Annane, Djillali

OBJECTIVE: A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN: Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING: Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS: A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS: A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS: A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

OBJECTIVES: We postulate that corticosteroid-related side effects in critically ill patients are similar across sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). By pooling data across all trials that have examined corticosteroids in these three acute conditions, we aim to examine the side effects of corticosteroid use in critical illness. DATA SOURCES: We performed a comprehensive search of MEDLINE, Embase, Centers for Disease Control and Prevention library of COVID research, CINAHL, and Cochrane center for trials. STUDY SELECTION: We included randomized controlled trials (RCTs) that compared corticosteroids to no corticosteroids or placebo in patients with sepsis, ARDS, and CAP. DATA EXTRACTION: We summarized data addressing the most described side effects of corticosteroid use in critical care: gastrointestinal bleeding, hyperglycemia, hypernatremia, superinfections/secondary infections, neuropsychiatric effects, and neuromuscular weakness. DATA SYNTHESIS: We included 47 RCTs ( n = 13,893 patients). Corticosteroids probably have no effect on gastrointestinal bleeding (relative risk [RR], 1.08; 95% CI, 0.87–1.34; absolute risk increase [ARI], 0.3%; moderate certainty) or secondary infections (RR, 0.97; 95% CI, 0.89–1.05; absolute risk reduction, 0.5%; moderate certainty) and may have no effect on neuromuscular weakness (RR, 1.22; 95% CI, 1.03–1.45; ARI, 1.4%; low certainty) or neuropsychiatric events (RR, 1.19; 95% CI, 0.82–1.74; ARI, 0.5%; low certainty). Conversely, they increase the risk of hyperglycemia (RR, 1.21; 95% CI, 1.11–1.31; ARI, 5.4%; high certainty) and probably increase the risk of hypernatremia (RR, 1.59; 95% CI, 1.29–1.96; ARI, 2.3%; moderate certainty). CONCLUSIONS: In ARDS, sepsis, and CAP, corticosteroids are associated with hyperglycemia and probably with hypernatremia but likely have no effect on gastrointestinal bleeding or secondary infections. More data examining effects of corticosteroids, particularly on neuropsychiatric outcomes and neuromuscular weakness, would clarify the safety of this class of drugs in critical illness.

OBJECTIVES: To perform a systematic review and meta-analysis to assess the efficacy and safety of corticosteroids in patients with sepsis. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Library, up to January 10, 2023. STUDY SELECTION: We included randomized controlled trials (RCTs) comparing corticosteroids with placebo or standard care with sepsis. DATA EXTRACTION: The critical outcomes of interest included mortality, shock reversal, length of stay in the ICU, and adverse events. DATA ANALYSIS: We performed both a pairwise and dose-response meta-analysis to evaluate the effect of different corticosteroid doses on outcomes. We used Grading of Recommendations Assessment, Development and Evaluation to assess certainty in pooled estimates. DATA SYNTHESIS: We included 45 RCTs involving 9563 patients. Corticosteroids probably reduce short-term mortality (risk ratio [RR], 0.93; 95% CI, 0.88–0.99; moderate certainty) and increase shock reversal at 7 days (RR, 1.24; 95% CI, 1.11–1.38; high certainty). Corticosteroids may have no important effect on duration of ICU stay (mean difference, –0.6 fewer days; 95% CI, 1.48 fewer to 0.27 more; low certainty); however, probably increase the risk of hyperglycemia (RR, 1.13; 95% CI, 1.08–1.18; moderate certainty) and hypernatremia (RR, 1.64; 95% CI, 1.32–2.03; moderate certainty) and may increase the risk of neuromuscular weakness (RR, 1.21; 95% CI, 1.01–1.45; low certainty). The dose-response analysis showed a reduction in mortality with corticosteroids with optimal dosing of approximately 260 mg/d of hydrocortisone (RR, 0.90; 95% CI, 0.83–0.98) or equivalent. CONCLUSIONS: We found that corticosteroids may reduce mortality and increase shock reversal but they may also increase the risk of hyperglycemia, hypernatremia, and neuromuscular weakness. The dose-response analysis indicates optimal dosing is around 260 mg/d of hydrocortisone or equivalent.

RATIONALE: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency. OBJECTIVES: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP. PANEL DESIGN: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting. METHODS: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework. RESULTS: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence. CONCLUSIONS: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP.

Abstract Context Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. Objective To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress. Design and Participants Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration). Main Outcome Measure We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. Results Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50–100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. Conclusions Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.