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 CareQueen’s University

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

• 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

• 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

• 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 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

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

QuickTime™ and a decompressor

are needed to see this picture.


• 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


• 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


• 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


• 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)


• 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

• 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 pain

Oligoanalgesia -- ? sensitization of CNS, increased post-operative 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 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

• 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 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

• 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• Intoxicated• History of psychotic disorder• Weight > 130 kg• Allergy to study medications


• 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


• 1:1 nursing care• 2 physicians

• Sedating MD• Operating MD

• Continuous monitoring:• ECG• SaO2

• Oral/Nasal ETCO2

• NIBP at 3-minute intervals

• Supplemental O2 not routinely administered unless desaturation < 92%1

1ACEP Clinical Policy: Procedural Sedation and Analgesia in the Emergency Department, 2005


• 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


• 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


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

• 63 patients enrolled prior to termination of enrollment


p <0.001 by Cochrane-Armitage Trend Test

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

Ketamine

(n=32) Fentanyl (n=31)

Odds ratio at threshold

None 17 ( 53.1%) 5 ( 16.1%) 5.9

Mild 8 ( 25.0%) 10 ( 32.3%) 3.8

Moderate 7 ( 21.9%) 11 ( 35.5%) 12.3

Severe 0 ( 0.0%) 5 ( 16.1%)


• 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)


• 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


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


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

• 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 inconsistently…

“at discretion of treating MD”


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



Study # 3


• 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%)


• 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%


• 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%)


• 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


• 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?


• 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


• 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


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

• This study among them…


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




• 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


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




• 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


• 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%)


• 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?


• 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


• 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


Oxygen Desaturation

YES NO

Abnormal ETCO2

YES 21 9

NO 15 18


• Conclusion:• ETCO2 abnormalities do not appear to

precede oxygen desaturation in patients breathing room air


• 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

• 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:

• 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 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

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

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

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