Hydrocortisone in Severe Community-Acquired Pneumonia.

BACKGROUND: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Do We Need to Administer Fludrocortisone in Addition to Hydrocortisone in Adult Patients With Septic Shock? An Updated Systematic Review With Bayesian Network Meta-Analysis of Randomized Controlled Trials and an Observational Study With Target Trial Emulation.

OBJECTIVES: This systematic review and Bayesian network meta-analysis evaluated the efficacy and safety of hydrocortisone combined with fludrocortisone or hydrocortisone alone, compared with placebo in adult patients with septic shock. DATA SOURCES: By extending a prior Cochrane review, databases, including PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov , along with other relevant websites, were searched until August 31, 2023. STUDY SELECTION: Randomized controlled trials (RCTs) and observational studies using target trial emulation were included. DATA EXTRACTION: The primary outcome was short-term mortality with an emphasis on 28- or 30-day mortality as the main measure and in-hospital or ICU mortality as the nearest surrogate of this measure. Three of the most common adverse events, namely, gastroduodenal bleeding, superinfection, and hyperglycemia, were also considered. DATA SYNTHESIS: A total of 19 studies involving 95,841 patients were included. Hydrocortisone plus fludrocortisone showed the lowest short-term mortality versus placebo (odds ratio [OR]: 0.79; 95% credible interval [CrI], 0.64-0.99; number needed to treat [NNT]: 21, range: 12-500; low certainty of evidence) in terms of informative priors. The surface under the cumulative ranking curve values for hydrocortisone plus fludrocortisone, hydrocortisone alone, and placebo were 0.9469, 0.4542, and 0.0989, respectively. Consistent results were observed in RCTs alone and those using a daily 200-mg dose of hydrocortisone. Although gastroduodenal bleeding or superinfection showed no clear increase, hyperglycemia risk increased. The ORs were 0.53 for placebo versus hydrocortisone plus fludrocortisone and 0.64 for placebo versus hydrocortisone alone, with very low certainty of evidence. CONCLUSIONS: In adults with septic shock, hydrocortisone plus fludrocortisone improved short-term survival with minimal adverse events compared with hydrocortisone alone or placebo. However, these findings are not definitive due to the limited certainty of evidence and wide NNT range. Additional large-scale, placebo-controlled RCTs are needed to provide conclusive evidence.

Effectiveness and safety of continuous subcutaneous hydrocortisone infusion in managing adrenocortical insufficiency in adult patients: a systematic review.

Oral hormone replacement therapy has been and continues to be the cornerstone of adrenocortical insufficiency management. However, the introduction of continuous subcutaneous hydrocortisone infusion (CSHI) shows great potential for advancing the management of adrenocortical insufficiency. It resembles the circadian rhythm of physiological cortisol secretion and was shown to have a promising outcome in terms of quality of life (QOL) and clinical outcomes in the literature. We conducted a systematic search strategy including MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and the online trials registers at ClinicalTrials.gov without geographic restrictions. Research investigations where self-reported quality of life (QOL) was assessed as a variable in adult individuals with confirmed adrenal disease, treated by CSHI, and results were presented in English. All articles included were published between 2014 and 2023, even though we had no timeframe limitations in our inclusion criteria. A total of six studies were included, with 63 subjects enrolled, and the average age was 40 years, a study showed a significant reduction in the average total daily dose of HC from 47.5 mg to 31.4 mg on CSHI, while other two studies estimated a reduction in the hospitalization rate due to adrenal crisis from 2.6 to 1.3 admissions per year on CSHI. Most of the studies on subjective well-being and quality of life have shown significant improvement. Overall, CSHI shows great potential as a treatment method for Adrenal insufficiency. It improves the quality of life and lowers hospitalization rates, resulting in increased patient satisfaction and acceptance. Additional comprehensive research is necessary to strengthen these discoveries, gain a deeper understanding of the effectiveness and safety of this treatment approach, and provide guidance for medical practitioners.

Efficacy and Safety of Hydrocortisone, Ascorbic Acid, and Thiamine Combination Therapy for the Management of Sepsis and Septic Shock: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

INTRODUCTION: This systematic review aimed to assess the efficacy and safety of hydrocortisone, ascorbic acid, and thiamine (HAT) combination therapy in patients with sepsis and septic shock. METHODS: We conducted a database search in MEDLINE, Embase, CENTRAL, Web of Science, and CNKI for randomised controlled trials (RCTs) comparing HAT against placebo/standard of care or against hydrocortisone in sepsis/septic shock patients. Outcomes included mortality, ICU/hospital length of stay (LOS), vasopressor durations, mechanical ventilation durations, change in SOFA at 72 h, and adverse events. RCT results were pooled in random-effects meta-analyses. Quality of evidence was assessed using GRADE. RESULTS: Fifteen RCTs (N = 2,594) were included. At 72 h, HAT reduced SOFA scores from baseline (mean difference [MD] -1.16, 95% confidence interval [CI]: -1.58 to -0.74, I2 = 0%) compared to placebo/SoC, based on moderate quality of evidence. HAT also reduced the duration of vasopressor use (MD -18.80 h, 95% CI: -23.67 to -13.93, I2 = 64%) compared to placebo/SoC, based on moderate quality of evidence. HAT increased hospital LOS (MD 2.05 days, 95% CI: 0.15-3.95, I2 = 57%) compared to placebo/SoC, based on very low quality of evidence. HAT did not increase incidence of adverse events compared to placebo/SoC. CONCLUSIONS: HAT appears beneficial in reducing vasopressor use and improving organ function in sepsis/septic shock patients. However, its advantages over hydrocortisone alone remain unclear. Future research should use hydrocortisone comparators and distinguish between sepsis-specific and comorbidity- or care-withdrawal-related mortality.

Efficacy and safety of topical corticosteroid treatment under occlusion for severe alopecia areata in children: a single-centre retrospective analysis.

BACKGROUND: Alopecia areata (AA) has a poor clinical course in children. There are no reliable therapeutic options for children with severe AA, including alopecia totalis (AT) and alopecia universalis (AU). OBJECTIVES: We evaluated the efficacy and adverse effects of a potent topical corticosteroid (TCS) under occlusion in paediatric patients with severe AA. METHODS: We reviewed records of 23 patients under the age of 10 years with AT or AU treated with a potent TCS (0.05% clobetasol propionate or 0.3% diflucortolone valerate) for 8 h under occlusion with a plastic film. We used the Severity of Alopecia Tool (SALT) to measure clinical improvement. The primary endpoint was a SALT score of ≤ 20 at 6 months. We analysed the change in cortisol levels to identify the long-term safety of TCS therapy on the hypothalamus-pituitary-adrenal axis. RESULTS: Nineteen of the 23 patients (83%) reached SALT ≤ 20 at 6 months. Six patients relapsed over the 6-month follow-up period. Four patients were suspected of having adrenal insufficiency. However, the cortisol levels of the patients recovered to normal within 1 month of lowering the TCS potency or changing to nonsteroidal treatments. Limitations include the retrospective design and small sample size. CONCLUSIONS: This study shows that a potent TCS occlusion may be a safe treatment option in paediatric patients with severe AA. Further long-term studies are required to evaluate the safety and recurrence of TCS occlusion therapy for paediatric AA.

Low-Dose Corticosteroids for Critically Ill Adults With Severe Pulmonary Infections: A Review.

Importance: Severe pulmonary infections, including COVID-19, community-acquired pneumonia, influenza, and Pneumocystis pneumonia, are a leading cause of death among adults worldwide. Pulmonary infections in critically ill patients may cause septic shock, acute respiratory distress syndrome, or both, which are associated with mortality rates ranging between 30% and 50%. Observations: Corticosteroids mitigate the immune response to infection and improve outcomes for patients with several types of severe pulmonary infections. Low-dose corticosteroids, defined as less than or equal to 400 mg hydrocortisone equivalent daily, can reduce mortality of patients with severe COVID-19, community-acquired pneumonia, and Pneumocystis pneumonia. A randomized clinical trial of 6425 patients hospitalized with COVID-19 who required supplemental oxygen or noninvasive or invasive mechanical ventilation reported that dexamethasone 6 mg daily for 10 days decreased 28-day mortality (23% vs 26%). A meta-analysis that included 7 randomized clinical trials of 1689 patients treated in the intensive care unit for severe bacterial community-acquired pneumonia reported that hydrocortisone equivalent less than or equal to 400 mg daily for 8 days or fewer was associated with lower 30-day mortality compared with placebo (10% vs 16%). In a meta-analysis of 6 randomized clinical trials, low-dose corticosteroids were associated with lower mortality rates compared with placebo for patients with HIV and moderate to severe Pneumocystis pneumonia (13% vs 25%). In a predefined subgroup analysis of a trial of low-dose steroid treatment for septic shock, patients with community-acquired pneumonia randomized to 7 days of intravenous hydrocortisone 50 mg every 6 hours and fludrocortisone 50 µg daily had decreased mortality compared with the placebo group (39% vs 51%). For patients with acute respiratory distress syndrome caused by various conditions, low-dose corticosteroids were associated with decreased in-hospital mortality (34% vs 45%) according to a meta-analysis of 8 studies that included 1091 patients. Adverse effects of low-dose corticosteroids may include hyperglycemia, gastrointestinal bleeding, neuropsychiatric disorders, muscle weakness, hypernatremia, and secondary infections. Conclusions and Relevance: Treatment with low-dose corticosteroids is associated with decreased mortality for patients with severe COVID-19 infection, severe community-acquired bacterial pneumonia, and moderate to severe Pneumocystis pneumonia (for patients with HIV). Low-dose corticosteroids may also benefit critically ill patients with respiratory infections who have septic shock, acute respiratory distress syndrome, or both.

Efficacy and safety of a hydrocortisone aceponate-containing ear spray solution in dogs with erythemato-ceruminous otitis externa: A randomised, multicentric, single-blinded, controlled trial.

BACKGROUND: Erythemato-ceruminous otitis externa (ECOE) is frequently seen in dogs affected with an allergic skin disease, with recurrent secondary bacteria and yeast overgrowths (detected on cytological examination). OBJECTIVES: The objective of the study was to compare the efficacy and safety of an ear spray containing only hydrocortisone aceponate glucocorticoid diester (HCA) to a control product (CTRL), an approved otic formulation containing prednisolone-miconazole-polymyxin combination, in dogs with ECOE. ANIMALS: In total, 97 and 104 dogs with ECOE were respectively randomly assigned to the tested ear treatment product group (HCA) or the commercially available ear treatment control product group (CTRL). MATERIALS AND METHODS: Dogs were treated for 7-14 days, as needed. At Day (D)0, D7, D14, D28 and D42, Otitis Index Score-3, hearing test, pruritus and pain visual analogue scales, and cytological scores were graded. The overall response to treatment also was assessed. RESULTS: All clinical parameters decreased rapidly and in a similar way without any significant difference at any time between treatment groups. A good-to-excellent response to treatment was seen in >90% of dogs of both groups as early as D14. The treatment was considered safe in all dogs. CONCLUSIONS AND CLINICAL RELEVANCE: A 7- to 14-day ear topical application of HCA alone to dogs with ECOE accompanied with bacterial and/or fungal (yeast) overgrowth was safe and led to no statistical difference in improvement of clinical scores relative to the CTRL combination. Based on these results, it may be necessary to reconsider the routine use of antimicrobial drugs such as antibiotics and antifungals as a first-line treatment for ECOE that is likely to have been caused by an allergic reaction.

The Timing of Initiating Hydrocortisone and Long-term Mortality in Septic Shock.

BACKGROUND: Previous studies on the association between the timing of corticosteroid administration and mortality in septic shock focused only on short-term mortality and produced conflicting results. We performed a retrospective review of a large administrative database of intensive care unit (ICU) patients to evaluate the association between the timing of hydrocortisone initiation and short- and long-term mortality in septic shock. We hypothesized that a longer duration between the first vasopressor use for sepsis and steroid initiation was associated with increased mortality. METHODS: Data were extracted from the Medical Information Mart in the Intensive Care-IV database. We included adults who met Sepsis-3 definition for septic shock and received hydrocortisone. The exposure of interest was the time in hours from vasopressor use to hydrocortisone initiation (>12 as late and ≤12 as early). The primary outcome was 1-year mortality. Secondary outcomes included 28-day mortality, 90-day mortality, in-hospital mortality, and length of hospital stay. Cox proportional hazard models were used to estimate the association between exposure and mortality. Competing risk regression models were used to evaluate the association between exposure and length of hospital stay. RESULTS: A total of 844 patients were included in this cohort: 553 in the early group and 291 in the late group. The median time to hydrocortisone initiation was 7 hours (interquartile range, 2.0-19.0 hours). After multivariable Cox proportional hazard analysis, we found that hydrocortisone initiation >12 hours after vasopressor use was associated with increased 1-year mortality when compared with initiation <12 hours (adjusted hazard ratio, 1.39; 95% confidence interval, 1.13-1.71; P = .002, E-value = 2.13). Hydrocortisone initiation >12 hours was also associated with increased 28-day, 90-day, and in-hospital mortality and prolonged length of hospital stay. CONCLUSIONS: In patients with septic shock, initiating hydrocortisone >12 hours after vasopressor use was associated with an increased risk of both short-term and long-term mortality, and a prolonged length of hospital stay.

Contact allergy to corticosteroids: Is the European baseline series sufficient?

BACKGROUND: Patients are consecutively screened for contact allergy to corticosteroids with budesonide and tixocortol-21-pivalate in the European baseline series. Centres using TRUE Test also include hydrocortisone-17-butyrate. A supplementary corticosteroid patch test series is used in case of suspicion of corticosteroid contact allergy or when a marker of corticosteroid contact allergy is positive. OBJECTIVE: The aims were to evaluate (1) the efficacy of corticosteroids in the TRUE Test and (2) co-sensitization patterns. METHODS: This retrospective study analysed patients patch tested with TRUE Test corticosteroids plus supplementary corticosteroid series in the period 2006-2020 at the Department of Dermatology and Allergy Centre, Odense University Hospital. RESULTS: Of 1852 patients tested, 119 were sensitised to TRUE Test corticosteroids and supplementary testing found additional reactions to other corticosteroids in 19 of 119 patients. TRUE Test corticosteroids gave more positive and stronger reactions compared to allergens in petrolatum/ethanol. Fourteen percent of sensitised patients were co-sensitised to multiple corticosteroid groups. Baeck group 3 corticosteroids accounted for 9 of 16 patients not identified by TRUE Test. CONCLUSIONS: Budesonide, hydrocortisone-17-butyrate, and tixocortol-21-pivalate in combination are sensitive corticosteroid markers. In case of clinical suspicion of corticosteroid contact allergy, patch testing with supplementary corticosteroids is highly recommended.

A Closer Look at Opioid-Induced Adrenal Insufficiency: A Narrative Review.

Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors for OIAI are not well known. OIAI can be diagnosed by a variety of tests, such as the morning cortisol test, but cutoff values are not well established and it is estimated that only about 10% of patients with OIAI will ever be properly diagnosed. This may be dangerous, as OIAI can lead to a potentially life-threatening adrenal crisis. OIAI can be treated and for patients who must continue opioid therapy, it can be clinically managed. OIAI resolves with opioid cessation. Better guidance for diagnosis and treatment is urgently needed, particularly in light of the fact that 5% of the United States population has a prescription for chronic opioid therapy.

Prevalence of contact allergy to corticosteroids in a Danish patient population.

BACKGROUND: Allergic contact dermatitis to corticosteroids can be a challenging diagnosis as corticosteroids are used in the treatment of dermatitis. The prevalence of contact allergy to corticosteroid varies between previous studies. OBJECTIVE: To study the prevalence of sensitization to budesonide, tixocortol-21-pivalate and hydrocortisone-17-butyrate in a Danish patient population from 2006-2020, cross-sensitization, risk factors and clinical relevance. METHODS: A retrospective analysis of patch test data and MOAHLFA index was performed among 6823 patients consecutively patch tested with TRUE test as part of the baseline series. RESULTS: A positive patch test for corticosteroids was found in 185 patients (1.2% budesonide, 1.6% tixocortol-21-pivalate, 1.0% hydrocortisone-17-butyrate) without gender difference. For women, the prevalence of tixocortol-21-pivalate sensitization increased significantly from 1.3% in 2006-2008 to 2.9% in 2018-2020. Tixocortol-21-pivalate sensitization had more frequently clinical relevance in women (61.3%) compared to men (34.5%). Age above 40 years was positively associated to corticosteroid sensitization. Budesonide and hydrocortisone-17-butyrate accounted for 67.7% of co-sensitizations. CONCLUSIONS: The prevalence of corticosteroid sensitization was 2.7%. Age was the only risk factor for corticosteroid sensitization. The frequency of corticosteroid sensitization was stabile over time except for tixocortol-21-pivalate sensitization for women. About one third of sensitized patients had co-sensitizations to other corticosteroid groups.

Are Corticosteroid Injections Associated With Secondary Adrenal Insufficiency in Adults With Musculoskeletal Pain? A Systematic Review and Meta-analysis of Prospective Studies.

BACKGROUND: Corticosteroid injection is a common treatment for individuals experiencing musculoskeletal pain, and it is part of the management of numerous orthopaedic conditions. However, there is concern about offering corticosteroid injections for musculoskeletal pain because of the possibility of secondary adrenal insufficiency. QUESTIONS/PURPOSES: In this systematic review and meta-analysis of prospective studies, we asked: (1) Are corticosteroid injections associated with secondary adrenal insufficiency as measured by 7-day morning serum cortisol? (2) Does this association differ depending on whether the shot was administered in the spine or the appendicular skeleton? METHODS: We searched the Allied and Complementary Medicine (AMED), Embase, EmCare, MEDLINE, CINAHL, and Web of Science from inception to January 22, 2021. We retrieved 4303 unique records, of which 17 were eventually included. Study appraisal was via the Downs and Black tool, with an average quality rating of fair. A Grading of Recommendations, Assessment, Development, and Evaluations assessment was conducted with the overall certainty of evidence being low to moderate. Reflecting heterogeneity in the study estimates, a pooled random-effects estimate of cortisol levels 7 days after corticosteroid injection was calculated. Fifteen studies or subgroups (254 participants) provided appropriate estimates for statistical pooling. A total of 106 participants received a spine injection, and 148 participants received an appendicular skeleton injection, including the glenohumeral joint, subacromial bursa, trochanteric bursa, and knee. RESULTS: Seven days after corticosteroid injection, the mean morning serum cortisol was 212 nmol/L (95% confidence interval 133 to 290), suggesting that secondary adrenal insufficiency was a possible outcome. There is a difference in the secondary adrenal insufficiency risk depending on whether the injection was in the spine or the appendicular skeleton. For spinal injection, the mean cortisol was 98 nmol/L (95% CI 48 to 149), suggesting secondary adrenal insufficiency was likely. For appendicular skeleton injection the mean cortisol was 311 nmol/L (95% CI 213 to 409) suggesting hypothalamic-pituitary-adrenal axis integrity was likely. CONCLUSION: Clinicians offering spinal injections should discuss the possibility of short-term secondary adrenal insufficiency with patients, and together, they can decide whether the treatment remains appropriate and whether mitigation strategies are needed. Clinicians offering appendicular skeleton injections should not limit care because of concerns about secondary adrenal insufficiency based on the best available evidence, and clinical guidelines could be reviewed accordingly. Further research is needed to understand whether age and/or sex determine risk of secondary adrenal insufficiency and what clinical impact secondary adrenal insufficiency has on patients undergoing spinal injection. LEVEL OF EVIDENCE: Level IV, therapeutic study.

[Chronic psychological stress exacerbates aortic medial calcification via glucocorticoids].

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D3 (VitD3) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD3, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11ß-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD3, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.

BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

External Corroboration That Corticosteroids May Be Harmful to Septic Shock Endotype A Patients.

OBJECTIVES: We previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A. DESIGN: Secondary analysis of publicly available transcriptomic data. SETTING: Multiple adult ICUs. PATIENTS: Adults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50). INTERVENTIONS: Randomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms. MEASUREMENTS AND MAIN RESULTS: Endotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05). CONCLUSIONS: This exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.

Single daily dosing versus divided dosing intravenous ondansetron to prevent chemotherapy-induced nausea and vomiting among children: A comparative randomized double-blind controlled trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a common complication in cancer treatment. Ondansetron is an effective antiemetic drug widely used to prevent CINV; however, the effective administrative dosing strategies among pediatrics remain unclear. The study aimed to investigate clinical effectiveness of single daily dosing versus divided dosing ondansetron. METHODS: In all, 194 children undergoing chemotherapy were randomized to receive either single daily dosing (0.3 mg/kg/dose) or divided dosing (0.15 mg/kg/dose every 8 hours) intravenous ondansetron for 24 hours. Clinical parameters including number of emesis episodes, nausea scores, appetite levels, parent's satisfaction, and adverse effects within 24 hours were analyzed. RESULTS: No significant differences were found between the two dosing strategies concerning number of emesis episodes and parent's satisfaction. However, nonleukemic hematologic malignancies and concurrent administration of intrathecal methotrexate-hydrocortisone-cytarabine (IT-MHA) were associated with increased risk of acute-phase vomiting. Interestingly, none of the patients aged under 7 years, receiving divided dosing ondansetron, presented nausea symptoms compared with those receiving single daily dosing (p-value .034). No significant differences regarding headache were observed between the two dosing strategies and none of the patients experienced QTc prolongation. CONCLUSION: Ondansetron administered as divided dosing should be considered among children aged under 7 years to prevent chemotherapy-induced nausea and among patients receiving low emetogenic chemotherapy to maintain their appetite. Both administrative dosing strategies were well tolerated with no significant adverse effects.

Effect of hydrocortisone versus methylprednisolone on clinical outcomes in oncology patients with septic shock.

BACKGROUND: Corticosteroids are used as adjunctive treatment of critical illness-related corticosteroid insufficiency in patients with septic shock. This study aims to compare the impact of hydrocortisone versus methylprednisolone on duration of septic shock in critically ill oncology patients. METHODS: Single-center, retrospective cohort study of adult patients receiving hydrocortisone ≥200 mg/day or methylprednisolone ≥40 mg/day with septic shock. The primary outcome was time to shock reversal defined as time to systolic blood pressure ≥90 mmHg without vasopressors for ≥24 h. RESULTS: Eighty-eight patients were included, 49 patients received hydrocortisone and 39 patients received methylprednisolone. Solid tumor malignancy was more common in the hydrocortisone group, while hematological malignancy was more common in the methylprednisolone group (p = 0.009). Time to shock reversal was similar between hydrocortisone and methylprednisolone groups (72.4 versus 70.4 h; p = 0.825). Intensive care unit mortality occurred in 51.02% versus 53.85% of patients in hydrocortisone versus methylprednisolone, respectively (p = 0.792). Patients who received methylprednisolone had higher rates of mechanical ventilation (89.74% versus 55.1%, p < 0.001) and longer intensive care unit and hospital lengths of stay (4.2 versus 11.4 days and 14.3 versus 25.7 days; p < 0.001) compared to hydrocortisone. No differences were seen in incidence of steroid-related adverse effects between groups. CONCLUSIONS: In oncology patients with septic shock, the use of hydrocortisone versus methylprednisolone does not appear to affect time to shock reversal.