The Multi-Strategy Intervention to Enhance Quality of Anesthesia Care for Obese Patients: A Factorial Randomized Controlled Trial
Phase: NA
Conditions: Obesity, Bariatric Surgery Candidate, Tracheal Intubation Morbidity, Nausea and Vomiting, Postoperative, Hyperglycemia Drug Induced, Gastric Reflux
Sponsor: YingHsuanTai

1 
 
Official Title: 
The Multi-Strategy Intervention to Enhance Quality of Anesthesia Care for 
Obese Patients: A Factorial Randomized Controlled Trial 
Protocol Number: N202101039 
Date of the Document: 2020/12/05 
Principal Investigator: Ying-Hsuan Tai 
Affiliation: Department of Anesthesiology, Shuang Ho Hospital, Taipei 
Medical University, Taiwan 
  
 

2 
 
Background 
 
Obesity is a significant global epidemic, affecting approximately 650 million people 
worldwide in 2016.1 The prevalence of obesity has risen in the recent decades and exerted a 
heavy burden on healthcare system.2 Obesity substantially increases the risk of metabolic, 
cardiovascular, respiratory diseases, and several types of cancers, which impairs quality of life 
and shortens life expectancy.2  
Patients with obesity represent a challenge in perioperative and anesthetic management 
because of the altered anatomy and physiology associated with obesity. The obesity-related 
pathology in the setting of surgery includes gastroesophageal reflux3, poor visualization of 
vocal cord during tracheal intubation4, abnormal cardiovascular hemodynamics5, and 
postoperative nausea and vomiting (PONV)6, which contribute to higher perioperative risk and 
negatively affect patient’s recovery after surgery.7 (Figure 1) 
 
 
Figure 1: Anesthesia challenges for obese patients 
 
Gastroesophageal reflux and aspiration risk during positive ventilation 
Obesity is a risk factor for the development of gastroesophageal reflux disease.3 Several 
physiologic abnormalities associated with obesity prolong esophageal acid exposure, including 
lower esophageal sphincter abnormalities, susceptibility to the development of hiatal hernia, 
higher intragastric pressure and gastric capacity.3,8 Study has showed that obese people are 
prone to a hypotensive lower esophageal sphincter, defined as a basal pressure < 10 mmHg or 
13.6 cmH2O.8 In addition, transient relaxations of the lower esophageal sphincter are more 
common in obese patients.9 Study has also reported that almost half obese patients are comorbid 

3 
 
with hiatal hernia, which is clearly a predisposing factor for gastroesophageal reflux.10 Obese 
patients were also found to have increased intra-abdominal pressure, resulted from the 
gravitational force of the adipose tissue on the abdominal cavity.11 These pathologies may 
contribute to the risk of pulmonary aspiration when protective airway reflexes are depressed in 
general anesthesia.12  
Aspiration is the most significant etiology of airway complications and anesthesia death.13 
To prevent pulmonary aspiration during anesthesia, it is important to determine the level of 
inspiratory pressure minimizing gastric insufflation during pulmonary ventilation. A 
randomized trial has showed that inspiratory pressure of 15 cmH2O can decrease the occurrence 
of gastric insufflation during induction of anesthesia for non-paralyzed non-obese patients.14 
Although morbid obesity predisposes to the development of pulmonary aspiration during 
anesthesia13, there is still little evidence regarding the safe inspiratory pressure to prevent the 
occurrence of gastric insufflation during positive ventilation. 
 
Poor glottis visualization during tracheal intubation 
Obese patients present a unique challenge to airway management for anesthesia providers. 
Obesity-related obstructive sleep apnea and reduced neck movement contribute to a higher risk 
of difficulty intubation.15 Previous study has showed that video laryngoscopy provides better 
glottis visualization and reduces the time to successful intubation with similar intubation 
success rates compared to Macintosh direct laryngoscopy in morbidly obese patients.4,16 
However, video or direct laryngoscopy may be inappropriate for patients with limited mouth 
opening, loose teeth or dental prosthesis. It remains unclear for the utility of other video 
intubating devices used in obese population.  
Video intubating stylet is a useful tool for the placement of tracheal tubes. For tracheal 
intubation, a tracheal tube is preloaded over the video stylet, which is passed through the oral 
cavity to visualize the epiglottis and guided to glottic opening via a monitor.17 Video intubating 
stylet has been reported to be more effective and safer than Macintosh laryngoscope in the 
placement of double‐lumen tubes in thoracic surgery.18-20 Video intubating stylet has also been 
demonstrated useful in tracheal intubation for cervical spine-immobilized patients.21,22 
Nevertheless, previous work in obese patients was limited. 
 
Hemodynamic instability in bariatric surgery 
Obesity is commonly associated with a variety of neurohormonal, metabolic, and 
hemodynamic alterations that potentially change cardiac structure and functions.5 The 
dysregulations of hemodynamics may contribute to left and right ventricular dysfunction and 
even predispose to heart failure in severely obese patients.5 The cardiovascular abnormality 
may precipitate the occurrence of hemodynamic instability when obese patients with 
preoperative fasting experience pneumoperitoneum and reverse Trendelenburg positioning in 
bariatric surgery.7,23  
Obese patients have a higher cardiovascular risk after noncardiac surgery due to their 

4 
 
comorbid cardiovascular and metabolic diseases, including cardiac arrest and myocardial 
infarction.24 In addition, obesity negatively affects respiratory system and significantly alters 
lung function, which is characterized by a reduction in vital capacity and total lung capacity 
with a restrictive pattern.25 Study has showed that patients undergoing bariatric surgery have an 
increased risk of major respiratory complications.26 However, there are still few effective 
strategies in reducing postoperative complications after bariatric surgery. 
There are commercial devices for measuring cardiac output (CO) through minimal invasive 
approaches.27 The major principles and techniques of CO measurement include the Fick 
principle, arterial waveform analysis techniques, and the Doppler principle.28 ProAQT® device 
(Pulsion Medical Systems, Munich, Germany) is a modular platform on the basis of PiCCO™ 
pulse contour algorithm.28 ProAQT® allows the continuous evaluation and real-time 
visualization for hemodynamic status and supports goal-directed hemodynamic therapy (GDHT) 
in surgical patients. Meta-analysis of randomized trials suggests that the application of 
perioperative GDHT may facilitate recovery in patients following major abdominal surgery.29 
Regardless of the broad use of minimally invasive CO monitoring in anesthesia and critical 
care, the evidence for its benefits in obese patients is limited. It is unclear whether application 
of minimally invasive CO monitoring in guiding intraoperative administration of fluid, inotrope, 
and vasopressor improves patient outcomes after bariatric surgery. Strong clinical data support 
the use of minimally invasive CO monitors in patients undergoing abdominal surgery although 
these studies generally did not focus on obese patients.29 
 
Postoperative nausea and vomiting in obese patients 
PONV is a common adverse event among patients following bariatric procedures with a 
reported rate of 18% to 82%.30-32 PONV may increase the risk of wound dehiscence and prolong 
the length of stay in the post-anesthesia recovery room.33 Besides, PONV represents one of the 
frequent reasons for unanticipated re-hospitalization after bariatric surgery.34 In particular, 
morbidly obese people have a greater risk of PONV compared to those with body mass index 
< 35 kg·m-2 after bariatric surgery.35  
Current practice guidelines recommend the use of single or multiple types of antiemetics as 
PONV prophylaxis according to Apfel risk prediction score.36 However, these guidelines are 
primarily based on evidence derived from general population.7,23 There are few studies 
investigating the clinical strategy to mitigate PONV risk pertinent to obese patients. In addition, 
it remains unclear whether intravenous dexamethasone, a common prophylactic agent for 
PONV, is associated with potential adverse effects in obese people, such as hyperglycemic 
response, wound infection and delayed healing.7,23,37 Since obese patients are susceptible to the 
injury of hyperglycemia and associated wound infection38,39, it is of great importance to 
elucidate the risk and benefits of dexamethasone in the prevention of PONV. 
 

5 
 
Research Objective 
The main objective of this study is to investigate the optimal anesthesia for obese patients 
undergoing bariatric surgery in the strategies of positive pulmonary ventilation, tracheal 
intubation technique, hemodynamic monitoring, and PONV prophylaxis, as the followed: 
1. To evaluate the effectiveness and adverse effect of intravenous dexamethasone for PONV 
prophylaxis 
2. To determine the safe inspiratory pressure to prevent the occurrence of gastric insufflation 
during facemask ventilation using point-of-care ultrasonography of antrum 
3. To compare the effectiveness and safety between video intubating stylet and video 
laryngoscope in the placement of tracheal tubes 
4. To apply minimally invasive CO monitors in guiding goal-directed hemodynamic therapy 
and assess its impact on major complications and postoperative recovery 
 
Novelty and Implication 
1. Considering the growing prevalence of obesity and its potential impact on perioperative 
care, the optimal anesthesia strategy for obese patients should be further explored. 
2. Investigation of perioperative use of dexamethasone will enrich the current literature of 
PONV prophylaxis for obese patients. 
3. The study will determine the airway pressure threshold to prompt gastric insufflation during 
positive ventilation, providing a practical guidance in the airway management of anesthesia 
and cardiopulmonary resuscitation. 
4. This study will evaluate the application of video intubating stylet in the tracheal intubation 
of obese patients, offering another evidence-based intubation technique. 
5. This research will also provide valuable evidence regarding the treatment effect of 
intraoperative GDHT in obese patients, which may offer an important implication for 
precision hemodynamic management in the obese people. 
6. The study will provide important evidence for an Enhanced Recovery After Surgery (ERAS) 
protocol of bariatric surgery. 

6 
 
Materials and Methods 
We will conduct a factorial parallel randomized controlled trial using permuted block 
randomization and stratified randomization and conforming to the CONSORT Statement to 
investigate multiple clinical outcomes in obese patients undergoing laparoscopic sleeve 
gastrectomy (LSG) at Shuang Ho Hospital, Taipei Medical University, New Taipei City, 
Taiwan.40-42 Four randomizations will be conducted, including intravenous dexamethasone for 
PONV, various inspiratory pressure of mask ventilation, three tracheal intubation techniques, 
and goal-directed hemodynamic therapy using minimally invasive cardiac output monitoring. 
(Figure 2) A computer-generated list of randomizations will be applied for these group 
allocations. Each patient will be randomly assigned a specific study number and group in four 
randomizations, and these assignments will be then enclosed in envelopes and sealed. 
Inclusion criteria are patients aged ≥ 20 years with body mass index ≥ 30 kg·m-2 undergoing 
LSG at Shuang Ho Hospital. Exclusion criteria are as the following: 
 
1. Pregnant or lactating women 
2. Severe cardiopulmonary distress, including left ventricular ejection fraction < 40%, double 
or triple vessel disease, New York Heart Association functional classification ≥ 3, peripheral 
oxygen saturation by pulse oximetry (SpO2) < 90% in room air, and moderate to severe 
pulmonary hypertension. 
3. Previous esophageal, gastric, or duodenal surgery. 
4. Previous head and neck surgery or radiation therapy 
5. Previous cervical spine injury 
6. High-degree cardiac arrythmia, including atrial fibrillation and severe atrioventricular block 
7. Use of cardiac pacemaker or automated implantable cardioverter defibrillator 
8. Chronic kidney disease, stage ≥ 4 (estimated glomerular filtration rate < 30 ml·min-1) 
9. Planned transferal to intensive care unit for mechanical ventilation 
10. QTc prolongation determined by a standard 12-lead electrocardiogram 
11. Patients using emetogenic or antiemetic drugs within 24 hours before surgery 
12. Patients requiring rapid sequence induction or fiberoptic awake intubation 
13. Patient refusal to participate 
 
The flow diagram for research conduction is shown in Figure 2. Before surgery, all 
paticipants will be evaluated for morphometric and airway characteristics regarding difficult 
airway, including interincisor distance (< 3 cm or not)43, mentohyoid distance (< 4 cm or not), 
thyromental distance (< 6.5 cm or not)44, neck movement (< 80 degrees or not)45, neck 
circumference measured at the thyroid cartilage (> 43 cm or not)46, modified Mallampati score47, 
upper lip bite test48, and mandibular prognathism test49.  
 

7 
 
 
 
Figure 2: Flow diagram for research conduction 
 

8 
 
Substudy 1: An evaluation of the effect of intravenous dexamethasone on postoperative 
nausea and vomiting: a double-blind, placebo-controlled trial 
 
At the operating room, patients will be initially placed in a ramped position and then moved 
into a reverse Trendelenburg position to achieve a 30-degree incline of the thorax before 
preoxygenation. Each patient will be randomly assigned 1:1, stratified by presence of diabetes 
mellitus, to one of each of the following two interventions: dexamethasone (8 mg intravenously) 
and placebo (0.9% sodium chloride). The envelopes of group allocation will be opened just 
before the induction of general anesthesia.  
After preoxygenation using facemask with pure oxygen 10 l·min-1 until end-tidal fractional 
oxygen concentration in the expired air (EtO2) ≥ 80%, general anesthesia will be induced with 
propofol 1.5–2.0 mg·kg-1 ideal body weight and fentanyl 1–2 μg·kg-1 total body weight. 
Tracheal intubation will be facilitated with rocuronium 0.8–1.0 mg·kg-1 ideal body weight. 
After induction, a radial artery catheterization will be performed for continuous monitoring of 
arterial pressure and measurement of serum glucose. In the designated patients, 8 mg of 
dexamethasone or placebo will be given intravenously within 10 minutes after the induction of 
anesthesia. Anesthesia will be maintained with 2–3 vol% sevoflurane and 60% oxygen in 
nitrogen, whereas the fraction of inspired oxygen (FiO2) 0.8–1.0 will be used during 
pneumoperitoneum to ensure oxygen saturation higher than 92%. If the value of surgical pleth 
index (CARESCAPE B650 Monitor, GE Healthcare, Chicago, IL, USA) is more than 50 or 
heart rate or blood pressure increases by more than 20% from baseline values during surgery, 
an intravenous bolus of fentanyl 25 or 50 μg will be given. Besides, the concentration of 
sevoflurane can be adjusted as clinically appropriate.  
After surgery, all patients will receive supplemental oxygen, and pain will be relieved with 
ketorolac 15 to 30 mg. The need for postoperative opioids will be at the discretion of the 
anesthesiologist, and the dose will be adjusted according to clinical needs. Patients who request 
rescue antiemetic therapy or who have an emetic episode will be given droperidol 1.25 mg. If 
symptoms persist, metoclopramide 10 mg will be administered. 
Primary outcome is the incidence of PONV, which includes any nausea, emetic episodes 
(retching or vomiting), or both during the first 24 postoperative hour. At the 2nd and 24th 
postoperative hours, trained investigators who are blinded to the group allocation will record 
the number of emetic episodes, the time each one occurs, and self-reported worst nausea episode 
during the preceding duration on an 11-point scale (0: no nausea and 10: the most severe nausea). 
Secondary outcomes are serum glucose levels of post-induction, end of surgery, and the 24th 
postoperative hour. We will also evaluate risk factors for PONV according to Apfel risk 
prediction model, including age, sex, smoking status, body mass index, history of PONV or 
motion sickness, duration of anesthesia, and the use of intraoperative and postoperative 
intravenous opioids. Research staff blinded to group allocation will determine and document 
any episodes of surgical site infection and delayed wound healing within 30 days after surgery. 

9 
 
Substudy 2: An investigation of the threshold inspiratory pressure for gastric insufflation 
using ultrasonography of gastric antrum: a double-blind randomized controlled trial 
 
We will measure the antral area of each participant lying in supine position on the operating 
table, using a portable ultrasound device (LOGIQ™, GE Healthcare, Chicago, IL, USA, fitted 
with a 1.5 to 5.0 MHz convex transducer). We will determine the longitudinal (D1) and 
anteroposterior (D2) diameters of the cross-section of antrum in the sagittal plane passing 
through abdominal aorta.50 To obtain a standardized scanning level, the aorta and left lobe of 
the liver are employed as internal landmarks. The relaxed diameters of the antrum are measured 
between antral contractions. The area of gastric antrum is calculated using the formula: antral 
area = D1×D2×π / 4. In addition, the gastric fluid volume will be calculated with a validated 
model based on the cross-sectional area of the gastric antrum, described previously.51 
Patients will be randomized into one of the four groups defined by the applied inspiratory 
pressure (10, 15, 20, or 25 cmH2O) using blocked randomization. During induction of 
anesthesia, normal saline 20 ml will be immediately infused after the administration of 
rocuronium 0.8–1.0 mg·kg-1 ideal body weight.52 After loss of eyelash reflex, a Guedel 
oropharyngeal airway (Biçakcilar, Istanbul, Turkey) will be placed into the oral cavity to assure 
adequate mouth opening. A facemask will be applied firmly to the patient's face to ensure an 
adequate seal. A two-handed head-tilt jaw-thrust maneuver will be performed to establish an 
open airway. Once apnea determined by end-tidal capnography occurs, a mechanical ventilation 
with the assigned peak inspiratory pressure will be initiated. The pressure-controlled mode will 
be used with an inspiratory-to-expiratory ratio of 1:2 and no positive end-expiratory pressure 
(PEEP), at a frequency of 15 breath·min-1 and with 100% oxygen, by the ventilator (Carestation 
620, Datex-Ohmeda, Inc., Madison, WI, USA).53  
Real-time ultrasonography of the antrum will be performed by the same anesthesiologist who 
performs the preoperative ultrasonography. Another anesthetist will perform continuous 
auscultation over epigastric area. Researchers performing ultrasonography and auscultation are 
blinded one to another regarding the detection of gastric insufflation and the inspiratory 
pressure of pressure-controlled ventilation. The ultrasonography screen will be concealed from 
the anesthetist performing the auscultation. Facemask ventilation will be continued for 2 min. 
The trachea will be thereafter intubated, and the antral area will be measured again.  
Primary outcome is the episode of gastric insufflation. The ultrasonographic diagnosis of 
gastric insufflation is defined as the presence of an acoustic shadow phenomenon and/or a 
comet-tail artifact into the antrum.14 A typical whoosh sound with gurgling while auscultating 
over the epigastrium defines the diagnosis of gastric insufflation by auscultation method.54 
Secondary outcomes are specific respiratory parameters of anesthesia monitoring, recorded at 
time 30, 60, 90, and 120 s during facemask ventilation and after tracheal intubation, including 
SpO2, EtO2, the end-tidal carbon dioxide concentration in the expired air (EtCO2), minute leak 
volume (ml·min-1), measured peak airway pressure, and tidal volume.  
 

10 
 
Substudy 3: A comparison of video intubation stylet and video laryngoscope in tracheal 
intubation: an open-label randomized controlled trial 
 
Eligible patients will be randomly allocated 1:1:1, stratified by body mass index > 50 kg·m-
2, to group 1 (video intubating stylet), group 2 (video laryngoscopy), or group 3 (direct 
laryngoscopy). Tracheal intubation will be performed by experienced attending 
anesthesiologists who have performed at least 100 cases each with Trachway® video intubating 
stylet, GlideScope® video laryngoscopy, and Macintosh direct laryngoscopy. The 
anesthesiologist performing tracheal intubation is blinded to all preoperative evaluations. 
In group 1, a tracheal tube (ConvaTec, Berkshire, England, UK) in appropriate sizes is 
preloaded over the Trachway® video intubating stylet (TVI-4050, Markstein Sichtec Medical 
Corp, Taichung, Taiwan), which is introduced into oral cavity to visualize the epiglottis and 
guided to glottis via a monitor after full neuromuscular blockade is achieved. In group 2, a 
tracheal tube is preloaded over a GlideRite® stylet, which is specifically designed to work with 
GlideScope® video laryngoscope (Verathon Medical, Bothell, WA, USA). GlideScope® blade 
size 3 (GS-3) or 4 (GS-4) is used in all patients. In group 3, tracheal tubes are prepared with a 
hockey stick-shaped stylet, and direct laryngoscopy is performed using a size‐3 or -4 Macintosh 
blade (Rüsch Inc., Duluth, GA, USA). In all patients, backward, upward, and rightward pressure 
on the larynx and Sellick maneuvers are allowable to obtain the best glottic view.55,56 If the 
initial intubation attempt fails or is terminated for desaturation (defined as SpO2 < 92%) or need 
to change the patient’s position, the intubation device will be removed, and manual bag mask 
ventilation will be performed. Intubation failure is defined as more than three intubation 
attempts or need to change intubation devices. Any intubation rescue techniques will be used at 
the discretion of the staff anesthesiologist. 
Primary outcome is the best glottis visualization, graded according to Cormack and Lehane's 
classification with external laryngeal pressure applied.57 Glottic views graded as III or IV are 
regarded as difficult. Secondary outcomes are number of intubation attempts, the percentage of 
glottic opening (POGO) score, time to intubation, lowest SpO2 during intubation, and ease of 
intubation. Each video stylet or laryngoscope blade insertion is defined as an intubation attempt. 
Minor adjustments of patient’s position or tube stylet are not considered separate attempts. The 
POGO score is defined by the best glottis visualization (0%, 25%, 50%, 75%, or 100%).58 Time 
to intubation is defined as the interval between intubating stylet or laryngoscope insertion into 
oral cavity and EtCO2 detected. Ease of intubation is a subjective assessment of 
anesthesiologists, rated as (1) very easy, (2) easy, (3) moderate, (4) difficult, and (5) 
impossible.59 Safety outcomes are upper airway injury (bleeding, abrasion or laceration), dental 
injury (bleeding, trauma, fracture), respiratory complications (laryngospasm, bronchospasm, 
aspiration), cough (mild, moderate, severe), sore throat (mild, moderate, severe), and 
hoarseness (noticed by the patient only, apparent to an observer). Research staff blinded to 
group allocation will evaluate the complications at the 2nd and 24th postoperative hours.

11 
 
Substudy 4: An investigation of the putative benefits of goal-directed hemodynamic 
therapy targeting cardiac index in obese patients undergoing laparoscopic sleeve 
gastrectomy: an open-label randomized controlled trial 
 
At the operation room, we will apply the Masimo Radical 7 pulse oximetry (Masimo Corp., 
Irvine, CA, USA) to the fingers of all enrolled patients to measure perfusion index and SpO2 
throughout the surgery. After the placement of a tracheal tube, patients will receive ventilator 
support with the tidal volume 6–8 ml·kg-1 ideal body weight, a respiratory rate of 10–15 min-1 
and PEEP 5 cmH2O applied by the ventilator.60 The FiO2 will be set at 0.3–0.7 to maintain SpO2 
≥ 98% throughout the surgery. Each patient will be randomly allocated to one of each of the 
following two groups: goal-directed hemodynamic therapy and control. 
In both groups, intraoperative maintenance rate of crystalloid fluids is 3 ml·kg-1·hr-1 ideal 
body weight. ProAQT®-derived hemodynamic data and peripheral perfusion index and SpO2 
will be acquired at the following time points: 5 min after induction of anesthesia, 5 min after 
start of pneumoperitoneum and head-up tilting, 5 min after end of pneumoperitoneum, cessation 
of volatile anesthetics, and 5 min after extubation. Subjects of the GDHT group will be managed 
according to the ERAS algorithm utilizing ProAQT® parameters to maintain the cardiac index 
≥ 2.5 l·min-1·m-2.61 In brief, if cardiac index < 2.5 l·min-1·m-2, a bolus of 150 ml of crystalloid 
fluid will be given until the stroke volume variation is < 10%. If cardiac index < 2.5 l·min-1·m-
2 despite the stroke volume variation of ≥ 10% following fluid challenge, continuous 
intravenous infusion of dopamine 5–10 μg·kg-1·min-1 will be administered. If mean arterial 
pressure is < 70 mmHg despite cardiac index ≥ 2.5 l·min-1·m-2, intravenous infusion of 
norepinephrine 2–10 μg·min-1 will be used. (Figure 3) 
Subjects allocated to the control group are hemodynamically managed as per 
anesthesiologist preference. Typically, isolated hypotension (20% decrease in mean arterial 
pressure below baseline or < 60 mmHg) is treated by single or consecutive boluses of 
norepinephrine 5 or 10 μg. If hypotension persists, repeat boluses of ephedrine 4 mg will be 
administered until mean arterial pressure is above 60 mmHg. If hypotension is accompanied by 
signs of hypovolemia (urine output < 0.5 ml·kg-1·hr-1 and/or an increase in heart rate > 20% 
above baseline), crystalloid or colloid fluids will be given until urine output and/or heart rate 
are normalized. If hypotension persists despite volume challenge, norepinephrine will be used.  
In both groups, the fluid, inotrope, and vasopressor responsiveness, ProAQT® parameters 
(cardiac index, stroke volume variation, systemic vascular resistance, and mean arterial 
pressure), and the signals of pulse oximetry (perfusion index and SpO2) will be evaluated and 
recorded for each 15-min interval throughout the surgery. In control group, the ProAQT® 
monitoring will be concealed from the anesthetist in charge. Artifact-free signals are considered 
valid for statistical analysis. At the end of surgery, all participants will receive a manual 
recruitment maneuver of 30 to 40 cmH2O for 10 s three times. In all patients, cessation of 
volatile anesthetics will be timed to facilitate early awakening after wound closure. All patients 

12 
 
will be decurarized from rocuronium-induced neuromuscular blockade with sugammadex 
dosed at 2 mg·kg-1 ideal body weight + 40%.62 
 
 
 
Figure 3: Goal-directed hemodynamic algorithm to guide intraoperative fluid therapy 
and the use of inotrope and vasopressor 
 
Primary outcome is a composite of major complications according to the European 
Perioperative Clinical Outcome definitions within 30 days after surgery, including myocardial 
ischemia or infarction, arrhythmia, acute kidney injury, gastrointestinal bleeding, anastomotic 
breakdown, surgical site infection, and hospital-acquired pneumonia.63 Secondary outcomes 
comprise longitudinal changes of ProAQT® parameters (cardiac index, stroke volume variation, 
systemic vascular resistance, and mean arterial pressure) and signals of pulse oximetry 
(peripheral perfusion index and SpO2), relative change of arterial partial pressure of oxygen 
(PaO2)/FiO2, PaO2/FiO2, serum glucose, base excess values after induction of anesthesia and at 
the end of surgery, clinically relevant hypotensive episodes (decrease in mean arterial pressure 
> 20% for more than 15 min requiring vasopressors), need for intensive care, time to ambulation, 
time to first oral intake, and length of hospital stay. Episodes of major complications will be 
evaluated by research staff blinded to group assignment. 
 

13 
 
Sample Size Estimation 
According to prior study64, at least 80 patients in each group of GDHT and control are needed 
to detect a significant difference, accepting a type I error of 5% and type II error of 10% with 
anticipated incidence of postoperative major complications 30% in GDHT group and 55% in 
control group in Substudy 4.65 To allocate 60 subjects to each group of video intubating stylet, 
video laryngoscopy, and direct laryngoscopy in Substudy 3, a total of 180 subjects are needed 
for the factorial trial. There are about 120 obese people undergoing LSG at our hospital per year. 
Considering the patient selection criteria and possible patient refusal, an estimated sample of 
90 patients will be recruited per year in this trial. Therefore, it will take about 2 years for patient 
recruitment. 
 
Statistical Analysis 
Baseline patient characteristics and outcome variables will be compared between two groups 
using chi-square tests or Fisher’s exact tests for categorical variables and either t tests or 
Wilcoxon rank sum tests for continuous variables, as appropriate. For three and four group 
comparisons, chi-square tests or Fisher’s exact tests will be used for categorical variables and 
either one-way ANOVA or Kruskal-Wallis rank test for continuous variables, as appropriate. 
Post hoc pairwise comparisons will be performed using the Bonferroni correction. For 
longitudinal data, generalized linear mixed models or generalized estimating equations models 
will be used to analyze the association between exposure variables and outcomes of interest. 
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. A 
two-sided significance level of 0.05 will be 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). 
 
 

14 
 
References 
1. World 
Health 
Organization. 
Fact 
sheets: 
Obesity 
and 
overweight. 
https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight (accessed on 
December 5, 2020). 
2. Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 
2019;15:288-98. 
3. Chang P, Friedenberg F. Obesity and GERD. Gastroenterol Clin North Am. 2014;43:161-
73. 
4. Ruetzler K, Rivas E, Cohen B, Mosteller L, Martin A, Keebler A, Maheshwari K, Steckner 
K, Wang M, Praveen C, Khanna S, Makarova N, Sessler DI, Turan A. McGrath video 
laryngoscope versus Macintosh direct laryngoscopy for intubation of morbidly obese 
patients: a randomized trial. Anesth Analg. 2020;131:586-93. 
5. Alpert MA, Omran J, Bostick BP. Effects of obesity on cardiovascular hemodynamics, 
cardiac morphology, and ventricular function. Curr Obes Rep. 2016;5:424-34. 
6. Ziemann-Gimmel P, Schumann R, English W, Morton J, Wadhwa A. Preventing nausea and 
vomiting after bariatric surgery: is the Apfel risk prediction score enough to guide 
prophylaxis? Obes Surg. 2020;30:4138-40. 
7. Thorell A, MacCormick AD, Awad S, Reynolds N, Roulin D, Demartines N, Vignaud M, 
Alvarez A, Singh PM, Lobo DN. Guidelines for perioperative care in bariatric surgery: 
Enhanced Recovery After Surgery (ERAS) Society Recommendations. World J Surg. 
2016;40:2065-83. 
8. Mora F, Cassinello N, Mora M, Bosca M, Minguez M, Ortega J. Esophageal abnormalities 
in morbidly obese adult patients. Surg Obes Relat Dis. 2016;12:622-8. 
9. Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased 
transient lower esophageal sphincter relaxation. Gastroenterology. 2007;132:883-9. 
10. Suter M, Dorta G, Giusti V, Calmes JM. Gastro-esophageal reflux and esophageal motility 
disorders in morbidly obese patients. Obes Surg. 2004;14:959-66. 
11. Varela JE, Hinojosa M, Nguyen N. Correlations between intra-abdominal pressure and 
obesity-related co-morbidities. Surg Obes Relat Dis. 2009;5:524-8. 
12. Smith G, Ng A. Gastric reflux and pulmonary aspiration in anaesthesia. Minerva Anestesiol. 
2003;69:402-6. 
13. Robinson M, Davidson A. Aspiration under anaesthesia: risk assessment and decision-
making. BJA Education. 2014;14:171-5 
14. Bouvet L, Albert ML, Augris C, Boselli E, Ecochard R, Rabilloud M, Chassard D, 
Allaouchiche B. Real-time detection of gastric insufflation related to facemask pressure-
controlled ventilation using ultrasonography of the antrum and epigastric auscultation in 
nonparalyzed patients: a prospective, randomized, double-blind study. Anesthesiology. 
2014;120:326-34. 

15 
 
15. De Jong A, Molinari N, Pouzeratte Y, Verzilli D, Chanques G, Jung B, Futier E, Perrigault 
PF, Colson P, Capdevila X, Jaber S. Difficult intubation in obese patients: incidence, risk 
factors, and complications in the operating theatre and in intensive care units. Br J Anaesth. 
2015;114:297-306. 
16. Yumul R, Elvir-Lazo OL, White PF, Sloninsky A, Kaplan M, Kariger R, Naruse R, Parker 
N, Pham C, Zhang X, Wender RH. Comparison of three video laryngoscopy devices to 
direct laryngoscopy for intubating obese patients: a randomized controlled trial. J Clin 
Anesth. 2016;31:71-7. 
17. Ong J, Lee CL, Lai HY, Lee Y, Chen TY, Shyr MH. A new video intubating device: trachway 
intubating stylet. Anaesthesia. 2009;64:1145. 
18. Hsu HT, Chou SH, Chen CL, Tseng KY, Kuo YW, Chen MK, Cheng KI. Left endobronchial 
intubation with a double-lumen tube using direct laryngoscopy or the Trachway® video 
stylet. Anaesthesia. 2013;68:851-5. 
19. Chen PT, Ting CK, Lee MY, Cheng HW, Chan KH, Chang WK. A randomised trial 
comparing real-time double-lumen endobronchial tube placement with the Disposcope® 
with conventional blind placement. Anaesthesia. 2017;72:1097-106. 
20. Yang M, Kim JA, Ahn HJ, Choi JW, Kim DK, Cho EA. Double-lumen tube tracheal 
intubation using a rigid video-stylet: a randomized controlled comparison with the 
Macintosh laryngoscope. Br J Anaesth. 2013;111:990-5. 
21. Seo H, Kim E, Son JD, Ji S, Min SW, Park HP. A prospective randomised study of a rigid 
video-stylet vs. conventional lightwand intubation in cervical spine-immobilised patients. 
Anaesthesia. 2016;71:1341-6. 
22. Yoon HK, Lee HC, Park JB, Oh H, Park HP. McGrath MAC video laryngoscope versus 
Optiscope video stylet for tracheal intubation in patients with manual inline cervical 
stabilization: a randomized trial. Anesth Analg. 2020;130:870-8. 
23. Nguyen NT, Wolfe BM. The physiologic effects of pneumoperitoneum in the morbidly 
obese. Ann Surg. 2005;241:219-26. 
24. Tsai A, Schumann R. Morbid obesity and perioperative complications. Curr Opin 
Anaesthesiol. 2016;29:103-8. 
25. Pouwels S, Smeenk FW, Manschot L, Lascaris B, Nienhuijs S, Bouwman RA, Buise MP. 
Perioperative respiratory care in obese patients undergoing bariatric surgery: implications 
for clinical practice. Respir Med. 2016;117:73-80. 
26. Avriel A, Warner E, Avinoach E, Avnon LS, Shteinberg M, Shteinberg D, Heimer D, Yona 
S, Maimon N. Major respiratory adverse events after laparascopic gastric banding surgery 
for morbid obesity. Respir Med. 2012;106:1192-8. 
27. Drummond KE, Murphy E. Minimally invasive cardiac output monitors. BJA Education. 
2012;12:5-10. 
28. Kobe J, Mishra N, Arya VK, Al-Moustadi W, Nates W, Kumar B. Cardiac output monitoring: 

16 
 
technology and choice. Ann Card Anaesth. 2019;22:6-17. 
29. Sun Y, Chai F, Pan C, Romeiser JL, Gan TJ. Effect of perioperative goal-directed 
hemodynamic therapy on postoperative recovery following major abdominal surgery: a 
systematic review and meta-analysis of randomized controlled trials. Crit Care. 
2017;21:141. 
30. Badaoui R, Alami Chentoufi Y, Hchikat A, Rebibo L, Popov I, Dhahri A, Antoun G, 
Regimbeau JM, Lorne E, Dupont H. Outpatient laparoscopic sleeve gastrectomy: first 100 
cases. J Clin Anesth. 2016;34:85-90. 
31. Ziemann-Gimmel P, Goldfarb AA, Koppman J, Marema RT. Opioid-free total intravenous 
anaesthesia reduces postoperative nausea and vomiting in bariatric surgery beyond triple 
prophylaxis. Br J Anaesth. 2014;112:906-11.  
32. Halliday TA, Sundqvist J, Hultin M, Walldén J. Post-operative nausea and vomiting in 
bariatric surgery patients: an observational study. Acta Anaesthesiol Scand. 2017;61:471-9. 
33. Weingarten TN, Hawkins NM, Beam WB, Brandt HA, Koepp DJ, Kellogg TA, Sprung J. 
Factors associated with prolonged anesthesia recovery following laparoscopic bariatric 
surgery: a retrospective analysis. Obes Surg. 2015;25:1024-30. 
34. Berger ER, Huffman KM, Fraker T, Petrick AT, Brethauer SA, Hall BL, Ko CY, Morton JM. 
Prevalence and risk factors for bariatric surgery readmissions: findings from 130,007 
admissions in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement 
Program. Ann Surg. 2018;267:122-31. 
35. Groene P, Eisenlohr J, Zeuzem C, Dudok S, Karcz K, Hofmann-Kiefer K. Postoperative 
nausea and vomiting in bariatric surgery in comparison to non-bariatric gastric surgery. 
Wideochir Inne Tech Maloinwazyjne. 2019;14:90-5. 
36. Nathan N. Management of postoperative nausea and vomiting: the 4th consensus guidelines. 
Anesth Analg. 2020;131:410. 
37. Polderman JAW, Farhang-Razi V, van Dieren S, Kranke P, DeVries JH, Hollmann MW, 
Preckel B, Hermanides J. Adverse side-effects of dexamethasone in surgical patients: an 
abridged Cochrane systematic review. Anaesthesia. 2019;74:929-39. 
38. Eisenberg D, Bell RL. The impact of bariatric surgery on severely obese patients with 
diabetes. Diabetes Spectrum. 2003;16:240-5. 
39. Thelwall S, Harrington P, Sheridan E, Lamagni T. Impact of obesity on the risk of wound 
infection following surgery: results from a nationwide prospective multicentre cohort study 
in England. Clin Microbiol Infect. 2015;21:1008. 
40. Kernan WN, Viscoli CM, Makuch RW, Brass LM, Horwitz RI. Stratified randomization for 
clinical trials. J Clin Epidemiol. 1999;52:19-26. 
41. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated 
guidelines for reporting parallel group randomized trials. Ann Intern Med. 2010;152:726-
32.  

17 
 
42. Boutron I, Altman DG, Moher D, Schulz KF, Ravaud P; CONSORT NPT Group. 
CONSORT Statement for Randomized Trials of Nonpharmacologic Treatments: A 2017 
Update and a CONSORT Extension for Nonpharmacologic Trial Abstracts. Ann Intern Med. 
2017;167:40-7. 
43. Practice guidelines for management of the difficult airway: an updated report by the 
American Society of Anesthesiologists Task Force on Management of the Difficult Airway. 
Anesthesiology. 2003;98:1269-77. 
44. Shiga T, Wajima Z, Inoue T, Sakamoto A. Predicting difficult intubation in apparently 
normal patients: a meta-analysis of bedside screening test performance. Anesthesiology. 
2005;103:429-37. 
45. Wilson ME, Spiegelhalter D, Robertson JA, Lesser P. Predicting difficult intubation. Br J 
Anaesth 1988;61:211-6. 
46. Gonzalez H, Minville V, Delanoue K, et al. The importance of increased neck circumference 
to intubation difficulties in obese patients. Anesth Analg. 2008;106:1132-6. 
47. Samsoon GL, Young JR. Difficult tracheal intubation: a retrospective study. Anaesthesia. 
1987;42:487-90. 
48. Detsky ME, Jivraj N, Adhikari NK, Friedrich JO, Pinto R, et al. Will this patient be difficult 
to intubate?: the rational clinical examination systematic review. JAMA. 2019;321:493-503. 
49. Calder I, Calder J, Crockard HA. Difficult direct laryngoscopy in patients with cervical 
spine disease. Anaesthesia. 1995;50:756-63. 
50. Bouvet L, Miquel A, Chassard D, Boselli E, Allaouchiche B, Benhamou D. Could a single 
standardized ultrasonographic measurement of antral area be of interest for assessing gastric 
contents? a preliminary report. Eur J Anaesthesiol. 2009;26:1015-9. 
51. Kruisselbrink R, Arzola C, Jackson T, Okrainec A, Chan V, Perlas A. Ultrasound assessment 
of gastric volume in severely obese individuals: a validation study. Br J Anaesth. 
2017;118:77-82. 
52. Ishigaki S, Masui K, Kazama T. Saline flush after rocuronium bolus reduces onset time and 
prolongs duration of effect: a randomized clinical trial. Anesth Analg. 2016;122:706-11. 
53. Cajander P, Edmark L, Ahlstrand R, Magnuson A, de Leon A. Effect of positive end-
expiratory pressure on gastric insufflation during induction of anaesthesia when using 
pressure-controlled ventilation via a face mask: a randomised controlled trial. Eur J 
Anaesthesiol. 2019;36:625-32. 
54. Dawson J. Nasogastric tube incidents and the use of the 'whoosh test'. Crit Care. 
2007;11:419. 
55. Knill RL. Difficult laryngoscopy made easy with a "BURP". Can J Anaesth. 1993;40:279-
82.  
56. Sellick BA. Cricoid pressure to control regurgitation of stomach contents during induction 
of anaesthesia. Lancet. 1961;2:404-6. 

18 
 
57. Cormack RS, Lehane J. Difficult tracheal intubation in obstetrics. Anaesthesia. 
1984;39:1105-11. 
58. Biro P, Ruetzler K. The reflective intubation manoeuvre increases success rate in 
moderately difficult direct laryngoscopy: a prospective case-control study. Eur J 
Anaesthesiol. 2015;32:406-10. 
59. Ruetzler K, Guzzella SE, Tscholl DW, Restin T, Cribari M, Turan A, You J, Sessler DI, 
Seifert B, Gaszynski T, Ganter MT, Spahn DR. Blind intubation through self-pressurized, 
disposable supraglottic airway laryngeal intubation masks: an international, multicenter, 
prospective cohort study. Anesthesiology. 2017;127:307-16. 
60. De Jong A, Chanques G, Jaber S. Mechanical ventilation in obese ICU patients: from 
intubation to extubation. Crit Care. 2017;21:63. 
61. Feldheiser A, Conroy P, Bonomo T, Cox B, Garces TR, Spies C. Development and 
feasibility study of an algorithm for intraoperative goal-directed haemodynamic 
management in noncardiac surgery. J Int Med Res. 2012;40:1227-41. 
62. Van Lancker P, Dillemans B, Bogaert T, Mulier JP, De Kock M, Haspeslagh M. Ideal versus 
corrected body weight for dosage of sugammadex in morbidly obese patients. Anaesthesia. 
2011;66:721-5. 
63. Jammer I, Wickboldt N, Sander M, Smith A, Schultz MJ, Pelosi P, et al. Standards for 
definitions and use of outcome measures for clinical effectiveness research in perioperative 
medicine: European Perioperative Clinical Outcome (EPCO) definitions: a statement from 
the ESA-ESICM joint taskforce on perioperative outcome measures. Eur J Anaesthesiol. 
2015;32:88-105. 
64. Nicklas JY, Diener O, Leistenschneider M, Sellhorn C, Schön G, Winkler M, Daum G, 
Schwedhelm E, Schröder J, Fisch M, Schmalfeldt B, Izbicki JR, Bauer M, Coldewey SM, 
Reuter DA, Saugel B. Personalised haemodynamic management targeting baseline cardiac 
index in high-risk patients undergoing major abdominal surgery: a randomised single-centre 
clinical trial. Br J Anaesth. 2020;125:122-32. 
65. Rosner B. Fundamentals of Biostatistics. 7th ed. Boston, MA: Brooks/Cole; 2011.