Purpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in... Show morePurpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in the prevention of death in septic patients. Here we evaluated the association between hydrocortisone treatment and mortality in patients diagnosed with sepsis in a large-scale clinical dataset.Methods: Data from patients between 2008 and 2019 were extracted from the retrospective Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients who received hydrocortisone after diagnosis were matched using propensity-score matching with patients who did not, to balance confounding (by indication and contraindication) factors between the groups. 90-day mortality and survivors' length of hospital stay was compared between patients who did or did not receive hydrocortisone.Results: A total of 31,749 septic patients were included in the study (mean age: 67, men: 57.3%, in-hospital mortality: 15.6%). 90-day mortality was higher among the 1802 patients receiving hydrocortisone when compared with the 6348 matched non-users (hazard ratio: 1.35, 95% CI: 1.24-1.47). Hydrocortisone treatment was also associated with increased in-hospital mortality (40.9% vs. 27.6%, p < 0.0001) and prolonged hospital stay in those who survived until discharge (median 12.6 days vs. 10.8 days, p < 0.0001). Stratification for age, gender, ethnicity, occurrence of septic shock, and the need for vasopressor drug administration such as (nor) epinephrine did not reveal sub-population(s) benefiting of hydrocortisone use.Conclusion: Hydrocortisone treatment is associated with increased risk of death as well as prolonged hospital stay in septic patients. Although residual confounding (by indication) cannot be ruled out completely due to the observational nature of the study, the present study suggests clinical implication of hydrocortisone use in patients with sepsis. Show less
Hulst, A.M. van; Akker, E.L.T. van den; Verwaaijen, E.J.; Fiocco, M.; Rensen, N.; Litsenburg, R.R.L. van; ... ; Heuvel-eibrink, M.M. van den 2023
Background: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who... Show moreBackground: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding.Methods: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect.Results: The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect-2.05 (95% confidence interval (CI)-6.00-1.90). Also, no benefit from hydrocortisone compared to pla-cebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL.Conclusions: Hydrocortisone, when compared to placebo, had no additional effect in redu-cing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hy-drocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Trial registration: NetherlandsTrial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/).(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). Show less
Hulst, A.M. van; Verwaaijen, E.J.; Fiocco, M.F.; Pluijm, S.M.F.; Grootenhuis, M.A.; Pieters, R.; ... ; Heuvel-Eibrink, M.M. van den 2021
Background: Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by... Show moreBackground: Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care.Methods: In a national center setting, pediatric ALL patients between 3 and 18 years are enrolled in an Identification study, which identifies patients with clinically relevant dexamethasone-induced neurobehavioral side effects using the Strengths and Difficulties Questionnaire (SDQ). Contributing factors, such as genetic susceptibility, dexamethasone pharmacokinetics as well as psychosocial and family factors are studied to determine their influence in the inter-patient variability for developing dexamethasone-induced neurobehavioral side effects.Patients with clinically relevant problems (i.e. a rise of >= 5 points on the SDQ Total Difficulties Score after 5 days of dexamethasone) are subsequently included in a randomized double-blind placebo-controlled trial with a cross-over design. They receive two courses placebo followed by two courses hydrocortisone during dexamethasone treatment, or vice versa, each time at least 16 days without study medication in between. The primary endpoint is change in SDQ score. The secondary endpoints are sleep (measured with actigraphy and the Sleep Disturbance Scale for Children) and HRQoL (Pediatric Quality of Life Questionnaire).Discussion: The results of our current study may contribute to the management of future ALL patients who experience dexamethasone-induced neuropsychological problems as it may improve HRQoL for patients who suffer most from dexamethasone-induced neurobehavioral side effects. Furthermore, by investigating multiple risk factors that could be related to inter-patient variability in developing these side effects, we might be able to identify and treat patients who are at risk earlier during treatment. Show less
In this dissertation, we aimed to identify the influence of cortisol exposure and cognitive performance on the clinical course of bipolar disorder. Data regarding sociodemographics, disease... Show moreIn this dissertation, we aimed to identify the influence of cortisol exposure and cognitive performance on the clinical course of bipolar disorder. Data regarding sociodemographics, disease characteristics and genetic analysis of the cortisol receptors, were collected of 366 patients with bipolar disorder (BD). Part of this cohort participated in the longitudinal study, including the Test for Attentional Performance, prospectively registration of mood, and the collection of hair samples to assess long term cortisol. The main findings are as follows: 1) Several Glucocorticoid Receptor (GR) gene polymorphisms, in particular the 9β polymorphism (rs6198), relate with clinical characteristics of BD. The most important relations were with the number of (hypo)manic episodes, and second, with seasonal patterns of mood episodes, especially hypomania. 2) Higher long term cortisol exposure is associated with more psychiatric co morbidity in BD patients., and with an older age at onset, indicating a subgroup of patients. 3) Medication as potential confounder on cognitive performance, appeared to relate with the type (mainly antipsychotics) and the number of different types of medication used. Summarizing, cortisol exposure is associated with several clinically relevant phenomena defining course of BD and give insight in possible subgroups of patients with higher cortisol exposure. Show less
Verweij, E.J.; Hogenbirk, K.; Roest, A.A.W.; Brempt, R. van; Hazekamp, M.G.; Jonge, E. de 2012
