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Objective To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. Participants A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. Design/methods The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. Results The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO 2 /FiO 2  < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence). Conclusions Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

PurposeCorticosteroids are now recommended for patients with severe COVID-19 including those with COVID-related ARDS. This has generated renewed interest regarding whether corticosteroids should be used in non-COVID ARDS as well. The objective of this study was to summarize all RCTs examining the use of corticosteroids in ARDS.MethodsThe protocol of this study was pre-registered on PROSPERO (CRD42020200659). We searched online databases including MEDLINE, EMBASE, CDC library of COVID research, CINAHL, and COCHRANE. We included RCTs that compared the effect of corticosteroids to placebo or usual care in adult patients with ARDS, including patients with COVID-19. Three reviewers abstracted data independently and in duplicate using a pre-specified standardized form. We assessed individual study risk of bias using the revised Cochrane ROB-2 tool and rated certainty in outcomes using GRADE methodology. We pooled data using a random effects model. The main outcome for this review was 28-day-mortality.ResultsWe included 18 RCTs enrolling 2826 patients. The use of corticosteroids probably reduced mortality in patients with ARDS of any etiology (2740 patients in 16 trials, RR 0.82, 95% CI 0.72–0.95, ARR 8.0%, 95% CI 2.2–12.5%, moderate certainty). Patients who received a longer course of corticosteroids (over 7 days) had higher rates of survival compared to a shorter course.ConclusionThe use of corticosteroids probably reduces mortality in patients with ARDS. This effect was consistent between patients with COVID-19 and non-COVID-19 ARDS, corticosteroid types, and dosage.

Objective To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). Participants A multispecialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Data sources Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. Results Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity. Conclusions Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.

We have reported previously on the use of noninvasive positive-pressure ventilation (NPPV) to assist spontaneous breathing in high-risk hypoxemic patients (ie, Pao2/fraction of inspired oxygen [Fio2] ratio, ≤ 100) who are undergoing diagnostic fiberoptic bronchoscopy (FOB). The efficacy of this intervention in patients with less severe forms of hypoxemia (ie, Pao2/Fio2 ratio, < 200) is unknown. Twenty-six patients with Pao2/Fio2 ratios ≤ 200 who required bronchoscopic BAL for suspected nosocomial pneumonia were entered into the study. Thirteen patients were randomized during FOB to receive NPPV, and 13 patients were randomized to receive conventional oxygen supplementation by Venturi mask. The primary end points were changes in the Pao2/Fio2 ratio during FOB and within 60 min of terminating the procedure. At study entry, the two groups were similar in terms of age, simplified acute physiologic score II values, and cardiorespiratory parameters. During FOB, the mean (± SD) Pao2/Fio2 ratio increased by 82% in the NPPV group (261 ± 100 vs 139 ± 38; p < 0.001) and decreased by 10% in the conventional oxygen supplementation group (155 ± 24 to 139 ± 38; p = 0.23). Sixty minutes after undergoing FOB, the NPPV group had a higher mean Pao2/Fio2 ratio (176 ± 62 vs 140 ± 38; p = 0.09), a lower mean heart rate (91 ± 18 vs 108 ± 15 beats/min; p = 0.02), and no reduction in mean arterial pressure in comparison to a 15% decrease from the baseline in the control group. One patient in the NPPV group and two patients in the control group required nonemergent intubation. Major bacterial isolates included Staphylococcus aureus (7 of 30 isolates; 23%) and Pseudomonas aeruginosa (12 of 30 isolates; 40%). In patients with severe hypoxemia, NPPV is superior to conventional oxygen supplementation in preventing gas-exchange deterioration during FOB with better hemodynamic tolerance.

Background. Glucocorticoids (GCs) have been shown to reduce mortality and the need for invasive mechanical ventilation (IMV) in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). It has been suggested that serum cytokines levels are markers of disease severity in ARDS, although there is only limited evidence of a relationship between the longitudinal cytokine profile and clinical outcomes in patients with SARS-CoV-2-induced ARDS treated with GC. Methods. We conducted a single-center observational study to investigate serial plasma cytokine levels in 17 patients supported with non-invasive ventilation (NIV) in order to compare the response in five patients who progressed to IMV versus 12 patients who continued with NIV alone. All patients received methylprednisolone 80 mg/day continuous infusion until clinical improvement. Results. The study groups were comparable at baseline. All patients survived. Although IL-6 was higher in the NIV group at baseline, several cytokines were significantly higher in the IMV group on day 7 (IL-6, IL-8, IL-9, G-CSF, IP-10, MCP-1, MIP-1α) and 14 (IL-6, IL-8, IL-17, G-CSF, MIP-1α, RANTES). No significant differences were observed between groups on day 28. Conclusions. Patients in the IMV group had higher inflammation levels at intubation than the NIV group, which may indicate a higher resistance to glucocorticoids. Higher GC doses or a longer treatment duration in these patients might have allowed for a better control of inflammation and a better outcome. Further studies are required to define the prognostic value of cytokine patterns, in terms of both GC treatment tailoring and timely initiation of IMV.

An updated meta-analysis incorporating nine randomized trials ( n  = 816) investigating low-to-moderate dose prolonged glucocorticoid treatment in acute respiratory distress syndrome (ARDS) show moderate-to-high quality evidence that glucocorticoid therapy is safe and reduces (i) time to endotracheal extubation, (ii) duration of hospitalization, and (iii) mortality (number to treat to save one life = 7), and increases the number of days free from (i) mechanical ventilation, (ii) intensive care unit stay, and (iii) hospitalization. Recent guideline suggests administering methylprednisolone in patients with early moderate-to-severe (1 mg/kg/day) and late persistent (2 mg/kg/day) ARDS (conditional recommendation based on moderate quality of evidence).

Purpose During the 2009 H1N1 influenza A virus pandemic, a minority of patients developed rapidly progressive pneumonia leading to acute lung injury (ALI)—acute respiratory distress syndrome (ARDS). A recent meta-analysis provides support for prolonged corticosteroid treatment in ALI-ARDS. We prospectively evaluated the response to oseltamivir and prolonged corticosteroid treatment in patients with ALI-ARDS and suspected H1N1 influenza. Methods From June 24 through 12 July 2009, 13 patients with suspected H1N1 pneumonia and ALI-ARDS were admitted to the intensive care unit (ICU) of a tertiary care hospital. H1N1 influenza was confirmed with real-time reverse transcriptase-polymerase chain reaction assay in eight patients. Oseltamivir and corticosteroid treatment were initiated concomitantly at ICU admission; those with severe ARDS received methylprednisolone (1 mg/kg/day), and others received hydrocortisone (300 mg/day) for a duration of 21 ± 6 days. Results Patients with and without confirmed H1N1 influenza had similar disease severity at presentation and a comparable response to treatment. By day 7 of treatment, patients experienced a significant improvement in lung injury and multiple organ dysfunction scores ( P  < 0.001). Twelve patients (92%) improved lung function, were extubated, and discharged alive from the ICU. Hospital length of stay and mortality were 18.7 ± 9.6 days and 15%, respectively. Survivors were discharged home without oxygen supplementation. Conclusions In ARDS patients, with and without confirmed H1N1 influenza, prolonged low-to-moderate dose corticosteroid treatment was well tolerated and associated with significant improvement in lung injury and multiple organ dysfunction scores and a low hospital mortality. These findings provide the rationale for developing a randomized trial.

Prolonged, low-dose glucocorticoids (GCs) have shown the highest efficacy among pharmacological and non-pharmacological treatments for COVID-19. Despite the World Health Organization’s recommendation against their use at the beginning of the pandemic, GCs at a dose equivalent to dexamethasone 6 mg/day for 10 days are now indicated in all COVID-19 cases who require respiratory support. However, the efficacy of the intervention depends on the timing of initiation, the dose, and other individual factors. Indeed, patients treated with similar GC protocols often experience different outcomes, which do not always correlate with the presence of comorbidities or with the severity of respiratory involvement at baseline. This prompted us to critically review the literature on the rationale, pharmacological principles, and clinical evidence that should guide GC treatment. Based on these data, the best treatment protocol probably involves an initial bolus dose to saturate the glucocorticoid receptors, followed by a continuous infusion to maintain constant plasma levels, and eventually a slow tapering to interruption. Methylprednisolone has shown the highest efficacy among different GC molecules, most likely thanks to its higher ability to penetrate the lung. Decreased tissue sensitivity to glucocorticoids is thought to be the main mechanism accounting for the lower response to the treatment in some individuals. We do not have a readily available test to identify GC resistance; therefore, to address inter-individual variability, future research should aim at investigating clinical, physiological, and laboratory markers to guide a personalized GC treatment approach.

The meta-analysis by Ruan et al. incorporated four randomized trials from the 1980s that investigated short-term (24–48 h) massive daily corticosteroid doses (up to 120 mg/kg methylprednisolone equivalent), an intervention that is obsolete and discredited by the present pathophysiological understanding of ARDS [2]. [...]the inclusion of these trials in the meta-analysis is mostly responsible for the inconsistency reported in their letter. [...]the conclusion by Ruan et al. that the benefits of corticosteroid treatment decreased over time are not supported by the actual findings of the cited trials (Figure 3 in [4], Figure 4 in [5] and Table 5 in [3]). In our analysis [2] the pooled relative risk estimate for hospital mortality (Fig. 1) with corticosteroids was 0.64 (95% confidence interval (CI) 0.46–0.89).

To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients