|Ahead of print publication
Effect of nitrous oxide on clinical outcome in patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia: a randomized controlled trial
Barkha Bindu, Gyaninder Pal Singh, Mihir Prakash Pandia
Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||30-Sep-2021|
|Date of Acceptance||21-Jan-2022|
|Date of Web Publication||15-Jul-2022|
Mihir Prakash Pandia,
Correspondence to: Mihir Prakash Pandia, MD
Source of Support: None, Conflict of Interest: None
Nitrous oxide (N2O) is a unique anesthetic agent that has both advantages and disadvantages, especially in neurosurgical patients. Various studies evaluating the use of N2O in different surgical populations have been inconclusive so far. In this prospective, single-blinded, randomized study, 50 patients of either sex, aged 18-60 years, were enrolled and randomly allocated into N2O or N2O free group. Data including demographics, intraoperative vitals, blood gases, intravenous fluids, anesthetic drug consumption, brain condition, emergence and recovery time, duration of surgery and anesthesia, duration of postoperative ventilation, perioperative complications, condition at discharge, and duration of intensive care unit & hospital stay were recorded. There was no significant difference in intensive care unit or hospital stay between the groups. However, a significant difference in intraoperative heart rate and mean arterial pressure was observed. The incidence of intraoperative tachycardia and hypotension was significantly higher in the N2O free group. Other intra- and post-operative parameters, perioperative complications, and conditions at discharge were comparable. Use of N2O anesthesia for cerebellopontine tumor surgery in good physical grade and well-optimized patients neither increases the length of intensive care unit or hospital stay nor does it affect the complications and conditions at discharge. However, future studies in poor-grade patients with large tumors and raised intracranial pressure will be required to draw a definitive conclusion.
Keywords: brain bulge; cerebellopontine tumor surgery; complications; hospital stay; infratentorial compartment; intensive care unit stay; neuroanesthesia; nitrous oxide; pneumocephalus; sevoflurane
|How to cite this URL:|
Bindu B, Singh G, Pandia M. Effect of nitrous oxide on clinical outcome in patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia: a randomized controlled trial. Med Gas Res [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.medgasres.com/preprintarticle.asp?id=351105
| Introduction|| |
Nitrous oxide (N2O), for many decades, has been an indispensable component of general anesthesia. The use of N2O as a basic component of general anesthesia has been questioned due to the evolution of newer anesthetic agents and anesthesia techniques and the recognition of various adverse effects of N2O.
N2O as an anesthetic agent has both advantages and disadvantages. Major concerns with its use include its short duration of action, ability to expand air-filled spaces, postoperative nausea and vomiting (PONV), bone marrow depression, demyelination, neuronal degeneration, and neurotoxicity, subacute combined degeneration of the spinal cord, postoperative myocardial ischemia and health risks to operating room personnel. It also increases cerebral blood flow and cerebral metabolic rate, impairs cerebral autoregulation, and may increase intracranial pressure (ICP), thus making its use in neurosurgical procedures further questionable. On the other hand, it has an anesthetic sparing effect resulting in less cardiovascular and respiratory depression, less potential for drug interactions, predictable pharmacokinetics, rapid induction and recovery from anesthesia, and a combination of amnesic and analgesic properties.
Various studies performed in neurosurgical patients so far have not shown any conclusive evidence of specific harm caused by the use of N2O. Most of the previous studies in neurosurgical patients evaluated the effect of N2O in supratentorial surgeries and did not find significant differences either in complications or in length of stay when compared with air., However, there is limited literature specifically addressing the effect of N2O in infratentorial compartment surgeries, which is tighter compared to the supratentorial compartment. The infratentorial compartment harbors important structures like the brainstem, cranial nerves, cerebellum, and ascending and descending tracts within a limited space. Any complication here is likely to have more severe adverse effects, thereby increasing the length of stay. Currently, anesthesia for infratentorial tumor surgeries involves the use of inhalational anesthetic agents, both with and without N2O.
We conducted this randomized controlled trial with the hypothesis that the use of N2O will increase complications and thus the length of intensive care unit (ICU) and hospital stay. Our primary objective was to compare the mean duration of ICU stay and hospital stay in patients undergoing elective cerebellopontine tumor excision surgery under sevoflurane anesthesia with and without N2O. We also compared intraoperative brain condition, emergence, and recovery from anesthesia, hemodynamic parameters, perioperative complications, duration of postoperative ventilation, and condition at discharge.
| Subjects and Methods|| |
The randomized controlled study was conducted after obtaining approval from the Institute Ethics Committee of All India Institute of Medical Sciences, New Delhi (Ref. No. IECPG-5/28.10.2015, RT-3/27.11.2015; dated November 30, 2015; Additional file 1) and registered at Clinical Trials Registry India (CTRI/2016/01/006574) on January 28, 2016. This study followed the CONsolidated Standards Of Reporting Trials (CONSORT) statement [Additional file 2]. In the absence of prior adequately powered studies, the sample size for the present study was calculated based on the data of ICU and hospital stay of patients operated for cerebellopontine tumors over 2 months at the investigators’ institute. Considering a significant difference of 12 hours in the length of ICU stay and 2 days in the length of hospital stay between the two groups, 22 patients were required in each group (confidence interval 95%; power 90%). Assuming 10% dropouts, 50 patients (25 in each group) were recruited.
Patient recruitment started on March 9, 2016 and ended on March 30, 2017. All patients admitted for cerebellopontine angle tumor surgery were screened for eligibility. Adult patients aged between 18-60 years with American Society of Anesthesiologists physical status class I & II, posted for elective cerebellopontine angle tumor surgery with an anticipated duration of anesthesia of more than 6 hours were included in the study. Patients with poor sensorium (Glasgow Coma Scale < 15), hemoglobin < 10 g/dL, body mass index > 35 kg/m2, uncontrolled diabetes or hypertension, bleeding disorders, history of smoking, pregnant females, patients planned for surgery in sitting position, pneumocephalus on computer tomography scan, pneumothorax, patients with a history of pulmonary, renal, cardiac or hepatic disorders and patients not willing to participate were excluded. Patients with features of raised ICP or dilated ventricles were also excluded. However, patients who had ventriculoperitoneal shunt were included. Written informed consent [Additional file 3] was obtained from all patients before enrollment. All patients underwent preoperative evaluation a day before surgery and were fasted for 8 hours before surgery. Patients were allocated using computer-generated randomization to either N2O or N2O-free group; allocation concealment was done using serially numbered identical opaque envelopes. Twenty-five patients were included in each group.
In the operating room, standard monitoring (electrocardiography, non-invasive blood pressure, and pulse oximetry) was started. The radial artery of the non-dependent arm was cannulated under local anesthesia; baseline values of heart rate (HR), invasive blood pressure (mean arterial pressure), oxygen saturation, and arterial blood gases were recorded before induction of anesthesia. After preoxygenation, general anesthesia was induced with fentanyl (Verve Human Care Laboratories, Dehradun, Uttarakhand, India) 2μg/kg and thiopentone (Neon Laboratories Limited, Mumbai, Maharashtra, India) 4–6 mg/ kg. Rocuronium (Celon Laboratories Pvt. Ltd. Medchal, Telangana, India) 1 mg/kg was used for facilitating tracheal intubation; an additional dose of thiopentone (Neon Laboratories Limited) 1-2 mg/kg was given before laryngoscopy and intubation to prevent the pressor response to intubation. General anesthesia was maintained using sevoflurane, with N2O (60%) in the N2O group and medical air in the N2O-free group, with oxygen concentration 40% in both groups. A total minimum alveolar concentration (MAC) of 0.8-1.2 was maintained with a gas flow rate of 2 L/min in each group. Intraoperatively, a continuous infusion of fentanyl (1μg/kg/h) and rocuronium (5 μg/kg/min) was started and titrated as per requirement. Patients were placed in Park bench position and the head was fixed with headpins. Mannitol (20% w/v; Albert David Limited, Ghaziabad, Uttar Pradesh, India) in a dose of 1 g/kg was administered at the start of skin incision over 20-30 minutes. Dexamethasone was used in all patients. Muscle relaxant infusion was stopped once craniotomy was done, to enable facial nerve monitoring, and was restarted once tumor excision was completed. Use of any other drugs, intravenous fluids (crystalloids and colloids), blood and blood products was at the discretion of the attending anesthesiologist who was aware of the group allocation of the patient. Intraoperative monitoring included electrocardiography, HR, mean arterial pressure, oxygen saturation, end-tidal carbon dioxide, MAC, central venous pressure, core body temperature, urine output, intravenous fluid administered, blood loss, blood transfusion, and arterial blood gases. Intraoperative parameters were recorded pre-induction, at induction, pin insertion, skin incision, followed by hourly intervals, at skin closure, and extubation or shifting (if not extubated). Intraoperatively, end-tidal carbon dioxide was maintained in the range of 32 ± 2 mmHg and gradually increased to 35-40 mmHg at the time of dural closure. End-tidal carbon dioxide was correlated with the partial pressure of carbon dioxide in all patients. Rocuronium and fentanyl infusion was switched off at the end of dural closure. Sevoflurane was tapered to a MAC of 0.5 at the start of skin closure. Both N2O and sevoflurane were switched off after the removal of headpins. Neuromuscular block was reversed (unless planned for postoperative mechanical ventilation) and the trachea was extubated after assessing neurological recovery. Patients with more than 3 episodes of intraoperative brainstem handling causing hemodynamic fluctuations, presence of brain bulge during the closure of craniotomy, intraoperative blood loss of > 40% of total blood volume, patient not following commands, and any other neurosurgical concerns hampering the safe extubation of patients was planned for elective postoperative ventilation. All patients were shifted to neurosurgical ICU for postoperative monitoring and observation or postoperative mechanical ventilation. Patients requiring mechanical ventilation were sedated using fentanyl and midazolam infusion, titrated to a Ramsay Sedation Scale score of 2-3. Every morning, sedation was stopped, and Glasgow Coma Scale was assessed. Sedative infusions were restarted if indicated. The trachea was extubated once standard extubation criteria were fulfilled.
Intraoperatively, the operating surgeon (unaware of the group allocation) assessed the brain condition (degree of brain bulge) based on a three-point scale immediately after opening the cranial cavity and again after opening the dura mater. Intraoperative brain bulge was graded as grade I (protrusion of brain matter within the margin of the inner table of the skull), grade II (within the margin of the outer table of the skull), and grade III (outside the margin of the outer table of the skull). The attending anesthesiologist (aware of group allocation) recorded any intraoperative complications (brady/tachycardia, hypo/hypertension, venous air embolism, brain bulge, increased airway pressure, desaturation, etc.), emergence time (time between discontinuation of anesthetics to eye-opening spontaneously or on verbal prompting repeated every 2 minutes), extubation time (time between discontinuation of anesthetics and extubation of trachea) and recovery time (time between discontinuation of anesthetics to the ability to recall their name and age). Any postoperative complications (early - within 48 hours, late - after 48 hours of surgery), ICU stay, and hospital stay were recorded by an independent observer not aware of group allocation. Mean duration of ICU stay and hospital stay were the primary outcome measures of this study.
The software Stata 12.0 (StataCorp LP, College Station, TX, USA) was used for statistical analysis. Categorical and continuous data are expressed in frequency (%) and mean (standard deviation)/median (range), respectively. Categorical variables were compared using Fisher’s exact test between the two groups. Continuous variables that followed normal distribution were compared using Student’s t-test for comparison of mean between the two groups. Continuous variables that did not follow normal distribution were compared using the Wilcoxon rank-sum test for comparison of median between the two groups. The primary outcomes of the study were the length of ICU stay and length of hospital stay and were compared using the Wilcoxon rank-sum test. Secondary outcomes (i.e. intra- and post-operative clinical and monitoring parameters) were compared using Wilcoxon rank-sum test or Generalized Estimating Equation, for comparison both within and between groups and intra- and post-operative complications were compared using Fisher’s exact test. A P value less than 0.05 was considered statistically significant. The statistical methods of this study were reviewed by the biostatistician of All India Institute of Medical Sciences, New Delhi, India.
| Results|| |
The study was conducted over 18 months. A total of 137 patients were screened and 50 patients (25 in each group) were enrolled in the study. Two patients were excluded after enrollment and data of the remaining 48 patients were analyzed [Figure 1]. Demographics and baseline tumor characteristics were comparable between the two groups (P > 0.05; [Table 1]). Intraoperative parameters were comparable between the two groups [Table 2]. No significant differences were observed between the groups in electrocardiography recordings, oxygen saturation, end-tidal carbon dioxide, MAC, central venous pressure, core body temperature, and arterial blood gases. Overall, 15 patients (7 in the N2O group; 8 in the N2O-free group) were extubated in the operating room. The emergence time, extubation time, and recovery time in these patients were comparable between the two groups [Table 2]. Seventeen patients in the N2O group and 16 patients in the N2O-free group required postoperative mechanical ventilation. All but one patient in each group were weaned off the ventilator within 48 hours of surgery. Duration of postoperative ventilation and total consumption of fentanyl and midazolam in ICU were comparable between the two groups [Table 2]. There was no significant difference in the duration of ICU and hospital stay between the groups [Table 2]. Conditions at discharge were comparable between the two groups (P = 0.540); postoperative neurological status was the same as the preoperative status (i.e. no deterioration in Glasgow Coma Scale by > 1 point or no new motor/sensory deficit) in 15 (62%) and 17 (71%) patients in the N2O and N2O-free groups, respectively.
|Figure 1: CONsolidated Standards Of Reporting Trials (CONSORT) diagram.|
Note: MEP: Motor evoked potential; TIVA: total intra-venous anesthesia.
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|Table 1: Demographic data and baseline tumor characteristics of patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia|
Note: aData are expressed as mean ± SD. bData are expressed as number. cData are expressed as number (percentage). dData are expressed as median (range). The data were analyzed by Student’s f-test (age, body mass, height), Fisher’s exact test (sex, ASA physical status), or Wilcoxon rank-sum test (tumor volume). ASA: American Society of Anesthesiologists.
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|Table 2: Intraoperative and postoperative data of patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia|
Note: aData are expressed as mean ± SD. bData are expressed as median (range). The data were analyzed by Wilcoxon rank-sum test. ICU: Intensive care unit; n1: number of patients in N2O group (out of 24); n2: number of patients in N2O-free group (out of 24).
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Intraoperative incidence of brain bulge was comparable between the two groups [Table 3]. Intraoperative incidence of tachycardia and hypotension was significantly higher in the N2O-free group, while the incidence of bradycardia was significantly higher in the N2O group [Table 3].
|Table 3: Intraoperative complications of patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia|
Note: Data are expressed as number (percentage) and were analyzed by Fisher’s exact test. *Protrusion of brain matter within the margin of the inner table of the skull (Grade I); within the margin of the outer table of the skull (Grade II); outside the margin of the outer table of the skull (Grade III). Induction phase: From the beginning of anesthesia induction till 5 minutes post-intubation; maintenance phase: from 5 minutes post-intubation till the start of dural closure; closure phase: From the start of dural closure till last skin suture; post-surgical phase: after skin closure till shifting of the patient from operating room.
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Intraoperative hemodynamic parameters, i.e. HR and mean arterial pressure, showed statistically significant difference between the two groups at some time points [Figure 2]. The HR was higher in N2O-free group starting from incision (P = 0.95), through the 1st (P = 0.0594), 2nd (P = 0.0165), 3rd (P = 0.002), and 4th hours (P = 0.016) after incision, till the end of surgery (skin closure, P = 0.078; extubation/shifting, P = 0.32; [Figure 2]A). Similarly, mean arterial pressure was higher in the N2O group from the 1st hour after incision (P = 0.012), through the 2nd (P = 0.293), 3rd (P = 0.023) and 4th hours (P = 0.022), till the end of surgery (skin closure, P = 0.034; extubation/shifting, P = 0.322; [Figure 2]B). There was no significant difference in the incidence of various postoperative complications, early as well as late, between the two groups [Table 4].
|Figure 2: Intraoperative hemodynamic trends of patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia.|
Note: (A) Heart rate. (B) Mean arterial pressure. Data are expressed as mean ± SD (n = 24). *P < 0.05 (generalized estimating equation).
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|Table 4: Postoperative complications of patients undergoing cerebellopontine tumor surgery under sevoflurane anesthesia|
Note: Data are expressed as number (percentage) and were analyzed by Fisher’s exact test. PONV: Postoperative nausea vomiting.
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| Discussion|| |
Though N2O has traditionally been a ubiquitous component of general anesthesia, there has been ongoing controversy regarding its use, particularly in neurosurgical patients. Recent studies in this context have been the Evaluation of Nitrous Oxide in the Gas Mixture of Anaesthesia (ENIGMA) trials,, the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) posthoc analyses,, and the General Anaesthesia versus Local Anaesthesia for carotid surgery (GALA) trial. With evidence emerging about various complications associated with its use, N2O has fallen out of favor in several parts of the world.
The primary objective of the present study was to evaluate the effect of N2O on clinical outcomes in terms of length of ICU and hospital stay that is likely to be prolonged in case of any unfavorable event. However, we did not find any clinically significant differences in either length of stay or any complication.
The ENIGMA I trial showed that avoidance of N2O in major surgeries reduces the incidence of postoperative complica- tions, though the duration of ICU and hospital stay is not significantly affected. The ENIGMA I trial used 80% oxygen in the N2O-free group and 30% oxygen in the N2O-based group. It has been speculated that the vast difference in oxygen concentrations between the two groups probably resulted in lesser complications in the N2O-free group. Our study found no significant difference in the duration of ICU and hospital stay. We used 40% oxygen in both groups, possibly explaining the similar incidence of postoperative complications in both groups in our study.
One of the major reasons often cited for avoiding N2O is its propensity to expand air spaces. We did not find a statistically significant difference in the incidence of these complications. Pneumocephalus occurred in all but one patient in both groups in our study, and pneumothorax occurred in one patient in each group, supporting the view that the use of N2O alone does not increase the incidence of pneumocephalus or pneumothorax. It has earlier been pointed out that there is insufficient data to implicate N2O in causing postoperative tension pneumo- cephalus or its ability to affect cerebral hemodynamics. Domino et al. studied the effect of continuation of N2O after dural closure on ICP in patients undergoing craniotomies and observed no difference in ICP. They suggested that it is not necessary to discontinue N2O before dural closure for reasons of avoiding expansion of intracranial air and increasing ICP. The findings of our study also do not support these effects with the use of N2O.
Other major studies evaluating the use of N2O were the post hoc analyses of the IHAST trial. The IHAST trial was conducted to study the effect of induced systemic hypothermia on protection from perioperative cerebral injury in patients of cerebral aneurysm surgery. It was followed by two posthoc analyses. McGregor et al. analyzed the effect of N2O and found that N2O did not influence the development of delayed ischemic neurological deficit. Outcomes at 3 months were similar between the groups. A subsequent analysis that included only those patients who were subjected to temporary intravascular occlusion found that N2O increased the risk of delayed ischemic neurological deficit, but did not influence the neurological outcome at 3 months. Though we did not compare the outcome at 3 months, the condition at discharge was not different between the two groups in our study.
In a study involving supratentorial tumor surgeries, Singh et al. reported that the use of N2O did not influence the duration of ICU or hospital stay. Opioid and muscle relaxant consumption was higher in the N2O-free group, probably contributing to delayed emergence in this group. The incidence of hypertension and tachycardia was higher in the N2O-free group. However, the major limitation of this study was its grossly inadequate sample size, as also highlighted by other anthor. Our findings were similar to those of Singh et al. concerning the duration of ICU and hospital stay. However, we found comparable emergence time, extubation time, and recovery time between the two groups, which was probably because of the similar dose consumption of opioids and muscle relaxants in both groups in our study.
Our results show that the intraoperative course was more stable in the N2O group. The incidence of tachycardia and hypotension was significantly higher in the N2O-free group. We targeted a MAC of 0.8-1.2 during the surgery in both groups. Although we did not measure the amount of inhalation agent consumed in this study, a higher amount of sevoflurane was possibly used in the N2O-free group which probably resulted in a higher incidence of hemodynamic fluctuations.
Lampe et al. studied the use of N2O in 26 patients undergoing surgery for acoustic neuroma. They found that N2O did not increase the incidence of morbid outcomes, prolonged hospitalization, or postoperative complications. However, intraoperative brain condition, fluids, duration of emergence and recovery, duration of ICU stay, and incidence of PONV were not studied. Our study evaluated all these parameters along with several other perioperative complications to evaluate the quality of recovery. Also, our study was adequately powered to study clinical outcomes in terms of length of ICU stay and hospital stay.
Other studies evaluating N2O in different surgical populations have not found any significant difference in terms of time to home readiness, pain and nausea scores, analgesic and antiemetic administration, and frequency of adverse events, or the incidence of surgical site infection. The GALA trial investigators in a subgroup analysis did not find any definite effect of N2O on death, stroke, or myocardial infarction within 30 days after surgery. Our study also did not find a significant difference in the incidence of various postoperative complications.
A study has cited PONV as one of the main reasons for avoiding N2O. In neurosurgical patients, any N2O-associated vomiting may be confused with primary neurogenic causes, or vomiting may produce transient increases in ICP, both of which are of concern. The ENIGMA II trial reported a significantly higher incidence of severe nausea and vomiting in the N2O group, but it was concluded that the emetogenic effects of N2O can be controlled with antiemetic prophylaxis. The use of routine antiemetic prophylaxis in patients may contribute to the similar incidence of PONV in both groups in our study.
In our study, we did not find any adverse events or other significant differences between the two groups. However, patients in the nitrous group were more hemodynamically stable with faster emergence (though statistically insignificant). The inherent analgesic property of N2O in providing stable intraoperative hemodynamics, thereby having other anesthetic drug sparing effects (not studied in this study) with faster emergence can be an advantage with the use of this time-tested drug. So within the limits of this study, the use of N2O might rather be an advantage (unless there is definite evidence against the use of N2O in larger trials).
Our study has a few limitations. Since the anesthesiologist managing the case intraoperatively was aware of the group allocation (for patient safety), bias on part of the anesthesiologist is possible. However, this bias was limited since the observer who recorded the primary outcome of the study was blinded to the group allocation. Secondly, the long-term follow-up of patients was not carried out in this study. Moreover, patients with only good American Society of Anesthesiologists physical status with no signs of raised ICP were included and thus the results of this study may not apply to poor grade physical status patients. Although we did not measure the amount of inhalation agent consumed, a higher amount of sevoflurane might be used in the N2O-free group which probably resulted in a higher incidence of hemodynamic fluctuations. Estimation of end-tidal concentration of the sevoflurane and depth of anesthesia is desirable to compare the requirement of anesthetic agent in the two groups and this remains a limitation of our study. A large number (approximately two-thirds) of patients in each group were mechanically ventilated overnight (considering patient safety). This was mainly due to surgery continuing till late night hours. The sample size of our study was small. Hence, the findings of our study must be interpreted keeping the sample size in mind. Lastly, surgeons with varying years of experience operated upon the enrolled patients and could have affected the outcome to some extent. Future studies are required to address these limitations.
In conclusion, N2O based anesthesia does not affect the length of ICU and hospital stay in good physical grade (American Society of Anesthesiologists physical status class I & II) patients with no evidence of raised ICP undergoing elective surgery for cerebellopontine angle tumors. It does not affect intraoperative brain condition, emergence, recovery, duration of postoperative ventilation, condition at discharge, and incidence of various intraoperative and postoperative complications. Hence, within the limitations of this study, there is no evidence at present to dogmatically avoid N2O in well-optimized patients undergoing cerebellopontine tumor surgeries. However, future studies will be required especially in poor physical grade patients with large tumors and raised ICP to draw a definite conclusion.
BB and GPS have contributed to the concept, design, literature search, data acquisition, data analysis, manuscript preparation, manuscript editing, and manuscript review. MPP has contributed to the concept, design, manuscript preparation, manuscript editing, and manuscript review. All authors approved the final manuscript for publication.
Conflicts of interest
Data were presented as a poster at the 45th Annual Meeting of the Society for Neuroscience in Anesthesiology and Critical Care (SNACC) held in Boston, MA, USA from October 19th - 20th, 2017. The authors declare no conflicts of interest.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial- ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Additional file 1: Hospital ethics approval.
Additional file 2: CONSORT checklist.
Additional file 3: Informed consent form.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]