A Comparison of Intra-op Ketamine vs Placebo in Patients Having Spinal Fusion

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02424591
• Collaborator: (none)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 26
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

Postoperative pain is severe after major spine surgery. Opioids such as morphine and hydromorphone are routinely used for postoperative pain control. These drugs have significant side effects, most importantly respiratory depression, nausea, constipation and tolerance. Moreover, many spine surgery patients have used opioid pain medication for back pain long term, leading to pre-surgical opioid tolerance and increased postoperative pain. This has led to a search for adjuvant medications to reduce the use of opioids and reduce opioid mediated side effects and tolerance.

Ketamine is an intravenous anesthetic with analgesic properties in subanesthetic doses. Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are involved in central pain sensitization via wind-up phenomenon and altered pain memory, a process which can be blocked by ketamine. NMDA receptor antagonists may prevent the development of tolerance to opioids and hyperalgesia. Ketamine has been safely used to decrease pain in numerous studies. Ketamine can also act as an antidepressant with hours of administration.

Ketamine has rapid brain uptake and subsequent re-distribution with a distribution half-life of 10-15 minutes and an elimination half-life of 2 hours. Ketamine does not cause respiratory depression.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: Ketamine; Other: Placebo	Phase 4

Detailed Description

This is a prospective, single-blinded, placebo controlled single center trial. One hundred subjects (50 in each arm) will be enrolled. Subjects undergoing multilevel spinal fusion will be screened and have the study introduced and discussed with them during the preadmission visit. Subjects may also contact study personnel or be contacted by study personnel before admission. Upon admission on the day of surgery, patients will be re-screened, recruited, have informed consent obtained. After consent is achieved in the pre-admission clinic prior to surgery, patients will be asked to fill out Beck's depression inventory (BDI), post-operative quality of recovery score(QoR-15) form, visual analog scale (VAS) for pain and short form McGill pain questionnaire to establish baseline scores. These forms can be completed at pre-admission testing, at home or on the day of surgery. The three forms will be on postoperative days (POD) 1, 2 and 3; only the VAS will be given in the Post-Anesthesia Care Unit (PACU). Eligible subjects will be assigned to either the ketamine or placebo group based on a computer generated randomization (randomization.com). Baseline demographic data as well as medical history and medication list will be recorded.

Anesthetic management for this study will be exactly the same management that we are currently providing for patients undergoing multilevel spinal fusions. The only difference in care between the placebo group and the treatment group will be the addition of a low dose ketamine infusion in the treatment group. The placebo group will receive a fentanyl infusion at 1 mcg/kg/hr during the surgery and a morphine PCA for postoperative pain control. The placebo group will receive additional fentanyl as needed on the operating room and additional morphine as needed in the recovery room.

Anesthetic management for both groups will start with IV placement and routine (American Society of Anesthesiologists - ASA ) monitors. An arterial catheter may be placed at the discretion of the attending anesthesiologist. After preoxygenation, general anesthesia will be induced with Propofol 1 to 2 mg/kg, fentanyl 1 to 2 mcg/kg, and rocuronium .6 mg/kg. Maintenance of anesthesia will be a propofol infusion starting at 150 mcg/kg/min, fentanyl 1 mcg/kg/hr. Additionally, the ketamine group will receive a ketamine infusion at a rate of 10 mcg/kg/min starting after intubation and terminated at the start of skin closure. All patients will be treated with zofran and ofirmev during surgical closing. Pre-induction midazolam will be administered at the discretion of the anesthesiologist. No NSAIDS will be given because of bleeding risk. Sevoflurane may be used for brief periods at the beginning and end of the procedure to cover times when total intravenous anesthesia (TIVA) is not practical, i.e. when moving or positioning the patient. Additional fentanyl and rocuronium boluses can be given as needed. Administration of corticosteroids per surgeon's request will be recorded. Anesthetics will be titrated to maintain a Bispectral (BIS) index of 40 to 60. Patients will be awakened, extubated and transferred to the PACU after following simple commands. Morphine patient controlled anesthesia (PCA) at a setting of 1 mg dose with a 6 minutes lockout will be started immediately on arrival in PACU. While in the PACU, all subjects who do not have adequate pain control will receive rescue dose of morphine 2 mg. to 4 mg. as indicated by a numeric pain Rating Scale score > 3 or upon subjects' request. All narcotics and other pain medication given will be recorded. Postoperative nausea will be treated with droperidol .625 mg IV. If the patient's pain cannot be controlled with PCA morphine then a pain consult will be obtained. The pain service will be free to administer any medication deemed necessary to control the patient's pain.

PACU Monitoring: Once in the PACU, all patients will be monitored by PACU nurses per nursing protocol. The following questionnaires: 1) VAS for pain will be administered in the PACU. On postoperative day 1, 2 and 3 the McGill short form, VAS, Beck Depression Inventory (BDI) and QoR15 will be given.

The subjects who enroll in this study will be asked to fill out questionnaires at five different times. The questionnaires include The Beck depression inventory, McGill's short form pain questionnaire, Quality of Recovery - 15 form (QoR15) and the visual analog scale (VAS) for pain. The forms will be filled out at five separate times; preoperatively in pre-surgical testing or in the pre-surgical holding area of Tisch hospital, in the post anesthesia care unit of Tisch hospital after the surgery, on postoperative day #1, on postoperative day #2 and on postoperative day #3. In the PACU on the day of surgery, only the VAS will be given.

All subjects will be carefully monitored for safety and efficacy. While the ketamine or placebo is administered in the operating room, an anesthesiologist, Certified Registered Nurse Anesthetist (CRNA) or anesthesia resident will be present. In the PACU patients will have 1:1 or 1:2 nursing care. An anesthesiologist is immediately available in the PACU should a problem arise.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Prospective, Randomized, Single Blinded Comparison of Intraoperative Ketamine Infusion Versus Placebo in Patients Having Spinal Fusion
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ketamine ketamine group will be infused after intubation and terminated at the start of skin closure	Drug: Ketamine; Infusion at a rate of 10 mcg/kg/min; Other Names: Ketalar
Placebo Comparator: Placebo placebo group will have standard of care rather than ketamine infusion	Other: Placebo; Placebo IV

Outcome Measures

Primary Outcome Measures

1. Scores on Questionnaires [Post-op Day 3]

   Quality of Recovery 15 questions questionnaires that ask, on a scale of 0-10, with 0 always being bad and 10 always being best, how the patient is recovering. The total number is reviewed, so the highest total score possible is 150 and the lowest is 0.

Secondary Outcome Measures

1. Pain Score [Post-op Day 3]

   McGill Short Form measures pain in different ways. The first part of the form lists 15 adjectives for pain, for which the answers can be none (0), Mild (1), Moderate (2) and Severe (3). Descriptors 1-11 represent the sensory dimension of pain experience and 12-15 represent the affective dimension. A score of 0 is good, and a score of 45 indicates extreme pain. The lower the score the less pain a subject feels (better), as the scores go up, so do the pain levels (worse). PPI (Present Pain Intensity) asks patients to measure pain from 0 (no pain) to 5 (excruciating). Again, a lower score is ideal.

2. Beck's Depression Inventory [Post-op Day 3]

   Beck's Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures attitudes and symptoms of depression. Each sentence has a rating from 0 to 3 and the sentences go from mild to fairly severe descriptions of moods. The numbers are tabulated, the lowest possible score is 0 and the highest is 63. A score of 1-10 indicates normal ups and downs. 11-16 indicates a mild mood disturbance; 17-20, borderline clinical depression; 21-30, moderate depression; 31-40, severe depression; over 40, extreme depression

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adult (>/=18)

2. male or female

3. Undergoing surgery for multilevel (>2 level) spinal fusion from a posterior approach.

4. General anesthesia

5. English speakers such that they can complete the pain score and satisfaction questionnaires whose scores are a critical outcome variable.

6. If female, subject is non-lactating and is either: a. Post-menopausal or post hysterectomy; b. Of childbearing potential but is not pregnant at time of baseline as determined by pre-surgical pregnancy testing.

7. Subject is American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.

Exclusion Criteria:

1. Cognitively impaired (by history)

2. Subject with a history of psychosis

3. Subject known to have significant hepatic disease

4. Subject for whom opioids or ketamine are contraindicated

5. Patients with narrow angle glaucoma

6. Increased intracranial or intraocular pressure

7. If female, is either pregnant or lactating.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU School of Medicine	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: John Ard, MD, NYU School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004603. Review. Update in: Cochrane Database Syst Rev. 2015;7:CD004603.
• Loftus RW, Yeager MP, Clark JA, Brown JR, Abdu WA, Sengupta DK, Beach ML. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010 Sep;113(3):639-46. doi: 10.1097/ALN.0b013e3181e90914.
• Machado-Vieira R, Salvadore G, Diazgranados N, Zarate CA Jr. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther. 2009 Aug;123(2):143-50. doi: 10.1016/j.pharmthera.2009.02.010. Epub 2009 May 3. Review.
• Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995 Sep;62(3):259-274. doi: 10.1016/0304-3959(95)00073-2. Review.
• Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991 Mar;44(3):293-299. doi: 10.1016/0304-3959(91)90100-C.
• Yamauchi M, Asano M, Watanabe M, Iwasaki S, Furuse S, Namiki A. Continuous low-dose ketamine improves the analgesic effects of fentanyl patient-controlled analgesia after cervical spine surgery. Anesth Analg. 2008 Sep;107(3):1041-4. doi: 10.1213/ane.0b013e31817f1e4a.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02424591
• Other Study ID Numbers: 14-00599
• First Posted: Apr 23, 2015
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by NYU Langone Health: Anesthesia Recovery Period; Spinal Fusion
• Additional relevant MeSH terms: Pain, Postoperative; Ketamine

Study Results

Participant Flow

Recruitment Details	Patients were approached either at pre-admission testing or at the peri-op area of the hospital. All patients were spoken to privately and given time to ask questions. After consent was signed, a copy was given to the subject and a copy put into the medical record.
Pre-assignment Detail	One patient was excluded because his surgery was cancelled.

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine group will be infused after intubation and terminated at the start of skin closure Ketamine: Infusion at a rate of 10 mcg/kg/min	placebo group will have standard of care rather than ketamine infusion Placebo: Placebo IV
Period Title: Overall Study
STARTED	22	23
COMPLETED	20	20
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Ketamine	Placebo	Total
Arm/Group Description	ketamine group will be infused after intubation and terminated at the start of skin closure Ketamine: Infusion at a rate of 10 mcg/kg/min	placebo group will have standard of care rather than ketamine infusion Placebo: Placebo IV	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	65	65	65
Sex: Female, Male (Count of Participants)
Female	12 60%	8 40%	20 50%
Male	8 40%	12 60%	20 50%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%
Preoperative Opioid Use (Count of Participants)
Count of Participants [Participants]	9 45%	8 40%	17 42.5%
Prior Back Surgery (Count of Participants)
Count of Participants [Participants]	11 55%	13 65%	24 60%
Visual Analog Scale (VAS) Pain Score (points) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [points]	7	3.5	6
American Society of Anesthesiologists Physical Status Score (Count of Participants)
I	0 0%	1 5%	1 2.5%
II	10 50%	8 40%	18 45%
III	10 50%	11 55%	21 52.5%

Outcome Measures

1. Primary Outcome

Title	Scores on Questionnaires
Description	Quality of Recovery 15 questions questionnaires that ask, on a scale of 0-10, with 0 always being bad and 10 always being best, how the patient is recovering. The total number is reviewed, so the highest total score possible is 150 and the lowest is 0.
Time Frame	Post-op Day 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine group will be infused after intubation and terminated at the start of skin closure Ketamine: Infusion at a rate of 10 mcg/kg/min	placebo group will have standard of care rather than ketamine infusion Placebo: Placebo IV
Measure Participants	20	20
Median (Inter-Quartile Range) [points]	95	101

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Pain Score
Description	McGill Short Form measures pain in different ways. The first part of the form lists 15 adjectives for pain, for which the answers can be none (0), Mild (1), Moderate (2) and Severe (3). Descriptors 1-11 represent the sensory dimension of pain experience and 12-15 represent the affective dimension. A score of 0 is good, and a score of 45 indicates extreme pain. The lower the score the less pain a subject feels (better), as the scores go up, so do the pain levels (worse). PPI (Present Pain Intensity) asks patients to measure pain from 0 (no pain) to 5 (excruciating). Again, a lower score is ideal.
Time Frame	Post-op Day 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine group will be infused after intubation and terminated at the start of skin closure Ketamine: Infusion at a rate of 10 mcg/kg/min	placebo group will have standard of care rather than ketamine infusion Placebo: Placebo IV
Measure Participants	20	20
Median (Inter-Quartile Range) [points]	11	10.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Beck's Depression Inventory
Description	Beck's Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures attitudes and symptoms of depression. Each sentence has a rating from 0 to 3 and the sentences go from mild to fairly severe descriptions of moods. The numbers are tabulated, the lowest possible score is 0 and the highest is 63. A score of 1-10 indicates normal ups and downs. 11-16 indicates a mild mood disturbance; 17-20, borderline clinical depression; 21-30, moderate depression; 31-40, severe depression; over 40, extreme depression
Time Frame	Post-op Day 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Placebo
Arm/Group Description	ketamine group will be infused after intubation and terminated at the start of skin closure Ketamine: Infusion at a rate of 10 mcg/kg/min	placebo group will have standard of care rather than ketamine infusion Placebo: Placebo IV
Measure Participants	20	20
Median (Inter-Quartile Range) [points]	8	9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Data was reviewed for adverse events intraoperative through post-op day 3.
Arm/Group Title	Ketamine		Placebo
Arm/Group Description	ketamine group will be infused after intubation and terminated at the start of skin closure Ketamine: Infusion at a rate of 10 mcg/kg/min		placebo group will have standard of care rather than ketamine infusion Placebo: Placebo IV
All Cause Mortality
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.