Analgesia / Pain

#### ANALGESIA / PAIN MANAGEMENT

J Anaesthesiol Clin Pharmacol. 2018 Oct-Dec;34(4):450-457

# Meloxicam in the management of post-operative pain: Narrative review.

Bekker A, Kloepping C, Collingwood S

Oral formulations of meloxicam, a preferential cyclooxygenase-2 (COX-2) inhibitor, have long been used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as various pain syndromes of skeletomuscular origin (e.g., low back pain). However, these preparations are rarely indicated for the treatment of acute pain due to a poor dissolution rate and consequently a slow onset of action. The recent introduction of an intravenous (IV) NanoCrystal Colloidal Dispersion formulation opens up the possibility of using this drug during the perioperative period. The present review summarizes the pharmacologic properties of meloxicam, including its pharmacokinetics, adverse effects, and tolerability. In addition, we critically examined a number of recently completed clinical trials that evaluated the efficacy and safety of meloxicam IV in the treatment of post-operative pain. Literature retrieval was performed through PubMed and Medline (through March 2018) using combinations of the terms meloxicam, acute pain, and pharmacology. In addition, bibliographical information, including contributory unpublished data, was requested from the company developing the drug. Clinical trials suggest that single IV doses of 30 mg meloxicam significantly reduce post-operative pain as well as opioid requirements. We conclude that meloxicam IV is an effective and well-tolerated analgesic agent for the management of moderate to severe post-operative pain.

J Trauma Acute Care Surg. 2019 Feb;86(2):181-188

# Ketamine infusion for pain control in adult patients with multiple rib fractures: Results of a randomized control trial.

Carver T, Kugler N, Juul J, Peppard W, Drescher K, Somberg L, Szabo A, Yin Z, Paul J

BACKGROUND: Rib fractures occur in up to 40% of trauma patients and are associated with increased mortality. Opiate-based pain regimens remain the cornerstone of rib fracture management; however, concerns around opioids have fostered interest in alternative analgesics. Ketamine is currently being used in lieu of opioids, but little evidence exists supporting its use within the trauma population.

METHODS: A prospective, randomized, double-blind placebo-controlled trial of adult patients with three or more rib fractures admitted to a Level I trauma center was conducted. Exclusion criteria included age older than 64 years, Glasgow Coma Scale score less than 13, and chronic opiate use. The experimental arm received low-dose ketamine (LDK) at 2.5 μg·kg·min while the placebo cohort received an equivalent rate of 0.9% normal saline. All infusions were continued for 48 hours. The primary outcome was reduction in numeric pain score (NPS) during the first 24 hours. Secondary outcomes studied included oral morphine equivalent (OME) utilization, length of stay, epidural rates, pulmonary complications, and adverse events.

RESULTS: Forty-five (49%) of 91 patients were randomized to the experimental arm. Both groups were similar in makeup. Overall, 74.7% were male, had a median age of 49 years, and an Injury Severity Score (ISS) of 14. Low-dose ketamine was not associated with a significant reduction in 24-hour NPS or OME totals. Subgroup analysis of 45 severely injured patients (ISS, >15) demonstrated that LDK was associated with a significant reduction in OME utilization during the first 24hours (35.7 vs. 68, p = 0.03), 24 hours to 48 hours (64.2 vs. 96, p = 0.03), and overall (152.1 vs. 198, p = 0.048). No difference in other secondary outcomes or adverse events was noted.

CONCLUSION: Low-dose ketamine failed to decrease NPS or OME within the overall cohort, but a decrease in OME was observed among patients with an ISS greaterthan 15. Confirmatory studies are necessary to determine if LDK is a useful adjunct among severely injured patients.

Acta Anaesthesiol Scand. 2019 Jan 15 Epub ahead of print

# Does the addition of fentanyl to ketamine improve haemodynamics, intubating conditions or mortality in emergency department intubation: A systematic review.

Ferguson I, Bliss J, Aneman A

BACKGROUND: Ketamine is an induction agent frequently used for general anaesthesia in emergency medicine. Generally regarded as haemodynamically stable, it can cause hypertension and tachycardia and may cause or worsen shock. The effects of ketamine may be improved by the addition of fentanyl to the induction regime. We conducted a systematic review to identify evidence with regard to the effect of adding fentanyl to an induction regime of ketamine and a paralyzing agent on post-induction haemodynamics, intubating conditions and mortality.

METHODS: We conducted a search of the Cochrane library, EMBASE, MEDLINE, PROQUEST, OpenGrey and clinical trial registries. Prominent authors were contacted in order to identify additional literature pertinent to the research question. Studies were included if they pertained to intubation of adult patients in the prehospital or emergency department environments and included an induction regime of ketamine and a paralysing agent, with at least one outcome measure of haemodynamics, intubating conditions or mortality. Search results were reviewed by two investigators independently, adjudicated by a third investigator where disagreement occurred.

RESULTS: One observational study was identified that partially answered the research question.

DISCUSSION: Only one observational study was identified that partially answered the research question. This paper demonstrated that the use of fentanyl as a pretreatment increases the incidence of post-induction hypotension, a phenomenon that was seen with propofol, midazolam and ketamine. The difference in hypotension between these agents was not statistically significant. The impact of this on patient-orientated outcomes is unclear.

JAMA Pediatr. 2019 Feb 1;173(2):140-146

# Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial.

Frey T, Florin T, Caruso M, Zhang N, Zhang Y, Mittiga M

Importance: Timely analgesia is critical for children with injuries presenting to the emergency department, yet pain control efforts are often inadequate. Intranasal administration of pain medications provides rapid analgesia with minimal discomfort. Opioids are historically used for significant pain from traumatic injuries but have concerning adverse effects. Intranasal ketamine may provide an effective alternative.

Objective: To determine whether intranasal ketamine is noninferior to intranasal fentanyl for pain reduction in children presenting with acute extremity injuries.

Design, Setting, and Participants: The Pain Reduction With Intranasal Medications for Extremity Injuries (PRIME) trial was a double-blind, randomized, active-control, noninferiority trial in a pediatric, tertiary, level 1 trauma center. Participants were children aged 8 to 17 years presenting to the emergency department with moderate to severe pain due to traumatic limb injuries between March 2016 and February 2017. Analyses were intention to treat and began in May 2017.

Interventions: Intranasal ketamine (1.5 mg/kg) or intranasal fentanyl (2 µg/kg).

Main Outcomes and Measures: The primary outcome was reduction in visual analog scale pain score 30 minutes after intervention. The noninferiority margin for this outcome was 10.

Results: Of 90 children enrolled, 45 (50%) were allocated to ketamine (mean [SD] age, 11.8 [2.6] years; 26 boys [59%]) and 45 (50%) to fentanyl (mean [SD] age, 12.2 [2.3] years; 31 boys [74%]). Thirty minutes after medication, the mean visual analog scale reduction was 30.6 mm (95% CI, 25.4-35.8) for ketamine and 31.9 mm (95% CI, 26.6-37.2) for fentanyl. Ketamine was noninferior to fentanyl for pain reduction based on a 1-sided test of group difference less than the noninferiority margin, as the CIs crossed 0 but did not cross the prespecified noninferiority margin (difference in mean pain reduction between groups, 1.3; 90% CI, -6.2 to 8.7). The risk of adverse events was higher in the ketamine group (relative risk, 2.5; 95% CI, 1.5-4.0), but all events were minor and transient. Rescue analgesia was similar between groups (relative risk, 0.89; 95% CI, 0.5-1.6).

Conclusions and Relevance: Ketamine provides effective analgesia that is noninferior to fentanyl, although participants who received ketamine had an increase in adverse events that were minor and transient. Intranasal ketamine may be an appropriate alternative to intranasal fentanyl for pain associated with acute extremity injuries. Ketamine should be considered for pediatric pain management in the emergency setting, especially when opioids are associated with increased risk.

Scand J Trauma Resusc Emerg Med. 2019 Feb 7;27(1):11

# Prehospital intravenous fentanyl administered by ambulance personnel: a cluster-randomised comparison of two treatment protocols.

Friesgaard K, Kirkegaard H, Rasmussen C, Giebner M,Christensen E, Nikolajsen L

BACKGROUND: Prehospital acute pain is a frequent symptom that is often inadequately managed. The concerns of opioid induced side effects are well-founded. To ensure patient safety, ambulance personnel are therefore provided with treatment protocols with dosing restrictions, however, with the concomitant risk of insufficient pain treatment of the patients. The aim of this study was to investigate the impact of a liberal intravenous fentanyl treatment protocol on efficacy and safety measures.

METHODS: A two-armed, cluster-randomised trial was conducted in the Central Denmark Region over a 1-year period. Ambulance stations (stratified according to size) were randomised to follow either a liberal treatment protocol (3 μg/kg) or a standard treatment protocol (2 μg/kg). The primary outcome was the proportion of patients with sufficient pan relief (numeric rating scale (NRS, 0-10) < 3) at hospital arrival. Secondary outcomes included abnormal vital parameters as proxy measures of safety. A multi-level mixed effect logistic regression model was applied.

RESULTS: In total, 5278 patients were included. Ambulance personnel following the liberal protocol administered higher doses of fentanyl [117.7 μg (95% CI 116.7-118.6)] than ambulance personnel following the standard protocol [111.5 μg (95% CI 110.7-112.4), P = 0.0001]. The number of patient with sufficient pain relief at hospital arrival was higher in the liberal treatment group than the standard treatment group [44.0% (95% CI 41.8-46.1) vs. 37.4% (95% CI 35.2-39.6), adjusted odds ratio 1.47 (95% CI 1.17-1.84)]. The relative decrease in NRS scores during transport was less evident [adjusted odds ratio 1.18 (95% CI 0.95-1.48)]. The occurrences of abnormal vital parameters were similar in both groups.

CONCLUSIONS: Liberalising an intravenous fentanyl treatment protocol applied by ambulance personnel slightly increased the number of patients with sufficient pain relief at hospital arrival without compromising patient safety. Future efforts of training ambulance personnel are needed to further improve protocol adherence and quality of treatment.

Am J Emerg Med. 2018 Oct 22;Epub ahead of print

# Prehospital ketamine administration to pediatric trauma patients with head injuries in combat theaters.

Hill G, April M, Maddry J, Schauer S

BACKGROUND: Head injuries frequently occur in combat. Tactical Combat Casualty Care (TCCC) guidelines recommend pre-hospital use of ketamine for analgesia. Yet the use of this medication in patients with head injuries remains controversial, particularly among pediatric patients. We compare survival to hospital discharge rates among pediatric head injury subjects who received prehospital ketamine versus those who did not.

METHODS: We queried the Department of Defense Trauma Registry (DODTR) for all pediatric (<18 years of age) subjects from January 2007 to January 2016. We performed a sub-analysis of subjects with an abbreviated injury severity score for the head of 3 (serious) or higher and at least one documented Glasgow Coma Score (GCS) ≤13.

RESULTS: Of the 3439 pediatric patients within our dataset, 555 subjects met inclusion criteria for head injury - 36 (6.5%) received prehospital ketamine versus 519 (93.5%) who did not. There was no significant difference noted between groups regarding median age (10 versus 8, p = 0.259), percent male gender (72.2% versus 76.3%, p = 0.579), mechanism of injury (p = 0.143), median composite injury scores (22 versus 20, p = 0.082), median ventilator-free days (28 versus 27, p = 0.068), median ICU-free days (27.5 versus 27, p = 0.767), median hospital days (3.5 versus 4, p = 0.876) or survival to discharge (66.7% versus 70.7%, p = 0.607).

CONCLUSIONS: Within this data set, we were unable to detect any differences in mortality among pediatric head trauma subjects administered ketamine compared to subjects not receiving this medication in the prehospital setting.

Open Access Emerg Med. 2018 Oct 18;10:149-164

# The role of inhaled methoxyflurane in acute pain management.

Porter K, Dayan A, Dickerson S, Middleton P

Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications.

Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data.

Anesth Analg. 2018 Nov 9;Epub ahead of print

# Analgesic Efficacy and Safety of Intravenous Meloxicam in Subjects With Moderate-to-Severe Pain After Open Abdominal Hysterectomy: A Phase 2 Randomized Clinical Trial.

Rechberger T, Mack R, McCallum S, Du W Freyer A

BACKGROUND: An intravenous (IV) formulation of meloxicam was developed for moderate-to-severe pain management. This study evaluated the safety and efficacy of meloxicam IV after open abdominal hysterectomy. Meloxicam IV is an investigational product not yet approved by the US Food and Drug Administration.

METHODS: Women (N = 486) with moderate-to-severe pain after open abdominal hysterectomy were enrolled in this multicenter, randomized, double-blind, placebo- and active-controlled trial. Subjects were randomized to receive a single dose of meloxicam IV (5-60 mg), placebo, or morphine (0.15 mg/kg) in ≤6 hours after morphine dosing on postoperative day 1 and were evaluated for 24 hours. Rescue morphine (≈0.15 mg/kg IV) was available if needed for pain not relieved by the study medication. In an open-label extension (N = 295), meloxicam IV was administered once daily for the remaining hospital stay (or per the investigator's discretion). The coprimary efficacy end points were the summed pain intensity difference (SPID24) and total pain relief (TOTPAR24) from hour 0 to 24 hours after dosing. Effect size, the standardized difference between means reported in standard deviation (SD) units, was calculated to indicate the magnitude of the difference in the mean analgesic effect measured for different intervention groups.

RESULTS: Subjects who received morphine or meloxicam IV had a median time to first perceptible pain relief within 6-8 minutes. Morphine and meloxicam IV 5-60 mg produced statistically significant differences than placebo in SPID24 and TOTPAR24. SPID24 (standard error [SE]) for meloxicam IV 5-60 mg ranged from -56276.8 (3926.46) to -33517.1 (3930.1; P < .001); SPID24 (SE) for morphine and placebo were -29615.8 (3869.2; P < .001) and 4555.9 (3807.1), respectively. SPID24 effect sizes (95% confidence intervals) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 1.93 (1.61-2.25), 2.00 (1.65-2.35), 1.70 (1.35-2.05), 1.28 (0.95-1.60), 1.25 (0.90-1.61), and 1.12 (0.77-1.45) SDs, respectively. TOTPAR24 (SE) for meloxicam IV 5-60 mg ranged from 3104.5 (155.28) to 4130.4 (191.17; P < .001); TOTPAR24 (SE) for morphine and placebo were 2723.3 (188.4; P < .001) and 1100.6 (185.4), respectively. TOTPAR24 effect sizes (95% confidence interval) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 2.03 (1.70-2.35), 2.05 (1.70-2.40), 1.78 (1.43-2.13), 1.35 (1.03-1.67), 1.37 (1.01-1.72), and 1.10 (0.75-1.45) SDs, respectively. The mean total opioid consumed (SD) during the double-blind phase was 4.6 (8.17), 5.3 (8.85), 5.9 (7.85), 8.5 (9.67), 9.3 (9.47), 9.6 (8.12), and 16.0 (10.15) mg for patients in the 60, 30, 15, 7.5, and 5 mg meloxicam IV, morphine, and placebo groups, respectively. Generally, meloxicam IV was well tolerated, evidenced by the incidence of adverse events compared to placebo and lack of deaths and treatment-related serious adverse events.

CONCLUSIONS: A meloxicam IV dose of 5-60 mg was generally well tolerated and appeared to reduce opioid consumption in subjects with moderate-to-severe pain after open abdominal hysterectomy. Once-daily administration of meloxicam IV produced analgesic effect within 6-8 minutes postdose that was maintained over a 24-hour dosing interval.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

BMC Anesthesiol. 2019 Jan 31;19(1):18

# Differences in pain treatment between surgeons and anaesthesiologists in a physician staffed prehospital emergency medical service: a retrospective cohort analysis.

Schaller S, Kappler F, Hofberger C, Sattler J, Wagner R, Schneider G, Blobner M, Kanz K

BACKGROUND: Although pain treatment is an important objective in prehospital emergency medicine the incidence of oligoanalgesia is still high in prehospital patients. Given that prehospital emergency medicine in Germany is open for physicians of any speciality, the prehospital pain treatment may differ depending on the primary medical education. Aim of this study was to explore the difference in pain treatment between surgeons and anaesthesiologists in a physician staffed emergency medical service.

METHODS: Retrospective single centre cohort analysis in a physician staffed ground based emergency medical service from January 2014 until December 2016. A total of 8882 consecutive emergency missions were screened. Primary outcome measure was the difference in application frequency of prehospital analgesics by anaesthesiologist or surgeon. Univariate and multivariate logistic regression analysis was used for statistical analysis including subgroup analysis for trauma and acute coronary syndrome.

RESULTS: A total of 8238 patients were included in the analysis. There was a significant difference in the application frequency of analgesics between surgeons and anaesthesiologists especially for opioids (p < 0.001, OR 0.68 [0.56-0.82]). Fentanyl was the most common administered analgesic in the trauma subgroup, but significantly less common used by surgeons (p = 0.005, OR 0.63 [0.46-0.87]). In acute coronary syndrome cases there was no significant difference in morphine administration between anaesthesiologists and surgeons (p = 0.49, OR 0.88 [0.61-1.27]).

CONCLUSIONS: Increased training for prehospital pain treatment should be implemented, since opioids were administered notably less frequent by surgeons than by anaesthesiologists.

World J Emerg Med. 2019;10(1):27-32

# Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury.

Vahedi H, Hajebi H, Vahidi E, Nejati A, Saeedi M

BACKGROUND: Rapid and effective pain relief in acute traumatic limb injuries (ATLI) is one of the most important roles of emergency physicians. In these situations, opioid addiction is an important concern because of the dependency on opioids. The study aims to compare the effectiveness of intravenous (IV) fentanyl versus morphine in reducing pain in patients with opioid addiction who suffered from ATLI.

METHODS: In this double-blind randomized clinical trial, 307 patients with ATLI, who presented to the emergency department (ED) from February 2016 to April 2016, were randomly divided into two groups. One group (152 patients) received 0.1 mg/kg IV morphine. The other group (155 patients) received 1 mcg/kg IV fentanyl. Patients' demographic data, pain score at specific intervals, vital signs, side effects, satisfaction and the need for rescue analgesia were recorded.

RESULTS: Eight patients in the morphine group and five patients in the fentanyl group were excluded. Pain score in the fentanyl group had a significant decrease at 5-minute follow-up (P value=0.00). However, at 10, 30, and 60-minute follow-ups no significant differences were observed between the two groups in terms of pain score reduction. The rescue analgesia was required in 12 (7.7%) patients in the fentanyl group and in 48 (31.6%) patients in the morphine group (P value=0.00). No significant difference was observed regarding side effects, vital signs and patients' satisfaction between the two groups.

CONCLUSION: Fentanyl might be an effective and safe drug in opioid addicts suffering from ATLI.

Ann Emerg Med. 2019 Mar 27. pii: S0196-0644(19)30102-7

# Prehospital Analgesia With Intranasal Ketamine (PAIN-K): A Randomized Double-Blind Trial in Adults.

Andolfatto G, Innes K, Dick W, Jenneson S, Willman E, Stenstrom R, Zed P, Benoit G

STUDY OBJECTIVE: We compare intranasal ketamine with intranasal placebo in providing pain reduction at 30 minutes when added to usual paramedic care with nitrous oxide.

METHODS: This was a randomized double-blind study of out-of-hospital patients with acute pain who reported a verbal numeric rating scale (VNRS) pain score greater than or equal to 5. Exclusion criteria were younger than 18 years, known ketamine intolerance, nontraumatic chest pain, altered mental status, pregnancy, and nasal occlusion. Patients received usual paramedic care and were randomized to receive either intranasal ketamine or intranasal saline solution at 0.75 mg/kg. The primary outcome was the proportion of patients with VNRS score reduction greater than or equal to 2 at 30 minutes. Secondary outcomes were pain reduction at 15 minutes, patient-reported comfort, satisfaction scores, nitrous oxide consumption, and incidence of adverse events.

RESULTS: One hundred twenty subjects were enrolled. Seventy-six percent of intranasal ketamine patients versus 41% of placebo patients reported a greater than or equal to 2-point VNRS reduction at 30 minutes (difference 35%; 95% confidence interval 17% to 51%). Median VNRS reduction at 15 minutes was 2.0 and 1.0 and at 30 minutes was 3.0 and 1.0 for ketamine and placebo, respectively. Improved comfort at 15 and 30 minutes was reported for 75% versus 57% and 61% versus 46% of ketamine and placebo patients, respectively. Sixty-two percent of patients (95% confidence interval 49% to 73%) versus 20% (95% confidence interval 12% to 32%) reported adverse events with ketamine and placebo, respectively. Adverse events were minor, with no patients requiring physical or medical intervention.

CONCLUSION: Added to nitrous oxide, intranasal ketamine provides clinically significant pain reduction and improved comfort compared with intranasal placebo, with more minor adverse events.

Clin Pharmacol Drug Dev. 2019;Epub ahead of print

# A Phase 3, Randomized, Placebo-Controlled Evaluation of the Safety of Intravenous Meloxicam Following Major Surgery.

Bergese S, Melson T, Candiotti K, Ayad S, Mack R, McCallum S, Du W, Gomez A, Marcet J

An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Safety was evaluated via adverse events, clinical laboratory tests, vital signs, wound healing, and opioid consumption. The incidence of adverse events was similar between meloxicam IV- and placebo-treated subjects (63.0% versus 65.0%). Investigators assessed most adverse events as mild or moderate in intensity and unrelated to treatment. Adverse events of interest (injection-site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound-healing events) were similar between groups. Over the treatment period, meloxicam IV was associated with a 23.6% (P = .0531) reduction in total opioid use (9.2 mg morphine equivalent) compared to placebo-treated subjects. The results suggest that meloxicam IV had a safety profile similar to that of placebo with respect to numbers and frequencies of adverse events and reduced opioid consumption in subjects with moderate to severe postoperative pain following major elective surgery.

J Emerg Med. 2019 Apr;56(4):455-456

# THINK of Ketamine for Headache.

Goodnough R

QUOTE:"The THINK (Treatment of Headache with Intranasal Ketamine) trial is a timely addition to the literature (9). Benish et al. report a well-designed, prospective, single-blind trial comparing 1–2 doses of intranasal ketamine (0.75 mg/kg, with the option for 0.25 mg/kg 30 min later) to i.v. metoclopramide (10 mg) and diphenhydramine (25 mg) (9). Providers could opt to administer i.v. ketorolac (30 mg) or dexamethasone (10 mg) in the control arm (9). Ketamine displayed a clinically significant decrease in pain at 30 min (mean change in VAS 29.0 mm), though it was not superior to the control arm (mean change in VAS 22.2 mm) (9). A decrease in 13–18 mm has been described as clinically significant (1,3). The intervention and control arm showed similar rates of adverse effects (65.4 and 66.7%, respectively); though there was a higher incidence of mood changes and feelings of unreality in the ketamine group, the study was not powered to detect these differences (9). The majority (80%) of the control arm additionallyreceived i.v. ketorolac, which implies a similar effectiveness of intranasal ketamine to the combined administration of i.v. diphenhydramine, metoclopramide, and NSAID therapy at 30 min (9). The disparate outcomes demonstrated by previously published literature on ketaminein management of primary headache compared to the THINK trial may be reflective of variations in ketamine dosing, routes, or rate of infusion, or by the selection of metoclopramiderather than other dopamine antagonists. Amidst the current opioid epidemic, comfort withketamine as a viable intervention for pain relief adds to the emergency medicine provider’s armamentarium of nonopioid analgesics and, therefore, the investigation of ketamine to manage pain from primary headache is appealing. Further, the intranasal route of administration may limit the need for placement of i.v. lines or administration of multiple parenteral medicationsin this population."

Ann Emerg Med. 2019 May;73(5):e47-e49

# Is Low-Dose Ketamine an Effective Alternative to Opioids for Acute Pain?

Kirschner J, Hunter B

Summary: In adult emergency department (ED) patients with acute pain, low-dose intravenous ketamine (0.3 to 0.5 mg/kg) may provide pain relief within 10 minutes that is similar to that of single-dose intravenous morphine (0.1 mg/kg).

Data Sources: A medical librarian searched MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects from inception through February 2017. The Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched for gray literature, and bibliographies were searched for additional citations. Only English-language studies were included.

Study Selection: Two reviewers screened all titles and abstracts, and discrepancies were resolved by discussion or an adjudicator. Included studies were randomized trials of low-dose intravenous ketamine less than or equal to 0.5 mg/kg compared with intravenous opioids in adult ED patients with acute pain (≤1 week’s duration). Studies had to report a change in either a visual analog scale or numeric rating scale score within 60 minutes.

Data Extraction and Synthesis: Mean visual analog scale or numeric rating scale score, mean changes, and SDs were abstracted for all points less than or equal to 120 minutes, although details of data abstraction were not reported. The primary outcome was change in mean pain score at 10 minutes or closest point to 10 minutes with available data. The secondary outcome of adverse events was not predefined, but all adverse events reported in the individual trials were recorded. The difference in change in visual analog scale or numeric rating scale score between ketamine and opioids was meta-analyzed with random-effects models. Results were reported with 95% confidence intervals. The quality of individual trials was assessed with the Cochrane Risk of Bias Tool.

Acad Emerg Med. 2019;Epub ahead of print

# Psychiatric Outcomes of Patients With Severe Agitation Following Administration of Prehospital Ketamine.

Lebin J, Akhavan A, Hippe D, Gittinger M, Pasic J, McCoy A, Vrablik M

BACKGROUND: Ketamine is an emerging drug used in the management of undifferentiated, severe agitation in the prehospital setting. However, prior work has indicated that ketamine may exacerbate psychotic symptoms in patients with schizophrenia. The objective of this study was to describe psychiatric outcomes in patients who receive prehospital ketamine for severe agitation.

METHODS: This is a retrospective cohort study, conducted at two tertiary academic medical centers, utilizing chart review of patients requiring prehospital sedation for severe agitation from January 1, 2014, to June 30, 2016. Patients received either intramuscular (IM) versus intravenous (IV) ketamine or IM versus IV benzodiazepine. The primary outcome was psychiatric inpatient admission with secondary outcomes including ED psychiatric evaluation and nonpsychiatric inpatient admission. Generalized estimating equations and Fisher's exact tests were used to compare cohorts.

RESULTS: During the study period, 141 patient encounters met inclusion with 59 (42%) receiving prehospital ketamine. There were no statistically significant differences between the ketamine and benzodiazepine cohorts for psychiatric inpatient admission (6.8% vs. 2.4%, difference = 4.3%, 95% CI = -2% to 12%, p = 0.23) or ED psychiatric evaluation (8.6% vs. 15%, difference = -6.8%, 95% CI = -18% to 5%, p = 0.23). Patients with schizophrenia who received ketamine did not require psychiatric inpatient admission (17% vs. 10%, difference = 6.7%, 95% CI = -46% to 79%, p = 0.63) or ED psychiatric evaluation (17% vs. 50%, difference = -33%, 95% CI = -100% to 33%, p = 0.55) significantly more than those who received benzodiazepines, although the subgroup was small (n = 16). While there was no significant difference in the nonpsychiatric admission rate between the ketamine and benzodiazepine cohorts (35% vs. 51%, p = 0.082), nonpsychiatric admissions in the benzodiazepine cohort were largely driven by intubation (63% vs. 3.8%, difference = 59%, 95% CI = 38% to 79%, p < 0.001).

CONCLUSIONS: Administration of prehospital ketamine for severe agitation was not associated with an increase in the rate of psychiatric evaluation in the emergency department or psychiatric inpatient admission when compared with benzodiazepine treatment, regardless of the patient's psychiatric history.

J Spec Oper Med. Spring 2019;19(1):70-74.

# Battlefield Analgesia: Adherence to Tactical Combat Casualty Care Guidelines.

Schauer S, Fisher A, April M, Carter R, Cunningham C, Aden J, Fernandez J DeLorenzo R

BACKGROUND: Low rates of prehospital analgesia, as recommended by Tactical Combat Casualty Care (TCCC) guidelines, have been demonstrated in the Joint Theaters combat setting. The reasons for this remain unclear. This study expands on previous reports by evaluating a larger prehospital dataset for determinants of analgesia administration.

METHODS: This was part of an approved quality assurance project evaluating adherence to TCCC guidelines across multiple modalities. Data were from the Prehospital Trauma Registry, which existed from January 2013 through September 2014, and comprises data from TCCC cards, Department of Defense 1380 forms, and after-action reports to provide real-time feedback to units on prehospital medical care.

RESULTS: Of 705 total patient encounters, there were 501 documented administrations of analgesic medications given to 397 patients. Of these events, 242 (34.3%) were within TCCC guidelines. Special Operations Command had the highest rate of overall adherence, but rates were still low (68.5%). Medical officers had the highest rates of overall administration. The low rates of administration and adherence persisted across all subgroups.

CONCLUSION: Rates of analgesia administration remained low overall and in subgroup analyses. Medical officers appeared to have higher rates of compliance with TCCC guidelines for analgesia administration, but overall adherence to TCCC guidelines was low. Future research will be aimed at finding methods to improve administration and adherence rates.

Reg Anesth Pain Med. 2019 Feb 7;Epub ahead of print

# Intravenous meloxicam for the treatment of moderate to severe acute pain: a pooled analysis of safety and opioid-reducing effects.

Viscusi E, Gan T, Bergese S, Singla N, Mack R, McCallum S, Du W(7), Hobson S(6).

BACKGROUND AND OBJECTIVES: To describe the safety and tolerability of intravenous meloxicam compared with placebo across all phase II/III clinical trials.

METHODS: Safety data and opioid use from subjects with moderate to severe postoperative pain who received ≥1 dose of intravenous meloxicam (5-60 mg) or placebo in 1 of 7 studies (4 phase II; 3 phase III) were pooled. Data from intravenous meloxicam 5 mg, 7.5 mg and 15 mg groups were combined (low-dose subset).

RESULTS: A total of 1426 adults (86.6% white; mean age: 45.8 years) received ≥1 dose of meloxicam IV; 517 (77.6% white; mean age: 46.7 years) received placebo. The incidence of treatment-emergent adverse events (TEAEs) in intravenous meloxicam and placebo-treated subjects was 47% and 57%, respectively. The most commonly reported TEAEs across treatment groups (intravenous meloxicam 5-15 mg, 30 mg, 60 mg and placebo, respectively) were nausea (4.3%, 20.8%, 5.8% and 25.3%), headache (1.5%, 5.6%, 1.6% and 10.4%), vomiting (2.8%, 4.6%, 1.6% and 7.4%) and dizziness (0%, 3.5%, 1.1% and 4.8%). TEAE incidence was generally similar in subjects aged >65 years with impaired renal function and the general population. Similar rates of cardiovascular events were reported between treatment groups. One death was reported (placebo group; unrelated to study drug). There were 35 serious adverse events (SAEs); intravenous meloxicam 15 mg (n=5), intravenous meloxicam 30 mg (n=15) and placebo (n=15). The SAEs in meloxicam-treated subjects were determined to be unrelated to study medication. Six subjects withdrew due to TEAEs, including three treated with intravenous meloxicam (rash, localized edema and postprocedural pulmonary embolism). In trials where opioid use was monitored, meloxicam reduced postoperative rescue opioid use.

CONCLUSIONS: Intravenous meloxicam was generally well tolerated in subjects with moderate to severe postoperative pain.

Scand J Trauma Resusc Emerg Med. 2019 Feb 26;27(1):23

# Changes in anaesthetic use for trauma patients in German HEMS - a retrospective study over a ten-year period.

Wafaisade A, Caspers M, Bouillon B, Helm M, Ruppert M, Gäßler M

BACKGROUND: Airway management and use of intravenous anaesthetics to facilitate tracheal intubation after major trauma remains controversial. Numerous agents are available and used for pre-hospital rapid-sequence induction (RSI). The aim was to investigate usage and potential changes in administration of intravenous anaesthetics for pre-hospital RSI in trauma patients over a ten-year period.

METHODS: Based on a large helicopter emergency medical service (HEMS) database in Germany between 2006 and 2015, a total of 9720 HEMS missions after major trauma leading to RSI on scene were analysed. Administration practice of sedatives and opioids were investigated, while neuromuscular blocking agents were not documented in the database.

RESULTS: With respect to administration of sedatives, independent from trauma mechanism and specific injury patterns the use of Etomidate decreased dramatically (52 to 6%) in favour of a more frequent use of Propofol (3 to 32%) and Ketamine (9 to 24%; all p < 0.001) from 2006 to 2015. The use of Benzodiazepines increased slightly, while the utilization rate of Barbiturates remained constant. In patients with Shock Index > 1 at initial contact, the administration rate of Etomidate dropped significantly as well. This decline was mainly substituted by Ketamine and particularly Propofol. In patients with GCS ≤ 8 upon initial contact, a similar distribution compared to the general trauma population could be observed. With respect to opioids, mainly Fentanyl has been administered for RSI in trauma patients (2006: 69, 6% to 2015: 60.2%; p < 0.001), while the use of sufentanyl showed a significant increase (0.2 to 8.8%; p < 0.001).

CONCLUSIONS: This large study analysed prehospital administration of anaesthetics in trauma patients, showing a substantial change from 2006 to 2015 despite the lack of any high-level evidence. Etomidate has shifted from the main sedative substance to virtual absence, indicating that the recommendation of an established national guideline was transferred into clinical practice, although based on weak evidence as well. The pre-hospital use of Propofol showed a particular increase. Fentanyl has been the main opioid drug for RSI in trauma, however Sufentanyl has become increasingly popular. The mechanisms and advantages of the different substances still have to be elucidated, especially in head injury and bleeding trauma.

Mil Med. 2019 Mar 1;184(Suppl 1):542-544

# Prehospital Use of Ketamine: Effectiveness in Critically Ill and Injured Patients.

Zietlow J, Berns K, Jenkins D, Zietlow S

BACKGROUND: The military use of ketamine is well established. The benefits of prehospital civilian use have not been extensively reported.

METHODS: A retrospective review was performed of patients with prehospital ketamine use in Mayo One's air and critical care ground transport.

RESULTS: The medical records were reviewed from 2014 to 2016 to assess the efficacy of Ketamine. During this time frame, 158 (167 instances) patients were treated with ketamine for analgesia (38%), sedation (44%), or procedural (18%) use. The patient population had a mean age of 49 (range: 1-100), with 105 (67%) male patients. Indications included trauma (69%), which was further broken down into blunt (57%), penetrating (4%), and miscellaneous (8%), and medical illness (31%). The mean ketamine dose was 52.6 mg (range: 5-200 mg) via intravenous route. Ketamine was utilized in 61% of patients after other medications were ineffective. Overall success rate was 98%. Mean pain scale before and after ketamine use was 9/10 and 3/10, respectively. Ketamine use increased yearly from 21 (13%) in 2014, 56 (36%) in 2015, and 81 (51%) in 2016.

CONCLUSION: Prehospital ketamine use is effective alone or in conjunction with other medications for analgesia, sedation, and procedural use in trauma and critically ill patients with minimal hemodynamic and respiratory consequences.

Ann Emerg Med. 2019 Aug;74(2):241-250

# Prehospital Analgesia With Intranasal Ketamine (PAIN-K): A Randomized Double-Blind Trial in Adults.

Andolfatto G, Innes K, Dick W, Jenneson S, Willman E, Stenstrom R, Zed P), Benoit G

STUDY OBJECTIVE: We compare intranasal ketamine with intranasal placebo in providing pain reduction at 30 minutes when added to usual paramedic care with nitrous oxide.

METHODS: This was a randomized double-blind study of out-of-hospital patients with acute pain who reported a verbal numeric rating scale (VNRS) pain score greater than or equal to 5. Exclusion criteria were younger than 18 years, known ketamine intolerance, nontraumatic chest pain, altered mental status, pregnancy, and nasal occlusion. Patients received usual paramedic care and were randomized to receive either intranasal ketamine or intranasal saline solution at 0.75 mg/kg. The primary outcome was the proportion of patients with VNRS score reduction greater than or equal to 2 at 30 minutes. Secondary outcomes were pain reduction at 15 minutes, patient-reported comfort, satisfaction scores, nitrous oxide consumption, and incidence of adverse events.

RESULTS: One hundred twenty subjects were enrolled. Seventy-six percent of intranasal ketamine patients versus 41% of placebo patients reported a greater than or equal to 2-point VNRS reduction at 30 minutes (difference 35%; 95% confidence interval 17% to 51%). Median VNRS reduction at 15 minutes was 2.0 and 1.0 and at 30 minutes was 3.0 and 1.0 for ketamine and placebo, respectively. Improved comfort at 15 and 30 minutes was reported for 75% versus 57% and 61% versus 46% of ketamine and placebo patients, respectively. Sixty-two percent of patients (95% confidence interval 49% to 73%) versus 20% (95% confidence interval 12% to 32%) reported adverse events with ketamine and placebo, respectively. Adverse events were minor, with no patients requiring physical or medical intervention.

CONCLUSION: Added to nitrous oxide, intranasal ketamine provides clinically significant pain reduction and improved comfort compared with intranasal placebo, with more minor adverse events.

Am J Emerg Med. 2019 May 31 Epub ahead of print

# Tranexamic acid in traumatic hemorrhage: Evidence argues for a prehospital administration.

Boutonnet M, Osorio Cajes G, Pasquier P, Ausset S

We read with interest the study of El-Menyar et al. comparing the mortality, thromboembolic events (VTE) and need for blood transfusion in trauma patients receiving or not receiving prehospital tranexamic acid (TXA). In this 21-months comparative retrospective study, 204 trauma patients were compared after 1:1 matching. 102 patients receiving TXA were matched to 102 patients not receiving TXA but transfused in the 4 h following admission. Neither the overall mortality rate [OR 0.78 (95% CI 0.42–1.45)], nor the VTE [OR 2.0 (CI 95% 0.37–11.40)] differed between the two groups. However, the median amount of blood transfusion was greater in the control group [8 units (range 1–40) vs 3 (range 0–40), p = 0.01] as well as the use of massive blood transfusion [OR 0.35 (95% CI 0.19–0.67)], defined as ten or more units of red blood cells over a 24 hour period or >40 ml/kg packed-red blood cells (PRBC) in 2 h or less. We fully agree with the authors when they state that prehospital TXA administration reduced the need for massive transfusion and the amount of blood transfusion. The authors pointed out two limitations. First the study was probably underpowered for mortality. Second, TXA was also administered to non-coagulopathic patients or to patients without active bleeding. Interestingly, in a recent study, conducted in a comparable mature trauma care system we compared the mortality of patients receiving or not, early administration of TXA (prehospital or in emergency room (ER)) . We believe that our study addresses these two limitations. We included 470 trauma patients receiving TXA and 327 not receiving TXA managed in the six Level-1 trauma centers in Paris area. After propensity score weighting, mortality was lowered by the use of TXA in patients requiring PRBC transfusion in the ER [hazard ratio 0.3 (CI 95% 0.3–0.6)] but not in patients who did not require emergent transfusion. Moreover, in a German retrospective study, including 516 trauma patients, prehospital administration of tranexamic acid in trauma patients was associated with significant improvement in early mortality (24 h mortality 5.8% vs 12.4%, p = 0.01). These results enhanced the conclusions of the CRASH-2 study which exhibited a 10% of mortality improvement with the early empiric use of TXA in trauma patients with (or at risk of) severe hemorrhage. Thus, despite the respective limitations of these studies, the preponderance of the evidence suggests that prehospital or early administration of TXA in mature trauma care systems improve mortality in the most hemorrhagic of the trauma patients.

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Ann Emerg Med. 2019 Aug;74(2):233-240

# Randomized Trial of Intravenous Lidocaine Versus Hydromorphone for Acute Abdominal Pain in the Emergency Department.

Chinn E, Friedman B, Naeem F, Irizarry E, Afrifa F, Zias E, Jones M, Pearlman S, Chertoff A, Wollowitz A, Gallagher E

STUDY OBJECTIVE: We compare the efficacy and safety of intravenous lidocaine with that of hydromorphone for the treatment of acute abdominal pain in the emergency department (ED).

METHODS: This was a randomized, double-blind, clinical trial conducted in 2 EDs in the Bronx, NY. Adults weighing 60 to 120 kg were randomized to receive 120 mg of intravenous lidocaine or 1 mg of intravenous hydromorphone. Thirty minutes after administration of the first dose of the study drug, participants were asked whether they needed a second dose of the investigational medication to which they were randomized. Patients were also stratified according to clinical suspicion of nephrolithiasis. The primary outcome was improvement in pain scores of 0 to 10 between baseline and 90 minutes. An important secondary outcome was need for "off-protocol" parenteral analgesics, including opioids and nonsteroidal anti-inflammatory drugs.

RESULTS: We enrolled 154 patients, of whom 77 received lidocaine and 77 received hydromorphone. By 90 minutes, patients randomized to lidocaine improved by a mean of 3.8 points on the 0-to-10 scale, whereas those randomized to hydromorphone improved by a mean of 5.0 points (mean difference 1.2; 95% confidence interval 0.3 to 2.2). Need for off-protocol "rescue" analgesics occurred for 39 of 77 lidocaine patients (51%) and 20 of 77 hydromorphone patients (26%) (difference 25%; 95% confidence interval 10% to 40%). Adverse events were comparable between groups. Among the subset of 22 patients with nephrolithiasis, lidocaine patients reported a mean improvement of 3.4 points on the pain scale, whereas hydromorphone patients reported a mean improvement of 6.4 points (mean difference 3.0; 95% confidence interval 0.5 to 5.5).

CONCLUSION: Intravenous hydromorphone was superior to intravenous lidocaine both for general abdominal pain and a subset of patients with nephrolithiasis. A majority of patients randomly allocated to lidocaine required additional analgesics.

Anesth Analg. 2019 Jul 17;Epub ahead of print

# Oligoanalgesia in Patients With an Initial Glasgow Coma Scale Score ≥8 in a Physician-Staffed Helicopter Emergency Medical Service: A Multicentric Secondary Data Analysis of >100,000 Out-of-Hospital Emergency Missions.

Helm M, Hossfeld B, Braun B, Werner D, Peter L, Kulla M

BACKGROUND: Oligoanalgesia, as well as adverse events related to the initiated pain therapy, is prevalent in out-of-hospital emergency medicine, even when a physician is present. We sought to identify factors involved in insufficient pain therapy of patients presenting with an initial Glasgow Coma Scale (GCS) score of ≥8 in the out-of-hospital phase, when therapy is provided by a physician-staffed helicopter emergency medical service (p-HEMS).

METHODS: This was a multicenter, secondary data analysis of conscious patients treated in primary p-HEMS missions between January 1, 2005, and December 31, 2017. Patients with a numeric rating scale (NRS) pain score ≥4, GCS score ≥8 on the scene, without cardiopulmonary resuscitation (CPR), and a National Advisory Committee for Aeronautics (NACA) score <VI were included. Multivariable logistic binary regression analyses were used to identify characteristics of oligoanalgesia (NRS ≥4 at handover or pain reduction <3). Linear regression analysis was used to identify changes in pain treatment within the study period.

RESULTS: We analyzed data from 106,730 patients (3.6% missing data at variable level). Of these patients, 82.9% received some type of analgesic therapy on scene; 79.1% of all patients received analgesic drugs, and 38.6% received nonpharmacological interventions, while 37.4% received both types of intervention. Oligoanalgesia was identified in 18.4% (95% confidence interval [CI], 18.1-18.6) of patients. Factors associated with oligoanalgesia were a low NACA score and a low NRS score, as well as central nervous system or gynecological/obstetric complaints. The use of weak opioids (odds ratio [OR] = 1.05; 95% CI, 0.68-1.57) had no clinically relevant association with oligoanalgesia, in contrast to the use of strong or moderate opioids, nonopioid analgesics, or ketamine. We observed changes in the analgesic drugs used over the 12-year study period, particularly in the use of strong opioids (fentanyl or sufentanil), from 30.3% to 42.3% (P value <.001). Of all patients, 17.1% (95% CI, 16.9-17.3) did not receive any type of pain therapy.

CONCLUSIONS: In the studied p-HEMS cohort, oligoanalgesia was present in 18.4% of all cases. Special presenting complaints, low NACA scores, and low pain scores were associated with the occurrence of oligoanalgesia. However, 17.1% of patients received no type of pain therapy, which suggests a scope for further improvement in prehospital pain therapy. Pharmacological and nonpharmaceutical pain relief should be initiated whenever indicated.

Anesth Analg. 2019 Jul 17;Epub ahead of print

Ketamine Administration During Hospitalization Is Not Associated With Posttraumatic Stress Disorder Outcomes in Military Combat Casualties: A Matched Cohort Study.

Highland K, Soumoff A, Spinks E, Kemezis P, Buckenmaier C

BACKGROUND: Ketamine is routinely used within the context of combat casualty care. Despite early concerns that ketamine administration may be associated with elevated risk of posttraumatic stress disorder (PTSD), more recent evidence suggests no relationship. Because PTSD occurs with regular frequency in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Service Members (SMs) and combat-related injuries are associated with higher likelihood of PTSD, it is important to investigate the relationship between ketamine exposure during inpatient medical and surgical care and PTSD symptoms in OIF/OEF SMs.

METHODS: Medical record data from OIF/OEF SMs medically evacuated from combat (N = 1158) included demographic characteristics, injury severity, body areas injured, and PTSD Checklist (PCL) scores. The primary analysis assessed the association between ketamine versus nonketamine exposure on positive PTSD screen (logistic regression) and PCL scores (linear regression) after using 1:1 propensity score matching to adjust for available potential confounding variables. Because there were 2 primary outcomes, the binary positive PTSD screen (yes/no) and continuous PCL score, the significance level was set at P ≤ .025. In sensitivity analyses, propensity scores were used to match ketamine to nonketamine records in a 1:4 ratio, as well as to conduct inverse probability treatment weighting (IPTW). Regressions examining the relationship between ketamine exposure and outcomes were repeated for unconditional, 1:4 matching, and IPTW models.

RESULTS: In the sample, 107 received ketamine and 1051 did not. In the logistic regression, the probability of a positive PTSD screen was not significantly different between ketamine versus nonketamine patients (odds ratio [OR] = 1.28; 95% confidence interval [CI], 0.48-3.47; P = .62). In the linear regression, PCL scores were not significantly different between ketamine versus nonketamine patients (mean difference = 1.98 [95% CI, -0.99 to 4.96]; P = .19). The results were consistent in the unconditional, 1:4 matching, and IPTW models.

CONCLUSIONS: No differences in PTSD screening risk or symptom levels between ketamine exposed and nonexposed were found. Given the small sample size, wide Cis of the effects, and additional confounds inherent to retrospective studies, future studies are needed to examine the complex relationships between ketamine and psychological symptoms.

Sports Med Arthrosc Rev. 2019 Sep;27(3):112-118

Perioperative Pain Management and Avoidance of Long-term Opioid Use.

Patzkowski M, Patzkowski J.

The opioid epidemic continues to be a problem in the United States and prescription opioid overdose fatalities continue to rise. Chronic opioid use threatens military readiness and puts service members at risk for medical separation from military service. Orthopedic surgeons commonly prescribe opioid medications for postsurgical patients. Long-term opioid use can be the result of acute, postoperative opioid intake. Overprescribing may increase the risk of long-term opioid use, medication diversion and adverse outcomes. Preoperative administration of opioids dramatically increases the risk of continued use up to 1 year after surgery. Strategies to minimize opioid use include opioid-specific preoperative counseling, multimodal analgesia with opioid-sparing oral and intravenous medications, regional anesthesia, minimizing tourniquet use, and preoperative behavioral health evaluation.

Medicine (Baltimore). 2019 Oct;98(40):e17133

# Early preoperative versus postoperative administration of meloxicam in pain control, patient global status improvement, knee function recovery of arthroscopic knee surgery.

Hou J, Li W, Chen Y, Yang L, Li L, Zhao L

BACKGROUND: This study aimed to investigate the efficacy and safety between early preoperative administration and postoperative administration of oral meloxicam in patients underwent arthroscopic knee surgery (AKS).

METHODS: Totally 296 patients with the intention to undergo AKS were recruited and randomly allocated as 1:1 ratio into early preoperative analgesia (EPA) group and postoperative analgesia (POA) group. Pain visual analog scale (VAS) score and severity (at rest and at flexion), patient global assessment (PGA) score, the consumption of rescue analgesia (pethidine), and adverse events were evaluated during the perioperation. And knee range of motion (ROM), International Knee Documentation Committee (IKDC) score, and Lysholm score were assessed at baseline and at 3 months after AKS.

RESULTS: Both pain VAS score and severity (at rest and at flexion) were decreased at 4, 8, and 12 hours, but similar at -24, -2, 24, 36, and 48 hours after AKS in EPA group compared with POA group. Besides, PGA score was lower at 4, 8, 12, and 24 hours, but similar at -24, -2, 36, and 48 hours after AKS in EPA group compared with POA group. As to the consumption of pethidine in perioperative period, it was decreased in EPA group compared with POA group. No difference was observed in knee ROM, IKDC score, Lysholm score, and adverse effects between EPA group and POA group.

CONCLUSION: Early preoperative administration of meloxicam was a superior approach in pain control compared with postoperative administration in treating patients underwent AKS.

J Trauma Acute Care Surg. 2019 Nov;87(5):1181-1188

# Ketamine infusion for pain control in elderly patients with multiple rib fractures: Results of a randomized controlled trial.

Kugler N, Carver T, Juul J, Peppard W, Boyle K, Drescher K, Szabo A, Rein L, Somberg L, Paul J

BACKGROUND: Rib fractures are associated with increased mortality, particularly in the elderly. While opiate-based pain regimens remain the cornerstone of rib fracture management, issues related to opioids have driven research into alternative analgesics. Adjunctive ketamine use in lieu of opioids continues to increase but little evidence exists to support its efficacy or safety within the elderly trauma population.

METHODS: A prospective, randomized, double-blind placebo-controlled trial of elderly patients (age, ≥65 years) with three or more rib fractures admitted to a Level I trauma center was conducted. Exclusion criteria included Glasgow Coma Scale score less than 14, and chronic opiate use. Groups were randomized to either low-dose ketamine (LDK) at 2 μg·kg·min or an equivalent rate of 0.9% normal saline. The primary outcome was reduction in numeric pain scores (NPS). Secondary outcomes included oral morphine equivalent (OME) utilization, epidural rates, pulmonary complications, and adverse events.

RESULTS: Thirty (50.8%) of 59 were randomized to the experimental arm. Groups were similar in makeup. Low-dose ketamine failed to reduce 24-hour NPS or OME totals. Subgroup analysis of 24 patients with Injury Severity Score greater than 15 demonstrated that LDK was associated with a reduction in OME utilization the first 24-hours (25.6 mg vs. 42.6 mg, p = 0.04) but at no other time points. No difference in other secondary outcomes or adverse events was noted.

CONCLUSION: Low-dose ketamine failed to affect NPS or OME within the overall cohort, but a decrease in OME was observed in those with an Injury Severity Score greater than 15. Additional studies are necessary to confirm whether LDK benefits severely injured elderly patients.

LEVEL OF EVIDENCE: Therapeutic, level I.

J Emerg Med. 2019 Oct;57(4):587-588

Ketamine: Safe Until It's Not - A Terrifying Trip to the K-Hole.

Simon E

On a daily basis we, as emergency medicine providers, discuss drugs and their side effect profiles. We often survey our colleagues regarding rare reported phenomena that have not been previously encountered. In my short emergency medicine career, I've heard the praises of ketamine thousands of times over: “Ketamine is safe and effective.” “You can never give too much ketamine.” “You can theoretically get an emergence reaction, but I haven't seen it.” I will be the first to admit that I used ketamine for nearly every procedural sedation that I performed—until my little adventure to the K-hole.

J Trauma Acute Care Surg. 2019 Oct;87(4):883-891

# Ketamine/propofol admixture vs etomidate for intubation in the critically ill: KEEP PACE Randomized clinical trial.

Smischney N, Nicholson W, Brown D, Gallo De Moraes A, Hoskote S, Pickering B, Oeckler R, Iyer V, Gajic O, Schroeder D, Bauer P

BACKGROUND: Periintubation hypotension is associated with poor outcomes in the critically ill. We aimed to determine if an admixture of ketamine and propofol for emergent endotracheal intubation in critically ill patients was superior to etomidate. Primary endpoint was the change in mean arterial pressure from baseline to 5 minutes postdrug administration.

METHODS: Emergent-use, stratified (shock status and unit type), multiunit, randomized, parallel-group superiority clinical trial was conducted at a tertiary academic medical center. Adult medical/surgical and transplant/oncologic intensive care unit patients undergoing emergent intubation were assigned randomly to receive either ketamine/propofol admixture (0.5 mg/kg of ketamine and propofol each) or reduced dose etomidate (0.15 mg/kg) for emergent intubation.

RESULTS: One hundred sixty participants were randomized, and 152 (79 ketamine/propofol admixture, 73 etomidate) were included in the intention-to-treat analysis. There was no statistically significant difference in mean arterial pressure change from baseline to 5 minutes postdrug administration (treatment difference [ketamine/propofol admixture-etomidate]: -2.1 mm Hg; 95% confidence interval, -6.9 mm Hg to +2.7 mm Hg; p = 0.385). In addition, no statistically significant difference was demonstrated in the change of mean arterial pressure from baseline at 10 minutes and 15 minutes postdrug administration, no statistical difference in the use of new-onset vasoactive agents or difficulty of intubation between groups. More patients in the etomidate group required non-red blood cell transfusions (16 [22%] vs. 8 [10%], p = 0.046). For patients who had adrenal testing performed, more patients in the etomidate group developed immediate adrenal insufficiency (13 [81%] of 16 vs. 5 [38%] of 13, p = 0.027). Serious adverse events were rare, 2 (3%) (cardiac arrest, hypotension) in ketamine/propofol admixture and 4 (5%) (hypertension, hypotension) in etomidate (p = 0.430).

CONCLUSION: In a heterogeneous critically ill population, ketamine/propofol admixture was not superior to a reduced dose of etomidate at preserving per-intubation hemodynamics and appears to be a safe alternative induction agent in the critically ill.

LEVEL OF EVIDENCE: Therapeutic/Care Management, level II.

TRIAL REGISTRY: ClinicalTrials.gov, NCT02105415, Ketamine/Propofol Admixture "Ketofol" at Induction in the Critically Ill Against Etomidate: KEEP PACE Trial, IRB 13-000506, Trial Registration: March 31, 2014.