Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia: A Randomized Double-Blind Trial

doi:10.1016/j.annemergmed.2012.01.017

Annals of Emergency Medicine

Volume 59, Issue 6, June 2012, Pages 504-512.e2

https://doi.org/10.1016/j.annemergmed.2012.01.017 Get rights and content

Study objective

We determine whether a 1:1 mixture of ketamine and propofol (ketofol) for emergency department (ED) procedural sedation results in a 13% or more absolute reduction in adverse respiratory events compared with propofol alone.

Methods

Participants were randomized to receive either ketofol or propofol in a double-blind fashion. Inclusion criteria were aged 14 years or older and American Society of Anesthesiology class 1 to 3 status. The primary outcome was the number and proportion of patients experiencing an adverse respiratory event as defined by the Quebec Criteria. Secondary outcomes were sedation consistency, efficacy, and time; induction time; and adverse events.

Results

A total of 284 patients were enrolled, 142 per group. Forty-three (30%) patients experienced an adverse respiratory event in the ketofol group compared with 46 (32%) in the propofol group (difference 2%; 95% confidence interval −9% to 13%; P=.80). Three ketofol patients and 1 propofol patient received bag-valve-mask ventilation. Sixty-five (46%) patients receiving ketofol and 93 (65%) patients receiving propofol required repeated medication dosing or progressed to a Ramsay Sedation Score of 4 or less during their procedure (difference 19%; 95% confidence interval 8% to 31%; P=.001). Six patients receiving ketofol were treated for recovery agitation. Other secondary outcomes were similar between the groups. Patients and staff were highly satisfied with both agents.

Conclusion

Ketofol for ED procedural sedation does not result in a reduced incidence of adverse respiratory events compared with propofol alone. Induction time, efficacy, and sedation time were similar; however, sedation depth appeared to be more consistent with ketofol.

Introduction

Procedural sedation and analgesia is used in the emergency department (ED) to efficiently and humanely perform necessary painful procedures.¹ Ketamine and propofol are 2 medications commonly used for this purpose because they possess many characteristics deemed desirable by clinicians.2, 3 However, ketamine use is limited by its propensity to cause emesis and recovery agitation, and by its prolonged recovery time compared with that of propofol.4, 5 Propofol itself is limited by dose-dependent hypotension and respiratory depression,6, 7, 8 especially when combined with opioids.9, 10, 11, 12, 13 The opposing physiologic effects of ketamine and propofol suggest the potential for synergy, and this has led to interest in their combined use, commonly termed “ketofol,” to facilitate ED procedural sedation.14, 15, 16 The use of ketofol has been described in numerous non-ED settings,17, 18, 19, 20, 21 and its use for ED procedural sedation has been accomplished with each drug in separate syringes, as well as mixed in the same syringe.22, 23, 24, 25, 26, 27 The combination has been demonstrated to be chemically stable and physically compatible when mixed in polypropylene syringes.28, 29

The potential advantages of ketofol over propofol alone include the provision of deep sedation with lower doses of propofol, thus potentially limiting propofol-associated adverse respiratory effects; the provision of ketamine analgesia without the increased adverse respiratory effects associated with concomitant opioid administration; and the mitigation of propofol-induced hypotension.30, 31 The potential advantages of ketofol over ketamine-alone procedural sedation include shorter recovery time and a lower incidence of ketamine-associated emesis and recovery agitation.26, 32

The potential synergy of ketamine and propofol used in combination may result in fewer adverse respiratory events than when propofol is used alone for ED procedural sedation.

Our goal was to determine whether a single-syringe mixture of ketamine and propofol in a 1:1 ratio for ED procedural sedation in patients aged 14 years or older results in a 13% or more absolute reduction in adverse respiratory events as described by predefined criteria (the Quebec Criteria)³³ when compared with propofol alone.

Section snippets

Study Design

This was a randomized, double-blind trial approved by the University of British Columbia Clinical Research Ethics Board. Before study launch, the methods were registered with ClinicalTrials.gov (NCT01211158), and a “no objection letter” was obtained from Health Canada (file no. 9427-2649-21C).

Subjects were assigned to receive either propofol or ketofol by a computer-generated block randomization schedule, with variable block sizes to a maximum of 10.

Setting and Selection of Participants

The study was performed between December 2010

Characteristics of Study Subjects

The flow of study subjects is illustrated in Figure 1, which represents all patients sedated during the study period. There were no cases of sedations occurring with agents other than ketofol or propofol. The 2 groups were similar with regard to demographic characteristics and procedures performed (Table 2). The most commonly performed procedures were orthopedic, comprising 60% of each group. Fifty-nine ketofol patients (41%) and 50 propofol patients (35%) received preprocedural analgesia. No

Limitations

The use of the Quebec Criteria for reporting adverse events is limited by the fact that the decision to intervene is based on the judgment of the clinician. Different clinicians may have different intervention thresholds in the face of a potentially adverse event.

The variety of procedures performed had differing requirements for sedation and analgesia. The use of the same weight-based dosing schedule for procedures of varied painfulness may have affected the incidence of adverse events.

Discussion

To our knowledge, this study is the largest reported randomized double-blind comparison of ketamine-propofol combination versus propofol alone for ED procedural sedation and analgesia. Using the widely accepted intervention-based Quebec Criteria,³³ we found that, when targeting deep sedation, the incidence of adverse respiratory events is not lessened when a 1:1 single-syringe mixture of ketamine and propofol is used compared with using propofol alone.

Ketamine is known to preserve respiratory

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Endoscopic retrograde cholangiopancreatography (ERCP) is a widely used diagnostic and therapeutic procedure. Effective sedation is crucial to enhance patient comfort and optimize endoscopist performance. Various sedation protocols, including Propofol and Dexmedetomidine (Pro-Dex), Ketamine and Propofol (Keto-Fol), Propofol and Midazolam (Pro-Mid), and Propofol alone, have been utilized during ERCP. This retrospective study aims to compare the safety and efficacy of these four sedation protocols.
A retrospective analysis was conducted on data from 600 patients who underwent ERCP between 2018 and 2021, with each patient receiving one of the four sedation protocols. Protocol assignment was based on the endoscopist's preference. Data on hemodynamic parameters, sedation level, recovery time, and procedure-related complications were collected.
Baseline data showed no significant differences among the groups pre-procedure. The Pro-Dex group exhibited significantly lower mean total propofol dose, shorter recovery time, and faster achievement of Ramsay Sedation Scale (RSS) score 3–4 compared to the other groups. The Pro-group demonstrated significantly longer hospital stay than the other three groups (median, 4.19 ± 1.1 vs. 3.48 ± 1.2 days in the KP groups, p = 0.042). There were no significant variations in the incidence of respiratory depression, hypotension, or bradycardia among the four groups. Additionally, notable trends were found for hemodynamic measures, total propofol dosage, time to reach the desired level of sedation (as measured by the Ramsay Sedation Scale), and hospital stay based on BMI categories, indicating that higher BMI is linked to more serious outcomes.
Our retrospective study demonstrates that the Pro-Dex protocol offers superior sedation quality, faster recovery, and fewer complications compared to the other protocols during ERCP. However, the incidence of ERCP-related adverse events did not significantly differ among the four sedation protocols. These findings can aid clinicians in selecting the most appropriate sedation protocol for ERCP, considering patient and endoscopist preferences.
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We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency department (ED) and ICU. We performed a systematic review and network meta-analysis to enable direct and indirect comparisons between available medications.
We searched Medline, EMBASE, Cochrane, and PubMed from inception to 2 March 2023 for RCTs comparing two or more procedural sedation and analgesia medications in all patients (adults and children >30 days of age) requiring emergent procedures in the ED or ICU. We focused on the outcomes of sedation recovery time, patient satisfaction, and adverse events (AEs). We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates.
We included 82 RCTs (8105 patients, 78 conducted in the ED and four in the ICU) of which 52 studies included adults, 23 included children, and seven included both. Compared with midazolam-opioids, recovery time was shorter with propofol (mean difference 16.3 min, 95% confidence interval [CI] 8.4–24.3 fewer minutes; high certainty), and patient satisfaction was better with ketamine-propofol (mean difference 1.5 points, 95% CI 0.3–2.6 points, high certainty). Regarding AEs, compared with midazolam-opioids, respiratory AEs were less frequent with ketamine (relative risk [RR] 0.55, 95% CI 0.32–0.96; high certainty), gastrointestinal AEs were more common with ketamine-midazolam (RR 3.08, 95% CI 1.15–8.27; high certainty), and neurological AEs were more common with ketamine-propofol (RR 3.68, 95% CI 1.08–12.53; high certainty).
When considering procedural sedation and analgesia in the ED and ICU, compared with midazolam-opioids, sedation recovery time is shorter with propofol, patient satisfaction is better with ketamine-propofol, and respiratory adverse events are less common with ketamine.
Dexmedetomidine versus propofol: An effective combination with ketamine for adult procedural sedation: A randomized clinical trial
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Recently, drug combination protocols have been preferred over single drugs in procedural sedation and analgesia (PSA). This study aimed to compare the effectiveness and hemodynamic profile of ketamine-dexmedetomidine (ketodex) and ketofol as drug combinations with ketamine as a single medication for PSA in the emergency department (ED).
This prospective, randomized, double-blind clinical trial was performed among adult patients (≥18 years) requiring PSA for a painful procedure in the ED. 135 patients were enrolled and assigned into three equal groups to receive either ketodex, ketofol, or ketamine. Additional ketamine was used as a rescue agent for inadequate sedation in three groups. Oxygen saturation, heart rate, and blood pressure were recorded from baseline until 120 min after induction of PSA. Adverse events, hemodynamic variables, induction, and recovery time were recorded and compared between groups.
The mean age of the patients was 38.16 ± 19.09 years and no differences were observed between the three groups in terms of demographic variables, pain scores, and procedures between the three groups. Respiratory events had similar incidences between the three groups. The O2 reduction was less in the Ketodex group in comparison with Ketofol and Ketamine groups (1.9%, 6.5%, and 3.8%, P = 0.015). No patient needed endotracheal intubation. Changes in mean arterial pressure from the baseline in Ketamine and Ketofol groups compared to Ketodex was higher (difference was 12.9 mmHg [95% CI, 9.5 to 20.3] and 8.6 mmHg [95% CI, 3.4 to 13.7]. Tachycardia in the Ketamine group had a significantly higher incidence. The recovery time was statistically shorter in the Ketofol group in comparison with other groups. The differences between Ketofol with Ketamine and Ketodex groups were 9.8 min (95% CI, [2.5 to 17.1]) and 8.3 min (95% CI, [1.5 to 15.1]).
Ketodex, as well as ketofol, were effective and safe combinations with good recovery profiles and hemodynamic stability for adult PSA in ED.
Evidence-based airway management protocol for a critical ill patient in medical intensive care unit: Systematic review
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Airway management outside the theatre is performed either to resuscitate a physiologically unstable critically ill patients or to secure an emergency airway in the absence of essential equipments. It is a life saving procedure for critically ill and injured patients. Delaying in securing airway or awaking the patient is not an option in case of difficult airway in intensive care unit. Therefore, developing and implementation of an evidence-based airway management protocol is important.
This review was conducted to develop a clear airway management protocol for a critical ill patient in medical intensive care unit.
After formulating the key questions, scope, and eligibility criteria for the evidences to be included, a comprehensive search strategy of electronic sources was conducted. The literatures were searched using advanced searching methods from data bases and websites to get evidences on airway management of a critical ill patient. Duplication of literatures was avoided by endnote. Screening of literatures was conducted based on the level of significance with proper appraisal. This review was carried out in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 statement.
A total of 626 articles were identified from data bases and websites using an electronic search. Of these articles, 95 were removed for duplication and 305 studies were excluded after reviewing their titles and abstracts. At the screening stage, 79 articles were retrieved and evaluated for the eligibility. Finally, 40 studies related to airway management of a critical ill patient in medical ICU were included in this systematic review.
A critical ill patient needs oxygenation and ventilation support. A focused and rapid assessment, with special attention of the airway and hemodynamic status of the critical ill patient is paramount. An appropriate airway management option should be employed to resuscitate or to control an emergency airway of a critical ill patent. This could be non invasive ventilation or invasive airway intervention.
Procedural Sedation With Dexmedetomidine in Combination With Ketamine in the Emergency Department
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Dexmedetomidine is an alternative agent for procedural sedation in the emergency department thanks to its ability to maintain hemodynamic and respiratory stability. Dexmedetomidine must, however, be combined with a powerful analgesic.
Our aim was to evaluate the quality and safety of procedural sedation using the combination of dexmedetomidine and ketamine for patients undergoing painful procedures in the emergency department.
This prospective interventional single-center study was conducted in an academic emergency department of an urban hospital in Brussels, Belgium. Patients received a bolus injection of 1 µg/kg dexmedetomidine over 10 min and then a continuous infusion of 0.6 µg/kg/h followed by a bolus of 1 mg/kg ketamine. The painful procedure was carried out 1 min later. The level of pain was evaluated with a numerical rating scale from 0 (no pain) to 10 (maximal pain). The level of patient comfort for the procedure was measured using a comfort scale.
Thirty patients were included. Overall, 90% of patients felt little or no pain (n = 29 of 30) or discomfort (n = 28 of 30) during the procedure. One patient experienced apnea with desaturation, which was resolved by a jaw-thrust maneuver. Although 23% of patients had significant arterial hypertension, none required drug treatment.
The combination of dexmedetomidine and ketamine provides conscious sedation, bringing comfort and pain relief to patients in optimal conditions for respiratory and hemodynamic safety. However, sedation and recovery times are longer than with conventional drug combinations. The dexmedetomidine–ketamine combination should therefore be recommended for nonurgent procedures and fragile patients.
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We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation.
We conducted a randomized clinical trial comparing the rapidity of onset, level of sedation, and adverse effect profile of ketamine compared to a combination of midazolam and haloperidol for behavioral control of emergency department patients with severe psychomotor agitation. We included patients with severe psychomotor agitation measured by a Richmond Agitation Score (RASS) ≥+3. Patients in the ketamine group were treated with a 5 mg/kg intramuscular injection. Patients in the midazolam and haloperidol group were treated with a single intramuscular injection of 5 mg midazolam and 5 mg haloperidol. The primary outcome was the time, in minutes, from study medication administration to adequate sedation, defined as RASS ≤-1. Secondary outcomes included the need for rescue medications and serious adverse events.
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: Provide feedback on this article at the journal’s Web site, www.annemergmed.com.

: A podcast for this article is available at www.annemergmed.com.

: Supervising editor: Steven M. Green, MD

: Author contributions: GA, RBA-L, and EW conceived the study. GA, RBA-L, PJZ, and EW performed the background literature review and designed the study. GA, SMS, SS, and SM supervised conduct of the trial and data collection. EW tabulated data and provided statistical analyses. GA drafted the article, and all authors contributed substantially to its revision and approved the final version of the article. GA takes responsibility for paper as a whole.

: Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). Dr. Andolfatto is supported by a Vancouver Coastal Health Research Institute Mentored Clinical Scientist Award (FAS # F09-05828).

: Earn CME credit: Continuing Medical Education is available for this article at http://www.ACEP-EMedHome.com.

: Please see page 505 for the Editor's Capsule Summary of this article.

: Publication date: Available online March 7, 2012.

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Pain management and sedation/original researchKetamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia: A Randomized Double-Blind Trial

Study objective

Methods

Results

Conclusion

Introduction

Section snippets

Study Design

Setting and Selection of Participants

Characteristics of Study Subjects

Limitations

Discussion

Ann Emerg Med

Emerg Med Clin North Am

Am J Emerg Med

Br J Anaesth

Am J Emerg Med

Ann Emerg Med

Ann Emerg Med

Int J Pediatr Otorhinolaryngol

J Cardiothorac Vasc Anesth

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

J Emerg Nurs

Procedural sedation and analgesia in the emergency department

J Pharm Pract

Ketamine—its pharmacology and therapeutic uses

Anesthesiology

Hemodynamic effects of propofol: data from over 25,000 patients

Anesth Analg

Sub-dissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial

Acad Emerg Med

Randomized clinical trial of propofol with and without alfentanil for deep procedural sedation in the emergency department

Acad Emerg Med

The surgical stress response, preemptive analgesia, and procedural sedation in the ED

Acad Emerg Med

Comparison of propofol-fentanyl with propofol-fentanyl-ketamine combination in pediatric patients undergoing interventional radiology procedures

Paediatr Anaesth

Propofol⧸alfentanyl and propofol/ketamine procedural sedation in children with acute lymphoblastic leukaemia: safety, efficacy and their correlation with pain neuromediator expression

Eur J Cancer Care

Combining ketamine and propofol (“ketofol”) for emergency department procedural sedation and analgesia: a review

West J Emerg Med

Propofol and propofol-ketamine in pediatric patients undergoing cardiac catheterization

Pediatr Cardiol

Pain management and sedation/original research
Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia: A Randomized Double-Blind Trial