Gianfranco Umberto Meduri

Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study

Abstract.Context: In patients with hypoxemic acute respiratory failure (ARF), randomized studies have shown noninvasive positive pressure ventilation (NPPV) to be associated with lower rates of endotracheal intubation. In these patients, predictors of NPPV failure are not well characterized. Objective: To investigate variables predictive of NPPV failure in patients with hypoxemic ARF. Design: Prospective, multicenter cohort study. Setting: Eight Intensive Care Units (ICU) in Europe and USA. Patients: Of 5,847 patients admitted between October 1996 and December 1998, 2,770 met criteria for hypoxemic ARF. Of these, 2,416 were already intubated and 354 were eligible for the study. Results: NPPV failed in 30% (108/354) of patients. The highest intubation rate was observed in patients with ARDS (51%) or community-acquired pneumonia (50%). The lowest intubation rate was observed in patients with cardiogenic pulmonary edema (10%) and pulmonary contusion (18%). Multivariate analysis identified age >40xa0years (OR 1.72, 95% CI 0.92–3.23), a simplified acute physiologic score (SAPS II) ≥35 (OR 1.81, 95% CI 1.07–3.06), the presence of ARDS or community-acquired pneumonia (OR 3.75, 95% CI 2.25–6.24), and a PaO2:FiO2 ≤146 after 1xa0h of NPPV (OR 2.51, 95% CI 1.45–4.35) as factors independently associated with failure of NPPV. Patients requiring intubation had a longer duration of ICU stay (P<0.001), higher rates of ventilator-associated pneumonia and septic complications (P<0.001), and a higher ICU mortality (P<0.001). Conclusions: In hypoxemic ARF, NPPV can be successful in selected populations. When patients have a higher severity score, an older age, ARDS or pneumonia, or fail to improve after 1xa0h of treatment, the risk of failure is higher.

A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome

Objective: In randomized studies of heterogeneous patients with hypoxemic acute respiratory failure, noninvasive positive pressure ventilation (NPPV) was associated with a significant reduction in endotracheal intubation. The role of NPPV in patients with acute respiratory distress syndrome (ARDS) is still unclear. The objective was to investigate the application of NPPV as a first‐line intervention in patients with early ARDS, describing what happens in everyday clinical practice in centers having expertise with NPPV. Design: Prospective, multiple‐center cohort study. Setting: Three European intensive care units having expertise with NPPV. Patients: Between March 2002 and April 2004, 479 patients with ARDS were admitted to the intensive care units. Three hundred and thirty‐two ARDS patients were already intubated, so 147 were eligible for the study. Interventions: Application of NPPV. Measurements and Main Results: NPPV improved gas exchange and avoided intubation in 79 patients (54%). Avoidance of intubation was associated with less ventilator‐associated pneumonia (2% vs. 20%; p < .001) and a lower intensive care unit mortality rate (6% vs. 53%; p < .001). Intubation was more likely in patients who were older (p = .02), had a higher Simplified Acute Physiology Score (SAPS) II (p < .001), or needed a higher level of positive end‐expiratory pressure (p = .03) and pressure support ventilation (p = .02). Only SAPS II >34 and a Pao2/Fio2 ≤175 after 1 hr of NPPV were independently associated with NPPV failure and need for endotracheal intubation. Conclusions: In expert centers, NPPV applied as first‐line intervention in ARDS avoided intubation in 54% of treated patients. A SAPS II >34 and the inability to improve Pao2/Fio2 after 1 hr of NPPV were predictors of failure.

A Comparison of Noninvasive Positive-Pressure Ventilation and Conventional Mechanical Ventilation in Patients with Acute Respiratory Failure

BACKGROUND AND METHODSnThe 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.nnnRESULTSnWithin 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).nnnCONCLUSIONSnIn 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.

Noninvasive mechanical ventilation via face mask in patients with acute respiratory failure who refused endotracheal intubation

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. (Crit Care Med 1994; 22:1584–1590)

H1N1 influenza A virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment

PurposeDuring 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.MethodsFrom 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 (1xa0mg/kg/day), and others received hydrocortisone (300xa0mg/day) for a duration of 21xa0±xa06xa0days.ResultsPatients 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 (Pxa0<xa00.001). Twelve patients (92%) improved lung function, were extubated, and discharged alive from the ICU. Hospital length of stay and mortality were 18.7xa0±xa09.6xa0days and 15%, respectively. Survivors were discharged home without oxygen supplementation.ConclusionsIn 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.

Nuclear factor-kappaB- and glucocorticoid receptor alpha- mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids.

To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naïve cells to longitudinal plasma samples led to divergent directions in NF-kappaB and GRalpha activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GRalpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappaB nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1beta (regulated, GRalpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRalpha-mediated activity (p = 0.04) and a progressive increase in NF-kappaB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappaB-driven response). By days 3-5, no overlap was observed between groups for NF-kappaB and GC-GRalpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS.To test the hypothesis that the interaction between nuclear factor-ĸB (NF-ĸB) and glucocorticoid receptor α (GRα) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1–10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7–10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-ĸB and GRα nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naïve cells to longitudinal plasma samples led to divergent directions in NF-ĸB and GRα activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GRα-mediated activity (p = 0.0001) and a correspondent reduction in NF-ĸB nuclear binding (p = 0.0001) and transcription of TNF-α and IL-1β (regulated, GRα-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRα-mediated activity (p = 0.04) and a progressive increase in NF-ĸB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-ĸB-driven response). By days 3–5, no overlap was observed between groups for NF-ĸB and GC-GRα nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-ĸB nuclear staining (13 ± 1.3 vs. 7 ± 2.9; p = 0.01) and a lower ratio of GRα:NF-ĸB in nuclear staining (0.5 ± 0.2 vs. 1.5 ± 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRα to downregulate NF-ĸB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS.

Glucocorticoids and inflammation revisited: the state of the art. NIH clinical staff conference.

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.

Diagnostic workup for ARDS 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.

Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.

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 60u2009min of < 9 &mgr;g/dL) after cosyntropin (250 &mgr;g) administration and a random plasma cortisol of < 10 &mgr;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 < 400u2009mg/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 1u2009mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 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.

Understanding ARDS-associated fibroproliferation

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