Combination Ketamine and Propofol vs Propofol for Emergency Department Sedation: A Prospective Randomized Trial

Procedural sedation (PS) is common in the Emergency Department (ED) for painful or anxiety-producing procedures. In our ED these procedures commonly include fracture and dislocation management and reduction, abscess incision and drainage, lumbar puncture, extensive wound debridement, dilatation and curettage, chest tube placement and cardioversion. Generally a sedative-hypnotic agent is combined with an analgesic in order to provide this sedation. The ideal agents to utilize remain unclear. The ED environment is substantially different than the operative suite or many outpatient areas and literature from these areas has limited applicability.

In many ED's, including our own, propofol combined with either a short acting or long acting narcotic has become very commonly utilized. Propofol has many advantages including rapid onset, rapid recovery, strong sedative and amnestic properties, and euphoric effects. However like many sedative-hypnotics it possesses strong respiratory depressive properties and has cardio-depressant and vasodilatation effects that can lead to hypotension. These effects can be potentiated by concomitant narcotic administration as opioid agonists posses similar properties.2

ED literature on complications associated with propofol sedation is variable, secondary to significant differences in rapidity of administration of the medication, the type of analgesic provided, the definitions of complications, the amount of pre-oxygenation provided, and the variability in experience of medical providers. Most literature suggests that the overall rate of sub-clinical respiratory depression, measured by indicators such as end-tidal CO2 changes, is approximately 30-40% of patients1-3. The clinical importance of these changes is unclear. Clinical respiratory depression, measure by hypoxemia, need for verbal or tactile stimulation, bag valve mask ventilation (BVM), and airway positioning, is reported in 1-25% of patients, with the need for BVM ranging from 0-4.6% of patients1-6. It is noteworthy that one study, utilizing a slow infusion rate and only long-acting narcotics administered greater than 20 minutes prior to the start of sedation, prospectively demonstrated only a 0.88% rate of hypoxemia and a 0% rate of BVM while maintaining a similar total average dose, patient satisfaction, and successful outcome6. However this has not been replicated, and the data from other ED studies seems to suggest rates of clinical respiratory depression of 10-12% with BVM use averaging 4%1-6. The only clear conclusion to be drawn from the medical literature in this regard is that some respiratory depression and need for airway management can occur, but the rate is likely heavily dependent on exact protocols and definitions, make comparison between centers and studies difficult.

Because of interest in developing effective sedation regimens that might mitigate some of the complications of propofol plus narcotic regimens (hereafter termed propofol sedation), a technique of combining propofol and ketamine has been described for use in the ED. This combination is long-standing in some settings 7-10 and its use in the ED has been described 9,12,13. Ketamine is a dissociative hypnotic that acts by binding N-methyl-D-aspartate (NMDA) receptors, blocking their excitatory function. It has analgesic, amnestic, and dissociative, effects 9-12. It has the beneficial properties of maintaining respiratory drive, maintaining muscular airway control while still providing pain relief and dissociation. Its use as a single agent for ED sedation in adults has been limited by concern about dysphoria at anesthetic doses as well as post-sedation nausea and vomiting. It can also cause tachycardia and hypertension. However the intuitive off-setting of the somewhat opposite side effects of propofol and ketamine have created significant interest in sedation regimens utilizing both agents. (ie propofol decrease heart rate (HR), blood pressure (BP), respiratory drive and airway maintenance, is euphoric and is an anti-emetic. Ketamine increases HR, BP and increases or maintains respiratory drive and airway maintenance, but is dysphoric and can be nauseating.) An ED study was published in 2007 describing the use of a fixed dose mixture of 1:1 propofol and ketamine (also termed "Ketofol") in a single syringe, allowing for easy dose titration 12. This study showed high patient and physician satisfaction (mean of 10 on a 1-10 scale), high rates of procedural success, and an extremely low rate of complications (2.5% rate of hypoxemia, 0.9% rate of BVM ventilation)12. Another study, in children with different dosing parameters, recently suggested a similarly low rate of BVM (0%) but a higher rate of respiratory depression (15%)13. Interestingly this study used a lower amount of ketamine and higher dose of propofol, which perhaps contributed to the increased rate of respiratory depression. Retrospective data from our use of fixed dose 1:1 ketamine and propofol demonstrates a similar safety profile with 7% of patients having some respiratory depression or requiring airway management and an absolute rate of 2% requiring BVM. We have commonly used this combination in our ED since 2007.

Currently in our ED both propofol sedation and ketamine plus propofol sedation are variably employed, depending mainly on prescriber preference. Because the literature has significant variability in the reported complication rates of the two regimens, no firm conclusion is possible about the relative equivalence or superiority of one regimen compared to the other. Attending physician preference currently dictates the choice of an agent for our patients in lieu of any robust evidence to guide our selection. Further, there is no data to measure the relative patient satisfaction and provider ease of utilization of either of these regimens, important factors in the selection of sedation agents.

We plan to conduct a prospective, randomized, equivalence trial of a fixed ratio of 1:1 ketamine and propofol vs propofol alone sedation. We will measure sub-clinical and clinical respiratory depression, the need for active airway management, unpleasant complications such as post-sedation nausea and vomiting, dysphoria and emergence reactions, patient and provider satisfaction, and post-procedure and follow up pain.