American Journal of Emergency Medicine 33 (2015) 601.e5-601.e7

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American Journal of Emergency Medicine

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Case Report

Short (low-dose) ketamine infusion for managing acute pain in the ED: case-report series

Abstract

A convenience sample of 14 patients received an Analgesic dose of ketamine infusion for acute pain in the emergency department (ED). low-dose ketamine (LDK) was defined as the administration of 0.2 to 0.4 mg/kg of ketamine, and infusion was defined as a drip of ketamine diluted in 50 to 100 mL of normal saline piggyback administered over 10 to 15 minutes. Pain intensity was measured using validated Numeric rating scale in 8 of the 14 cases, 5 were documented nonquantitatively, and 1 case was not documented. Fourteen cases in which patients received LDK infusion in the ED were identified. Doses ranged from 10 to 35 mg. Patients received opioids in the ED before LDK infusion in 12 of the 14 cases. Signifi- cant improvement in pain was observed in 11 of the 14 cases. None of the patients required Rescue analgesia. Two patients reported mild adverse reactions. The administration of analgesic dose of ke- tamine infusion in the ED may be a safe and effective analgesic mo- dality for ED patients with acute painful conditions who have a history of chronic opioid use or who are refractory to Opioid pain medications. More prospective randomized controlled trials are needed before widespread use of LDK infusion for analgesia in the ED can be recommended.

Patients with prior chronic opioid use or with preexisting chronic painful conditions who present to the emergency department (ED) with acute pain or acute exacerbation of their chronic pain present a great challenge to emergency physicians in terms of their pain manage- ment. Some of these patients are tolerant to doses of opioids that most emergency physicians are not comfortable giving; some refuse opioids because of their prior history of abuse and/or dependence. Furthermore, opioids at higher doses may cause significant side effects including re- spiratory depression, Hemodynamic compromise, vomiting, and pruri- tus. This is where ketamine, in its subdissociative dose, poses a potentially enticing analgesic alternative.

There have been several recent studies looking at subdissociative dose (0.1-0.6 mg/kg) ketamine for analgesia (eg, [1, 2]). Ketamine infu- sions, on the other hand, have received little study in the acute pain set- ting. The potential advantage of ketamine being given slowly is the reduction of ketamine’s most common and use-limiting adverse effects of dysphoria, nausea, and dream-like state. Currently, ketamine infusion is being used as second-line treatment for patients with chronic pain and is given over several hours to days [1, 2]. So far, to our knowledge, the only studies to look at ketamine infusions in the acute pain setting is Gurnani et al [3], where victims of trauma were given a subcutaneous bolus of ketamine initiated in the field followed by a subcutaneous infu- sion over 24 hours, with promising results. And in the study of Galinski et al [4], where patients were randomized to morphine alone or

morphine with LDK given over 10 minutes and found the patients who received ketamine had a statistically significant decrease in their morphine requirements.

Here, we present a case series of 14 patients from our ED who were given intravenous infusions of ketamine at 0.2 to 0.4 mg/kg mixed in 50 to 100 mL of normal saline administered over 10 minutes.

A retrospective chart review was conducted for patients to whom we administered an infusion of 0.2 to 0.4 mg/kg ketamine for pain con- trol in the Maimonides Medical Center ED. Maimonides Medical Center is a tertiary care community hospital and academic institution. The ED has a volume of 120000 visits annually. Approval was obtained for ex- emption from the Maimonides Institutional Review Board.

The electronic medical record system was used to identify adult patients who received ketamine from any of the authors between February 2012 and 2014. The records were reviewed to identify those who received subdissociative ketamine for pain control. Patients were excluded if they did not receive ketamine as infusion; or for whom no specific documentation of ketamine was given as infusion could be found. Patients were also excluded if ketamine was given at higher than subdissociative doses. Subdissociative doses of ketamine via infu- sion were defined as 0.2 to 0.4 mg/kg of ketamine administered in a pig- gyback of 50 to 100 mL of normal saline over 10 minutes for pain control. Each patient chart was then reviewed; and demographic data, doses of ketamine, side effects, and use of opioid analgesics before and/or after administration were tabulated and analyzed. The data collection was not blinded.

We identified 14 cases in which subdissociative ketamine infu- sion was given for pain control (Table 3). The patients in the series ranged between the ages of 22 and 74 years with a mean age of 44 years (Table 3). Fifty percent were men, and 50% were women (Table 3). The most common chief complaints were abdominal pain (31%), back pain (19%), and chest pain (19%). None of the pa- tients in the study were recreational Drug users. Thirty-three percent of patients used opioids at home; and 86% of them received opioids in the ED before ketamine administration, namely, morphine (56%) and hydromorphone (25%) (Table 1).

Pain improvement was documented by physician or nurse on an 11-point numerical rating scale in 8 of 14 cases (Table 2). In the re- maining cases, there were no records of pain scale use–instead, the patient’s level of pain was documented nonquantitatively. None of the patients required rescue analgesia within 1 hour of keta- mine administration. Of the 14 patients, 13 received pain medica- tions in the ED before ketamine.

There were no dangerous adverse effects recorded of subdissociative ketamine infusion in the case series. However, of the 14 patients, 9 were not placed on a monitor before or during the administration of ketamine infusion. One patient complained of tinnitus and uneasiness during the

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Table 1

Medications in the ED before ketamine

Patient Medications in the ED before ketamine

Morphine 8 mg, morphine 5 mg

Hydromorphone 2 mg, hydromorphone 1 mg

Hydromorphone 1 mg

Morphine 5 mg, ketorolac 30 mg

Morphine 5 mg, morphine 5 mg

Morphine 10 mg, oxycodone 5 mg/acetaminophen 325 mg 1 tab

Ibuprofen 800 mg, methocarbamol 1.5gm, diazepam 10 mg, ketorolac 15 mg

Diazepam 5 mg, ketorolac 30 mg, morphine 5 mg, diazepam 5 mg,

oxycodone 5 mg/acetaminophen 325 mg 1 tab

None

Hydromorphone 4 mg, hydromorphone 4 mg

Morphine 10 mg

Ketorolac 10 mg, morphine 5 mg

Hydromorphone 1 mg

Oxycodone 5 mg/acetaminophen 325 mg 1 tab, morphine 5 mg,

oxycodone 5 mg/acetaminophen 325 mg 1 tab, morphine 5 mg

Table 2

Pain scores

Patient	Triage pain score	Preketamine pain score	Postketamine pain score
1	10	Not documented	3
2	10	Not documented	“Improved”
3	7	5	“Better”
4	6	Not documented	“Controlled”
5	5	Not documented	“Slightly improved”
6	10	Not documented	0
7	8	8	7
8	10	9	0
9	3	10	1
10	5	10	4
11	6	7	6
12	10	Not documented	“Much better”
13	6	9	5
14	7	Not documented	Not documented

infusion. One patient complained of dizziness. None of the patients experienced tachycardia, hypertension, dysphoria, nausea, vomiting, dream-like state, hallucinations, or emergence reactions.

Ketamine is a noncompetitive N-methyl D-aspartate receptor antag- onist that blocks the release of excitatory neurotransmitter glutamate and provides anesthesia, amnesia, and analgesia by virtue of decreasing central sensitization and “wind-up” phenomenon [5]. When given at subdissociative (analgesic) doses of 0.1 to 0.6 mg/kg, either as an ad- junct to opioid analgesic or as a single agent, ketamine provides good analgesia while preserving airway patency, ventilation, and cardiovas- cular stability [4]. In addition, an analgesic dose of ketamine may in- crease the analgesic potency of opioids, thus decreasing their dosing

requirements [6]. Based on the aforementioned facts, ketamine offers an attractive option for providing safe and effective pain control for pa- tients in the ED.

Three recent studies that evaluated subdissociative doses of keta- mine given as Intravenous push for acute pain prehospital or in the ED demonstrated a significant percentage of minor side effects that includ- ed dizziness, nausea, and feeling of unreality [7-9]. Jennings et al [7] conducted a randomized, controlled, open-label trial looking at keta- mine and morphine vs morphine alone in the prehospital arena in pa- tients with traumatic pain. Ketamine was dosed at 10 to 20 mg as initial bolus followed by increments of 10 mg every 3 minutes until pain free or a serious adverse event (eg, hypotension or respiratory depression), or the patient arrived at the ED. Of the 70 patients who re- ceived ketamine, 11% experienced feeling of disorientation, 4% reported nausea, and 4% had decreased consciousness. Ahern et al [8] conducted a prospective observational study of 15 ED patients. Patients were given

0.5 mg of hydromorphone and 15 mg of ketamine intravenously, with 80% reporting any adverse effect; 6 patients reported dizziness, 5 nausea, 5 fatigue, 5 mood changes, and 3 headache. Lester et al [9] conducted a retrospective case series of 34 ED patients who received intravenous LDK for acute pain. There is a mention of 1 patient experiencing a dysphoric reaction. Galinski et al [4] conducted a prospective, double- blind, randomized, control trial of 73 ED patients with acute pain. All patients were given an initial 0.1 mg/kg morphine bolus intravenously followed by either ketamine 0.2 mg/kg over 10 minutes or morphine

0.1 mg/kg intravenously. Of 33, 12 (36%) of patients had neuropsychiatric effects and 8 (6%) had nausea and vomiting.

Thus, ketamine infusion seems a potentially better option to offset these side effects. Ketamine infusions have been used at least as far back as the 1980s. Currently, ketamine infusions are being given perioperatively as well as for patients with chronic pain and/or refractory depression [1,10,11].

Gurnani et al [3] published–to our knowledge–the first study of ketamine infusions for acute pain with excellent results. This was a double-blind trial of 40 adult patients with acute musculoskeletal trauma. After a patient was evaluated by an acute care physician, they were randomized into either the morphine or ketamine group. The morphine group would receive 0.1 mg/kg of morphine intravenously every 4 hours, whereas the ketamine group received subcutaneous ketamine bolus 0.25 mg/kg followed by infusion at

0.1 mg/kg per hour. The infusion was continued for 24 hours. Both received either placebo intravenous normal saline or placebo subcuta- neous saline. The investigators found that patients assigned to the ketamine group had significantly lower pain scores, were less sedated, and required significantly less supplemental analgesia for fracture mobilization. Two patients reported dreams, both after the initial bolus; otherwise the morphine group had more adverse effects (nausea, vomiting, and Urinary retention).

Table 3

Demographics

Patient	Age	Sex	Chief complaint	Medical history	Opioid use at home
1	74	F	Fall, painful wrist	Hypertension, Hypothyroidism	None
2	30	M	Abdominal pain	Depression, diverticulitis, chronic abdominal pain	None
3	29	F	Chest pain	CVA, diabetes, hypertension, Mitral valve replacement, end-stage renal disease	None
4	22	M	Chest pain	Thoracic outlet syndrome, upper extremity Venous thrombus	Oxycodone/acetaminophen
5	46	F	Back pain/leg weakness	Lung cancer, pleural effusion	None
6	51	M	Burn–skin	Chronic obstructive pulmonary disease	Morphine
7	49	M	Back pain, chronic	Hypertension	None
8	50	F	Back pain	None	Unknown
9	60	F	Abdominal pain	Brain tumor, diverticulitis, gastritis, pancreatic mass	None
10	40	F	Sickle cell crisis	Sickle cell disease	Methadone, hydromorphone
11	51	F	Abdominal pain	Anxiety, chronic obstructive pulmonary disease, depression, gastritis	Morphine
12	54	M	Neuropathic foot pain	Parkinson, anxiety	None
13	43	M	Abdominal pain	hiatal hernia, pancreatic neuroendocrine tumor	Oxycodone
14	60	M	Traumatic chest pain after a fall	Hypertension, hypothyroidism, coronary artery disease, arrhythmia, hyperlipidemia	None

Abbreviations: M, male; F, female; CVA, stroke.

A. Goltser et al. / American Journal of Emergency Medicine 33 (2015) 601.e5–601.e7 601.e7

The use of ketamine infusions perioperatively has been recently looked at by the Cochrane review [10]. Although the doses and dura- tions of infusions used in the included studies varied widely, most treat- ment arms showed favorable results for decreasing pain and opiod requirements in the ketamine treatment arms.

Outpatient ketamine infusions for chronic pain show mixed results. These, however, are based on retrospective data and case reports [1,2,11]. In the case series of Patil and Anitescu [1], patients were given ketamine at 0.5 mg/kg over 30 to 45 minutes after pretreatment with midazolam, with increases in dosage as tolerated on subsequent infusions, going up as high as 1.5 mg/kg. Most of the reported side ef- fects were mild, and none of the patients had to stop infusions because of the side effects. Most common adverse events were hypertension (12%), hallucination (10%), and sedation (8%). Zempsky et al [11] ad- ministered LDK infusions to 5 admitted pediatric patients with acute sickle cell vasoocclusive crises. The starting doses ranged from 0.06 mg/kg per hour to 0.1 mg/kg per hour with titration upward based on tolerance and attending preference, with a maximum rate of 0.2 mg/kg per hour. Duration of the infusions ranged from 19 to 90 hours. Of the 5 patients, 2 achieved adequate pain control, and 2 of 5 who had infu- sions discontinued due to side effects (1 patient exhibited nystagmus, unresponsiveness, agitation, and increased blood pressure; and the second experienced dysphoria and asked to be taken off). One patient who had infusion discontinued due to inadequate pain control.

This case series describes short low-dose intravenous ketamine infu- sions for acute pain in ED patients. Of the 14 patients enrolled, 10 had a history of chronic pain, which make our population different from most prior studies looking at LDK in the ED. Compared with Lester et al [9], however, who had a comparable patient population, the efficacy was similar, 71% had significantly reduced pain scores compared with 54% in Lester et al [9]. Similar to Lester et al [9], 1 patient in our series had an adverse event (dysphoria and tinnitus). However, compared with Intravenous bolus dosing of ketamine, none of the patients in this case series experienced nausea or vomiting or emergence reaction or had any significant change in vital signs or mental status.

Besides the well-described limitations of a case series, our study was limited for the most part to patients who the treating physician felt did not respond to opioid pain medications, many of whom had a history of chronic pain and/or opioid use. These results therefore should not be ex- trapolated to opioid naive patients. Our study did not detect any signif- icant changes in hemodynamics, however, most of our patients were not on continuous cardiac monitoring and had recorded vital signs at 2- to 4-hour intervals as is standard in our ED for nonmonitored pa- tients. All of our study patients were felt to be Hemodynamically stable patients or at low risk for hemodynamic decompensation by the treating physician. Because the study is retrospective, many charts are missing postanalgesia pain scores as well as specific documentation on presence/absence of adverse reactions.

Ketamine infusion is a potentially enticing alternative to ketamine push for having less incidence of adverse effects of ketamine while maintaining ketamine’s proven Analgesic efficacy. So far, ketamine has shown great potential, especially for patients who do not respond to opioid medications. At this time, however, more research is needed be- fore implementing widespread use of subdissociative dose ketamine

infusion for acute pain in the ED. Further study is also necessary for ketamine for pain control in hemodynamically unstable patients for whom opioids pose a danger of hemodynamic decompensation.

Anatoliy Goltser, MD Department of Emergency Medicine Brookdale University Hospital Medical Center 1 Brookdale Plaza, Brooklyn, NY 11212

Corresponding author. Tel.: +718 240 5000

E-mail address: agoltser435@gmail.com

Emil Soleyman-Zomalan, MD Texas Health Resources, Arlington Memorial Hospital 800 West Randol Mill Rd. Arlington TX 76012

E-mail address: emil@soleyman.com

Frayda Kresch, MD¹ Sergey Motov, MD² Department of Emergency Medicine Maimonides Medical Center 4802 Tenth Ave, Brooklyn, NY 11219

E-mail addresses: fkresch@maimonidesmed.org (F. Kresch) smotov@maimonidesmed.org (S. Motov)

¹Tel.: +1 718 283 6029; fax: +1 718 635 7274

²Tel.: +1 718 283-6029; fax: +1 718 635 7274

http://dx.doi.org/10.1016/j.ajem.2014.09.029

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