Sedation & Analgesia

MOA: selective alpha2 receptor agonist.

Metabolism/Elimination: Liver 🡪 excreted by kidneys. Will require dose adjustment in liver failure due to decreased metabolism.

Effects: sedation, analgesia, anxiolysis[1] , cardiovascular stabilizing effects, reduced anesthetic requirements. ↓CBF and CMRO2[2] . Has been shown to be neuroprotective in cerebral ischemia, TBI, [8-10]

• • • Dexmedetomidine has been shown to be associated with a reduction in ICU length of stays, mechanical ventilation duration, and delirium incidence [11]. It has also been shown to decrease opioid requirements.

    • However, when compared to propofol in neurocritical care patients precedex was shown to have similar duration of infusions, duration of mechanical ventilation, and incidence of hypotension, and incidence of  bradycardia.[12]

Adverse Effects: bradycardia, hypotension, dry mouth, atrial fibrillation

Considerations: does not interfere with respiratory drive, making it an ideal agent for vent weaning. Preserves normal sleep architecture[3] .

• • • In double-blinded RCT dexmedetomidine was compared with sedation with lorazepam and was shown to have more days alive without coma, lower prevalence of coma, better at achieving sedation goals, and had similar brain function after discharge from the ICU. [13]

    • A small study (n=85) of patients with TBI showed that the use of dexmedetomidine significantly decreased the sedative and opioid requirements. [14]

Common uses: Another preferred agent for NSICU sedation due to the necessity of frequent exams [15], given that it can be shortly paused.  Ventilator weaning: patients may be switched from propofol to dexmedetomidine given less interference with respiratory drive.

Dosing: loading dose of 1 mcg/kg over 10 minutes, followed by an infusion from 0.2-1.5 mcg/kg/hr, titrated by 0.2 mcg/kg/hr every 30 minutes. (Rarely exceed >1mcg/kg/hr at MUSC)

• • • Doses higher than 1.5 mcg/kg/hr do NOT provide any additional clinical efficacy [16]

    • Peak effect within 15-30 mins, and dose-dependent duration of 60-120 mins

MOA: activation of GABAA chloride channel

Effects: sedation, anxiolysis, anterograde amnesia, and hypnosis

Adverse Effects: prolonged sedation when run as prolonged infusions, ↑delirium in critically ill patients, vasodilation 🡪 hypotension [1] [11]. Prolonged cognitive and neurologic impairment following brain injury.[17]

Considerations: ensure adequate volume status to avoid hypotension

Common uses: refractory intracranial hypertension, status epilepticus, withdrawal syndromes; adjuncts for vent dyssynchrony, agitation.

Drug-specific characteristics

Midazolam (Versed)

• • • Metabolism/Elimination: metabolized by liver[2]  to an active renally eliminated metabolite. Therefore, midazolam may have prolonged effects in patients with severe renal dysfunction. Accumulates in fat tissue after ~48hrs of infusion 🡪 prolonged duration of effects after infusion is discontinued

    • May cause CNS depression when taken with a CYP3A4 inhibitor[3] .[18]

    • Dosing: 0.5-5mg or 0.01-0.05 mg/kg over ≥2 mins, may repeat Q10-15min. Loading dose 0.5-5mg Q1-5min (if needed), followed by 1-8mg/hr (0.01-0.1mg/kg/hr).

Lorazepam (Ativan)

• • • Metabolism/Elimination: metabolized by liver to an inactive metabolite.

    • Side effects: administration of large doses over short periods of time may cause an anion gap metabolic acidosis[4] .

    • Dosing: 0.5-2mg Q4-6H. Status epilepticus: 4mg at max rate of 2mg/min; may repeat at 3-5 mins if seizures continue.

Flumazenil

• • • MOA: selective GABA receptor antagonist 🡪 competitively reverses effects of benzodiazepines

    • Adverse Effects: anxiety, agitation, tremor, myoclonus, insomnia, seizures

      • To remember these effects → opposite of benzos

    • Uses: not commonly used in ICU due to risk of precipitating withdrawal

• Current Recommendations: The Society of Critical Care Medicine recommend using propofol [5] or dexmedetomidine [6] over benzodiazepines for sedation of critically ill, mechanically ventilated patients. [6]

• Main takeaways: benzos induce sedation, anxiolysis, anterograde amnesia, and hypnosis by activating GABAA channels. Midazolam is metabolized by liver (CYP3A4/5) to an active metabolite that may hang around in patients with renal failure, and can build up in adipose tissue. Lorazepam has no active metabolite, but may cause an AGMA at high doses. Flumazenil precipitates symptoms of BZD/EtOH withdrawal. In general, we avoid using benzos solely for sedation, as they carry a risk of increased delirium. However they do have a place for controlling seizures in refractory intracranial HTN, status epilepticus, alcohol withdrawal, and as adjuncts for agitation. [7] 

MOA: stimulate ì and ê receptors

Effects: analgesia, euphoria, sedation

Metabolism/Elimination: hepatic metabolism with renal elimination of metabolites

Adverse Effects: tolerance[1] , intestinal dysmotility, CNS depression 🡪 respiratory depression and hypotension. Tolerance does NOT develop with GI side effects.

Considerations: ALL ICU patients on opioids should be on a stimulant laxative [2] [3] to prevent constipation or gastric ileus. Once a patient has been on an opioid infusion for ≥ 7 days, then they will be at risk of opioid withdrawal[4] .

• • Common uses: given as boluses for PRN pain management or ventilator dyssynchrony. Run as infusions for persistent pain, ventilator dyssynchrony, or as a component of general ICU sedation.

• • The Society of Critical Care Medicine (SCCM) 2018 guidelines recommend opioids as first-line therapy for non-neuropathic pain and as the drug class of choice for analgosedation. Analgosedation [5] is an “analgesia-first” sedation approach, in which they recommend that an analgesic should be used before a traditional sedative (e.g. propofol, dexmedetomidine) to reach the sedative goal. [6]

    • Protocol-based (analgesia/analgosedation) pain and sedation assessment and management program: ↓ sedative requirements, ↓duration of mechanical ventilation, and ↓pain intensity.

Drug-specific characteristics

Fentanyl

• • • Metabolism/Elimination: hepatically metabolized to inactive metabolite[6] , which is renally excreted. Therefore, fentanyl is safe to use in patients with renal insufficiency.

    • Adverse Effects: Fentanyl is highly lipid soluble, so when run as a continuous infusion for prolonged periods of time, may lead to prolonged sedation, respiratory depression, and difficulty with vent weaning. (Long-ish context sensitive half time)

    • Dosing:

      • Loading: 25-100mcg or 1-2 mcg/kg; may repeat if severe pain persists. Peak effect time is ~5 minutes after administration.

• • • • Maintenance: start at rate of 25-50mcg/hr and titrate Q30-60 mins to clinical effect (usually between 50-200mcg/hr)

• • • • PRN 25-100 mcg for bedside procedures (eg central lines)

Hydromorphone

• • • Metabolism/Elimination: hepatically metabolized. ~30% metabolized to active metabolite that is renally excreted.

    • Dosing: VERY potent. 1mg IV hydromorphone is the equivalent of 5mg IV morphine. Lasts about 6 times longer than fentanyl[7] , and so is usually avoided in the NSICU due to frequent neurologic exams.

      • Intermittent: 0.5-2mg loading with 0.2-0.6mg Q1-2H PRN or 0.5mg Q3H PRN

      • Continuous (rarely used): 0.5-3mg/hr

Morphine

• • • Metabolism/Elimination: hepatically metabolized to two ACTIVE metabolites[8] , which are renally excreted. Not a good choice for patients with renal insufficiency.

    • Adverse Effects: stimulates histamine release à hypotension. DO NOT use in patients who are hemodynamically unstable or at risk of hypotension. Causes contraction of the sphincter of Oddi[9]  so use with caution in patients with biliary tract dysfunction or acute pancreatitis.

    • Uses: primarily used for air hunger and/or agitation, overall discomfort in patients who have transitioned to comfort care.

    • Dosing: analgesia: 1-4mg Q1-4hrs PRN; air hunger – see UPenn’s Comfort Care Guidelines for Providers (Appendix B)[19]

Remifentanil

• • • Metabolism/Elimination: extremely rapid metabolism by nonspecific plasma esterases 🡪 safe to use in patients with renal or hepatic disease.

    • Adverse Effects: due to rapid metabolism, patients can become extremely painful within only minutes of a remifentanil drip being stopped. Boluses may cause chest wall rigidity. Hypotension, headache, pruritis, nausea, vomiting.

    • Uses: commonly used in neurosurgery cases where patients need to remain unparalyzed for SSEP[10] s or other forms of neuromonitoring, but are required to remain absolutely still. Shown to ↓rate of delirium when compared with fentanyl and midazolam[20].  Typically reserved for ORs, rarely used for ICU sedation at MUSC.

MOA: inhibits NMDA receptors[1] 

Metabolism/Elimination: metabolized by liver to norketamine (33% as strong), but no renal dose adjustment needed. Highly lipophilic, so there is concern for accumulation in adipose tissue of obese patients.

Effects: dissociative anesthesia, sympathomimetic 🡪 ↑HR and BP[2] ; paradoxically may cause hypotension when patients are catecholamine depleted

• Adverse Effects: hallucinations[3]  (which may be very distressing), BP changes

• Hallucinations and psychotic effects may be mitigated by co-administering with benzodiazepines

Common uses: Used commonly in NSICU as ajdjunct with propofol for cases of refractory / super refractory status epilepticus

• Dosing: initial 0.1-0.5 mg/kg bolus, followed by 0.2-0.5 mg/kg/hr infusion

General Characteristics: most commonly haloperidol and olanzapine

MOA:  inhibits dopamine receptors[1] 

Metabolism/Elimination: hepatic metabolism, decreased in elderly patients

Effects: sedative, anxiolytic, antipsychotic

Adverse Effects: extrapyramidal side effects (parkinsonism, acute dystonia, tardive dyskinesia, akathisia and perioral tremor), QT prolongation[2] , GI discomfort

Considerations: Dopaminergic tone is key in recovery after brain injury, and the presence of chronically high dopamine antagonists after brain injury may impair cognitive and motor recovery. [21, 22]

• • • •  Multiple rat models show that administration of haloperidol decreases recovery after brain injury [23]. Interestingly, this impairment was not noted in rats treated with olanzapine [24].

Common uses: adjuncts in severe agitation, sundowning/ delirium in the elderly, nausea/ vomiting not resolved by zofran

Dosing:

• • • • Haldol: 1-10mg bolus dosing for acute agitation; then q2-q6h prn for ongoing agitation

      • Olanzapine: 25-100mg QHS for sundowning; 25-200mg in divided doses throughout the day for ongoing agitation

1.     Nickson, C. Sedation in ICU. 2020  [cited 2021; Available from: https://litfl.com/sedation-in-icu/.

2.     Chester, K., Greene, K., Brophy, G., Sedation in the Critical Care Unit, in Textbook of Neuroanesthesia and Neurocritical Care. 2019, Springer: Singapore. p. 299-318.

3.     Sessler, C.N., et al., The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med, 2002. 166(10): p. 1338-44.

4.     Rajajee, V., B. Riggs, and D.B. Seder, Emergency Neurological Life Support: Airway, Ventilation, and Sedation. Neurocrit Care, 2017. 27(Suppl 1): p. 4-28.

5.     Deogaonkar, A., et al., Bispectral Index monitoring correlates with sedation scales in brain-injured patients. Crit Care Med, 2004. 32(12): p. 2403-6.

6.     Devlin, J.W., 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. Critical care medicine, 2018. 46(9): p. e825-e873.

7.     Jones, G.M., et al., Predictors of severe hypotension in neurocritical care patients sedated with propofol. Neurocrit Care, 2014. 20(2): p. 270-6.

8.     Maier, C., et al., Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology, 1993. 79(2): p. 306-12.

9.     Schoeler, M., et al., Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol, 2012. 12: p. 20.

10.   Chrysostomou, C. and C.G. Schmitt, Dexmedetomidine: sedation, analgesia and beyond. Expert Opin Drug Metab Toxicol, 2008. 4(5): p. 619-27.

11.   Constantin, J.M., et al., Efficacy and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of randomized controlled trials. Anaesth Crit Care Pain Med, 2016. 35(1): p. 7-15.

12.   Owusu, K.A., et al., DEXmedetomidine compared to PROpofol in NEurocritical Care [DEXPRONE]: A multicenter retrospective evaluation of clinical utility and safety. Journal of Critical Care, 2020. 60: p. 79-83.

13.   Pandharipande, P.P., et al., Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA, 2007. 298(22): p. 2644-53.

14.   Humble, S.S., et al., ICU sedation with dexmedetomidine after severe traumatic brain injury. Brain Injury, 2016. 30(10): p. 1266-1270.

15.   Tsaousi, G.G., M. Lamperti, and F. Bilotta, Role of Dexmedetomidine for Sedation in Neurocritical Care Patients: A Qualitative Systematic Review and Meta-analysis of Current Evidence. Clin Neuropharmacol, 2016. 39(3): p. 144-51.

16.   Venn, R.M., M.D. Karol, and R.M. Grounds, Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret. Br J Anaesth, 2002. 88(5): p. 669-75.

17.   Schallert, T., T.D. Hernandez, and T.M. Barth, Recovery of function after brain damage: severe and chronic disruption by diazepam. Brain Res, 1986. 379(1): p. 104-11.

18.   Horn, J., Hansten, PPD., Drug Interactions with CYP3A4: An Update, in Pharmacy Times. 2015: Heart Health.

19.   Laura Dingfield, M., Anessa Foxwell, CRNP ACHPN., Rachel Klinedinst, CRNP ACHPN, Rebecca Stamm, MSN RN CCNS CCRN, Tanya Uritsky, PharmD BCPS, CPE Comfort Care Guidelines for Providers. [pdf] 06/2018; Available from: https://www.med.upenn.edu/uphscovid19education/assets/user-content/documents/palliative-care/comfort-care/comfort-care-guideline.pdf.

20.   Liu, D., et al., The influence of analgesic-based sedation protocols on delirium and outcomes in critically ill patients: A randomized controlled trial. PLoS One, 2017. 12(9): p. e0184310.

21.   de la Tremblaye, P.B., et al., Elucidating opportunities and pitfalls in the treatment of experimental traumatic brain injury to optimize and facilitate clinical translation. Neurosci Biobehav Rev, 2018. 85: p. 160-175.

22.   Cramer, S.C., et al., Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke. Stroke, 2009. 40(9): p. 3034-8.

23.   Hoffman, A.N., et al., Administration of haloperidol and risperidone after neurobehavioral testing hinders the recovery of traumatic brain injury-induced deficits. Life Sci, 2008. 83(17-18): p. 602-7.

24.   Wilson, M.S., C.J. Gibson, and R.J. Hamm, Haloperidol, but not olanzapine, impairs cognitive performance after traumatic brain injury in rats. Am J Phys Med Rehabil, 2003. 82(11): p. 871-9.