Ed procedural sedation analgesia an evidence based review for 2008
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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

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?


    Question 1

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

    Question 1


    Short acting psa agents

    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


    Short acting agents

    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


    Etomidate vs propofol

    Etomidate vs Propofol

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


    Etomidate vs propofol1

    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


    Etomidate vs propofol2

    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


  • Etomidate vs propofol3

    Etomidate vs Propofol


    Etomidate vs propofol4

    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


    Etomidate vs propofol5

    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)


  • Etomidate vs propofol6

    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


    Question 2

    Question 2

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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


    Ketamine vs fentanyl5

    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


    Ketamine vs fentanyl6

    Ketamine vs fentanyl

    • 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


    Ketamine vs fentanyl8

    Ketamine vs fentanyl

    • 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


    Ketamine vs fentanyl10

    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)


  • Ketamine vs fentanyl11

    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


    Ketamine vs fentanyl12

    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


    Ketamine vs fentanyl13

    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


    Question 3

    Question 3

    • Should I routinely give patients supplemental oxygen during PSA?


    Supplemental o 2 for psa

    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”


    Supplemental o 2 for psa1

    Supplemental O2 for PSA

    Study # 3

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


    Supplemental o 2 for psa2

    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%)


    Supplemental o 2 for psa3

    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%


  • Supplemental o 2 for psa4

    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%)


    Supplemental o 2 for psa5

    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


  • Supplemental o 2 for psa6

    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?


    Supplemental o 2 for psa7

    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


  • Supplemental o 2 for psa8

    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


  • Question 4

    Question 4

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


    Etco 2 monitoring during psa

    ETCO2 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

    ETCO2 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

    ETCO2 Monitoring during PSA

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


    Etco 2 monitoring during psa3

    ETCO2 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

    ETCO2 Monitoring during PSA

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


    Etco 2 monitoring during psa5

    ETCO2 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

    ETCO2 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

    ETCO2 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

    ETCO2 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

    ETCO2 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

    ETCO2 Monitoring during PSA


    Etco 2 monitoring during psa11

    ETCO2 Monitoring during PSA

    • Conclusion:

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


    Etco 2 monitoring during psa12

    ETCO2 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

    • 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:

    • 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:

    • 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

    • 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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