Study design
This study protocol is a randomized, within-patient, controlled, double-blind, single- center trial (See Fig. 1). This clinical trial was designed on the basis of interventional Trials SPIRIT [19] guidelines (See Additional file 1) as well as abiding by the checklist set out in the Consolidated Standards of Reporting Trials (CONSORT 2010) [20]statement (see Additional file 2). The study have obtained an official authorization from the Ethics Committee of Ningxia Medical University (2018–231) and was registered in the China Clinical Trial Registration Center (NO.ChiCTR1900021374) for the clinical trial protocol. We will summarize the complete schedule of participant enrollment, intervention, and evaluation in table 1.
Study setting
This study will be conducted by a trained researcher in the Anorectal Department, Yinchuan Hospital of Traditional Chinese Medicine affiliated to Ningxia Medical University. The department is the only national-level anorectal specialty in our district, with visiting more than 6,000 outpatient and inpatient approximately 1200 people annually. Hence, we have sufficient patient to achieve a suitable and cross-sectional sample size.
Study population
According to the study design, a total of 200 eligible participants will be recruited from 28 April 2019 in the Anorectal Department. To eliminate the complex factors that may interfere with dressing, we will recruit patients with relatively consistent or close of wound conditions as far as possible.
Inclusion criteria
- Chinese-speaking and ranging from 18 to 60 years old;
- Meeting the diagnosis of perianal abscess [21] and are suffering from acute pain (moderate to severe intensity) induced by dressing after perianal abscess surgery.
- Being able to take deep breaths to use use self-managing devices (similar to oxygen mask);
- Signing the informed consent.
Exclusion criteria
- Having contraindications to the use of nitrous oxide/oxygen (such as intracranial hypertension, maxillofacial traumatism, gas embolism, unventilated gas in the body, requiring pure oxygen inhalation) [22];
- Impairing cognitive function and being difficult to report pain;
- Being diagnosed with other life-threatening situations or instability of vital signs.
Randomization, allocation concealment, and blinding
A total of 200 participants will be randomly assigned to either intervention or control group in a 1:1 fashion with a computer-generated list. Taking into account selection bias and confounding factors, the random numbers of each participant will be generated by an independent statistical expert who works for the School of Public Health and Management, Ningxia Medical University with applying Random Allocation Software version 1.0.0 [23]. The expert will not be involved in the recruitment, gas distribution, date collection. Then, the random numbers will be stored and sealed in a designated research office to ensure concealment [15]. In order to maintain a double-blind environment, nurses and researchers are blinded and not allowed to touch the random numbers unless they can put forward justifiable reason and get the approval from the project supervisor. Only the project leader who is in charge of gas distribution and treatment delivery can have access to the envelope [23]. In addition, the two gas cylinders (Ningfeng Oxygen Company, Yinchuan, China) containing premixed nitrous oxide/oxygen and oxygen are strictly identical on the package, and all cylinders are marked with the letters A or B. The intervention group will receive premixed nitrous oxide/oxygen contained in gas cylinders tag the letter A. While the control group will obtain oxygen stored in cylinders with B. No medical staffs, researchers and patients know what the letter indicates. The treatment method (the nature of the gas inhaled by patients) is blind for everyone. According to study rules of the protocol, the investigators will know the answer until completing all the trials.
Interventions
To build the same conditions, dressing for all post-operative wounds is performed by a regular surgeon who has received medicine college education for 5 years or longer and more than 3 years of clinical experience in the Anorectal Department. The patients will receive an informed consent form and get an explanation from investigators regarding the aim, benefits and possible risks of the trial before the study is carried out. Eligible patients will be randomly allocated into two groups, inhaling premixed nitrous oxide/oxygen or oxygen with a one-way valve, specially designed oral–nasal mask [15]. The patients hold the self-administered mask that can be controlled by their own negative pressure to inhale gas until the dressing is over. Regular pain treatment will also be conducted as usual. In this study, we designed that the intervention group will get nitrous oxide/oxygen plus conventional analgesic therapy comparing with the control group receives oxygen plus conventional analgesic therapy. In general, inhalation of these two gases is a safe intervention strategy with no severe adverse effects on patients. Even if any undesired events during the nitrous oxide/oxygen intervention happen, short and mild, which usually disappear when the patients are exposed to the air [16]. Finally, each participant is endowed with undeniable right to withdraw from the study at any time, of course, the reason of dropout will also be recorded and analyzed by the Data Monitoring Committee (DMC) and the data collector.
Outcome measurement
1. Baseline data
Demographic details of each patient (age, sex, nationality, weight, height, education level, occupation, etc.) and clinical characteristics (such as classification of perianal abscesses and post-operation wound size) will be recorded using in-house-designed questionnaire at baseline (T0). Physiological parameters including blood pressure, heart rate, respiratory rate, oxygen saturation and temperature will also be collected.
2. Primary outcome measure
The primary outcome is the change in pain score assessed on the Changhai Pain Rating Scale (it combines the characteristics of the Faces Pain Scale Revised, Numerical Rating Scale and Visual Analogue Scale). The researchers will measure and record the primary measure with the patients self-report scale at T0 (3 min before dressing), T1 (5 min after the beginning of dressing) and T2 (5 min after dressing finished) respectively. The percentage change in pain score at T1 and T2 will be then calculated.
3. Secondary outcome measures
Secondary outcomes measures cover physiological parameters, adverse events, patients and medical staffs’ satisfaction, Ramsay sedation score and patients’ acceptance. Noninvasive electronic manometer (OMRON, HEM–7120) and digital monitoring of oxygen saturation (OXIMETER, PC–60B) will be used to monitor the physiological parameters. And these parameters will be recorded by data collector at T0, T1 and T2. However, adverse events in secondary outcome measures, such as nausea, vomiting, numbness, drowsiness, over sedation and dizziness [14] will be carefully recorded after performing inhalation gas and handled properly. Patients and medical staffs’ satisfaction (a five-point satisfaction scale, 1 = very dissatisfied; 5 = very satisfied) with pain management will be obtained at T2. Also, acceptance from the patients (they are asked if they would still accept this new analgesic gas in case of acute pain with moderate to severe, yes / no) will be recorded at 5 min after the whole intervention. Finally, total time of the patient inhales gas will be also minuted.
Sample size determination
The determination of its sample size was on the basis of preliminary experimental data collected in the Anorectal Department for 30 patients. and our previous studies involved burn-dressing and cancer breakthrough pain [15, 24]. The data indicated that 55% of participants receiving premixed nitrous oxide/oxygen had a meaningful change in pain score (a drop at least one-third of pain score [25]) at T1 and T2, while 15% of patients receiving oxygen was. That is, we designed the intensity of pain as the primary outcome of this trial, so when the difference between the two groups is the most obvious and decimal in two places, the pilot experiments showed that the mean ± standard deviation of the control group is 7.67 ± 0.67, while the experimental group is 4.47 ± 0.86. To assess the efficacy of the new analgesic gas, statistical power of 90% (β = 0.10) and type–1 error rate of 0.05 (a two-tail test) is needed. So a sample size of 87 is sufficient. Considering a possible 15% dropout rate, ultimately, we decided that 200 patients in total will be recruited to meet the Chinese Food and Drug Administration standard.
Data management
In order to ensure the quality of the collected data and the smooth implementation of the study protocol, all the researchers will obtain professional and targeted training concerning aim, design (randomized and double-blind), data collection and the management of adverse effects as well as withdrawal records and analysis involved in the trail before the study [23]. Not just have the DMC and auditing system been set up to monitor data collection and patients safety throughout the study, but double check method of data has been established for quality control. The monitors and auditors are responsible for checking this password-protected database periodically, but they are blind to random allocation. They are not involved in research design, data collection and management, manuscript writing and publication, etc. Microsoft Office 2010 (Redmond, WA, USA) will be elected to input data, this is the responsibility of the data collector [23]. During the database established, anonymity runs the study and personal information (name, number, etc.) of participants are kept confidentiality in other locked cabinet. In other words, all data involved in the study will be entered by two people independent of the protocol through double password entry. Only when the final statistical analysis is performed, the researchers can be access to the database. If there is missing data, a sensitivity analysis is necessary. All original records will be kept at least 3 years, both electronic and paper.
Data analysis
The statistic analysis of the data will be conducted by a statistician with SPSS version 22.0 (Chicago, IL, USA) in the light of the CONSORT statement [20]for guiding control randomized trials (CRTs). Multiple imputation and/or last observation carried forward (LOCF) will be used to handle the missing data. Descriptive statistics (such as population demographic data) will be performed by medians (inter-quartile ranges, IQR), means (standard deviations, SD), and proportions (exact binomial 95% confidence interval, CI). Comparison of mean between two groups will be analyzed by t-test (normal distribution, homogeneity of variance) or Mann-Whitney test (non-normal distribution, two-sample), while categorical variables (comparison of proportions for the two groups) will be assessed by Chi-squared tests or Fisher’ s exact test.When P values (two-sided) is less than 0.05, we will consider that there is significantly statistical.