Effect of Spectral Edge Frequency and Patient State Index (Electroencephalography) - Guided Anesthetic Care on Delirium After Laparoscopic Surgery: the EMODIPOD Randomized Controlled Trial
Phase: NA
Conditions: Delirium, Emergence Delirium, Anesthesia, General, Electroencephalography, Laparoscopy, Surgical Procedures, Operative
Sponsor: Yale University

 
1
NCT03330236 
EEG - Guided Anesthetic Care and Postoperative Delirium 
September 20, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2
Impact of electroencephalogram – guided anesthetic care on 
delirium after laparoscopic surgery: a randomized controlled trial 
 
 
 
 
Department of Anesthesiology 
Central South University Xiangya Hospital 
 
Department of Anesthesiology 
University of California Davis 
 
Department of Anesthesia and Perioperative Care 
University of California San Francisco 
 
Department of Anesthesiology 
Yale University School of Medicine 
 
 
 
 
Revised on: September 20, 2019 
Prepared by: Lingzhong Meng, MD 
 
 
 
 
 

 
3
Section A: Study Protocol 
 
 
Study Intervention:  
Electroencephalogram – guided anesthetic care using SedLine Brain Function Monitoring 
 
Principal Investigators:  
E Wang, MD, PhD 
Adrian W. Gelb, MB ChB 
Hong Liu, MD 
Lingzhong Meng, MD 
 
Study Design:  
E Wang, MD, PhD 
Adrian W. Gelb, MB ChB 
Hong Liu, MD 
Lingzhong Meng, MD  
 
Name of Institutions:  
• Department of Anesthesiology, Xiangya Hospital, Central South University School of 
Medicine, Changsha, Hunan Province, China (E Wang, MD, PhD);  
• Department of Anesthesiology, University of California Davis, David, CA (Hong Liu, MD) 
• Department of Anesthesia and Perioperative Care, University of California San Francisco, 
San Francisco, CA (Adrian W. Gelb, MB ChB) 
• Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 
(Lingzhong Meng, MD). 
 
 
Version of Protocol: 6th version (September 20, 2019) 
  
 
 

 
4
Contents 
 
1. 
Background 
2. 
Purpose of the study 
3. 
Recruitment of subjects 
4. 
Study design 
5. 
Randomization and blinding 
6. 
Intervention protocol 
7. 
Data collection 
8. 
Outcome 
9. 
Adverse events 
10. 
Severe adverse events 
11. 
Unmask of blindness 
12. 
Data management 
13. 
Statistical analysis 
14. 
Quality control and quality assurance 
15. 
Ethics requirement and written informed consent 
16. 
Preservation of documents 
17. 
Declaration of interests 
18. 
References 
  
 
 

 
5
1. 
Background 
 
Delirium is an acute brain dysfunction characterized by inattention, disorganized thinking, and a 
fluctuating course. Delirium is a common complication after surgery, with an incidence up to 70%, 
depending on patient’s age and type of surgery [1]. Patients who experience postoperative delirium 
is associated with a longer ICU stay, prolonged mechanical ventilation, increased hospital length 
of stay and health care cost. They also are at increased risk for institutionalization, death, and 
dementia after hospital discharge. Delirium prevention is expected to reduce morbidity, mortality, 
hospital length of stay (LOS) and cost, as well as improve the quality of life.  
 
Multiple modifiable and unmodifiable risk factors have been recognized, such as age, type of 
surgery, ICU admission, pain, and certain medications. Age is a typical example of unmodifiable 
risk factor. The modifiable risk factors are the targets of delirium prevention. One of the modifiable 
risk factors is the dosing of sedative or anesthetic agents. Certain features of the intraoperative 
electroencephalogram (EEG) have been associated with postoperative delirium [2-5]. It was shown 
that patients with increased low-frequency EEG activity during the rewarming phase of cardiac 
surgery are at increased risk for postoperative complications, including delirium [2]. EEG burst 
suppression (BS) is associated with increased incidences of postcoma delirium in ICU patients [3] 
and postoperative delirium in surgical patients being admitted to ICU after surgery [4].  
 
The advancement of technology allows non-invasive, continuous and convenient EEG monitoring 
with the adhesive probe placed on patient’s forehead. However, the monitor itself is not the goal 
because pure monitoring without meaningful and effective intervention does not change the 
outcome. A monitor is valuable only if effective interventions guided by this monitor exist and 
these interventions improve patient outcome. This principle applies in the clinical use of EEG 
monitoring. The previous randomized controlled trials investigating the effect of processed EEG 
– guided anesthetic care on postoperative delirium after general anesthesia was based on the 
derived number (0-100) provided by BIS monitor. The incidence and duration of EEG burst 
suppression was not characterized in these studies [6-8]. The characteristic of EEG frequencies, 
i.e. delta, theta, alpha, and beta, was not reported. In addition, the incidence and character of post-
anesthesia care unit (PACU) delirium was not investigated. However, PACU delirium have a 
strong association with postoperative delirium [9-11].  
 
SedLine® (Masimo, CA) Brain Function Monitoring is an FDA-approved non-invasive EEG 
monitoring technology. SedLine is different from BIS in many regards. It simultaneously displays 
four channels of frontal, bilateral EEG waveforms. The Patient State Index (PSI) is a processed 
EEG parameter that is related to the effect of anesthetic agents (i.e. the popular numeric depth 
concept). The Density Spectral Array (DSA) provides left and right spectrograms representing the 
power of the EEG across the frequency range on both sides of the brain. It also provides the burst 
suppression information (%) and the real-time spectral edge EEG frequency. These parameters are 
meant to be used in clinical practice to guide anesthesia management.    
 
1) Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis and treatment. 
Crit Care Clin. 2008;24(4):657-722 

 
6
2) Hofsté WJ, Linssen CA, Boezeman EH, Hengeveld JS, Leusink JA, de-Boer A. Delirium 
and cognitive disorders after cardiac operations: relationship to pre- and intraoperative 
quantitative electroencephalogram. Int J Clin Monit Comput. 1997;14(1):29-36. 
3) Andresen JM, Girard TD, Pandharipande PP, Davidson MA, Ely EW, Watson PL. Burst 
suppression on processed electroencephalography as a predictor of postcoma delirium in 
mechanically ventilated ICU patients. Crit Care Med. 2014;42(10):2244-51.  
4) Fritz BA, Kalarickal PL, Maybrier HR, Muench MR, Dearth D, Chen Y, Escallier KE, Ben 
Abdallah A, Lin N, Avidan MS. Intraoperative Electroencephalogram Suppression 
Predicts Postoperative Delirium. Anesth Analg. 2016;122(1):234-42.  
5) Soehle M, Dittmann A, Ellerkmann RK, Baumgarten G, Putensen C, Guenther U. 
Intraoperative burst suppression is associated with postoperative delirium following 
cardiac surgery: a prospective, observational study. BMC Anesthesiol. 2015;15:61.  
6) Radtke FM, Franck M, Lendner J, Krüger S, Wernecke KD, Spies CD. Monitoring depth 
of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not 
postoperative cognitive dysfunction. Br J Anaesth. 2013;110 Suppl 1:i98-105. 
7) Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, Mears SC. 
Sedation depth during spinal anesthesia and the development of postoperative delirium in 
elderly patients undergoing hip fracture repair. Mayo Clin Proc. 2010;85(1):18-26.  
8) Chan MT, Cheng BC, Lee TM, Gin T; CODA Trial Group. BIS-guided anesthesia 
decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 
2013;25(1):33-42.  
9) Card E, Pandharipande P, Tomes C, Lee C, Wood J, Nelson D, Graves A, Shintani A, Ely 
EW, Hughes C. Emergence from general anaesthesia and evolution of delirium signs in the 
post-anaesthesia care unit. Br J Anaesth. 2015;115(3):411-7.  
10) Neufeld KJ, Leoutsakos JM, Sieber FE, Wanamaker BL, Gibson Chambers JJ, Rao V, 
Schretlen DJ, Needham DM. Outcomes of early delirium diagnosis after general anesthesia 
in the elderly. Anesth Analg. 2013;117(2):471-8.  
11) Sharma PT, Sieber FE, Zakriya KJ, Pauldine RW, Gerold KB, Hang J, Smith TH. Recovery 
room delirium predicts postoperative delirium after hip-fracture repair. Anesth Analg. 
2005;101(4):1215-20. 
 
 
2. 
Purpose of the study 
 
To investigate the impact of the anesthetic care guided by EEG monitor (SedLine) on (1) the 
incidence of delirium in post-anesthesia care unit (PACU) and within the first five days after 
laparoscopic surgery and (2) the incidence of in-hospital complications and 30-day mortality in 
adult patients after laparoscopic surgery.  
 
3. 
Recruitment of subjects 
 
Potential participants will be identified within 7 days before the scheduled surgery by the research 
team. 
 
3.1 
Inclusion criteria 
 

 
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1) Age ≥ 50 years; 
2) ASA Physical Score I-III 
3) Scheduled to undergo an elective laparoscopic intra-abdominal surgery under general 
anesthesia with endotracheal intubation; 
4) Extubation expected after surgery; 
5) Scheduled to stay in hospital for > 3 days after surgery. 
 
3.2 
Exclusion criteria 
 
Patients will be excluded if they meet any of the following criteria. 
 
1) Refuse to participate; 
2) Emergent surgery; 
3) Trauma surgery; 
4) Preoperative history of stroke, schizophrenia, major depression, Parkinson’s disease, 
epilepsy, or dementia; 
5) Inability to communicate in the preoperative period due to illiteracy, language difficulties, 
or significant hearing or visual impairment; 
6) Inability to complete MMSE and delirium survey; 
7) Severe cardiac disease including low-output cardiac failure defined as a preoperative left 
ventricular ejection fraction < 30%, or arrhythmia with pacemaker or AICD placement; 
8) Severe hepatic dysfunction being evaluated for liver transplantation or with a Child‐Pugh 
Class C classification; 
9) Severe renal dysfunction requiring renal replacement therapy before surgery; 
10) Those with preoperative ASA classification of 4 or who are unlikely to survive for more 
than 5 days after surgery. 
 
3.3 
Criteria of drop out 
 
1) Withdrawal of consent by the participants themselves; 
2) Procedure converted to open surgery (patients will be followed for intention-to-treat 
analysis); 
3) Loss of follow‐up (patients may be excluded from per-protocol analysis); 
4) Ordered to exit by the investigators or attending physicians (occurrence of severe 
complications or adverse events); 
5) Cases of unmasked blindness (patients will be excluded from per-protocol analysis); 
6) Patients who remain intubated after surgery (patients will be excluded from per-protocol 
analysis). 
 
For drop out cases, the detailed reasons will be recorded and the therapeutic effects recorded in the 
previous encounter will be regarded as the final results. The Case Report Forms (CRFs) of these 
cases will be preserved for future reference. 
 
3.4 
Criteria of Rejection 
 

 
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Enrolled cases who meet any of the following criteria will be excluded from further per-protocol 
analysis. 
 
1) Intervention protocol is not executed; 
2) No or incomplete study record; 
 
Enrolled cases who meet any of the following criteria will be excluded from further as-treated 
analysis. 
 
Unable to evaluate the effectiveness of intervention (e.g., missing SedLine data).  
 
For rejected cases, the detailed reasons will be recorded and CRFs will be preserved for reference. 
The results of these cases will be excluded in analysis of therapeutic effects. 
 
3.5 
Criteria of Study Interruption 
 
Study will be interrupted in the following situations: 
 
1) Severe safety issues occurred during the study; 
2) Serious mistakes found in the protocol; 
3) Fund or management problem of the investigators; 
4) Study terminated by the administrative authority. 
 
Study interruption may be transient or permanent. All recorded CRFs will be preserved for 
reference in case of study interruption. 
 
4. 
Study design 
 
4.1 
Type of the study 
 
The study is a prospective, double blinded, randomized and controlled parallel trial. (The only 
people who know the patient’s assignment are the study coordinator and the anesthesia team who 
takes care of the patient during surgery.) 
 
4.2 
Sample size calculation 
 
The incidence of postoperative delirium is about 14% in in elderly patients who underwent 
laparoscopic surgery for colorectal cancer [Tei et al., 2016]. We assume that the incidence of 
postoperative delirium will be reduced by 1/3 in patients receiving EEG-guided care [Chan et al., 
2013]. With a two‐sided significance and power set at 0.05 and 80%, respectively, the sample size 
required to detect the reduction is 742 patients per group. Taking into account a loss‐to‐follow‐up 
rate of about 5%, we plan to enroll 780 patients in each group. 
 
1) Tei M, Wakasugi M, Kishi K, Tanemura M, Akamatsu H. Incidence and risk factors of 
postoperative delirium in elderly patients who underwent laparoscopic surgery for 
colorectal cancer. Int J Colorectal Dis. 2016 Jan;31(1):67-73.  

 
9
2) Chan MT, Cheng BC, Lee TM, Gin T; CODA Trial Group. BIS-guided anesthesia 
decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 
2013;25(1):33-42.  
 
5. 
Randomization and blinding 
 
5.1 
Randomization 
     
1) A biostatistician who does not participate in data management and statistical analysis will 
generate random numbers in a 1:1 ratio; 
2) The results of randomization will be sealed in sequentially numbered envelops, stored at 
the site of investigation, and managed by the study coordinator. 
3) Timing of randomization of individual patient: 30-60 mins before surgery 
 
5.2 
Blinding     
 
1) A study coordinator will be assigned to distribute the EEG monitor, open the randomization 
envelope, inform the anesthesiologist of the patient’s assignment, enforce the execution of 
the study protocol, collect the data during surgery, and coordinate the overall research 
effort; 
2) For each recruited patient, the anesthesiologist is one of the two persons who know the 
patient assignment. The other person is the study coordinator who opens the randomization 
envelope. The anesthesiologist will be instructed of how to use the EEG monitor to guide 
the anesthesia care per research protocol if the patient is assigned to the intervention arm; 
3) For each recruited patient, the study coordinator is the only research team member who 
comes to the Operating Room to monitor the execution of the study protocol; 
4) Two research personnel, different to the study coordinator, will be responsible for 
postoperative follow-up including delirium assessment starting at the post-anesthesia care 
unit. These two personnel are blinded to patient randomization; 
5) The anesthesiologist who executes the study protocol and the research personnel who 
collects postoperative outcome data do not share any information related to patient 
assignment; 
6) Statistical analysis will be performed independently by the designated statistician at Yale 
University. 
 
6. 
Intervention protocol 
 
6.1 
Monitor used in the intervention group 
 
1) Name: SedLine Brain Function Monitoring; 
2) Product specification: FDA-approved non-invasive EEG monitor; 
3) Manufacturer: Masimo Corporation, Irvine, CA. 
 
6.2 
Monitor used in the control group 
 
1) Name: SedLine Brain Function Monitoring; 

 
10 
2) Product specification: FDA-approved non-invasive EEG monitor; 
3) Manufacturer: Masimo Corporation, Irvine, CA. 
 
6.3 
Monitoring 
 
1) All recruited patients from either control or intervention group will receive SedLine EEG 
monitoring; 
2) A study coordinator will distribute the monitor 30 mins before the arrival of the patient in 
the Operating Room; 
3) The probe of SedLine monitor will be placed on patient’s forehead after the patient’s arrival 
in the Operating Room and before the anesthesia induction; 
4) The monitor data will be collected by the study coordinator. 
 
6.4 
Anesthetic care guided by EEG monitoring 
 
1) The monitor screen in the control arm is covered and blinded to the anesthesiologist; 
2) The monitor in the intervention arm is used by the anesthesiologist to adjust the anesthetic 
care. 
3) The goal in the intervention arm is to maintain SEF 10-15 throughout surgery. Avoid burst-
suppression. 
4) In the intervention arm, the anesthesia induction is achieved via propofol pump infusion 
(slow and controlled). The goal is to avoid burst-suppression and maintain SEF > 10 
throughout anesthesia induction.   
5) The anesthesia maintenance is achieved via the protocol detailed below (6.5). The SedLine-
guided intervention protocol is detailed in the Supplemental remark 1. SedLine-Guided 
Intervention Flow Chart. 
 
6.5 
Anesthesia protocol for both intervention and control group 
 
1) During the study period (from preop to postop day 5), anticholinergics such as scopolamine 
are strictly prohibited; atropine or glycopyrrolate can only be used for treatment of 
bradycardia; the use of midazolam for anxiolysis is allowed but not encouraged; 
2) In both arms, the anesthesia induction is per standard care using agents of lidocaine, 
propofol, sufentanyl and muscle relaxant. The administration of propofol in the 
intervention arm is via pump infusion and guided by SedLine. 
3) The anesthesia is maintained using propofol infusion (0-200 mcg/kg/min) and remifentanil 
infusion (0.05-0.2 mcg/min/kg). Sufentanyl and muscle relaxant boluses can be used 
during surgery. 
4) The anesthetic adjustment in the control arm is per the conventional practice (EEG 
monitored but blinded to anesthesia team) and in the intervention arm per the 
Supplemental remark 1. SedLine-Guided Intervention Flow Chart. 
 
7. 
Data collection 
 
7.1 
Preoperative data 
 

 
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1) Determine patient’s eligibility based on the inclusion and exclusion criteria; 
2) Mini-mental Status Exam; 
3) Demographic data, past medical and surgical history, medications taken at home and in 
hospital; 
4) Electrocardiogram, echocardiogram if available; 
5) Lab results. 
 
7.2 
Intraoperative data 
 
1) Surgical details including type and time of surgery; 
2) Anesthetic details including the name and dose of any drugs used during surgery; 
3) The total dose of propofol used for anesthesia induction and maintenance; 
4) Inputs and outputs including the name and volume of the fluid being administered, the 
estimated blood loss, the urine output, and any blood products being transfused;  
5) EEG data including the occurrence, duration and percentage of burst-suppression, SEF and 
PSI (specific to SedLine monitor). 
 
7.3 Postoperative data 
 
1) PACU Delirium: Occurrence of delirium in PACU will be assessed using the CAM-ICU 
30 mins after extubation and before PACU discharge.  
2) Postoperative Delirium (POD): POD will be assessed twice daily (8:00‐10:00 am, and 
18:00‐20:00 pm) for 5 days from postoperative day 1 to 5 or until the patient is discharged 
home if the patient stays in hospital < 5 days. CAM is used for delirium assessment if the 
patient is on the floor; otherwise, CAM‐ICU is used if the patient is in the ICU. 
Investigators for POD assessment will be trained by a psychiatrist to use CAM and CAM-
ICU before the trial is commenced. 
3) Non-delirium Complications: Any complications occurred within the first 30 days after 
surgery (for example: cardiac events, cerebrovascular events, renal injury, GI 
complications, infections, etc.) will be documented. Patients will be assessed via phone 
call if they are discharged before day 30 after surgery. 
4) Subjective Pain Score:  It will be assessed at PACU and 24 hours after surgery using the 
Numeric Rating Scale (NRS) (an 11‐point scale where 0 indicates no pain and 10 indicates 
the worst pain). 
5) Subjective Sleep Quality: It will be assessed at 8:00 am during the first postoperative day 
using the NRS (an 11‐point scale where 0 indicates the best possible sleep and 10 indicates 
the worst possible sleep). 
6) Length of Hospital Stay: The readiness for discharge will be used as the last day of 
hospitalization. 
7) All-cause 30-day Mortality: Patients or family members will be called for assessment.  
8) Adverse Events: If an adverse event occurs during patient hospitalization, it will be 
followed up until its disappearance or therapy ends. 
 
8. 
Outcome 
 
8.1 
Primary outcome 

 
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Incidence of postoperative delirium during the first 5 days after surgery. 
 
8.2 
Secondary outcomes 
 
The secondary outcomes are as follows: 
 
1) Incidence of emergence delirium; 
2) Composite complication classified as Clavien-Dindo grade II or greater within 
postoperative 30 days; 
3) 24-hour postoperative nausea and vomiting (PONV);  
4) MMSE score change; 
5) Length of hospital stay; 
6) Intensive care unit (ICU) admission; 
7) 30-day hospital readmission; 
8) 30-day all-cause mortality 
 
Postoperative complications are as follows: 
 Myocardial ischemia or infarction 
 Arrythmia requiring treatment 
 Circulatory insufficiency (requiring a vasopressor or inotropic agent infusion for more 
than 6 hours) 
 Ischemic stroke 
 Hemorrhagic stroke 
 Acute lung injury 
 Pulmonary embolism 
 Pulmonary infection requiring antibiotic treatment 
 Hypoxemia or respiratory insufficiency requiring supportive treatment including 
intubation, CPAP, BiPAP, high-flow (>10 L/min) face mask or nasal cannula for more 
than 6 hours 
 Acute kidney injury requiring treatment 
 Urinary tract infection requiring antibiotic treatment 
 Ileus 
 Sepsis 
 Anastomotic leakage requiring treatment 
 Urinary retention requiring treatment 
 Pleural or intra-abdominal effusion requiring intervention 
 Wound dehiscence requiring intervention 
 Bowel obstruction requiring treatment 
 Deep venous thrombosis requiring treatment 
 Subcutaneous emphysema requiring treatment 
 Surgical bleeding or hematoma requiring intervention 
 Surgical site infection (superficial or deep, but not organ or space) requiring antibiotic 
treatment or procedural treatment (not at bedside) 
 Surgical site infection (pelvic or intra-abdominal infection or abscess, i.e., organ or 
space) requiring antibiotic treatment or procedural treatment (not at bedside)     

 
13 
 Delayed emergence requiring treatment 
 
 
The Clavien-Dindo Classification (https://www.assessurgery.com/clavien-dindo-classification/) 
 
Grades 
Definition 
Grade I 
Any deviation from the normal postoperative course without the need for pharmacological 
treatment or surgical, endoscopic and radiological interventions 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics and 
electrolytes and physiotherapy. This grade also includes wound infections opened at the 
bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for grade I 
complications. 
Blood transfusions and total parenteral nutrition are also included. 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
       - IIIa 
Intervention not under general anesthesia 
       - IIIb 
Intervention under general anesthesia 
Grade IV 
Life-threatening complication (including CNS complications)* requiring IC/ICU-management 
       - IVa 
single organ dysfunction (including dialysis) 
       - IVb 
Multiorgan dysfunction 
Grade V 
Death of a patient 
*brain hemorrhage, ischemic stroke, subarrachnoidal bleeding, but excluding transient ischemic 
attacks (TIA); IC: Intermediate care; ICU: Intensive care unit. 
 
 
8.3 
Additional outcomes 
 
1) NRS pain score at PACU and 24 hours after surgery; 
2) NRS score of subjective sleep quality at 8:00 am of postoperative day 1. 
 
9. 
Adverse events 
 
9.1 
Definition 
 
1) An adverse event indicates any unpredictable, unfavorable medical event that is associated 
with any medical intervention and occurs during the study period. It can be related to the 
study protocol or otherwise. It can manifest as any uncomfortable signs (including 
abnormal laboratory findings), symptoms or transient morbidity; 
2) Predicted adverse events in this study: 
• Tachycardia: heart rate > 100 beats per minute or, in case of a baseline value > 83 beats 
per minute, an increase of more than 20% from baseline; 
• Hypertension: systolic blood pressure > 160 mmHg or, in case of a baseline value > 133 
mmHg, an increase of more than 20% from baseline; 
• Bradycardia: heart rate < 55 beats per minute or, in case of a baseline value < 69 beats per 
minute, a decrease of more than 20% from baseline (before study drug infusion); 
• Hypotension: systolic blood pressure < 95 mmHg or, in case of a baseline value < 119 
mmHg, a decrease of more than 20% from baseline; 

 
14 
• Recall: the patient remembers the details of the event(s) that occurs during the period when 
the patient is under appropriate general anesthesia per standard of care. 
 
Note: for heart rate and blood pressure, the average values measured before surgery are used as 
baseline values. 
 
9.2 
Management 
 
1) Therapy will be provided according to standard clinical practice; 
2) The study protocol can be stopped temporarily or permanently if considered necessary by 
the attending anesthesiologist or the principal investigators. The time and reasons of study 
interruption will be recorded in CRFs. 
 
Management of predicted adverse events in this study: 
 
1) Bradycardia: administration of medication (e.g. atropine iv bolus) and/or adjustment of 
anesthetic agents; 
2) Hypotension: intravenous fluid bolus, administration of medication (vasopressor iv bolus 
or infusion), and/or adjustment of anesthetic agents; 
3) Tachycardia: administration of medication (esmolol or diltiazem) and/or adjustment of 
anesthetic agents; 
4) Hypertension: administration of medication (labetalol or nicardipine) and/or adjustment of 
anesthetic agents; 
 
9.3 
Recording 
 
1) Any adverse event should be documented, including type, timing, duration, management, 
and sequelae; 
2) Any adverse event should be followed up until it is completely resolved or the therapy is 
terminated. 
 
10. 
Severe adverse events 
 
10.1 
Definition 
 
A severe adverse event indicates any unpredictable medical events that lead to death, threat of life, 
prolonged length of hospital stay, persistent disability or dysfunction, or other severe event. 
 
10.2 
Management 
 
In case of any severe adverse events, the study protocol will be stopped and treatment will be 
initiated immediately. 
 
10.3 
Recording and reporting 
 

 
15 
1) In case of any severe adverse event, apart from active treatment and record as above, the 
principal investigator and the Ethics Committee will be informed within 24 hours in written 
report; 
2) In case of study drug related death, immediately stop the clinical trial, report the event to 
the Ethics Committee as soon as possible, record in detail and carefully preserve the related 
documents; 
3) Any severe adverse event must be followed up until it is completely resolved or the therapy 
is terminated. 
 
11. 
Unmask of blinding 
 
For an individual patient, at the completion of the study (30 days after surgery), all data are checked 
to ensure its quality and input into the database, the database will be locked up and the blindness 
will be unmasked. 
 
12. 
Data management 
 
1) Investigators should promptly, completely, and correctly record data in the CRF based on 
the original observation; 
2) The PIs and the study coordinator will monitor if the study is carried out according to the 
protocol. The completed CRFs, after signed by the PIs, will be sent to the investigator who 
is responsible for data management; 
3) Data input will be performed by an investigator and checked out by another independent 
investigator. CRFs will be stored in sequential order; 
4) Data management can be inspected by the Clinical Research Ethics Committee of both 
Yale University and Central South University at any time. 
 
13. 
Statistical analysis 
 
13.1 
General principles 
 
1) Numeric variables will be presented as mean (standard deviation) or median (minimum, 
maximum; or interquartile range). Categorical variables will be presented as number of 
cases (percentage); 
2) Two-tailed tests will be used in all statistical analysis, and a p value of less than 0.05 will 
be considered to be of statistical significance for the primary outcome. The Benjamini-
Hochberge procedure will be applied to control for the multiple testing for all secondary 
outcomes. 
 
13.2 
Patient recruitment and drop‐out status 
 
The status of patient recruitment and drop-out will be summarized and listed. Comparison of the 
overall drop-out rate between the two groups will be performed with chi-square test. 
 
13.3 
Patient populations used for analysis 
 

 
16 
1) The modified intention-to-treat (ITT) population: The modified ITT population includes 
all patients who undergo randomization, surgery (as long as the skin incision is made), and 
have the primary outcomes data collected. Patients whose surgery is cancelled or aborted 
in the middle of surgery (after skin incision) will be included in this population. 
 
The primary outcome is regarded as not collected in the following situations: 
a) death (within postoperative 5 days); 
b) early hospital discharge (for non-medical reasons and within postoperative 5 days); 
c) intubated/sedated/comatose for more than 24 hours (within postoperative 5 days); 
d) withdraw consent (within postoperative 5 days); 
e) data missing.  
 
2) The per-protocol population: The patients from the modified ITT population will be 
included in the per-protocol population if they fulfill the eligibility, intervention, and 
outcome assessment specified by the protocol.  
 
The following patients are excluded:  
a) ineligible patients 
b) randomization allocation error; 
c) SedLine monitor malfunction (not working at all or >50% of the anesthetic duration 
(PSI <75) without monitoring data); 
d) SedLine monitor not blinded in the usual care group; 
e) being anesthetized with inhalational anesthetics; 
f) surgery aborted or converted to open. 
 
3) As-treated population from the SedLine-guided care group: This population is a subset of 
the per-protocol population. For patients from the SedLine-guided care group, they are 
regarded as fulfilling the as-treated criteria if the below-10 SEF AUC (left + right) is less 
than 10 (or the median value of the AUC, if AUC < 10 gives less than 300 patients). These 
patients are regarded as having received effective SedLine-guided intervention. This rule 
does not apply to patients from the per-protocol population from the usual care group.  
 
13.4 
Demographics and baseline characteristics 
 
1) Descriptive statistics of demographic information and baseline characteristics (such as 
previous history of comorbidity and medication) will be presented; 
2) Comparison of baseline numeric variables (such as age, etc.) between groups will be 
performed with independent sample t-test or Wilcoxon rank sum test. Comparison of 
categorical variables (such as gender, presence of a comorbidity, etc.) between groups will 
be performed with chi-square test or Fisher exact test. Information (e.g., p-values) will only 
be used in selecting covariates for later sensitivity (adjusted) analysis of the primary 
outcome. 
 
13.5 
Effectiveness evaluation 
 
Evaluation of primary endpoint 

 
17 
 
The incidence of postoperative delirium within 5 days after surgery will be calculated. Comparison 
between groups will be performed with chi-square or Fisher’s exact test. The relative risk and the 
corresponding 95% confidence interval (CI) will be calculated to measure the magnitude of 
difference in risk of having postoperative delirium between groups. 
 
Evaluation of secondary endpoints 
 
1) Non-normal continuous endpoints will be analyzed by the Wilcoxon rank sum test. The 
Hodge-Lehman method will be used to estimate median of between-group difference with 
95% CI. 
2) Time-to-event variables (length of ICU stay, length of hospital stay) will be analyzed by 
the Wilcoxon rank sum test or by survival analysis, with difference between groups 
assessed with Log-Rank test. 
3) The incidence of postoperative complications and 30-day mortality will be compared with 
Chi-square test or Fisher's exact test as appropriate. 
 
Sensitivity analysis 
 
In the ITT dataset, we will perform a sensitivity analysis by fitting a multivariable logistic 
regression model of the primary outcome with covariate adjustment. Prognostic or risk factors of 
postoperative delirium shown in previous literature, and baseline and perioperative variables that 
differed between groups (p < 0.10) together with the intervention factor (administration of 
dexmedetomidine or not) will be entered into the regression model, As the incidence of delirium 
is not a rare event, the odds ratio (OR) estimate from the logistic regression analysis will possibly 
overestimate  the relative risk (RR) – our measure of effect size in this study, we will convert the 
OR into RR using the Zhang and Yu method (Zhang J, Yu KF. What's the relative risk? A method 
of correcting the odds ratio in cohort studies of common outcomes. Jama 1998;280:1690-1) 
 
Subgroup analysis 
 
Subgroup analysis will be based on the ITT dataset per age (<65 years or ≥65 years old), body 
mass index (< or ≥25), smoker or not, alcoholism or not, Charlson comorbidity score (<2 or ≥2), 
preoperative MMSE score (<24 or ≥24), diagnosis of the surgical lesion (benign vs. malignant), 
ASA physical status classification (I-II or III), baseline systolic blood pressure (<130 or ≥130 
mmHg), propofol dose used for anesthesia maintenance (divided by the median value), and 
anesthesia time (divided by the median value). 
 
14. 
Quality control and quality assurance 
 
14.1 
For investigators/care givers 
 
1) Trial protocol will be thoroughly explained to all investigators/care givers before the start 
of the trial. The trial protocol must be strictly adhered throughout the trial period; 
2) All expected and unexpected findings will be documented promptly and correctly in order 
to guarantee the reliability of the values; 

 
18 
3) The monitors and instruments that are used during the study period will be checked and 
corrected regularly in order to guarantee their normal function; 
4) Data analysis will be performed by the statisticians and investigators; 
5) Any conclusions must be derived from the original data. 
 
14.2 
For participants 
 
1) Possible benefits and risks associated with the study will be clearly explained to every 
potential participant; 
2) Written informed consent must be signed by every enrolled patient, or by the authorized 
surrogate of the patient; 
3) If the enrolled patients refuse to participate in the study during the study period, the patient 
will be excluded for further study. 
 
14.3 
Study termination 
 
1) If a study-related death occurs during the study period, the study will be stopped. A report 
will be sent to the Ethics Committee. Restart of the study will need an approval from the 
Ethics Committee; 
2) The study will be terminated after accomplishment of patient recruitment and data 
collection. Decision will be made by the principal investigator. 
 
15. 
Ethics requirement and written informed consent 
 
1) Helsinki declaration and Chinese guidelines of Good Clinical Practice will be strictly 
followed. The study protocol must be approved by the Ethics Committee before the study 
can be started; 
 
2) For every potential participant, investigators have the responsibilities to fully explain the 
study purpose, procedures, as well as possible risks in a written informed manner. They 
must let every potential participant know that he/she has the right to withdraw his/her 
consent at any time during the study period. Every potential participant must be given a 
written informed consent. Every participant or the authorized surrogate of the patient must 
sign the consent before they can be enrolled in the study. Written informed consents will 
be kept as a part of the clinical trial documents. 
 
16. 
Preservation of documents 
 
Investigators will carefully preserve all documents and data of the clinical trial according to the 
Good Clinical Practice requirement. 
 
17. 
Declaration of interests 
 
None declared. 
 
18. 
References 

 
19 
 
Included under each section, respectively. 
 

 
20 
Section B: Written Informed Consent with Trial Description 
 
 
“Impact of electroencephalogram – guided anesthetic care on delirium after laparoscopic 
surgery: a randomized controlled trial” 
 
 
1. 
Why do we invite you to participate in this study? 
 
We invite you to participate in this randomized and controlled study investigating the Impact of 
electroencephalogram – guided anesthetic care on delirium after laparoscopic surgery. The 
study is organized by Yale University Department of Anesthesiology and will be performed in 
Central South University Xiangya Hospital. We are expected to enroll 1560 participants who are 
scheduled to undergo elective laparoscopic surgery. 
 
Before you decide to participate in the study, please read the following description carefully which 
will help you to understand the purpose and contents of the study, to understand the potential 
benefits from the study that it may bring to you, as well as the potential risks that you may 
encounter during the study. You are welcome to discuss your concerns with your doctors, relatives 
and/or friends freely before making the decision. If you have any questions or would like to get 
more information about the trial, please do contact us. 
 
2. 
What is the purpose of this study? 
 
We are looking at if the anesthetic care guided by EEG (the electrical activity of the brain) 
monitoring will lower the chances of having delirium after surgery. Delirium is a common problem 
after surgery and can often occur in older patient after surgery. It can present as inability to 
concentrate, disturbances in your perception, changes in your level of consciousness and 
impairment of your normal thinking. Patients who get delirium after surgery tend to stay in 
hospitals longer, suffer from more complications and recovery slower than patients who don't get 
delirium. 
 
We don't know exactly why or how delirium occurs. There are many risk factors. Some are 
modifiable. Some are not. One of the potential risk factors is deep anesthesia, referring to the 
overdose of anesthetic drugs. The depth of anesthesia can be assessed using EEG monitoring. 
However, whether the anesthetic care guided by EEG monitoring can reduce the chance of 
delirium after surgery is poorly studied. A good quality study is needed to understand if we can 
reduce delirium via EEG – guided care. 
 
3. 
Do I have to participate in? 
 
The decision to participate in the study is entirely voluntary. You make the decision to take part in 
or not, and can withdraw consent at any time without giving any reasons during the study. If you 
decide to participate, please sign the written informed consent form. You can keep a signed 
informed consent form and a copy of study description. Withdrawal from the study does not affect 
your treatments throughout your hospital stay. In such case, your data and information will not be 

 
21 
used in the study. On the other hand, if you or we think the study is affecting your normal treatment 
or outcome, the researchers will also stop the study. 
 
During the period of study participation, please tell researchers your true medical history and 
current physical status, as well as whether you have participated in any other studies currently or 
recently, or if you have any newly developed discomfort. If you do not abide the study protocol or 
develop any study‐related harm, the researchers can terminate your participation in the study. 
 
4. 
If I participate, what do I need to do? 
 
If you agree to participate in this study, we will give you a recruitment number and establish a 
research records for you. We will collect your demographic and baseline information before 
surgery; we will visit you and assess your neurocognitive function after surgery. The occurrence 
of delirium will be assessed in the post-anesthesia care unit (PACU) and twice daily on 
postoperative day 1 to 5. Each assessment will last about 5 minutes or less. During the rest period 
of postoperative hospitalization, we will follow you up daily and record the occurrence of other 
complications. At 30 days after surgery, we will call you (in case you have been discharged from 
the hospital) to assess your health status. All the above inspection and assessment are free of charge 
and the only thing you need to do is to cooperate with our investigators. 
 
5. 
Will participation in this study bring me extra cost or reward? 
 
The EEG monitoring used in study is free. Participation in the study will not bring you extra cost 
or gain you any extra rewards. 
 
6. 
Do I get any benefit from participating in the study? 
  
Participation in the study will help us to understand how to reduce the chance of delirium after 
surgery. The results of this study will contribute to the improvement of anesthetic practice. 
 
7. 
What kind of anesthesia will I receive during surgery? What kind of analgesia will I 
use after the surgery? 
 
Anesthetic regimen will not be changed no matter whether you participate in this study or not 
during surgery, nor the pain relief strategy after surgery. Participants will be randomly divided into 
two groups. Patients in the intervention group will receive EEG monitoring and the anesthetic care 
will be additionally guided by the monitor. Patients in the control group will receive the same EEG 
monitoring; however, the monitor screen will be covered and blinded to your anesthesiologist. 
Your anesthesiologist will manage the anesthetic care in a conventional manner. Your assignment 
to either group will be randomized.    
 
8. 
Are there any potential risks or adverse effects to me? 
 
The EEG monitor itself is non-invasive. It connects to you via an adhesive probe like a sticker. 
The potential risks of having this monitor include, even though not reported, skin injury or other 
unforeseeable events. Any adverse events occurred during the study period will be managed 

 
22 
promptly according to routinely clinical practice. In case of any harmful consequence resulted 
directly from the study, participant will be compensated according to the corresponding legal 
provisions. 
 
9. 
Will my personal information be confidential? 
 
Some data obtained from you during the study will be published in the form of scientific papers, 
but your personal information (including name, age, education and etc.) will be kept confidential 
and your personal privacy will be protected according to law. Non‐research team personnel will 
not be allowed to obtain your information, unless permitted by yourself. Your information 
(recorded in written or other forms) will be preserved for 5 years and then destroyed 5 years after 
the end of the study. If the information needs to be preserved for more than 5 years, we will obtain 
your permission by telephone, and will inform you how long and in what way your information 
will be preserved and used in the future. All research members and institutions involved in the 
study will maintain confidentiality. In order to ensure that the study is carried out in accordance 
with the regulations, administrative members or the ethics committee members may access your 
personal information when necessary. 
 
10. 
How can I get more information? 
 
If you have any questions about the study, or suffer from any discomfort and injury during the 
study, or want to obtain more information of the study, please do not hesitate to contact the research 
members: Lingzhong Meng, MD, E Wang, MD and Adrian Gelb, MB ChB.  
 
If you have any questions regarding the ethical issues of the study, please contact the Clinical 
Research Ethics Committee at Yale University, Central South University, and University of 
California San Francisco.  
 
Signature page 
 
Informed consent and signature: 
 
I have read the informed consent for this trial carefully. The study protocol has been explained to 
me in full detail. I totally understand the purpose and nature of the study, as well as my rights and 
risks during the study. 
 
I would like to participate in the study voluntarily; and I can confirm that I cooperate with the 
research members according to the study protocol and the contents listed in informed consent and 
participate in the trial throughout the entire course of the study. 
 
 
Patient (or legally authorized representative)  
 
Printed Name (or legally authorized representative): 
  
 

 
23 
Signature: 
 
 
 
Date: 
  
 
<Relationship between legally authorized representative and patient (e.g., parent or legal 
guardian)> 
 
 
Person Obtaining Consent 
 
Printed Name & Title: 
 
 
Signature: 
 
 
 
Date: 
  
 
 
 
 
 

 
24 
Section C: Neurocognitive and Delirium Assessment 
 
See Supplemental Remarks 2-4  
 
 
 

 
25 
Section D: Definitions of Postoperative Complications 
 
Complications 
Definition 
Circulatory insufficiency 
Requirement of inotropic agents or vasopressors after surgery 
Acute myocardial 
ischemia or 
infarction 
Concentration of cardiac troponin I exceed the diagnostic criteria 
for myocardial ischemia or infarction as well as new Q waves (lasts 
for 0.03 s) or continuous (4 days) abnormal ST‐T segment 
Arrhythmia 
Confirmed by 12‐lead electrocardiogram and necessitated medical 
treatment and/or cardioversion 
Pulmonary infection 
New infiltrate on chest radiograph combined with temperature 
over 38°C and leukocytosis 
Acute respiratory failure 
Severe hypoxemia or hypercapnia requiring endotracheal 
intubation and mechanically assisted ventilation  
Stroke 
Persisted new focal neurologic deficit and confirmed by neurologic 
imaging 
Acute kidney injury 
Creatinine elevation meeting the current diagnostic criteria 
Wound infection or 
dehiscence 
Wound infection (purulent discharge or positive bacterial culture) or rupture 
that required secondary suturing 
Ileus 
Abdominal distention, bloating, and "gassiness", Diffuse, 
persistent abdominal pain, Nausea and/or vomiting, Delayed 
passage of or inability to pass flatus, or Inability to tolerate an oral 
diet, for more than 3-5 days 
Anastomotic leakage 
Extravasation of contrast agent in the body cavity or 
retroperitoneal space that required percutaneous drainage 
Severe sepsis 
Two or more criteria of systemic inflammatory response syndrome, 
with known infection and new onset dysfunction of at least one 
system 
Urinary tract infection 
Confirmed by urinalysis and urine culture and necessitated 
antibiotic therapy 
 
 

 
26 
Section E: Case Report Form 
 
 
Impact of electroencephalogram – guided anesthetic care on 
delirium after laparoscopic surgery: 
a prospective, randomized and controlled trial 
 
 
Case Report Form 
 
 
Initiator: Yale University and Central South University 
 
Research Centers: Central South University, Xiangya Hospital, Changsha, Hunan Province, 
China 
 
 
Study Sequence No.  
_ _ _ _ 
Medical record No  
_ _ _ _ _ _ _ _ 
Date (YYYY‐MM‐DD) 
 
20 _ _‐_ _‐_ _ 
Study Coordinator  
________________ 
Anesthesiologist 
 
________________ 
Outcome Assessor-1  
________________ 
Outcome Assessor-2  
________________ 
  
 
 

 
27 
Illustration 
 
1. This is a prospective, randomized controlled study. All recorded data must be timely, 
accurate and complete. 
2. If error(s) occurs in filling data, please use ONE strikethrough line and refill the correct 
data, and sign name of the corrector and date of correction. Attention: Do not cover the 
original data; do not use the eraser or correction fluid; do not cross more than one 
strikethrough line. 
3. Every page and every item of the case report form (CRF) must be completed. Fill “√” in 
the “□” to indicate selection;  “UK”  to  indicate  “do  not  know” or “unknown”,  “NA”  to  
indicate  “cannot  provide”  or  “not applicable”. 
4. Patient’s abbreviated name (initials of the last and first name) will be recorded in the form 
of left aligned acronym of Chinese phonetic alphabet. For example: 
Zhang Wei will be recorded as: ZW; 
Zhang Xiao‐Wei will be recorded as: ZXW; 
Ou-Yang Xiao‐Wei will be recorded as: OYXW. 
For studies in the USA, the initial of the first name is placed before the initial of the last 
name. For example: 
John Webber will be recorded as: JW (John is the first name). 
5. The number of recruited patients will be recorded in four numbers. For example: 
No. 1 will be recorded as: 0001; 
No. 12 will be recorded as: 0012; 
NO. 123 will be recorded as: 0123; 
NO. 1234 will be recorded as: 1234. 
6. Numeric data such as body weight and height will be recorded with one decimal, for 
example: 
Body weight 65 kg will be recorded as: 65.0 kg; 
Height 165.5 cm will be recorded as: 165.5 cm. 
7. Date will be recorded as year‐month‐day, for example:  
January 1st of 2016 will be recorded as: 2016-01-01; 
December 16th of 2016 will be recorded as: 2016-12-16. 
8. Duration of education is the actual years of education. 
9. The time will be recorded in the form of hh:mm, and use a 24‐hour clock. For example: 
9:35 in the morning will be recorded as: 09:35; 
2:05 in the afternoon will be recorded as: 14:05. 
10. If investigators have any questions during the study period, please contact the principle 
investigator (Prof. E Wang or Prof. Lingzhong Meng). In case of severe adverse events 
which must be recorded, responsible investigator must report to the supervising authorities 
including the principal investigators and the Ethics Committees within 24 hours. 
  
 
 

 
28 
Contact numbers for reporting serious adverse events: 
 
Responsible parties 
Contact numbers 
*Principal investigator: Prof. Lingzhong 
Meng, Department of Anesthesiology, Yale 
University 
(949) 732-8811 (USA) 
*Principal investigator: Prof. E Wang, 
Department of Anesthesiology, Central South 
University Xiangya Hospital 
 
*Clinical Research Ethics Committee, Central 
South University Xiangya Hospital 
 
*Department of Drug Safety Supervision, 
Hunan Municipal Food and Drug 
Administration 
 
*Department of Drug Research and 
Supervision, Division of Safety Supervision, 
State Food and Drug Administration 
 
 
 (Attention: Severe adverse events must be reported within 24 hours!) 
  
 
 
 

 
29 
Flow chart of the study 
 
Screen Recruitment 
Intraoperative 
Postoperative follow‐up 
PACU D1 D2 D3 D4 D5 D6‐discharge D30±3 
Inclusion/exclusion criteria 
X 
X 
Informed consent 
X 
Demographic data 
X 
X 
Preoperative diagnosis 
X 
X 
Previous medical history 
X 
X 
Physical examination 
X 
X 
Auxiliary examination 
X 
X 
MMSE 
X 
X 
Baseline CAM 
X 
X 
Anesthesia 
X 
Study protocol execution 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
Delirium assessment* 
X 
X 
X 
X X 
X 
Adverse events 
X 
X 
X 
X X 
X 
X 
NRS of severity of pain 
X 
X 
NRS of subjective sleep quality 
X 
Use of other drugs 
X 
X 
X 
X X 
X 
X 
Postoperative complications** 
X 
X 
X 
X X 
X 
X 
X 
All‐cause 30‐day mortality 
X 
 
*Delirium will be assessed at PACU and twice daily (8:00‐10:00 am and 18:00‐20:00 pm) during 
postoperative day 1 to 5. 
**Patients will be followed up until postoperative day 30. 
 
 
 

 
30 
Inclusion Criteria: 
Age ≥ 50 years 
Y□ 
N□ 
ASA physical score I-III 
Y□ 
N□ 
Scheduled to undergo elective laparoscopic surgery under general anesthesia 
with endotracheal intubation 
Y□ 
N□ 
Able to undergo MMSE and CAM assessment 
Y□ 
N□ 
Extubation expected after surgery 
Y□ 
N□ 
Scheduled to stay in hospital > 3 days after surgery 
Y□ 
N□ 
*Subjects cannot be enrolled in the study if any one of the above is "N" 
 
Exclusion Criteria: 
Refuse to participate 
Y□ 
N□ 
Emergent surgery or trauma patients 
Y□ 
N□ 
Preoperative cognitive impairment characterized by MMSE of 23 or less 
Y□ 
N□ 
Preoperative history of stroke, TIA, schizophrenia, Parkinson’s disease, 
epilepsy, or dementia 
Y□ 
N□ 
Inability to communicate in the preoperative period due to language 
difficulties, or significant hearing or visual impairment 
Y□ 
N□ 
Severe cardiac disease including low-output cardiac failure defined as a 
preoperative left ventricular ejection fraction < 30% or arrhythmia with 
pacemaker or AICD placement 
Y□ 
N□ 
Severe hepatic dysfunction being evaluated for liver transplantation or with a 
Child‐Pugh Class C classification 
Y□ 
N□ 
Severe renal dysfunction requiring renal replacement therapy before surgery Y□ 
N□ 
Those with preoperative ASA classification of 4 or who are unlikely to 
survive for more than 24 hours after surgery 
Y□ 
N□ 
*Subjects cannot be enrolled if anyone of the above is “Y” 
 
 

 
31 
Baseline information and medical history 
 
Abbreviated name: 
Gender:   
□ Male; □ Female 
Nationality: 
Occupation: 
Marital status:  
□ Married; □ Unmarried; □ Others 
Age (years): 
Date of birth (YYYY‐MM): 
19_ _‐ _ _ 
Height: 
_ _ _. _ cm 
Weight: 
_ _ _. _ kg 
Highest degree of education: 
□ No school; □ Elementary school; □ Middle school; □ High School; □ College; □ Master degree; □ Doctor degree 
Duration of education:     _ _ years 
Date of hospital admission:     20_ _ - _ _ - _ _ 
Preoperative surgical diagnosis: 
Surgery being scheduled:      □ Stomach; □ Colorectal; □ Small intestine; □ Liver; □ Pancreas; □ 
Gallbladder; □ Kidney; □ Bladder; □ Retroperitoneal; □ Combined; □ Other (please specify: 
_______________________) 
ASA physical classification: 
□ ASA I: No organic pathology or patients in whom the pathological process is localized and does not cause any 
systemic disturbance or abnormality; 
□ ASA II: A patient with mild systemic disease that results in no functional limitation; 
□ ASA III: A patient with severe systemic disease that results in functional impairment; 
□ ASA IV: Severe systemic disease that is a constant threat to life; 
□ ASA V: Moribund condition in a patient who is not expected to survive without the operation. 
Medication within one month (including sedatives, analgesics and anticholinergics) 
Drug 
Dose 
Route 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most recent preoperative blood/biochemical examination 
Hb (g/L) 
 
Na (mmol/L) 
 
Hct (%) 
 
K (mmol/L) 
 
Platelet 
 
Cr (umol/L) 
 
INR 
 
BUN (mmol/L) 
 
ALB (g/L) 
 
ALT (IU/L) 
 
GLU (mmol/L) 
 
AST (IU/L) 
 
HbA1c 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
32 
Preoperative 
comorbidity 
Cognitive 
function 
MMSE Score: ___; □ Dementia 
Neuropsychiatric 
diagnosis 
□ None; □ Stroke; □ TIA; □ Schizophrenia; □ Parkinson’s disease; □ 
Epilepsy; □ Depression  
Cardiovascular 
system 
□ None; □ CAD; □VHD; □ Congenital heart disease;  
□ Hypertension; □ Arrhythmia; □ Cardiomyopathy; 
□ Others: ___________________ 
□ Current NYHA classification: ____ 
□ I: No symptoms and no limitation in ordinary physical activity, e.g. 
no shortness of breath when walking, climbing stairs etc. 
□ II: Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
□ III: Marked limitation in activity due to symptoms, even during less‐ 
than‐ordinary activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
□ IV: Severe limitations. Experiences symptoms even at rest. Mostly 
bedbound patients. 
Respiratory 
system 
□ None; □ COPD; 
□ Chronic bronchitis; □ Asthma; 
□ Smoke (>10 cigarettes/d, > 1 year), ____ packs/d, _____ years 
□ Others: __________________ 
 
Metabolic 
disorders 
□ None; □ Diabetes; □ Thyroid disease; □ Hyperlipidemia; 
□ Hepatic dysfunction (ALT and/or AST ≥ 5 times of upper limit); 
□ Renal dysfunction (Cr ≥ 177 μmol/L); 
□ Electrolyte disorder; □ Morbid obesity; BMI ____ 
□ Others: _________________ 
 
Others  
□ Alcoholism* 
 _____ ml/day; _____ years 
□ GI disorders; 
□ AIDS; □ Cancer 
□ History of allergy: ____________ 
□ Others: _________________ 
 
History of 
surgery 
□ No 
□ Yes 
Date 
Surgery 
Anesthesia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Two drinks or more daily, or weekly consumption of the equivalent of 150 ml of alcohol. 
 
 

 
33 
Updated Charlson Comorbidity Index Score = _____ 
 
Comorbidity 
Charlson 
weight score 
Score of the 
patient 
Myocardial infarction 
0 
Congestive heart failure 
2 
Peripheral vascular disease 
0 
Cerebral vascular disease 
0 
Dementia 
2 
Chronic lung disease 
1 
Rheumatic diseases 
1 
Ulcer of digestive tract 
0 
Mild liver disease 
2 
Diabetes without chronic complications 
0 
Diabetes with chronic complications 
1 
Hemiplegia or paraplegia 
2 
Renal disease 
1 
Malignant tumor (including leukemia and lymphoma) 
2 
Moderate / severe liver disease 
4 
Metastasis of solid tumors 
6 
AIDS/HIV 
4 
Total score 
24 
 
 
Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, Januel JM, Sundararajan V. Updating 
and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge 
abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676-82.  
 
 
 

 
34 
Preoperative drugs 
 
Use of sedatives & analgesics during the night before surgery: □ No; □ Yes 
Check if yes 
Drug 
Dose 
Route 
□ 
 
 
 
□ 
 
 
 
□ 
 
 
 
Premedications:  □ No; □ Yes 
Check if yes 
Drug 
Dose 
Route 
□ 
Scopolamine 
 
 
□ 
Atropine 
 
 
□ 
Glycopyrrolate 
 
 
□ 
Midazolam 
 
 
□ 
Other: 
 
 
□ 
Other: 
 
 
□ 
Other: 
 
 
 
 
 
 
 
 

 
35 
Intraoperative 
 
Date of surgery (YYYY‐MM‐DD): 20_ _ ‐ _ _ ‐ _ _ 
Name of surgery: ____________________ 
Anesthesia techniques and drug details 
□ GA; □ Combined GA-epidural; □ Other: __________________ 
Anesthesia induction (HH:MM): _ _: _ _  
Extubation (HH:MM): _ _: _ _ 
Duration of anesthesia (from anesthesia induction to extubation): _ _ _ mins 
Skin incision (HH:MM): _ _: _ _ 
Skin closure (HH:MM): _ _: _ _ 
Duration of surgery (from skin incision to closure): _ _ _ mins 
Anesthesia induction 
Check if yes 
Drug 
Dose 
Route 
□ 
Lidocaine 
 
 
□ 
Propofol 
 
 
□ 
Sufentanil 
 
 
□ 
Rocuronium 
 
 
□ 
Fentanyl 
 
 
□ 
Succinylcholine 
 
 
□ 
Midazolam 
 
 
□ 
Morphine 
 
 
□ 
Etomidate 
 
 
□ 
Other: 
 
 
□ 
Other: 
 
 
Anesthesia maintenance 
Check if yes 
Drug 
Dose 
Route 
□ 
Propofol  
 
infusion 
□ 
Remifentanil  
 
infusion 
□ 
Sufentanil 
 
 
□ 
Sevoflurane 
 
 
□ 
Dexmedetomidine 
 
 
□ 
Fentanyl 
 
 
□ 
Morphine 
 
 
□ 
Rocuronium 
 
 
□ 
Vecuronium 
 
 
□ 
Cisatracurium 
 
 
□ 
Other: 
 
 
□ 
Other: 
 
 

 
36 
Epidural drugs 
Check if yes 
Drug 
Dose 
Route 
□ 
Lidocaine 
 
 
□ 
Ropivacaine 
 
 
□ 
Bupivacaine 
 
 
□ 
Fentanyl 
 
 
□ 
Other: 
 
 
□ 
Other: 
 
 
Other drugs 
Check if yes 
Drug 
Dose 
Route 
□ 
Dexamethasone 
 
 
□ 
Methylprednisolone 
 
 
□ 
Hydrocortisone 
 
 
□ 
Ondansetron 
 
 
□ 
Tropisetron 
 
 
□ 
Atropine 
 
 
□ 
Glycopyrrolate 
 
 
□ 
Scopolamine 
 
 
□ 
Neostigmine 
 
 
□ 
Penehyclidine 
 
 
□ 
Other:  
 
 
□ 
Other:  
 
 
Intraoperative inputs 
Check if yes 
Name 
Total volume (mL) 
□ 
0.9% NS 
 
□ 
LR 
 
□ 
Plasmalyte 
 
□ 
5% Albumin 
 
□ 
Colloid: ________ 
 
□ 
PRBC 
 
□ 
FFP 
 
□ 
Platelet 
 
□ 
Cellsaver 
 
□ 
Other: 
 
□ 
Other:  
 
□ 
Other: 
 
□ 
Other:  
 
□ 
Other: 
 
□ 
Other:  
 
Intraoperative outputs 

 
37 
Check if yes 
Name 
Total volume (mL) 
□ 
Estimated blood loss 
 
□ 
Urine output 
 
□ 
Other: 
 
□ 
Other: 
 
Lowest hemoglobin (Hb) level during surgery if available _ _. _ (g/L)  
Highest lactate level during surgery if available _ _. _ (mmol/L) 
Procedure converted to open surgery: Yes □; No □; Reason: ____________________ 
Procedure aborted: Yes □; No □; Reason: ____________________ 
 
Postoperative 
Extubation at the end of surgery: □ Yes; □ No 
PACU admission: □ Yes; □ No 
Date 
(YYYY-MM-
DD): 
20 _ _ - _ _ - _ _ 
Time in (hh: mm): 
 _ _ : _ _ 
Time out (hh: mm): 
 _ _ : _ _ 
PACU length: 
 _ _ _ mins 
ICU admission: □ Yes; □ No 
Date (YYYY-MM-DD) 
in: 
20 _ _ - _ _ - _ _ 
Time in (hh: mm) 
 _ _ : _ _ 
Date 
(YYYY-MM-DD) 
out: 
20 _ _ - _ _ - _ _ 
ICU days: _ _ days 
Details of extubation if not extubated at the end of surgery in the Operating Room 
Location: □ PACU; □ ICU 
Duration from the end of surgery to extubation: _ _ hours, or, _ _ days 
 
 
 

 
38 
Delirium Assessment (performed at both PACU and floor/ICU) 
 
Date 
Time 
RASS 
Feature 1: 
Feature 2: 
Feature 3: 
Feature 4: 
Delirium 
‐5 to 
+4 
Acute 
Onset or 
Fluctuating 
Course 
Inattention Altered Level 
of 
Consciousness 
Disorganized 
Thinking 
Diagnosis 
PACU 
30 
mins 
after 
extubation 
to 
Discharge 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
POD 
1 
8:00-
10:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
16:00-
18:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
POD 
2 
8:00-
10:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
16:00-
18:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
POD 
3 
8:00-
10:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
16:00-
18:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
POD 
4 
8:00-
10:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
16:00-
18:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
POD 
5 
8:00-
10:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
16:00-
18:00 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
 
Diagnosis of Emergence Delirium: □ Yes   □ No  
 
Diagnosis of POD: □ Yes   □ No  
 

 
39 
Record of adverse events 
 
An adverse event indicates any unpredictable, unfavorable medical event that is associated with 
any medical intervention and occurs during the study period. It can be related to the study or not. 
 
A severe adverse event indicates any unpredictable medical events that lead to death, threat to life, 
prolonged length of stay in hospital, persistent disability or dysfunction, or other severe results. 
 
Any adverse event should be followed up until it is completely resolved or therapy terminated.  
 
Is there any new adverse event within 24 hours after surgery: □Yes; □No 
Is there any new severe adverse event within 3 days after surgery: □Yes; □No  
(Report form of severe adverse event see attached table) 
 
 
Start time 
End time 
Diagnostic 
evidence 
Mode 
of 
occurrence 
Is it severe 
adverse 
event? 
Treatment1 
Outcome2 
Related to 
study? 
Recall3 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Hypotension4 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Bradycardia5 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Hypertension6 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Tachycardia7 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Hypoxemia8 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Other: 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Other: 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
Other: 
 
 
 
□ Persistent 
□ Transient 
□ Yes 
□ No 
 
 
□ Yes 
□ No 
 
 
 
 
 
1Treatment refers to any intervention that intends to reverse or treat the adverse event; 
2Outcomes include: A=Recovered, B=Deteriorated, C=Persist, D=Recovered but with sequelae, 
E=Fatal, F=No follow‐up (reasons must be explained); 
3Recall means the patient can recall the surroundings or an event related to the surgery while under 
general anesthesia.  
4Defined as SBP< 90 mmHg or a decrease of more than 20% from the baseline value; 
5Defined as HR< 50 bpm or a decrease of more than 20% from the baseline value; 
6Defined as SBP> 160 mmHg or an increase of more than 20% from baseline; 
7Ddefined as HR > 100 bpm or an increase of more than 20% from baseline; 
8Defined as SpO2 < 90%. 
 
 

 
40 
NRS of pain severity 
(0 = no pain and 10 = the worst possible pain) 
 
PACU 
24 hours after surgery 
Score 
 
 
 
 
Use patient‐controlled analgesia pump after surgery 
□ No 
□ Yes 
□ PCIA 
 
 
□ Morphine 
□ Sufentanil 
□ Others 
Total dose within 24 hours: 
□ PCEA 
 
 
□ Sufentanil 125ug+1% ropivacaine 
30ml)/250ml 
□ Others 
Total dose within 24 hours: 
 
 
 

 
41 
Analgesics and other drugs administered during the first 7 days after surgery 
 
(Route of administration to be documented) 
Drug 
Day of 
surgery POD 1 
POD 2 
POD 3 
POD 4 
POD 5 
POD 6 
POD 7 
□ Fentanyl (mcg) 
 
 
 
 
 
 
 
 
□ Morphine (mg) 
 
 
 
 
 
 
 
 
□ Sufentanil (mcg) 
 
 
 
 
 
 
 
 
□ Hydromorphone (mg) 
 
 
 
 
 
 
 
 
□ Meperidine (mg) 
 
 
 
 
 
 
 
 
□ Midazolam (mg) 
 
 
 
 
 
 
 
 
□ Flurbiprofen (mg) 
 
 
 
 
 
 
 
 
□ Parecoxib (mg) 
 
 
 
 
 
 
 
 
□ Penehyclidine 
hydrochloride (mg) 
 
 
 
 
 
 
 
 
□ Scopolamine (mg) 
 
 
 
 
 
 
 
 
□ Atropine (mg) 
 
 
 
 
 
 
 
 
□ Glycopyrrolate (mg) 
 
 
 
 
 
 
 
 
□ Hydrocortisone (mg) 
 
 
 
 
 
 
 
 
□ Dexamethasone (mg) 
 
 
 
 
 
 
 
 
□ Methylprednisolone 
(mg) 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
□ Other: 
 
 
 
 
 
 
 
 
 
Note: Record the daily consumption at 18:00 pm. For patients who are admitted after 18:00 pm, 
record the daily consumption at the next 18:00 pm. 
  
 
 

 
42 
Postoperative complications 
(Patients will be followed up until 30 days after surgery; diagnostic criteria listed in brackets) 
Complications of organs/systems 
 
Diagnostic 
Evidence 
□ Respiratory insufficiency (hypoxemia or hypercapnia, 
requiring mechanical ventilation for any duration after 
surgery) 
□ Yes 
□ No 
 
□ Pulmonary embolism (confirmed by clinical 
manifestations and imaging study) 
□ Yes 
□ No 
 
□ Acute myocardial infarction [increase of troponin T 
concentration above the hospital laboratory’s 
myocardial infarction threshold and either new Q waves 
(duration of at least 0.03 seconds) or persistent changes 
(4 days) in ST‐T segment] 
 
□ Yes 
□ No 
 
□ Circulatory insufficiency (requirement of inotropic 
agents or vasopressors for any duration after surgery) 
□ Yes 
□ No 
 
□ New onset arrhythmia (confirmed by 12‐leads 
electrocardiography and necessitating medical treatment 
and/or cardioversion) 
□ Yes 
□ No 
 
□ Stroke (persisted new focal neurologic deficit and 
confirmed by neurologic imaging) 
 
□ Yes 
□ No 
 
□ Acute kidney injury  
(KDIGO defines AKI as any of the following: 
• Increase in serum creatinine by 0.3mg/dL or 
more within 48 hours or 
• Increase in serum creatinine to 1.5 times 
baseline or more within the last 7 days or 
• Urine output less than 0.5 mL/kg/h for 6 hours) 
□ Yes 
□ No 
□ Baseline Cr: ___  
□ Peak Cr within 48 
hours: ___ 
□ Peak Cr within 7 
days: ___ 
□ Urine output: ___ 
mL/kg/h 
for 
___ 
hours 
 
□ Deep vein thrombosis (confirmed by venous 
ultrasonography/venography) 
□ Yes 
□ No 
 
□ Disseminated intravascular coagulation (manifestation 
of abnormal bleeding, together with prolonged 
PT/aPTT, declined platelet/fibrinogen levels, as well as 
increased fibrin degradation products (including D‐ 
dimer)) 
□ Yes 
□ No 
 
□ Ileus (at least one for each of the two following 
criteria: (1) presence of vomiting OR abdominal 
distension and (2) absence of flatus/stool OR not 
tolerating oral diet, in the absence of any precipitating 
complications) 
□ Yes 
□ No 
 
Surgical complications 
 
Diagnostic 
Evidence 
□ Wound dehiscence (wound rupture that required 
secondary suturing) 
□ Yes 
□ No 
 
□ Incisional hernia (requirement of secondary surgery) 
□ Yes 
 

 
43 
□ No 
□ Surgical bleeding (bleeding after surgery that required 
secondary surgical hemostasis) 
□ Yes 
□ No 
 
□ Anastomotic leakage (extravasation of contrast agent 
in the body cavity or retroperitoneal space that required 
percutaneous drainage) 
 
□ Yes 
□ No 
 
□ Gastrointestinal hemorrhage (decrease of hemoglobin 
level combined with positive occult blood test results 
that required treatment) 
 
□ Yes 
□ No 
 
□ Delayed oral intake (lack of bowel movement, 
flatulence, and requirement of intravenous fluid therapy 
for more than one week after surgery) 
□ Yes 
□ No 
 
Infectious complications 
 
Diagnostic 
Evidence 
□ Severe sepsis/septic shock (two or more criteria of 
systemic inflammatory response syndrome, with known 
infection and new onset dysfunction of at least one 
system or requirement of vasopressors to maintain 
blood pressure) 
□ Yes 
□ No 
 
□ Intra‐abdominal abscess (confirmed by 
ultrasonography or CT scan and required percutaneous 
drainage) 
 
 
□ Yes 
□ No 
 
□ Pulmonary infection (new infiltrate on chest 
radiograph combined with temperature of over 38°C 
and leukocytosis) 
□ Yes 
□ No 
 
□ Wound infection (pus expressed from the incision, 
and bacteria cultured from the pus)  
 
□ Yes 
□ No 
 
□ Urinary tract infection (confirmed by urinalysis and 
urine culture and necessitated antibiotic therapy) 
□ Yes 
□ No 
 
Other complications 
Time of earliest 
diagnosis 
Diagnostic 
Evidence 
□ 
 
 
□ 
 
 
 
 

 
44 
Hospital discharge information 
 
Discharge from hospital, date 
(YYYY‐MM‐DD) 
20 _ _-_ _-_ _ 
Actual duration of hospitalization 
(days) based on discharge from 
hospital 
___ days 
Postoperative diagnosis (including 
pathological diagnosis, metastasis 
and tumor stage information) 
 
Survival at 30 days after surgery 
□Yes; □ No 
If death within 30 days, date of death: 20_ _ - _ _ - _ _ 
That is _ _ days after surgery 
Cause of death: 
 
Hospital readmissions within 30 days 
after surgery 
□Yes; □ No 
If readmission within 30 days, date: 20_ _ - _ _ - _ _ 
That is _ _ days after surgery 
Cause of readmission: 
 
 
 
 

 
45 
Supplemental remark 1. SedLine-Guided Intervention Flow Chart 
 
 
 
 
 

 
46 
 
Supplemental remark 2. Mini-Mental State Examination (MMSE) 
(A Chinese version is needed.) 
 
MMSE to be assessed within 48 hours before surgery and on POD 7 or before discharge. 
 
Instructions: Score one point for each correct response within each question or activity. 
Patient name:  
Study sequence #:   
Date of surgery: 20_ _ - _ _ - _ _  
Date of the 1st test: 20_ _ - _ _ - _ _; Date of the 2nd test: 20_ _ - _ _ - _ _ 
Maximum 
Score 
Questions 
Patient’s 
Score 
Pre-op 
POD 5 
5 
“What is the year? Season? Date? Day? Month?” 
 
 
5 
“Where are we now? State? County? Town/city? Hospital? Floor?” 
 
 
3 
The examiner names three unrelated objects clearly and slowly, then 
the instructor asks the patient to name all three of them. The patient’s 
response is used for scoring. The examiner repeats them until patient 
learns all of them, if possible. 
 
 
5 
“I would like you to count backward from 100 by sevens.” (93, 86, 79, 
72, 65, …) 
Alternative: “Spell WORLD backwards.” (D-L-R-O-W) 
 
 
3 
“Earlier I told you the names of three things. Can you tell me what 
those were?” 
 
 
2 
Show the patient two simple objects, such as a wristwatch and a pencil, 
and ask the patient to name them. 
 
 
1 
“Repeat the phrase: ‘No ifs, ands, or buts.’” 
 
 
3 
“Take the paper in your right hand, fold it in half, and put it on the 
floor.” 
(The examiner gives the patient a piece of blank paper.) 
 
 
1 
“Please read this and do what it says.” (Written instruction is “Close 
your eyes.”) 
 
 
1 
“Make up and write a sentence about anything.” (This sentence must 
contain a noun and a verb.) 
 
 
1 
“Please copy this picture.” (The examiner gives the patient a blank 
piece of paper and asks him/her to draw the symbol below. All 10 
angles must be present and two must intersect.) 
 
 
30 
Total  
 
 
 
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state: A practical method for grading the 
cognitive state of patients for the clinician.” J Psychiatr Res 1975;12:189-198. 
 

 
47 
Supplemental remark 3.  
The Confusion Assessment Method (CAM) Instrument for patients NOT in ICU  
(A Chinese version is needed.) 
 
Aspects 
Assessments 
Conclusion 
Day-1 
Day-2 
Day-3 
Day-4 
Day-5 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
1. [Acute Onset] 
Is there evidence of an acute change in 
mental status from the patient's baseline? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
2A. [Inattention] 
Did the patient have difficulty focusing 
attention, for example, being easily 
distractible, or having difficulty keeping 
track of what was being said? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
2B. (If present or 
abnormal) 
Did this behavior fluctuate during the 
interview, that is, tend to come and go or 
increase and decrease in severity? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
3. [Disorganized 
thinking] 
Was the patient's thinking disorganized 
or incoherent, such as rambling or 
irrelevant conversation, unclear or 
illogical flow of ideas, or unpredictable 
switching from subject to subject? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
4. [Altered level of 
consciousness] 
Overall, how would you rate this 
patient's level of consciousness? (Alert 
[normal]; Vigilant [hyperalert, overly 
sensitive to environmental stimuli, 
startled very easily], Lethargic [drowsy, 
easily aroused]; Stupor [difficult to 
arouse]; Coma; [unarousable]; 
Uncertain) 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
5. [Disorientation] 
Was the patient disoriented at any time 
during the interview, such as thinking 
that he or she was somewhere other than 
the hospital, using the wrong bed, or 
misjudging the time of day? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 

 
48 
6. [Memory 
impairment] 
Did the patient demonstrate any memory 
problems during the interview, such as 
inability to remember events in the 
hospital or difficulty remembering 
instructions? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
7. [Perceptual 
disturbances] 
Did the patient have any evidence of 
perceptual disturbances, for example, 
hallucinations, illusions or 
misinterpretations (such as thinking 
something was moving when it was 
not)? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
8A. [Psychomotor 
agitation] 
At any time during the interview did the 
patient have an unusually increased level 
of motor activity such as restlessness, 
picking at bedclothes, tapping fingers or 
making frequent sudden changes of 
position? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
8B. [Psychomotor 
retardation] 
At any time during the interview did the 
patient have an unusually decreased 
level of motor activity such as 
sluggishness, staring into space, staying 
in one position for a long time or moving 
very slowly? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
9. [Altered sleep-
wake cycle] 
Did the patient have evidence of 
disturbance of the sleep-wake cycle, 
such as excessive daytime sleepiness 
with insomnia at night? 
 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
 
 
 

 
49 
The Confusion Assessment Method (CAM) Diagnostic Algorithm 
 
Features 
Description & Assessments 
Conclusion 
Day-1 
Day-2 
Day-3 
Day-4 
Day-5 
AM 
PM 
AM 
PM 
AM 
AM 
PM 
AM 
PM 
AM 
Feature 1:  
Acute Onset and 
Fluctuating 
Course 
This feature is usually obtained from a 
family member or nurse and is shown by 
positive responses to the following 
questions: Is there evidence of an acute 
change in mental status from the patient's 
baseline? Did the (abnormal) behavior 
fluctuate during the day, that is, tend to 
come and go, or increase and decrease in 
severity? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
Feature 2: 
Inattention  
 
This feature is shown by a positive 
response to the following question: Did the 
patient have difficulty focusing attention, 
for example, being easily distractible, or 
having difficulty keeping track of what 
was being said? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
Feature 3:  
Disorganized 
thinking  
 
This feature is shown by a positive 
response to the following question: Was 
the patient's thinking disorganized or 
incoherent, such as rambling or irrelevant 
conversation, unclear or illogical flow of 
ideas, or unpredictable switching from 
subject to subject? 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
Feature 4:  
Altered Level of 
consciousness  
 
This feature is shown by any answer other 
than "alert" to the following question: 
Overall, how would you rate this patient's 
level of consciousness? (alert [normal]), 
vigilant [hyperalert], lethargic [drowsy, 
easily aroused], stupor [difficult to arouse], 
or coma [unarousable]) 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 

 
50 
Is the patient 
delirious? 
The diagnosis of delirium by CAM 
requires the presence of features 1 and 2 
and either 3 or 4. 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
□ Yes 
□ No 
 
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new 
method for detection of delirium. Ann Intern Med. 1990;113(12):941-8. 
 
 
 

 
51 
Supplemental remark 4.  
CAM‐ICU Worksheet for patients in PACU and ICU 
 
The first step, assess the sedation state using Richmond Agitation Sedation Scale (RASS) 
 
Richmond Agitation Sedation Scale (RASS) 
 
Score 
Term 
Description 
+4 
Combative 
Overtly combative, violent, immediate danger to staff 
+3 
Very agitated 
Pulls or removes tube(s) or catheter(s); aggressive 
+2 
Agitated 
Frequent non‐purposeful movement, fights ventilator 
+1 
Restless 
Anxious but movements not aggressive or vigorous 
0 
Alert and calm 
 
‐1 
Drowsy 
Not fully alert, but has sustained awakening (eye opening/eye contact) to voice (10 seconds) 
‐2 
Light sedation 
Briefly awakens with eye contact to voice (less than 10 seconds) 
‐3 
Moderate sedation 
Movement or eye opening to voice (but no eye contact) 
‐4 
Deep sedation 
No response to voice, but movement or eye opening to physical stimulation 
‐5 
Unarousable 
No response to voice or physical stimulation 
 
 
Procedure for RASS Assessment 
 
Steps 
Patient 
Score 
Observe patient  
Patient is alert, restless, or agitated 
 
0 to +4 
If not alert, state patient’s name and say to 
open eyes and look at speaker 
Patient awakens with sustained eye opening and eye contact 
-1 
Patient awakens with eye opening and eye contact, but not sustained 
-2 
Patient has any movement in response to voice but no eye contact 
-3 
When no response to verbal stimulation, 
physically stimulate patients by shaking 
shoulder and/or rubbing sternum 
Patient has any movement to physical stimulation 
-4 
Patient has no response to any stimulation 
-5 

 
52 
 
 
Patient RASS Scores 
 
Location/date 
PACU 
POD-1 
POD-2 
POD-3 
POD-4 
POD-5 
Time 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
53 
If the RASS score is > ‐4 (‐3 through +4), delirium is assessed using the CAM‐ICU Worksheet 
CAM‐ICU Worksheet 
 
Features 
Score 
Check here 
if present 
Feature 1: Acute Onset or Fluctuating Course 
Is the patient different than his/her baseline mental status?  
OR 
Has the patient had any fluctuation in mental status in the past 24 hours as evidenced by fluctuation on a 
sedation/level of consciousness scale (i.e., RASS/SAS), GCS, or previous delirium assessment? 
Either question Yes 
□ 
Feature 2: Inattention 
Letters Attention Test (See training manual for alternate Pictures) Directions: Say to the patient, “I am going to 
read you a series of 10 letters.           Whenever you hear the letter ‘A,’ indicate by squeezing my hand.” Read 
letters from the following letter list in a normal tone 3 seconds apart. 
S A V E A H A A R T or C A S A B L A N C A or A B A D B A D A A Y 
Errors are counted when patient fails to squeeze on the letter “A” and when the patient squeezes on any letter other 
than “A.” 
Number of Errors >2 
□ 
Feature 3: Altered Level of Consciousness 
Present if the Actual RASS score is anything other than alert and calm (zero) 
RASS 
anything other than zero 
□ 
Feature 4: Disorganized Thinking 
Yes/No Questions (Use group A or group B to test, if necessary, group A and B can be used interchangeably) 
Group A:  
1. 
Will a stone float on water? 
2. 
Are there fish in the sea? 
3. 
Does one pound weigh more than two pounds? 
4. 
Can you use a hammer to pound a nail?  
Group B: 
1. 
Will a leaf float on water? 
2. 
Are there elephants in the sea? 
3. 
Does two pounds weigh more than one pound? 
4. 
Can you use a hammer to saw wood?  
Combined number of 
errors >1 
□ 

 
54 
Errors are counted when the patient incorrectly answers a question.  
Command 
Say to patient: “Hold up this many fingers” (Hold 2 fingers in front of patient) 
“Now do the same thing with the other hand” (Do not repeat number of fingers) 
*If the patient is unable to move both arms, for 2nd part of command ask patient to “Add one more finger” 
An error is counted if patient is unable to complete the entire command. 
Overall CAM‐ICU 
Feature 1 plus 2 and either 3 or 4 present = CAM‐ICU 
positive 
Criteria Met 
□CAM‐ICU Positive (Delirium Present) 
Criteria Not Met 
□CAM‐ICU Negative (No Delirium) 
 
Patient CAM-ICU Assessment 
 
Location/date 
PACU 
POD-1 
POD-2 
POD-3 
POD-4 
POD-5 
Time 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Positive/ 
negative 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
□ P 
□ N 
 
References: 
 
Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation 
Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-44. 
Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus 
RS, Bernard GR. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale 
(RASS). JAMA. 2003;289(22):2983-91. 
Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R. Delirium 
in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). 
JAMA. 2001;286(21):2703-10. 
 
 

 
55 
 
 
 
 
 
 
 

 
56 
Supplemental remark 4. Child‐Pugh Grade 
 
Child‐Pugh grade A, 5 to 6 points; grade B, 7 to 9 points; grade C, 10 to 15 points. 
 
Index 
Abnormal degree score 
1 
2 
3 
Hepatic 
encephalopathy* 
No 
1‐2 
3‐4 
Ascites** 
No 
Light 
Moderate or severe 
Serum 
bilirubin 
(μmol/L) 
<34.2 
34.2‐51.3 
>51.3 
Serum albumin (g/L) 
≥35 
28‐34 
<28 
PT (second) 
 
≤14 
15‐17 
≥18 
 
*Hepatic encephalopathy: grade 1, prodromal stage; grade 2, precoma; grade 3, comatose; grade 4, coma. 
**Ascites: light, shifting dullness below the midaxillary line; moderate, shifting dullness between the midclavicular line and midaxillary 
line; severe, shifting dullness beyond the midclavicular line. 
  
 
 

 
57 
Supplemental remark 5. Serious Adverse Event (SAE) 
 
Report type 
□ 1st time report 
 
□ Follow‐up report 
□ Summary report 
Report date: 20_ _‐_ _‐_ _ 
 
Trial center name: 
Contact person: 
Tel: 
Trial headquarter 
Yale University Dept. of 
Anesthesiology 
203.785.2802  
203.785.6664  
anesthesiology@yale.edu 
Trial title 
Impact of electroencephalogram – guided anesthetic care on 
delirium after intra-abdominal surgery: a randomized and 
controlled trial 
Subject (patient) 
Abbrev. name: 
Study sequence #: 
Gender: □ M □ F 
Date of birth: 20 _ _‐_ _‐_ _ 
Diagnosis: 
Situation of SAE 
□ Prolong hospitalization; □ Dysfunction; □ Endanger life; 
□ Death; □ Others (please specify ___________) 
Date of occurrence: 20 _ _‐_ _‐_ _ 
Management of study 
protocol 
□ Continue; □ Protocol revision; □ Temporary suspension; 
□ Permanent suspension 
Outcome of SAE 
□ Symptoms subsided (sequela □ Yes; □ No) 
□ Symptoms continued 
□ Death (date of death: 20 _ _‐_ _‐_ _) 
Relationship of SAE with the 
study 
□ Certainly related; □ Possibly related;  
□ Possibly unrelated; □ Unrelated; 
□ Cannot determine 
Previously reported SAE 
In China: 
 □ Yes  □ No □ Unknown 
Outside China: 
 □ Yes  □ No □ Unknown 
Occurrence and treatment of SAE in detail: 
 
 
 

 
58 
 
 
 
Date is recorded as YYYY‐MM‐DD 
 
Department of reporter: 
 
Name of reporter: 
 
Signature of reporter: 
 
 
 
 

 
59 
Section F: Baseline demographics and characteristics 
 
Intervention 
(n=) 
Control 
(n=) 
p value 
Age (year) 
 
 
 
Male (n=) 
 
 
 
BMI (kg/m2) 
 
 
 
Education (years) 
 
 
 
Preoperative comorbidity 
Hypertension (n=) 
 
 
 
Coronary heart disease (n=) 
 
 
 
Arrhythmia (n=) 
 
 
 
 
Hx of cardiac surgery (n=) 
 
 
 
Stroke (n=) 
 
 
 
COPD (n=) 
 
 
 
Diabetes mellitus (n=) 
 
 
 
Liver dysfunction1 (n=) 
 
 
 
 
Renal dysfunction2 (n=) 
 
 
 
 
Chronic smoking3 (n=) 
 
 
 
Alcoholism4 (n=) 
 
 
 
Charlson Comorbidity Index (score)  
 
 
 
Hx of non-cardiac surgery (n=) 
 
 
 
Preoperative medication 
Anticholinergic 
 
 
 
 
Antidepressant 
 
 
 
Antipsychotic 
 
 
 
Insulin for diabetes mellitus  
 
 
 
Chronic use of benzodiazepine 
 
 
 
 
Preoperative laboratory tests 
Hematocrit< 30% 
 
 
 
 
 
Albumin < 30 g/L 
 
 
 
Glucose < 4.0 or > 10.0 mmol/L 
 
 
 

 
60 
Sodium < 135.0 or > 145.0 mmol/L 
 
 
 
Potassium< 3.5 or > 5.5 mmol/L 
 
 
 
Dehydration index5 > 36 
 
 
 
Preoperative ASA classification 
II 
 
 
 
III 
 
 
 
 
Data are mean (SD) or number (%). BMI = body mass index; COPD = chronic obstructive pulmonary disease; ASA = American Society 
of Anesthesiologists.  
1Alanine transaminase and/or aspartate transaminase more than five times the upper limit of normal.  
2Serum creatinine > 177 µmol/L.  
3Smoking half a pack of cigarettes per day for at least 2 years.  
4Two drinks or more weekly, or weekly consumption of the equivalent of 150 ml of alcohol. 5Dehydration index = 
[(BUN/3.55)/(Scr/88.4)]x10; BUN = blood urea nitrogen in mmol/L; Scr = serum creatinine in μmol/L. 
  
 
 

 
61 
Section G: Occurrence of non‐delirium complications after surgery 
 
 
Intervention 
(n=) 
Control 
(n=) 
p value 
Circulatory insufficiency 
 
 
 
Acute myocardial infarction 
 
 
 
New onset arrhythmia 
 
 
 
Pulmonary infection 
 
 
 
Stroke 
 
 
 
Acute renal failure 
 
 
 
Wound dehiscence 
 
 
 
Ileus 
 
 
 
Surgical bleeding 
 
 
 
Anastomotic leakage 
 
 
 
Gastrointestinal hemorrhage 
 
 
 
Wound infection 
 
 
 
Severe sepsis 
 
 
 
Urinary tract infection 
 
 
 
Data are number (%). 
 
 

 
62