The Effect of Intraoperative Neuromuscular Blockade on Postoperative Atelectasis in Patients Undergoing Thoracic Surgery With One Lung Ventilation: Moderate vs. Deep Block
Conditions: Thoracic Surgery, One-lung Ventilation
Sponsor: Kyung Hee University Hospital at Gangdong

 
Section #1 - Protocol Identification 
 
Study Title: 
The Effect of Intraoperative Neuromuscular Blockade on Postoperative 
Atelectasis in Patients Undergoing Thoracic Surgery With One Lung 
Ventilation: Moderate vs. Deep Block 
NCT number 
NCT03503565 
Document date 
2017.12. 
Institution Name 
Kyung Hee Medical Center at Gangdong 
Investigator 
Hyungseok Seo 
Contact Information: 
1. Full address  
2. Phone No. 
3. Fax  No. 
4. e-mail address 
1. Department of Anesthesiology and Pain Medicine, Kyung Hee 
University Hospital at Gangdong, 892 Dongnam-ro Gangdong-
gu, Seoul, Korea (05278)  
2. Tel: 82-2-440-7809, Cell: 010-2930-6885 
3. Fax: 82-2-440-7808 
4. seohyungseok@gmail.com 
 

 
 
Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
2.1.1 Objectives.  
Primary object is to compare the intensity of neuromuscular blockade on 
postoperative pulmonary complications.  
 
2.1.2 Clinical hypotheses.  
Primary hypothesis is that maintaining deep neuromuscular blockade with 
sugammadex reversal can improve postoperative atelectasis in patients 
undergoing thoracic surgery with one lung ventilation.  
2.2 Background & 
Rationale, Significance of 
Selected Topic & 
Preliminary Data  
 
Neuromuscular blocking agents can be used to secure a good surgical field, 
but it can also cause delayed extubation or postoperative pulmonary 
complications (Ref 1,2,3) Traditionally, rocuronium which is commonly used 
non-depolarizing agent are usually reversed by cholinesterase inhibitor such as 
neostigmine or pyridostigmine. These drugs act by increasing the 
concentration of acetylcholine at neuromuscular junction (a competing 
antagonist), not by direct antagonists. Consequently, there is a risk of 
pulmonary complications when cholinesterase inhibitor is not used 
appropriately. Use of sugammadex can reverse neuromuscular blockade 
quickly, thereby being helpful for spontaneous deep breathing postoperatively.  
 In a previous study (Ref 1), moderate NMB was not guaranteed during 
surgery because intraoperative TOF monitoring was not used and the outcome 
was focused on the correlation between reversal agent and overall incidence of 
postoperative pulmonary complications. However, in the present study, we 
repeatedly measure TOF ratio or PTC during surgery, thereby maintaining the 
intensity of intraoperative NMB. Moreover, we repeatedly measure lung 
compliance during surgery and investigate the correlation between the intensity 
of intraoperative NMB and postoperative atelectasis, which is evaluated by 
quantitative technique.  
 
Particularly in thoracic surgery, one lung ventilation is usually required for 
surgical procedure. During one lung ventilation, the compliance of ventilated 
lung is decreased and resistance can be increased, thereby risk of atelectasis 
being increased. Furthermore, after thoracic surgery, although patients were 
encouraged to deep breathe, it is difficult to take a deep breath because of 
various factors. (i.e. pain, chest tube, long retracted time, postoperative 
interstitial edema, etc.) Therefore, postoperative atelectasis is much more 
important in patients undergoing thoracic surgery than other type of surgery.  
 
 For preventing postoperative atelectasis, intraoperative intensity of 
neuromuscular blockade can be a crucial factor. Because deep neuromuscular 
blockade provide a good lung compliance during mechanical ventilation, peak 
inspiratory pressure can be decreased, thereby reducing risk of ventilation 
induced lung injury, particularly in one lung ventilation situation.(Ref 4) 
However, there has been still lack of quantitative evidence that deep block is 
superior to moderate block in the thoracic surgery with one lung ventilation  
 
For assessment of postoperative atelectasis, plain chest radiography may be 
used. However, plain chest radiography can provide only a qualitative 
assessment of atelectasis. Computed tomography can assess whole lung by 
density (HU) and enable a quantitative assessment of postoperative 
atelectasis. Moreover it can indicate the location of atelectasis more clearly 
than plain chest radiography, thus provide detailed information about 
postoperative lung state. To assess the effect of maintaining deep block and 

sugammadex reversal on the postoperative atelectasis, using chest CT can 
provide a much more quantitative and valuable information than conventional 
chest radiography. 
2.3 Study Design 
 
A double blinded, randomized, observational, single center study.  
 
The total number of patients was 118 and the randomization was sequenced 
into blocks of four and six patients using randomization software.  
 
Patient population: Patients receiving open or thoracoscopic lobectomy, bi-
lobectomy, or sleeve lobectomy.  
 
Inclusion criteria:  
1. Patients receiving scheduled unilateral lung lobectomy.  
2. Patients age ≥19  
3. Patients of ASA PS 1 or 2 
Exclusion criteria: 
1. Patients receiving bilateral lung lobectomy 
2. Patients BMI > 35.0 or < 18.5 kg/m2 
3. Patients of contraindicated to epidural patients controlled analgesia 
4. Patients with neuromuscular disease (i.e. myasthenia gravis) 
5. Patients with major burn (more than 3rd degrees) 
6. Patients with compromised cardiopulmonary function. 
 
Group description 
Group M: maintaining moderate neuromuscular blockade (TOF count 1 or 2) 
during surgery and reversal using sugammadex 2 mg/kg after surgery  
 
Group D: maintaining deep neuromuscular blockade (PTC 1 or 2) during 
surgery and reversal using sugammadex 4 mg/kg after surgery 
 
2.4 Study Flowchart 
 
 
 

 
 
2.5 Study Procedures 
Anesthesia was induced and maintained with target controlled infusion of 
propofol and remifentanil. Rocuronium 0.6 mg/kg was used to facilitate tracheal 
intubation. Neuromuscular blockade (NMB) was monitored by TOF watch and 
maintained a moderate block status of TOF count 1 or 2 on TOF watch by 
continuous IV rocuronium infusion until main surgical procedure completed in 
group M (Moderate block group). In group D (Deep block group), NMB was 
maintained a deep block status of PTC 1 or 2 on TOF watch.  
Pressure controlled mechanical ventilation was performed with peak inspiratory 
pressure (PIP) 13 cmH2O and 5 cmH2O of positive end-expiratory pressure. 
Respiratory rate is adjusted between 8 and 17 to maintaining PaCO2 35-40 
mmHg. If PaCO2 < 40 mmHg was not obtained when the respiratory rate was 
more than 17, PIP can be increased. If PaO2 < 80 mmHg or SpO2 < 96% 
during OLV, increase PIP by 1 cmH2O until 20 cmH2O. When PIP > 20 
cmH2O was necessary, FiO2, which is usually ~0.5, can be increased by 0.1.  
After the end of surgery, group M was received 2 mg/kg of sugammadex for 
the reversal of NMBA when a second twitch is present on TOF watch, but in 
group D, patients are received sugammadex 4 mg/kg. To maintain blindness, 
each reversal agent was prepared just before general anesthesia induction by 
an independent nurse who did not participate in the surgery. To make the total 
volume of 10 ml, each dose of reversal agent was prepared in a 10 ml syringe 
and the remaining volume was filled with 0.9% NaCl. When TOF ratio reaches 
0.9 and spontaneous respiratory movement is well-recovered, patient was 
extubated and delivered to intensive care unit or PACU. On POD#1, chest CT 
is checked and pulmonary function test is performed after chest tube is 
removed. 
 
Blindness 
 
Because the present study was double blind, assigned group of the patient  
was not revealed to both patient and physicians (including surgeon, attending 
anesthesioloigist, and radiologist). To maintain blindness, only a study 
modulator controlled the intensity of NMB during surgery and attending 
anesthesiologist filled clinical research form without sharing TOF monitoring 
information. In each patient, the volume of sugammadex was equalized to 10 
ml by the remained volume filling with 0.9% NaCl. 
 
Pulmonary complications 
 
1. Atelectasis calculation: (Ref 4) 
The lung area was delineated manually. To calculate atelectasis, a region of 
interest was laid out that encircled the dense part of the lung, excluding large 
vessels. For further analysis, the lung was divided into four categories: areas 
with densities ranging from -1000 to -900 Hounsfield units (HU) were classified 
as overaerated, from -900 to -500 HU as normally aerated, from -500 to -100 

HU as poorly aerated, and from -100 to +100 HU as nonaerated (atelectasis). 
The proportion of nonaerated lung tissue (-100 to +100 HU) was calculated by 
dividing the area of the region of interest with the whole lungs. 
 
2. Pneumonia: (Ref 5) 
Two or more serial chest radiographs with at least one of the following (one 
radiograph is sufficient for patients with no underlying pulmonary or cardiac 
disease): 
1) new or progressive and persistent infiltrates 
2) consolidation 
3) cavitation; 
at least one of the following 
1) fever (>38.0 C) with no other recognized cause 
2) WBC count < 4000/ml or >12,000/ml 
3) for adults >70 yr, altered mental status with no other recognized cause; 
and at least two of the following 
1) new onset of purulent sputum or change in character of sputum, or 
increased respiratory secretions, or increased suctioning requirements 
2) new onset or worsening cough, or dyspnea, or tachypnea 
3) crackles or bronchial breath sounds 
4) worsening 
gas 
exchange 
(hypoxaemia, 
increased 
oxygen 
requirement, increased ventilator demand). 
 
3. Pleural effusion 
: diagnosed on radiograph imaging. 
 
4. Acute Respiratory Distress Syndrome (ARDS): (Ref 5) 
Bilateral opacities not fully explained by effusions, lobar/lung collapse or 
nodules on chest radiograph or CT scan and Respiratory failure not fully 
explained by ca rdiac failure or fluid overload. Need objective assessment (e.g. 
echocardiography) to exclude hydrostatic edema if no risk factor present and 
PaO2:FIO2 < 300mmHg) with PEEP or CPAP 5 cmH2O.  
 
Other measurement parameters:  
demographics, intraoperative lung compliance (hourly), perioperative ABGA, 
postoperative WBC, CRP, hospital stay, ICU stay, incidence of desaturation 
(SpO2 <95% in room air), incidence of re-intubation, pre and postoperative 
laboratory findings. 
 
2.6 Study Duration 
Approximately 18 months, expected. 
2.7 Specific Drug Supply 
Requirements  
N/A 
2.8 Adverse Experience 
Reporting 
Reporting Procedures for Exchange of Adverse Event Information. 
 
(i) For purposes of this Agreement the below terms shall be defined as 
follows: 
 
  “Adverse Event” or “AE” shall mean any untoward medical occurrence in a 
Study subject who is administered the Study Drug regardless of whether or not 
a causal relationship with the Study Drug exists.  By way of example and 
without limitation, an AE can be any unfavorable and unintended sign (for 
example, an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the Study Drug.  
 
  “Device Deficiency” shall mean inadequacy of a Study Drug device related to 
its identity, quality, durability, reliability, safety or performance, such as 

malfunction, misuse or use error and inadequate labeling. 
 
  “Incident” shall mean any malfunction or deterioration in the characteristics 
and/or performance of a Study Drug device, as well as any inadequacy in the 
labeling or the instructions for use which, directly or indirectly, might lead to or 
might have led to the death of a patient, or user, or of other persons or to a 
serious deterioration in the state of health. 
 
  “Medical Device Event” shall mean any malfunction or deterioration in the 
characteristics and/or the performance of a Study Drug device, as well as any 
inadequacy in the labeling or the instructions for use which led to or could have 
led to an untoward event for the user or any other person. 
 
  “Serious Adverse Event” or “SAE” shall mean any untoward medical 
occurrence in a Study subject who is administered the Study Drug that results 
in death, a life-threatening drug experience, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly/birth defect, cancer, or is a new 
cancer if the cancer is the condition of the study, or overdose.  Other important 
medical events that may jeopardize the patient or may require intervention to 
prevent one of the outcomes listed previously should also be considered 
“serious”. 
             
  “Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean 
any Serious Adverse Event, the nature, severity or frequency of which is not 
consistent with information in the most current investigator’s brochure, or with 
respect to a marketed product the most current Summary of Product 
Characteristics (SPC) or Package Insert. 
 
(ii) Serious Adverse Event and Suspected Unexpected Serious Adverse 
Reaction, Medical Device Event, Potential Incident, Device Deficiency or 
Incident Reporting:  Principal Investigator shall forward to MSD’s Global Safety 
(“MSD GS”) group, any SAE and SUSAR, Medical Device Event, Device 
Deficiency or Incident information, including, but not limited to, all initial and 
follow-up information involving any Study subject in the Study. Notification shall 
be in the form of a completed CIOMS I/MedWatch (or other mutually agreed 
upon format) immediately but no later than 1 business day of learning of the 
information. If learned during a weekend or holiday, report within one business 
day or no later than three (3) calendar days (whichever is shorter)from the day 
of learning of the information. This information shall be transmitted to MSD GS 
using the contact information provided below or such other modified contact 
information as provided by MSD in writing.  All information shall be transmitted 
in the English language and contain the reporter’s name and the Study subject 
identifier code.   SUSAR information will be reported unblinded if the Study 
Drug has been blinded in the Study.  Randomization codes for all other SAEs 
will be provided to MSD GS at end of Study if the Study Drug has been blinded 
in the Study. 
 
(iii) MSD may define certain Non-Serious Events of Interest.  If any Non-
Serious Events of Interest are defined, Merck will provide such information in 
writing to Principal Investigator at the time of Protocol approval, execution of 
this Agreement or anytime thereafter.  Reporting of any defined Non-Serious 
Events of Interest will be handled in the same manner as SAEs unless mutually 
agreed otherwise in writing by the parties.   
 
(iv) All reports of Study Drug exposure during pregnancy or lactation 
(including a female partner of a male Study subject using the Study Drug), 
whether associated with an AE or not, must be reported to MSD GS in 

accordance with the timelines and contact information for an SAE.  Principal 
Investigator shall follow pregnancies to term to obtain the outcome of the 
pregnancy.  The outcome of the pregnancy shall be forwarded to MSD GS. 
 
(v) Institution and Principal Investigator shall fully comply with all of their 
respective reporting obligations to the applicable regulatory authorities with 
respect to any AE, SAE or SUSAR that arises from the Study. 
 
(vi) SAE reports and any other relevant safety information are to be forwarded 
to MSD GS facsimile number:  215-993-1220. 
2.9 References 
1. Use of sugammadex in lung cancer patients undergoing video-associated 
thoracoscopic lobectomy. Cho H.C., Lee J. H, Lee S.C., Park S.Y., Rim J.C. 
Choi.S.R. Korean J Anesthsiol 2017 70(4):420-425 
2. Intermediate acting non-depolarizing neuromuscular blocking agents and 
risk of postoperative respiratory complications: prospective propensity score 
matched 
cohort study. 
Sundrup M.G., Henneman J.P. et al. 
BMJ 
2012;345:e6329 
3. Nondepolarizing neuromuscular blocking agents, reversal, and risk of 
postoperative 
pneumonia. 
Bulka 
C.M., 
Terekhov 
M.A., 
Martin 
B.J., 
Dmochowski R.R., Hayes R.M., Ehrenfeld J.M. Anesthesiology 2016; 125:647-
55 
4. Prevention of atelectasis in morbidly obese patients during general 
anesthesia and paralysis. Renius H., Jonsson L., et al. Anesthesiology 2009; 
111:979–87 
5. Standards for definitions and use of outcome measures for clinical 
effectiveness research in perioperative medicine: European Perioperative 
Clinical Outcome (EPCO) definitions. Jammer I.B., Wickboldt N., et al. Eur J 
Anaesthesiol 2015; 32:88–105