Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

Abstract

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.

Keywords: Acute respiratory distress syndrome; Duration; Glucocorticoid; Glucocorticoid receptor; Pharmacodynamic; Randomized trial; Receptor affinity.

Fig. 1

Relations on natural logarithmic scales between mean levels of nuclear NF-κB and nuclear GC-GRα during the natural progression of ARDS, and in response to prolonged methylprednisolone treatment. Mean intracellular changes of nuclear GC-activated GRα and NF-κB were observed by exposing peripheral blood mononuclear cells of a healthy volunteer to ARDS patient plasma samples collected longitudinally (days 1, 3, 5, and 8) and after randomization to methylprednisolone treatment (randomization day (R) and post-randomization days 3, 5, 7, and 10). The mean values of nuclear NF-κB are plotted against the mean nuclear GC-GRα levels. Improvers had a pre-defined improvement in lung injury score [45] and/or gas exchange component by day 7. The left panel shows ARDS patients with adaptive and maladaptive responses. In improvers, an inverse relationship was observed between these two transcription factors, with the longitudinal direction of the interaction shifting leftwards (decreased NF-κB) and upward (increased GC-GRα). Conversely, in non-improvers, NF-κB increased over time, while GC-GRα showed no significant changes. We defined the first interaction as GC-GRα-driven, and the second interaction as NF-κB-driven [80]. The right panel shows non-improvers-survivors randomized after day 8 of ARDS to methylprednisolone (n = 11) vs. placebo (n = 6). After natural logarithmic transformation and adjustment for repeated measurements, partial correlations among responses to plasma from the methylprednisolone group were − 0.92 (p < 0.0001) both for nuclear NF-κB and nuclear GRα. For responses to plasma from the placebo group, no significant relationship was found between nuclear NF-κB and nuclear GRα (r = 0.11; p = 0.70) [7]. Prolonged methylprednisolone treatment was associated with upregulation in all measurements of GC-GRα-activity leading to reduction in NF-κB DNA-binding and transcription of inflammatory cytokines. Glucocorticoid treatment changed the longitudinal direction of systemic inflammation from dysregulated (NF-κB-driven, maladaptive response) to regulated (GRα-driven, adaptive response) with significant improvement in indices of alveolar-capillary membrane permeability and markers of inflammation, hemostasis, and tissue repair. Reproduced with permission from reference [5]

Fig. 2

Glucocorticoid receptor α as a cellular rheostat of homeostatic corrections. The glucocorticoid receptor α (GRα) acts as a cellular rheostat to ensure that a proper response is elicited by the neuroendocrine and immune systems throughout the three phases of homeostatic corrections. The serial sequence of regulatory functions includes the: (1) activation and reinforcement of innate immunity (ready-reinforce), (2) downregulation of pro-inflammatory transcription factors (repress), and (3) promotion of disease resolution (resolve- restore).by switching production from pro-inflammatory to pro-resolving mediators, while at the same stimulating antifibrotic and antioxidant molecules that limit tissue damage and fibrosis, to help achieve optimal restoration of anatomy and function of the affected tissues, and (4) parallel support of adaptive immunity. Modified with permission from reference.[4]. TLR2 toll-like receptor 2, purinergic receptor P2Y2R; NLRP3 NOD-like receptor pyrin containing 3, APR acute phase response, TF transcription factor, NF-κB nuclear factor-κB, AP-1 activator protein-1, AnxA1 annexinA1, AnxA1 receptor, ALXR A4 lipoxin receptor, GILZ glucocorticoid-induced leucine zipper, TGFβ transforming growth factor β

Fig. 3

Concentration–time profiles for different dosing regimens that have been used in the treatment of early ARDS. Glucocorticoid average plasma concentrations were simulated on the basis of published pharmacokinetic parameters for hydrocortisone (HC), methylprednisolone (MP) and dexamethasone (DX) and converted to MP equivalent concentrations using their reported relative receptor affinity (RRA) and fraction unbound to plasma proteins (f_u) [8, 9]. Pharmacokinetic parameters used for the simulations were as previously described: Clearance 18, 21, and 17 L/h; volume of distribution 33, 64, and 103 L for HC, MP and DX, respectively. The conversion to MP equivalent concentrations for HC and DX was performed according to the relationship: MP equivalent plasma concentration = HC or DX concentration × (f_{u,HC or DX}/f_u,MP) × (RRA_{HC or DX}/RRA_MP). The applied value for RRA and f_u were 9, 42, 100 and 0.20, 0.23, 0.32 for HC, MP and DX, respectively, as previously reported [8, 9]. f_u determines the fraction of the drug concentration that is not bound to plasma proteins and is thus available to enter cells and interact with GC receptors, i.e., the fraction of the concentration that is pharmacologically active

Fig. 4

Methylprednisolone pharmacokinetics in ARDS patients. a Time-dependent increase in methylprednisolone clearance [CLt (L/Hr)] in patients treated with a 1 mg/kg loading dose, followed by a 1 mg/kg/day continuous infusion. The high systemic inflammatory state may be responsible for the impaired methylprednisolone metabolism observed in early ARDS at the beginning of therapy. High levels of pro-inflammatory cytokines are known to inhibit the expression and activity of hepatic drug metabolizing enzymes, including multiple cytochrome P450 isozymes relevant for the metabolism of methylprednisolone. Inflammation resolves progressively during continuous therapy, leading to re-establishment of homeostatic conditions of drug metabolizing enzyme systems. This is reflected by a time-dependent increase in methylprednisolone clearance. 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. Methylprednisolone clearance is impaired during time period 1 and its concentrations are high enough to trigger genomic and non-genomic GC effects. This most likely establishes initial control of the generalized inflammatory state [33]. Inflammatory control is at least partially established during period 2 within 2 days of therapy, leading to an increased hepatic methylprednisolone clearance, secondary to re-established drug metabolizing activity. The concentrations are maintained around 203 ± 147 ng/mL during period 3, exerting prolonged sustained anti-inflammatory activity. Reproduced with permission from Yates et al. [34]. Importantly, ARDS patients receiving similar GC doses experience a substantial variability in the resulting plasma concentrations due to between-patient variability; this may affect nati-inflammatory response to treatment

Fig. 5

Protocol for prolonged methylprednisolone treatment in patients with early ARDS. This protocol was recommended in the 2017 guidelines of the Multispecialty Task Force of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (Supplemental Digital Content 5, https://links.lww.com/CCM/C918) [35] Vitamin supplementation was not part of the recommended protocol. The dosage is adjusted to ideal body weight and rounded up to the nearest 10 mg (e.g., 77 mg rounded up to 80 mg). Thereafter I would state that 80 mg is an example for a patient with an ideal body weight of 77. Day 0, intravenous bolus (80 mg in 50 cc normal saline) over 30 min. Day 0-to ICU discharge: infusion is done by adding the daily dosage to 240 cc of normal saline and running it at 10 cc/h. If necessary, infusion can be changed to bolus every 6 h (1/4 daily dose) or in the last 6 days to every 12 h (1/2 daily dose). If on day 3–5 there is no improvement or even worsening oxygenation indices the condition is considered “unresolving ARDS”. In this case, a protocol of similar duration of treatment, but with double the daily dose of methylprednisolone (starting with 160 mg/day) is initiated. If the patient is extubated before day 14, the methylprednisolone infusion is advanced to day 15 of drug therapy and tapered according to schedule. Oral administration should be delayed to 5 days after extubation, because enteral absorption of methylprednisolone, and likely other GCs, is compromised for days after extubation. Rapid tapering can be associated with rebound systemic inflammation in the presence of suppressed adrenal function with worsening of lung physiology and an increased mortality risk [60]. If patients worsen significantly, then GC treatment should be restarted again, and after improvement followed by slow tapering, to comply with the Food and Drug Administration’s package insert warnings (Reference ID: 3,032,293) [61]. Vitamin supplementation: ascorbic acid 1.5 g every 6 h mixed in 100 ml saline solution × 4 doses per day; thiamine 100 mg every 12 h mixed in 100 ml dextrose 5% in water × 2 doses per day; vitamin D 480,000 IU dose (30 ml) × 1 dose. Recheck vitamin D level on day 5; if low, supplement 96,000 IU/day for 5 days