The ability to perform procedural sedation and analgesia (PSA) is essential to the practice of Emergency Medicine (EM). Which agent an Emergency Provider chooses to use depends on a variety of factors, including provider comfort and preference, ease of access and, most importantly, perceived safety of the medications.
Propofol and Ketamine are two commonly used agents for PSA, each with their own benefits and drawbacks. Propofol has amnestic qualities, but is also associated with hypotension, loss of airway reflexes and hypoventilation requiring intervention. Whereas ketamine maintains airway reflexes while providing analgesia, but can be associated with tachycardia, hypertension, nausea, vomiting and the dreaded emergence reaction, which can often be distressing to the patient. Overall, significant adverse reactions are low but PSA is still a potentially high-risk procedure.
Ketofol, a 1:1 combination of Ketamine and Propofol, has been thought anecdotally to be a compromise of sorts between the two individual choices, having a lower incidence of adverse respiratory events, hypotension, vomiting and emergency reactions.
Is there a difference in the frequency of airway and respiratory adverse events between a mixture of propofol and ketamine in a 1:1 ratio in a single syringe (ketofol) versus propofol as a single agent?
Eligible patients 18 years or older who required deep procedural sedation to facilitate the performance of a painful procedure in the ED, between April 2013 and April 2015 at 3 different clinical sites (rural, urban and tertiary care).
1:1 Ketofol (ketamine 100 mg in 10mL plus propofol 100 mg in 10 mL, total 20 mL syringe) given in titrated aliquots on weight based dosing schedule
Propofol (200 mg in 20 mL, total 20 mL syringe) given in titrated aliquots on weight based dosing schedule
Primary: Occurrence of a respiratory event defined as hypoxia (SpO2 = 93%), hypoventilation (respiratory rate 8 breaths/min), apnea (no capnography trace for >/=15 seconds), laryngospasm or aspiration (persistent hypoxia plus infiltrates on chest radiograph), and the occurrence of a rescue intervention (increased oxygen flow rate, airway repositioning/opening, use of an airway adjunct, bag-valve-mask ventilation, or intubation)
Secondary: Hypotension (SBP < 90 mm Hg) and patient satisfaction
Multicenter, randomized, double-blind clinical trial
Patients who were unable to provide informed consent; pregnant; allergic to ketamine, soy products, or eggs; had a reduced level of consciousness or known raised intracranial pressure; had uncontrolled hypertension (blood pressure >160/90 mm Hg), abdominal aortic aneurysm, or symptomatic ischemic heart disease; had heart failure or recent myocardial infarction; or had other severe systemic disease (American Society of Anaesthesiologists class IV or greater).
- 591 patients randomized for treatment
- 573 patients included in analysis
- Propofol: n = 292
- Ketofol: n = 281
- Study was powered to demonstrate a 10% reduction in the primary outcome measure with 90% power requiring a sample size of 526 patients
- Primary Endpoint: Occurrence of respiratory event and rescue intervention
- Overall: 8.3% (48/573)
- Propofol = 4.7% vs Ketofol = 3.6%
- Absolute difference = 2.1% (95% CI -2% to 5%) NO STATISTICALLY SIGNIFICANT DIFFERENCE
- BVM ventilation occurred more frequently in propofol group
- Secondary Endpoint: Hypotension and patient satisfaction
- Hypotension: Propofol 8% vs Ketofol 1%
- Absolute difference = 7% (95% CI 4%-10%)
- Patient Satisfaction: Identical medians and ranges
- Hypotension: Propofol 8% vs Ketofol 1%
- Exploratory Secondary outcomes
- Increased severe emergence delirium with Ketofol (absolute difference of 3%, NNT to avoid 1 episode is 33)
- Pain scores @ 30 minutes lower in Ketofol group
- This is the largest study to compare Ketofol in a 1:1 ratio in a single syringe with equivalent volume 1% propofol for procedural sedation/analgesia
- Multi-center study increasing external validity
- Blinding and randomization well-performed
- Clinically important endpoint that is relevant to the patient
- Possible selection bias given it is a convenience sample (less recruitment during peak ED times and overnight given necessity to have additional consulting ED physician)
- Ketofol had to be prepared in same department as study, so possible some unblinding occurred
- Use of prophylactic oxygen and administration of analgesia prior to PSA was not controlled
- Combined physiologic and intervention based outcome measure could be confounded by different physicians having different intervention thresholds
“Ketofol and propofol resulted in a similar incidence of adverse respiratory events requiring the intervention of the sedating physician. Although propofol resulted in more hypotension, the clinical relevance of this is questionable, and both agents are associated with high levels of patient satisfaction.”
While anecdotally Ketofol has been thought to be a safer alternative than propofol in the use of procedural sedation and analgesia in the ED, the results of this large multi-center study does not support this claim.
Potential Impact To Current Practice
This study does not impact current practice. There is no dominant, “one approach to rule them all.” Providers should continue to employ agents they are comfortable using and that are appropriate for the specific clinical scenario.
There appears to be no safety benefit regarding a 1:1 ketofol preparation vs proprofol, nor any difference in patient satisfaction. Future studies regarding comparison of Ketofol and Ketamine could potentially be useful given concerns over Ketamine induced emergence reaction.
REBEL EM: The POKER Trial: Go All in on Ketofol?
St. Emlyn’s: JC: Is Ketofol with the hassle?