Pharmacology of Procedural Sedation

AACN Advanced Critical Care Volume 23, Number 4, pp.349 354 2012, AACN ECG Challenges Earnest Alexander, PharmD, and Gregory M. Susla, PharmD Department Editors Pharmacology of Procedural Sedation Danyel Adams, PharmD Katelyn R. Dervay, PharmD, BCPS Many unpleasant, uncomfortable, and painful procedures take place throughout various areas in the hospital, including the emergency department, intensive care units, general medicine floors, and procedural areas. These procedures can include, but are not limited to, cardioversion, orthopedic injury reduction, burn debridement, endoscopy, bronchoscopy, and interventional imaging. 1,2 Patients may experience anxiety about undergoing these procedures as they can cause pain and discomfort. This anxiety can occur in both adults and children and can lead to agitation, an increased stress response, and ultimately a patient who is unable to cooperate. 2 The care provider s goal is to minimize pain and anxiety experienced by patients, to ensure a safer environment for both the patient and the health care team, and to increase the chance of a successful procedure. 1,2 Currently, procedural sedation is one of the best ways to accomplish this goal. Procedural sedation, previously known as conscious sedation, is defined as a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows patients to tolerate unpleasant procedures while maintaining cardiorespiratory function. 2(p861) Multiple pharmacological agents are capable of providing procedural sedation and/or analgesia. Commonly used agents include propofol, benzodiazepines, ketamine, opioids, and etomidate. To facilitate the initiation of a procedure and timely recovery from sedation, clinicians want to choose agents that have a fast onset of action and a short duration of action, in addition to minimal adverse effects. The duration of action of these commonly used agents varies; therefore, the anticipated length of the procedure and the duration of sedation required should be considered for dosing and monitoring purposes. 1 Medications are commonly administered as bolus doses over continuous infusions to account for the length of the procedure. The potential adverse effects, most significantly hemodynamic changes and respiratory depression, of these sedative, analgesic, and dissociative agents should also be monitored. 3 Emergency equipment must be readily available, and all patients undergoing procedural sedation should be appropriately monitored. In this column, we discuss the commonly used agents and highlight pertinent differences in characteristics and appropriate monitoring practices for procedural sedation. Danyel Adams is Clinical Pharmacy Specialist, Emergency Medicine, Pharmacy Services, Baystate Medical Center, 759 Chestnut St, Springfield, MA 01199 (danyel.adams@baystatehealth.org). Katelyn R. Dervay is Pharmacotherapy Specialist, Emergency Medicine, Department of Pharmacy Services, Tampa General Hospital, Tampa, Florida. The authors declare no conflicts of interest. DOI: 10.1097/NCI.0b013e31826e18d1 349

Drug Update AACN Receptors and Neurotransmitters Some available agents used for procedural sedation mimic the activity of γ-aminobutyric acid (GABA), which is known as an inhibitory neurotransmitter because of its activity at GABA receptors found on inhibitory neurons throughout the central nervous system. The 2 types of GABA receptors are GABA A and GABA B. General anesthetics and benzodiazepines act on GABA A, which is associated with a chloride ion channel, and activation of these receptors leads to hyperpolarization of the neuron, resulting in sedation, anxiolysis, and hypnosis. 4 In addition, some agents, such as ketamine, work by inhibiting N-methyl-D-aspartate (NMDA) receptors that are also found throughout the central nervous system. When NMDA receptors are activated by excitatory neurotransmitters, such as glutamate, an influx of calcium enters the neuron, resulting in neuronal excitation. Inhibition of these receptors prevents the excitation and results in a sedative and dissociative effect. 4 Opioid μ recepto rs, the pharmacological target for opioid analgesics, are G-protein coupled receptors and are found throughout the central and peripheral nervous system. 3 Stimulation leads to a cascade of events that ultimately inhibit excitability of the neurons and neurotransmitter release and result in analgesia, euphoria, and sedation. 4 Propofol Propofol facilitates sedation and amnesia through its activity on the GABA and NMDA receptors but does not elicit analgesic properties. 5 Because of the lack of analgesic activity, an additional agent for pain control is needed for painful procedures. 3 Propofol s fast onset of action and short duration of action make it an ideal sedative agent for short procedures (Table 1). 5 Reduced recovery times were seen with propofol when compared with midazolam in a study conducted in an emergency department. 2 The reduced recovery time can potentially facilitate faster discharge times and increase patient satisfaction. Adverse effects of propofol include respiratory depression and hypotension. These cardiopulmonary effects can be enhanced by coadministration of other sedative or analgesic agents. 3 In the setting of procedural sedation, propofol is administered as an initial intravenous bolus dose and can be followed by additional bolus doses if needed, depending on the patient and the duration of the procedure (Table 2). To prevent dosedependent hypotension, which is more profound after bolus administration but can occur at any Table 1: Pharmacokinetics and Cardiopulmonary Effects of Sedative and Analgesic Agents a Medication Name Onset of Action (IV) Duration of Action Cardiopulmonary Effects Propofol 30-60 s 5-10 min Decreased blood pressure Respiratory depression Opioids Fentanyl 1-2 min 30-60 min Decreased blood pressure Morphine 5-10 min 3-5 h Respiratory depression Hydromorphone 5-10 min 4-5 h Benzodiazepines Midazolam 2-5 min 30-80 min Decreased blood pressure Lorazepam 15-20 min 4-6 h Respiratory depression Diazepam 2-5 min 15-60 min Etomidate 10-20 s 3-5 min None Ketamine 30-40 s 60 min Decreased blood pressure Increased heart rate Ketofol 30-60 s 60 min None (theoretically) Abbreviation: IV, intravenous. a Data from references 5, 6, 8 to 10, 12, and 14 to 17. 350

VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 Drug Update Table 2: Initial Dosing and Titration of Sedative and Analgesic Agents and Adjunct Medications a Medication Name Initial Bolus Dosing (IV) Titration Opioids Fentanyl 0.5-1.5 mcg/kg 0.5-1.5 mcg/kg every 1-3 min as needed Morphine 0.1 mg/kg or 1-2 mg 0.05-0.1 mg/kg or 1-2 mg every 5-15 min as needed (max 15 mg) Hydromorphone 0.1-0.5 mg 0.1-0.5 mg every 5-10 min Sedatives Midazolam 0.1 mg/kg 0.1 mg/kg every 2 min as needed Lorazepam 1-2 mg 1 mg every 5-10 min as needed Diazepam Up to 10 mg (varies based on Not recommended procedure) Anesthetics Propofol 1 mg/kg 0.5 mg/kg every 3-5 min as needed Etomidate 0.1-0.2 mg/kg 0.05 mg/kg every 3-5 min as needed Ketamine 1-2 mg/kg 0.5 mg/kg every 5-10 min as needed Ketofol 0.5 mg/kg propofol and 0.5 mg/kg ketamine (1:1 ratio) Not recommended Antisialogogues Atropine 0.01 mg/kg (max 0.4 mg) Prior to or with administration of ketamine Glycopyrrolate 0.005 mg/kg (max 0.2 mg) Prior to or with administration of ketamine Antidote medications Naloxone Reversal: 1-2 mcg/kg 1-2 mcg/kg every 2-3 min (max 10 mg) Flumazenil Reversal: 10-20 mcg/kg or 0.2 mg over 15 s 10-20 mcg/kg or 0.2 mg every 60 s (max 1 mg) Abbreviations: IV, intravenous; max, maximum. a Data from references 3, 5, 6, 8 to 10, and 12 to 22. time, give the initial bolus in small increments. This prolonged delivery time has the potential to result in less-significant hemodynamic changes. Propofol use has the potential to lead to propofol-related infusion syndrome. 5 However, this syndrome is more common with larger doses and extended infusions, so it is not a major concern with the smaller bolus doses used for procedural sedation. Note that propofol is manufactured in a lipid emulsion and should not be used in patients with egg and soy allergies. Benzodiazepines Benzodiazepines, such as lorazepam, midazolam, and diazepam, are well known as anxiolytic agents. These agents can also cause sedation and retrograde amnesia. 6 These pharmacological effects are a result of activity at the GABA receptors. The class as a whole lacks analgesic properties, similar to propofol; therefore, coadministration of an analgesic agent is necessary prior to the initiation of painful procedures. Of the benzodiazepines, midazolam is most commonly used in the setting of procedural sedation because of its fast onset and short duration of action (Table 1). The adverse effects associated with benzodiazepine use are similar to those of other sedative agents and include respiratory depression and hypotension, which can be more profound when a combination of sedative and analgesic agents is given. 6 When benzodiazepines are administered with other agents, such as opioids, decreased initial bolus doses should be considered because of the possibility of additive cardiopulmonary adverse effects (Table 1). Because of these additive effects, decreased doses should also be considered if additional doses are needed to complete the procedure. 351

Drug Update AACN In addition to hemodynamic and respiratory effects, the administration of benzodiazepines can result in paradoxical excitement in 10% to 15% of patients. This reaction can manifest as agitation, hyperactivity, increased anxiety, or sometimes aggression and is most commonly seen in children and older adults. 3,7 Clinicians may choose to warn family members and patients about this possible reaction, as it is unexpected after the administration of a sedative agent. If this type of reaction does occur, the patient should be kept safe and monitored closely. Flumazenil, to be discussed later, may be considered for severe cases. 7 Etomidate Etomidate was introduced in 1972 and exerts its pharmacological effect, primarily sedation, through its activity at the GABA receptors. Sedation is facilitated via bolus dosing (Table 2). Because etomidate lacks analgesic properties, analgesic agents should be coadministered to promote patient comfort and cooperation during painful procedures. 8 The rapid onset of sedation and rapid recovery time (Table 1) associated with etomidate are desirable for shorter procedures, such as cardioversions or reductions, and may lead to more rapid discharge and potentially increased patient satisfaction. Etomidate differs from other sedative agents with regard to its minimal effect on hemodynamics 3 ; for this reason, it is an appropriate choice for patients with baseline hypotension and hemodynamic instability. Clinicians should note that a myoclonus reaction, a period of involuntary twitching of the muscles, may be seen after administration, as this reaction could be perceived as increased agitation or a seizure. 8 Adrenal suppression may be experienced following etomidate administration; however, this effect is transient and can be treated with exogenous steroids if needed. The suspected mechanism for this effect is inhibition of endogenous steroid production, which can last for 12 to 14 hours after a single dose. Etomidate is not used in repeated doses or as a continuous infusion in the intensive care setting for this reason. 3 Opioids Opioids, such as fentanyl, morphine, and hydromorphone, are agents commonly used throughout the hospital setting for reduction and control of pain. The analgesic effect is exerted as a result of activity at the μ receptors. 9 Fentanyl is the opioid most commonly used for procedural sedation and is often used in addition to another sedative or dissociative agent. Onset of analgesia with fentanyl is rapid following administration, and because of its short halflife, the recovery time is short (Table 1). 9 Dosedependent respiratory depression is associated with the use of opioids, which can result in an additive effect when other sedative agents, such as midazolam or propofol, are coadministered. All opioids have the potential to cause hypotension, especially when used in combination with other sedative agents. This effect will be more profound in patients with baseline hypovolemia. 3 Fentanyl has a lesser effect on hemodynamics when compared with other opioids, such as morphine (known to cause hypotension due to venodilation and histamine release). 9 Because fentanyl has fewer hemodynamic effects, a fast onset, and a short duration of action, it stands out among this class of agents as the ideal opioid for procedural sedation. Although hydromorphone is widely used in the intensive care setting for analgesic purposes, it is not commonly used for procedural sedation. Ketamine Ketamine historically has been used the most in the pediatric population; however, more literature is becoming available on its use, efficacy, and safety in the adult patient population. It is a unique procedural sedation agent, because it has multiple pharmacological properties that are desirable. It is considered a dissociative agent that creates a trance-like state and causes amnesia in patients. In addition to its sedative and dissociative effects, ketamine has analgesic activity. 1 This dual sedative-analgesic activity is beneficial, because only a single agent may be needed for painful procedures. In addition, ketamine may be a potential option for patients with drug abuse habits who have developed tolerance to opioids, benzodiazepines, or propofol. 1 It exerts its activity via the NMDA receptors and inhibits the binding of glutamate. 10 Ketamine has a rapid onset of action when given as a bolus dose (Table 2) but has a longer half-life than other sedative agents, which leads to longer recovery times (up to 60 minutes) (Table 1). 10 The longer recovery times, compared with those for agents such as propofol, may make ketamine a lessappealing option for some short procedures, because increased nursing resources may be required as a result of a longer period of monitoring following the procedure. Conversely, the 352

VOLUME 23 NUMBER 4 OCTOBER DECEMBER 2012 Drug Update longer duration of action can prove useful in lengthy procedures. Ketamine also differs from other agents with respect to adverse effects. Unlike the reduction in blood pressure seen with other sedative agents, a dose-related increase in heart rate and blood pressure is seen after administration of ketamine, potentially making it a good option for patients who are hypotensive or who may be at increased risk of developing hypotension with other sedative agents. 3 In addition, an increase in inotropic effects is noted. The increased inotropy causes increased myocardial oxygen demand; therefore, ketamine should be used with caution in patients with ischemic heart disease. 3 Respiratory function is not significantly affected. An emergence reaction can occur with ketamine, both when the medication is active and when its dissociative and sedative effects are waning. 10 This reaction is due to the inhibition of glutamate and can manifest as dreaming, nightmares, or hallucinations due to confusion between imaginary and real stimuli. 1 Benzodiazepines can prevent and manage these emergence reactions and should be given toward the end of the procedure. Older children and adults should be encouraged to think pleasant thoughts prior to administration in order to decrease these unpleasant emergence reactions. In addition, reducing auditory, visual, and physical stimuli may reduce associated agitation. 3 Increased intracranial pressure has also been associated with ketamine, although controversy is noted in the literature regarding this effect. 3 Previous literature suggests that increased intracranial pressure can occur after administration of a single dose of ketamine. Finally, increased oral secretions, which can be managed with atropine or glycopyrrolate, and nystagmus have been noted with the administration of ketamine (Table 2). 1,11 Clinicians should consider warning family members, especially of children, of the eye movements and the aimless stare they may observe. Ketofol The literature on procedural sedation shows an increase in the use of ketofol. It is not a Food and Drug Administration-approved agent in its own right but is a combination of ketamine and propofol. This combination can represent either coadministration via separate bolus doses or the mixing of the 2 agents together in a single syringe to be used for intravenous administration. The concept behind this combination of agents is to balance the hemodynamic adverse effects by administering smaller doses of each. The combination is usually dosed in a 1:1 ratio. 12 In theory, the increase in heart rate and blood pressure with ketamine should counteract the hypotension associated with propofol administration and vice versa. 1 Decreased hypersalivation and fewer and less severe emergence reactions have been noted, because the dose of ketamine is less than that which causes the previously mentioned unwanted effects. 12 In addition, ketamine has analgesic properties, so the addition of an analgesic agent would not be necessary. However, clinicians should note the following considerations before using ketofol. First, the pharmacokinetic differences between the agents need to be examined. Propofol is shorter acting than ketamine, so if additional sedation is needed to complete a procedure, redosing of ketofol could lead to accumulation and extended action of ketamine. A recommendation would be to consider rebolusing with propofol alone and not with the combination of agents if additional sedation is needed. 11 Second, stability data on the combination in a single syringe are still limited. Also, if a patient has a reaction to the combination, the causative agent, propofol or ketamine, could not be determined. Finally, evidence for use is still limited. Studies have been small but are increasing, and additional studies are needed to validate the efficacy of ketofol for procedural sedation. 1 Monitoring and Managing Cardiopulmonary Events As previously stated, monitoring is essential for patients undergoing procedural sedation. Because of the hemodynamic and respiratory adverse effects that can accompany the use of these sedative, analgesic, and dissociative agents, patients vital signs should be closely monitored in addition to patients comfort. Pulse oximetry and cardiac monitoring should be used to assess heart rate, blood pressure, respiratory rate, and oxygen saturation. 2 Physical monitoring of patients should also be incorporated to identify additional signs of hemodynamic instability, respiratory distress, and comfort, including such effects as cyanosis, chest wall motion, and increased agitation. Depth of sedation also should be assessed by monitoring patients responsiveness. 3 Because of the extensive monitoring required during procedural sedation, the practitioner sedating and monitoring the patient should not be responsible for the 353

Drug Update AACN procedure itself; assistance should be sought. 13 Note that the monitoring period does not end with the completion of the procedure; it should be continued throughout the recovery phase until sedation has fully waned. Emergency equipment should be readily available throughout the procedure and the recovery phase in case a negative cardiopulmonary event occurs. In the event of cardiopulmonary events, the offending agent(s) should be discontinued. Supplemental oxygen, suction, continuous positive airway pressure, or mechanical ventilation (if needed) can be used to manage respiratory depression. 13 Fluids can be given to help alleviate hypotension. In cases of opioid or benzodiazepine use, sedation and adverse effects can be mitigated with the administration of antidotes. Naloxone will facilitate the reversal of opioid effects, and administration should be completed as a titration of the dose in small increments. This method of administration allows for the reversal of adverse effects without complete reversal of analgesia. 3 Longterm opioid users have the potential to experience withdrawal symptoms if the opioid effect is completely negated. Reversal of benzodiazepine effects can be facilitated by the administration of flumazenil. The administration of flumazenil is recommended for use in acute benzodiazepine overdose only in patients not regularly taking benzodiazepines. 3 The use of flumazenil in chronic users of benzodiazepine can lead to withdrawal symptoms and potentially seizures; therefore, its use is contraindicated in this patient population. Long-term substance use and abuse should be considered before the administration of opioid and benzodiazepine reversal agents. No reversal agents are available for other sedative and dissociative agents, such as etomidate, propofol, and ketamine, and patients experiencing cardiopulmonary adverse effects should be monitored and managed with supportive care. Summary Propofol, opioids, benzodiazepines, and ketamine are sedative and analgesic agents commonly used during painful procedures requiring sedation and analgesia. Ketofol may be considered; however, more efficacy data are needed to fully support its use. In the era of drug shortages, clinicians should be aware of, and familiar with, all the sedative and analgesic agents for procedural sedation, in case a preferred agent is unavailable. Multiple adverse effects are associated with the use of these sedative and analgesic agents, so monitoring is essential, and emergency equipment should be readily available. 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