Pharmacologic Management of Neuroscience Patients

Timothy F. Lassiter

Amy I. Henkel

OVERVIEW

Role of the Pharmacist in Patient Management

Historically, the profession of pharmacy has been devoted exclusively to dispensing a high-quality drug product. With advances in technology, pharmacists have been safely able to devote less time to drug distribution services while assuming new roles in multidisciplinary patient management. Pharmacists today undergo extensive training, enabling them to contribute to the care of the patient on a number of fronts. At the same time, as medical science has advanced, pharmacologic management of patients has become increasingly complex. Pharmacists are drug therapy experts whose primary responsibility is preventing and solving drug-related
problems and providing drug information to all health care providers and patients. These circumstances have empowered pharmacists to become proactively involved in patient care as part of the multidisciplinary health care team. Pharmacists also develop and implement drug therapy monitoring plans, such as scheduling and reviewing serum drug concentrations, to achieve therapeutic end points and avoid toxicity.¹

Impact of Pharmacotherapy on the Nervous System

Pharmacotherapy has a tremendous impact on the assessment and care of the neuroscience patient. For example, many drugs commonly prescribed in the acute care setting can alter the level of consciousness (LOC). This is an obvious desired end point for narcotic analgesics, benzodiazepines, and other sedatives. However, many other drugs can also alter the LOC, either as a side effect (clonidine, H₂-receptor antagonists) or as a symptom of toxicity (relative overdose of imipenem in a patient with renal failure). Toxicity is of particular concern in the elderly and any patient in the intensive care unit (ICU). In both cases, patients may be more sensitive to the pharmacologic effects or toxicities of a medication. This sensitivity is frequently compounded by an impaired ability to eliminate the offending agent because of renal or hepatic insufficiency. Despite the risks involved, properly managed adjuvant pharmacotherapy can indeed save lives. Selection of drug products with a favorable neurological profile increases the potential for a good outcome in the neuroscience patient.

Therapeutic Decision Making

Determining optimal pharmacologic management of the neuroscience patient depends on numerous factors. Ultimately, a risk-benefit assessment must be made for each therapeutic decision. Occasionally, this process results in a drug being prescribed that carries with it a high risk of producing a deleterious effect, but it is also potentially lifesaving. This is frequently the case when amphotericin B or an aminoglycoside is prescribed. Another example is a patient given sedatives and neuromuscular blockers for ventilator compliance at the expense of a reliable neurological examination.

After a careful risk-benefit assessment has been made, a comparable therapy can be selected over another based on relative cost. Such decisions become more difficult when a more expensive drug can potentially shorten a hospitalization or avoid an expensive adverse effect. Studies that comprehensively examine costs from a pharmacoeconomic perspective are being conducted more routinely in today’s health care environment.

COMMONLY USED DRUGS ALONG THE CONTINUUM OF CARE

Discussion of drug therapy in this chapter focuses on practical information necessary to manage the neuroscience patient. Tables are included for a quick reference. Drugs are addressed by body systems. For those who want more detailed information, pharmacology texts should be consulted.

Hemodynamic Support and Associated Drugs

In addition to proper fluid management, neuroscience patients in the ICU often require therapy with vasoconstrictors, vasodilators, or inotropes. Proper monitoring is essential and typically includes frequent measurement of mean arterial pressure, heart rate, central venous pressure, urine output, and cardiac output. The goal is to meet the oxygen requirements of the body. More definite therapeutic end points, such as specifically targeted oxygen delivery values or a minimum acceptable blood pressure, are controversial. Therapy must be individualized for each patient. Hemodynamic regimens often involve multiple drugs, making physical and chemical compatibility an issue with respect to concomitant fluids and intravenous (IV) access. The pharmacist can help solve these complex problems. Never assume compatibility when appropriate data are lacking.

In the neuroscience patient, recent research has focused on cerebral oxygen delivery and consumption optimization, rather than cerebral perfusion pressure, as a therapeutic end point for hemodynamic manipulation. This is particularly useful when vasodilators and other antihypertensives are prescribed because of the complex interrelationships between vascular tone and cerebral perfusion in the setting of an acute neurological insult.

Vasoconstrictors

Vasoconstrictors are helpful when hypotension is the result of a loss of vascular tone. This is commonly due to either sepsis or spinal shock. They are relatively contraindicated in untreated hypovolemic or cardiogenic shock. A high-dose requirement of vasoconstrictors for a prolonged period is an ominous sign because these drugs preserve blood pressure at the expense of organ perfusion. Extended periods of vital organ hypoperfusion contribute to multiple organ dysfunction syndrome, which carries with it a high mortality rate.

Dopamine is notable in that its pharmacologic effects are dose dependent. At moderate doses, inotropic (increased cardiac contractility) and chronotropic (increased heart rate) effects predominate. At high doses, it is a potent vasoconstrictor, effectively overriding any selective vasodilation activity. The use of low-dose dopamine as a renal protective therapy has been widely disproved and fallen out of favor.² Phenylephrine is a potent vasoconstrictor devoid of direct inotropic or chronotropic activity. Some clinicians consider it the drug of choice for spinal shock, and it is being used more frequently for septic shock. Reflex bradycardia develops occasionally with its use. Norepinephrine is a potent vasoconstrictor with concomitant inotropic and chronotropic activity. Epinephrine acts as a positive inotropic or chronotropic agent at low doses and a vasoconstrictor with higher infusion rates (Table 12-1).

Regardless of the dose prescribed, great care must be taken to avoid extravasation of these vasoactive substances. This complication can produce extensive skin necrosis due to intense local vasoconstriction. Local instillation of phentolamine (an α-receptor blocker) is indicated when this occurs.

Inotropic Agents

The inotropic agents are useful when cardiac contractility needs to be increased to optimize cardiac output. Careful titration is necessary because these agents can increase heart rate. Excessive tachycardia can be deleterious due to decreased cardiac output resulting from shortened filling time and diminished stroke volume, or from prolonged excessive myocardial oxygen demand in the setting of ischemic heart disease. The inotropic agents can also cause vasodilation, which is usually tolerated poorly in this setting (Table 12-2).

Dobutamine is the most frequently prescribed positive inotropic agent. It is usually well tolerated and infrequently causes tachycardia. Milrinone is a newer agent that has inotropic activity
without direct chronotropic activity. Its ability to raise cardiac output is in part due to its vasodilator activity, so blood pressure must be monitored closely. Milrinone may provide an advantage in right-sided heart failure due to specific effects on the pulmonary vasculature. Patients with severely impaired cardiac contractility are sometimes prescribed both milrinone and dobutamine. Isoproterenol is used infrequently as an inotropic agent because of its strong concomitant chronotropic activity. It is useful, however, for treating symptomatic bradycardia unresponsive to atropine.

TABLE 12-1 VASOCONSTRICTOR AGENTS

DRUG	DOSE	ADVERSE EFFECTS	COMMENTS
Dopamine	4-8 mcg/kg/min	Tachycardia compared to equipotent dose of dobutamine, skin necrosis with extravasation	Inotropic dose, may begin to see vasoconstrictor effects
	8-20 mcg/kg/min	Tachycardia, hypertension, skin necrosis with extravasation	Prolonged high doses produce organ hypoperfusion and renal dysfunction
Phenylephrine	0.5-5 mcg/kg/min	Reflex bradycardia, skin necrosis with extravasation	May be drug of choice for spinal shock, may be useful when other vasoconstrictors cause excessive tachycardia
Norepinephrine	2 mcg/min, titrate to effect, (typically <30 mcg/min)	Tachycardia, skin necrosis with extravasation	Useful for patients not responding to dopamine, organ hypoperfusion and renal dysfunction with prolonged high doses
Epinephrine	2-10 mcg/min 10-20 mcg/min	Tachycardia See above	Primarily inotropic effect Vasoconstricting dose, preserves coronary and cerebral flow

Vasodilators

Vasodilators are routinely prescribed for the neuroscience patient.

They can be used in patients with impaired cardiac output to decrease the workload of the heart (afterload) and improve cardiac performance. More typically, they are used to control blood pressure in hypertensive patients with neurological sequelae. Blood pressure goals must be individualized to prevent further damage related to elevated pressures without also worsening cerebral ischemia. As mentioned previously, the most common side effects are hypotension and tachycardia (Table 12-3).

The calcium channel blockers are frequently used vasodilator agents. Nicardipine is available in IV form and is a smooth-acting vasodilator when given as a continuous infusion. A newer IV agent for infusion, Clevidipine, acts similarly to nicardipine but has a much faster onset of action. Clevidipine is formulated in a lipid emulsion and requires frequent line changes to avoid microbial contamination. Nifedipine given orally has been used extensively to treat hypertension in neuroscience patients. It is more potent than nicardipine. Careful monitoring of vital signs and neurological status is required because nifedipine has rarely been associated with worsened ischemic stroke when administered sublingually. Nimodipine, although an effective antihypertensive, is only indicated for prevention of cerebral vasospasm. In addition to having antihypertensive properties, calcium channel blockers may help interrupt the development of secondary brain injury after trauma. Verapamil and diltiazem are effective when given as an IV bolus or infusion for supraventricular arrhythmias. They also lower blood pressure but are not routinely used for acute hypertensive situations. Verapamil and diltiazem are often prescribed chronically to treat hypertension. Sustained-release oral dosage forms are available. They should not be crushed and given through any kind of enteral feeding tube, because this will place the patient at risk for hypotension from the relative overdose. Similarly, immediaterelease calcium channel blockers given once daily are likely to be ineffective unless they have a long half-life like amlodipine.

TABLE 12-2 INOTROPIC AGENTS

DRUG	DOSE	ADVERSE EFFECTS	COMMENTS
Dobutamine	2.5 mcg/kg/min titrate up to 20 mcg/kg/min	Hypotension, ischemia, tachycardia	Wean slowly (1 mcg/kg/min/hr), useful for low cardiac output unresponsive to fluids
Dopamine Epinephrine Norepinephrine			See Table 12-1 for details
Milrinone	50 mcg/kg over 10 min ×1, then 0.375-0.75 mcg/kg/min	Hypotension, ischemia, tachycardia
Isoproterenol	2-10 mcg/min	Tachycardia, hypotension, ischemia	Excessive tachycardia limits use to severe bradycardia only

Nitroglycerin is a vasodilator but is often ineffective in managing severe hypertension. Sodium nitroprusside is a potent arterial and venous vasodilator that has been used for many years for hypertensive urgencies and emergencies. It should be avoided in patients with acute neurological injury because it tends to override any remaining vascular protection and expose the brain to excessively high pressures. High doses given for a prolonged period can lead to thiocyanate toxicity, particularly if the risk of renal failure
is high. Unexplained acidosis is usually the first sign. Concomitant administration of sodium thiosulfate has been advocated to prevent thiocyanate toxicity. Fenoldopam is a new dopamine receptor agonist that may be an alternative to nitroprusside. It provides effective blood pressure lowering with additional effects on the kidney. Fenoldopam’s ability to increase renal blood flow and promote natriuresis has been held by some clinicians as a renal sparing therapy.

TABLE 12-3 VASODILATORS

DRUG	DOSE	ADVERSE EFFECTS	COMMENTS
Calcium Channel Blockers
Clevidipine	1-2 mg/hr, titrate q60-90 secs up to 32 mg/hr Onset: 1-2 mins	Hypotension, tachycardia	Mixed in lipid emulsion; change product q12h to avoid microbial contamination
Nicardipine	5 mg/hr IV, titrate q15min up to 15 mg/hr Onset: 1-5 mins	Hypotension, tachycardia	Fluid load can be substantial, typical concentration = 0.1-0.2 mg/mL
Nifedipine	PO: 10-30 mg q6-8h. Max daily dose = 180 mg Onset: 5-15 mins	Hypotension, tachycardia, headache, flushing	SL has been associated with worsened ischemic stroke
Nimodipine	60 mg PO q4h ×21 days	Hypotension, tachycardia	Only for treatment of vasospasm after aneurysmal subarachnoid hemorrhage, 30 mg q2h has been used in hypotensive patients
Verapamil	PO: 80 mg q8h up to 480 mg/day	Heart block, worsened congestive heart failure, constipation	IV useful for supraventricular arrhythmias, not for acutely elevated BP
Diltiazem	PO: 30 mg q6h up to 360 mg/day IV: 0.25 mg/kg bolus, may repeat ×1 with 0.35 mg/kg. Infusion range 5-15 mg/hr	Similar to verapamil, but less pronounced	See verapamil. IV form for SVT or AF only
Nitroglycerin	20-300 mcg/min Onset: 1-2 mins	Hypotension, headache, methemoglobinemia	Tachyphylaxis can occur, oral and topical forms available: provide “nitrate free” interval daily to lessen tachyphylaxis
Sodium Nitroprusside	0.5-10 mcg/kg/min Onset: 1-2 mins	Hypotension, cyanide toxicity, especially with concurrent renal failure	Avoid in setting of increased intracranial pressure; some advocate concurrent sodium thiosulfate to minimize risk of cyanide toxicity
Fenoldopam	0.1-1 mcg/kg/min Onset: 10 mins	Hypotension, headache, nausea, blurred vision	Promotes natriuresis and increased renal blood flow, potential renal protective effect
Beta Blockers
Labetolol	IV: 10-20 mg over 2 mins, may increase to 40-80 mg and repeat q10min up to total of 300 mg (see comments) Onset: 5 mins	Bradycardia, bronchospasm,worsened glucose control in diabetes, worsened congestive heart failure	May be the drug of choice for many neuroscience patients; may use continuous infusion starting at 0.5-2 mg/min
Metoprolol	IV: 5 mg q5min up to 15 mg PO: 25 mg q12h up to 100 mg q6h	See labetolol, cardiac selective up to 200 mg/day	IV maintenance doses up to 20 mg q6h have been tolerated, but expensive
Esmolol	500 mcg/kg ×1, then 25-50 mcg/kg/min up to 400 mcg/kg/min Onset: 1-3 mins	See labetolol	Also useful for supraventricular tachycardia, very short acting
Enalaprilat	IV: 0.625-5 mg over 5 min q6h Onset: 15 mins PO: 2.5-40 mg/day	Hypotension, hyperkalemia rash, cough, laryngeal edema	Intensity of response depends on fluid status of patient. IV form at least twice as potent as oral

Beta blockers (metoprolol, atenolol, others) are also useful antihypertensives. Esmolol is an ultra-short-acting beta blocker that can be given as escalating IV boluses or by a continuous infusion. It is also effective for supraventricular tachycardia. In addition to slowing heart rate, labetalol also has peripheral vasodilating effects. Many consider it to be the drug of choice for acutely managing hypertension in the neuroscience population because of its safety record and because it does not cause as much tachycardia as other potent vasodilators. All beta blockers have negative inotropic effects that can limit their use in patients with congestive heart failure. They can also worsen glucose control in patients with diabetes, worsen pulmonary function in asthmatics, and (rarely) cause hyperkalemia. The angiotensin-converting enzyme inhibitor enalaprilat is available for IV use in the acute care setting. The relative efficacy of this drug fluctuates depending on the volume status of the patient. Hypovolemic patients tend to have an exaggerated response, whereas fluid-overloaded patients tend to respond poorly. Enalaprilat also can cause hyperkalemia.

Anticonvulsants

Anticonvulsants are a mainstay of therapy for patients with seizure disorders. These agents are effective for control of seizures from various etiologies. Most patients with seizure disorders can be managed with pharmacotherapy alone. More than 30 different drugs are used to control convulsive episodes, but most patients are effectively managed with two or three agents used alone or in combination. A review of commonly used anticonvulsants is presented in Table 12-4. A more complete discussion of selected agents and nursing implications follows.

Phenytoin (Dilantin)

Phenytoin is a member of the hydantoin class of anticonvulsants. It blocks synaptic post-tetanic potentiation and subsequent propagation of electrical discharge in the motor cortex. The drug blocks sodium transport and thereby stabilizes membrane sensitivity to hyperexcitable states. Phenytoin is used for management of partial and generalized seizures. It may be used alone or in combination with other drugs. When used in combination, it is often possible to reduce the adverse effects of the respective agents and achieve a synergistic effect on controlling seizures. Phenytoin has been used prophylactically in neurosurgical patients to prevent seizures in the postoperative period, and has demonstrated efficacy in reducing post-traumatic seizures.³ However, recent data suggest phenytoin may contribute to cognitive impairment when used in subarachnoid hemorrhage patients.⁴

Serum Concentration Monitoring. The accepted therapeutic range for phenytoin is 10 to 20 mg/L. At concentrations above this, side effects such as nystagmus, ataxia, and altered cognition are more apparent. The half-life of phenytoin varies considerably among patients and increases with dosage and plasma level. Steady state levels are normally reached in 7 to 14 days but may take up to 28 days in some patients. Except when patients are loaded with phenytoin, obtaining levels more frequently than every 3 to 4 days is rarely necessary.

Phenytoin is highly protein bound, with about 90% of drug in serum bound to albumin. Only the unbound (free) drug is available to exert a pharmacologic effect. Serum phenytoin levels are normally reported as total drug concentrations. Thus, the free concentration is approximately 10% of the total phenytoin concentration, or 1 to 2 mg/L. In patients with hypoalbuminemia, total serum phenytoin levels may appear low when the active free phenytoin component may actually be normal or high. In such patients, measurement of free levels is a better indicator of clinical response. When free phenytoin concentrations are not readily available, total phenytoin levels may be estimated by the following equation:

Adjusted phenytoin level = measured phenytoin/[(serum albumin) (0.2) + 0.1]

Drug interactions with agents that displace phenytoin from albumin (e.g., valproic acid) will also increase the free concentration and lead to enhanced therapeutic effect or toxicity.

Administration. Phenytoin is available as an IV preparation, chewable tablets, oral suspension, and extended-release capsules. The IV and capsule formulations contain phenytoin sodium, whereas the chewable tablets and suspension contain phenytoin acid. Phenytoin sodium contains 92% phenytoin. In some patients, changing formulations may result in altered serum concentrations due to the different percentages of phenytoin. The extended-release capsule formulation is the only oral form approved for once-daily dosing, though daily doses exceeding 400 mg are usually divided.

Administration of phenytoin can present problems for patients receiving enteral feedings. The suspension tends to settle out in the bottle, making it difficult to deliver a specific dose consistently. Vigorous shaking is required to resuspend the drug. When administered concurrently with tube feedings, phenytoin may bind with the feeds, reducing absorption of the drug. Although theoretically possible with all oral forms, this is most frequently reported with the suspension formulation. If serum levels begin declining in patients previously maintained on a fixed dosing regimen, administration may need to be staggered with feedings to allow time for complete absorption. Chewable tablets may be crushed and put down feeding tubes, and the capsules may be emptied and instilled through the tube. The extended phenytoin sodium contained in the capsule formulation retains its delayed-release properties even when removed from the capsule shell if administered without crushing.

Parenteral formulations of phenytoin are insoluble in water and contain solvents (propylene glycol and alcohol) to produce a solution. These solvents contribute to the problems associated with parenteral administration. Manufacturers recommend direct push into a running IV line at no more than 50 mg/min. Rates exceeding this lead to cardiac toxicity and hypotension. When administering large loading doses, however, this can be inconvenient. Dilution in various fluids can cause precipitation of the drug. Although not recommended by manufacturers, various researchers have studied administration of phenytoin in 0.45% and 0.9% sodium chloride or lactated Ringer’s solution with good results. Most studies mixed the drug in 100 to 500 mL of fluid and used an in-line filter to prevent transmission of microcrystals to the patient. This technique may offer an alternative to IV push when large doses of phenytoin are given. Intramuscular (IM) administration is not advisable because absorption is highly erratic, and the extreme alkaline pH of the injection causes tissue damage.

Drug Interactions. Phenytoin is subject to interactions with many other drugs. As mentioned previously, any agents that displace phenytoin from binding sites will potentiate its effect. Warfarin, tricyclic antidepressants, and aspirin are examples of agents that cause displacement interactions. Because phenytoin is metabolized in the liver, drugs inhibiting (e.g., fluconazole, valproic acid) or inducing (e.g., phenobarbital, carbamazepine) hepatic metabolism may alter serum phenytoin concentrations (pharmacokinetic interaction). In addition, phenytoin can alter effects of other anticonvulsants by unpredictable complex mechanisms. Phenytoin may increase or decrease the action of phenobarbital and valproic acid and decrease the effect of carbamazepine (pharmacodynamic interaction). Patients should be carefully monitored when adding or discontinuing any medications when taking phenytoin. Drug-food interactions may also be clinically relevant. Long-term phenytoin administration can lower folic acid levels in patients, whereas folate replacement therapy may decrease its anticonvulsant effects.

Side Effects and Toxicities. With increasing plasma levels, common side effects include nystagmus, drowsiness, ataxia, fatigue, and cognitive impairment. Gastrointestinal (GI) symptoms of nausea, vomiting, or diarrhea are seen frequently. Administering phenytoin with meals can reduce the occurrence of these effects. Some patients may develop a drug-induced fever while on phenytoin. Patients may develop an erythematous morbilliform rash requiring discontinuation of the drug. Gingival hyperplasia is a frequent side effect with long-term phenytoin use. Patients should be counseled on the importance of good oral hygiene to minimize this problem. Rare complications include hepatotoxicity and blood dyscrasias, including thrombocytopenia.

TABLE 12-4 ANTICONVULSANT AGENTS

DRUG	COMMON DOSES	THERAPEUTIC SERUM LEVEL	ADVERSE EFFECTS	COMMENTS
Barbiturates
Phenobarbital	3—5 mg/kg/day	15-40 mg/L	Sedation, rash, ataxia, hyperactivity, respiratory depression, hypotension (IV)	Induces hepatic metabolism—may increase elimination of drugs
Primidone (Mysoline)	10-25 mg/kg/day	5-20 mg/L	Sedation, ataxia, nausea, dizziness, rash (similar to phenobarbital)	Active metabolites: PEMA and phenobarbital
Hydantoins
Phenytoin (Dilantin)	4-8 mg/kg/day	10-20 mg/L	Nystagmus, rash, sedation, fever, gingival hyperplasia, ataxia, hypotension and bradycardia, pain on injection (IV)	IV administration: limit 50 mg/min as direct push into running IV line. Enzyme inducer
Fosphenytoin (Cerebyx)	4-8 mg PE/kg/day	10-20 mg/L	Pruritis, significantly less cardiotoxicity; otherwise similar to phenytoin	150 mg PE/min maximum IV administration
Other Agents
Carbamazepine (Tegretol, Carbatrol)	10-35 mg/kg/day	4-12 mg/L	Dizziness, ataxia, nystagmus, rash, diplopia, aplastic anemia	Induces own metabolism and metabolism of other drugs
Valproic acid (Depakene, Depakote, Depacon)	15-60 mg/kg/day	50-100 mg/L	Nausea, vomiting, diarrhea, drowsiness, liver toxicity	Hepatic enzyme inhibitor. IV should be divided every 6 hours
Clonazepam	2-20 mg/day	20-80 ng/mL	Drowsiness, ataxia	Tolerance to anticonvulsant effect may occur
Felbamate (Felbatol)	15-45 mg/kg/day	Not established	Nausea, vomiting, diarrhea, anxiety, insomnia, headache, hypophosphatemia, rash	Risk of fatal aplastic anemia, liver failure; use recommended only if benefits exceed risks
Gabapentin (Neurontin)	900-4,800 mg/day	Not established	Drowsiness, ataxia, dizziness, fatigue	No known interactions with other anticonvulsants; beneficial in pain management
Lamotrigine (Lamictal)	100-500 mg/day	Not established	Dizziness, diplopia, headache, ataxia, nausea, severe skin rash	Slow dosage titration required; approved for monotherapy
Topiramate (Topamax)	200-900 mg/day	Not established	Drowsiness, dizziness, fatigue, parasthesias, impaired cognition	Dosage titration over 8 weeks
Tiagabine (Gabitril)	32-56 mg/day	Not established	Dizziness, somnolence, asthenia, tremor, anxiety, confusion	Rare incidence of serious rash
Oxcarbazepine (Trileptal)	300-1,800 mg/day	Not established	Headache, drowsiness, fatigue, dizziness, hyponatremia	Lacks hematologic toxicity seen with carbamazepine
Zonisamide (Zonegran)	100-400 mg/day	Not established	Impaired memory, drowsiness, ataxia, nystagmus, diplopia, nephrolithiasis	Long plasma half-life of 50-68 hours
Levetiracetam (Keppra)	1,000-3,000 mg/day	Not established	Asthenia, headache, pain, dizziness, somnolence	No titration required; therapy initiated at therapeutic dose
Pregabalin (Lyrica)	75-300 mg/day	Not established	Diplopia, somnolence, ataxia, arthralgias,thrombocytopenia	C-V controlled substance, also for neuropathic pain
Lacosamide (Vimpat)	100-400 mg/day	Not established	Diplopia, somnolence, ataxia, PR prolongation	C-V controlled substance
Refractory Status Epilepticus
Midazolam	0.1-0.2 mg/kg bolus; maintenance IV at 0.04-2 mg/kg/hr	Not established	Hypotension, respiratory depression	Tachyphylaxis may develop rapidly requiring frequent dose titrations
Propofol	1-2 mg/kg bolus; maintenance IV at 2-10 mg/kg/hr	Not established	Hypotension, respiratory depression	Cardiac depressant effects at high doses
Pentobarbital	10-20 mg/kg bolus; maintenance IV at 1-5 mg/kg/hr	Not established	Hypotension, respiratory depression, cardiac depressant	Typically requires fluid and/or pressor support

Fosphenytoin (Cerebyx)

Due to the adverse effects associated with parenteral phenytoin, fosphenytoin was developed. It is a water-soluble phosphate ester of phenytoin, which is converted to phenytoin in the blood stream by plasma esterases. Because of molecular weight differences, fosphenytoin is dosed in “phenytoin equivalents,” or PEs. Thus, 100 mg PE of fosphenytoin delivers 100 mg of phenytoin. Because it lacks the propylene glycol solvent, fosphenytoin is better tolerated from a cardiovascular standpoint. The maximum rate of administration for fosphenytoin is 150 mg PE/min, compared with 50 mg/min for parenteral phenytoin. Due to the time needed for conversion, faster administration does not equate to faster onset of pharmacologic effect. The formulation has a less basic pH of 9 (compared with pH 12 for phenytoin), so tissue damage and pain from injection are reduced. As a result, fosphenytoin may be given intramuscularly if necessary. As phenytoin is the active component of fosphenytoin, other side effects noted previously with phenytoin are also observed. Pruritus has also been observed in patients receiving fosphenytoin; this is attributed to the phosphate component of the formulation. Although ease of administration and reduced side effects are significant benefits, fosphenytoin is considerably more expensive than phenytoin. Therefore, some health care centers restrict the use of fosphenytoin to patients without central venous access who cannot tolerate enteral phenytoin.

Valproic Acid (Depakene, Depakote, Depacon)

Valproic acid is a carboxylic acid compound that exerts its anticonvulsant activity through increasing brain levels of γ-aminobutyric acid. There may also be some effect on potassium channels and direct membrane-stabilizing effects. The drug is usually used for treatment of absence seizures or in combination with other agents for control of various convulsive disorders. The enteric-coated formulation, divalproex sodium (Depakote), is metabolized to valproic acid in the gut. An IV formulation, valproate sodium (Depacon), is also available. Dosing is the same for all three products. However, the manufacturer currently recommends that Depacon be dosed no less frequently than 6-hour intervals unless trough serum levels are monitored.

An extended-release form of divalproex sodium (Depakote ER) is indicated for both seizure control and migraine headache prophylaxis. The tablet is formulated to be administered as a single daily dose, but some epileptologists opt to dose twice daily when used for seizures. Also, there is potential for confusion between the two Depakote formulations, so extra scrutiny is required to ensure that the proper dosage form for the patient is selected.

Serum Concentration Monitoring. The accepted therapeutic range for valproate is 50 to 100 mg/L. However, some studies have shown that higher levels may be necessary for effective seizure control. Most toxicities associated with valproic acid do not seem to be correlated with serum concentration as much as with total dose administered. Steady state plasma levels are normally achieved in 2 to 4 days.

Drug Interactions. Valproic acid is a potent inhibitor of hepatic microsomal enzymes. As such, drugs that are metabolized in the liver are eliminated more slowly from the body. Phenobarbital clearance is decreased considerably when combined with valproic acid. Valproate is greater than 90% bound to plasma proteins, creating the potential for displacement interactions. These effects may occur simultaneously, leading to unpredictable results when valproic acid is combined with other anticonvulsants. Combinations with phenytoin or carbamazepine are representative of this phenomenon, leading to increased toxicities or loss of seizure control when adding or removing agents from a patient’s regimen.

Side Effects and Toxicities. GI complaints are the most frequently reported problem with valproic acid therapy; they include nausea, vomiting, indigestion, diarrhea, and anorexia. These can be reduced by administering the dose with food or by changing to an enteric-coated formulation. Central nervous system (CNS) symptoms of drowsiness, ataxia, and tremor are also reported. Hepatotoxicity may occur, usually within the first 6 months of therapy. This has been most commonly reported in children younger than 2 years on multiple anticonvulsants. Minor elevations in liver function test results are often seen and appear to be dose related. Some physicians recommend L-carnitine treatment to protect against hepatotoxicity, but this has not been clearly proven effective. Elevations in serum ammonia levels may also occur with valproic acid, which may be independent of any liver dysfunction. Valproic acid also affects platelet aggregation and may cause thrombocytopenia and other blood dyscrasias. Reduction in dose usually results in an increase in the platelet count.

Carbamazepine (Tegretol)

Carbamazepine is an iminostilbene derivative chemically related to the tricyclic antidepressants. It is believed to reduce polysynaptic responses and block post-tetanic potentiation via sodium channel blockade. The drug is useful in the treatment of generalized and partial epilepsy.

Serum Concentration Monitoring. Serum levels from 4 to 12 mg/L are considered therapeutic for carbamazepine. Steady state levels are initially reached in 3 to 5 days. Carbamazepine, however, has the unique property of inducing its own metabolism (autoinduction). The initial drug half-life of carbamazepine ranges from 25 to 65 hours, but decreases to 12 to 17 hours with long-term dosing. This effect is seen in the first few days of therapy and is normally complete in 3 to 4 weeks. Thus, patients stabilized on a given dose early in the course of therapy may experience decreased levels and loss of seizure control with time. Frequent monitoring and dosage adjustments are necessary in the first few months of treatment to optimize drug therapy.

Drug Interactions. In addition to inducing its own metabolism, carbamazepine can induce the metabolism of other drugs. Interactions have been documented with valproic acid, warfarin, and ethosuximide, resulting in decreased blood levels of these agents. Carbamazepine is 76% bound to plasma proteins; thus, displacement interactions are less a problem than with other anticonvulsants. Other drugs induce (phenobarbital, phenytoin, primidone) or inhibit (valproic acid, cimetidine, erythromycin) the metabolism of carbamazepine and require careful monitoring with concomitant use.

Side Effects and Toxicities. The most common side effects of carbamazepine therapy are drowsiness, dizziness, headache, diplopia, nausea, and vomiting. These may be minimized by slow titration of dose and tend to decrease with time. Serious bone marrow toxicities have been reported, including aplastic anemia, agranulocytosis, and thrombocytopenia; fortunately, these are rare. Leukopenia is the most common blood abnormality seen in about 10% of patients but is usually transient. Skin rashes may occur, ranging from a mildly eczematous form to a Stevens-Johnson syndrome. Carbamazepine
may also induce a hyponatremic hypo-osmolar condition similar to the syndrome of inappropriate antidiuretic hormone (SIADH).

Phenobarbital

Phenobarbital is a barbiturate that exerts its anticonvulsant effect by depression of postsynaptic excitatory discharge. Therapeutic levels are between 15 and 40 mg/L. The half-life is extremely long (100 hours); thus, steady state levels will not be reached for 3 to 4 weeks after initiating therapy. However, this does allow for convenient once-daily dosing in most patients.

Drug Interactions. Phenobarbital is a potent inducer of hepatic microsomal enzymes. Thus, it may reduce blood concentrations of any drug cleared by the liver, including phenytoin, carbamazepine, and valproic acid. Phenobarbital metabolism may be inhibited by valproic acid or ethanol.

Side Effects and Toxicities. The primary side effects of phenobarbital are sedation, fatigue, and depression. Tolerance to these effects develops with long-term use. In children and the elderly, the drug may produce opposite effects, causing insomnia and hyperactivity. Hypotension can occur with IV administration. IM injections are painful and can produce tissue necrosis. Respiratory depression can be profound after IV phenobarbital injections, especially when combined with benzodiazepines.

Other Agents

Many new anticonvulsants have been introduced over the last 2 decades. These agents have the advantage of more favorable efficacy to toxicity profiles for many patients. Serum concentration monitoring is also not routinely advocated with the newer agents, as blood levels do not correlate as closely to effect as with the older seizure medications. Other anticonvulsants include felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), tiagabine (Gabitril), topiramate (Topamax), oxcarbazepine (Trileptal), levetiracetam (Keppra), zonisamide (Zonegran), pregabalin (Lyrica), and lacosamide (Vimpat), among others. These agents are indicated for adjunct use in various convulsive disorders. Lamotrigine, topiramate, and oxcarbazepine have demonstrated efficacy as monotherapy in recent trials and are approved for use as single agents for various seizure types. Some patients have developed severe, life-threatening rashes requiring hospitalization while taking lamotrigine, especially when combined with valproic acid. Patients presenting with a rash while on lamotrigine should normally have therapy discontinued.

Gabapentin, levetiracetam, pregabalin, and lacosamide are unique among the anticonvulsants because they have not been found to interfere with the metabolism of other seizure medications. This is a desirable property when adding these agents to complex medication regimens. Felbamate has been noted to cause aplastic anemia and liver failure in some patients. Given this, the Food and Drug Administration (FDA) warned that patients should be withdrawn from felbamate treatment when possible. Current recommendations state that felbamate should only be used in patients refractory to other agents. When the risk of uncontrolled seizures outweighs the potential risk of hematologic or hepatic problems, physicians are encouraged to obtain informed consent and should perform frequent monitoring for associated symptoms.

Oxcarbazepine is an analogue of carbamazepine that appears to lack the hematologic toxicities seen with carbamazepine. Other adverse effects, however, are comparable between the two agents. It also does not appear susceptible to autoinduction as with carbamazepine. Dosage reductions are required for patients with varying degrees of renal impairment managed on gabapentin, pregabalin, or levetiracetam, as they are predominantly eliminated by the kidney.

Long-Term Management of Anticonvulsants

Patients with epilepsy or other secondary seizure disorders often require long-term therapy with anticonvulsants to keep symptoms under control. Maintaining adherence to their medication regimen is crucial, because the most frequent cause of seizures in this population is abrupt withdrawal from anticonvulsants. Patients will need to be counseled on the importance of maintaining dosing schedules, potential side effects and their management, and the possibility for other drugs to interact with their antiepileptic medications. Frequent blood level monitoring may be necessary, especially when titrating doses of newly added agents. Establishing a relationship with a community pharmacist is essential to ensure safe management of this disease. Pharmacists can help patients understand the side effects they encounter and provide close monitoring for drug interactions with prescription and nonprescription medications.

Sedation and Neuromuscular Blockade

The decision to give neuroscience patients sedatives is complex. On one hand, untreated agitation can contribute to ventilator noncompliance, self-extubation, and decannulation; can induce or worsen hypertension; and can elevate intracranial pressure (ICP). However, agitation can also be an important symptom of hypoxemia, evolving sepsis, worsening neurological injury, or pain. Potentially reversible causes of agitation must be identified and treated before giving sedatives because the patient’s neurological assessment will be compromised once therapy is started.

After the decision to implement sedation has been made, careful monitoring is important. Aspiration precautions should be instituted when appropriate. Respiratory depression and hypotension are common side effects of sedative regimens, so excessive sedation should be avoided. Prolonged sedation from overzealous administration of these drugs can delay extubation⁵, ⁶ and complicate brain death protocols. Sedation can also mislead clinicians into suspecting acute neurological deterioration and prompt otherwise unnecessary computed tomography scans. For these reasons it is preferable to titrate sedative administration according to a sedation scale, such as the Ramsay, rather than giving an arbitrary amount. Newer technologies, such as the bispectral index or BIS monitor, may also improve ability to monitor level of sedation. Continuous infusions of sedatives are probably more likely to result in excessive sedation than intermittent administration. Either way, the patient must be allowed to recover at regular intervals to allow neurological assessment. Recent research has focused on developing shorter-acting sedatives to minimize these concerns and make them easier to use. Specific details regarding the use of individual sedatives and neuromuscular blockers can be found in Table 12-5.

Benzodiazepines

Benzodiazepines are commonly used for sedation of the neuroscience patient. They can be given as an intermittent IV bolus or a continuous infusion. Benzodiazepines are relatively insoluble in water. This can be an important consideration when fluid limitation
is necessary and dose requirements are high. This situation commonly occurs in neuroscience patients with benzodiazepine tolerance for whatever reason (tachyphylaxis) or a history of significant ethanol abuse (accelerated metabolism). The pharmacist should be consulted before dilution when concentrated continuous infusions are required.

TABLE 12-5 SEDATION AND NEUROMUSCULAR BLOCKADE

DRUG	DOSE^a	ADVERSE EFFECTS	COMMENTS
Benzodiazepines
Diazepam	0.1-0.2 mg/kg q1-2h Onset: 1-3 mins	Excessive sedation, respiratory depression, hypotension	Commonly used for initial control of seizures, active metabolite, vein irritant Considerably higher doses may be necessary in patients tolerant to benzodiazepines (see text)
Lorazepam	0.04 mg/kg q2-4h Onset: 5-15 mins	See diazepam	See diazepam, inactive metabolites, predictable response in critically ill
Midazolam	0.025-0.035 mg/kg q1-2h Onset: 1-3 mins Infusion: 0.05-5 mcg/kg/min	See diazepam, prolonged sedation, especially with continuous infusions	Unpredictable elimination in critically ill patients
Propofol	Bolus: 1-2 mg/kg Infusion: 5-50 mcg/kg/min	Cardiovascular depression, infection risk with long hang times hypotension	No withdrawal syndrome, quick recovery, expensive, does not directly lower intracranial pressure
Pentobarbital	3-5 mg/kg over 30 mins, then 1 mg/kg/hr Onset: < 1 min	Cardiac depression	Serum concentration of 30-50 mcg/mL may produce coma with low risk of cardiac side effects; must have level <10 mcg/mL to determine brain death
Dexmedetomidine	0.2-0.7 mcg/kg/hr (may load with 1 mcg/kg over 10 mins)	Hypotension, bradycardia	Sedation with arousability maintained, no depression of respiratory drive
Neuromuscular Blockers
Pancuronium	0.01-0.015 mg/kg q1-2h	Tachycardia	Active metabolite accumulates in renal failure, “train-of-four” monitoring with nerve stimulator best for monitoring efficacy
Vecuronium	0.01-0.015 mg/kg; repeat q1h or start 1 mcg/kg/min infusion	Prolonged paralysis increasingly reported	Partially active metabolite may accumulate in renal failure, expensive, use “train-of-four” monitoring
Cisatracurium	0.1 mg/kg, then 1-3 mcg/kg/min	Minimal histamine release	Does not accumulate in renal or hepatic failure, expensive, monitor “train-of-four”
^aSedative doses provided are for parenteral management of acute agitation only. Considerably higher doses are occasionally required with long-term use (see text). Chronic oral dosing (where appropriate) will differ and is highly patient specific.

Diazepam is the oldest injectable benzodiazepine. It is still frequently used for initial control of seizures. Lorazepam has also been available for several years and is particularly useful in patients with hepatic dysfunction because its elimination tends to be preserved under these conditions compared with actions of other benzodiazepines. Midazolam is the newest parenteral benzodiazepine, and some clinicians consider it the drug of choice due to its short half-life. However, more recent data have shown that the duration of sedation of all injectable benzodiazepines is roughly equal. In fact, numerous case reports describe long recovery times (i.e., days) after midazolam infusions are stopped in critically ill patients. Midazolam has also been used as a high-dose continuous infusion to control refractory status epilepticus.

Flumazenil is a specific benzodiazepine antagonist that can quickly reverse excessive sedation from these drugs. However, using flumazenil this way is specifically discouraged because it can cause severe withdrawal symptoms and seizures in benzodiazepine-tolerant patients. Patients who receive flumazenil should be monitored closely because it is very short acting. Resedation after it wears off is common.

Other Sedatives

Propofol is a very short-acting sedative frequently used in the neuro-ICU. It is particularly useful when the anticipated duration of sedation is short, because recovery is rapid. Patients with long-term sedation requirements should receive a different agent because the short sedation duration is no longer advantageous. Individual propofol preparations should not hang for longer than 12 hours because it is provided as a lipid emulsion and is therefore an excellent medium for microbial growth. It is also a significant source of calories that needs to be considered when feeding regimens are titrated. Propofol has also been associated with cardiac toxicity and pancreatic injury; patients should be monitored for symptoms of organ dysfunction with prolonged use.

Dexmedetomidine (Precedex) is a centrally acting α-agonist with unique sedative properties. It induces sedation, mimicking natural sleep, while allowing the patient to remain easily arousable with no effect on respiratory function. Hypotension or bradycardia may be an issue in patients receiving the drug. Dexmedetomidine is typically more expensive compared to other sedatives as it is not available as a generic product. Haloperidol is a useful sedative and is particularly effective for patients experiencing delirium. Low doses tend to be prescribed, often with disappointing results; however, a properly titrated dose can be safe and effective. Conversely, higher doses can cause akathisia, which may be confused with agitation and lead to adverse effects from continued administration. Prolongation of the
QT interval may also occur with frequent dosing. Close monitoring is key to successful haloperidol use. Haloperidol can lower seizure threshold and is usually not used in patients with known epilepsy. It can also cause hypotension if administered too quickly. Newer atypical antipsychotics such as risperidone, quetiapine, aripiprazole, or olanzapine have a more favorable safety profile and are being used more frequently to control delirium. The barbiturate pentobarbital is usually reserved for inducing pharmacologic coma in the setting of status epilepticus or elevated ICP unresponsive to other treatment. High doses can suppress cardiac function. Serum pentobarbital concentrations can be monitored, but the correlation with efficacy or toxicity is poor. Low concentrations (<10 mcg/mL) need to be documented before declaring brain death in patients who have received high doses of pentobarbital.

Long-Term Management of Sedatives

Long-term sedative use should be reserved for patients in whom agitation secondary to a residual neurological deficit places them or others at risk for harm. Sedatives should be carefully withdrawn at intervals to make sure they are still indicated because excessive or unnecessary sedation can mask or impede neurological recovery. Fall precautions should be observed, even in patients taking these drugs chronically. Aspiration is also a long-term risk. Sudden discontinuation of long-term benzodiazepine therapy can precipitate a withdrawal reaction. Depending on the benzodiazepine, the onset can be delayed for as long as 7 days after cessation of therapy. Extreme agitation with hyperdynamic vital signs is a routine symptom. Seizures are not uncommon. The shorter-acting benzodiazepines alprazolam and lorazepam may have a higher risk of seizure with sudden withdrawal.

Neuromuscular Blockade

Occasionally, a patient may be so combative that neuromuscular blockade (NMB) is warranted. Other indications include short-term paralysis for a bedside procedure or elevated ICP unresponsive to other treatments. NMB is also used to decrease the work of breathing in patients with acute respiratory distress syndrome and increase ventilator compliance, particularly when nonphysiologic modes, such as inverted inspiratory:expiratory ratio, are used. Pancuronium, vecuronium, and cisatracurium are the most frequently prescribed neuromuscular blockers in the ICU setting. Specific details are listed in Table 12-5.

Careful monitoring is important when continuous NMB is prescribed. All neuromuscular blockers are associated with tachyphylaxis. Therefore, as the patient becomes “tolerant” to a drug, higher doses are required. Patients requiring amounts that greatly exceed maximum recommended doses will usually respond to a different agent. Doses should be titrated so that one or two twitches are maintained when a “train-of-four” is assessed by a nerve stimulator. Failure to monitor carefully increases the risk of excessively prolonged NMB after the drug is stopped. Complete blockade lasting several days after drug discontinuation has been reported, particularly with vecuronium, resulting in abnormal neuromuscular weakness lasting several weeks after initial recovery. In addition, excessive doses waste health care dollars because NMB regimens are very expensive. Patients receiving neuromuscular blockers to improve respiratory status may achieve ventilator compliance goals while technically “subtherapeutic” from a train-of-four perspective. Using this as a therapeutic end point is appropriate and should limit episodes of prolonged NMB and reduce drug wastage.

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