POKER (2016)

In Review

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. 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

• 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