Intraoperative Low-dose Ketamine Infusion as the Main Analgesic in Burn Patients

The purpose of this study is to determine whether a low-dose ketamine infusion can be used as the main intra-operative analgesic in different burn patients, and thereby reduce the total intra-operative opioid requirement. Secondary objectives are to determine whether this low-dose ketamine infusion will lengthen the amount of time to the first narcotic given in the recovery room or ICU, and whether pain scores for awake patients will be lower post-operatively.

Study Overview

• Status: Unknown
• Conditions: Burns
• Intervention / Treatment: Drug: Ketamine; Drug: Sodium chloride

Detailed Description

Burn patients suffer from several types of pain (due to stimulation of mechanoreceptors, nociceptors, and chemical stimulation) as well as other injuries. Multiple agents are used to control pain in this special group. Due to different pain mechanisms and the up-regulation of the mu receptors, numerous pain controlling modalities should be sought. Opioids are the mainstay in treating pain in such patients. Adjuvant non-opioid agents are less effective if used alone. These agents include non-steroidal, anti-inflammatory drugs (NSAIDs), α-2 antagonists, local anesthetics and ketamine. Regional blocks can be used in the perioperative period if there are no contraindications, but catheters cannot be left in place for an extended period of time. Opioids have many side effects such as respiratory depression, nausea, vomiting, itching, urinary retention, and hyperalgesia. The latter is of concern in any patient on chronic opioids, including burn patients.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) antagonist that has been successfully used in burn intensive care units (BICUs) to provide pain for dressing changes. It also has been in use in BICUs to supplement the analgesic effect of opioids. Ketamine exerts its clinical analgesic effect mainly by NMDA antagonism, but it also interacts with other receptors such as AMPA monoaminergic, nicotinic, muscarinic, and mu, delta, and kappa opioid receptors. It resembles local anesthetics in its interaction with sodium channels. Low dose ketamine infusion (LDKI) has been used as a postoperative analgesic in different patients group for various duration of time. Some studies have shown some benefit to using intraoperative low-dose ketamine in non-burn surgery in order to reduce post-operative opiate requirement. Little is known, from the literature, if an intraoperative low-dose ketamine infusion can be used as the main analgesic in burn patients in general, and in severely burned patients in specific.

Previous studies have shown that ketamine potentiates the analgesic effects of low-dose fentanyl and, to a lesser degree, low-dose morphine by stimulation of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). It also increases the duration of opioid-induced analgesia, delays opioid induced tolerance, and plays a role in preventing opioid-induced hyperalgesia by delaying desensitization and by improving resensitization of ERK 1/2 signaling. From this pharmacologic standpoint, it is advantageous over other pain modalities in hemodynamically-compromised burn patients.

Ketamine is being used extensively in burn ICUs but the low-dose infusion of ketamine did not capture as much attention in treating burn patients in the operating room (OR). Burn patients come to the OR numerous times for wound debridement, skin grafting or unrelated surgeries. The use of inhalation anesthetics poses the risk of hypotension in these hemodynamically fragile patients. Opioids are still the main agents in treating such patients in the OR and they are sometimes given in very high doses, due to the resistance and up-regulation of the mu opioid receptors mentioned above. These doses are often not very effective in controlling pain and can lead to hypotension if combined with potent inhalation agents.

• Study Type: Interventional
• Enrollment (Anticipated): 46
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Recruiting
      • Loyola University Medical Center
      • Contact: Katharine Miles, MD; Phone Number: 708-216-4174; Email: katharine.miles@lumc.edu
      • Contact: Jane Wido; Phone Number: 708-216-5119; Email: jwido@lumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All adult burn patients aged 18-80 presenting to the operating room, both intubated and non-intubated
• Patients having a procedure performed in Russo operating rooms at Loyola University Medical Center

Exclusion Criteria:

• Allergy to ketamine or benzodiazepines
• Ketamine use in the preceding 24 hours
• Children (patients under age 18), prisoners, pregnant or breastfeeding women, patients with psychosis, patients with developmental delay, and any condition which, in the opinion of the investigator, would prevent full participation in this study or would interfere with the evaluation of the trial endpoints.
• Increased intracranial pressure at the discretion of the investigator
• Increased intraocular pressure at the discretion of the investigator
• Porphyria at the discretion of the investigator
• Thyroid disorders at the discretion of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine; Participants randomized to this arm will receive ketamine (1 mg/ml solution) infused at 0.2 mg/kg/hour (0.2 ml/kg/h) for a maximum of 20 ml/hour.	Drug: Ketamine; Ketamine is a medication used for starting and maintaining anesthesia. Participants randomized to the ketamine arm will receive 1 mg/ml solution infused at 0.2 mg/kg/hour (0.2 ml/kg/h) for a maximum of 20 ml/hour.; Other Names: Ketalar
Placebo Comparator: Placebo; Participants randomized to this arm will receive 0.9 mg/ml sodium chloride, infused at a rate of 0.2 ml/kg/hour	Drug: Sodium chloride; Participants randomized to the placebo arm will receive 0.9 mg/ml sodium chloride, infused at a rate of 0.2 ml/kg/hour; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative fentanyl	For all participants, the dose of intraoperative fentanyl will be recorded in micrograms and compared between the two arms.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to the first narcotic	For all participants, the hours to the first dose of post-operative narcotic will be recorded and compared between the two arms.	24 hours

Collaborators and Investigators

• Sponsor: Loyola University
• Investigators: Principal Investigator: Katharine Miles, MD, Loyola University

Publications and helpful links

General Publications

• Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015 Jul;16(7):1402-9. doi: 10.1111/pme.12705. Epub 2015 Feb 3.
• Gupta A, Devi LA, Gomes I. Potentiation of mu-opioid receptor-mediated signaling by ketamine. J Neurochem. 2011 Oct;119(2):294-302. doi: 10.1111/j.1471-4159.2011.07361.x. Epub 2011 Sep 20.
• Kaur S, Saroa R, Aggarwal S. Effect of intraoperative infusion of low-dose ketamine on management of postoperative analgesia. J Nat Sci Biol Med. 2015 Jul-Dec;6(2):378-82. doi: 10.4103/0976-9668.160012.
• Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013 Jun;19(6):370-80. doi: 10.1111/cns.12099. Epub 2013 Apr 10.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2018
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: February 8, 2017
• First Submitted That Met QC Criteria: February 8, 2017
• First Posted (Actual): February 10, 2017

Study Record Updates

• Last Update Posted (Actual): March 14, 2019
• Last Update Submitted That Met QC Criteria: March 13, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Ketamine; Anesthesia; Burns
• Additional Relevant MeSH Terms: Wounds and Injuries; Burns; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 209459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan to share individual participant data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No