2.1. Study design
The present study was a prospective, randomized, controlled, and single-blind trial with one experimental arm (CCBT group) and one control arm (UC group). We independently randomized participants to receive either five sessions of CCBT + UC or UC alone. The primary study outcomes were state anxiety compared between two groups. Secondary outcomes included symptom of depression and insomnia, BP, HR stress biomarkers, and satisfaction with intervention compared between two groups. Participants were recruited from the Otolaryngology Department through the First Hospital of Shanxi Medical University from September 20, 2019, to January 10, 2020. All interested and eligible participants completed full informed consent prior to study procedures. Designing and reporting of this clinical trial reference CONSORT guidelines [26] (see Supplementary Table 1 for CONSORT Checklist).
2.2 Participants
Inclusion criteria were the following: (1) aged 18–60 years; (2) diagnosis of CRS and scheduled to undergo FESS within a week; (3) general anesthesia can be acceptable as a form of anesthesia; (4) be able to answer the questionnaires and participate in the interventions; (5) be willing to participate in the study. Exclusion criteria included the following: (1) diagnosis of definite history of psychiatric illness, substance abuse/dependence within 12 months before enrollment; (2) undergoing a surgery that was postponed for more than a week or changed to emergent surgery; (3) currently receiving any psychiatric or psychological treatment, including psychiatric medication; (4) the Patient Health Questionnaire Depression Scale-9 (PHQ-9) score ≥20 and (5) those who had serious cardiovascular and respiratory diseases.
2.3 Study assessments
A psychological therapist holding M.A.degree had given training to researchers aiming at the consistency of psychological assessment. The intervention designer is a doctoral student in nursing who had provided intervention flow and some observing details to researchers. A team of researchers (two nursing graduate students and a psychological therapist) collaborates with hospital staff from the Otolaryngology Department enrolled patients. Participants were identified and confirmed from surgical-plan lists by the Electronic Medical Record System. Then they were approached by researchers and written informed consent would be obtained according to the ethical requirements before any study procedure. The next step was that the severity of emotional distress(depression) was assessed according to PHQ-9. If the patients were demonstrated severe depression or a high risk of suicide (PHQ-9 score ≥20), they would be excluded and referred to a psychiatrist [27]. Finally, participants who had serious cardiovascular and respiratory diseases were excluded further. After enrollment, baseline questionnaires about demographic and medical information was collected. Participants were randomly assigned via a concealed random digital table and admission order to ensure blinding of study staff and participants until baseline assessments were completed. A study staff was along blinded to collect and analyze data for group assignment during the study.
Baseline characteristics included sex, age, education, principal diagnosis, surgery type, and anesthesia grading. The baseline measures were collected on the day after hospitalization. The measures and outcomes were obtained from patients at baseline (T1), one hour before anesthesia administration (T2), on the 48 hours after surgery (T3) and post-intervention (T4). There was no evidence of harm or unintended effects in either the intervention or control groups. (see Figure 1 that shows the schedule of study assessment, and intervention time points.)
2.4 Study interventions
2.4.1. Introduction
The potential participants were given a brief introduction about the study program before beginning the five-session intervention, especially the importance of mental health for postoperative recovery. Eligible inpatients who were willing to participate were registered and kept in touch by study staff.
2.4.2 CPCBT-Perio software program intervention
The CCBT group received the optimized CCBT (CPCBT-Perio) intervention in addition to UC. The CPCBT-Perio is a non-internet-based computer program that includes registration and therapy conducted in a medical setting. The program is based on condition-surgery and CBT elements, which comprised five sessions, and each session took about 20 minutes to complete. The preoperative preparation time is usually only 3 ( ±1) days for patients with FESS since admission and postoperative recovery time is about 7 (±2) days. The time points of intervention are 2-day, 1-day before operation and 2-day, 3-day, and 4-day post operation. All sessions would finish before discharge. Since this program was standardized and straightforward, a nursing graduate student assisted participants with CCBT treatment. Participants in the CCBT group entered their information into the program and were provided instructions on how to use the software, and the first treatment was administered soon after registration. Each session starts by logging into the admission number. Next time logging in, individualized treatment will continue. The treatment modules within the program included cognitive therapy, cognitive consolidation, and behavioral relaxation therapy. The primary components of the cognitive therapy module included the following:
Session 1: Preoperative psychological preparation;
Session 2: Preoperative physical preparation and introduction to the surgical environment;
Session 3: Management of postoperative pain, insomnia, and anti-thrombus;
Session 4: Postoperative exercise and diet;
Session 5: Education on steps following hospital discharge.
The behavioral therapy module included relaxing training, such as imaginative relaxing exercise, progressive muscle relaxation, breathing exercises, relaxing sleep exercise, and a mindfulness meditation body scan. Homework as cognitive consolidation was then provided for participants to answer questions in the form of a game, in which the questions served as a review of the previous cognitive therapy module. The cognitive therapy module and behavioral therapy module were presented via video. (see Supplemental table 2 for outlines precisely the content of the sessions)
The studies have revealed that CBT can relieve anxiety and depression for patients with surgery [16]. The CPCBT-Perio procedure was developed based on CBT theory and method, similar to the standard CCBT. That is changing unreasonable cognition and thoughts and providing better management of stress and coping with tension. The unique feature of the CPCBT-Perio is that learning identifies core beliefs and negative thoughts about surgery and helps patients reorganize and rationalize cognition by video. Simultaneously, some skills for relaxing had been provided with coping with preoperative anxiety and postoperative insomnia. On the computer interface, they express CBT utilizing clear operational steps, highly structured multiple media interactions. The psychological knowledge about emotion management was included in the CPCBT-Perio program the same as standard CCBT. The contents of operation and anesthesia which were reviewed and passed by clinical nursing specialists and psychotherapists were unique and customized for surgical patients.
2.4.3 Usual Care intervention
In the case of UC, patients were administered the FESS routine care conducted according to the Perioperative Care Manual and Consensus on ERAS [28].To match the CCBT group, participants randomized to this condition, including five sessions, focused on education about the illness, surgery, anesthesia, and postoperative nursing. These sessions were developed in consultation with clinical nursing specialists. A 20-minute verbal briefing per session was administered to participants by study staff. Topics included the introduction of illness and surgery; Preoperative psychological and physical preparation; Postoperative disease care; Activities and diet after surgery; Education on steps following hospital discharge.
2.5 Measures and Outcomes
2.5.1 Primary outcome measure
State-Trait Anxiety Inventory (STAI) was developed by Spielberger C.D and Gorsuch R.L to measure transient and enduring levels of anxiety [29]. Historically, the STAI is considered to assess and differentiate clinical anxiety levels as the gold standard test [30]. The first part of the STAI -“State scale”(STAI-S) assesses current state of anxiety at a particular moment asking how respondents feel “right now” [29]. If detecting change over a relatively short period of time, many have opted to solely use the STAI-S subscale for the detection of longitudinal change. The second part of the STAI- “The Trait scale” (STAI-T) evaluates relatively stable aspects of “anxiety proneness” including general states of calmness,confidence, and security [31]. While overall reliability analysis using Cronbach's alpha shows that these scales are reliable (alpha = 0.90 and 0.81 for State and Trait scales, respectively) [32]; we obtained a reliability value of 0.80 and 0.85 The patients remained constant visible anxiety from the afternoon before surgery to the immediate preoperative period [33] and preoperative waiting is the trigger point for high-level anxiety [6]. Anxiety and tension should be controlled or decreased before surgery and anesthesia administration (T2) to less bleeding and the smooth operation of FESS for a surgeon [14]. We administered the STAI-S assessment at T1, T2, and T4. Past studies display that STAI-S score ≥38 was considered to be moderate and severe anxiety [34].
2.3.3 Secondary outcome measure
The Patient Health Questionnaire Depression Scale-9 (PHQ-9) can establish provisional depressive disorder diagnoses as well as grade depressive symptom severity [27]. The Chinese version of the PHQ-9 Cronbach's alpha values of PHQ-9 was 0.83 for inpatients in general hospitals study [35], while we obtained a value of 0.80. The physical discomfort such as nasal tamponade, pain, bleeding and postoperative sleep disturbances may be come along after surgery [36]. Depression symptoms may gradually appear with the complications after surgery. Athens Insomnia Scale (AIS) was developed by Soldatos to quantify sleep difficulty based on ICD-10 criteria [37]. As assessed by Cronbach's alpha, internal reliability was 0.89 in the original study [37], while we obtained a value of 0.90. General anesthesia and physical discomfort can cause postoperative insomnia [38]. Considering the physical discomfort of the patients after surgery, we chose to assess at 48 hours after surgery. We administered the PHQ-9 and AIS assessment at T1, T3, and T4. The PHQ-9 score ≥5 was considered a clinical depressive state [27] and the AIS score ≥ 6 was a cutoff distinguishing between insomnia patients and controls in 90% of cases [39]
The psychological state before and after operation often affects the stability of vital signs of patients [40]. The values of Blood Pressure (BP) including of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) and Heart Rate (HR) are collected at T1~ T4.
Abelson et al. found that cognitive intervention can significantly reduce the concentration of cortisol and ACTH in patients by adjusting the function of the hypothalamic-pituitary-adrenal (HPA) axis [41]. Peripheral venous blood was collected at baseline and before anesthesia, the latter of which is associated with increased anxiety [42]. We collected venous blood of the patients who were under inpatient between 6:00 a.m. and 8:00 a.m. on the day of admission (T1) and operation (T2). Blood samples were taken before breakfast to minimize the effects of circadian variation. A single venipuncture collected 5~8 ml blood into purple and yellow plain tubes (with coagulants and separation gel). After standing at room temperature for 30 min, the blood sample centrifuged for 15 min at 1,800 g. Plasma Cor and ACTH levels were measured by chemiluminescence assay (CLIA) and microparticles CLIA. These measurements aimed to determine whether CCBT can result in a change of stress biomarkers, such as Cortisol and ACTH.
We also collected data on participant satisfaction, in which participants completed a brief 10-item satisfaction survey on either the day of discharge (T4) or the day of withdrawing from the study if applicable. Internal reliability for this scale was high at 0.87 (Cronbach’s alpha) (see Supplemental Information table 3 for Satisfaction Survey Questionnaire).
2.4 Data Analysis
According to a previous study [43], the average value of SAI in control subjects is 44.7±10.3. To have a difference greater than 5 in average levels of state anxiety between groups, and with a power of 0.80 at the 5% significance level, we estimated a sample size of 46 patients per arm according to the value of the standard deviation, σ = 10 (PASS 11.0). Allowing for a 10% dropout rate, approximately 50 cases were ultimately included per group.
Analyses of the outcomes were conducted by IBM SPSS Statistics, version 23.0 (2010 SPSS Inc., IBM Company, Armonk, NY, USA). Descriptive statistics (percentages, means, and standard deviations [SD]) were used to summarize baseline participant characteristics and scores on the self-report measures. Chi-square and Student t tests were performed to test differences of between-group on baseline characteristics and changes from baseline in the outcome measures. We used linear mixed models in SPSS to analyze between-group differences on each outcome at each study time point. Anxiety state was the primary outcome with the T2 (i.e., before - anesthesia) timepoint representing the main study time point, and the T4 (post - intervention) time point as an exploratory outcome. To evaluate the impact of the intervention conditions on changes in the primary outcome (STAI-S), as well as secondary outcomes (PHQ-9 and AIS), 2 (intervention) × 3 (time) repeated-measures ANOVA models were conducted. Effect sizes were also calculated for each outcome variable by dividing the mean difference between time points by the pooled standard deviation [44]. Two-way ANOVA compared Cortisol and ACTH between two groups. Mann-whitney U tests were used analyzed the data of nonnormally distribution variables. All of the tests were two-sided, and statistical significance was set at p < 0.05.