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Ketamine - Due to its safety profile and reliable effect it has gained wide acceptance among pediatric population. It has profound analgesic and amnestic action, without affecting pharyngo-laryngeal reflexes and hence maintains an intact airway and spontaneous respiration. Onset, duration and total dosage needed varies according to the route of administration. It is usually accompanied by excessive salivation and frequently needs to be combined with an anticholinergic. Ketamine is safe for use in adults, but careful patient selection is mandatory after ruling out usual contraindications22,23. Ketamine has an overall excellent safety profile for both adult and pediatric population22,24.
Propofol - Propofol is a potent, ultra-short-acting sedative agent, which has gained popularity for emergency department procedural sedation. It is a phenolic compound and is thought to mediate GABA activity. Propofol has no analgesic properties. Many characteristics of propofol made it attractive for emergency department procedural sedation, including rapid induction of sedation and an extremely short half-life, leaving the patient with no residual sedation soon after the procedure is over25. Although the use of propofol during PSA is increasing, some institutions across the world have restricted its use secondary to safety concerns. There have been concerns over the safety profile of propofol for PSA in ER due to the possibility of achieving a deeper than anticipated state of sedation and therefore encountering more serious complications, however recent literature have described increasing use of propofol for PSA in ER27-29. Weaver CS26 found in a study that ER PSA with propofol is safe. Similarly a systematic review conducted by Hohl CM30 et al found no significant difference in the safety profile and proportion of successful procedural sedation between midazolam and propofol, and also found propofol to be slightly more cost effective then midazolam because of its early recovery profile. Zed PJ31 et al in a prospective study found that when propofol is administered as a standardized protocol it is a safe and effective agent for PSA in ER, and is also associated with high patient and physician satisfaction. In a recently conducted randomized controlled trial, Miner JR32 et al concluded that ketamine and propofol are both safe and effective agents for procedural sedation in the ED, and the patients who received ketamine had higher rates of subclinical respiratory depression, higher rates of recovery agitation, and longer times to regain baseline mental status than patients who received propofol.
Etomidate - Etomidate is an ultrashort acting non-barbiturate imidazole derivative, which possesses little analgesic effect. Onset of action is usually within one minute when administered intravenously. The duration of effect is brief, lasting three to five minutes at standard dosages. Etomidate is metabolized rapidly by the liver, and the duration of effect may be longer in patients with liver failure33. The only contraindication to etomidate is hypersensitivity to the medication, but caution should be taken during pregnancy (etomidate is a pregnancy category C drug), and the general precautions regarding procedural sedation and patient selection also should be considered. Side effects are usually rare, and there is no histamine release and hence minimal cardiovascular effect. The medication has few to no hemodynamic effects, and its neutral cardiovascular profile is one of the most appealing aspects of this agent. Adrenocortical suppression has been reported after the use of a single bolus of etomidate34, but the significance of this effect is believed to be inconsequential 35 and whether the adrenocortical suppression is clinically significant remains controversial.
Muscle twitching generally is well tolerated, and emergence nausea and vomiting have been reported. Respiratory depression and hypoxia are possible. The incidence appears to be 3 to 15 percent 36-39. Patients have responded well to supplemental oxygen; in rare instances, patients have required bag-valve-mask-assisted ventilation36-38. Etomidate has been shown to be safe and effective for PSA, and is an excellent choice of agent 36-39.
Dexmedetomidine: Dexmedetomidine is an alpha2 agonist 4,5 and pharmacologically related to clonidine. Dexmedetomidine has an affinity for alpha2 receptors eight times greater than that of clonidine.6 It exerts its effects by binding to alpha2 receptors presynaptically and post synaptically in the locus ceruleus and in the spinal cord. It decreases the release of norepinephrine and suppresses sympathetic activity7 , which results in decreased heart rate and blood pressure. The sedation and anxiolytic properties are exerted when dexmedetomidine binds to alpha2 receptors in the locus ceruleus (a nerve cluster that lies near the brain's fourth ventricle) and analgesia produced by binding of the drug to adrenoreceptors in the spinal cord.7 Dexmedetomidine has been shown to be safe and effective as a sedating agent. It is comparable with propofol without the concerns raised with propofol use.9 Although dexmedetomidine preserves respiration, at higher doses it will decrease HR, cardiac output, stroke volume, and mean arterial pressures.16
Several drugs are also given as combinations for procedural sedation, which offers the combined advantages, helps to circumvent the possible side effects and may also lead to the reduction of total doses required:
1. Ketamine, atropine (or glycopyrrolate), and midazolam (benzodiazepine).
2. Midazolam and fentanyl
3. Systemic agents (propofol or etomidate) and analgesic
The combination of ketamine and atropine is used since, a common side effect of ketamine is to increase salivation and secretions; atropine counteracts it by decreasing the secretions.
The clinical effects of titration of oral medication for the purposes of sedation are unpredictable. Repeated dosing of orally administered sedative agents may result in an alteration of the state of consciousness deeper than the intent of the practitioner. Therefore, during PSA there must be one person available whose only responsibility is to monitor the patient and institute bag-mask ventilation and cardiopulmonary resuscitation if necessary10. Except in unusual circumstances; the maximum recommended dose of an oral medication should not be exceeded.
REVERSAL OF SEDATION: Rarely should reversal of agents be used in procedural sedation if the drugs are used appropriately. The commonly used agents are:
Naloxone- It is administered to antagonize opioid induced respiratory depression and sedation. It should be carefully titrated specially in patients who are opioid dependent since it may precipitate sudden severe pain as it also antagonizes the analgesic effect of opioid. It has a very fast onset of action with peak effect in 1-2 minutes and effect of total dose of 0.4 to 0.8 mg lasting for 1 to 4 hours. Incremental dose of 20 to 40 µg may be given every few minutes till the ventilation of the patient improves. Infusion rate between 3-10 µg/hr may be started if prolonged ventilatory depression is anticipated.40
Flumazenil- It's a pure benzodiapine antagonist, and can be used for reversal of benzodiapine sedation, with onset of action less than 1 minute and it promptly reverses the hypnotic effect of the benzodiazepines. The usual total dose is 0.6 to 1.0 mg which is usually given as a gradual titrated dose of 0.2 mg / minute until the desired level of reversal is achieved. It may also be given as an IV infusion if over dosage with a long standing benzodiazepine is suspected.41
COMPLICATIONS - PREVENTION AND MANAGEMENT
Review of literature has shown that serious adverse events are rare in the practice of procedural sedation.42
1. Inadequate amnesia or analgesia:
A. Dosage of amnesic or analgesic agents is based upon patient weight. As per rule, the elderly need less, muscular young men need more, and agitated children may also require slightly more medication.
B. Allow sufficient time for the agents to work.
2. Decreasing oxygen saturation: apply nasal cannula or a non-rebreather mask for increased oxygenation. Occasionally, a bag-valve-mask with positive pressure ventilation may be required transiently. Adverse airway events leading to respiratory compromise can be detected by capnography.14, 16, 43
3. Prolonged recovery: Prolonged offset of sedation is dependent on several factors of which the most important are drug distribution in the patient, and the patient's own clearance of the sedation agents. Be prepared to recover the patient for a prolonged period, with adequate oxygenation and clearance of any airway secretions.
4. Post procedure emesis: Depending on the condition of the patient, do suction and observe. Rescue antiemetics may be required in certain group of patients.
Procedural sedation and analgesia is becoming a common practice in the ER, involving mostly EP, but everyone should be mindful of the complexity of the procedures and the high level of skills required for its accomplishment. PSA span from a continuum of attaining anxiolysis and pain relief to deep sedation. It may be attained through both intravenous and intramuscular administration of sedative and analgesic agents, while simultaneously allowing independent airway control throughout the procedure. This technique offers the combined advantage of patient comfort and safety in the setting of proper monitoring, adequate intravenous access and experienced personnel. Newer shorter acting agents like dexmedetomidine and remifentanyl are being used as useful drugs for PSA, but continued research and prospective studies with these drugs will help ascertain their further use for PSA. Capnometry and BIS are some of the adjuncts which are useful in monitoring the depth of the sedation. In fact, it is anticipated that with BIS monitoring, in combination with short acting agents, desired levels of sedation can be more easily achieved, while minimizing associated complications and duration of ER stay. With continued research and appropriate training, PSA is progressively falling under the domain of EP. Therefore, standard guidelines and research will help pave the way for the betterment of PSA.