General spectrum of activity


Typical daily dosing range (admixture in preservative-free solutions)

Common adverse effects

Gram positive


10–20 mg /1 mL NS

Headache, mental status changes, possible hyponatremia


5–10 mg/1 mL NS

None reported

Gram negative


4–8 mg/1 mL NS



4–8 mg/1 mL NS



30 mg/1 mL NS


Polymyxin B

5 mg/1 mL NS

Hypotonia, seizures, meningeal inflammation


10 mg/3 mL NS

Meningeal inflammation


Amphotericin B deoxycholate

0.5 mg/3 mL SWI

Nausea, vomiting

Procedure for intraventricular/intrathecal antimicrobial administration: [2, 5]

  • Withdraw CSF volume equivalent to volume of drug to be administered.

  • Inject drug solution into the proximal port of the ventriculostomy or lumbar device.

  • Slowly flush solution into drain with a small amount of normal saline. Instillation of small volumes (<3 ml) over 1–2 min appears to be safe. Rapid administration of solution may cause brain tissue damage.

  • Clamp ventriculostomy tubing or lumbar drain for at least 15 min to allow injected solution to equilibrate in the CSF. Closely monitor patients with persistent elevated intracranial pressure who may not tolerate interruptions in CSF drainage during clamping.

Drug metabolism, the process of parent-drug breakdown into smaller active or non-active compounds, may be affected by neurologic injury. Different doses of medications may be necessary in the setting of decreased or increased drug metabolism. For example, traumatic brain injury increases hepatic metabolic capacity and may increase dosing requirements for medications frequently used in neurocritically ill patients such as phenytoin. Major enzyme-inducing antiepileptic drugs (AEDs) such as phenytoin stimulate the rate of metabolism of most coadministered AEDs, including valproic acid, lamotrigine, and topiramate, among others, and the affected agents may require subsequent dose increases. Valproic acid, a broad enzyme inhibitor, inhibits the metabolism of phenytoin leading to increased serum concentrations and consequently increased risk of phenytoin toxicity.

22.2 Hyponatremia [9]

Hyponatremia (serum sodium <135 mEq/L) and hypernatremia (serum sodium >150 mEq/L) are common findings in neurocritically ill patients. Both hyponatremia and hypernatremia are associated with potentially significant complications in neurocritically ill patients including cerebral edema (hyponatremia), elevated ICP (hyponatremia), agitation, delirium, seizures, tremors, or coma.

22.2.1 Cerebral Salt Wasting (CSW) vs SIADH

CSW is defined as renal loss of salt with concomitant extracellular fluid loss. CSW has been commonly described in patients with subarachnoid hemorrhage. A major difference between CSW and SIADH is that in CSW there is a decrease in extracellular fluid volume (ECFV) leading to hypovolemia. Fluid restriction should be avoided in most neurocritically ill patients. Table 22.2 describes a variety of medications and medical conditions that can cause SIADH.

Table 22.2
General causes of SIADH [9]

Drug induced



Carbamazepine, oxcarbazepine, eslicarbazepine



Methylenedioxymethamphetamine (MDMA or “ecstasy”)

CNS disorders (stroke, demyelinating disorders, TBI)


Cyclophosphamide, ifosfamide

Pulmonary conditions (infections, respiratory failure)

Phenothiazine antipsychotic agents (chlorpromazine, prochlorperazine, thioridazine)

Serotonin-reuptake inhibitors

Surgical procedures
Tricyclic antidepressants (such as amitriptyline, nortriptyline, etc.)

22.3 Hypernatremia

Hypernatremia is a common medical condition in neurocritically ill patients. It is most caused by an increase in salt-free water or loss of serum sodium or most commonly iatrogenic in nature due to use of hypertonic solutions in this patient population. Conditions including diabetes insipidus are among other common causes of hypernatremia. Table 22.3 describes the strategies employed in the treatment of both hyponatremia and hypernatremia.

Table 22.3
Treatments for hyponatremia and hypernatremia [9, 10]



Correct underlying cause

Hypotonic solutions


 Modest/non-statistically significant slow increase in plasma sodium at 3 weeks

 Generally avoid dextrose 5% water in neurocritically ill patients due to risk of cerebral edema

 Increased incidence of nephrotoxicity

 May consider 0.45% sodium chloride

 Rapid overcorrection may result in cerebral edema as water uptake by brain cells increases the dissipation of accumulated electrolytes and organic osmolytes

Diuresis with loop diuretics (euvolemic and hypervolemic)

Fludrocortisone: 0.1–0.4 mg/day

Vasopressin analogs

 May require potassium supplementation

 Titrated to normalized urine output in diabetes insipidus, serum sodium correction, and urine-specific gravity

 Desmopressin (IV/SQ): 0.5–4 mcg every 8–12 h

 Vasopressin IV infusion: 1–15 units per h (titrated to normalized urine output)

Hypertonic saline

 In patients with severe symptoms, may correct up to 5 meq/L within first hour or until resolution of symptoms

 Maximum recommended increase: 8–12 mEq/L per 24 h, 18 meq/L per 48 h

 Rapid overcorrection may lead to central pontine myelinolysis

 Correct more slowly in patients with chronic hyponatremia

Oral sodium supplementation

Vasopressin antagonists (oral tolvaptan, injectable conivaptan) in euvolemic and hypervolemic hyponatremia


 CYP 3A4 substrates/inhibitors

 Increased cost

 Phlebitis (conivaptan)

22.4 Hemodynamic Management

Patients in the Neuro ICU commonly require treatment for hemodynamic instability. See Table 22.4 for outline of common etiologies and management points.

Table 22.4
Common etiologies and management for hemodynamic instability



Euvolemia is usually the clinical goal for fluid status in neurocritically ill patients, especially in patients with aneurysmal SAH (aSAH)

Nicardipine and clevidipine are drugs of choice in patients who require immediate control of blood pressure

Nimodipine can cause hypotension in aSAH. Standard dose is 60 PO q4h for 21 days. May be adjusted to 30 mg PO q2h in patients with hypotension. A recent publication of nimodipine use in aSAH patients concluded that nimodipine dose reductions due to changes in mean arterial pressure may be associated with unfavorable clinical outcome [7]



Dose: 5 mg/h up to 15 mg/h

Dose: 1–2 mg/h up to 21 mg/h. Infusion rates up to 32 mg/h have been studied for short periods of time

Half-life: 3 min (longer with prolonged infusions)

Shorter half-life: 1 min

Patients with spinal cord injury often experience neurogenic shock and require adjunctive medications to manage hypotension and bradycardia. Pseudoephedrine and theophylline have both been used in patients with spinal cord injury as an adjunct to facilitate the discontinuation of intravenous vasopressors

Midodrine is also useful in neurocritically ill patients with hypotension requiring adjunctive therapy to facilitate the discontinuation of continuous intravenous infusion vasopressors

Droxidopa, a novel oral synthetic precursor to norepinephrine, may be useful in neurocritically ill patients with neurogenic orthostatic hypotension. As more clinical trials become available, the role of Droxidopa may be expanded for other uses in neurocritically ill patients

Adrenergic agents should be avoided in patients with Guillain-Barré syndrome, as these patients have increased sensitivity to these agents and use can worsen weakness

Resuscitation with albumin is associated with worse outcomes in traumatic brain injury and is therefore not recommended in this setting

22.5 Analgesia and Sedation

Current guidelines support the use of non-benzodiazepine sedatives, dexmedetomidine and propofol, as first-line pharmacologic treatment when continuous intravenous sedation is necessary, with the majority of recommendations based on evidence from studies including only general ICU patients. Propofol is preferred over benzodiazepines in patients requiring frequent neurologic assessments (e.g., hourly) due to its relatively shorter half-life and decreased risk of delirium. Propofol is limited by potentially severe adverse effects including hypotension and accumulation usually with prolonged use (>48 h) leading to propofol-related infusion syndrome (PRIS) with characteristics including acute refractory bradycardia, hypertriglyceridemia, cardiovascular failure, metabolic acidosis, rhabdomyolysis, and renal failure. Analgesia should be optimized first to address underlying pain followed by a focus on anxiolysis as pain often manifests as agitation. Various pain scales including the critical care pain observation tool (CPOT) may be utilized to adequately assess pain in order administer appropriate pharmacologic interventions. See Tables 22.5 and 22.6.

Table 22.5
Commonly used intravenous analgesics in neurocritical care [12]

Comparative dose (IV)

Usual infusion dose

Time to onset (min)

Half-life (h)

Clinical pearls


100–200 mcg

0.7–10 mcg/kg/h



High lipophilicity can lead to prolonged duration of action especially after repeated dosing or infusion


1.5 mg

7–15 mcg/kg/h




10 mg

0.07–0.5 mg/kg/h



Active metabolites (M6-G active)

M3G inactive metabolite potentially neurotoxic


2.5 mg

Not recommended

Oral: 30


Weak NMDA receptor antagonist

IV: 10–20

Potential to prolong QT interval

Potential to increase intracranial pressure

Table 22.6
Commonly used intravenous sedative agents in neurocritical care [13, 14]


Onset of action (min)

Time to arousal

Clinical pearls


LD: Not generally recommended


Up to 10 min

No active metabolites; does not cause respiratory depression

 Note: terminal t1/2 of 2 h

May cause hypotension and bradycardia

May have clinical utility in patients with persistent dysautonomia of central origin refractory to opiates, adrenergic blockade, and bromocriptine

MD: 0.2–1.4 mcg/kg/h

May have clinical utility in patients with traumatic brain injury who are not mechanically ventilated and require a continuous infusion of a sedative to facilitate care

Added benefit in control of shivering


LD: 0.02–0.06 mg/kg


Up to 6 h

May cause respiratory depression and hypotension

MD: 0.01–0.1 mg/kg/h

No active metabolites

IV formulation contains propylene glycol (risk of anion gap metabolic acidosis)


LD: 0.02–0.2 mg/kg


Up to 2 h

May cause respiratory depression and hypotension

MD: 0.04–0.2 mg/kg/h

Has active metabolites

IV formulation does not contain propylene glycol


LD: 2.5–1 mg/kg

Immediate (<1)

Up to 15 min

May cause respiratory depression, hypotension, hypertriglyceridemia, pancreatitis, propofol infusion syndrome (metabolic acidosis, bradycardia, cardiac arrest, rhabdomyolysis, renal failure)

Contraindicated in patients with hypersensitivity to egg or soy products

Monitor pH, bicarbonate, triglycerides, lipase with prolonged therapy (>48 h) or high doses (>80 mcg/kg/min)

MD: 25–75 mcg/kg/min

LD loading dose, MD maintenance dose

22.6 Antiepileptic Drugs

Many antiepileptic drugs (AEDs) are available for use in status epilepticus, and their use varies amongst institutions (see Table 22.7). See Chap. 12 for a more comprehensive clinical overview.

Table 22.7
Medications commonly used in status epilepticus [8]



Clinically relevant pharmacokinetic interactions with other AEDs

Recommended target drug levels



LD: 10–20 mg

Minimal clinically significant drug-drug interactions

Dose guided by clinical response

May be an effective add-on therapy in RSE

Improved safety and tolerability compared to other benzodiazepines. Decreased sedation compared to other benzodiazepines

MD: up to 60 mg/day (divided twice daily)


LD: 0.25 mg/kg IVP over 1–2 min(up to 10 mg per dose); may repeat in 5 min

Longer half-life compared to other benzodiazepines

Dose guided by clinical response

Rapid redistribution

Has active metabolites

IV formulation contains propylene glycol

IV solution may be administered rectally if no IV access


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Jan 31, 2018 | Posted by in NEUROSURGERY | Comments Off on Pharmacology
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