Pilot Study: The Effect of Intraoperative Ketamine on Analgesia Post-Cardiac Surgery and Prevention of Chronic Pain
Phase: PHASE4
Conditions: Pain, Postoperative
Sponsor: Jewish General Hospital

Research Protocol – Aug 23 2017  
1 
 
 
 
 
 
Pilot Study: The Effect of Intraoperative 
Ketamine on Analgesia Post-Cardiac Surgery 
and Prevention of Postoperative Pain 
JGH Protocol #: 16-289 
NCT02925858 
 
 
Primary Investigator: Dr. Matthew Cameron 
Co-Investigator: Dr. Francois Béïque 
Co-Investigator: Dr Roshanak Charghi 
Co-Investigator: Dr Khadija Al Wahaibi 
Co-Investigator: Dr Karen Tam 
 
 
 
 
 
 

Research Protocol – Aug 23 2017  
2 
 
Background 
 
Pain control post-sternotomy is an essential part of fast-track surgery, a program to 
promote early recovery.  Up to 75% of patients complain of moderate-to-severe pain after 
cardiac surgery, with poorly controlled pain leading to an increased risk of myocardial ischemia 
and chronic post-sternotomy pain, which is seen in 11% of patients.1-2 Given the relative 
contraindications to epidural analgesia and non-steroidal anti-inflammatories after coronary 
artery bypass grafting (CABG) surgery, options for multimodal analgesia are limited.3   
 
Ketamine is an NMDA antagonist which potentiates the release of inhibitory 
neurotransmitters, modulating the sensory processing of pain.4 Ketamine is a well-established 
treatment for a variety of pain syndromes, and is approved by Health Canada to be used as a 
supplemental agent during anesthesia.5-7 There is a growing literature showing that Ketamine 
contributes to pain control after surgery as well.  It has been shown that Ketamine decreases 
opioid needs after spine surgery, as well as after thoractomy.8-10 While these studies used the 
racemic form of Ketamine, the only version approved for use in Canada, a Finnish study on the 
cardiac surgery population evaluated the S(+) enantiomer of Ketamine, which has not been 
available in Canada.  This was shown to reduce postoperative opioid requirements by 20%.11  
There are limited downsides to the administration of Ketamine. The most common 
adverse effects of ketamine in awake patients include nightmares, hallucinations, a dissociative 
state, headaches, and hepatotoxicity.5,12 In clinical studies of low dose Ketamine used for 
perioperative pain control, there has not been shown to be a significant increase in side effects 
between treatment and placebo groups.9 

Research Protocol – Aug 23 2017  
3 
 
Ketamine, while used at times, is not routinely used during cardiac anesthetics. It has 
not been studied for its effect on postoperative pain control and its effect on post-sternotomy 
chronic pain.  
Given that the S(+) enantiomer of Ketamine previously studied in cardiac surgery 
patients is not available in Canada, this study will investigate the racemic form of Ketamine that 
is available in Canada, which, to our knowledge, has not been studied in the cardiac surgery 
population. This is the form of ketamine will has well established use during anesthesia care 
and the form of ketamine with which the vast majority of the literature on postoperative pain 
has been based. 
 
Specific Aim & Hypothesis 
The main goal of this pilot study is to assess the effect of an intraoperative intervention, 
the administration of ketamine, on analgesia post-cardiac surgery.  This pilot study will also 
help assess the feasibility of recruiting and retaining patients, safely administering a blinded 
medication in the operating room, accurately measuring a primary outcome of postoperative 
narcotic consumption, and blinding those involved in the care of cardiac surgery patients. 
 
The long-term goal of this study and subsequent follow-up studies is to improve pain 
control after cardiac surgery, with the hope of allowing patients to perform earlier 
physiotherapy, regain functional status, and allow for an earlier discharge from hospital. 
The specific aim of this study is to ascertain whether an intraoperative infusion of 
racemic Ketamine can improve postoperative pain control after CABG surgery.  The hypothesis 
is that the intraoperative administration of this medication will improve postoperative pain 

Research Protocol – Aug 23 2017  
4 
 
control demonstrated through a decrease in postoperative opioid consumption of more than 
25%. 
 
Study Design 
 
This is a randomized, blinded, placebo-controlled pilot study.  A stratified block 
randomization procedure will be used to ensure that each group has an equal number of men, 
and an equal number of women. Blocks will be made in groups of 4 for each sex.  Given that the 
majority of cardiac surgery patients are male, each group is not expected to be made of an 
equal number of men and women.  The randomization procedure will be done with pre-
prepared numbered envelopes. Separate piles of envelopes will be kept to randomize each sex 
separately.  Each envelope will contain the group assignment of either “Ketamine” or 
“Placebo”.  Group assignment papers will be inserted in the envelopes in a random order.  A list 
of the group assignment in each numbered envelope will be kept separate from study materials 
while the study is being carried out. This measure will help ensure that the research 
coordinator will be blinded during data collection. A separate list will be made by a co-
investigator not involved in the data analysis denoting which envelopes corresponded to 
“Group A” and “Group B” to allow for the primary investigator to be blinded during data 
analysis, and for the study coordinator to ensure stratified randomization has distributed an 
equal number of patients of each sex in each group by the end of the study. 
Either the cardiac surgeon, the cardiac anesthetist or a nurse involved in the patients’ 
care will ask the patient if the research coordinator can approach the patient to discuss 

Research Protocol – Aug 23 2017  
5 
 
inclusion in the study.  The research coordinator will then discuss risks and benefits of being 
included in the study and obtain consent.   
On the day of the procedure the research coordinator will randomly select a numbered 
envelope for the appropriate sex, and hand this to one of the two other co-investigators prior 
to surgery.  One of the two co-investigators will prepare the study drug. 
The intervention group will receive Ketamine, while the placebo group will have an 
identical syringe of normal saline prepared.  The placebo will be prepared to blind the cardiac 
anesthetist caring for the patient.  This blinding is important as the quantity of narcotic 
administered during the surgery is at the anesthetist’s discretion, and knowing whether or not a 
co-analgesic is being administered may affect the quantity of narcotic administered.  The 
quantity of narcotic administered could be considered a co-intervention of the primary 
outcome, so we are taking all precautions to ensure that the amount of narcotic administered is 
not influenced by the anesthesiologist’s knowledge of the study drug.   
The cardiac anesthesiologist will receive the medication in the operating room, 
delivering a bolus prior to skin incision and administering the medication at a rate determined 
by the patient’s weight. The dose of medication administered should not have any 
hemodynamic effects, and so unblinding of the cardiac anesthetist should not be necessary.  If, 
for whatever reason unblinding should become necessary, the co-investigator who prepared 
the medication will make the primary anesthetist aware of the contents of the study drug. 
 
Upon transfer to the intensive care unit, nurses and intensive care physicians will be 
made aware that the patient is involved in the study.  The research coordinator will have 
documented the volume of study drug administered in the anesthetic record at the end of the 

Research Protocol – Aug 23 2017  
6 
 
case. If the treatment allocation needs to be known by the intensive care team, they will be 
able to contact the primary investigator to be immediately unblinded. 
 
Patients will be asked if they would allow the research coordinator to call them at 3 and 
6 months after surgery to ask if any pain is present at the site of incision, followed by ten yes or 
no questions about the pain, and what medications they may be taking for pain, if the pain is 
still present.  These questions can be found in the attached questionnaire.14 
 
Study Population 
 
The study population will be patients coming for CABG surgery via midline sternotomy 
at the Jewish General Hospital.  This population was selected to ensure all patients have a 
similar incision and number of chest tubes, two of the main contributing factors to 
postoperative pain.  Patients with a left ventricular ejection fraction less than 50% will be 
excluded, as these patients are more likely to require a longer duration of circulatory support 
and mechanical ventilation.  Extended mechanical ventilation and sedation will make it difficult 
to assess the primary outcome of the study.  Patients with a history of regular opioid use will be 
excluded, as these patients have an increased tolerance to opioids and require larger doses to 
achieve adequate pain control. Including these patients in a small randomized study would risk 
having a significant effect on the primary outcome.  Patients with known hepatic or renal 
dysfunction will be excluded as well, given the theoretical accumulation of ketamine. Patients 
with a contraindication to ketamine will also be excluded, such as those with a previous 
cerebrovascular accident, or with known hypersensitivity to the drug. Patients unable to 

Research Protocol – Aug 23 2017  
7 
 
provide consent will also be excluded, as the reporting of pain in these patients will likely be 
unreliable.   
 
Exposure 
 
Exposure will be randomized to an intervention or placebo.  The intervention arm will 
consist of ketamine as a 0.5mg/kg as a bolus, and a 0.5mg/kg/hr infusion throughout the 
surgery.  For an 80kg patient, with a Ketamine concentration of 10mg/mL, this would amount 
to a 2mL bolus and 2mL of fluid administration per hour of surgery, or approximately 10mL of 
fluid for the duration of a surgery.  The placebo arm will consist of a saline infusion at the same 
volumes.  This dose of ketamine is based on previous studies that have shown effectiveness in 
surgical populations.1-4 The doses at which Ketamine will be administered is not expected to 
have any hemodynamic effects, and therefore compliance by the anesthesiologist with the 
treatment is be expected to be near 100%.  
Both treatment arms will receive a full cardiac anesthetic in addition to the study 
intervention. Since the total quantity of intraoperative opioids administered will depend on 
infusion rate and duration of anesthesia, the total dose administered will be noted for each 
patient.  
 
Postoperative opioids will be prescribed at a dose and frequency according to the 
standard postoperative orders for cardiac surgery patients. An intensive care nurse will 
administer opioids at the doses prescribed on the post-operative orders. This strict protocol for 
pain management improves the internal validity of the trial, understanding that this may 

Research Protocol – Aug 23 2017  
8 
 
somewhat decrease external validity in comparison to other centers who do not manage 
postoperative pain with the same regimen. 
 
Outcomes 
 
The primary outcome is the quantity of opioid administered over the first 48 hours 
postoperatively. Forty-eight hours was selected as the duration to monitor opioid consumption, 
as this is the period during which pain post-cardiac surgery has been shown to be most 
intense.1 This primary outcome was selected as it will be reliably documented and 
straightforward to assess, given the strict guidelines for documentation of opioids.  
 
 There will be several secondary outcomes. The quantity of opioids used at 24 hours will 
be noted.  Postoperative pain will be measured daily via the “brief pain inventory” by the 
research coordinator on postoperative days 0, 1, and 2.13 Patients will be asked their current 
pain, the worst and best pain levels throughout the day, as well as their average pain levels. The 
need for additional analgesic medications will be assessed as a binary outcome for each type of 
additional medication (NSAIDs, additional opioids, gabapentinoids, etc), measuring whether or 
not additional agents are added to treat poorly controlled pain.  Additional analgesics would 
likely affect the dose of post-operative opioids administered, making it a co-intervention which 
may need to be accounted for in the analysis. The presence or absence of postoperative nausea 
and vomiting requiring treatment, as well as the diagnosis of delirium will be measured as 
binary outcomes.  Intensive care unit and hospital length of stay will be measured in number of 
days, while the time to extubation, time to first mobilization to a chair, and time to first 
ambulation will be measured in number of hours after arrival to the intensive care unit through 

Research Protocol – Aug 23 2017  
9 
 
chart review.  While the dose of ketamine used in this study is not likely to cause psychological 
side effects, the number of patients reporting hallucinations or severe nightmares will be 
tracked. 
 
On follow-up phone call at 3 and 6 months patients will be asked whether or not they 
have persistent pain at the site of the sternotomy.  Whether or not persistent pain is present 
will be noted, along with any medications that they may be taking for the pain.  If persistent 
pain is present, they will be asked ten yes or no descriptive questions about the pain concerning 
to determine if it is neuropathic in origin.14  The answer to each question, as well as the overall 
score will be noted. 
 
Confounders 
 
Possible baseline confounders will be tracked to look for differential distribution 
between intervention groups.  These will include age, sex, body mass index, left internal 
mammary harvesting. We will stratify our randomization by sex to ensure sexes are balanced in 
the 2 groups, as sex has been shown to be one of the main confounders for postoperative pain.  
With a relatively small sample size of 80 patients, a differential distribution of confounders 
between groups is possible, and an adjustment will be done in our analysis for any factor that is 
differentially distributed. Injuries during cardiac surgery such as rib fracture and dislocation, or 
fractured sternum may contribute to postoperative pain as well. Unfortunately, these variables 
often go undetected and cannot be adequately tracked.  We will therefore rely on 
randomization to ensure equal distribution in both groups. 
 

Research Protocol – Aug 23 2017  
10 
 
Analysis Plan 
 
While nearly complete compliance is expected with the therapy, an intention-to-treat 
analysis will be performed in case any unforeseen issues with compliance arise during the 
study. Continuous data such as postoperative opioid dose, intensive care unit and hospital 
length of stay, and time to mobilization and ambulation will be evaluated using the t test if it is 
determined that the means are normally distributed, or the Wilcoxon Rank Sum test if the 
means are not normally distributed.  Ordinal data such as visual analog scale scores and binary 
data such as need for additional analgesics and the presence or absence of PONV will be 
evaluated by a Chi-Square test. If confounding is suspected due to baseline differences in the 
variables noted above, we will perform a propensity score depending on the variable(s) and the 
size of the difference. As a secondary analysis, data will be analyzed in subgroups by sex to look 
for any potential difference in response. 
 
Sample Size & Power Analysis 
 
Using the data in the trial evaluating S(+)-Ketamine, an estimate of 125mg of oxycodone 
over the 48 hours post cardiac surgery was used as a baseline.1 In this same study, both the 
intervention and controls groups had standard deviation of oxycodone of 45mg. To detect a 
decrease in opioid requirements of 25% with a power of 80% and a two-sided alpha of 0.05, a 
total of 68 patients would be required in the trial, with 34 in each group. For a power of 90%, a 
total of 90 patients would be required in the trial with 45 patients in each arm. The Jewish 
General Hospital, a McGill University teaching hospital, performs approximately 600 cardiac 
surgeries per year, with approximately 350 CABG surgeries via sternotomy.  The goal will be to 

Research Protocol – Aug 23 2017  
11 
 
enroll 80 patients.  With the nature of this study and the need for hospitalization post-cardiac 
surgery, there should be minimal, if any, drop-outs or loss to follow-up, and therefore the 
sample size of 80 patients should allow for a power of over 80%. 
 
Strengths & Limitations 
 
Strengths of the study include the ability to randomize, and the ability to blind the 
patients, nurses, anesthesiologists and pain evaluators. This study will be performed at a single 
center, which allows for easier standardization of therapy, at the same time limiting 
generalizability of the findings. The primary outcome, opioid use, is easily measurable. 
Limitations will include the inter-individual variability in both patient thresholds for analgesia 
request, and nurse thresholds to administer analgesia.  Injury during cardiac surgery may 
contribute to pain (rib fracture or dislocation), and will not be able to be accurately measured. 
 
Timetable 
 
The Jewish General Hospital currently performs approximately 350 CABG surgeries per 
year, which is approximately 30 per month.  Once ethics approval is obtained, and 
organizational logistics are arranged, the goal would be to recruit 80 patients over the span of 
four months. Another 2 to 3 months will likely be required for full data analysis and manuscript 
preparation. 
 
 
 

Research Protocol – Aug 23 2017  
12 
 
 
References 
1. Kuperberg KG, Grubbs L. Coronary artery bypass patients’ perceptions of acute postoperative 
 
pain. Clin Nurse Specialist 1997;11:116–122. 
2. Gjeilo KH, Klepstad P, Wahba A, Lydersen S, Stenseth R. Chronic Pain after cardiac surgery: a 
 
prospective study. Acta Anaesthsiol Scand. 2010 Jan;54(1):70-8 doi: 10.1111/j.1399-
 
6576.2009.02097.x. Epub 2009 Aug 13 
3. Chou R, Gordon DB, de Leon-Casasola OA, et al. Guidelines on the Management of 
 
Postoperative Pain. J Pain 2016;17(2);131-57 
4. Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD.  Role of Ketamine in Acute 
Postoperative Pain Management: A Narrative Review.  BioMed Research International. 
2015. 1-10. 
5. Government of Canada. https://health-products.canada.ca/dpd-bdpp/info.do?code  
=87290&lang=en. Last accessed March 13 2017.  
6. P.Azari, D. R. Lindsay, D. Briones, C. Clarke,T.Buchheit, and S. Pyati, “Efficacy and safety of  
ketamine in patients with complex regional pain syndrome: a systematic review,” CNS 
Drugs, vol.26, no. 3, pp. 215–228, 2012. 
7. R. F. Bell, C. Eccleston, and E. A. Kalso, “Ketamine as an adjuvant to opioids for cancer pain,”  
The Cochrane Database of Systematic Reviews, no. 11, Article ID CD003351, 2012. 
8. 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;113:639-46. 

Research Protocol – Aug 23 2017  
13 
 
9.  Duale C, Sibaud F, Guastella V, Vallet L, Gimbert Y-A, Taheri H, Filare M, Schoeffler, Dubray C.   
Perioperative ketamine does not prevent chronic pain after thoracotomy. Euro J Pain 
2009;13: 497-05. 
10.  Ketamine spares morphine consumption after transthoracic lung and heart surgery without  
adverse hemodynamic effects. Neshar N, Serovian I, Marouani N, Chazan S, Weinbroum  
AA.  Pharm Research 2008;58:38-44. 
11. Lahtinen P, Kokki H, Hakala T, Hynynen M.  S(+)-Ketamine as an Analgesic Adjunct Reduces 
 
Opioid Consumption After Cardiac Surgery.  Anesth Analg 2004;99:1295-1301. 
12. N.Katalinic, R. Lai,A. Somogyi, P. B.Mitchell, P. Glue, and C. K. Loo, “Ketamine as a new  
treatment for depression: a review of its efficacy and adverse effects,”The Australian 
and New Zealand Journal of Psychiatry, vol. 47, no. 8, pp. 710–727, 2013. 
13. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS.  Validity of the Brief Pain  
Inventory for Use in Documenting the Outcomes of Patients with Noncancer Pain. Clin J  
Pain 2004;20:309-318. 
14. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with  
nervous or somatic lesions and development of a new neuropathic pain diagnostic 
questionnaire (DN-4). Pain 114 (2005) 29-36.