Article Text
PDF
Abstract
Introduction Delirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate objective assessment of the pupillary light responses in comatose patients in the intensive care unit (ICU). Whether automated pupillometry might predict delirium in critically ill patients is not known. We hypothesise that automated pupillometry could predict the occurrence of delirium in critically ill patients without primary brain injury, requiring more than 48 hours of invasive mechanical ventilation in the ICU.
Methods and analysis The PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) study is a prospective cohort study, which will be conducted in eight French ICUs in the Paris area. We aim to recruit 213 adult patients requiring invasive mechanical ventilation for more than 48 hours. Automated pupillometry (Neurological Pupil Index; NPi-200, Neuroptics) will be assessed two times per day for 7 days. Delirium will be assessed using the Confusion Assessment Method in ICU two times per day over 14 days in non-comatose patients (Richmond Agitation and Sedation Scale ≥−3).
The predictive performances of the seven automated pupillometry parameters (ie, pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, NPi and symmetry of pupillary responses) measured to detect the delirium occurrence within 14 days will be the main outcomes. Secondary outcomes will be the predictive performances of the seven automated pupillometry parameters to detect complications related to delirium, ICU length of stay, mortality, functional and cognitive outcomes at 90 days.
Ethics and dissemination The PODIUM study has been approved by an independent ethics committee, the Comité de Protection des Personnes (CPP) OUEST IV—NANTES (CPP21.02.15.45239 32/21_3) on 06 April 2021). Participant recruitment started on 15 April 2022. Results will be published in international peer-reviewed medical journals and presented at conferences.
Trial registration number NCT05248035; clinicaltrials.gov.
- Adult intensive & critical care
- Neurophysiology
- Adult neurology
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
STRENGTHS AND LIMITATIONS OF THIS STUDY
A comprehensive prospective multicentre study is being conducted to examine the correlation between changes in pupillometry and the occurrence of delirium in mechanically ventilated patients within the intensive care unit (ICU).
The study will involve the assessment of delirium using a validated scale known as the Confusion Assessment Method in ICU, which will be carried out over a span of 14 days. A centralised follow-up will also be conducted at 90 days following the admission of patients to the ICU.
Throughout the inclusion and follow-up period of the study, the investigators will remain unaware of the results obtained from automated pupillometry to ensure unbiased analysis.
Given the observational nature of this study, we will solely report associations between variables and not causal relationships.
The pragmatic design of this study, unfortunately, does not permit hourly measurements of delirium or automated pupillometry.
Introduction
Background and rationale
Delirium affects more than 50% of patients requiring invasive mechanical ventilation (IMV) in the intensive care unit (ICU). In the short term, delirium is associated with adverse events (ie, accidental extubation and catheter removal) and an increase in the duration of mechanical ventilation and the length of hospital stay.1 2 In delirious patients, mortality is three times higher and half of survivors have cognitive sequelae.3 4
Guidelines recommend using delirium screening scales such as the Confusion Assessment Method in ICU (CAM-ICU) or the Intensive care delirium screening checklist to implement early measures to prevent delirium.5–7 These scales require to wait for awakening of patients and require time and team training. Two clinical scores, E-PRE-DELIRIC and PRE-DELIRIC, were validated to predict the risk of delirium on the day of ICU admission, but their performance is moderate area under the curve (AUC) Receiver Operating Characteristic curve (ROC) 0.67 (95% CI 0.64 to 0.71) and 0.75 (95% CI 0.72 to 0.78) respectively, and they are not used in clinical practice either.8
Delirium is linked to autonomic dysfunction, which can result in changes in size and response of the pupils.9 Pupillometry studies could be indicative of subsyndromal delirium, especially in sedated patients. Automated pupillometry (AP) is an easy-to-use device that allows for accurate objective assessment of the pupillary light response. AP is reproducible with submillimetre accuracy (<0.05 mm), and it allows the acquisition of dynamic parameters in addition to pupillary diameter. These include quantitative measurement of pupillary reactivity, speed or latency of pupil contraction after a standardised light stimulus even in case of sedation exposure.10 This tool is increasingly used in ICU for monitoring brain-injured patients at the bedside.11–13
In non-brain-injured patients, AP has been evaluated in a monocentric study to predict the occurrence of delirium in ICU.14 Interestingly, the decrease in pupillary diameter variation after 48 hours of IMV was independently associated with the occurrence of delirium in a sample size of 100 patients.
Hypothesis
We hypothesise that AP parameters may predict the risk of delirium in adult patients requiring invasive mechanical ventilation in the ICU. AP could allow early identification of high-risk patients who might benefit from pharmacological interventions to prevent or treat hyperactive symptoms related to ICU delirium.
Objectives
The primary objective of PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) is to determine whether the seven AP parameters measured at D0 (ie, inclusion time after 48 hours of initiation of IMV) allow predicting the occurrence of delirium over the next 14 days in ICU. The secondary objectives of this trial are presented in table 1.
Study objectives and associated endpoints
Methods and analysis
Design overview
The PODIUM study is an investigator-initiated, prospective multicentre study conducted in eight ICUs in the Paris area. Adult patients requiring invasive mechanical ventilation within the first 24 hours of admission will be eligible for the study. Inclusion and exclusion criteria are presented in box 1. The study design is presented in table 2 and in figure 1. We report the study protocol according to the Standard Protocol Items: Recommendations for interventional Trials statement.15
Eligibility criteria
Eligibility criteria
Patient requiring invasive mechanical ventilation during the first 24 hours of ICU stay.
Inclusion criteria
Adult (over 18 years old).
Invasive mechanical ventilation for more than 48 hours.
Close relative informed consent.
Exclusion criteria
Patients presenting with delirium (CAM-ICU positive) in the absence of sedation on the day of inclusion.
Acute or chronic neurological disease: brain-injured patients (traumatic brain injury, stroke, cardiac arrest, cerebral oedema, hypoglycaemic coma, meningitis/encephalitis/brain abscesses…), dementia with MMSE <24 or MOCA <26.
Pre-existing chronic ophthalmologic pathologies that may modify the photomotor reflex (cataract, amyloidosis, Horner syndrome…).
Moribund patient (SAPS2 >80).
Length of stay in the ICU > 72 hours.
Transfer from another ICU, readmission to the ICU.
Non-French-speaking patients, no affiliation to a social security regiment.
ICU, Intensive Care Unit; IMV, Invasive Mechanical Ventilation; MMSE, Mini Mental State Examination; MOCA, Montreal Cognitive Assessment; SAPS2, Simplified Acute Physiology Score 2.
Summary of the chronology of the study with data collected
Study setting and population. AP, automated pupillometry; CAM ICU, confusion assessment method for the intensive care unit; D, day; ICU, intensive care unit; IMV, invasive mechanical ventilation; RASS, Richmond Agitation and Sedation Scale; SAPS2, Simplified Acute Physiology Score 2; SmRSq, Simplified modified Rankin Scale Questionnaire; tMOCA, Telephone Montreal Cognitive Assessment.
Patients will be prospectively recruited among patients admitted in eight French ICUs, after more than 48 hours of IMV (screening phase of 48 hours). The close relative will be informed for inclusion of the patients in the PODIUM trial by the investigators during the screening phase (see online supplemental material 1). The key eligibility criteria include the previous IMV duration (screening phase of 48 hours) and the expected IMV duration after inclusion at least of 48 hours. Patients will be considered eligible for enrolment if they fulfil the inclusion criteria and none of the exclusion criteria, as defined in figure 1.
Supplemental material
After inclusion (performed by the investigator or by a doctor representing the investigator), AP will be assessed two times per day until D7 or IMV discontinuation, by a nurse or intensivist not directly involved in the care of patient. The seven AP parameters are pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, Neurological Pupil Index (NPi), symmetry or asymmetry of the reflex in both. The investigator will remain blinded to AP results throughout the inclusion and follow-up period of the study. Routine neurological monitoring in ICU includes the Richmond Agitation and Sedation Scale (RASS) score every 4 hours. If the patient is not comatose (RASS score ≥ −3), assessment of delirium using the CAM-ICU will be performed two times per day by a nurse or intensivist until D14 (or ICU discharge).
AP device and parameter acquisition
NPi-200 is a handled infrared camera able to measure accurately the pupil size and reactivity to a light stimulus. These parameters will be measured by nurses or by the investigating physician not involved in the patient’s care. The AP parameters are measured for both eyes from D0 onwards, two times per day, if the patient is under IMV and up to a maximum of 7 days (D7), using the NPi-200 Neuroptics device.
While acknowledging that ambient light conditions can influence the parameters of AP, we noted the presence or absence of a window in each patient room and we also recorded the time of day at each AP measurement.16
The seven AP parameters are: the pupillary diameter, the variation of the pupillary diameter, the pupillary constriction speed, the pupillary dilatation speed, the photomotor reflex latency, the NPi and the symmetry or asymmetry of the pupillary diameter in both eyes.
Study endpoints
Primary endpoint: delirium assessment
In non-comatose patients, delirium will be assessed two times per day with the CAM-ICU scale (see online supplemental material 2). Non-comatose patients are defined by a score on the RASS ≥−3.3 17
The CAM ICU scale is recognised as one of the leading assessment tools for delirium in the ICU. It has undergone extensive development, validation and is routinely utilised with a once-daily assessment.5 18 However, in a previous study, the nurse-to-intubated-and-ventilated-patient ratio was high (1:1), and the adherence to the CAM ICU assessment was found to be low at 45%.19 Consequently, to ensure better compliance with the PODIUM protocol, it is advisable to initiate the CAM ICU assessment at a low frequency. Implementing an hourly assessment could potentially result in a decreased rate of compliance.
Secondary endpoints
Please see table 1 for the full list of secondary endpoints.
Follow-up in ICU
Critical care management will follow international guidelines.7 Sedation management will be based on local sedation protocols. However, participating centres will be advised to follow recommendations (PADIS (Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility and Sleep) guidelines) for the management of agitation (RASS >+1) and delirium (CAM ICU is positive)7 (see online supplemental material 3).
During follow-up, patients who have regained capacity will be asked to provide written informed consent (see online supplemental material 1). A centralised follow-up will be performed by a trained research assistant at D90. Patients or their relatives will be contacted by telephone. Functional and cognitive status will be assessed by the simplified modified Rankin Score score and the T-MOCA score, respectively.20–23
Statistical considerations
Sample size calculation
The number of patients requiring mechanical ventilation for more than 48 hours in the ICU of the Bichat Claude Bernard hospital is between 15 and 30 patients each month. The rate of delirium in this population is 66%.24
For sample size calculation, according to the study of Favre et al using the NPi-200 for prediction of delirium in ICU (DOI: 10.1186/s13054-020-2796-8, variation of pupillary diameter is about 4% between patients who experienced delirium and those who did not during ICU stay14); we assumed a sample of 213 inclusions to achieve 80% power to detect a difference of 4% in AP parameters at a 0.05 significance level. Relying on the active participation of the eight participating centres, we estimate that the inclusion time will be 24 months (assuming the number of inclusions at 1.5 patients per month per centre). To ensure the 213 planned inclusions and the 3-month follow-up of all included patients, a research duration of 27 months is expected. Participant recruitment started on 15 April 2022.
Statistical analyses
The analyses will be considering all enrolled patients. For each AP parameter at D0, the mean parameter value from right and left eyes will be used for analyses. TheAUC will be calculated according to the diagnosis of delirium in each patient. The Youden index will be calculated to define a dichotomisation threshold for the AP parameters and to estimate the sensitivity (SE), specificity (Sp), positive prediction value and negative prediction value. An internal validation by 10-fold method will be performed. Also, a threshold for the maximisation of the specificity (Sp) will be estimated. The significant level of all statistical analyses will be a two-sided 5% and the CI at 95%. All statistical analyses will be performed using SAS software (SAS Institute Inc., Cary, North Carolina) V.9.4 or later, or R software (R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org/) V.4.0 or later. All analyses will be conducted by a statistician according to a prespecified statistical analysis plan. A full statistical analysis plan has been written and is available in online supplemental material 4). All analyses’ results will be reported according to the Consolidated Standards of Reporting Trials 2010 guidelines.25
Data collection and management
Data collection will be done in electronic format using software CleanWeb. The software will fulfil the regulatory requirements and security norms. Data will be handled according to the French law. All original records (including consent forms, reports of suspected unexpected serious adverse reactions and relevant correspondences) will be archived at trial sites for 15 years. The clean trial database file will be anonymised and maintained for 15 years.
We will collect data on primary and secondary endpoints as well as potential risk factors of delirium (ICU medication, comorbidities and complications) detailed in table 2.
Data availability statement
The data of this study will be available on reasonable request from the corresponding author. The data will not be publicly available due to privacy or ethical restrictions.
Patient and public involvement
Patients and public were not involved in any of the phases of this study. Results of the trial will be made available to all participants via ClinicalTrials.gov as well as by email notification.
Trial status
Recruiting. The first inclusion occurred on the 15 April 2022 and the recruiting period will last 15 months. On 25 December, 54 patients have been included.
Ethics and dissemination
Legal obligations and approval
Sponsorship has been agreed by Assistance Publique—Hôpitaux de Paris (AP-HP, Clinical Research and Innovation Department) for this non-interventional human research study. AP-HP has obtained the favourable opinion of the independent ethics committee ‘Comité de Protection des Personnes (CPP) Sud- OUEST IV – NANTES’ (CPP21.02.15.45239 32/21_3) for the study protocol (version PODIUM−V.02.0; 7 January 2022). The trial will be carried out in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Any substantial modification to the protocol must be sent to the sponsor for approval. Once approval has been received from the sponsor, it must also obtain approval from the CPP before the amendment can be implemented. The information sheet and the consent form can be revised if necessary, particularly if there is a substantial amendment to the study or if adverse reactions occur. AP-HP is the owner of the data. The data cannot be used or disclosed to a third party without its prior permission.
Methods for obtaining information from research participants
In accordance with Article L.1122-1-1 of the French Public Health Code, no research mentioned in 3° of this article (like PODIUM protocol) can be carried out on a person without his/her free and informed non-opposition, obtained in oral after the person has been given the information specified in Article L.1122–1 of said Code.
The trustworthy persons/relatives of eligible patients will be informed of the modalities of implementation of the study through an information note (see online supplemental material 1) and oral explanations given by the investigating physician or any qualified person. This information will also be given to the patient concerned as soon as his neurological condition allows it.
Indeed, at the time of inclusion, the person participating in the research is often not in a state to give the non-opposition; the inclusion in the PODIUM protocol is, therefore, done without prior agreement of the patient. Inclusion in the PODIUM protocol is done as soon as the patient is consecutively hospitalised in ICU and requires IMV during the first 24 hours of admission and for a duration longer than 48 hours: it is, therefore, not always possible to obtain the non-opposition of the person before his inclusion in the trial.
The protocol, therefore, provides that the non-opposition of this person is not systematically sought at inclusion and that only the non-opposition of family members or the trusted person is sought and the informant (investigator or collaborator) will have sufficient time (the first 3 days of the patient’s resuscitation) to proceed with clear and informed information, imperatively before the patient’s inclusion in the research.
The information will be given to the patient and his non-opposition will be sought at the time when his neurological state allows it.
The information and the collection of the non-opposition of the patient or trusted person/relative is collected by the principal investigator, or by a physician who represents him/her, or by a qualified person in the participating centre.
Thus, two types of information document are provided for:
one for the trusted person/close relative if he/she is present at the time of inclusion when the patient is unable to be informed.
One for the patient as soon as he/she is able to consent to the continuation of the research.
A copy of the information document is given to the person participating in the research. The information given to the subject will be recorded in his or her medical file. Subjects may exit the study at any time and for any reason.
Data collection and quality control
The persons responsible for the quality control of clinical matters will take all necessary precautions to ensure the confidentiality of information relating to the study participants. These persons, as well as the investigators themselves, are bound by professional confidentiality. During or after the research, all data collected about the participants and sent to the sponsor by the investigators (or any other specialised collaborators) will be anonymised. Under no circumstances should the names, addresses and other protecter identifiers of the subjects involved be shown.
A data monitoring committee has not been convened, on the grounds that the study is low risk. This has been approved by the Sponsor, Steering Committee and the independent Ethical Board. The research data will be collected and monitored using an electronic Case Report Form (eCRF) through CleanWEB Electronic Observation Book and will be centralised on a server hosted by the AP-HP Operations Department. This research is governed by the CNIL ‘Reference Method for processing personal data for clinical studies’ (MR-001, amended). AP-HP, the sponsor, has signed a declaration of compliance with this ‘Reference Method’.
An independent Clinical Research Associate appointed by the sponsor will be responsible for the proper running of the study, for collecting, documenting, recording and reporting all handwritten data, in accordance with the Standard Operating Procedures applied within the Clinical Research and Innovation Department of AP-HP. The investigators agree to accept the quality assurance audits carried out by the sponsor as well as the inspections carried out by the competent authorities. All data, documents and reports may be subjected to regulatory audits. These audits and inspections cannot be refused on the grounds of medical secrecy. An audit can be carried out at any time by independent individuals appointed by the sponsor. The aims of the audits are to ensure the quality of the study, the validity of the results and compliance with the legislation and regulations in force. The persons who manage and monitor the study agree to comply with the sponsor’s audit requirements. The audit may encompass all stages of the study, from the development of the protocol to the publication of the results and the storage of the data used or produced as part of the study. Sponsor is responsible for access to the study database.
Safety considerations
The investigator can temporarily or permanently withdraw a subject from the study for any safety reason or if it is in the subject’s best interests. The investigating doctor may request unblinding of AP for any reason he considers essential.
Trials oversight committees
Two oversight committees have been established to oversee the conduct of this trial, the Steering Committee and Scientific Committee, the composition of each is listed at the end of this paper.
Publication plan
Scientific presentations and reports corresponding to the study will be written under the responsibility of the coordinating investigator of the study with the agreement of the principal investigators and the methodologist. The coauthors of the report and the publications will be the investigators and clinicians involved, on a pro-rata basis of their contribution in the study as well as the biostatistician and associated researchers. All trial sites will be acknowledged, and all investigators at these sites will appear with their names under ‘the PODIUM investigators’ in the final manuscript. Rules on publication will follow international recommendations.26
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @romsonnevil
Collaborators PODIUM study group: Jean-François Timsit, Lila Bouadma, Etienne De Montmollin, Michael Thy, Marc Doman, Hermann Do Rego, Michael Ejzenberg, Erwann Cariou, Simona Presente, Paul-Henri Wicky, Mario Rienzo, Mariem Dlela, Fariza Lamara, Jean-Paul Mira, Nathalie Marin, Juliette Pelle, Stephanie Cossec, Smina Hadj Mahfoud, Tchoubou Tona, Alain Combes, Alexandre Demoule, Yves Cohen, Stéphane Gaudry, Muriel Fartoukh, Khalil Chaibi, Jean-Luc Diehl, Eleonore Bouchereau, Antoine Troger, Julie Langlais, Nicolas Peron, Caroline Hauw-Berlemont, Emmanuel Guerot, Nicolas Brechot.
Contributors PJ contributed to the conception and design of the research protocol, assisted by RS, CC and VG. PJ, RS and CC wrote the first draft of the protocol and this manuscript. CT designed the statistical analysis plan. All authors critically revised and modified the protocol and the article. Co-investigators are presented in alphabetical order. They all approved the final version to be published.
Funding The PODIUM trial is supported by Assistance Publique—Hôpitaux de Paris (AP-HP), Clinical Research and Innovation Delegation (DRCI), Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75010 PARIS, grant number CRC-20012. The sponsor had no role in the trial design, trial conduct, data handling, data analysis or writing and publication of the manuscript.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.