ED Procedural Sedation & Analgesia: an evidence-based review for 2008

1. ED Procedural Sedation & Analgesia:an evidence-based review for 2008 David Messenger, MD, FRCPC Emergency Medicine & Critical Care Queen’s University

2. Challenges to Evidence-Based PSA Practice • Very few RCTs • Multiple drugs commonly used in practice • Multiple dosing protocols for each drug or combination • Multiple relevant outcomes of interest: • Safety/Adverse effects • Procedural success rates • Recovery times • No consistent way of reporting outcomes

3. Importance of Evidence-Based PSA Practice • Risk of serious adverse events small, but not non-existent with all drugs used for PSA • Wide variability in practice leads to wide variability in rates of adverse events - studies necessary to establish best practice • Political challenges persist, particularly in U.S., re. use of many of these drugs by non-anesthesiologists • Important to have rigorous evidence for the safety and appropriateness of these agents in the hands of EPs

4. 2007: The Year of ED PSA Research • Several significant publications: • Handful of observational studies • First published case report of aspiration requiring intubation associated with PSA • 3 RCTs (virtually doubles the existing level I evidence!) • Major clinical practice advisory on fasting pre-PSA • Clinical Practice Advisory on propofol sedation

5. The Plan • Ask 4 practical clinical questions and review 4 studies from 2007 that address them: • What’s the best short-acting sedative agent? • If I give an analgesic, which one is best? • Should I give supplemental oxygen to patients during PSA? • What’s the best way to monitor patients for respiratory depression during PSA?

6. Which of the ultra-short acting sedatives is best for deep sedation in the ED? Question 1

7. Short-Acting PSA Agents • Propofol use for ED PSA well-supported by several studies • 28 published series, ~4000 patients • Pooled rate of hypoxemia 5.8% (range 0 - 30%) • Pooled rate of assisted ventilation 2.1% (range 0 - 22%) • 1 intubation • Variable dosing strategies, adjunct drug use, supplemental oxygen use

8. Short-Acting Agents • Etomidate • Widely used in U.S. for PSA, but less evidence than for propofol • Several observational studies of etomidate for ED PSA • Dose range 0.1-0.2 mg/kg • One prior RCT in adults: • Fentanyl+etomidate vs Fentanyl+midaz for shoulder reduction • Shorter duration of sedation with etomidate

9. Etomidate vs Propofol Ann Emerg Med. 2007. 49(1):15-22

10. Etomidate vs Propofol • Enrolled healthy adult patients requiring ED procedural sedation • Randomized to either: • Etomidate 0.1 mg/kg bolus, then 0.05 mg/kg every 3-5 minutes • Propofol 1 mg/kg bolus, then 0.5 mg/kg every 3 minutes • Not blinded

11. Etomidate vs Propofol • Primary outcome: • Subclinical respiratory depression • ETCO2 change from baseline of ≥10 mmHg • SaO2 < 92% • Airway obstruction (defined as loss of capnograph waveform) • Secondary outcomes: • Airway events/interventions • Depth of sedation (BIS score & OAA/S) • Patient pain/recall/satisfaction • Powered to detect a 20% difference in subclinical respiratory depression • assuming 30% baseline rate in propofol group

13. Etomidate vs Propofol

14. Etomidate vs Propofol • Conclusions: • No significant difference in rate of subclinical respiratory depression • No difference in clinical events • Myoclonus seen more frequently with etomidate • ?responsible for lower rate of procedural success

15. Etomidate vs Propofol • Methodologic issues: • Drug dosing • Actual etomidate dosing was higher than protocol specified (mean dose 0.15 mg/kg vs 0.1 mg/kg) • ? impact of higher dose on outcome • Non-blinded study • Difficult given physical properties of propofol • No adjunct analgesic given with sedative • Despite many physicians’ clinical practice and previous RCT of etomidate for ED PSA (Burton, 2002)

16. Etomidate vs Propofol • Relevance to our practice: • Etomidate still only available through Health Canada SAP and not widely adopted for ED PSA here • No compelling evidence in support of using etomidate over other drugs for PSA in Canada • Propofol has an established track record, and appears to be the better agent

18. Question 2 • Unanswered question for both etomidate and propofol: • What’s the impact of adjunct analgesics on relative safety of each agent?

19. Adjunct Analgesics with PSA • Is amnesia equivalent to analgesia? • Treating pre-procedure pain is important • With some procedures, patients experience the most painful stimulus while sedated • Fracture reduction • Incision/Drainage • Unclear if pain that isn’t remembered is important • Anesthetized patients have hemodynamic responses to pain • Oligoanalgesia -- ? sensitization of CNS, increased post-operative pain • Analgesics may reduce the amount of sedative required

20. Adjunct Analgesics with PSA • Inconsistent use of adjunct analgesics in studies of propofol & etomidate • 2007 Clinical Practice Guideline recommends propofol as a solo agent (Miner & Burton, 2007) • …based on several studies by a single investigator (who wrote the guideline) • NO RCT has compared propofol with and without an adjunct analgesic in the ED setting • Safety/efficacy • Remains an area ripe for investigation

21. Adjunct Analgesics • Fentanyl or morphine most commonly used • Major concern is risk of increased respiratory depression when opioids are used with sedatives • Ketamine also has analgesic properties, even at low doses (0.1 - 0.5 mg/kg) • An alternative to opioids?

22. Ketamine-Propofol for PSA • Growing popularity in Canada • Little ED evidence for/against its use in PSA • Review of non-EM literature demonstrates no consistent/convincing benefit to the combination • But very heterogeneous collection of studies • Potential benefits: • Ketamine has analgesic properties • Opposite hemodynamic effects - ? less hypotension • ? Less respiratory depression • Potential downsides: • Emergence reactions • ? Prolonged sedation compared to propofol alone

23. Ketamine-Propofol for PSA • Willman & Andolfatto. 2007. Ann Emerg Med. 49(1):23-30 • Prospective observational study of titrated same-syringe “ketofol” mixture • No control group • Mixture provided effective & apparently safe sedation in their patients • Difficult to rationalize simultaneous titration of two drugs with durations of action that differ by an order of magnitude

24. Adjunct Analgesics for PSA • Messenger et al. 2007. Acad Emerg Med. 14(5 s1) [abstract] Low-dose ketamine versus fentanyl for analgesia during ED PSA with propofol: a randomized clinical trial • First ED RCT comparing adjunct analgesics administered with propofol PSA • Designed to assess safety (frequency of adverse events) as primary outcome • Hypothesis: ketamine will cause fewer and less severe adverse events than fentanyl

25. Ketamine vs fentanyl • Prospective, double-blind RCT • Attempted enrollment of consecutive patients • Inclusion Criteria: • Age 14-65 years • ASA Class I-II • Orthopedic or minor surgical procedure • Exclusion Criteria: • Active cardiac, pulmonary, hepatic, renal disease • Chronic opioid use/abuse • Intoxicated • History of psychotic disorder • Weight > 130 kg • Allergy to study medications

26. Ketamine vs fentanyl • 30 min washout period after opioids • Time = 0 (Study Drug Administered) • Ketamine 0.3 mg/kg IV or Fentanyl 1.5 µg/kg IV • Time = 2 min • Propofol 0.4 mg/kg IV bolus • Propofol 0.1 mg/kg IV q 30s prn • Target: no withdrawal to trapezius squeeze

27. Ketamine vs fentanyl • 1:1 nursing care • 2 physicians • Sedating MD • Operating MD • Continuous monitoring: • ECG • SaO2 • Oral/Nasal ETCO2 • NIBP at 3-minute intervals • Supplemental O2not routinely administered unless desaturation < 92%1 1ACEP Clinical Policy: Procedural Sedation and Analgesia in the Emergency Department, 2005

28. Ketamine vs fentanyl • Composite primary outcome: • Frequency of cardiorespiratory adverse events, graded by severity, using a 4-point ordinal scale (none, mild, moderate, severe) • Each subject scored based on most severe adverse event

29. Ketamine vs fentanyl

30. Ketamine vs fentanyl • Secondary outcomes: • Frequency of specific adverse events • Cumulative propofol doses • Times to recovery • MDs’ rating of of sedation and analgesia • Patients’ rating of recall, remembered pain, and overall satisfaction • 90% power to detect 3-fold reduction in odds of an adverse event (=0.05) • Estimated total sample size: 124 subjects

31. Ketamine vs fentanyl • Trial terminated early after interim analysis of first 61 subjects completed • 63 patients enrolled prior to termination of enrollment

32. Ketamine vs fentanyl

33. Ketamine vs fentanyl • p <0.001 by Cochrane-Armitage Trend Test • Overall odds ratio 5.1 (95% CI 1.9-13.6)

34. Ketamine vs fentanyl

35. Ketamine vs fentanyl • Trend towards higher sedating propofol dose in ketamine group • 1.5 mg/kg vs. 1.1 mg/kg • Difference = 0.4 mg/kg (95%CI 0.0-0.7 mg/kg) • Higher mean propofol dose to maintain sedation in ketamine group • 0.74 mg/kg vs. 0.36 mg/kg • Difference = 0.38 mg/kg (95%CI 0.46-0.66 mg/kg)

36. Ketamine vs fentanyl • No differences observed with respect to: • Time to optimal sedation • Duration of procedure • Time to recovery • MDs’ ratings of sedation and analgesia adequacy • Patients’ ratings of recall, remembered pain and satisfaction • No emergence reactions observed

37. Ketamine vs fentanyl Limitations: • No comparison to propofol alone • Results apply only to drug doses studied • New Adverse Event Scale as primary outcome • No other validated rating of clinical adverse event severity • Results consistent using other comparators: • Frequency of individual adverse events • MDs’ ratings of adverse event severity • No supplemental oxygen given • ? Exaggerated number of adverse events

38. Ketamine vs fentanyl Conclusions: • Marked safety difference • Fewer adverse events at all severity levels in ketamine group, despite higher cumulative propofol doses • Fentanyl-propofol combo should be used with caution • No difference in efficacy • Similar recovery times • Similar MD and patient satisfaction • Ketamine appears to be the better choice if you’re going to use an adjunct analgesic with propofol

40. Question 3 • Should I routinely give patients supplemental oxygen during PSA?

41. Supplemental O2 for PSA • Background: • Maintenance of spontaneous breathing a key goal of PSA • Transient hypoxemia may be frequent • As high as 30-40% in some PSA studies • Most studies have used supplemental O2 inconsistently… • “at discretion of treating MD”

42. Supplemental O2 for PSA Study # 3 Ann Emerg Med. 2007. 49(1):1-8.

43. Supplemental O2 for PSA • RCT design: • Blinded, randomized trial • Oxygen 2lpm by n/c vs compressed air 2lpm during sedation with fentanyl/midaz • Continuous SaO2 and ETCO2 monitoring • Primary outcome: • Oxygen desaturation <90% • Powered to detect 20% reduction in hypoxemia (assuming baseline rate of 30%)

44. Supplemental O2 for PSA • 80 patients included in analysis • Drug doses & other baseline characteristics similar between groups • Frequency of hypoxia: • Room air group: 5/36 • O2 group: 6/44 • Effect size 0%, 95%CI -15% - 15%

45. Supplemental O2 for PSA • Secondary analyses: • Defined “respiratory depression” as any one or more of: • SaO2 <90% • ETCO2 >50 mmHg or absolute change from baseline of ≥10% • Loss of ETCO2 waveform • No difference in RD between O2 and control group • 45% vs 52%, effect size 7% (95% CI -29% - 15%)

46. Supplemental O2 for PSA • Methodologic problems: • Did an interim analysis of data after 80/96 planned patients enrolled • In order to meet abstract submission deadline… • Lower incidence of hypoxemia (13.9% vs anticipated 30%), so study ended early • Study originally powered to detect a 20% reduction, underpowered to detect a smaller difference • Limitations: • Only studied one drug combination for moderate sedation • ? Applicability of results to more potent sedatives

47. Supplemental O2 for PSA • Conclusions: • No observed difference in hypoxemia when patients given routine O2, but underpowered to show small difference • WHO CARES??? • Does giving oxygen have a downside?

48. Supplemental O2 for PSA • Patients may develop respiratory depression well before the SaO2 drops • Hypoventilation, apnea, obstruction • MDs often miss RD prior to onset of hypoxemia • Deitch study: they missed it every time • Giving O2 may further delay recognition of RD • Hypoxemia may take longer to develop • Patients may require more aggressive interventions to correct/treat RD if its recognition is delayed

49. Supplemental O2 for PSA • Significance of respiratory depression and hypoxemia during PSA unclear • Complications with PSA are extremely rare, but do occur • Recent Canadian case report of aspiration requiring intubation after ED PSA (Cheung et al., 2007) • EP’s should strive to minimize potential risks to patients at all times • Prevention, early recognition and early treatment of respiratory events should be a primary focus of physicians performing PSA

50. Question 4 • Is there a better way to monitor patients’ respiratory status during sedation than just the SaO2?