9 - Neurologic and Psychiatric Therapeutics

Editors: Susla, Gregory M.; Suffredini, Anthony F.; McAreavey, Dorothea; Solomon, Michael A.; Hoffman, William D.; Nyquist, Paul; Ognibene, Frederick P.; Shelhamer, James H.; Masur, Henry

Title: Handbook of Critical Care Drug Therapy, 3rd Edition

Copyright 2006 Lippincott Williams & Wilkins

> Table of Contents > Chapter 9 - Neurologic and Psychiatric Therapeutics

Chapter 9

Neurologic and Psychiatric Therapeutics

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TABLE 9.1. Seizures Urgent Management

Drug	Dosage	Comment
Thiamine	100 mg IV/IM	To avoid Wernicke's encephalopathy in alcoholics after glucose administration
Dextrose 50%	25 50 ml IV	For hypoglycemic seizures
Diazepam	2.5 10 mg IV, repeat after 5 10 min if needed	May cause respiratory depression and hypotension Seizures may recur because duration of efficacy is short
Phenytoin	10 20 mg/kg IV	Maximum infusion rate 50 mg/min Precipitates if injected into glucose-containing solutions Arrhythmias develop during rapid administration; monitor ECG Can produce hypotension
Fosphenytoin	10 20 PE/kg IV	Fosphenytoin should be prescribed in PE Fosphenytoin 75 mg = phenytoin 50 mg Infusion rate should be 100 150 mg PE/min Continuous monitoring of ECG, BP, and respiration is essential during IV loading Peak phenytoin levels occur approximately 2 h after the end of the loading infusion Fosphenytoin should not be administered IM for the treatment of status epilepticus
Phenobarbital	10 20 mg/kg IV	Maximum infusion rate 50 mg/min Respiratory depression and hypotension should be anticipated
Thiopental	25 100 mg IV	Hypotension and apnea are expected 5 mg/kg induces general anesthesia, but with a variable response
Neuromuscular blocking agents	See Table 2.4	Neuromuscular blocking agents possess no anticonvulsant properties For intractable seizures or life-threatening acidosis or muscle contractions Use of these agents can mask seizure activity; therefore, EEG monitoring is required
General anesthesia		For intractable seizures or life-threatening acidosis or muscle contractions
ECG, electrocardiogram; EEG, electroencephalogram; IV, intravenous; IM, intramuscular; PE, phenytoin sodium equivalent; BP, blood pressure

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TABLE 9.2. Seizures Maintenance Therapy

Drug	Daily Dosage	Optimal Blood Level ( g/ml)	Comment
Carbamazepine	5 25 mg/kg PO divided tid-qid	4 8	Metabolized to active metabolite Side effects: nystagmus, dysarthria, diplopia, ataxia, drowsiness, nausea, blood dyscrasias, hepatotoxicity
Fosphenytoin	Maintenance dose: 4 6 mg/kg PE total daily dose IV/IM divided doses q8h Temporary substitution for oral Dilantin: same as daily oral Dilantin dose in mg	10 20 (measured as phenytoin) Free level 1 2	Fosphenytoin 75 mg = phenytoin 50 mg Maximum infusion rate 150 mg PE/min IV infusion requires continuous ECG, BP, and respiratory monitoring Administer fosphenytoin substitution doses at the same frequency as oral Dilantin Side effects: tingling, paresthesias after IV administration; other side effects similar to phenytoin
Gabapentin	900 mg PO divided tid		Side effects: fatigue, somnolence, dizziness, ataxia
Lamotrigine	25 mg PO every other day if on valproic acid + enzyme inducer; 50 mg/d if not on valproic acid, but on enzyme inducer		Side effects: rash, abnormal thinking, dizziness, ataxia, nervousness, somnolence, diplopia, nausea, vomiting, weight gain
Phenobarbital	2 5 mg/kg PO/IV qd	10 40	Maximum infusion rate 50 mg/min Side effects: drowsiness, nystagmus, ataxia, skin rash, learning difficulties
Phenytoin	4 8 mg/kg PO/IV qd	Total level:10 20 Free level 1 2	Maximum infusion rate 50 mg/min Side effects: nystagmus, ataxia, dyskinesias, sedation, gingival hyperplasia, hirsutism, blood dyscrasias, rashes, systemic lupus erythematosus, peripheral neuropathy
Primidone	5 20 mg/kg PO divided tid	Primidone: 5 15 Phenobarbital: 15 40	Metabolized to phenobarbital, which contributes to pharmacologic activity Side effects: sedation, nystagmus, ataxia, vertigo, nausea, skin rashes, megaloblastic anemia
Topiramate	Goal of 200 mg PO bid Starting dose 50 mg PO bid		Adequate fluid intake should be maintained to minimize the risk of kidney stone formation Side effects: psychomotor slowing, difficulty in concentrating, speech and language problems, somnolence and fatigue, kidney stone formation
Valproic acid	10 60 mg/kg PO divided tid	50 100	Side effects: nausea, vomiting, diarrhea, drowsiness, alopecia, weight gain, hepatotoxicity, thrombocytopenia, tremor
Valproate sodium injection	10 60 mg/kg IV divided tid-qid IV dose equals the oral dose when used as a temporary substitute for oral therapy		IV product is intended for temporary substitution of oral valproate in same daily dose and dosing interval IV dose should be infused as a 60 min infusion, but not faster than 20 mg/min
BP, blood pressure; ECG, electrocardiogram; IM, intramuscular; IV, intravenous; PE, phenytoin sodium equivalent; PO, by mouth

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TABLE 9.3. Increased Intracranial Pressure

Agent	Dosage	Comment
Adjunctive therapy		Airway and hemodynamic management may be indicated Neurosurgical consultation
Mannitol	0.25 1.0 g/kg IV, then 0.25 0.5 g/kg IV q4h	As needed to maintain ICP without exceeding serum osmolality of 320 400 mOsm Adverse effects: transient immediate hypervolemia followed by diuresis and hypovolemia; hyperosmolar state; possible rebound increase in ICP after termination, particularly if mannitol is retained by abnormal tissue; exacerbation of intracranial bleeding
Hypertonic saline 23.4%	Standard dose of 30 ml (120 mEq) over 15 20 min (2ml/min) Maximum dose 60 ml	Must be administered through a central line Administration without a central line is an absolute contraindication This is for acute osmotherapy with the goal of reduced ICP Obtain serum sodium after every dose of 30 ml of 23.4% saline
Hypertonic saline 3%	Mixture 3% saline (50% as acetate 50% as chloride) Or mixture as 3% saline (100% as chloride) Starting dose 40 50 ml/h Titrate to serum sodium goal (140 160 meq) Serum sodium concentration of 160 is the maximum tolerated serum sodium concentration Common bolus volume is 250 cc	Must be administered through a central line Administration without a central line is an absolute contraindication Obtain serum sodium levels every 2 4 h while infusing and immediately after bolusing
Hypertonic saline 2%	Given as an IV bolus or continuous infusion Serum sodium should be monitored every 4 h while in the infusion	No absolute contraindications
Furosemide	10 20 mg IV q4h	Titrated Decreases edema and CSF production Does not produce rapid decreases in ICP
Pentobarbital	3 5 mg/kg IV bolus, over 30 min then 1 mg/kg/h Loading dose:    10mg/kg/h for 3 h then    2mg/kg/h	Monitoring: EEG burst suppression, therapeutic level of 20 50 g/ml Burst suppression goal 1:10 to 1:30 ratio of complexes to seconds
Lidocaine	0.5 1.5 mg/kg IV or intratracheally	Useful with acute airway manipulations to reduce coughing Can precipitate seizures
Dexamethasone	4 20 mg IV q6h	Decreases brain swelling with vasogenic edema Increases mortality in head trauma
CSF, cerebral spinal fluid; EEG, electroencephalogram; ICP, intracranial pressure; IV, intravenous

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TABLE 9.4. Cerebral Vasospasm

Goal	Treatment	Comments
If arterial pressure excessively elevated, lower toward normal range	Trimethaphan or labetalol	Refer to Tables 3.11 and 3.12; vasodilator agents may increase intracranial blood volume and intracranial pressure and are usually avoided in symptomatic vasospasm
Ensure adequate intravascular volume	Colloid and/or crystalloid solutions as appropriate	Fluids maximize cardiac performance and blunt catecholamine release and activation of renin-angiotensin system; if cerebral edema is severe, may need invasive monitoring
Avoid arterial hypotension	If hypotension does not correct with fluids, use phenylephrine	CPP = mean arterial pressure - intracranial pressure Phenylephrine does not constrict cerebral vessels; alternatives are dopamine or norepinephrine, dobutamine
Ensure adequate oxygenation	Supplemental oxygen as needed	Maximize cerebral oxygen delivery
Decrease severity of neurologic deficits	Nimodipine 60 mg PO q4h for 21 d	Calcium channel blocker that affects cerebral vessels preferentially; in subarachnoid hemorrhage protects against calcium-induced ischemic cell damage through unknown mechanisms; no side effects except occasional hypotension
Reversal of neurologic deterioration caused by vasospasm	Expansion of intravascular volume and elevation of systemic arterial pressure	Rapid expansion of intravascular volume with colloid and crystalloid to pulmonary artery wedge pressure of 12 18 mm Hg; raise systemic arterial pressure in increments of 10 mm Hg with dopamine until deficits reverse; hazardous if initiated in the presence of an untreated or unruptured aneurysm
CPP, cerebral perfusion pressure; PO, by mouth

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TABLE 9.5. Psychiatric Disorders

Disorder	Treatment	Dosage	Comments
Anxiety and Agitation			Benzodiazepines are the treatment of choice in controlling psychotic agitation and when panic and phobic anxiety account for agitated behavior
Benzodiazepines	Diazepam	PO: 2 10 mg bid-qid	Rapid onset Especially useful for rapid tranquilization
		IV/IM: 2 10 mg q4 6h prn	Available in IV and oral liquid dosage forms Active metabolites accumulate with multiple doses Reduced metabolism in the elderly and patients with liver disease Potential for drug interactions May cause excessive sedation
	Lorazepam	PO: 0.5 3 mg bid-tid IV/IM: 1 2 mg q1 4h prn	Slower onset than diazepam Available in IV and oral liquid dosage forms No active metabolites May cause excessive sedation
	Alprazolam	PO: 0.25 1 mg bid-tid	Useful in patients who have a panic or phobic component to their anxiety Lower doses should be used in elderly patients, patients with liver disease or low albumin
Delirium			Neuroleptic medications are thought to be specific for the treatment of delirium and psychosis, attendant agitation may be controlled more effectively by the use of a benzodiazepine with a neuroleptic agent
Neuroleptics	Haloperidol	(See Table 9.6) Mild agitation: 0.5 2 mg IV Moderate agitation: 2 5 mg IV Severe agitation: 5 10 mg IV Continuous infusion: 2 10 mg/h Less severe symptoms: 0.5 2 mg PO/IV/IM qhs-bid	IV medication required in acute delirium IM administration is not recommended because of the potential for erratic absorption in hemodynamically unstable patients Oral dose has about half of the potency of the IV dose Torsade de pointes is a potential complication Monitor QT interval and electrolytes when using high doses or continuous infusions, or in combination with other drugs that prolong QT interval
Benzodiazepines	Lorazepam	IV/IM: 1 10 mg q1 4h prn	Promotes additional calming when used in combination or alternating with haloperidol May result in decreased doses of haloperidol needed for clinical effect Diazepam or midazolam may be used in place of lorazepam when agitation is explosive and rapid control is desired
Depression
Psychostimulants	Methylphenidate	PO: 2.5 20 mg bid	Useful in patients who are lethargic, hard to mobilize, listless, or who show no interest in their care Give the afternoon dose before 3:00 PM so that the ability to fall asleep is not impaired
Conventional antidepressants			Useful if the response to psychostimulants is partial or ineffective Tricyclic antidepressants have a slow onset, have anticholinergic side effects, and can affect the cardiac conduction system The patient's medical record should be reviewed to determine if he or she has previously been treated with antidepressants and to assess his or her response to these agents
	Doxepin	PO: 25 mg qhs	Useful in depressed patients who have difficulty in falling asleep Increase by 25 mg nightly until an adequate sleep dose is achieved
	Nortriptyline	PO: 25 mg qhs	Increase 25 mg weekly up to 75 mg qhs, aiming for a serum concentration between 50 150 ng/ml
Serotonin reuptake inhibitors			Potential adverse effects of this class of antidepressants are overstimulation, agitation, and increased anxiety
	Fluoxetine	PO: 20 mg q AM	Metabolized through the cytochrome P450 system and has the potential for drug interactions
	Paroxetine	PO: 20 mg q AM	Metabolized through the cytochrome P450 system and is a potent inhibitor of this enzyme system; serious potential for many drug interactions
	Sertraline	PO: 50 mg q AM	Least potential for drug interactions
	Nefazodone	PO: 50 mg qhs	Possesses antidepressant and antianxiety properties, so it is useful in patients with an anxiety component to their depression An alternative to doxepin
	Citalopram	20 mg PO qd starting up to 60 mg PO qd maximum	SSRI antidepressant and reduced anxiety
	Escitalopram	10 mg PO qd starting May increase to 20 mg after 1 wk	SSRI antidepressant and reduced anxiety
	Venlafaxine	75 mg qd total daily dose Immediate release 25 mg PO tid or 37.5 mg bid Sustained release 75 mg PO qd	SSRI antidepressant and reduced anxiety
	Bupropion	100 mg PO bid starting dose Maximum 450 mg PO in bid or sustained release	Side effects are seizures SSRI with decreased depression and anxiety
IM, intramuscular; IV, intravenous; PO, by mouth; SSRI, selective serotonin reuptake inhibitor

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TABLE 9.6. Guidelines for Intravenous Haloperidol

Severity of Agitation	Haloperidol Dose
Mild	0.5 2 mg
Moderate	2 5 mg
Severe	5 10 mg
Allow 10 to 15 minutes between doses. For continued agitation, double the previous dose. For continued agitation after 3 doses, give lorazepam 0.5 10 mg IV either concurrently or alternating with haloperidol every 30 minutes. Consider a haloperidol continuous infusion (2 10 mg/h) if the agitation is poorly controlled with intermittent IV doses. Once the patient is calm, determine the total dose of haloperidol administered, and give this dose over the next 24 hours. The daily requirement can be divided into 2 doses, with the largest dose administered at bedtime. Give this dose for 24 48 hours; if the patient remains calm, begin reducing the dose by 50% every day. If the patient is stable and able to take oral medications, the tapering doses may be given orally (the oral dose = 2 the IV dose). Monitor QT interval and decrease dose or discontinue if QT interval prolonged because of risk of serious arrhythmia.

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TABLE 9.7. Alcohol Withdrawal Drug Therapy

Drug	Typical Dosage	Comment
Supportive Care
Folate Thiamine	1 mg PO/IV/IM qd 100 mg IM/PO qd 3 d	Folate, thiamine, and multivitamins should be given before the administration of dextrose to avoid precipitating Wernicke's syndrome
Multivitamin Magnesium	1 PO qd 1 2 g IV/IM qd-tid 3 d	Fluid and electrolytes should be administered to correct fluid and electrolyte disturbances IV multivitamins 1 vial/day in IV fluid
Benzodiazepines		Although there is no evidence that one benzodiazepine is more effective than another, benzodiazepines with long half-lives and active metabolites may be beneficial in alcohol withdrawal because they may help to smooth a tapering effect Late-onset seizures have been reported in patients being treated with short-acting benzodiazepines
Diazepam	5 10 mg PO tid, tapering over 5 10 d	Active metabolites Long half-life
Lorazepam	1 2 mg IV q4 6h titrated to sedation, tapering over 5 10 d	No active metabolites Intermediate half-life Preferred agent in patients with liver disease
Control of Adrenergic Symptoms
Atenolol	25 50 mg PO qd
Metoprolol	5 20 mg IV q4h
Clonidine	0.1 0.4 mg PO q8 12h	Central acting sympathomimetic that may diminish the use of sedatives; weekly patch (0.1 0.3 mg) may be used but is delayed in onset
Other
Alcohol	5% solution for IV infusion	Postpones withdrawal, toxic, difficult to titrate, and generally is not recommended
Haloperidol	2.5 150 mg/day in divided doses	May lower the seizure threshold; usually not indicated even when withdrawal hallucinations occur
Phenytoin	15 mg/kg load then 300 mg per day	For treatment of seizures
IM, intramuscular; IV, intravenous; PO, by mouth Note: The need for prophylaxis in patients undergoing alcohol withdrawal has been questioned recently. Therapy based on symptoms may be equally effective and diminish the need to treat large numbers of patients who may not experience withdrawal.

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TABLE 9.8. Treatment of Withdrawal Reactions

Agent	Therapy	Comments
Alcohol		See Table 9.7
Benzodiazepines
Short, intermediate-acting	Lorazepam 2 mg PO qid-tid, then taper over 5 7 d
Long-acting	Diazepam 5 10 mg PO qid-tid 5 d, then taper over 5 7 d	Active metabolites are beneficial in tapering agent after discontinuation
Opiates
Replacement therapy	Methadone 20 mg PO or 10 mg IM 1 dose A second dose may be given if significant relief is not obtained 1 h after the 1st dose	Dosing for withdrawal reactions requires less methadone than dosing for methadone maintenance; some patients require 20 40 mg daily to avoid psychological withdrawal
Sympatholytic therapy	Clonidine 6 g/kg PO loading dose followed by 6 17 g/kg/d PO divided tid 7 d, then taper over 3 d	Hypotension may be associated with higher doses May use clonidine topical patches for tapering regimen Dose may be decreased by changing patches every 3 d
IM, intramuscular; PO, by mouth

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TABLE 9.9. Myasthenia Gravis

Problem	Management	Comment
Acute diagnosis	Edrophonium 2 mg (0.2 ml) IV initially, if tolerated 8 mg (0.8 ml) IV after 30 s (results in improvement in muscle strength, 5 min duration) Or Neostigmine 1.5 mg IM (duration 2 h)	Assessment of patient with fluctuating weakness of voluntary muscles with symptoms of diplopia, ptosis, difficulty swallowing Atropine sulfate (0.6 mg IV/IM) should be available to reverse muscarinic effects Monitor respiratory function, avoid aminoglycosides
Therapy	Chronic therapy: Neostigmine 7.5 30 mg PO qid or pyridostigmine 30 180 mg PO qid Corticosteroids (prednisone 60 100 PO qd) in patients who respond poorly to anticholinergics and have undergone thymectomy. Alternatively azathioprine may be given 2 3 mg/kg/d Plasmapheresis	Conversion to IV dose is 1:60 conversion; with the IV dose being 1/60 of the oral dose of neostigmine and pyridostigmine Thus 60 qid of pyridostigmine bromide equaling 1,240 mg TTL daily dose would equal 4mg/ day of IV neostigmine as an IV infusion given over 24 h
IM, intramuscular; IV, intravenous; PO, by mouth; TTL, total

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TABLE 9.10. Acute Spinal Cord Injury

Problem	Management	Comment
Airway	Skilled and experienced operator necessary to prevent secondary injury Neutral traction during placement of airway	Lesions above C3 C4 require intubation and mechanical ventilation because of loss of diaphragm (C3 C5) Lesions below C5 C6 may result in reduced vital capacity and flow and require mechanical ventilation
Hypotension	Fluid resuscitation often with central pressure monitoring Vasopressors (see Table 3.8) after fluid resuscitation	Causes other than spinal shock should be aggressively sought because of associated thoracic and abdominal trauma
Bradydysrhythmias	Atropine 0.5 1 mg IV Pacemaker	If cardiac accelerator nerves (T1 T4) are involved, bradycardia and bradydysrhythmias may occur because of loss of sympathetic tone and unopposed vagal activity
Tachydysrhythmias	-Blockers (see Table 3.6)	Often accompany autonomic hyperreflexia If hypertension present, -adrenergic blockade required with -blockers
Loss of neurologic function	Stabilization of spine by traction and surgical fixation Surgical decompression of subdural or epidural hematomas Methylprednisolone 30 mg/kg IV, infused over 15 min; after 45 min, continuous infusion (5.4 mg/kg/h) for 23 h	Methylprednisolone treatment should be initiated as soon as possible (i.e., within 3 h of injury) Recent trials suggest that when therapy is initiated 3 8 h after injury, patients should be maintained on therapy for 48 h
Autonomic hyperreflexia	Minimize episodes of noxious or visceral stimuli (e.g., bladder or bowel distension) Pharmacologic therapy: trimethaphan, phentolamine (see Table 3.12)	Usually when flaccid paralysis or spinal shock occurs, it occurs below level of injury
Abnormal response to depolarizing muscle relaxants	Avoid depolarizing agents 12 h after injury (e.g., succinylcholine) and use nondepolarizing neuromuscular blockade (see Table 2.4)	Massive amounts of K+ can be released from skeletal muscle to extracellular space following depolarizing muscle relaxant Magnitude of K+ release is a function of muscle mass affected and may occur before spasticity is apparent
IV, intravenous

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TABLE 9.11. Thrombolysis for Acute Ischemic Stroke

Agent	Dosage	Comments
Tissue plasminogen activator	0.9 mg/kg (maximum dose 90 mg) infused over 60 min, with 10% of total dose given as IV bolus over 1 min	Indicated for thrombotic arterial occlusion with no evidence of intracranial hemorrhage on CT scan Treatment should be started within 3 h after onset of symptoms Antithrombotic and antiplatelet drugs should be withheld for 24 h Contraindications intracranial hemorrhage, or other bleeding riska
CT, computed tomography aSuspicion of subarachnoid hemorrhage or other bleeding, recent intracranial surgery or head trauma, recent major surgery, uncontrolled hypertension, intracranial neoplasm, aneurysm or vascular malformation, recent treatment with heparin or warfarin, or platelet count <100,000/cu mm.

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TABLE 9.12. Experimental Therapies for Acute Hemorrhagic and Ischemic Stroke

Agent	Dosing	Comments
Acute Hemorrhagic Stroke
Recombinant activated factor VIIa (Table 8.2)	20,80 g/kg dosing in IV push over 2 min Presently in randomized phase III trial 80 g/kg is the preferred dose for hemorrhage Must administer within 3 h of onset of ICH	Many adverse events including myocardial ischemia, pulmonary embolus, and ischemic stroke have been documented in this setting
Ischemic Stroke
Tenecteplase	Phase 2-B study of TNK in acute ischemic stroke (TNK-S2B) Dosing: 0.1 mg/kg TNK, 0.25 mg/kg TNK, or 0.4 mg/kg TNK Given as an IV bolus within 3 h of onset	This is an experimental therapy and is currently only used in the clinical research setting with informed consent and IRB approval
Desmoteplase	62.5 g/kg, 90 g/kg, 125 g/kg IV given as a single bolus 3 9 h if patient has a perfusion mismatch on MRI or CT perfusion scans	This is an experimental drug and is currently only used in the clinical research setting with informed consent and IRB approval
CT, computed tomography; ICH, intracranial hemorrhage; IRB, institutional review board; MRI, magnetic resonance imaging