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
Ethics statement
This study was approved by the Ethics Committee of the Isfahan University of Medical Science (No. IR.MUI.MED.REC.1400.695). Written informed consent was obtained from all individual participants included in the study. The study protocol was registered at the Iranian Registry of Clinical Trials (No. IRCT20180129038549N16). This trial is reported in accordance with the CONSORT (Consolidated Standards of Reporting Trials) 2010 statement [21].
Study design
This was a multicenter, double-blinded, randomized (1:1 allocation ratio), parallel-group, superiority clinical trial in trauma patients admitted to the ED.
Participants and study setting
This study was conducted in the ED of Kashani and Al-Zahra, two university hospitals (level I trauma centers) in Isfahan, Iran, between December 2022 and December 2023. To avoid selection bias, the enrollment process was not restricted to any specific time of day or week, and every patient admitted to the ED was screened for eligibility. The inclusion criteria were as follows: (1) age between 18 and 65 years; (2) acute-onset moderate to severe pain (numeric rating scale [NRS] >5) related to multiple trauma (including head trauma [22]); (3) American Society of Anesthesiologists physical status I or II; (4) Glasgow Coma Scale >14; (5) stable hemodynamics; and (6) written informed consent. The exclusion criteria were the following: (1) history of psychotic disorders; (2) history of closed-angle glaucoma; (3) uncontrolled hypertension (systolic blood pressure >170 mmHg; diastolic blood pressure >110 mmHg); (4) globe trauma; (5) analgesic consumption in last 4 hours; and (6) current opioid abuser.
Randomization
An allocation list using random permuted blocks with block sizes of 2, 4, and 6 was created using an online tool [23]. The allocation list was concealed from researchers, treating clinicians, patients, and data analysts, but the nurses in charge of drug preparation were aware of it. A nurse in each hospital was responsible for preparing the medicines.
Interventions
After providing information to patients about the study, obtaining informed consent, and recording demographic information, initial pain score, symptoms, and vital signs were obtained. The racemic mixture of ketamine (Rotexmedica Gmbh) was used in this study. Patients in both groups received a total dose of 0.3 mg/kg ketamine. After enrollment, an independent researcher prepared two identical syringes (labeled as 1 for bolus and 2 for infusion) according to the allocation list and participant weight. In the bolus-only group (BO), syringe 1 contained 0.3 mg/kg ketamine, and syringe 2 contained saline 0.9%. In the bolus-and-infusion group (BI), both syringes contained 0.15 mg/kg ketamine. Both syringes were diluted with saline 0.9% to achieve a final volume of 5 mL.
For all patients, the first syringe was administered as an IV injection over 1 minute, followed by an IV infusion of the second syringe in 100 mL saline 0.9% over 30 minutes by a motor-powered infusion pump. Every drug administration was overseen by an emergency medicine specialist with expertise in Advanced Cardiac Life Support (ACLS). Patients were continuously monitored for changes in vital signs, including blood pressure, heart rate, respiratory rate, and oxygen saturation. Pain score, side effects, and Richmond Agitation Sedation Scale (RASS) were assessed at 5-, 30-, 60-, 90-, and 120-minute intervals following the start of the intervention. Side effects were inquired and documented. Patients were asked about the need for rescue analgesia at 30-, 60-, 90-, and 120-minute intervals. If a patient requested rescue analgesia, 5 mg of morphine was administered and recorded. Although the RASS has not been validated for this particular use in the ED, it is an observational tool that can quickly quantify level of consciousness [24].
Outcomes
The primary outcome of the study was the median decrease in pain scores, as measured by the NRS. Patients were asked to verbally rate their pain intensity from 0 (no pain) to 10 (worst pain). The sedation level, measured by the RASS, the prevalence of side effects, and the need for morphine rescue analgesia were considered as secondary outcomes. Additional analyses were conducted to evaluate changes in vital signs. RASS is one of the most commonly used scales to determine the sedation level, and it measures the severity of agitation and sedation with a score of +4 to −5 [25].
Sample size
Sample size calculation was performed using G*Power ver. 3.1 (Heinrich Heine University Düsseldorf). This calculation was based on a priori power analysis with a significance level (α) of 0.05, power (1−β) of 0.80, and effect size of 0.662 (calculated based on the literature). The total sample size was determined to be 78 participants, with an equal distribution between groups. Considering the dropout rate of 2.5%, we appointed a final sample size of 80.
Statistical analysis
Results were analyzed using IBM SPSS ver. 27 (IBM Corp). Continuous variables were presented as mean with standard deviation or median with interquartile range (IQR), and categorical variables were expressed as frequency and percentage. The chi-square test was used to compare qualitative variables. The Wilcoxon signed rank test and Mann-Whitney test were selected for analysis of variables without a normal distribution shown by the Kolmogorov-Smirnov test. Independent samples t-tests and paired t-tests were performed to compare continuous variables with normal distribution. The threshold for statistical significance was set to a P-value of <0.05.
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%).
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.
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).
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].
Limitations
Due to short follow-up period, we could not compare analgesic effects after 120 minutes or chronic pain development between study groups. Furthermore, our study only included a small sample size of 80 patients, which may limit the generalizability of the results. Additionally, the study did not compare ketamine administration with other analgesic drugs, which could have allowed for a more comprehensive assessment of the efficacy of ketamine. Finally, this study did not assess patient satisfaction.
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