Neurocrit Care https://doi.org/10.1007/s12028-019-00830-4 PHARMACOTHERAPY Pharmacotherapy Pearls for Emergency Neurological Life Support Theresa Human1*, Eljim Tesoro2* and Sarah Peacock3 © 2019 Neurocritical Care Society Abstract The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient’s organ function, medication allergies, potential adverse drug efects, drug interactions, critical illness, and age-related pathophysi- ologic changes. Medications used during ENLS include hyperosmolar therapy, antiseizures, antithrombotics, antico- agulant reversal hemostatic agents, antishivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors inotropes, and antimicrobials. This chapter focuses on key pharmacokinetic and pharmacodynamic characteristics, advantages and disadvantages, and clinical pearls of these therapies, thereby providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients. Keywords: ENLS, Pharmacotherapy, Medication, Adverse drug event, Drug interaction Introduction provider optimize medication management in the acute Neurocritical care patient management is highly com- period of neurologic injury. plicated, especially when trying to optimize therapy dur- ing the acute injury. Pharmacologic management must Chapter Outline be carefully considered in order to minimize cognitive • Hyperosmolar therapy dysfunction and avoid confounding patient neurologic • Antiseizure medications evaluations. During Emergency Neurological Life Sup- • Antithrombotic agents port (ENLS), pharmacotherapy must be individualized • Anticoagulant reversal and hemostatic agents for each patient, taking into account their age, comor- • Antishivering agents bidities, and chronic medications. Pharmacokinetic and • Neuromuscular blocking agents pharmacodynamic characteristics must be considered • Antihypertensive agents as they may change in acute illness and with neurocriti- • Sedation and Analgesia cal care interventions. Pharmacokinetic changes may • Vasopressors and inotropes include alterations in medication absorption, distribu- • Antimicrobials tion, metabolism, and elimination, while pharmacody- namic changes could result in loss of drug efect or an Hyperosmolar Therapy increase in toxicity. Tis chapter will focus on pharma- Mannitol and hypertonic saline (HS) are commonly used cotherapy and clinical pearls that will help the ENLS in neurologically injured patients in the acute setting to treat elevated intracranial pressure (ICP) and cerebral *Correspondence: [email protected]; [email protected] edema. HS is also used in the treatment of hyponatremia. 1 Departments of Clinical Pharmacy, Barnes-Jewish Hospital, Washington Both agents work by producing osmotically driven fuid University in St. Louis, St. Louis, MO, USA shifts and appear to be equally efective at equal osmolar 2 Department of Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, Chicago, IL, USA doses [1]. An online survey of neurointensivists reported Full list of author information is available at the end of the article that 90% of respondents utilize osmotic agents in the treatment of intracranial hypertension, with a fairly even mannitol and can also be increased with hyperglycemia. split in preference for HS (55%) versus mannitol (45%) Urine output and electrolyte balances should be care- [2]. It is important to determine which agent would be fully monitored to prevent hypotension, dehydration, and best in individual patients based on serum sodium con- electrolyte imbalances due to excessive diuresis. centrations, plasma osmolality, fuid status, and renal Unlike mannitol, HS provides intravascular expan- function. A summary of the characteristics of these sion; therefore, patients with decompensated heart fail- hyperosmolar agents can be found in Table 1. ure or pulmonary edema may be at increased risk of fuid Mannitol is an osmotic agent that is eliminated by the overload. HS may have a lesser risk of rebound cerebral kidneys. Caution should be used in patients with renal edema after discontinuation due to the diferences in the impairment as mannitol may accumulate and worsen refection coefcient, which describes the permeability cerebral edema, especially in those with blood brain bar- (1 = impermeable) of a substance relative to the BBB (1 rier (BBB) disruption due to injury and/or infammation. for HS vs. 0.9 of mannitol) [7, 8]. Caution should be used Te osmolar gap is the most useful monitoring method when administering HS to patients with chronic hypona- to detect the presence of unmeasured osmoles, such as tremia, as a rapid change in serum sodium may increase mannitol, and should be used to monitor drug elimina- the risk of osmotic demyelination syndrome. Although tion between doses. An osmolar gap of greater than there are some recommendations to use HS doses equi- 15–20 mOsm/kg indicates incomplete drug clearance osmolar to mannitol, there are multiple other studies that between doses and increases the risk of reverse osmotic show clinical beneft with variable concentrations, doses, shift and nephrotoxicity [3–6]. An osmolar gap can be and modes of administration of HS. At this time, there is calculated by subtracting the calculated osmolality from no information regarding an optimal protocol for the use the measured osmolality. Te laboratory tests (osmolal- of HS. In general, established protocols allow for consist- ity, sodium, glucose, and urea) necessary to calculate an ency of care among providers. For this reason, neurocrit- osmolar gap should be obtained as a trough or prior to ical care providers should work within their institution to the mannitol dose. A plasma osmolality of > 320 mOsm/ establish a consensus regarding treatment goals, develop kg is not a contraindication of ongoing administra- a protocol, monitor efcacy of the protocol, and then tion of mannitol, as this is not a valid measure of excess reassess and modify their protocol as needed to achieve Table 1 Hyperosmolar therapeutic agents for management of elevated intracranial pressure [1, 9–12] Agent Dosing Adverse reactions Clinical pearls Mannitol 0.5–1 g/kg over 5–15 min can be redosed Rebound ICP elevation with abrupt Requires inline flter (precipitates–crystal every 4–6 h discontinuation (with high, repeated formation) dosing) May require warming to dissolve crystals Acute kidney injury before administration Dehydration May be given via peripheral access Hypotension Duration of efect 90 min–6 h Electrolyte imbalances Monitor trough osmolar gap (goal < 20 mOsm/Kg) Hypertonic saline Concentration dependent (concentrations Pulmonary edema Central access required for 23.4% bolus listed are approximately equal osmolar Heart failure Central access for > 2% NaCl–acetate if to mannitol 1 g/kg) Acute kidney injury continuous infusion Bolus dosing Coagulopathy 3% NaCl boluses may be administered 3%: 5 mL/kg over 5–20 min (range Hypernatremia peripherally 2.5–5 mL/kg) Metabolic acidosis 5% NaCl may be administered safely in 5%: 3 mL/kg over 5–20 min (range Thrombophlebitis bolus doses for up to 72 h via periph- 2.5–5 mL/kg) Osmotic demyelination syndrome with eral line [13] 7.5%: 2 mL/kg over 5–20 min (range rapid correction Duration of efect 90 min–4 h 1.5–2.5 mL/kg) Controversial if continuous infusion is 23.4%: 30 ml over 10–20 min benefcial for ICP control, but should Other options be used for severe hyponatremia Continuous infusion titrated to a goal Na Monitor serum sodium every 4–6 h range (trough), avoid prolonged hyperna- tremia > 160 mEq/L Decrease chloride and increase acetate content if patients develop metabolic acidosis Use is discouraged in combination with tolvaptan or conivaptan ICP intracranial pressure the desired treatment goal. Trough serum sodium levels Clonazepam is an alternative agent but it is infrequently should be monitored prior to HS administration to guide used in the USA due to lack of an IV formulation; how- the HS dose and dosing interval. Te goal should be to ever, it is commonly used intravenously in Europe [15]. use the lowest efective dose in order to allow for ongoing Randomized controlled studies have evaluated loraz- drug administration and avoid sustained hypernatremia epam versus diazepam, phenobarbital, phenytoin, and [9]. IM midazolam [16–19]. Initial treatment with lorazepam followed by phenytoin appeared to be the most efective Nursing Considerations combination; however, the second-generation antiseizure Nursing care for patients requiring mannitol and HS agents were not available at the time, and many options includes monitoring patients for side efects and possible may also be efective. IM midazolam was found to be adverse reactions to these medications. Nursing assess- at least as efective as IV lorazepam in prehospitalized ment should include monitoring of neurologic examina- patients with status epilepticus [19]. While there may be tion, vital signs, and volume status. Monitoring volume concerns about administering benzodiazepines to non- status includes intake and output monitoring along with intubated patients, available data suggest respiratory assessment for dehydration and volume overload. Neu- depression is seen less frequently in those treated with rologic examination monitoring should occur frequently benzodiazepines for generalized convulsive status epilep- including intracranial