Recipient Organization
OHIO STATE UNIVERSITY - VET MED
1900 COFFEY ROAD, 127L VMAB
COLUMBUS,OH 43210
Performing Department
Clinical Sciences
Non Technical Summary
Sepsis (blood and tissue infection by bacteria) is the number one cause of foal mortality, having a negative impact in the US equine industry. Hypotension, shock and organ failure are common findings in foals with sepsis. The maturation of the hornmonal and cardiovascular systems in foals occurs in late gestation and early post-natal period, making them prone to mal-adaptation and organ dysfunction. These abnormalities, combined with immunosuppression, worsen their prognosis for survival. In response to severe infections, the hypothalamus (part of the brain) and pituitary gland stimulate the adrenal gland to produce hormones (e.g. cortisol, aldosterone) to mitigate the harmful effects of stress and infections. These hormones control inflammation, energy, electrolytes and blood pressure. Goals of this study: to determine the importance of adrenal gland failure in critically ill newborn foals, and to determine the association between hormones of the adrenal gland with survival. We hypothesize that in critically ill septic foals there is a poor response of the adrenal gland to release hormones that are essential for survival. This concept is known as relative adrenal insufficiency (RAI). A consequence of RAI in sick foals would be energy dysregulation, abnormal eletrolyte levels, low blood pressure, organ failure and death. This study will have clinical value in terms of prognosis and treatments.
Animal Health Component
(N/A)
Research Effort Categories
Basic
(N/A)
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
The overall goal of this project is to do a complete endocrine assessment of the adrenal gland cortex stress response in newborn foals with naturally occurring sepsis and to determine the clinical relevance of adrenal gland insufficiency (RAI) in these foals. To address these questions, we will profile secreted glucocorticoids, mineralocorticoids, and steroid precursors, and ACTH in healthy, septic, and sick non-septic newborn foals and determine their association with severity of disease and mortality. Objectives: (1) To assess the adrenocortical steroid response (glucocorticoids, mineralocorticoids, and precursors) in hospitalized foals, (2) To determine the prevalence of RAI (based on ACTH and steroid ratios) and its association with clinical/laboratory findings, and (3) To determine whether these endocrine factors are associated with severity of disease and mortality. Hypotheses: (1) Critically ill septic foals will have increased blood concentrations of steroids from the different adrenocortical layers, (2) these steroids will be abnormally low in foals with severe sepsis (supporting RAI), and (3) septic foals with a poor steroid response will be more likely to die. Expected results: Based on information from other species, and preliminary studies in our lab, we anticipate that adrenal gland insufficiency will be frequent in critically ill septic foals when compared to healthy or sick non-septic foals. Specifically, we expect that most septic foals will have an increased response of steroids from all cortical layers (cortisol, aldosterone, progesterone, DHEA, etc) and that foals with a poor response (RAI) will have severe sepsis and will be more likely to die. Significance: Foal sepsis/septicemia is the number one cause foal mortality. A major complication of sepsis is relative adrenal insufficiency (RAI) or critical illness-related corticosteroid insufficiency (CIRCI), which impairs the secretion of a number of adrenal gland corticosteroids and contribute to mortality. RAI is defined as an inappropriately low cortisol response to ACTH. Based on cortisol concentrations, RAI was recently documented in critically ill foals by us and others. We are proposing that in critically ill foals, RAI (hypoadrenocorticism) is associated with an impaired corticosteroid response from the different adrenocortical layers. This study will show that RAI, in addition of affecting metabolic and immune functions (cortisol), also disturbs mineral and fluid homeostasis (aldosterone), as well as organ differentiation (cortisol, DHEA, pregnenolone). This information could also have prognostic and therapeutic value. Without knowing the adrenal endocrine response to sepsis, in particular if RAI is suspected, it is difficult to justify the use of steroid analogs. Work will be submitted for presentation at various local and national meetings (ACVIM, AAEP). Information generated will be shared with practitioners in Ohio, Kentucky, and other locations.
Project Methods
Experimental Plan: Animals: Foals of < 7 days of age. Foals with a sepsis score >12 will be classified septic (n=30). Foals with a sepsis score <11 will be classified as sick non-septic (n=30). The control group (healthy foals, n=20) will be foals with no evidence of disease. Blood samples will be collected on admission into plain and ice cold EDTA/aprotinin tubes. Plasma and serum samples will be stored at -80 degrees C until analysis. Hormones will be determined in our laboratory. Cortisol, aldosterone, progesterone, 17alpha-hydroxyprogesterone, DHEA, androstenedione, pregnenolone, and ACTH will be determined with immunoassays validated for horses. Expected outcome: We anticipate that adrenal gland insufficiency will be frequent in critically ill foals. We expect that foals with severe disease will have impaired secretion on multiple adrenal steroids (cortisol, aldosterone, progesterone, DHEA, etc) and that foals with a poor response (RAI) will be more likely to die. The objectives/hypotheses of this study will address a clinically relevant problem of septic foals. We are confident that our objectives will be addressed in the stipulated time frame. Collaboration with private practices strengthens this project. This study will also be important in the training of veterinarians, clinical researchers, and veterinary medicine students interested in clinical research. A potential pitfall could be that major endocrine individual variations will not yield conclusive information. It is exactly for that particular reason that we established collaborations with equine hospitals with larger caseloads. Statistical Analysis: Calculation of sample size was based on the assumed statistical power of 0.8, mean plus or minus SD. Data will be expressed as mean plus or minus SD, medians, interquartile ranges and percentages. Association between variables will be determined by the Pearson or Spearman correlations, t-tests, Mann-Whitney U method, one-way ANOVA or Kruskal-Wallis ANOVA. Continuous variables will be categorized. Chi square test will be used for the univariate evaluation. Associated with survival will be coded as categorical for stepwise multivariate logistic regression analysis. Associations will be expressed as relative odds (odds ratios). Goodness of fit will be assessed by the Hosmer and Lemeshow method. Statistical software (SAS, SigmaStat) will be used for data analyses. Classroom teaching, laboratory instruction, data analysis and interpretation, continued education, comparative endocrinology, clinical training. It is our goal to demonstrate that our view on the response of the adrenal gland during disease in newborn foals is more complex and that hormones essential for regulating blood supply need more attention. This information will impact our understanding on equine and comparative endocrinology beyond our institution. It will have therapeutic implications. Presentations are meetings, sharing information with students, peers, colleagues, and horse owners; peer reviewed publications, better understanding on equine endocrinology, implementation of better treatments based on generated information.