Ketamine or Ketofol: Do We Have Enough Evidence to Know Which One to Use?

Ketamine and propofol are both commonly used emergency department (ED) procedural sedation agents. Their concurrent administration, often referred to as “ketofol,” is widely used for procedural sedation. A simple Google search can lead to many opinions on why we should use propofol, ketamine, or ketofol in a given situation for moderate or deep procedural sedation in the ED, but finding evidence that supports differences these opinions assume is much more difficult to come by. There is a growing body of research on these agent's relative strengths and weaknesses, but substantial differences among the agents that support many commonly held notions have been difficult to find in research studies. Much of this is due to the fact that the outcome measures we use in sedation trials lack the precision to detect subtle clinical differences. In the absence of improved accuracy and precision of the measurements we use in clinical trials, we are left to interpret what we have when we select an agent. In this issue of Academic Emergency Medicine, Lemoel et al.1 took a slightly different approach to sedation research and compared ketamine to ketofol for procedural sedation in adults using recovery reactions as the primary outcome rather than the more typical measures of respiratory depression or cardiovascular function. We've all heard that ketamine preserves respiratory capacity relative to propofol, but when ketamine and propofol are compared, ketamine appears to have the same as or a greater rate than subclinical respiratory depression and a similar need for preventive airway interventions that of propofol.2-4 While studies are limited to relatively healthy (American Society of Anesthesiologist Physical Status Score 1–2) patients at low risk of adverse events, there does not appear to be a big difference in the capacity of these drugs to cause airway problems at deep sedation doses. We have also seen very strong opinions regarding propofol's lack of analgesic properties and that since ketamine is an analgesic, it will be better for sedation, but this does not pan out in research. Recalled pain, satisfaction, and postprocedure pain are typically reported as the same between these agents.1, 2, 5-7 Even a small study of catecholamine levels did not detect a difference in stress levels for patients treated with and without an opioid added to propofol.8, 9 For the brief painful procedures typical of ED procedural sedation, it's unlikely that the negative effects of brief unrecalled pain are substantial enough to play a major role in our decision about which agents to use for sedation. In terms of cardiovascular effects, however, we have seen differences in the agents, and it appears that ketamine causes less hypotension than propofol.1, 3, 7 This has also been found for ketofol.6, 7, 10-13 Since most of the patients in sedation studies are relatively stable, this effect is difficult to appreciate as clinically significant, but when we look at sedation in unstable and critically ill patients, hypotension and bradycardia are more pronounced and likely to be significant.14 We can extrapolate these findings to assume that in critically ill patients or patients at risk, available studies would indicate that ketamine and ketofol are safer approaches to sedation than propofol and are less likely to cause hypotension. In terms of brief procedures on relatively stable in the ED, respiratory depression and pain do not appear to be have big differences that would guide our use between ketamine, propofol, and ketofol. Hypotension, on the other hand, appears worse with propofol than with ketofol10-12 or ketamine.2 This leaves us asking, in patients that are at risk for hypotension, should we use ketofol or ketamine? Studies that examine hypotension in ketamine versus ketofol in patients that are likely to experience hemodynamic compromise, such as patients with a ASA physical status score > 2, remain to be done. The other difference studies consistently find between ketamine, ketofol, and propofol is recovery agitation. This is variably defined in studies, but it appears that this event is very rare for propofol4, 15, 16 and less common with ketofol10-12 but occurs in 10% to 30% of ketamine sedations.1, 3 Since we know that propofol is more associated with hypotension than ketofol or ketamine, the difference in recovery agitation may be an important differentiator between ketamine and ketofol. The study in this issue of Academic Emergency Medicine by Lemoel et al.1 asks the question of what is the difference in recovery agitation between ketofol and ketamine, to give us an idea of the effect of ketofol relative to ketamine and allow us to decide to use it or not. This study was not designed to precisely detect respiratory depression or hypotension relative to previous works, but the change in primary outcome and emphasis is an important piece of progress in determining the relative strength and weaknesses of agents at our disposal. So which agents should we use? In a patient at low risk of cardiovascular compromise who needs brief sedation, there is not enough information to discern a difference between ketofol at > 2:1 ratio (higher ketamine proportions have demonstrated prolonged recovery times) and propofol,7 and there is no safety or analgesic benefit detected for ketamine to justify the risk of recovery agitation. For sicker patients at risk of hypotension, however, it is likely that ketamine and ketofol are superior to propofol. Given the lower rate of recovery agitation noted in the study in this issue of AEM and the equivocal rate of hypotension between ketamine and ketofol, it appears that ketofol is the better choice for patients at risk for hypotension.