A Comparison and Evaluation of International Guidelines on the Treatment of Severe SARS-CoV-2 Infection

Background: When the SARS-CoV-2 pandemic began, no uniform treatment and care strategies for critically ill COVID-19 patients were yet available. National and international treatment recommendations were formulated under time pressure, initially on the basis of indirect evidence from the treatment of similar diseases. In this article, we give an overview of the content, currency, and methodological quality of the existing national and international guidelines, with special attention to the care of critically ill patients.

Methods: Guidelines were identified by a comprehensive search, the included guidelines were assessed in standardized fashion with the AGREE II guideline assessment instrument and according to the AMWF rulebook criteria, and the core recommendations of the included and methodologically high-quality guidelines were compared.

Results: Nine of the 97 guidelines that were identified fulfilled the content criteria for inclusion, and 6 of these fulfilled the qualitative criteria; these 6 guidelines still differed, however, in the topics to which they devoted the most attention, as well as in their methodological quality and currency. The treatment strategies for patients with severe respiratory failure (lung-protective ventilation strategies and rescue measures) deviated little from established standards. Uniform recommendations were made, among other things, for the administration of dexamethasone, which was recommended in all of the guidelines for patients requiring oxygen treatment, as well as for antithrombotic drug prophylaxis and for the prone positioning of ventilated patients. Many recommendations were based on insufficient evidence, and some were contradictory, e.g., those regarding antibiotic treatment or the choice between high-flow oxygen administration via nasal canula (HFNC) and noninvasive ventilation (NIV).

Conclusion: The consultation of multiple high-quality international guidelines and guideline recommendations shared in online portals such as MagicApp are helpful sources of information for clinicians. In view of the continuing lack of strong evidence, further research on intensive care treatments is needed (aspects of ventilation, positioning therapy, and the role of extracorporeal membrane oxygenation [ECMO]).

During the SARS-CoV-2 pandemic, more than 250 million infections were diagnosed worldwide (as of November 2021) and more than 5 million deaths are currently attributed to the disease (1). Even though vaccination campaigns reduce the number or severity of cases, there is still a need for effective treatment strategies for critically ill patients (2).

Early in the pandemic, due to a lack of evidence and high time pressure, treatment recommendations were made on the evidence level of expert consensus and as so-called rapid guidelines. These guidelines vary in scope, clinical focus, methodological quality, and up-to-dateness; the constant process of updating and advancing is very challenging for the authors (3, 4, 5, 6, 7, 8).

With increasing availability of study data, it is possible and necessary that guideline development advances to higher levels of methodological quality. The authors of the German guideline “Recommendations on the In-hospital Treatment of Patients with COVID-19—A Living Guideline“ also managed to increase the quality level of the guideline from the initial S1 level to the current S3 level (9) by means of a rapid updating process.

Even today, however, not all of the relevant treatment recommendations are included in the various guidelines internationally available, the up-to-dateness and methodological quality of the guidelines varies, and recommendations differ from each other due to the small evidence base.

The project to build a COVID-19 Evidence Ecosystem (CEOsys), which is funded by the German Federal Ministry of Education and Research (BMBF, Bundesministerium für Bildung und Forschung) within the framework of the German Network University Medicine (NUM), evaluates scientific studies on pressing issues, synthesizes evidence and supports the development of clinical practice recommendations (10).

In this article, selected international guidelines, focusing on the intensive care treatment of COVID 19 patients, are presented, their methodologies evaluated and their recommendations compared. This analysis is intended to support the integration of evidence-based management recommendations with a broad spectrum of content and the greatest possible up-to-dateness into everyday clinical practice.

Methods

The methodology largely followed the process of systematic reviews. However, we decided against prior registration and stating an a priori question, as we did not intend to evaluate a specific intervention (eSupplement, eTables 1–3). The literature search was conducted in the Trip, ECRI, GIN, Medline (OVID), and magicapp.org databases with support of medical information specialists (KG). The independent review of the search results was performed by two authors (CS, MG), using pre-defined inclusion and exclusion criteria. The methodological quality (reliability) of the included guidelines was determined, using the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument (11, 12) as well as the level S1–S3 classification system of the AWMF guideline rules, by four authors (CS, MG, CG, SD) in a modified Delphi process (13, 14).

eTable 1

Presentation of search strategies with the respective search results. Results of the search of 5 March 2021

eTable 2

Presentation of the search strategy in Medline (via Ovid)

eTable 3

Presentation of additional results from the supplementary manual search by the authors

Only guidelines with acceptable methodological quality (mean total AGREE-II score >65%) were included.

Subsequently, the content was compiled according to predefined subject areas (eMethods) and the recommendations related to the treatment of severely or critically ill COVID-19 patients were compared.

During the project, existing updates have regularly been checked and integrated in the guideline to ensure its greatest possible up-to-dateness (last 10/21) (Box).

Box

Note

Results

Identified guidelines, evaluation and characteristics

The literature search yielded 1975 hits, 97 of which were guidelines on aspects of COVID-19. Seven of these guidelines met all inclusion and exclusion criteria; a supplemental search yielded two further guidelines (15, 16, 17). Of the resulting nine guidelines, five were of sufficient methodological quality and included for comparison (Table 1, eTable 4). In addition, the recommendations on drug therapy of the methodologically inconsistent multipart South African recommendations were included as a sixth guideline.

Table 1

Guidelines from literature search with AGREE-II (AGREE) and AWMF guideline appraisal tool ratings

eTable 4

Detailed methodological evaluation of the included guidelines according to AWMF and AGREE-II appraisal. The table shows the means of the results of the four independent authors

The guidelines reviewed show significant differences in scope (75 to 248 recommendations) and distribution of key content areas (Figure 1, eTable 5). Overall, the evidence base is inconsistent and weak (Figure 2, eTables 6–8); up-to-dateness (publication period from 1 March 2021 to 7 October 2021) as well as frequency and periodicity of revisions show significant variation (Table 1). Based on the AWMF classification, three guidelines were classed as S3 level, four guidelines were formally classed as S1 level, as they did not fulfill some AWMF sub-criteria, and two of the guidelines excluded based on the AGREE-II assessment did not fully achieve any of the AWMF criteria catalogues.

eTable 6

Presentation of the evidence ratings of the various recommendations by the authors

eTable 7

Presentation of strengths of recommendation and levels of evidence

eTable 8

Compilation and presentation of guideline recommendations

Figure 1

Relative distribution of content of the included guidelines according to standardized counting method in predefined categories

Figure 2

Relative distribution of the evidence quality of the guidelines included; number of recommendation with appraised evidence in brackets

eTable 5

Number and grouping of the topics covered in the various guidelines into topic areas

Content summary

Diagnosis

Specific recommendations on laboratory testing and diagnostic imaging are made in two guidelines (Germany [D], National Institute of Health [NIH]); obtaining blood cultures is recommended on admission to the intensive care unit (ICU) (D) and if the patient deteriorates over time (D, NIH).

Respiratory management

The oxygen saturation targets stated in the guidelines are typically in the range of SpO2  >90% (WHO) and SpO2 92–96% (D, NIH, Surviving Sepsis Campaign [SSC]).

There is heterogeneity in the recommendations on high-flow nasal cannula (HFNC) oxygen therapy and noninvasive ventilation (NIV); the indications and discontinuation criteria for both methods are similarly defined (D, Australian guidelines [AUS], World Health Organization [WHO]); for acute hypoxic failure, the NIH and SSC guidelines give preference to HFNC, while in their explanatory notes the German guidelines give preference to the use of NIV.

Awake prone positioning is recommended by most guidelines (D, AUS, NIH, WHO).

With regard to the indication for intubation, only the German guideline makes a specific recommendation, while the other guidelines emphasize the clinical evaluation of the disease course and the importance of timely intubation under controlled conditions (AUS, WHO, SSC).

For invasive ventilation, lung-protective tidal volumes (D, NIH, WHO, SSC) and plateau pressures (NIH, SSC) are recommended; with regard to positive end-expiratory pressure (PEEP) values, the guidelines differ in their recommendations. Whilst the German guideline recommends the use of the ARDS network table as guidance and emphasizes, together with the WHO, the need for reevaluation of the course at regular intervals, other guidelines make the general recommendation of a PEEP > 10  cm H2O for patients with moderate to severe acute respiratory distress syndrome (ARDS).

Alveolar recruitment maneuvers (i.e. ventilation strategies to open up areas of atelectasis in the lungs) are recommended on a case-by-case basis to bridge severe hypoxemia (D, AUS, NIH, SSC); however, stepwise escalating/deescalating PEEP maneuvers are rejected for this indication (NIH, SSC).

Prone positioning of ventilated patients is recommended by all guidelines with minor variations.

Recommendations on the use of muscle relaxants differ slightly. While their intermittent use or their continuous administration for a maximum of 48 hours is seen as an option to prevent ventilator-induced lung injury in individual cases (D, AUS, NIH, SSC), routine continuous administration of muscle relaxants is not recommended (AUS, WHO).

With regard to tracheotomy, the German guideline is the only guideline to make reference to the existing guideline on invasive mechanical ventilation (18).

The use of inhalative vasodilation, or more specifically nitric oxide, is only recommended in individual cases (D, NIH, SSC).

Transferal to a center equipped with extracorporeal membrane oxygenation (ECMO) capabilities is recommended by almost all guidelines above a certain level of disease severity; however, with regard to the actual treatment only two guidelines (D, SSC) make a recommendation; the NIH states that there is insufficient data available.

Other organ systems

Due to a lack of direct evidence, there are only few general recommendations, such as those on restrictive fluid management (D, WHO, SSC), infusion therapy and hemodynamic management (NIH, WHO, SSC).

The indication for renal replacement therapy follows the established indications (D); preference is given to continuous renal replacement therapy (D, NIH) with citrate anticoagulation (D) and in settings with limited resources prolonged intermittent renal replacement therapy is recommended (NIH).

Drug treatment

Pharmacological prophylaxis of venous thromboembolism (VET) is recommended by all guidelines for this patient population, typically starting with low-molecular-weight heparin (D, AUS, NIH, WHO). Current guidelines do no longer recommend intensified VTE prophylaxis or effect anticoagulation outside clinically established indications.

The German guideline does only recommend antimicrobial therapy in patients with signs of an additional infection (D); the NIH guideline regards available data as insufficient to make a recommendation, while SSC and WHO recommend additional, initially calculated antimicrobial therapy in severely ill patients with respiratory failure until bacterial coinfection has been ruled out.

All guidelines make a strong recommendation against the administration of chloroquine/hydroxychloroquine as well as lopinavir/ritonavir; likewise, the use of azithromycin is not recommended (D, AUS, ZA).

All guidelines recommend the administration of dexamethasone in patients requiring oxygen. The NIH guideline is the only guideline to recommend the combination of dexamethasone and remdesivir; the German guideline does not provide an opinion on this topic, due to the lack of sufficient evidence. According to the NIH guideline, treatment with dexamethasone in combination with baricitinib or tocilizumab may be supplemented by adding remdesivir in patients receiving HFNC oxygen therapy or NIV.

Treatment with janus kinase inhibitors (especially baricitinib), taking into account the contraindications, is recommended by three guidelines (D, AUS, NIH) for somewhat differing patient populations (Table 2, eTable 8); however, monotherapy or combination with tocilizumab are expressly not recommended.

Table 2

Compilation and presentation of selected guideline recommendations

Almost all guidelines advise against treatment with convalescent plasma; the WHO does not make a recommendation on this topic. Likewise, the use of specific or unspecific immunoglobulins is not recommended (AUS, NIH) or the available evidence is classed as insufficient (ZA, NIH). By contrast, the current guidelines uniformly recommend treatment with anti-SARS-CoV-2 monoclonal antibodies (D, AUS, NIH) for specific subgroups and only two somewhat older guidelines (ZA, SSC) deviate in this respect.

The recommendation situation with regard to remdesivir has become more uniform and is predominantly negative (Table 2).

Recommendations on the treatment with interleukin-6 antagonists (namely tocilizumab) are conflicting; the more recent guidelines (D, NIH, AUS, WHO) uniformly recommend their use for very specific subgroups (Table 2, eTable 8), one guideline advises against their use (ZA), another regards the available data as insuffienct (SSC).

The therapeutic administration of vitamin D₃ is not recommend (D, AUS, ZA) or the available data are regarded as insufficient (NIH). Negative recommendations or references to insufficient data (especially AUS) exist for a large number of other substances.

Table 2 provides an overview of the selected guideline recommendations; a comprehensive description is provided in the supplement (eTable 8).

Discussion

As the evidence base related to COVID-19 is rapidly evolving, the up-to-dateness of the recommendations poses a major problem which is further complicated by the low quality of the published papers and the lack of peer review (preprints) in some publications. Given the high publication density, it is crucial to establish a continuous evaluation process. The effort required is considerable and difficult to achieve in the longer term on a national level. The significant variation in the up-to-dateness of the guidelines reviewed makes it difficult to compare the recommendations. Identifying the guidelines remains an additional challenge despite the existence of several international compilation initiatives which we can recommend here (for details see eTable 9 and [19–21]). Collectively, this represents a significant barrier to clinical implementation of the most current evidence available. Due to the dynamic data situation, optimization of clinical care requires close updates of the published guidelines, i.e. a “living guideline” approach, good transparency of methodological quality and underlying evidence, as well as low-threshold access and good searchability. This situation points to the use of an online platform, as shown, for example, in the increasing use of the guideline portal of the MAGIC Foundation (app.magicapp.org/#/guidelines) by more and more guideline groups (currently D, AUS, WHO, NICE). From a user’s perspective, it would be worthwhile to add transparent methodological minimum requirements for inclusion.

eTable 9

Presentation of possible sources of recommendations and evidence

Methodological quality of the guidelines

The AGREE-II tool is an internationally recognized, validated instrument recommended for use in Germany (12). The results of the evaluations performed by us show good consistency with the results of previous applications during the pandemic (6, 7, 22). We could also identify the time pressure-related limited methodological quality or rigor of the guidelines found there and thus excluded three guidelines, among others, from further consideration. However, the very brief descriptions of the methodology in some of the currently published guideline versions make evaluations more difficult.

Methodological inhomogeneity observed within the various guidelines is probably due to differences in the revision status of individual recommendations. Thus, more recent recommendations are available that offer a higher level of methodological quality. It can be difficult to establish the up-to-dateness of specific recommendations within a main document, since revisions and versioning frequently only apply to parts of a guideline.

Content and key topics

The guidelines vary significantly in scope, content and key topics. There is currently no guideline available that provides up-to-date recommendations on all relevant aspects. Consequently, an up-to-date and comprehensive picture of the existing recommendations on the treatment of critically ill COVID-19 patients cannot be achieved by looking at one guideline in isolation, regardless of its quality. In the AWMF guideline portal, for example, the key word “COVID“ yields 85 entries related to German guidelines alone which address aspects of COVID-19. In addition, reference should be made to the large number of international guidelines on individual topics; with regard to intensive care treatment, examples include guidelines on extracorporeal lung support, nutrition and thromboprophylaxis in patients with COVID-19 (23, 24, 25). Reading these specific guidelines may be worthwhile for specific questions, but they are not the subject of this paper.

Discussion of important contradictions

There is striking discrepancy in the recommendations on the use of HFNC oxygen therapy and NIV. While the NIH and SSC guidelines explicitly give preference to HFNC oxygen therapy, the AWMF guidelines see an advantage in using NIV. Whereas the first two recommendations are comparatively old and appear to have not been updated in the process of guideline updating and are based exclusively on indirect evidence from non-COVID patients, the current German recommendation is based on first prospective data from COVID-19 patients.

The recommendation status for ECMO treatment remains open. Two guidelines make a weak recommendation for ECMO treatment as a rescue therapy (D, SSC), whereas two other guidelines leave it to the experts of ECMO centers to make a decision on a case-by-case basis (AUS, WHO). The NIH believes there is insufficient data to make a recommendation and explicitly refers to the web site and guideline of the Extracorporeal Life Support Organization (ELSO); it recommends ECMO centers to include their COVID-19 patients in ongoing trials, whenever possible.

The recommendations on the use of antibiotics are also somewhat contradictory. While the German guideline does not recommend prophylactic antibiotic administration if only a SARS-CoV-2 infection has been detected, the WHO ultimately follows in wording the recommendation of the SSC guideline which advocates initial empiric antibiotic therapy for ventilated patients because of the difficulty of distinguishing the condition from co-infection.

The at times contradictory recommendations for remdesivir have now become more consistent and are predominantly negative. Some discrepancies remain for the intermediate group of patients with oxygen requirements up to below the need for noninvasive ventilation. Currently, the available data are considered to be contradictory and thus inadequate (D, NIH) and there remain only two (weak) positive recommendations (AUS, SSC) on the basis of a potential (minor) benefit, while the costs of treatment are high.

The formally contradictory recommendations on the use of IL-6 antagonists (tocilizumab) can be resolved, at least to the extent, by noting that the negative recommendations were made in older guidelines (ZA 05/21, SSC 03/21) and consequently more recent evidence may not have been taken into account.

In summary, the weak evidence base in intensive care medicine appears to be a major cause of conflicting or missing recommendations. Thus, further research efforts would be desirable to improve this situation.

Strengths and weaknesses of our study

After the original literature search, we performed no update to reflect the publication of new guidelines. However, since we carried out our search more than one year after the start of the pandemic, we consider it unlikely that completely new guidelines have been published after our original search.

The guidelines included have been followed for updates up to the latest possible date and we have incorporated any changes. However, due to the high research volume and the significant differences in up-to-dateness among the guidelines evaluated, comparability remains limited.

In keeping with the aim of our study, we selected guidelines that are comprehensively covering the therapeutic spectrum of intensive care medicine. We have refrained from integrating specialized guidelines with a narrow focus which, however, may be able to address specific recommendations at a higher level of methodological quality.

Acknowledgement

We would like to thank Maria-Inti Metzendorf M.A., Cochrane Metabolic and Endocrine Disorders Group, Germany, for her support in our literature search which we carried out as part of the CEOsys work package 2.

Funding

This study was facilitated and conducted within the framework of the CEOsys network Germany (COVID ecosystem) which is funded by the German Federal Ministry of Education and Research (BMBF). [FKZ 01KX2021].

Conflict of interest

Dr. Nothacker received fees for moderating the guideline “Recommendations on the In-hospital Treatment of Patients with COVID-19“ from the German Society of Internal Intensive Care and Emergency Medicine (DGIIN, Deutsche Gesellschaft für Internistische Intensivmedizin und Notfallmedizin).

The remaining authors declare that no conflict of interest exists.

Manuscript received on 31 August 2021, revised version accepted on 10 December 2021

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Prof. Dr. med. Onnen Moerer
Klinik für Anästhesiologie
Universitätsmedizin Göttingen
Robert-Koch-Str. 40,
37075 Göttingen, Germany

Cite this as:

Struwe C, Golinski M, Grimm C, Dickel S, Grummich K, Nothacker M, Voigt-Radloff S, Meerpohl J, Moerer O on behalf of the CEOsys Network: A comparison and evaluation of international guidelines on the treatment of severe SARS-CoV-2 infection. Dtsch Arztebl Int 2022; 119: 23–30. DOI10.3238/arztebl.m2022.0006

►Supplementary material

eReferences, eMethods, eTables, eFigures, eBox:
www.aerzteblatt-international.de/m2022.0006

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