Ketamine/Propofol versus Single Agent for Procedural Sedation


Many thanks to Harwood and Michelle for hosting, and to our stellar presenters:
Tony, JoEllen, Brad, Vijay, Pikul and Mark.

By way of brief background, ED procedural sedation has evolved significantly over
the past 15 years. Back in the dark ages, our choices were benzo + narcotics, chloral
hydrate, or methohexital. Then ketamine gained popularity in kids, etomidate
made the leap from induction agent to procedural sedation drug, and most recently
propofol joined the game. As procedural sedation became more sophisticated,
one idea that has gained traction over the past 5 years is to mix ketamine and
propofol. Intuitively, it makes sense: propofol is anti-emetic and may smooth out
ketamine’s emergence reactions, but can cause significant respiratory depression
and hypotension. Ketamine has analgesic properties, and maintains respiratory
reflexes and blood pressure, but can cause nausea and bad trips. The combination
might allow decreased dosing of both agents and mitigate the side effects of each.

Article 1:
Andolfatto G, Willman G. A Prospective Case Series of Pediatric Procedural
Sedation and Analgesia in the ED Using Single-syringe Ketamine-Propofol
Combination (Ketofol). Acad Emerg Med. 2010;17:194-201.

In this article, the authors describe a prospective case series of 219 pediatric
patients who received ketofol for procedural sedation (majority orthopedic
procedures), examining effectiveness, recovery time, and adverse effect profile.
Physicians used a single syringe technique, with a 1:1 mixture of 10 mg/ml
ketamine and 10 mg/ml propofol. Titrated aliquots of 0.5 mg/kg ketofol (0.5 mg/kg
each of propofol and ketamine) were given at 30 second to 1 minute intervals at the
discretion of the treating physician. The median dose of medication administered
was 0.8 mg/kg each of ketamine and propofol, with a median recovery time of 14
minutes. Less than 1% of patients experienced unpleasant emergence requiring
treatment, although nearly 3 % of patients had unpleasant CNS symptoms.
Regarding airway events, 1.4% of patients required either stimulation or brief BVM,
and several other patients required airway repositioning. No patients vomited
during or after sedation. Procedural sedation was considered successful in all
patients, and patient/caretaker/medical provider satisfaction was high.

This was basically a “Mikey liked it” study, or as JoEllen described it, a marketing
study, without the methodologic rigor of a RCT. Children less than 1 year of age
were excluded, and there were few children included who were younger than 2.

The study was subject to selection bias, as physicians chose when to use ketofol and
when to choose a different agent. As there was no comparison arm, the authors
compared medication doses, recovery times and complications to published rates
for ketamine and propofol from past studies. In this regard, ketofol performed well,
with lower dosing, and improved emesis rates and recovery times compared to
ketamine, although demonstrating similar airway and emergence phenomena rates
to ketamine alone.

Article 2:
Shah A, Mosdossy G, et al. A Blinded, Randomized Controlled Trial to Evaluate
Ketamine/Propofol Versus Ketamine Alone for Procedural Sedation in
Children. Ann Emerg Med. 2011;57:425-33.

This trial has significantly improved methodology as compared with the Article
#1, as it is a blinded RCT. In this study, 136 children with isolated orthopedic
injuries were randomized to receive either 0.5 mg/kg ketamine and 0.5 mg/kg
propofol (K/P), or 1.0 mg/kg ketamine + intralipid placebo (K). These were
also the median doses of each medication administered. If additional sedation
was needed, the K/P group received extra propofol, and the K group received extra
ketamine, again in a blinded fashion. More patients in the K/P ended up needing
extra medication (more propofol). Their primary outcome, total sedation time,
was clinically not significant between the 2 groups (K/P 13 minutes, K 16
minutes), although it was statistically significant. There was 10% less vomiting
and 5% fewer unpleasant recovery reactions in the K group. Airway adverse
events were similar between the 2 groups, as was median total sedation time
and time to recovery. No patient in either group required BVM or other airway
intervention besides airway repositioning or supplemental oxygen. Medical
provider and patient satisfaction scores favored K/P, although confidence intervals
were wide. Methodology pearl: it was discussed that sedation time is a curious
choice of primary outcome, however it is an outcome measure that can be powered
to achieve a statistically significant result, as opposed to serious but rare adverse

Article 3:
David H, Shipp J. A Randomized Controlled Trial of Ketamine/Propofol Versus
Propofol Alone for Emergency Department Procedural Sedation. Ann Emerg
Med. 2011;57:435-441.

In this blinded RCT, 193 ED patients, both adults and children, received either
ketamine 0.5 mg/kg + propofol 1.0 mg/kg (K/P) or placebo + propofol 1.0 mg/
kg (P). All patients received fentanyl 5 minutes before sedation. Additional bolus

doses of 0.5 mg/kg of propofol were given as needed to both groups. There was
no statistically significant difference in the primary outcome of respiratory
depression between the 2 groups (K/P 22%, P 28%), although as Erik pointed
out, the study was underpowered for their primary outcome, implying a 20% risk
of a Type II error (false negative results, or beta error). Erik also mentioned the
common methodology mistake illustrated in the fishbone diagram describing study
flow, which does not identify the number of patients who were eligible for the study
but not approached about enrollment. This threatens the study’s internal validity.
For both groups, the only airway interventions required were either BVM or a
jaw thrust.

Secondary outcomes were provider satisfaction, sedation quality and total propofol
dose. There were no emergency reactions or serious adverse events identified
in either group. Physician/nurse satisfaction favored K/P, although as Andrea
pointed out, they didn’t assess patient satisfaction. There was likely also
incomplete blinding. There was a slight trend towards improved sedation quality in
the K/P group using their pain scale, although this was not statistically significant.



There was a fair amount of healthy discussion at the end of journal club about
attending preference and experience, both with single agents and with ketofol.
For Dan G, ketofol has revolutionized procedural sedation. Harwood is certainly
a super-user of ketofol, and believes that the literature supports improved patient
and provider satisfaction with ketofol over either agent alone. He prefers the
nuanced approach of maintaining each drug in its own syringe, to maintain dosing
independence and compensate for the different pharmacokinetics. Andrea is
concerned about the emergence phenomena associated with ketamine, and doesn’t
accept the concept of sub-dissociative dosing of ketamine, or that by giving lower
doses of ketamine you provide analgesia and avoid bad trips. She certainly uses
ketamine and ketofol, but prefers propofol, with additional narcotics as needed
for analgesia. Mike Lambert also likes the Michael Jackson drug. Others in the
room (me) prefer straight ketamine over ketofol for pediatric procedural sedation.
Effectiveness and recovery times are clinically similar for combo versus single
agent, and although side effect profile trends towards favoring ketofol, differences
are small with wide confidence intervals. I don’t see the benefit of 2 drugs over one,
except in older children/adults who are at more risk of emergence reactions…then I
add propofol. I avoid ketamine in children who are very anxious from the start, and
work to establish a calm/comfortable induction environment.

So, residents, just memorize all your attendings’ preferences. Or, better yet, as
pointed out that night, learn how to use a number of different procedural sedation
medications. Different agents may be more appropriate for different situations,
and depending on where you eventually practice, your choices may be restricted by
hospital regulations.