An Investigation of the Impact of Anesthetic Guidance of Depth of Anesthesia and Indirect Cardiac Output Monitoring on the Clinical Outcomes of Patients Undergoing Thoracic Surgery: A Factorial Parallel Randomized Controlled Trial
Phase: NA
Conditions: Anesthesia, Hemodynamic Instability, Postoperative Respiratory Complication
Sponsor: Taipei Medical University Shuang Ho Hospital

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TMU-Joint Institutional Review Board 
 
 
 
Protocol Title 
An investigation of the impact of anesthetic 
guidance of depth of anesthesia and indirect 
cardiac output monitoring on the clinical outcomes 
of patients undergoing thoracic surgery: A 
factorial parallel randomized controlled trial 
 
 
 
 
Protocol No: N202004045 
Version/Date：1/2020.04.26 
 
 

 
 
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List of Abbreviations: 
 
BIS: bispectral index 
CO: cardiac output 
CONSORT: Consolidated Standards of Reporting Trials 
ERAS: Enhanced Recovery After Surgery 
EEG: electroencephalography 
FiO2: fraction of inspired oxygen 
GDT: goal-directed therapy 
OLV: one-lung ventilation 
PaO2: arterial partial pressure of oxygen 

 
 
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1. 
Introduction 
Patients undergoing thoracotomy in thoracic surgery are prone to have complications of 
delayed recovery from general anesthesia and perioperative instable hemodynamics due to the 
relatively invasive procedures and patient’s underlying morbidity. Therefore, intraoperative 
monitoring and corresponding management are of great importance to prevent relevant 
complications in thoracic surgery. This study aims to investigate the clinical benefits of two 
intraoperative monitoring techniques in patients undergoing thoracotomy surgery, including 
depth of anesthesia and minimally invasive cardiac output monitoring. First, M-Entropy system 
will be used to measure the depth of anesthesia and be evaluated regarding the effect of spectral 
entropy guidance on postoperative recovery. Second, we will apply ProAQT device in guiding 
goal-directed hemodynamic therapy and assess its impact on occurrence of postoperative 
pulmonary complications and recovery. In this study, we will conduct a factorial parallel 
randomized controlled trial and use the method of stratified randomization to evaluate both two 
monitoring technologies in the same patient group. The results of this study will provide 
important evidence and clinical implication for precision anesthesia and enhanced recovery after 
surgery (ERAS) protocol in thoracic surgery.  
 
This study aims to investigate the clinical benefits of two intraoperative monitoring techniques 
in patients undergoing thoracotomy surgery, including M-Entropy system and ProAQT sensor, 
as follows: 
1) To evaluate the effect of M-Entropy guidance on the emergence from anesthesia and risk of 
postoperative delirium. 
2) To apply ProAQT in guiding goal-directed hemodynamic therapy and assess its impact on 
postoperative pulmonary complications and recovery. 
 
2. 
Background 
Thoracic anesthesia comprises a wide variety of diagnostic and therapeutic procedures 
involving the lungs, airways, and hemodynamic changes. The procedure of thoracotomy 
inevitably causes pneumothorax, which results in multiple physiology derangements, including 
ventilation-perfusion mismatch and hypoxia.1 Furthermore, one-lung ventilation (OLV) is 
commonly used to facilitate the visualization and surgical manipulation in video-assisted 
thoracotomy. However, OLV may also cause profound hemodynamic changes, including lung 
collapse, barotrauma and severe hypotension.1 The hemodynamic instability may further increase 
the risk of inadequate depth of anesthesia and thereafter its related complications, such as 
intraoperative awareness, post-traumatic stress disorder and cognitive dysfunction.2 Therefore, 
intraoperative monitoring and corresponding management are of great importance to prevent 
relevant complications in thoracic surgery.  
Because of the advances in monitoring technology in recent decades, the risk of mortality 
and morbidity of anesthetic practices has significantly declined.3 Among the newly-introduced 
technologies, electroencephalography (EEG)-based monitoring of anesthesia depth and indirect 
cardiac output monitoring are useful and minimally invasive in optimizing the anesthetic 
patients’ intraoperative hypnotic, cardiac output, and intravascular volume status.4,5 However, 
there is spare evidence regarding the effectiveness of the use of these two monitoring in guiding 
thoracic anesthesia. Accordingly, this study aims to investigate the effect of guidance of spectral 

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entropy and indirect cardiac output monitoring on the recovery from anesthesia and 
postoperative outcomes in patients undergoing thoracotomy. 
 
Anesthesia depth monitoring using spectral entropy 
Meta-analysis has showed that bispectral index (BIS)-guided anesthesia may enhance early 
recovery time in patients undergoing surgery with general anesthesia compared to clinical signs.6 
However, compared with BIS, M-Entropy™ system (GE Healthcare, Helsinki, Finland) is much 
less investigated regarding its clinical effectiveness. The use of entropy to track the anesthetic 
state of patients is a relatively new monitoring approach. Entropy measures the degree of 
disorder or the lack of synchrony or consistency in a system.7 Entropy-based analyses have been 
applied to the EEG and used to construct EEG-based indices meant to indicate the depth of 
anesthesia.7 Although EEG-based monitoring of anesthesia depth is widely used and effective in 
maintaining the optimal range of anesthesia depth in total intravenous anesthesia, there is spare 
evidence regarding the role of spectral entropy monitoring in volatile anesthesia regarding time 
to emergence from anesthesia as well as reduction in anesthetic agent use.8 Besides, whether 
entropy guidance in general anesthesia protects against development of postoperative delirium 
remains unclear in thoracic surgery. 
 
Indirect cardiac output monitoring in guiding intraoperative fluid and inotrope or vasopressor 
therapy 
There are several commercial devices in monitoring cardiac output (CO) through minimal 
invasive techniques.5 The major principles and techniques of CO measurement include the Fick 
principle, arterial waveform analysis techniques, the Doppler principle.9 ProAQT®  device 
(Pulsion Medical Systems, Munich, Germany) is a modular platform with intelligent 
visualization for real-time patient monitoring on the basis of PiCCO pulse contour algorithm.9 
ProAQT allows physiological interpretation of the patient’s hemodynamic status and supports 
goal directed therapy in surgical patients. Regardless of the broad use of minimally invasive CO 
monitoring in clinical practices, the evidence for its benefits in patients’ prognosis is conflicting.9 
Furthermore, it is unclear whether application of minimally invasive CO monitoring in guiding 
administration of intraoperative fluid, inotrope, and vasopressor improves outcomes in thoracic 
surgery.10 At present, the validity of this technology as a valid guide for fluid management when 
the chest is open remains unclear. Strong clinical outcomes data support the use of noninvasive 
stroke volume monitors in patients undergoing major surgery although these studies generally do 
not focus on thoracic surgical procedures.11-13  
 
The value of precision anesthesia in Enhanced Recovery After Surgery (ERAS) 
Patients undergoing thoracotomy are prone to have complications of delayed recovery from 
general anesthesia and perioperative instable hemodynamics due to the relatively invasive 
procedures and patient’s underlying morbidity.11,12,14,15 Current recommendations from the 
ERAS Society and the European Society of Thoracic Surgeons include short-acting anesthetics 
to facilitate early emergence, opioid-sparing analgesia, euvolemic fluid management, etc.16 In 
achieving early emergence from general anesthesia and euvolemic status during surgery, we 
could add important evidence and provide useful clinical implication to ERAS protocols by 
elucidating the effectiveness of precision guidance of anesthesia depth and goal-directed 

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hemodynamic therapy using real-time spectral entropy and minimally invasive CO monitoring in 
thoracic anesthesia.  
 
3. 
Criteria of Eligibility 
We will enroll the patients undergoing video-assisted thoracotomy at Shuang Ho Hospital, 
Taipei Medical University, New Taipei City, Taiwan. Exclusion criteria will be age < 20 years, 
pregnancy, end-stage renal disease, emergency surgery, presence of circulatory shock needing 
vasoactive drugs before surgery, any diagnosis of aortic diseases, cerebral vascular diseases or 
trauma, and high-degree cardiac arrythmia (e.g. atrial fibrillation), uses of cardiac pacemaker or 
automated implantable cardioverter defibrillator, New York Heart Association functional 
classification 4, long-term use of psychiatric medications, intraoperative blood loss > 1 L, 
intraoperative blood transfusion, planned or unanticipated transferal to intensive care unit for 
postoperative mechanical ventilation, and patient refusal to participate. 
 
4. 
Study Design 
We will use the design of factorial parallel randomized controlled trial to conduct these two 
studies in the same patient group. A computer-generated list of randomizations (Research 
Randomizer, www.randomizer.org) will be used for these group allocations. We will use 
stratified randomization method to ensure random allocations of these two treatments (spectral 
entropy and ProAQT goal-directed therapy) in all patients.17 Allocation will be concealed with 
sequentially numbered sealed opaque envelopes. The principal investigator will open the 
respective concealed envelope containing the patient allocation to the treatment arm on the day 
of surgery immediately before induction of anesthesia. In this trial, we will conform to the 
recommendations in the Consolidated Standards of Reporting Trials (CONSORT) statement.18,19 
In addition, we will follow the principle of intention-to-treat in our analyses of the trial results. 
 
5. 
Study Methods 
The effect of M-Entropy guidance of anesthesia depth on postoperative recovery: A single-
blind randomized controlled trial 
Standard monitoring will be applied, including five-lead electrocardiogram, pulse oximetry, 
capnography, radial artery catheterization for arterial blood pressure, and internal jugular vein 
cannulation for central venous pressure. Patients will be given balanced general anesthesia, 
including fentanyl 1–2 μgꞏkg-1 and propofol 1–2 mgꞏkg-1 for induction, and rocuronium 0.8 
mgꞏkg-1 to facilitate tracheal intubation. Anesthesia will be maintained using sevoflurane 2–3 
vol% in oxygen. An additional bolus of intravenous fentanyl 50 μg will be administered before 
surgical incision. Pressure-controlled ventilation with a positive end expiratory pressure of 5 cm 
H2O and peak pressure < 30 cm H2O will be applied for both double-lung ventilation and OLV. 
OLV will be initiated after patients are in the lateral decubitus position. During double-lung 
ventilation the inspiratory oxygen fraction will be set to 0.6, whereas 0.8–1.0 will be used for 
OLV to ensure oxygen saturation higher than 92%. For double-lung ventilation, tidal volumes up 
to 8 mlꞏkg-1 and a respiratory rate of 10–15 min-1 will be chosen, for OLV tidal volumes up to 6–
7 mlꞏkg-1 with a respiratory frequency of 10–15 min-1 will be used. In both groups re-inflating of 
the previously non-ventilated lung will be restarted by a manual recruitment maneuver with peak 
pressure 30 cm H2O for 10 s three times. Intravenous parecoxib 40 mg will be given promptly 
after induction of anesthesia, followed by parecoxib 20 to 40 mg every 12 hours for three days. 

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Intravenous as-needed analgesia with morphine and/or ketorolac will be used to relieve 
breakthrough pain, which will be switched to oral diclofenac on the postoperative 2nd or 3rd day. 
In the M-Entropy group, dosage of volatile anesthetics will be adjusted to achieve the 
response and state entropy values between 40 and 60 from the start of anesthesia to the end of 
surgery. In the control group, dosage of volatile anesthetics will be titrated according to clinical 
judgment. This will be to maintain mean arterial pressure and heart rate within 20% range of the 
baseline. In case of signs of inadequate anesthesia (e.g. movement, cough and swallowing), 
anesthetic dose will be increased. M-Entropy monitoring will be continued in the control group, 
but the entropy number and EEG waveform will be concealed from the anesthetist in charge. 
Entropy values, hemodynamic, and expiratory gas data will be recorded in 5-min intervals. In all 
patients, cessation of general anesthesia will be timed to facilitate early awakening after wound 
closure. After reversal of the neuromuscular blocking agent and response to verbal command, all 
subjects will be extubated at the operating room and then transferred to the postanesthetic care 
unit. In the postoperative period, surgeons, medical and nursing staff at the postanesthetic care 
unit will be blinded to group allocation.  
Primary outcome is time to spontaneous eye opening. Secondary outcomes include time to 
tracheal extubation, time to orientation in time and place, time to leave operating room, and 
events of emergence agitation, postoperative delirium, and intraoperative recall or awareness. 
We will use the Richmond Agitation-Sedation Scale to evaluate the level of agitation and 
sedation promptly after extubation.20 Events of delirium will be evaluated using the Confusion 
Assessment Method at the postanesthetic care unit 30 minutes after tracheal extubation.21 An 
independent adjudicator blinded to the group allocation will measure all the outcomes. 
 
The effect of application of ProAQT in guiding goal-directed hemodynamic therapy on 
postoperative recovery: A single-blind randomized controlled trial 
In both groups, intraoperative maintenance rate of crystalloid fluids is 3 mlꞏkg-1ꞏhr-1. 
ProAQT-derived hemodynamic data are acquired at three time periods: before surgical incision, 
during OLV and at the end of surgery. Subjects randomized to the GDT group will be managed 
according to the ERAS algorithm utilizing ProAQT variables (mean arterial pressure, stroke 
volume variation and cardiac index)22,23 If stroke volume variation is ≥ 10%, a bolus of 150 ml of 
crystalloid fluid will be given until the stroke volume variation is < 10%. If mean arterial 
pressure is < 70 mmHg and/or cardiac index < 2.5 lꞏmin-1ꞏm-2 despite the stroke volume 
variation of < 10% following fluid challenge, single or consecutive boluses of ephedrine 4 mg 
and/or continuous intravenous infusion of norepinephrine 2–10 μgꞏmin-1 will be administered. 
(Figure 1) 

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Subjects allocated to the control group are hemodynamically managed as follows. Isolated 
hypotension (defined as 20% decrease in mean arterial pressure below baseline or < 60 mmHg) 
is treated by a continuous intravenous infusion of norepinephrine 2–10 μgꞏmin-1. If hypotension 
persists, repeat boluses of ephedrine 4 mg will be administered until mean arterial pressure is > 
60 mmHg. If hypotension is accompanied by signs of hypovolemia (defined as urine output < 0.5 
mlꞏkg-1ꞏhr-1 and/or an increase in heart rate > 20% above baseline), crystalloid fluid will be 
administered until urine output and/or heart rate are normalized. Colloids are administered only 
when hypotension develops during acute hemorrhage. If hypotension persists despite volume 
challenges, norepinephrine will be administered. In both groups, fluid and inotrope or 

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vasopressor responsiveness and hemodynamic variables will be evaluated each 15 min, and more 
frequently in case of hemodynamic instability. ProAQT variables will be recorded every 15 min. 
The primary outcome is in-hospital postoperative pulmonary complication, including 
atelectasis, pleural effusion, pneumonia, empyema, pulmonary embolism, re-operation, and 
respiratory failure. The diagnosis of atelectasis and pleural effusion will be made based on 
routinely performed chest radiographs on postoperative days 1 and 3. Pneumonia will be 
diagnosed if a patient presents with fever, leukocytosis and new infiltrates on chest radiography. 
Pleural empyema and pulmonary embolism will be confirmed by spiral computed tomography 
scan. Respiratory failure is defined as described.24 Secondary outcomes include relative change 
of PaO2/FiO2, PaO2/FiO2 values after induction of anesthesia and at the end of surgery, acute 
kidney injury (defined by Acute Kidney Injury Network Criteria),25 cardiac complications 
(myocardial infarction diagnosed by electrocardiogram and troponin T serum concentration; 
newly developed atrial fibrillation), clinically relevant hypotensive episodes (decrease in mean 
arterial pressure > 20% for more than 15 min requiring vasopressors), newly developed stroke, 
and length of hospital stay. All outcomes will be determined again 30 days after surgery and 
documented by research staff blinded to group allocation. 
 
Statistical Analysis 
   The distributions of baseline patient characteristics and outcome variables will be compared 
between two groups using chi-square tests or Fisher’s exact test for categorical variables and 
either t tests or Wilcoxon rank sum tests for continuous variables, as appropriate. For time to 
event data, Kaplan-Meier method and log-rank test will be applied for group comparisons. 
Multivariable logistic regression, simple linear regression, or Cox proportional hazards 
regression analyses will be used to identify potential influential factors of outcomes of interest. A 
two-sided significance level of 0.05 was used to define statistically significant difference. All the 
statistical analyses will be conducted using Statistics Analysis System (SAS), Version 9.4 (SAS 
Institute Inc., Cary, NC, USA). 

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