Administration of Nebulized Ketamine for Managing Acute Pain in the Emergency Department: A Case Series

Ketamine administration in sub-dissociative doses in the emergency department (ED) results in effective pain relief in patients with acute traumatic and non-traumatic pain, chronic pain, and opioid-tolerant pain. This case series describes five adult ED patients who received nebulized ketamine for predominantly acute traumatic pain. Three patients received nebulized ketamine at 1.5 milligrams per kilogram (mg/kg) dose, one patient at 0.75 mg/kg, and one patient at 1 mg/kg. All five patients experienced a decrease in pain from the baseline up to 120 minutes. The inhalation route of ketamine delivery via breath-actuated nebulizer may have utility for managing pain in the ED.


INTRODUCTION
Ketamine is a non-competitive N-methyl-D-aspartate/ glutamate receptor complex antagonist that decreases pain by diminishing central sensitization, hyperalgesia, and "wind-up" phenomenon at the level of the spinal cord (dorsal ganglion) and central nervous system. 1 Ketamine administration in subdissociative (SDK) dose (0.1-0.3 milligrams per kilogram (mg/ kg)) in the emergency department (ED) results in effective pain relief in patients with acute traumatic and non-traumatic pain, chronic non-cancer and cancer pain, and opioid-tolerant pain by virtue of providing anti-hyperalgesia, anti-allodynia, and antitolerance. 2,3 Two commonly employed administration strategies of SDK administration in the ED include an intravenous (IV) route (push-dose, short infusion, or continuous infusion), and intranasal route. 4,5 However, in situations when IV access is unobtainable and /or mucosal atomization device is not readily available, nebulized routes of analgesic administration can be used. The nebulization of analgesics in the ED provides rapid, effective, and titratable analgesic delivery. It also results in less painful methods of analgesic delivery, minimizes analgesic toxicity and side effects (for example-opioids), and improves overall management of a variety of painful conditions in the ED. 6 Maimonides Medical Center, Department of Emergency Medicine, Brooklyn, New York Nebulized administration of ketamine has been studied in the areas of palliative care, therapy for asthma, and acute postoperative management of sore throat. [7][8][9] To our knowledge, there is no literature regarding analgesic efficacy and safety of nebulized ketamine's role in managing acute painful conditions in the ED.The following cases describe five patients presenting to the ED of a tertiary medical center between May-June 2019 with acute painful conditions and receiving nebulized ketamine at three different dosing regimens of 0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg via breathactuated nebulizer.

CASE SERIES
We describe five patients, ages 30-54, who presented to the ED with acute painful conditions: four patients with traumatic musculoskeletal pain, and one with abdominal pain (Table 1).

Case #1
A 44-year-old man without prior medical history presented to the ED with one-day history of traumatic injury to his right wrist and hand with severe 8/10 pain and moderate swelling along the dorsal aspect of the right hand and wrist. Radiographs were negative for acute fracture or dislocation. The patient received only two doses of nebulized ketamine at 0.75 mg/kg with change in pain score from eight at the baseline to one at 120 minutes (min) ( Table 2). The patient was discharged with a final diagnosis of wrist strain.

Case #2
A 43-year-old woman without prior medical history presented to the ED with a chief complaint of 8/10 severe bilateral knee pain over the prior six months with pain radiating to both of her calf muscles and associated with stiffness. On physical examination the patient had moderate right patellar tenderness, no appreciable joint effusion, and no evidence of infectious/inflammatory processes. She received a single dose of nebulized ketamine at 1 mg/kg with a change in pain score from eight at baseline to zero at 120 min ( Table 2). The patient was discharged with a final diagnosis of traumatic knee pain.

Case #3
A 30-year-old man without prior medical history presented to the ED with severe, 8/10 pain to his left hand after slamming it with a car door. On examination, the patient was noted to have swelling and tenderness to palpation at the dorsal aspect of the left hand/metacarpal region with decreased range of motion at the second through fifth metacarpal joints and intact neurovascular status. He received nebulized ketamine at 1.5 mg/ kg with change in pain score from eight at the baseline to two at 120 min ( Table 2). The patient was discharged with a final diagnosis of hand contusion.

Case #4
A 54-year-old man without prior medical history presented to the ED with severe, 9/10 acute lower back pain after a fall at home that resulted in the patient landing on his back and swelling, ecchymosis, or laceration. He received nebulized ketamine at 1.5 mg/kg with change in pain score from nine at the baseline to zero at 120 min ( Table 2). The patient was discharged with a final diagnosis of traumatic back pain.

Case #5
A 38-year-old woman without prior medical history presented to the ED with chief complaint of severe 9/10 crampy abdominal pain and nausea and single episode of loose stool. On examination, the patient had prominent epigastric and periumbilical tenderness without rebound and guarding. She received IV famotidine and ketorolac without appreciable pain relief and subsequently received two doses of nebulized ketamine at 1.5 mg/kg with change in pain score from nine at the baseline to zero at 120 min ( Table 2). The patient was discharged with a final diagnosis of viral gastroenteritis.
Three patients were male and two were female. None of the patients had absolute contraindications to ketamine such as allergy to ketamine, pregnancy, or history of schizophrenia. We used a standard verbal numeric pain-rating scale to evaluate patients' pain scores at the baseline and at 15, 30, 60, 90, and 120 min. 10 We used the Side-effects Rating Scale of Dissociative Anesthetics to describe side effects related to ketamine administration from baseline to 120 min. 11 Three patients received nebulized ketamine via breathactuated nebulizer at 1.5 mg /kg dose, one patient at 0.75 mg/kg, and one patient at 1 mg/kg. Two patients requested and received a second dose of nebulized ketamine. The dosages of nebulized ketamine (ordered and received) as well as baseline vital signs are presented in Tables 1 and 2. All five patients experienced a decrease in pain from baseline to 15 min, 30 min, 60 min, 90 min, and 120 min post medication administration ( Table 2).
One patient experienced dizziness of modest intensity that was self-limited after 60 min and felt fatigued at 90 min. Another patient experienced a mood change, self-described as feeling "relaxed and happy," at 15 min (Table 3). No patient experienced elevated heart rate and/or blood pressure during the observational period.

DISCUSSION
In situations when intravenous access and /or mucosal atomization devices are not readily available, inhalation (nebulization) route might be considered for provision of timely and effective analgesia in the ED. However, safety and efficacy of ketamine in a nebulized form as an analgesic in the ED setting has yet to be shown.
Nebulized administration of ketamine has been studied in the areas of palliative care, asthma therapy, and acute postoperative management of sore throat. 7-9,12,13 Five randomized trials have compared nebulized ketamine either in a fixed-dosing regimen (50 mg) or weight-based dosing (0.5 mg/kg, 1mg/kg, or 1.5 mg/kg) to placebo in reducing postintubational sore throat. The average decrease of postoperative throat pain decreased by 44-50% without any major side effects. 7-9, 12,13 Similarly, ketamine inhalation in healthy volunteers was easily tolerated and was not associated with oropharyngeal irritation, hypersalivation, stridor, laryngospasm, cough, dry mouth, hoarseness, dyspnea, tachypnea, aspiration, cardiac dysrhythmias, or desaturations. 14,15 Pharmacokinetic properties of inhaled ketamine have not been studied broadly, but a single observational study evaluated pharmacokinetics of S-ketamine administered via nebulization to 12 healthy volunteers at doses of 0.35, 0.5, and 0.7mg/kg and inhalation duration of 20-40 min. The study demonstrated a time to maximum concentration of 15-22 min and a maximum concentration of 128ng/ml. 15 In addition, based on the bioavailability of intranasal ketamine (25-50%) and oral ketamine (16-24%), the bioavailability to nebulized ketamine ranges between 20-40% of IV route. 16,17 To date, this case series is the first to describe the use of nebulized ketamine via breath-actuated nebulizer at three different dosing regimens, with titration as needed for patients presenting to the ED with acute traumatic and nontraumatic painful conditions. The breath-actuated nebulizer (BAN) (AeroEclipse, Trudell Medical International, London, Ontario, Canada) provides smaller particles and greater dose delivery efficiency than continuous jet nebulizers. In addition, BAN possesses dual modes of action: 1) continuous aerosol generation; and 2) breath-actuated (in response to the patient's

Drapkin et al.
Administration of Nebulized Ketamine for Managing Acute Pain in the ED inspiratory flow), ensuring that virtually no drug is lost to the environment. 18,19 Furthermore, BAN has a potential to provide greater compliance and safer patient environment that may impact overall pain management, patients satisfaction, and length of stay in the ED. All five patients had a decrease in pain from the baseline to 120 min with average change in pain score of 3.6 at 15 min, 4.6 at 30 min, 6.4 at 60 min, 7.6 at 90 min, and 7.8 at 120 min. Furthermore, only one patient experienced dizziness of modest intensity. While the descriptive nature of this report cannot be used to make any conclusion of safety and efficacy of nebulized ketamine in managing pain in the ED, the non-invasive route, titratability, and self-administration (by the patient) make this analgesic modality an attractive choice, especially when IV access is not readily available or unobtainable. There is a need for larger, dose-finding studies in a prospective, randomized fashion to fully evaluate the safety and efficacy of nebulized ketamine for analgesia in the ED.

CONCLUSION
The inhalation route of ketamine delivery via breath-actuated nebulizer for managing pain in the ED may add an additional modality to the analgesic armamentarium of ED clinicians in providing rapid, effective, and non-invasive pain relief.  Table 3. Severity of side effects using rating scale of dissociative anesthetics by patient and time.
Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.