15 Sedation

Akta Patel and Michelle Ghobrial

Abstract

Patients admitted to the neuroscience intensive care unit (neuro-ICU) may be one of the more complicated ICU populations to manage in regards to sedation, with respect to preservation and frequent assessment of the neurological examination. Providing adequate sedation to the patients in the neuro-ICU depends on determination of proper objective driven goals for sedation and the appropriate choice of agent based on the patient’s physiology. Propofol and benzodiazepines are the most commonly used drugs to treat sedation in this population; however, dexmedetomidine has proven to be a noninferior agent of choice. Fentanyl is primarily an analgesic but has some sedative properties and is also often used as an option in the neuro-ICU. This chapter focuses on sedation in the neuro-ICU population and discusses advantages and disadvantages of the previously mentioned medications.

neuro-ICU – intensive care unit – sedation – propofol – midazolam – dexmedetomidine – fentanyl

15 Sedation

15.1 Introduction

Proper attention to sedation is an essential component of the care of critically ill patients in the intensive care unit (ICU). Patients admitted to the neuroscience ICU (neuro-ICU) may be one of the more complicated ICU populations to manage in regards to sedation, with respect to preservation and frequent assessment of the neurological examination.

Sedation reduces the stress response, provides anxiolysis, improves tolerance of ventilatory support, decreases the cerebral metabolic rate of oxygen, and facilitates nursing care.
Prolonged use of sedatives may result in drug accumulation, oversedation, delayed extubation, and lengthened ICU stay.
Identifying underlying causes of agitation, such as pain, delirium, hypoxemia, hypoglycemia, hypotension, or withdrawal from alcohol and drugs, are important and treatment should be initiated prior to introducing sedatives. ¹ ^, ²

15.2 Indications for Sedation

Neurologic injury: Traumatic brain injury (TBI), severe intracranial hypertension, status epilepticus, paroxysmal sympathetic hyperactivity, and withdrawal/intoxication from alcohol or drugs are a few common disease states which often require sedation.
Patient safety: Cognitive dysfunction (dementia) and brain injury can cause agitation, restlessness, or combativeness prompting the use of sedation for the safety of the patient and staff.
Patient comfort: Procedures such as intracranial pressure monitors, intravascular catheters, or targeted temperature management require the use of a short-acting sedative. Note that analgesia should be addressed before initiating sedation.

15.3 Complications of Sedation

All sedation has risks. It is important to weight the risks and benefits before initiating sedatives in patients with a neurologic injury.
Sedation can compromise a patient’s neurologic examination which may be critical in patient populations like subarachnoid hemorrhage, stroke, or TBI.
Sedation can also compromise normal physiology
- Cardiac: Bradycardia, hypotension
- Pulmonary: Respiratory depression, CO₂ retention
- Cerebral: Low cerebral perfusion, decreased seizure threshold
Duration of sedation may be prolonged in patients who have chronic disease states like kidney failure, heart failure, or hepatic failure. Sedation may also be prolonged in morbid obesity or when therapeutic temperature management is implemented.

15.4 Assessment of Sedation

Sedation regimens must be individualized to account for differences in drug pharmacokinetic and pharmacodynamic properties.
- Objective, goal-directed sedation is the recommended standard to avoid oversedation and when applicable promote earlier extubation.
- In patients with neurologic injury, short-acting agents are preferred.
Reliable assessment tools for sedation such as the Richmond Agitation Sedation Scale (RASS) have made titration of drugs more precise and cost effective. Details regarding the RASS Scale can be found in Chapter 1.
- The RASS is a 10-point scale, validated and reliable in adult neuro-ICU patients, with four levels of anxiety or agitation (+1 to +4), one level to denote a calm and alert state (0), and five levels of sedation (−1 to −5) culminating in unarousable (−5). ³ ^, ⁴ ^, ⁵ (Table 15‑1)

**Table 15.1** Richmond Agitation Sedation Scale (RASS)
Score	Description
+4	Combative	Violent, danger to staff
+3	Very agitated	Pulls or removes tube(s) or catheters; aggressive
+2	Agitated	Frequent nonpurposeful movement, fights ventilator
+1	Restless	Anxious, apprehensive, but not aggressive
0	Alert & calm
−1	Drowsy	Awakens to voice (eye opening/contact) >10 sec
−2	Light sedation	Briefly awakens to voice (eye opening/contact) <10 sec
−3	Moderate sedation	Movement or eye opening to voice. No eye contact
−4	Deep sedation	No response to voice, but movement or eye opening to physical stimulation
−5	Unarousable	No response to voice or physical stimulation
Note: From Sessler et al. ³

15.5 Choice of Sedative

Propofol and benzodiazepines are among the most commonly used agents.
- These drugs have both sedative and anterograde amnestic properties but often lack analgesic properties. ²
Dexmedetomidine has sedative, analgesic, anesthetic, and anxiolytic properties.
Fentanyl is primarily an analgesic but has some sedative properties and is often used due to its short-acting duration in the neuro-ICU.
A continuous infusion of these agents provides a more constant level of sedation and improved patients’ comfort. It has been associated with prolonged mechanical ventilation and a longer ICU stay.
- Thus, intermittent dosing along with daily interruption of sedatives allowig patients to “wake up” may improve outcomes. ⁶
Table 15‑2 summarizes some of the pharmacological properties of some of the more commonly use sedative agents in the neuro-ICU.
Table 15‑3 provides studies of the agents being used for sedation in critically ill patients.

**Table 15.2** Pharmacological properties of sedative agents
Drug	Onset	Duration	Usual dose	Precautions for use	Significant adverse effects	Advantages
Propofol	1–2 min	Short term: 0.5–1 hour Variable: 25–50 hours (depends on dose and time of sedation)	5–50 mcg/kg/min; consider dose adjustment for obese patient	Hypotension, bradycardia, hepatic failure, pancreatitis	Hypotension, respiratory depression, bradycardia, PRIS, hypertriglyceridemia, pancreatitis	No significant drug interactions
Midazolam	2–5 min (IV)	2–6 hours (prolonged with CI)	1–2 mg q2–4 hours OR 1–5 mg/hour (0.02–0.1 mg/kg/hour)	Hepatic failure, end-stage renal failure or dialysis, delirium	Oversedation, delirium, respiratory depression	Less hemodynamic instability than propofol
Dexmedetomidine	5–10 min (with LD) 1–2 hours (without LD)	1–2 hours	LD: 1 mcg/kg (optional) MD: 0.2–0.7 mcg/kg/hour (up to 1.5 mcg/kg/hour)	Hepatic failure, symptomatic bradycardia	Hypo/hypertension, bradycardia, dry mouth	Minimal respiratory depression Lowers shivering threshold
Fentanyl	1–2 min peak: 5–10 min	0.5–1 hour	LD: 50–100 mcg (0.35–0.5 mcg/kg) MD: 25–100 mcg/hour (0.7–10 mcg/kg/hour) consider dose adjustment for obese patients	Potential drug interactions if used with CYP3A4 inhibitors or inducers	Muscle rigidity with high bolus doses, gastric dysmotility, hypotension, respiratory depression	Rapid onset
Ketamine	30 sec IV	Alpha phase—anesthetic effect duration 45 min Beta phase—analgesic effect duration 2.5 hours	Dosing protocols vary: Anesthesia LD: 1–4.5 mg/kg if solo agent 0.5–2 mg/kg if adjuvant drug over 1 min MD: 0.1–0.5 mg/min per manufacturer No dosing recommendations for off-label use	Nystagmus, increase in muscle, transient increase in blood pressure; requires continuous cardiac monitoring for duration of use	Tachyarrhythmias, delirium, hallucinations/emergence psychosis, increased ICP, severe respiratory depression/apnea can occur with rapid IV bolus of large dose	No respiratory compromise due to preserved pharyngeal and laryngeal reflexes (unless rapid loading dose given), no dose adjustment for obesity
Abbreviations: CI, continuous infusion; ICP, intracranial pressure; IV, intravenous; LD, loading dose; MD, maintenance dose; PRIS = propofol infusion syndrome.

**Table 15.3** Studies of the agents for sedation in critically ill patients
Study	Design	Patients	Intervention	Significant results
Chamorro 1996 ⁷	Multicenter, prospective, randomized, unblinded	98 patients from nine Spanish ICUs (14 were neurological or neurotrauma patients)	Propofol (n = 50) vs. midazolam (n = 48)	No significant difference regarding effectiveness of sedation between the groups Propofol time to waking 23 ± 16 minutes vs. midazolam 137 ± 185 minutes
Kelly 1999 ⁸	Multicenter, prospective, randomized, double-blind, pilot	42 neurotrauma patients from 11 ICUs	Propofol 2% plus NS (n = 23) vs. morphine plus intralipid (n = 19) All patients received low-dose (1–3 mg/hour) morphine for analgesia	Propofol group injury severity score was greater than the morphine group No significant difference in adverse events Propofol group required less adjunctive ICP therapy but more vasopressors
Sandiumenge Camps 2000 ⁹	Prospective, randomized, unblinded	63 patients from one Spanish ICU (43 were neurotrauma patients)	Propofol 2% (n = 32) vs. midazolam (n = 31)	Increased rate of failure in the propofol group attributed to inexperience with new formulation (as compared to historical data using the 1% formulation) No significant hemodynamic differences between the groups
Jakob 2012 ¹⁰	Two, multicenter, randomized, double-blind, phase 3	31 ICUs in 8 countries 44 ICUs in 9 countries	PRODEX: Propofol (n = 247) vs. dexmedetomidine (n = 251) MIDEX: Midazolam (n = 251) vs. dexmedetomidine (n = 249)	Dexmedetomidine was shown to be noninferior to the standard in both groups Patients in the dexmedetomidine group were more arousable and better able to communicate discomfort or pain
Erdman 2014 ¹¹	Multicenter, retrospective, cohort	190 patients from two neuro-ICUs	Propofol (n = 95) vs. dexmedetomidine (n = 95)	The frequency of severe bradycardia and hypotension were similar in both groups
Abbreviations: Dex, dexmedetomidine; ICP, intracranial pressure; ICU, intensive care unit; NS, normal saline; RASS, Richmond Agitation Sedation Scale.