Volume 70, August 2023, Pages 133-139Author links open overlay panel, , , , , AbstractBackground

Acute pain accounts for over 70% of Emergency Department (ED) visits. Sub-dissociative dose ketamine (0.1–0.6 mg/kg) is safe and effective for the management of acute pain in the ED. However, the optimal dose of intravenous ketamine that provides effective analgesia and minimizes the risk of adverse effects has yet to be identified. The objective of this study was to describe an effective analgesia dose range of IV ketamine for acute pain in the ED.

Methods

This multi-center, retrospective cohort study evaluated adult patients who received analgesic and sub-dissociative dose ketamine for the management of acute pain between May 5, 2018, and August 30, 2021, in 21 emergency departments at academic, community, and critical access hospitals across four states. Patients were excluded if they received ketamine for an indication other than pain, such as procedural sedation or intubation, or for whom there was incomplete documentation for the primary outcome. Patients who received a ketamine dose <0.3 mg/kg were stratified into the low-dose group, and those who received a dose of 0.3 mg/kg or higher to the high-dose group. The primary outcome was change in pain scores within 60 min using a standard 11-point numeric rating scale (NRS). Secondary outcomes included incidence of adverse effects and use of rescue analgesics. Continuous variables were compared between dose groups using student t-test or Wilcoxon Rank-Sum test. Linear regression was used to assess the association between the change in NRS pain scores within 60 min and dose after adjusting for baseline pain, requiring an additional dose of ketamine, and receiving an opioid.

Results

From 3796 patient encounters screened for receipt of ketamine, 384 patients met inclusion criteria including 258 in the low-dose group, and 126 in the high-dose group. The primary reason for exclusion was incomplete documentation of pain scores, or ketamine used for sedation. Median baseline pain scores were 8.2 in the low-dose group and 7.8 in the high-dose group (difference 0.5; 95% CI 0 to 1, p = 0.04). Both groups demonstrated significant reductions in their mean NRS pain scores within 60 min following the first administration of IV ketamine. There were no differences in the change in pain scores between both groups (−2.2 vs −2.6, mean difference 0.4, 95% CI -0.4 to 1.1, p = 0.34). Use of rescue analgesics (40.7% vs 36.5%, p = 0.43) and adverse effects were similar between groups, including early discontinuation of the ketamine infusion (37.2% vs. 37.3%, p = 0.99). Overall, the most common adverse effects were agitation (7.3%) and nausea (7.0%).

Conclusion

The analgesic efficacy and safety of high-dose sub-dissociative ketamine (≥0.3 mg/kg) was not superior to low-dose (< 0.3 mg/kg) for the management of acute pain in the ED. Low-dose ketamine <0.3 mg/kg is an effective and safe pain management strategy in this population.

Introduction

Acute pain is one of the most common clinical presentations in the Emergency Department (ED), accounting for over 70% of patient visits [1,2]. The safe and effective management of acute pain is critical for high-quality, patient-centered care [3]. Intravenous (IV) opioid analgesics have historically been a pharmacologic cornerstone for the management of severe acute pain in the ED [4]. While they continue to have a role in acute pain management, the consequences of the opioid epidemic have necessitated the search for alternatives to opioids and a transition to multimodal pain management [5]. The multimodal approach to traumatic and non-traumatic pain management reduces opioid requirements and the associated serious adverse effects, such as respiratory depression and the risk of opioid dependence [3,6,7].

Ketamine is a potent, non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that demonstrates a wide spectrum of dose-dependent pharmacologic effects, including analgesia, sedation, and dissociative anesthesia [5,8]. In 2017, the American College of Emergency Physicians (ACEP), the American Academy of Emergency Nurse Practitioners (AAENP), the Emergency Nurses Association (ENA), and the Society of Emergency Medicine Physician Assistants (SEMPA), issued a joint policy statement recognizing the use of sub-dissociative dose ketamine for analgesia in the ED as monotherapy or an adjunct agent to optimize the treatment traumatic and non-traumatic pain [3].

Previous prospective, randomized-controlled trials have demonstrated safety and efficacy at doses ranging from 0.1 mg/kg to 0.6 mg/kg IV for the management of acute pain in the ED [4,6,[9], [10], [11]]. Adverse effects from the Side Effects Rating Scale of Dissociative Anesthetics (SERSDA) have been observed within this dose range including agitation, changes in hearing, mood and/or vision, dizziness, fatigue, feelings of unreality, general discomfort, hallucinations, headaches, and nausea, which occur more frequently at higher doses [[7], [8], [9]]. The optimal dose of IV sub-dissociative ketamine that provides effective analgesia and minimizes the risk of adverse effects has yet to be identified. Data is also lacking to describe the dose at which no additional analgesic benefit is gained with increases in dose, also referred to as the “analgesic ceiling”.

The objective of this study was to evaluate the efficacy and safety of low-dose and high-dose IV sub-dissociative ketamine as an analgesic for acute pain in the ED to describe the dose range that provides effective analgesia without an increase in adverse effects.

Section snippetsStudy design and setting

This was a multicenter, retrospective cohort study evaluating all IV ketamine administrations for analgesia from May 5, 2018, and August 30, 2021, in 21 emergency departments at academic, community, and critical access hospitals across four states. The study was approved by the Institutional Review Board (IRB No.: 21-010335).

The study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [13].

Selection of participants

Patients were

Results

A total of 3796 patient encounters between May 5, 2018, and August 30, 2021, included the administration of IV ketamine in the ED, and were screened for eligibility. Of these, 384 individual patients met inclusion criteria and were analyzed: 258 in the low-dose group and 126 in the high-dose group (Fig. 1). There were no patients who received IV ketamine in the ED on more than one visit. The most common reasons for exclusion were incomplete documentation with respect to NRS pain score

Discussion

As a national priority, the opioid epidemic necessitated the search for novel and multimodal pain management strategies [12]. There is robust evidence provided by prospective, randomized-controlled trials for the analgesic efficacy and safety of IV sub-dissociative ketamine for acute pain in the ED at doses ranging from 0.1 mg/kg to 0.6 mg/kg when compared to opioids such as morphine and NSAIDs such as ketorolac [4,6,[9], [10], [11]]. Furthermore, the administration of IV sub-dissociative

Limitations

There are inherent limitations to this study due its retrospective nature. There was a large percentage of patients that were excluded from the study due to incomplete pain score documentation within 60 min of the first administration of IV ketamine. This introduces the potential for selection bias; however, we noted similar baseline characteristics between those who were included vs excluded apart from a higher mean dose of ketamine in those who were excluded. Based on clinical experience,

Conclusion

The analgesic efficacy and safety of high-dose sub-dissociative IV ketamine (≥ 0.3 mg/kg) was not superior to low-dose IV ketamine (< 0.3 mg/kg) for the management of acute pain in the ED. This study lends evidence to support the consideration of low-dose sub-dissociative ketamine at doses <0.3 mg/kg as monotherapy or as an adjunct agent for analgesia in the ED.

Author contributions

Aeryana Beaudrie-Nunn, Erin D. Wieruszewski, Emily J. Woods, Fernanda Bellolio, and Elizabeth A. Canterbury conceived the study. Aeryana Beaudrie-Nunn, Erin D. Wieruszewski, and Elizabeth A. Canterbury acquired, managed, and interpreted the data. Kristin C. Mara had complete access to the data and performed statistical analysis. Aeryana Beaudrie-Nunn drafted the manuscript, and all authors contributed substantially to its critical revision.

Funding

A portion of this study was funded by a research grant from the Mayo Midwest Pharmacy Research Committee.

CRediT authorship contribution statement

Aeryana N. Beaudrie-Nunn: Writing – review & editing, Writing – original draft, Validation, Investigation, Funding acquisition, Data curation, Conceptualization. Erin D. Wieruszewski: Writing – review & editing, Supervision, Project administration, Methodology, Funding acquisition, Conceptualization. Emily J. Woods: Writing – review & editing, Supervision, Project administration, Methodology, Conceptualization. Fernanda Bellolio: Writing – review & editing, Supervision, Project administration,

Declaration of Competing Interest

The authors of this study have no conflicts of interest to disclose.

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