A Randomized Double-blind Trial to Evaluate Ketamine-propofol Combination vs. Propofol Alone for Procedural Sedation and Analgesia in the Emergency Department.

Procedural sedation and analgesia (PSA) for painful procedures is the standard of care in emergency medicine.

The ideal PSA agent should be safe, easy to administer, provide analgesia and amnesia with rapid onset, quick recovery and a minimum of adverse effects. A variety of medications have been studied for procedural sedation but no single medication currently used meets all of these criteria. Two medications that are well known and often used for procedural sedation are propofol and ketamine. Both medications have been shown to be highly effective but each has important limitations in emergency practice. Propofol is known to cause respiratory depression, apnea, and hypotension in a dose-dependent fashion. Ketamine displays a longer recovery time than propofol and patients receiving ketamine sedation are prone to vomiting and unpleasant emergence reactions. The use of ketamine and propofol in combination is theoretically compelling as the sedative effects of propofol should logically balance the nauseant and psychomimetic effects of ketamine while the ability to achieve deep sedation with lower doses of ketamine should logically permit for a shorter physiologic recovery time compared ketamine alone. As well, ketamine provides an analgesic effect that is absent with propofol and has been shown to be safer than using opioid analgesia such as fentanyl when considering airway events. This study seeks to evaluate a ketamine-propofol combination that potentially provides effective procedural sedation and analgesia while exposing patients to less risks associated with respiratory depression as the differential effects of ketamine and propofol may lead to fewer adverse events than either medication used alone.

Propofol is a nonopioid, nonbarbiturate, sedative-hypnotic agent whose desirable properties include its rapid onset, short duration of action, and reliability in producing sedation. It also acts an anti-emetic but has no analgesic properties. Adverse effects include dose-related cardiovascular and respiratory depression and bradycardia. This dose-dependent respiratory depression, apnea and hypotension may present barriers to the widespread clinical utility of propofol. In addition, the lack of an analgesic effect may necessitate the use of other agents to provide pain relief during procedural sedation. The use of opioid analgesia in conjunction with propofol sedation is well known to increase the risk of adverse airway events.

Ketamine is an agent classified as a dissociative sedative and is known to provide efficacious and safe procedural sedation with the preservation of airway reflexes and respiratory drive. The use of ketamine for severe acute pain in the emergency department has been shown to decrease opioid requirements in trauma patients as well as reduce the pain of propofol injection. During deep sedation with propofol, the use of sub-dissociative ketamine for analgesia during emergency department procedural sedation results in fewer adverse airway events than does fentanyl. The main limitations of the use of ketamine alone for procedural sedation is its longer recovery time and the incidence of dysphoric emergence reactions, especially in adults.

Ketamine-propofol combination has been used successfully and safely for a variety of purposes, including gynecological and ophthalmological procedures, sedation for spinal anesthesia, and cardiovascular procedures in both adults and children. Ketamine and propofol mixed in the same syringe has been shown to be safe and effective in both the operating room and in the office setting. Combining ketamine with propofol appears to provide anesthetic synergy with a widened therapeutic index, permitting the induction of anesthesia and sedation at doses less likely to lead to respiratory depression. Thus, the combination of ketamine and propofol has received interest as an emergency department procedural sedation regimen that allows the provision of PSA using drug doses lower than typically required for each agent alone potentially resulting in fewer adverse effects and shorter recovery times. Propofol is a potent sedative and with anti-nauseant properties and is thought to likely mitigate the problematic adverse psychomimetic and nauseant effects of ketamine. Ketamine and propofol are known to be physically and chemically stable when mixed in polypropylene syringes and the mixture displays stable respiratory and hemodynamic parameters in healthy patients during general anesthesia. The use of ketamine and propofol in combination in the ED is limited. A pilot study of 20 children showed that ketamine and propofol administered from separate syringes to ED patients resulted in reliable deep sedation with few adverse effects. Prospective ED case series in children and in adults have shown that ketamine and propofol mixed in a single syringe in a 1:1 ratio (so called "ketofol") appears to be an effective ED PSA agent that is well tolerated and appears safe. To date, there has not been any randomized trial comparing single-syringe ketofol with other known ED PSA agents, thus the theoretical advantages of ketamine-propofol combination (ketofol) are not yet definitively known.