Effect of Preoperative Intervention With Folic Acid and Vitamin B12 on Postoperative Neurobehavioral Changes in Children
Phase: NA
Conditions: Delirium
Sponsor: Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University

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Effect of preoperative intervention with folic acid and vitamin B12 on 
postoperative neurobehavioral changes in children 
Clinical trial protocol 
Version number: V2.0                  Version time: May 7, 2020 
1、Research background 
Delirium (ED) and long-term cognitive dysfunction are common complications 
after children undergoing surgery under general anesthesia. The prevalence of delirium 
(ED) in pre-school children is about 38.8% [1]. Childhood delirium is defined as "the 
disorientation and cognitive changes that occur within a short period of time after the 
child is anesthetized and awakened, manifested as high responsiveness to stimulation 
and hyperactivity" [2]. Delirium (ED) during the recovery period usually appears within 
30 minutes after anesthesia resuscitation. It is a self-limiting process and subsides in 
about 5 to 15 minutes [3][4]. Restlessness and delirium during postoperative recovery 
can lead to wound cracking and hemorrhage, and even cause respiratory tract 
obstruction or other pulmonary complications. It could delay the children’s 
postoperative healing and prolong the hospital stays [6]. 
The long-term neurobehavioral changes caused by general anesthesia in children 
are mainly fine motor injuries. The Mayo Clinic's MASK research find that after 
multiple anesthesia, infants and young children's processing speed, motor coordination 
and visual motor integration related scores have significant statistical reductions by 
accurate factor analysis and cluster analysis statistical methods [5]. The integrity of the 
myelin sheath is a key structure to ensure the processing speed and motor coordination 
function of the brain. The clinical phenomenon observed by the MASK research and 
the basic research of Professor Jiang Hong get the same conclusion. In June 2019, a 
clinical research on the effects of general anesthesia drugs on the development of 
myelin sheath in children was published again in the top journal JAMA Oncology [6]. 
The research found that the greater exposure dose of the general anesthetic drug or 
longer anesthesia time cause lower integrity of the corpus callosum white matter, which 

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is related to the neurocognitive impairment. It shows that general anesthetic drugs may 
affect the white matter connection between the cerebral hemispheres, disrupt the 
effective communication between neurons, and cause impaired processing speed and 
attention. 
Folic acid, a one-carbon unit transferase coenzyme, participates in the synthesis of 
purine and thymine, is an important element of the nervous system. Vitamin B12 
participates in methyl conversion and folic acid metabolism in vivo, promoting the 
conversion of 5-methyltetrahydrofolate to tetrahydrofolate [7]. It has been reported that 
the lack of serum folic acid and B12 is associated with an increased risk of cognitive 
impairment [8]. Folic acid deficiency leads to impaired central nervous system 
methylation and results in insufficient methyl synthesis of myelin sheaths, 
neurotransmitters, membrane phospholipids and deoxyribonucleic acid [9]. Our 
previous studies showed that preoperative folic acid supplementation can alleviate 
myelin damage and cognitive impairment in young mice caused by sevoflurane [10]. 
Therefore, this research further explored the effect of preoperative folic acid and 
coenzyme B12 supplementation on children's delirium and long-term neurobehavioral 
changes after general anesthesia. 
 
references： 
1. Gomezpesquera E, Povesalvarez R, Martinezrafael B, et al. Cerebral Oxygen Saturation and 
Negative Postoperative Behavioral Changes in Pediatric Surgery: A Prospective Observational 
Research[J]. The Journal of Pediatrics, 2019. 
2. Sikich N, Lerman J. Development and psychometric evaluation of the pediatric anesthesia 
emergence delirium scale. Anesthesiology 2004;100:1138–45. 
3. Olympio MA. Postanesthetic delirium: historical perspectives. J Clin Anesth 1991;3:60–3. 
4. Moore JK, Moore EW, Elliott RA, et al. Propofol and halothane versus sevoflurane in paediatric 
day-case surgery: induction and recovery characteristics. Br J Anaesth 2003;90:461–6. 
5. Zaccariello MJ, Frank RD, Lee M, et al. Patterns of neuropsychological changes after general 
anaesthesia in young children: secondary analysis of the Mayo Anesthesia Safety in Kids research. 
British journal of anaesthesia 2019; 122: 671-81 

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6. Banerjee P, Rossi MG, Anghelescu DL, et al. Association Between Anesthesia Exposure and 
Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute 
Lymphoblastic Leukemia. JAMA Oncol. 2019 Jun 20. 
7. Dolatabadi HRD, Reisi P, Alaei H, Malekabadi HA, Pilehvarian AA. Folic acid and coenzyme 
Q10 ameliorate cognitive dysfunction in the rats with intracerebroventricular injection of 
streptozotocin. Iran J Basic Med Sci(2012) 15:719. 
8. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F. 
Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 
(2005)82:636–643. 
9. Calvaresi E, Bryan J. B vitamins, cognition, and aging: a review. J Gerontol B Psychol Sci Soc 
Sci (2001) 56:P327–PP39. 
10. Zhang L, Xue Z. Disrupted folate metabolism with anesthesia leads to myelination deficits 
mediated by epigenetic regulation of ERMN.EBioMedicine. 2019 May;43:473-486. 
 
2、Research Purpose 
Comparison of preoperative folic acid, VitB12 and placebo intervention on 
postoperative delirium and long-term neurobehavioral changes in children under 
general anesthesia. 
3、Experimental design 
3.1 Experiment type 
Randomized, double-blind, placebo-controlled, prospective research 
3.2 Randomized grouping： 
The block randomization method was used to randomize the participants. The SAS 
software was used to design the block randomization program. The participants were 
randomly grouped according to the random digital seeds generated by the software. The 
block length was 8. The patients were randomly divided into two groups, namely the 
intervention group (continuously taking folic acid and VitB12 for 3 days before surgery) 
and placebo group (continuously taking placebo for 3 days before surgery), and 
completed the preparation of drug blinding and emergency letters. Emergency letters 
are prepared at the same time as the drug is blinded. Each blind number is set with an 

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emergency envelope, which contains the case drug number and drug name, so that in 
case of an emergency, the individual cases are blinded and rescued. After unblinding, 
the corresponding case is treated as a shedding case. The emergency letter was sent to 
the researchers along with the drugs that had been blinded. The blind law is supervised 
by a supervisor who is responsible for coordinating and supervising the entire research 
work, to ensure the safety of the test participants and the reliability of the results, to 
distribute emergency letters, keep the blind base, and unblind the end of the test. 
3.3 Blind method： 
Before the operation, inform the patient and the family of the patient that the 
randomly assigned drugs may be folic acid and VitB12, or may be a placebo. Due to 
the pale yellow color after folic acid dissolution, it is planned to dissolve folic acid 
tablets and VitB12 in 20ml of brown sugar water to ensure the consistency of the drug 
properties in the intervention group and placebo group, to avoid the risk of blindness. 
All participants will be randomly divided into intervention group and placebo group. 
After randomization, the intervention group: patients took folic acid and VitB12 tablets 
for 3 days before surgery (2 years old children 0.4mg/d + VitB12 1.2μg/d, dissolved in 
20ml brown sugar water once a day.). Placebo group: Patients took the same dose of 
brown sugar water for 3 consecutive days before surgery. The choice of folic acid and 
VitB12 dosage is based on the children's tolerable upper intake levels (UL). This dosage 
is widely verified by toxicology experiments and has no side effects and average risk 
for almost all individuals. The maximum daily intake of nutrients, the use of this dose 
can avoid the adverse reactions caused by folic acid intervention to the greatest extent. 
Folic acid, VitB12 and placebo are all in light-shielding bottles, and the researchers 
distribute the medicine to the children every day. Patients and their families, 
anesthesiologists, surgeons, research recorders, and evaluators were unaware of the 
grouping and the composition of the drugs issued. 
3.4 Experimental grouping 
According to the results of random grouping, the children were randomly divided into 
intervention group and placebo group. 

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Intervention group: The patient took 20ml of brown sugar aqueous solution 
containing folic acid and VitB12 for 3 days before operation (the concentration of folic 
acid was 0.4mg/d + VitB12 1.2μg/d for 2 year old children, dissolved in 20ml brown 
sugar water once a day) Postoperatively, PAED scores were performed at the time of 
awakening, extubation, and every 10min within 30min after extubation, and all 
children's PAED scores were performed by the same measurer (total score 0-20, score 
≥ 10 points is defined as delirium during the recovery period). Long-term 
neurobehavioral changes were evaluated using the Gesell scale and followed up every 
six months until the age of three. 
Placebo group: The patients in the placebo group took 20 ml of brown sugar 
aqueous solution with the same concentration as the intervention group 3 days before 
the operation. Postoperatively, PAED scores were performed at the time of recovery, 
extubation, and every 10 minutes within 30 minutes after extubation. The PAED scores 
of all children were measured by the same person. (The total score is 0-20, and the score 
≥10 is defined as delirium during the recovery period). Long-term neurobehavioral 
changes were evaluated using the Gesell scale and followed up every six months until 
the age of three. 
4 Experiment object: 
4.1 Recruitment and sample size calculation: 
According to the literature review, the incidence of delirium in children during 
recovery is about 38.8% (Reference 1). The sample size was calculated based on the 
incidence of delirium in children in the placebo group at 38%, assuming a type of error 
probability α=0.05, test efficacy 1-β=0.8, considering folic acid and vitamin B12 
supplementation for 3 days can reduce the incidence of delirium to 23%. A chi-square 
test is planned to assess whether there is a difference in the incidence of delirium among 
the groups. Through the calculation of the PASS software, the required sample size is 
300; considering the 20% drop-out rate, a total of 360 hospitalized children are planned 
to be divided into 2 groups, 180 cases in each group. 
4.2 Inclusion criteria: 

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(1) ASA grade is Ⅰ ~ Ⅱ; 
(2) Children aged 6 months to 2 years old; 
(3) It is planned to undergo head, neck and maxillofacial surgery under general 
anesthesia, and the anesthesia time is less than 6 hours; 
4.3 Exclusion criteria: 
(1) Children with a history of respiratory tract infection within 1 week; 
(2) Children with congenital malformations such as congenital heart disease; 
(3) Children with central nervous system diseases or mental disorders or mental 
disorders; 
(4) Children with long-term use of sedative or analgesic drugs; 
(5) Children with severe liver and kidney dysfunction; 
(6) Received folic acid and VitB12 supplement treatment or taken related derivatives; 
(7) Have taken drugs that affect absorption within the past month, such as sulfonamides, 
aspirin, etc.; 
(8) Those who have participated in other relevant clinical research in the past 3 months; 
(9) Children with stunting 
4.4 Shedding cases 
After signing the informed consent and entering the clinical trial after screening, 
there were no cases that completed the entire clinical research. If an adverse event 
occurs, the patient or family member voluntarily requests to quit, open an emergency 
letter to uncover the blind, etc. 
4.5 experiment aborted 
(1) Those who are allergic to drugs; 
(2) Those who have serious adverse events or complications should not be accepted for 
the test; 
(3) Emergency blinding cases; 
(4) Patients or family members voluntarily request to withdraw; 
5、Elimination criteria 
(1) Those who do not meet the selection criteria after selection; 
(2) Violation of the regulations on the blind use of drugs; 

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(3) Failure to take the medicine at the prescribed dose affects the judgment of drug 
efficacy; 
(4) Incomplete information; 
6、experiment termination 
(1) Blind leaks; 
(2) The ethics committee terminates or suspends the experiment; 
(3) The rate of dismantling emergency letters exceeds 20%; 
(4) The incidence of complications or adverse events in the intervention group was 
significantly higher than that in the control group in the mid-term; 
 
7、experiment content 
According to the results of randomization, three groups of participants took
 folic acid and VitB12 or placebo daily three days before the operation. The c
hildren were fasted for 6 hours and fasted for 2 hours before surgery. After e
ntering the operating room, they monitored breathing, heart rate (HR), electroca
rdiogram, blood pressure, mean blood pressure, and oxygen saturation (SpO2). 
Through the peripheral venous system, 1-2 ml of blood was drawn according t
o different ages to measure the concentration of IL-6, TNF-a cytokines, folic a
cid and vitamin B12. Preoperative medication (atropine 0.02mg/kg, intravenous 
injection; dexamethasone 0.2mg/kg, intravenous injection).  After routine inductio
n (intravenous midazolam: 0.1 mg/kg, fentanyl 2 μg/ kg, propofol 3 mg/kg, ro
curonium at 0.6 mg/kg), tracheal intubation was performed under oral vision . 
After intubation, adjust the sevoflurane volatile tank to 2-3 vol%, the oxygen f
low rate to 2 L•min-1, the tidal volume VT 8~10ml/kg, the respiratory rate 18
~25 times/min, adjust the ventilator parameters Maintain end-tidal carbon dioxid
e (EtCO2) at 35~45mmHg.  Start the anesthesia maintenance process. Intraoperat
ive routine monitoring of heart rate, noninvasive blood pressure, oxygen saturat
ion, and end-expiratory carbon dioxide. All anesthetic drugs were stopped 5 to 
10 minutes before the end of the operation.  After the operation, 1-2 ml of blo
od was drawn through the peripheral venous system according to age to measu

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re the concentration of IL-6, TNF-a cytokines, folic acid and vitamin B12. Aft
er pressing, there is no bleeding and edema. The child was sent to the post-an
esthesia care unit (PACU) to continue monitoring and oxygen inhalation. After 
spontaneous breathing is restored and normal SpO2 and ETCO2 can be maintai
ned, the protective reflex is restored, and the tracheal tube is removed after th
e secretions are fully aspirated. After reaching the PACU standard, the child is
 safely returned to the ward. 
8、Evaluation index 
8.1 Main observation indicators: 
PAED scores were performed at the time of awakening, extubation, and every 
10min within 30min after extubation (total score 0~20, score ≥10 is defined as 
delirium in the awakening period). Long-term neurobehavioral changes were assessed 
using Gesell scale. 
8.2 Secondary observation index： 
(1) Changes in the induction period of anesthesia, intubation, and the operation center 
rate (HR) and mean blood pressure (MBP); 
(2) Changes in HR and MBP after entering the resuscitation room (T1), 5 minutes 
before extubation (T2), during extubation (T3), and 2 minutes after extubation (T4); 
(3) Extubation time and recovery time; 
(4) Ramsay sedation score after recovery, extubation and every 10min within 30min 
after extubation; 
(5) The postoperative pain CHEOPs scores were taken at the time of extubation and 
every 10 minutes within 30 minutes after extubation (the total score was less than 6 
points, there was no pain, and ≥10 points for corresponding analgesia treatment); 
(6) The use of narcotic drugs (eg pentazocine, propofol); 
(7) Changes in serum IL-6, TNF-α, folic acid and vitamin B12 levels before and after 
operation. Blood sequencing was used to detect metabolomics before and after surgery. 
(8) Other adverse events during the recovery period (eg nausea and vomiting, 
bronchospasm, respiratory depression, etc.); 
(9) Gesell scale score changes every six months before the age of three. 

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(10) Postoperative child scale score (PHBQ). 
(11) PAED scale score. 
9、 Adverse event 
9.1 Definition of adverse events 
Adverse event (Adverse Event, AE) refers to all adverse medical events that occur 
in clinical trial participants after receiving the test drug, which can be manifested as 
symptoms, signs, diseases, or abnormal laboratory tests, but may not be inferred from 
the test drug There is a clear cause and effect relationship. 
9.2 Adverse event records 
Any adverse events that occur during the test should be recorded in the participant’s 
research medical record and signed by the investigator, including the type, degree, 
appearance time, duration, treatment measures, and treatment process. 
9.3 Adverse event handling 
If any adverse event occurs in the clinical trial, regardless of whether there is a 
causal relationship with the test drug, the researcher should take the necessary measures 
to give treatment and rescue, and follow up the adverse event until the adverse event is 
relieved, or the participant's condition is stable , Or return to the baseline value, or the 
participant lost to follow-up. 
If the follow-up cannot be performed for some reason, it must be explained in the 
research medical record. 
In the course of follow-up of adverse events, the disease progresses to cases of 
serious adverse events, and the investigator should report according to the serious 
adverse event process after being informed. 
9.4 Assessment of adverse events 
(1) Grading of the severity of adverse events 
The severity of the adverse events during the trial should be graded. As a unified 
standard, the adverse events will be based on the Common Terminology Standards for 
Adverse Events (NCI-CTCAE V4.03) developed by the National Cancer Institute of 
the National Institutes of Health in the US Department of Health and Human Services. 
The severity of the incident is graded. According to the severity of adverse events, it is 

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divided into: 
Level 1: Mild; asymptomatic or mild symptoms; only clinical or diagnostic 
findings; no treatment required; 
Level 2: Moderate; minimal, local or non-invasive indications for treatment; age-
related instrumental daily life activities are limited*; 
Level 3: Severe or important medical significance, but not immediately life-
threatening; indications for hospitalization or prolonged hospitalization; disability; 
limited self-reasoning activities of daily life**; 
Level 4: Life-threatening and requires emergency treatment; 
Level 5: Death. 
Daily life activities (ADL) 
*Instrumental daily life activities include cooking, buying groceries or clothes, using the phone, 
managing money, etc. 
**Self-rational activities of daily living refer to bathing, dressing and undressing, eating, toileting, 
and taking medicine, rather than being bedridden. 
(1)  Evaluation of the association between adverse events and test drugs 
A. The causal analysis of the relationship between all adverse events and the test drug 
is judged according to five levels: positively related, likely related, likely related, 
possibly unrelated, and positively unrelated, and the first three are regarded as 
adverse reactions of the drug. The considerations for causal analysis include the 
following five aspects: 
B.  Is there a reasonable order of time between the start of the medication and the 
time when the suspected Adverse Drug Reaction (ADR) appears (medication 
appears); 
C.  Whether the suspected ADR complies with the drug's known ADR (in accordance 
with the literature); 
D.  Can the suspected ADR be explained by combined medication, previous 
medication, the patient's clinical situation, or the effects of other therapies (other 
interpretations); 
E.  Whether the suspicious ADR disappeared or reduced after drug withdrawal or 

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reduction (drug withdrawal reaction); 
F. Whether the suspicious ADR reappears after re-exposure to the same drug (reuse and 
reproduce); The investigator should evaluate the possible associations between adverse 
events and the trial drug and co-administration, refer to the table below. 
(2)  Judgment table of correlation of adverse events 
Considerations Medication 
appears 
In line with 
literature 
Other 
explanations 
Withdrawal 
disappears 
Reuse 
reproduction 
Definitely 
related 
＋ 
＋ 
－ 
＋ 
＋ 
Probably 
related 
＋ 
＋ 
－ 
＋ 
？ 
May be 
relevant 
＋ 
＋ 
± 
± 
？ 
May be 
irrelevant 
＋ 
－ 
± 
± 
？ 
Definitely 
irrelevant 
－ 
－ 
＋ 
－ 
－ 
Remark：“＋”certainty；“－”negative；“±”Difficult to affirm or deny：“？”Unknown； 
(3) The outcome of adverse events 
The following categories are used to evaluate the progress of adverse events: 
A. A. Recovery: The signs and symptoms disappear or the participant recovers; the 
test value returns to normal or returns to baseline; 
B. B. Improvement: the severity is reduced by one grade or more, or the mild 
symptoms and findings disappear, or the indicators return to the level before the 
trial treatment; 
C. C. Not recovered: symptoms, findings, and various indicators have not improved; 
according to the data of the last visit during the observation period, the severity has 
deteriorated relative to when it occurred, causing irreversible abnormalities; 
D. D. Recovery but with sequelae: some symptoms and findings are recovered, and 
some findings are transformed into sequelae; 
E. E. Death: There is a direct causal relationship with the adverse event discussed. 
"There is a direct cause and effect relationship" means that the adverse event in 
question is the cause of death or that the adverse event is indeed related to death; 
F. F. Unknown: During the administration of the test drug or immediately after the 

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trial protocol, the visit cannot be conducted due to the transfer or discharge of the 
participant. 
9.5 Serious adverse event 
9.5.1 Definition of serious adverse events 
A serious adverse event (Serious Adverse Event, SAE) refers to an adverse event 
occurring during the research phase that meets one or more of the following criteria: 
A.  Cause death; 
B.  Life-threatening; 
C.  result in hospitalization or prolonged hospitalization; 
D.  Permanent or severe disability/disability; 
E.  Congenital malformations/birth defects. 
Some medical events that have not yet resulted in death, life risk, or need for 
hospitalization should be considered serious when they are deemed to be harmful to the 
participant or require medical or surgical treatment to avoid the above-mentioned 
conditions after proper medical judgment. Adverse events. 
9.6 Recording and reporting of serious adverse events 
The participants collected serious adverse events (SAE) during the last follow-up 
period after signing the informed consent form. 
If a serious adverse event occurs during the trial, regardless of whether it is related 
to the test drug, the investigator should immediately take first aid measures, fill out the 
serious adverse event report form, and report to the Anesthesiology Department of the 
Ninth People's Hospital and the Ethics of the Ninth People's Hospital within 24 hours 
after being informed Committee. 
10、Data management 
The entire experiment process strictly implements the clinical trial quality 
management regulations. All paper CRF records are complete, true, clear, and objective. 
After entering the test data into the computer, the data is locked and stored. 
10.1 Establishment of a case report form (CRF) 
The case report form (CRF) is filled in truthfully by the investigator, and each 
selected case must complete the case report form. The investigator is responsible for 

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the accuracy and authenticity of the CRF information of each participant. Each 
completed case report form is checked by the inspector for consistency, and if there is 
any missing or mis-filled data, the questionnaire is passed online to the researcher who 
filled out the case report form answer.  If you need to modify it, follow the CFR 
instructions and make changes. 
10.2 Data entry and modification 
After the consistency review is completed, the data administrator performs data 
entry and management, and checks the logic of the entered data. The data found in the 
verification process that are missing, logically contradictory, and uncertain can be 
passed to the researcher who filled out the case report form in the form of an online 
question, and the researcher should answer and return as soon as possible. The data 
administrator revises, confirms, and enters the data based on the researchers' answers. 
In order to ensure the accuracy of the data, two data entry staff should independently 
enter and proofread double copies. All online questions, feedback and modifications 
have left traces. 
10.3 Data review, lock, transfer 
After the data entry, questioning and modification are completed, the data 
management personnel, main researchers, statistical analysts, sponsors, and supervisory 
management personnel jointly participate in the data (blind) review meeting, and 
perform blind review on the data. Sign a blind review resolution. The data administrator 
then locks the database. Normally, the locked database or file cannot be changed. After 
the database is locked, submit it to a statistical analyst for statistical analysis. 
11、Statistical analysis 
11.1 General principles 
Statistical analysis was completed using SAS and SPSS software. All statistical 
tests use a two-sided test, and a P value of less than or equal to 0.05 will be considered 
statistically significant. 
Statistical description: Quantitative data is described by mean, standard deviation, 
median, P25, P75, minimum and maximum values, and qualitative data is calculated by 
frequency percentage for statistical description. 

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Statistical assumptions: To show that the folic acid + VitB12 intervention group 
and the placebo group of four groups of participants had a 90% confidence level 
difference in the rate of delirium during the recovery period, you need to statistically 
test the following hypotheses: 
H0：
π
　0=π1，That is, the two groups of participants had the same incidence of 
delirium during the recovery period 
H1：
π
　0≠π1 The incidence of delirium during awakening was not equal between 
the two groups of participants (α=0.05, bilateral) 
If the above hypothesis test results accept H1, reject H0. Then, you need to compare 
the groups to determine whether there is a statistical difference between the groups, and 
whether there is a statistical difference between the groups. 
Hypothetical test:  Quantitative indicators were compared using analysis of 
variance test or non-parametric test (Mann-Whitney U test); classification indicators 
were used chi-square test or Fisher's exact probability method. 
11.3 Homogeneity analysis 
The demographics and relevant baseline characteristics of the selected cases in 
each group were compared using appropriate statistical methods to test whether the two 
groups were balanced and comparable. 
11.4 Index evaluation and analysis 
Chi-square test or exact probability method was used to test the incidence of 
delirium in children during the recovery period. For other secondary observation 
indicators, based on the type of data, use appropriate statistical methods for comparison. 
11.5 Security analysis 
Safety analysis is given to the safety data set (SS). List the frequency and number 
of adverse events and adverse reactions in each group, calculate the incidence and 
corresponding severity of adverse events and adverse reactions in each group, and use 
chi-square test or Fisher exact probability method for comparison. 
11.6 Compliance analysis 
According to the data recorded in the drug return form, ≥80% indicates good 
compliance.