Adverse events in Ketamine vs Ketofol

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Lemoel F. "Adverse Events With Ketamine Versus Ketofol for Procedural Sedation on Adults: A Double-blind, Randomized Controlled Trial". Academic Emergency Medicine. 2017. 24(12):1441-1449.
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Clinical Question

In adult patients that present with orthopaedic injury requiring procedural sedation in the hospital or pre-hospital setting, do patients that are treated with ketamine alone as compared with 1:1 ratio ketamine:propofol (ketofol), which treatment is more associated with unpleasant emergence reactions.

Bottom Line

Both provide adequate sedation, the ketamine only group had more unpleasant recovery reactions, more emesis, and more hypotension as compared to 1:1 ratio ketofol.

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.

In this trial of 152 patients managed at five emergency departments for orthopaedic injuries requiring procedural sedation, they compared the use of ketofol (ketamine and propofol in a 1:1 ratio) to ketamine plus intralipid (to act as propofol placebo) with the primary outcome of the rate of unpleasant emergence reaction post-sedation. The per-protocol analysis demonstrated a rate of unpleasant emergence twice as high with the ketamine group as compared to ketofol, 44.7% vs. 22.1%, respectively. The ketamine group also had a higher rate of hypotension (6.6% vs. 0%) and emesis (18.4% vs. 5.3%). Patient and provider satisfaction was equal for both treatments and level of sedation was similar in both arms. Unfortunately the outcomes involving resource allocation or time in ED were part of the original protocol but were not reported.

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

  • Multicenter, double-blind, randomized, controlled trial
  • N=152
    • Ketofol (n=76)
    • Ketamine + Placebo (n=76)
  • Setting: hospital and pre-hospital setting in 6 French Eds using mobile intensive care units
  • Enrollment: May 2012 to December 2015
  • Analysis: Per-protocol
  • Primary Outcome: rate of patients experiencing emergence reaction

Population

Inclusion Criteria

  • ≥ 18 years old
  • presenting orthopaedic injury
  • requiring procedural sedation

Exclusion Criteria

  • American Society of Anesthesiologists (ASA) physical status >2
  • known hypersensitivity to study drug
  • sustained thoracic, abdominal, spinal, or head injury
  • hemodynamic instability
  • intoxicated
  • schizophrenic
  • pregnant
  • prisoners
  • intravenous (IV) drug users
  • patients unable to give consent
  • porphyria
  • glaucoma

Baseline Characteristics

Ketamine Group displayed

  • Demographics: Median age 47 years, 57% male
  • Anthropomorphics: median ideal body weight 72 kg
  • ASA Class: Class 1 67%, Class 2 33%
  • Site of procedure: fracture reduction 54%, dislocation reduction 58%, other 0%
  • Localization: lower limb 47%, upper limb 53%

Interventions

  • Ketamine group: 1 mg/kg ketamine + intralipid (propofol placebo)
  • Ketofol group: 0.5 mg/kg ketamine + 0.5 mg/kg propofol

Every 4 minutes, physician assessment of under sedation led to half-doses of both drugs/placebo

Outcomes

Comparisons are Ketamine vs. Ketofol.

Primary Outcomes

Proportion of patients experiencing recovering reaction (defined as confusion, anxiety, unpleasant dreams or hallucinations, agitation, and aggressiveness)
44.7% vs. 22.3% (difference 22.4; 95% CI 7.4 to 36.1) NNT 5

Secondary Outcomes

Patients experiencing hypotension (SBP < 100mmHg)
6.6% vs. 0% (difference 6.6; 95% CI 0.5 to 14.5)
Rate of emesis
18.4% vs. 5.3% (difference 13.2; 95% CI 2.8 to 23.8)
Rate of airway or respiratory adverse event
18.4% vs. 17.1% (Difference 1.3; 95% CI –10.9 to 13.5)
Recovery reactions requiring intervention
27.6% vs 14.5% (difference 13.2, 95% CI 0.1–25.7)
Mean satisfaction of patients on a visual analogue scale
82mm vs. 83mm (difference 1.4 mm; 95% CI -6mm to 8.5mm)
Mean satisfaction of providers on a visual analogue scale
74mm vs. 74mm (difference 0 mm; 95% CI -10mm to 9mm)

Subgroup Analysis

Number of doses required to achieve sedation
initial dose: 69.7% vs. 56.6% (difference 13.2%; 95% CI -2.1 to 27.6)
one extra dose: 21% vs. 21% (difference 0)
two extra doses: 9.2% vs. 22.4% (difference 13.2%, CI 1.5 to 24.7)
Number of recovery reactions per patient
None: 55% vs. 78% (difference – 22.4; 95% CI –36.1 to –7.4)
One: 23.7% vs. 17.1% (difference 6.6; 95% CI –6.3 to 19.3)
At least two: 21% vs. 5% (difference 15.8; 95% CI 5.1 to 26.7)

Criticisms

  • serial injection of the drugs may have led to loss of blinding
  • the rate of recovery reaction was twice the estimate used for the power calculation

Funding

  • Not reported

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