Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}

Capnographic monitoring reduces the incidence of hypoxia in older patients undergoing gastrointestinal endoscopy under propofol sedation: Study protocol for a multicenter randomized controlled trial

Trial registration {2a and 2b}.

ClinicalTrials.gov , NCT05030870. Registered on September 1, 2021.

Protocol version {3}

The protocol version is 2.2, which was approved in November 22, 2021.

Funding {4}

This study was supported by the National Nature Science Foundation of China (Nos. U21A20357) .

Author details {5a}

Authors

Qiuyue Lian, Shaoyi Chen, Xiangyang Cheng, Jie Zhang, Weifeng Yu, Renlong Zhou, Diansan Su

Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

Email address:

Qiuyue Lian: l18724464815@163.com

Shaoyi Chen: docteurchensy@163.com

Xiangyang Cheng: 1647384344@qq.com

Jie Zhang: q150981@qq.com

Weifeng Yu: ywf808@yeah.net

Renlong Zhou: renlongzhou@shsmu.edu.cn

Diansan Su: diansansu@yahoo.com

Corresponding author

Diansan Su

Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China

Email address:

Diansan Su: +862168383702, Email:diansansu@yahoo.com

Co-corresponding author

Renlong Zhou

Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China

Email address:

Renlong Zhou: +862168383702, Email:renlongzhou@shsmu.edu.cn

Name and contact information for the trial sponsor {5b}

Sponsor:The National Nature Science Foundation of China (Nos. U21A20357)

Grant recipient: Diansan Su

Address:Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China

Tel:+862168383702

Role of sponsor {5c}

The funder had no role in the analyses and interpretation of the results or writing of the manuscript.

Introduction

Background and rationale{6a}

The sedation rate of gastrointestinal endoscopy varies in different countries. In China, the overall sedation rate for gastrointestinal endoscopy is ~50% [1], whereas in the USA, >98% gastrointestinal endoscopy procedures are performed under sedation [2, 3]. Cardiopulmonary complications, especially hypoxia, are the most common complications that occur during gastrointestinal endoscopy under sedation. Prolonged or severe hypoxia can cause ischemia of the coronary artery and permanent nervous system damage or even result in death [4, 5]. Thus, determining a method to reduce hypoxia incidence in gastrointestinal endoscopy under sedation is crucial.

Compared with the current clinical routine monitoring of pulse oxygen saturation (SpO2), capnographic monitoring can detect hypoventilation and respiratory depression earlier, thereby helping in providing earlier intervention [6]. Therefore, it is believed that capnographic monitoring would reduce the incidence of hypoxia. Nevertheless, whether capnographic monitoring should be routinely performed during gastrointestinal endoscopy under sedation with propofol remains controversial.

There are two major studies regarding this subject; however, their results are discrepant. The first investigation, a randomized, controlled study (ColoCap Study) conducted by Beltz et al., confirmed that additional capnographic monitoring of ventilatory activity in ASA I–III patients reduces the incidence of hypoxia during propofol sedation for colonscopy [7]. However, the second investigation, a cohort study, reported that additional capnographic monitoring did not improve patient safety or satisfaction, but it did increase the cost [8]. The fundamental problem was that the initial oxygen flow in the ColoCap Study was only 2 L/min, which is inconsistent with that in clinical practice (3–4 L/min). This inconsistency resulted in a hypoxia incidence of >50% in the control group. Another limitation of the ColoCap Study was that the depth of sedation between the two groups may have been inconsistent. Although the cohort study was designed to closely mimic clinical practice, it did not yield positive results. These conflicting results indicate that there is insufficient evidence regarding routine capnographic monitoring in patients.

Older patients comprise a vulnerable group who are more susceptible to hypoxia during gastrointestinal endoscopy performed under drug-induced sedation [9, 10]. However, to the best of our knowledge, whether this vulnerable group requires routine monitoring for capnography has not been investigated. Therefore, this study was designed to improve the security of gastrointestinal endoscopy under sedation in older patients.

Objectives {7}

Our aim is to investigate whether an additional capnographic monitoring-based intervention can reduce hypoxia incidence in older patients undergoing gastrointestinal endoscopy under sedation. Our primary objective is to measure the incidence of hypoxia (75% ≤ SpO2 < 90% for < 60 s). Our secondary objective is to measure the incidences of subclinical respiratory depression (90% ≤ SpO2 < 95%), severe hypoxia (SpO2 < 75% or 75% ≤ SpO2 < 90% for ≥60 s), and other adverse events (AEs) recorded via tools proposed by the World Society of Intravenous Anesthesia International Sedation Task Force. We predict that additional capnographic monitoring of ventilatory activity will reduce hypoxia incidence during propofol sedation for gastrointestinal endoscopy in older patients. Our aim is to provide credible evidence regarding reduced hypoxia incidence in older patients.

Trial design {8}

This study is a multicenter, randomized, single-blind, two-arm parallel-group, controlled with an active comparator, interventional superiority clinical trial. We intend to evaluate the impact of an additional capnographic monitoring-based intervention on hypoxia incidence in older patients.

This trial was conducted under the recommendations of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). The trial was registered on ClinicalTrials.gov (No. NCT05030870) on September 1, 2021. We presented the trial registration data in the form of Supplemental data.

Methods: participants, interventions, and outcomes

Study setting {9}

This study will enroll ~1800 participants from the Renji Hospital Shanghai Jiao Tong University School of Medicine, Henan Provincial People's Hospital, and Qilu Hospital of Shandong University. The ethics committee of the Renji Hospital Shanghai Jiao Tong University School of Medicine approved and supported this clinical trial (KY-2021014).

Eligibility criteria {10}

This clinical trial has three centers that recruited patients. A summary of the inclusion and exclusion criteria is presented in Table 1.

Table 1 Inclusion/exclusion criteria
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Who will take informed consent? {26a}

Trained anesthesiologists will explain this trial to the potential participants in detail, and the informed consent form will be provided. Participants can decide whether they wish to participate in the trial after sufficient time to deliberate. Subsequently, the participant or his/her trustee or guardian can sign the informed consent form, and they can withdraw at any time during the trial. Following this, baseline data will be collected from the patients, and they will be randomly allocated using the central random system. Participants can contact our team if they have any health concerns during the trial. The entire process of recruiting participants and obtaining their consent by the members of the research team will be performed in accordance with good clinical practice (GCP). In case of any AEs during the trial related to the study procedure or not, the researchers will immediately report to the director in charge of the clinical trial of the research institution and contact Professor Diansan Su.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Not applicable as no participant data and biological specimens were collected or used in ancillary studies.

Interventions

Explanation for the choice of comparators {6b}

For the choice of comparators, the central randomization system will be used for each study site. Following randomization, the participants will receive either standard monitoring (Arm2) or additional capnography (Arm1). The comparator in this trial is standard monitoring alone (Arm2).

Intervention description {11a}

Capnography-blinded arm (Arm2) and capnography-open arm (Arm1) constitute the interventions for the participants in this trial. The capnography-blinded arm involves standard monitoring, and the capnography-open arm involves additional capnography.

In both the groups, standard monitoring will include determining the heart rate, SpO2, electrocardiogram, and noninvasive blood pressure of the selected patients. In the capnography-open arm, a sampling line will be connected to a bedside portable monitor (Capnostream 20; Medtronic, Inc.) to ensure that the capnographic data of the patients are available for the additional noninvasive assessment of ventilation. A nasal cannula equipped with an oral sampling port to accommodate mouth breathers provided 2 L/min oxygen and continuously sampled CO2 content of both inspired and expired patient gas. The sampling line was connected to a portable bedside monitor (Capnostream 20; Medtronic, Inc.) displaying the time-based CO2 graphic waveform, numerical CO2 partial pressure (mmHg), derived respiratory rate, and SpO2 via integrated pulse oximetry. The height, shape, and rhythm of the capnogram provide a real-time assessment of ventilatory function. In the presence of supplemental oxygen during inspiration, the samples essentially contain no CO2, and the samples represent alveolar CO2 concentration during expiration, with a small amount of gas containing no CO2 from the patient physiologic dead space. For alveolar hyperventilation, the samples comprise reduced to no CO2. In the capnography-blinded arm, no sampling line will be connected to the bedside portable monitor, and the capnographic data of the patients will not be visible to ensure that only the integrated pulse oximetric readout of the monitor is visible.

Table 2 lists the AEs of anesthesia and sedation.

Table 2 Adverse events of anesthesia and sedation
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Criteria for discontinuing or modifying allocated interventions {11b}

If participants request to withdraw from the trial, we will discontinue the allocated intervention for a given trial participant.

Strategies to improve adherence to interventions {11c}

Adherence to interventions primarily refers to patient self-management adherence.

Relevant concomitant care permitted or prohibited during the trial {11d}

No concomitant care or interventions will be permitted during this trial.

Provisions for posttrial care {30}

If a participant suffers harm from this trial, he/she will receive financial compensation accordingly. The amount of compensation will be determined jointly by consulting the relevant departments and the participant.

Outcomes {12}

Primary outcome measures

The primary outcome of this study is the incidence of hypoxia (75% ≤ SpO2 < 90% for <60 s) in the two groups from the beginning to the end of the operation.

Secondary outcome measures

The secondary outcomes comprise the following:

  1. 1.

    The incidence of subclinical respiratory depression (90% ≤ SpO2 < 95%) in the two groups from the beginning to the end of the operation.

  2. 2.

    The incidence of severe hypoxia (SpO2 < 75% or 75% ≤ SpO2 < 90% for ≥60 s) in the two groups from the beginning to the end of the operation.

  3. 3.

    The incidence of other AEs recorded via tools proposed by the World Society of Intravenous Anesthesia International Sedation Task Force.

Participant timeline {13}

Table 3 presents the schedule for the enrollment, interventions, assessments, and visit of the participants.

Table 3 Schedule of the major study events
Full size table

When the participants will enter the gastrointestinal endoscopic operating room, they will be screened for eligibility by the investigator. If they meet the inclusion criteria but not the exclusion criteria, the investigator will provide them with the fully informed consent form. After signing the informed consent form, the patients will be allocated to either the capnographic monitoring group or the control group via the central randomization system.

In the capnographic monitoring group, the criteria for apnea is the absence of exhaled CO2; altered ventilation is defined as end-tidal CO2 reduced by more than half of the baseline, as shown by the capnogram; and the definition of hypoxia is 75%<SpO2 < 90%, <60s. In the control group, hypoxia is defined as SpO2 <90%.

In both the groups, any sign of apnea, altered ventilation, or hypoxia that prompts an intervention will comprise (i) increasing oxygen supplementation, (ii) a chin lift or jaw thrust maneuver, (iii) insertion of the oropharyngeal or nasopharyngeal airway with a chin lift or jaw thrust maneuver, (iv) artificial mask ventilation, and (v) tracheal intubation.

The duration of surgery is defined as the time from the beginning to the end of the gastrointestinal endoscopy, excluding the time of resuscitation.

Sample size {14}

Our previous study revealed that hypoxia incidence in patients during gastrointestinal endoscopy with propofol sedation was ~8 % [11]. The anticipated effect size of additional capnographic monitoring was 50%, implying that the hypoxia incidence power analysis assumes a reduction from 8% to 4%. The results of a conventional analysis were compared between the capnography-open and capnography-blinded groups to detect differences in proportions (hypoxia). We use PASS 11.0, randomization 1:1, power of 1 − β = 0.90, and a two-sided α level of 5%. We assume a 10% dropout rate. Thus, the results revealed that ~1800 patients would be required.

Recruitment {15}

The schedule of the major study events for each study visit is presented in Table 3. This study included older patients who are scheduled to undergo gastrointestinal endoscopy with propofol sedation. The patients (65 ≤ age <80 years) who met the inclusion criteria were preliminarily screened by the investigators and recruited by distributing recruitment materials to patients and their families. Additionally, we put up recruitment posters in the endoscopy centers explaining the advantages of our trial. The nasal catheters that will be used in our trial are free, and the trial is beneficial for participants. We estimate that the trial will easily recruit enough participants according to the number of patients admitted to the endoscopy centers per day.

The entire process of recruiting participants and obtaining their consent by the members of the research team will be consistent with GCP.

Assignment of interventions: allocation

Sequence generation {16a}

In this trial, we used stratified blocked randomization to design the central randomization system. Risk factors for hypoxia during sedated gastrointestinal endoscopy include patient factors, sedation factors, and endoscopic operation factors. Patient factors mainly include preexisting cardiopulmonary disease, obesity, and advanced age. The incidence of hypoxia during sedated gastrointestinal endoscopy varies among patients with different underlying conditions. However, the subjects in our trial were all ASA I–II patients and did not include patients with ASA III-IV, which means that the trial did not involve patients with previous severe cardiopulmonary disease. Additionally, the number of obese patients in the older population in China is extremely low, and stratification by obesity would provide little benefit. Our study only included ASA I–II older patients aged 65 to 80 years, who we can assume have similar physical conditions, and the incidence of hypoxia during sedated gastrointestinal endoscopy is approximately the same. Therefore, we did not stratify them by age, and only central stratification was used in our trial. Complete baseline data will be collected from participants, including name, gender, date of birth, etc. After assessing patient eligibility for inclusion, his/her informed consent will be obtained. We will randomly assign the participants in a ratio of 1:1 to the standard or additional capnographic monitoring group according to the allocation sequence of the central randomization system. The length of a random sequence is not fixed, and 4, 6, and 8 are random.

Concealment mechanism {16b}

After obtaining the signed informed consent, the participants will be randomly assigned to the standard or additional capnographic monitoring group according to the central randomization system. The random results, random number, and their relationship with groups will be kept confidential from the participants throughout the trial. The same nasal cannula with a CO2-collecting device will be used in both groups and connected to the capnographic monitoring device. The participants will not be aware of their own and others’ grouping before, during, and following gastrointestinal endoscopy.

Implementation {16c}

Designated doctors will generate the allocation sequence, enroll participants, and assign participants to interventions.

Assignment of interventions: blinding

Who will be blinded {17a}

After the interventions are assigned, only the trial participants will be blinded. The results in the central randomized system will be kept confidential from the participants throughout the entire trial. The same nasal cannula will be used in both the standard and additional capnographic monitoring group, and the sampling line will be connected to a portable beside monitor. The researcher will ensure that participants are not aware of their own or other’s assignment.

Procedure for unblinding if needed {17b}

As the trial is single-blind, patients interested in knowing their group could be informed by the investigator following the analysis of results.

Data collection and management

Plans for assessment and collection of outcomes {18a}

This study is an internal multicenter clinical trial. All data collection physicians will be specially trained by assessors. We will conduct regular online meetings to share the progress of the trial and discuss the problems encountered during the project. Moreover, we will conduct field visits to subcenters for quality control. We shall also regularly organize the trial data to check for any missing data, and to promote data quality, we intend to apply other methods and call the participants as well.

Plans to promote participant retention and complete follow-up {18b}

Not applicable, as the trial will not involve follow-up; thus, we have no plans to promote participant retention and complete the follow-up.

Data management {19}

The case report form (CRF) of the respective patients will be entered and/or filled in for all the collected patient data during this clinical trial. The study number, subject number, date of subject information, and informed consent will be appropriately documented in the patient CRF. We will archive the source data as per GCP guidelines. The data manager will be responsible for data processing and will conduct regular monitoring according to the sponsor’s standard operating procedures to ensure that the dates are adequate, accurate, and complete. The source data lock will occur only after the completion of the quality assurance procedures.

Confidentiality {27}

Participant information will be confidential and managed according to the Data Protection Act, NHS Caldecott Principles, The Research Governance Framework for Health and Social Care, and the conditions of Research Ethics Committee approval. The confidentiality of the data collected during the course of the research will be strictly maintained, and only the members of the trial team (or individuals from the sponsor organization or center sites relevant to the trial) will be allowed to access the data. All documents containing patient information are stored in a specific cabinet in the anesthesia department, locked and keyed for safekeeping. The permission of the principal investigator is required for the removal or access of the data. The participants will be allocated an individual trial identification number and their details will be stored in a secure database. This database is maintained by professional researchers, and only the principal investigator has access to the data set. The anonymized trial data are not to be shared with other researchers.

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

Not applicable as no biological specimens were collected as part of this trial.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

Data selection for statistical analysis

  1. 1.

    Full analysis set (FAS): According to the principle of intention-to-treat analysis, the full analysis set will include all subjects who are randomized to the study and receive the study treatment.

  2. 2.

    Per-protocol set (PPS): The PPS population will include all FAS patients without major protocol deviations that influence the evaluation of primary outcomes, such as the different dosages of sufentanil during the induction or lack of primary outcome data. The efficacy analysis will be performed on the FAS and PPS.

  3. 3.

    Safety analysis set (SAS): The safety population will comprise all subjects who receive the study treatment. Analyses of safety data in the study will be based on the safety population.

Statistical analysis plan

All statistical analyses in this trial will be programmed and calculated using Statistical Package for the Social Sciences version 23.0 (IBM Inc., Armonk, NY, USA). The normally distributed baseline continuous data will be represented by mean (standard deviation [SD]) and compared by using an unpaired t-test. The non-normally distributed continuous data will be presented as median (interquartile range [IQR]) and compared by using Mann–Whitney U test. We will use χ2 test, continuity correction χ2 test, or Fisher’s exact test to analyze the categorical variables. We intend to compare the incidences of hypoxia, subclinical hypoxia, severe hypoxia, and total hypoxia of the participants during gastrointestinal endoscopy under sedation via χ2 test, continuity correction χ2 test, or Fisher’s exact test.

Additional analyses

Safety analysis: general safety evaluations will be based on the incidence and type of AEs. Safety variables will be tabulated and presented for all the patients in safety sets. AEs will be coded using the tools proposed by the World Society of Intravenous Anesthesia International Sedation Task Force. The number (%) of subjects with any AEs will be summarized and compared via χ2 test, continuity correction χ2 test, or Fisher’s exact test.

Interim analyzes {21b}

Not applicable as we have no plans to conduct any interim analyses, and no one has the rights to access these interim results and decide to terminate the trial.

Methods for additional analyses (e.g., subgroup analyses) {20b}

The association between the baseline characteristics and intervention and the risk of total hypoxia cumulative incidence was examined using univariable- and multivariable-adjusted logistic regression models. The results were presented as the odds ratios and corresponding 95% confidence intervals.

Methods in the analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c}

Statistical analysis was performed based on intention-to-treat. Regardless of protocol adherence, the results of the outcome analyses will be randomly analyzed. The frequency and type of missingness of all the variables will be screened. If missingness is >5% of any variable, we will use multiple imputations. Complete case analysis will be performed as a sensitivity analysis, in case of missing data and imputation.

Plans to provide access to the full protocol, participant-level data, and statistical code {31c}

Not applicable as we have no plans to provide access to the full protocol, participant-level data, and statistical code.

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

Diansan Su, Jiangqiang Zhang, and Jianbo Wu are the members of the trial steering committee, and Diansan Su is responsible for preparing and revising the protocol and disseminating any changes. Renlong Zhou and Weifeng Yu are responsible for overseeing the study design and protocol and interpreting the study findings. Qiuyue Lian and Shaoyi Chen are responsible for coordinating data collection and analysis and writing the scientific manuscript. Xiangyang Cheng and Jie Zhang are responsible for overseeing any statistical analyses and ensuring that the study implementation on the floor follows the protocol.

Composition of the data monitoring committee, its role, and reporting structure {21a}

We do not have composition of the data monitoring committee (DMC).

Adverse event reporting and harms {22}

The nasal cannula with a port that is used for collecting exhaled CO2 samples, which are consequently used for capnographic monitoring, is similar to the original nasal cannula and does not have any additional risks. To date, to the best of our knowledge, there has been no evidence that this study may cause any risk or discomfort to the participants.

We will record any AEs that occur during the clinical trial, regardless of whether these events were associated with the intervention. Additionally, all the expected and unexpected trial-related AEs will be reported in the trial publications.

Frequency and plans for auditing trial conduct {23}

The investigators shall maintain all study data according to GCP requirements. The original study data and information will be retained for at least 5 years following trial completion. Data security and monitoring reports will be submitted to the ethical committee every 3 months.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

This clinical trial will be conducted according to the ethical committee approval. Any problem or protocol modifications during the trial will be communicated to the ethical committees, trial participants, trial registries, journals, and regulators in a timely manner. The ethical committee’s consent will be required to change the protocol.

Dissemination plans {31a}

The participants, healthcare professionals, the public, and other relevant groups in the form of articles will communicate the results of this trial.

Discussion

This study is the first randomized controlled trial designed to confirm the utility of capnographic monitoring in older patients during gastrointestinal endoscopy under sedation. The proportion of older patients who undergo gastrointestinal endoscopy under sedation is increasing annually worldwide. Ensuring the safety of older patients during gastrointestinal endoscopy under sedation is thus crucial.

Hypoxia is the most common and severe complication that occurs during gastrointestinal endoscopy under sedation, with the primary cause of hypoxia being hypoventilation due to propofol administration. Older patients are more susceptible to respiratory depression and hypoxia than adult patients [12, 13].

The early detection of respiratory depression in patients and timely and effective intervention measures can reduce the occurrence of severe hypoxia, hypercapnia, and even cardiac arrest, thereby improving patient prognosis [14]. Capnography monitoring is more sensitive and real-time than SpO2 in reflecting respiratory depression before the onset of hypoxia [15,16,17].

Currently, no unified conclusion has been drawn on whether end-tidal CO2 monitoring can effectively reduce the occurrence of hypoxia during endoscopy [18,19,20,21,22,23]. There is insufficient evidence for routine capnographic monitoring in all patients during sedated gastrointestinal endoscopy, and there have been few recent studies to add to the scant literature on this topic. Our study design avoids some of the limitations of the other studies and demonstrates more closeness to clinical settings. Our study is expected to provide a higher level of evidence and improve the safety of gastrointestinal endoscopy under sedation in older patients.

Therefore, future research should seek to resolve some of the limitations of this study. First, this was a single-blinded clinical study, which might cause potential bias. Second, our trial is not international, and the participating institutions of our experiment are all Grade III Class A general hospitals in China. The medications or methods of sedation vary among different institutions and countries. Fortunately, the selected intravenous anesthetics are widely used owing to their clinical compatibility, and the data obtained in our study could be represented in most clinical settings. Third, only older patients with ASA grades I–II were included in our trial, and those with ASA grades III–IV were excluded. We planned another group to be explored in the next study for older patients with higher ASA classifications. Therefore, further capnography monitoring research in gastrointestinal endoscopy under sedation is warranted.

Trial status

Trial registration: ClinicalTrials.gov, NCT05030870. Registered on September 1, 2021. The protocol version is 2.2, which was approved in November 22, 2021. This study was started on September 1, 2021, and the recruitment phase will last until December 2023.