Search

Background After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. Areas of uncertainty The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. Data sources Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. Therapeutic advances A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. Conclusions Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

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.

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs’ findings, GC plasma concentration–time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic–pituitary–adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings. Electronic supplementary material The online version of this article (10.1007/s00134-020-06289-8) contains supplementary material, which is available to authorized users.

Purpose Corticosteroids 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. Methods The 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. Results We 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. Conclusion The 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. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06394-2.

Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.To identify genetic susceptibility targets for ARDS.A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort.Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, SelplgThese findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.

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 60min of < 9 g/dL) after cosyntropin (250 g) administration and a random plasma cortisol of < 10 g/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 IV hydrocortisone < 400mg/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 1mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/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.

To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). 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). Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. 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. 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.

MicroRNA (miRNA) control gene transcription by binding to and repressing the translation of messenger RNA (mRNA). Their role in the acute respiratory distress syndrome (ARDS) is undefined.Blood leukocytes from 51 patients enrolled in a prior randomized trial of corticosteroids for ARDS were analyzed. After screening eight patients with microarrays for altered miRNA expression, 25 miRNAs were selected for further analysis using RT-PCR in all 51 patients.On day 0, the 51 patients had APACHE III score of 60.4 ± 17.7 and PaO2/FiO2 of 117 ± 49. 21 miRNA were expressed at increased levels in blood leukocytes at the onset of ARDS compared with healthy controls. These miRNA remained elevated at day 3 and increased further by day 7 (log2 fold change from 0.66 to 5.7 fold, P 0.05 compared to day 0). In a subgroup analysis (37 patients treated with corticosteroids and 14 treated with placebo), the interaction of miRNA expression over time and steroid administration was not significant suggesting that systemic corticosteroids had no effect on the miRNA detected in our study. In contrast, corticosteroids but not placebo decreased IL-6 and C-reactive protein at day 3 (P 0.001) demonstrating an early systemic anti-inflammatory response whereas both treatment arms had decreased values by day 7 (P 0.001).Expression of miRNA is increased in blood leukocytes of patients with ARDS at day 0 and day 3 and rises further by day 7, when systemic inflammation is subsiding. These effects appear independent of the administration of steroids, suggesting different inflammatory modifying roles for each in the resolving phases of ARDS.

In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.

Low-dose methylprednisolone therapy in adults with early acute respiratory distress syndrome reduces systemic inflammation, duration of mechanical ventilation, and ICU length of stay. We report a pilot randomized trial of glucocorticoid treatment in early pediatric acute respiratory distress syndrome.Double-blind, placebo-controlled randomized clinical trial.Le Bonheur Children's Hospital, Memphis, TN.Children (0-18 yr) with acute respiratory distress syndrome undergoing mechanical ventilation.Patients were randomly assigned to steroid or placebo groups within 72 hours of intubation. IV methylprednisolone administered as loading dose (2 mg/kg) and continuous infusions (1 mg/kg/d) on days 1-7 and then tapered over days 8-14. Both groups were ventilated according to the Acute Respiratory Distress Syndrome Network protocol modified for children. Daily surveillance was performed for adverse effects.Thirty-five patients were randomized to the steroid (n = 17, no death) and placebo groups (n = 18, two deaths). No differences occurred in length of mechanical ventilation, ICU stay, hospital stay, or mortality between the two groups. At baseline, higher plateau pressures (p = 0.006) and lower Pediatric Logistic Organ Dysfunction scores (p = 0.04) occurred in the steroid group; other characteristics were similar. Despite higher plateau pressures on days 1 (p = 0.006) and 2 (p = 0.025) due to poorer lung compliance in the steroid group, they had lower PaCO2 values on days 2 (p = 0.009) and 3 (p = 0.014), higher pH values on day 2 (p = 0.018), and higher PaO2/FIO2 ratios on days 8 (p = 0.047) and 9 (p = 0.002) compared with the placebo group. Fewer patients in the steroid group required treatment for postextubation stridor (p = 0.04) or supplemental oxygen at ICU transfer (p = 0.012). Steroid therapy was not associated with detectable adverse effects.This study demonstrates the feasibility of administering low-dose glucocorticoid therapy and measuring clinically relevant outcomes in pediatric acute respiratory distress syndrome. Changes in oxygenation and/or ventilation are consistent with early acute respiratory distress syndrome pathophysiology and results of similar clinical trials in adults. We propose and design a larger randomized trial to define the role of glucocorticoid therapy in pediatric acute respiratory distress syndrome.

Received: 10 December 2014 Accepted: 13 December 2014 Published online: 8 January 2015 Springer-Verlag Berlin Heidelberg and ESICM (outside the USA) 2014 G. U. Meduri ()) Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Memphis Veterans Affairs Medical Center, Memphis, TN, USA e-mail: gmeduri@uthsc.edu M. A. Eltorky Surgical Pathology Division, Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

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

Acute respiratory distress syndrome (ARDS) is defined by the association of bilateral infiltrates and hypoxaemia following an initial insult. Although a new definition has been recently proposed (Berlin definition), there are various forms of ARDS with potential differences regarding their management (ventilator settings, prone positioning use, corticosteroids). ARDS can be caused by various aetiologies, and the adequate treatment of the responsible cause is crucial to improve the outcome. It is of paramount importance to characterize the mechanisms causing lung injury to optimize both the aetiological treatment and the symptomatic treatment. If there is no obvious cause of ARDS or if a direct lung injury is suspected, bronchoalveolar lavage (BAL) should be strongly considered to identify microorganisms responsible for pneumonia. Blood samples can also help to identify microorganisms and to evaluate biomarkers of infection. If there is no infectious cause of ARDS or no other apparent aetiology is found, second-line examinations should include markers of immunologic diseases. In selected cases, open lung biopsy remains useful to identify the cause of ARDS when all other examinations remain inconclusive. CT scan is fundamental when there is a suspicion of intra-abdominal sepsis and in some cases of pneumonia. Ultrasonography is important not only in evaluating biventricular function but also in identifying pleural effusions and pneumothorax. The definition of ARDS remains clinical and the main objective of the diagnostic workup should be to be focused on identification of its aetiology, especially a treatable infection. Electronic supplementary material The online version of this article (doi:10.1007/s00134-016-4324-5) contains supplementary material, which is available to authorized users.

Introduction: Healthcare Associated Infections (HAI) are associated with increased cost, morbidity, and mortality. Risk factors for HAI are well established; however, the independent risk associated with an exaggerated inflammatory response has not been adequately studied. Hypothesis: The objective was to investigate baseline cytokine levels (IL-6, IL-10), their polymorphisms (RS1800795, RS1800896) and environment on the development of new HAI in ICU patients admitted with sepsis. Methods: This prospective observational study evaluated 78 patients admitted to ICU with early sepsis ( Results: Seventeen HAI were identified. The final regression model included APACHE II, invasive device score, antibiotics prior to ICU, and IL6 RS1800795. Based on the multivariate model, for every 1-point increase in APACHE II score there was a 3.4% increased risk for developing HAI. Cumulative invasive device score and early antibiotic use reduced the risk of HAI. In the univariate model, the presence of IL6 polymorphism RS1800795 CC or CG resulted in a higher risk of HAI, and this risk increased in the multivariate model. Conclusions: The higher risk associated with IL-6 polymorphism RS1800795 CG and CC genotypes is consistent with higher risk associated with the C allele reported in the literature. Severity of illness is a known contributor to HAI. Sepsis guideline adherence (early antibiotics and judicious device use) may prevent HAI. We found no significant association with cytokine levels in our models. More analysis with a larger sample is needed to fully explore the relationships of these variables.

Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of ARDS. In ARDS patients, glucocorticoid receptor-mediated down-regulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced down-regulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from controlled trials provides consistent strong level of evidence (grade 1B) for improving patient-centered outcomes. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.58 days; 95% CI, 2.93 -10.23; P

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

To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients.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.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.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 of9 microg/dL after adrenocorticotrophic hormone (250 microg) administration or a random total cortisol of10 microg/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 of200 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) foror = 7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg x kg(-1) x day(-1) foror = 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.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.

Objective Lung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1). Design Double-blind, placebo-controlled randomized trial. Setting Tertiary-care pediatric intensive care unit (ICU). Patients Mechanically ventilated children (0–18 years) with early ARDS. Interventions Blood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge. Results No differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p

Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). In ARDS patients, glucocorticoid receptor-mediated downregulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced downregulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from eight controlled trials (n = 622) provides consistent strong level of evidence for improving patient-centered outcomes and hospital survival. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.48 days; CI 95% 2.57-10.38, p

The macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine central to the response to endotoxemia, is a putative biomarker in acute lung injury (ALI). To explore MIF as a molecular target and candidate gene in ALI, the MIF gene and protein expression were examined in murine and canine models of ALI (high tidal volume mechanical ventilation, endotoxin exposure) and in patients with either sepsis or sepsis-induced ALI. MIF gene expression and protein levels were significantly increased in each ALI model, with serum MIF levels significantly higher in patients with either sepsis or ALI compared with healthy controls (African- and European-descent). The association of 8 MIF gene polymorphisms (single-nucleotide polymorphisms (SNPs)) (within a 9.7-kb interval on chromosome 22q11.23) with the development of sepsis and ALI in European-descent and African-descent populations was studied next. Genotyping in 506 DNA samples (sepsis patients, sepsis-associated ALI patients, and healthy controls) revealed haplotypes located in the 3' end of the MIF gene, but not individual SNPs, associated with sepsis and ALI in both populations. These data, generated via functional genomic and genetic approaches, suggest that MIF is a relevant molecular target in ALI.

Intensive Care Med DOI 10.1007/s00134-015-4027-3 Andreas Schwingshackl Gianfranco Umberto Meduri Dai Kimura Stephania A. Cormier Kanwaljeet J. S. Anand Corticosteroids in pediatric ARDS: all cards on the table Accepted: 8 August 2015 O Springer-Verlag Berlin Heidelberg and ESICM 2015 Dear Editor, Hardly any topic in modern critical care medicine remains as controver- sial as steroid administration in acute respiratory distress syndrome (ARDS), despite multiple adult ran- domized controlled trials (RCTs) and recent pediatric data. The article by Yehya et al. [1] and the editorial commentary by Peters et al. [2] are vital, since few, if any, therapeutic approaches are simultaneously asso- ciated with such profound potential benefits and risks as steroid therapy in critically ill patients. Marked contradiction, however, exists between the Yehya et al. data and the findings of well-designed and protocol-driven RCTs in adult ARDS patients. These studies consistently reported significant improvements in markers of systemic inflammation, ventilator-free days, ICU-free days, no changes or actually improved survival, and either no increase or decreases in infection rate [3, 4]. The findings of Yehya et al. cannot be interpreted because the specific indi- cations for corticosteroid use were not reported. To imply that any type of steroid, at any concentration, and CO RRESPONDENCE used for more than 24 h represents a protocol-driven treatment for pedi- atric ARDS (PARDS) is simply not justifiable. Further, grouping short-term (less than 24 h) and non-corticosteroid exposed patients together is an improper control for evaluating ster- oid therapy. Corticosteroids can exert important, non-genomic effects within minutes, including decreased cell adhesion, phosphokinase activa- tion, MCP-1 and H 2 O 2 release, CD63 translocation, TNF-a and IL-6 expression. Possible corticosteroid effects cannot be assessed unless exposed and non-exposed patients are categorically separated. Thus, proposing that this single-center, observational study ‘‘has relevance for clinical practice’’, a conclusion unsupported by data, will likely mis- lead and confound many bedside physicians. Undoubtedly, the most likely explanation for Yehya et al.’s findings are (1) selection of steroid therapy for the sickest patients (con- founding by indication) and (2) rebound effects resulting from abrupt discontinuation of corticosteroids, as is well documented by worsening PaO 2 /FiO 2 ratios and increasing CRP levels. Owing to the wide-ranging impli- cations and inherent responsibility of publishing patient data, it is impera- tive that we treat this topic with the utmost equipoise until clear evidence for or against steroid use in ARDS/ PARDS is gained. Whether compar- ative effectiveness research (CER) can provide such evidence is ques- tionable, since the US Food and Drug Administration, European Medicines Agency, or other labeling agencies do not consider this research methodol- ogy Level 1 evidence. CER studies can ‘‘adjust’’ the outcomes for measured confounders, and boot- strapping techniques like propensity scoring can reduce the margin of inferential errors, but only large, well- designed RCTs can control for unmeasured and non-measurable confounders. We recommend caution in drawing conclusions from a data set with multiple confounding vari- ables and improper controls. Statistical approaches such as propensity score matching can only take into account measured con- founding factors, whereas randomized trials allow for control- ling of both measured and unmeasured confounders. The bene- ficial or no-harm results reported in adult RCTs cannot be disregarded unless systematically investigated in pediatric patients. We recently pub- lished a feasibility RCT investigating prolonged low-dose methylpred- nisolone in pediatric ARDS [5] and, undoubtedly, there is an urgent need to conduct a large-scale, well-de- signed RCT in PARDS. References 1. Yehya N, Servaes S, Thomas NJ, Nadkarni VM, Srinivasan V (2015) Corticosteroid exposure in pediatric acute respiratory distress syndrome. Intensive Care Med. doi: 10.1007/s00134-015-3953-4 2. Peters MJ, Ray S, Kneyber M (2015) Corticosteroids for paediatric ARDS: unjustified—even unjustifiable? Intensive Care Med. doi: 10.1007/s00134-015-3963-2 3. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU (2005) Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med

Background Health care-associated infections (HAIs) are the target of many well-known preventive measures in the intensive care unit (ICU); however, little is known about post-sepsis-induced immunosuppression. Objectives This study explores the relationship between baseline plasma levels of inflammatory cytokines interleukin 6 (IL-6), IL-10, and IL-6:IL-10 and subsequent development of HAIs in patients with admitted with sepsis. Methods Prospective observational study was conducted among veterans admitted to the ICU with sepsis and monitored daily through ICU discharge (up to 28 days) to investigate HAI development. Baseline plasma IL-6 and IL-10 levels were measured with a multiplex bead based assay. Exaggerated systemic inflammation was defined as the fourth quartile (IL-6 and IL-10) compared with other quartiles. Results We recruited 78 patients over 18 months, primarily older (65.5 ± 12.6 years) men (94.9%) with underlying comorbidities (93.9%) and a high severity of illness (Acute Physiologic and Chronic Health Evaluation II score 20.6 ± 6.4). Seventeen patients (21.7%) developed at least 1 HAI, and candidemia was the leading infection. Patients with exaggerated baseline systemic inflammation developed a nonsignificantly higher proportion of HAI as compared with those not developing HAI (IL-6: 31.6% vs 18.6%, P = .55; IL-10: 26.3% vs 20.3%, P = .43). Discussion Patients with exaggerated systemic inflammation had a higher severity of illness, but not a statistically significant higher incidence of HAI. A larger, more adequately powered sample with serial cytokine measures is needed. Routine surveillance cultures are needed. Health care-associated infection may occur in the absence of fever, and the emerging incidence of Candida is a concern. Immune suppression after sepsis should be recognized as a risk for HAI development. Antibiotic therapy should be targeted with prompt de-escalation of empiric therapy per established guidelines to preserve normal flora.

The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon–intron boundaries, and 2 kb of 5′ UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P < 0.001), with an additional SNP associated with the ALI phenotype (P = 0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P = 0.002) and with ALI (P = 0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P < 0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5′ of the MYLK gene in both European and African Americans and an additional 3′ region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI.

Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock protein-bound glucocorticoid receptors that translocate into the nucleus, where they regulate the transcriptional activity of responsive genes by binding to specific promoter DNA sequences (transactivation) or by interacting with transcription factors (transrepression). By interacting with different signaling pathways, newly characterized nuclear receptor coregulators enhance or diminish the actions of glucocorticoids, thus explaining the gene-, cell-, tissue- and context-dependent actions of glucocorticoids. Glucocorticoids modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular [T helper (Th)1-directed] immunity and promote humoral (Th2-directed) immunity and tolerance. The past decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance of inflammatory, autoimmune and allergic diseases. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in the glucocorticoid sensitivity, dependency and resistance of these diseases. Although glucocorticoids increase susceptibility to opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, such as that observed in septic shock and acute respiratory distress syndrome, when administered in a sustained fashion throughout the course of the disease. Glucocorticoids produce their cardiovascular, metabolic and antigrowth side effects through molecular mechanisms distinct from those involved in immunomodulation. Fortunately, the first generation of tissue- and immune- versus cardiovascular/metabolic effect-selective glucocorticoids is available for study and further improvement. ‘Designer’ glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases.

Two recent small randomized trials evaluating a 5- to 12-day course of low dose hydrocortisone in patients with septic shock have reported a significant clinical improvement and a reduction in mortality. Recent studies indicate that an overaggressive and unregulated systemic inflammatory response is a major determinant of outcome in sepsis. In septic shock, nonsurvivors as opposed to survivors have over time: (1) significantly higher NF-kB activity in peripheral mononuclear cells, (2) persistent elevation in circulating inflammatory cytokine levels, and (3) elevated ACTH and cortisol levels. Current research recognizes that cytokines can cause a concentration-dependent resistance to endogenous glucocorticoids (GC). It is postulated that an excess of cytokine-induced transcription factors, such as NF-kB, may form complexes with activated glucocorticoid receptors (GCR), preventing GCR interaction with DNA. When T cells are incubated with a combination of cytokines, GC resistance is induced in a cytokine concentration-dependent fashion and reversed by removal of cytokines. Prolonged treatment with physiological doses of exogenous GCs may be necessary to compensate adequately for the inability of target organs to respond to endogenous cortisol and for the inability of the host to produce appropriately elevated levels of GCs. This hypothesis is supported by the laboratory findings of a recent randomized study of patients with unresolving acute respiratory disease.

We have previously reported that in acute respiratory distress syndrome (ARDS), nonsurvivors have persistent elevation in pulmonary and circulating proinflammatory cytokine levels over time and a high rate of nosocomial infections antemortem. In these patients, none of the proven or suspected nosocomial infections caused a transient or sustained increase in plasma proinflammatory cytokine levels above preinfection values. We hypothesized that cytokines secreted by the host during ARDS may favor the growth of bacteria. We conducted an in vitro study of the growth of three bacteria clinically relevant in nosocomial infections, evaluating their in vitro response to various concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. We found that all three bacterial species showed concentration-dependent growth enhancement when incubated with one or more tested cytokines and that blockade by specific neutralizing cytokine MoAb significantly inhibited cytokine-induced growth. When compared with control, the 6-h growth response (cfu/ml) was maximal with IL-1beta at 1,000 pg for Staphylococcus aureus (36 +/- 16 versus 377 +/- 16; p = 0.0001) and Acinetobacter spp. (317 +/- 1,147 versus 1,124 +/- 147; p = 0.002) and with IL-6 at 1,000 pg for Pseudomonas aeruginosa (99 +/- 50 versus 509 +/- 50; p = 0.009). The effects of cytokines were seen only with fresh isolates and were lost with passage in vitro on bacteriologic medium without added cytokines. In this study we provide additional evidence for a newly described pathogenetic mechanism for bacterial proliferation in the presence of exaggerated and protracted inflammation.

Ineffective lung repair in patients with unresolving acute respiratory distress syndrome (ARDS) is accompanied by progressive fibroproliferation, inability to improve lung injury score (LIS), progressive multiple organ dysfunction syndrome (MODS), and an unfavorable outcome. Our aim was to investigate the relationship between fibrogenesis, pulmonary and extrapulmonary organ dysfunction, and outcome during the natural course of ARDS and in response to prolonged methylprednisolone treatment. We investigated 29 patients with ARDS. We obtained serial measurements of plasma and BAL procollagen aminoterminal propeptide type I (PINP) and type III (PIIINP) levels and components of the lung injury score (LIS) and MODS score. A reduction in LIS greater than one point from day 1 to day 7 of ARDS divided patients in improvers (group 1, n = 7) and nonimprovers (n = 22). Nonimprovers included those who were recruited (day 9 +/- 3 of ARDS) into a prospective, randomized, double-blind, placebo-controlled trial investigating prolonged methylprednisolone therapy in unresolving ARDS (group 2, n = 17), and those who died (all by day 10 of ARDS) prior to meeting eligibility criteria for the randomized trial (group 3, n = 5). On day 1 of ARDS, plasma PINP or PIIINP levels were elevated in all patients. By day 7 of ARDS, mean plasma PINP or PIIINP levels were unchanged in group 1 but increased significantly in group 2 (p = 0. 0002) and group 3 (p = 0.03). On day 7, patients with plasma PINP levels less than 100 ng/ml were 2.5 times more likely to survive (95% CI: 0.855-7.314), and patients with plasma PIIINP levels greater than 25 ng/ml were nine times more likely to die (95% CI: 1. 418-55.556). In group 2, patients taking placebo (n = 6) had no change in plasma PINP or PIIINP levels over time, while patients treated with methylprednisolone (n = 11) had a rapid and sustained reduction in mean plasma and bronchoalveolar lavage (BAL) PINP and PIIINP levels. By day 3 of treatment, mean plasma PINP and PIIINP levels (ng/ml) decreased from 100 +/- 9 to 45 +/- 8 (p = 0.0001) and 31 +/- 3 to 12 +/- 3 (p = 0.0008), respectively. After 8 to 15 d of methylprednisolone, mean BAL PINP and PIIINP levels (ng/ml) decreased from 63 +/- 25 to 6 +/- 23 (p = 0.002) and 42 +/- 5 to 10 +/- 3 (p = 0.003), respectively. Estimated partial correlation coefficients indicated that as plasma PINP and PIIINP levels decreased over the first 7 d of methylprednisolone treatment, positive end-expiratory pressure, creatinine, bilirubin, and temperature also decreased, while PaO2:FIO2 increased. In early ARDS, plasma PINP and PIIINP levels are elevated and continue to increase over time in those not improving. Among nonimprovers, those randomized to prolonged methylprednisolone treatment had a rapid and significant reduction in plasma and BAL aminoterminal propeptide levels and similar changes in lung injury and MODS scores. These findings provide additional evidence of an association between biological efficacy and physiologic response during prolonged methylprednisolone treatment of unresolving ARDS.

The role of noninvasive positive-pressure ventilation delivered through a face mask in patients with acute respiratory failure is uncertain. We conducted a prospective, randomized trial of noninvasive positive-pressure ventilation as compared with endotracheal intubation with conventional mechanical ventilation in 64 patients with hypoxemic acute respiratory failure who required mechanical ventilation.Within the first hour of ventilation, 20 of 32 patients (62 percent) in the noninvasive-ventilation group and 15 of 32 (47 percent) in the conventional-ventilation group had an improved ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2) (P=0.21). Ten patients in the noninvasive-ventilation group subsequently required endotracheal intubation. Seventeen patients in the conventional-ventilation group (53 percent) and 23 in the noninvasive-ventilation group (72 percent) survived their stay in the intensive care unit (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.4; P=0.19); 16 patients in the conventional-ventilation group and 22 patients in the noninvasive-ventilation group were discharged from the hospital. More patients in the conventional-ventilation group had serious complications (66 percent vs. 38 percent, P=0.02) and had pneumonia or sinusitis related to the endotracheal tube (31 percent vs. 3 percent, P=0.003). Among the survivors, patients in the noninvasive-ventilation group had shorter periods of ventilation (P=0.006) and shorter stays in the intensive care unit (P=0.002).In patients with acute respiratory failure, noninvasive ventilation was as effective as conventional ventilation in improving gas exchange and was associated with fewer serious complications and shorter stays in the intensive care unit.

To determine the diagnostic accuracy of computed tomography (CT) for pneumonia in patients with adult respiratory distress syndrome (ARDS).CT scans were obtained within 1 week of bronchoscopic sampling in 31 patients receiving mechanical ventilation for ARDS for more than 48 hours. Of 11 patients with pneumonia, five developed symptoms less than 11 days after the onset of ARDS (early ARDS). CT scans were rated for pneumonia independently by four radiologists who were unaware of the clinical diagnosis. Diagnostic accuracy was defined by means of the area under the receiver operating characteristic curve, or A2.Diagnostic accuracy for pneumonia was fair (A2 = 0.69 +/- 0.04 [standard error]) owing to 70% true-negative ratings (vs 59% true-positive ratings). The generalizability coefficient was good (0.79). No single CT finding was significantly different for the presence of pneumonia. Nondependent opacities predominated in 10 (91%) of 11 patients with pneumonia and 12 (60%) of 20 without pneumonia. Nondependent opacities predominated in nine (56%) of 16 patients with early ARDS and 13 (87%) of 15 with late ARDS.CT has fair diagnostic accuracy for ventilator-associated pneumonia in patients with ARDS owing primarily to identification of patients without pneumonia. No single CT sign was significantly different for pneumonia, but dependent atelectasis was more common in patients with early ARDS without pneumonia.

In asthmatic patients with acute respiratory failure (ARF), placing an endotracheal tube is associated with a high rate of complications and results in increased airway resistance. In acute asthma, mask-continuous positive airway pressure (CPAP) decreases airway resistance and the work of breathing (WOB), but does not improve gas exchange. In COPD with ARF, adding intermittent positive pressure ventilation to mask-CPAP results in an additional improvement in WOB and is highly effective in correcting gas exchange abnormalities. In our medical ICU, noninvasive positive pressure ventilation (NPPV) is used as first-line interventional therapy in eligible patients with hypercapnic ARF. We report our experience with NPPV in 17 episodes of asthma and ARF over a 3-year period.A face mask was secured with head straps, avoiding a tight fit, and connected to a ventilator (PB-7200). Initial ventilatory settings included CPAP at 4 +/- 2 cm H2O to offset intrinsic positive end-expiratory pressure and pressure support ventilation (PSV) at 14 +/- 5 cm H2O aiming at a respiratory rate less than 25 breaths/min and an exhaled tidal volume of 7 mL/kg or more. PSV was then adjusted following arterial blood gas results.Mean age was 35.4 +/- 11.3 years; 10 patients were female. The mean (+/- SE) for different physiologic values are reported at initiation, less than 2 h, 2 to 6 h, and 12 to 24 h into NPPV. pH was 7.25 +/- 0.01, 7.32 +/- 0.02 (p = 0.0012), 7.36 +/- 0.02 (p0.0001), and 7.38 +/- 0.02; PaCO2 was 65 +/- 2, 52 +/- 3(p = 0.002), 45 +/- 3(p0.0001), and 45 +/- 4; PaO2 fraction of inspired oxygen was 315 +/- 41, 403 +/- 47, 367 +/- 47, and 472 +/- 67 (p = 0.06); and respiratory rate was: 29.1 +/- 1, 22 +/- 1 (p0.0001), 20 +/- 1, and 17 +/- 1. NPPV was well tolerated, and only two patients required sedation. Initial delivered minute ventilation was 16 +/- 4 L/min. The mean (+/- SD) peak inspiratory pressure to ventilate in the NPPV-treated patients was 18 +/- 5 cm H2O and always less than 25 cm H2O. There was no complication or problem with expectorating of secretions. Oral intake (liquid diet) was preserved. Two patients required intubation (35 min and 89 h into NPPV) for worsening PaCO2. Duration of NPPV was 16 +/- 21 h. All patients survived. Length of hospital stay was 5 +/- 4 days.In asthmatic patients with ARF, NPPV via a face mask appears highly effective in correcting gas exchange abnormalities using a low inspiratory pressure (25 cm H2O). A randomized study is in progress to assess fully the role of NPPV in status asthmaticus.

Background Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome. Methods We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-α) and interleukins (ILs) 1β, 2,4,6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days 1,2,3,5,7,10, and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time. Results Of the 27 patients, 13 survived ICU admission and 14 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1β or IL-6 level >400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival. Conclusions Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-α, IL-1β, IL-6, and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1β and IL-6 levels were consistent and efficient predictors of outcome.

Clinical criteria, radiographic findings, and analysis of a tracheal aspirate are inaccurate for diagnosing ventilator-associated pneumonia (VAP). This article reviews both invasive and noninvasive diagnostic techniques, discusses microbiologic and microscopic analysis of lower airway secretions, and considers factors influencing the results of these tests. The differential diagnosis of fever and pulmonary densities in ventilated patients is discussed, and a systematic diagnostic approach for the evaluation of patients with suspected VAP is presented.

OBJECTIVE To evaluate the response to noninvasive ventilation in a group of terminally ill patients with acute respiratory failure who refused endotracheal intubation. DESIGN Case series. SETTING Medical intensive care units (ICUs) in a university health science center. PATIENTS Eleven patients, nine with hypercapnic and two with hypoxemic acute respiratory failure. Mean age of patients was 64 yrs. INTERVENTION Mechanical ventilation was delivered via a face mask. The initial ventilatory setting was continuous positive airway pressure mode, with pressure-support ventilation of 10 to 20 cm H2O, titrated to achieve a respiratory rate of < 25 breaths/min and a tidal volume of 5 to 7 mL/kg. Ventilatory settings were adjusted based on results of arterial blood gases. Mean duration of mechanical ventilation was 44 hrs. MEASUREMENTS AND MAIN RESULTS Mechanical ventilation via face mask was effective in correcting gas exchange abnormalities in seven of 11 patients, all of whom survived and were discharged from the ICU. Four patients with hypercapnic acute respiratory failure died. Mechanical ventilation via face mask was effective in improving respiratory acidosis in three patients and had no effect in one patient. Two of the four patients could not be weaned from mechanical ventilation and opted for discontinuation of this method. Removal of the ventilator while retaining the mask for oxygen supplementation was a nontraumatic experience to the patient and family. Even when respiratory failure did not resolve, mechanical ventilation via face mask was effective in lessening dyspnea and allowed the patient to maintain autonomy and continuous verbal communication. CONCLUSIONS We conclude that mechanical ventilation via face mask offers an effective, comfortable, and dignified method of supporting patients with end-stage disease and acute respiratory failure.

Background: Ventilator-associated pneumonia, a leading cause of sepsis in patients with acute respiratory failure, is difficult to distinguish clinically from other processes affecting patients receiving mechanical ventilation. We conducted a prospective study of patients with suspected ventilator-associated pneumonia to identify the causes of fever and densities on chest radiographs and to evaluate the diagnostic yield and efficiency of tests used alone and in combination. Methods: The 50 patients entered into the study underwent a systematic diagnostic protocol designed to identify all potential causes of fever and pulmonary densities. Diagnoses responsible for fever were established by strict diagnostic criteria for 45 of the 50 patients. The prevalence of specific conditions and diagnostic yield of individual tests were used to formulate a simplified diagnostic protocol. Results: The diagnostic protocol identified 78 causes of fever (median 2 per patient). Infections were the leading causes of fever and pulmonary densities. Of the 45 patients with fever, 37 had one or more infections identified (67 sources). Most infections (84 percent) were one of four types: pneumonia, sinusitis, catheter-related infection, or urinary tract infection. Ventilator-associated pneumonia occurred in only 42 percent. All but nine infections (87 percent) were directly or indirectly related to insertion of a catheter or a tube. Concomitant infections were frequent (62 percent), particularly in patients with sinusitis (100 percent), catheter-related infections (93 percent), and pneumonia (74 percent). Of concomitant infections, 60 percent were caused by a different pathogen. Noninfectious causes of fever were more common in the 22 patients with adult respiratory distress syndrome. Histologically proved pulmonary fibroproliferation was the only cause of fever in 25 percent of patients with adult respiratory distress syndrome. Radiographic densities were caused by an infection in only 20 patients (19 pneumonia, 1 empyema). In more than 50 percent of the 25 patients without adult respiratory distress syndrome, congestive heart failure, and atelectasis were the sole causes of pulmonary densities, and fever always originated from an extrapulmonary site of infection. Used in combination, bronchoscopy with protected sampling, computed tomographic scan of the sinuses, and cultures of maxillary sinus aspirate, central intravenous or arterial lines, urine, and blood identified 58 of the 78 sources of fever (74 percent). Conclusions: The observations in this study document the complex nature of acute respiratory failure and fever and underscore the need for accuracy in diagnosis. The frequent occurrence of multiple infectious and noninfeetious processes justifies a systematic search for source of fever, using a comprehensive diagnostic protocol. A simplified diagnostic protocol was devised based on the diagnostic value of individual tests.

Pulmonary fibroproliferation (PFP) is directly or indirectly the leading cause of death in patients with late ARDS. We previously reported our experience using intravenous corticosteroids (IVC) in 8 patients with late ARDS and now have expanded our observation to a total of 25 patients with severe fibroproliferation (mean lung injury score [LIS] 3) and progressive respiratory failure (RF). Thirteen patients had open-lung biopsy before treatment. Patients were started on IVC treatment (IVCT) an average of 15 +/- 7.5 days into mechanical ventilation (MV). Significant physiologic improvement (SPI) to IVCT was defined as a reduction in LIS of greater than 1 point or an increase in PaO2:FIO2 ratio of greater than 100. We observed three patterns of response: rapid responders (RR) had an SPI by day 7 (n = 15); delayed responders (DR) had an SPI by day 14 (n = 6); nonresponders (NR) were without SPI by day 14 (n = 4). Overall the following significant mean changes were seen within 7 days of IVCT: LIS from 3 to 2 (p = 0.001), PaO2:FIO2 from 162 to 234 (p = 0.0004), PEEP from 11 to 6.8 cm H2O (p = 0.001), chest radiograph score from 3.8 to 3.0 (p = 0.009), and VE from 16 to 13.6 L/min (p = 0.01). Development of pneumonia was related to the pattern of response. Surveillance bronchoscopy was effective in identifying pneumonia in eight afebrile patients. Nineteen of 25 (76 percent) patients survived the ICU admission. Comparisons were made between survivors (S) and nonsurvivors (NS) and among the three groups of responders. At the time ARDS developed, no physiologic or demographic variable could discriminate between S and NS. At the time of IVCT, only liver failure was more frequent in nonsurvivors (p = 0.035). Histologic findings at open-lung biopsy and pattern of physiologic response clearly predicted outcome. The presence of preserved alveolar architecture (p = 0.045), myxoid type fibrosis (p = 0.045), coexistent intraluminal bronchiolar fibrosis (p = 0.0045), and lack of arteriolar subintimal fibroproliferation (p = 0.045) separated S from NS. ICU survival rate was 86 percent in responders and 25 percent in nonresponders (p = 0.03). Only one death resulted from refractory respiratory failure.

Ventilator-associated pneumonia is a frequent complication of mechanical ventilation, and it carries a significant added mortality. Proper recognition and treatment of pneumonia are associated with improved outcome. Clinical manifestations of pneumonia, chest radiograph findings, and routine analysis of the tracheal aspirate are inadequate, alone or in combination, in diagnosing pneumonia. This article discusses the methodologies that are presently available for diagnosing pneumonia in ventilated patients. Correct use of these techniques helps the clinician to establish a diagnosis with a high degree of reliability and facilitates the rational use of antibiotic treatment.