Effects of nalbuphine and sufentanil on stress response and immune response in patients undergoing thoracoscopic unilateral lobectomy : A randomized controlled trial

doi:10.21203/rs.3.rs-5255274/v1

Background:

According to the statistics of the American Cancer Society in 2024, the incidence of lung cancer ranks second, but its mortality rate ranks first. Thoracoscopy is one of the commonly used surgical methods in recent years. This study was to investigate the effects of nalbuphine on stress response, immune function and analgesic effect in patients after thoracoscopic surgery.

Methods

This study was a prospective trial of patients after thoracoscopic lung cancer resection. The cohort was randomly divided into two groups : nalbuphine group ( RN group ) and sufentanil group ( RS group ). Thoracic paravertebral nerve block was performed before surgery in both groups. RN group : 0.75% ropivacaine ( 10ml ) + nalbuphine ( 0.2mg / kg ) + normal saline = 20ml. RS group : 0.75% ropivacaine ( 10ml ) + sufentanil ( 0.2µg / kg ) = 20ml. After surgery, all patients were rescued with PCIA. RN group : nalbuphine 2 mg / kg + normal saline = 150 ml, RS group : sufentanil (2 µg / kg ) + normal saline = 150 ml.

Results:

Compared with RS group, ( 1 ) CD3 in T2 and T3 RN group was higher ( P < 0.05 ). ( 2) ACTH in RN group was lower at T3 ( P < 0.05 ). ( 3 ) IL-6 in RN group was lower at T3 ( p < 0.05 ) ; ( 4 ) compared with RS group, the VAS scores of patients in RN group were significantly lower within 2 hours and 24 hours after operation ( P < 0.05 ).

Conclusion :

In patients undergoing thoracoscopic lobectomy, nalbuphine can reduce stress response and immunosuppression, reduce postoperative inflammatory response, relieve postoperative rest pain, and facilitate postoperative rehabilitation.

nalbuphine

sufentanil

thoracoscopy

stress response

immune response

According to the statistics of the American Cancer Society in 2024, the incidence of lung cancer ranks second, but its mortality rate ranks first ^[1]. At present, video-assisted thoracoscopic surgery is the most commonly used treatment for lung cancer surgery, which has less trauma and better survival rate than open surgery ^[2].

Paravertebral nerve block ( PVB ) was first created by Hugo Sellheim in 1905 and used to relieve abdominal pain^[3]. In 1922, Arthur Lawen improved Hugo Sellheim 's technique. By 1979, Eadon and Wyatt re-examined the role of PVB and re-emphasized this technology^[4]. PVB can be used for unilateral block, bilateral block, and continuous catheter block^[5]. Both ropivacaine and bupivacaine are commonly used local anesthetics for thoracic paravertebral nerve block. In order to prolong the action time of local anesthetics and reduce the side effects of local anesthetics, TPVB 's local anesthetics are often supplemented with : dexmedetomidine ^[6], sufentanil ^[7], naloxone ^[8], buprenorphine ^[9], nalbuphine^[10], epinephrine ^[11], etc.

Nalbuphine is a new semi-synthetic opioid receptor analgesic. Compared with other opioids, nalbuphine has mild adverse reactions such as nausea and vomiting, respiratory depression, and urinary retention^[12]. Compared with other opioid receptor agonist antagonists ( such as butorphanol, dezocine ), nalbuphine has a longer half-life and longer action time. However, there are few studies on the effect of nalbuphine on the postoperative immune system. The latest research^[13] shows that: Nalbuphine-6-glucuronide ( N6G ) is one of the glucuronic acid metabolites of nalbuphine, which can promote stronger analgesic effect. The analgesic effect of N6G is enhanced by increasing the affinity and selectivity of μ and κ receptors. Studies have pointed out that nalbuphine can effectively slow down the inflammatory response, and can block the peripheral and central sensitization process, reduce the acute and chronic pain after surgery, which is conducive to the rapid recovery of patients after surgery. Yingping Jia et al. ^[14] showed that in patient-controlled intravenous analgesia ( PCIA ) after tonsillectomy in children, the nalbuphine group could reduce the stress response after tonsillectomy in children and reduce postoperative pain.

Because there are few studies comparing the effects of nalbuphine and sufentanil on stress response, this study used nalbuphine as a thoracic paravertebral nerve block adjuvant combined with PCIA multimodal analgesia compared with sufentanil as an adjuvant to observe its effect on postoperative stress response and immunosuppression in patients undergoing thoracoscopic unilateral lobectomy. Improve postoperative pain management efficiency and accelerate patient recovery.

Research Design

This is a prospective, randomized clinical trial. The aim of this study was to compare the effects of nalbuphine and sufentanil on stress response and immune response in patients undergoing thoracoscopic lobectomy. The study was approved by the hospital ethics committee ( Ethical No. : 2022038 ), with the consent of the patient and signed informed consent.

Randomly selected respondents who had no mental illness and had the ability to participate in the questionnaire survey from March 2023 to January 2024. ASA I or II, aged 18-65 years, BMI 18-32 kg / cm² .Exclusion criteria : communication disorder ; history of opioid allergy ; history of mental illness, history of chronic pain, history of alcohol dependence, history of long-term use of other analgesic drugs ; history of drug abuse ; liver and kidney function indicators were significantly abnormal ( higher than the normal value of 2 times or more ) ; coagulation dysfunction. In this study, 150 eligible patients were recruited and divided into two groups, one group was nalbuphine group ( RN group ) and the other group was sufentanil group ( RS group ), with 75 cases in each group.

Methods

All patients were fasted and forbidden to drink before operation. After entering the operating room, the electrocardiogram ( ECG ), pulse oxygen saturation ( SpO₂ ), mean arterial pressure ( MAP ) and bispectral index ( BIS ) were monitored.Conventional open peripheral venous access, intravenous infusion of compound sodium chloride injection, mask oxygen inhalation( 2 L / min ), ultrasound-guided radial artery and right internal jugular vein puncture, catheterization, detection of invasive arterial blood pressure and central venous pressure. Before the operation, the two groups of patients took a lateral decubitus position, and T3-4 and T6-7 were selected as the puncture points to perform ultrasound-guided paravertebral nerve block on the affected side. After the puncture needle reached the target position, local anesthetics were injected. RN group : 0.75 % ropivacaine ( 10ml ) + nalbuphine hydrochloride ( 0.2mg / kg ) + normal saline = 20ml, 10ml was injected into each gap. RS group : 0.75 % ropivacaine ( 10ml ) + sufentanil ( 0.2μg / kg ) + normal saline = 20ml, 10ml was injected into each gap. After 10 min, the block plane was tested by acupuncture.

All patients were given the same induction regimen : intravenous injection of midazolam ( 0.03 mg / kg ), sufentanil ( 0.2 μg / kg ), propofol ( 1.5 mg / kg ) and rocuronium ( 0.6 mg / kg ). Manual ventilation. After the patient 's consciousness disappeared and the jaw was completely relaxed, the orotracheal intubation was guided by the visual laryngoscope, and the bronchial occluder was placed under the guidance of the fiberoptic bronchoscopy. Mechanical ventilation was performed after successful positioning. The PCV-VG mode was used in the ventilator during the operation. The tidal volume was set at 6-8ml / kg, the respiratory rate was 14-20 times / min, the PEEP value was set at 3-5cmH2O, the inhalation oxygen flow rate was 1-2L / min, SpO2 > 90 %, assisted low-dose sevoflurane ( 0.6%--1% ) inhalation anesthesia, intravenous infusion of remifentanil ( 0.1-0.3μg / kg / min ), propofol ( 4-12mg / kg / h ), according to the depth of anesthesia，the amount of anesthetic drugs was adjusted to maintain the bispectral index BIS value between 40 and 60. End-tidal carbon dioxide ( PETCO₂ ) was monitored to maintain PETCO₂ at 35 ~ 45 mmHg. Vasoactive drugs ( norepinephrine, atropine, dopamine ) were prepared during the operation. The dosage of each drug was reasonably adjusted according to the intraoperative conditions, so that the fluctuation range of HR and MAP did not exceed ± 20 % of the basic value.

After operation, both RN group and RS group were given intravenous analgesia pump ( PCIA ). The drug in PCIA of RN group : nalbuphine hydrochloride ( 2mg / kg ) + normal saline = 150ml. Drugs in PCIA of RS group : sufentanil ( 2μg / kg ) + normal saline = 150ml. There was no background infusion. The PCIA volume was 2 ml and the locking time was 15 minutes. The patients were sent to the post-anesthesia care unit the Postanesthesia Care Unit (PACU) to reach the standard of discharge and returned to the ward. If the pain score was > 4 points, PCIA compression was performed to relieve the pain. If severe nausea and vomiting occurred, ondansetron 48 mg was given.

Observational indicators :

Main indicators :

The levels of CD3, CD4, IL-6, ACTH and COR in serum were measured before operation ( T1 ), 2 h after operation ( T2 ) and 24 h after operation ( T3 ). Collect 5ml venous blood of patients before operation ( T1 ), 2h after operation ( T2 ) and 24h after operation ( T3 ), and then centrifuge at 2800r / min for 10 min by centrifuge, remove the serum, and detect the levels of CD3, CD4, IL-6, ACTH and COR in serum according to the ELISA kit detection method.

Secondary indicators :

( 1 ) Collect basic data including : patient 's age, gender, ASA classification, body mass index ( BMI ), operation time, hospitalization days.

( 2 ) The mean arterial pressure and heart rate were collected at the time of entering the operating room, after thoracic paravertebral nerve block and during skin incision.

( 3 ) Postoperative resting and active VAS scores were collected : resting 2h, 12h, 24h and 12h, 24h, 48h after activity. The time from the first time to get out of bed after operation, the number of PCIA compressions, the length of hospital stay, and whether nausea and vomiting occurred.

Sample size

Since there is no accurate comparison of the effects of nalbuphine and sufentanil on postoperative immune and stress responses, the main indicators are defined as postoperative immune indicators. It is assumed that the difference between the two groups is as high as 20 %. According to the unilateral test using PASS15.0 software to test the efficiency of the inspection at the level of α = 0.025,1 − β = 0.8, it was determined that each group should contain at least 60 participants.

Statistical analysises

SPSS26.0 software was used for data analysis. The measured data were expressed as (±s). The data between groups were compared by independent sample t test. The data without normal distribution were analyzed by M ( Q1, Q3 ). Mann-Whitney test was used. The measured data were analyzed by 2 test. P < 0.05 indicated that the difference was statistically significant.

For 150 patients, 5 cases were excluded due to the failure of thoracic paravertebral nerve block in the RN group during the follow-up period, and 4 cases were lost to follow-up after operation. In the RS group, 4 cases were excluded due to the failure of thoracic paravertebral nerve block, and 6 cases were excluded from follow-up after operation. Finally, there were 66 cases in the RN group and 65 cases in the RS group, a total of 131 cases, as shown in Chart 1.

General address data

There was no significant difference in baseline characteristics between the two groups ( P > 0.05 ), as shown in Table 1.

Table 1
	Group RN(n = 66)	Group RS(n = 65)	t/χ²	P
age(\(\:\overline{x}\)±s, years)	56.24 ± 7.44	56.24 ± 7.17	-0.569	0.570
Gender(M/F, n)	27/39	35/30	2.199	0.138
Body weight(\(\:\overline{x}\)±s, kg)	64.86 ± 7.38	63.58 ± 7.08	1.012	0.313
ASA(Ⅰ/Ⅱ, n)	44/22	50/15	1.700	0.192

There was no significant difference in mean arterial pressure and heart rate between the two groups at admission, after TPVB block and at skin incision ( P > 0.05 ), as shown in Table 2.

Table 2
Time	Group	MAP(mmHg)	Hear rate(times/min)
preoperatively	Group RN(n = 66)	102.71 ± 13.19	78.14 ± 8.57
	Group RS(n = 65)	104.49 ± 8.61	81.20 ± 12.20
T		-0.913	-1.665
P		0.363	0.098
After TPVB	Group RN(n = 66)	95.98 ± 12.60	80.80 ± 8.93
	Group RS(n = 65)	100.08 ± 12.26	78.35 ± 8.28
T		-1.884	1.627
P		0.062	0.106
skin incision incision	Group RN(n = 66)	88.51 ± 11.40	79.65 ± 8.57
	Group RS(n = 65)	86.40 ± 10.75	82.20 ± 8.00
T		1.092	-1.785
P		0.277	0.081

Compared with the RS group, the CD3 of the RN group was higher at T2 and T3, and the difference was statistically significant ( P < 0.05 ), and the increase of CD3 in the RN group was significantly higher than that in the RS group,as shown in Chart 2.

There was no significant difference in CD4 between RN group and RS group at all time points ( P > 0.05 ), as shown inTable 3.

Table 3
Group	T1	T2	T3
Group RN(n = 66)	27.25 ± 10.82	37.03 ± 12.47	50.23 ± 12.58
Group RS(n = 65)	27.80 ± 8.32	36.79 ± 11.80	49.93 ± 15.59
T	-0.322	0.114	0.123
P	0.748	0.910	0.149

Compared with the RS group, ACTH in the RN group was lower at T3, and the difference was statistically significant ( P < 0.05 ), as shown in Chart 3.

There was no significant difference in COR levels between the RN group and the RS group at all time points ( P > 0.05 ), as shown in Table 4.

Table 4
Group	T1	T2	T3
Group RN(n = 66)	5.25 ± 2.00	4.72 ± 1.64	4.45 ± 2.04
Group RS(n = 65)	4.94 ± 2.00	4.34 ± 1.59	4.68 ± 2.30
T	0.876	1.351	-0.599
P	0.383	0.179	0.550

Compared with the RS group, the IL-6 of the RN group was lower at T3, and the difference was statistically significant ( P < 0.05 ), as shown in Chart 4.

Comparison of resting and dynamic VAS scores between the two groups of patients : Compared with the RS group, the VAS scores of patients in the RN group were significantly lower at 2h and 24h after surgery, and the difference was statistically significant ( P0.05 ). as shown in Table 5.

Table 5
Group	VAS score at rest			VAS score in active
	postoperative 2h	postoperative 12h	postoperative 24h	activities post 2h 12h	activities post 24h 24h	activities post 48h 48h
Group RN(n = 66)	1.5(1 ~ 2)	2(1 ~ 2)	1(1 ~ 1)	6(5 ~ 7)	6(5 ~ 7)	5(4 ~ 6)
Group RS(n = 65)	2(1 ~ 2)	2(1 ~ 2)	1(1 ~ 2)	6(5 ~ 7)	6(6 ~ 7)	5(4 ~ 6)
Z	-2.158	-0.842	-2.085	-0.650	-1.073	-0.383
P	0.031	0.400	0.037	0.516	0.283	0.702

There was no significant difference in the incidence of postoperative nausea and vomiting between the two groups after the activity ( P > 0.05 ), as shown in Table 6.

Table 6
Group	nausea and vomiting
Group RN (n = 66)	8(12)
Group RS (n = 65)	13(20)
χ²	1.510
P	0.219

Lung resection is the gold standard for the treatment of non-small cell lung cancer .Studies have shown that^[15]VATS is closely related to perioperative complications, pain and related duration and significant reduction of hospital stay. The most significant advantage of nalbuphine is that it has little effect on respiratory and cardiovascular function, does not increase cardiac load, does not change heart rate and blood pressure, and does not lead to more severe respiratory depression and prolonged duration ^[16]. Sufentanil is an opioid drug with high selectivity for µ receptor agonists. The efficacy of sufentanil is about 5 to 10 times that of fentanyl. It is reported that the efficacy of fentanyl is 50–100 times that of morphine[17], which indicates that the equivalent dose ratio of sufentanil to morphine is 250–1000 :1. It has been reported[18] that the same dose of nalbuphine and morphine have similar analgesic effects, and the equivalent dose ratio of sufentanil to nalbuphine should be 250–1000 :1. According to the above literature, the equivalent dose ratio of sufentanil to nalbuphine was 1000 : 1.

After anesthesia and surgical treatment, various inflammatory factors are released by the stressed body, and the inflammatory factors enter the blood, causing systemic inflammatory response and affecting the postoperative rehabilitation of patients, which is a common factor leading to postoperative pain ^[19]. During the perioperative period, due to the stimulation of surgery or pain, the immune system is inhibited to varying degrees. Immune function indicators include CD3 T cells, CD4 T cells, CD8 T cells, NK cells and B cells. The degree of inflammatory reaction was consistent with the degree of surgical injury. It has been reported^[20] that a decrease in total T cells ( CD3 cells ) and a decrease in WBC counts are associated with infectious diseases and sepsis. In the current study, a low percentage of CD3 cells is a factor that causes systemic inflammatory response syndrome ( SIRS ) after percutaneous nephrolithotomy. The decrease in the proportion of T cells may indicate impaired cellular immune function, which is not enough to resist the invasion of harmful factors after surgery. Because anesthetic drugs can cause stress response in the human body, thus affecting the normal level of T lymphocytes. The administration of nalbuphine can reduce the total amount of anesthetic drugs to a certain extent and reduce the degree of stress response, thereby improving the patient 's immune dysfunction. It has been reported ^[21] that the high density of CD3 and CD8 T cells is closely related to the recurrence rate of breast cancer patients. The higher the activity, the lower the recurrence rate and the higher the survival rate of patients. Therefore, it is beneficial for cancer patients with high cell density of CD3 and CD8. It has been reported^[22] that the number of CD3 and CD4 increased significantly after nalbuphine was used in hysteroscopic surgery. In this experiment, the increase of CD3 in the nalbuphine group was greater than that in the sufentanil group, but there was no significant difference in CD4 between the two groups, indicating that the immunosuppressive effect of the nalbuphine group was weaker than that of the sufentanil group. This may be related to the fact that nalbuphine, as an adjuvant, can provide better analgesic effects, or that nalbuphine has a certain protective effect on the immune system. The specific mechanism needs further study.

The main indicators of endocrine stress response include adrenaline, norepinephrine, ACTH and cortisol. The increase of ACTH and cortisol in plasma after operation is related to the severity of surgical injury ^[23]. However, there are few data on the effects of infiltration anesthesia or nerve block on stress response. Bin AN ^[24]et al. found that multimodal analgesia of nalbuphine and PCIA can effectively alleviate the stress response and inflammatory response of patients after radical gynecological malignant tumor surgery, reduce the pain perception of patients, and have high safety. After 24 hours, ACTH in the nalbuphine group was significantly lower than that in the sufentanil group, but there was no significant difference in COR between the nalbuphine group and the sufentanil group, indicating that nalbuphine may reduce postoperative stress response. The specific mechanism needs further study. The ACTH in the nalbuphine group was lower than that in the sufentanil group, which was consistent with the results of Yingping Jia et al. ^[14] using nalbuphine or sufentanil PCIA in children after tonsillectomy and adenoidectomy. The levels of ACTH and IL-6 in the nalbuphine group were lower than those in the sufentanil group, but the results of COR in this experiment were inconsistent with those in this experiment, which needed further study.

The tissue damage caused by surgery can activate the immune system in the periphery, leading to the infiltration of inflammatory cells and the release of inflammatory mediators (IL-1, IL-6, etc.) ^[25]. Single lung ventilation and other factors during thoracic surgery make the lungs prone to ischemia-reperfusion injury, leading to oxidative stress, lung injury, and the release of inflammatory factors ^{[26, 27]} .Effective regional nerve blockade causes less oxidative stress after surgery^[28]. Some studies have explored the relationship between nerve block and inflammatory factors, and found that nerve block inhibits the increase of inflammatory factors in plasma, thereby reducing pain stimuli^{[29, 30]}. Negative emotions can alter the permeability of the blood-brain barrier, leading to the infiltration of central inflammatory cells into the periphery and further enhancing the neuroinflammatory state^[31]. Therefore, a good analgesic effect can alleviate negative emotions, thereby reducing inflammatory factors. At the same time, a low inflammatory response can alleviate pain, and the two interact with each other. In our study, the concentration of IL-6 inflammatory factors in the nalbuphine group was lower than that in the sufentanil group 24 hours after surgery, but no significant difference was observed before and 2 hours after surgery. This may increase the intake of nalbuphine 24 hours after surgery, enhance intravenous analgesia, and more effectively inhibit postoperative inflammation. Meng et al. ^[32]found in orthognathic surgery experiments that the plasma levels of NF - α, IL-6, and MDA in the nalbuphine group were significantly lower than those in the sufentanil group, while the SOD level was higher than that in the sufentanil group. The VAS score was positively correlated with the plasma levels of TNF - α, IL-6, and MDA, and negatively correlated with the SOD level, which is consistent with this study.

Chen et al. ^[33] found in emergency outpatient induced abortion that compared to sufentanil with equivalent efficacy, nalbuphine had better analgesic effects at 2 and 3 hours after surgery. This study found that the pain scores of the nalbuphine group were better than those of the sufentanil group at rest 2 hours and 24 hours after surgery, indicating that its analgesic effect was better than that of the sufentanil group, while there was no difference in pain scores between the two groups during activity. This is because nalbuphine can effectively alleviate visceral pain ^[34], thereby reducing pain caused by rest. The lack of statistical difference after 12 hours of rest may be due to the effective relief of pain by thoracic paravertebral nerve block, resulting in less use of PCIA dosage in patients and a decrease in nalbuphine intake, without sufficient dosage to alleviate visceral pain. The 24-hour difference may be due to the disappearance of the analgesic effect of thoracic paravertebral nerve block, and the increased use of PCIA by patients, leading to an increase in the intake of nalbuphine. Paola et al. ^[35] found that nalbuphine can effectively control acute pain in burn patients after surgery, which may be one of the reasons why nalbuphine has a better analgesic effect than sufentanil in the resting state. Kang et al. ^[36] found in a retrospective cohort study of nalbuphine and sufentanil after cesarean section that nalbuphine had a better analgesic effect on uterine contraction pain than sufentanil. Deng et al. ^[37] found in a colonoscopy study that the incidence of nausea in the nalbuphine group was significantly higher than that in the sufentanil group. This is inconsistent with the results of this study, as there was no statistically significant difference in the incidence of nausea and vomiting between the two groups of patients in this experiment. Chen et al. ^[38] found no difference in the incidence of nausea and vomiting between nalbuphine and sufentanil in laparoscopic surgery for gynecological malignancies, which is consistent with the results of this study. The occurrence of different adverse reaction results may be due to insufficient sample size in this experiment and Chen's experiment. Deng et al. also mentioned in their experiment that there may be no difference in the case of insufficient sample size, and their experimental sample size is large enough (240 cases).

In summary, nalbuphine as an adjuvant for paraspinal nerve block and postoperative analgesia has a better comprehensive effect on patients undergoing thoracoscopic lobectomy than sufentanil. It can reduce stress response, immune suppression, and the degree of resting pain at 2 and 24 hours after surgery, which is beneficial for patient recovery.

PCIA:Patient-controlled intravenous anagesia

ASA: Visual Analogue Score

BMI: Body Mass Index

ECG: Electrocardiograph

SPO2: Oxygen Saturation

MAP:mean arterial pressure

TPVB:Thoracic paravertebral block

IL-6：Interleukin-6

ACTH：adrenocorticotropic hormone

COR：Cortisol

ELISA: Enzyme-linked immunosorbent assay

VAS:Visual analog score

WBC: white blood cells count

SOD :superoxide dismutase

MDA :malondialdehyde

TNF-α:factor-α

Acknowledgements

We would like to express our gratitude to all the thoracic and cardiac surgeons and anesthesiologists who participated in the collaboration of this study. We would also like to thank the committee for their valuable feedback.

Funding

This study was funded by the Science and Technology Development Program of Kaifeng City, China (2303042).

Author Information

Chengxu Du, Qianyi Cheng, and Pan Chen made similar contributions to this work.

Authors and Affiliations

Chengxu Du

The Seventh People 's Hospital of Zhengzhou City, 450000, China

Qianyi Cheng

Huaihe Hospital of Henan University, Kaifeng City, 450000, China

Pan Chen

Huaihe Hospital of Henan University, Kaifeng City, 450000, China

Wenqi Xin

Huaihe Hospital of Henan University, Kaifeng City, 450000, China

Contributions

Wenqi Xin contributed to the design and guidance of the study, including Chengxu DU to collect samples and data interpretation, and Qianyi Cheng and Pan Chen contributed to the preparation of the manuscript. Wenqi Xin have reviewed the manuscript and approved its submission.

Corresponding author

Correspondence to WenQi Xin， Email ：[email protected]

Ethics approval and consent to participate

We obtained a review by the Ethics Committee of Huaihe Hospital, Henan University, No. 2022038.

Consent for publication

Not applicable

Clinical trial number:

Not applicable

Competing interests

The authors declares that there are no competing interests

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Chart 1 To 4 are available in the Supplementary Files section.

No competing interests reported.

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Chart 1
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Chart 2
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Chart 3
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Chart 4

Effects of nalbuphine and sufentanil on stress response and immune response in patients undergoing thoracoscopic unilateral lobectomy : A randomized controlled trial

Status:

Version 1

Abstract

Background:

Methods

Results:

Conclusion :

BACKGROUND

Methods

Results

General address data

Discussion

Abbreviations

Declarations

References

Chart 1 To 4

Additional Declarations

Supplementary Files

Status:

Version 1