Subdissociative Ketofol

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Messenger DW, et al. "Subdissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial". Acad Emerg Med. 2008. 15(10):877-86.
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Clinical Question

In older adolescent or adult patients requiring procedural sedation, is a fixed non-dissociative dose of ketamine plus titratable propofol superior to fixed-dose fentanyl plus titratable propofol for adverse events and appropriate sedation.

Bottom Line

This fixed, sub-dissociative dose ketamine with propofol suggests a safer alternative to fixed dose fentanyl with the same titratable propofol, in terms of adverse event, shorter time for recovery, and oxygen desaturation events. This does not reflect other trials where larger doses of ketamine are employed or where same syringe combination titration is employed and thus modality requires further study.

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, prospective, randomized controlled trial
  • N=63
    • Ketamine+Propofol (n=32)
    • Fentanyl+Propofol (n=31)
  • Setting: Emergency Department of a 460-bed, university-affiliated tertiary care hospital
  • Enrollment: December 2004 - February 2006
  • Analysis: ITT
  • Primary Outcome: frequency of cardiorespiratory clinical events and interventions, graded by relative severity or invasiveness, stratified as none, mild, moderate, and severe.

Population

Inclusion Criteria

  • treating physician determined procedural sedation appropriate for patient presenting with either:
    • fracture or dislocation requiring reduction
    • abscess requiring incision and drainage

Exclusion Criteria

  • < 14 or > 65 years
  • American Society of Anesthesiology (ASA) Class III or greater
  • history of significant active cardiac, pulmonary, hepatic, or renal disease
  • > 130 kg
  • history of physician-diagnosed obstructive sleep apnea
  • chronic use of opioids
  • history of recent substance abuse or prior opioid dependence
  • acute intoxication with drugs or alcohol
  • history of psychotic disorder
  • history of allergy or sensitivity to any study medication

Baseline Characteristics

Presented the Ketamine group

  • Age, years (mean ± SD) 35.6 ± 17.0
  • Gender (%)
    • Female 12 (37.5)
    • Male 20 (62.5)
  • Weight, kg (mean ± sd) 74.5 ± 15.9
  • Procedure type (%)
    • Orthopedic procedures 31 (96.9)
    • Upper extremity 18 (56.3)
    • Lower extremity 12 (37.5)
    • Other 1 (3.1)
    • Abscess I&D 1 (3.1)
  • Mean preprocedure pain score (mean ± SD) 4.6 ± 2.4
  • IV opioid analgesia in 2 hours preceding PSA (%) 12 (37.5)
  • Total dose, mg of morphine (median [IQR]) 6.2 [3.6, 10.0]
  • Baseline vital signs (mean ± sd)
    • Heart rate (beats ⁄ min) 88.1 ± 14.8
    • sBP (mm Hg) 141.9 ± 17.7
    • dBP (mm Hg) 83.6 ± 10.7
    • Mean arterial pressure (mm Hg) 105.1 ± 11.5
    • Oxygen saturation (%) 98.4 ± 1.5
    • ETCO2 (mm Hg) 39.4 ± 5.8

Interventions

  • Ketamine IV 0.3 mg⁄ kg ketamine or Fentanyl IV 1.5 mcg ⁄ kg at Time 0.
  • After 2 minutes, all patients received Propofol IV 0.4 mg ⁄ kg, followed by additional 0.1 mg⁄ kg boluses every 30 seconds until adequate sedation

Outcomes

Comparisons are Ketamine+Propofol vs. Fentanyl+Propofol

Primary Outcomes

Any intervention or event
46.9% vs. 83.9%, OR 5.1 95% CI 1.9-13.6; P < 0.001
None 53.1% vs. 16.1%
Mild 25.0% vs. 32.3%
Moderate 21.9% vs. 35.5%
Severe 0.0% vs. 16.1%

Secondary Outcomes

Comparisons are Ketamine+Propofol vs. Fentanyl+Propofol, Difference (95% CI)

Propofol dose required to achieve adequate sedation, mg ⁄ kg (mean ± SD)
1.5 ± 0.9 vs. 1.1 ± 0.6, 0.4 (0.0, 0.7)
Supplemental propofol administered after sedation achieved, mg ⁄ kg (mean ± SD)
0.74 ± 0.64 vs. 0.36 ± 0.42, 0.38 (0.46, 0.66)
Time from study drug administration to adequate sedation, minutes (median [IQR])
6.7 [5.9, 8.4] vs. 5.4 [3.8, 8.9]
Length of procedure, minutes (median [IQR])
7.9 [4.1, 10.8] vs. 5.9 [2.7, 10.0]
Recovery time,minutes (median [IQR])
28.0 [10.0, 52.5] vs. 37.0 [19.5, 40.3]
Sedating physician’s opinion (1–10 scale) of the adequacy of sedation (mean ± SD)
7.2 ± 2.2 vs. 7.6 ± 1.9, -0.4 (-1.4, 0.6)
Sedating physician’s opinion (1–10 scale) of the adequacy of analgesia (mean ± SD)
6.6 ± 2.3 vs. 7.3 ± 2.2, -0.7 (-1.8, 2.3)
Operating physician’s opinion (1–10 scale) of the adequacy of sedation (mean ± SD)
7.4 ± 2.2 vs.8.0 ± 2.0, -0.6 (-1.7, 0.4)
Patient’s recall (1–10 scale) of procedure (mean ± SD)
3.2 ± 3.0 vs. 4.1 ± 3.7, -0.9 (-2.6, 3.4)
Patient’s pain remembered (1–10 scale) during procedure (mean ± SD)
2.1 ± 2.2 vs. 2.3 ± 2.0, -0.3 (-1.3, 0.8)
Patient’s overall satisfaction (1–10 scale) with sedation (mean ± SD)
9.4 ± 1.4 vs. 9.4 ± 1.4, 0 (-0.7, 1.4)
Emergence phenomena
0 vs. 0
Sedating physician’s rating (1–10 scale) of overall adverse event severity (mean ± SD)
1.6 ± 1.0 vs. 3.2 ± 1.8, 1.6 (-2.3, -0.9)

Adverse Events

Oxygen saturation below 92%
38.7% vs. 75% (ARR 39.9%; 95% CI = 17.6% to 62.2%)
Oxygen Saturation below 80%
Fentanyl group, NNH 2.8 (95% CI = 1.9 to 5.7)

Criticisms

  • Patients disproportionately recruited during daytime hours
  • Primary outcome is an unvalidated composite surrogate outcome
  • Blinding potentially violated: sedating physician accurately able to guess patent allocation 78%, P<0.001

Funding

  • Resident research grant from the Physicians’ Services Incorporated Foundation (Grant R04-43)

Further Reading

  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