Emergency Neuropharmacology





Management of acute neurologic disorders in the emergency department is multimodal and may require the use of medications to decrease morbidity and mortality secondary to neurologic injury. Clinicians should form an individualized treatment approach with regard to various patient specific factors. This review article focuses on the pharmacotherapy for common neurologic emergencies that present to the emergency department, including traumatic brain injury, central nervous system infections, status epilepticus, hypertensive emergencies, spinal cord injury, and neurogenic shock.


Key points








  • Benzodiazepines must be optimally dosed and immediately followed by appropriate antiepileptic medications for status epilepticus, because drug efficacy diminishes with prolonged seizure duration.



  • Prompt initiation of empiric anti-infectives with adequate central nervous system penetration is associated with decreased mortality and adverse outcomes.



  • Appropriate selection and timely administration of medications to support airway and hemodynamics is critical to decrease secondary neurologic injury for patients presenting with traumatic neurologic emergencies.



  • Evidence-based, patient-specific blood pressure goals should be targeted using rapid-acting antihypertensives to decrease hematoma expansion, morbidity, and mortality.




Introduction


The management of acute neurologic disorders in the emergency department is often multimodal and may require the use of medications to reduce morbidity and mortality secondary to neurologic injury. To optimize patient care, clinicians should form an individualized treatment approach with regard to patient age, weight, comorbidities, drug–drug interactions, and goals of care. Pharmacokinetic properties (drug absorption, distribution, metabolism, and elimination) must be taken into consideration to achieve optimal efficacy and minimize adverse effects. This article focuses on the pharmacotherapy for common neurologic emergencies that present to the emergency department, including traumatic brain injury (TBI), central nervous system (CNS) infections, status epilepticus (SE), hypertensive emergencies, spinal cord injury, and neurogenic shock.


Status epilepticus


SE is defined as continuous seizure activity that persists beyond 5 minutes or recurrent seizures without recovery to baseline. Rapid initiation of appropriate pharmacotherapy, in conjunction with supportive care measures, is paramount to prevent neurologic sequelae and reduce mortality. , Choice of treatment depends on several factors, including the availability of parenteral access, duration of seizure activity, individualized patient characteristics, and institutional formulary and policy. Many antiepileptics are prone to drug interactions among themselves ( Fig. 1 ) and other drugs that are metabolized via the hepatic cytochrome system (eg, diltiazem, warfarin, protease inhibitors). Historically, algorithms have categorized treatment into emergent, urgent, and refractory SE. Management of seizures induced by specific toxicologic agents or those that persist beyond 24 hours despite intravenous (IV) anesthetics, defined as super-refractory SE, are beyond the scope of this review.




Fig. 1


Select antiepileptic drug–drug interactions. CBZ, carbamazepine; CLOB, clobazam; LTG, lamotrigine; MID, midazolam; PHNBRB, phenobarbital; PHT, phenytoin and fosphenytoin; SJS, Stevens-Johnson Syndrome; TEN, toxic epidermal necrolysisl; VPA, valproic acid. Red boxes indicate a major interaction, which may be life threatening and/or require medical intervention to minimize or prevent serious adverse effects. Yellow boxes indicate a moderate interaction which may result in exacerbation of the patient’s condition. Green boxes indicate minor or clinically insignificant interactions.

( Data from Micromedex: Drug Interactions Tool. Truven Health Analytics; 2020.)


Emergent Treatment


Benzodiazepines (BZD) are standard of care for initial treatment of SE. BZDs modulate type A gamma-aminobutyric acid receptors to suppress seizure activity and are more likely to be effective when administered soon after seizure onset, as receptors begin to internalize with prolonged seizure duration. , In adults without IV access, intramuscular midazolam is preferred. , To date, no significant differences in efficacy or safety between IV lorazepam or diazepam have been established. Phenobarbital may be used as an alternative if BZDs are not readily available.


Inadequate dosing of BZDs is common and associated with higher rates of respiratory complication and progression to refractory SE. A full dose of IV lorazepam or diazepam may be repeated once within 5 to 10 minutes if termination of the seizure is not achieved. Dosing and administration considerations are outlined in Table 1 .



Table 1

Pharmacologic therapies for SE

Data from Refs. ,










































































































Initial Dose Administration Goal Serum Concentration Serious Adverse Effects/Considerations
Emergent
Lorazepam 0.1 mg/kg (max 4 mg/dose) may repeat once IVP up to 2 mg/min N/A Hypotension, respiratory depression, contains propylene glycol
Midazolam 10 mg for >40 kg
5 mg for 13–40 kg
IM N/A Hypotension, respiratory depression
Diazepam 0.2 mg/kg (max 10 mg/dose) may repeat once IVP up to 5 mg/min N/A Hypotension, respiratory depression, contains propylene glycol
Urgent
Phenobarbital 15–20 mg/kg IV up to 100 mg/min 15–40 μg/mL Hypotension, respiratory depression, contains propylene glycol
Phenytoin 20 mg/kg (max 1500 mg/dose) IV up to 50 mg/min Total: 10–20 mcg/mL
Free: 1–2 μg/mL
Arrhythmia, hypotension, hepatotoxicity, purple glove syndrome, contains propylene glycol
Fosphenytoin 20 mg PE/kg (max 1500 mg/dose) IV up to 150 mg PE/min Total: 10–20 μg/mL
Free: 1–2 μg/mL
Arrhythmia, hypotension, hepatotoxicity
Levetiracetam 60 mg/kg (max 4500 mg/dose) IV up to 450 mg/min N/A Rare
Valproic acid 40 mg/kg (max 3000 mg/dose) IV up to 6 mg/kg/min 50–150 μg/mL Hepatotoxicity, hyperammonemia, pancreatitis, thrombocytopenia
Refractory
Clobazam 10 mg twice daily Enteral only N/A Hypotension, respiratory depression
Topiramate 200–400 mg every 6–12 h (max 1600 mg/d) Enteral only 5–20 μg/mL (not routinely monitored) Metabolic acidosis
Lacosamide 200–400 mg IV over 15–30 min N/A Bradycardia, PR prolongation, dizziness
Ketamine 1–2 mg/kg bolus then 1–10 mg/kg/h infusion Slow IV push followed by infusion N/A Hypertension, tachycardia, salivation, laryngospasm, transient apnea, psychiatric
Midazolam 0.2 mg/kg then 0.05–2 mg/kg/h infusion IV bolus followed by continuous infusion N/A Tachyphylaxis after prolonged use
Propofol 1–2 mg/kg then 20–200 μg/kg/min infusion IV bolus followed by continuous infusion, titrated based on EEG N/A Requires intubation, hypotension, bradycardia, respiratory depression, metabolic acidosis, rhabdomyolysis, renal failure, hypertriglyceridemia
Pentobarbital 5–15 mg/kg then 0.5–5 mg/kg/h infusion IV bolus followed by continuous infusion, titrated based on EEG N/A Requires intubation, hypotension, bradycardia, respiratory depression, paralytic ileus, contains propylene glycol

Abbreviations: EEG, electroencephalography; IM, intramuscular; IVP, intravenous push; N/A, not applicable.


Urgent Treatment


A second-line antiepileptic medication is recommended if seizures do not abate with adequate doses of BZDs. Fosphenytoin, levetiracetam, or valproic acid are all viable options. The Established Status Epilepticus Treatment Trial (ESETT) randomized children and adults with BZD-refractory SE to receive fosphenytoin 20 mg/kg, levetiracetam 60 mg/kg, or valproic acid 40 mg/kg. The primary outcome, clinical cessation of SE with improvement in mental status at 60 minutes after the start of the drug infusion, was similar between all groups (45%, 47%, and 46%, respectively). Of note, approximately 70% of initial BZD doses in ESETT were inadequate and may have contributed to overall response rates. Greater rates of intubation and hypotension occurred in the fosphenytoin arm (26.4% and 3.2%, respectively) and more deaths occurred in the levetiracetam arm compared with others; however, these differences were not statistically significant. Two similar trials conducted in pediatric patients found no difference in the cessation of seizures between phenytoin and levetiracetam. ,


Fosphenytoin can be infused at a higher rate compared with phenytoin, and is associated with less hypotension, cardiac arrhythmias, and infusion site pain; however, there are insufficient data regarding the comparative efficacy. Thus, fosphenytoin is preferred owing to patient tolerability; however, phenytoin is considered an effective alternative.


Given the relatively low success rates of all antiepileptic agents, clinicians must initiate these agents early (preferably with or immediately subsequent to the second dose of BZD) and be prepared for endotracheal intubation with ketamine or propofol if termination of seizure is not achieved. IV phenobarbital is a reasonable alternative to the aforementioned agents, but is associated with higher rates of adverse events.


Refractory Status Epilepticus


Seizures that do not respond to a BZD plus 1 antiepileptic drug are considered refractory SE. There is no robust evidence to guide therapy in this stage and clinical response rate to a third medication may be as low as 2%. Continuous infusion sedatives (midazolam, propofol, ketamine, and pentobarbital) have been used in conjunction with electroencephalography monitoring in those with general tonic–clonic refractory SE. Data are insufficient to suggest any superiority of specific treatments and combinations of medications with unique mechanisms of action may be required.


Central nervous system infections


Infections of the CNS are neurologic emergencies that require prompt recognition and treatment. Clinicians in the emergency department should be cognizant of common pathogens, empiric treatments, CNS penetration of anti-infectives, and the role of adjunctive agents such as glucocorticoids. The key goals of treatment include eradication of infection, mitigation of symptoms, and prevention of complications, such as deafness and coma. We review treatment considerations for bacterial meningitis, encephalitis, brain and spinal abscesses, and ventriculitis.


Timing of Antibiotic Administration


Delayed initiation of antibiotics for the treatment of acute meningitis is strongly associated with adverse outcomes and increased mortality. , Current guidelines strongly recommend administration of empiric antibiotics within 1 hour of suspected diagnosis. When possible, cerebral spinal fluid (CSF) and blood cultures should be obtained before antibiotic administration in an effort to identify a causative pathogen. Data regarding the impact of antibiotics on time to CSF sterilization are conflicting and range from as early as 15 minutes to 4 hours.


Central Nervous System Penetration


For antibiotics to reach the site of infection within the CNS at therapeutic concentrations, they must penetrate the blood–brain and/or blood–CSF barrier(s). Several factors govern a drug’s ability to do so, including the extent of meningeal inflammation, affinity to drug efflux pumps, molecular weight, lipophilicity, ionization, and protein binding. Table 2 provides a comparison of CNS penetration between anti-infectives.



Table 2

Comparative CNS penetration

Data from Nau R, Sorgel F and Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010; 23(4): 858-83.












Agents that Achieve Therapeutic CSF Concentration with or Without Inflammation Agents that Achieve Therapeutic CSF Concentration with Inflammation Agents with Poor CSF Concentration
Acyclovir
Ciprofloxacin
Fluconazole
Foscarnet
Ganciclovir
Isoniazid
Linezolid
Metronidazole
Moxifloxacin
Pyrazinamide
Rifampin
Sulfonamides
Trimethoprim
Voriconazole
Ampicillin ± sulbactam aztreonam
Cefepime
Ceftazidime
Ceftriaxone
Cefuroxime
Colistin
Daptomycin
Ethambutol
Imipenem
Meropenem
Nafcillin
Ofloxacin
Penicillin G
Piperacillin/tazobactam
Ticarcillin ± clavulanic acid
Vancomycin
Aminoglycosides Amphotericin B
Cephalosporins (first and second generation) a
Clavulanic acid
Doxycycline
Itraconazole b
Sulbactam
Tazobactam

a Cefuroxime is an exception.


b Effective against Cryptococcus neoformans .



In general, medications that are ideal for treatment of CNS infections have smaller molecular weights, moderate lipophilicity, low protein binding, and exist in a nonionized form. The pH of CSF can be significantly lower than blood pH in cases of severe bacterial meningitis; therefore, weak acids such as cephalosporins and penicillins diffuse more readily out of the CNS compartments and into the blood. Larger cephalosporins such as ceftriaxone, have minimal affinity to drug efflux pumps and thus can still achieve adequate CNS concentration. Vancomycin is hydrophilic with a high molecular weight and must be dosed aggressively to achieve optimal bactericidal CSF concentration. A loading dose of 20 to 35 mg/kg actual body weight (not to exceed 3000 mg) should be administered for critically ill patients.


Bacterial Meningitis


Empiric antibiotics should target the most likely bacterial pathogens known to cause meningitis. Common pathogens of bacterial meningitis include S pneumoniae, group B Streptococcus, Neisseria meningitidis, Haemophilus influenzae, and Listeria monocytogenes ; however, the etiology depends on age, vaccination status, past medical history, and the presence of additional risk factors ( Table 3 ). Therapy should be continued for at least 48 to 72 hours or until an infectious process has been excluded. Historically, cefotaxime was the cephalosporin of choice in neonates; however, in 2019 it was discontinued by the last remaining manufacturer in the United States. Ceftazidime may be used as an alternative third-generation cephalosporin in this population or in those with risk factors for Pseudomonas .



Table 3

Common pathogens and empiric therapy based on risk factor

Data from Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39(9): 1267-84.












































Risk Factor Common Pathogens Empiric Therapy
Age
<1 mo Group B streptococcus , E coli, K pneumoniae, L monocytogenes Ampicillin + ceftazidime or aminoglycoside
1 mo to <2 y S pneumoniae, group B
Streptococcus, N meningitidis, H influenzae, E coli
Vancomycin + ceftriaxone or ceftazidime
≥2 y to <50 y S pneumoniae, N meningitidis Vancomycin + ceftriaxone or ceftazidime
≥50 y S pneumoniae, N meningitidis, L monocytogenes, aerobic Gram-negative bacilli Vancomycin + ceftriaxone or ceftazidime + ampicillin
Basilar skull fracture S pneumoniae, H influenzae, group A beta-hemolytic streptococci Vancomycin + ceftriaxone or ceftazidime
Immunocompromised S pneumoniae, N meningitidis, aerobic gram-negative bacilli , L monocytogenes Ceftriaxone or ceftazidime + ampicillin
Penetrating head trauma, CSF shunt, postneurosurgery S aureus (methicillin-resistant S aureus ), coagulase-negative staphylococci (methicillin-resistant S epidermidis ) , aerobic gram-negative bacilli ( P aeruginosa ) Vancomycin + ceftazidime or cefepime or meropenem
Pregnancy S pneumoniae, L monocytogenes,
N meningitidis
Vancomycin + ceftriaxone or ceftazidime + ampicillin


Role of Dexamethasone


Inflammation of the subarachnoid space is thought to be a contributing factor to morbidity and mortality. Thus, adjunctive corticosteroids have been used to attenuate this inflammatory response. A meta-analysis of 25 randomized controlled trials (including 4121 adults and children) determined that corticosteroids significantly decreased hearing loss (13.8% vs 19.0%) and neurologic sequelae (17.9% vs 21.6%) in patients with bacterial meningitis in high-income countries. Corticosteroids did not reduce mortality in the overall population; however, death was significantly lower in a subgroup analysis of adults with S pneumoniae .


Dexamethasone has been most commonly studied, with a recommended dose of 0.15 mg/kg (maximum, 10 mg) every 6 hours for 2 to 4 days. , To prevent additional inflammation caused by antibiotic-induced bacteriolysis, the Infectious Disease Society of America guidelines recommend that steroids be administered with, or 10 to 20 minutes before, antibiotics. , European guidelines allow for administration up to 4 hours after the initiation of antibiotics; however, this recommendation is based on expert opinion; randomized controlled trials evaluating the timing of corticosteroids have not yet been conducted. Dexamethasone should be discontinued if bacterial meningitis is ruled out or if the pathogen causing meningitis is a bacterium other than H influenzae type b or S pneumoniae . Data to support the routine use of dexamethasone in neonates are insufficient.


Encephalitis


Herpes simplex virus, West Nile virus, and enteroviruses are the most commonly diagnosed etiologies of encephalitis in the United States. In addition to supportive care measures, IV acyclovir is considered the standard of care for herpes simplex virus encephalitis. Acyclovir requires dose adjustment in patients with renal insufficiency and adequate hydration is recommended to decrease the risk of acyclovir-induced nephrotoxicity. Transplant patients on immunosuppressive therapy and those with human immunodeficiency virus are at higher risk for cytomegalovirus and may require treatment with a combination of antivirals, including ganciclovir and foscarnet. There is not a routine role for corticosteroids in the treatment of encephalitis, unless severe edema is present.


Brain Abscess


Bacteria account for more than 95% of brain abscesses in immunocompetent patients. Abscesses are most frequently polymicrobial and empiric therapy must provide coverage against gram-negative, gram-positive, and anaerobic bacteria. , IV ceftriaxone combined with metronidazole is acceptable for most patients. Vancomycin should be added if the patient has risk factors for methicillin-resistant S aureus and ceftazidime or cefepime may be used in place of ceftriaxone if Pseudomonas is suspected. Patients with immunosuppression are at a higher risk of infection caused by fungi, yeast, and toxoplasmosis; therefore, voriconazole and trimethoprim-sulfamethoxazole should be added for empiric treatment until a definitive pathogen is identified. Duration of therapy is variable, but prolonged courses of antibiotics for 6 to 8 weeks are often required.


Adjunctive dexamethasone may reduce antibiotic penetration through the blood-brain barrier and subsequently prolong treatment. Corticosteroids are only recommended for patients with profound perifocal edema with midline shift or those at risk of herniation. Although seizures are a frequent complication of brain abscesses, prophylactic antiepileptic medication is not routinely recommended. ,


Ventriculitis and Cerebrospinal Fluid Shunt Infections


Broad-spectrum antibiotics that provide coverage against methicillin-resistant Staphylococcus aureus and Pseudomonas bacteria are paramount for empiric treatment of these infections until a causative pathogen is identified. Regimens should include a β-lactam with activity against Pseudomonas (eg, ceftazidime, cefepime, meropenem) plus vancomycin. Piperacillin–tazobactam does not achieve adequate CNS penetration and should be avoided. Intraventricular instillation of antibiotics may be required in patients who do not respond to systemic antibiotics.


Traumatic brain injury


TBI is defined as an alteration in brain function or other evidence of brain injury caused by an external force. Emergency care involves airway, breathing, and circulatory management to prevent hypoxemia and hypotension, prevention of post-traumatic seizures, intracranial pressure (ICP) management, correction of coagulopathy, and analgesic and sedative administration as required. Timely pharmacotherapeutic interventions in this population can help to decrease secondary injury, morbidity, and mortality. ,


Airway and Hemodynamic Management


Hypoxemia and hypotension lead to worsened cerebral ischemia and have been associated with increases in morbidity and mortality. The cerebral perfusion pressure (CPP) must be adequate to decrease cerebral ischemia. This is done by maintaining or increasing the mean arterial pressure (MAP) and decreasing the ICP. See Table 4 for specific blood pressure targets in patients with TBI. , , The MAP can be increased via multiple mechanisms to achieve adequate CPP. IV isotonic crystalloid fluids are the mainstay of initial resuscitation for trauma patients with hypotension, especially in resource-limited settings. However, hypotonic fluids (eg, dextrose 5%, sodium chloride 0.45%, lactated Ringers solution) should be avoided because they may worsen cerebral edema. If the blood pressure target has not been achieved after adequate resuscitation with crystalloids and/or blood products, vasopressors (eg, phenylephrine, norepinephrine) may be used to maintain MAP (ie, CPP).


Jul 11, 2021 | Posted by in EMERGENCY MEDICINE | Comments Off on Emergency Neuropharmacology
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