Procedural sedation involves the utilization of sedative agents to temporarily reduce pain and discomfort during brief surgical procedures [31]. This sedation technique aims to achieve proper sedation and pain control while maintaining the patient’s capacity for autonomous breathing and preserving airway reflexes intact [32]. Moreover, the prevalence of procedural sedation in pediatric emergency departments (PEDs) has been on a rising trend in recent years [33]. The utilization of such sedative techniques when dealing with painful conditions in pediatrics, such as wound suturing, abscess drainage and bone reduction, has been consistently reported to be safe and effective [34]. Hence, we aimed to investigate the efficacy and safety of ketamine as a pre-procedural sedative agent in the process of bone reductions in PEDs. Our findings fill a notable gap in literature by specifically focusing on fracture reductions, a context underrepresented in broader sedation studies.

Our pooled analysis demonstrated that ketamine was associated with an overall adverse event rate of 24%. This rate increased slightly to 26% when ketamine was combined with agents such as midazolam or propofol, suggesting that combination regimens may not necessarily reduce overall adverse event risk (See Fig. 2 for individual outcome plots). In contrast, Bhatt et al. (2017) reported a lower overall adverse event rate of 11.7%, though their population included a broader array of procedures and sedative combinations. This difference may be attributable to variations in study populations, procedural types, and sedation protocols [3]. When compared with Bellolio et al. (2016), our adverse event rate broadly aligned for several individual outcomes, though slightly higher in total. Thus, our findings largely align with Bellolio et al. in supporting ketamine’s favorable airway safety profile [35]. Compared to Green et al. (2009), who reported vomiting in 8.4% and recovery agitation in 7.6% of 8,282 sedations, our findings revealed a higher incidence of vomiting at 13% and agitation at 17%. This divergence may be partially explained by differences in dosing protocols, as Green et al. identified unusually high IV doses and IM administration as significant independent predictors of emesis and agitation [36]. Our findings are also consistent with Wells et al. (2024), which directly compared ketamine monotherapy versus ketamine with midazolam for pediatric orthopedic reductions. They observed a statistically significant increase in hypoxia with midazolam coadministration (5% vs. 0%), consistent with our pooled hypoxia rates (5% for combination vs. 2% for ketamine monotherapy) [16]. This reinforces our conclusion that combining ketamine with sedatives like midazolam may elevate respiratory risks, albeit mild and reversible with non-invasive measures. Similarly, our findings align with Foo TY et al. (2020), who found that ketofol (ketamine + propofol) shortened recovery times compared to single agents, it did not significantly affect adverse outcomes such as apnea, desaturation, nausea, or vomiting, slightly confirming our observation that ketamine-propofol combinations maintained a modest adverse event rate of 26% and did not outperform ketamine monotherapy in terms of safety, which supports our assertion that combination therapy may not always translate into clinically superior outcomes in pediatric bone reductions [37]. Notably, high I² values in many pooled estimates indicate considerable heterogeneity, possibly stemming from differences in study design, sedation protocols, and outcome definitions. This limits generalizability and mandates cautious interpretation of pooled outcomes.

Notably, this overall adverse event rate was mildly increased to 26% of patients who received ketamine combined with an additional agent, such as midazolam or propofol. Furthermore, these variations in the adverse event rates, depending on whether ketamine was used alone or in combination, remained persistent among the individual adverse event analyses. Ketamine monotherapy was associated with higher rates of vomiting (13%) compared to combination therapy (7%). This vomiting rate is slightly higher than the 5.2% reported by Bhatt et al. and the 8.1% reported by Bellolio et al. for ketamine, which may be due to differences in dose, patient demographics, or adjunctive use of antiemetics, as their study also observed a significant association between higher ketamine doses and vomiting [3, 35]. Green et al. further reinforced this by showing that both the total dose and route of administration (IM vs. IV) were strong predictors of emesis. Additionally, their analysis noted that omission of benzodiazepines or anticholinergics increased the risk of vomiting, both of which were inconsistently used across our included studies [36]. Also, Wells et al. reported no difference in vomiting, agitation, or apnea rates between ketamine monotherapy and combination groups, supporting the notion that the increased hypoxia risk may not translate to more severe respiratory compromise, aligning with our findings of no intubation and only one case of laryngospasm [16].

In addition, while ketamine monotherapy was associated with mild agitation (17%), when combined with other drugs, it was associated with a high risk of hallucinations (28%). This is consistent with Power et al. (2024), who demonstrated that ketamine could induce a broad range of positive symptoms in healthy adults, with hallucinations being the most pronounced [38]. This is consistent with other studies, which reported that ketamine was associated with a high risk of vomiting in children due to its action on the various neurotransmitters in the brain, which eventually can influence the central nervous system, resulting in stimulation of vomiting centers in the brain [39]. Additionally, it was reported that combined therapies containing ketamine might amplify the risk of hallucinations by activating multiple receptor systems and increasing the excitability of the cerebral cortex [38, 40]. Green et al. also found that low IM dose, high IV dose, and older age were associated with higher odds of agitation (ORs 2.9, 2.1, and 1.02 per year, respectively), which are consistent with our findings that combination therapy and dosing patterns influence neuropsychiatric effects [36].

Furthermore, our pooled analysis reported that pediatric patients receiving ketamine monotherapy were associated with an overall low risk of airway complications. This is evident by the observed low incidence of apnea (1%), low oxygen saturation (1%), and hypoxia (2%). Importantly, no intubation was required, and only one case of laryngospasm was observed, reinforcing ketamine’s favorable respiratory profile (See Figure 3 for individual outcome plots). Bhatt et al. reported similarly low rates of serious airway events with ketamine monotherapy, noting 0.4% for serious adverse.

reported a laryngospasm incidence of 4.2 per 1000 sedations (0.42%) with ketamine, consistent with our findings [35]. These findings are largely consistent, supporting ketamine’s low respiratory risk profile in pediatric sedation. Moreover, no incidents where endotracheal intubation was required were reported, and only one case of laryngospasm was observed. This finding contrasts with prior studies, which reported a relatively high incidence of laryngospasm in pediatric patients under the administration of ketamine [35, 36]. However, this could be explained by the relatively higher dose of ketamine utilized (> 5 mg/kg), compared to most of the studies included in our review.

Notably, in the combination therapy, the risk of hypoxia increased slightly to 5%, aligning with prior reports that midazolam co-administration may elevate this risk [41, 42]. Wells et al. reported that the risk of hypoxia was statistically significantly increased during the co-administration of midazolam 5% compared to ketamine monotherapy 0%; however, this increase was only clinically mild and resolved with repositioning and supplemental oxygen therapy [16]. Bhatt et al. further corroborated this, reporting significantly higher odds of oxygen desaturation with ketamine-fentanyl (OR, 2.5) and ketamine-propofol (OR, 2.2) combinations compared to ketamine monotherapy [3]. Similarly, Bellolio et al. found hypoxia in 14.8 per 1000 sedations (1.5%) overall, and higher rates in studies using etomidate and propofol [35]. Green et al. identified benzodiazepine use and high IV doses as independent predictors of respiratory adverse events, reinforcing our conclusion that combination therapy may increase hypoxia risk through cumulative pharmacodynamic effects [36]. However, this increase was clinically mild and resolved with non-invasive measures, such as repositioning and supplemental oxygen. Overall, we can conclude that our findings are consistent with the already established safety profile of ketamine from the literature [43].

Regarding efficacy outcomes, ketamine demonstrated high procedural success in pediatric fracture reductions. The success rate for ketamine monotherapy was 86%, while combination regimens showed superior efficacy at 99%. This discrepancy may reflect ketamine’s limited sedative depth in more complex cases, as 25% of patients receiving ketamine monotherapy required redosing. Subgroup analysis showed consistent trends across both RCTs and observational studies, supporting the robustness of this finding. Additionally, Multi-modal sedation with more than one agent could have the ability to enhance muscle relaxation and improve patient cooperation compared to single agent sedation [44].

Procedural timing metrics also revealed important differences. Patients receiving ketamine monotherapy had a mean sedation duration of 42.6 min and a recovery time of 44.13 min [37, 45]. When ketamine was combined with other agents, sedation duration was significantly shorter (19.7 min), but recovery time was markedly longer (76.7 min). This is clinically relevant because in PEDs with high rates of admissions, shorter recovery times, as seen with ketamine monotherapy administration, may improve the workflow by accelerating the discharge process and freeing up resources faster. However, longer sedation durations, if co-existing with limited monitoring capacities, could result in delaying discharge and slowing the workflow of the PEDs [46].

Based on our findings and evidence from literature, guidelines recommend the utilization of ketamine as a sedative agent in the PEDs in all pediatric populations except in children under the age of 12 months and those who are associated with specific conditions, such as pulmonary hypertension and intracranial hypertension [46,47,48]. Our findings align with existing recommendations from guidelines in demonstrating the effectiveness and safety of ketamine as a sedative agent in bone reduction in PEDs. Furthermore, our analysis reported that ketamine monotherapy should be utilized in procedures requiring rapid recovery. However, in older patients or those who require deeper sedation and are prone to more emergent reactions, the utilization of a combination of ketamine and other sedative agents might be more beneficial due to greater potency and less need for additional dosing.

Additionally, our review demonstrated that ketamine was generally well-tolerated with a favorable safety profile that is consistent with established evidence from the literature. This helps regulate the workflow of the PEDs by minimizing the need for monitoring the patients; however, in difficult cases or in patients receiving combination therapy, physicians should be prepared for rare respiratory events with supplemental oxygen and other airway tools if needed [46]. Preventive measures could also help mitigate some adverse effects associated with ketamine use; thus, we recommend the consideration of administering an antiemetic to reduce the risk of vomiting or a low dose of benzodiazepine to lower the risk of hallucinations preemptively if needed [49, 50].

Finally, compared to other sedative agents such as nitrous oxide and Penthrox, although direct comparisons in the literature are lacking, we can hypothetically conclude that ketamine offers similar efficacy and safety with two notable advantages: it does not require fasting before administration, and its preferred intravenous route eliminate the need for patient’s cooperation and allows physicians to tailor the administered dosage according to the patient’s needs [51, 52].

This study’s limitations include significant heterogeneity among the included studies due to variations in the study designs, utilized doses, co-existing medications and protocols of ketamine administration, as well as differences in the baseline characteristics of the included population. Additionally, some of the studies included had risks of bias that ranged from some concern to high. This observed heterogeneity and risk of bias could affect the validity and generalizability of our findings; however, it should be noted that among the individual studies, the reported outcomes were usually similar in the effect estimate. Another limitation is the lack of a comparator arm and the dependence on the absolute effect estimate size to interpret our findings. Future research should prioritize well-designed, prospective RCTs comparing ketamine to other sedatives specifically for pediatric fracture reduction with a uniform protocol to eliminate heterogeneity. Dose-optimization studies and large-scale registry data are also needed to refine sedation protocols and reduce redosing rates.