Chapter 7 – Neuropharmacology in the Neurocritical Care Unit




Abstract




From protein binding alterations to frequent drug–drug interactions, from hypermetabolic states to anuria, there exists a multitude of reasons that the therapeutic interventions of choice must be individualized in a critically ill patient. The principles of clinical pharmacology provide the basis of optimizing a safe and effective drug regimen. The four major subdivisions of pharmacology include pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology. Simply stated, pharmacokinetics and pharmacodynamics focus on what the body does to the drug and what the drug does to the body, respectively. The following pharmacokinetic and pharmacodynamics factors must be taken into consideration to optimize effectiveness and to minimize toxicity.





Chapter 7 Neuropharmacology in the Neurocritical Care Unit



Sarah M. Adriance



Introduction


From protein binding alterations to frequent drug–drug interactions, from hypermetabolic states to anuria, there exists a multitude of reasons that the therapeutic interventions of choice must be individualized in a critically ill patient. The principles of clinical pharmacology provide the basis of optimizing a safe and effective drug regimen. The four major subdivisions of pharmacology include pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology. Simply stated, pharmacokinetics and pharmacodynamics focus on what the body does to the drug and what the drug does to the body, respectively. The following pharmacokinetic and pharmacodynamics factors must be taken into consideration to optimize effectiveness and to minimize toxicity.




  • Pharmacokinetics (PK)




    • Drug absorption



    • Drug distribution



    • Drug metabolism



    • Drug elimination



    • Drug dosing



    • Mediation compliance



    • Medication adverse drug events



    • Body weight



    • Body fluid volume




  • Pharmacodynamics (PD)




    • Drug interactions



    • Drug tolerance



    • Drug receptor availability



    • Genetic factors.



The key component to the subdivision of pharmacotherapeutics is monitoring for a clinical or therapeutic response to ensure maintenance of the desired outcome. This may include targeting adequate drug level concentrations in the serum. Overall this chapter aims to provide the clinician with the pharmacologic knowledge to select an appropriate drug regimen for the neurocritically ill adult patient. This chapter is not inclusive of all medications used in the course of care, but highlights common medications in the following classes: sedatives, analgesics, antiepileptics, osmotics, antishivering agents, and medications used to prevent and treat cerebral vasospasm.


Some fundamental pharmacology terms used in this chapter:




  • Elimination half-life – The time necessary to reduce drug concentration in the blood, plasma, or serum to one-half after steady state has been reached. Elimination half-life of a drug refers to the elimination of the parent drug molecule and not any metabolites, if present.



  • Enzyme induction – Faster metabolism of a compound due to an increase in either enzyme content or rate of enzymatic process. An inducer increases clearance and decreases steady-state concentrations of other substrates.



  • Enzyme inhibition – Slower metabolism of a compound, usually due to competition for an enzyme system. An inhibitor decreases clearance and increases steady-state concentrations of other substrates.



  • Linear pharmacokinetics – Serum concentrations of drug change proportionally with an increase in dose (most drugs follow).



  • Nonlinear pharmacokinetics – Serum concentrations of drug change disproportionally (greater increase) with an increase in dose (e.g. phenytoin).



Sedatives


Sedation is a broad term used in critical care that can encompass the administration of various pharmaceutical classes of medications that are general central nervous system (CNS) depressants. These include benzodiazepines and other benzodiazepine receptor agonists, opioid analgesics, barbiturates, sedative-hypnotics, α2-agonists, and neuroleptics, which are all of diverse chemical structures. The underlying needs of the patient must be carefully assessed so an appropriate medication can be selected and therapy can be optimized.


It has been documented in critically ill patients that continuous infusion analgesic and sedative agents can contribute to increased duration of mechanical ventilation and longer lengths of stay in the intensive care unit (ICU) and hospital [Reference Kress, Pohlman, O’Connor and Hall1]. Likewise, complications can arise with undersedation, such as agitation, anxiety, increased intracranial pressure (ICP), patient harm, removal of lines and devices, and ventilator dysynchrony [Reference Seder, Riker, Jagoda, Smith and Weingart2,Reference Mirski, Muffelman, Ulatowski and Hanley3]. While balancing sedation in any critical ill patient is important, the neurocritically ill patient presents unique challenges. Because the bedside clinician in the neurosciences critical care unit (NCCU) relies on an accurate neurologic exam as the principal means of assessing patient status, including improvement and deterioration, many drugs used in the course of managing sedation have the potential to also alter consciousness and interfere with this ever-important exam. Sedation requirements, including agent selection, must be considered carefully when a high-quality neurologic assessment is also necessary.


Common sedation indications in the NCCU include the following:




  • Patient comfort




    • Agitation



    • Anxiety



    • Fear



    • Pain




  • Increased ICP



  • Ventilator dysynchrony.


In the NCCU, general treatment principles to keep in mind during the provision of sedation are:




  1. 1. Analgesia is not provided by the majority of agents used to help manage sedation in the ICU and therefore one must consider pain as a source of agitation, anxiety or delirium, and treat it first.



  2. 2. A short-acting agent may allow for frequent interruption of therapy for an accurate neurologic exam.


Thoughtful sedation decisions also incorporate the following drug factors: route of administration, pharmacokinetics, on and off effects, and tolerability. With respect to the management of intracranial hypertension specifically, adequate sedation is important to control pain, autonomic stress, and agitation, which are factors that can negatively affect ICP.


When surveyed, practice in the NCCU revealed that the most common analgesic and sedative used were fentanyl and propofol, respectively [Reference Teitelbaum, Ayoub and Skrobik4], although it is important to note that no specific agent has evidence of superiority over another and safety and efficacy data specific to the neurocritically ill patient population are lacking. Additionally, patients may display a variable physiologic response due to genetic differences in the µ-opioid receptor. A brief discussion of the major analgesic and sedative classes used in a neurocritically ill patient follows. Refer to Table 7.1 for more specific pharmacologic and pharmacotherapeutic information for commonly used agents to manage sedation in the NCCU.




Table 7.1 Common IV sedation agents






















































Agent, Class IV Dosinga Key pharmacologyb Therapeutic considerations
Fentanyl

Analgesic, opioid
Intermittent

25–50 μg q 0.5–1 h

Continuous

25–100 μg/kg/h, titrate by

25 μg/h q 15–30 min
Onset: 1–2 min

Elimination t½: 0.5–1 h;

2–4 h repeated dosing

Metabolism: Hepatic

Excretion: Renal
• Reduce dose in severe renal impairment and moderate hepatic impairment. Avoid in severe hepatic impairment

• Hypercarbia may occur due to respiratory depression and lead to cerebral vasodilation and increased ICP
Hydromorphone

Analgesic, opioid
Intermittent

0.4–0.8 mg q 2–3 h
Onset: 5–15 min

Elimination t½: 2–3 h

Metabolism: Hepatic, active metabolite (H3G)

Excretion: Renal
• Reduce dose in severe renal and hepatic impairment

• Accumulation of active metabolites in renal impairment can lead to neuroexcitation

• Hypercarbia may occur due to respiratory depression and lead to cerebral vasodilation and increased ICP
Morphine

Analgesic, opioid
Intermittent

2.5–5 mg q 3–4 h
Onset: 5–10 min

Elimination t½: 3–4 h

Metabolism: Hepatic, active metabolites (M3G, M6G)

Excretion: Renal
• Reduce dose in moderate and severe renal impairment and severe hepatic impairment

• Accumulation of active metabolites in renal impairment can lead to neuroexcitation

• Hypotension may occur secondary to histamine release

• Hypercarbia may occur due to respiratory depression and lead to cerebral vasodilation and increased ICP
Remifentanil

Analgesic, opioid
Continuous

Load 0.5–1 μg/kg

Maintenance

0.05–0.2 μg/kg/min, titrate by 0.05 μg/kg/min q 5 min
Onset: 1–3 min

Elimination t½: 3–10 min

Metabolism: Plasma esterases

Excretion: Renal
• Base dose on IBW in obese patients (>30% over IBW)

• Dose reduce in elderly
Dexmedetomidine

Sedative, α2-agonist
Continuous

Load not recommended in critically ill

Maintenance

0.2–1.5 μg/kg/h, titrate by 0.2 μg/kg/h q 30 min
Onset: 5–10 min

Elimination t½: 2–3 h

Metabolism: Hepatic

Excretion: Renal
• Reduce dose in severe hepatic impairment

• Systemic hypotension adverse effect may impair CPP

• Bradycardia occurs commonly
Lorazepam

Sedative, benzodiazepine
Intermittent

0.25–1 mg q 5–30min

Continuous

0.5–2 mg/h, titrate by 0.5 mg/h q 0.5mg q 30min
Onset: 2–10min

Elimination t½: 12–14 h

Metabolism: Hepatic

Excretion: Renal

• Avoid in severe renal and hepatic impairment

• Hypercarbia may occur due to respiratory depression and may cause cerebral vasodilation and increased ICP (high doses)

• Systemic hypotension may impair CPP (high doses)

• IV formulation contains propylene glycol. High doses (≥1 mg/kg/day or ≥10 mg/h) may lead to accumulation and toxicity
Midazolam

Sedative, benzodiazepine
Intermittent

0.5–2 mg q 5–30 min

Continuous

1–4 mg/h, titrate by 1 mg/h q 30 min
Onset: 3–5 min

Elimination t½: 2–6 h

Metabolism: Hepatic, active metabolite

(1- hydroxymidazolam)

Excretion: Renal
• Prolonged sedation with prolonged infusion, especially in severe renal impairment

• Accumulation of active metabolite in renal impairment can lead to increased sedation and adverse effects

• Hypercarbia may occur due to respiratory depression and lead to cerebral vasodilation and increased ICP (high doses)

• Systemic hypotension may impair CPP (high doses)
Propofol

Sedative, hypnotic

Continuous

5–100 μg/kg/min, titrate by 5–10 μg/kg/min q 5–10 min
Onset: 1–2 min

Elimination t½: 30–60 min (wake-up time, however, is ≤15 min in infusions ≤72 h in duration)

Metabolism: Hepatic

Excretion: Renal
• Can decrease ICP via effects on cerebral metabolism

• Systemic hypotension may impair CPP

• Risk of PRIS increases at high doses (≥80 μg/kg/min), monitor for acidosis and creatinine kinase when used ≥48 h.

• Provides considerable IV lipid load, monitor triglycerides, and caloric intake (1.1 kcal/mL).

• Contraindicated in patients with severe allergy to egg and soy proteins




a Intermittent doses provided are initial starting doses and are based on approximate equipotent doses of medications in the same class.



b Values based on normal organ function


CPP cerebral perfusion pressure; GI gastrointestinal; h hour; H3G hydromorphone-3-glucuronide; IBW ideal body weight; ICP intracranial pressure; IV intravenous; kcal kilocalorie; kg kilogram; M3G morphine-3-glucuronide; M6G morphine-6-glucuronide; μg microgram; mg milligram; min minute; ICP intracranial pressure; N/V nausea, vomiting; PRIS propofol-related infusion syndrome; half-life; q every



Opioid Analgesics


Opioids are a core component of pain management in the ICU and can also provide mild sedative effects. Opioids exert their effects through interaction with three opioid receptors (δ, μ, κ). These receptors are widely distributed in CNS and peripheral tissues, including vascular, cardiac, airway, and gastrointestinal systems, leading to their diverse effects. Advantages of the commonly used opioids in the ICU include a rapid onset of action and short duration of action (especially with fentanyl and remifentanil) and reversibility with naloxone, an opioid receptor antagonist. Note naloxone should not be used to reverse opioid effects in order to perform a routine neurologic assessment due to potential precipitation of hypertension, tachycardia, and agitation. Lower doses of naloxone are recommended in critically ill patients. For example, 0.4 mg of naloxone may be diluted in 10 mL of normal saline to a final concentration of 40 μg/mL. Initial dosing of 40–80 μg aliquots may be used. Patients who have received longer-acting opioids may experience return of respiratory depression or sedation after the effects of naloxone dissipate, which can range from 30 to 60 minutes. Respiratory depression should be anticipated with opioids, especially at higher doses. Be aware that opioids can cause miosis and potentially interfere with an exam, signaling neurological deterioration with elevated ICP. Opioids as a class can also cause pruritus, chest wall or muscle rigidity (high doses), nausea/vomiting, and gastrointestinal dysmotility. The drug–drug interactions of major concern are those involving coadministration of other CNS and respiratory depressants, which may lead to exaggerated effects on these organ systems. The hepatic metabolism of fentanyl specifically involves the cytochrome P450 (CYP) enzymes, mainly 3A4. Administration of inducers of CYP450 3A4 (e.g. carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin) may increase the clearance of fentanyl, and inhibitors of CYP450 3A4 (e.g. antidepressants, azole antifungals, clarithromycin, diltiazem, erythromycin, protease inhibitors) can decrease its clearance. Hydromorphone undergoes hepatic metabolism via glucuronidation, and morphine via conjugation and therefore have fewer drug–drug interactions.



Benzodiazepines


The activity of the major inhibitory neurotransmitter γ–aminobutryic acid (GABA) is enhanced following administration of benzodiazepines. This class of medications binds to various subunits of the GABAA-gated chloride channel to modulate the effects of GABA and produce in varying degrees: anxiolysis, sedation, hypnosis, muscle relaxation, anterograde amnesia, and anticonvulsant activity. Benzodiazepines do not provide analgesia. Advantages of the commonly used benzodiazepines in the ICU (midazolam, lorazepam) include a rapid onset of action and reversibility with flumazenil, a GABAA receptor antagonist. Note that flumazenil should not be used to reverse benzodiazepine effects in order to perform a routine neurologic assessment. Caution with its use must be used in the neurocritically ill patient or in chronic users of benzodiazepines as its administration may lead to increase in ICP, hypertension, and lowering of the seizure threshold. Patients who have received longer-acting benzodiazepines may experience return of sedation after the effects of flumazenil dissipate, which can range from 20 to 60 minutes. Lower doses of benzodiazepines normally do not effect respiration in normal adults, but caution should be taken in those with impaired hepatic function (e.g. alcoholics, cirrhotics) or when other CNS depressants are present. Higher doses of benzodiazepines will decrease blood pressure and increase heart rate. These effects are more pronounced in patients with underlying cardiac disease. The drug–drug interactions of major concern are those involving coadministration of other CNS, cardiac, and respiratory depressants, which may lead to exaggerated effects on these organ systems. The hepatic metabolism of midazolam specifically involves the CYP enzymes, mainly 3A4. Administration of inducers of CYP450 3A4 (e.g. carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin) may increase the clearance of midazolam and inhibitors of CYP450 3A4 (e.g. antidepressants, azole antifungals, clarithromycin, diltiazem, erythromycin, protease inhibitors) can decrease its clearance. Lorazepam undergoes hepatic metabolism via glucuronidation and therefore has fewer drug–drug interactions.



Propofol


Propofol is thought to act primarily at the GABAA receptors in the CNS, although its exact mechanism is unknown. In addition to its sedative and hypnotic effects, propofol can also suppress electroencephalography (EEG) activity and therefore may be used as an anticonvulsant in higher doses. Propofol decreases cerebral oxygen utilization with subsequent reductions in arterial cerebral blood flow requirements, which leads to cerebral vasoconstriction. Propofol may be used to manage ICP second to this effect. Like the benzodiazepines, propofol does not provide analgesia. Advantages of this agent in the ICU include a rapid onset of action, an ultra-short duration of action, and rapidly titratable properties. Hypotension should be anticipated with propofol administration, which is more pronounced in patients with underlying cardiac disease or hypovolemia, in the elderly, or when other cardiac depressants are present. The drug–drug interactions of major concern are those involving coadministration of other CNS and cardiac depressants, which may lead to exaggerated effects on these organ systems. Respiratory depression is a common adverse effect.



Dexmedetomidine


Dexmedetomidine is a selective α2-agonist with sedative and mild analgesic properties. It primarily acts in the locus coeruleus to decrease sympathetic outflow and modulate pain pathways. Additional peripheral effects (vasoconstriction and hypertension) can occur at the α2b-receptor, which are observed when high doses are administered, such as loading doses. Dexmedetomidine may also be used in the NCCU for its antishivering effects, which are discussed further in another section of this chapter, and for the treatment of autonomic instability that may occur following neurologic injury. Comparative to the benzodiazepines or propofol, dexmedetomidine does not cause as much CNS depression and is devoid of respiratory depression at usual doses. The major advantage of this agent in the NCCU is related to its lighter sedative effects compared to other agents, which can preserve the neurological assessment. Hypotension and bradycardia are common with dexmedetomidine administration. Generally this agent is not well tolerated in hypovolemic patients or in the setting of hemodynamic instability. The drug–drug interactions of major concern are those involving coadministration of other CNS and cardiac depressants, which may lead to exaggerated effects on these organ systems.



Antiepileptics


Seizures and status epilepticus (SE) etiologies in the NCCU are numerous and commonly occur as a complication of neurological disease (e.g. stroke, anoxic brain injury, CNS infection, brain tumor, head trauma), antiepileptic drug (AED) discontinuation or noncompliance, metabolic derangements, and side effects of medications. Following immediate diagnosis, the timely administration (5 to 10 minutes) and the selection of an effective AED have proven crucial in prevention of neuronal damage and permanent brain injury. An EEG is used to confirm or exclude the diagnosis and to monitor the response to AEDs.


This section of the chapter will focus on the recommended pharmacologic treatments specifically for SE, as well as seizure prophylaxis in specific neurologic injuries. Following is a section on therapeutic drug level monitoring and key drug–drug interactions. The less frequently used agents such as ketamine, corticosteroids, and immunomodulation with intravenous immunoglobulin (IVIG) or plasma exchange are not highlighted here, but more information may be obtained from recent guidelines [Reference Brophy, Bell and Claassen5].


Current treatment recommendations for the management of SE are characterized as emergent, urgent or refractory treatments [Reference Brophy, Bell and Claassen5]. To summarize the clinical approach outlined in the recent guidelines, every patient that presents with SE needs the following, regardless of whether immediate control of SE was achieved:




  1. 1. An emergent treatment medication (i.e. benzodiazepine)



  2. 2. A second AED added for urgent treatment



  3. 3. An AED for maintenance therapy, which may be a scheduled dosing regimen of the urgent treatment AED selected.


If 20 minutes from the time of seizure onset has passed and SE is not controlled, refractory SE treatments (RSE) must be considered. The overall goal of treatment is to obtain control of SE within 60 minutes of seizure onset. While the treatment of SE focuses greatly on early and effective medication intervention, there are nonpharmacological measures that are standards of care and should not be missed [Reference Brophy, Bell and Claassen5].


It is important to emphasize that emergent treatment with a benzodiazepine is supported by randomized controlled trial data. In a pivotal trial, lorazepam successfully stopped more SE within 20 minutes of initiation and sustained control for at least 40 minutes when compared to phenobarbital, phenytoin, or combination therapy of phenytoin with diazepam [Reference Treiman, Meyers and Walton6]. Benzodiazepines exert their antiepileptic activity by increasing the major CNS inhibitory neurotransmitter GABA by binding to the GABAA receptor. From a pharmacologic perspective, their greater effectiveness in terminating SE can be explained by a more lipid-solubility compared to other AEDs, which allows the drug to enter the CNS more quickly. When IV access is not available for lorazepam, frequently used for in-hospital SE, midazolam and diazepam offer alternative routes of administration. However, the duration of antiepileptic action is shorter with these agents, which can translate into earlier seizure recurrence. Dose-related respiratory depression and systemic hypotension have been described as the most common adverse effects of benzodiazepines in SE trials. There are no definitive data for which AED should be added next. Due to overlapping mechanisms of action of many AEDs, selection may be based on minimizing side effects while optimizing efficacy. Guidelines also provide a graded recommendation based on available evidence and expert opinion. Refer to Table 7.2 for pharmacologic and therapeutic considerations of all the recommended agents, including those for RSE.




Table 7.2 Antiepileptics for status epilepticus
























































































Agent Timing Initial dosing Key pharmacology Notable AEs and therapeutic considerations
Lorazepam Emergent 0.1 mg/kg IVP up to 2 mg/min (max 4 mg/dose); may repeat in 5–10 min MOA: Binds to GABAA receptor, allows entry of Cl and results in decreased neuronal firing

Protein binding: >90%

Onset: 2–10 min

Metabolism: Hepatic, glucuronidation

Elimination t½: 12–14 h

Excretion: Renal
AEs: Hypotension and respiratory depression (dose dependent)

• IV formulation contains propylene glycol. High doses (≥1mg/kg/day or ≥10mg/h) may lead to accumulation and toxicity
Midazolam Emergent 0.2 mg/kg IM (max 10 mg)

0.2 mg/kg intranasal

0.5 mg/kg buccal
MOA: Binds to GABAA receptor, allows entry of Cl and results in decreased neuronal firing

Protein binding: >90%

Onset: 3–5 min

Metabolism: Hepatic, CYP3A4, (1- hydroxymidazolam)

Elimination t½: 2–6 h

Excretion: Renal
AEs: Hypotension and respiratory depression (dose dependent)

• Accumulation of active metabolite in renal impairment can lead to increased sedation and adverse effects

• Shorter duration of action (<2 h, dose dependent)
Diazepam Emergent

0.15 mg/kg IVP up to 5 mg/min

(max 10 mg/dose); may repeat in 5 min

0.2mg/kg rectal gel
MOA: Binds to GABAA receptor, allows entry of Cl resulting in decreased neuronal firing

Protein binding: >90%

Onset: <1 min (IV)

Metabolism: Hepatic, CYP3A4, 2C19 active metabolites

Elimination t½: 20–50 h

Excretion: Renal
AEs: Hypotension and respiratory depression (dose dependent)

• Anticonvulsant duration is 20–30 minutes, but drug elimination is much longer so sedation may linger, especially with rectal gel

• IV formulation contains propylene glycol ; accumulation and toxicity may occur

• Shorter duration of action (20–30 min)
Phenytoin,

Fosphenytoin
Emergent

Urgent

Refractory
Load 20 mg/kg IV up to 50 mg/min (fosphenytoin 20mg/kg PE up to 150 mg PE/min); may give additional 5–10 mg/kg (5–10 mg/kg PE) in 10 min

Use TBW unless obese (>125% IBW)

Obese: adjusted weight = IBW + (1.33)(TBW – IBW)

Maintenance empiric 5–7 mg/kg/day divided two to three doses

See text for therapeutic drug monitoring
MOA: Prolongs recovery of activated voltage-gated Na+ channels in neuron to stabilize against repetitive neuronal firing

Protein binding: >90%

Onset: 0.5–1 h

Metabolism: Hepatic, CYP2C9, 2C19

Elimination t½: 12–29 h (dose and hepatic function dependent)

Excretion: Renal
AEs: Arrhythmias, hypotension (especially rapid IV administration) injection site pain, phlebitis, purple glove syndrome, tissue necrosis, hepatotoxicity (routinely monitor transaminases), various dermatologic conditions

• Fosphenytoin conversion to phenytoin in 15 min

• Lack of propylene glycol and ethanol diluents in fosphenytoin and a more physiologic pH may cause less local and systemic effects.

• IV formulation contains propylene glycol ; accumulation and toxicity may occur
Sodium valproate

Emergent

Urgent

Refractory
20–40 mg/kg IV; may give additional 20 mg/kg in 10 min

Maintenance empiric 5–10 mg/kg/day in three divided doses ideally

usual 15 mg/kg/day

(max 60 mg/kg/day)

See text for therapeutic drug monitoring
MOA: Exact mechanism unknown, but thought to be involved in increasing concentrations of GABA

Protein binding: 80–90% (concentration dependent)

Onset: 1 h

Metabolism: Extensive hepatic (primarily glucuronidation and mitochondrial β-oxidation; minor CYP450 2C9, 2C19) with many active metabolites

Elimination t½: 15 h (increased in elderly and liver disease, decreased with other AEDs)

Excretion: Renal
AEs: Hepatoxocity, encephalopathy hyperammonemia, pancreatitis, rash, thrombocytopenia, elevation of hepatic transaminases

• Routinely monitor transaminases

• Not recommended in significant hepatic impairment
Phenobarbital Emergent

Urgent

Refractory
Initial 20 mg/kg IV over 50 mg/min; may give additional 5–10 mg/kg in 10 min

Maintenance 1–3 mg/kg/day in two to three divided doses

See text for therapeutic drug monitoring
MOA: Binds to GABAA receptor, allows entry of Cl and results in decreased neuronal firing

Protein binding: 20–40 %

Onset: 5 min

Metabolism: Hepatic, CYP2C9, 2C19

Elimination t½: 53–140 h

Excretion: Renal

AEs: Hypotension, respiratory depression, various dermatologic conditions, injection site pain, thrombophlebitis

• IV formulation contains propylene glycol; accumulation and toxicity may occur
Levetiracetam Emergent

Urgent

Refractory
1000–3000 mg IV over 15 min MOA: Exact mechanism unknown; thought to involve regulation of presynpatic neurotransmitter release

Protein binding: <10%

Onset: Rapid

Metabolism: Small amount of enzymatic hydrolysis

Elimination t½: 6–8 h

Excretion: Renal
AEs: Somnolence

• Minimal drug–drug interactions
Midazolam continuous infusion Urgent

Refractory

Load 0.2 mg/kg IV over 2 mg/min

Maintenance 0.05–2 mg/kg/h infusion; titrate to CEEG

Breakthrough seizure 0.1–0.2 mg/kg bolus and increase by 0.05–0.1 mg/kg/h q3–4 h
See above See above

• Tachyphylaxis with prolonged infusion use
Propofol continuous infusion Refractory Load 1–2 mg/kg IV

Maintenance 20–200 μg/kg/min infusion; titrate to CEEG

Breakthrough seizure may bolus 1mg/kg and increase by 5–10 μg/kg/min q5min
MOA: GABAA receptor agonist (exact MOA unknown)

Protein binding: 97–99%

Onset: 1–2 min

Metabolism: Hepatic

Elimination t½: 30–60 min (wake-up time, however, is ≤15 min in infusions ≤72 h in duration)

Excretion: Renal
AEs: Hypotension, respiratory depression, cardiac failure, rhabdomyolysis, metabolic acidosis, PRIS

• Risk of PRIS increases at high doses (≥80 μg/kg/min); monitor for acidosis and creatinine kinase when used ≥48 h

• Provides considerable IV lipid load; monitor triglycerides and caloric intake (1.1kcal/mL)

• Contraindicated in patients with severe allergy to egg and soy proteins
Pentobarbital

continuous infusion

Refractory Load 5–15 mg/kg IV over ≤50 mg/min; may give additional 5–10 mg/kg

Maintenance 0.5–5 mg/kg/h infusion; titrate to CEEG

Breakthrough seizure 5mg/kg bolus, increase infusion by 0.5–1 mg/kg/h q 12 h
MOA: Binds to GABAA receptor, allows entry of Cl and results in decreased neuronal firing

Protein binding: 45–70%

Onset: Immediate

Metabolism: Hepatic

Elimination t½: 15–50 h (dose dependent)

Excretion : Renal

AEs: Hypotension frequently requiring vasopressor support, respiratory depression, myocardial depression, paralytic ileus

• IV formulation contains propylene glycol ; accumulation and toxicity may occur
Lacosamide Refractory 200–400 mg IV over 30 min MOA: Exact mechanism unknown, but may decrease neuronal firing by enhancement of slow inactivation of Na channels

Protein binding: <15%

Onset: 1–4 h

Metabolism: Hepatic, CYP3A4, 2C9, 2C19

Elimination t½: 13 h

Excretion: Renal
AEs: PR interval prolongation, hypotension
Topiramate Refractory 200–400 mg enterally

300–16000 mg/day divided two to four times daily
MOA: Blocks voltage-gated Na channels in neuron, enhances GABAA receptor activity, antagonizes AMPA/kainite of glutamate receptor, weakly inhibits carbonic anhydrase all of which may play a role in its anticonvulsant activity

Protein binding: 15–41%

Onset: 1–4 h

Metabolism: Small hepatic, CYP3A4, 2C19

Elimination t½: 21 h

Excretion: Renal
AEs: Metabolic acidosis


AEs adverse effects; Cl chloride; CEEG continuous electroencephalogram; GABA γ-aminobutyric acid; GI gastrointestinal; h hour; IBW ideal body weight; IV intravenous; IVP intravenous push; kg kilogram; mg milligram; min minute; MOA mechanism of action; N/V nausea, vomiting; PE phenytoin equivalents; PRIS propofol-related infusion syndrome; half-life; TBW total body weight; q every

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