POKER (2016)

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Ferguson I, Bell A, Treston G, et al. "Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine-The POKER Study: A Randomized Double-Blind Clinical Trial". Ann Emerg Med. 2016. 68(5):574-582.
PubMed

Clinical Question

In adult patients requiring sedation in the emergency department, is the combination of ketamine and propofol (ketofol) superior to propofol alone with respect to adverse respiratory effects requiring physician intervention?

Bottom Line

In this large trial exploring 1:1 Ketofol compared to propofol alone, there was no difference in respiratory events or requiring intervention. They observed more mild agitation in the propofol arm but not leading to meaningful interference in procedure and the ketofol arm was associated with more (pleasant) hallucinations, emergence phenomena, and longer time to discharge.

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

  • Multicenter, double-blind, randomized, controlled trial
  • N=573
    • Propofol (n=292)
    • Ketofol (n=281)
  • Setting: 3 hospitals in Australia
    • Bundaberg Base Hospital (mixed rural regional hospital, annual ED census = 50 000)
    • Queen Elizabeth II Memorial Hospital (mixed urban district hospital, annual ED census = 60 000)
    • Liverpool Hospital (mixed tertiary hospital, annual ED census = 76 000)
  • Enrollment: April 2013 to April 2015
  • Analysis: Per-Protocol
  • Primary outcome: occurrence of a respiratory event
    • Defined as: hypoxia (SPO2 ≤ 93%), hypoventilation (RR ≤ 8 breaths/min), apnea (no capnography trace for ≥ 15 sec), laryngospasm or aspiration (persistent hypoxia plus infiltrates on CXR), occurrence of a rescue intervention (increased oxygen flow rate, airway repositioning/opening, use of an airway adjunct, bag-valve-mask ventilation, or intubation)
  • Secondary outcomes: hypotension (SBP < 90 mmHg) and patient satisfaction
    • Exploratory outcomes: vomiting, aspiration (hypoxia and new aspirates on CXR), median sedative dose, median duration of sedation, occurrence of emergence delirium, patient recollection and pain scoring, clinician satisfaction

Population

Inclusion Criteria

  • 18years and older
  • Treating physician determined required deep procedural sedation to facilitate a painful procedure

Exclusion Criteria

  • Unable to provide informed consent
  • Pregnant
  • Allergic to ketamine, soy products, or eggs
  • Reduced level of consciousness
  • Known raised intracranial pressure
  • Uncontrolled hypertension (blood pressure >160/90 mm Hg)
  • Abdominal aortic aneurysm
  • Symptomatic ischemic heart disease
  • Heart failure
  • Recent myocardial infarction
  • Other severe systemic disease
    • American Society of Anaesthesiologists class IV or greater

Baseline Characteristics

Presented as Ketofol group

  • Age, y, median (IQR), range: 50(31-65)18-95
  • Male%: 49
  • Weight, kg:
    • Median(IQR), range: 78(68-91), 44-150
  • Pain score before procedure, median (IQR): 4(1-6)
  • Baseline systolic BP, median (IQR), mmHg: 137(124-148)
  • Fasted ≥3 h, % (95%CI): 95(92-98)
  • Procedure, %
    • Upper limb fracture reduction: 28
    • Lower limb fracture reduction: 9
    • Abscess incision and drainage: 20
    • Shoulder reduction: 12
    • Other joint reduction: 14
    • Cardioversion: 10
    • Other indication: 8
  • Comorbidities %
    • Ischemic heart disease: 5
    • Hypertension: 20
    • Diabetes mellitus: 8
    • Epilepsy: 1
    • Asthma: 4
  • Prophylactic oxygen use %: 99.6
    • Oxygen flow rate (IQR), L/min: 4(3-6)
  • Morphine
    • Patients receiving %: 22
    • Median dose (IQR), mg: 5(5-10)
    • Mean dose (95% CI), mg/kg: 0.02(0.02-0.04)
  • Fentanyl
    • Patients receiving %: 11
    • Median dose (95% CI), mg/kg: 75 (50-100)
    • Mean dose (95% CI), mcg/kg: 0.1(0.06-0.14)
  • Study drug
    • Dose administered, median (IQR), mL/kg: 0.125 (0.07-0.19)
    • Propofol, median (IQR), mg/kg: 0.675(0.7-1.9)
    • Ketamine, median (IQR), mg/kg: 0.675(0.7-1.9)

Interventions

  • Study Medication preparation:
    • Ketofol: Ketamine 100mg in 10mL + Propofol 100mg in 10mL = 20mL
    • Propofol: Propofol 200mg in 20mL = 20mL
  • Dosing, using weight-based bracketing (see Table E1):
    • Initial bolus: 0.05 mL/kg
    • Additional aliquots: 0.025 mL/kg every 60 seconds
    • If all 20mL used, then Propofol 100mg/10mL (1%) used for additional sedation

Outcomes

Comparisons are Propofol % vs. Ketofol %, Difference %(95%CI)

Primary Outcomes

Composite endpoint (occurrence of any respiratory event and intervention)
9 vs. 7, NS
Airway Events
Desaturation (SpO2 ≤93%)
8 vs. 6
Apnea (loss of ETCO2 ≥15sec)
5 vs. 4
Hypoventilation (RR ≤8)
4 vs. 9
Airway obstruction
0 vs. 0
Laryngospasm
0 v. 0
Aspiration
0 vs. 0
Occurrence of any airway event
10 vs. 8, NS
Respiratory interventions
Increased oxygen flow rate
5 vs. 4
Airway repositioned/opened
12 vs. 9
Airway adjunct use
0.6 vs 0.3
Bag-valve-mask use
3 vs. 1
Occurrence of any respiratory intervention
16 vs. 14, NS

Secondary Outcomes

Hypotension <90 mmHg
8 vs. 1, 7(4-10)
Patient Satisfaction with sedation, Median (IRQ)[range]
10(10-10)[0-10] vs. 10(10-10)[0-10], 0(0-0)

Exploratory Outcomes

Mild agitation
20 vs. 12, 8(2 to 14)
Procedural interference
4 vs. 2, NS
Procedural failure
0.3 vs. 0, NS
Vomiting
3 vs. 4, NS
Hallucinations, All
15 vs. 35, 20(13 to 27)
Hallucinations, Pleasant
10 vs. 25, 15(9 to 21)
Hallucinations, Unpleasant
1 vs. 3, NS
Emergence delirium, Any
20 vs. 27, 7(4 to 10)
Emergence delirium, Minor
18 vs. 22, NS
Emergence delirium, Severe
2 vs. 5, 3(0.4 to 6)
Time from sedation to DKS >7min; Mean (95% CI)
24(22-26) vs. 33(29-37), 9(7 to 11)

Criticisms

Study limitations include:

  • Selection bias
    • Use of a convenience sample
    • Patient recruitment occurring outside of peak times / overnight
  • Unblinding
    • Study drug prepared in same department
    • Unblinding not assessed
  • Use of physiologic and intervention-based outcomes which are somewhat subjective due to differences among physicians regarding triggers of intervention.
  • Single country study with a secondary outcome of patient satisfaction that may not correlate to patient populations outside of Australia.

Funding

Research grant from the Queensland Emergency Medicine Research Foundation

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