Tugas: Journal Reading

O P I O I D - F R E E T O TA L I N T R AV E N O U S A N E S T H E S I A F O R T H Y R O I D A N D
PA R AT H Y R O I D S U R G E R Y: P R O T O C O L F O R A R A M D O M I Z E D , D O U B L E -
BLIND, CONTROLLED TRIAL
Dan wang1,2†, yu-qin long1,2†, yan sun1,2†, ya-juan zhu1,2,
xiao-mei feng3, hong liu4, fu-hai ji 1,2* and ke peng 1,2*

Rahmat Naufal (FAL)

PROGRAM PENDIDIKAN DOKTER SPESIALIS
ANESTESIOLOGI DAN TERAPI INTENSIF
FAKULTAS KEDOKTERAN UNIVERSITAS JENDERAL SOEDIRMAN
2023
 Opioid-free Total Intravenous Anesthesia For Thyroid
And Parathyroid Surgery: Protocol For A Randomized,
ANESTESI UNSOED

Double-blind, Controlled Trial

Dan Wang1,2†, Yu-qin Long1,2†, Yan Sun1,2†, Ya-juan Zhu1,2, Xiao-mei Feng3, Hong Liu4, Fu-hai Ji 1,2* and Ke Peng 1,2*
1Department of Anesthesiology, First Aliated Hospital of Soochow University, Suzhou, China, 2Institute of Anesthesiology,
Soochow University, Suzhou, China, 3Department of Anesthesiology, University of Utah Health, Salt Lake City, UT, United
States, 4Department of Anesthesiology and Pain Medicine, University of California, Sacramento, Sacramento, CA, United
States

Background: opioid-free anesthesia (OFA) may improve postoperative outcomes by reducing opioid-related adverse eects. This study aims to evaluate the eects of OFA on
postoperative nausea and vomiting (PONV), postoperative pain, and 30-day outcomes after thyroid and parathyroid surgery.

Methods: this two-center, randomized, double-blind, controlled trial will include 400 adult patients scheduled for thyroid and parathyroid surgery. Patients will be randomly assigned,
1:1 and stratified by sex and site, to an OFA group (esketamine, lidocaine, and dexmedetomidine) or a control group (opioid-based anesthesia with sufentanil). All patients will receive
propofol-based total intravenous anesthesia and PONV prophylaxis with dexamethasone and ondansetron. The primary outcome is the incidence of PONV (defined as experiencing any
event of nausea, retching, or vomiting) during the first 48 h postoperatively. The secondary outcomes include the severity of PONV, antiemetic rescue therapy, pain scores at rest and
while coughing, need for rescue analgesia, perioperative adverse eects related to anesthetics or analgesics (hypotension, bradycardia, hypertension, tachycardia, desaturation,
dizziness, headache, hallucination, and nightmare), time to extubation, length of post-anesthesia care unit stay, length of postoperative hospital stay, patient satisfaction, and a
composite of 30-day major adverse events (myocardial infarction, cardiac arrest, cerebrovascular accident, coma, acute renal failure, pulmonary embolism, sepsis, septic shock, deep
neck space infection, reintubation, reoperation, blood transfusion, failure to wean o ventilator, and death). Analyses will be performed in the modified intention-to-treat population.

Discussion: we hypothesize that our OFA regimen reduces PONV after thyroid and parathyroid surgery. We will also investigate whether OFA leads to improvements in postoperative
pain and major adverse events. Our results will oer evidence for optimizing anesthesia regimens in patients who undergo thyroid and parathyroid surgical procedures.

KEYWORDS
2 Opioid-free anesthesia, total intravenous anesthesia, postoperative nausea and Vomiting, postoperative outcomes, thyroid and parathyroid surgery
ANESTESI UNSOED
BACKGROUND

Opioid-free anesthesia (OFA) may improve postoperative

outcomes by reducing opioid-related adverse effects. This
study aims to evaluate the effects of OFA on postoperative
nausea and vomiting (PONV), postoperative pain, and 30-day
outcomes after thyroid and parathyroid surgery.

3
ANESTESI UNSOED METHODS
OFA group PRIMARY OUTCOME
• incidence of PONV (defined as experiencing any
(esketamine, lidocaine, event of nausea, retching, or vomiting
and dexmedetomidine)
)

400 OUTCO SECONDARY OUTCOME

patients ME • severity of PONV
control group • antiemetic rescue therapy
• pain scores at rest and while coughing
(opioid-based • need for rescue analgesia
• perioperative adverse eects related to anesthetics or analgesics (hypotension,
anesthesia with bradycardia, hypertension tachycardia, desaturation, dizziness, headache,
sufentanil). hallucination, and nightmare)
• time to extubation
• length of post-anesthesia care unit stay
• length of postoperative hospital stay
• patient satisfaction
• 30-day major adverse events (myocardial infarction, cardiac arrest, cerebrovascular
accident, coma, acute renal failure, pulmonary embolism, sepsis, septic shock, deep
neck space infection, reintubation, reoperation, blood transfusion, failure to wean o
ventilator, and death)

• This two-center, randomized, double-blind, controlled trial

• 400 adult patients scheduled for thyroid and parathyroid surgery
• randomly assigned, 1:1 and stratified by sex and site
4
• All patients will receive propofol-based total intravenous anesthesia and PONV prophylaxis
with dexamethasone and ondansetron.
PRESENTATION TITLE
DISCUSSION

Hypothesize
• OFA regimen reduces PONV after thyroid and parathyroid

surgery

• investigate whether OFA leads to improvements in

postoperative pain and major adverse events

Evidence for optimizing

anesthesia regimens in
patients who undergo
thyroid and parathyroid
5 surgical procedures
 DISCUSSION
PRESENTATION TITLE

• Postoperative nausea and vomiting (PONV) are common complications after anesthesia and
surgery
• Thyroid and parathyroid surgery are at high risk of PONV (incidence of 40–60%)
• PONV leads to discomfort and unsatisfaction of patients.
• Opioid-free anesthesia (OFA) is a multimodal anesthesia strategy using α-2 agonists,
Nmethyl-D-aspartate (NMDA) antagonists, and local anesthetics to replace opioids
• Some studies found that OFA was associated with reduced incidence and severity of PONV
and decreased postoperative opioid requirements
• Despite the application of prophylaxis, reducing PONV is still a major challenge in
anesthesia clinical practice

o Recent randomized studies questioned the benefits of OFA  OFA did not
improve PONV or pain outcomes but may even cause harms
o To date, the definitions of OFA vary significantly in the existing literature, and
6 the effects of OFA on postoperative outcomes are largely unknown.
RECENT STUDIES
STUDIES
PRESENTATION TITLE

LIMITED
A retrospective ch
art
of 515 patients un review
dergo
thyroid or parathy ing
BY
roid
surgery suggested
tha
postoperative opio t
prescription was re id No randomized cl
d
after the implemen uced assessed the use of inical trial has
OFA in thyr
parathyroid surger oid and
tatio
an opioid-free anal n of y
gesia
protocol
the study design

A survey study of
90 patients
showed that an op
ioid-free
postoperative anal
regimen was feasib gesic
le
patients reported sa and the
tisfaction
with pain control
the definition of op
ioid free (for
postoperative anal
gesia other than fo
anesthesia during
surgery),
r
lack of adequate co
ntrol

7
ANESTESI UNSOED THIS STUDY
Traditional
opioid-
based
anesthesia
the effects
of the OFA
regimen VS (OA)
regimen
with
sufentanil
and
propofol

compare
PONV after postoperative
Thyroid and pain and 30-
Parathyroid day major
surgery adverse
8 events
9
ANESTESI UNSOED
ANESTESI UNSOED

S T U D Y D E S I G N A N D S TAT U S

This is an investigator-initiated, two-center, double-blind, parallel-group,

randomized controlled trial with superiority design. This study will include a total of
400 adult patients undergoing thyroid and parathyroid surgery at two academic
medical centers
Pingjian
Shizi
g
Medical
Medical
Center
Center

In These two centres >2,000 thyroid and parathyroid procedures

10
are performed each year.
 STUDY FLOW DIAGRAM
PRESENTATION TITLE

11
E L I G I B I LT Y C R I T E R I A
ANESTESI UNSOED
Inclusion Exclution
criteria criteria
a goiter causing tracheal compression or dyspnea

Patients who are ≥18 Hyperthyroidism or hypothyroidism

years old with
American Society of obstructive sleep apnea syndrome

Anesthesiologists left ventricular ejection fraction <40%, second-degree

or greater atrioventricular block, sick sinus syndrome,
or severe bradycardia [heart rate (HR) < 50 beats/min]
(ASA) physical status serious liver or renal dysfunction (Child Pugh grade C
or need for renal replacement therapy)
I–III and scheduled
for thyroid and
epilepsy or seizures

parathyroid surgery chronic pain or preoperative use of sedatives and

analgesics

under general allergies to any medication in this study

anesthesia pregnancy or breastfeeding

12 Inability to communicate preoperatively

R A N D O M I Z AT I O N A N D B L I N D I N G
ANESTESI UNSOED

• Management will generate a randomization list using an online tool (https://www.

sealedenvelope.com/randomisation/)
• Allocation ratio of 1:1
• The allocation details will be concealed using sealed opaque envelopes which are
stored in a locked cabinet.
• independent research nurse to prepare the study medications in identical syringes with
the labels of medication number and patient number
• All study medications (esketamine, lidocaine, dexmedetomidine, sufentanil, and
normal saline placebo) are colorless and clear fluids
• Patients, anesthesiologists, surgeons, other healthcare providers, and investigators
responsible for data collection and outcome assessment will be blinded to the group
allocation until the completion of final analysis.

13
14
PRESENTATION TITLE
 STUDY INTERVENTION
ANESTESI UNSOED

15
 ANESTHETIC MANAGEMENT
PRESENTATION TITLE
• All patients will fast for 6–8 h and receive no premedication

• After entering the operating room, patients will receive a standard monitoring
• Electrocardiography
• Non-invasive cuff blood pressure
• Pulse oximetry (SpO2)

Intra
Anesthetic
Operative
Depth
Analgesia
Bispectral index Surgical pleth
(BIS, Aspect index (SPI, GE
Medical Systems, Healthcare,
16
Newton, MA) Helsinki, Finland).
 ANESTHETIC MANAGEMENT
PRESENTATION TITLE

perioperative
Aldrete score
• Endotracheally intubated with Dexmedeto Profilaxis PONV ≥9  Move
OFA intravenous cisatracurium 0.2 mg/kg. midine from PACU
• infusion and : PACU (Post to Surgical
GROUPS Mechanical ventilation 8–10 ml/kg
• Dexamethasone 5 Anesthesi Care Ward
(predicted body weight) boluses of Unit)
esketamine mg after
• frequency of 12–18 breaths/mins, oxygen
anesthesia supplementatio
• Inspired oxygen fraction of 50%.
induction n of 3 L/min
• The end-tidal carbon dioxide will be
OA • Ondansetron 4 via a nasal
maintained at 35–45 mmHg. boluses of catheter
mg at the end of
GROUPS • The depth of anesthesia will be titrated
to BIS values of 45–55 via the manual
sufentanil surgery
adjustment of propofol infusion
Electrocardiography Additional Therapy:
Non-invasive cuff blood • Ondancentron 4mg (anti
pressure emetic Rescue)
Pulse oximetry (SpO2) • intravenous flurbiprofen
axetil 50 mg every 12 h (two
17 days post operative)
OUTCO
MES
NRS
(Numeric
Rating Scale)
 EFFICIENCY AND CONCISTENCY
ANESTESI UNSOED

• Each center will be provided by a multidisciplinary team consisting

of an attending anesthesiologist and a resident or nurse anesthetist
and surgeons who have already performed ≥200 thyroid and
parathyroid surgical procedures within the setting of this study

• Perioperative care in the two study groups will be identical except for
the study interventions.

18
STUDY OUTCOMES
PRIMARY
ANESTESI UNSOED

OUTCOMES
The incidence of PONV (defined as
experiencing any event of nausea, retching, or
vomiting) during the first 48 h postoperatively
SECONDARY OUTCOME
• severity of PONV
• antiemetic rescue therapy
• pain scores at rest and while coughing  NRS
• need for rescue analgesia
• perioperative adverse effects related to anesthetics or analgesics
(hypotension, bradycardia, hypertension tachycardia, desaturation,
dizziness, headache, hallucination, and nightmare)
• time to extubation
• length of post-anesthesia care unit stay
• length of postoperative hospital stay
• patient satisfaction
• 30-day major adverse events (myocardial infarction, cardiac arrest,
cerebrovascular accident, coma, acute renal failure, pulmonary
embolism, sepsis, septic shock, deep neck space infection, reintubation,
reoperation, blood transfusion, failure to wean o ventilator, and death)
 National Surgical Quality Improvement Program (NSQIP) from the
American College of Surgeons (ACS)

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PRESENTATION TITLE
MEASSUREMENT
Severity of PONV Numeric Rating Scale
0 = none,
1 = mild (not interfering with activities of daily living)
2 = moderate (sometimes interfering with activities of
daily living),
3 = severe (inability to do any activities of daily living
≥3 = vomits)

Hypotension (defined as a decrease in mean Desaturation (defined as SpO2 < 95%) after Patients Satisfaction Rate:
extubation will be treated with oxygen
blood pressure [MBP] > 30% of baseline or supplementation of 5–10 L/min via the nasal 5 = highly satisfied
MBP < 65 mmHg) will be treated with catheter. 4 = satisfied
intravenous ephedrine 6–10 mg or 3 = neutral
Tachycardia (defined as HR > 100
phenylephrine 50–100 µg beats/min) will be treated with 2 = dissatisfied
intravenous esmolol 20 mg 1 = very dissatisfied

Bradycardia (defined as HR < 50 Hypertension (defined as an increase in

beats/min) will be treated with MBP > 30% of baseline) will be treated
intravenous atropine 0.3–0.5 mg with intravenous urapidil 5 mg

The values of MAP and HR will be recorded at seven timepoints:

20 1. Baseline 2. anesthesia induction 3. immediately after tracheal intubation 4
skin incision 5. 30 mins into the surgery 6. the end of surgery, and 7.
immediately after tracheal extubation .
PRESENTATION TITLE
D ATA C O L L E C T I O N A N D

R E G I S T R AT I O N
• Trained independent investigators who are unaware of group assignment will
collect patients’ demographic data and baseline characteristics
• All data will be entered into the electronic case report forms (eCRFs) under the
supervision of trained research personnel
• After de-identification, the database will be sent to an independent statistician
from the Department of Epidemiology and Biostatistics, School of Public
Health, Medical College of Soochow University
• The process of data collection and registration will be monitored by the data
monitoring committee (DMC) independent of the trial investigators.
• The DMC consists of three independent clinicians (a professor of clinical
anesthesiology, a professor of surgery, and a pharmacologist).

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ANESTESI UNSOED

SAFETY MONITORING
• The dose or infusion rate of the study medications in both groups are well within the

current clinical norms.

• Any adverse event related to the study interventions or not must be reported within
24 h to the DMC (data monitoring committee) on a “Adverse Event Form.”

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ANESTESI UNSOED
SAMPLE SIZE
CALCULATION
Previous studies and meta-
analysis reported that the
receiving the OFA strategy, that is
incidence of PONV after thyroid
and parathyroid surgery under
opioid-based propofol anesthesia
was ∼44%
23
We expect that the incidence of
To allow for possible dropouts, a
PONV would be 30% in patients
total of 400 patients (n = 200 in
each group) will be enrolled. The
an absolute reduction of 14%.
sample size is calculated using
Based on this assumption, 183
the PASS software (version
patients in each group would be
15.0.5, NCSS, LCC, Kaysville,
required with a power of 80%
UT).
and at an α level of 0.05.
ANESTESI UNSOED STATISTICAL ANALYSIS
• The demographic data and baseline characteristics will be presented using
descriptive statistics only, without conducting between-group comparisons

• Betweengroup differences will be analyzed using the independent t test,

repeated measures analysis of variance, or MannWhitney rank sum test, Chi-
squared test, or Fisher’s exact test, as appropriate.

• For the primary and secondary outcomes, the therapeutic effects of study
interventions will be assessed using mean difference or odds ratio with 95%
confidence intervals.

24
 S TAT I S T I C A L A N A LY S I S
PRESENTATION TITLE
The primary outcome of PONV
incidence
• Analyzed using a multivariate
logistic regression model
adjusting for several baseline
covariates (sex, smoking status,
history of motion sickness or
PONV, and trial site).
Secondary Outcome
• Corrections will be made for
multiple comparisons by
calculating the false discovery
rate using the Benjamini–
25
Hochberg method.
Subgroup analyses for the
incidence of PONV
• performed according to sex
(female vs. male), Apfel’s
PONV risk score (0–2 vs. 3–4),
and trial site
All data will be analyzed using the SPSS
software (version 19.0; IBM SPSS,
Chicago, IL) by the independent
statistician. A two-sided P value < 0.05
indicates a statistically significant
difference
ANESTESI UNSOED
DISCUSSION
Perioperative opioid administration is associated
with adverse effects, such as PONV, sedation,
respiratory depression, ileus, delirium, and
hyperalgesia
Opioid increasing opioid use also contributes to opioid
medications are addiction, epidemic of opioid abuse, and opioid-
related deaths
the standard A retrospective study reported that intraoperative
use of ketorolac was associated with a reduced
treatment for cancer recurrence rate when compared with other
analgesics (sufentanil, ketamine, or clonidine)
surgical stress Based on the recently published consensus Practice
guideline from the Society of Onco-Anesthesia and
response and Perioperative Care, multimodal analgesia consisting
of paracetamol, non-steroidal anti-inflammatory
postoperative drugs, oral pregabalin/gabapentin, with or without
dexamethasone should be encouraged starting from
pain the preoperative period in patients undergoing head
neck onco-surgeries (Grade of recommendations:
A/B; Level of consensus: strong consensus)

26
 O FA R E G I M E N R E C E N T S T U D I E S
ANESTESI UNSOED

• In our OFA regimen, intraoperative anti-nociception will be provided with the use of esketamine, lidocaine,
and dexmedetomidine. Esketamine is an S (+) isomer of ketamine, acting on NMDA receptors to exert anti-
nociceptive and anesthetic effects
• Compared with racemic ketamine, esketamine has the advantages of less adverse effects and a shorter
recovery time, In addition, esketamine has been shown to counter the remifentanil-induced respiratory
depression
• Studies suggested that intravenous lidocaine reduced postoperative pain, opioid consumption, PONV, and
length of hospital stay
• Dexmedetomidine is an α-2 agonist possessing sedative, sympatholytic, and analgesic effects
• Our recent studies have shown the favorable effects of perioperative dexmedetomidine for patients
27
undergoing cardiac or aortic surgery
 O FA R E G I M E N R E C E N T S T U D I E S
PRESENTATION TITLE Ziemann-Gimmel et al.

Opioid free TIVA strategy

with ketamine,
dexmedetomidine, and
propofol reduced the However, anesthesia maintenance
incidence and severity of was different between the two
PONV after bariatric surgery. groups (TIVA with propofol vs.
inhalational anesthetics), which may
have confounded their results.

A recent randomized study showed

that OFA with dexmedetomidine,
esketamine and sevoflurane did
not reduce PONV or pain after
A significant limitation is that a higher
gynecological laparoscopic
sevoflurane concentration was used in
surgery
the OFA group than that in the OA
group.

28
 O FA R E G I M E N R E C E N T S T U D I E S
PRESENTATION TITLE

Beloeil et al. (18) investigated the effects of standard

balanced anesthesia with either remifentanil plus morphine
or dexmedetomidine (the OFA group) on opioid-related
adverse events. However, their study was stopped early due
to severe bradycardia in five patients and asystole in three of
them.

Dexmedetomidine was infused at 1.2 ± 2 µg/kg/h

until the end of surgery. With such a high dose of
dexmedetomidine, it is plausible that the associated
29 risks of OFA outweigh the benefits.
CRITICAL APPRACIAL

EVIDENCED-BASED
MEDICINE
 EVIDENCE BASED MEDICINE
PRESENTATION TITLE

• The study clearly defined about Opioid related

effects with PONV (Post operative Nausea and
Vomiting) and opioid-related adverse effects.
• The group of patients has choosen and allocated
in two groups wich are Opiod Free Anesthesia
(OFA) gruoup and Opioid Anesthesia (OA)
group
• Its large enough patients with thyroid and
parathyroid surgery with GA elective procedure.
• This is an investigator-initiated, two-center,
double-blind, parallel-group, randomized
controlled trial with superiority design. This
study will include a total of 400 adult patients
undergoing thyroid and parathyroid surgery at
two academic medical centers (Shizi Medical
Center and Pingjiang Medical Center) of the
First Affiliated Hospital of Soochow University,
31 Suzhou, China. In these two centers, ∼2,000
thyroid and parathyroid procedures are
performed each year
PRESENTATION TITLE

Yes, The result of this harm study is important

Some studies found that OFA was associated with reduced
incidence and severity of PONV
and decreased postoperative opioid requirements.
However, recent randomized studies questioned the benefits of
OFA, suggesting that OFA did not improve PONV or pain outcomes
but may even cause harms
To date, the definitions of OFA vary significantly in the existing
literature, and the effects of OFA on postoperative outcomes are
largely unknown.
32
PRESENTATION TITLE

• Until now, OFA has been used for several types of surgery (such as
bariatric, breast, gynecological, spinal, and coronary artery bypass
grafting) . But its effect in thyroid and parathyroid surgery has yet to be
determined.
• In our OFA regimen, we will use a low dose of dexmedetomidine infusion
(0.2 µg/kg/h), intravenous lidocaine (1 mg/kg), and esketamine (a single
dose of 0.3 mg/kg during induction and additional boluses of 0.1 mg/kg
intraoperatively) for intraoperative analgesia.
• To reduce PONV, all our patients will receive propofol-based TIVA and
PONV prophylaxis with dexamethasone and ondansetron.
• Thus, the first strength of our study is that it represents the first
randomized clinical trial to assess the effects of OFA on PONV,
postoperative pain, and 30-day outcomes after thyroid and parathyroid
surgery.
• Another strength is that we plan to enroll a total of 400 patients from two
33
medical centers in this trial, which is an adequate number of patients
powered for the primary outcome.
PRESENTATION TITLE
RESULT

In conclusion, this randomized clinical trial is designed to

determine the effects of OFA, as compare to OA, on PONV
in adults undergoing thyroid and parathyroid surgery. We
expect that our OFA regimen would lead to decreased
incidence and severity of PONV as well as improvements
in postoperative pain and major adverse events in these
patients .

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THANK YOU