Time‐Variant Increase in Methylprednisolone Clearance in Patients with Acute Respiratory Distress Syndrome: A Population Pharmacokinetic Study

Yates, Charles R.; Vysokanov, Alexander; Mukherjee, Arnab; Ludden, Thomas M.; Tolley, Elizabeth A.; Meduri, G. Umberto; Dalton, James T.

doi:10.1177/00912700122010276

Cited by 22 publications

(20 citation statements)

References 37 publications

(37 reference statements)

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“…While the above simulations are based on average pharmacokinetic parameters in healthy individuals, GC elimination may be impaired in ARDS patients due to the well-described downregulation of drug metabolizing enzymes in generalized acute inflammation [ 33 ]. Yates et al reported that ARDS patients had an on average ~ 50% reduced clearance for methylprednisolone compared to normal values at therapy onset, which returned to normal values with reduction of systemic inflammation within a few days [ 34 ]. Correspondingly, methylprednisolone plasma concentrations were elevated relative to healthy individuals in the early treatment phase (Fig.…”

Section: Pharmacological Principles Of Glucocorticoid Actionsmentioning

confidence: 99%

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Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

et al. 2020

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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.

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Section: Pharmacological Principles Of Glucocorticoid Actionsmentioning

confidence: 99%

“…It took about 2 days (41.1 h) of methylprednisolone therapy to achieve 50% of the improvement in clearance towards the re-establishment of homeostasis. [ 34 ]. b Methylprednisolone plasma concentration–time profile in ARDS patients receiving the aforementioned dosing regimen.…”

Section: Pharmacological Principles Of Glucocorticoid Actionsmentioning

confidence: 99%

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

et al. 2020

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“…[30–32] Animal studies have shown that in acute lung injury, prolonged corticosteroids were shown to be effective in reducing edema and collagen deposition in lung, while premature withdrawal rapidly negated these positive effects. [3334] This seems a plausible explanation for the negative results observed in these studies with short course of high-dose MP.…”

Section: Corticosteroids For Prevention Of Ardsmentioning

confidence: 99%

Corticosteroids and ARDS: A review of treatment and prevention evidence

Khilnani

Hadda

2011

Lung India

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To systematically review the role of corticosteroids in prevention of acute respiratory distress syndrome (ARDS) in high-risk patients, and in treatment of established ARDS. Primary articles were identified by English-language Pubmed/MEDLINE, Cochrane central register of controlled trials, and Cochrane systemic review database search (1960–June 2009) using the MeSH headings: ARDS, adult respiratory distress syndrome, ARDS, corticosteroids, and methylprednisolone (MP). The identified studies were reviewed and information regarding role of corticosteroids in prevention and treatment of ARDS was evaluated. Nine trials have evaluated the role of corticosteroid drugs in management of ARDS at various stages. Of the 9, 4 trials evaluated role of corticosteroids in prevention of ARDS, while other 5 trials were focused on treatment after variable periods of onset of ARDS. Trials with preventive corticosteroids, mostly using high doses of MP, showed negative results with patients in treatment arm, showing higher mortality and rate of ARDS development. While trials of corticosteroids in early ARDS showed variable results, somewhat, favoring use of these agents to reduce associated morbidities. In late stage of ARDS, these drugs have no benefits and are associated with adverse outcome. Use of corticosteroids in patients with early ARDS showed equivocal results in decreasing mortality; however, there is evidence that these drugs reduce organ dysfunction score, lung injury score, ventilator requirement, and intensive care unit stay. However, most of these trials are small, having a significant heterogeneity regarding study design, etiology of ARDS, and dosage of corticosteroids. Further research involving large-scale trials on relatively homogeneous cohort is necessary to establish the role of corticosteroids for this condition.

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“…P‐Glycoprotein as a determinant of intracellular cortisol accumulation. Our laboratory characterized methylprednisolone disposition in ARDS patients in an attempt to gain insight into the mechanism(s) of GC resistance 119. Interestingly, we found that the one individual who failed to respond to methylprednisolone therapy actually experienced deteriorating clearance over the course of therapy.…”

Section: Iii: Factors Affecting Cellular Response To Glucocorticoidsmentioning

confidence: 99%

Systemic Inflammation‐Associated Glucocorticoid Resistance and Outcome of ARDS

Meduri¹,

Yates

2004

Annals of the New York Academy of Sciences

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Dysregulated systemic inflammation with excess activation of pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB)-activated by inflammatory signals-compared to the anti-inflammatory transcription factor glucocorticoid receptor-alpha (GRalpha)-activated by endogenous or exogenous glucocorticoids (GCs)-is an important pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS). Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time. Recent data indicate that failure to improve in ARDS (unresolving ARDS) is frequently associated with failure of the activated GRs to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance; it is potentially reversible with prolonged GC supplementation. In the first part of this paper, after a brief description of inflammation in ARDS and our model of translational research, we review the two cellular signaling pathways that are central to the regulation of inflammation-the stimulatory NF-alphaB and the inhibitory GRalpha. In the second part, we review findings of recent studies indicating that excessive inflammatory activity in patients with unresolving ARDS may induce noncompensated GC resistance in target organs. In the third part, we review factors affecting cellular response to GC and potential mechanisms involved in inflammation-associated GC resistance.

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Time‐Variant Increase in Methylprednisolone Clearance in Patients with Acute Respiratory Distress Syndrome: A Population Pharmacokinetic Study

Cited by 22 publications

References 37 publications

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

Corticosteroids and ARDS: A review of treatment and prevention evidence

Systemic Inflammation‐Associated Glucocorticoid Resistance and Outcome of ARDS

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