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ED Procedural Sedation & Analgesia: an evidence-based review for 2008. David Messenger, MD, FRCPC Emergency Medicine & Critical Care Queen ’ s University. Challenges to Evidence-Based PSA Practice. Very few RCTs Multiple drugs commonly used in practice

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

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Ed procedural sedation analgesia an evidence based review for 2008
ED Procedural Sedation & Analgesia:an evidence-based review for 2008

David Messenger, MD, FRCPC

Emergency Medicine & Critical Care

Queen’s University


Challenges to evidence based psa practice
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


  • Importance of evidence based psa practice
    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


    2007 the year of ed psa research
    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


    The plan
    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?



    Short acting psa agents
    Short-Acting PSA Agents sedation in the ED?

    • 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


    Short acting agents
    Short-Acting Agents sedation in the ED?

    • 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


    Etomidate vs propofol
    Etomidate vs Propofol sedation in the ED?

    Ann Emerg Med. 2007. 49(1):15-22


    Etomidate vs propofol1
    Etomidate vs Propofol sedation in the ED?

    • 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


    Etomidate vs propofol2
    Etomidate vs Propofol sedation in the ED?

    • 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


  • Etomidate vs propofol3
    Etomidate vs Propofol sedation in the ED?


    Etomidate vs propofol4
    Etomidate vs Propofol sedation in the ED?

    • 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


    Etomidate vs propofol5
    Etomidate vs Propofol sedation in the ED?

    • 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)


  • Etomidate vs propofol6
    Etomidate vs Propofol sedation in the ED?

    • 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


    Question 2
    Question 2 sedation in the ED?

    • Unanswered question for both etomidate and propofol:

      • What’s the impact of adjunct analgesics on relative safety of each agent?


    Adjunct analgesics with psa
    Adjunct Analgesics with PSA sedation in the ED?

    • 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


  • Adjunct analgesics with psa1
    Adjunct Analgesics with PSA sedation in the ED?

    • 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


    Adjunct analgesics
    Adjunct Analgesics sedation in the ED?

    • 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?


    Ketamine propofol for psa
    Ketamine-Propofol for PSA sedation in the ED?

    • 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


  • Ketamine propofol for psa1
    Ketamine-Propofol for PSA sedation in the ED?

    • 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


    Adjunct analgesics for psa
    Adjunct Analgesics for PSA sedation in the ED?

    • 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


    Ketamine vs fentanyl
    Ketamine vs fentanyl sedation in the ED?

    • 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


  • Ketamine vs fentanyl1
    Ketamine vs fentanyl sedation in the ED?

    • 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


    Ketamine vs fentanyl2
    Ketamine vs fentanyl sedation in the ED?

    • 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


    Ketamine vs fentanyl3
    Ketamine vs fentanyl sedation in the ED?

    • 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


    Ketamine vs fentanyl4
    Ketamine vs fentanyl sedation in the ED?


    Ketamine vs fentanyl5
    Ketamine vs fentanyl sedation in the ED?

    • 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


    Ketamine vs fentanyl6
    Ketamine vs fentanyl sedation in the ED?

    • Trial terminated early after interim analysis of first 61 subjects completed

    • 63 patients enrolled prior to termination of enrollment


    Ketamine vs fentanyl7
    Ketamine vs fentanyl sedation in the ED?


    Ketamine vs fentanyl8
    Ketamine vs fentanyl sedation in the ED?

    • p <0.001 by Cochrane-Armitage Trend Test

  • Overall odds ratio 5.1 (95% CI 1.9-13.6)


  • Ketamine vs fentanyl9
    Ketamine vs fentanyl sedation in the ED?


    Ketamine vs fentanyl10
    Ketamine vs fentanyl sedation in the ED?

    • 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)


  • Ketamine vs fentanyl11
    Ketamine vs fentanyl sedation in the ED?

    • 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


    Ketamine vs fentanyl12
    Ketamine vs fentanyl sedation in the ED?

    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


    Ketamine vs fentanyl13
    Ketamine vs fentanyl sedation in the ED?

    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


    Question 3
    Question 3 sedation in the ED?

    • Should I routinely give patients supplemental oxygen during PSA?


    Supplemental o 2 for psa
    Supplemental O sedation in the ED?2 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”


    Supplemental o 2 for psa1
    Supplemental O sedation in the ED?2 for PSA

    Study # 3

    Ann Emerg Med. 2007. 49(1):1-8.


    Supplemental o 2 for psa2
    Supplemental O sedation in the ED?2 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%)


    Supplemental o 2 for psa3
    Supplemental O sedation in the ED?2 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%


  • Supplemental o 2 for psa4
    Supplemental O sedation in the ED?2 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%)


    Supplemental o 2 for psa5
    Supplemental O sedation in the ED?2 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


  • Supplemental o 2 for psa6
    Supplemental O sedation in the ED?2 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?


    Supplemental o 2 for psa7
    Supplemental O sedation in the ED?2 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


  • Supplemental o 2 for psa8
    Supplemental O sedation in the ED?2 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


  • Question 4
    Question 4 sedation in the ED?

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


    Etco 2 monitoring during psa
    ETCO sedation in the ED?2 Monitoring during PSA

    • Capnography:

      • Continuous breath-sampled measurement of exhaled CO2 (nasal, or nasal-oral sampling)

      • Provides a number (capnometer) as well as a waveform (capnograph)

      • Capnometry correlates with blood pCO2

        • Increases with hypoventilation

        • Decreases with partial airway obstruction

    • Capnograph loss suggests apnea or complete airway obstruction

      • More subtle changes in waveform

        morphology also suggest abnormal

        breathing patterns


    Etco 2 monitoring during psa1
    ETCO sedation in the ED?2 Monitoring during PSA

    • Growing literature suggests that capnography may be a valuable respiratory monitoring tool during PSA

      • This study among them…


    Etco 2 monitoring during psa2
    ETCO sedation in the ED?2 Monitoring during PSA

    Ann Emerg Med. 2007. 49(1):9-13


    Etco 2 monitoring during psa3
    ETCO sedation in the ED?2 Monitoring during PSA

    • Prospective convenience sample of 125 children sedated with propofol for fracture reduction

      • Monitored ETCO2 via nasal sampling

      • All patients given 1lpm O2 by N/C

    • Outcomes of interest:

      • Hypoxemia (SaO2 <90%)

      • Hypercarbia (ETCO2 >50mmHg or increase of 10 mmHg from baseline)

      • Apnea (loss of ETCO2 waveform >30s)

      • Airway interventions


    Etco 2 monitoring during psa4
    ETCO sedation in the ED?2 Monitoring during PSA

    • Capnography change preceded clinical detection of adverse events in 11/14 cases


    Etco 2 monitoring during psa5
    ETCO sedation in the ED?2 Monitoring during PSA

    • Similar study in adultsBurton et al., Acad Emerg Med. 2006. 13(5):500-504

      • 60 PSA encounters in 59 patients

      • Defined abnormal capnography as:

        • ETCO2 change from baseline of ≥10 mmHg (up or down)

        • ETCO2 level ≤30 or ≥50 mmHg

    • All patients given O2 2lpm by N/C


    Etco 2 monitoring during psa6
    ETCO sedation in the ED?2 Monitoring during PSA

    • 20/60 encounters had predefined “acute respiratory events” observed

      • SaO2 <92%

      • increased O2 due to apnea, hypoventilation or desat

      • BVM, airway insertion

      • repositioning, patient stimulation, reversal agent

  • Abnormal ETCO2 findings in 17/20

    • ETCO2 change preceded event in 14/20 (70%)


  • Etco 2 monitoring during psa7
    ETCO sedation in the ED?2 Monitoring during PSA

    • Both studies suggest a benefit to ETCO2 monitoring for early detection of adverse respiratory events

      • Performed better than clinician observation and oximetry monitoring in patients who received supplemental O2

  • What about patients breathing room air?


  • Etco 2 monitoring during psa8
    ETCO sedation in the ED?2 Monitoring during PSA

    • Messenger et al. CJEM 2007. 9(3) [abstract]

      • Prospective observational study nested within RCT of analgesic adjuncts to propofol sedation

      • 63 patients breathing room air

      • Observed ETCO2 changes relative to oxygen saturation

        • Hypoxemia = SaO2 <92%

        • Abnormal ETCO2:

          • ETCO2 >50 mmHg

          • Rise/Fall of ≥10 mmHg from baseline

          • Absent waveform >30s


    Etco 2 monitoring during psa9
    ETCO sedation in the ED?2 Monitoring during PSA

    • Hypoxemia observed in 36/63 patients

    • Abnormal capnography observed in 30/63 patients

      • Loss of waveform: 12/30

      • ETCO2 >50 mmHg: 6/30

      • ETCO2 rise ≥10 mmHg: 7/30

      • ETCO2 fall ≥10 mmHg: 11/30


    Etco 2 monitoring during psa10
    ETCO sedation in the ED?2 Monitoring during PSA


    Etco 2 monitoring during psa11
    ETCO sedation in the ED?2 Monitoring during PSA

    • Conclusion:

      • ETCO2 abnormalities do not appear to precede oxygen desaturation in patients breathing room air


    Etco 2 monitoring during psa12
    ETCO sedation in the ED?2 Monitoring during PSA

    • Research still to be done:

      • Does ETCO2 monitoring actually help reduce the frequency of adverse respiratory events?

      • What are the ETCO2 changes most likely to predict adverse respiratory events?

  • ETCO2 monitoring:

    • Will likely evolve into standard of care for ED PSA… momentum is strong

    • For physicians familiar with its use and interpretation, likely will be useful for helping reduce adverse events

    • Use it if you have it (with supplemental O2); otherwise, keep patients on room air and observe patient and pulse oximeter closely


  • Summary
    Summary sedation in the ED?

    • Evidence supporting PSA practice is increasing, but much remains to be done

    • Need more studies focusing on:

      • Comparison of drugs and drug doses

      • Prevention and early detection of respiratory depression


    Our 4 questions
    Our 4 Questions: sedation in the ED?

    • Which short-acting Agent is best for ED PSA?

      • Propofol

  • Which adjunct analgesic is safest when given with short-acting sedatives?

    • Pick ketamine over fentanyl


  • Our 4 questions1
    Our 4 Questions: sedation in the ED?

    • Should I give my patients supplemental oxygen?

      • Not if you want to detect respiratory depression early….

      • Unless….

  • How can I better monitor my patients’ breathing during PSA?

    • Consider capnography in patients if you give supplemental oxygen


  • Summary1
    Summary sedation in the ED?

    • Etomidate does not appear to offer any advantage over propofol for ED PSA

      • Stick with the white stuff…

  • Ketamine is a safer adjunct analgesic for propofol than fentanyl

    • Beware opioid-propofol combinations for PSA

  • Supplemental oxygen may not reduce the frequency of hypoxemia, and may only serve to delay the recognition of respiratory depression during ED PSA

    • Consider keeping your patient on room air if no other respiratory monitoring device is used

  • ETCO2 monitoring appears to identify RD prior to adverse respiratory events in preoxygenated patients

    • Ideal practice appears to be to provide O2 and incorporate capnometry into PSA monitoring


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