Ketofol vs Propofol for ED Procedural Sedation

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Andolfatto G, et al. "Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia: A Randomized Double-Blind Trial". Annals of Emergency Medicine. 2012. 59(6):504-512.
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Clinical Question

In adults requiring procedural sedation in the Emergency Department, is the combination of ketamine and propofol superior than propofol alone with respect to adverse effects and sedation efficacy.

Bottom Line

The addition of ketamine may have a propofol sparing effect, but the combination "ketofol" is associated with more adverse effects when compared to propofol alone.

Major Points

The concept of combining ketamine to offset the dose related cardiopulmonary depression from propofol and offer some analgesia has been discussed since the turn of the century.[1] Theoretically the propofol may also suppress the emergence delirium associated with ketamine. There have been various trials discussing the use of 1:1 ratio Ketofol,(Ketofol vs Propofol for ED Procedural Sedation)[2][3][4] with the largest of which showed similar outcomes between the two group (POKER (2016)) and many more discussing other ratios and doses.

When comparing the two drugs directly, a greater risk of adverse effects is seen with ketamine[5] as well as a longer recovery.[6] Perhaps the use of lower discordant doses of ketamine should be used for propofol sparing effects. (Subdissociative Ketofol) [7] Despite the numerous trials exploring the optimal dose and ratio, the issue of the use of Ketofol continues.[8][9] With considerations such as emergence phenomena, sedation, analgesia, and time to ED discharge, further research is required and ongoing.

Guidelines

American College of Emergency Physicians Clinical Policy (2014, adapted)[10]

The following are potential options for procedural sedation in adults:
  1. Propofol (level A recommendation)
  2. "Ketofol" (level B recommendation)
  3. Ketamine (level C recommendation)

The Canadian Consensus Guidelines for Procedural Sedation (1999)[11] were last updated prior to much of the newer research on ketofol and do not reflect its use.

The American Society of Anesthesiologists Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists (2002)[12] do not specifically address employing a combination of propofol and ketamine, but contains several relevant points;

  • Neither ketamine nor propofol has a pharmacologic antagonist
  • The dissociative properties of ketamine can mask traditional signs of depth of sedation (eg. eye closure, respiratory rate depression) and failure to recognize this may lead to unintentional levels of sedation and/or general anesthesia
  • Practitioners administering an anesthetic induction agent for sedation should be qualified to rescue patients from all levels of sedation, including general anesthesia

Design

  • Single-centre, double-blind, randomized, controlled trial
  • N=284
    • Ketofol (n=142)
    • Propofol alone (n=142)
  • Setting: Lions Gate Hospital, Canadian 250-bed community teaching hospital and Level III trauma center
  • Enrollment: December 2010 to September 2011
  • Analysis: Intention-to-treat
  • Primary outcome: Number and proportion of patients experiencing a respiratory adverse event as defined by the Quebec Criteria[13]:
    • Oxygen desaturation
    • Central apnea
    • Partial upper airway obstruction
    • Complete upper airway obstruction
    • Laryngospasm
    • Clinically apparent pulmonary aspiration
  • Secondary Outcomes
    • Sedation consistency
    • Total medication dosage
    • Sedation efficacy
    • Induction time
    • Procedure time
    • Sedation time
    • Recovery time
    • Incidence of adverse events

Population

Inclusion Criteria

  • requirement for procedural sedation as determined by the treating emergency physician
  • ≥ 14 years
  • American Society of Anesthesiology Class 1 to 3 status [14]

Exclusion Criteria

  • unable to give informed consent
  • pregnant
  • known allergy to either study medication

Baseline Characteristics

Presented as Ketofol(n=142) vs Propofol(n=142), n(%) unless otherwise specified

  • Age
    • 14-21 29(20) vs. 15(11)
    • 22-49 45(32) vs. 48(34)
    • 50-74 48(34) vs. 56(39)
    • ≥75 20(14) vs. 23(16)
  • Male 71(51) vs. 69(49)
  • ASA Class
    • 1&2 137(97) vs. 138(97)
    • 3 5(3) vs. 4(3)
  • Weight [kg(IRQ)] 73 (60-82) vs. 74 (64-86)
  • Procedure
    • Fracture reduction 61(43) vs. 65(46)
    • Dislocation reduction 24(17) vs. 21(15)
    • Incision and drainage 28(20) vs. 23(16)
    • Cardioversion 17(12) vs. 21(15)
    • Chest tube insertion 3(2) vs. 6(4)
    • Laceration repair 5(3) vs. 2(1)
    • Hernia reduction 2(1) vs. 0
    • Gastroscopy 1(1) vs. 0
    • Stool disimpaction 1(1) vs. 4(3)

Interventions

  • Randomized to Ketofol (Ketamine:Propofol at a 1:1 ratio) or Propofol alone
    • Ketofol: 0.375 mg/kg initial bolus of each ketamine and propofol
      • then 0.188 mg/kg each of ketamine and propofol Q1min to maintain Ramsay Sedation Score (RSS) <5
    • Propofol alone: 0.75 mg/kg Propofol initial bolus
      • then 0.375 mg/kg of propofol Q1min to maintain RSS <5

Outcomes

Primary Outcomes

Presented as Ketofol No(%)[95%CI] vs. Propofol No(%)[95%CI]; Difference%[95%CI]; NNH

--Incidence of Resp Events--

Patients experiencing a respiratory event
43(30)[23-28] vs. 46(32) [25-41]; 2[-9-13]; NS
Oxygen desaturation
38(27)[20-35] vs. 36(25)[19-33]; 2[-9-12]; NS
Central apnea
15(11)[7-17] vs. 13(9)[6-15]; 2[-5-9]; NS
Partial upper airway obstruction
11(8)[4-13] vs. 11(8)[4-13]; 0[0]; NS
Complete upper airway obstruction
6(4)[2-9] vs. 4(3)[1-7]; 1[-3-6]; NS
Laryngospasm
0 vs. 0; 0[0]; NS
Clinically apparent pulmonary aspiration
0 vs. 0; 0[0]; NS

--Resp Interventions--

Stimulation/airway repositioning
5(4)[2-8] vs. 14(10)[6-16]; 6[0.4-13]; 16
Stimulation/airway repositioning plus oxygen
35(25)[18-32] vs. 31(22)[16-29]; 3[-7-13]; NS
Stimulation/airway repositioning, oxygen, plus bag-valve-mask
3(2)[0.7-6] vs. 1(1)[0.1-4]; 1[-2-5]; NS

Secondary Outcomes

Presented as Ketofol No.(%)[95%CI] vs. Propofol No.(%)[95%CI]; Difference%[95%CI], NNT

Patients with RSS <5 during procedure or requiring repeated dose during procedure
65(46)[38-54] vs. 93(65)[57-73]; 19[8-31]; 5
Patients with RSS <5 during procedure
52(37)[29-45] vs. 75(53)[45-61]; 16[5-27]; 6
Patients requiring repeated dosing during procedure
28(20)[15-28] vs. 63(44)[36-52]; 24[12-33]; 4
Efficacious sedation
129(91)[85-95] vs. 126(89)[83-93]; 2[5-9]; 50

Presented as Ketofol Median(IRQ)[range] vs. Propofol Median(IRQ)[range]

Induction time to RSS 5, min
2(1-3)[1-6] vs. 2(1-3)[1-10]
Induction total doses required to reach RSS 5, No.
2(2-3)[1-7] vs. 2(1-3)[1-9]
Procedure time, min
4(2-7)[1-28] vs. 5(2-7)[1-13]
Sedation time, min
7(4-9)[1-29] vs. 7(4-9)[1-18]
Recovery time, min
8(7-10)[1-26] vs. 6(2-8)[2-13]
Total dose each Ketamine and propofol, mg/kg each
0.7(0.6-0.9)[0.4-1.6] vs. 1.5(1.1-2.0)[0.7-5.1]

Adverse Events

Presented as Ketofol No.(%)[95%CI] vs. Propofol No.(%)[95%CI]; Difference%[95%CI]; NNH

Respiratory Adverse Events
See Primary Outcomes
Procedural agitation
5(3.5)[1.6-8.0] vs. 15(11.0)[6.5-16.7]; 7.5[1-14]; 13
Hypotension
0 vs. 1(0.7)[0.2-3.8]; 0.7[2-4]; NS
Muscular rigidity
0 vs. 2(1)[0.2-4.4]; 1[-1-5]; NS
Rash
1(0.7)[0.2-3.8] vs. 0; 0.7[-2-4]; NS
Recovery agitation receiving treatment
6(4)[2.0-8.9] vs. 0; 4[0.8-9]; NS
Recovery agitation no treatment
4(3)[1.1-7.0] vs. 0; 3[-0.3 to 7]; NS

Criticisms

  • Generally painful procedures
  • included only generally health adults
  • Single Centre
  • inconsistencies between Clinicaltrials.gov protocol, methods, and reported results
  • Loss of blinding possible as nothing was done to mask muscle tone (sunglasses for nystagmus)

Funding

The primary author supported by the Vancouver Coastal Health Research Institute Mentored Clinical Scientist Award.

Further Reading

References

  1. Mortero RF, Clark LD, Tolan MM, et al. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg. 2001 Jun;92(6):1465-9.
  2. Phillips W, Anderson A, Rosengreen M, et al. Propofol Versus Propofol/Ketamine for Brief Painful Procedures in the Emergency Department: Clinical and Bispectral Index Scale Comparison. J Pain Palliat Care Pharmacother. 2010 Dec;24(4):349-55.
  3. Andolfatto G, Willman E. A Prospective Case Series of Single syringe Ketamine–Propofol (Ketofol) for Emergency Department Procedural Sedation and Analgesia in Adults Acad Emerg Med. 2011 Mar;18(3):237-45.
  4. Nejati A, Moharari RS, Ashraf H, et al. Ketamine⁄Propofol Versus Midazolam⁄Fentanyl for Procedural Sedation and Analgesia in the Emergency Department: A Randomized, Prospective, Double-Blind Trial. Acad Emerg Med. 2011 Aug;18(8):800-6.
  5. Miner JR, Gray RO, Bahr J, et al. Randomized Clinical Trial of Propofol Versus Ketamine for Procedural Sedation in the Emergency Department. Acad Emerg Med. 2010 Jun;17(6):604-11.
  6. Uri O, Behrbalk E, Haim A, et al. Procedural Sedation with Propofol for Painful Orthopaedic Manipulation in the Emergency Department Expedites Patient Management Compared with a Midazolam/Ketamine Regimen J Bone Joint Surg Am. 2011 Dec 21;93(24):2255-62.
  7. Shy BD, Strayer RJ, Howland MA. Independent Dosing of Propofol and Ketamine May Improve Procedural Sedation Compared With the Combination “Ketofol.” Ann Emerg Med. 2013 Feb;61(2):257.
  8. Messenger DW, Murray HE, Dungey PE, et al. Subdissociative-dose Ketamine versus Fentanyl for Analgesia during Propofol Procedural Sedation: A Randomized Clinical Trial Acad Emerg Med. 2008 Oct;15(10):877-86.
  9. David H, Shipp J. A Randomized Controlled Trial of Ketamine/Propofol Versus Propofol Alone for Emergency Department Procedural Sedation. Ann Emerg Med. 2011 May;57(5):435-41.
  10. Godwin SA, Burton JH, Gerardo CJ et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2014 Feb;63(2):247-58.e18
  11. Innes G, Murphy M, Nijssen-Jordan C, et al. Procedural sedation and analgesia in the emergency department. Canadian Consensus Guidelines. J Emerg Med 1999 Jan-Feb;17(1):145-56
  12. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. "Anesthesiology" 2002 Apr;96(4):1004-17. PMID: 11964611
  13. Bhatt M, Kennedy RM, Osmond MH, et al. Consensus-based ecommendations for standardizing terminology and reporting adverse events for emergency department procedural sedation and analgesia in children. Ann Emerg Med. 2009;53:426-435
  14. American Society of Anesthesiology Classification System