Clinical trial NCT02651324
Conditions: Idiopathic Scoliosis Post-operative Pain
Sponsor: Albany Medical College
Start date: 2013-05-01; Completion date: 2017-12-01
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study hypothesizes that the addition of a low-dose ketamine infusion to usual post-operative pain management will improve pain control as evidenced by an improvement in post-operative pain scores for patients undergoing spinal fusion for idiopathic scoliosis.

Detailed description:
After consenting, patients will be randomized by the pharmacy. In the operating room patients will receive ketamine/placebo 0.5mg/kg bolus prior to the surgical incision, followed by ketamine/placebo 0.2mg/kg continuous infusion up to 48hours. All the patients will also receive 15mg/k IV acetaminophen at the end of the surgery, followed by every 6hr for 48hrs. Rest of the pain regimen will be the usual post-operative pain management for spinal fusion for idiopathic scoliosis, which includes morphine PCA, IV ketorolac from POD 1, and flexaril from POD 1.

All the patients and parents will fill out a survey at 0hr, 24hr and 48hr grading their level of satisfaction with the post-operative pain.

Arms: arm 1: A ketamine bolus of 0.5mg/kg will be given and then the ketamine infusion of 0.2 mg/kg/hr will be initiated prior to incision. Intra-operative opioids will be at the discretion of the attending anesthesiologist. Postoperative management will include continuation of the study drug as well as a standardized morphine patient-controlled analgesia (PCA) and acetaminophen 15 mg/kg IV every 6 hours. On postoperative day 1, patients are started on ketorolac 0.5 mg/kg up to 15 mg IV q8h. On postoperative day 2 they are transitioned to ibuprofen 10 mg/kg up to 600 mg. The ketamine infusion will continue for 48 hours post operatively at which point the PCA is discontinued and patients are transitioned to oral pain medications (Roxicet or Lortab and Flexeril) as per the current protocol. arm 2: A placebo (saline) will be given in place of ketamine
Interventions: intervention 1: Ketamine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in Postoperative Pain Control 
After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
Version date: 7/16/2013 
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A Prospective Randomized Double Blind Controlled Trial 
Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control after Spinal Fusion for 
Idiopathic Scoliosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Laura Leduc, MD 
 
Department of Anesthesiology 
 
 
 
Albany Medical Center 
 
 
 
47 New Scotland Ave 
 
 
 
Albany, NY  12208 
 
 
 
518-262-4300 
 
 
CO-INVESTIGATOR: 
 
 
Mauree Beard, MD  
Department of Anesthesiology 
 
 
 
Albany Medical Center 
 
 
 
47 New Scotland Ave 
 
 
 
Albany, NY  12208 
 
 
 
518-262-4300 
 
 
 
 


A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in Postoperative Pain Control 
After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
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A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
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A. STUDY BACKGROUND AND PURPOSE 
Hypothesis:  The addition of a low-dose ketamine infusion to usual post-operative pain 
management will improve pain control as evidenced by an improvement in post-operative 
pain scores for patients undergoing spinal fusion for idiopathic scoliosis. 
 
Adolescent idiopathic scoliosis is the most common form of scoliosis and occurs most 
commonly in girls. In 0.2-0.5% of cases, the curve in idiopathic scoliosis increases 
despite conservative, non-operative management and surgical intervention is required. 
Patients present for spinal fusion for correction of scoliosis in their adolescent years. 
Spinal fusion for idiopathic scoliosis is associated with significant postoperative pain 
which at this time is primarily managed with opiate pain medications. We aim to show an 
improvement in post-operative pain scores by adding a low dose infusion of ketamine 
intra- and post- operatively.  
 
Ketamine antagonizes the N-methyl-D-aspartate (NMDA) receptor. Its action is related to 
central dissociation of the cerebral cortex and is thus referred to as a “dissociative 
anesthetic”. Depending on the situation and dose, ketamine can be used for many 
different purposes ranging from pre-operative sedation and pain control to general 
anesthesia. For the purposes of this study, ketamine will be used as an adjunctive 
treatment for postoperative pain control. The dose appropriate for this purpose is a 0.5 
mg/kg slow bolus prior to incision followed by an infusion of 0.2 mg/kg/hr (Cote). For 
comparison purposes, an induction dose of ketamine is 1-2 mg/kg with onset of action 
less than 60 seconds and duration of action of 10-20 minutes (Barash). Repeated bolus 
doses and prolonged infusion times will prolong the duration of action. According to Dr. 
Cote, ketamine has “one of the best safety profiles of any anesthetic agent,” and he refers 
to a study by Green et. al which reviewed inadvertent overdoses of ketamine of 5-100x 
the intended dose (in the emergency room setting) and identified no long term 
complications despite short term respiratory depression and prolonged sedation. 
 
The safety of ketamine as an adjunct for acute postoperative pain control has been well 
established in the literature. A review article published in 2004 concluded that adverse 
effects were not increased with small dose ketamine after review of 37 trials involving 
2385 patients, of whom 232 were children (Subramaniam 2004).  
 
Ketamine has been used safely in clinical trials in the pediatric population. Da Conceicao 
and colleagues used ketamine after tonsillectomy in patients 5-7 years old. They 
demonstrated that the use of a single, small dose of ketamine could reduce the frequency 
of rescue analgesia post-tonsillectomy without unwanted side effects (Da Conceicao 
2006). 
 
Ketamine has been extensively studied as an analgesic in the postoperative setting. Many 
articles have been published with conflicting results. In 2010, Carstensen and Moller 
reviewed 11 randomized, double-blinded clinical trials of ketamine added to opioid in IV 
PCA for postoperative pain. They found that 6 studies showed significantly improved 
postoperative analgesia and 5 studies showed no significant clinical improvement 
(Carstensen 2010). 


A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
Version date: 7/16/2013 
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Several studies indicate that ketamine can decrease opioid usage and improve pain 
control postoperatively with minimal side effects. In 2008, Yamauchi et al. showed that a 
ketamine bolus of 1 mg/kg followed by an infusion of .042 mg/kg/hr or .083 mg/kg/hr 
lowered the pain scores after cervical spine surgery in patients 20-70 years of age 
(Yamauchi 2008). A prospective, randomized double-blinded study in 2007 demonstrated 
a significant reduction in cumulative morphine consumption after thoracic surgery 
(Michelet 2007). Another prospective, double-blind, randomized study published in 2012 
demonstrated that low-dose ketamine added to IV-PCA fentanyl after the Nuss procedure 
in pediatric patients reduced pain scores, consumption of fentanyl and incidence of 
nausea and vomiting without increasing side effects (Cha 2012). In this study, a ketamine 
bolus of 0.3 mg/kg was given 10 minutes prior to the end of the operation followed by an 
infusion of 0.15 mg/kg/hr. A review article published in 2011 concluded that not only 
was postoperative ketamine administration safe, but it was also effective in reducing 
morphine requirements after thoracic surgery and in some cases increased patient 
satisfaction (Mathews 2011). A randomized, double-blind control trial from 2008 
concluded that low-dose ketamine after major abdominal surgery improved postoperative 
analgesia with a significant decrease of morphine consumption when its administration 
was continued for 48 hours postoperatively, with a lower incidence of nausea and with no 
side effects of ketamine (Zakine 2008).  
 
There are not yet any studies evaluating the efficacy of an intra-operative and post-
operative ketamine infusion for improvement in pain control in patients undergoing 
surgical correction of idiopathic scoliosis. We aim to show an improvement in patient 
pain scores and patient satisfaction in this specific population by adding a small bolus of 
ketamine pre-incision and a low dose ketamine infusion to the intra- and post-operative 
pain control regimen.  
 
We will use the visual analog scale (VAS) for scoring postoperative pain.  The VAS has 
been shown to have validity and reliability for measuring acute pain (Libman 2000 and 
Bijur 2001). 
 
B. STUDY DESIGN 
Surgical repair of idiopathic scoliosis is performed electively. In our hospital, this 
operation is performed by Dr. Allen Carl, a co-investigator on this study. We aim to 
enroll approximately 50 of his patients. Upon scheduling the operation, Dr. Carl will 
inform the patients and families that we are running a research study which will give 
them ample time to consider participation. They will have the opportunity in the clinic to 
ask questions of Dr. Carl regarding the protocol. They will also be contacted by the 
anesthesia team in the days prior to surgery for usual preoperative care. At that time, they 
will be asked if they would like to talk with an anesthesiologist about the study and if so, 
they will be contacted by one of the anesthesia investigators. 
 
Actual enrollment will be done upon arrival to the hospital on the morning of surgery. 
After enrollment, patients will be randomized to either the treatment group (to receive 


A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
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ketamine) or the control group (to receive saline). Randomization will be simple and will 
be performed by the pharmacy. Investigators and patients will be blinded to treatment 
group. Based on the patient’s weight in the pre-operative care unit on the morning of 
surgery, the pharmacy will mix and provide standardized solutions for bolus and infusion 
in the operating room. Once the weight has been obtained, the anesthesia team will 
contact the pharmacy and once the medication (or saline) is ready, it will be delivered to 
the operating room. Surgery will not be delayed for the medication and there is ample 
time during induction of anesthesia for the medication to be prepared. 
 
Patients will be unblinded by request at the completion of the study or in the event of a 
serious, unanticipated side effect for which we need the information to ensure patient 
safety. 
 
We estimate that the average pain score of the control group will be 4-8.   This is based 
on current average pain scores in the posterior spinal fusion population where ketamine 
infusions are not currently used but the patients otherwise follow the same protocol as 
listed below. 
 
Patients generally stay in the Pediatric Intensive Care Unit (PICU) postoperatively for 
approximately 5-7 days. We don’t anticipate that our study will increase or decrease the 
length of stay in the PICU.  The full time commitment for each subject will not exceed 
the length of hospital stay. If serious side effects were to occur, the treatment would be 
unblinded and immediate care would be given to address the problem. If necessary, 
hospitalization or PICU time would be lengthened to adequately treat any problems and 
this would be reported in the study. 
 
Inclusion criteria are ASA I, II, III patients presenting for spinal fusion for idiopathic 
scoliosis. Patients will be English-speaking and able to give assent to the study. Parents 
will need to give consent for minors and the vast majority of these patients are minors. 
Therefore we will obtain consent from guardians and assent from patients. Exclusion 
criteria include any contraindication to ketamine, previous spinal surgery, opioid 
dependence or chronic pain condition, significant developmental delay and pregnancy. A 
urine pregnancy test is not a specific component of our data as it is already part of the 
preoperative process and surgery would be canceled in the event of a positive pregnancy 
test. 
 
As mentioned above, the study will be presented to patients in the preoperative visit by 
Dr. Carl. Patients will then be contacted by the anesthesia team by phone in the days 
preceding scheduled surgery. Consent and assent will be obtained in the preoperative care 
unit, in person, prior to initiation of sedation. 
 
The location of the research is Albany Medical Center, Main Campus and the duration is 
the length of hospital stay: 5-7 days. 
 
Methods: 


A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
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Anesthesia induction will be at the discretion of the anesthesia attending. Maintenance of 
anesthesia includes approximately 0.5 MAC of volatile anesthetic and a remifentanil 
infusion, supplemented by a propofol infusion as necessary. A ketamine bolus of 0.5 
mg/kg or saline bolus will be given and then the ketamine or saline infusion of 0.2 
mg/kg/hr will be initiated prior to incision. Intra-operative opioids will be at the 
discretion of the attending anesthesiologist.  Postoperative management will include 
continuation of the study drug as well as a standardized morphine patient-controlled 
analgesia (PCA) and acetaminophen 15 mg/kg (up to 1 gram) IV every 6 hours for 8 
doses which will be initiated in the PACU.  Starting at midnight going into postoperative 
day 1, patients are started on ketorolac 0.5 mg/kg up to 15 mg IV q8h for 24 hours. At 
that time they are transitioned to ibuprofen 10 mg/kg po (up to 600 mg) with meals. The 
ketamine or saline infusion will continue for ~ 48 hours post operatively at which point 
the PCA is discontinued (typically around noon) and patients are transitioned to oral pain 
medications (Roxicet or Lortab and Flexeril) as per the current protocol.  All medications 
listed above with the exception of IV acetaminophen and ketamine are part of the current 
“Spinal Fusion Pediatric Critical Care” physician order set. 
 
In the event of side effects from the ketamine as described in Section E, the anesthesia 
pain service will be contacted and changes to the pain regimen will be made. If side 
effects are noted but not bothersome to the patient, then a 10% decrease in the infusion 
rate will be made. If the side effects are concerning to the patient, such as dysphoria or 
hallucinations, then the infusion will be decreased by 50% and an anesthesia attending 
will be contacted. If side effects are severe then the infusion will be discontinued and an 
anesthesia attending will be contacted. 
 
Pain scores will be solicited hourly from patients by the bedside nurse. We will record the 
highest (or worst) pain rating from each 4 hour time period for data analysis up until the 
end of postoperative day 2. 
 
C. SUBJECT POPULATION  (WHO, WHAT, WHERE) 
Patients will be recruited from Dr. Allen Carl’s clinical practice. Approximately 50 
patients will be enrolled. The population of patients is adolescents and young adults who 
present for repair of idiopathic scoliosis. The majority of these patients are pediatric and 
this is justified for the research as we aim to improve the pain control specifically for this 
group of patients. 
 
D. DATA ANALYSIS 
Please refer to attached data collection sheets for details on data collection. Our primary 
endpoint is patient satisfaction. Our secondary endpoints are pain scores, opioid usage 
(including total morphine consumption) and length of hospital stay. Identifiers on the 
data collection sheets will include a subject number and a medical record number. These 
data sheets will be kept strictly confidential and data will be analyzed only by subject 
number. 
 
Data analysis will be performed by the investigators with the help of our statistician. Data 
analysis will be performed on campus of the Albany Medical Center and identifying 


A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
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information will not be removed from the site. Only members of the investigation team 
and individuals who are helping with data analysis will have access to the data and data 
will thereafter be contained in the Anesthesia Research Office. 
 
Under the guidance of our statistician, we estimate that we need up to 50 patients enrolled 
to demonstrate the desired effect. (Based on a two-proportion sample size, assuming 70% 
of patients currently report “unsatisfactory” pain control, and assuming a 25% 
improvement in pain score, with an alpha of 0.05 and power of 0.8).  The assumption that 
70% of patients currently report unsatisfactory pain control is an estimate based on the 
fact that we know most patients are significantly uncomfortable after this operative for a 
period of several days. 
 
Our primary responsibility is optimal care of our patients throughout the study period. If 
at any time a patient needs to be removed from the study then we will do so. Inadequate 
pain control is unlikely to be a cause for removal from the study but if a patient or family 
is unhappy with care, they can certainly be removed at any time and the data would 
reflect this.  
 
e. RISKS 
The risks of the study include the risks of adding ketamine to the post-operative 
management. As previously demonstrated, low-dose infusions of ketamine have been 
shown in the anesthesia literature to be safe with a low incidence of side effects. 
However, patients will be informed that possible side effects of ketamine include 
dysphoria, hallucinations (pleasant or otherwise), vivid dreams, sialorrhea, and increased 
blood pressure and heart rate. There are not described long term side effects from a low 
dose ketamine infusion administered perioperatively. Side-effects that have been noticed 
in other studies resolve with a decrease in the infusion rate of the ketamine. We will have 
a step-wise protocol in place to decrease the ketamine (or saline) infusion if side-effects 
are noted. Patients will have access to the Anesthesia Pain Service (APS) 24 hours a day, 
7 days a week as well as access to the investigators. The APS currently manages many 
patients throughout the hospital who are receiving ketamine infusions for postoperative 
pain control. 
 
F. BENEFITS 
The major benefit for patients is the potential for improved pain control after a major 
operation that is associated with significant post-operative pain. Control patients will also 
have ready access to clinicians who can help to control postoperative pain. 
Intraoperatively, ketamine improves the evoked potentials which are monitored to 
minimize the risk of postoperative disability. Additionally, they will be contributing to 
improvement in postoperative pain management for future patients. Overall, we feel that 
the risks posed by the study are small and the potential benefits are quite large. There are 
minors involved in the study and they will have the same benefits described above. 
 
G. CONFIDENTIALITY 
Data will be maintained with the strictest confidentiality. Initial forms will be 
handwritten and data will be entered into a password protected computer file. A 


A Prospective Randomized Double Blind Controlled Trial Evaluating the Efficacy of Ketamine for Improvement in 
Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
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randomized master key linking subjects to their study number will be used and destroyed 
at the completion of the study and data analysis. 
 
H. OPTIONS 
At any point in the study, the subject may choose to discontinue participation and opt for 
standard treatment. 
 
I. REFERENCES 
 
Barash, P, et al. Clinical Anesthesia. Philadelphia: Lippincott, Williams & Wilkins, 2006. 
Bijur, PE, et al. Reliability of the Visual Analog Scale for Measurement of Acute Pain. 
Acad Emerg Med 2001;8:1153-1157. 
Carstensen, M. and Moller, A. M. Adding ketamine to morphine for intravenous patient-
controlled analgesia for acute postoperative pain: a qualitative review of randomized 
trials. British Journal of Anaesthesia 2010; 104 (4): 401-6. 
Cha, MH, et al. Beneficial Effects of Adding Ketamine to Intravenous Patient-Controlled 
Analgesia with Fentanyl after the Nuss Procedure in Pediatric Patients. Yonsei Med J 
2012; 53(2):427-432. 
Cote, C, Lerman J, and Todres D.  A Practice of Anesthesia for Infants and Children. 
Philadelphia: Saunders Elsevier, 2008. 
Da Conceicao, MJ, et al. Effect of intravenous single dose of ketamine on postoperative 
pain in tonsillectomy patients. Pediatr Anesth 2006; 16: 962-967 
Green, SM, et al. Inadvertent ketamine overdose in children: clinical manifestations and 
outcome. Ann Emerg Med. 1999 Oct;34(4 Pt 1):492-7. 
Libman, M, et al. Independent validation of the minimum clinically important change in 
pain scores as measured by visual analog scale [abstract]. Acad Emerg Med. 2000;7:550. 
Matthews, TJ., et al. Does adding ketamine to morphine patient-controlled analgesia 
safely improve post-thoracotomy pain? Interactive CardioVascular and Thoracic Surgery 
2012; 14: 194-199. 
Michelet, P, et al. Adding ketamine to morphine for patient-controlled analgesia after 
thoracic surgery: influence on morphine consumption, respiratory function, and nocturnal 
desaturation. Br J Anaesth 2007;99:396-403. 
Subramaniam, Kathirvel, et al. Ketamine as Adjuvant Analgesic to Opioids: A 
Quantitative and Qualitative Systematic Review. Anes Analg 2004;99:482-95. 
Tsui, Ban, et al. Adjunct continuous intravenous ketamine infusion for postoperative pain 
relief following posterior spinal instrumentation for correction of scoliosis: a case report. 
Pediatr Anesth; 2007:383-386. 


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Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis 
Leduc, MD 
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Yamauchi, Masanori, et al. Continuous Low-Dose Ketamine Improves the Analgesic 
Effects of Fentanyl Patient-Controlled Analgesia After Cervical Spine Surgery. Anesth 
Analg 2008;107:1041-4. 
Zakine, Jerome, et al. Postoperative Ketamine Administration Decreases Morphine 
Consumption in Major Abdominal Surgery: A Prospective, Randomized, Double-Blind, 
Controlled Study. Anesthesia &Analgesia 2008; 106:1856-61.