In current HAP and VAP international guidelines, less than 10% of recommendations were supported by high-quality evidence. Low and very low evidence predominate in HAP/VAP treatment and diagnosis recommendations. Guidelines are redacted by groups of experts, who can give strong recommendations based on personal opinions, not only on literature evidence. The major implication is that further randomized controlled trials are an unmet clinical need, urgently required.
With the GRADE methodology, high-quality evidence is based on RCTs without major limitations, and exceptionally on observational studies with large magnitude effect [6, 7]. In the infectious diseases field, with rare diseases and heterogeneous clinical presentations, conducting RCTs might be difficult, lowering the overall quality of evidence. A study conducted on IDSA guidelines from 1994 to 2010 found that only 14% of the recommendations were linked to high-quality evidence (level of evidence A in the original article, based on RCTs), while the majority of the recommendations relied on expert opinion and case studies [17]. In HAP and VAP, despite being common hospital-acquired infections and a major concern for morbidity and mortality in intensive care unit [18, 19, 22], the involvement of critically ill patients might represent a limitation for conducting interventional studies and to generalize conclusions from observational cohorts in non-critically ill patients. Individual recommendations issued in guidelines may not always be supported by high-quality evidence, and evidence-based medicine practice should be based on profound knowledge of CPGs and literature, to properly evaluate bedside patient management.
Feasibility of interventional studies has also to be considered, together with ethical implications, appropriateness of the study design, practical limitations, and costs. The majority of recommendations were issued on HAP/VAP treatment. In HAP and VAP, often caused by multidrug-resistant pathogens, the delay in appropriate antimicrobial treatment represents a poor prognostic factor and is mainly driven by the pathogen extended resistance pattern itself [23,24,25,26,27]. Appropriate antibiotic treatment is hence pivotal and challenging. The majority of treatment recommendations regarded antibiotic choice and duration (data not shown), addressing key bedside clinical decisions. Nonetheless, for HAP/VAP treatment, none of the recommendations issued was based on high-quality evidence. The majority of evidence was rated low and very low, and only a third of strong recommendations was supported by moderate quality of evidence. The lack of a gold standard for HAP/VAP diagnosis and the geographical and in-hospital variability of etiology and antimicrobial susceptibility are partly responsible for the lack of high-quality evidence supporting these practices (Table 4). Interventional studies on general hygiene measures, effectiveness of epidemiological surveillance, and collateral care, such as bed positioning, might be performed with less difficulties, explaining the greater quantity of high-quality evidence recorded in HAP/VAP prevention. These data point out the need of collaboration to realize large RCTs, increasing the quality of evidence.
Table 4 Challenges for high-quality studies in the infectious diseases field, in ICU patients and in HAP/VAP The revision of clinical guidelines in several medical fields, such as cardiology, emergency medicine, gastroenterology, interventional medicine, hepatology, and nephrology, reported similar findings, with an overall scarcity of high-quality evidence [9,10,11,12,13,14,15, 17, 28, 29]. This low amount of high-quality evidence represents a call for collaboration to plan large well-conducted new research and simultaneously shows the importance of expert opinion in particular fields.
In the EBM era, CPGs represent an important and valuable tool in bedside clinical decisions and for patient management. Our study results reinforce the importance of literature knowledge to accurately translate CPGs and their recommendations in clinical practice and represent a call of wide collaboration to realize well-designed research in treatment, diagnosis, and prevention of HAP and VAP. Importantly, some clinical questions cannot be answered with high-quality evidence, because the clinical questions themselves are too complex and the antibiotic resistance profiles are profoundly different between sites and keep evolving. Furthermore, among the earliest HAP/VAP guidelines in the pre-GRADE era, with the possible exception of single antibiotic coverage for patients with Pseudomonas aeruginosa and shock absence, few recommendations based on lower grade of evidence were revised by subsequent studies. This implies the pivotal importance of high-quality studies in areas where there is a high degree of uncertainty, with potential adverse implications.
Several limitations can be found in the study. First, the more recent assessed guideline was written in 2017, including literature published until September 2016. Since then, new evidence might have been published on the addressed topic. Most CPGs are updated in periods longer than 5 years, with difficult incorporation of emerging evidence until next iteration. Published literature should be periodically reassessed, to update CPGs references and recommendations, creating a dynamic document. The creation of an adaptation framework for integration of new evidence in CPGs [30] would avoid outdated recommendations and will improve implementation in clinical practice. Second, literature supporting each recommendation was not revised and quality of evidence was not reassessed. Evidence and recommendation rating analyses were based on the classification reported in original papers, with no changes in the rating assigned to the literature by CPGs writing committees. Lastly, CPGs on HAP/VAP issued by other scientific societies without explicitly reported recommendations or quality of evidence assessment were excluded from the analysis. Despite these limitations, there are important strengths. The study provides a detailed analysis of quality of evidence used to write HAP/VAP international guidelines, an important evaluation in evidence-based medicine. The results point out the difficulty of performing RCTs and providing high-quality evidence in critically ill patients. Areas in which higher quality evidence are scarce reveal research opportunities, to assess unmet clinical needs in HAP/VAP management.