Clinical trial NCT03448068
Conditions: Laparoscopic Gastric Bypass Surgery Ketamine
Sponsor: Mayo Clinic
Start date: 2018-04-16; Completion date: 2020-01-09
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Opioid medications such as morphine, hydrocodone and oxycodone are standard for treating pain after surgery, however there are disadvantages. Because of the way opioids work, gastric bypass patients may have an increased risk of having sedation or problems with breathing. In patients with sleep apnea, opioids may increase the risk of severe apnea.

Ketamine is an alternative pain medicine that can be used to treat pain after surgery and may have fewer effects on breathing. Using ketamine as part of the regimen may be a better choice for laparoscopic gastric bypass patients.

This study is being done to find out if intraoperative ketamine infusion combined with continuation for twenty-four hours post-surgery provides superior pain control and decreases post-operative opioid use versus standard non-ketamine therapy.

Detailed description:

Arms: arm 1: 1. Ketamine 0.3 mg/kg (IBW) bolus with induction.
2. Ketamine infusion 0.2 mg/kg/hr. (IBW) initiated after induction and terminated after 24 hours.
3. Ketamine infusion will not be titrated.
4. Remaining care will be identical to standard therapy group. arm 2: 1. Calculation ideal body weight (IBW)
2. Pre-op dexamethasone
3. Pre-op midazolam at discretion of anesthesiologist
4. Anesthesia Induction - Propofol and fentanyl, anesthesiologist discretion. Neuromuscular block with succinylcholine and/or rocuronium at discretion of anesthesiologist. Orotracheal intubation.
5. Anesthesia Maintenance - Sevoflurane/rocuronium. Addl. doses of fentanyl, discretion of anesthesiologist.
6. Emergence from anesthesia - Acetaminophen, Ketorolac and Ondansetron unless contraindicated. Sugammadex depending on twitch response per drug manufacturer recommended protocol.
7. Post-Op Analgesia - Hydromorphone, acetaminophen and ketorolac
8. Other post-op care as per usual surgical routine
Interventions: intervention 1: Ketamine intervention 2: Standard therapy
Intervention descriptions: intervention 1: Ketamine 0.3 mg/kg (IBW) bolus with induction. Ketamine infusion 0.2mg/kg/hr. (IBW) initiated after induction and terminated after 24 hours.

Ketamine infusion not titrated. intervention 2: Pre-op dexamethasone 4mg IV and midazolam 1-2mg IV Anesthesia Induction - Propofol 2-3mg/kg IV, Fentanyl 1mcg/kg IV, neuromuscular block w/succinylcholine and/or rocuronium, orotracheal intubation Anesthesia maintenance - Sevoflurane/rocuronium, fentanyl 0.5-1mcg/kg Anesthesia emergence - Acetaminophen 1g, ketorolac 30 mg IV, ondansetron 4mg IV, sugammadex 2mg/kg or 4 mg/kg dose depending on twitch Post-op anesthesia - Hydromorphone patient-controlled analgesia (PCA) 0.2 mg/8 min, acetaminophen 1 g IV Q8 around the clock (ATC) x 3 addl. doses, ketorolac 15 mg IV Q6 ATC x 3 addl. doses.

Other standard surgical post-op care

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Low-dose ketamine infusions for 
perioperative pain management in 
patients undergoing laparoscopic gastric 
bypass 
 
NCT03448068 
 
November 12, 2019 


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Gorlin/Ketamine   12Nov2019   V4 
CONFIDENTIAL 
 
 
 
 
 
 
Low-dose ketamine infusions for perioperative pain management in patients 
undergoing laparoscopic gastric bypass 
 
 
PI:  Andrew W. Gorlin, M.D. 
Sub-I(s): David M. Rosenfeld, M.D. 
Statistician: Matthew R. Buras 
IRB#: 17-000301 
 
 
Initial Version: 
09Dec2016 
Revised: 
15Feb2017 V2 
Revised: 
28Mar2018 V3 
Revised: 
12Nov2019  V4


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Gorlin/Ketamine   12Nov2019   V4 
CONFIDENTIAL 
 
Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic 
research policies and procedures. 
 
 
Background 
Obesity has become a public health crisis in the developed world, especially in the 
United States. According to the CDC, more than one-third (36.5%) of adults in the 
United States are obese as defined by a BMI greater than or equal to 30. A 2013 study 
estimated that 6.6% of the US population is morbidly obese (BMI > 40) (Sturm) 
Negative health consequences of obesity include cardiovascular disease, obstructive 
sleep apnea (OSA), systemic hypertension, pulmonary hypertension, diabetes, 
musculoskeletal problems and various malignancies (Adams BJA 2000). Given the 
severe health consequences of obesity and the difficulty that many patients have 
maintaining a healthy weight, surgical management of obesity has become an effective 
therapeutic option for many patients with morbid obesity (Elder Gastroenterology 2007). 
 
The Roux-en-Y gastric bypass is considered the “gold standard” for weight loss surgery 
and it is frequently performed laparoscopically. It involves anastomosing the proximal 
portion of the stomach to the jejunum, bypassing most of the stomach and duodenum 
and restricting food intake (Ogunnaike A&A2002). Despite the efficacy and overall 
safety of weight reduction surgery, obese patients pose significant challenges for 
perioperative physicians and are at higher risk for adverse events postoperatively, 
especially pulmonary complications (Adams BJA 2000). 
 
Obese patients have increased oxygen consumption, increased CO2 production, 
reduced lung FRC and reduced chest wall compliance all of which puts them at risk for 
hypoxemia and hypercarbia particularly in the postoperative period (Adams BJA 2000). 
Opioids and other central nervous system depressants commonly administered 
perioperatively may potentiate these gas exchange problems and increase risk for 
adverse event. 
 
Most concerning, however, is the association between obesity and obstructive sleep 
apnea (OSA) which is a risk factor for perioperative respiratory depression as well as 
respiratory arrest and death (Chung A&A2008, also multiple case reports). Up to 70% 
of patients undergoing bariatric surgery have OSA (Frey Obes Surg 2003). OSA is a 
disorder characterized by reduced tone in the upper airway muscles during sleep which 
causes periodic airway obstruction with subsequent apnea and oxygen desaturation. 
Obese patients are at particular risk of developing OSA at least in part due to fat 
deposits in the pharyngeal walls leading to reduced airway diameter (Romero Chest 
2010). In addition, as discussed above, obese patients are more vulnerable to 
disordered gas exchange and have less reserve for tolerating brief periods of 
obstruction. 
 
OSA patients are especially vulnerable to apneic events postoperatively due to surgical 
stress, the residual effects of anesthesia, disruption of the normal sleep cycle and 


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Gorlin/Ketamine   12Nov2019   V4 
CONFIDENTIAL 
 
exposure to central nervous system depressants (Benumof Curr Op Anesth 2004). 
Opioids in particular are problematic as they cause respiratory depression and have 
been shown to depress the muscle tone of the upper airway (Craven 2007, White J 
Physiol 2009). However, poorly managed abdominal pain may itself compromise 
respiratory effort resulting in hypoventilation. Clinicians are often confronted with the 
challenge of balancing the risks of opioid therapy versus the respiratory consequences 
suboptimal pain control. Non-opioid analgesics such as acetaminophen and NSAIDs 
can be helpful and have little effect on the respiratory system or OSA (Chung). Other 
drugs such as dexmedetomidine and gabapentin have also shown promise for reducing 
perioperative opioids, though both drugs are also central nervous system depressants 
and it is unknown what effect they may have on airway muscle tone during sleep 
(Chung). 
 
Ketamine is an NMDA antagonist that, at high doses (>1mg/kg), induces dissociative 
anesthesia with minimal effects on ventilation and airway reflexes (Gorlin). Low dose 
ketamine infusions (<0.3mg/kg/hour) have proven efficacy for reducing pain scores as 
well as reducing post-operative opioid consumption in a wide variety of surgical 
procedures (Gorlin JAnesthClinPharm 2016 ). Furthermore, even at anesthetic doses, 
ketamine has no negative effect on pharyngeal muscle tone (Drummond BJA 1996). 
For these reasons, low dose ketamine may be an ideal analgesic adjunct for patients 
undergoing gastric bypass. Sollazzi et al demonstrated lower PACU pain scores and 
opioid consumption in patients undergoing gastric bypass who received a combined 
ketamine/clonidine infusion in the operating room (Sollazzi SurgObesRelDis2009). 
However, to our knowledge, there have been no studies looking at combined 
intraoperative and postoperative ketamine infusions for gastric bypass. 
 
Our hypothesis states that in laparoscopic gastric bypass patients intraoperative 
ketamine infusion combined with continuation for twenty-four hours post-surgery 
provides superior pain control and decreases post-operative opioid use versus standard 
non-ketamine therapy. 
 
Study Objectives 
 
Primary Objective 
• To assess the efficacy of a standardized bolus and infusion dose of 
intravenous ketamine on perioperative opioid requirements in gastric 
bypass surgical patients. 
 
Secondary Objective 
• To assess the efficacy of a standardized bolus and infusion dose of intravenous 
ketamine on perioperative pain scores, patient satisfaction with pain 
management, and length of stay in hospital in gastric bypass surgical patients. To 
assess the safety and tolerability of intravenous ketamine by examining presence 
of post-operative nausea and vomiting, pruritus, sedation, agitation, 
hallucinations, delirium, and adverse respiratory events. 


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Study Design and General Description 
 
• Randomization after consent is obtained to either ketamine or standard 
therapy 
 
• Standard therapy group study protocol 
o Calculation of ideal body weight (IBW) – see calculator 
o Pre-operative dexamethasone 4mg IV 
o Pre-operative midazolam 1-2mg IV for anxiolysis at discretion of 
anesthesiologist 
o Induction of anesthesia 
 Propofol 2-3mg/kg IV (IBW) at discretion of anesthesiologist 
 Fentanyl 1mcg/kg IV (IBW) 
 Neuromuscular blockade with succinylcholine and/or rocuronium at 
the discretion of the anesthesiologist 
 Orotracheal intubation 
o Maintenance of anesthesia 
 Sevoflurane/rocuronium 
 Additional doses of fentanyl 0.5-1mcg/kg (IBW) at discretion of 
anesthesiologist 
o Emergence from anesthesia 
 Acetaminophen 1g IV unless contraindicated 
 Ketorolac 30mg IV unless contraindicated 
 Ondansetron 4mg IV unless contraindicated 
 Suggamedex 2mg/kg or 4mg/kg dose (Actual BW) depending on 
twitch response per drug manufacturer’s recommended protocol 
o Post-operative analgesia 
 Hydromorphone PCA 0.2mg/8 min 
 Acetaminophen 1g IV Q8 ATC x 3 additional doses 
 Ketorolac 15mg IV Q6 ATC x 3 additional doses 
o Other post-operative care as per usual surgical routine 
 
• Ketamine therapy group 
o Ketamine 0.3mg/kg (IBW) bolus with induction 
o Ketamine infusion 0.2mg/kg/hr. (IBW) initiated after induction 
and terminated after 24 hours 
o Ketamine infusion will not be titrated 


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o Ketamine infusion may be terminated if the patient is having side-effects 
relating to the drug; Pain Service will follow the patient and assist with 
troubleshooting and determining the need for infusion termination 
o The remainder of care will be identical to the standard therapy group 
 
Number of Subjects 
 
We will enroll up to 45 subjects to attain our goal of 17 subjects per group for a total of 34 
accrued subjects.  This is to ensure our goal is met based on the randomization list, as 
well as to account for any withdrawals that occur throughout the study. 
 
 
Primary Study Outcome 
 
Total cumulative perioperative opioid dose measured in morphine equivalents from 
induction of anesthesia until 48 hours after induction of anesthesia. 
 
Secondary Study Outcomes 
 
Visual analog pain scores measured from PACU arrival until 48 hours after induction of 
anesthesia. PONV and pruritus recorded from PACU arrival until discharge from 
hospital. Length of stay in hospital will be recorded.  Patient satisfaction with pain 
management will be measured by questionnaires that patients complete at the time of 
discharge and at the postoperative visit with the surgeon or via telephone about 30 
days after surgery. 
 
Primary Safety Outcomes 
 
There will be careful and continuous monitoring, intervention and recording of 
hemodynamics, sedation, agitation, hallucinations, delirium, and adverse 
respiratory events. 
Standardized nursing procedures will be used including vital signs, RASS sedation 
scores, according to standard intensive post-surgical requirements. Standardized 
single dose regimen for ketamine. 
 
Data 
• Pre-operative data 
o Age 
o Gender 
o Height, weight, BMI 
o ASA classification 
o Medical problems 
o Surgical history 
o Home medications 
o Home CPAP? 
o Allergies 


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o Presence of active chronic pain? If so, what is it? 
o Currently taking opioids on a daily basis for the past 1 month or greater? If 
so, quantitate daily dose in morphine equivalents (ME) 
 
• Post-operative data 
o Total opioid dose in ME from OR to discharge 
 May look separately at OR, PACU, 1st 24 hours, 2nd 24 hours 
o Pain scores over course of hospitalization 
 May look separately at PACU, 1st 24 hours, 2nd 24 hours 
o PONV 
 Need for additional anti-emetics during hospitalization 
o Pruritus 
 Need for anti-histamines during hospitalization 
o Sedation 
 Average RASS scores 1st 24 hours 
 Any episodes of (-)3 or worse RASS 
 Any evidence of sedation in nursing notes 
o Agitation 
 Average RASS scores 1st 24 hours 
 Any episodes of (+) RASS scores 
 Any evidence of agitation from nursing notes 
o Hallucinations 
 Ketamine drip d/c 
 Review nursing and Pain Service notes 
o Delirium 
 Ketamine drip d/c 
 Review nursing and clinical notes 
o Adverse respiratory events 
 Rapid response events 
 Naloxone administration 
 Change in level of care (intermediate or ICU) 
 Review of nursing notes and clinician progress notes 
o Length of Stay 
 Hours 
o Use of CPAP while inpatient. Y/N 
o Patient satisfaction with pain management questionnaires 
 First questionnaire will be completed by the patient at the time of 
discharge from the hospital. 
 Second questionnaire will be completed by the patient at the 
postoperative visit with the surgeon or via phone contact with the 
patient on or around 30 days after surgery if there has been no 
postoperative visit. 


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Subject Selection Enrollment and Withdrawal 
Inclusion Criteria 
• Patients > or equal to18 years old and < 70 years old undergoing laparoscopic 
gastric bypass at Mayo Clinic Arizona 
• BMI > or equal to 35 
• Consent obtained as per Mayo Clinic policy 
 
Exclusion Criteria 
 
• Intolerance to ketamine 
• History of schizophrenia, schizoaffective disorder or other psychiatric diagnosis 
with psychotic features 
• Presence of unstable cardiovascular disease. (The presence of acute coronary 
syndrome, unstable angina, hypertension emergency, acute TIA or stroke.) 
• Presence of acute elevation of intracranial or intraocular pressure 
• Presence of seizure disorder 
• History of substance abuse or addiction 
• Creatinine > 1.5 
• End-stage liver disease 
• Pregnancy 
 
• Patients with chronic pain and/or chronic opioid therapy: 
o In order to more closely replicate the study patient population of interest 
we will not exclude this patient population 
o However, we will exclude patients taking >50 morphine equivalents (ME) 
per day for greater than 1 month prior to surgery 
 
 
Subject Recruitment, Enrollment and Screening 
Appointment calendars will be screened. Those eligible will be consented by physician 
or study coordinator either in POE or Surgery Clinic. 
 
 
Study Procedures 
• Patient Consent 
o Patients who appear to meet the inclusion criteria and none of the exclusion 
criteria will be invited to participate in this study.  The study will be explained 
to the patient, including risks and benefits by the Study Coordinator, and one 
of the physicians, if available. 


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o Each patient who agrees to participate will be required to sign and date an 
informed consent document prior to any study-specific testing and 
procedure.  A copy of the signed and dated consent will be provided to the 
patient. 
 
• Method for Assigning Patients to Treatment Groups  
o If the patient meets inclusion/exclusion criteria and consents to participate in 
the study, the morphine equivalents will be calculated by one of the 
investigators.   
o The REDCap database will be completed with the inclusion/exclusion criteria 
and morphine equivalents.  REDCap will provide the randomization group for 
the patient. 
o The randomization group will be conveyed to the study team by the Study 
Coordinator. 
 
• Data Collection and Monitoring 
o All required data is collected during the hospitalization from the electronic 
medical record.   
o The floor nurses will follow the already existing ketamine guidelines for Pain 
Service and stopping criteria.   
o The investigators will carefully monitor the subject during hospitalization for 
any adverse events. 
 
• Discharge from the Hospital 
o At the time of discharge from the hospital, the patient will complete the 
Patient Satisfaction with Pain Management at Discharge questionnaire.   
 
• Postoperative Visit 
o At the postoperative visit with the surgeon, the Patient Satisfaction with Pain 
Management questionnaire at Post-op Visit will be completed by the patient.  
If no postoperative visit is scheduled, this will be done via telephone contact 
on or around 30 days after surgery.  We will allow a window of 30-60 days in 
case there is difficulty reaching the patient..   
 
• Adverse events 
o Adverse events will be captured and monitored for the first 30 days following 
surgery to ensure patient safety. 
• Data Entry into REDCap 
o The residents will complete data entry into the REDCap database. 
 
 


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Time Frame 
Enrollment will be completed within 48 months. 
 
Statistical Plan 
 
Sample Size and Power Calculation 
Our primary hypothesis is to check if the new management will keep patient to get less 
“48 hours morphine equivalent (mg)“. A sample size of 17 in each group will have 80% 
power to detect a probability of 0.746 that an observation in new management group is 
less than an observation in control group using a Wilcoxon (Mann-Whitney) rank-sum test 
with a 0.050 one-sided significance level. In other words, we will arrange the total doses 
at 48 hours of patients from smallest to biggest. If 13 or more out of first 17 comes from 
the new management group, we will claim a success. 
 
Statistical Methods 
Basic patient characteristics, using mean+SD or median (range) for continuous variable 
and frequency (% percentage) for categorical data, will be summarized in a table. 2- group 
t-test, Wilcoxon rank sum test, Pearson Chi-square test or Fisher exact test will be used to 
compare the two kinds of management when appropriate. The “48 hours morphine 
equivalent (mg)” will be compared between the two groups using Wilcoxon Rank sum test. 
A p-value less than 0.05 will be treated as statistical significant. All statistical analyses will 
be performed by SAS version 9.4 software (SAS institute Inc, Cary NC). 
 
Adverse Event Reporting Period 
For this study, the follow-up period is defined as 30 days following surgery. 
 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This 
safety monitoring will include careful assessment and appropriate reporting of adverse 
events. Medical monitoring will include a regular assessment of the number and type of 
serious adverse events 
 
 
Data Security and Confidentiality 
All electronic data will be stored in a password-protected database (RedCap). The data 
storage will be restricted to facility computers that are password protected. Relevant 
clinical information will be reported only with collective data with no identities revealed. 
 
Study Monitoring Plan 
Subjects will be closely monitored for adverse events during treatment. 
All study- 
related AEs must be followed until resolution or stabilization. The investigator will allow 
adequate time for such monitoring activities. 
 


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Funding Source 
The study is funded by Mayo Clinic. 
 
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