High-dose Dexamethasone Group Research Articles

Does dexamethasone therapy affect intimal hyperplasia after injury in rat abdominal aorta models?

Intimal hyperplasia is a normal adaptive feature of arteries in response to injuries, which include invasive vascular interventions. Its development limits the long-term success of bypass grafts. Various pharmacological agents have been successfully employed in experimental models to reduce the degree of intimal hyperplasia. In our study, we investigated the efficacy of dexamethasone in reducing intimal hyperplasia in rat abdominal aortas after partial transection and primary repair. In this study, 20 Wistar Albino rats were randomly selected and divided into four groups to compare the effects of low- and high-dose dexamethasone on intima and media thickness compared to the control. Group A (n=5) was the control group, where only skin incision and laparotomy were performed. For Group B (n=5), a median laparotomy was performed, the abdominal aorta was partially transected, and repaired with an 8.0 prolene suture. Doses of 0.1 mg/kg and 0.2 mg/kg dexamethasone were administered in Group C (n=5) and Group D (n=5), respectively. After two weeks, all rats were euthanized, and the repaired abdominal aortas were excised and examined histopathologically. Intima and media thicknesses were measured using the 'Olympus AnalySIS 5' program (Olympus Corporation, Japan) after digital photos were taken. Based on the measurements, we demonstrated that after transection and repair of the abdominal aorta, the intima/media ratio was not significantly different between the low-dose dexamethasone and non-dexamethasone groups. The intima/media ratio was significantly lower in the high-dose dexamethasone group than in the non-dexamethasone and low-dose dexamethasone groups. After vascular interventions, dexamethasone treatment may reduce intimal hyperplasia and increase patency by providing vascular remodeling.

Hematologic Response to Steroid Use in Patients with Primary Immune Thrombocytopenia: A Research Study in a Salvadoran Population

Introduction. Thrombocytopenia Immune (ITP) is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults. The use of high-doses dexamethasone has proven efficacy and safety in previously untreated patients with immune thrombocytopenia even though these findings are not entirely clear yet. AIM. The primary goal to assess the global response (platelets >30 x 109/L) and complete response (platelets >100 x 109/L) within the different implemented regimes in previously untreated adult with primary immune thrombocytopenia. Further goals aimed to describe the clinical characteristic of patients with primary immune thrombocytopenia and the most frequent adverse events in the use of steroids. Results. A total of 44 patients were treated with steroids, 16 patients in the high-dose dexamethasone (HD-DXM) group, 23 patients received methylprednisolone (MTP) and 5 patients with prednisone (PDN). The female gender was the most affected in all the groups with 61.3% (n=27) presenting more cases than the female sex in the methylprednisolone group 65.2% (n=15), although without significant statistical difference (P = 0.384). The mean age of onset was 38, 44, and 40 years, respectively (P = 0.352). The most frequent clinical manifestations were purpura sicca (petechiae and bruising) with 75%, 91.3% and 60.0%, for the dexamethasone, methylprednisolone and prednisone groups, respectively. The mean platelet count in the groups was around the mean of 26 x 109/L, with the methylprednisolone group presenting the lowest values (3 x 109/L). The overall response was different for the three groups (87.5% vs 95.6% vs 100%, P = 0.43) with a complete response of 56.2% vs 60.8% vs 80.0% (P = 0.85). Early response was achieved in the methylprednisolone group with 3.5 days, versus dexamethasone with 4.0 days and prednisone with 7 days. The sustained response at 6 months was lower in the prednisone group 80.0%. The most frequent adverse events occurred in the HD-DXM group with fatigue in 31.2% (n = 5) followed by edema, hyperglycemia and insomnia with 18.7% (n = 3). Conclusions. Our study demonstrated that PDN provides greater overall responses as initial treatment in ITP. MTP provides the fastest responses followed by HD-DXM. The sustained response was maintained in the HD-DXM Group. The HD-DXM group presented 68.7% cases with at least one adverse event associated with the use of the steroid. The findings suggest continuing to perform more studies in our population.

Baricitinib in Combination with High-Dose Dexamethasone As First-Line Treatment for Newly Diagnosed Immune Thrombocytopenia: A Prospective, Multicenter, Randomized Trial

Introduction: High-dose dexamethasone is among the standard initial therapeutic options for patients with newly diagnosed immune thrombocytopenia (ITP). Although most patients achieve initial remission, optimal first-line therapy remains a challenge due to the low rates of sustained response and the high incidence of corticosteroid-dependency. Antiplatelet autoantibodies and splenic macrophages play central roles in the pathogenesis of ITP. Baricitinib, a Janus-associated kinase 1/2 (JAK1/2) inhibitor, can inhibit antigen presentation by innate immune cells and subsequent T-cell activation while also alleviating B-cell abnormalities and antibody production. The results of our single-arm pilot study suggested that baricitinib might increase the rate of durable response in patients with steroid-resistant or relapsed ITP (NCT05446831, presented at EHA2023, P1594). Accordingly, we further conducted a randomized, controlled trial to evaluate the efficacy and safety of baricitinib plus high-dose dexamethasone as first-line therapy for adulthood ITP. Methods: This multicenter, open-label, randomized, controlled, phase 2 trial was conducted in 10 different tertiary medical centers in China. Adult patients with newly diagnosed, treatment-naïve, confirmed primary ITP who had a platelet count <30×10⁹/L, or a platelet count <50×10⁹/L with clinically significant bleeding, were eligible for this study. Patients were randomly assigned at a 1:1 ratio to receive baricitinib (2 mg daily for 6 consecutive months) plus high-dose dexamethasone (40 mg daily for 4 consecutive days, repeated in the case of lack of response by Day 10) or high-dose dexamethasone alone. The primary endpoint was durable response at the 6-month follow-up. Efficacy endpoints were analyzed in the intention-to-treat population. Safety profiles were analyzed in all patients receiving at least one dose of study medications. The study protocol was approved by the ethics committee or institutional review board of each participating center and was registered with ClinicalTrials.gov (NCT 05932524). Results: A total of 172 patients were screened, of which 132 patients were eligible for this study. Patients were randomly assigned to receive baricitinib plus high-dose dexamethasone (n=66) or high-dose dexamethasone monotherapy (n=66). Four patients did not receive allocated treatment, leaving 128 patients in the safety analysis set. At the 6-month follow-up, a significantly higher proportion of participants in the baricitinib plus high-dose dexamethasone group (42/66, 63.6%) than in the high-dose dexamethasone monotherapy group (25/66, 37.9%) achieved durable response (OR 2.870, 95% CI 1.416-5.816; p=0.003). Initial response was achieved by 52 (78.8%) patients in the combination group and 47 (71.2%) patients in the monotherapy group. No significant difference was observed in the median time from initial treatment to response between the two groups. Complete response (at any time during the treatment) was achieved by 40 (60.6%) patients in the combination group and 35 (53.0%) patients in the monotherapy group. Patients responding to treatment in the combination group showed significantly longer durations of response than responders in the monotherapy group. Patients in both groups reported significantly improved health-related quality of life. The most common adverse events were infections (15/64, 23.4%) and insomnia (12/64, 18.8%) in the combination group, and insomnia (10/64, 15.6%) and anxiety or mood disorders (9/64, 14.1%) in the monotherapy group. No grade 4 or worse adverse events or treatment-related deaths were reported in either group. No thrombotic events, major adverse cardiovascular events (MACE), treatment-related bleeding or anemia were observed. Treatment discontinuation due to an adverse event was reported in 2 (3.1%) patients in the combination group and 3 (4.7%) patients in the monotherapy group. Conclusions: This is the first study reporting JAK inhibition as a first-line therapy for ITP. Baricitinib at 2 mg daily plus high-dose dexamethasone was well tolerated in patients with newly diagnosed ITP and might contribute to achieving a higher rate of durable response.

Comparison of Efficacy and Safety of Low-Dose Versus High-Dose Dexamethasone in Hospitalized COVID-19 Patients: A Meta-Analysis.

The aim of this study is to compare the efficacy and safety of low-dose and high-dose dexamethasone in hospitalized coronavirus disease 2019 (COVID-19) patients. The current meta-analysis was conducted in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was carried out using PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase. Outcomes assessed in the current meta-analysis included 28-day mortality, intensive care unit (ICU) admission, mechanical ventilation, length of ICU admission (days), and length of hospital stay (days). For safety, we compared hypoglycemia and the incidence of infection between the high-dose dexamethasone group and the low-dose dexamethasone group. A total of four studies fulfilled the inclusion criteria and were included in this meta-analysis.No significant difference was found between the two groups in terms of ICU admission (risk ratio (RR): 0.72, 95% confidence interval (CI): 0.41-1.28, p-value: 0.27),length of stay in ICU in days (mean difference (MD): -0.05, 95%CI: -3.96-3.87, p-value: 0.98, I-square: 94%),length of hospital stay in days (MD: -0.94, 95%CI: -1.94-0.06, p-value: 0.07), need of mechanical ventilation (RR: 0.72, 95%CI: 0.36-1.48, p-value: 0.38), and 28-day mortality (RR: 0.90, 95% CI: 0.50-1.64, p-value: 0.74). The current study showed that higher doses of dexamethasone failed to enhance efficacy compared to low-dose dexamethasone. Thus, based on the findings of this meta-analysis, low-dose dexamethasone can be recommended for these patients.

Long-term exposure to high-concentration dexamethasone in the inner ear via intratympanic administration

The first-line treatment for inner ear disorders is usually oral/systemic steroids. Intratympanic steroid therapy is an alternative option; however, it requires multiple office visits owing to the short residence time of steroids in the inner ear (systemic: 24 h, intratympanic: 2–3 h). Therefore, intratympanic injections of higher steroid concentrations could result in longer drug exposure, providing better treatment outcomes. This study aimed to develop a prototype for high-concentration steroids and examine their safety and feasibility in vivo. Using wild-type Institute for Cancer Research mice, high-concentration steroids (50 mg/mL dexamethasone), typical steroid concentrations (3.3 mg/mL dexamethasone), and sterile saline were administrated into the middle ear cavity via tympanic membrane injection. Auditory brainstem response analysis, vestibular function tests, and morphological analyses were performed to examine the safety and utility of High-conc Dex. One month post-injection, the frequency-averaged auditory brainstem response thresholds of high-dose dexamethasone-treated mice were not significantly different from those of low-dose dexamethasone- and saline-treated mice at all tested frequencies. Furthermore, the total points on vestibular function tests were similar between the three groups. Morphologically, no damage to the inner ear/middle ear mucosa was observed in all groups. Two months post-injection, dexamethasone could still be detected in the high-dose dexamethasone group. Altogether, our data successfully demonstrates the feasibility and safety of high-dose dexamethasone for in vivo use in the middle ear and ensure that the drug localizes to the inner ear. Further research is warranted to develop this new treatment strategy and further characterize its effects in vivo.

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure

The benefit of high-dose dexamethasone and oxygenation strategies vs standard of care for patients with severe acute hypoxemic respiratory failure (AHRF) caused by COVID-19 pneumonia is debated. To assess the benefit of high-dose dexamethasone compared with standard of care dexamethasone, and to assess the benefit of high-flow nasal oxygen (HFNo2) or continuous positive airway pressure (CPAP) compared with oxygen support standard of care (o2SC). This multicenter, placebo-controlled randomized clinical trial was conducted in 19 intensive care units (ICUs) in France from April 2020 to January 2021. Eligible patients were consecutive ICU-admitted adults with COVID-19 AHRF. Randomization used a 2 × 3 factorial design for dexamethasone and oxygenation strategies; patients not eligible for at least 1 oxygenation strategy and/or already receiving invasive mechanical ventilation (IMV) were only randomized for dexamethasone. All patients were followed-up for 60 days. Data were analyzed from May 26 to July 31, 2021. Patients received standard dexamethasone (dexamethasone-phosphate 6 mg/d for 10 days [or placebo prior to RECOVERY trial results communication]) or high-dose dexamethasone (dexamethasone-phosphate 20 mg/d on days 1-5 then 10 mg/d on days 6-10). Those not requiring IMV were additionally randomized to o2SC, CPAP, or HFNo2. The main outcomes were time to all-cause mortality, assessed at day 60, for the dexamethasone interventions, and time to IMV requirement, assessed at day 28, for the oxygenation interventions. Differences between intervention groups were calculated using proportional Cox models and expressed as hazard ratios (HRs). Among 841 screened patients, 546 patients (median [IQR] age, 67.4 [59.3-73.1] years; 414 [75.8%] men) were randomized between standard dexamethasone (276 patients, including 37 patients who received placebo) or high-dose dexamethasone (270 patients). Of these, 333 patients were randomized among o2SC (109 patients, including 56 receiving standard dexamethasone), CPAP (109 patients, including 57 receiving standard dexamethasone), and HFNo2 (115 patients, including 56 receiving standard dexamethasone). There was no difference in 60-day mortality between standard and high-dose dexamethasone groups (HR, 0.96 [95% CI, 0.69-1.33]; P = .79). There was no significant difference for the cumulative incidence of IMV criteria at day 28 among o2 support groups (o2SC vs CPAP: HR, 1.08 [95% CI, 0.71-1.63]; o2SC vs HFNo2: HR, 1.04 [95% CI, 0.69-1.55]) or 60-day mortality (o2SC vs CPAP: HR, 0.97 [95% CI, 0.58-1.61; o2SC vs HFNo2: HR, 0.89 [95% CI, 0.53-1.47]). Interactions between interventions were not significant. In this randomized clinical trial among ICU patients with COVID-19-related AHRF, high-dose dexamethasone did not significantly improve 60-day survival. The oxygenation strategies in patients who were not initially receiving IMV did not significantly modify 28-day risk of IMV requirement. ClinicalTrials.gov Identifier: NCT04344730; EudraCT: 2020-001457-43.

Tacrolimus Plus High-Dose Dexamethasone Versus High-Dose Dexamethasone Alone As First-Line Treatment for Adult Immune Thrombocytopenia: The Phase 2, Open Label, Randomized Trial (TARGET 020)

▪IntroductionImmune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission.MethodsThis open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts <30×10 9/L, or < 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained >50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080).ResultsTotal 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups.ConclusionsLow-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:It includes information or discussion of off-label drug use of tacrilimus.

All-trans retinoic acid plus high-dose dexamethasone as first-line treatment for patients with newly diagnosed immune thrombocytopenia: a multicentre, open-label, randomised, controlled, phase 2 trial

High-dose dexamethasone is the standard initial treatment for patients with immune thrombocytopenia, but many patients still relapse and require further treatments. All-trans retinoic acid has been shown to exert immunomodulatory effects and promote thrombopoiesis, and so we aimed to assess the activity and safety of all-trans retinoic acid plus high-dose dexamethasone as a first-line treatment for newly diagnosed patients with immune thrombocytopenia. This multicentre, open-label, randomised, controlled, phase 2 trial was done at six different tertiary medical centres in China. Eligible participants were adults (aged >18 years) with treatment-naive, newly diagnosed, primary immune thrombocytopenia who had either a platelet count of less than 30 × 109 platelets per L or a platelet count of less than 50 × 109 platelets per L and clinically significant bleeding. We randomly assigned (1:1) participants to receive either all-trans retinoic acid (10 mg orally twice daily for 12 weeks) plus high-dose dexamethasone (40 mg/day intravenously for 4 consecutive days) or high-dose dexamethasone alone using a central, web-based randomisation system. If patients did not respond by day 14, the 4-day course of dexamethasone was repeated. The primary endpoint was 6-month sustained response, defined as the maintenance of a platelet count of at least 30 × 109 platelets per L and at least 2-times higher than the baseline count and the absence of bleeding, with no need for rescue medication at this time. The primary endpoint was analysed by intention-to-treat and safety was assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT04217148, and is now completed. Between Jan 1, 2020, and June 30, 2020, 132 patients were randomly assigned to either all-trans retinoic acid plus high-dose dexamethasone (n=66) or high-dose dexamethasone alone (n=66). Three patients did not receive their allocated treatment, leaving 129 in the safety analysis set. At 6 months, a significantly higher proportion of participants in the all-trans retinoic acid plus high-dose dexamethasone group (45 [68%] of 66) than in the high-dose dexamethasone monotherapy group (27 [41%] of 66) had a sustained response (OR 3·095, 95% CI 1·516-6·318; p=0·0017). The most common adverse events were dry skin (31 [48%] of 64 patients), headaches (12 [19%]), and insomnia (12 [19%]) in the combination group, and insomnia (ten [15%] of 65 patients) and anxiety or mood disorders (eight [12%]) in the monotherapy group. Both treatments were well tolerated and no grade 4 or worse adverse events occurred. There were no treatment-related deaths. The combination of all-trans retinoic acid and high-dose dexamethasone was safe and active in newly diagnosed patients with primary immune thrombocytopenia, providing a sustained response. This regimen represents a potential first-line treatment in this setting, but further studies are needed to validate its efficacy and safety. The Beijing Municipal Science and Technology Commission, the National Natural Science Foundation of China, the Beijing Natural Science Foundation, the National Key Research and Development Program of China, and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China.

Therapy of Adults Affected By Idiopathic Thrombocytopenic Purpura with 3 Cycles Pulses of High-Dose Dexamethasone (HD-DXM): A Prospective Randomized Clinical Trial

Introduction : Idiopathic thrombocytopenic purpura(ITP) is an autoimmune disorder characterized by platelet destruction leading to decreased platelet count and an increased risk of bleeding. The first line treatment of ITP is still corticosteroid therapy. Prednisone (PDN) is the standard corticosteroid therapy in ITP practical guideline. Recent studies suggested pulsed high-dose dexamethasone (HD-DXM) given at a dose 40 mg/day to a 4-day course treatment as an alternative corticosteroid to reduce the duration and the adverse effect of corticosteroid therapy. In this randomized controlled clinical trial our aim was to compare the efficacy and the relapse free survival time of 3 therapy cycles of HD-DXM versus conventional treatment with PDN for untreated adult patients with ITP.Method : This was a monocenter, randomized, controlled , clinical trial approved by ethics committee on medical research in Isfahan University of Medical Sciences(IUMS) and also registered in clinical trial.gov(NCT02914054). The eligible patients for this study were aged 18 or older of both genders with newly diagnosed primary ITP according to the international working group (IWG) guideline .Eligible patients were randomly assigned to either enroll conventional Prednisone therapy or pulses of high dose Dexamethasone (HD-DXM) treatment. In HD-DXM arm, DXM was administered intravenously at 40 mg in 500cc normal saline (0.9% saline) during 1 hour for consecutive 4 days and then stopped. This cycle was repeated in 14 days interval to receive 3 cycles of treatment. Patients in PDN arm received PDN orally at 1.0 mg/kg body weight daily for 4 consecutive weeks. After achieving responses the medication tapered gradually to less than 15mg daily or terminated over 4-6 weeks aimed at maintaining platelet count over 30 ×109/L. Cell blood count was performed every week in the first month of treatment and then each month to 1 one year or until loss of response. Baseline parameters such as platelet count were compared between two arms by Fisher exact test. A logistic regression model was used to evaluate the correlation between response and baseline parameters. All patients entered to study provided written informed consent in accordance with the Declaration of Helsinki.Results : 36 cases were given high dose Dexamethasone another 36 cases were given prednisone as control group. The following results were obtained: (1) at the end of the 3rd cycle, the overall response rate was higher in the HD-DXM group than in the prednisone group; (2) the relapse rate of the HD-DXM group was lower than the control group after 12 months discontinuation;(3) Adverse effect of corticosteroid therapy was less than the control group (p value<0.05).Conclusion : Treatment with 3 cycles of HD-DXM pulses is an effective method for untreated ITP patients with less adverse effect of corticosteroid in comparison with conventional prednisone therapy. DisclosuresNo relevant conflicts of interest to declare.

Comparative study of intravenous high-dose dexamethasone versus intravenous methylprednisolone as an emergent therapy in severe primary immune thrombocytopenia

Background In severe immune thrombocytopenia (ITP), high-dose methylprednisolone (MP) alone or combined with intravenous immunoglobulin showed some efficacy. Reports of use of high-dose dexamethasone (HD-DXM) in this setting are lacking. Objectives To compare between the efficacy and safety of HD-DXM versus MP as an emergency therapy in patients with severe ITP. Patients and methods A total of 50 adult patients with primary severe ITP were divided into two groups (25 in each): HD-DXM was given 40 mg/day intravenous for 4 days, and MP was given 1 g/day intravenous for 3 days. Platelet count was compared on admission and on days 3 and 5 of therapy. After 1 week, response was defined as platelet count more than 30×109/l and complete response when platelet more than 100×109/l. Results The baseline characteristics of the two groups are well balanced. Mean platelet count on third day showed no significant difference between the two groups (P=0.19). On day 5, HD-DXM group achieved significantly higher platelet count (90.13±11.41×106/ml vs. 65.11±10.38×106/ml) than in MP group (P≤0.001). Response and complete response rates after 1 week of therapy were statistically significant higher in HD-DXM group than in MP group (92 vs. 76%; P≤0.001). Hypertension and hyperglycemia were more significant in MP group (28 and 40%, respectively) than in HD-DXM group (8 and 12%, respectively; P=0.01 and 0.01, respectively). Conclusion HD-DXM alone could provide an effective and well-tolerated corticosteroid modality in emergency setting of patients with severe ITP. Prospective randomized trials of HD-DXM alone or in combination with intravenous immunoglobulin for higher efficacy are warranted.

Efficacy of Different Doses of Dexamethasone as Pre-emptive Analgesia in Patients Undergoing Total Abdominal Hysterectomy under General Anaesthesia: A Prospective Non Randomised Placebo Controlled Study

Introduction: Pre-emptive analgesia reduces postoperative analgesic requirement, avoiding side-effects that occur with parenteral narcotics. Dexamethasone, a long acting synthetic corticosteroid with predominantly glucocorticoid activity is one of the entities used for pre-emptive analgesia. The optimum dose of dexamethasone for pre-emptive analgesia is not defined. Aim: To study the efficiency of different (low, intermediate and high) doses of dexamethasone as pre-emptive analgesia in patients undergoing total abdominal hysterectomy under general anaesthesia. Materials and Methods: The prospective non randomised placebo controlled dose range study was conducted in the Department of Anaesthesiology, at a tertiary care institute at Srinagar, Jammu and Kashmir, India, over a period of two years from July 2017 to June 2019. Eighty female patients (age 40-65 years, American Society of Anaesthesiologists (ASA) I and II) scheduled for total abdominal hysterectomy were divided into four groups (Groups A, B, C and D) on the basis of dexamethasone dose. Group A with low dose (0.1 mg/kg), group B with intermediate dose (0.12-2 mg/ kg), group C with high dose (&gt;0.2 mg/Kg) and group D with no dexamethasone. Early and late acute postoperative pain {Visual Analog Scale (VAS) score}, cumulative analgesic consumption upto 24 hours, intraoperative blood sugar levels, Postoperative Nausea and Vomiting (PONV), and adverse events were recorded. Analysis of variance (ANOVA) was used for intergroup comparison of means and Chi-square test was used for categorical variables. Results: The mean age (years) of group A was 52.3±8.87, group B was 48.3±5.23, group C was 49.8±6.85 and group D was 51.7±4.46. Postoperative VAS score for 0 hour, 1 hour, 2 hour, 3 hour, 4 hour was more in patients who had not received dexamethasone pre-emptively (p-value &lt;0.05). VAS score at 6 hour, 12 hour, 24 hour was more in patients who had not received dexamethasone pre- emptively. There was a statistically significant difference in VAS score at 6, 12, 24 hours when low dose dexamethasone group was compared with intermediate and high dose dexamethasone groups (p-value &lt;0.05). Rescue analgesia consumption was significantly less in patients who received intermediate to high dose dexamethasone. Blood sugar levels increased significantly in patients receiving dexamethasone, but returned to baseline after 24 hours. The incidence of nausea and vomiting and the need for rescue antiemetic was significantly less in patients receiving dexamethasone (p-value &lt;0.05). The incidence of postoperative adverse effects was not different among these groups (p-value &gt;0.05). Conclusion: Intermediate and high dose dexamethasone, given preoperatively in patients undergoing abdominal hyster-ectomy produces better postoperative analgesia with added antiemetic benefit.

Evaluation of treatment plan by three-period pulses of high-dose dexamethasone among patients with primary immune thrombocytopenia on platelet count response and adverse events: A randomized Clinical trial.

Background:Primary immune thrombocytopenia (ITP) decreases platelet count as well as increases the risk of bleeding due to platelet destruction in an autoimmune disorder. For many years, prednisone (PDN) has been the standard first-line treatment in ITP practical guidelines. The current randomized clinical trial compared the efficacy of treatments between three-pulse high-dose dexamethasone (HD-DXM) and the traditional PDN regimen among untreated patients with ITP in accordance with platelet count responses and adverse events.Materials and Methods:We randomly assigned eligible patients with ITP to receive PDN or a three-pulse regimen of HD-DXM. In the HD-DXM group, 40 mg of DXM was administered intravenously for 4 consecutive days and was repeated in 14-day intervals for three pulses of treatment. Patients in the PDN group received 1.0 mg/kg of PDN orally per day for 4 consecutive weeks. The Mann–Whitney test was used for comparing the median of platelet count between the two groups, and logistic regression was used to evaluate odds ratio (OR) in the response rate of platelet count between the two groups. Blindness was not applied for both patients and physicians.Results:The initial response rate of platelet count in the HD-DXM group was significantly higher than the PDN group (P < 0.05). According to the results of logistic regression, the initial and sustained response (SR) rate of platelet count in the HD-DXM group was significantly higher than the PDN group (OR: 5.68 and 4.17, respectively, P < 0.05). In fact, in the HD-DXM group, more patients reached SR after the 8-month follow-up (88.9% vs. 66.6%, P < 0.05).Conclusion:In patients with ITP disease who have not received any kind of treatment, HD-DXM was more effective than conventional PDN therapy.

Combination of ATRA and High-Dose Dexamethasone As First-Line Treatment in Adult Immune Thrombocytopenia:a Randomized, Phase 2, Open-Label Trial

Introductions Immune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by immune-mediated platelet destruction and impaired platelet production. As the immunosuppressive therapy, high-dose dexamethasone (HD-DXM) has been recommended as the standard first-line treatment. Nevertheless, approximately half of ITP patients relapse within 6 months and require further therapies. All-trans retinoic acid (ATRA) is a derivative of vitamin A that has an immunomodulatory effect on hemopoiesis. Our previous study demonstrated that ATRA could induce a more rapid and long-lasting response in patients with corticosteroid-resistant or relapsed ITP (Lancet haematology, 2017). In addition, we found that ATRA corrected impaired platelet production by regulating the complement-IL-1β loop and TNFAIP3/NF-κB/SMAD7 signaling pathway in ITP (Br J Haematol, 2018; Haematologica, 2019). These findings suggested that the addition of ATRA to HD-DXM in treatment-naive patients could improve sustained response rate based on the synergetic function. Here, we present the results of the first prospective, multicenter, randomized, controlled trial with the largest cohort to date comparing the efficacy and safety of HD-DXM plus ATRA vs HD-DXM as first-line therapy in newly diagnosed adult primary ITP patients. Methods In this open-label, randomized, phase 2 trial, we enrolled adult ITP patients from 6 different tertiary medical centers in China. Eligible subjects had confirmed newly-diagnosed, treatment-naive ITP; platelet counts &amp;lt;30×109/L or platelet counts &amp;lt; 50×109/L and significant bleeding symptoms (WHO bleeding scale 2 or above).Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral ATRA (10 mg twice daily) plus HD-DXM or HD-DXM monotherapy for 12 weeks. DXM was administered orally at 40 mg daily for 4 consecutive days to both arms. The 4-day course of dexamethasone was repeated on days 11 to 14 in the case of lack of response by day 10(Figure 1). The primary endpoint was 6-month sustained response (SR) defined as platelet counts maintained &amp;gt; 50×109/L without any additional ITP-modifying therapy at the 6-month follow up. Key secondary endpoints were initial response by day 14 (OR: platelet count ≥30×109/L and at least 2-fold increase of the baseline platelet count and absence of bleeding; CR: platelet count ≥100×109/L), duration of response (DOR), bleeding scores, and adverse events (AEs). Results Between June 2015, and July 2018, 300 patients were randomly allocated into either ATRA plus HD-DXM (n=150) or HD-DXM monotherapy (n=150). At the 6-month follow-up, the proportion of patients with SR was significantly higher in the ATRA plus HD-DXM group than in the HD-DXM monotherapy group (61% vs 37%, p= 0.009). So far, the increase of almost one quarter is very encouraging. The combination of ATRA and HD-DXM resulted in a higher incidence of early OR at day 14 compared with HD-DXM monotherapy (83% vs 67%, P=0.031), and the CR rate was 60.0% (ATRA+HD-DXM) vs 40.6% (HD-DXM) (P=0.015). Throughout the follow-up period, overall DOR was greater in the combination group, estimated by the Kaplan-Meier analysis. Fewer patients in the combination group than in the monotherapy group relapsed during follow-up (p&amp;lt; 0.001), and the median time to relapse was 75 days (ATRA+HD-DXM) vs 48 days (HD-DXM). Bleeding was more effectively controlled in the ATRA plus HD-DXM arm, with fewer bleeding events and lower bleeding scores. There was no difference between the 2 groups in terms of rescue treatments. All subjects tolerated the treatment well, and no grade 4 adverse events or treatment-related death were reported. No statistically significant differences were observed in the incidence of treatment-related AEs between the two groups. Conclusions ATRA plus HD-DXM is an effective and safe treatment for ITP as a first-line therapy that can provide a sustained prolonged response in adults. This therapy could be a new treatment option for ITP subjects. Disclosures No relevant conflicts of interest to declare.

Efficacy and safety of short course high-dose Dexamethasone as first-line treatment regimen for childhood newly diagnosed immune thrombocytopenia

Objective To compare the efficacy and safety of short course and high-dose Dexamethasone (HDD) and conventional Prednisone as first-line strategy for children newly diagnosed as primary immune thrombocytopenia (ITP). Methods This study analyzed pre-experimental data of a single center prospective randomized controlled clinical trial.Newly diagnosed but untreated ITP patients enrolled at the Department of Blood and Cancer Center, Beijing Children's Hospital, Capital Medical University from November 2016 to May 2017 were randomized into HDD group[Dexamethasone 0.6 mg/(kg·d), intravenous injection for 4 days]and Prednisone group[Prednisone 2 mg/(kg·d) for 14-28 days and then tapered within 1-2 months, the course of treatment less than 3 months]. Initial response, sustained response and adverse effects after therapy were observed in 2 groups. Results Sixty-six children with ITP were included in the study: 32 patients were in the HDD group and 34 patients were in the Prednisone group.Two groups were matched in the baseline characteristics including gender, age, platelet counts and disease course before therapy and bleeding assessment (all P>0.05). The initial response (the response of HDD group within 10 days of treatment and Prednisone group within 28 days of treatment): overall initial response had no statistical difference between the HDD group and the Prednisone group[90.6%(29/32 cases) vs.100.0%(34/34 cases), χ2=1.528, P>0.05]. HDD group had a lower incidence of complete response compared with that in the Prednisone group[54.4%(19/32 cases) vs.94.1%(32/34 cases), χ2=11.330, P=0.001]; median time of response in two groups showed no statistically difference (2 d vs.1 d, Z=-0.149, P>0.05). There was no significant difference in the recovery of skin and mucosal bleeding after treatment between the Dexamethasone group and the Prednisone group (Z=-1.413, -1.031, all P>0.05). The sustained response (the response lasted for up to 6 months and above): overall and complete sustained response had no statistically difference between the HDD group and the Prednisone group [92.9%(26/28 cases) vs.85.3%(29/34 cases), P=0.594; 78.9% (15/19 cases) vs.81.3%(26/32 cases), P=1.000]. Log-rank test showed no significant difference in the duration of response between 2 groups (P=0.341). The side effects in the Prednisone group included weight gain or Cushing sign (94.1%) and mental and emotional changes (23.5%); in the HDD group 15.6% of children had infection, without other glucocorticoid-related side effects.There was no significant difference in the incidence of infection between two groups[15.6%(5/32 cases) vs.26.5%(9/34 cases), P=0.281]. All of the above infections were of respiratory tract infections and mild gastrointestinal infections. Conclusions Efficacy of the HDD group in the initial and sustained responses is similar, but side effects were apparently lower compared with that in the Prednisone group.However, a large multicenter randomized controlled clinical study is necessary to confirm this result. Key words: Dexamethasone; Child; Immune thrombocytopenia; First-line therapy

First line treatment of adult patients with primary immune thrombocytopenia: a real-world study

Immune thrombocytopenia (ITP) is an autoimmune disease with a mild to severe risk of bleeding complications. First line treatment includes corticosteroids, immunoglobulins, or other. In this large cohort study, first-line strategies for treatment-naive adult primary ITP was studied in a real-world setting. Records from all adult ITP patients who received first-line treatment between January 2010 and December 2017 at Qilu Hospital were reviewed retrospectively (n = 699). During the study period, 271 patients were treated with high-dose dexamethasone (HDD) and 289 patients were treated with conventional prednisone (alone or in combination with other drugs). Initial responses were similar for the two groups (88.56% vs. 86.51%, P = 0.462), but patients in the HDD group responded earlier than the prednisone group (3 days vs. 5 days, P < 0.001). The sustained response (SR) at 6 months was lower in the HDD group than in the prednisone group (35.4% vs. 47.1%, P = 0.040). However, the SR at 12 months and at the end of our follow-up were not significantly different between the groups. Overall duration of response (DOR) in the prednisone group was longer than in the HDD group throughout the follow-up period (P = 0.007). However, the incidence of SR and overall DOR were not significantly different between the HDD group and the prednisone 3 months group (prednisone terminated within 3 months). The presence of anti-GPIb-IX autoantibodies was a predictive factor for a poor initial response to corticosteroids therapy (P < 0.05). However, neither of the two antiplatelet autoantibodies were correlated with the opportunity to achieve SR and overall DOR in both groups throughout the follow-up period (P > 0.05). Adverse events were more frequent and long-lasting in the prednisone group. Our study showed that HDD provided an effective and more rapid response as initial treatment of ITP, with comparable long-term prognosis and better tolerance when compared with conventional PDN (less than 3 months) in the real-world setting.

Anti-inflammatory liposomes have no impact on liver regeneration in rats.

IntroductionSurgical resection is the gold standard in treatment of hepatic malignancies, giving the patient the best chance to be cured. The liver has a unique capacity to regenerate. However, an inflammatory response occurs during resection, in part mediated by Kupffer cells, that influences the speed of regeneration. The aim of this study was to investigate the effect of a Kupffer cell targeted anti-inflammatory treatment on liver regeneration in rats.MethodsTwo sets of animals, each including four groups of eight rats, were included. Paired groups from each set received treatment with placebo, low dose dexamethasone, high dose dexamethasone or low dose anti-CD163 dexamethasone. Subsequently, the rats underwent 70% partial hepatectomy. The two sets were evaluated on postoperative day 2 or 5, respectively. Blood was drawn for circulating markers of inflammation and liver cell damage; liver tissue was sampled for analysis of regeneration rate and proliferation index.ResultsThe high dose dexamethasone group had significantly lower body and liver weight than the placebo and anti-CD163-dex groups. There were no differences in liver regeneration rates between groups. Hepatocyte proliferation was completed faster in the placebo group, although this was not significant. The anti-CD163-dex group showed increased blood levels of albumin and alanine aminotransferase and a diminished inflammatory response in terms of significantly reduced haptoglobin, α2-macroglobulin and Interleukine-6.ConclusionLow dose dexamethasone targeted to Kupffer cells does not affect histological liver cell regeneration after 70% hepatectomy in rats, but reduces the inflammatory response judged by circulating markers of inflammation.

Anti-CD163-dexamethasone protects against apoptosis after ischemia/reperfusion injuries in the rat liver.

AimThe Pringle maneuver is a way to reduce blood loss during liver surgery. However, this may result in ischemia/reperfusion injury in the development of which Kupffer cells play a central role. Corticosteroids are known to have anti-inflammatory effects. Our aim was to investigate whether a conjugate of dexamethasone and antibody against the CD163 macrophage cell surface receptor could reduce ischemia/reperfusion injury in the rat liver.MethodsThirty-six male Wistar rats were used for the experiments. Animals were randomly divided into four groups of eight receiving anti-CD163-dexamethasone, high dose dexamethasone, low dose dexamethasone or placebo intravenously 18 h before laparotomy with subsequent 60 min of liver ischemia. After reperfusion for 24 h the animals had their liver removed. Bloods were drawn 30 min and 24 h post ischemia induction. Liver cell apoptosis and necrosis were analyzed by stereological quantification.ResultsAfter 24 h' reperfusion, the fraction of cell in non-necrotic tissues exhibiting apoptotic profiles was significantly lower in the high dose dexamethasone (p = 0.03) and anti-CD163-dex (p = 0.03) groups compared with the low dose dexamethasone and placebo groups. There was no difference in necrotic cell volume between groups. After 30 min of reperfusion, levels of haptoglobin were significantly higher in the anti-CD163-dex and high dose dexamethasone groups. Alanine aminotransferase and alkaline phosphatase were significantly higher in the high dose dexamethasone group compared to controls after 24 h' reperfusion.ConclusionsWe show that pharmacological preconditioning with anti-CD163-dex and high dose dexamethasone reduces the number of apoptotic cells following ischemia/reperfusion injury.

Ultrasound-guided single injection transversus abdominis plane block of isobaric bupivacaine with or without dexamethasone for bariatric patients undergoing laparoscopic vertical banded gastroplasty: a comparative study of different doses

Background Dexamethasone has anti-inflammatory properties that can prolong postoperative analgesia when added to isobaric bupivacaine transversus abdominis plane (TAP) block for bariatric patients undergoing laparoscopic vertical banded gastroplasty. Patients and methods A total of 111 bariatric patients, scheduled for laparoscopic vertical banded gastroplasty under ultrasound-guided TAP block, were randomized blindly into three parallel groups: Group BC that received TAP block using 20 ml of isobaric bupivacaine hydrochloride 0.25%+2 ml saline 0.9%; low-dose dexamethasone group (Group DB4) that received TAP block using 20 ml of isobaric bupivacaine hydrochloride 0.25%+4 mg dexamethasone; and high-dose dexamethasone group (Group DB8) that received TAP block using 20 ml of isobaric bupivacaine hydrochloride 0.25%+8 mg dexamethasone. Results Postoperatively, pain scores were significantly lower in Group BD4 and Group BD8 compared with Group BC at rest and on movement at 6, 8, 12, and 24 h. There was a significant difference with respect to the duration of analgesia ( P = 0.0001), 24 h consumption of paracetamol ( P = 0.0001), 24 h consumption of meperidine hydrochloride ( P = 0.001), the number of patients who needed meperidine hydrochloride rescue analgesic ( P = 0.008), time to ambulation ( P = 0.0001), and incidence of postoperative nausea and/or vomiting ( P = 0.03) among groups. Conclusion Adding dexamethasone (4 or 8 mg) to isobaric bupivacaine TAP block reduces postoperative pain, reduces analgesic requirement, and promotes early ambulation in bariatric patients undergoing laparoscopic vertical banded gastroplasty in comparison with isobaric bupivacaine TAP block alone.

Long-Term Effect of High-Dose Dexamethasone with or without Low-Dose Dexamethasone Maintenance in Untreated Immune Thrombocytopenia

Background: To tackle the problems associated with high-dose dexamethasone (HD-DXM) in patients with immune thrombocytopenia (ITP). Aim: To compare the efficacy of HD-DXM with or without low-dose dexamethasone maintenance in untreated ITP patients. Results: Dexamethasone (40 mg/day) was given in 4-day pulses every 14 days for 3 cycles in 61 patients with ITP. Among them, 30 cases were given dexamethasone (0.035 mg/kg per day) for maintenance between pulsed HD-DXM and after 3 HD-DXM courses (HD-DXM-M group) and another 31 cases did not receive dexamethasone maintenance (HD-DXM-nM group). The control group comprised the patients who received prednisone (prednisone group). The following results were obtained: (1) at the end of the 3rd cycle, the overall response rate (ORR) was higher in the HD-DXM group than in the prednisone group; (2) the ORR of the HD-DXM group peaked after the 3rd cycle; (3) the ORR after each course was higher in the HD-DXM-M group than in the HD-DXM-nM group; (4) in the 12th month after HD-DXM discontinuation, the relapse rate of the HD-DXM-M group was lower than that of the other groups (prednisone and HD-DXM-nM). Conclusion: Treatment with 3 cycles of HD-DXM pulses with low-dose dexamethasone maintenance is an effective method for untreated ITP.

High-dose glucocorticoid aggravates TBI-associated corticosteroid insufficiency by inducing hypothalamic neuronal apoptosis

Emerging experimental and clinical data suggest that severe illness, such as traumatic brain injury (TBI), can induce critical illness-related corticosteroid insufficiency (CIRCI). However, underlying mechanisms of this TBI-associated CIRCI remain poorly understood. We hypothesized that dexamethasone (DXM), a synthetic glucocorticoid, which was widely used to treat TBI, induces hypothalamic neuronal apoptosis to aggravate CIRCI. To test this hypothesis, we have evaluated the dose effect of DXM (1 or 10mg/kg) on the development of acute CIRCI in rats with fluid percussion injury-induced TBI and on cultured rat hypothalamic neurons in vitro (DXM, 10−5–10−8mol/L). Corticosterone Increase Index was recorded as the marker for CIRCI. In addition, MTT and TUNEL assays were used to measure the viability and apoptosis of hypothalamic neurons in primary culture. Moreover, high-resolution hopping probe ion conductance microscopy (HPICM) was used to monitor the DXM-induced morphological changes in neurons. The incidence of acute CIRCI was significantly higher in the high-dose DXM group on post-injury day 7. Cellular viability was significantly decreased from 12h to 24h after the treatment with a high-dose of DXM. A significantly increase in TUNEL positive cells were detected in cultured cells treated with a high-dose of DXM after 18h. Neurites of hypothalamic neuron were dramatically thinner and the numbers of dendritic beadings increased in neurons treated with the high dose of DXM for 12h. In conclusion, high-dose DXM induced hypothalamic neurons to undergo apoptosis in vivo and in vitro, which may aggravate TBI-associated CIRCI.