After Research Ethics Board approval at Medical Ethics Committee, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China（The project has been approved since 28/6/2019 and the approval number is 2019007, and the study has been retrospectively registered in Chinese Clinical Trial Registration with the registration number ChiCTR2100052321, date of registration 24/10/2021.）we conducted a prospective randomised, double-blind, controlled clinical trial from September 2019 to November 2019.This was a single-centre study in the Zhongnan hospital in Wuhan, Hubei, P.R. China. That all methods used in the experiment are followed in accordance with the relevant guidelines and regulations.
Study design and population
Twelve subjects were enrolled in the study, among which 10 subjects successfully completed the clinical trial and 2 subjects withdrew from the study due to personal reasons. All the 10 subjects who completed the experiment cooperated or had poor cooperation record.Subject selection (including control group selection if necessary)：1) Inclusion criteria : Healthy adults aged from 18 to 45 years old had a balanced and reasonable gender distribution. Subjects: Co hemoglobin COHb < 3%, Subjects: methemoglobin MetHb < 2%, subjects: ctHb > 10g/ dL; No smoking history/no smoking history; No history of cardiopulmonary diseases; Those who have passed thephysicalexamination; The subject voluntarily signs a written informed consent to participate in the clinical trial. 2) Exclusion criteria: Smokers or those exposed to high carbon monoxide levels; Those with coagulation dysfunction or artificial blood vessels; People with past heart and lung diseases; There is skin disease, infection or trauma around the measurement site, so that this parameter cannot be measured; Patients with mental illness, epilepsy or other diseases resulting in involuntary movement of the body; Physical condition can lead to high methemoglobin; Subjects should be excluded from clinical trials if they are undergoing procedures that are likely to create undue medical risks for them; Pregnant women; With grey nails; The clinical trial personnel judge that the compliance is not good and the protocol cannot be strictly implemented; Subjects enrolled in other clinical trials within 30 days; Patients with other diseases not suitable for clinical trials; Unwilling to sign informed consent.
Pulse oxygen clinical range of 70%-100%, pulse oxygen SpO2 less than 70%, may lead to life-threatening. SpO2 was divided into nine platforms (Figure 4), and induced hypoxia test was conducted on the subjects. The hypoxia process was induced, and the brain oxygen saturation of the subjects changed from high to low, covering the clinical range of 50%-80%. Two data groups were obtained on each gradient platform, and each data group was recorded as follows: cerebral oxygenometer value rSO2: rSO2 left 1 and rSO2 right 1 at the beginning of blood drawing and rSO2 left 2 and rSO2 right 2 at the end of blood drawing, calculated
So let's call the mean rSO2; Blood gas analysis value Sa/vO2: SjvO2 was obtained by blood gas analysis of venous blood, and SaO2 was obtained by blood gas analysis of arterial blood. Sa/vO2 was calculated according to the formula 0.7×SjvO2+0.3×SaO2 weighted average.
Method and time selection for evaluating, recording and analyzing validity parameters.Pulse oxygen clinical range of 70%-100%, pulse oxygen SpO2 less than 70%, may lead to life-threatening. SpO2 was divided into nine platforms (Table 1), and induced hypoxia test was conducted on the subjects. The hypoxia process was induced, and the brain oxygen saturation of the subjects changed from high to low, covering the clinical range of 50%-80%. Two data groups were obtained on each gradient platform, and each data group was recorded as follows: cerebral oxygenometer value rSO2: rSO2 left 1 and rSO2 right 1 at the beginning of blood drawing and rSO2 left 2 and rSO2 right 2 at the end of blood drawing, calculated. So let's call the mean rSO2; Blood gas analysis value Sa/vO2: SjvO2 was obtained by blood gas analysis of venous blood, and SaO2 was obtained by blood gas analysis of arterial blood. Sa/vO2 was calculated according to the formula 0.7×SjvO2+0.3×SaO2 weighted average.
Absolute accuracy of calculation as defined in this clinical protocol, if ≤10%, brain oxygenometer can be clinically accepted as an instrument for displaying absolute value of tissue oxygen saturation. Auxiliary Bland-Altman analysis with difference (rSO2(I)−Sa/vO2(I)) . As y axis, bland-Altman plot was drawn with (rSO2i+Sa/vO2i) /2 as X axis. The excluded data were explained to calculate the mean deviation Bs, variance S 2 of the total deviation and variance S 2 of different individual deviation, and the consistency limit Bs±1.96SD was analyzed. If the accuracy of trend calculation is less than 5% as defined in Chapter 15 of this clinical protocol, the brain oxygenometer can be clinically accepted as an instrument for displaying trends in tissue oxygen saturation. Bland-altman diagram is plotted with the difference [δ rSO2(j)− δ Sa/vO2(j)] as y axis and [δ rSO2(j)+ δ Sa/vO2(j)]/2 as X axis. The excluded data are explained. Average deviation Bs, variance of population deviation and variance of different individual deviation were calculated, and consistency limit Bs±1.96SD was analyzed. Finally Ten people were selected for the final experiment. We will conduct experiments according to the following procedures(Figure 3), experiments were carried out using a lowering oxygen platform(Figure 4).
Equipment and procedures
The subject was not sedated or anesthetized the night before the test; The blood gas analyzer must be calibrated before use to ensure its measurement accuracy (SaO2 accuracy is not less than 1%), and must be used in accordance with the manufacturer's recommendations and auxiliary materials; Preparation of consumable materials: single vena cava puncture catheter, arterial indwelling needle, arterial blood gas sampler, 2ml syringe, 5ml syringe, heparin salt solution, disposable pressure sensor. After testing the normal gas path can produce different partial pressure of oxygen gas mixing instrument, to achieve the mixed output of O2, N2 and CO2, the concentration of O2 in the output gas FiO2 can be read directly from the equipment; Non-invasive ECG monitoring device and gas monitoring device were used to monitor physiological parameters of subjects. The standard monitor pulse oximeter sensor was placed on the right index finger of the subject. The forehead of the subject is cleaned with alcohol cotton ball. After confirming that the forehead skin of the subject is clean, dry and intact without any powder, oil or lotion, the sensors of the test instrument are placed on the left and right forehead respectively. Put on the respirator mask and perform the oxygen-lowering process according to Figure 1. The oxygen-lowering process (according to figure 4) lasts for 1 minute on each platform and the EtCO2 is kept at ±5 mmHg of the baseline value. FiO2 on each SpO2 platform was recorded to make subjects feel adapted to the deoxygenation process, and each FiO2 value was used as the reference value for subsequent adjustment on each platform. The subjects were placed supine under local anesthesia with 2% lidocaine. The left or right radial artery was punctured with an indent needle, and the catheter was sealed with a pressure sensor connected with prefilled heparinized salt solution. Under local anesthesia with 2% lidocaine, ultrasound guided, the central venous catheter was retrograde penetrated into the right internal jugular vein, and the catheter was placed to the bulb of the internal jugular vein. After the location of the catheter was determined, the pressure sensor of prefilled heparinized salt solution was connected. Medical instrument for the test: Brain tissue oxygen saturation monitor, model: MOC-100; Medical instrument for control: Blood gas analyzer, model: ABL90 FLEX.
Accordinng to figure 4 platform 1: The pulse oximeter showed 98%±2%, which was the baseline value of the subjects. After two minutes, 0.5-1ml venous blood sample was slowly extracted, and the extraction time should be > 30s. To reduce the return of non-jugular blood to the jugular bulb. When taking venous blood samples, 0.5-1ml of arterial blood samples were also taken. The cerebral oxygen saturation value rSO2 was recorded at the beginning and end of venous blood sampling. After the first venous blood sample was taken, the platform was kept stable for 1 minute, and the process of the first group of blood samples was repeated to obtain the second venous blood sample, the second arterial blood sample, and the cerebral oxygen saturation values of the two groups before and after the venous blood sample was taken. Oxygen was lowered and FiO2 value was adjusted so that the value of the standard monitor pulse oximeter was 95%±2%. After two minutes, the blood sample was repeated to obtain two groups of venous blood samples and arterial blood samples, and the oxygen saturation values of the left and right cerebral brain of the four groups were obtained. Continue to drop oxygen to the pulse oximetry values of each platform, repeat the previous steps to obtain blood and brain oximetry monitoring values, and complete the platform 3-7 test; The subjects were provided with atmosphere, and the baseline value was restored. After two minutes, the blood sampling process of previous steps was repeated. Two groups of venous blood samples and arterial blood samples were obtained in total, and four groups of cerebral oxygen saturation values were obtained. FiO2 value was adjusted so that the pulse oximeter value of the standard monitor was displayed as 100%. After two minutes, the blood sampling process of the previous steps was repeated. Two groups of venous blood samples and arterial blood samples were obtained, and the oxygen saturation values of the left and right cerebral brain of the four groups were obtained. The subjects breathed directly into the atmosphere, returned to baseline values, and 5 minutes later, the experiment ended. After the completion of the test, the jugular vein, arterial catheter, test instruments, standard monitor, pulse oxygen monitor and physiological monitoring instruments were removed, and the subjects were observed for 2 hours. The medical staff checked that the subjects were safe and allowed to leave. 2 days later, the subjects were followed up by telephone to see if there was any abnormality, or the wound of catheterization was examined in outpatient department, and antibiotics were added. (according to figure 4 and figure 5)
Statistical design, methods and analysis procedures
In this clinical trial, absolute accuracy and trend accuracy were confirmed to be the main indexes to verify the effectiveness of brain oxygenometer. Refer to the accuracy definition of pulse oximeter and the accuracy definition of brain oximeter in relevant research , and the absolute accuracy of brain oximeter
(Arms) was defined as the root mean square difference between the cerebral oximeter monitoring value and the weighted value Sa/vO2 of blood oxygen saturation measured by the Co-oximeter. The trend accuracy of oximeter was defined as the root mean square of the difference between the change of oximeter value and the change of Sa/vO2, a weighted value of blood oxygen saturation, measured by the corresponding Co-oximeter.
1)Statistical software: Processing and analysis of data sets by Matlab2016;
2) Basic principles: All statistical inferences adopt two-sided test, the test level with statistical significance is set at 0.05, and the confidence interval of parameters is estimated by 95% confidence interval;
3) Missing data: Missing data is not estimated in this study;
4) Eliminating data: Eliminate unstable data sets. From the beginning of collection of jugular vein blood samples to the end of collection, data with changes of blood oxygen saturation measured by quality control equipment (pulse oximeter) exceeding 3% should be eliminated. If the blood oxygen platform has been unstable, all data of the subject shall be removed; The blood oxygen platform is unstable, there is air leakage in the blood drawing process, and the data groups with blood gas separation time exceeding 1.5 hours should be eliminated; Data can be excluded if it is confirmed by review that the test conditions for some data are outside the test protocol;
5) Check outliers: calculate the average of the difference value of the data group. If the difference value of the data group exceeds 4 times of the average value, the data group is judged as an outlier;
Absolute accuracy verification
1) Absolute accuracy of calculation:
The absolute accuracy of the brain tissue oxygen saturation monitor is defined as the root mean square value of the rSO2-SA /vO2 difference, and the calculation formula is:
Wherein, rSO2 is the of rSO2 left 1 and the of rSO2 right 1 displayed by the brain oxygen meter at the beginning of blood drawing, and the brain oxygen meter at the end of blood drawing .The mean values of rSO2 left 2 and rSO2 right 2; Sa/vO2 refers to SjvO2 obtained by blood gas analysis of venous blood and SaO2 obtained by blood gas analysis of arterial blood after blood sampling. The weighted average value calculated according to the formula 0.7×SjvO2+0.3×SaO2; I represents the ith valid data group. Root mean square calculation was performed on the difference between the effective data sets of the subjects, and the accuracy was obtained, if ≤10%, the acceptable range;
2)Auxiliary Bland-Altman analysis: Take difference（rSO2(i)−Sa/vO2(i)）as Y-axis, and take （rSO2(j)+Sa/vO2(j)）/2 was X-axis, bland-Altman plot was drawn, excluded data were explained, average deviation Bs, of total deviation and of different individual deviation were calculated, and consistency limit Bs± 1.96sd was analyzed.
3) Correlation analysis: linear regression, correlation coefficient calculation, precision Sres.
Trend accuracy verification
(1)The trend accuracy of the brain tissue oxygen saturation monitor was defined as the root mean square value of △rSO2-△Sa/vO2 difference. The first effective data point rSO2(1) of the first platform range is taken as the baseline value, and the change between the monitor display value and the baseline △rSO2(j) when collecting the j+1 effective blood sample is calculated according to Formula (2). Change △Sa/vO2(j) between the weighted mean of blood gas analysis and baseline within the corresponding platform range was calculated according to Formula (3). Trend accuracy was calculated according to Formula (4). If root mean square ≤5%, it was clinically acceptable.
In the type: j = 1, 2, …, m；m=n−1
2) Auxiliary Bland-Altman analysis: Bland-altman plot with difference [ΔrSO2(j)−ΔSa/vO2(j)] as y axis and [ΔrSO2(j)+ΔSa/vO2(j)]/2 as X axis. The mean deviation Bs, the of the population deviation and theʊ of different individual deviation were calculated, and consistency limit Bs± 1.96sd was analyzed.
3) Correlation analysis: linear regression, calculated correlation coefficient Sres, calculated precision Sres.
The correlation between the adverse events occurred in the test and the test device was analyzed, and the safety of the test device was described and evaluated.