Gianfranco Umberto Meduri

University of Tennessee Health Science Center

The glucocorticoid receptor alpha (GRα), a pivotal component of the ancient glucocorticoid (GC) signaling system that emerged nearly 450 million years ago, has been instrumental in directing vertebrate evolution and is essential for survival, regulating fertility and fetal development, the function of every organ and circulating cells, metabolism,...

In the last half-century, understanding pro- and antiinflammatory actions as opposite biological effects (“a tug of war”) has become obsolete. • Rather, emerging evidence suggests a more complex relation between pro- and antiinflammatory actions, with complementary coregulation (dualism), respectively, between the glucocorticoid (GC)- activated glu...

In critical illness, glucocorticoid (GC) receptor alpha (GC-GRα) regulatory and coregulatory actions are associated with an enormous bioenergetic and metabolic cost, and GC-GRα’s function is codependent with (i) mitochondrial cell bioenergetic and adaptation functions and (ii) reserves of essential micronutrients. ° Crosstalk between neuroendocrine...

Exogenous glucocorticoids (GCs) are agonist compounds that bind to the GC receptor (GRα), producing a rapid pharmacological response. • The view of GCs’ actions as solely antiinflammatory and immunosuppressive is obsolete, impacting the design of randomized controlled trials (RCTs) in critical illness and clinical practice. • GC treatment should be...

Background: Corticosteroids could improve outcomes in patients with community-acquired pneumonia (CAP). However, we hypothesize that corticosteroid effectiveness varies among individual patients, resulting in inconsistent outcomes and unclear clinical indication. Therefore, we developed and validated a predictive, causal model based on baseline cha...

WHISTLEBLOWER STORY: The Destruction of the Memphis Lung Research Program and the Global Human and Economic Repercussions. Why research with improved outcomes was blocked by institutions created to protect research and the public? Who enforces regulatory compliance to protect the rights of patients, the accused, and the interests of society?

Prolonged, low-dose glucocorticoids (GCs) have shown the highest efficacy among pharmacological and non-pharmacological treatments for COVID-19. Despite the World Health Organization’s recommendation against their use at the beginning of the pandemic, GCs at a dose equivalent to dexamethasone 6 mg/day for 10 days are now indicated in all COVID-19 c...

Low-Dose Hydrocortisone and Septic ShockCorticosteroids have been evaluated as a therapy for septic shock for more than 50 years. However, uncertainty persists about their effects on mortality. Pirracchio and colleagues undertake a patient-level meta-analysis to answer this important question.

Introduction Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7–10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day ⁻¹ . A comparative RCT with a higher dose and a longer duration of intervention was lacking. Methods We conducted a multi-center, open...

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 t...

Purpose: Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clin...

A detailed analysis of misrepresentations in the LaSRS RCT

In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respirato...

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...

PurposeCorticosteroids are now recommended for patients with severe COVID-19 including those with COVID-related ARDS. This has generated renewed interest regarding whether corticosteroids should be used in non-COVID ARDS as well. The objective of this study was to summarize all RCTs examining the use of corticosteroids in ARDS.Methods The protocol...

Background Mortality attributable to coronavirus disease-19 (COVID-19) 2 infection occurs mainly through the development of viral pneumonia-induced acute respiratory distress syndrome (ARDS). Research Question The objective of the study is to delineate the clinical profile, predictors of disease progression, and 30-day mortality from ARDS using th...

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption...

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....

In March 2020, an expert panel called the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by Professor Paul E. Marik, with the goal of continuously reviewing the rapidly emerging basic science, translational, and clinical data in order to gain insight into and to develop a treatment protocol for COVID-19. At the same time, ma...

Background: In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylpredn...

Background Mortality attributable to coronavirus disease-19 (COVID-19) 2 infection occurs mainly through the development of viral pneumonia-induced acute respiratory distress syndrome (ARDS). Research Question The objective of the study is to delineate the clinical profile, predictors of disease progression, and 30-day mortality from ARDS using th...

Introduction COVID-19 disease progresses through a number of distinct phases. The management of each phase is unique and specific. The pulmonary phase of COVID-19 is characterized by an organizing pneumonia with profound immune dysregulation, activation of clotting, and a severe microvascular injury culminating in severe hypoxemia. The core treatme...

Background In hospitalized patients with COVID-19 pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could...

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 f...

Abstract An updated meta-analysis incorporating nine randomized trials (n = 816) investigating low-to-moderate dose prolonged glucocorticoid treatment in acute respiratory distress syndrome (ARDS) show moderate-to-high quality evidence that glucocorticoid therapy is safe and reduces (i) time to endotracheal extubation, (ii) duration of hospitalizat...

Re-analysis of the randomized trial on Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome. CCM 2018 During active intervention methylprednisolone was safe and effective in achieving disease resolution. Our findings support rapid glucocorticoid discontinuation post-extubation as likely cause of d...

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

Rationale: 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. Methods: A genome-wide associa...

Objectives: In the Acute Respiratory Distress Syndrome Network randomized controlled trial, methylprednisolone treatment was associated with increased return to mechanical ventilation with partial loss of early improvements. We hypothesize a causal relationship between protocol-driven rapid discontinuation of methylprednisolone post extubation and...

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 Soc...

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). Participants: A multispecialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and t...

Background: We aimed to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patients' data of randomized placebo-controlled trials and to explore subgroup differences. Methods: We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Control...

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). Participants: A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the Eur...

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 Soc...

Background Authors of recent meta-analyses have reported that prolonged glucocorticoid treatment is associated with significant improvements in patients with severe pneumonia or acute respiratory distress syndrome (ARDS) of multifactorial etiology. A prospective randomized trial limited to patients with sepsis-associated ARDS is lacking. The object...

Background: 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. Methods: Blood leukocytes from 51 patients enrolled in a prior randomized trial of corticosteroids for ARDS were analyzed. After screening eight p...

Systemic inflammation and duration of immobilization are strong independent risk factors for the development of intensive care unit-acquired weakness (ICUAW). Activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) results in muscle wasting during disuse-induced skeletal muscle atrophy (ICU bed rest) and septic shock. In a...

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 improves survival and can be signif...

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...

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, cor...

Purpose: To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS). Methods: We conducted two sets of intention-to-treat analyses: (1) a primary analysis of individual patients' data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment...

Randomized Clinical Trial (RCT) evaluating the effects of low-dose prolonged hydrocortisone infusion on resolution of MODS in severe sepsis.

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. This study explores the relationship between baseline plasma levels of inflammatory cytokines interleukin 6 (IL-6), IL-10, and IL-6:IL-10 and subsequen...

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 cli...

Understanding ARDS-associated lung fibroproliferation requires viewing (1) ARDS as a disease of multifactorial etiology and not as a syndrome and (2) fibroproliferation as an integral part of the disease process and not as a separate temporal component. Although the term “syndrome” (aggregate of symptoms and signs) was applied in its original descr...

Community-acquired pneumonia (CAP) has a significant impact on public health in terms of short-term and long-term morbidity and mortality. Irrespective of microbiological etiology, the host's inability to fully downregulate systemic inflammation is the dominant pathogenetic process contributing to acute and long-term morbidity and mortality in CAP....

Abstract published in Critical Care Medicine Vol 40, No 12, 488 (Suppl.).

Purpose: To improve 2007 Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) severity criteria to predict intensive care unit (ICU) admission in patients hospitalized with pneumonia. Methods: A composite score that included the 2007 IDSA/ATS criteria for severe pneumonia and additional significant variables identified by r...

The Office of Research Integrity (ORI) or other regulatory organizations do not control how academic institutions implement their written policies related to the conduct of inquiry/investigation on scientific misconduct. Today, academic institutions can freely operate in ways that are contrary to their written guidelines without consequences. Witho...

Evaluate the effects of methylprednisolone on markers of inflammation, coagulation, and angiogenesis during early acute respiratory distress syndrome. Retrospective analysis. Four intensive care units. Seventy-nine of 91 patients with available samples enrolled in a randomized, blinded controlled trial. Early methylprednisolone infusion (n = 55) co...

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 signific...

PURPOSE: To investigate whether baseline protein expression levels of pro-inflammatory cytokines, anti-inflammatory cytokines, or their ratios influence the development of subsequent HAI (health care associated infections) in patients with sepsis. METHODS: Prospective observational study of 78 Veterans admitted to MICU with sepsis. Baseline plasma...

Experimental and clinical evidence show a strong association between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). This article reviews eight controlled studies evaluating corticosteroid treatment initiated before day 14 of ARDS. Available data provide a consistent strong level of evidence for imp...