Clinical trial NCT03241485
Conditions: Pain
Sponsor: University of Chicago
Start date: 2018-06-19; Completion date: 2020-09-01
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized clinical trial in patients undergoing robotic myocardial revascularization with intraoperative extubation. Patients will be randomized into placebo or intrathecal morphine groups to assess postoperative pain scores and patient satisfaction. Patients will also be assessed for side effects from the intervention.

Detailed description:
Following Institutional Review Board approval and informed patient consent, 120 patients scheduled for elective robotic myocardial revascularization without cardiopulmonary bypass and anticipated intraoperative tracheal extubation will be studied. Patients will be randomized into one of two groups. Group A (placebo, control group) will receive intrathecal normal saline, Group B (morphine group) intrathecal morphine. All procedures will occur and administered medications given immediately prior to induction of general anesthesia in the operating room. Power analysis indicates that 60 patients per Group is appropriate, as further described below. Inclusion criteria include any patient undergoing elective robotic myocardial revascularization without anticipated use of cardiopulmonary bypass and with anticipated intraoperative tracheal extubation. Exclusion criteria include emergency surgery, ejection fraction less than 40%, preoperative use of inotropic agents or intraaortic balloon pump, anticipated use of cardiopulmonary bypass, previous cardiothoracic surgery, anticipated postoperative tracheal intubation, severe pulmonary disease, morbid obesity (BMI \>35 kg/m2), severe renal dysfunction (creatinine \> 1.5) recent history of opioid abuse, preoperative use of opioids, or any contraindication to intrathecal injection (patient refusal, difficult patient anatomy, pre-existing coagulopathy, morphine allergy).

Routine preoperative data will be collected (see Preoperative Data Sheet). Following intravenous access and routine mild sedation, each patient will be transported to the operating room and assume the sitting position. Following routine skin preparation, a routine lumbar intrathecal injection will be made via a 22-g spinal needle. The injectate will be either morphine (5 mcg/kg, maximum dose of 1 mg) or normal saline. The injectate will be prepared by a co-Investigator not directly involved in patient care. Thus, all preoperative, intraoperative, and postoperative caregivers will be blinded to intrathecal injectate composition (all injectates will be standardized to a total of 1.0 ml). All patients will have port incisions injected with 60 ml of 0.25% bupivacaine by the surgeon after the completion of surgery.

Following intrathecal injection, the patient will then assume the supine position. An arterial catheter will be inserted and general endotracheal anesthesia will be induced. Intraoperative anesthetic technique will be standardized and equivalent between Groups (see Intraoperative Anesthetic Protocol Sheet). The anesthetic protocol will allow tracheal extubation to occur in the operating room immediately after surgery (if clinically indicated).

Surgical technique will not be altered in any way. All patients in both Groups will be operated on by the same surgeon. Routine intraoperative data will be collected (see Intraoperative Data Sheet). In all patients, tracheal extubation will be attempted in the operating room immediately after surgery (if clinically indicated).

Both Groups will receive routine postoperative care and identical postoperative analgesic protocols to assess adequacy of postoperative analgesia (see Postoperative Analgesia Protocol and Postoperative Data Sheets). The American Pain Society Outcome Questionnaire (APS-POQ) will be administered to patients prior to discharge (see data sheet).15

Arms: arm 1: 60 patients will be randomly assigned to this arm. The patients in this arm will receive intrathecal saline. arm 2: 60 patients will be randomly assigned to this arm. The patients in this arm will receive intrathecal morphine.
Interventions: intervention 1: Intrathecal morphine intervention 2: Placebo
Intervention descriptions: intervention 1: 5 micrograms/kilogram of intrathecal morphine administered in the spinal space, not to exceed 1mg intervention 2: Saline intrathecal given in the same manner as the intervention groups.

Protocol documents:
Prot_SAP_001.pdf: 
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Study Title: Randomized, double blinded, placebo controlled trial comparing intrathecal 
morphine with placebo in patients undergoing robotic totally endoscopic beating heart coronary 
revascularization and intraoperative extubation (TECAB) 
NCT #: 03241485 
Protocol Version Date: 26JUN2019 
PI: Richa Dhawan. MD MPH 
 
 
 
 
 
 
 
 
 


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MATERIALS AND METHODS  
This clinical trial was approved by the University of Chicago Institutional Review Board (IRB) 
and was registered at Clinicaltrials.gov (NCT03241485) on August 7, 2017 prior to patient 
enrollment.  This manuscript conforms to the Consolidated Standards of Reporting Trials 
guidelines.  The trial was conducted in adherence to the original protocol, which is available 
upon request.  This randomized, placebo-controlled, double-blinded clinical trial was conducted 
at The University of Chicago Medical Center.  Patients were screened for eligibility and 
informed consent obtained on day of surgery in the preoperative area by a member of the study 
team.  Inclusion criteria were patients undergoing elective totally endoscopic CABG without 
anticipated cardiopulmonary bypass (CPB) support and with anticipated intraoperative 
extubation.  Exclusion criteria included emergency surgery, anticipated CPB support, anticipated 
postoperative extubation, previous cardiothoracic surgery, left ventricular ejection fraction less 
than 40%, preoperative cardiac support (intravenous [IV] inotropes and/or 
vasoconstrictors/intraaortic balloon pump), severe pulmonary disease (home oxygen requirement 
and/or recent steroid use), renal dysfunction (serum creatinine greater than 1.5 mg/dL), hepatic 
impairment, preoperative opioid use and/or history of opioid abuse, morbid obesity (body-
massindex greater than 35 kg/m2), and any contraindication to intrathecal injection (morphine 
allergy, coagulopathy, patient refusal).  Selected exclusion criteria reflect patient characteristics 
that would not likely allow for immediate tracheal extubation and assessment of pain scores.  The 
primary outcome is postoperative morphine equivalent consumption in the first 24 h after 
surgery.  Secondary outcomes include postoperative pain scores, opioid-related side effects, and 
self-reported patient satisfaction.    
  


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Following written informed consent, patients were randomized to receive either 
intrathecal morphine (5 mcg/kg, Morphine Group) or intrathecal placebo (sterile saline, Placebo 
Group).  Based on previous clinical trials, the dose of intrathecal morphine was selected to 
potentially facilitate postoperative analgesia without hindering immediate extubation.11,12    
Prior to study commencement, a study statistician created a computer generated 
randomization list (using simple randomization) to allocate study arm assignments in 1:1 ratio, 
which was provided to an operating room pharmacist who prepared the appropriate intrathecal 
solution.  On the day of surgery, the principal investigator assessed the patient for eligibility, 
obtained informed consent, and enrolled the participant in the trial.  After informed consent, the 
pharmacist, based on the sequentially numbered randomization list, prepared either a placebo or 
morphine syringe.  Ultimately, a three ml syringe (total volume one ml clear solution) was 
delivered to the anesthesia caregiver.  All syringes, regardless of saline or morphine solution, 
appeared identical.  All caregivers were blinded to Group assignment throughout hospital stay.  
Both Groups were treated identically during the preoperative/intraoperative period.   
Following application of standard American Society of Anesthesiologists monitors and achieving 
IV access, one mg IV midazolam was given and the patient assumed the sitting position.  After 
normal prepping/draping and local infiltration with lidocaine, a 24-gauge Sprotte (Pajunk, 
Germany) needle was inserted via the L3-4 or L4-5 interspace (introducer-assisted) under sterile 
conditions.  Upon free return of clear cerebrospinal fluid (CSF), the one ml study solution was 
injected and the Sprotte needle removed.  The patient then assumed the supine position, a radial 
arterial line was inserted, and general anesthesia induced.  
Intraoperative anesthetic technique was standardized in all patients.  Induction consisted 
of IV midazolam (2-4 mg), sufentanil (0.5 mcg/kg), propofol (1 mg/kg), and rocuronium (0.6 


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mg/kg).  Following intubation, inhaled desflurane was adjusted to maintain a Bispectral Index 
(BIS® system; Aspect Medical Systems, USA) value of 40-60 and a mean arterial blood pressure 
within 20% baseline value.  Supplemental propofol and rocuronium were allowed throughout, 
consistent with the goal of intraoperative extubation.  A single-lumen endotracheal tube (8.0) 
was used, through which either an Arndt Blocker (Cook Critical Care, Bloomington, IN) or 
EZBlocker (Teleflex Life Sciences Ltd., Athlone, Ireland) was inserted and positioned via 
fiberoptic guidance to facilitate one-lung ventilation when required.  While on two-lung 
ventilation, mechanical ventilation parameters were standardized (tidal volume 5 ml/kg ideal 
body weight, respiratory rate appropriate for normocarbia, FiO2 100%, and positive end-
expiratory pressure 5 cm H2O).  Post-induction, a 9 French double-lumen introducer was 
inserted via the right internal jugular vein and intraoperative transesophageal echocardiography 
was used throughout.  
All patients underwent totally endoscopic CABG without CPB support, via standard 
robotic thoracic ports (Figure 1) and the Da Vinci® surgical system (Da Vinci, Intuitive Surgical, 
USA).  The left and/or right internal thoracic artery served as conduits.  Typically, IV heparin 
was administered (100-150 units/kg; activated clotting time goal 250 seconds) prior to distal 
anastomoses, which was ultimately reversed with IV protamine (1 mg/100 units heparin).  All 
patients had thoracic port incisions injected with 0.25% bupivacaine (30 ml total divided volume) 
at the conclusion of surgery.  Once surgery was finished, consultation between the attending 
surgeon and anesthesiologist determined timing of attempted extubation (intraoperative or 
immediately postoperative). If intraoperative extubation was attempted, IV sugammadex (2 
mg/kg) and ondansetron (4 mg) were administered.  IV ketorolac (15 mg) was allowed if 
emergence tachycardia/hypertension occurred.  Extubation was accomplished once specific 


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criteria were met. IV fentanyl was allowed if clinically indicated (pain) prior to transport to the 
intensive care unit (ICU).  
Postoperative care was standardized in all patients.  Patients not undergoing 
intraoperative extubation were extubated at the earliest clinically appropriate time in the ICU 
once the same specific intraoperative extubation criteria were met.  The dates of patient 
enrollment in the clinical trial were June 19, 2018 to August 31, 2020.  Postoperative analgesic 
technique in the ICU consisted of IV fentanyl (25 mcg as needed) initially (June 19, 2018 to 
February 8, 2019), then transitioned to IV morphine (patient-controlled analgesia [PCA] pump: 2 
mg dose, lockout interval 8 minutes) later (February 19, 2019 to August 31, 2020).  The reason 
for this transition was the University of Chicago experienced an IV morphine drug 
shortage/unavailability during the initial period of the study.  During the entire study period, IV 
fentanyl (25 mcg), IV ketorolac (15 mg every six h, maximum four doses) and/or IV 
hydromorphone was administered in the ICU, if needed.  Once discharged to the surgical ward, 
all patients received oral hydrocodone-acetaminophen (5 mg-325 mg), oxycodone (5 mg), and/or 
tramadol (50 mg), if needed.  Morphine equivalents were then calculated as previously 
described.13 Equivalent doses to 1.0 mg IV morphine and conversion factors used for specific 
drugs were IV fentanyl (0.01 mg/0.10), IV hydromorphone (0.15 mg/6.70), oral hydrocodone 
(3.0 mg/0.30), oral oxycodone (2.0 mg/0.50), and oral tramadol (15 mg/0.06).   
  
  
  
  


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Data Collection  
Data was collected by research team members and nurses who were blinded to Group 
assignment.  Preoperative data was collected from electronic medical records.  Postoperatively, a 
data collection sheet was given to ICU/surgical ward nurses to capture secondary outcomes. In 
addition, patient electronic medical records were accessed for verification.  Pain was evaluated in 
the ICU and surgical ward per nurse at 1, 2, 6, 12, 24, and 48 h following ICU admission via a 
visual analog scoring (VAS) system (0 to 10 scale, 0 = no pain, 10 = worst pain imaginable) at 
rest and with cough.    
Opioid-related side effects (nausea/vomiting, pruritus, urinary retention, and respiratory 
depression) were evaluated in all patients daily by nurses until hospital discharge.  Patients were 
questioned regarding occurrence of nausea/vomiting and pruritus.  Urinary retention was defined 
as need for reinsertion of a urinary catheter or straight catherization after Foley catheter removal.  
Opioid-specific respiratory depression was defined as prolonged tracheal re-intubation secondary 
to hypercarbia (arterial blood gas analysis) and/or escalation of respiratory support following 
extubation thought to be secondary to hypercarbia.     
Prior to hospital discharge, patients completed the Revised American Pain Society  
Outcome Questionnaire, which evaluates subjective experiences of pain following surgery.14  
  
Power Analysis/IRB Termination  
Recent clinical research indicates that when comparing two different intraoperative anesthetic 
techniques in patients undergoing cardiac surgery, a reduction in postoperative morphine 
requirements during the initial 24 h from a median of 10 mg to 6 mg was observed.15  With a 


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one-sided significance level of 0.05 and anticipated 5 mg mean difference (standard deviation of 
8 mg), calculated power was 96% for 120 patients total (60 per Group). Initial IRB approval was 
for study inclusion of 120 patients (60 per Group).  
Interim analysis of data for presentation in abstract form yielded statistically significant 
differences between the two Groups regarding primary and secondary outcomes. Thus, on 
9/21/2020 the IRB chose to permanently close the study for enrollment because “the primary end 
point of this study had been met with statistical significance with fewer number of subjects than 
what was originally planned”.  
  
Statistical Analysis  
Variables were summarized as mean ± SD for normally distributed continuous variables, median 
(25th-75th percentile) for continuous variables with evidence of non-normality or for ordinal 
variables, and frequency counts and percentages for categorical variables.  For the primary 
outcome (amount of postoperative morphine use) and secondary outcomes (i.e. pain scores, 
patient satisfaction), comparisons between the treatment Groups were performed using the 
Wilcoxon rank-sum test (otherwise known as the Mann-Whitney U test).  For side effects 
(secondary outcomes) and other categorical variables, comparisons were made using the 
chisquared test.  However, if there was an expected cell count of <5, then Fisher’s exact test was 
utilized.   
For pain medication and pain score data, differences between treatment Groups were 
calculated along with 95% confidence intervals (CIs) using the cendif command in Stata, based 
on the Hodges-Lehmann method and consideration of all pairwise differences between the two 


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sets of observations.  In addition, box plots were generated for pain scores, stratified by treatment 
Group and time.  As a sensitivity analysis, and to obtain an overall estimate of treatment effect 
on pain, mixed-effects models were fit (Appendix 2).  
Statistical significance was defined as a two-tailed p < 0.05 based on tests of superiority; 
no formal adjustment for multiple testing or interim looks was made.  Statistical analyses were 
performed using Stata 16 (StataCorp LLC, College Station, TX).