Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

BACKGROUND: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. STUDY DESIGN AND METHODS: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. RESULTS: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11ß-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11ß-HSD2 activity. Hepatic 11ß-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11ß-HSD1 in subcutaneous adipose tissue. CONCLUSION: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Cardiometabolic and psychological effects of dual-release hydrocortisone: a cross-over study.

BACKGROUND: Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs. METHODS: An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment. RESULTS: Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15-20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (-1.23 kg, P = 0.006) and BMI (-0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI. CONCLUSION: Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.

Pneumococcal Meningitis Complicated by Spinal Cord Dysfunction and Acute Polyradiculopathy.

Background: Meningitis caused by Streptococcus pneumoniae is associated with devastating clinical outcomes. A considerable number of patients will develop long-term neurologic complications. Hearing loss, diffuse brain edema, and hydrocephalus are frequently encountered. Acute spinal cord dysfunction and polyradiculopathy can develop in some patients. Case Report: A 63-year-old female was admitted to our hospital with sudden-onset bilateral lower extremity weakness. On admission, the patient had evidence of spinal cord dysfunction given the abnormal motor and sensory physical examination findings and the absent sensation with a sensory level at dermatome T4 on neurologic examination. Computed tomography myelography did not show evidence of spinal cord compression or transverse myelitis. Cerebrospinal fluid examination was positive for pneumococcal meningitis. The patient was treated with antibiotics and steroids. Nerve conduction studies demonstrated the absence of response, suggesting damage to the peripheral nerves and polyradiculopathy. The patient was treated with plasmapheresis for possible Guillain-Barré syndrome; however, she did not improve despite appropriate antibiotics, steroids, and plasmapheresis. She developed persistent quadriparesis, sensory impairments in upper and lower extremities, and bowel and bladder sphincter dysfunction. Conclusion: Our case demonstrates the development of spinal cord dysfunction (supported by the sudden onset of paraplegia and the presence of a sensory level) and polyradiculopathy (flaccid paralysis, ascending weakness, and absence of response in neurophysiologic studies suggesting severe damage to the peripheral nerves). The appearance of either complication is unusual, and the simultaneous occurrence of both complications is even more uncommon.

Blood Pressure measurements are site dependent in a cohort of patients with neurological illness.

Blood pressure (BP) management is a crucial part of critical care that directly affects morbidity and mortality. While BP has become a mainstay in patient care, the accuracy and precision of BP measures across commonly used sites (left upper arm, right upper arm, etc.) and methods have not been established. This study begins to fill this gap in literature by testing the null hypothesis that BP measurement does not vary according to site. This is a prospective, non-randomized, cross-sectional study of 80 neurocritical care unit patients. Near simultaneous non-invasive blood pressure (NIBP) readings from 4 different locations (bilateral upper arm, bilateral wrist) and, when available, intra-arterial blood pressure readings (IABP) were included. Pearson correlation coefficients and one-way repeated measures ANOVA were used to observe the systolic, diastolic, and mean arterial pressure (MAP) correlations. The BP measured at the four most common sites (left upper arm, left wrist, right upper arm, right wrist) had adequate correlation coefficients but were statistically significantly different and highly unpredictable. The median inter-site systolic variability was 10 mmHg (IQR 2 to 10 mmHg). The median inter-site MAP variability was 6mmHg with an interquartile range (IQR) of 3 to 9 mmHg. As expected, the values correlated to show that patients with high BP in one site tended to have high BP in another site. However, the unpredictable inter-site variability is concerning within the clinical setting where oftentimes BP measurement site is not standardized but resulting values are nevertheless used for treatment. There is prominent inter-site variability of BP measured across the 4 most common measurement sites. The variability persists across non-invasive (NIBP) and invasive (IABP) methods of assessment.

Chemical Meningitis and Status Epilepticus Caused by Accidental Epidural Administration of Digoxin.

Intrathecal administration of digoxin occurs very rarely. Some case reports of inadvertently administering it when performing spinal/epidural anesthesia were described. We report for the first time a case of a chemical meningitis and status epilepticus caused by accidental epidural administration of digoxin. A 26-year-old female underwent epidural anesthesia for a planned cesarean section (CS). Post operatively the patient became lethargic, agitated and encephalopathic, she was intubated and transferred to our hospital intensive care unit (ICU). She had seizures on admission. Electroencephalogram (EEG) was performed and showed generalized slowing and status epilepticus with a focus noted in the right temporal region which resolved after antiepileptic medication administration. A lumbar puncture (LP) was performed; cerebro-spinal fluid (CSF) was suggestive for meningitis. However, there was no evidence for viral or bacterial infections. Within a day of admission, the referring hospital informed us that the patient received 250 mcg of digoxininadvertently-through epidural injection. The patient remained intubated for four days. She became more responsive and alert and was eventually extubated. After extubation, the patient was responsive and full neurological exam and brain imaging were normal. She was discharged from the hospital after seven days.

Screening for Impaired Glucose Tolerance (Prediabetes) and Prevention of Type 2 Diabetes.

The enormous implications caused by type 2 diabetes on patients, families and health systems in the U.S. require health care providers to apply measures that reduce its burden. Scientific evidence clearly shows that proper screening of populations at risk, implementation of interventions proven beneficial in preventing type 2 diabetes and the use of modern technology in educating patients to adopt a healthier lifestyle are paramount in decreasing the incidence of type 2 diabetes. In this article, we try to answer some of the questions raised by both patients and health care providers about how lifestyle modifications can play a key role in ameliorating and reversing impaired glucose tolerance and type 2 diabetes.