Ketofol vs Propofol for ED Procedural Sedation

In Review

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.
PubMed • Full text • PDF

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. 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) 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 as well as a longer recovery. Perhaps the use of lower discordant doses of ketamine should be used for propofol sparing effects. (Subdissociative Ketofol) Despite the numerous trials exploring the optimal dose and ratio, the issue of the use of Ketofol continues. 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)

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) 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) 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:
  • 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

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