The research project will be carried out following the research plan and the principles enunciated in the current version of the Declaration of Helsinki (amendment 2013) by the World Medical Association and the ICH-GCP Guidelines E6(R2). Specific national and local regulatory authority requirements will be followed as applicable.
Risk categorisation
SQUEEZE is a prospective cohort study collecting clinical data on non-cardiac surgery patients. No research-related interventions are anticipated, and all patients will receive routine care according to the standards laid out in each institution. There is no risk of study participation contributing towards any adverse events. Therefore, there will be no reporting of adverse events.
Some countries may choose to nest within this study additional assessments of patient outcome or add biological sample collection or physiological assessments to add translational aspects – details of such studies will be provided outside this primary protocol.
Institutional Review Board (IRB) or equivalent
In all cases, prior to study initiation, the local Principal Investigator (PI) at each centre must liaise with the national coordinator (NC) and ensure that they have taken the appropriate steps to seek authorisation from relevant national/regional/local bodies to permit appropriate research study conduct. No substantial changes will be made to the protocol without prior IRB approval, except where necessary to eliminate apparent immediate hazards to study participants.
Participant Information and Informed Consent
There are three anticipated approaches:
- This study may be considered to constitute research that requires individual patient consent.
- In some countries, it may be possible to successfully seek a waiver of individual patient consent from an appropriate regulatory authority - in the UK; this is the Confidentiality Advisory Group (CAG) of the Health Research Authority (HRA).
- In some countries, this may be permissible without consent, as there is no intervention, the data is being collected routinely, and only fully pseudonymised data leaves the hospital.
The SSC consider that the ideal approach is waived informed consent (2, above) because it minimises the risk of introducing selection bias. This approach was used in the UK national study SNAP-2 in 2017 and globally in the International Surgical Outcomes Study (5, 6). Patients at increased risk of receiving postoperative vasopressors are likely to be more severely unwell, possibly with delirium, possibly having emergency surgery – all conditions predispose to difficulties obtaining informed consent. Therefore, by mandating individual informed consent, we might systematically exclude patients of the most significant interest and consequently undermine the generalisability of our findings. Significant differences between participants and non-participants may threaten the validity of results from observational studies (7).
Consent procedures and provision of patient information will be conducted following local practice. If consent is required, it will be obtained as follows: prior to surgery, the patients will be presented with the IRB-approved ICF providing sufficient time and information for the participant to make an informed decision about their participation in the study, i.e., explaining the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and any discomfort participation may entail.
In emergency surgery, when there may not be enough time to collect consent or a patient may not be able to give consent, according to the Principal Investigator's judgement, consent may be obtained after surgery. In this case, consent must be obtained within seven days of surgery or as deemed appropriate by Principal Investigator. Patients included in Cohort B can also give their consent after surgery; this is because it will not be known if a patient is eligible for the study until during surgery, and at some sites, it may not be possible to take consent from all patients undergoing surgery (especially as the percentage of eligible patients is expected to be small)
Each participant will be informed that participation in the study is voluntary and that he/she may withdraw from the study at any time and without explanation. Withdrawal of consent will not affect his/her subsequent medical assistance and treatment, and no further data will be collected. While already collected, encoded data will be pseudonymised, and analysis may be performed up to the point of data collection.
The participant will be informed that his/her medical records will be examined by authorised individuals other than their treating physician. The participant will read and consider the statement, have the opportunity to ask questions before signing and dating the ICF and be given a copy of the signed document. Patients will confirm that they were given adequate time to reach a decision. The ICF must also be signed and dated by the investigator (or designee) and will be retained as part of the study records.
Participant privacy
The investigator affirms and upholds the principle of the participant's right to privacy and shall comply with applicable privacy laws. Expressly, the anonymity of the participants shall be guaranteed when presenting the data at scientific meetings or publishing them in scientific journals.
Individual subject medical information obtained because of this study is considered confidential, and disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject identification code numbers, and only pseudonymised data will be recorded in the central database.
For data verification purposes, authorised representatives of the sponsor or an ethics committee may require direct access to parts of the medical records relevant to the study, including participants’ medical history.
International considerations
This study will permit individuals from any country to express an interest in participation. Providing they can satisfy the SSC and ESAIC, they can deliver the study following appropriate standards and sample a representative population from several hospitals within that country.
However, as this study is funded and supported by a European organisation, the priority is to consider healthcare environments that are most similar to Europe (acknowledging that within Europe, there is a degree of variation). Patient data from patients in all countries within the Council of Europe (47 member states), Canada and USA, Australia and New Zealand will be analysed and reported in the main manuscript.
Information from other continents (Africa, Asia and South America) is no less valuable but will be reported separately to avoid considering incomparable healthcare environments together. For example, comparing patients enrolled in the African Surgical Outcomes Study (ASOS) (8) with those in the Europe Surgical Outcomes Study (EuSOS) (4) demonstrates significant differences.
Country-level datasets will be compared and presented sensitively and with suitable emphasis on the inherent limitations of these comparisons, including international differences in patterns of surgical disease and genetic backgrounds, as well as in healthcare systems. Comparisons will be made between countries grouped by income status (high/middle/low-income, according to worldbank.org), but we also accept significant limitations to this methodology.
Suppose there is sufficient interest from a continent with an identified suitably experienced leader who wishes to coordinate activity in their region. In that case, the SSC and ESAIC will look upon this proposal favourably, which could result in a distinct analysis and manuscript.
Early termination of the project
As an observational study, premature termination resulting from ethical or safety concerns is exceedingly unlikely.
Amendments, Changes
Only the SSC or persons delegated by the SSC are entitled to amend the protocol. National Coordinators (NC) Local Principal Investigators (PI) will receive timely notification of changes and will be required to submit amendments locally. Written documentation of the amendments' approval will be provided to the sponsor, and substantial amendments to the protocol will be only implemented after necessary local approvals. In consideration of the observational nature of the study, the necessity of protocol deviations to protect the rights, safety and well-being of human subjects without prior approval of the sponsor and the IRB appears remote. Such deviations must be documented and reported to the sponsor and the IRB as soon as possible.
Publication of results
The results of SQUEEZE and its sub-studies will be published in peer-reviewed international medical journals and presented at Euroanaesthesia and national meetings.
As recommended by the International Committee of Medical Journal Editors, authorship will be considered based on contributions to the recruitment of patients, data acquisition and cleaning, analysis and interpretation of the data, manuscript writing, and submission of national/local grants AND final approval of the version to be published AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Members of the SSC and other particularly committed investigators (see below) that fulfil those criteria will be part of the Writing Group. The members of the Writing group and the “SQUEEZE Investigators” will be authors of the publications derived from SQUEEZE. When submitting a manuscript, the corresponding author will specify the group name as “SQUEEZE Investigators”. According to the recommendations issued by the International Committee of Medical Journal Editors, the article's by-line identifies who is directly responsible for the manuscript, and MEDLINE lists as authors and collaborators, whichever names appear on the by-line. To ensure that MEDLINE will list the names of individual group members who are collaborators, there will be a note associated with the by-line stating that the individual names are elsewhere in the paper and those names are collaborators. The local PI will be asked to submit names of staff actively involved from their institution at the End of Study Reporting Form.
Presentation at international meetings will be restricted to the members of the SSC or their delegates. National Coordinators will qualify for presentation at national meetings after approval by the SC and the sponsor. ESAIC Clinical Trial Network will be acknowledged in all publications and presentations.
Data sharing and secondary analyses
After the pooled results are published, centres will be allowed to use their own data for local presentation and publication. Duplicate data publication is not permitted.
The pseudonymised pooled dataset may be available for secondary analyses upon specific request in the form of a detailed study proposal (including authorship rules) to the SSC. Only collaborators may have access to the study data. The final approval of these potential secondary analyses rests with the SC. Prior to journal submission, any paper originating from the pooled data will be reviewed by the SSC, which is also entitled to require revisions. Authorship of any publication derived from the pooled data set will include the group name "SQUEEZE Investigators” with a by-line clearly stating that the individual names are elsewhere in the paper. For transparency, the original paper has to be referenced in all articles of secondary analyses. Requests for data sharing for individual-level meta-analyses are to be addressed to the Sponsor and SC.