Low-dose ketamine vs fentanyl during ED PSA with - CCFP-EM

ED Procedural Sedation &
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
• Multiple dosing protocols for each drug or
• Multiple relevant outcomes of interest:
• Safety/Adverse effects
• Procedural success rates
• Recovery times
• No consistent way of reporting outcomes
Importance of EvidenceBased PSA Practice
• Risk of serious adverse events small, but not nonexistent 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
• 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
• Major clinical practice advisory on fasting prePSA
• Clinical Practice Advisory on propofol sedation
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?
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
• Etomidate
• Widely used in U.S. for PSA, but less evidence
than for propofol
• Several observational studies of etomidate for
 Dose range 0.1-0.2 mg/kg
• One prior RCT in adults:
 Fentanyl+etomidate vs Fentanyl+midaz for shoulder
 Shorter duration of sedation with etomidate
Etomidate vs Propofol
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Ann Emerg Med. 2007. 49(1):15-22
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 Propofol
• Primary outcome:
• Subclinical respiratory depression
 ETCO2 change from baseline of ≥10 mmHg
 SaO2 < 92%
 Airway obstruction (defined as loss of capnograph
• 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
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Etomidate vs Propofol
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Etomidate vs Propofol
• Conclusions:
• No significant difference in rate of
subclinical respiratory depression
• No difference in clinical events
• Myoclonus seen more frequently with
• ?responsible for lower rate of procedural success
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 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
• Propofol has an established track record,
and appears to be the better agent
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
• 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
 Oligoanalgesia -- ? sensitization of CNS, increased postoperative pain
 Analgesics may reduce the amount of sedative required
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
• Fentanyl or morphine most commonly
• 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
• 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 PSA
• Willman & Andolfatto. 2007. Ann Emerg Med. 49(1):23-30
• Prospective observational study of titrated samesyringe “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
• 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
• 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
History of psychotic disorder
Weight > 130 kg
Allergy to study medications
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
• 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 fentanyl
• 1:1 nursing care
• 2 physicians
• Sedating MD
• Operating MD
• Continuous monitoring:
Oral/Nasal ETCO2
NIBP at 3-minute intervals
• Supplemental O2 not routinely administered unless
desaturation < 92%1
Clinical Policy: Procedural Sedation and
Analgesia in the Emergency Department, 2005
Ketamine vs fentanyl
• Composite primary outcome:
• Frequency of cardiorespiratory adverse
events, graded by severity, using a 4-point
ordinal scale (none, mild, moderate,
• Each subject scored based on most severe
adverse event
Ketamine vs fentanyl
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 fentanyl
• Trial terminated early after interim
analysis of first 61 subjects completed
• 63 patients enrolled prior to termination
of enrollment
Ketamine vs fentanyl
Ketamine vs fentanyl
K eta m ine
F entany l
Odds ratio a t
th resho ld
17 ( 53. 1%)
5 ( 16.1 % )
M ild
8 ( 25.0 % )
10 ( 32. 3%)
M ode rate
7 ( 21.9 % )
11 ( 35. 5%)
0 ( 0. 0%)
5 ( 16.1 % )
Seve re
 p <0.001 by Cochrane-Armitage Trend Test
• Overall odds ratio 5.1 (95% CI 1.9-13.6)
Ketamine vs fentanyl
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 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 fentanyl
• 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 fentanyl
• 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
• Should I routinely give patients
supplemental oxygen during 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
 “at discretion of treating MD”
Supplemental O2 for PSA
Study # 3
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Ann Emerg Med. 2007. 49(1):1-8.
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 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 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
 Loss of ETCO2 waveform
• No difference in RD between O2 and control group
 45% vs 52%, effect size 7% (95% CI -29% - 15%)
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
• ? Applicability of results to more potent sedatives
Supplemental O2 for PSA
• Conclusions:
• No observed difference in hypoxemia when
patients given routine O2, but
underpowered to show small difference
• Does giving oxygen have a downside?
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
• 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 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
• Is there a better way to monitor
patients’ respiratory status during
sedation than just the SaO2?
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
ETCO2 Monitoring during PSA
• Growing literature suggests that
capnography may be a valuable
respiratory monitoring tool during PSA
• This study among them…
ETCO2 Monitoring during PSA
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Ann Emerg Med. 2007. 49(1):9-13
ETCO2 Monitoring during PSA
• Prospective convenience sample of 125
children sedated with propofol for fracture
• 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
ETCO2 Monitoring during PSA
• Capnography change preceded clinical
detection of adverse events in 11/14 cases
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ETCO2 Monitoring during PSA
• Similar study in adults
Burton 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
 ETCO2 level ≤30 or ≥50 mmHg
• All patients given O2 2lpm by N/C
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%)
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?
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
 Hypoxemia = SaO2 <92%
 Abnormal ETCO2:
 ETCO2 >50 mmHg
 Rise/Fall of ≥10 mmHg from baseline
 Absent waveform >30s
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
ETCO2 Monitoring during PSA
Oxygen Desaturation
ETCO2 Monitoring during PSA
• Conclusion:
• ETCO2 abnormalities do not appear to
precede oxygen desaturation in patients
breathing room air
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
• 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
Our 4 Questions:
• Which short-acting Agent is best for ED
• Propofol
• Which adjunct analgesic is safest when
given with short-acting sedatives?
• Pick ketamine over fentanyl
Our 4 Questions:
• Should I give my patients supplemental
• Not if you want to detect respiratory depression
• Unless….
• How can I better monitor my patients’
breathing during PSA?
• Consider capnography in patients if you give
supplemental oxygen
• 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
• 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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