Sedation and Analgesia in Neurocritical Care

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Introduction

Sedatives and analgesic agents are vital to provide appropriate care to neurocritically ill patients, but because they directly affect the central nervous system, judicious administration is necessary. Significant advancements have been made to guide us in prescribing these agents using an individualized patient-based approach. We present a practical, comprehensive, and up-to-date review of sedation and analgesia in the Neurointensive Care Unit.

Sedation in the Neurocritical Care Unit

Definitions and Goals

In neurocritical care, sedation has two distinct purposes: 1) To maintain patient comfort and safety (general indication); and 2) To produce a level of sedation that addresses a specific pathological phenomenon including, but not limited to, elevation in intracranial pressure (ICP), 1 shivering during targeted temperature management (TTM),2 refractory status epilepticus,3 potential modulation of spreading cortical depression,4 paroxysmal sympathetic hyperactivity,5 central hyperventilation [93,94], or aggression and agitation due to drug or alcohol intoxication or withdrawal.6

Sedation for Comfort and Safety

Prior to initiation of sedation, it is necessary to evaluate and treat potential underlying causes of agitation/discomfort, such as pain, hypoxemia, hypoglycemia, hypotension, fever, and alcohol or drug withdrawal. When the decision is made to administer sedation to maintain patient comfort and safety, it is beneficial to provide frequent reorientation cues and optimize the patient’s environment to maintain normal sleep-wake patterns to reduce anxiety and agitation.8

Evidence from multiple randomized controlled trials supports administering the lowest possible dose of sedatives to achieve the minimal level of sedation required to maintain patient comfort and safety. Ideally, this should be accomplished by incrementally reducing the level of consciousness to maintain a state of amnesia, hypnosis, and analgesia while allowing the patient to participate in a comprehensive neurological examination. Studies that compare levels of sedation demonstrate that deeper sedation is independently associated with a longer duration of mechanical ventilation, longer length of ICU stay, and reduced survival.-12 Preventative strategies and nursing-driven, protocol based dosing algorithms for pharmacologic interventions are key to keeping patients calm, comfortable, safe and cooperative while avoiding over-sedation.13,14

If pharmacologic sedation is necessary to optimize patient comfort, the choice of agent should be driven by the specific indication, sedation goal, clinical pharmacology of the medication (including onset and offset and medication side effect profile), and the patient’s specific pathophysiology including organ function and concomitant illnesses. <Table 4> Patient-targeted sedation strategies should be employed using a structured approach to assess the patient and provide protocol-driven drug escalation and de-escalation. In general, sedatives should be titrated to a Richmond Agitation-Sedation Scale (RASS) of 0 to -2 for comfort purposes to maintain a light level of sedation.15 Intermittent sedation may be effective, but sometimes it may be necessary to escalate to a continuous infusion. A balance must be achieved to optimize comfort and safety while preserving the ability to perform the neurological exam.

Scheduled interruptions of continuous sedative infusions should occur at least daily to allow for serial neurological examinations. These interruptions have been shown to contribute to use of lower doses of benzodiazepines, reduction of the duration of mechanical ventilation, and reduction of ICU length of stay.9,11 Sedation interruption, however, is not completely without risks. Patients in the Neuro ICU are prone to becoming disinhibited when sedation is lifted, which puts them at risk for potential injury, including self-extubation, deleterious ICP/cerebral perfusion pressure (CPP) alterations, or cerebral hypoxia and ischemia.16,17 Of note, scheduled interruptions of continuous sedation infusions should not be made for patients who are receiving sedation to treat pathological phenomena, as discussed below.

Sedation Targeting Specific Pathological Phenomena

If sedation is being used to treat a specific pathological phenomenon, a therapeutic goal must be set and the appropriate agent to achieve this goal must be identified. The key neuro-specific indications for sedation are outlined below.

Control of Intracranial Pressure (ICP): Sedation should be considered among the first treatment options for patients with elevated ICP. Sedative agents can reduce ICP through various mechanisms. Agents such as midazolam and propofol can decrease the cerebral metabolic rate (CMRO2), causing a reflexive reduction in cerebral blood flow (CBF).18-20 This reduction in CBF translates to a decrease in the total cerebral blood volume and ultimately a reduction in ICP. The goal of sedation should be to achieve an ICP <20 mmHg while optimizing CPP (>55-60 mmHg). Sedation can also be useful to control ICP by reducing agitation, pain, and ventilator dyssynchrony. When sedation is used to control ICP in the setting of intracranial hypertension, it should be titrated to achieve the ICP goal while considering and managing adverse effects when larger doses are necessary.

Seizure Suppression: The anticonvulsant benefits of midazolam, propofol, ketamine, and barbiturates are commonly employed to treat refractory and super refractory status epilepticus.21-23 The doses these patients require are generally much higher than the doses given for sedation. The therapeutic goal for these agents may be either seizure suppression or burst suppression, and they are titrated based on the waveforms on continuous electroencephalogram (EEG). Because very high doses of sedatives are generally required to achieve the desired effect, careful monitoring for adverse drug reactions and toxicity is critical.3

Management of Shivering during Targeted Temperature Management (TTM): The term "targeted temperature management" (TTM) is appropriate to be used when a specific level of temperature is targeted in an individual patient. Thus, TTM in the neurocritically ill can be used to maintain normothermia, or obtain hypothermia. Shivering is an anticipated consequence and potentially a major adverse effect of TTM and can occur even with mild hypothermia. Control of shivering is essential for effective cooling, as shivering increases systemic and cerebral energy consumption and metabolic demand and combats the cooling process, making it difficult to attain and sustain the target temperature.24 Pharmacologic treatment with sedation can be effective in controlling or preventing shivering by lowering the shiver threshold. The Bedside Shiver Assessment Scale (BSAS) is a validated bedside assessment tool that allows the practitioner to easily assess the patient’s level of shivering.2 <Table 1> Sedation can be titrated to minimize shivering. Studies in healthy volunteers have demonstrated dexmedetomidine may reduce the shiver threshold by 0.7 to 2 °C.25-29 Midazolam and analgesic agents are commonly employed, and though they do not provide similar shiver threshold reducing benefits, they assist with ventilator synchrony and potentially blunt the endogenous stress response that may be caused by excessive shivering.30

A recent International Cardiac Arrest Registry study found that the utilization of as-needed muscle paralysis in cardiac arrest patients receiving TTM increased odds of good outcomes compared with escalating sedation doses and avoidance of neuromuscular blockade.31 Neverrtheless, these findings should be further investigated in prospective studies because deeper sedation is associated not only with prolonged Neuro ICU stay and ventilatory support, but also with increased delirium and infection rates as well as delayed wakening. This may affect serial neurological assessments leading to erroneous prognostication and inappropriate withdrawal of life support.


Table 1: Bedside Shiver Assessment Tool

Attenuation of Paroxysmal Sympathetic Hyperactivity: Paroxysmal sympathetic hyperactivity (PSH) is a syndrome that causes episodes of increased activity of the sympathetic nervous system leading to increased heart rate, respiratory rate, blood pressure, diaphoresis, hyperthermia, and motor (posturing) activity. Although PSH is the accepted term in a recent consensus, at least 31 eponyms, including PAID, storming, and dysautonomia, have been described.32 Sedative agents are often useful to attenuate excessive autonomic activation and assist in reducing motor hyperactivity.5

Reduction of Central Neurogenic Hyperventilation:

Central Neurogenic hyperventilation (CNH) is an abnormal breathing pattern due to intracranial pathology. CNH is characterized by hyperventilation, hypocapnia, alkalemia, and possibly increased arterial oxygen partial pressure without a cardiopulmonary or metabolic explanation.33 Thus, in patients who are hyperventilating, prior to making a diagnosis of CNH, it is necessary to ensure the tachypnea is not a response to an underlying metabolic acidosis due to renal failure, hypoperfusion, hepatic failure or decompensated diabetes mellitus. CNH can cause cerebral vasoconstriction, seizures, decreased mental status, and acid-base and electrolyte imbalances (hypocalcemia, hypokalemia, alkalemia). Unfortunately, the pathophysiology of CNH is poorly understood, but it is often the result of a functional disconnection between medullary respiratory centers and the pons.34 These patients can be challenging to manage, and a sedation regimen with a single agent frequently does not suffice. Hence, use of multiple sedatives (i.e. midazolam and propofol) or concomitant use of analgesics with sedatives are sometimes employed.

Acute Respiratory Distress Syndrome:

Treatment of Acute Respiratory Distress Syndrome (ARDS) in neurocritically ill patients is challenging. Although interruption of continuous infusions of sedatives is desirable for neurological examinations, there is mounting evidence of an adverse impact by doing so in early ARDS. Hence, patients with severe ARDS should be deeply sedated and even paralyzed to improve oxygenation, decrease lung inflammation, and improve survival.35-37 Lung unit shear stress with wide fluctuations in intra-alveolar volume is the most accepted hypothesis for the aforementioned outcomes. The most recent studies utilize this strategy with PaO2/FIO2 ratio < 100, and the regimen includes deep sedation (RASS -4 to -5) and neuromuscular blockage with high doses of cisatracurium for 48 hours during the early phase of ARDS.

Assessment

There are an abundance of subjective scales available for monitoring sedation in the critical care population. Of the available scales, the Riker Sedation-Agitation Scale (SAS)38 <Table 3> and Richmond Agitation-Sedation Scale (RASS)15 <Table 2> have the highest inter-rater reliability in the general ICU population and have been validated to allow the provider to effectively measure the depth of sedation and thus titrate medications accordingly. The RASS is generally recommended when sedation is being used to achieve patient comfort in neurologically ill patients, as it is one of the only scales that included this population in its validation assessments. The target sedation score varies based on the patient and clinical scenario. Of note, a recent investigation of patients with subdural hematoma demonstrated a correlation between temporal trend changes in RASS scores (RASS dispersion) and CAM-ICU positivity, which was helpful in identifying delirium caused by new neurological injuries.39

The bispectral index (BIS) is a quantitative EEG that can be helpful to monitor the depth of sedation in patients receiving general anesthesia, but its use in the neurointensive care unit for patients who need sedation for comfort and safety is controversial. While BIS monitoring has been shown to correlate with both the SAS and the RASS in acute brain injury patients,40 and it may be reliable during continuous propofol infusions in patients with traumatic brain injuries,41 it is unreliable in the setting of hypothermia, shock, or shivering. Furthermore, in non-comatose, non-paralyzed patients, movement leads to artifact which can result in interpretation complications.42-44 Therefore, use of BIS monitoring is generally discouraged in neurocritical care patients being sedated to optimize comfort and safety, and if it is used, it should be interpreted with caution.

If sedation is being used to treat a specific pathologic phenomenon, assessment scales are less relevant and it is recommended to choose a more appropriate, goal-specific tool (EEG waveforms, ICP, CPP, BSAS) to assist in medication titration. It should be kept in mind that sedation can alter EEG amplitude and suppression ratio.45 However, in patient’s post-cardiac arrest, these alterations do not appear to affect the relationship between these EEG parameters and patient outcomes.


Table 2: Richmond Agitation-Sedation Scale (RASS)"
Table 3: Riker Sedation-Agitation Scale (SAS)

Nursing Assessment Considerations for Patients on Sedation

Nurses play a unique and vital role in the administration, titration, routine monitoring and assessment of patients on sedation in the neurocritical care unit. Nursing assessments of sedated patients should include use of sedation scales, close monitoring of vital signs, and performance of routine physical examinations. As described above, the SAS38 and RASS15 are used most frequently to assess the depth of sedation and adjust sedatives accordingly to achieve the sedation goal in the neurocritical care setting. Level of sedation and need for medication titration should be routinely assessed and documented throughout the shift. A patient’s inability to meet the goals of sedation or intolerance of a given medication can be identified based on the neurological exam, hyper- or hypotension, tachy- or bradycardia or brady- or tachypnea. Nurses should be aware that every patient will respond to medications differently. Some patients may require more than one agent to achieve the desired level of sedation. Additionally, during routine assessments, nurses should attempt to identify possible causes of anxiety, discomfort or pain and correct them prior to increasing sedative infusions.46 All efforts should be made to maintain a quiet, low stimulation environment in the room when patients are on sedation in order to achieve maximal effects. A bolus administration of the sedative may be required before suctioning, turning, body care, and transportation. Furthermore, the wake-sleep cycle should be maintained and the patient frequently reoriented whenever possible, including with the family. It is important to be aware that sedation administration is a dynamic process that requires ongoing evaluation and titration throughout the day, and that achievement of sedation goals may require frequent interdisciplinary discussions and medication adjustments.

Nursing staff should routinely clarify the treatment plan and sedation goals with providers during daily rounds or whenever concerns or questions arise about the ability to meet sedation goals without causing side effects. This information should also be clearly communicated between nurses during hand-off between shifts, and a bedside assessment involving both the off-going and oncoming nurses should be performed for each patient. This helps to ensure that caregivers clearly understand the patient’s current physical exam, expected level of sedation, and the current infusion rates required to meet this goal.

Sedation Agent Selection

In general, when administering sedation in the neurointensive care unit, it is necessary to have a predefined goal and all efforts should be made to minimize sedation depth and duration while achieving this goal. Accordingly, short-acting agents without active metabolites are preferred. However, appropriate selection of sedative agents in the Neuro ICU should be determined based on several factors, including 1) the indication for sedation; 2) the clinical pharmacology/pharmacokinetics of each medication including onset and offset, side effect profile, drug interactions, and effect on cerebral physiology; and 3) the individual patient characteristics, including organ dysfunction and concomitant illnesses, as these may have a dramatic effect on both pharmacokinetics and pharmacodynamics. Despite the plethora of trials comparing sedative regimens, no sedative drug was found to be clearly superior.47,48 Common agents used in the Neuro ICU include benzodiazepines, propofol, dexmedetomidine, clonidine, ketamine, barbiturates, valproic acide, propranolol, and neuroleptic agents.49-52<Table 4, 5>

Notably, when considering agents for general ICU sedation, several studies and a meta-analysis showed that a benzodiazepine-based regimen is associated with a slightly longer length of stay, longer duration of mechanical ventilation, and potentially increased delirium versus non-benzodiazepine regimens.47,53-56 Based on these results, propofol or dexmedetomidine/clonidine are preferred over benzodiazepine strategies in general critically ill, mechanically ventilated adults.

Benzodiazepines

Benzodiazepines exert their pharmacologic effects by enhancing the effects of gamma-aminobutyric acid (GABA) at the GABAA receptor, which results in sedation, anxiolysis, and hypnosis.57 Benzodiazepines have been shown to lower ICP19 and promote seizure freedom and burst suppression in refractory epilepticus.21 Adverse effects include respiratory depression, delirium, and hypotension resulting in concomitant decreased CPP, especially at high doses or with rapid titration.57 Vasopressors may be required to offset the adverse blood pressure effects. Prolonged infusion can lead to tachyphylaxis and tolerance, resulting in potential medication withdrawal if the drug is rapidly discontinued. Symptoms of benzodiazepine withdrawal include tremors, agitation, hypertension, and even seizures.48 Flumazenil could be administered to reverse the sedation effects in cases of benzodiazepine overdoses.58 Flumazenil reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABAA receptor. There are many complications that must be taken into consideration when administering flumazenil, including lowering the seizure threshold, agitation, and anxiousness. Flumazenil's short half-life may require multiple doses and careful patient monitoring to prevent recurrence of overdose symptoms.

Midazolam is a short-acting benzodiazepine. Its pharmacologic profile makes it advantageous for patients with acute neurologic injuries so, along with propofol, it is considered a first line agent for sedation in this population.57 Midazolam has a quick onset (2-5 minutes) and relatively intermediate duration of activity (1-2 hours). These properties make it a good choice for administration via intermittent boluses (2-5mg IVP in 5-minute intervals) as needed for agitation. This as-needed dosing strategy can provide effective sedation while reducing the likelihood of over-sedation. However, prolonged sedation can occur, particularly in patients receiving high dose continuous infusions or patients with renal dysfunction, due to the accumulation of the active metabolite alpha-hydroxy midazolam.10,59,60 Midazolam is metabolized by the liver. It inhibits the CYP450 pathway, which may lead to drug interactions, although few are clinically relevant. Midazolam decreases CBF and cerebral blood volume, which may have mild ICP lowering effects in patients with intracranial hypertension.19 Although all benzodiazepines exert anticonvulsant activity, midazolam is the benzodiazepine of choice for treatment of refractory status epilepticus due to the concern for propylene glycol toxicity with other benzodiazepine agents such as lorazepam and diazepam when administered at high doses in continuous infusions.3

Lorazepam is an intermediate-acting benzodiazepine that has a rapid onset of action like midazolam, but delayed peak effects (10-15 minutes).3 61 Unlike midazolam, lorazepam is metabolized by glucuronidation without cytochrome P450 involvement, which makes this agent appropriate for patients with renal or liver dysfunction, particularly on an as-needed basis. The use of lorazepam is limited by the fact that its diluent, propylene glycol, can cause toxicity (metabolic acidosis and renal failure) at high doses.62-64

Diazepam is a long-acting benzodiazepine with a rapid onset of action (2-5 min), long distribution phase (20-120 hrs), and prolonged duration of action due to its active metabolites desmethyldiazepam, oxazepam, and hydroxyl-diazepam.61,65,66 As a result of its long duration of action, diazepam is not commonly used in the Neuro ICU for sedation, but it is commonly used in small doses as a muscle relaxant. Diazepam can also be used to prevent benzodiazepine withdrawal in patients that have required long term, high dose benzodiazepine infusions during their ICU admission. Diazepam can be administered intravenously, intramuscularly, rectally and orally.

Clonazepam is an intermediate-acting benzodiazepine, and as it is available in the United States only in oral form, it is often considered for use in the neurointensive care setting when weaning benzodiazepine infusions that have been administered for sedation over a long time period to prevent withdrawal or in cases of refractory status epilepticus when converting intravenous agents to oral agents.

Clobazam is a selective, partial agonist for GABAA receptors, with better selectivity for the subunits responsible for anxiolytic and anticonvulsant effects than for those involved in sedation.67 Although its use may be limited due to lack of availability in intravenous formulation, it has gained popularity among Neuro ICU providers recently.

Propofol

Propofol is an ultra-short-acting general anesthetic agent that works by enhancing GABA transmission and inhibiting presynaptic glutamate release by decreasing NMDA receptor activation. Propofol is commonly used for sedation in neurocritically ill patients. This clinical practice is supported by its favorable pharmacodynamics and pharmacokinetics in patients with acute neurologic injury, including ultra-short action (onset 1-2 minutes), easy titration and preservation of CBF/CMRO2 ratio at conventional doses.68-73 Propofol is also commonly used in exceptionally large doses for refractory and super refractory status epilepticus as well as intracranial hypertension.21,23,74 Propofol is formulated in a 10% lipid emulsion, therefore triglycerides should be regularly monitored in patients, especially at these elevated doses. Common adverse effects include hypotension and bradycardia, which can often be successfully managed with intravenous fluids, vasopressors, and slow titration. Respiratory depression is also a known effect of propofol, so patients receiving propofol should have a controlled airway.

Propofol-related infusion syndrome (PRIS) is a rare but serious complication of propofol use. It was first described in a pediatric case series and later found to also exist in the adult population.75-78 The syndrome is thought to be secondary to direct impairment of mitochondrial beta-oxidation of fatty acids. In addition, it causes disruption of the electron transport chain as well as blockage of beta-adrenoreceptors and cardiac calcium channels.79,80 Risk factors for PRIS include young age, low body mass index (BMI), doses >80 mcg/kg/min for more than 48 hours, high APACHE II score, and concomitant vasopressor or corticosteroid use. PRIS should be suspected in patients with any risk factors that develop one or more of the following: persistent metabolic acidosis, hyperlactatemia, hyperkalemia, refractory hypotension, rhabdomyolysis and/or ventricular arrhythmias. In fact, acidosis and rhabdomyolysis in patients on propofol are considered highly indicative clinical warning signs of PRIS.81 Thus, whenever propofol is used for EEG suppression in status epilepticus or for treatment of refractory ICP elevations, patients should be monitored closely, as high continuous infusion rates (100-300 mcg/kg/min) are often required for these patients. Although PRIS is often irreversible, aggressive and timely management is critical for patient survival. Management includes immediate propofol withdrawal, early use of cardiac pacing, vasopressor and inotropic support, acute hemodialysis, and even acute extracorporeal membrane oxygenation (ECMO) support if available. Pertinent PRIS-related lab values including triglycerides, creatine kinase (CK), lactate, pH, and potassium should be considered whenever the aforementioned risk factors for PRIS are present or there is clinical suspicion of the syndrome. Although there are not specific monitoring protocols validated at this time, Stovell and colleagues concluded that a rise in both CK and triglycerides can be attributed to propofol alone represents a “pre-PRIS” state where the patient is at risk of developing the full sequelae of PRIS. In these cases, it would be advisable to reduce the propofol dose or substitute for another drug to avoid morbidity and mortality. It is commonly misunderstood that production of green color urine may be a sign of toxicity; however, it is merely a phenolic metabolite that may cause a green hue in the urine. It may occur with continuous infusion or in rare instances with a single induction dose. The transient presence of green urine is benign and self-limited, as it resolves after propofol discontinuation.82

Dexmedetomidine

Dexmedetomidine is a central-acting a2A-adrenergic agonist with both sedative and mild analgesic properties.83 It has a short duration of action (t ½ of 1.5 to 2.5 hours in normal volunteers with a mean t ½ of 3.14 hours in ICU patients) and is eliminated through hepatic metabolism.84 It works through activation of the α2 adrenoceptor in the locus ceruleus.85 Interestingly, there is experimental evidence indicating dexmedetomidine’s effects on the a2A-adrenoceptor subtype may be neuroprotective due to reduction of excitatory neurotransmitter release.86-92 Bolus doses are often avoided due to risk of acute hemodynamic changes, including rapid hypertension followed by severe hypotension and bradycardia. Hemodynamic effects can also be seen with a continuous infusion, but starting an infusion at a low dose (0.1-0.2 mcg/kg/hr) and titrating it slowly may mitigate some of these deleterious effects.69 Assessing and optimizing volume status and cardiac performance for patients on dexmedetomidine are important as well. Although rebound effects are common after discontinuation of clonidine, a medication with a similar mechanism of action, this does not appear to be the case when dexmedetomidine is abruptly withdrawn from adult patients, even after prolonged infusions.93 There are, however, some reports of dexmedetomidine withdrawal in pediatric ICU patients after prolonged infusions (> 3 days), manifested as agitation, hypertension, tachycardia, emesis, and increased muscle tone.94,95

Dexmedetomidine is unique in that it provides sedation without diminishing the central respiratory drive, which makes it very appealing in the Neuro ICU for non-intubated patients or patients being weaned for extubation.96 Additionally, its mechanism of action allows serial neurological exams to be performed easily because patients on dexmedetomidine should be arousable to stimulation, but should quickly return to a restful state when stimulation is discontinued.

Although dexmedetomidine pharmacokinetics are not significantly altered in patients with renal impairment, dose reduction is recommended in patients with hepatic impairment due to reduced clearance of the drug. The effects are also prolonged in patients with acute neurologic injury, so dexmedetomidine should be titrated judiciously in this population and it may be necessary to aggressively wean the drip to perform a neurological evaluation.84

Dexmedetomidine is commonly used as monotherapy for sedation or in combination with other agents including propofol, midazolam and fentanyl, as a dose-sparing agent.69,97 Dexmedetomidine is also commonly used for reduction of shivering in patients being treated with TTM.6,7,25,27 Additionally, it can be helpful for patients with sympathetic symptoms of ethanol withdrawal such as tremor, hypertension and tachycardia, but because it has no GABA activity, it cannot treat the underlying mechanism of ethanol withdrawal.98

Clonidine

Clonidine is a centrally acting alpha-2 selective adrenergic agonist. It has been postulated that clonidine exerts its sedative effects via stimulation of the pre-synaptic alpha-2 adrenoceptors of the locus ceruleus, decreasing norepinephrine release. Clonidine also has action on the cholinergic, purinergic, and serotonergic pathways, resulting in mild analgesia.99 Clonidine has poor specificity for alpha-2 adrenoreceptors with an α-2:α-1 selectivity ratio of approximately 220:1, compared to dexmedetomidine with a ratio of 1620:1.100 The evidence to support the use of clonidine in the critically ill adult population is limited. Clonidine is often considered as an adjunctive agent when there is an inadequate response to opioids and benzodiazepines, to help facilitate weaning sedative continuous infusions in preparation for extubation, and in preventing opioid or ethanol withdrawal.101-104 Enteral clonidine can be initiated at a dose of 0.1-0.3 mg every 6-8 hours and titrated up to 0.4 mg every 6 hours based on clinical response. If transitioning from dexmedetomidine infusion, the recommendation is to reduce the dexmedetomidine infusion 25% with each dose of clonidine. Known side effects of clonidine include hypotension and rarely bradycardia, as well as rebound tachycardia and hypertension after clonidine withdrawal.99 Withdrawal symptoms generally occur within 24-48 hours of drug discontinuation.105 Reinstitution of the previously tolerated dose may be the best management strategy if withdrawal symptoms emerge and then a slow scheduled taper to discontinue. Clonidine can be administered via oral, sublingual, transdermal, or intravenous routes. However, only the oral and transdermal formulations are available in North America. Transdermal administration should be avoided because it takes 3-4 days to reach a steady state and absorption cannot be guaranteed in the ICU patient. Generic versions of clonidine are available, making this intervention inexpensive.

Ketamine

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with additional effects on opioid and muscarinic receptors, resulting in both sedation and analgesia.106 Ketamine has a rapid onset (0.5-1 minute) and short duration of action (5-10 minutes), leading to a dissociative effect without adversely affecting respiratory drive or systemic hemodynamics, making it ideal for non-intubated patients that require mild to moderate sedation. Ketamine can also potentiate other sedatives and analgesic agents and may allow for dose minimization when used in combination with other drugs. At high doses (1 to 10 mg/kg/h), ketamine provides a novel treatment for refractory status epilepticus.22,107 A recent systematic review showed that ketamine administration led to seizure cessation in 56.5% of adult patients and 63.5% of pediatric patients when administered in combination with midazolam, propofol, or pentobarbital.22,107,108 Ketamine is extensively metabolized by the CYP450 isoenzymes (CYP3A4, CYP2C9, CYP2B6) and has an active, potent metabolite (norketamine).106 Common adverse effects are emergence psychosis and hallucinations. These adverse effects can negatively influence the neurological exam and therefore should be considered carefully when ketamine is weaned.109 A recent protocol demonstrated successful weaning of intravenous ketamine over 5 days (0.5 mg/kg/h per day decrease) in the ICU while initiating oral agents.110 Other adverse effects that should be considered include hypertension, tachycardia, and hypersalivation during administration. The use of ketamine in patients with intracranial hypertension has been debated for years as early studies suggested it raised ICP, but later research and a recent meta-analysis concluded that it was not associated with an increased risk of ICP elevation.20,109,111,112 However, mydriasis can be observed during administration of ketamine due to profound inhibition of peripheral muscarinic signaling, and this finding can mislead the ICU team to unnecessary brain imaging for suspected intracranial hypertension.

Barbiturates

Barbiturates produce sedation by inhibiting GABAA channels.68 Barbiturates are extremely lipophilic which allows for quick onset, but exceedingly long duration of action. Barbiturates are metabolized via the CYP450 system and are potent inducers of these isoenzymes, resulting in many significant drug interactions. Of note, there is usually a delay before the CYP induction occurs.113 Barbiturates are commonly used for refractory status epilepticus, refractory intracranial hypertension, procedural and ICU sedation.

Pentobarbital has a long duration of action due to its long half-life ranging from 53-140 hours and high lipophilicity, and is rarely used in the Neuro ICU for sedation.114 However, it is used at supra-therapeutic doses as an anticonvulsant or for burst-suppression in patients with refractory and super refractory status epilepticus and in patients with malignant intracranial hypertension.3,21,109,115,116 At high doses, 5-15 mg/kg bolus over 30 minutes followed by 0.5-10 mg/kg/hr, barbiturates are thought to reduce cerebral metabolism and cerebral blood volume. Common adverse effects include respiratory depression, gastroparesis, arterial hypotension and bradycardia requiring mechanical ventilator support and vasopressors. In the setting of elevated gastric residuals volumes, a post-pyloric feeding tube can be considered. Per the 2016 SCCM/ASPEN nutrition support guidelines, elevated gastric residuals would be defined as volumes of higher than 500 mL, however historic practice in the neuro intensive care unit would define this as volumes of greater than 200 mL, although checking residuals regularly is no longer recommended.117-119 However, if the patient has clinical suspicion of ischemic bowel disease, the tube feeds should be discontinued until better characterization of this condition. Additionally, all patients receiving high doses of barbiturates must have scheduled application of eye ointment or moisture goggles to prevent corneal abrasions; deep venous thrombosis (DVT) prophylaxis (mechanical and pharmacologic if appropriate) to prevent DVT due to immobility; and scheduled turns to prevent pressure ulcers. Lastly, consideration should be made as to the length of time a patient may take to wake up after administration of pentobarbital. It can often take days for patients to awaken, and this can be longer for older and obese patients, and patients with poor metabolism. Due to its high lipophilicity, pentobarbital will autotaper and therefore no infusion titration downward is generally necessary.

Phenobarbital

Phenobarbital is a barbiturate that is available in enteral and intravenous formulations, and when administered enterally has rapid (0.5-4 hours) and complete (more than 95%) absorption.120,121 The large volume of distribution (0.5-0.7 L/kg) allows for quick entry into the central nervous system, much like pentobarbital, however the long half-life (50-180 hours) and the lack of safety with continuous infusion administration may limit rapid titratability.121 Phenobarbital dose adjustment may be considered in patients with renal dysfunction, however there are no specific recommendations. Phenobarbital has been shown to be effective in managing ICU agitation that is refractory to traditional therapies, in patients that require prolonged sedation in the ICU, to prevent or treat alcohol or benzodiazepine withdrawal, and in refractory and super refractory status epilepticus.122,123 Providers must be aware that phenobarbital does not provide analgesia and therefore should be given in combination with analgesics if pain is suspected. Sedation doses that have been published range from 65-800 mg/day, generally given in 3-4 divided doses.124,125 Dosing may be initiated in adult patients intravenously at 1-2 mg/kg/day divided every 6-12 hours and titrated at each dose to produce the desired sedation goal. Transition to enteral formulations is accomplished by using a 1:1 conversion. Evaluation of phenobarbital levels may be warranted in obese patients, when drug-drug interactions have been identified, in patients with liver dysfunction, and in those with suspected toxicity. Total serum concentrations of 5-40 mg/L are desired and can be obtained at any time during the dosing interval.

Phenobarbital can also be administered for refractory status epilepticus.3 A bolus dose of 20mg/kg given intravenously no faster than 50-100 mg/min is recommended and may be administered in 2-3 aliquots to minimize side effects. If seizure cessation is not achieved after the initial load, the bolus dose may be repeated. Maintenance doses should be initiated to achieve the desired clinical effect, seizure cessation or burst-suppression. Therapeutic drug monitoring may be useful to ensure absorption or to assist in titration; however, no target value for treatment of status epilepticus has been established. Rare recommendations for supra-therapeutic levels of phenobarbital to treat super refractory status epilepticus have been considered. When higher than recommended levels are being targeted, consideration of airway and hemodynamic effects must be addressed.

Side effects beyond excessive sedation include respiratory distress, laryngospasm (which may occur with rapid administration), hypotension, bradycardia, and elevated liver enzymes. When large intravenous doses are being administered, propylene glycol toxicity must be considered.64 Propylene glycol toxicity may present with lactic acidosis and acute kidney injury.

Valproic Acid

Valproic Acid is an anticonvulsant and mood stabilizing agent commonly used for seizure treatment in the ICU setting. Valproate works on various pathways implicated in the development of agitation and delirium, blocking voltage-dependent sodium and calcium channels, potentiating GABA activity, and reducing glutamine effect at NMDA receptors. Valproic acid is administered IV or enterally. The onset of enteral valproate is 2-4 hours, and the half-life is 9 to 19 hours. Intravenous valproic acid has an immediate onset with a peak around 1 hour. Both formulations are extensively protein bound, metabolized via the hepatic system, and eliminated in the urine. Caution should be exhibited when using valproate in patients with pre-existing liver dysfunction. The most common side effects of valproate are hyperammonemia, tremor, and thrombocytopenia.126 Serial ammonia monitoring is not necessary, however levels should be checked if patient exhibits manifestations of hyperammonemia.

There is a paucity of evidence for the use of valproate in the treatment for agitation, however recent case reports suggest it is safe and effective for use in cases of refractory agitation. In these reports, an average daily dose of 500-1500 mg divided into 1 to 4 doses was commonly utilized.49,51,126-128 In one study, ~50% of patients received loading doses of 20-30 mg/kg.51 Serum drug level monitoring may be beneficial with a recommended trough level in the normal therapeutic range of 50-100 mcg/mL. Decreased agitation, delirium, opioid requirements, benzodiazepine requirements, and dexmedetomidine use were seen. This agent may be beneficial in patients who 1) are not mechanically ventilated due to the lack of respiratory effects, 2) are going to be transitioned to the floor/home setting, 3) have agitation refractory to traditional agents, and 4) have a history of bipolar or seizure disorders.

Propranolol

Propranolol is a highly lipophilic, non-selective beta-adrenergic antagonist which readily crosses the blood brain barrier. The sedative mechanism of propranolol is postulated to work via interactions with beta-receptors in the medial septal and medial preoptic area, leading to decreased norepinephrine action and alterations in the sleep-wake cycle. It is administered enterally and is rapidly and completely absorbed. It undergoes hepatic metabolism to active and inactive compounds with metabolites excreted in urine. Although no formal dose reduction recommendations exist, it should be used with caution in patients with renal or hepatic impairment as this can increase exposure to the drug and may lead to beta-blocker toxicity. Doses for this indication are not well established, however a starting dose of propranolol 10 mg every 8 hours with uptitration as tolerated is reasonable. Common adverse effects include hypotension, bradycardia, gastrointestinal discomfort, hypoglycemia, and bronchospasm.

There is limited evidence supporting the use of propranolol as a sedative agent in critically ill patients. In a small retrospective case series, it was shown to decrease the use of sedative and opioid agents, when combined with various psychoactive agents.52

Neuroleptic Agents

Neuroleptic agents are commonly used in the ICU to manage psychosis and delirium. Due to their mechanism of action, they can also produce profound sedation with minimal respiratory depression. Commonly utilized agents include haloperidol, a first-generation antipsychotic, and various second generation antipsychotics, including quetiapine, olanzapine, and risperidone. Haloperidol is often used as it can be administered intravenously and has a rapid onset of action. The most common side effects include QTc prolongation and extrapyramidal symptoms. Caution should be utilized in patients with baseline prolonged QT intervals or those on concomitant QT prolonging agents. A starting dose of 2 to 5 mg may be used with rapid titration to effect. Olanzapine can also be administered intravenously and has a rapid onset of action. It can also lead to QT prolongation, however there is a lower incidence versus haloperidol. Quetiapine and risperidone must be given enterally and have a longer onset of 1 to 1.5 hours. These two agents are also associated with QT prolongation and extrapyramidal symptoms. Due to the high propensity for QT prolongation, a baseline EKG is recommended. Subsequent EKG monitoring should be performed as clinically appropriate.

Neuroleptic agents may be useful in the management of patients with underlying psychiatric disorders or hyperactive delirium. They can be utilized as adjunctive therapy in patients requiring high doses of conventional agents. Care should be taken to ensure these agents are discontinued prior to ICU discharge or when they are no longer necessary for the patient’s condition.

Agent Selection Guide

Sedation for Comfort and Safety

When comparing propofol to benzodiazepines in the general ICU population, propofol did not reduce overall mortality, but did show a reduction in the ICU length of stay.53,54,129 Dexmedetomidine may have advantages over benzodiazepines, as it does not cause respiratory depression and provides some analgesic effects. When compared to lorazepam and midazolam, dexmedetomidine resulted in less delirium and reduced mechanical ventilator days, but did not reduce hospital or ICU length of stay.4755,56,130 When propofol and dexmedetomidine were compared, no difference in time at target sedation level, duration of mechanical ventilation, or ICU length of stay was noted.47 A meta-analysis comparing clinical outcomes in patients sedated with a benzodiazepine regimen to those sedated with non-benzodiazepine regimens suggested a slightly longer length of stay and longer mechanical ventilation times in patients receiving benzodiazepines.131 In addition, there is moderate quality evidence to support an association between benzodiazepines and increased risk of delirium.132 Thus, in general, a non-benzodiazepine based regimen is recommended when sedation is needed for comfort and safety. However, the patient’s organ function and pharmacokinetics should serve as the ultimate determinant for sedative agent selection. <Table 5>

There is current interest in the use of population-specific protocols targeting patients with neurological injury to manage analgesia across institutions. A recent study examining the impact of protocolized analgesia and sedation in the neurocritical care unit showed increased analgesia use, decreased sedative use, and reduced medication-associated costs with implementation of a nurse-driven analgesia-based sedation protocol.133

Control of Elevated Intracranial Pressure

Sedatives and analgesics should be used in combination to treat agitation and intracranial hypertension, as they work via different mechanisms. Propofol has been shown to reduce CMRO2 with subsequent reduction in cerebral blood volume which leads to reduction in intracranial pressure.18,72,134 The addition of analgesics will further prevent rapid spikes in ICP by preventing hypertension, excessive movement, coughing, ventilator asynchrony, and elevations of intrathoracic pressure. The combination of propofol and fentanyl, or propofol and midazolam, or propofol and morphine appears to have positive effects on ICP control. These agents are short-acting and may allow for performance of serial neurological assessments. Caution should be taken when sedation and analgesia are held for routine neurological assessments in patients with elevated ICP as rebound refractory intracranial hypertension and agitation can occur.116

Seizure Suppression

Although limited data for valproic acid for sedation in the ICU exists, it may be a natural choice for patients with both seizures and need for sedation. Caution with the numerous drug interactions and in patients with pre-existing liver dysfunction.

In cases of refractory and super refractory status epilepticus, sedative agents can be useful both for their sedative and anticonvulsant effects. Propofol and midazolam high dose continuous infusions are commonly employed to suppress ongoing seizures or achieve burst suppression. Both the Neurocritical Care Society and the European Federation of Neurological Societies endorse these agents for this indication.3,135,136 In more refractory cases, high dose ketamine can be added.107,135 Data suggest the combination of ketamine and midazolam is particularly effective.107 Lastly, when dealing with super refractory status epilepticus that is resistant to these regimens, supra-therapeutic doses of barbiturates may be indicated.21,122,135,136

Management of Shivering during TTM

Analgesia and sedation are both recommended to prevent shivering in patients undergoing TTM. Numerous studies have evaluated the use of pharmacological agents for reduction of vasoconstriction and shivering thresholds. Sedatives and hypnotics including midazolam, lorazepam, diazepam, dexmedetomidine, propofol, and buspirone have led to shiver threshold reductions ranging from 0.5°C to 2.4°C when used as monotherapy. Several agents have been evaluated in combination and found to result in synergistic reductions. Many analgesic agents have also been evaluated both as monotherapy and in combination. The most effective opioid is meperidine which has shown reductions in shiver threshold between 1.2°C and 2.2°C. The Bedside Shiver Assessment Score is a validated tool that can assist decision-making to initiate and titrate these agents.30 Algorithms for the order to add agents are also available.2 The variation of pharmacokinetics and pharmacodynamics of each agent during hypothermic conditions must be considered, and patients on sedatives for reduction of shivering should be monitored both for medication efficacy (shiver control) and safety (adverse drug reactions, drug interactions, drug accumulation).

Attenuation of Paroxysmal Sympathetic Hyperactivity

Patients with PSH require treatment with sedation and analgesia. As-needed doses of analgesia (often fentanyl) provide abortive therapy, while scheduled oral medications, including propranolol, or continuous infusions are often required for preventative treatment. Benzodiazepines are also commonly added and high doses are often required.

Blunting of Central Neurogenic Hyperventilation

Judicious utilization of intravenous opioids (fentanyl or morphine) has been demonstrated to be efficacious in the treatment of CNH. These medications are particularly helpful at correcting hyperlactatemia secondary to increased work of breathing.137 If a patient responds to intravenous fentanyl, this can effectively be transitioned to a transdermal fentanyl patch.138


Table 4: Sedation Medications in Neurointensive Care UnitTable 4: Sedation Medications in Neurointensive Care Unit
"Table 5: Suggested Treatment Options for Sedation-Analgesia in the Neurointensive Care Unit"

PRN- as needed; CI- continuous infusion, CrCl ?, CIWA …

Prevention and Management of Complications

To prevent medical complications of sedative administration, it is important to carefully select a sedative agent after reflecting on the indication for sedation, the patient’s clinical condition and the specific concomitant organ dysfunction. Subsequently, it is necessary to properly monitor patients on sedation through evaluation of their neurological examination and vital signs and use of sedation scales, and titrate then wean sedatives off carefully.

In general, sedation medications cause systemic arterial hypotension which leads to decreased cerebral perfusion pressure (CPP) due to several factors including decrease in preload (venodilation - benzodiazepines), myocardial contractility (negative inotropy – propofol), chronotropy (bradycardia- dexmedetomidine), and systemic vascular resistance (arterial vasodilation- propofol). These side effects are more pronounced in patients with conditions leading to decreased mean arterial blood pressure (MAP) such as hypovolemia, left or right ventricular dysfunction, sepsis, or use of beta-blockade. Hence, these conditions must be recognized and treated prior to bolus administration of sedatives. In addition, judicious administration of continuous infusions is advised.

Weaning Sedatives

Management of sedation and mechanical ventilation should be integrated, as it is often necessary to continue sedation for patient comfort and safety until they are ready for extubation or a tracheostomy has been placed. Ideally, mechanical ventilation weaning protocols should include spontaneous breathing trials during which patients are taken off sedation. Although there are RCTs that showed a reduction of duration on mechanical ventilation with daily interruption of sedation, some authors have questioned this practice because of the implicit risk of uncontrolled intracranial hypertension and other cerebral adverse events during these sedation weaning trials.17,139 Skoglund et al demonstrated a significant increase in ICP and increased levels of cortisol (a surrogate of stress) during daily liberation trials.17 In contrast, the same group found that sedation vacation facilitates recognition of relevant neurological exam findings in traumatic brain injury patients.140 Finally, Helbok et al conducted a small prospective study to analyze the relationship between brain tissue oxygenation, clinical exam, and ICP during wake-up tests in patients with severe acute neurologic injury. Although, only 2% of wake-up tests detected new neurologic deficits, 30% of trials needed to be aborted due to uncontrolled intracranial hypertension (ICP > 20 mmHg), agitation or systemic or cerebral oxygen desaturation.16 In 70% of these unsuccessful trials cerebral hypoxia occurred (PbtO2 < 20 mmHg).16 In summary, a more judicious and methodical approach to sedation weaning appears to be appropriate in patients with underlying intracranial hypertension.

Nursing Considerations in Weaning Sedation

As noted, nursing assessment of patients on sedation is a dynamic process. When sedation is being weaned, nurses must be hypervigilant to determine the least amount of sedation needed to ensure the patient remains safe and comfortable. Nurses should collaborate with the interdisciplinary team to reassess goals prior to weaning continuous infusions and develop strategies to assist with the weaning process such as intermittent use of other appropriate medications to treat anxiety or pain.

As sedation is being weaned, it is important to regularly assess patients to screen for delirium. Studies have shown that patients with extended stays in the ICU and patients with acute neurological injury are at increased risk for delirium. Early identification and treatment of delirium has been shown to decrease morbidity and mortality.141


Analgesia in the Neurocritical Care Unit

According to the International Association of Pain, ‘‘pain is defined as an unpleasant sensory and emotional experience associated with real or potential tissue damage, or described in terms of such damage.”142 Pain is common among patients in the intensive care unit, affecting up to 50% of patients.143-145 Patients in the Neuro ICU may uniquely experience pain due to various etiologies including trauma, cerebral edema, intracranial hemorrhage, intracranial or spinal surgical procedures, intracranial or spinal tumors, intracranial or spinal infections, myopathies and neuropathies, to list a few. Pain should always be considered as an etiology for agitation and anxiety. Although recent practice trends recommend minimization of analgesia, its use to control agitation has been shown to reduce the need for sedative agents, increase ventilator-free days, and reduce the ICU length of stay.61,143,146,147

Assessment

Assessment of pain and the adequacy of analgesia in patients in the Neuro ICU is particularly challenging. Because pain is subjective, patients’ self-reports provide the most valid measurement of the experience, but this can only be relied upon in awake patients. Approaches to the measurement of pain in awake patients include verbal and numeric self-rating scales, behavioral observation scales, and assessments of physiological responses. Verbal self-rating scales are performed by presenting patients with a linear graph labeled at one extreme “no pain” and “worst pain” on the other. Patients indicate the best mark on the graph that represents the intensity of their pain. The Numeric Self-Rating scale is similar in that patients are asked to numerically rate the intensity of their pain from 0-10, with 0 indicating no pain and 10 the most extreme pain. The Numeric Self-Rating scale is easy to administer and has been validated with significant correlations with other measures of pain intensity.

Assessment scales in unresponsive patients rely primarily on indirect clinical signs of pain including tachycardia, hypertension, elevated ICP, and grimacing. Obviously, these physiologic signs are neither specific nor sensitive to pain, as each has many other potential causes. The Behavioral Pain Scale and the Critical Care Pain Observation Tool are both used in this population, but their reliability in patients with acute brain injury is uncertain.148,149 The Behavioral Pain Scale relies on the assumption that if a patient has pain, visible signs of discomfort and physiological symptoms will be present. The absence of physiologic symptoms, however, does not necessarily mean absence of pain. Inexperienced clinicians may interpret the results inappropriately and pain can be under-recognized and undertreated. The opposite could occur as well, if other causes of behavioral and physiologic changes are not ruled out and misinterpreted as pain, leading to overtreatment. The Critical Care Pain Observation Tool similarly relies on observation of facial expressions, body movements, muscle tension, ventilation compliance or vocalization (if extubated) and evidence of pain with movement. Each observation has a fixed scale and the points are totaled to give a pain indication score. The higher the score, the more support for the presence of severe pain, but the relationship is not linear, meaning a score of 4 is not twice as intense as a 2. Lastly, The Nociception Coma Scale has recently emerged as a valid and sensitive clinical tool to assess pain in brain injured patients.150 This scale constitutes the first step to better management of patients recovering from coma. The Nociception Coma Scale is similar to the previous behavioral scales described where motor function, verbal response, visual response, and facial expression are all graded on a predetermined scale and added together to produce a total score that indicates the intensity of pain. <Table 6-9>


"Table 6: Self-reporting pain assessment scales"
Table 7: Behavioral Pain Scale
Table 8: Critical Care Pain Observation Tool
Table 9: Nociception Coma Scale

Nursing Assessment Considerations for Patients Receiving Analgesia

Ongoing assessment of pain in both intubated and non-intubated patients should be a routine part of the care of Neuro ICU patients. Many patients undergo painful procedures or have discomfort due to underlying pathology. Assessment of pain with a consistent tool, such as those outlined above, should be performed on a regular basis.155 Utilization of the same pain scale provides a consistent measure for both the patient and nurse.

Pain control should be pursued in a protocolized and stepwise fashion. Obtaining a baseline pain score on admission, if possible, can help to direct the individualized plan of treatment for each patient. Nurses should consider any physiologic changes such as tachycardia, hypertension or tachypnea as potential indicators of pain. Alternate forms of pain management should always be considered prior to administration of analgesia. Dimming of lights, repositioning, music, and temperature adjustment can be adjunctive therapies to assist in pain management.155 The patient’s report of pain should be documented before and after each intervention or medication administration.

The plan for a patient’s pain management should be reviewed daily during interdisciplinary rounds and providers should be notified of ineffective pain management to adjust medications as needed.

Analgesia Selection

Opioids are the mainstay for analgesia control in the Neuro ICU. In addition to providing analgesia, they also have sedative properties and can augment the functions of sedation to facilitate tolerance of an endotracheal tube, decrease the cough reflex, and blunt reactions to noxious stimuli. Opioids bind to the mu receptors in the central nervous system to produce analgesic effects.

Fentanyl, sufentanil, remifentanil, hydromorphone, and morphine are opioids that are commonly used in the Neuro ICU due to their ease of titration, quick onset, and short duration of action. Agents such as meperidine and extended-release formulations of opioids are not generally recommended for sedation in the Neuro ICU due to their long half-lives; however, meperidine is often used to control shivering in patients undergoing TTM. <Table 10>

Fentanyl is the most commonly used opioid in the ICU due to its lack of hemodynamic adverse effects. Fentanyl has a quick onset and short duration of action. Due to its high lipid solubility, it may accumulate in fatty tissue after prolonged infusions and cause delayed awakening after discontinuation. It is metabolized by the liver and accumulation may occur in those with liver impairment. Fentanyl does not have an active metabolite which further makes it an ideal agent for use in the Neuro ICU. Uncommonly, fentanyl causes chest wall rigidity. In patients with a concern for elevated ICP, fentanyl may not be the desired analgesic agent because chest wall rigidity can lead to reduced venous jugular return and increased cerebral blood volume, which can increase ICP. Discontinuation of fentanyl is the treatment if such an occurrence arises.

Sufentanil is a synthetic opioid that is approximately 5 to 10 times more potent than its parent drug fentanyl, due to its greater lipid solubility and higher receptor affinity. Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring, which is believed to reduce its duration of action when compared to fentanyl.156 Sufentanil has a rapid onset of action, similar to fentanyl, with rapid redistribution and elimination half-life which is primarily dependent on hepatic blood flow. Due to its high potency, sufentanil administration may cause more significant respiratory depression and bradycardia compared to fentanyl.

Remifentanil is an ultra-short-acting opioid with potent mu-receptor activity. Its half-life is 3-10 minutes and it is rapidly metabolized by non-specific plasma esterases. It is therefore a great choice for patients with renal or liver dysfunction. Due to its ultra-short activity, this agent can be used in patients that require wake-up tests or as a bridge to extubation.

Hydromorphone is a semi-synthetic opioid that is commonly used for intermittent sedation in the Neuro ICU. It may be administered intravenously, intramuscularly, subcutaneously, or orally. The IV formulation has a quick onset of action of 5 to 10 minutes with peak effect evident within 10 to 20 minutes. The oral formulation has a longer onset of 15 to 30 minutes with a peak effect of 30 to 60 minutes. Both oral and IV formulations have a similar duration of 3 to 4 hours. Parenteral doses are approximately 5 times more potent than enteral doses, so one-fifth of the oral dose will provide similar analgesia. Hydromorphone is metabolized by the liver to inactive metabolites and excreted via the urine, so caution should be utilized in patients with hepatic or renal impairment. Transitioning to continuous infusion hydromorphone may be useful in patients with escalating fentanyl or morphine infusion requirements. Additionally, hydromorphone may be the drug of choice in patients with opioid tolerance with new acute pain control concerns.

Morphine may be administered intravenously, subcutaneously, intramuscularly, intrathecally, transdermally, rectally, or orally. When administered orally it is absorbed through the gastrointestinal mucosa and undergoes substantial hepatic first-pass effect. Therefore, its oral bioavailability is relatively low (~25%). Peak plasma drug concentrations are reached immediately after intravenous administration, 15 to 20 minutes after subcutaneous or intramuscular administration, and 30 to 90 min after oral administration.157-159 Slow release oral formulations have been developed which deliver the dose over 8 to 24 hours depending on the formulation. The slow release and transdermal formulations are generally reserved for patients outside of the ICU, as the ability to rapidly titrate the dose and the delayed time of effect is often a deterrent for use in the acute setting.

After absorption, morphine is rapidly distributed within the body, including the brain. Morphine has a large volume of distribution, and approximately one third of the circulating drug is bound to plasma proteins.159,160 Morphine has a high systemic clearance and a short half-life of approximately two hours, although its duration of activity generally considered much longer than fentanyl, sufentanil or remifentanil. The primary site of morphine metabolism is the liver, where it undergoes rapid glucuronidation. However, extrahepatic metabolism of the drug can account for up to 30% of its total clearance. This extrahepatic metabolism may play a relatively important role in morphine metabolism in patients with severe liver failure. In the liver, the principal metabolite is the morphine-3-glucuronide (M3G). This metabolite has no pharmacological effect and is primarily excreted in the urine. Another important metabolite is morphine-6-glucuronide (M6G), which appears to be at least as potent as morphine. M6G has a half-life of approximately 1-2 hours. This active metabolite is also excreted in the urine and may accumulate significantly in case of renal insufficiency. Less than 10% of the dose is excreted unchanged in the urine.

Adjuvants to Opioid Therapy

Non-opioid strategies are increasingly being utilized in the general ICU population due to concerns regarding adverse effects and potentially prolonged ICU lengths of stay with opioid analgesics. Acetaminophen has been evaluated in critically ill patients to determine its efficacy and opioid sparing potential. Acetaminophen is a non-opioid analgesic that may be administered via the oral, rectal, or intravenous routes. It has a rapid onset of action around 5 to 10 minutes when given intravenously or 1 hour when administered orally. The duration of action is similar regardless of route of administration at around 4 to 6 hours. It is primarily hepatically metabolized to sulfate and glucuronide conjugates, while small amounts are metabolized by the CYP system to a toxic intermediate metabolite, NAPQI. At therapeutic doses, this metabolite is conjugated rapidly for excretion, however at toxic doses (>4 g per day), NAPQI can accumulate and cause significant hepatic cell damage. It is generally well tolerated with the most common side effect being nephrotoxicity. In the general population, utilization of scheduled acetaminophen has been shown to decrease opioid requirements and improve pain intensity.161-163 Although there is an increasing utilization of IV acetaminophen as adjunctive therapy for craniotomy procedures, recent evidence did not show an opioid-sparing effect in patients following craniotomy procedures.164,165 Furthermore, another group found that IV acetaminophen was more effective than PO acetaminophen in the neurocritical care population at relieving pain within 30 min of dosing, but this difference was not sustained over 6 hours.166

Preventing and Managing Complications of Analgesia

All opioids share the adverse effects of decreased level of consciousness, respiratory depression, hypoactive gastrointestinal motility, miosis, tolerance, and possible dependence. Morphine, secondary to its histamine release, can cause hemodynamic instability. Both fentanyl and remifentanil have minimal hemodynamic adverse effects at usual sedative doses, although monitoring is recommended. Optimization of fluid status and use of vasopressors may be necessary if hemodynamic instability occurs.

Morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by mu-receptors in the bowel.167 Use of a peripheral mu-receptor antagonist (methylnaltrexone, naloxegol) may be beneficial in patients with ileus and/or gastric hypoactivity secondary to opioid administration.

Several hypotheses exist about how opioid tolerance develops, including opioid receptor phosphorylation resulting in a change in the receptor conformation, functional decoupling of receptors leading to receptor desensitization, mu-receptor internalization or down-regulation, and upregulation of the cAMP pathway.168 Dependence needs to be considered in patients with more than 7-10 days of continued administration of opioids and an opioid wean should be employed using scheduled oral agents.168,169 Withdrawal symptoms include irritability, perspiration, mydriasis, hypertension, tachycardia, nausea, diarrhea, and severe headache. Symptom resolution can be seen with administration of opioid agonists, alpha-2 adrenergic agonists, and other non-opioid agents.170

Prolonged sedation is of particular concern with morphine as it has active metabolites (morphine-3-glucoronide, morphine-6-flucoronide) that can accumulate. Risk of accumulation is highest for elderly or obese patients or patients with renal failure. Alternative agents should be considered in these clinical scenarios.

All opioids can potentially affect ICP. The literature is inconclusive but some studies indicate that bolus dosing of opioids may transiently increase ICP due to a reduction in blood pressure and CBF.111,171,172 This appears to be more common with morphine, but it can occur with any intravenous opioid. Additionally, hypercarbia due to respiratory depression may lead to cerebral vasodilation and increased ICP. Monitoring respiratory status and ICP (when of concern) in all patients receiving intravenous opioids is imperative.68


Table 10: Analgesia Medications in Neurointensive Care Unit

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