Abstract GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality ...of evidence (i.e., confidence in estimates of effect) is required if clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the “optimal information size” OIS). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0, and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest an RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.
Abstract Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes ...important to patients. Evidence can be indirect in one of four ways. First, patients may differ from those of interest (the term applicability is often used for this form of indirectness). Secondly, the intervention tested may differ from the intervention of interest. Decisions regarding indirectness of patients and interventions depend on an understanding of whether biological or social factors are sufficiently different that one might expect substantial differences in the magnitude of effect. Thirdly, outcomes may differ from those of primary interest—for instance, surrogate outcomes that are not themselves important, but measured in the presumption that changes in the surrogate reflect changes in an outcome important to patients. A fourth type of indirectness, conceptually different from the first three, occurs when clinicians must choose between interventions that have not been tested in head-to-head comparisons. Making comparisons between treatments under these circumstances requires specific statistical methods and will be rated down in quality one or two levels depending on the extent of differences between the patient populations, co-interventions, measurements of the outcome, and the methods of the trials of the candidate interventions.
Despite availability of reliable guidelines development methods, the risk of producing less reliable documents may be higher when the guidelines are developed rapidly.
The aim of this study was to ...assess quality of guidelines on coronavirus disease 2019 (COVID-19), developed in the early stages of COVID-19 pandemic and assess if recommendations for pharmacotherapy were supported by evidence.
We performed the search for documents, that considered antiviral therapies and contained a recommendations for clinicians. The quality of the guidelines was assessed using the AGREE II-Global Rating Scale Instrument and series of additional criteria.
The analysis included 40 publications. The median of quality of documents assessed with the AGREE II-GRS tool was 2.0 (interquartile range 1.5-2.5). Most documents did not fulfill the rigour of guideline development quality criteria. The AGREE II-GRS scores did not differ significantly across the type of the document, issuing institution and the mode of publication. 75% of documents provided recommendations for the use of antiviral medications despite apparent lack of sufficient evidence supporting such treatments. Of the included documents, 75% were not updated within the 2 months after the publication of the first randomized controlled trial on COVID-19 antiviral therapy.
Most guidelines or guidance documents published during the early phase of the COVID-19 pandemic were of poor quality, contained recommendations for the use of antiviral therapy for SARS-CoV-2 infection despite only very low quality of evidence available, and were not updated on a regular basis.
This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence ...(also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA).
We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically.
Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies.
Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.
This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can rate the certainty of evidence (also known as ...quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias, and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables.
We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests.
Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies.
Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. Although several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.
Clinical decisions should be based on the totality of the best evidence and not the results of individual studies. When clinicians apply the results of a systematic review or meta-analysis to patient ...care, they should start by evaluating the credibility of the methods of the systematic review, ie, the extent to which these methods have likely protected against misleading results. Credibility depends on whether the review addressed a sensible clinical question; included an exhaustive literature search; demonstrated reproducibility of the selection and assessment of studies; and presented results in a useful manner. For reviews that are sufficiently credible, clinicians must decide on the degree of confidence in the estimates that the evidence warrants (quality of evidence). Confidence depends on the risk of bias in the body of evidence; the precision and consistency of the results; whether the results directly apply to the patient of interest; and the likelihood of reporting bias. Shared decision making requires understanding of the estimates of magnitude of beneficial and harmful effects, and confidence in those estimates.
Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal ...strategies for the diagnosis of DVT in ambulatory adults.
The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B).
Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.
To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008.
A consensus committee of 68 international experts ...representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Some recommendations were ungraded (UG). Recommendations were classified into three groups: 1) those directly targeting severe sepsis; 2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and 3) pediatric considerations.
Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥ 65 mm Hg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of ≤ 100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose ≤ 180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C).
Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.
Objective
To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.
Design
A consensus committee of 68 international ...experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
Methods
The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations.
Results
Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a Pa
o
2
/Fi
o
2
ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient
without
ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients
with
early ARDS and a Pa
o
2
/F
i
o
2
<150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5–10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency (2C).
Conclusions
Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.
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