particularly dexamethasone) for intervertebral disk disease may be associated with a higher risk of urinary tract infection.
Mann and coworkers251 retrospectively examined the recurrence rates of dogs with Hansen type I intervertebral disk disease managed medically with either glucocorticoids or NSAIDs. Dogs were scored according to the level of spinal hyperpathia and neurologic defects; recurrence occurred at least 4 weeks after the initial episode and was identified through communication with owners. Of the 78 dogs studied, 39 (50%) experienced recurrence. Schnauzers were less likely to experience recurrence than any other breed. Recurrences were less likely with methylprednisolone (n = 12; four recurrences) or NSAIDs (n = 36; 12 recurrences) compared with with other glucocorticoids (n = 30; 23 recurrences). The specific NSAIDs or alternative glucocorticoids were not delineated. Timing of methylprednisolone therapy was not an important risk factor; however, only 16 dogs were treated with methylprednisolone, and it is not clear whether the sample size was sufficiently large to detect a difference. The study supports a clinical trial that compares NSAIDs and methylprednisolone.
Levine and coworkers retrospectively reviewed the medical management of cervical and thoracolumbar disk disease.256,257 One veterinary teaching hospital and several emergency clinics in the same state were involved. Inclusion criteria focused on ensuring that presentation and clinical condition were related only to intervertebral disk disease. A prospective client questionnaire was included in assessment. Animals were classified as to success, recurrence, or failure in regard to initial therapy. For thoracolumbar disease (n = 223),256 response to NSAIDs and glucocorticoids was studied. Antiinflammatory drugs used included deracoxib (n = 25), carprofen (n = 42), and others (n = 80) versus 143 dogs receiving none. Glucocorticoids used (n = 105 compared with none in 118) included prednisone (51), dexamethasone (n = 46), and methylprednisolone (n = 8). Glucocorticoids were associated with a lower quality-of-life score, contributing to a lower success score in animals that did, versus did not, receive glucocorticoids. No predictive factor for success could be identified with regard to the specific drug chosen, dose, or duration. In contrast, NSAIDs were associated with a higher quality-of-life score; the success rate between treatment and no treatment with NSAIDs did not differ. For cervical disease (n = 88),257 use of NSAIDs (n = 43, compared with n=45 receiving no treatment) was associated with success. The most common drugs used included deracoxib (n = 21) and carprofen (n = 18). Glucocorticoids (30 receiving, 58 not) did not influence success or quality of life.
Glucocorticoids have been used extensively to control the inflammatory response to disk extrusion. Additional potential benefits include reduction of edema and improved spinal cord blood flow. Controversy, however, surrounds efficacy, the proper drug, and the proper dosing regimen (including route, dose, interval, and duration of therapy). Dexamethasone stands out among the glucocorticoids as the one most likely to be associated with severe and potentially fatal gastrointestinal complications when used to treat dogs with disk extrusion.258 Potential complications include gastrointestinal hemorrhage, ulceration, pancreatitis, and colonic ulceration and perforation.
Methylprednisolone may be the preferred glucocorticoid for treatment of disk extrusion. At high doses (30 mg/kg intravenous bolus followed by 5.4 mg/kg per hour), it inhibits oxygen radical formation and thus inhibits lipid peroxidation.259 In humans neurologic function appears to improve after treatment with methylprednisolone within 8 hours of the injury (compared with placebo). At higher doses (60 mg/kg), however, lipid peroxidation appears to be promoted. Cats with experimentally induced spinal damage underwent neurologic recovery more rapidly with methylprednisolone than with other drugs.260A more recent study using a similar model in dogs failed to show a significant difference in neurologic improvement with administration of either methylprednisolone or lazaroids, but the model of spinal cord damage may not have been sufficient for evaluation of the drug.261
Levine and coworkers253reported on a retrospective comparison of the adverse events associated with dexamethasone (n = 49) versus no treatment (n = 80) and other glucocorticoid therapy (primarily methylprednisolone sodium succinate but also prednisone [n = 23]) for treatment of acute thoracolumbar intervertebral disk herniation in dogs. Two teaching hospitals were involved in the study. All treatments were implemented by the referring veterinarian within 48 hours of admission, and dogs treated with glucocorticoids within the month preceding the episode were excluded. Episode duration was less than 7 days, and surgeries were performed within 36 hours of admission. Of the 161 dogs studied, 87 were dachsunds. No signalment differences occurred among treatment groups. Median duration was less at 5 days for the dexamethasone group compared with the other treatment groups at 6 days, but this difference was not significant when corrected for confounding factors. Likewise, client cost was least (by just under 20%) for the alternative glucocorticoid group compared with the no-treatment group (most expensive), but the differential was negated by confounding factors. The mean dexamethasone dose was 2.25 mg ± 4.28 m/kg (range 1 to 30 mg/kg; dose was not associated with adversity, although the power to detect a relationship was not clear). Doses of the other glucocorticoids were not provided. The dexamethasone group tended to be characterized by a smaller proportion of immediate improvement compared with the other groups, but no difference was found among groups in short-term outcome (29-day follow-up). Adversities that were greater in the dexamethasone group compared with the no-treatment group (with the alternate group generally tending to differ) included vomiting and diarrhea (packed cell volume was lower, but patients were not anemic). UTIs also were more frequent in the dexamethasone-treated patients (11 of 16 that were evaluated); not all patients were tested for infection. Female dogs were more likely to develop UTIs. Less than 20% of dogs examined were positive for UTIs in the other groups. Overall, the dexamethasone group was 3.4 times more likely to develop an adverse effect compared with other groups, with 45 of 49 developing complications compared with 53 of 80 for the no-treatment group. Interestingly, dogs at one institution were 6 times as likely to develop an adverse effect compared with those at the other institution. It is not clear if this was a reporting differential or a true effect.
Side effects associated with methylprednisolone may be rare unless animals have previously been treated with NSAIDs or glucocorticoids.262 Methylprednisolone should be administered after disk extrusion, including before surgical decompression (assuming other antiinflammatory drugs have not been administered), by way of slow intravenous injection within 8 hours of spinal trauma. The initial dose of 30 mg/kg should be followed at 2 and 6 hours with 15 mg/kg intravenously.262
Other drugs that have been recommended for treatment of disk extrusion include prednisolone sodium succinate, dimethylsulfoxide, NSAIDs, and narcotic antagonists. Clinical studies have not been performed with these drugs. Mannitol is not recommended for animals with disk extrusion because of its risk of increased hemorrhage in the gray matter of the spinal cord.
In animals with severe spinal hyperesthesia, 3 to 5 days of oral prednisolone or (not and) NSAIDs can accompany confinement therapy. The risk of gastrointestinal ulceration is a cause for concern. In addition, decreased inflammation may lead to increased activity, with subsequent need for surgical intervention.262
Postoperative analgesics should include opioids. NSAIDs can be used for 3 to 5 days postoperatively; carprofen may be the drug of choice because of its apparent relative cyclooxygenase-2 specificity. The use of drugs that decrease bladder sphincter hypertonicity (phenoxybenzamine, 5 to 15 mg every 24 hours) are discussed elsewhere.
A phase I trial in dogs (n = 39) with naturally occurring traumatic paraplegia or paraparesis investigated the ability of 4-aminopyridine (4-AP) to restore conduction in (presumed) demyelinated nerve fibers. Injuries generally (77%) reflected thoracolumbar degenerative disk disease resulting in chronic, complete paraplegia. Treatment (0.5 to 1 mg/kg intravenously) of 4-AP generally improved hind limb (n = 18) increased response to pain (n = 10) and partial recovery of the cutaneous trunci muscle reflex (n = 9). Effects became evident in 15 to 45 minutes but reversed within a few hours of administration. Remaining animals (36%) either did not improve or exhibited slightly improved hind limb reflex tone. Although higher doses led to more dramatic improvement, side effects, including diazepam-responsive seizures and hyperthermia, occurred.263 N-acetylcysteine (NAC) is among the drugs studied for its impact on oxygen radicals. Baltzer and coworkers264 found no effect of pretreatment with intravenous NAC in dogs (n = 70) with acute spinal injury on urinary concentrations of 15F2t isoprostane, a prostanoid metabolite, or neurologic function 42 days after surgery, when compared with placebo.
Treatment of ocular disease can be implemented both locally and systemically. Local administration includes both topical (cornea or conjunctival sac) and directed therapy, the latter including intraocular (aqueous [anterior] or vitreal [posterior] chamber), subconjunctival (targeting anterior chamber and its associated structure), and retrobulbar (targeting the posterior chamber or choroids) routes. Although movement into the eye from topical or local delivery is facilitated by the ability to use higher drug concentrations in the vehicle, delivery might be offset, regardless of the route of administration, by intraocular pressure (IOP), which causes consistent outflow of fluid and any drug that it contains. Although inflammation will facilitate drug penetration in both the anterior and posterior ocular chambers, resolution of inflammation (or, potentially, severe inflammation) may be associated with reduced drug penetrability. Inflammation also may alter penetrability by virtue of its impact on pH (discussed later).
Directed (local) ophthalmic therapy is appealing for three reasons: (1) As with other sites, topical therapy allows use of drugs at concentrations that are likely to be therapeutic but likely to be associated with adverse effects if the drug is applied topically, thus limiting the effective use of the drug. (2) Adversity is reduced with topical administration. Examples include the antimicrobials polymyxin B, bacitracin, and neomycin, each of which is characterized by a high incidence of nephrotoxicity with systemic administration. Drugs that cause agonistic or antagonistic sympathetic or parasympathetic effects in the eye can cause profound cardiovascular and other systemic side effects when given systemically at doses necessary to cause a therapeutic ocular response. The safe use of antiinflammatories such as NSAIDs and glucocorticoids is facilitated with topical delivery. However, even if glucocorticoids are topically applied, sufficient drug may reach systemic circulation to affect the adrenal axis. (3) Ophthalmic delivery avoids the blood–eye barrier at both the ciliary and retinal epithelium presented to systemically delivered drugs. However, as with the skin, drugs applied topically with the intent of intraocular effects must penetrate a protective barrier. Most drug is absorbed through the corneum; this is balanced by drug flow from the sclera in response to a constant outward pressure. The cornea comprises several layers that vary in their chemical nature and thus drug penetrability. The lipid-soluble epithelium is several layers thick and presents the major barrier to penetration of topically applied drugs. Ingredients added to ophthalmic preparations with the intent to facilitate drug delivery include surfactants that increase the permeability of the corneal epithelium. The next deepest layer is the water-soluble stroma, followed by the innermost lipid-soluble endothelium. Topically applied vehicles and the drugs they carry must balance water and lipid solubility to ensure not only dissolution of the drug but also its movement into and through the different layers of the cornea. Drug pKa and environmental pH directly influence drug ionization as well as drug dissolution (and, as discussed later, drug stability), both of which will alter drug penetrability; changes in vehicle or local pH may change drug penetrability. Inflammation may change the slight alkalinity of the tears (7.4) to become more acidic, which will ionize and thus reduce penetrability of the drug.
Drugs intended for ophthalmic preparations are most commonly prepared as either solutions (drops) or ointments. Although easier to administer (facilitating owner compliance) and more rapid in onset (greater immediate contact over a larger surface area), the effect of drops is reduced by a shorter contact time; solutions are characterized by rapid dilution with tears. The volume of the subconjunctival sac, which acts as a reservoir for the drug, can expand to 30 to 50 μl. The optimal drop size for ophthalmic delivery is 20 μl. Whereas tear turnover is 15% in the nonirritated or untreated eye, it becomes 30% with drug delivery or in the inflamed eye; 80% of tears containing diluted drug exiting through the lacrimal duct. As such, a 5-minute contact time can be expected with drops applied 4 times or more a day (recommended). Further, the optimum time before adding a second drop is 5 minutes. Contact time of the drug with the cornea can be prolonged by increasing the concentration of the drug (often prepared as 1% or 100 mg/dL), preparation viscosity, or addition of surfactants that increase corneal epithelial permeability. Drug movement into the eye also can be facilitated by manipulation of the pH: Because tears are slightly alkaline (7.4), increasing the pH such that it is slightly basic will decrease the un-ionized and thus absorbable proportion of a basic drug. Devices such as canulas allow more effective topical subpalpebral or nasolacrimal administration of solutions in selected species. Ointments allow a longer contact time and thus thrice-daily administration. Less drug enters the lacrimal passages, which may be an advantage for some drugs. However, disadvantages of ointments include the potential for reduced owner compliance (more difficult to administer compared with solution) and slower onset of action. Indeed, drug movement through the ointment into the cornea may be so slow that concentrations may remain subtherapeutic. Other disadvantages of ointments include impaired vision, impaired penetration of other drugs simultaneously administered ophthalmic ally (particularly solutions), and potentially impaired corneal healing.
The advantages of topical ophthalmic drug delivery are offset to some degree by drug safety considerations. More so than other topically applied drugs, the vehicle of ophthalmic preparations must be formulated such that adverse (ophthalmic) drug reactions are minimized. Considerations include tonicity (must be similar to tears, such as 1.4% NaCl; reasonable range is 0.7 to 2%), which is often accomplished using phosphate buffer. The pH (generally buffered at 3.5 to 10.5) must be appropriately balanced, yet altering pH for safety considerations may alter drug delivery. Not only might lipid solubility (because of changes in ionization) be affected (see previous discussion), but dissolution and stability also may be affected, with positive changes in one often causing negative changes in the other. As with many drugs in solution, ophthalmic preparations may lose potency with storage, and strict adherence to expiration dates is indicated. Tonicity and pH are less important for drugs prepared as ointments. Although stability tends to be better overall in ointments, stability may nonetheless be reduced, particularly in water-based ointments. In contrast to solutions, a disadvantage of ointments is their potential to cause inflammation should the vehicle (not the drug itself) penetrate intraocular tissues. In contrast to drugs administered on the skin, ophthalmic preparations generally should be sterile. All should be prepared aseptically, although this does not ensure sterility. Methods that might facilitate sterility include autoclaving, filtering, and adding preservatives (e.g., benzalkonium chloride, phenol, and merbromin); however, each can be irritating to intraocular tissues and may interfere with diagnostic (culture) procedures. A major disadvantage of compounded ophthalmic preparations is the absence of quality-control procedures documenting product stability, potency, and sterility.
General anesthetics, with the exception of ketamine, generally lower IOP. In contrast, opioids generally increase IOP. Local anesthetics block sodium channels, thus impeding impulse conduction through nerve fibers. Their duration is variable and is affected by pH as well as manipulation of chemical structure. The presence of an ester in topically applied preparations shortens duration of action, whereas the addition of an amide prolongs anesthetic effects. Esters include proparacaine (0.5%; 15-second onset; 20-minute duration), tetracaine (longer-acting but more toxic), whereas amides, which are generally applied as local (rather than topical) drugs, include lidocaine (5-minute onset, 2- to 4-hour duration) and bupivacaine (≥20-minute onset, 6- to 8-hour duration). Other topical products include benoxinate, butacaine, phenocane, dibucaine, and piperocaine. All local anesthetics inhibit blood vessel formation and corneal epithelialization and may cause minute punctate corneal ulcers. Some can actually cause systemic toxicity with topical administration because of rapid (i.e., conjunctival) absorption. The loss of sensation removes protective reflexes; therefore these drugs should be used only under direct veterinary supervision (i.e., not sent home with clients).
Autonomic drugs are generally, but not exclusively, used to treat glaucoma and control associated ocular pain through paralysis of ciliary muscles.
Stimulation (contraction) of the constrictor muscle of the iris is mediated by the parasympathetic (cholinergic; acetylcholine) system, leading to miosis. Flow of aqueous humor is subsequently facilitated. The cholinergic system also controls formation of aqueous humor at the level of the ciliary body. Longitudinal contraction of the ciliary body also occurs and may help lower IOP (e.g., glaucoma) possibly by distending the trabecular meshwork; some miotics may actually decrease outflow by effects on other ciliary sites. Parasympathomimetic drugs include pilocarpine (0.5 to 6%), which directly interacts with cholinergic receptors as well as stimulates secretory glands (which is why it is used for treatment of keratitis sicca); echothiophate (0.03 to 0.25%) or demecarium bromide (0.125 and 0.25%; the most toxic) and isoflurophate (0.025%) are parasympathomimetics are irreversible inhibitors of acetylcholinesterase. The use of these drugs in animals wearing anticholinergic flea preparations should be done cautiously. Echothiophate is among the most effective drugs, in part because it is irreversible and therefore can be used only twice daily. Carbachol (3%) is both act both directly and indirectly, with a longer duration of action than pilocarpine (allowing thrice-daily treatment). Pilocarpine must be given several times a day and may cause pain on application. The use of a 4% pilocarpine gel in dogs has not been reported. Miotics should not be used in the presence of inflammation of the anterior chamber (i.e., anterior uveitis) because of the risk of anterior synechia.
Parasympatholytic drugs relax the cilary body, causing cycloplegia and mydriasis. Drugs include atropine (1%; up to 4% to 5% in horses; longest acting), homatropine (0.5% and 2%; intermediate acting), scopolamine (0.3 to 0.5%; used primarily before intraocular surgery), and tropicamide (1%). Topical anticholinergics are much more effective than systemic drugs. These drugs are not used to treat glaucoma and, in fact, are contraindicated in some types of glaucoma. Rather, because these drugs cause cycloplegia, they are useful in the relief of pain associated with spasms of the ciliary muscle, which often accompany anterior uveitis. Tear production may be decreased by parasympatholytic drugs. Tropicamide is rapid in onset and of short duration (2 to 3 hours, although mydriasis and cyclopegia may last up to 12 hours in some cats and dogs); therefore it is often used for ocular examinations.
Contraction of the dilator muscle is mediated by the sympathetic (epinephrine) system by way of alpha receptors, leading to mydriasis (dilation) and, as with parasympathomimetic drugs, as a result of constriction of ciliary body vasculature, decreased formation of aqueous humor and decreased IOP.
Sympathomimetic drugs include epinephrine (which does not penetrate the eye well), which directly interacts with alpha more than beta receptors (used as a 1:1,000 dilution to control conjunctival or scleral hemorrhage or to prolong effects of local anesthetics), phenylephrine (0.125% solution for vasoconstriction; 10% as mydriatic; onset of action in 1 hour, duration up to 24 hours), largely limited to alpha receptor stimulation (30- to 60-minute onset with 4-hour duration), and dipivefrin, a lipid-soluble drug that acts indirectly by causing epinephrine release (used to decrease IOP; 30 to 60 minutes to onset). Sympatholytics include alpha antagonists (thymoxamine) which inhibits the dilator muscle, causing miosis. Beta antagonists, represented by timolol (0.5%) (others include Optimpranolol, 0.3% and Betagan, 0.5%), act to decrease IOP by decreasing aqueous humor production. These drugs may be limited in their usefulness although may be effective for treatment of ocular hypertension.
The newest class of drugs developed to treat glaucoma are the topically applied prostaglandins. These drugs target the trabecular meshwork or collagen of the ciliary body such that outflow obstruction is decreased. Examples include bimatoprost and travoprost.
In addition to the impact of drugs targeting the autonomic nervous system, reduced production of aqueous humor can be accomplished by carbonic anhydrase inhibitors, which also have diuretic effects (the latter probably has limited effect on aqueous humor formation). Topical products include dorzolamide and brinzolamide. Systemic drugs include acetazolamide and the newer drugs, methazolamide and dichlorphenamide. These drugs can reduce aqueous humor production by up to 50% and are often used in combination with autonomic drugs. Aqueous humor production is also rapidly decreased by osmotic diuretics, including mannitol and glycerin. Mannitol (given intravenously) is limited to emergency therapy (two treatments) of glaucoma or to reduce IOP before surgery. Additional potential benefits of osmotic agents include reduction in vitreous humor volume (a potential advantage with lens disruption) and resolution of corneal edema (topical only). Glycerol has the disadvantage of being less effective than mannitol but can be administered (orally) at home by the pet owner; care must be taken to avoid emesis.
Drugs used to treat ocular inflammation include glucocorticoids (systemic and local) and NSAIDS (topical). Drugs that act to modulate the immune system (e.g., cyclosporine; topical or systemic) also control the inflammatory response. Glucocorticoids target in situ mediators (eicosanoids: prostaglandins and leukotrienes), preformed biogenic amines (histamine, serotonin), and the immune system (macrophage processing, T-cell expansion). Additionally, glucocorticoids are antiangiogenic (inhibit vascularization). Glucocorticoids are indicated for any inflammatory condition of ocular tissues (e.g., conjunctivitis, blepharitis, episcleritis, keratitis, iridocylitis). Glucocorticoids inhibit healing, increase the potential for infection, and also stimulate collagenase. Collagen breakdown in the stroma can result in corneal perforation, and therefore glucocorticoids are contraindicated in the presence of an ulcer. Topical glucocorticoids are available in solution, suspension, and ointment. Preparations include hydrocortisone, 0.1% dexamethasone, and 1% prednisolone acetate (generally the drug of choice).
In contrast to glucocorticoids, NSAIDs principally target eicosanoids and thus are more limited in their control of inflammation (although they may have other effects). However, topically applied NSAIDs also can decrease inflammation; examples include flurbiprofen (0.03%) and diclofenac (0.1%), which are available as topical preparations. Cyclosporine specifically targets T-helper cells and thereby controls the immune response. Available as a 2% solution, cyclosporine is indicated for the treatment of keratitis sicca, pigmentary keratitis, and other ocular immune-mediated disorders.
Antihistamines rarely are useful topically, although systemic therapy may be helpful with allergic ocular reactions.
Proteases responsible for tissue destruction and perpetuation of inflammation are produced by ocular epithelial and stroma cells as well as inflammatory cells and select bacteria (e.g., Pseudomonas). Acetylcysteine is an effective protease inhibitor that also is monolithic; consequently, it is useful for treatment of keratoconjunctivitis sicca. The low pH must be buffered before topical administration (7 to 7.5); although it can be used as a 20% solution, 5% would be less irritating.
Because of the ability to administer high concentrations of antibiotics, traditional classification of bacteriostatic versus bactericidal (fungistatic or fungicidal, virostatic or virucidal) may not be relevant to antiinfective drugs.
Topical antibacterial drugs are available as single or multiple antibiotic agents. Drugs that target gram-negative organisms include the water-soluble, weakly basic aminoglycosides (also effective against Staphylococcus spp.) tobramycin (0.3%; drug of choice for treatment of Pseudomonas), gentamicin (available with the glucocorticoid betamethasone), and neomycin (generally available only in combination with other antibiotics). Polymyxin B also is a water-soluble drug that is notable for its nephrotoxicy when given systemically. The fluorinated quinolones also target gram-negative organisms, including Pseudomonas as well as Staphyloccoccus. In contrast to the aminoglycosides, the fluorinated quinolones are lipid soluble. Drugs include ciprofloxacin and ofloxacin and its congener levofloxacin. Note that systemic fluorinated quinolone has been associated with retinal degeneration in cats; a similar finding has not been reported after topical use. Drugs that target gram-positive organisms include the lipid-soluble erythromycin (0.5%; bacteriostatic), the efficacy of which is limited by resistance, and the water-soluble bacitracin, which, like polymyxin B, is most known for its nephrotoxicity associated with systemic therapy. Triple antibiotic combinations include neomycin, polymyxin B, and bacitracin. Broad-spectrum topical antibiotics include chloramphenicol (prohibited for use in food animals), tetracyclines (drugs of choice for ocular Mycoplasma or Chlamydia), and the sulfonamides. Each is lipid soluble.
Topical antifungal antimicrobials include the polyene natamycin. Its spectrum includes all fungal agents except dermatophytes. The imidazoles (i.e., miconazole, fluconazole, and itraconazole) must be compounded from intravenous solutions. Their spectrum includes opportunistic, dimorphic fungi and dermatophytes.
Antiviral drugs are indicated for treatment of herpes keratitis. Drugs indicated for acute therapy include trifluridine (1%; probably the most effective); idoxuridine (0.1%; intermediate efficacy; must be compounded), and vidarabine (least effective and least irritating). These drugs tend to be irritating but must be administered no less than 5 times a day. For chronic therapy (chronic carrier state), betadine can be diluted (1:30); failure to dilute may be caustic to the eye.
Aqueous solutions may be insufficient for replacement of tears because they cannot adhere to the epithelium. Polyvinylpyrrolidone (1.67%) is an artificial mucin that replaces mucopolysaccharides in the precorneal tear film and thereby stabilizes the film. Bicarbonate-based buffer will normal maintain pH, thus facilitating healing. Artificial tears are indicated to compensate for insufficient tear production, decrease loss of fluid from the cornea resulting from evaporation, and facilitate penetration of water-soluble drugs. Other protectants include methylcellulose (0.5 to 1%); hydroxyethyl cellulose; hydroxypropyl methylcellulose; and polyvinyl alcohol (1.4%), which may be too irritating.
Solutions that might be used for intraoperative flushing (rinsing or a wetting agent) include eye washes (commercial formulas preferred), povidine–iodine (2% to 4% in saline), and benzalkonium chloride (1:5000; incompatible with fluoresceine, nitrates, salicylate, and sulfonamides). Zinc sulfate (0.2% and 0.25% solution; 0.5% ointment) is a mild astringent and antiseptic that can be used for mild conjunctivitis.
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