Comparison of the efficacy of bolus low-dose ketamine versus bolus plus infusion low-dose ketamine on pain management in emergency departments: a randomized clinical trial

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Clin Exp Emerg Med. 2025;12(3):259-266

Publication date (electronic) : 2025 January 14

doi : https://doi.org/10.15441/ceem.24.244

Reza Azizikhani, Ali Sanaei, Farhad Heydari, Saeed Majidinejad, Keihan Golshani, Fateme Sadeghi, Pardis Rafiei

Department of Emergency Medicine, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Correspondence to: Farhad Heydari Department of Emergency Medicine, Faculty of Medicine, Isfahan University of Medical Sciences, Hezar Jerib Ave, Isfahan 8174673461, Iran Email: farhad_heidari@med.mui.ac.ir

Received 2024 April 23; Revised 2024 September 11; Accepted 2024 October 4.

Abstract

INTRODUCTION

Acute pain is a common chief complaint in the emergency department (ED). It is the patient’s right to receive appropriate analgesia, and failure to address pain could cause agitation and subsequently disturb the department’s environment. Furthermore, pain has unfavorable physiologic effects on the cardiovascular, respiratory, neuroendocrine, and immune systems in already traumatized patients [1].

More than 30 years after the first study of oligoanalgesia in the ED [2], oligoanalgesia, opioid abuse, preventable adverse drug events, and failure to prevent chronic pain are still major problems worldwide [2–4]. The inability of healthcare providers to acknowledge pain due to misconceptions about the reliability of patients or poor use of validated pain scoring scales, reluctance to change practice patterns, lack of awareness of newer treatment modalities and courses, and crowded environments are possible causes [2–6].

Some of the more commonly used analgesic drugs in the ED include opioids, nonsteroidal anti-inflammatory drugs, and paracetamol. Each of these drug groups has specific pharmacodynamic and pharmacokinetic effects that result in different side effects, duration of action, interactions, and cost/benefit ratios [2,7]. Based on this, one of the recommendations in recent pain control guidelines is adopting a multimodal analgesia approach to use different pathways, harness synergistic effects, and decrease dose-related side effects [3,7,8]. Ketamine is a promising drug for this purpose [8].

Ketamine is an attractive option in acute pain management as it reduces opioid tolerance, hyperalgesia, and central sensitization. This can prevent the development of chronic pain syndromes following trauma and surgical procedures [9,10].

Ketamine can be used in intravenous (IV), intramuscular, intranasal, oral, or intrathecal routes. The anesthetic induction dosage varies between 1 and 4.5 mg/kg, with a mean dose of 2 mg/kg. The most studied subdissociative dose range of ketamine is an IV bolus of 0.3 to 0.5 mg/kg, with or without an infusion [8]. Adverse effects include hallucinations, dizziness, and sedation, and these are dose-related [10,11].

Several systematic reviews of randomized controlled trials (RCTs) in an emergency setting found that low-dose ketamine might have higher or equivalent efficacy and safety as an adjunct or single agent for managing acute pain [12–18]. However, ketamine has troublesome adverse effects (increased emergence reactions, salivation, and vomiting) that may prevent emergency physicians and nurses from using it [8,10]. One possible solution is IV infusion of ketamine instead of or concurrently with IV bolus. Short IV infusions of ketamine led to a reduction in psychoperceptual side effects (a feeling of unreality) while maintaining the analgesic effect [5,18]. Prior studies on IV infusion of ketamine were mostly focused on perioperative analgesia with acceptable results [11]. However, the evidence on ketamine infusion in EDs is limited. In two studies with a similar methodology that directly compared 0.3 mg/kg ketamine IV push with short IV infusion in 15 minutes, patients in the short IV infusion arm experienced lower rates and severity of side effects with no difference in analgesic efficacy. Reported rates of adverse effects were still significant in both groups [17,18]. After these studies, an RCT showed that the analgesic efficacy of a short infusion of ketamine with a lower dose (0.15 mg/kg) was noninferior to high-dose infusion (0.3 mg/kg) [19]. The only study that concomitantly used ketamine bolus and infusion was a noncontrolled, fixed-dose, feasibility trial of 15 mg IV bolus followed by 20 mg infusion for 1 hour in 38 patients that resulted in significant analgesia with the high rate of patient satisfaction [20].

Considering that ketamine is highly lipophilic (volume of distribution, 3–5 L/kg) with an alpha half-life of 2 to 4 minutes and beta half-life of 2 to 4 hours [9], we hypothesized that a small bolus followed by a slow infusion in 30 minutes would have faster and longer analgesia with lower rates of side effects. The objective of this study was to compare the analgesic effect of 0.3 mg/kg IV bolus with 0.15 mg/kg IV bolus plus 30 minutes 0.15 mg/kg IV infusion in trauma patients with moderate to severe pain. The secondary objective of this study was to evaluate the side effects profile of these two protocols.

METHODS

RESULTS

The CONSORT flow chart of the study is illustrated in Fig. 1. A total of 244 patients were screened for eligibility, and of these, 80 patients were recruited, and of these 77 were analyzed. No statistically significant difference was observed between study groups in terms of demographic characteristics, mechanism of injury, or weight (Table 1). Median age was 36 years (IQR, 27–51 years), and mean age was 38.72±14.13 years. Sixty-six patients (85.7%) were male. The most prevalent mechanism of injury was road traffic accidents (66.2%), followed by falling (15.6%) and assault (11.7%).

Fig. 1.

CONSORT (Consolidated Standards of Reporting Trials) study flowchart. ASA, American Society of Anesthesiologists; BO, bolus-only; BI, bolus-and-infusion.

Table 1.

The baseline characteristics of patients (n=77)

Outcomes

Median pain scores in each group and the reduction from baseline in NRS scores are shown in Table 2. Both groups achieved a statistically significant reduction in pain from baseline (P<0.001). After 30 minutes, the BI group experienced lower pain scores (Fig. 2). At 120 minutes, four patients (10.5%) in the BO group and three patients (7.7%) in the BI group reported an NRS score of 0.

Table 2.

Reduction in pain score between the two groups (n=77)

Fig. 2.

Mean pain score over time in the bolus-only (BO) group and bolus-and-infusion (BI) group. NRS, numeric rating scale.

Vital signs at baseline and 30 minutes after the start of intervention are provided in Table 3. Blood pressure increased in both groups, but no statistically significant difference was evident. Other vital signs remained stable during the study in both groups. No significant differences in vital sign measurements were found between the two interventions. Patients in the BI group (n=19) required less rescue analgesia than those in the BO group (n=25), but this difference was not statistically significant (Table 4).

Table 3.

Changes in the vital signs in the two study groups (n=77)

Table 4.

Comparison of morphine consumption over time and RASS between the two groups (n=77)

The most common side effects were feelings of unreality, hallucination, agitation, and nausea. No statistically significant difference was observed between study groups in any side effect or the mean maximum deviation of RASS (Fig. 3, Tables 4, 5).

Fig. 3.

Mann-Whitney U-test of the Richmond Agitation Sedation Scale (RASS) in the bolus-only (BO) group and bolus-and-infusion (BI) group 30 minutes after the start of the intervention.

Table 5.

Comparison of the prevalence of adverse events in the two groups

DISCUSSION

Both BO and BI groups showed significant pain reduction in patients, but no significant difference was seen between the two groups. After the 30-minute interval, less pain was reported in the BI group, but this difference was not significant. In addition, the two groups were the same in terms of side effects.

No previous study has compared a single bolus with a bolus plus infusion of ketamine in the ED. Ketamine infusion in an emergency setting was first studied in an out-of-hospital RCT [26]. The first group received a bolus of morphine plus ketamine (0.2 mg/kg) followed by an infusion of ketamine (0.2 mg/kg/hr), and the second group received the same bolus and an infusion of saline. Infusion in both groups continued until arrival to the ED. In this study, adding ketamine infusion was not superior to saline infusion and did not reduce morphine usage and final pain scores. It is important to note that the short duration of prehospital emergency care meant that patients only received a mean dose of about 0.1 mg/kg of ketamine over 35 minutes. This low dose of ketamine could explain the absence of a significant difference. In our study, both groups received the same total dose, and the BI group did not show significantly better results.

The first prospective trial in an ED setting was a single-arm, fixed-dose, feasibility trial of 15 mg ketamine IV push followed by 20 mg IV infusion over 1 hour, resulting in a median reduction in pain score of 4 and acceptable patient satisfaction (85%) [20]. The first study that directly compared ketamine (0.3 mg/kg) IV push with the same dose via 15-minute infusion, concluded that ketamine given via infusion was associated with significantly lower rates of adverse effects including a feeling of unreality and sedation, with no difference in analgesic efficacy [18]. Another study with this method reported similar results [17]. After these studies, an RCT showed that a short infusion of ketamine with a lower dose (0.15 mg/kg) was noninferior to a high-dose infusion (0.3 mg/kg) at 30 minutes, but at 15 minutes, patients in the high-dose group experienced a greater change in NRS. Adverse effects were similar in both groups [19]. This suggests that ketamine side effects may be more strongly correlated with administration speed than total dose, as studies with bolus doses as low as our study had similar adverse effects as studies with higher bolus doses but infusion of a similar dose resulted in a lower rate of side effects. On the other hand, the analgesic efficacy of low-dose ketamine may not have a linear dose-response relationship and is not rate-related, and ketamine with a total dose greater than 0.3 mg/kg was not superior to lower dosages and different administration routes, resulting in similar analgesia [17–19,27]. To date, no study has compared a 0.15 mg/kg bolus with infusion at the same or a higher dose.

After a closer look at our results, we observed that patients showed diverse responses to ketamine administration. While some reported complete resolution of pain, others experienced minimal analgesia and needed multiple doses of rescue analgesia. Indeed, there is a need for larger studies to discern the patient subgroups that would derive the greatest benefit from ketamine administration.

In overcrowded, understaffed, or underequipped departments, infusion may not be feasible; since psychotropic side effects are the main barrier to ketamine administration in the ED, (S)-ketamine should be considered in future experiments [12].

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Notes