The effects of computer-assisted cognitive-behavior therapy as an adjunct to enhance postoperative recovery during perioperative period: study protocol for a randomized controlled trial

Background: Some serious surgeries may pose likelihood of developing complications such as anxiety, depression, insomnia, chronic pain, which may aggravate discomfort, impair quality of life and even increase mortality after surgery. Non-pharmacological mind–body interventions for psychosomatic symptom is are an area of growing interest. CBT is the most recommended treatment for anxiety, depression, insomnia and pain. However, access to trained therapists is limited. A growing amount of research is producing effective evidence of CCBT. But , CCBT used for surgery patients have been not reported at present, and the effectiveness and feasibility have been not research ed and validated too. The primary aim of this trial is to explore targeted psychotherapy technique based on CCBT for surgical patients and assess the effectiveness and feasibility of the newly developed software of CCBT-Prs to improve anxiety, depression, insomnia and postoperative pain as an adjunct to UC by subjective and objective indexes. Methods and analysis : It is a prospective, multi-centers, randomized controlled superiority trial which comprises two parallel groups (CCBT-Prs +UC and UC alone) . Participants who has been scheduled for surgery will be randomized to either of the two groups : (1) receiv ing CCBT- Prs software intervention based on UC as trial group (2) receiving UC intervention only as control group. All participants will undergo assessments using STAI-S, PHQ-9, AIS and VAS-Pain-10 at various time points in the perioperative period. Blood samples will be collected at baseline and pre - anesthesia to assess for Stress hormone markers(Cor and ACTH). Functional near infrared spectroscopy( fNIRS) will be applied to evaluate brain function before and after intervention. Discussion: Some difficulty is inevitable and encountered in all clinical trials. The ultimate aim is that mental health services benefit more non-psychiatric inpatients. CCBT can have more wider dissemination and implementation in mental health. Ethics and dissemination

The effects of computer-assisted cognitivebehavior therapy as an adjunct to enhance postoperative recovery during perioperative period: study protocol for a randomized controlled trial CURRENT   immune function decrease,7 even cognitive impairment8 and postoperative delirium. 9 It is found that perioperative anxiety and depression have been associated with increased mortality after cardiac surgery.10 It is generally known that pain has become a side effect for most surgery and someone may be suffered from chronic postoperative pain, especially incidence of orthopedic / trauma patients up to 57%.11 Over anxiety as the most common negative emotional factor was a predictor to lead moderate and severe pain after operation(72%). 12 The pain and other physical discomfort by surgery can interfere with sleep during postoperative recovery, and prior insomnia in patients increases the risk of postoperative sleep problems. 13 It is found that general anesthesia can lead to sleep rhythm disorder and / or the change of biological clock gene, which can change the sleep structure and sleep quality of postoperative patients, so that it may increase the incidence of postoperative complications, such as postoperative delirium, postoperative 4 cognitive dysfunction, immune suppression, cardiovascular adverse events and so on.14 Moreover, patients with insomnia often complain that disturbances of mood and cognitive abilities is always accompanying by different levels of anxiousness, fatigue, pain and physical discomfort.15 As a result of these complications, not only the length of hospital stays and average hospitalization expenses were extended, but also patients have worse surgical experience and satisfaction. 16 Fatma Celik et al think that it is valuable for surgeons to gain a better understanding of how to identify and reduce surgical anxiety in their patients. 17 We hope to find some ways that are easy, cheap, harmless and standardized to identify and relieve psychosomatic symptom of patients during the perioperative period.  a review of orthopedic surgery about non-pharmacological   sleep aids reducing post-operative pain, CBT-I as a non-pharmacological sleep aid, has   been shown to increase the quality of sleep and sleep time, decrease pain, and help patients maintain those gains28.

CCBT for psychosomatic symptom of physical illness
Although

Objectives {7}
The trial has two main objectives: 1.
To test the clinical efficacy of the CCBT-Prs software package as an adjunct Usual Care(UC) compared to UC alone.

2.
To explore targeted psychotherapy for surgical patients at higher risk for poor outcome and explanatory mechanisms of action for CCBT.

7
The trial hypotheses are: 1. a) CCBT-Prs software package will be more effective in reducing anxiety, depression, insomnia and postoperative pain for surgery patients in comparison to UC.

2.
b) The mediators of treatment effects for CCBT on changes may be beliefs about disease, character trait , social support, attribution mode, the response to disease.

Trial design {8}
This study is a prospective, randomized, controlled, assessor blinded, multicenters, superiority trial with two arms, including one experimental arm and one control arm. The study population will be independently randomized to receive either 5 sessions of CCBT-Pre +UC or alone UC (see Fig. 1). Exclusion criteria include psychosis, organic mental disorder, or current high risk of suicide, substance abuse or dependence within the 12 months prior to enrollment, antisocial personality disorder or unstable medical condition. Patients was postponed 8 operation for more than a week or changed to emergent surgery will be excluded. Patients who are currently enrolled in another intervention study that could potentially impact the primary outcome will also be excluded from the study.
All participants will be evaluated by two researchers (a therapist and a nursing graduate students) who will also verify patient diagnosis and eligibility.

Who will take informed consent? {26a}
Individuals will be identified and confirmed from surgical plan lists by the Electronic Medical Record System. All participants will be evaluated by two researchers (a therapist and a nursing graduate students) who will also verify patient diagnosis and eligibility.
Once a candidate is eligible for enrollment, he or she will be approached by researcher to discuss the study in detail. Before initiation of any study procedures, written informed consent will be obtained according to the ethical requirements. As all participants will continue to be treated by their doctor in charge, participants will be required to obtain permission from their doctor practitioners prior to study enrollment.

Additional consent provisions for collection and use of participant data and biological specimens {26b}
At the same time blood bio-markers, fNIRS as objective markers could not involve and analyzed for each subject because of trauma and individual will. Additional consent provisions for collection has been written in informed consent. If participant would like to consent and will receive a small amount of cash compensation after the end of the test .

Explanation for the choice of comparators {6b} UC (Usual Care)
Patients in the control group will undergo surgery and subsequent hospital stay according to the conventional treatment. Program schedule is the same as the routine of care.
Participants will be permitted to continue using hypnotics or analgesic during the study period. There will be no restrictions on treatment options for participants who receive treatments from their doctors in charge. All changes in conventional treatment, along with the reasons for those changes, will be recorded throughout the study period. Perioperative diseases and psychological care routine will be carried out in accordance with Perioperative Care Manual and consensus on ERAS.39 All surgery patients were assessed and screened using Psychological Experience Scale 1,2 like any other patients on admission. Once mild to moderate emotional problems are identified, regular psychological support will be provided by a therapist. Severe emotional problems are consulted further by psychiatrists.

CCBT-Prs software package
CCBT-Prs is a computer program that includes registration, evaluation, and therapy.The patients who were selected and randomized grouping to CCBT-Prs intervention group will access to assessment and intervention from the software package.

Criteria for discontinuing or modifying allocated interventions {11b}
Patients was postponed operation for more than a week or changed to emergent surgery will be excluded or discontinue interventions.
The study intervention is non-invasive, so it carries minimal risk. But participants are undergoing high-risk surgery, it is expected that they may encounter several adverse events unrelated to the study intervention during. An adverse event may be consisting of any unfavorable and unexpected sign, symptom or discomfort temporally associated with this study. All adverse events will be reported, and serious adverse events will be immediately reported to the Institutional Research Ethics Committee of First Hospital of Shanxi Medical University. An adverse event includes changes in the patient's depression.
PHQ-9 will be monitored and reported and once suicide idea were perceived, the participant will be dropped out of the study for further clinical evaluation and management.

Strategies to improve adherence to interventions {11c}
A researcher in the research group specifically intervened the subjects with specialized tools and comfortable room rooms to improve the comfort of interventions. Making an appointment in advance and keeping track of the treatment progress of the subjects greatly increase the adherence and completion rate of the intervention.

Relevant concomitant care permitted or prohibited during the trial {11d}
Patients in the control group will undergo surgery and subsequent hospital stay according to the conventional treatment. Program schedule is the same as the routine of care.
Participants will be permitted to continue using hypnotics or analgesic during the study period. There will be no restrictions on treatment options for participants who receive treatments from their doctors in charge. All changes in conventional treatment, along with the reasons for those changes, will be recorded throughout the study period. Perioperative diseases and psychological care routine will be carried out in accordance with Perioperative Care Manual and consensus on ERAS.39 All surgery patients were assessed and screened using Psychological Experience Scale 1,2 like any other patients on admission. Once mild to moderate emotional problems are identified, regular psychological support will be provided by a therapist. Severe emotional problems are consulted further by psychiatrists.

Provisions for post-trial care {30}
The study intervention is non-invasive, so it carries minimal risk.

Baseline and clinical characteristics
Baseline characteristics will include gender, age, education, marital status, employment status, main diagnosis, operation method, anesthesia. Moreover, treatment history will include past medical history, other prior treatments, current treatment (medication and others) at baseline and all changes in conventional treatment throughout the study period. At the same time, the factors that personality characteristics, social support, disease coping that may affect therapeutic outcome are assessed and collected at baseline. The most important of all, the baseline of anxiety, depression, pain, insomnia for 12 participant are assessed and collected.

Primary outcome
The primary outcome of the study is exploratory to assess effects of the intervention on anxiety, depression, pain and sleep. The outcomes include both psychological and physiological. A trained research team member who remains blinded to treatment allocation will perform baseline anxiety, depression, pain, and insomnia assessments. to 'worst imaginable pain'. Subjects are asked to place a mark along the 10cm long line to indicate the intensity of their pain. The distance between the 'no pain' anchor to this mark is then measured and denotes the pain intensity Score, the higher the score, the more severe the pain.50 Pain medication intake in the first 48 h postoperative will be ascertained and recorded from the medical record.

Secondary outcomes
To assess study feasibility, we will evaluate compliance to the study protocol. Adherence to the interventions schedule will be assessed by calculating drop-out rates. For example, the difference that total number of participants in the CCBT group less total number of people who have finalized the entire process of CCBT divide by the total number of participants in the CCBT group.
Another evaluation indicator is satisfaction survey about personal feelings of interventions program, and the brief satisfaction survey was designed by ourselves. At the day of discharge or if a participant withdraws from the study, the individuals will be asked to 14 complete a brief satisfaction survey. This survey asks about the patients' satisfaction of their body health, mental health and taken care overall in the perioperative period.
Participants randomized and grouped will be asked about their experience completing practices, as well as a future study design will consider their feedback related to the study intervention.
At present, the treatment effect of CBT is mainly assessed by the scale. However, the results of the scale are subjective and limits the understanding of the biological mechanism of CBT. Compared with the evaluation results of the scale, biological markers are more objective, which is helpful to further explain the biological mechanism of CBT.51

Vital signs
The psychological state before and after operation often affects the stability of vital signs of patients.

The values of Blood Pressure(BP) including of Systolic Pressure(SP) and
Diastolic Pressure (DP) and Heart Rate(HR) are collected and recorded at 7 A.m during the intervention period. The effectiveness of the intervention can also be demonstrated by connecting the data together to observe the stability of the curve.

Brain function
Functional near infrared spectroscopy(fNIRS) will be applied to evaluate brain function before and after intervention. Cerebration in the cerebral cortex are observed and recorded by concentration changes local blood Oxygen (Oxy -Hb, Deoxy -Hb, total-Hb) including the prefrontal cortex and bilateral temporal lobes cortex. Near-infrared spectroscopy(NIRS) is a technology that can fire near-infrared light through the surface of an organism,using near-infrared light to be absorbed by hemoglobin in the cerebral cortex to detect of blood oxygen in the cerebral cortex. The technology can detect the changes of cerebral blood volume in the range of 2~3cm from the epidermis of the head and capture brain activation response easily.It is also known as"fNIRS functional NIRS ","Quantitative imaging of brain function". Prefrontal cortex is key brain region affecting mood and cognition function.52 The participants decide whether or not to conduct fNIRS before and after intervention according to their wishes. Finally, the content of Oxy -Hb, Deoxy -Hb, total-Hb will analyzed as brain function markers to find characteristic of function change before and after intervention.

Stress bio-markers
Ableson et al found that Cognitive intervention can significantly reduce the concentration of Adrenocorticotropic Hormone (ACTH) and Cortisol (Cor) in the patients by adjusting the function of Hypothalamic-Pituitary-Adrenal (HPA) axis.53 Blood will be collected to investigate whether CCBT results in a favorable modulation of stress bio-markers such as ACTH and Cor. Blood sample collection for CCBT group will occur at baseline and before anesthesia. At each time, approximately 5 cc will be collected. Then ACTH and Cor will be tested and analyzed by Laboratory. Table 1 show that the schedule of study enrollment, assessment and intervention time points. for a 10% dropout rate, about 100 cases will be included in per group in the actual study.

Recruitment {15}
Individuals will be identified and confirmed from surgical plan lists by the Electronic Medical Record System. All participants will be evaluated by two researchers (a therapist and a nursing graduate students) who will also verify patient diagnosis and eligibility.
Once a candidate is eligible for enrollment, he or she will be approached by researcher to discuss the study in detail.

Sequence generation {16a}
After obtaining consent, enrolled participants will be randomly assigned to one of two groups using randomization in a 1:1 allocation by a random digital table. The random digital tables will be produced by SPSS22.0 and distributed to different centers. Then each participant will be grouped randomly and assigned to one of the two treatment groups by order of admission. The stratified sampling is used to achieve sample equalization.
Outcome collectors and data administrators will be blinded to the group assignment.

Concealment mechanism {16b}
After obtaining consent, enrolled participants will be randomly assigned to one of two groups using randomization in a 1:1 allocation by a random digital table. The random digital tables will be produced by SPSS22.0 and distributed to different centers. The random digital tables were Concealed in opaque, sealed envelopes.Then each participant will be grouped randomly and assigned to one of the two treatment groups by order of admission.

Implementation {16c}
All participants will be evaluated by two researchers (a therapist and a nursing graduate students) who will also verify patient diagnosis and eligibility. The random digital tables will be produced by SPSS22.0 and distributed to different centers. Then each participant will be grouped randomly and assigned to one of the two treatment groups by order of admission.A researcher (Non-data collectors) in the research group specifically intervened the subjects with specialized tools and comfortable room rooms to improve the comfort of interventions

Who will be blinded {17a}
Data collectors and data administrators will be blinded to the group assignment.

Procedure for unblinding if needed {17b}
(1)When all subjects have completed the trial, it can be uncovered.
(2) If serious adverse events occur, suspicious unintended serious adverse reactions, it can be uncovered after asking the leading researcher.

Data collection and management
Plans for assessment and collection of outcomes {18a}

Data collection and management
Standardized data collection and management system will be used to collect and manage data, such as Case Record Form and Electronic Data Capture(EDC) system ResMan (www.medresman.org). To ensure in process quality control (in-process QC) and real-time online quality control (on-line QC) during the management of data. After the trial is completed, primary data and statistical results will be uploaded to the clinical trial public management platform ResMan. The results will be shared to ResMan after one year.

Plans to promote participant retention and complete follow-up {18b}
A researcher (Non-data collectors) in the research group specifically intervened the subjects with specialized tools and comfortable room rooms to improve the comfort of interventions. Making an appointment in advance and keeping track of the treatment progress of the subjects can help to greatly increase the adherence and completion rate of the intervention. Case Record Forms and reasonable flow scheme were prepared for subjects. Follow-up management will be carried out by WeChat.

Data management {19}
Standardized data collection and management system will be used to collect and manage data, such as Case Record Form and Electronic Data Capture(EDC) system ResMan (www.medresman.org). To ensure in process quality control (in-process QC) and real-time online quality control (on-line QC) during the management of data.
After the trial is completed, primary data and statistical results will be uploaded to the clinical trial public management platform ResMan. The results will be shared to ResMan after one year.

Confidentiality {27}
All subjects will be arranged by numbers and made to maintain the confidentiality of patient data.

Plans for collection, laboratory evaluation and storage of biological specimens
for genetic or molecular analysis in this trial/future use {33}

Stress bio-markers
Ableson et al found that Cognitive intervention can significantly reduce the concentration of Adrenocorticotropic Hormone (ACTH) and Cortisol (Cor) in the patients by adjusting the function of Hypothalamic-Pituitary-Adrenal (HPA) axis.53 Blood will be collected to investigate whether CCBT results in a favorable modulation of stress bio-markers such as ACTH and Cor. Blood sample collection for CCBT group will occur at baseline and before anesthesia. At each time, approximately 5 cc will be collected. Then ACTH and Cor will be tested and analyzed by Laboratory.

Statistical methods for primary and secondary outcomes {20a}
Statistical analysis and reporting of this trial will be conducted in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines. Data will be analyzed by SPSS 22.0 version. For baseline variables, demographic and clinical characteristics will be analyzed by descriptive statistical method. The self-assessment questionnaires for primary outcomes provide numerical score assimilated to continuous variable. Continuous data will be reported as means ± standard deviations or median (quartile 1 and quartile 3) depending on distribution and assessed using analysis of variance (ANOVA). Categorical data will be reported as proportions and assessed with the use of a Chi-square or Fisher's exact test. A trajectory analysis will be performed to assess changes in the presence or changes primary outcomes in over time by Hierarchical Linear Model (HLM). All tests will be two-sided, with p values <0.05 considered statistically significant. The study will record the proportion of patients eligible who meet inclusion, decide to participate, complete the trial because the overall feasibility of conducting the trial will be accessed.
Patients who not start, complete or continue with their prescribed treatment will be analyzed based on the intention-to-treat principle.54

Interim analyses {21b}
Statistical analysis and reporting of this trial will be conducted in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines. Data will be analyzed by SPSS 22.0 version. For baseline variables, demographic and clinical characteristics will be analyzed by descriptive statistical method. The self-assessment questionnaires for primary outcomes provide numerical score assimilated to continuous variable. Continuous data will be reported as means ± standard deviations or median (quartile 1 and quartile 3) depending on distribution and assessed using analysis of variance (ANOVA). Categorical data will be reported as proportions and assessed with the use of a Chi-square or Fisher's exact test. A trajectory analysis will be performed to assess changes in the presence or changes primary outcomes in over time by Hierarchical Linear Model (HLM). All tests will be two-sided, with p values <0.05 considered statistically significant. The study will record the proportion of patients eligible who meet inclusion, decide to participate, complete the trial because the overall feasibility of conducting the trial will be accessed.

Methods for additional analyses (e.g. subgroup analyses) {20b}
Statistical analysis and reporting of this trial will be conducted in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines. Data will be analyzed by SPSS 22.0 version. For baseline variables, demographic and clinical characteristics will be analyzed by descriptive statistical method. The self-assessment questionnaires for primary outcomes provide numerical score assimilated to continuous variable. Continuous data will be reported as means ± standard deviations or median (quartile 1 and quartile 3) depending on distribution and assessed using analysis of variance (ANOVA). Categorical data will be reported as proportions and assessed with the use of a Chi-square or Fisher's exact test. A trajectory analysis will be performed to assess changes in the presence or changes primary outcomes in over time by Hierarchical Linear Model (HLM). All tests will be two-sided, with p values <0.05 considered statistically significant. The study will record the proportion of patients eligible who meet inclusion, decide to participate, complete the trial because the overall feasibility of conducting the trial will be accessed.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Patients who not start, complete or continue with their prescribed treatment will be analyzed based on the intention-to-treat principle.54 Plans to give access to the full protocol, participant level-data and statistical code {31c} Standardized data collection and management system will be used to collect and manage data, such as Case Record Form and Electronic Data Capture(EDC) system ResMan (www.medresman.org). After the trial is completed, primary data and statistical results will be uploaded to the clinical trial public management platform ResMan.
The results will be shared to ResMan after one year. The full protocol can be accessed by URL(http://www.chictr.org.cn/listbycreater.aspx).

Composition of the coordinating centre and trial steering committee {5d}
The coordinating centre is composed of President Wang Binquan, President Xu Yong, Director Li Yuling and responsible for coordination and communication of different subcenters overseeing the trial.

Composition of the data monitoring committee, its role and reporting structure {21a}
The data monitoring committee (DMC) is composed of President Wang Binquan, President Xu Yong, Director Li Yuling and responsible for interim data audit and final data audit. The DMC state that it is independent from the sponsor and competing interests.

Adverse event reporting and harms {22}
22 The study intervention is non-invasive, so it carries minimal risk. But participants are undergoing high-risk surgery, it is expected that they may encounter several adverse events unrelated to the study intervention during. An adverse event may be consisting of any unfavorable and unexpected sign, symptom or discomfort temporally associated with this study. All adverse events will be reported, and serious adverse events will be immediately reported to the Institutional Research Ethics Committee of First Hospital of Shanxi Medical University. An adverse event includes changes in the patient's depression.
PHQ-9 will be monitored and reported and once suicide idea were perceived, the participant will be dropped out of the study for further clinical evaluation and management.

Frequency and plans for auditing trial conduct {23}
The data monitoring committee (DMC) will audit trial conduct in the medium term and at the end term.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
The trial is currently ongoing and recruiting. This study will be conducted at the in-patient department at head and neck surgery, department of orthopedics, general surgery, cardiac surgery in the pilot hospital. The potential participants will be informed of the study objectives and asked their willing to participate, when they contact with the study researcher. All participation is voluntary and fully anonymity all the way. They will be required to provide written informed consent before starting and can drop out at any time.
All participants will receive UC from their doctors in charge and that half of the recruited participants will be informed of receiving CCBT in addition to their UC. The above will be informed to each participant in detail by researchers.

Dissemination plans {31a}
23 Regardless of the outcome, study outcomes will be published in international journals.

Significance
Mind-body practices are more and more popular in Non-pharmacological interventions for psychosomatic disease. Few studies have investigated application of CCBT in the perioperative period during complex surgeries. Therefore, this study will use a comparative randomized controlled trial design, exploring clinical effects of CCBT software in mind-body practices in multiple diseases during the perioperative period. This study was planned to address the lack of trials examining the administration of CCBT relieving negative emotion, pain and insomnia in patients with surgery. If results are positive, the findings of this study will provide valuable evidence to facilitate the development of nonpharmacological interventions for treating psychosomatic symptom. Most important of all, it can meet the mental health needs of non-psychotic inpatients with physical health problems and relieve a conflict from shortage of psychotherapists and strong demand for psychological services . (55) If future direction of the study is to determine a large advantage in cost effectiveness of the CCBT-Prs than UC, CCBT will be used more widely in clinical.

Limitations
The foreseen limitations of this study are the following. First, subjective and objective measures will be wished to evaluation treatment effect in the study protocol because patients with insomnia underestimate their actual sleep time, or some implicit character of some Chinese people. However, using polysomnography monitoring sleep brings significant burden on participants. At the same time blood bio-markers, fNIRS as objective markers could not involve and analyzed for each subject because of trauma and individual 24 will. Additional consent provisions for collection has been written in informed consent. If participant would like to consent and will receive a small amount of cash compensation after the end of the test .The second limitation is that we will be unable to elucidate specific effects of the CCBT program because a psychological placebo group to control for non-specific factors will not be employed, such as psychological counseling or some health education software. The third limitation is the lack of follow-up to the subjects and the lack of knowledge of the long-term effects of CCBT intervention.

Trial Status
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Supplementary Files
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