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Study objectiveAlthough ketamine is one of the most commonly used sedatives to facilitate painful procedures for children in the emergency department (ED), existing studies have not been large enough to identify clinical factors that are predictive of uncommon airway and respiratory adverse events. MethodsWe pooled individual-patient data from 32 ED studies and performed multiple logistic regressions to determine which clinical variables would predict airway and respiratory adverse events. ResultsIn 8,282 pediatric ketamine sedations, the overall incidence of airway and respiratory adverse events was 3.9%, with the following significant independent predictors: younger than 2 years (odds ratio [OR] 2.00; 95% confidence interval [CI] 1.47 to 2.72), aged 13 years or older (OR 2.72; 95% CI 1.97 to 3.75), high intravenous dosing (initial dose ≥2.5 mg/kg or total dose ≥5.0 mg/kg; OR 2.18; 95% CI 1.59 to 2.99), coadministered anticholinergic (OR 1.82; 95% CI 1.36 to 2.42), and coadministered benzodiazepine (OR 1.39; 95% CI 1.08 to 1.78). Variables without independent association included oropharyngeal procedures, underlying physical illness (American Society of Anesthesiologists class ≥3), and the choice of intravenous versus intramuscular route. ConclusionRisk factors that predict ketamine-associated airway and respiratory adverse events are high intravenous doses, administration to children younger than 2 years or aged 13 years or older, and the use of coadministered anticholinergics or benzodiazepines. Article Outline• Abstract • Data Collection and Processing • Results • Characteristics of Study Subjects • Appendix SEE EDITORIAL, P. 169. Introduction BackgroundThe efficacy and safety of ketamine to facilitate painful procedures for children in the emergency department (ED) have been documented in 57 published series totaling nearly 10,000 patients.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 This dissociative agent is the most commonly used sedative in the United States for this indication.58, 59, 60, 61, 62, 63, 64 Airway and respiratory adverse events occur in 1.4% to 6.6% of ketamine sedations,2, 19 including laryngospasm in approximately 0.4%.2 Given the rarity of these airway events, previous investigations have, because of their small size, been unable to determine whether they are related to ketamine dose, administration route, or coadministered drugs (eg, anticholinergics, benzodiazepines) or whether they are related to patient variables such as age or underlying illness.55 Editor's Capsule SummaryWhat is already known on this topic Ketamine is commonly used for pediatric sedation. Although its complications are well known, their frequency and the factors that predispose patients to complications are not. What question this study addressed This 8,282 individual-patient (32 reports) meta-analysis summarizes complications of ketamine use and their association with patient demographics and characteristics of the sedation procedure. What this study adds to our knowledge The study suggests that respiratory and airway events are more common in teenagers and infants younger than 2 years, those receiving higher intravenous doses, and those receiving concurrent benzodiazepines or anticholinergics. How this might change clinical practice Physicians using ketamine for sedation may want to rethink their intravenous dosing strategy and their use of concurrent benzodiazepines or anticholinergics. ImportanceIf specific differences in ketamine technique or patient variables are predictive of airway adverse events, then emergency physicians may elect to modify their administration technique or patient selection to minimize such adverse events. Goals of This InvestigationWe pooled original data from all available series of ED ketamine sedation in children to identify clinical predictors of airway and respiratory adverse events. Secondary goals were to perform similar analyses for the subsets of children with laryngospasm and apnea. Materials and MethodsStudy DesignWe performed a meta-analysis in accordance with Quality of Reporting of Meta-analyses (QUOROM) guidelines65 of all available original data from existing ketamine case series. All included trials had local ethics committee approval. We searched the PubMed electronic database for articles of any language published between 1966 and May 2008, using the key words “ketamine” and “emergency.” The reference lists of identified articles were examined for additional studies missed by the MEDLINE search. Finally, we contacted authors of identified ketamine series to determine whether they were aware of other reports missing from our listing. We included full-length reports that contained a discrete series of parenteral ketamine administrations in children (defined as age ≤21 years) for ED procedural sedation. We excluded abstracts, case reports, case-control studies, series with fewer than 20 subjects, and series in which the individual patient data did not include doses and adverse effects or had been discarded by their study authors. We also excluded reports in which propofol was coadministered because the latter drug is a more potent respiratory depressant63, 64 than the more commonly coadministered midazolam and might confound the analysis of airway adverse events. Data Collection and ProcessingWe contacted study authors of qualifying reports and asked them to submit their original data in electronic format to a central repository, with their submission stripped of all patient identifiers and restricted to the variables selected for the meta-analysis. Authors were queried about any missing data points and were asked to recode their variables as needed to comply with our study definitions. Outcome MeasuresThe primary outcome for this study was the overall occurrence of airway and respiratory adverse events, with secondary outcomes the specific occurrence of laryngospasm and apnea. We defined airway/respiratory adverse events as an occurrence of any of the following: upper airway obstruction (stridor, hypoventilation, or oxygen desaturation that resolved with repositioning of the airway), apnea (cessation of spontaneous respirations considered to be significant by observers and recorded as such), abnormal oxygen saturation (decrease in oxygen saturation to ≤90% at any point), or laryngospasm (stridor or other evidence of airway obstruction that did not improve with airway alignment maneuvers). Candidate predictor variables were selected according to previous literature and biological plausibility of association with airway adverse events. The ketamine technique variables chosen were route (coded as intravenous versus intramuscular), initial dose (in mg/kg), total dose (in mg/kg), the presence or absence of coadministered anticholinergics (eg, atropine, glycopyrrolate), and the presence or absence of coadministered benzodiazepines (eg, midazolam, diazepam). The patient variables chosen were age, American Society of Anesthesiologists (ASA) physical status,63, 64 and oropharyngeal procedural indication (coded as present versus absent). Primary Data AnalysisWe examined the frequency distributions for the continuous variables, and if their distributions were found to be bimodal the variables were instead dichotomized at logical thresholds. We performed separate multiple logistic regression analyses for each of the 3 outcomes (ie, airway and respiratory adverse events, laryngospasm, apnea). For each multivariate analysis, we restricted the number of predictor variables to approximately 10% of the number of airway and respiratory event outcome observations to minimize the risk of overfitting, in accordance with standard recommendations.66, 67, 68, 69 We used this a priori approach according to our judgment of the highest biological plausibility of association. We calculated the likelihood ratios and area under the receiver operating characteristic curve for each model and performed goodness-of-fit analyses with the Hosmer-Lemeshow test. All such analyses were performed with Stata 9 software (StataCorp, College Station, TX). Because of concerns about potential underreporting of adverse events in retrospective research, we also performed mirrored analyses by using just the subset with prospectively obtained data. Our a priori intent was that if the prospective subset analyses disagreed from their overall counterparts, then the prospective subsets would be deemed the more reliable, given their stronger methodology. If the prospective subset analyses agreed with their overall counterparts, then the overall analysis would be considered reliable. ResultsThe results of the literature search and article processing are shown in Figure 1. Data from 32 reports were ultimately included (Table 1), comprising 8,353 aggregate ketamine sedations. We then excluded 71 individual sedations (0.85%) from the overall database for the following reasons: missing total ketamine dose (n=47), missing documentation of benzodiazepine use (n=12), use for intubation rather than procedural sedation (n=10), missing age (n=1), and age greater than 21 years (n=1). There were no airway or respiratory adverse events in this excluded group.
Characteristics of Study SubjectsCharacteristics of the 8,282 remaining sedations are shown in Table 2. The overall rate of airway or respiratory adverse events was 3.9%, including 0.3% with laryngospasm and 0.8% with apnea. No children were intubated or received paralytics in the management of these adverse events, and the 95% confidence interval of this 0% incidence ranges up to 0.04%.
When we examined the frequency distributions for the outcomes stratified by age, we visually observed bimodal distributions (Figure 2). Accordingly, rather than using age as a continuous variable, we divided it into 3 groups according to the figure and compared children younger than 2 years and aged 13 years or older to the reference group of those in between.
Initial ketamine dose was not collected in 5 studies10, 11, 12, 20, 32 comprising 1,536 sedations (18.5%). As with age, the frequency distributions for outcomes stratified by initial and total dose (Figure 3, Figure 4, Figure 5, Figure 6) were also not log-linear and therefore not appropriate for retention as continuous variables. They also differed between intramuscular and intravenous routes, with an apparent threshold at the lower end of intramuscular dosing and at the higher end of intravenous dosing. Accordingly, we divided dose into 3 groups and compared those with low intramuscular dosing (total dose <3.0 mg/kg) and those with high intravenous dosing (initial dose ≥2.5 mg/kg or total dose ≥5.0 mg/kg) to the reference group of the remainder.
The type of procedure was missing in 43 (0.5%) sedations, and given that oropharyngeal procedures were unusual in the overall data set (3.4%), we coded these missing entries as nonoropharyngeal. Coadministered anticholinergic use was not recorded in 322 sedations (3.9%) in one study12; however, because the practice pattern at this institution during this period was to administer anticholinergics, we coded these as positive. Given that multiple studies coded ASA physical status as either class 1 or 2, we dichotomized this variable as ASA 1 or 2 versus ASA greater than or equal to 3. ASA status was missing in 10 cases from a single study,25 and because this author believed that these children were almost certainly ASA 1 or 2, we coded them in this fashion. Unadjusted comparisons of predictor variables by outcome are shown in Appendix E1, Appendix E2, Appendix E3 (available online at http://www.annemergmed.com). The final predictor variable list thus included no continuous variables, 2 three-part categorical variables (age and dose), and 5 binary variables (route, oropharyngeal procedure, ASA, anticholinergic, benzodiazepine). The number of total outcomes was sufficient to include all predictor variables for total airway and respiratory adverse events and for apnea, but not for laryngospasm. Given only 22 occurrences of laryngospasm, before data analysis we selected the 3 variables that we judged to have the highest biological plausibility of association: age, dose, and oropharyngeal procedure. The multiple logistic regression analyses are shown in Table 3, Table 4, Table 5 for the total sample and for the prospective subset, demonstrating multiple significant independent predictors for each outcome.
Given the unexpected association of anticholinergics with airway and respiratory adverse events and a known potentially confounding influence of age on this factor,31 post hoc we repeated our analyses, adjusting for age as a continuous rather than categorical variable, but again confirmed this same outcome (data not shown). Given the unexpected higher rate of airway and respiratory adverse events in children aged 13 years or older, post hoc we contrasted dosing by the presence or absence of airway and respiratory adverse events in this subset and overall dosing by age strata. We found similar dosing between groups (Appendix E4, available online at http://www.annemergmed.com) and that clinicians used lower doses on a milligram per kilogram basis with increasing age, particularly for the intravenous route (Appendix E5; available online at http://www.annemergmed.com). LimitationsThe principal limitation of this report is the heterogeneity of the collated studies and the observational nature of the data. Although the studies are similar in that they include children receiving ketamine for ED procedures, there is substantial variation in procedural indications, ages, doses, and other clinical variables, as might be expected from 32 studies coming from multiple countries. As shown in Table 1, there were differences in the rates of outcome measures between studies; these may have resulted from heterogeneity in practice style or adverse event surveillance or may be due to chance alone. It is possible that 1 or 2 larger studies with an unusual experience might have biased the overall analysis. Similarly, individual clinician practice variation in children judged at higher or lower risk of airway and respiratory adverse events may have affected the observed associations. Unfortunately, the direction and magnitude of these effects, if present, cannot be ascertained. Alternatively, this same diversity could be argued as a major strength of the analysis because our findings are likely to have substantial external validity, given the wide spectrum of collective input. A second limitation is that our multivariate modeling did not fit the data as strongly for overall airway and respiratory adverse events as it did for the subsets with laryngospasm and apnea. Accordingly, our findings for the overall group are likely less reliable than for the 2 subsets. We believe that this reflects the multiple types of adverse events studied (eg, partial airway obstruction, respiratory depression, laryngospasm, apnea) that are clinically distinct and influenced by differing factors. This suggests that future research should target specific individual adverse events rather than combining them into a heterogenous global category. A third limitation is that we were unable to study several important clinical variables because of their inconsistent recording in the collated studies. The use of supplemental oxygen might be expected to affect the incidence of hypoxemia. The presence of underlying upper respiratory infection, wheezing, or excessive salivation would be expected to increase the risk of laryngospasm.70 Coadministered opioids may increase the risk of apnea. Differential dosing of benzodiazepines or anticholinergics might result in different effects. Specific underlying medical conditions (eg, sleep apnea, snoring) may have influenced the outcomes. Length of procedure may have influenced the association between doses and adverse events. Unfortunately, our data cannot shed light on these factors. A fourth limitation relates to the weaknesses inherent in multiple logistic regression modeling. Some variables required dichotomization because they did not meet the distributional requisites of the technique, and it is possible that our choice of dichotomization thresholds affected the results in a direction that cannot be predicted. Further, there may have been nonindependence of the variables or interaction among variables that was not accounted for by the models. A final limitation is that the a priori definitions of adverse events were not uniform throughout the studies. Although we asked authors to recode their data as appropriate to conform to our meta-analysis definitions, there may be some under- or overreporting of adverse events according to these differences. DiscussionIn this original-data meta-analysis of 8,282 sedations collated from 32 previously published series, we report the largest ED ketamine sample to date. In contrast to a previous study of 1,021 children that failed to identify any significant predictors of ketamine-associated airway and respiratory adverse events,55 our much larger study identified multiple independent predictors of such events. Clinicians can use these findings to modify their patient selection, dosing, and use of coadministered medications. Furthermore, these results provide insight into the possible underlying pathophysiology of ketamine sedation adverse events. Our data confirm the established thinking that overall airway and respiratory adverse events are more common in the youngest children60 because we observed approximately twice the rate of such events in those younger than 2 years. However, this age threshold was not a predictor for the subsets of children with laryngospasm or apnea, and thus this overall observed effect would appear to principally result from other airway adverse events such as partial airway obstruction. This is not unexpected, given the anatomic differences in infants relative to older children that predispose them to airway malalignment. An unexpected finding in this analysis was that age greater than or equal to 13 years predicted more apnea, less laryngospasm, and almost 3 times the rate of overall airway and respiratory adverse events. Adolescence has not been previously suggested as such a risk factor, and an underlying explanation for this finding is not apparent. One possibility that we considered was that clinicians might continue to use milligram per kilogram dosing in this age group when instead a fixed adult-style dose may be more appropriate; however, doses were no higher in adolescents with airway and respiratory adverse events (Appendix E4, available online at http://www.annemergmed.com), and clinicians were already using lower milligram per kilogram dosing in this age range, particularly for the intravenous route (Appendix E5, available online at http://www.annemergmed.com). We found that high intravenous doses of ketamine (initial dose ≥2.5 mg/kg or total dose ≥5.0 mg/kg) increased by several-fold the risk of airway and respiratory adverse events, primarily through an increase in apnea. Lower loading doses (eg, 1.5 mg/kg intravenous60) produce satisfactory dissociation and procedural conditions, and thus there is no clinical advantage to using such large initial doses. The higher rate of adverse events associated with high total ketamine doses may reflect the enhanced cumulative risk from multiple, repeated doses of this drug. We found that low intramuscular doses of ketamine (<3.0 mg/kg) exhibited significantly fewer overall airway and respiratory adverse events, a finding at odds with a previous study that observed no such difference.54 There were no occurrences of either laryngospasm or apnea in the 682 children receiving lower dosing. This strongly supports the contention of McGlone et al18 that low intramuscular dosing is likely to be the safest overall format for ED ketamine. Such dosing is typically below the threshold of clinical dissociation60 and thus is suitable only for minor procedures requiring only analgesia and anxiolysis or minor procedures using local anesthesia. This apparent advantage of subdissociative dosing appears to apply only to the intramuscular route because we observed no apparent decrease in airway adverse events with roughly equipotent intravenous ketamine (<1 mg/kg) (Figure 5, Figure 6). Other than the 2 dosing subgroups identified above (high intravenous dose, low intramuscular dose), we found no other apparent association of ketamine dose to airway and respiratory adverse events (Figure 3, Figure 4, Figure 5, Figure 6). This is in marked distinction to other parenteral procedural sedation agents (eg, opioids, sedative/hypnotics) in which proportional dose-related increases in such events are evident over the full spectrum of doses administered.63, 64 This suggests that, as long as excessively high intravenous doses are avoided, emergency physicians may use doses such as 2 mg/kg intravenously rather than 1 mg/kg intravenously, or 5 mg/kg intramuscularly rather than 3 mg/kg intramuscularly, without increased risk of adverse events. Oropharyngeal procedures are thought to increase the risk of ketamine-associated airway adverse events.60, 71 Laryngospasm has been observed in 8.2% of children when ketamine is used for endoscopy.71 We observed conflicting results for this factor. Despite significant unadjusted associations and prediction in the overall multivariate models, this factor was not a significant predictor in the more reliable prospective subset of the data (Table 3, Table 4, Table 5). Typical ED oropharyngeal procedures involve substantially less throat stimulation than endoscopy, and this difference likely explains the lack of additional risk evident from our data. With all nondissociative agents, the risk of adverse events is thought to be proportional to the degree of underlying physical illness, as is typically quantified by using the ASA physical status classification.63, 64 Such an association has not been similarly observed with ketamine,55, 71, 72 and the cardiopulmonary support characteristic of this drug may make it preferable to other sedatives in children with substantial underlying illness.60 Our data support this latter premise because ASA class greater than or equal to 3 was not associated with any significantly greater risk of airway and respiratory adverse events. Of the 92 such children with higher ASA status, there were no occurrences of apnea and only 1 occurrence of laryngospasm. The relative safety of ketamine by the intravenous or intramuscular route has been a source of debate27, 60, 73 and has been studied in 1 controlled trial.27 Although our unadjusted comparisons demonstrate an increased risk of airway and respiratory adverse events with the intravenous route relative to intramuscular, this effect was no longer significant when controlling for other variables, including the use of high intravenous dosing. Thus, as long as high intravenous dosing is avoided, our data suggest similar risk between these 2 routes of administration. The coadministration of atropine or glycopyrrolate has traditionally been recommended with ketamine to mitigate hypersalivation and its associated risk of airway and respiratory adverse events.60 Despite this, some emergency physicians regularly omit such adjunctive therapy without apparent problem.31 Indeed, an anticholinergic was used in only 65% of children in the current aggregate sample. A surprising finding in our study was that overall airway and respiratory adverse events (but not the subsets of laryngospasm or apnea) were significantly higher—not lower—in the group receiving concurrent anticholinergics. This was true in both the simple comparison and after adjusting for the other variables, with all findings unequivocal. Given the potential confounding influence of age on this factor,31 we repeated our analyses, adjusting for age as a continuous rather than categorical variable, but again confirmed this same outcome. We are unable to explain the basis for this paradoxic result, which is the opposite of conventional wisdom. Regardless, our data are statistically robust and do not support the regular or routine use of such adjunct agents. Two ED randomized controlled trials of ketamine with and without midazolam have shown no measurable benefit to such adjunctive therapy to prevent emergency reactions,6, 52 and one of the 2 showed greater oxygen desaturation with midazolam.52 Our data strongly support the concept that overall airway and respiratory adverse events, particularly apnea, are significantly more frequent when benzodiazepines are coadministered. Although it is possible that some subsets of children may benefit from prophylactic benzodiazepines,74 there are currently no criteria to identify these children. In summary, risk factors for ketamine-associated airway and respiratory adverse events are high intravenous doses, administration to children younger than 2 years or aged 13 years or older, and the use of coadministered anticholinergics or benzodiazepines. Such risk is not independently altered by route (intravenous versus intramuscular), oropharyngeal procedures, or underlying physical illness. This information can be used to help risk-stratify children before ED sedation and guide ketamine administration technique. Our data do not support the regular or routine use of anticholinergics or benzodiazepines, although the effect of these agents on emesis and unpleasant recovery reactions was not studied. AppendixIn addition to the authors listed at the beginning of the article, the following investigators and institutions participated in this study. Department of Emergency Medicine, Akdeniz University School of Medicine, Antalya, Turkey: Cem Oktay; Department of Emergency Medicine, Queens Elizabeth II Hospital, Hertfordshire, UK: J. P. Saetta, MD, Victoria Holloway, MD; Emergency Department, Princess Margaret Hospital for Children, Perth, Australia: Peter Heinz, MD; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX: Alan H. Bleiberg, MD; Department of Paediatrics, Starship Children's Hospital, Auckland, New Zealand: David Herd, BSc, MBChB; Division of Pediatric Emergency Medicine, LeBonheur Children's Medical Center, Memphis, TN: Sandip A. Godambe, MD, PhD, Jay Pershad, MD; Division of Emergency Medicine, St. Louis Children's Hospital, Washington University, St. Louis, MO: Jan D. Luhmann, MD, Robert M. Kennedy, MD; Department of Emergency Medicine, Ellis Hospital, Schenectady, NY: Robert J. Dachs, MD; Sunshine Hospital, Melbourne, Australia: Stephen J. Priestley, MD; Department of Emergency Medicine, Royal Children's Hospital, Brisbane, Australia: Jason P. Acworth, MD.
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Ann Emerg Med. 2000;35:297–299. Abstract | Full Text | Full-Text PDF (20 KB) | CrossRef a Department of Emergency Medicine, Loma Linda University Medical Center and Children's Hospital, Loma Linda, CA b Department of Pediatrics, University of Minnesota, Minneapolis, MN c Division of Emergency Medicine, Children's Hospital and Harvard Medical School, Boston, MA d Royal Lancaster Infirmary, Lancaster, UK e Division of Emergency Medicine, Children's National Medical Center, Washington, DC f Division of Emergency Medicine, Boston Medical Center, Boston, MA g Department of Anaesthesia, University Children's Hospital, Zurich, Switzerland h Division of Pediatric Emergency Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA i Department of Pediatrics, University of Chicago, Chicago, IL j Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO k Emergency Department, Royal Darwin Hospital, Darwin, Northern Territory, Australia l Division of Emergency Medicine, Miami Children's Hospital, Miami, FL m Department of Pediatrics, Medical University of South Carolina, Charleston, SC
Provide feedback on this article at the journal's Web site, www.annemergmed.com. Supervising editors: Kathy N. Shaw, MD, MSCE; Michael L. Callaham, MD. Drs. Shaw and Callaham were the supervising editors on this article. Dr. Green did not participate in the editorial review or decision to publish this article. Author contributions: SMG conceived and designed the study. The methodology was critiqued and revised with extensive input from MGR, BK, LB, DA, RDP, JEW, and GT. All authors reviewed and recoded their data to comply with study definitions, and before data analysis the study protocol was critiqued and refined by all authors. SMG performed the data analysis, and a writing committee composed of SMG, MGR, and BK then created the article. All authors critiqued the draft, and there were substantial revisions. SMG takes responsibility for the 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 that might create any potential conflict of interest. The authors have stated that no such relationships exist. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Earn CME Credit: Continuing Medical Education is available for this article at: www.ACEP-EMedHome.com. Publication date: Available online February 7, 2009. Reprints not available from the authors. PII: S0196-0644(08)02084-2 doi:10.1016/j.annemergmed.2008.12.011 © 2008 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.
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FULL TEXT
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