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Ketofol: Is this the “Game Changer” of Procedural Sedation & Analgesia?

Posted Mar 20 2013 12:00am


What is the “ideal agent” for sedation?
When talking about procedural sedation and analgesia, our goal is to minimize pain and anxiety, with the appropriate agent that matches the needs of our patient and the clinical scenario. So what are some qualities of this “ideal agent?” In a perfect world, it would have: 
  • Minimal adverse effects
  • Rapid onset and offset of action
  • Pharmocokinetic predictability across a spectrum of patients
Ketofol (combination of ketamine and propofol) may be this Holy Grail. Why you ask? Well, ketamine gives you a dissociative sedative, analgesic, and amnestic effect, while propofol gives you rapid sedation and antiemetic effects. It is important to discuss the specifics of each medication before moving on to the combination drug.


Ketamine basics
Ketamine is a dissociative anesthetic that is a phencyclidine derivative and provides sedation, analgesia, and amnesia. It works by inhibiting catecholamine uptake, which exerts a sympathomimetic effect.

The typical dose is 1–2 mg/kg IV or 4–5 mg/kg IM. Additional doses may be required at increments of 0.5-1 mg/kg. Major adverse outcomes include airway obstruction, hypoxia, apnea, and laryngospasm. In a meta-analysis, of 8,282 patients, Green et al stated that the total incidence of these major adverse outcomes was only 3.9%. Vomiting occurs in about 7 – 26% of patients.

What about the elevated intraocular pressure (IOP) and intracranial pressure (ICP) that we are always hearing about? Well in 2012, Drayna et al published a study in Am J Emerg Med which found minimal, transient elevations of IOP that were not clinically meaningful. The largest difference from baseline IOP occurred at 15 minutes with an estimated change of only 1.09 mmHg.



Propofol basics
Propofol is a lipophilic, ultra short-acting hypnotic agent, which works by potentiating GABA receptors on the neuronal lipid membranes. It does not provide any analgesia, and therefore should not be used as a sole agent for sedation. Note that one of its advantages is its anti-emetic property with a very low incidence of vomiting.

Typical dosing is 1-2 mg/kg bolus followed by either a continuous infusion at 0.05-0.1 mg/kg/min or by 0.5 mg/kg boluses every 2 - 3 minutes. The Pediatric Sedation Research Consortium published a paper in Anesth Analg looking at 49,836 propofol sedation cases and found no instances of death associated with propofol. CPR was required in 2 cases, aspiration occurred in 4 cases, oxygen desaturation (less than 90% for longer than 30 sec duration) occurred in 716 cases, and central apnea occurred in 143 cases.

How do you mix ketofol? There is no real standard dosing regimen established, but most studies and authors recommend a 1:1 ratio to provide ease of administration. The medications can be mixed or given sequentially. Recently I listened to a PEM ED Podcast by Andrew Sloas on ketofol dosing. 

His regimen is fairly simple. Ketamine comes in a 50 mg/mL concentration, so if you take a 10 mL saline flush and empty 2 mL and draw up 2 mL of ketamine you have 100 mg of ketamine. Propofol comes in a standard 10 mg/mL concentration. So if you fill a 10 mL syringe with this you have 100 mg of propofol. If you mix the two in a new 20 or 30 mL syringe you get 100 mg ketamine + 100 mg propofol = 200 mg total. Now every one mL has 10 mg of ketofol. Your starting dose of this will be 0.5 mg/kg followed by another 0.5 mg/kg after about 30-60 sec. From then on for maintenance you can use 0.25 mg/kg as needed.

What is the evidence for ketofol? Alletaget al published a meta-analysis called on ketamine, propofol, and ketofol use for pediatric sedation. The majority of the studies compared propofol/fentanyl to ketofol. The two largest and most recent studies on ketofol vs either propofol or ketamine alone will be discussed here (highlighted in yellow). Both studies took place in the ED setting which is pertinent to our practice.

Study
Year
# of Patients
Comparison
Andolfatto et al
2012
284
Propofol vs Ketofol
Shah et al
2011
136
Ketamine vs Ketofol
Chiaretti et al
2010
20
Propofol/Fentanyl vs Ketofol
Erden et al
2009
60
Propofol/Fentanyl vs Ketofol
Aouad et al
2008
63
Propofol/Fentanyl vs Ketofol
Tosun et al
2008
32
Propofol/Fentanyl vs Ketofol
Akin et al
2005
60
Propofol/Fentanyl vs Ketofol
Tomatir et al
2004
43
Propofol vs Ketofol



Round 1: Ketamine vs ketofol  Shah et al (2011) conducted a blinded, randomized trial of 136 pediatric patients (ages 2 – 17 years) that required orthopedic procedures and randomized them to ketofol 1 mg/kg versus ketamine 1 mg/kg.

Results:
  • Median dose of ketamine = 1 mg/kg (ketamine group) vs 0.5 mg/kg (ketofol group) 
  • Median total sedation time = 16 min (ketamine) vs 13 min (ketofol). This was not statistically significant. 
  • Median recovery time = 12 min (ketamine) vs 10 min (ketofol). This was also not statistically significant. 
  • Number of adverse events = 36% (ketamine) vs 21% (ketofol). Much more vomiting in the ketamine group (12%) compared to ketofol group (2%). 
  • No patients required BVM ventilation or intubation. 
  • Satisfaction scores: Significantly higher in the ketofol versus the ketamine group for patients/parents, nurses, and physicians. 
  • Recovery times were not statistically different between both groups, which was thought to be because ketamine 1 mg/kg may have been underdosed. This contrasts prior studies documenting a recovery time of 25-108 min (ketamine) versus 14-15 min (ketofol)
Conclusion: Ketofol has slightly better median total sedation time and recovery time (although not statistically significant) with far fewer adverse reactions, specifically vomiting. Physician, nursing, and patient/parent satisfaction scores were significantly better with ketofol.




Round 2: Propofol vs ketofol
Andolfatto et al  (2012) performed a blinded randomized trial of 284 patients over the age of 14 in an ED setting comparing propofol 0.75 mg/kg versus ketofol 0.75 mg/kg.

Results:
  • Adverse respiratory event (primary outcome) = 32% (propofol) vs 30% (ketofol) 
  • Subsequent dosing needed in 65% (propofol) vs 46% (ketofol) of patients 
  • Both groups had similar satisfaction scores. 
Important points:
  • The propofol bolus dose of 0.75 mg/kg was significantly lower than the more universally used 1 mg/kg dose. This may be why the number of patients having respiratory events was so close to the ketofol group. 
  • The dosing of propofol was q1 minute, despite the more traditional interval of q3 minutes. This increased dosing frequency may have contributed to the higher incidence of hypoxia and BVM ventilation (25%) than in the literature (8-14%). 
Conclusion: Ketofol did not result in a reduced incidence of adverse respiratory events compared to propofol. There was also no difference in induction time, efficacy, and sedation time. Sedation depth appeared to be better in the ketofol group.


And the winner is?
It's a draw. Based on the studies reviewed, it is difficult to say if ketofol is the Holy Grail. Overall, it appears that ketofol could have a slightly better time to sedation, and length of sedation, but this is not statistically significant based on available evidence. However, it does appear that ketofol does have a more steady sedation depth not requiring as many subsequent doses.  

In the end, it would be great to see a three-armed study comparing ketofol, ketamine, and propofol with appropriate and clinically equivalent dosing for each. This would help clarify the muddy evidence.


References
  1. Alletag MJ, Auerbach MA, Baum CR. Ketamine, propofol, and ketofol use for 
  2. pediatric sedation. Pediatr Emerg Care. 2012 Dec;28(12):1391-5. PMID 23222112
  3. Andolfatto G, Abu-Laban RB, Zed PJ, Staniforth SM, Stackhouse S, Moadebi S, Willman E. Ketamine-propofol combination (ketofol) versus propofol alone for emergency department procedural sedation and analgesia: a randomized double-blind trial. Ann Emerg Med. 2012 Jun;59(6):504-12.e1-2. PMID 2240195
  4. Cravero JP, Beach ML, Blike GT, Gallagher SM, Hertzog JH; Pediatric Sedation Research Consortium. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth Analg. 2009 Mar;108(3):795-804. PMID: 19224786
  5. Drayna PC, Estrada C, Wang W, Saville BR, Arnold DH. Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure. Am J Emerg Med. 2012 Sep;30(7):1215-8. PMID: 22169582
  6. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011 May;57(5):449-61. PMID  21256625
  7. Green SM, Roback MG, Krauss B, et al; Emergency Department Ketamine Meta-Analysis Study Group. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009 Aug;54(2):158-68.e1-4. PMID 19201064
  8. Shah A, Mosdossy G, McLeod S, Lehnhardt K, Peddle M, Rieder M. A blinded, randomized controlled trial to evaluate ketamine/propofol versus ketamine alone for procedural sedation in children. Ann Emerg Med. 2011 May;57(5):425-33  PMID 20947210
  9. Sloas A. Sedation & Ketofol. PEM EDPodcast. June 2012
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