Volatile Anesthetics

Both IV (with the exception of ketamine) and volatile anesthetics reduce CMRO2, however with IV anesthetics there is a concomitant reduction in CBF. Volatile anesthetics, which are vasodilators, do not reduce CBF. In fact, they raise it.

Sevoflurane Desflurane Isoflurane N2O CBF + + + + + + CPP – – – – – – ICP +/- +/- +/- +/- CMRO2 – – – +

Note that of all the volatile anesthetics, isoflurane produces the most significant reduction in neural activity and is in fact the only inhaled agent capable of producing an isoelectic EEG at normal concentrations (in this case, ~ 2 MAC) [Data adapted from Dunn PF. Clinical Anesthesia Procedures of the Massachusetts General Hospital, 7th ed. LWW (Philadelphia) p. 444-5, 2007]

High concentrations of inhaled anesthetics can abolish the autoregulatory response, although at < 1 MAC autoregulation is generally intact – a study of 14 patients showed that 1.2 MAC sevoflurane with and without 60% nitrous oxide had a negligible effect on cerebrovascular carbon dioxide reactivity [Cho S et. al. Anesthesiology 85: 755, 1996]. IV anesthetics, by contrast, do not disrupt autoregulation [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier (China) p. 454, 2007]

Hyperventilation to a PaCO2 < 35 mm Hg attenuates vasodilation due to volatile anesthetics.

IV Induction Agents

Thiopental, propofol, and etomidate all decrease CMRO2, ICP, and CBF. Propofol and thiopental must be used with caution, however, as they can decrease MAP below the level at which autoregulation can reasonably be expected to compensate. Etomidate has the unfortunate side effect of producing occasional myoclonus, and some authors recommend avoiding in patients with a history of seizures.

Opiates

Opiates decreased CBF and may decrease ICP when ventilation is held constant [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier (China) p. 456, 2007]. That said, they must be used with caution in patients with CNS injuries, as they can decrease both the level of consciousness and the ventilatory rate. Additionally, opiates have been shown to increase ICP in TBI patients – Sperry et. al. studied nine patients with severe head trauma, giving them fentanyl and sufentanil while paralyzed and mechanically ventilated. Fentanyl increased ICP 8 +/- 2 mmHg, and sufentanil 6 +/- 1 mmHg (statistically significant). Fentanyl decreased MAP 11 +/- 6 mmHg, sufentanil 10 +/- 5 mmHg (also statistically significant) [Sperry RJ et. al. Anesthesiology 77: 416, 1992] Ketamine

α2-agonists

According to Stoelting, alpha-agonists do not affect ICP, slightly reduce CBF and MAP, thus reduce CPP [Stoelting RK. Basics of Anesthesia, 5th ed. Elsevier (China) p. 456, 2007]. There is very little published data on dexmedetomidine – a retrospective study of 39 neurosurgical patients in the ICU showed a mean decrease in ICP and a mean increase in CPP following administration of dexmedetomidine, both of which were statistically-insignificant at the majority of time points between 0 and 30 hours [Aryan HE et. al. Brain Inj. 20: 791, 2006]

Ketamine

Ketamine is generally not used in patients with intracranial disease, because when given on its own and without ventilatory control, it is known to increase PCO2, ICP, CBF, and CMRO2. Original reports of elevated CSF pressure following ketamine were measured in the lumbar spine [Gardner AE et. al. Anesthesiology 35: 226, 1971; Evans J et. al. Lancet 1: 40, 1971]. Gardner subsequently published two case reports of ICP elevations following ketamine – the first was a 13 year-old boy with a glioma, given 2 mg/kg and allowed to breath spontaneously (ICP went from 42 to 113 cm H2O, PaCO2 from 52 to 38). The second was a patient with normal baseline ICP who had undergone a surgical procedure in the past – after 2 mg/kg, his ICP increased from 4 to 15 cm H2O (PaCO2 not measured) [Gardner AE et. al. Anesth Analg 51: 741, 1972]

Ketamine: The Data

The idea that ketamine is absolutely contraindicated in head injury patients has been refuted by several authors. Takeshita studied 10 healthy patients prior to surgery, giving them 3 mg/kg ketamine (two divided doses), and found that CSF flow increased from 47 to 76 cc/100g/min (62%), cerebral vascular resistance dropped by 28%, yet there were no changes in CMRO2. Of note, Takeshita did not report how CBF was measured, and did not measure or publish ICP [Takeshita H et. al. Anesthesiology 36: 69, 1972]. Albanèse, in a study of eight patients with TBI. All patients were initially sedated with propofol infusion and mechanical ventilation was instituted. Ketamine was then given, and in all three doses studied (1.5, 3, and 5 mg/kg) was associated with a significant decrease in ICP (mean +/- SD: 2 +/- 0.5 mmHg [P < 0.05], 4 +/- 1 mmHg [P < 0.05], and 5 +/- 2 mmHg [P < 0.05]). There were no significant differences in cerebral perfusion pressure, jugular vein bulb oxygen saturation, and middle cerebral artery blood flow velocity. Ketamine induced a low-amplitude fast-activity electroencephalogram, with marked depression, such as burst suppression [Albanèse J et. al. Anesthesiology 87: 1328, 1997]

Lidocaine

Lidocaine is thought to decrease both CBF and CMRO2.

Paralytics

Succinylcholine

Succinylcholine has traditionally been considered a risk in patients with elevated ICP, as the defasciculation phase is thought to elevated intracranial pressures. This can be ameliorated by a defasciculating dose of a non-depolarizing NMBD. Kovarik et. al. studied the effects of succinylcholine in 10 mechanically ventilated patients (GCS score 3-10, median 6) being treated for increased ICP in an intensive care unit. SCh (1 mg/kg) was administered intravenously and the above variables were monitored for 15 min. Neither saline nor SCh caused any significant change in cerebral perfusion pressure, MAP, V mca, EEG, or ICP [Kovarik WD et. al. Anesth Analg 78: 469, 1994]. This was confirmed by a double-blind crossover study of 11 mechanically TBI patients (GCS < 9) given a bolus of suxamethonium (1 mg kg-1) or an equal volume of saline (0.02 mL kg-1) before physiotherapy, which showed no significant changes in intracranial pressure or cerebral perfusion pressure (CPP) following the administration of either [Brown MM et. al. Eur J Anaesthesiol 13: 474, 1996]

Non-Depolarizing NMBDs

Non-depolarizing NMBDs do not affect ICP unless they release histamine or cause hypotension.

Antihypertensives

Labetalol (IV boluses) and nicardipine (IV infusion) are ideal for managing hypertension because they do not affect ICP. Nitroglycerin [Greenberg M. Greenberg’s Handbook of Neurosurgery] and nitroprusside, by contrast, may increase ICP and should be used with caution.

Antipsychotics

Typical Agents

Haloperidol

Butyrophenone (phenylbutylpiperidine) antipsychotic, potent D2 antagonist. Derivative of meperidine (a phenylpiperidine analgesic) and closely related to droperidol. Can be given intravenously or intramuscularly. Relatively little sedation. QTc prolongation (and torsade de pointes followed by fatal ventricular arrhythmias) is problematic – there is a Black Box Warning for IV (but not oral or IM) haloperidol. High incidence of extrapyramidal effects

Although atypical agents are thought to have less QTc prolongation, a recent retrospective analysis found a 2-fold risk for sudden cardiac death among both typical and atypical antipsychotic users (as compared to non users) [Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med, 2009, 360:225–235 [PMID: 19144938]]. Mean increase in QTc 4.7s, lower than most anti-psychotics, although it important to note that only haloperidol (and droperidol) have been definitively linked to torsades [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003]. Retrospective analysis has shown a mortality benefit when using haloperidol in critically ill patients [Milbrandt EB et al. Crit Care Med 33: 226, 2005]

First-line treatment for delirium according to the SCCM Guidelines [Jacobi J et al. Crit Care Med 30: 119, 2002]

Start at 2 to 5 mg every 6 to 12 hours (maximum effect at 20 mg/day)

Atypical Agents

Risperidone

A benzisoxazole-derivative antipsychotic agent and chemically unrelated to other antipsychotic agents. Mechanism of action not completely worked out but likely involves antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors (also an α2-antagonist). Available in tablet form or as a solution. Peak in 1 hour. Hepatic metabolism. Mild sedation only

Start with 1 mg q 12h. Renal adjustment required. Binds to the IKr channel and can prolong the QTc interval [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001] leading to a mean increase in QTc 10 [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003] to 12 seconds. Notably, although this is significantly higher than haloperidol, there is no convincing evidence that risperidone has ever caused torsades or sudden death [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001]

Pricing: Risperdal 1MG Tablets (JANSSEN): $6.33 each ($12.66/day, AHFS Drug Information, 2011)

Aripiprazole

Can be given intramuscularly, also available as a solution. Relatively little sedation.

Quetiapine

A dibenzothiazepine-derivative antipsychotic agent. Mechanism of action related to antagonism at serotonin type 1 and type 2 receptors as well as dopamine (D1, D2) receptors. Also blocks α1 (orthostatic hypotension), α2, and H1 (sedating) receptors. Available in tablet form only. Peaks in 1.5 hours. Hepatic metabolism. Moderately sedating [Miller DD. Prim Care Companion J Clin Psychiatry 6 (Suppl 2): 3, 2004]

Start with 25 mg PO q12h. Binds to the IKr channel and can prolong the QTc interval (mean increase in QTc 14.5s [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003]), but it is not clear that it can cause torsade de pointes or ventricular fibrillation [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001]

Pricing: SEROquel 25MG Tablets (ASTRAZENECA): $3.53 each ($7.06/day, AHFS Drug Information, 2011)

Olanzapine

Tablet form only. Peaks in 6 hours. Start with 2.5 mg PO qhs. Moderately sedating [Miller DD. Prim Care Companion J Clin Psychiatry 6 (Suppl 2): 3, 2004]

Binds to the IKr channel and can prolong the QTc interval (mean increase in QTc 6.4s [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003]), but it is not clear that it can cause torsade de pointes or ventricular fibrillation [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001]

Pricing: ZyPREXA 2.5MG Tablets (LILLY): $10.90 each ($10.90/day, AHFS Drug Information, 2011)

Dexmedetomidine

Both the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) [Pandharipande PP et al. JAMA 298: 2644, 2007] and the Safety and Efficacy of Dexmedetomidine Compared to Midazolam (SEDCOM) [Riker R et al. JAMA 301: 489, 2009] studies suggest that dexmedetomidine may decrease delirium when compared to benzodiazepines

Summary: Antipsychotics in the ICU

• Haloperidol: proven association with torsades (although sudden death risk may not be different than atypicals). Inexpensive. Versatile. First-line according to SCCM Guidelines
• Sedation: quetipine and olanzapine
• Solution Form: risperidone
• IM Form: haldol, aripiprizole