Faculty Bibliography

Ezetimibe is widely used in combination with statins to reduce low-density lipoprotein. We sought to examine the impact of ezetimibe when added to statins on patient-important outcomes. Medline, EMBASE, CINAHL, and CENTRAL were searched through July, 2016. Randomized controlled trials (RCTs) of ezetimibe combined with statins versus statins alone that followed patients for at least 6 months and reported on at least one of all-cause mortality, cardiovascular deaths, non-fatal myocardial infarctions (MI), and non-fatal strokes were included. Pairs of reviewers extracted study data and assessed risk of bias independently and in duplicate. Quality of evidence was assessed using the GRADE approach. We conducted a narrative review with complementary subgroup and sensitivity analyses. IMPROVE-IT study enrolled 93% of all patients enrolled in the 8 included trials. Our analysis of the IMPROVE-IT study results showed that in patients at high risk of cardiovascular events, ezetimibe added to statins was associated with i) a likely reduction in non-fatal MI (17 fewer/1000 treated over 6 years, moderate certainty in evidence); ii) a possible reduction in non-fatal stroke (6 fewer/1000 treated over 6 years, low certainty); iii) no impact on myopathy (moderate certainty); iv) potentially no impact on all-cause mortality and cardiovascular death (both moderate certainty); and v) possibly no impact on cancer (low certainty). Addition of ezetimibe to moderate-dose statins is likely to result in 17 fewer MIs and possibly 6 fewer strokes/1000 treated over 6 years but is unlikely to reduce all-cause mortality or cardiovascular death. Patients who place a high value on a small absolute reduction in MI and are not adverse to use of an additional medication over a long duration may opt for ezetimibe in addition to statin therapy. Our analysis revealed no increased specific harms associated with addition of ezetimibe to statins.

OBJECTIVES: To explore the importance, challenges, and opportunities using qualitative research to enhance development of clinical practice guidelines, using recent guidelines for family-centered care in the ICU as an example. METHODS: In developing the Society of Critical Care Medicine guidelines for family-centered care in the neonatal ICU, PICU, and adult ICU, we developed an innovative adaptation of the Grading of Recommendations, Assessments, Development and Evaluations approach to explicitly incorporate qualitative research. Using Grading of Recommendations, Assessments, Development and Evaluations and the Council of Medical Specialty Societies principles, we conducted a systematic review of qualitative research to establish family-centered domains and outcomes. Thematic analyses were undertaken on study findings and used to support Population, Intervention, Comparison, Outcome question development. RESULTS: We identified and employed three approaches using qualitative research in these guidelines. First, previously published qualitative research was used to identify important domains for the Population, Intervention, Comparison, Outcome questions. Second, this qualitative research was used to identify and prioritize key outcomes to be evaluated. Finally, we used qualitative methods, member checking with patients and families, to validate the process and outcome of the guideline development. CONCLUSIONS: In this, a novel report, we provide direction for standardizing the use of qualitative evidence in future guidelines. Recommendations are made to incorporate qualitative literature review and appraisal, include qualitative methodologists in guideline taskforce teams, and develop training for evaluation of qualitative research into guideline development procedures. Effective methods of involving patients and families as members of guideline development represent opportunities for future work.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with 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 these critically ill patients with high mortality.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with 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 these critically ill patients with high mortality.

OBJECTIVE: To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU. METHODS: We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We assembled an international multidisciplinary team of 29 members with expertise in guideline development, evidence analysis, and family-centered care to revise the 2007 Clinical Practice Guidelines for support of the family in the patient-centered ICU. We conducted a scoping review of qualitative research that explored family-centered care in the ICU. Thematic analyses were conducted to support Population, Intervention, Comparison, Outcome question development. Patients and families validated the importance of interventions and outcomes. We then conducted a systematic review using the Grading of Recommendations, Assessment, Development and Evaluations methodology to make recommendations for practice. Recommendations were subjected to electronic voting with pre-established voting thresholds. No industry funding was associated with the guideline development. RESULTS: The scoping review yielded 683 qualitative studies; 228 were used for thematic analysis and Population, Intervention, Comparison, Outcome question development. The systematic review search yielded 4,158 reports after deduplication and 76 additional studies were added from alerts and hand searches; 238 studies met inclusion criteria. We made 23 recommendations from moderate, low, and very low level of evidence on the topics of: communication with family members, family presence, family support, consultations and ICU team members, and operational and environmental issues. We provide recommendations for future research and work-tools to support translation of the recommendations into practice. CONCLUSIONS: These guidelines identify the evidence base for best practices for family-centered care in the ICU. All recommendations were weak, highlighting the relative nascency of this field of research and the importance of future research to identify the most effective interventions to improve this important aspect of ICU care.

Sepsis is as a dysregulated systemic response to infection. Morbidity and mortality of the syndrome are very high worldwide. Recent definitions have redefined criteria for sepsis. The new definition (Sepsis-3) classifies sepsis as infection with organ dysfunction (the old 'severe sepsis'). Septic patients are at risk for secondary injuries, thus aggressive source control, resuscitation, and antibiotic therapy are the mainstays of management. Central to sepsis physiology is vasodilated shock. Many patients respond to i.v. fluid therapy. Pathophysiology also includes energy failure, or a cellular inability to oxidize fuel, and immune incompetence, often manifest by susceptibility to superinfections. Sepsis treatment is optimized by timely resuscitation and control of infection. Early recognition and resuscitation are associated with improved outcomes, although no single resuscitation end point is as good as overall patient assessment. Dynamic resuscitation metrics might be useful to avoid overinfusion of fluid therapies. Antibiotics should treat likely pathogens, with broader coverage for sicker patients (e.g. those with septic shock). Avoidance of iatrogenic injury, such as ventilator-induced lung injury from large tidal volumes, helps to prevent subsequent tissue damage and worsened systemic response. Single-agent therapies to block the systemic response have not fulfilled promise in sepsis, probably because part of the complex syndrome is adaptive. However, early aggressive care based on bundles is associated with improved outcomes. Research opportunities include understanding the role of neurological, endocrine, immune, and metabolic pathophysiology in the syndrome.