Roman Jaeschke

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

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. 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. Results: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). 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.

Grading quality of evidence and strength of recommendations.

Abstract Users of clinical practice guidelines and other recommendations need to know how much confidence they can place in the recommendations. Systematic and explicit methods of making judgments can reduce errors and improve communication. We have developed a system for grading the quality of evidence and the strength of recommendations that can be applied across a wide range of interventions and contexts. In this article we present a summary of our approach from the perspective of a guideline user. Judgments about the strength of a recommendation require consideration of the balance between benefits and harms, the quality of the evidence, translation of the evidence into specific circumstances, and the certainty of the baseline risk. It is also important to consider costs (resource utilisation) before making a recommendation. Inconsistencies among systems for grading the quality of evidence and the strength of recommendations reduce their potential to facilitate critical appraisal and improve communication of these judgments. Our system for guiding these complex judgments balances the need for simplicity with the need for full and transparent consideration of all important issues. Clinical guidelines are only as good as the evidence and judgments they are based on. The GRADE approach aims to make it easier for users to assess the judgments behind recommendations

Measurement of health status. Ascertaining the minimal clinically important difference.

In recent years quality of life instruments have been featured as primary outcomes in many randomized trials. One of the challenges facing the investigator using such measures is determining the significance of any differences observed, and communicating that significance to clinicians who will be applying the trial results. We have developed an approach to elucidating the significance of changes in score in quality of life instruments by comparing them to global ratings of change. Using this approach we have established a plausible range within which the minimal clinically important difference (MCID) falls. In three studies in which instruments measuring dyspnea, fatigue, and emotional function in patients with chronic heart and lung disease were applied the MCID was represented by mean change in score of approximately 0.5 per item, when responses were presented on a seven point Likert scale. Furthermore, we have established ranges for changes in questionnaire scores that correspond to moderate and large changes in the domains of interest. This information will be useful in interpreting questionnaire scores, both in individuals and in groups of patients participating in controlled trials, and in the planning of new trials.

GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables

This article is the first of a series providing guidance for use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments (HTAs), and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence is collected and summarized, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterized as strong or weak (alternative terms conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarizing evidence in succinct, transparent, and informative summary of findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADEs approach to formulating questions, assessing quality of evidence, and developing recommendations.

GRADE guidelines: 9. Rating up the quality of evidence.

The most common reason for rating up the quality of evidence is a large effect. GRADE suggests considering rating up quality of evidence one level when methodologically rigorous observational studies show at least a two-fold reduction or increase in risk, and rating up two levels for at least a five-fold reduction or increase in risk. Systematic review authors and guideline developers may also consider rating up quality of evidence when a dose-response gradient is present, and when all plausible confounders or biases would decrease an apparent treatment effect, or would create a spurious effect when results suggest no effect. Other considerations include the rapidity of the response, the underlying trajectory of the condition, and indirect evidence.

Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit

Objective:To revise the “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult” published in Critical Care Medicine in 2002. Methods:The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks® database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (–) an intervention. A strong recommendation (either for or against) indicated that the intervention’s desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase “We recommend …” is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase “We suggest …” is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. Conclusion:These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials.

BACKGROUND: In the past only physiological and clinical outcomes have been used to assess the effect of asthma interventions and the effect of the intervention on the lives of the patients has not been determined. The objective of this study was to assess health related impairment of quality of life in adult asthmatic patients and to develop a questionnaire for measuring quality of life in clinical trials in asthma. METHODS: Impairment of quality of life in adults with asthma was evaluated from structured interviews in which patients were asked to identify the parts of their daily lives affected by asthma. On the basis of these results, an asthma quality of life questionnaire was developed in an interviewer and self administered form and tested for comprehension and acceptability. A total of 150 adults with asthma and with a wide range of airway hyperresponsiveness were enrolled from previous clinical trials, local asthma clinics, and notices in the media. RESULTS: Areas of quality of life impairment included symptoms classically associated with asthma, responses to environmental stimuli, the need to avoid these stimuli, limitation of activities, and emotional dysfunction. Areas of impairment were similar across strata of airway hyperresponsiveness, age, and treatment requirements and between sexes, thus allowing a single questionnaire suitable for all adults with asthma to be developed. The questionnaire contains 32 items and takes 5-10 minutes to administer; in the pretesting it was shown to be acceptable to a wide range of patients. CONCLUSIONS: The questionnaire includes areas of quality of life impairment that are important to adult asthmatic patients. It has been designed to be responsive to within subject change and therefore may be used as a measure of outcome in clinical trials in asthma.

Incidence of and Risk Factors for Ventilator-Associated Pneumonia in Critically Ill Patients

A recent international prevalence study involving more than 1000 intensive care units indicated that pneumonia is responsible for almost half of the infections in critically ill patients in Europe [1]. Ventilator-associated pneumonia accounts for approximately 90% of infections in patients requiring assisted ventilation [2, 3]. An independent contribution to mortality conferred by ventilator-associated pneumonia was recently suggested [4, 5]. Although debate persists about the mortality attributable to ventilator-associated pneumonia among other causes of death in critically ill patients [1, 4-7], there is little doubt that ventilator-associated pneumonia causes substantial morbidity by increasing the duration of mechanical ventilation and intensive care unit stay [4, 5]. It is therefore important to understand the factors that are predictive of ventilator-associated pneumonia, to identify patients at highest risk, and to target these patients for the most effective preventive strategies as determined by randomized trials [8, 9]. Risk factors for nosocomial pneumonia have been evaluated in hospitalized elderly persons [10], heterogeneous groups of hospitalized patients breathing spontaneously or requiring assisted ventilation [11], and similar mixed populations admitted to the intensive care unit [2, 12-15]. Investigations in ventilated critically ill patients only are needed to identify independent predictors of ventilator-associated pneumonia. Most studies of risk factors for ventilator-associated pneumonia have been conducted at single institutions, and different predictors have been examined. In cohort studies using multivariable analyses [16-21], only reintubation [17, 19, 21] and antibiotic use [18, 20] were identified as risk factors in more than one report. However, a direct relation between antibiotics and pneumonia was found in one study [18], whereas an inverse relation was found in another [20]. We examined factors associated with ventilator-associated pneumonia. We explored baseline and time-dependent characteristics, including measures of illness severity, factors relating to mechanical ventilation, variables in the gastropulmonary route of infection, and drug exposure. Methods Patients We used a multicenter national database of 1200 patients who received mechanical ventilation for 48 hours or more and were enrolled from October 1992 to May 1996 in a double-blind, concealed, randomized trial of sucralfate compared with ranitidine to determine rates of ventilator-associated pneumonia and gastrointestinal bleeding [22]. Patients were followed until death, discharge, or clinical suspicion of ventilator-associated pneumonia as determined by the attending intensivist. Bronchoalveolar lavage or protected specimen brush was indicated for patients with a clinical suspicion of ventilator-associated pneumonia. A diagnosis of ventilator-associated pneumonia was considered only in patients who were receiving mechanical ventilation or who stopped receiving ventilation for less than 48 hours. In the absence of a reference standard for diagnosing pneumonia in critically ill patients [23, 24], each patients clinical, laboratory, and radiographic data were independently reviewed by one of four pairs of adjudicators blinded to treatment group. The readers in each adjudication pair decided on the presence or absence of ventilator-associated pneumonia, resolving any disagreement through discussion. Consensus was achieved on all cases. The adjudicated outcome was used for the primary analysis [177 cases]. However, each case of pneumonia was classified according to four additional definitions: 1) the bedside clinicians diagnosis [233 cases]; 2) the modified Centers for Disease Control and Prevention criteria [25], which require a new radiographic infiltrate persistent for 48 hours or more plus a body temperature greater than 38.5 C or less than 35.0 C, a leukocyte count of more than 10 cells 109/L or less than 3 cells 109/L, purulent sputum or change in character of sputum, or isolation of pathogenic bacteria from an endotracheal aspirate [211 cases]; 3) a Clinical Pulmonary Infection score of 7 or more [26] [194 cases]; or 4) a positive culture from bronchoalveolar lavage (>104 colony-forming units/mL) or protected specimen brush (<103 colony-forming units/mL) (97 cases). Statistical Analysis We expressed continuous variables as the mean (SD) or as the median and interquartile range if their distribution was skewed. We used the Student t-test to compare continuous variables and the chi-square test to compare proportions. All statistical tests were two-tailed. We performed a forward stepwise Cox proportional-hazards regression analysis to evaluate potential risk factors for ventilator-associated pneumonia. The Cox model assesses the effect of each risk factor on the hazard rate of ventilator-associated pneumonia over time, adjusted for other factors in the model and allowing for censoring because of death or discharge. The hazard function in the Cox model can be used to estimate the event rate per day over the duration of stay in the intensive care unit. Independent variables recorded at baseline included age; sex; primary diagnosis; medical or surgical status; hospital admission in the fall or winter compared with spring or summer; location before admission to the intensive care unit; treatment center; Acute Physiology and Chronic Health Evaluation II score; Acute Physiology score; Multiple Organ Dysfunction score [27]; Glasgow Coma Scale score; and chronic comorbid conditions, such as alcoholism, a smoking history of 10 or more pack-years, asthma, bronchiectasis, pulmonary fibrosis, cancer, and HIV infection; organ transplantation; and recent corticosteroid therapy or chemotherapy. Additional independent variables evaluated daily throughout the intensive care unit stay were classified as illness severity measures (daily Multiple Organ Dysfunction score and change in Multiple Organ Dysfunction score from baseline), ventilation variables (mechanical ventilation, change or reinsertion of endotracheal tube, discontinuation and reinstitution of mechanical ventilation, and tracheostomy), nutritional variables (nasoenteral nutrition, gastrostomy feeding, jejunostomy feeding, enteral nutrition through any route, central parenteral nutrition, peripheral parenteral nutrition, and insulin requirement of more than 15 U/d), witnessed aspiration, and drug exposure (stress-ulcer prophylaxis with ranitidine or sucralfate, paralytic agents, and antibiotics). The Multiple Organ Dysfunction Score combines measures of physiologic dysfunction in six domains: the cardiovascular system (heart rate x right atrial pressure/mean arterial pressure), pulmonary system (Pao 2:Fio 2 ratio), the renal system (serum creatinine concentration), the hepatic system (serum bilirubin level), the hematologic system (platelet count), and the central nervous system (Glasgow Coma Scale score) [25]. These continuous variables are constructed in 5 categories so that 0 represents normal function and 4 reflects marked physiologic derangement and is associated with a mortality rate greater than 50%. Composite scores provide a quantitative measure of global physiologic dysfunction at a discrete point in the intensive care unit stay. For individual domains, either the raw data or their score provides a measure of dysfunction in the system of interest. Variables that were associated with ventilator-associated pneumonia in the univariable analysis and had a P value less than 0.10 were entered into a multivariable regression analysis. Factors were considered significant if the P value was less than 0.05 in the multivariable analysis. We calculated risk ratios and 95% CIs for all significant predictors of ventilator-associated pneumonia in the multivariable analysis using all five definitions. We tested for all pairwise interactions between significant risk factors in the multivariable model. We also tested for interactions between predictors in the multivariable model and factors that were significant in the univariable analysis. Finally, we investigated the possibility that the effects of risk factors may vary over the duration of stay in the intensive care unit; this was done by using a nonproportional Cox model testing the interaction of each variable in the final model with time. For example, we hypothesized that the influence of antibiotics on ventilator-associated pneumonia may vary over time. Time was considered both a continuous variable and a discretized variable by using 3-day and 5-day intervals. We did not consider antibiotics administered 24 hours before the diagnosis of ventilator-associated pneumonia, so that drugs prescribed in response to early ventilator-associated pneumonia would be excluded [28]. Role of Study Sponsor Our funding sources had no role in the acquisition, analysis, or interpretation of data or in the submission of this report. Results Of the 1200 patients enrolled in this study, 186 were excluded (85 were discharged, 71 died, and 30 had pneumonia in the first 48 hours), leaving 1014 patients ventilated for 48 hours or more who were free of pneumonia at admission to the intensive care unit. Of these patients, 177 (17.5%) developed ventilator-associated pneumonia 9.0 5.9 days after admission (median, 7 days [interquartile range, 5 to 10 days]). The characteristics of patients with and without ventilator-associated pneumonia are shown in Table 1. The total duration of mechanical ventilation among patients with ventilator-associated pneumonia was 19.3 16.0 days (median, 15 days [interquartile range, 9 to 23 days]) compared with 10.2 10.5 days (median, 7 days [interquartile range, 4 to 11 days]) in other patients (P < 0.001). Among the 177 patients with ventilator-associated pneumonia, 131 (74.0%) had bronchoscopic testing with bronchoalveolar lavage or protected specimen brush. Patients in the following admitting diagnostic categories

GRADE guidelines: 7. Rating the quality of evidence--inconsistency

This article deals with inconsistency of relative (rather than absolute) treatment effects in binary/dichotomous outcomes. A body of evidence is not rated up in quality if studies yield consistent results, but may be rated down in quality if inconsistent. Criteria for evaluating consistency include similarity of point estimates, extent of overlap of confidence intervals, and statistical criteria including tests of heterogeneity and I(2). To explore heterogeneity, systematic review authors should generate and test a small number of a priori hypotheses related to patients, interventions, outcomes, and methodology. When inconsistency is large and unexplained, rating down quality for inconsistency is appropriate, particularly if some studies suggest substantial benefit, and others no effect or harm (rather than only large vs. small effects). Apparent subgroup effects may be spurious. Credibility is increased if subgroup effects are based on a small number of a priori hypotheses with a specified direction; subgroup comparisons come from within rather than between studies; tests of interaction generate low P-values; and have a biological rationale.

GRADE guidelines: 8. Rating the quality of evidence-Indirectness

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.