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Intensive Care Medicine Aug 2022Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We... (Randomized Controlled Trial)
Randomized Controlled Trial
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 clinical outcomes.
METHODS
This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up.
RESULTS
Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications.
CONCLUSIONS
In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications.
Topics: Adult; Community-Acquired Infections; Critical Illness; Humans; Methylprednisolone; Pneumonia; Respiration, Artificial; Treatment Outcome
PubMed: 35723686
DOI: 10.1007/s00134-022-06684-3 -
JAMA May 2022The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain.
OBJECTIVE
To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline.
DESIGN, SETTING, AND PARTICIPANTS
An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021.
INTERVENTIONS
Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group).
MAIN OUTCOMES AND MEASURES
The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure.
RESULTS
Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]).
CONCLUSIONS AND RELEVANCE
Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01560052.
Topics: Administration, Oral; Adult; Disease Progression; Double-Blind Method; Female; Glomerulonephritis, IGA; Humans; Kidney; Male; Methylprednisolone; Proteinuria; Renal Dialysis; Renal Insufficiency
PubMed: 35579642
DOI: 10.1001/jama.2022.5368 -
Intensive Care Medicine Dec 2020Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Glucocorticoids; Humans; Hypothalamo-Hypophyseal System; Methylprednisolone; Pituitary-Adrenal System; Respiratory Distress Syndrome
PubMed: 33150472
DOI: 10.1007/s00134-020-06289-8 -
Respiratory Research Nov 2022Acute respiratory distress syndrome (ARDS) is an acute and critical disease among children and adults, and previous studies have shown that the administration of... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Acute respiratory distress syndrome (ARDS) is an acute and critical disease among children and adults, and previous studies have shown that the administration of corticosteroids remains controversial. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to evaluate the safety and efficacy of corticosteroids.
METHODS
The RCTs investigating the safety and efficacy of corticosteroids in ARDS were searched from electronic databases (Embase, Medline, and the Cochrane Central Register of Controlled Trials). The primary outcome was 28-day mortality. Heterogeneity was assessed using the Chi square test and I with the inspection level of 0.1 and 50%, respectively.
RESULTS
Fourteen RCTs (n = 1607) were included for analysis. Corticosteroids were found to reduce the risk of death in patients with ARDS (relative risk (RR) = 0.78, 95% confidence interval (CI): 0.70-0.87; P < 0.01). Moreover, no significant adverse events were observed, compared to placebo or standard support therapy. Further subgroup analysis showed that variables, such as adults (RR = 0.78; 95% CI: 0.70-0.88; P < 0.01), non-COVID-19 (RR = 0.71; 95% CI: 0.62-0.83; P < 0.01), methylprednisolone (RR = 0.70; 95% CI: 0.56-0.88; P < 0.01), and hydrocortisone (RR = 0.79; 95% CI: 0.63-0.98; P = 0.03) were associated with 28-day mortality among patients who used corticosteroids. However, no association was found, regarding children (RR = 0.21; 95% CI: 0.01-4.10; P = 0.30).
CONCLUSION
The use of corticosteroids is an effective approach to reduce the risk of death in ARDS patients. However, this effect is associated with age, non-COVID-19 diseases, and methylprednisolone and hydrocortisone use. Therefore, evidence suggests patients with age ≥ 18 years and non-COVID-19 should be encouraged during the corticosteroid treatment. However, due to substantial differences in the use of corticosteroids among these studies, questions still remain regarding the dosage, optimal corticosteroid agent, and treatment duration in patients with ARDS.
Topics: Child; Adult; Humans; Adolescent; Hydrocortisone; Respiratory Distress Syndrome; Adrenal Cortex Hormones; Methylprednisolone; Randomized Controlled Trials as Topic
PubMed: 36333729
DOI: 10.1186/s12931-022-02186-4 -
JAMA Oct 2021Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.
OBJECTIVE
To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation.
DESIGN, SETTING, AND PARTICIPANTS
Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.
INTERVENTION
Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses.
MAIN OUTCOMES AND MEASURES
The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2).
RESULTS
Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.
CONCLUSIONS AND RELEVANCE
Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03640949.
Topics: Aged; Cardiovascular Agents; Confidence Intervals; Denmark; Double-Blind Method; Epinephrine; Female; Glucocorticoids; Heart Arrest; Humans; Hyperglycemia; Hyponatremia; Male; Methylprednisolone; Neurologic Examination; Placebos; Return of Spontaneous Circulation; Treatment Outcome; Uncertainty; Vasoconstrictor Agents; Vasopressins
PubMed: 34587236
DOI: 10.1001/jama.2021.16628 -
The New England Journal of Medicine Dec 2022Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown.
METHODS
We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes.
RESULTS
A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001).
CONCLUSIONS
Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.).
Topics: Humans; Methylprednisolone; Prospective Studies; Cardiac Surgical Procedures; Insulin
PubMed: 36342116
DOI: 10.1056/NEJMoa2212667 -
Frontiers in Cellular and Infection... 2023Many children with (MP) pneumonia (MPP) developed sequelae such as bronchiolitis/bronchitis obliterans (BO). Early corticosteroid therapy might prevent disease...
BACKGROUND
Many children with (MP) pneumonia (MPP) developed sequelae such as bronchiolitis/bronchitis obliterans (BO). Early corticosteroid therapy might prevent disease progression. This study aimed to use "early" corticosteroid and observe the treatment outcome in patients with MPP.
METHODS
Patients who had pulmonary infiltrations on chest imaging within 5 days of the disease course and were suspected of having MP infection on admission were enrolled. Among them, patients whose disease course was within 10 days on admission were ultimately enrolled. We analyzed their data including the clinical features, the starting time and dose of corticosteroid therapy, and the treatment outcome. According to chest imaging, we divided patients into two groups (Group A: bronchiolitis-associated lesions or ground-glass opacities; Group B: pulmonary segmental/lobar consolidation).
RESULTS
A total of 210 patients with confirmed MPP were ultimately enrolled. There were 59 patients in Group A and 151 patients in Group B. Patients in Group A were more prone to have allergy histories, hypoxemia, wheezing sound, and wet rales on auscultation than those in Group B. Corticosteroid treatment was initiated between 5 and 10 days of disease onset in all patients and 6-7 days in most patients. Methylprednisolone was prescribed in all patients within 10 days of disease onset, and the highest prescribed dose was at least 2 mg/kg/day. In Group A, methylprednisolone >2 mg/kg/day was prescribed in 22 patients, and among them, 8 patients with diffuse bronchiolitis-associated lesions received high-dose methylprednisolone therapy. After 3 months, lung CT revealed slightly segmental ground-glass opacity in three patients. In Group B, methylprednisolone >2 mg/kg/day was prescribed in 76 patients, and among them, 20 patients with pulmonary lobar consolidation received high-dose methylprednisolone therapy. After 3 months, chest imaging revealed incomplete absorption of pulmonary lesions in seven patients. Among them, five patients with consolidation in more than one pulmonary lobe ultimately had slight BO.
CONCLUSION
In hospitalized patients with MPP, particularly severe MPP, the ideal starting time of corticosteroid treatment might be 5-10 days, preferably 6-7 days, after disease onset. The initial dosage of corticosteroid therapy should be decided according to the severity of the disease. MPP patients with diffuse bronchiolitis-associated lesions/whole lobar consolidation on imaging might require high-dose corticosteroid therapy.
Topics: Child; Humans; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Adrenal Cortex Hormones; Methylprednisolone; Treatment Outcome
PubMed: 37082710
DOI: 10.3389/fcimb.2023.1135228 -
The European Respiratory Journal Apr 2023Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking.
METHODS
We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction ( / ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14.
RESULTS
677 randomised patients were included. Findings are reported as methylprednisolone (n=337) dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in / ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points.
CONCLUSION
Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia.
Topics: Adult; Humans; COVID-19; Methylprednisolone; SARS-CoV-2; COVID-19 Drug Treatment; Dexamethasone; Oxygen; Treatment Outcome
PubMed: 36356972
DOI: 10.1183/13993003.01514-2022 -
BMJ Case Reports Mar 2020Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive titres. He deteriorated...
Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive titres. He deteriorated despite appropriate antibiotics and developed confusion and disorientation. Lumbar puncture revealed lymphocytosis with high protein and low glucose. MRI showed diffuse demyelination. Pulse steroids resulted in rapid clinical, biochemical and radiological recovery.
Topics: Adult; Anti-Bacterial Agents; Brain Diseases; Brucellosis; Demyelinating Diseases; Diagnosis, Differential; Drug Therapy, Combination; Glucocorticoids; Humans; Male; Methylprednisolone; Prednisolone
PubMed: 32152068
DOI: 10.1136/bcr-2019-233798 -
Medicine Jul 2022A combination of methylprednisolone sodium succinate (MSS) and granisetron hydrochloride (GH) is generally devoted to treating the chemotherapy-induced nausea and...
A combination of methylprednisolone sodium succinate (MSS) and granisetron hydrochloride (GH) is generally devoted to treating the chemotherapy-induced nausea and vomiting. To date, none of these novel mixtures have been commercially available. The present study was aimed at investigating physical and chemical compatibility and stability of a combination of MSS with GH in 0.9% sodium chloride injection for 72 hours at 4°C and 25°C. A mixture of MSS (0.4-0.8 mg/mL) with GH (0.03 mg/mL) was prepared and stored in both polyvinyl chloride bags and glass bottles using 0.9% sodium chloride injection as a diluent. The study was performed using a validated and stability-indicating high-performance liquid chromatography method. The physical compatibility was assessed by a spectrometer. Furthermore, the pH measurement of each sample was measured electronically. All test solutions stored at 4°C or 25°C had a no >2% loss of the initial concentration throughout the 72-hour study period. All solutions remained clear and colorless throughout the study and were without precipitation or turbidity in any of the batches. The drug mixtures of MSS (0.4-0.8 mg/mL) and GH (0.03 mg/mL) in 0.9% sodium chloride injections were physically and chemically stable for at least 72 hours when stored at 4°C or 25°C in polyvinyl chloride bags or glass bottles.
Topics: Chromatography, High Pressure Liquid; Drug Stability; Granisetron; Humans; Methylprednisolone Hemisuccinate; Polyvinyl Chloride; Sodium Chloride
PubMed: 35839031
DOI: 10.1097/MD.0000000000029674