A Prospective Case Series of Pediatric Procedural Sedation and Analgesia in the Emergency Department Using Single-Syringe Ketamine-Propofol Combination

The above mentioned article describes a prospective case series evaluating the effectiveness, recovery time and adverse events associated with intravenous (IV) ketofol  (mixed 1:1 ketamine-propofol) for emergency department (ED) procedural sedation and analgesia (PSA) in children. Multiple previous studies have shown the effectiveness of achieving moderate to deep sedation using propofol alone. In addition, propofol is short acting and has unique anti-emetic qualities. The mean doses, as reported in the literature, required for sedation with propofol alone ranges from 2.8 – 3.5 mg/kg. However, as a pure sedative with no analgesic qualities, propofol has most often been combined with a narcotic analgesic, such as fentanyl and alfentanyl, when used for painful procedures.

The main concern with propofol, with or without analgesics, is dose-dependent respiratory depression and hypotension. Ketamine, on the other hand, has the unique qualities of providing analgesia at low doses and very predictable “dissociation” at higher doses (typically greater than 1.0 – 1.5 mg/kg/IV).  The main concerns with the use of ketamine is emesis (reported to be 8.4% in a recent meta-analysis), clinically important recovery agitation (reported to be 1.4% in a previous study), and laryngospasm (1.4% reported in a recent meta-analysis). The study rational was that the combination of ketamine and propofol would be beneficial in that the sedative effects of propofol would balance the nauseant and psychometric effects of ketamine. In addition, the combination would be both effective and safe in producing deep sedation for painful procedures due to the lower doses required compared to the use of either agent alone.

Of the 219 children given this combination, sedation was deemed effective by the treating physicians and nurses in all of the patients.  However, there was no objective measure of the depth of sedation, so it is unclear the true depth of sedation achieved in each patient. The median dose of ketofol was 0.8 mg/kg (range 0.2 to 3.0 mg/kg), with 96% receiving less than 1.5 mg/kg of each drug. This is less than the median dosages normally required to achieve deep sedation with either agent alone. With respect to recovery time, children receiving this medication had a median recovery time of 14 minutes (range 3 to 41 minutes), which is longer than the reported recovery time of propofol alone but shorter than that of ketamine alone (25-103 minutes reported in previous studies).  Emesis did not occur in any of the patients, emergence phenomena requiring intervention occurred in two patients (0.9%), and airway interventions were required in 3 patients (1.4%, but none requiring endotracheal intubation).

Limitations

1) There was no objective measurement of depth of sedation; 2) The mean age was 13 years, with only 10% of patients under 2 years of age receiving ketofol, so the effectiveness and safety in patients under 2 years of age remains uncertain; 3) The majority of the patients had two Emergency Department Physicians (EDPs) present for the procedures, which may not be practical in other settings. As such, no definitive conclusions with respect to improved ED flow or reduced costs can be drawn from this study.; 4) This was not a randomized trial so, based on this study alone, no definitive conclusions can be made as to the improved efficacy of achieving adequate sedation of ketofol over other medications or combinations of medications, including ketamine alone, propofol alone or propofol with an opiode. There is also no mention of the relative and absolute contraindications of the use of dissociative doses of ketamine, especially active bronchospasm, airway abnormalities, increased intra-ocular pressure or increased intra-cranial pressure. As such, no definitive conclusions as to the improved efficacy of achieving adequate levels of sedation when using of ketofol over ketamine alone, or  ketamine with other agents. As such, larger, multi-centered randomized trials are needed to support any conclusions as to the improved efficacy of this combination of medications; 6) The study is underpowered to draw definitive conclusions with respect to rare, but serious, adverse events.

Conclusions

1) In children over the age of 2 years of age, ketofol (mixed 1:1 in a single syringe), appears to be an effective combination in achieving adequate sedation for orthopedic procedures and lacerations (together accounting for 87% of the patients given ketofol in this study); 2) In this small cohort, serious airway events in children over 2 years of age seem to be rare and comparable to other regimens utilizing propofol and ketamine; 3) Vomiting occurs less often with ketofol compared to historical controls that were sedated with ketamine; 4) Hypotension occurs less often with ketofol compared to historical controls sedated with propofol; 5) The median recovery time is faster with ketofol compared to ketamine.

Contribute to the Discussion

Your experience and comments play an important role in understanding the clinical implications of this article.  Please take a few minutes to comment on your experience or express your opinion on the clinical utility of ketofol.

Invited Commentary By:

Robert G. Flood, MD

Director, Pediatric Emergency Medicine

Cardinal Glennon Children’s Hospital

Reference

Academic Emergency Medicine 2010; 17:194–201

2 thoughts on “A Prospective Case Series of Pediatric Procedural Sedation and Analgesia in the Emergency Department Using Single-Syringe Ketamine-Propofol Combination

  1. Joe Cravero

    This study adds to the collected experience with “ketofol” and as such is helpful for those who are considering the use of the drug. Several aspects of the study are worth noting for those who are considering the use of this medication for procedural sedation in the future. It might first be important to note that terminology is difficult in any study involving deep sedation with combinations of drugs such as is used here. The authors prefer the term “procedural sedation” – as is common in emergency medicine circles. When ketamine and propofol are combined many pediatricians and anesthesiologists would term the results deep sedation or anesthesia (no response to painful stimulation). In this study the authors do not report depth of sedation so it is not possible to know which of these patients would meet these other commonly used definitions of depth of sedation/anesthesia. Other issues that might be considered when reading this study and considering its results include:

    1. The relative doses of ketamine and propofol in “Ketofol” preparations varies from study to study. In this case the mixture was 1:1 for the dose in milligrams. This is a bit higher for the dose of ketamine than has been used in some other studies of this combination.
    2. There is no information given in the study on how the combination was mixed or exactly when it was mixed relative to when the sedation was given – and no information offered on the stability of this mixture. Given the fact that many of the preparations of propofol now available do not have any preservatives, there is increasing concern about possible contamination of this drug. Pharmacologists also are concerned about the use of drug mixtures that have not been tested for stability and compatibility. For instance, do the drugs interact in a way that decreases the potency of one or the other over time? Do the drugs “layer out” over time – and is the relative percentage of each drug the same from the bottom to the top of the syringe over time? When making up a combination like this, it is best to be sure it is used right away – and check with your hospital rules about self-mixing of drugs for administration to patients such as is described in this study.
    3. Each sedation was attended by at least one physician – and 80% were attended by 2 physicians. Apparently a nurse was also present and a respiratory therapist was in attendance at each encounter. This is a significant investment in personnel and expertise. The excellent safety outcomes reported in this study should be considered in this light – those without this number of trained providers at each procedural sedation encounter should noy extrapolate their own potential experience to these outcomes.
    4. Unfortunately there is little information on the specific training of the individuals who provided the sedation/anesthesia – personal communication is described.
    5. The timing of the dosing of the medication and the absolute dose delivered were left up to the discretion of the treating physician. The median dose was 0.8mg/kg for each drug but the range was from 0.2mg to over 3mg/kg. In addition, the use of pretreatment opioids was up the discretion of the treating physician. As such it is impossible to describe a protocol for giving this medication combination from the data in this study – essentially individual judgment guided the therapy and, as the authors note, there could be a lot of selection bias in terms of who might have been eliminated from consideration.
    6. “Successful” sedation in this study was defined as conditions where the treating physician did not feel it was necessary to give more medication. It is very hard to know what this means since some providers might tolerate movement or vocalizations and others might not. The actual state of the patient during the procedure is unknown.
    7. As has been pointed out by the review of this paper and the authors in the original manuscript, the age of the patients involved here was primarily late childhood and adolescence. As such the data is not applicable to toddlers and younger patients.
    8. While 219 patients are more than previously reported, it is a small number when one considers that truly worrisome events during sedations in relatively well patients should be extremely rare. The study is observational and underpowered to address safety issues.
    9. Recovery times were described as “short” – lasting less than 30 minutes in almost all cases. Unfortunately we are not informed of the duration of the procedures in this study. To be fair, duration of recovery can only be considered meaningful if we understand the duration of the sedation. For instance, if the procedures lasted only 3 minutes a 20 minute recovery is (perhaps) “good” but not outstanding. On the other hand if the procedures lasted an hour, a 30 minute recovery would be excellent. It is impossible to really compare the performance of Ketofol as delivered in this study without more information of the duration of the procedure.

    Joe Cravero

  2. Sue Kost MD

    I am a fan of this combination based on a personal case series of probably close to 100 patients, but my preference is to titrate the agents individually on an “as-needed” basis, rather than the “all-in-one-syringe” technique. I’m a PEM doc by training who works on a sedation service. Most of my ketamine-propofol combo experience has been in the interventional radiology world, where I use propofol for the prep and planning stages (drapes, initial imaging, getting the trays ready, etc.) and then push a little ketamine for the painful parts (local anesthetic, puncture of the peritoneum, etc.). Seems to work very well, but I agree that we could use more objective data, especially in younger kids.

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