Early Hydrocortisone Research Articles

Early intravenous hydrocortisone in sepsis: A randomized control trial (Protocol)

Background: The evidence of the appropriate timing of hydrocortisone is still weak and controversial. Observational studies showed a trend towards greater benefits when hydrocortisone was given earlier in the course of septic shock resuscitation. This study evaluates the effects of early intravenous low-dose hydrocortisone administered at the beginning of the onset of sepsis-induced hypotension compared with standard care. Methods: This study is a single-center, parallel-group, double-blinded, randomized control trial, conducted in a non-trauma emergency department. Adult patients with sepsis-induced hypotension will be included. Patients will be randomly assigned in a 1:1 ratio to receive early intravenous low-dose hydrocortisone or standard care. Blood inflammatory biomarkers at baseline will be collected. The primary outcome is 28-day mortality. Resuscitation-related secondary outcomes and safety outcomes will also be observed. Outcomes will be compared between groups. Subgroup analyses considering inflammatory biomarker levels will also be performed to evaluate the effect of early intravenous hydrocortisone, especially in patients with hyperinflammation. Hypothesis: We hypothesize that early intravenous low-dose hydrocortisone administration in patients with sepsis-induced hypotension would result in less mortality and improve resuscitation outcomes, especially in subgroup of patients with hyperinflammation. Ethics and dissemination: The study protocol was approved by the Siriraj Institutional Review Board with the certificate of approval number Si 917/2023. Trial registration: Clinicaltrial.gov NCT06217939

Early, low-dose hydrocortisone and near-term brain connectivity in extremely preterm infants.

Postnatal steroids are used to prevent bronchopulmonary dysplasia in extremely preterm infants but may have adverse effects on brain development. We assessed connectivity metrics of major cerebral and cerebellar white matter pathways at near-term gestational age among infants who did or did not receive a standardized regimen of hydrocortisone during the first 10 days of life. Retrospective cohort study. Infants born <28 weeks: Protocol group (n = 33) received at least 50% and not more than 150% of an intended standard dose of 0.5 mg/kg hydrocortisone twice daily for 7 days, then 0.5 mg/kg per day for 3 days; Non-Protocol group (n = 22), did not receive protocol hydrocortisone or completed <50% of the protocol dose. We assessed group differences in near-term diffusion MRI mean fractional anisotropy (FA) and mean diffusivity (MD) across the corticospinal tract, inferior longitudinal fasciculus, corpus callosum and superior cerebellar peduncle. Groups were comparable in gestational age, post-menstrual age at scan, medical complications, bronchopulmonary dysplasia, and necrotizing enterocolitis. No significant large effect group differences were identified in mean FA or MD in any cerebral or cerebellar tract. Low dose, early, postnatal hydrocortisone was not associated with significant differences in white matter tract microstructure at near-term gestational age. This study compared brain microstructural connectivity as a primary outcome among extremely preterm infants who did or did not receive early postnatal hydrocortisone. Low dose hydrocortisone in the first 10 days of life was not associated with significant differences in white matter microstructure in major cerebral and cerebellar pathways. Hydrocortisone did not have a significant effect on early brain white matter circuits.

Neurodevelopment at 24 months corrected age in extremely preterm infants treated with dexamethasone alternatives during the late postnatal period: a cohort study

The administration of dexamethasone has been associated with suboptimal neurodevelopment. We aimed to compare the development of extremely premature infants treated or not with alternatives to dexamethasone: betamethasone, hydrocortisone hemisuccinate. This retrospective cohort study included infants born before 29 weeks of gestational age, treated or not with late (day ≥ 7) postnatal steroids (betamethasone, hydrocortisone hemisuccinate). The neurodevelopment outcome was evaluated at 24 months corrected age, after adjustment on comorbidities of extreme prematurity. In order to analyse their overall development, data about growth and respiratory outcomes were collected. Among the 192 infants included, 59 (30.7%) received postnatal steroids. Suboptimal neurodevelopment concerned 37/59 (62.7%) postnatal steroid-treated and 43/133 (38.1%; p = 0.002) untreated infants. However, in multivariable analysis, only severe neonatal morbidity (p = 0.007) and male gender (p = 0.027) were associated with suboptimal neurodevelopment outcome at 24 months. Conclusions: Betamethasone or hydrocortisone hemisuccinate treatment was not an independent risk for suboptimal neurological development, growth and respiratory outcomes assessed at 24 months corrected age in extremely premature infants. Registration number: The study was registered on the ClinicalTrials.gov register: NCT05055193.What is Known:• Late postnatal steroids are used to treat bronchopulmonary dysplasia• Meta-analyses warned against the neurological risk of dexamethasone use during neonatal period. Early or late hydrocortisone hemisuccinate has been evaluated in multiple studies, none of which have reported an adverse effect on neurodevelopment at least to 2 years. Data about the use of betamethasone are scarce.What is New:• The risk of suboptimal neurodevelopment was higher among extremely premature infants who received postnatal steroids when compared to those who did not.• Betamethasone and hydrocortisone hemisuccinate treatment was not an independent risk factor for suboptimal neurodevelopment at 24 months corrected age.

728: OUTCOMES AND TIMING OF STRESS-DOSE HYDROCORTISONE IN PEDIATRIC SEPTIC SHOCK

Introduction: Sepsis is a major contributor to pediatric morbidity and mortality worldwide. Pediatric sepsis is defined as systemic inflammatory response syndrome (SIRS) in the presence of suspected or confirmed infection. Pediatric septic shock is defined as sepsis with cardiovascular organ dysfunction. In vasoactive-inotropic recalcitrant septic shock, stress dose corticosteroids are often administered for presumed critical illness related corticosteroid insufficiency (CIRCI). However, there is not consistent data to support the use of stress dose hydrocortisone (HCT) in septic shock. To further investigate clinical outcomes related to timing of HCT, we hypothesized that children with vasoactive-inotropic recalcitrant septic shock who received early HCT (< 6 hours) would have lower vasoactive-inotropic scores (VIS) in the first 48 hours, a decreased length of stay (LOS) and increased ventilator-free days (VFD). Methods: A retrospective chart review was performed from November 2017 to December 2021 of subjects 0 to < 18 years, admitted to the pediatric intensive care unit (PICU) meeting the definition for septic shock, requiring vasopressors and/or inotropes and given HCT for CIRCI. We measured VIS, PICU and hospital LOS and VFD. Subjects with chronic steroid use or who received etomidate were excluded. Results: Of 227 subjects screened, 23 met criteria for analysis. Seven subjects received HCT within 6 hours of vasopressor initiation (early group), while 16 received HCT >6 hours (late group). Initial VIS average was 10.96 in the early group and 10.78 in the late group. At 48 hours, average VIS in the early group was 9.51 and 1.44 in the late group. Average PICU LOS was 15.58 for the early group and 10.82 for the late group. Average hospital LOS was 37.47 for the early group and 19.76 for the late group. VFD average was 15.32 in the early group and 16.61 in the late group. Pediatric Index of Mortality 3 (PIM-3) average in the early group was 2.02 and 1.61 in the late group. Mortality incidence was 2 in 7 in the early group, and 4 in 16 in the late group. Conclusions: Preliminary data suggests there is an increased VIS at 48 hours, increased PICU and hospital LOS, and decreased VFD with early administration of HCT. Although PIM-3 scores were higher in the early group, mortality was similar between groups.

Postnatal corticosteroid use for prevention or treatment of bronchopulmonary dysplasia in England and Wales 2012–2019: a retrospective population cohort study

ObjectiveDescribe the population of babies who do and do not receive postnatal corticosteroids for prevention or treatment of bronchopulmonary dysplasia (BPD).DesignRetrospective cohort study using data held in the National Neonatal...

EBNEO Commentary: A network meta-analysis of postnatal corticosteroids for bronchopulmonary dysplasia: Has the most appropriate treatment been revealed?

Ramaswamy VV, Bandyopadhyay T, Nanda D, Bandiya P, Ahmed J, Garg A, Roehr CC, Nangia S. Assessment of Postnatal Corticosteroids for the Prevention of Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-analysis. JAMA Pediatr 2021; 175(6): e206826. PMID 33720274. Systemic postnatal corticosteroids (PNCs) reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants but may contribute to long-term neurodevelopmental harm. The need to identify a treatment regimen with a reassuring risk-benefit balance remains.1 In an extraordinary feat of data aggregation, Ramaswamy and colleagues include 62 randomised clinical trials (RCTs) enrolling 5559 neonates in a systematic review and network meta-analysis (NMA) to determine which of 14 distinct PNC exposures (Table) may be most appropriate.2 The authors suggest moderately early-initiated medium cumulative dose systemic dexamethasone is the best regimen. Unlike traditional pairwise meta-analyses, NMAs compare multiple interventions, adding relevance to clinical scenarios with various alternative treatment options. NMAs also allow indirect comparisons between interventions, linking them through a common comparator.3 For example, no RCTs have compared early systemic hydrocortisone (EHC) to late-initiated low-cumulative dose systemic dexamethasone (LaLdDx), but a shared comparison to placebo in separate RCTs allows a relative risk estimation. The validity of NMA results relies on specific assumptions. A critical one is that the data linked to produce indirect evidence display ‘transitivity’.3 In essence, that aggregation may be justified by similarities in key population characteristics. Tools that guide this subjective judgement include assessment of whether the populations are similar on important effect modifiers and whether the indirect comparisons could be assessed in head-to-head trials. Extending the example above, we consider the tools against the PREMILOC (EHC) and DART (LaLdDx) trials.4, 5 A meta-regression identified the baseline risk of developing BPD as an important effect modifier for the effect of PNCs on death or cerebral palsy.6 The rates of death or BPD in the control groups of PREMILOC and DART were 49% and 91%, respectively, questioning their similarity.4, 5 In turn, a hypothetical trial of EHC versus LaLdDx would presumably compare prophylactic EHC to LaLdDx only amongst infants remaining on mechanical ventilation at 14 days. Exposing subjects to LaLdDx irrespective of respiratory status would raise ethical concerns. However, the indirect comparison generated by the NMA is not of prophylactic EHC versus expectant management with rescue LaLdDx. Though we focus on EHC versus LaLdDx as an example, these concerns extend to various comparisons. One could argue that transitivity is generally violated when comparing interventions applied in distinct stages of disease progression, and that use of PNCs as prophylaxis versus treatment of evolving severe BPD are distinct indications best suited to distinct comparisons.3 Lastly, we should avoid labelling the PNC regimen most effective against BPD as ‘most appropriate’. Although a reduction in BPD with various PNC regimens is probable, the avoidance of risk for adverse long-term neurodevelopmental outcomes is uncertain, and the latter will guide appropriateness. Further, as the authors acknowledge, the quality of evidence supporting the conclusion is low. Despite these points of caution, Ramaswamy and colleagues add a rich contribution to the literature, shining a helpful light on the path forward. Conclusively arriving at best practice will require additional high-quality research, followed by cautious data synthesis that prioritises long-term outcomes of importance to patients and their families. URL: https://ebneo.org/postnatal-corticosteroids-meta-analysis. None.

Early (&lt; 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Early (&lt; 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Hydrocortisone for Preventing Mortality and Bronchopulmonary Dysplasia in Preterm Infants with or without Chorioamnionitis Exposure: A Meta-Analysis of Randomized Trials.

This study sought to assess whether infants exposed to chorioamnionitis are the optimal population to benefit the most from early postnatal hydrocortisone delivery in preventing bronchopulmonary dysplasia (BPD). This meta-analysis was conducted to discover the efficacy of hydrocortisone in preterm infants with and without chorioamnionitis. From the earliest available date until March 2018, studies, review articles, and papers published in PubMed, Ovid, and Web of Science were reviewed. Randomized controlled trials comparing hydrocortisone with placebo/no intervention in preterm infants with a known status of chorioamnionitis exposure were included. Early postpartum low-dose hydrocortisone prevents the combined outcome of neonatal BPD or death in infants weighing less than 1,000 g with chorioamnionitis exposure (odds ratio [95% confidence interval]: 0.52 [0.32-0.79]; risk difference: -0.15 [-0.24 to -0.06]; number needed to treat: 6 [4-16]) but not in infants without chorioamnionitis exposure. Further secondary analysis showed no significant difference between the hydrocortisone group and the placebo group in individual outcomes of BPD or death, regardless of infant exposure to chorioamnionitis. Early application of low-dose hydrocortisone could potentially prevent BPD or death in infants weighing less than 1,000 g with exposure to chorioamnionitis. This finding provides the basis for further study in this target group.

Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis

Early lung inflammation has been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD). We aimed to establish the efficacy and safety of systemic hydrocortisone for the prevention of BPD. A systematic review and meta-analysis were undertaken, with a detailed electronic literature search. Trials involving preterm infants were included if they were randomised to receive systemic hydrocortisone or a placebo. The primary outcome was the composite of survival without BPD at 36-week postmenstrual age (PMA). Results are presented as relative risk (RR) or risk difference (RD) with 95% confidence intervals (CIs), along with numbers needed to treat (NNT) or harm (NNH). After filtering, 12 studies using early (within 1 week of birth) and two using late hydrocortisone were identified. Early systemic hydrocortisone significantly increased the chances of survival without BPD (RR 1.13, 95% CI [1.01, 1.26], NNT 18), and survival without moderate-to-severe neurodevelopmental impairment (1.13 [1.02, 1.26], NNT 14). Infants who received hydrocortisone had a higher risk of intestinal perforation (1.69 [1.07, 2.68], NNH 30), primarily with concurrent treatment for patent ductus arteriosus.Conclusion: Early systemic hydrocortisone is a modestly effective therapy for the prevention of BPD in preterm infants, although some safety concerns remain. No conclusions could be drawn for late hydrocortisone due to the paucity of studies.What is Known:• Preterm infants are at high risk of developing bronchopulmonary dysplasia (BPD) and early lung inflammation plays a significant role in its pathogenesis.• Both early and late systemic dexamethasone seems to reduce the incidence of BPD, but its use is associated with serious neurodevelopmental impairment at follow-up.What is New:• Early systemic hydrocortisone significantly improved survival without BPD at 36 weeks and survival without moderate to severe neurodevelopmental impairment on follow up.• Incidence of gastrointestinal perforation associated with concurrent treatment for PDA was significantly higher, although early systemic hydrocortisone reduced the need for treatment of PDAs.

Placental Findings and Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants.

To investigate the relationship between histologic findings of the placenta and response to early postnatal hydrocortisone treatment used to prevent bronchopulmonary dysplasia (BPD) in extremely preterm infants. In an exploratory analysis of the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, detailed placental analyses were performed on the basis of standardized macroscopic and histologic examinations. Placental histology, categorized into 3 groups, was correlated to neonatal outcomes and response to hydrocortisone treatment. Of 523 randomly assigned patients, 457 placentas were analyzed. In total, 125 out of 457 (27%) placentas were classified as normal, 236 out of 457 (52%) placentas were classified as inflammatory, and 96 out of 457 (21%) placentas were classified as vascular. Placental inflammation was associated with a significant, increased rate of BPD-free survival at 36 weeks' postmenstrual age, independent of gestational age, treatment group, and sex (adjusted odds ratio: 1.72, 95% confidence interval [CI]: 1.05 to 2.82, P = .03). Regarding the response to treatment, the strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, P = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, P = .06). Adjusted to gestational age and treatment groups, placental inflammation was associated with significantly fewer patent ductus arteriosus ligation (adjusted hazard ratio: 0.58, 95% CI: 0.36 to 0.95, P = .03). Placental histology was not found to be associated with other adverse events related to preterm birth. With these findings, we confirm that early low-dose hydrocortisone confers benefits in extremely preterm infants overall and we suggest there is a higher treatment effect in those born after placental vascular disease.

Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth

ObjectiveTo determine whether early hydrocortisone treatment in extremely preterm infants affects neurodevelopmental outcomes at 2 years of age according to gestational age at birth.Patients and methodsThis is an exploratory analysis...

Early hydrocortisone for multiple trauma patients may lower the incidence of nosocomial pneumonia

Background Early post-traumatic pneumonia increases the duration of mechanical ventilation (MV), hospitalization, and risk of death. In this study, the efficacy of hydrocortisone therapy in the prevention of nosocomial pneumonia in multiple trauma patients has been assessed. Patients and methods Six hundred patients who were admitted with multiple trauma were randomly assigned into two groups. The early hydrocortisone (EH) group consisted of 300 patients who received intravenous hydrocortisone 200 mg/day within 24 h from admission or trauma for 5 days and 100 mg, 50 mg on the following 2 days, respectively. The no early hydrocortisone group consisted of 300 patients who received placebo. All patients were followed up for the incidence of noscomial pneumonia. The days of ICU stay, MV, and mortality rates were calculated in both groups as secondary outcomes. Results The incidence of nosocomial pneumonia in the EH group was significantly lower than the no early hydrocortisone group [120 (40%) vs. 240 (80%), P Conclusion The use of early intravenous stress dose of hydrocortisone in patients with multiple trauma may be associated with lower incidence of nosocomial pneumonia but with no difference in mortality.

Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

Protective effect of early low-dose hydrocortisone on ventilator-associated pneumonia in the cancer patients: a propensity score analysis

BackgroundVentilator-associated pneumonia (VAP) is a care-related event that could be promoted by immune suppression caused by critical diseases, malignancies and cancer treatments. Low dose of hydrocortisone was proposed for modulation of immune response in the critically ill population.MethodsIn this monocentric observational study, all cancer patients mechanically ventilated for more than 48 h were included. Effect of low-dose hydrocortisone administered during the first 48 h of mechanical ventilation was evaluated applying inverse probability weighting analysis after propensity score assessment. VAP impact on 1-year mortality, ICU length of stay and mechanical ventilation duration was secondarily determined.ResultsWithin this cohort, 190 cancer patients were followed. VAP was confirmed in 22.1% of cases in the early hydrocortisone group and confirmed in 42.6% of cases in the no or late hydrocortisone group. Early hydrocortisone exhibited a protective effect on the risk of VAP (OR 0.23; 95% CI 0.12–0.44; P < 0.0001). VAP was associated with 1-year mortality (HR 1.60; 95% CI 1.10–2.34; P = 0.017) and increased ICU length of stay (mean extra length of stay: 4.2 days; 95% CI 0.6–7.8).ConclusionsImmune modulation with low-dose hydrocortisone administered in the first days of mechanical ventilation could protect from VAP occurrence in cancer patients.

Early hydrocortisone improves survival without bronchopulmonary dysplasia in extremely preterm born infants.

Commentary on: Baud O, Maury L, Lebail F, Ramful D,El Moussawi F, Nicaise C, Zupan-Simunek V, Coursol A, Beuchée A, Bolot P, Andrini P, Mohamed D, Alberti C, PREMILOC trial study group. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet. 2016 Apr 30;387 (10030): 1827–36. https://doi.org/10.1016/s0140-6736(16)00202-6. Epub 2016 Feb 23. Olivier Baud and colleagues investigated in a large RCT the effect of a 10-day course of low-dose prophylactic hydrocortisone given to extremely preterm infants born between 24 and 27 weeks of gestational age. Survival without bronchopulmonary dysplasia (BPD) was significantly higher in the group of infants receiving hydrocortisone than in controls receiving placebo. This effect was most pronounced in females and in infants exposed to chorioamnionitis before birth. For the secondary outcomes, the treatment group exhibited lower odds for PDA ligation, higher numbers of patients extubated on day 10 and higher proportion of patients weaned from any supplemental oxygen at 36 weeks of postmenstrual age. Despite recommendations against the use of postnatal steroids because of adverse long-term neurodevelopmental outcomes, neonatologists across the world use these drugs to treat BPD 1. The fact that ELBW infants can suffer from adrenal insufficiency, particular the sickest ones, has been shown earlier and might make early supplementation reasonable 2. Furthermore, the connection between low cortisol levels and early inflammation promoting the development of BPD from early on has been described previously and potentially justifies the treatment with steroids 3. This well-designed trial is one of the largest on this subject and provides us with important information on short-term outcome as well as on the safety of hydrocortisone treatment. It seems promising that even the lowest dose ever tested had a beneficial effect on primary outcome of survival without BPD. This trial also gives assurance with the regard to the feared side effect of gastrointestinal perforation, and very fortunately, even the two-year follow-up data are available and giving reassurance with regard to neurodevelopmental outcome 4, 5. Caution is warranted with regard to the higher incidence of late-onset sepsis in the treatment group. Although not statistically significant, a six percent difference between the groups might be of clinical interest. Treatment with postnatal steroids to prevent BPD seems to be a hot topic. The recent trial by Bassler et al. and the updated Cochrane review are suggesting a benefit for using early inhaled steroids in extreme preterm infants 6, 7. However, the long-term risk/benefit ratio for treatment with steroids still needs to be identified for either application way even beyond the two-year data currently available for this trial. A weakness might be the fact that the study was discontinued prior to targeted sample size of 786 infants. Nevertheless, the sequential analytical design allowed appropriate analysis after the fourth interim analysis anyway. Neonatologists around the world are faced with an increasingly immature population consequently leading to a higher prevalence of BPD, which makes prevention and treatment strategies inevitable. Early supplementation with hydrocortisone as described in this trial might be a promising way forward. The question whether this treatment strategy could be particularly beneficial in infants not exposed to antenatal steroids has not been addressed here. Further studies on this subject focusing on type of steroid, timing of treatment, dosage and duration of treatment are needed. https://ebneo.org/2017/09/early-hydrocortisone-improves-survival-without-bronchopulmonary-dysplasia-in-extremely-preterm-born-infants/ None. None.

Long-term postnatal steroid effect in very low birth weight infants

We examined whether hydrocortisone exposure≤1week in very low birth weight infants (VLBWI) was associated with poor neurodevelopmental outcomes at corrected 18months. Further, the clinical factors associated with worse long term outcome were also evaluated. Of a total of 191 VLBWI, the clinical data for these infants relating were retrospectively collected for analysis. Among the 191 VLBWI, 115 (60.2%) infants were exposed to early postnatal hydrocortisone≤1week of life in our NICU of Seoul St. Mary’s Hospital, The Catholic University of Korea between December 2012 and December 2014. The morbidities were significantly higher in the group with early hydrocortisone exposure group. At corrected age of 18months, 109/183 (59.6%) infants in the early hydrocortisone exposure group had significantly lower scores in all three (cognitive, language and motor) composites of Bayley Scales of Infant and Toddler Development III. The multivariable logistic regression analysis showed that only periventricular leukomalacia (PVL) is consistently associated with poor long-term outcomes. Our results suggest that early hydrocortisone exposure≤1week in VLBWI may not increase the risk for poor long-term outcomes compared to those not exposed. Only PVL is considered as a risk factor for poor long-term neurodevelopmental outcomes.

Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age

Dexamethasone to prevent bronchopulmonary dysplasia in very preterm neonates was associated with adverse neurodevelopmental events. Early low-dose hydrocortisone treatment has been reported to improve survival without bronchopulmonary dysplasia but its safety with regard to neurodevelopment remains to be assessed. To assess whether early hydrocortisone therapy in extremely preterm infants is associated with neurodevelopmental impairment at 2 years of age. An exploratory secondary analysis of the PREMILOC (Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants) randomized clinical trial conducted between 2008 and 2014 in 21 French neonatal intensive care units. Randomization was stratified by gestational age groups. Neurodevelopmental assessments were completed from 2010 to 2016. After birth, patients were randomly assigned to receive placebo or hydrocortisone (0.5 mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days). The prespecified exploratory secondary outcome of neurodevelopmental impairment was based on a standardized neurological examination and the revised Brunet-Lézine scale (global developmental quotient score and subscores; mean norm, 100 [SD, 15]). The minimal clinically important difference on the global developmental quotient was 5 points. Of 1072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21-23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, -2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups. In this exploratory analysis of secondary outcomes of a randomized clinical trial of extremely preterm infants, early low-dose hydrocortisone was not associated with a statistically significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive assessment of the neurodevelopmental safety of hydrocortisone in extremely preterm infants. clinicaltrials.gov Identifier: NCT00623740.

Randomised trial of early neonatal hydrocortisone demonstrates potential undesired effects on neurodevelopment at preschool age

We evaluated the neurodevelopment and growth of five- to seven-year-old children who had participated in a randomised trial of early low-dose hydrocortisone treatment to prevent bronchopulmonary dysplasia. The 51 infants in the original study had birthweights of 501-1250 g and gestational ages of 23-30 weeks, required mechanical ventilation during the first 24 hours and received hydrocortisone or a placebo for 10 days. The majority (80%) of the 90% who survived to five- to seven years of age participated in this follow-up study and their growth, neuromotor, cognitive and speech development were evaluated. Some neurodevelopment impairment was observed in 61% of the hydrocortisone group and 39% of the placebo group, ranging from minor neurological dysfunction to severe neurological conditions (p = 0.182). The mean full-scale intelligence quotient (IQ) was 87.8 (15.3) in the hydrocortisone group and 95.7 (15.0) in the placebo group (p = 0.135), and the mean performance IQ was 88.3 (14.5) and 99.1 (14.0) (p = 0.034), respectively. A fifth (22%) of the hydrocortisone group required physiotherapy, but none of the placebo group did (p = 0.034). The age-standardised growth was comparable between both groups. Early hydrocortisone treatment may have undesired effects on neurodevelopment at preschool age, and further safety studies are required.

Early Administration of Hydrocortisone Replacement After the Advent of Septic Shock

To investigate the impact of early initiation of hydrocortisone therapy on the clinical course of septic shock and on cytokine release. Prospective study in patients with septic shock treated with low doses of hydrocortisone. ICUs and general wards. Over a 2-year period, 170 patients with septic shock treated with low doses of hydrocortisone were enrolled. Blood was sampled from 34 patients for isolation of peripheral blood mononuclear cells and cytokine stimulation before and 24 hours after the start of hydrocortisone. None. After quartile analysis, patients were divided into those with early initiation of hydrocortisone (< 9 hr after vasopressors, n = 46) and those with late initiation of hydrocortisone (> 9 hr after vasopressors, n = 124). After adjusting for disease severity and type of infection, a protective effect of early hydrocortisone administration against unfavorable outcome was found (hazard ratio, 0.20; p = 0.012). Time of discontinuation of vasopressors was earlier among patients with initiation of hydrocortisone within 9 hours. Production of tumor necrosis factor-α was lower among patients who had had hydrocortisone early. In patients receiving hydrocortisone for septic shock, early initiation of treatment was associated with improved survival. This treatment was also associated with attenuated stimulation of tumor necrosis factor-α.

Counteraction of early circulatory derangement by administration of low dose steroid treatment at the onset of established endotoxemic shock is not directly mediated by TNF-α and IL-6

BackgroundOnce a septic condition is progressing, administration of steroids in the pro-inflammatory phase of septic shock ought to yield maximal effect on the subsequent, devastating inflammatory response. Recently, a retrospective study showed that early initiation of corticosteroid therapy improved survival in septic shock. We aimed to prospectively evaluate effects of early administrated hydrocortisone therapy on physiologic variables in a porcine model of septic shock. ExperimentEight anesthetized pigs were given a continuous infusion of endotoxin during this 6h prospective, randomized, parallel-grouped placebo-controlled experimental study. At the onset of endotoxemic shock, defined as the moment when the mean pulmonary arterial pressure reached the double baseline value, the pigs were either given a single intravenous dose of hydrocortisone (5mgkg−1) or the corresponding volume of saline. ResultsMean arterial pressure and systemic vascular resistance index were significantly higher (both p<0.05), and heart rate was significantly lower (p<0.05), in the endotoxin+hydrocortisone group as compared to the endotoxin+saline group. Body temperature and blood hemoglobin levels increased significantly in the endotoxin+saline group (both p<0.05). Urinary hydrocortisone increased significantly in both groups (p<0.05). There were no significant differences in the plasma levels of TNF-alpha, IL-6 or nitrite/nitrate between the groups. ConclusionEarly treatment with hydrocortisone ameliorates some endotoxin mediated circulatory derangements, fever response and microvascular outflow. Our results suggest that these effects are not directly mediated by the pro-inflammatory cytokines TNF-alpha or IL-6, nor by NO.