G. Umberto Meduri

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine

Objective:To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients. Participants:A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate. Design/Methods:The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence. Results:The task force coined the term critical illness–related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness–related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness–related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of <9 &mgr;g/dL after adrenocorticotrophic hormone (250 &mgr;g) administration or a random total cortisol of <10 &mgr;g/dL. The benefit of treatment with glucocorticoids at this time seems to be limited to patients with vasopressor-dependent septic shock and patients with early severe acute respiratory distress syndrome (Pao2/Fio2 of <200 and within 14 days of onset). The adrenocorticotrophic hormone stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome who should receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for ≥7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg·kg−1·day−1 for ≥14 days is recommended in patients with severe early acute respiratory distress syndrome. Glucocorticoids should be weaned and not stopped abruptly. Reinstitution of treatment should be considered with recurrence of signs of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recommended to treat critical illness–related corticosteroid insufficiency. The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation. Conclusion:Evidence-linked consensus statements with regard to the diagnosis and management of corticosteroid deficiency in critically ill patients have been developed by a multidisciplinary, multispecialty task force.

Nosocomial Sinusitis in Patients in the Medical Intensive Care Unit: A Prospective Epidemiological Study

A prospective observational cohort study of nosocomial sinusitis was carried out in two medical intensive care units. Sinusitis was diagnosed by computed tomographic scanning and the culture of sinus fluid obtained by puncture of a maxillary sinus. Clinical and epidemiological data were collected at the time of admission to the unit and daily thereafter. Specimens from the nares, oropharynx, trachea, and stomach were cultured on admission and daily thereafter. The cumulative incidence of nosocomial sinusitis was 7.7%, and the incidence rates were 12 cases per 1,000 patient-days and 19.8 cases per 1,000 nasoenteric tube-days. Risk factors for nosocomial sinusitis, as determined by multiple logistic regression analysis, included nasal colonization with enteric gram-negative bacilli (odds ratio [OR], 6.4; 95% confidence interval [95% CI], 2.2-18.8; P = .007), feeding via nasoenteric tube (OR, 14.1; 95% CI, 1.7-117.6; P = .015), sedation (OR, 15.9; 95% CI, 1.9-133.5; P = .011), and a Glasgow coma score of < or = 7 (OR, 9.1; 95% CI, 3.0-27.3; P = .0001).

Noninvasive mechanical ventilation in patients with acute respiratory failure.

OBJECTIVES a) To describe the introduction of noninvasive means to provide positive-pressure ventilation in acute respiratory failure; b) to describe the physiologic response to noninvasive ventilation; c) to review the current published literature on using noninvasive ventilation in patients with acute hypercapnic and/or hypoxemic respiratory failure; d) to describe the technique of applying mask ventilation and current recommendations for using noninvasive ventilation and current recommendations for using noninvasive ventilation in patients with acute respiratory failure; and e) to discuss the advantages and disadvantages of noninvasive ventilation. DATA SOURCES All relevant articles published in the English medical literature from 1988 through August 1994 were retrieved through a MEDLINE search, as well as from the authors experience. STUDY SELECTION Studies were selected based on the use of positive-pressure mechanical ventilation delivered, using facial or nasal masks in various acute settings of respiratory failure. DATA EXTRACTION The authors extracted all applicable data. DATA SYNTHESIS Studies were analyzed according to the type of respiratory failure (hypercapnic vs. hypoxemic) and underlying conditions where noninvasive ventilation seemed to be a better alternative. The results were evaluated based on types of masks used and modes of ventilation. Outcome measures were compared based on studies that randomized patients with acute respiratory failure to receive noninvasive vs. conventional therapy. Complications of noninvasive ventilation, mainly local, were compared with those complications seen endotracheal intubation in acute respiratory failure patients. CONCLUSIONS Noninvasive ventilation is a safe and effective means of ventilatory support for many patients with acute respiratory failure. Noninvasive ventilation is well tolerated, principally because it allows the patient to be in control and to continue verbal communication, and should be strongly considered in managing terminally ill patients with potentially reversible causes of respiratory failure. The duration of mechanical ventilation and its associated complications are significantly decreased in hypercapnic respiratory failure with noninvasive ventilation.

Effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome.

Objective: Evaluate the effects of methylprednisolone on markers of inflammation, coagulation, and angiogenesis during early acute respiratory distress syndrome. Design: Retrospective analysis. Setting: Four intensive care units. Subjects: Seventy-nine of 91 patients with available samples enrolled in a randomized, blinded controlled trial. Interventions: Early methylprednisolone infusion (n = 55) compared with placebo (n = 24). Measurements and Main Results: Interleukin-6, tumor necrosis factor &agr;, vascular endothelial growth factor, protein C, procalcitonin, and proadrenomedullin were measured in archived plasma. Changes from baseline to day 3 and day 7 were compared between groups and in subgroups based on the precipitating cause of acute respiratory distress syndrome. Methylprednisolone therapy was associated with greater improvement in Lung Injury Score (p = .003), shorter duration of mechanical ventilation (p = .005), and lower intensive care unit mortality (p = .05) than control subjects. On days 3 and 7, methylprednisolone decreased interleukin-6 and increased protein C levels (all p < .0001) compared with control subjects. Proadrenomedullin levels were lower by day 3 with methylprednisolone treatment (p = .004). Methylprednisolone decreased interleukin-6 by days 3 and 7 in patients with pulmonary causes of acute respiratory distress syndrome but only at day 3 in those with extrapulmonary causes of acute respiratory distress syndrome. Protein C levels were increased with methylprednisolone on days 3 and 7 in patients with infectious and/or pulmonary causes of acute respiratory distress syndrome (all p < .0001) but not in patients with noninfectious or extrapulmonary causes of acute respiratory distress syndrome. Proadrenomedullin levels were decreased with methylprednisolone on day 3 in patients with infectious or extrapulmonary causes of acute respiratory distress syndrome (both p ⩽ .008) but not in noninfectious or pulmonary acute respiratory distress syndrome. Tumor necrosis factor, vascular endothelial growth factor, and procalcitonin were elevated but not differentially affected by methylprednisolone therapy. Conclusions: In early acute respiratory distress syndrome, administration of methylprednisolone was associated with improvement in important biomarkers of inflammation and coagulation and clinical outcomes. Biomarker changes varied with the precipitating cause of acute respiratory distress syndrome, suggesting that the underlying mechanisms and response to anti-inflammatory therapy may vary with the cause of acute respiratory distress syndrome.

Prolonged glucocorticoid treatment in acute respiratory distress syndrome : Evidence supporting effectiveness and safety

I n this issue of Critical Care Medicine, Tang et al (1) provide a systematic review and meta-analysis of nine controlled studies (n 648) evaluating the effectiveness of prolonged glucocorticoid treatment (PGCT) in patients with acute lung injury and acute respiratory distress syndrome (ARDS) (2–10). These studies (Table 1) consistently report a significant improvement in PaO2:FiO2 (2–10) and a significant reduction in markers of systemic inflammation (2–10), multiple organ dysfunction score (2, 5, 6, 8–10), duration of mechanical ventilation (2,4–6,10), and intensive care unit length of stay (2, 3, 5, 6, 10) (all with p values 0.05) without an increased rate of complications. The reduction in duration of mechanical ventilation is twoto three-fold greater than the reduction reported with low tidal volume ventilation or the conservative strategy of fluid management (11, 12). The more rapid resolution of lung injury and multiple organ dysfunction scores observed in these trials could positively affect long-term physical recovery (13) and survival (5). The relevance of these findings to public health and healthcare economics urges investment in clinical investigation of this inexpensive and highly effective anti-inflammatory therapy. Because of differences in study design and patient characteristics and the limited size of the studies (1–4), the cumulative mortality summary should be interpreted with some caution. Nevertheless, all four studies (2–5) (n 334) investigating treatment initiated within 3 days of meeting acute lung injury and ARDS criteria showed a significant reduction in mortality, with an overall 24% absolute reduction in mortality (risk ratio, 0.69; 95% confidence interval, 0.56–0.84). Two of the five studies (6, 9) investigating treatment initiated after 5–7 days of meeting ARDS criteria showed a significant reduction in mortality, whereas three studies (7, 8, 10) found no difference in mortality, with an overall 15% absolute reduction in mortality (risk ratio, 0.75; 95% confidence interval, 0.55–1.02) that increased to 19% for the larger subgroup of patients (n 233) randomized before day 14 of ARDS (risk ratio, 0.65; 95% confidence interval, 0.45–0.94) (6, 8–10). In the three studies without a mortality benefit (7, 8, 10), treatment was associated with significant early physiologic improvement; however, rapid dosage reduction (8) or premature removal after extubation (as acknowledged by the authors) (10) might have affected final outcome. In the ARDS Network trial, the treated group had— before removal of treatment—a noteworthy 9.5 days’ reduction in duration of mechanical ventilation (p 0.006) (10). The ARDS Network trial reported a lower mortality for patients (n 132) randomized before day 14 (27% vs. 36%; p 0.14) and higher mortality for patients (n 48) randomized after day 14 of ARDS (8% vs. 35%; p 0.01) (10). The latter subgroup, however, had large imbalances in baseline characteristics and an uncharacteristically low mortality in the control group, and the mortality difference lost significance (p 0.57) when adjusting for these imbalances (14, 15). Treatment decisions involve a tradeoff between benefits on the one hand and risks, burdens, and, potentially, costs on the other (16). As an aggregate (n 648), absolute and relative reduction in mortality is substantial for all patients (18% and 35%) and even greater when treatment is initiated before day 14 of ARDS (21% and 38%). While awaiting a larger confirmatory trial in early acute lung injury and ARDS, this meta-analysis provides evidence of a sizable reduction in duration of mechanical ventilation and intensive care unit stay and a considerable survival benefit with the potential saving of one life for every four treated patients (1). In the United States alone, this could translate to tens of thousands of lives saved per year and several billion dollars in reduced healthcare expenditures (17). Furthermore, the low cost of off-patent methylprednisolone—in the United States approximately

Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis

240 for 28 days of intravenous therapy (5)—makes this treatment globally and equitably available. In their systematic review, Tang et al (1) report that PGCT at low-to-moderate doses was not associated with an increased rate of major complications, including infections and neuromyopathy. This counterintuitive finding deserves further elucidation and provides an opportunity to debunk common fallacies about glucocorticoid treatment-associated complications. Most misconceptions originate from the findings of sepsis and ARDS trials conducted in the 1980s that investigated a massive daily dose of glucocorticoids (methylprednisolone, up to 120 mg/kg/day) over a short time interval (24–48 hours). The experimental model supporting this treatment protocol relied on the intravenous administration of a lethal bolus of lipopolysaccharide that could be offset only by administering an equally massive dose of glucocorticoids before or within a brief experimentally generated inflammatory window (18–20). This experimental model did not replicate human sepsis or acute lung injury and was discredited in the early 1990s (18). Since then, longitudinal measurements of inflammatory cytokines in ARDS patients have clearly shown that significant systemic and pulmonary inflammation persists 28 days into the disease process (21–24) and that PGCT (14–21 days) followed by slow tapering is essential to achieve and sustain biological resolution of the disease process (21, 25). In recent years, substantial evidence has accumulated showing that systemic inflammation, the central pathogenetic process in ARDS (21, 22, 24), is also implicated in the type of morbidity— *See also p. 1594.

Glucocorticoid Treatment in Community-acquired Pneumonia without Severe Sepsis: No Evidence of Efficacy

Background Our aim was to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patient data from randomized, placebo-controlled trials and to explore subgroup differences. Methods We systematically searched Medline, Embase, Cochrane Central, and trial registers (all through July 2017). Data from 1506 individual patients in 6 trials were analyzed using uniform outcome definitions. We investigated prespecified effect modifiers using multivariable hierarchical regression, adjusting for pneumonia severity, age, and clustering effects. Results Within 30 days of randomization, 37 of 748 patients (5.0%) assigned to corticosteroids and 45 of 758 patients (5.9%) assigned to placebo died (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], .46 to 1.21; P = .24). Time to clinical stability and length of hospital stay were reduced by approximately 1 day with corticosteroids (-1.03 days; 95% CI, -1.62 to -.43; P = .001 and -1.15 days; 95% CI, -1.75 to -.55; P < .001, respectively). More patients with corticosteroids had hyperglycemia (160 [22.1%] vs 88 [12.0%]; aOR, 2.15; 95% CI, 1.60 to 2.90; P < .001) and CAP-related rehospitalization (33 [5.0%] vs 18 [2.7%]; aOR, 1.85; 95% CI, 1.03 to 3.32; P = .04). We did not find significant effect modification by CAP severity or degree of inflammation. Conclusions Adjunct corticosteroids for patients hospitalized with CAP reduce time to clinical stability and length of hospital stay by approximately 1 day without a significant effect on overall mortality but with an increased risk for CAP-related rehospitalization and hyperglycemia.

Management of patients hospitalised with community- acquired pneumonia: dexamethasone reduces length of stay by 1 day

Conflict of Interest Statement: S.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.G.C. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.S. has been paid lecture fees by Farmaceutici (up to

Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome A Randomized Controlled Trial

1000), AstraZeneca (

Persistent Elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS: Plasma IL-1β and IL-6 Levels Are Consistent and Efficient Predictors of Outcome Over Time

1,001–