Hayes J.A. et al. Published online ahead of print, 2020 Jul 7. Anesth Analg.
The numbers of procedural sedation for medical procedures in children have increased during the past decade, facilitating procedures such as lumbar punctures, fracture reductions, and upper gastrointestinal tract endoscopies. Ketamine and propofol, either alone or in combination are commonly used. To evaluate the combination of these medications, also known as “ketofol”, Hayes et al. conducted a systematic review and meta-analysis of the combination of propofol and ketamine for procedural sedation in children.
Hayes et al. conducted a comprehensive search of multiple databases for relevant studies from database inception to March 2019, as well as the reference lists of the review articles. Articles for additional trials not identified by the electronic search of the primary databases were also included. They evaluated parallel-group randomized controlled trials of pediatric patients who required sedation or general anesthesia to undergo diagnostic or therapeutic procedures with ketofol and comparator of any other kind of sedative/analgesic. The search yielded 3430 citations and 29 trials eligible for inclusion. Study personnel independently rated the overall quality of evidence for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Also, studies were assessed for the ratio of propofol to ketamine as low ratio (≤3:1) versus high ratio (>3:1). For primary analysis, study compared ketofol to a comparator group consisting of single or combinations of sedatives. Subgroup analysis compared ketofol to single or combinations of sedatives, depending on the outcome assessed.
Primary outcomes were clinically significant hemodynamic and respiratory adverse events with or without the need for intervention. Secondary outcomes were the incidence and/or severity of important adverse events, such as nausea and/or vomiting and dysphoria/hallucinations or emergence delirium during the recovery phase, pain on injection of study medications, etc.
In this systematic review and meta-analysis, the authors suggested that ketofol in comparison to the comparator group (that included all single and combinations of sedatives) likely results in a lower risk of hypotension (RR 0.52, 95% CI, 0.37–0.73; P = .0001) and possibly bradycardia (RR 0.61, 95% CI, 0.38–0.98; P = .04), most likely due to sympathomimetic effect of ketamine.
Results also showed that when compared to the comparator group, ketofol has minimal to no effect on the risk of apnea (RR 0.71, 95% CI, 0.37–1.35; P = .29) and desaturation (RR 0.92, 95% CI, 0.68–1.25; P = .60) but a slightly increased risk of other respiratory events, such as coughing and laryngospasm (RR 1.74, 95% CI, 1.07–2.83; P =.02). The authors explained that the reduction in apnea with ketamine and/or dexmedetomidine compared to ketofol suggests that the addition of propofol to ketamine, even in a ratio of ≤ 3:1, minimizes the beneficial effects of ketamine on airway tone and respiratory drive.
There was no difference for nausea/vomiting and emergence agitation between the ketofol and comparator group (RR 0.83, 95% CI 0.52 to 1.34; P=0.45), but subgroup comparisons confirmed a lower risk of nausea and/or vomiting with ketofol compared to ketamine and/or dexmedetomidine (RR 0.48, 95% CI 0.23 to 0.99; P=0.03) which could be explained by propofol’s antinausea and antidelirium effects.
There was a reduction in risk with ketofol compared to the propofol-alone subgroup for the pain with intravenous administration (RR 0.18, 95% CI 0.08 to 0.38; P<0.00001) which may be explained by the local anesthetic effect of ketamine.
Even though the study included an extensive database search and use of GRADE to evaluate the confidence in the estimates, not restricting the comparator group to one consistent sedative or combination of sedatives, or the trials to one specific procedural intervention is likely the reason for the moderate to high degree of heterogeneity for some of the outcomes evaluated. Therefore, any results reported from comparing ketofol to the aggregate comparator group should be interpreted with caution given the degree of heterogeneity observed, and that the more specific subgroup comparisons be evaluated for a better understanding of how ketofol compares to each of these different regimens.