Sedation Management in the Neuroscience ICU

Educational Objectives

The goal of this program is to improve the management of sedation in the neuroscience intensive care unit (neuro ICU). After hearing and assimilating this program, the clinician will be better able to:

1. Cite Brain Trauma Foundation guidelines on control of intracranial pressure in patients with traumatic brain injury.
2. Administer benzodiazepines to control status epilepticus seizures.

Summary

Sedation in the intensive care unit (ICU): the Society of Critical Care Medicine (SCCM) guidelines suggest that dexmedetomidine or propofol are preferable to benzodiazepines as sedative agents for patients who are critically ill and mechanically ventilated because of improved short-term outcomes, eg, duration of mechanical ventilation, ICU length of stay (LOS), delirium (Devlin et al [2018]); however, these were based on the SEDCOM trial (Riker et al [2009]) and are conditional recommendations based on low-quality evidence; there are no sedation guidelines endorsed by neurologic societies because the studies excluded patients in the neuroscience ICU (neuro ICU) or with significant neurologic impairment; meta-analyses are available but note poor-quality data

The ANIST trial (Mirski et al [2010]): assessed patients with and without brain injury; sedation with fentanyl-propofol diminished mean Adapted Cognitive Exam (ACE) scores by 12 points, while fentanyl-dexmedetomidine increased ACE scores by 6 points (statistically significant); there were no serious adverse events; although the study is not broadly applicable to the neuro ICU population, it does suggest that dexmedetomidine maintains a patient’s intellectual capacity to cooperate with neurologic examination

Erdman et al (2014): study compared the safety of dexmedetomidine and propofol use for intubated patients in the neuro ICU and found no difference in the composite outcome (bradycardia and hypotension); safety was relatively equal

Srivastava et al (2014): in postoperative surgical patients, adequate sedation and decreased mean arterial pressure (MAP) were achieved in the dexmedetomidine, propofol, and midazolam groups; the dexmedetomidine group experienced a decreased heart rate (HR); time to extubation was decreased in the propofol group; the dexmedetomidine group required ≈50% of the fentanyl dose of other groups

DEXPRONE study (Owusu et al [2020]): dexmedetomidine was more commonly used for facilitating extubation and neurologic assessment; propofol was more commonly used to manage agitation; there was no difference in adverse effects; there were more deaths in the propofol group, but their Glasgow Coma Scale (GCS) scores were lower and there were more patients with stroke; there is no conclusive evidence as to which agent is better

Other indications: the Brain Trauma Foundation traumatic brain injury guidelines (Carney et al [2017]) — propofol is recommended as first-line therapy for controlling intracranial pressure (ICP); barbiturates are recommended to control refractory elevated ICP (level IIB evidence); targeted temperature management (TTM) guidelines from the Neurocritical Care Society (Madden et al [2017]) — dexmedetomidine, propofol, or midazolam can reduce temperature by 0.5°C to 2.4°C (wide range); no medication is preferred over another; status epilepticus (SE) — guidelines (Glauser et al [2016]) state that benzodiazepines are the drugs of choice; therapies for refractory SE include continuous anesthetics, barbiturates, and propofol; Alkhachroum et al (2020) — with ketamine use for super-refractory seizure epilepticus (SE), seizure burden decreased by 50% in 80% of patients, and seizure activity terminated in 63%; however, it did not affect long-term outcomes

Dexmedetomidine: a selective alpha-2 agonist; higher doses affect alpha-1 (causes hypotension and hypertension with bolus dosing); it acts as an anesthetic, analgesic, and sedative without respiratory depression, but it does not achieve deep sedation; pharmacokinetics — has an onset of 20 to 30 min without a loading dose, duration of 1 to 2 hr, and half-life of 2 to 3 hr; exclusively metabolized in the liver (half-life is extended to ≈7.5 hr in severe hepatic dysfunction); adverse effects — include bradycardia, negative inotropy, and hypotension; does not affect ICP or the oxygen extraction ratio; has a small effect on cerebral metabolism (CM); however, it decreases MAP, which can result in decreased cerebral perfusion pressure; key points — dexmedetomidine should be used for adjunctive pain control, sedation, and possibly TTM

Propofol: a gamma-aminobutyric acid (GABA) receptor agonist with dose-dependent effects; does not affect pain; protects cerebral autoregulation (ie, maintains carbon dioxide responsiveness); a lower dose is used for sedation, with a higher initial dose for ICP and seizure control; has rapid onset (30 sec to 2 min), duration of 3 to 10 min, and 2 half-lives (40 min in well-perfused tissues, eg, brain, and 3-12 hr in peripheral tissues); with longer use (ie, >1 wk), the peripheral half-life extends to 30 to 70 hr but the well-perfused half-life does not change; extensively metabolized by the liver; may cause propofol-related infusion syndrome (PRIS; metabolic acidosis, bradycardia, renal failure, cardiac arrest); pharmacodynamics — increases triglycerides and caloric intake (1.1 kcal/mL); decreases ICP, cerebral electrical activity, cerebral blood flow (CBF), and CM; can be used for sedation, ICP control, TTM, and seizure control; contraindicated in patients with egg and soy allergies; the risk for PRIS increases with duration of therapy

Midazolam: a GABA receptor agonist; dosing and titration depend on the indication; has an onset of 3 to 5 min, duration of 1 to 2 hr, and mean half-life of 3 hr; accumulates in peripheral tissues; the half-life is longer (≤2.5-fold) in the elderly and those with congestive heart failure, hepatic and renal dysfunction, and obesity; metabolized by cytochrome P450 3A4 in the liver and interacts with several drugs; adverse effects — include tachyphylaxis, tolerance, prolonged duration of mechanical ventilation, and increased delirium and posttraumatic stress disorder; uses — similar to those of propofol (but with a lesser effect on MAP); decreases CM and electrical activity; can be used for sedation, TTM (less useful), ICP control, and seizure control

Ketamine: an N-methyl-d-aspartate receptor antagonist; can have additional actions at muscarinic, nicotinic, and mu opioid receptors and can cause, eg, nystagmus, salivation, bronchodilation, pain control; at lower doses, it protects pharyngeal and laryngeal reflexes but shuts them down at higher doses; has an onset of 30 sec to 30 min, duration of 15 min to 1 hr, and 2 half-lives, with peripheral accumulation; it is metabolized in the liver; norketamine is the active metabolite; adverse effects — include hallucinations, emergence phenomena (eg, euphoria, distorted perceptions), and increased pulmonary secretions; liver failure and hemorrhagic cystitis can occur with long-term use; pharmacodynamics — CM and CBF responses differ based on brain location; there is no effect on ICP; it may increase MAP (interactions with catecholamines), decrease airway resistance, and increase lung compliance (affects ventilatory status); it is effective for refractory seizures; its use as a routine sedative is unclear; not beneficial for ICP control

Barbiturates: phenobarbital and pentobarbital are GABA receptor agonists; phenobarbital (bolus dosing) is used only for seizures; pentobarbital (infusion) can also be used for ICP control; pharmacokinetics — phenobarbital (least lipophilic) has the lowest plasma and brain protein binding ratio, resulting in longer onset (5-15 min); the duration is 10 to 12 hr; has a prolonged half-life (≈80 hr; ≤140 hr in hepatic dysfunction); pentobarbital has an onset of 3 to 5 min, duration of 15 to 45 min, and a half-life of 15 to 50 hr; it accumulates in hepatic failure; adverse effects — include undesirable neurologic effects, myocardial suppression, cardiac arrest, Stevens-Johnson syndrome, ileus, immune suppression, apnea, and metabolic acidosis (because of the propylene glycol suspension vehicle); requires monitoring of serum levels; interactions — include a wide range of drugs, eg, opioids, benzodiazepines, ketamine, propofol, carbamazepine, and valproic acid; barbiturates are highly effective and drastically decrease CM, CBF, and ICP; they eliminate almost all cortical activity above basal metabolism (≤60% decrease in CBF and CM with burst suppression)

Neuroprognostication and brain-death examination: require holding drugs for 4 to 5 half-lives

Readings

Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Ketamine to treat super-refractory status epilepticus. Neurology. 2020;95(16):e2286-e2294. doi:10.1212/WNL.0000000000010611; Carney N, Totten AM, O'Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80(1):6-15. doi:10.1227/NEU.0000000000001432; Dericioglu N, Arslan D, Arsava EM, et al. Efficacy and safety of ketamine in refractory/super-refractory nonconvulsive status epilepticus: Single-center experience. Clin EEG Neurosci. 2021;52(5):345-350. doi:10.1177/1550059420942677; Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299; Erdman MJ, Doepker BA, Gerlach AT, et al. A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients. Crit Care Med. 2014;42(7):1696-1702. doi:10.1097/CCM.0000000000000328; Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. doi:10.5698/1535-7597-16.1.48; Madden LK, Hill M, May TL, et al. The Implementation of Targeted Temperature Management: An Evidence-Based Guideline from the Neurocritical Care Society. Neurocrit Care. 2017;27(3):468-487. doi:10.1007/s12028-017-0469-5; Mirski MA, Lewin JJ 3rd, Ledroux S, et al. Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST). Intensive Care Med. 2010;36(9):1505-1513. doi:10.1007/s00134-010-1874-9; Opdenakker O, Vanstraelen A, De Sloovere V, et al. Sedatives in neurocritical care: an update on pharmacological agents and modes of sedation. Curr Opin Crit Care. 2019;25(2):97-104. doi:10.1097/MCC.0000000000000592; Owusu KA, Kurczewski L, Armahizer MJ, et al. DEXmedetomidine compared to PROpofol in NEurocritical Care [DEXPRONE]: A multicenter retrospective evaluation of clinical utility and safety. J Crit Care. 2020;60:79-83. doi:10.1016/j.jcrc.2020.07.021; Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489-499. doi:10.1001/jama.2009.56; Srivastava VK, Agrawal S, Kumar S, et al. Comparison of dexmedetomidine, propofol and midazolam for short-term sedation in postoperatively mechanically ventilated neurosurgical patients. J Clin Diagn Res. 2014;8(9):GC04-GC7. doi:10.7860/JCDR/2014/8797.4817.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Bernard’s lecture includes off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Bernard was recorded at the Jefferson Neurocritical Care Symposium, held February 2-3, 2024, in Philadelphia, PA, and presented by Thomas Jefferson University. For information on upcoming CME activities from this presenter, please visit Jefferson.edu. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

NE151101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

More Details - Certification & Accreditation