Prospective, Randomized Trial Comparing Effect of General Anesthesia With and Without Neuromuscular Blockade on Postoperative Pulmonary Complications in Elective Cardiac Surgical Patients
Phase: PHASE4
Conditions: Neuromuscular Blockade, Postoperative Complications
Sponsor: University of Chicago

 
1 
 
Prospective, Randomized Trial Comparing Effect of General Anesthesia With 
and Without Neuromuscular Blockade on Postoperative Pulmonary 
Complications in Elective Cardiac Surgical Patients 
 
Protocol # 15-1016 
 
 
Principal Investigator: 
Rebecca M. Gerlach, MD, FRCPC 
Assistant Professor 
Department of Anesthesia and Critical Care 
University of Chicago 
 
Co-Investigators: 
 
Mark A. Chaney, MD 
Professor 
Director of Cardiac Anesthesia 
Program Director, Adult Cardiothoracic Anesthesia Fellowship 
Department of Anesthesia and Critical Care 
University of Chicago 
 
 
 
 
 
Sajid Shahul, MD, MPH 
Associate Professor 
Department of Anesthesia and Critical Care 
University of Chicago 
 
Takeyoshi Ota, MD, PhD 
Assistant Professor 
Co-Director, Center for Aortic Diseases 
Department of Surgery 
University of Chicago 
 
Valluvan Jeevanandam, MD 
Professor 
Section Chief, Cardiothoracic Surgery 
Department of Surgery 
University of Chicago 
 
 
Corresponding Investigator: Rebecca M. Gerlach, MD, FRCPC 
Assistant Professor 
Department of Anesthesia and Critical Care 
University of Chicago 
5841 S. Maryland Ave, MC 4028 
Telephone:  (773) 702-3794 
Email:  rgerlach@dacc.uchicago.edu 
 
 
 

 
2 
Introduction 
Neuromuscular blockers (NMB) are medications commonly used by anesthesiologists 
during surgery to induce paralysis/muscle relaxation and facilitate the technical performance of 
surgery. However, the residual effect of neuromuscular blockade during the immediate 
postoperative period has been associated with an increased incidence of postoperative pulmonary 
complications. 1-6. Residual neuromuscular blockade is a contributing factor to adverse events 
including delayed discharge from recovery, need for tracheal reintubation, impaired oxygenation 
and ventilation, aspiration, atelectasis and pneumonia. 3,6,7 These effects are likely mediated by 
decreased airway tone and impaired respiratory effort persisting during recovery from 
anesthesia.8,9 Despite awareness of this problem for the last 35 years, residual neuromuscular 
blockade after anesthesia remains a common adverse event and has been the focus of initiatives 
by the Anesthesia Patient Safety Foundation as recently as February 2016.10,11 
Despite widespread utilization of NMB during cardiac surgery, very little is known about 
residual neuromuscular blockade in patients following cardiac surgery. A recent large, 
retrospective study of a non-cardiac surgical database has linked intermediate-acting 
neuromuscular blockade and postoperative pulmonary complications in a dose-dependant manor. 
6 Patients undergoing cardiac surgery are even more susceptible to the detrimental effects of 
residual neuromuscular blockade than in non-cardiac surgical patients, however no recent clinical 
studies have been directed at this population. The few studies that have examined NMB in 
cardiac surgical populations have served to shift routine practice away from older, long-acting 
NMB agents (e.g. pancuronium) toward the intermediate-acting agents (e.g. rocuronium or 
cisatracurium) commonly used during non-cardiac surgery.12-16 Yet, cardiac surgical patients 
experience physiologic conditions not associated with non-cardiac surgery, such as exposure to 
hypothermic cardiopulmonary bypass which is known to decrease muscle strength substantially 

 
3 
even in the absence of NMB.17,18 Additionally, the clinical effects of NMB may be intensified 
during hypothermia via complex pharmacokinetic and pharmacodynamic interactions not yet 
fully understood. 19-24 Cardiac surgical patients may also be more susceptible to the harmful 
effects of residual neuromuscular blockade due to significant comorbidities predisposing them to 
postoperative pulmonary complications.25-28  Concern over detrimental effects of NMB have led 
some to call for minimizing or eliminating the continuous use of NMB during cardiac surgery, as 
acceptable surgical conditions may be achieved with adequate depth of anesthesia and blunting of 
the physiologic response to surgery.29,30 Given the traditional role of neuromuscular blockade in 
the management of cardiac surgical patients, prospective data is needed to determine the effect of 
NMB in cardiac surgical patients as well as the surgical tolerability of protocols that minimize 
intraoperative paralysis. 
The proposed prospective, randomized trial will assess the impact of neuromuscular 
blockade on early (<72 hours post-ICU admission) postoperative respiratory complications. This 
clinical study will prospectively investigate two groups of patients undergoing elective cardiac 
surgery at the University of Chicago.  In the experimental group, a very short-acting depolarizing 
NMB (succinylcholine) will be used for tracheal intubation and no other subsequent muscle 
relaxants throughout surgery.  In the control group, an intermediate-acting non-depolarizing 
NMB (cisatracurium) will be used throughout the intraoperative period (our standard practice) 
and will be re-administered to maintain a moderate to deep level of muscle relaxation until the 
conclusion of surgery.  Both groups will be monitored with peripheral nerve stimulators (ulnar 
and facial nerve) throughout the intraoperative period and immediate postoperative period. 
Residual neuromuscular blockade during the immediate postoperative period will be assessed in 
both groups objectively and subjectively.  

 
4 
Recent clinical studies support the use of intraoperative acceleromyography for titration 
of NMB based on the motor response of nerve stimulation.31 Since during cardiac surgery, 
anesthesiologists have limited access to the patient’s arms due to patient positioning, both the 
adductor pollicis and orbicularis oculi sites will be monitored with a TOF-Watch to provide for 
correlation as well as redundancy in the event of intraoperative disturbance of the adductor 
pollicis site due to surgeon positioning. 
The primary outcome to be examined is the composite event of a postoperative 
pulmonary complication linked to residual NMB. Surgical tolerability (assessed via specifically 
designed cardiac surgeon rating scale and examination of undesired patient movement during 
anesthesia) and subjective/objective signs of postoperative weakness (patient questionnaire, 
neuromuscular blockade monitoring) are the secondary outcomes to be assessed. 
 
Methods 
 A prospective, randomized protocol was designed to assess the impact of low/single dose NMB 
on the incidence of early respiratory complications in cardiac surgery. Reported incidence of 
respiratory complications after cardiac surgery ranges from 0.5-30% depending upon the 
particular complication and population subset being examined. The current study focuses on a 
pre-defined composite measure of respiratory complications that are potential sequelae of NMB-
associated effects on respiratory muscle weakness. This primary outcome measure will include 
the following and will be determined through prospective observation for 72 hours following 
admission to the intensive care unit (ICU) postoperatively.  (See “Data Collection: Respiratory 
Complications”) 
1. Failure to extubate within 24 hours of ICU admission time 
 Determined via documentation of extubation time 

 
5 
2. Need for tracheal re-intubation (<72 hours post-ICU admission) 
 Determined via documentation of respiratory therapy/intubation events 
3. Pneumonia 
 Defined by radiologist report or ICU attending assessment of new or progressive 
pulmonary infiltrate on chest x-ray AND 
 Clinical findings suggesting systemic infection (fever >38°C or <36°C OR WBC 
count >12,000/mm3 or <4,000/mm3) OR antibiotic therapy OR positive respiratory 
cultures/purulent sputum 
4. Pulmonary aspiration 
 Diffuse infiltrates or consolidation of dependant lung segments on chest x-ray 
consistent with aspiration 
  AND clinical findings consistent with aspiration pneumonitis, including 
increasing oxygen requirements, suspected aspiration or increased work of 
breathing 
5. Need for noninvasive respiratory support with CPAP or BiPAP therapy  
 Documented use required during first 72 hours post-ICU admission 
 Composite scoring of respiratory events does not include continuation of CPAP 
therapy as prescribed preoperatively for known obstructive sleep apnea (OSA) 
 Includes escalation of therapy (BiPAP treatment when previously CPAP only was 
needed) 
6. ARDS (mild, moderate or severe) (<72 hours post-ICU admission) based on Berlin 
definition: 
 Bilateral opacities on chest x-ray consistent with pulmonary edema 
 Arterial blood gas and ventilator setting evidence of PAO2/FiO2 ratio <300 

 
6 
 Not fully explained by cardiac failure or fluid overload 
7. Mortality attributed to respiratory event (<72 hours post-ICU admission) 
 Hypoxic or hypercarbic respiratory arrest 
Secondary outcomes in the study will be:  
1. Surgical Tolerability 
 Measured by a designed instrument that will be completed by the surgeon and 
anesthesia staff and will include reporting of the following (See “Data 
Collection: Surgical Tolerability”) 
o Patient movement: Major (limb movement, coughing on ventilator), 
minor (diaphragm movement), none 
o Movement interfering with surgical progress: Yes, no 
o Surgical conditions: Excellent, good, poor 
o Total dose supplemental propofol required for suppression of 
movements 
o BIS recorded during patient movement 
2. Weakness (See “Data Collection: Postoperative”) 
 Blinded assessment of patient experience of weakness or respiratory 
difficulties on postoperative survey (See “Postoperative Survey”) 
Study Risk and Benefits 
When continuous muscle relaxation is omitted, there is a risk of movement under 
anesthesia (e.g. coughing, limb muscle movement), which may interfere with surgery. Movement 
under anesthesia occurs occasionally even when muscle relaxation is provided continuously 
(during standard of care), but in the absence of muscle relaxation (non-standard of care), these 
movements may be more pronounced. Other anesthesia medications (i.e. anesthetic agents, 

 
7 
analgesic agents) are provided when muscle relaxation is not being administered to minimize 
these risks. In our study, midazolam and fentanyl (standard of care medications) will be 
administered in doses to avoid the potential for inadvertent movement. In the low dose muscle 
relaxant group, inadvertent patient movement will be treated with additional anesthesia with 
propofol, increasing the dose of volatile anesthetic, administering pain medication or if necessary 
for patient safety, administering muscle relaxants as required (i.e. reverting to standard of care). 
The risk of movement under anesthesia when low dose muscle relaxant is used is reasonable 
because providing anesthesia without muscle relaxation is an established technique used for other 
types of surgery (e.g. non cardiac). 
As muscle relaxation has been associated with harmful effects (e.g. postoperative 
pulmonary complications), the use of low doses has some potential benefit. Results from this 
study may help future patients having cardiac surgery by providing guidance to the best way to 
conduct anesthesia to minimize respiratory complications. 
Monitoring of Safety 
There will be ongoing (case by case) review of adverse events and safety information 
between the principal investigator and co-investigators and any events will be addressed. 
Unanticipated problems requiring a revision to the protocol will be submitted to the IRB for 
review. A Data Safety Monitoring Board has been convened and will review the results early in 
the study as well as halfway through enrolment to address any safety concerns. A continuing 
review with examination of preliminary data will be conducted after 50 patients have been 
recruited. 
Unanticipated problems (i.e. unexpected events that are related or possibly related to 
participation in the research that suggest that the research places subjects or others at risk of 
unknown harm or increased frequency of harm) will be reported to the IRB within 10 working 

 
8 
days of the investigator’s knowledge of the event. In the event of a fatal or life-threatening 
unanticipated problem, enrolment will be halted and the IRB chair notified by phone 
immediately. A major deviation from the protocol will be reported within 10 working days via 
the “Unanticipated Problem” form. A minor deviation will be summarized at the time of 
continuing review on the “Continuing Review Form”. 
Power Calculation: 
Previous studies of respiratory complications after cardiac surgery have suggested 
incidence rates ranging from 0.5-30%.26,27,33-35 Many of these studies include atelectasis and 
pleural effusions in their composite calculation of respiratory complications, which are 
problematic because of diagnostic difficulty and less clear relationship to NMB use. The current 
study will focus solely on the respiratory complications previously defined. Assuming this 
composite has a potential incidence of 20% and that the effect size is 0.5, a total of 47 patients 
will be required in each arm to achieve a power of 80% with a p=0.05. A total of 100 patients 
will be recruited to account for crossover.  
Inclusion Criteria 
All patients >18 years old undergoing elective cardiac surgery (coronary artery bypass 
grafting [CABG], valve replacement or CABG + valve replacement) requiring cardiopulmonary 
bypass at the University of Chicago with one of two surgeons (Dr. Jeevanandam or Dr. Ota). 
Exclusion criteria 
Emergency surgery, extremes of age (<18 or >90 years), previous cardiac surgery, clinical 
contraindications to succinylcholine or cisatracurium, anticipated difficult tracheal intubation, 
preoperative mechanical ventilation, preoperative pharmacologic/mechanical hemodynamic 
support. 
Study Protocol 

 
9 
 Institutional Review Board approval will be obtained and the study will be registered 
with www.clinicaltrials.gov prior to commencement.  All patients enrolled in the study will be 
randomized to either a standard protocol (Group CIS) or the single-dose NMB protocol (Group 
SUX) (See “Intraoperative Protocol”). All study and anesthetic drugs will be administered by the 
anesthesia care team. The neuromuscular blocking agents being studied will be dispensed by the 
operating room pharmacy, as is routine, and drawn up in the operating room for intravenous 
administration. ICU providers and surgeons will be blinded to the study group assignment, and 
intraoperative and postoperative care will otherwise be routine. 
No compensation will be provided to study participants. Patients will be identified by 
review of operative room schedules and consent will occur prior to the standard preoperative 
interview. The data set created from study information will be maintained following study 
completion but all patient identifiers will be deleted. This will be maintained for a minimum of 6 
years. Consent forms with patient identifying information will be held in a locked file in a locked 
office for a minimum of 6 years. Randomization will be performed by computer generation. Data 
analysis will be performed on an intention to treat basis. 
Data Collection 
 The investigators will collect the following data points. 
Patient Factors – See “Data Collection: Preoperative” 
Intra-operative Factors – See “Data Collection: Intraoperative and Data 
Collection: Surgical Tolerability” 
Post-operative factors – See “Data Collection: Postoperative, Data Collection: 
Respiratory Complications, Data Collection: Postoperative Survey” 
 
 

 
10
 
 

 
11
Intraoperative Protocol 
 
Patients are to receive the same standardized doses of medications as a total for the case. 
Induction/maintenance medications are to be administered with induction or prior to CPB, as 
hemodynamics allow. IV boluses of phenylephrine (100mcg), vasopressin (1 unit), ephedrine 
(10mg) or norepinephrine (8mcg) may be administered as required. 
 
Induction/maintenance: 
 Midazolam 0.1mg/kg 
 Fentanyl 15 mcg/kg 
 Isoflurane: titrated to maintain BIS <55 or prevent patient movement, minimum of 0.6% 
while on CPB 
 Propofol bolus (0.2-0.5 mg/kg): as needed for patient movement 
 Propofol infusion started (25-50 mcg/kg/min) at “drapes down”, Isoflurane stopped 
 Appropriate antibiotic administration according to hospital protocol 
 
Mechanical Ventilation Parameters 
 Tidal volume 6mL/kg of ideal body weight: male IBW = 50 + 2.3(height in inches – 60), 
female IBW = 45.5 + 2.3(height in inches – 60) 
 RR appropriate to maintain pCO2 between 35-45 mmHg 
 FiO2 100% intraoperatively 
 PEEP 5 
 
Neuromuscular Blockade 
Group SUX 
 Succinylcholine 1mg/kg 
 No additional muscle relaxants 
for case 
 
Group CIS 
 Cisatracurium 0.2mg/kg 
 Supplemental cisatracurium as dictated by 
peripheral nerve stimulator on the hand to 
maintain 1-2 twitches 
 Last dose given at sternum closure 
 
 
TOF monitoring 
 Place TOF-Watch monitor on left arm (ulnar nerve monitoring) and along facial nerve 
(orbicularis oculi monitoring) 
 Left arm will be secured at the patient’s side with the TOF-Watch hand stabilizer in place 
while allowing the hand/thumb free movement for measurement with TOF-Watch 
 Assess TOF at times indicated on intraoperative data collection sheet 
 Continue to monitor TOF ratio in group SUX even after initially returns to 100% and 
record changes during CPB/hypothermia 
 

 
12
Data Collection: Preoperative 
 
Group Assignment 
(circle one): 
Group SUX 
Group CIS 
MRN: 
________________________ 
Height ___________cm  
Weight___________kg 
Ideal Body Weight_______________kg 
Age: 
__________________________ 
Gender (circle one):  M   /   F 
Preoperative creatinine: 
_________________mg/dL 
Surgical Date (mth/day/year) 
 
_______/________/________ 
 
Diagnosis: 
 
 
Proposed Surgery: 
 
 
Anesthesiologist (circle): 
Chaney     Gerlach     
Other:________________ 
Surgeon (circle): 
Jeevanandam       Ota 
 
 
YES 
NO 
Pulmonary disease (long-term bronchodilator/steroid use) 
 
 
 Obstructive sleep apnea diagnosis 
CPAP therapy:  Yes__________cmH2O     
NO_________ 
 
 
 Active smoker (current ppd:____________________) 
 
 
 Smoking history (quit date:____________________) 
 
 
Extracardiac Arteriopathy/PVD (claudication/carotid 
disease/vascular surgery, >50% stenosis) 
 
 
 HTN 
 
 
 Diabetes Mellitus 
 
 
 History of CVA 
 
 
Neurologic dysfunction (severely affecting ambulation or day-
to-day function) 
 
 
 Preop functional status, partially dependant 
 
 
 Preop functional status, totally dependant 
 
 
Active endocarditis (still using antibiotics) 
 
 
Critical preoperative state (preop cardiac arrest or dialysis) 
 
 
Unstable angina (rest angina, IV nitrates, IABP) 
 
 
LV dysfunction (LVEF <30%) 
 
 

 
13
Recent MI (<90 days) 
 
 
Pulmonary hypertension (PA systolic >60mmHg) 
 
 
Isolated CABG 
 
 
Thoracic aortic surgery 
 
 
Post-infarct septal rupture 
 
 
 
 
Preop Meds 
YES 
NO 
Cardiac 
Beta-blocker 
 
 
 
ACEi 
 
 
 
ARB 
 
 
 
Nitroglycerin 
 
 
 
Diuretic 
 
 
 
ASA 
 
 
 
Plavix 
 
 
 
Statin 
 
 
Pulmonary 
Bronchodilators 
 
 
 
Steroids 
 
 
Diabetes 
Insulin 
 
 
 
Oral hypoglycemics 
 
 
Other 
Antibiotics 
 
 

 
14
Data Collection: Intraoperative 
Time Point 
TOF EYE 
Bladder Temp 
(Celsius) 
BIS 
measurement 
Baseline (pre-muscle 
relaxant) 
 
 
 
Post-intubation 
 
 
 
Skin incision 
 
 
 
Sternotomy 
 
 
 
Heparin admin 
 
 
 
CPB 10 min 
 
 
 
CPB 30 min 
 
 
 
CPB 60 min 
 
 
 
CPB 90 min 
 
 
 
CPB 120 min 
 
 
 
CPB 180 min 
 
 
 
CPB 240 min 
 
 
 
CPB separation 
 
 
 
10 min post-Protamine 
 
 
 
Chest closure 
 
 
 
Drapes down 
 
 
 
 
 
TIME 
 
DATA 
Induction 
 
Initial ABG (FiO2 1.0) 
 
Incision 
 
Post-Protamine ABG 
(FiO2 1.0) 
 
 
CPB on 
 
 
 
CPB off 
 
Chest closure 
 
Out of OR 
 
Lowest CPB temp 
 
ICU arrival 
 
Last OR patient temp 
 
 
Intraoperative Drug Totals 
 
Midazolam ______________mg 
Phenylephrine _____________mcg 
Fentanyl  ______________mcg 
Vasopressin _____________units 
Cisatracurium __________mg 
Ephedrine _______________mg 
Propofol ______________mg 
Norepinephrine ___________mcg 
 
Epinephrine______________mcg 
Blood Product Units: RBC______ FFP_____ Plt________Cryo_____ 
 

 
15
Data Collection: Surgical Tolerability 
 
Surgical Tolerability Assessment Tool (to be asked of primary surgeon at 
conclusion of surgery): 
 
 Did you notice patient movement?   YES   /   NO 
 
o If yes, how severe was the movement? 
 
MAJOR (limb movement, coughing on ventilator) 
 
MINOR (diaphragm movement) 
 
o Did movement interfere with surgical progress?  YES   /   NO 
 
 How were the surgical conditions, compared to expected? (1 being poor and 
5 being excellent) 
 
1………2……….3………..4……….5 
(POOR  …  GOOD  …   EXCELLENT) 
 
Patient Movement Record (to be completed by anesthesiologist) 
 
Clinical Scenario 
BIS 
Major 
movement 
(Y/N) 
Interfere with 
Surgery (Y/N) 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
 

 
16
Data Collection: Postoperative 
 
ICU arrival time: 
 _____________:_____________ 
ICU arrival hemodynamic 
support: 
 
ICU arrival spontaneous 
movement/resp effort* 
  YES    /    NO 
TOF assessment at 20 min TOF EYE______________________ 
 
*Observed by investigator for 20min following ICU arrival – includes any gross movement of 
limbs or respiratory effort 
 

 
17
Data Collection: Respiratory Complications 
 
Composite incidence of respiratory complication: 
Document presence of any of the following conditions during the first 72 hours 
postoperative (i.e. from the time of admission to the ICU) 
See criteria defined in protocol 
 
YES 
NO 
Failure to extubate within 24h of ICU admission 
 
 
Need for re-intubation within 72h 
 
 
Pneumonia  
 
 
Aspiration 
 
 
Unanticipated need for noninvasive respiratory support 
(CPAP/BiPAP) during first 72h 
 
 
ARDS (PaO2/FiO2 ratio <300) 
 
 
Mortality attributed to respiratory arrest 
 
 
 
Outcomes: 
 
ICU admission date/time:_______________________________ 
 
Tracheal extubation date/time:_________________________ 
 
ICU discharge date/time:________________________________ 
 
Hospital discharge (or death) date/time:___________________________ 
 
 

 
18
Data Collection: Postoperative Interview 
 
To be completed with patient on Post-op Day #7. Interviewer will be blinded to the patient group. 
 
INTRAOPERATIVE AWARENESS? 
YES / NO 
 Do you remember any events from during your surgery, from the time you “went to 
sleep” to the time you were brought to the intensive care unit? 
IF YES:  ________________________________________________________ 
 
PERI-EXTUBATION WEAKNESS? 
YES / NO 
 At the time that you had the breathing tube removed, do you remember feeling weak, 
having a hard time breathing or coughing, or needing your breathing supported with a 
machine? 
IF YES:  ________________________________________________________ 
 If you had a hard time breathing, do you remember why this was (CHECK ALL THAT 
APPLY)? 
o DUE TO PAIN 
o DUE TO MUSCLE WEAKNESS 
o DUE TO SLEEPINESS 
o DUE TO FATIGUE/BEING TIRED 
o DUE TO SORE THROAT/MOUTH SWELLING 
 
LEFT ARM PROBLEMS?  
YES / NO 
 Are you or did you have any unusual symptoms in your left arm (such as pain, numbness, 
tingling) since your surgery? 
IF YES:  ________________________________________________________ 
 
POSTOPERATIVE PULMONARY COMPLICATIONS? 
YES / NO 
 Do you believe you had a breathing complication after your surgery? 
IF YES:  ________________________________________________________ 
 
 

 
19
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