2.1. WHO guideline development process
The guidelines were developed following the standard recommendations described in the WHO Handbook for guideline development (5) and according to a scoping proposal approved by the WHO Guidelines Review Committee.
In summary, the process included: (i) identification of the primary critical outcomes and priority topics and formulation of the related PICO questions; (ii) retrieval of the evidence through specific systematic reviews of each topic using an agreed standardized methodology; (iii) assessment and synthesis of the evidence; (iv) formulation of recommendations; and (v) writing of the guidelines’ content and planning for the dissemination and implementation strategy; and (vi) revision of the recommendation regarding the use of 80% fraction of inspired oxygen (high FiO2) in surgical patients under general anaesthesia with tracheal intubation.
The initial plan for the guidelines included a section dedicated to best implementation strategies for the developed recommendations, based on a systematic review of the literature and expert advice. However, given the very broad scope and length of the present document and following consultation with the methodologist and the Guidelines Review Committee secretariat, the Guideline Steering Group decided not to include this section. A short chapter is included to address this aspect in the guidelines and two separate implementation documents (6, 7) were developed and launched by WHO in 2018.
The development of the guidelines involved the formation of four main groups to guide the process and their specific roles are described in the following sections.
WHO Guideline Steering Group
The WHO Guideline Steering Group was chaired by the director of the Department of Service Delivery and Safety (SDS). Participating members were from the SDS IPC team, the SDS emergency and essential surgical care programme, the Department of Pandemic and Epidemic Diseases, and the IPC team at the WHO Regional Office of the Americas.
The Group drafted the initial scoping document for the development of the guidelines. In collaboration with the Guidelines Development Group (GDG), it then identified the primary critical outcomes and priority topics and formulated the related questions in PICO format. The Group identified systematic review teams, the guideline methodologist, the members of the GDG and the external reviewers. It supervised also the evidence retrieval and syntheses, organized the GDG meetings, prepared or reviewed the final guideline document, managed the external reviewers’ comments and the guideline publication and dissemination. The members of the WHO Steering Group are presented in the Acknowledgements section and the full list including affiliations is available in the Annex (section 6).
Guidelines Development Group
The WHO Guideline Steering Group initially identified 20 external experts and stakeholders from the six WHO regions to constitute the GDG. GDG membership was updated in September 2018 to include an additional eight anaesthetists. Representation was ensured from various professional and stakeholder groups, including surgeons, nurses, IPC and infectious disease specialists, researchers and patient representatives. Geographical representation and gender balance were also considerations when selecting GDG members. Members provided input for the drafting of the scope of the guidelines, the PICO questions and participated in the identification of the methodology for the systematic reviews. In addition, the GDG appraised the evidence that was used to inform the recommendations, advised on the interpretation of the evidence, formulated the final recommendations based on the draft prepared by the WHO Steering Group and reviewed and approved the final guideline document. The members of the GDG are presented in the Annex (section 6.1).
Systematic Reviews Expert Group
Given the high number of systematic reviews supporting the development of recommendations for the guidelines, a Systematic Reviews Expert Group (SREG) was created. This group included researchers and professionals with a high level of expertise in the selected topics and the conduct of systematic reviews. While some of the reviews were conducted by the WHO IPC team, most SREG experts volunteered to conduct the systematic reviews as an in-kind contribution of their institutions to the development of the guidelines.
The SREG undertook the systematic reviews and meta-analyses and prepared individual summaries, which are available as web appendices to the guidelines. It assessed also the quality of the evidence and prepared the evidence profiles according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.
Some SREG members were also part of the GDG. However, according to the Guideline Review Committee’s instructions and to avoid any intellectual conflict, experts leading the systematic reviews were excluded from consensus decision-making for the development of recommendations related to the topic they reviewed, in particular when voting was necessary. As a member of the SREG, the GDG chair was equally excluded from decision-making on recommendations that were based on systematic reviews conducted by himself and his team. Furthermore, in sessions where the chair presented the evidence from systematic reviews conducted by his team, another GDG member was identified to act as the chair. The members of the GDG are presented in the Acknowledgements and the full list including affiliations is available in the Annex (section 6.1).
External Peer Review Group
This group included five technical experts with a high level of knowledge and experience in the fields of surgery and IPC. The group was geographically balanced to ensure views from both high- and LMICs; no member declared a conflict of interest. The group reviewed the final guideline document to identify any factual errors and commented on technical content and evidence, clarity of the language, contextual issues and implications for implementation. The group ensured that the guideline decision-making processes had incorporated contextual values and preferences of potential users of the recommendations, health care professionals and policy-makers. It was not within the remit of this group to change the recommendations formulated by the GDG. However, very useful comments were provided in some cases, which led to modifications of the recommendation text or the explanations provided within the remarks. The members of the WHO External Peer Review Group are presented in the Acknowledgements and the full list including affiliations is available in the Annex (section 6.4).
2.2. Evidence identification and retrieval
The SREG retrieved evidence on the effectiveness of interventions for the prevention of SSI from randomized controlled trials (RCTs) and non-randomized studies as needed. The Guideline Steering Group provided the SREG with the methodology and a briefing on the desired output of the systematic reviews and the members of these groups agreed together on the format and timelines for reporting. Using the assembled list of priority topics, questions and critical outcomes from the scoping exercise identified by the WHO Guideline Steering Group, the GDG and the guideline methodologist, the SREG conducted 27 systematic reviews between December 2013 and October 2015 to provide the supporting evidence for the development of the recommendations. The systematic review used as the basis for the recommendation on the use of high FiO2 was updated to April 2018 and an additional independent systematic review on adverse events potentially associated with the recommended use of high FiO2 was commissioned and conducted up to April 2018.
To identify relevant studies, systematic searches of various electronic databases were conducted, including Medline (Ovid), the Excerpta Medica Database, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials and WHO regional databases. All studies published after 1 January 1990 were considered. In a few reviews, the GDG and the SREG judged that relevant studies had been published before 1990 and no time limit was used. Studies in at least English, French and Spanish were included; some reviews had no language restrictions. A comprehensive list of search terms was used, including Medical Subject Headings. Criteria for the inclusion and exclusion of literature (for example, study design, sample size and follow-up duration) for the reviews were based on the evidence needed and available to answer the specific research questions. Studies from LMICs and high-income countries were considered. Search strategies and summaries of evidence for each systematic review are reported in web Appendices 2–27 (https://www.who.int/infection-prevention/publications/ssi-web-appendices/en/). The GDG was consulted again for re-evaluation of the updated evidence and reconsideration of the recommendation on the use of high FiO2, first in December 2017/January 2018 and then in October/December 2018.
Two independent reviewers screened the titles and abstracts of retrieved references for potentially relevant studies. The full text of all potentially eligible articles was obtained and then reviewed independently by two authors based on inclusion criteria. Duplicate studies were excluded. Both authors extracted data in a predefined evidence table and critically appraised the retrieved studies. Quality was assessed using the Cochrane Collaboration tool to assess the risk of bias of RCTs (8) and the Newcastle-Ottawa Quality Assessment Scale for cohort studies (9). Any disagreements were resolved through discussion or after consultation with the senior author, when necessary.
Meta-analyses of available comparisons were performed using Review Manager version 5.3 (10), as appropriate. Crude estimates were pooled as odds ratios (OR) with 95% confidence intervals (CI) using a random effects model. The GRADE methodology (GRADE Pro software; http://gradepro.org/) was used to assess the quality of the body of retrieved evidence (11, 12). Based on the rating of the available evidence, the quality of evidence was graded as “high”, “moderate”, “low” or “very low” ().
GRADE categories for the quality of evidence.
The results of the systematic reviews and meta-analyses were presented at four GDG meetings held in June 2014, in February, September and November 2015, and online GDG consultations were held between December 2017 and December 2018 for the re-assessment of the updated evidence on high FiO2. The evidence profiles and decision-making tables were reviewed to ensure understanding and agreement on the scoring criteria. According to a standard GRADE decision-making table proposed by the methodologist, recommendations were formulated based on the overall quality of the evidence, the balance between benefits and harms, values and preferences and implications for resource use. These were assessed through discussion among members of the GDG. The strength of recommendations was rated as either “strong” (the panel was confident that the benefits of the intervention outweighed the risks) or “conditional” (the panel considered that the benefits of the intervention probably outweighed the risks). Recommendations were then formulated and the wording was finalized by consensus. If full consensus could not be achieved, the text was put to the vote and the recommendation was agreed upon according to the opinion of the majority of GDG members.
In some conditional recommendations, the GDG decided to use the terminology “the panel suggests considering…” because they considered that it was important to stimulate the user to undertake a thorough decision-making process and to give more flexibility, especially because these recommendations involve important remarks about resource implications and feasibility in LMICs. Areas and topics requiring further research were also identified. After each meeting, the final recommendation tables were circulated and all GDG members provided written approval and comments, if any.
The systematic reviews targeted patients of any age. In general, these guidelines are valid for both adult and paediatric patients unless specified in the text of the recommendation or in the remarks. In several systematic reviews, no study was retrieved on the paediatric population and thus the GDG discussed whether the recommendations are valid in this population topic by topic. As a result, there are recommendations that are either inapplicable in the paediatric population or not proven due to lack of evidence. Based on the evidence reviews up to April 2018, the strength of the recommendation on the use of high FiO2 was revised from strong to conditional following consultation of the GDG, and the chapter of the guidelines dedicated to this topic update was duly revised. The updated guidelines were then issued in December 2018.
Draft chapters of the guidelines containing the recommendations were prepared by the WHO secretariat and circulated to the GDG members for final approval and/or comments. Relevant suggested changes were incorporated in a second draft. If GDG comments involved substantial changes to the recommendation, all members participated in online or telephone discussions to reach a final agreement on the text. The second draft was then edited and circulated to the External Peer Review Group and the Guideline Steering Group. The draft document was further revised to address their comments. Suggested changes to the wording of the recommendations or modifications to the scope of the document were not considered in most cases. However, in 3 specific recommendations, most reviewers suggested similar changes and these were considered to be important by the Guideline Steering Group. In these cases, further discussions were undertaken with the GDG through teleconferences and consensus was achieved to make slight changes in the text of the recommendations to meet the reviewers’ comments under the guidance of the methodologist.
The guideline methodologist ensured that the GRADE framework was appropriately applied throughout the guideline development process. This included a review of the PICO questions and the results of the systematic reviews and meta-analyses, including participation in re-analyses when appropriate, thus ensuring their comprehensiveness and quality. The methodologist also reviewed all evidence profiles and decision-making tables before and after the GDG meetings and provided guidance to the GDG in formulating the wording and strength of the recommendations.
