Electrical Cardioversion Clinical Trial
Official title:
A Randomized Double-blind Trial to Evaluate Ketamine-propofol Combination vs. Propofol Alone for Procedural Sedation and Analgesia in the Emergency Department.
When patients come to the Emergency Department with injuries and infections they often need
to have painful procedures performed that are essential to allowing them to recover. To
accomplish this, doctors often use "procedural sedation". This involves giving medications
through an intravenous line in order to relieve the patient's pain and to make them drowsy
while the painful procedure is being performed. This allows the medical staff to perform
necessary procedures to patients without causing pain and anguish.
There are several types of medications and combinations of medications that are used for
procedural sedation. Each medication has its advantages and its disadvantages. Consequently,
research is necessary to determine which medication or combination of medications is the
most effective and the safest. This study will compare the use of one drug (Propofol) versus
the use of a combination of Propofol with another drug (Ketamine). Both of these drugs are
already used for procedural sedations in the emergency department but it is not known which
of them is the best or the safest.
The investigators believe that the combination of ketamine and propofol together will work
as good or better than propofol alone and be a safer option as well. Propofol is a well
known sedative that is used in many emergency departments and the clinical experience with
it has been very good because it acts quickly and wears off quickly. However, propofol is
not a good pain-killer and it can also cause patients to stop breathing. This is why
monitoring a patient's breathing and vital signs is essential for any procedural sedation.
It is known that ketamine is a good pain-killer and helps patients to maintain their
breathing. Doctors sometimes use ketamine alone for procedural sedation but patients take a
very long time to wake up when ketamine only is used.
Thus, the investigators think that by combining ketamine with propofol the investigators can
perform painful procedures using procedural sedation without causing patients to stop
breathing as often as with propofol alone. Also, the ketamine the investigators use will
help treat their pain and make them more comfortable.
The investigators plan to enroll 284 patients over the course of about one year. The primary
outcome of adverse respiratory events, as well as the secondary outcomes will be assessed
during the course of the sedation and recovery period, approximately one hour. Quality of
life score and pain will be assessed by telephone interview 3 days after the procedure.
Procedural sedation and analgesia (PSA) for painful procedures is the standard of care in
emergency medicine.
The ideal PSA agent should be safe, easy to administer, provide analgesia and amnesia with
rapid onset, quick recovery and a minimum of adverse effects. A variety of medications have
been studied for procedural sedation but no single medication currently used meets all of
these criteria. Two medications that are well known and often used for procedural sedation
are propofol and ketamine. Both medications have been shown to be highly effective but each
has important limitations in emergency practice. Propofol is known to cause respiratory
depression, apnea, and hypotension in a dose-dependent fashion. Ketamine displays a longer
recovery time than propofol and patients receiving ketamine sedation are prone to vomiting
and unpleasant emergence reactions. The use of ketamine and propofol in combination is
theoretically compelling as the sedative effects of propofol should logically balance the
nauseant and psychomimetic effects of ketamine while the ability to achieve deep sedation
with lower doses of ketamine should logically permit for a shorter physiologic recovery time
compared ketamine alone. As well, ketamine provides an analgesic effect that is absent with
propofol and has been shown to be safer than using opioid analgesia such as fentanyl when
considering airway events. This study seeks to evaluate a ketamine-propofol combination that
potentially provides effective procedural sedation and analgesia while exposing patients to
less risks associated with respiratory depression as the differential effects of ketamine
and propofol may lead to fewer adverse events than either medication used alone.
Propofol is a nonopioid, nonbarbiturate, sedative-hypnotic agent whose desirable properties
include its rapid onset, short duration of action, and reliability in producing sedation. It
also acts an anti-emetic but has no analgesic properties. Adverse effects include
dose-related cardiovascular and respiratory depression and bradycardia. This dose-dependent
respiratory depression, apnea and hypotension may present barriers to the widespread
clinical utility of propofol. In addition, the lack of an analgesic effect may necessitate
the use of other agents to provide pain relief during procedural sedation. The use of opioid
analgesia in conjunction with propofol sedation is well known to increase the risk of
adverse airway events.
Ketamine is an agent classified as a dissociative sedative and is known to provide
efficacious and safe procedural sedation with the preservation of airway reflexes and
respiratory drive. The use of ketamine for severe acute pain in the emergency department has
been shown to decrease opioid requirements in trauma patients as well as reduce the pain of
propofol injection. During deep sedation with propofol, the use of sub-dissociative ketamine
for analgesia during emergency department procedural sedation results in fewer adverse
airway events than does fentanyl. The main limitations of the use of ketamine alone for
procedural sedation is its longer recovery time and the incidence of dysphoric emergence
reactions, especially in adults.
Ketamine-propofol combination has been used successfully and safely for a variety of
purposes, including gynecological and ophthalmological procedures, sedation for spinal
anesthesia, and cardiovascular procedures in both adults and children. Ketamine and propofol
mixed in the same syringe has been shown to be safe and effective in both the operating room
and in the office setting. Combining ketamine with propofol appears to provide anesthetic
synergy with a widened therapeutic index, permitting the induction of anesthesia and
sedation at doses less likely to lead to respiratory depression. Thus, the combination of
ketamine and propofol has received interest as an emergency department procedural sedation
regimen that allows the provision of PSA using drug doses lower than typically required for
each agent alone potentially resulting in fewer adverse effects and shorter recovery times.
Propofol is a potent sedative and with anti-nauseant properties and is thought to likely
mitigate the problematic adverse psychomimetic and nauseant effects of ketamine. Ketamine
and propofol are known to be physically and chemically stable when mixed in polypropylene
syringes and the mixture displays stable respiratory and hemodynamic parameters in healthy
patients during general anesthesia. The use of ketamine and propofol in combination in the
ED is limited. A pilot study of 20 children showed that ketamine and propofol administered
from separate syringes to ED patients resulted in reliable deep sedation with few adverse
effects. Prospective ED case series in children and in adults have shown that ketamine and
propofol mixed in a single syringe in a 1:1 ratio (so called "ketofol") appears to be an
effective ED PSA agent that is well tolerated and appears safe. To date, there has not been
any randomized trial comparing single-syringe ketofol with other known ED PSA agents, thus
the theoretical advantages of ketamine-propofol combination (ketofol) are not yet
definitively known.
Methodology Experimental Design: This study will be a prospective, double-blind, randomized
clinical trial. A systematic review of the literature on propofol use in emergency
department procedural sedation using explicit criteria was carried out. Trials were selected
based on the following criteria: 1) propofol alone was the sedation agent used, 2) At least
a 30 minute "washout" period between pre-procedural analgesic use before the commencement of
procedural sedation, 3) Propofol used in an intermittent bolus technique, 4) Patients
greater than 14 years of age, 5) Study published less than 10 years previously, 6) Study
performed in the emergency department.
Nine studies were identified totaling 1679 patients. These were reviewed with respect to
reported airway events based on the Quebec Criteria definitions for airway events. The
composite adverse airway event from these studies was 21% (95% CI 19.05% to 22.95%).
The composite Quebec Criteria adverse event rate for studies of ketamine-propofol sedation
was then determined from the available literature. Three studies were identified with a
total enrollment of 166 patients. Airway event data from a prospective case series (n=328)
performed at LGH was also included. The pooled results yielded a composite adverse airway
event rate of 8% (95% CI 5.87% to 10.73%).
Based on these data (21% event rate in the propofol arm, 8% anticipated event rate in the
ketamine-propofol arm), 129 subjects would be needed in each group (total 258 subjects) to
have 80% power to detect a difference of this magnitude or greater (alpha 0.05, two-sided
calculation). An additional 10% enrollment will be added to the total enrollment to offset
potential drop-outs, resulting in a total sample size of 284 subjects (142 in each arm).
Written, informed consent will be obtained from all patients or from a parent/guardian in
those under the age of 18 years.
Enrollment Projection: The emergency department at Lions Gate Hospital presently performs an
average of 55 procedural sedations per month. Assuming a 50% enrollment rate (based on local
enrollment experience in other ED randomized trials), it would be expected that full study
enrollment would occur within 12 months.
All patients will receive pre-procedural analgesia at the discretion of the treating
physician. For entry into the study there will be a minimum 30-minute "washout" period
between analgesic use and the commencement of the procedural sedation. Sealed envelopes
containing a randomized assignment to either propofol-alone or ketamine-propofol will be
prepared using a web-based random number generator. Block randomization will be done (random
block sizes) to ensure an approximate of allocations between the two arms of he study
throughout enrollment, thus maximizing statistical power if any unanticipated events lead to
trial termination prior to complete enrollment. Data, including crossovers or contamination
(both of which are exceedingly unlikely) will be analysed on an Intent to Treat principle.
Identical pre-prepared syringes will contain either propofol-alone or ketamine-propofol
mixture, prepared by trained and in-serviced registered nurses. Medications will be overseen
by the emergency department clinical pharmacist. To assist in blinding, patients will wear
reflective sunglasses in order to obscure eye movements (nystagmus - a known effect of
ketamine) from the study investigators.
All sedations will be performed under continuous cardiorespiratory monitoring as directed
under the Vancouver Coastal Health Authority Guidelines for Emergency Department Procedural
Sedation and Analgesia. All procedural sedation events will require the attendance of a
certified emergency physician, registered nurse, and respiratory therapist. Vital signs
including heart rate, respiratory rate, oxygen saturation, and end-tidal carbon dioxide will
be monitored continuously and recorded every 2 minutes. Blood pressure will be recorded
every 4 minutes.
A separate, standardized data sheet will be used to collect the time of study drug
administration, time of procedure start, time of procedure completion, and time of
physiologic recovery. Recovery will be assessed after completion of the procedure by the use
of a modified Aldrete Scale every 2 minutes until full recovery, defined as a minimum
cumulative score of 8. The attending physician will be asked to document any complications
that occurred during the procedure and if any interventions were necessary. The nurse caring
for the patient will also be asked to record any adverse events occurring during the
recovery phase. To evaluate the success of study blinding, at the conclusion of each
sedation the attending physician and nurse will be asked to independently guess whether the
patient in question received propofol-only or ketamine-propofol. Primary and secondary
outcomes will be assessed during the course of the sedation procedure and recovery, less
than one hour in the vast majority of cases. Quality of Life and pain scores will be
assessed by telephone interview 72 hours after the sedation procedure.
Analysis: Statistical consultation prior to the study launch was obtained through the VCHRI
Centre for Clinical Epidemiology and Evaluation (C2E2).
Analysis of primary outcome:
The number proportion of patients suffering a respiratory AE will be reported by treatment
group. A 95% CI for the difference between treatment groups will be determined. The equality
of the two proportions will be tested using Fisher's exact test.
Analysis of secondary outcomes:
Quality of sedation. The number and proportion of patients with a RSS < 5 during the
procedure, or requiring further sedation at any time during the procedure will be reported
for each treatment group. The equality of the two proportions will be tested using Fisher's
exact test. For all other secondary outcomes only descriptive analyses are planned.
Analysis of safety outcomes:
Frequencies and percentages of complications and adverse events (excluding respiratory) by
treatment group will be reported with 95% CI's.
Interim Analyses:
There are no planned interim analyses for either efficacy or safety.
The Mann-Whitney test will be used to compare differences in satisfaction levels (measured
on an ordinal scale) between groups.
A p value <0.05 will be considered statistically significant.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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