Effects of different fractions of inspired oxygen on gas embolization during hysteroscopic surgery: A double‐blind, randomized, controlled trial

Gas embolism is a common complication of hysteroscopic surgery that causes serious concern among gynecologists and anesthesiologists due to the potential risk to patients. The factors influencing gas embolism in hysteroscopic surgery have been extensively studied. However, the effect of the oxygen concentration inhaled by patients on gas embolism during hysteroscopic surgery remains elusive. Therefore, we designed a double‐blind, randomized, controlled trial to determine whether different inhaled oxygen concentrations influence the occurrence of gas embolism during hysteroscopic surgery.

anesthesiologists because it can be insidious but deadly and the treatment options are limited.GE is a condition in which gas enters the blood vessels and causes a blockage that can lead to ischemia and hypoxia.Previous studies have shown that the incidence of GE during hysteroscopic surgery is 10% to 50%. 3,4During hysteroscopic surgery, gases that enter the uterus during the dilation of the cervix, gases that are not drained from the instruments, and gases that are generated by vaporization of distention fluid can enter the bloodstream through damaged arteries and veins in the uterine cavity, causing GE. 5 Clinical symptoms vary from asymptomatic to cardiac arrest, depending on the amount of gas, speed of its entry into the blood vessel, and location of gas entry. 6When gas emboli reach the lung through the inferior vena cava, they can cause hypoxemia, pulmonary vasoconstriction, increased pulmonary artery pressure, and overload of the right ventricle, ultimately leading to heart failure. 4In addition, gas entering the pulmonary arterioles can stimulate the release of histamine and serotonin, causing pulmonary edema. 3,4,7Therefore, effective prevention of GE during hysteroscopic surgery appears to be particularly important.
Previous studies on GE during hysteroscopic surgery have mainly focused on the incidence of GE; the influence of surgical location, surgical instruments, and anesthetics; and the monitoring of GE. 5,[7][8][9][10] Intriguingly, in our clinical observation, we found that GE did not occur when patients were administered 100% oxygen, but different degrees of GE occurred when 50% oxygen was inhaled with the same surgical instruments and surgical personnel.A study comparing the effects of 100% oxygen, 50% oxygen in nitrogen, and 50% oxygen in nitrous oxide controlled ventilation on venous air embolization responses in pigs indicated a small hemodynamic change after venous air embolism in the 100% oxygen group, which suggested that 100% inspiratory oxygen is preferable to oxygen in air for surgeries with a high risk of venous air embolism. 11Oxygen (100%) can not only increase arterial oxygen saturation and improve the oxygen supply to peripheral tissues but also reduce nitrogen content and embolus volume, which is conducive to the absorption of air embolus. 12The effect of the oxygen concentration inhaled by patients on GE during hysteroscopic surgery remains elusive.Therefore, we hypothesize that the occurrence of GE is, to some extent, associated with the oxygen concentration inhaled by patients during hysteroscopic surgery.
Here, we designed a double-blind, randomized, controlled trial to determine whether different inhaled oxygen concentrations influence the occurrence of GE during hysteroscopic surgery.

| MATERIAL S AND ME THODS
The prospective, double-blind, randomized controlled trial was per- After randomization using a digital table and opaque envelopes, 160 patients (two patients dropped out) were randomly assigned to group 30%, group 50%, or group 100%, with inhaled oxygen concentrations of 30%, 50%, and 100% in ambient air, respectively.A digital table means that the numbers of 1, 2, or 3 are randomly generated by Excel to represent the groups of 30%, 50%, and 100%, respectively, and put into the opaque envelope in order, which is opened by anesthesiologists.The data recorder, analyst, and cardiac ultrasound researcher were blinded to the experimental grouping.
The ventilation frequency was 10 to 12 times per minute.PetCO 2 was maintained at 35 to 45 mm Hg.Positive end-expiratory pressure was not applied.Sevoflurane (Shanghai Hengrui) (2%-3%) was administered for anesthesia maintenance.Before extubation, a recruitment maneuver was used to prevent atelectasis in each patient.All operations were performed by the same surgeon.The surgical instruments, the patient's surgical position (supine), and the type of irrigation fluid were also the same.Each patient underwent bipolar resection (HF-Resection Electrodes, Olympus Winter & Ibe GmbH).Echocardiography (Philips Ultrasound CX50, PHILIPS) was performed by the same operator.Each diagnosis corresponds to the same type of surgery.

| Data collection
The demographic, clinical, and intraoperative characteristics, including age, height, weight, body mass index (BMI), ASA status, type of surgery, operative time, duration of GE, intrauterine pressure, amount of intravasation, and oxygen concentration, were recorded.The primary outcome was the incidence of GE.Transthoracic echocardiography (TTE, four-chamber view) was used to evaluate whether GE occurred, and the images (Figure 2 (Table 1).Before the start of surgery, the four-chamber view was continuously monitored.The first record was made before the start of surgery.After the operation began, images were recorded every minute until the end of the operation.If there were gas emboli, the image was recorded until the gas emboli disappeared.In the clinic, a speckle may be formed in the heart cavity during intravenous infusion or injection.Therefore, the TTE images of grade I or II can be regarded as no GE; otherwise, the grades of III to V are regarded as GE.
The secondary outcomes included mean arterial pressure (MAP), heart rate (HR), PetCO 2 at the time of the most severe embolization, the duration of GE, and hemodynamic instability.The most severe embolization is when the most bubbles are seen in the heart cavity, and the data recorder is informed by the personnel in charge of TTE.
The duration of GE was the period from the discovery of gas emboli in the right atrium or ventricle to the disappearance of gas emboli.Cardiovascular disturbances probably resulting from GE are as follows: a sudden decrease in MAP by >30% from baseline or a sudden decrease in PetCO 2 by >20% from baseline or SPO 2 ≤ 95 or ST-segment change of >2 mm from baseline or bradycardia (HR <60 beats/min) and tachycardia (HR >100 beats/min).Hemodynamic instability was defined as the presence of at least two of these clinical signs.Severe GE was defined as grades IV and V.

| Sample size calculation
The sample size was calculated by a priori power analysis.A target α value was 0.05 and β value was 0.2.According to the incidence of GE at different oxygen concentrations in the preliminary test, inhaled oxygen concentrations of 30% and 50% were compared with 100% inhaled oxygen concentration.A 26% increase in the occurrence of GE resulted in a group size of 52 patients.Assuming a dropout rate of 5%, the total number of patients was set as 160.

| Statistical analyses
Statistical analyses were performed with IBM SPSS version 26.0 software (IBM, Armonk, NY, USA).No interim analysis was planned.
The data are presented as numbers and percentages or medians.
The incidence of GE among the three groups was compared with the trend χ 2 test.Others were compared using Kruskal-Wallis rank sum test and χ 2 test.P < 0.05 was considered statistically significant.

| RE SULTS
From May 2021 to November 2021, 160 patients were included and randomly divided into three groups: group 30% (n = 52, 30% O 2 ), group 50% (n = 54, 50% O 2 ), and group 100% (n = 54, 100% O 2 ).There were no significant differences in demographic characteristics in age, height, weight, BMI, type of surgery, or ASA status (Table 2), or in intraoperative characteristics in duration of operation, intrauterine pressure, amount of intravasation, duration of embolization, HR, MAP, and PetCO 2 at the time of the most severe embolization (Table 3) among the three groups.
Table 4 shows the number of different embolization grades in the three groups.We regarded images of grade I or II as the absence of GE and grade III or V as the occurrence of GE.As shown in Table 5, the number of gas emboli in the 30%, 50%, and 100% groups was 36 TA B L E 1 Definition of the grade of TTE images.The demographic characteristics were similar in the three groups."Other" includes transcervical resection of polyp and transcervical resection of endometrium.
(69.2%), 30 (55.6%), and 24 (44.4%),respectively.The incidence of GE gradually decreased with increasing inhaled oxygen concentration.There was a significant difference between the three groups (P = 0.031).Paradoxical embolism was observed in one patient in the 50% group.
The patient also had ST-segment depression, decreased oxygen saturation, and many gas emboli in the left atrium and left ventricle present on TTE.

| DISCUSS ION
In the present study, the influence of different inhaled oxygen concentrations on the incidence of GE during hysteroscopic surgery was investigated.We found that with increasing inhaled oxygen concentration, the incidence of GE decreased.This suggests that higher inhaled oxygen concentrations may reduce the incidence of GE during hysteroscopic surgery.
Three inhaled oxygen concentrations, 30%, 50%, and 100%, were selected in our study for the following reasons.First, according to Miller's anesthesia, 13 impaired blood oxygenation occurs in most people under anesthesia, so it is common practice to increase the inhaled oxygen concentration appropriately, usually by 30% to 50%. 14 addition, more than one study of perioperative oxygen concentration has used a minimum oxygen concentration of 30%. 15,16Therefore, to ensure the oxygenation function of patients and to be as close to the oxygen concentration in the air as possible, we chose an oxygen concentration of 30%.Second, in our clinical practice, we usually use 2 L of fresh gas and set the inhaled oxygen concentration of the anesthesia machine to 50%, so a 50% oxygen concentration was also included in the study.Finally, to investigate whether 100% inhaled oxygen concentration could reduce the incidence of GE during hysteroscopic surgery, an oxygen concentration of 100% was TA B L E 3 Intraoperative characteristics of the three groups.

TA B L E 5
Incidence of GE in the three groups.Note: Data are presented as number (percentage).We compared the three groups using a trend χ 2 test.

GE
a There was significant difference between the three groups (P < 0.05).GE, gas embolism.

TA B L E 6
ORs for different fractions of inspired oxygen concentration and the occurrence of GE.
selected for the study.However, studies have shown that high inspired oxygen fractions cause rapid absorption of gas behind closed airways, resulting in atelectasis. 17,18With the increase in inhaled oxygen concentration, hypoxic pulmonary vasoconstriction weakens and atelectasis further develops. 19In our study, the surgery time was usually no longer than 25 min, which caused the atelectasis resulting from high inspired oxygen to appear to be more negligible than GE, indicating that the high inspired oxygen concentration in our study was safe for the patients.In addition, a recruitment maneuver was used to prevent atelectasis in each patient before extubation.
Nitrogen is much less soluble in the blood than carbon dioxide or oxygen and thus has a greater capacity for bubble formation. 20,21ntilation with 100% oxygen facilitates washout of nitrogen. 224][25] In addition, a higher oxygen concentration facilitated oxygenation, which could treat hypoxemia.Previous studies suggested that the time of brain gas clearance was significantly shorter with 100% inhaled oxygen than with inhaled air 26 and that there were smaller hemodynamic changes with the use of 100% inspiratory oxygen than with the use of air after GE. 11 There were no significant differences in the duration of embolization or HR, MAP, and PetCO 2 at the time of the most severe embolization among the three groups.This may be due to the limited number of cases of severe GE in all three groups.In addition, the number of bubbles in the heart cavity is not necessarily proportional to clinical manifestations.According to the statistical results, when the inhaled oxygen concentrations were 30%, 50%, and 100%, the cases of grade V images were one, two, and two, respectively, but this did not indicate that the higher the inhaled oxygen concentration was, the more severe the GE.The two cases of grade V images with 100% inhaled oxygen concentration may have been caused by the large amount of intravasation and the abundance of blood vessels at the resection site, which resulted in excessive gas entry with fluid from multiple damaged vessels.If the patient had a severe GE, the operation was stopped.
Compared with previous studies focusing on the influence of surgical operation on GE, our study used clinical observation to focus on ventilation during anesthesia, which is innovative.Furthermore, we did not find relevant reports on the effect of inhaled oxygen concentration on GE during hysteroscopic surgery.
However, there are also some limitations of this study.For obese or overweight patients, excess fat may affect the results of ultrasound monitoring.Due to the discontinuity of TTE images, GE of higher grades may be underestimated.In addition, due to the need for surgery, each patient had different intrauterine pressures, and the amount of intravasation could not be controlled.However, there was no significant difference between the three groups.Given the low incidence of severe GE in the three groups, whether 100% oxygen concentration can reduce the severity of GE needs to be further tested.

| CON CLUS ION
Oxygen concentration is an independent risk factor for the occurrence of GE.In hysteroscopic surgery, a higher oxygen concentration inhaled by patients may reduce the incidence of GE, indicating that a higher inhaled oxygen concentration, especially 100%, could be recommended for patients during hysteroscopic surgery.However, whether 100% oxygen can reduce the severity of GE needs to be further tested.

ACK N OWLED G M ENTS
The authors wish to acknowledge American Journal Experts for language editing.

FU N D I N G I N FO R M ATI O N
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors have no conflicts of interest.Note: Data are presented as number (percentage).Abbreviations: GE, gas embolism; MAP, mean arterial pressure; PetCO 2 , end-tidal carbon dioxide partial pressure; SPO 2 , oxygen saturation as measured by pulse oximetry; ST-segment depression, electrocardiographic change.
from February 24, 2021, to May 20, 2021, at West China Second University Hospital and approved by the Chinese Ethics Committee of Registering Clinical Trials (Chairperson Taixiang Wu, reference number: ChiECRCT20210033) on February 23, 2021.It was prospectively registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2000033202, principal investigator Xi Deng; registration date: May 23, 2020).The study was approved by the institutional research ethics committee before the experiment was started and was conducted in accordance with the principles set forth in the Declaration of Helsinki and Consolidated Standards of Reporting Trials (CONSORT) guidelines.The CONSORT flow diagram is shown in Figure 1.After written informed consent was obtained from the patients, 162 adult patients aged between 20 and 65 years with an American Society of Anesthesiologists (ASA) status of I to III undergoing elective hysteroscopic surgery were recruited.The exclusion criteria included all types of heart disease, transfer to laparoscopic surgery, thrombotic disease, and refusal to undergo cardiac ultrasound.
, gas emboli are indicated by the white arrows) of TTE were assessed as grade I to V F I G U R E 1 The consolidated standards of reporting trials flow diagram.TTE, transthoracic echocardiography.F I G U R E 2 Five grades of transthoracic echocardiography (TTE) images.(a-d) show grade I, II, III, and IV of the TTE images, respectively.(e and f) show grade V of the TTE images.White arrows indicate gas emboli.LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
Deng, Hao Li, and Xuemei Lin designed the study.Xi Deng, Jieshu Zhou, and Min Diao collected the data.Xi Deng analyzed the data, drafted the manuscript, and was further modified by Hao Li.Hao Li and Xuemei Lin contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.All authors have read and approved the final manuscript.

TA B L E 7
Clinical parameter changes that might be the result of the GE.
Demographic characteristics of the three groups.

Table 6
segment depression, and decreased oxygen saturation.The number of patients in each group who experienced changes in vital signs is shown in Table7.The number of patients with hemodynamic instability in the 30%, 50%, and 100% groups was zero, two (3.7%), and one (1.8%),respectively.One patient in group 100% had ventricular arrhythmia.All of the patients with GE showed a drop in PetCO 2 .
Data are presented as median [interquartile range].Heart rate, mean arterial pressure (MAP), and end-tidal carbon dioxide partial pressure (PetCO 2 ) recorded when gas embolism (GE) peaked.Number of different grades of the TTE images in the three groups.