Critical illness-related corticosteroid insufficiency in dogs with systemic inflammatory response syndrome: A pilot study in 21 dogs.

Critical illness-related corticosteroid insufficiency (CIRCI) refers to a lack of adequate corticosteroid activity, which occurs in up to 48% of dogs with sepsis. However, data regarding the occurrence of CIRCI in critically-ill dogs are still scarce. This study aimed to assess: (1) the relationship between CIRCI and clinicopathological inflammatory markers, hypotension and mortality; and (2) the impact of low-dose hydrocortisone treatment on survival. Twenty-one dogs diagnosed with systemic inflammatory response syndrome (SIRS) were enrolled in a prospective case-control study. All dogs were initially evaluated for adrenal function with an ACTH stimulation test and dogs with Δcortisol ≤ 3 µg/dL were diagnosed with CIRCI. Mean arterial pressure (MAP), white blood cell (WBC), band neutrophils (bNs), c-reactive protein (CRP), and 28-day mortality rate were assessed. Fourteen dogs were treated with low-dose hydrocortisone. The relationships between CIRCI and MAP, WBC, bN, CRP, basal cortisol and mortality were investigated, as was the association between mortality and hydrocortisone treatment. Ten of 21 (48%) dogs were diagnosed with CIRCI. Increased bNs were associated with the presence of CIRCI (P = 0.0075). CRP was higher in dogs with CIRCI (P = 0.02). Fourteen of 21 (66%) dogs died during the study (6/14 had CIRCI). Basal hypercortisolemia (>5 µg/dL) was associated with increased risk of mortality (P = 0.025). Based on our diagnostic criteria, CIRCI occurs frequently in dogs with SIRS and was associated with increased bNs and increased CRP. In this study, CIRCI and low-dose hydrocortisone treatment were not significantly associated with mortality, but basal hypercortisolemia was associated with increased mortality.

Retrospective evaluation of the use of hydrocortisone for treatment of suspected critical illness-related corticosteroid insufficiency (CIRCI) in dogs with septic shock (2010-2017): 47 cases.

OBJECTIVE: To evaluate characteristics of septic shock patients treated with hydrocortisone (HC) due to suspicion of critical illness-related corticosteroid insufficiency (CIRCI) as compared to septic shock patients without suspicion of CIRCI. DESIGN: Retrospective study between February 2010 and October 2017. SETTING: University teaching hospital ICU. ANIMALS: Data were collected for 47 dogs with septic shock. Twenty-one dogs were treated with HC (HC-treated) due to suspicion of CIRCI. Twenty-six dogs did not receive HC (non-HC-treated). INTERVENTIONS: HC was administered either as an intermittent IV bolus or as a constant rate infusion (CRI) to those patients with suspected CIRCI. MEASUREMENTS AND MAIN RESULTS: Significantly higher baseline APPLEfull scores and predicted mortality were detected in the HC-treated patients compared to non-HC-treated patients (0.87 vs 0.44 for predicted mortality, P = 0.039). Patients in the HC-treated group were on more vasopressors and cardiotonics than those in the non-HC-treated group (2.5 vs 1.5, P <0 .001). All patients initially responded to vasopressor administration, with average time to resolution of hypotension being 90 minutes for the HC-treated group compared to 60 minutes for the non-HC-treated group (P = 0.640). However, HC-treated patients took significantly longer to have a sustained resolution (a systolic blood pressure > 90 mm Hg or a mean blood pressure > 65 mm Hg for at least 4 h) of their hypotension after starting vasopressors, as compared to their non-HC-treated counterparts (8.5 vs 4 h, P = 0.001). Three (14.3%) HC-treated patients survived to discharge compared to 9 (34.6%) non-HC-treated patients, but this was not statistically significant. CONCLUSIONS: HC-treated patients had a higher baseline risk of mortality than non-HC-treated patients. There was no significant difference in survival between the HC-treated and non-HC-treated septic shock patients. Further studies are needed to evaluate the use of HC in patients with suspected CIRCI.

Diagnosis and treatment of primary central nervous system lymphoma with the primary lesion in the hypothalamus: a case report.

BACKGROUND: Primary central nervous system lymphoma is a rare extra-nodal lymphoma of the central nervous system. Primary central nervous system lymphoma lesions usually appear in the vicinity of the ventricle, and there are few reports of primary central nervous system lymphoma with hypothalamic-pituitary lesions. CASE PRESENTATION: We treated a 56-year-old male with primary central nervous system lymphoma with the primary lesion in the hypothalamus, which was found by magnetic resonance imaging after sudden onset of endocrinological abnormalities. Initially, he was hospitalized to our department for hyponatremia. Endocrinological examination in conjunction with head magnetic resonance imaging and endoscopic biopsy revealed hypothalamic hypopituitarism and tertiary hypoadrenocorticism caused by a rapidly growing, diffuse large B-cell lymphoma in the hypothalamus. Remission of the tumor was achieved by high-dose methotrexate with whole brain radiotherapy, and some of the hormone responses were normalized. CONCLUSIONS: While primary central nervous system lymphoma is rare, it is important to note that hypopituitarism can result and that the endocrinological abnormalities can be partially restored by its remission.

Mechanisms of kidney dysfunction in the cirrhotic patient: Non-hepatorenal acute-on-chronic kidney damage considerations.

Renal dysfunction is a common finding in cirrhotic patients and has a great physiologic, and therefore, prognostic relevance. The combination of liver disease and renal dysfunction can occur as a result of systemic conditions that affect both the liver and the kidney, although primary disorders of the liver complicated by renal dysfunction are much more common. As most of the renal dysfunction scenarios in cirrhotic patients correspond to either prerenal azotemia or hepatorenal syndrome (HRS), physicians tend to conceive renal dysfunction in cirrhotic patients as mainly HRS. However, there are many systemic conditions that may cause both a "baseline" chronic kidney damage and a superimposed kidney dysfunction when this systemic condition worsens. The main aim of this article is to review some of the most important non prerenal non-HRS considerations regarding acute on chronic kidney dysfunction in cirrhotic patients, including renal manifestation of related to non-alcoholic steatohepatitis (NASH) viral hepatitis, the effect of cardiorenal syndrome in cirrhotics and corticosteroid-deficiency associated renal dysfunction.

A retrospective analysis of adrenal crisis in steroid-dependent patients: causes, frequency and outcomes.

BACKGROUND: Adrenal patients have a lifelong dependency on steroid replacement therapy and are vulnerable to sudden death from undertreated adrenal crisis. Urgent treatment with parenteral steroids is needed, often with IV saline for volume repletion. Episodes of adrenal crisis are, for most patients, relatively infrequent and they may not be well prepared to respond. This study explores how patients recall previous episodes of adrenal crisis and their satisfaction with UK emergency medical treatment. METHODS: We invited members of the main UK support groups representing steroid-dependent adrenal patients to complete an online questionnaire identifying the number, causes and location of previous adrenal crises (episodes needing injected steroids and/or IV fluids). Respondents were asked to rate the adequacy of their medical treatment in 2 successive questionnaires, conducted 2013 and 2017-18. RESULTS: Vomiting was the major factor identified as a cause of adrenal crisis, indicated by 80% of respondents. The most common location, at 70%, was the home. Of the 30% away from home, 1 in 3 were overseas or travelling long-distance. Self-treatment played an increasing role in emergency response: in the 5 year interval between questionnaires an increasing number of patients self-injected. By the time of the 2017-18 survey self-injection was the most common method of initial treatment, with less than two-thirds travelling to hospital for follow-up medical treatment. This finding help to explain the higher rate of adrenal crisis identified in patient surveys than in hospital records. Satisfaction with medical care received stayed constant between the 2 surveys despite growing resourcing pressures across the NHS. Two-thirds were happy with the quality of the medical treatment they received for their most recent adrenal emergency; timeliness was the main factor influencing satisfaction. CONCLUSIONS: Around one-third of adrenal patients report sub-optimal treatment at emergency medical departments. Medical staff have a low probability of encountering adrenal crisis and may be unfamiliar with either the urgency of adrenal crisis or the specific treatment response it requires. Comprehensive protocols for emergency medical staff with detailed patient education and training are needed in how to respond to this infrequently encountered - but acutely life-threatening - scenario.

Critical Roles of Endogenous Glucocorticoids for Disease Tolerance in Malaria.

During malaria, the hypothalamic-pituitary-adrenal (HPA) axis is activated and glucocorticoid (GC) levels are increased, but their essential roles have been largely overlooked. GCs are decisive for systemic regulation of vital processes such as immune responses, vascular function, and metabolism, which are crucial in malaria. Here, we introduce GCs in general, followed by their versatile roles for disease tolerance in malaria. A complementary comparison is provided with their role in sepsis. Finally, potential translational implications are considered. The failed clinical trials of dexamethasone against cerebral malaria in the past have diminished the interest in GCs in malaria. However, the issue of relative corticosteroid insufficiency has barely been explored in malaria patients, but may hold promise for a better understanding and treatment of specific malaria complications.

[Functional diagnostics in endocrinology]. / Funktionsdiagnostik in der Endokrinologie.

When investigating many endocrinological diseases, basal laboratory parameters are not sufficient to distinguish between physiological and pathological hormone secretion. Functional diagnostics plays a decisive role in this context. Stimulation and suppression tests are used depending on whether under- or over-function needs to be diagnosed. This review article discusses selected functional tests, each of which plays an important role in current guidelines. Indications and test principles, including their performance, reliability, and limitations, are discussed. Topics covered include the ACTH stimulation test for the diagnosis of adrenal cortex insufficiency and the dexamethasone inhibition test for suspected Cushing's syndrome, as well as functional tests for the diagnosis of primary hyperaldosteronism, pheochromocytoma, acromegaly, growth hormone deficiency, thyroid nodules and suspicion of medullary thyroid carcinoma, insulinoma, and Zollinger-Ellison syndrome. Functional tests that are explicitly not recommended are also addressed.

Hipersensibilidad a corticoides y manejo en asma severa. A propósito de un caso / Hipersensitivity to corticosteroids and management of severe bronchial asthma. Case study

Resumen Las reacciones de hipersensibilidad a corticoides son raras en la población general, se dividen en dos categorías: Inmediatas, típicamente mediadas por Inmunoglobulina E (IgE), donde se incluye la anafilaxia luego de la administración de un fármaco en un corto período. Su prevalencia descrita es de 0,3-0,5%. Otra reacción es la 'no inmediata', que se manifiesta en un tiempo mayor de una hora después de la administración del fármaco. Se revisó la literatura con el objetivo de mejorar y aclarar el tratamiento en pacientes asmáticos que poseen esta condición. Se encontró que las vías posibles para generar estas reacciones son intranasal, aerosol por inhalador, oral y parenteral. Frente a esta condición se requiere una evaluación estrecha y detallada de la historia clínica, síntomas y reacciones secundarias al fármaco sospechoso. Finalmente, al momento de elegir tipo de corticoide a usar es primordial la seguridad del paciente logrando, además, el control de la enfermedad.

Hypersensitivity reactions to corticosteroids are rare in the general population, they fall into two categories: 'immediate', typically mediated by immunoglobulin E (IgE), which includes anaphylaxis after administration of a drug in a short period of time. Its reported prevalence is 0.3-0.5%. Another reaction is 'not immediate', which manifests itself in a time longer than one hour after the administration of the drug. We reviewed the literature with the aim of improving and clarifying the treatment in asthmatic patients with this condition. It was found that the possible routes to generate these reactions are intranasal, aerosol by inhaler, oral and parenteral. Facing this condition requires a close and detailed evaluation of the clinical history, symptoms and side reactions to the suspected drug. Finally, when choosing which corticosteroid to use, the patient's safety is paramount, and control of the disease is also essential.

Incidence and risk factors for hypoadrenocorticism in dogs treated with trilostane.

The aim of this study was to describe the incidence and permanence of hypoadrenocorticism associated with trilostane treatment and to assess potential risk factors for hypoadrenocorticism. A retrospective cohort study was conducted using case records for 156 dogs treated with trilostane after a diagnosis of hyperadrenocorticism. Occurrences of hypoadrenocorticism were categorised as either transient or permanent. After initiation of treatment with trilostane, the estimated cumulative incidence of hypoadrenocorticism was 15% by 2 years and 26% by 4.3 years, respectively. Occurrences of hypoadrenocorticism were transient in 14/19 (74%) affected study dogs. The risk of hypoadrenocorticism was not significantly associated with trilostane dose rate and other potential risk factors assessed were not significantly associated with subhazard of hypoadrenocorticism, but effect estimates for most were imprecise. In conclusion, approximately 15% of dogs being treated with trilostane developed hypoadrenocorticism within the first 2 years of treatment and about one quarter became affected by 4 years. However, first occurrences of hypoadrenocorticism were mostly transient. Over the range of dose rates studied, each 1mg/kg/day increase in trilostane dose rate resulted in, at most, only a small increase in the risk of developing hypoadrenocorticism.

Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.

OBJECTIVE: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. PARTICIPANTS: A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. DESIGN/METHODS: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. RESULTS: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence). CONCLUSIONS: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).

OBJECTIVE: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). PARTICIPANTS: A multispecialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). DATA SOURCES: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. RESULTS: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity. CONCLUSIONS: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.

Central diabetes insipidus unmasked by corticosteroid therapy for cerebral metastases: beware the case with pituitary involvement and hypopituitarism.

Patients with intra-cerebral metastases often receive glucocorticoids, particularly in the presence of peri-lesional vasogenic cerebral oedema. We present a case of presumptive lung carcinoma with cerebral metastases where central diabetes insipidus was unmasked after glucocorticoid administration and correction of undiagnosed central hypocortisolism.

Diminished adrenal sensitivity to endogenous and exogenous adrenocorticotropic hormone in critical illness: a prospective cohort study.

INTRODUCTION: Adrenal dysfunction may represent critical illness-related corticosteroid insufficiency (CIRCI), as evidenced by a diminished cortisol response to exogenous adrenocorticotropic hormone (ACTH), but this concept and its clinical significance remain highly controversial. We studied the adrenal response to exogenous ACTH as a function of the endogenous cortisol-to-ACTH ratio, a measure of adrenal sensitivity, and of clinical variables, during critical illness and recovery from the acute phase. METHODS: We prospectively included 59 consecutive septic and nonseptic patients in the intensive care unit with treatment-insensitive hypotension in whom CIRCI was suspected; patients having received etomidate and prolonged corticosteroids were excluded. An ACTH test (250 µg) was performed, followed by a second test after ≥7 days in acute-phase survivors. Serum total and free cortisol, ACTH, and clinical variables were assessed. Patients were divided according to responses (delta, Δ) of cortisol to ACTH at the first and second tests. RESULTS: Patients with low (<250 nM) Δ cortisol (n = 14 to 17) had higher baseline cortisol and ACTH but lower cortisol/ACTH ratios than patients with a normal Δ cortisol (≥250 nM) in the course of time. A low Δ cortisol in time was associated with more-severe disease, culture-positive sepsis, and prolonged activated prothrombin time. Results for free cortisol were similar. CONCLUSIONS: Even though the pituitary-adrenal axis is activated after stress during critical illness, diminished adrenal sensitivity to endogenous ACTH predicts a low increase of cortisol to exogenous ACTH, suggesting adrenal dysfunction, irrespective of the stage of disease. The data further suggest a role of disease severity and culture-positive sepsis.

Controversies surrounding critical illness-related corticosteroid insufficiency in animals.

OBJECTIVES: To describe the controversies surrounding critical illness-related corticosteroid insufficiency (CIRCI) and the use of hydrocortisone in critically ill patients, and to present published diagnostic and therapeutic strategies in companion veterinary species. ETIOLOGY: Critical illness-related corticosteroid insufficiency may be due to hypothalamic-pituitary-adrenal (HPA) axis dysfunction, alterations in cortisol-plasma protein binding, target cell enzymatic changes, changes in glucocorticoid receptor (GR) function, or a combination of these or other factors present during critical illness. DIAGNOSIS: Appropriate tests to diagnose CIRCI are unknown. The diagnosis in people is currently based on response to treatment with hydrocortisone. There is currently no consensus on appropriate diagnostic feature(s) in veterinary species. THERAPY: Low-dose hydrocortisone is the treatment of choice for patients with CIRCI. PROGNOSIS: If the patient survives the critical illness, prognosis for resolution of CIRCI and hydrocortisone dependence is very good.

Critical illness-related corticosteroid insufficiency after multiple traumas: a multicenter, prospective cohort study.

BACKGROUND: Given that the observed prevalence and time course of critical illness-related corticosteroid insufficiency (CIRCI) remain inconsistent in trauma patients, the present study was designed to investigate the prevalence, time course, and effect of CIRCI on the outcome of critically ill patients with multiple injuries. METHODS: In this multicenter, prospective cohort study, patients with multiple injuries in seven intensive care units in China were enrolled. Adrenocorticotropic hormone (ACTH) stimulation tests were performed by administering intravenously 250 µg of synthetic ACTH on Days 1, 2, 3, 5, and 7 after traumatic injury. CIRCI was defined as baseline cortisol level of less than 10 µg/dL or a Δcortisol (difference baseline and highest cortisol level at 30 or 60 minutes after ACTH stimulation) less than 9 µg/dL. The incidence and time course of CIRCI and 28-day mortality were recorded. RESULTS: CIRCI occurred in 54.3% (38 of 70) of the patients with multiple injuries, including 10 patients with total cortisol level of less than 10 µg/dL and 28 patients with Δcortisol of less than 9 µg/dL. Most (94.7%) diagnosis of CIRCI was made in the first 48 hours after traumatic injury. The CIRCI patients had significantly more severe illness on the day of admission. At each time point, the baseline cortisol level was comparable between the CIRCI and non-CIRCI patients, while Δcortisol in the CIRCI group was significantly lower compared with the non-CIRCI group. The CIRCI patients with a Δcortisol of less than 9 µg/dL had a significantly higher 28-day mortality (39.3%) compared with those with a baseline cortisol level of less than 10 µg/dL (10.0%) and non-CIRCI patients (6.3%). Only Δcortisol of less than 9 µg/dL but not baseline cortisol level of less than 10 µg/dL seemed to be an independent risk factor for death (odds ratio, 1.19; p = 0.023). CONCLUSION: CIRCI is common in critically ill trauma population and usually occurs in the early stages. Only the results of the ACTH stimulation test but not baseline cortisol level was associated with poor prognosis. LEVEL OF EVIDENCE: Prognostic study, level II.

A new way of thinking: hydrocortisone in traumatic brain-injured patients.

Data suggest that treatment of critical illness-related corticosteroid insufficiency after traumatic brain injury (TBI) with a stress dose of hydrocortisone may improve the neurological outcome and the mortality rate. The mineralocorticoid properties of hydrocortisone may reduce the rate of hyponatremia and of brain swelling. The exaggerated inflammatory response may cause critical illness-related corticosteroid insufficiency by altering the function of the hypothalamic-pituitary-adrenal axis, and hydrocortisone is able to restore a balanced inflammatory response rather than inducing immunosuppression. Hydrocortisone could also prevent neuronal apoptosis. Considering side effects, corticosteroids are not equal; when a high dose of synthetic corticosteroids seems detrimental, a strategy using a stress dose of hydrocortisone seems attractive. Finally, results from a large multicenter study are needed to close the debate regarding the use of hydrocortisone in TBI patients.

Critical illness-related corticosteroid insufficiency in children.

Adequate adrenocortical function is essential for survival in critical illness. Most critically ill patients display elevated plasma cortisol concentrations, which reflects activation of the hypothalamic-pituitary-adrenal axis and is considered to be a homeostatic adaptation. However, many critically ill patients have 'relative' or 'functional' adrenal insufficiency, which is characterized by an inadequate production of cortisol in relation to an increased demand during periods of severe stress. Recently, the term 'critical illness-related corticosteroid insufficiency' (CIRCI) was coined. CIRCI occurs as a result of a decrease in adrenal steroid production or tissue resistance to glucocorticoids. An international task force of the American College of Critical Care Medicine issued recommendations for the diagnosis and management of this condition in adult patients. We review the prevalence, diagnosis, and therapeutic approach to adrenal insufficiency in critically ill children. We found a lack of consensus within the pediatric field as to the optimal approach to CIRCI, and call for an international task force to establish unified guidelines.

Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats.

INTRODUCTION: The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in severe traumatic brain injury (TBI) is not fully defined and no effective treatments for TBI-induced CIRCI are available to date. Despite growing interest in the use of stress-dose hydrocortisone as a potential therapy for CIRCI, there remains a paucity of data regarding its benefits following severe TBI. This study was designed to investigate the effects of stress-dose hydrocortisone on CIRCI development and neurological outcomes in a rat model of severe traumatic brain injury. METHODS: Rats were subjected to lateral fluid percussion injury of 3.2-3.5 atmosphere. These rats were then treated with either a stress-dose hydrocortisone (HC, 3 mg/kg/d for 5 days, 1.5 mg/kg on day 6, and 0.75 mg on day 7), a low-dose methylprednisolone (MP, 1 mg/kg/d for 5 days, 0.5 mg/kg on day 6, and 0.25 mg on day 7) or control saline solution intraperitoneally daily for 7 days after injury. RESULTS: We investigated the effects of stress-dose HC on the mortality, CIRCI occurrence, and neurological deficits using an electrical stimulation test to assess corticosteroid response and modified neurological severity score (mNSS). We also studied pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), after stress-dose HC or a low dose of MP was administered, including apoptosis detected by a TUNEL assay, blood-brain barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and claudin-5 expression. We made the following observations. First, 70% injured rats developed CIRCI, with a peak incidence on post-injury day 7. The TBI-associated CIRCI was closely correlated with an increased mortality and delayed neurological recovery. Second, post-injury administration of stress-dose HC, but not MP or saline increased corticosteroid response, prevented CIRCI, reduced mortality, and improved neurological function during the first 14 days post injury dosing. Thirdly, these beneficial effects were closely related to improved vascular function by the preservation of tight junctions in surviving endothelial cells, and reduced neural apoptosis in the PVN of hypothalamus. CONCLUSIONS: Our findings indicate that post-injury administration of stress-dose HC, but not MP reduces CIRCI and improves neurological recovery. These improvements are associated with reducing the damage to the tight junction of vascular endothelial cells and blocking neuronal apoptosis in the PVN of the hypothalamus.

Effects of glucocorticoids on traumatic brain injury related critical illness-related corticosteroid insufficiency.

BACKGROUND: Traumatic brain injury (TBI) is a heterogeneous condition that can lead to critical LLLness-related corticosteroid insufficiency (CIRCI) causing a high mortality and morbidity. Glucocorticoids were widely used in the clinical management of TBI, but their benefit has been challenged in some studies and their efficacy, especially for treating CIRCI in TBI patients, remains unclear. METHODS: We conducted a meta-analysis of published data to determine if the controversy is related to clinical dosing and timing of glucocorticoids (GCs) application. We analyzed published reports in four databases (MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and CBMdisc). The published data were stratified into not only low- and high-dose GCs group but also short- and long-term GCs group to compare their effectiveness in improving TBI outcomes. RESULTS: We totally identified 16 reports. For low-dose patients, the pooled relative risks (RRs) for two clinical outcomes of death or a combination of death and severe disability were 0.95 (95% confidence interval (CI): 0.80 to 1.13) and 0.95 (95% CI: 0.83 to 1.09), respectively. The risks for infection and gastrointestinal bleeding were 0.85 (95% CI: 0.50 to 1.45) and 0.64 (95% CI: 0.15 to 2.70), respectively. For high-dose group, the pooled RR of death is 1.14 (95% CI: 1.06 to 1.21). The pooled RRs for infection and gastrointestinal bleeding for the high-dose patients were 1.04 (95% CI: 0.93 to 1.15) and 1.26 (95% CI: 0.92 to 1.75), respectively. For long-term use group, the pooled RRs for two clinical outcomes of death or a combination of death and severe disability were 0.98 (95% CI: 0.87 to 1.12) and 1.00 (95% CI: 0.90 to 1.11), respectively. The risks for infection and gastrointestinal bleeding were 0.88 (95% CI: 0.71 to 1.11) and 0.96 (95% CI: 0.35 to 2.66), respectively. For short-term use group, the pooled RR of death is 1.15 (95% CI: 1.07 to 1.23), and importantly the effects on infections were beneficial in terms of TBI patients suffering from CIRCI. CONCLUSIONS: This meta-analysis suggests an increased risk of death for TBI patients on a high dose and short term of glucocorticoids compared with those on a low dose and long term, for whom a trend towards clinical improvement is evident. In addition, stress-does of GCs further decrease the pneumonia incidence in TBI patients suffering from CIRCI. A large-scale multicenter randomized controlled trial is warranted for testing (1) the efficacy of stress-dose GCs treatment in the sub-acute phase of TBI (4-21 days after initial trauma), when CIRCI is most likely to occur; (2) the hypothesis that stress-dose GCs could boost patients' stress function and ensure survival.