General spectrum of activity
Antimicrobial
Typical daily dosing range (admixture in preservative-free solutions)
Common adverse effects
Gram positive
Vancomycin
10–20 mg /1 mL NS
Headache, mental status changes, possible hyponatremia
Daptomycin
5–10 mg/1 mL NS
None reported
Gram negative
Gentamicin
4–8 mg/1 mL NS
Seizures
Tobramycin
4–8 mg/1 mL NS
Seizures
Amikacin
30 mg/1 mL NS
Seizures
Polymyxin B
5 mg/1 mL NS
Hypotonia, seizures, meningeal inflammation
Colistimethate
10 mg/3 mL NS
Meningeal inflammation
Fungal
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.
Drug induced | Other | |
|---|---|---|
Desmopressin | Carbamazepine, oxcarbazepine, eslicarbazepine | Malignancy |
Vasopressin | Methylenedioxymethamphetamine (MDMA or “ecstasy”) | CNS disorders (stroke, demyelinating disorders, TBI) |
Oxytocin | 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.
Hyponatremia | Hypernatremia |
|---|---|
Correct underlying cause | Hypotonic solutions |
Demeclocycline | |
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 | |
Hepatotoxic | |
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
Hypotension | Hypertension | |
|---|---|---|
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] | Nicardipine | Clevidipine |
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.
Comparative dose (IV) | Usual infusion dose | Time to onset (min) | Half-life (h) | Clinical pearls | |
|---|---|---|---|---|---|
Fentanyl | 100–200 mcg | 0.7–10 mcg/kg/h | <1 | 2–4 | High lipophilicity can lead to prolonged duration of action especially after repeated dosing or infusion |
Hydromorphone | 1.5 mg | 7–15 mcg/kg/h | 5–10 | 2–3 | |
Morphine | 10 mg | 0.07–0.5 mg/kg/h | 5–10 | 3–4 | Active metabolites (M6-G active) |
M3G inactive metabolite potentially neurotoxic | |||||
Methadone | 2.5 mg | Not recommended | Oral: 30 | 9–59 | Weak NMDA receptor antagonist |
IV: 10–20 | Potential to prolong QT interval | ||||
Potential to increase intracranial pressure |
Dosing | Onset of action (min) | Time to arousal | Clinical pearls | |
|---|---|---|---|---|
Dexmedetomidine | LD: Not generally recommended | 1–3 | 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 | ||||
Lorazepam | LD: 0.02–0.06 mg/kg | 5–20 | 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) | ||||
Midazolam | LD: 0.02–0.2 mg/kg | 1–5 | 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 | ||||
Propofol | 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 |
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.
AED | Dosing | Clinically relevant pharmacokinetic interactions with other AEDs | Recommended target drug levels | Comments |
|---|---|---|---|---|
Clobazam | 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) | ||||
Diazepam | 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 | ||||
Fosphenytoin
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