Effect of Early Postoperative Oral Carbohydrate on Postoperative Recovery of the Unilateral Knee Arthroplasty: a Randomized, Single-blind, Parallel-controlled, Multicenter Study
Phase: EARLY_PHASE1
Conditions: Postoperative Oral Carbohydrates, Postoperative Recovery, Unilateral Knee Arthroplasty
Sponsor: Hongwei Shi

Protocol version: May 17，2023
PROTOCOL
Effect of early postoperative oral carbohydrate on postoperative recovery of the
unilateral knee arthroplasty : a randomized, single-blind, parallel-controlled,
multicenter study
May 17,2023

Protocol version: May 17，2023
Effect of early postoperative oral carbohydrate on postoperative recovery of the
unilateral knee arthroplasty : a randomized, single-blind, parallel-controlled,
multicenter study
1. Research background
In recent years, the concept of accelerated rehabilitation surgery (enhanced recovery
after surgery, ERAS) has developed vigorously, using a series of optimized
evidence-based medical support with preoperative, intraoperative and postoperative
programs to reduce postoperative physiological and psychological stress trauma
response, so as to achieve the goal of accelerating patient rehabilitation[1].
Perioperative fasting water ban management is an important component of ERAS.
Studies have found that prolonged preoperative drinking and fasting will increase the
postoperative insulin resistance, cause hypertension, and increase the risk of
postoperative infection, which is not conducive to the postoperative recovery of [2].
Oral carbohydrates for at least 2h before anesthesia can reduce the perioperative stress
response, improve patient comfort and satisfaction, and promote the postoperative
rehabilitation of [3]. The [4] of the Chinese Expert Consensus and Path Management
Guide for Accelerated Rehabilitation Surgery (2018 edition) advocates the early
postoperative recovery of diet. Studies have shown that the early recovery of oral
eating, drinking water and early oral assisted nutrition after elective abdominal
surgery can promote the recovery of intestinal motor function, help to maintain
intestinal mucosa function, prevent microflora imbalance and displacement, and can
reduce the incidence of postoperative infection and shorten the postoperative
hospitalization time by [5]. At present, shortening the perioperative water fasting time
needs to be concentrated in the preoperative stage. Although the guidelines and a
small number of studies recommend the early recovery of diet after surgery, there is
no clear stipulation on the recovery time of postoperative diet and drinking water, and
most domestic hospitals still perform fasting for at least 6h after surgery.
Carbohydrates are perioperative good oral nutritional fluids. In recent years, studies
have shown that preoperative oral carbohydrates can not only supplement the lost

Protocol version: May 17，2023
water and energy, improve their thirst and hunger, but also improve the postoperative
metabolism and stress changes, reduce postoperative insulin resistance, shorten the
hospital stay, and accelerate the [6] recovery of patients compared with clear water.
Furthermore, preoperative oral carbohydrate has been confirmed by many studies and
does not increase the risk of reflux aspiration in [7]. However, most of the current
clinical studies of oral carbohydrate effects on postoperative recovery focus on the
preoperative oral phase, and only a few small samples have shown that postoperative
oral carbohydrate improves postoperative comfort [8]. Therefore, further systematic
studies on the effects of early postoperative oral carbohydrates on postoperative
recovery remain lacking.
Directory of reference
[1] Miller TE, Roche AM, Mythen M. Fluid management and goal-directed therapy as
an adjunct to Enhanced Recovery After Surgery (ERAS). Can J Anaesth. 2015
Feb;62(2):158-68.
[2] Rizvanović N, Nesek Adam V, Čaušević S, Dervišević S, Delibegović S. A
randomised controlled study of preoperative oral carbohydrate loading versus fasting
in
patients
undergoing
colorectal
surgery.
Int
J
Colorectal
Dis.
2019
Sep;34(9):1551-1561. doi: 10.1007/s00384-019-03349-4. Epub 2019 Jul 15. PMID:
31309323.
[3] Nygren J, Thorell A, Ljungqvist O. Preoperative oral carbohydrate therapy. Curr
Opin Anaesthesiol. 2015 Jun;28(3):364-9. doi: 10.1097/ACO.0000000000000192.
PMID: 25827282.
[4] Surgery Branch of Chinese Medical Association, Anesthesiology Branch of
Chinese Medical Society. Chinese Expert Consensus and
Path Management
Guidelines for Accelerating Rehabilitation Surgery (2018) [J]. Chinese Journal of
Anesthesiology, 2018,38 (001): 8-13.
[5] Yang R, Tao W, Chen YY, Zhang BH, Tang JM, Zhong S, Chen XX. Enhanced
recovery after surgery programs versus traditional perioperative care in laparoscopic
hepatectomy: A meta-analysis. Int J Surg. 2016 Dec;36(Pt A):274-282. doi:

Protocol version: May 17，2023
10.1016/j.ijsu.2016.11.017. Epub 2016 Nov 10. PMID: 27840308.
[6] Bethune Orthopaedic Accelerated Rehabilitation Alliance, Bethune Charity
Foundation
Orthopaedic
Professional
Committee
of
trauma,
Joint
Surgery
Professional Committee of Bethune Charity Foundation, etc. Guidelines for the
management of perioperative fasting fasting in orthopaedic surgery [J]. Chinese
Journal of Trauma and Orthopedics, 2019,21 (10): 829-834.
[7] MD Smith,
Mccall J , Plank L , et al. Preoperative carbohydrate treatment for
enhancing recovery after elective surgery[J]. Cochrane Database Syst Rev, 2014,
8(8):CD009161.
[8] Noba L , Wakefield A . Are carbohydrate drinks more effective than preoperative
fasting: A systematic review of randomised controlled trials[J]. Journal of Clinical
Nursing, 2019, 28.
[9] Wang Cuilan, Huang Yuting, Zeng Qing, et al. Study on postoperative fasting
water prohibition time under ERAS concept [J]. Clinical Medical Engineering,
2022,29 (4): 2.
1. Study purpose and study endpoint
1.1 Study Purpose
1.1.1 Main study objective: To evaluate the effect of early postoperative oral
carbohydrate on postoperative recovery of the unilateral knee arthroplasty.
1.1.2 Secondary study objectives: To evaluate the effect of early oral carbohydrate
administration on the comfort and safety of patients undergoing unilateral knee
arthroplasty.
1.2 Study endpoint
1.2.1 Primary study endpoints
Fasting insulin resistance index in venous blood was checked 1d after surgery;
（Fasting blood glucose (fasting plasma glucose, FPG) and fasting insulin (fasting
insulin, FINS) were measured 1 day after surgery. FPG, detected by oxidase method,
FINS detection by radioimmunoassay, using steady state mode assessment to
calculate the steady state model insulin resistance index (homeostatic model

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assessment for insulin resistance, HOME-IR): FPG (mmol/L) FINS (mU / L) / 22.5.）
1.2.2 Secondary study endpoints
1.2.2.1 Effectiveness study endpoint
1) Fasting insulin resistance index in venous blood was checked on the day of the
surgery;
2) Fasting insulin resistance index in venous blood was checked 3d after surgery;
3) Fasting pre-albumin levels in venous blood on the day of surgery, 1d and 3d after
surgery.
4)
Fasting level of retinol-binding protein in venous blood on the day of surgery，1d
and 3d after surgery;
5) The 15-item recovery quality rating scale (QoR-15);
6) NRS score of thirst and hunger at 2h, 6h and 8h after surgery;
7) Abating distension within 24h after surgery;
7) The incidence of hypoxemia and reflux aspiration within 24h after surgery(SpO2
<91% under air inhalation was defined as hypoxemia; vomiting associated with
severe coughing followed by hypoxemia and lung rales);
9) Time of anal exhaust for the first time after surgery;
10) The degree of nausea and vomiting;
11) Length of hospitalization;
12) Postoperative analgesic effect: patients consumed total sufentanil at 48 hours after
surgery, number of effective pressure times of the analgesic pump, remediation of
analgesia(The salvage analgesic dose was converted to morphine equivalent)；
13) Postoperative subject satisfaction score.
1.2.2.2. Safety study endpoint
1) The incidence and severity of various adverse events (AE) from the start of oral
carbohydrates to the end of the trial;
2) The incidence and severity of adverse events such as nausea, vomiting and
hypoxemia from the first start of drug administration to the end of the trial;
3) Number of antiemetic drugs used within 24h after the first start todrug
administration;

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2. Expected results
Oral carbohydrates in the early postoperative period can improve patient nutritional
status, improve comfort and satisfaction without increasing the incidence of adverse
events.
3. Design and method of the study
3.1.1 Screening period
Patients undergoing unilateral total knee arthroplasty of the lower limbs or
monocondylar arthroplasty, screened with informed consent to enroll patients, met all
enrollment criteria and did not meet any of the exclusion criteria.
3.1.2 The perioperative management protocol
Pre-operative management ：All patients actively controlled blood pressure, blood
glucose, correction of anaemia and hypoproteinaemia, and increased protein intake.
The dietary plan was informed by the ward nurse one night before surgery, all patients
fasted solid food 6 hours before surgery and 200ml of sugary drinks were taken 2-3
hours before surgery.
Intraoperative management: All patients underwent lumbar anesthesia, selected L3-4 or
L2-L3 gap puncture, and the anesthesia plane was controlled below T7. The restrictive
liquid management strategy was adopted, 6ml crystalloid · kg-1 · h-1 supplemented
physiological requirements, blood loss was supplemented with hydroxyethyl starch
fluid, concentrated red blood cells were infused with Hb <80 g / L, and the patient
blood pressure and heart rate fluctuation was less than the base value ± 20%. At 30
min before the start of the procedure, 40mg of analgesia at 5mg IV and 2mg of
prophylactic antivomiting 30min before the end of the procedure.
Analgesia management:
1. Non-steroidal anti-inflammatory analgesics were given during the operation, and
returned to the ward to continue on time；
2. After the operation, the adductor muscle tube block and analgesia should be
performed according to the surgical incision site；
3. Sufentanil PCIA analgesia pump, formula: Sufen 150 ug + Segen 6mg + NS250ml;
continuous: 3ml / h, control: 5ml, lock: 8min, limit: 35ml / h, adjust the parameters

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according to the pain condition to meet the patient NRS pain score 3；
4. If the patient started PCIA treatment, the subject's NRS pain score 4 and 3 bolus
did not relieve, and the investigator judged the opioid relief analgesia such as
sufentanil or oxycodone until the NRS pain score 3 and recorded；
Management within the PACU:
Eligible patients were screened before surgery, and an informed consent form was
signed. Patients enrolled in the experiment were randomly assigned into one of the
three groups. They are early feeding group (EOF 1, EOF 2) and late feeding group
(control group). Late feeding group (Group C): Group C patients observed 30min
vital signs, returned to the ward to fast and drink for at least 6 h, and gradually drink
and eat after anal exhaust. Early drinking water group (EOF 1): EOF 1 group received
water in the resuscitation room; early drinking carbohydrate group (EOF 2): EOF 2
group received 200ml 12.5% carbohydrate (100ml containing 12.5g maltodextrin,
fructose and glucose) in the resuscitation room.
To evaluate the resuscitation room of patients in the early feeding group: Steward
awake score of 6 and awake level 3,5ml / kg lean weight 12.5% carbohydrate or water
according to the need of consent. The process of drinking carbohydrates or water is to
take 30ml orally first. After observing no abnormal swallowing, the patient was
instructed to drink the remaining drinks as needed. After the patient returned to the
ward, the liquid diet began to gradually excessive into the normal diet. When the
patient was able to tolerate a normal diet, the intravenous fluids were stopped.
Evaluation process of drinking index：
1）Steward Score: awake: 0-no response to stimulus; 1-some response to stimulus;
2-full awake.(2) Respiratory tract patency: 0-patient's respiratory tract needs support;
1-patient's respiratory tract can maintain patency without support; 2-patient can cough
according to the doctor's guidance.(3) Body mobility: 1 point-the patient has no body
activity; 2 points-the unconscious activity of the patient's limb; 3 points-the patient's
limb can carry out the conscious activities；
2）Grade of sobriety：according to the awake degree of the patient's consciousness:
Grade 0: the patient is completely in the sleep state, No response when calling; Level

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1: The patient is falling asleep, However, head and neck movement, eye opening, or
limb movement occurs during breathing; Grade 2: the patient is awake, Have the same
performance as level 1, At the same time can also open the mouth, stretch the tongue;
Grade 3: the patient is in an awake state, Have the same performance as the level 2, At
the same time, they can also clearly tell their own name, age and other information;
Grade 4: The patient is awake, Have the same performance as level 3, It can also
accurately identify the surrounding environment, And tell you clearly where you are.3.
3 ）The early feeding group (EOF 1 and EOF2 group) did not need to wait for
peristalsis. According to the wishes of the patients, the dose was completed within 2
hours after the operation
4. Subject recruitment and protective measures
4.1 Inclusion criteria

Age 18-79 years;

Patients undergoing unilateral total knee arthroplasty or unicondylar joint
replacement;

Normal diet;

ASA grade I~Ⅲ;

BMI 18-30 kg / m2;

No intraspinal anesthesia contraindications.
4.2 Exclusion criteria:

Preoperative existence of gastric emptying disorders, such as gastrointestinal
obstruction, gastroesophageal reflux, or previous gastrointestinal surgery;

Patients with diabetes mellitus, severe renal dysfunction, or other severe
metabolic diseases;

History of motion sickness;

Mental disorder, alcoholism, or a history of substance abuse;

Patients with abnormal swallowing function;

The operation time is greater than 3 hours;

Maltodextrin fructose allergy or intolerance;
4.2 Standards for dropout cases: signed the informed consent form and screened the

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qualified withdrawal cases in the pre-intervention, during the intervention and after
the intervention follow-up process after entering the study.
4.3 Case exclusion criteria:

Signed the informed consent, entered the study but was found not to meet the
inclusion criteria during the project supervision or after the completion of the
study;

Did not sign the informed consent;

The intervention was not performed according to the treatment standards and had
poor compliance;

Failed to accept the intervention, did not comply with or assume the
corresponding responsibilities and obligations of the informed agreement.
5 Informed consent
5.1 The Informed Consent Form
The informed consent was in accordance with the ethical principles outlined in the
Declaration of Helsinki. The informed consent form detailed the study protocol and
process, and fully explained the risks of the study.
The informed consent form also states that the records of the individual identity must
be kept confidential, but the research team and regulators can access the subject
information.
5.2 Informed consent process and record
Informed consent begins before the individual consent to participate in clinical studies
and continued throughout the course of the clinical study.
5.3 Confidential
Personal patient information will be given as confidential information. All patient data
obtained from the patient cases will be kept as confidential. Patients will be identified
by their name acronym and the numbers provided at the time of study inclusion.
Patients or their families will be aware of the anonymity of the data and their right to
protect their privacy. However, it is also important to understand the fact that the data
will be submitted to the subject responsible unit or the government management
authority, and may also be submitted to institutions such as the Ministry of Health for

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inspection and evaluation. The participating physician will keep a list of patient
personal data (patient data and corresponding patient names) for confirmation of the
record.
6. Quality control and quality assurance
6.1 Qualification of research unit and researcher qualification
The research unit shall have the experience in drug research, the facilities and
conditions of the department where the project belongs shall meet the needs of safe
and effective clinical research, and the researchers shall have the professional
expertise, qualifications and ability to undertake the clinical research, and shall be
trained in GCP regulations.
6.2 Training of the researchers
Before the start of the study, the research leaders of each center should organize the
researchers to study the program, and only the researchers who have passed the
program training can participate in the study to ensure that the researchers have a
consistent understanding of the protocol. For important assessment scales, relevant
personnel in the participating centers need systematic training and even obtain
corresponding qualification certificates.
6.3 Surveillance of clinical trials
The hospital ethics committee and institutional review board may conduct a
systematic review of the clinical trial-related activities and documents, to evaluate
whether the trial was conducted in accordance with the test protocol, SOP, and
relevant regulations, and whether the test data are timely, true, accurate, and complete
records. The audit should be performed by those who do not directly involve the
clinical trial.
7. Organization and management of the research
7.1 Change of the scheme
All additional or referenced appendices are integral parts of the scheme. No one shall
make any modifications or revisions to any part of the research protocol, as signed by
the investigator and the principal of the project, unless these changes or revisions have
been fully discussed. And through the unanimous consent of the researcher and the

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subject leader.
Any agreed modifications will be recorded and will be signed by the investigator and
the project leader and filed with the protocol.
7.2 Retention of the records
The investigator shall keep all the detailed original documents of the subject and
record the trial process, medication status, laboratory examination data, safety data
and efficacy assessment in the case report form. The recorded data shall be complete,
timely and clear. The original documents and medical records should be clear, detailed
and easily identified by those participating in this clinical trial.
The case report form and the original files can only be modified by the investigator.
No modification to the case report form and the original file shall smear the original
data off. The correct way to modify is to line the original data, and then write the
modified data next to the original data, and sign the date and the name of the
modification.
Test data shall be retained until 5 years after the termination of the test.
7.3 Early termination of the study
The leader of the project decides to stop or interrupt the study in advance in the case
of force majeure, and should inform the doctors involved in the study in writing.
Similarly, any participating unit that decides to withdraw from the study for any
reason should also notify the project leader in written form.
7.4 Research, supervision and inspection
7.4.1 Research supervision
Inspectors must follow the drug clinical trial quality management specification (GCP)
and standard operation procedures (SOP), visit the research unit regularly or
according to the actual situation, supervise the clinical trial work and progress, check,
confirm all data records and reports, correct and complete, consistent with the original
data, ensure the clinical trial in accordance with the clinical trial protocol, the
researchers should actively cooperate with the inspectors. The specific contents of the
inspector include:
a) Ensure that the test undertaking unit has appropriate conditions, including staffing

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and training, complete laboratory equipment, good operation, various inspection
conditions related to the test, an estimated sufficient number of subjects, and the
participants to be familiar with the requirements in the test plan;
b) Monitor the implementation of the trial program during the trial, confirm that the
informed consent of all subjects is obtained before the trial, understand the enrollment
rate of the subjects and the progress of the trial, and confirm that the selected subjects
are qualified;
c) Confirm that the records and reports of all data are correct and complete, and that
all case report forms are entered correctly and consistent with the original data. All
errors or omissions have been corrected or indicated, signed and dated by the
Investigator.
d) Verify that all adverse events are recorded, and that serious adverse events shall be
reported and recorded within the specified time;
e) Clearly and truthfully record the failed visits, unconducted tests, and undone checks
should be made, and whether the errors and omissions should be corrected;
f) The written inspection report shall be completed after each visit, which shall state
the date, time, name of the inspector, the findings of the inspection, etc.
7.4.2 On-site inspection
The responsible unit may conduct an on-site inspection of the research at a clinical
research institution. The audit includes the required test documents, records of the
informed consent process, and the consistency of the eCRF and the original
documents. But also the content and scope of the inspection can be increased
according to the situation. The investigator agrees to participate at a reasonable time
and in a reasonable manner.
8. Investigators' responsibilities
8.1 Participation of doctor responsibilities
The participating physicians will conduct the study following the study protocol and
confirm the accuracy of the data entered. The participating physicians should be
responsible for obtaining written signed informed consent for data collection from the
study subjects.

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8.2 Responsibility of the project leader
The project leader takes all reasonable steps and provides sufficient resources to
ensure the implementation of the research, mainly involving the following aspects:
a) Ensure that the study complies with relevant national and local regulations,
including ethical requirements, patient data protection regulations, etc.
b) Ensure the effectiveness of quality control and analysis of research results.
9. Share results
The intellectual property rights, trial data and research results related to this study are
jointly owned by Nanjing First Hospital and the Department of Anesthesiology.
The intellectual property rights, trial data and research results related to this clinical
study are owned by Nanjing First Hospital and the Anesthesiology Department.
10. Ethics principles and requirements for clinical research
Clinical research will follow the world medical congress "declaration of Helsinki" and
the national health and family planning commission of the People's Republic of China
"involving people biomedical research ethics review method" and other relevant
provisions, the specific implementation of informed consent, the privacy protection,
research free and compensation, risk control, special subject protection and research
related damage compensation principles and requirements. The clinical study was
performed before the ethics committee approved the trial protocol. Before each
subject is enrolled in the study, the investigator has the responsibility to present the
subject or / and his legal agent about the purpose, procedures of the study and possible
risks, and sign a written informed consent form that their participation in the clinical
study is completely voluntary, that they may refuse to participate or withdraw from
the study at any time at any stage of the trial without discrimination and retaliation,
and their medical treatment and interests are not affected. The informed consent form
should be retained as a clinical research document for future reference to effectively
protect the subjects' personal privacy and data confidentiality.