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 foal mortality, having a negative impact to the US equine industry. Hypotension, shock and organ failure are common findings in foals with sepsis. The maturation of the hormonal 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, ombined with immunosuppression, worsen their prognosis for survival. The ypothalamus (part of the brain) is the master regulator of the stress response to sepsis, including cardiovascular function. The renin-angiotensin-aldosterone system (RAAS) represents a series of factors from the kidney, liver, adrenal gland, hypothalamus and pituitary gland that control blood pressure. We speculate that septic foals with poor tissue perfusion (cold extremities, tachycardia, recumbent) will have an enhanced hypothalamic and RAAS response and that foals with a poor hormonal response will be more likely to die. This study could have clinical implications, as RAAS and cardiovascular modulation with fluids and drugs could be considered in septic foals with tissue hypoperfusion.
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 assess endocrine components of the hypothalamic-pituitary axis involved with the stress and vasomotor response to sepsis in critically ill foals. The objectives of this study are: (1) to assess the hypothalamic-pituitary and RAAS response in septic (n=50), sick non-septic (n=30) and healthy foals (n=20), and (2) to determine the association between endocrine factors with clinical/ laboratory findings, severity of sepsis and survival. We hypothesize that most septic foals 1) will have an enhanced hypothalamic-pituitary and RAAS response that 2) will be associated with severity of sepsis, and that 3) foals with a poor endocrine response will be more likely to die. If proven correct, this could be a clinical justification to use hormones and analogs (e.g. AVP) in septic foals with evidence of tissue hypoperfusion and hypotension. Expected outcome: Based on information from other species and preliminary work, we anticipate endocrine dysregulation in critically ill foals when compared to healthy or sick non-septic foals. Specifically, we expect that most septic foals will have an increased hypothalamic/RAAS response (↑AVP, CRH, ACTH, renin, ANGII, and aldosterone) and that foals with a poor response will have severe sepsis and will be more likely to die. Strength of the study: We believe that our objectives/hypotheses are sound and will address clinically relevant problems of septic foals (hypotension, hypoperfusion, organ failure, volume depletion, dehydration). Based on previous work, we assume that our objectives can be addressed in the stipulated time frame with this number of foals. Collaboration between academia and private practices to address an important equine problem strengthens this proposal. This, as previous studies, is central to the training of the next generation of internist / clinical researchers. A graduate student has been included on this project. The graduate student will be responsible for various aspects of the study including blood sample collection and processing, information retrieval from the medical records, laboratory assays, statistical analysis, manuscript preparation, nad presentation of results at local and national meetings. We will use data generated from this project to seek further extramural funding (USDA, MAF, AQHA) to address clinically relevant, but forgotten problems of horses. For example, this proposal is a simplistic approach to the complexity of cardiovascular regulation in acute disease. Our next step is to generate more mechanistic and interventional information on the pathogenesis of equine sepsis.
Project Methods
Animals and inclusion criteria: Critically ill septic foals (n=50) of less than one week of age with documented evidence of sepsis (defined as a sepsis score >14, or positive blood bacterial culture)47,48 admitted to the OSU VMC, Hagyard Equine Institute and Rood and Riddle Equine Hospital (Lexington, KY) (enclosed letters of collaboration - appendix) during a period of two years (2011-2012 foaling seasons) will be included in the study. Foals with a sepsis score <11 and admitted for reasons other than sepsis (peripartum asphyxia, meconium impaction, trauma) will be classified as sick non-septic (n=30). Foals with sepsis scores from 11-14 will not be included as we want to clearly separate sick non-septic foals (sepsis score <11) from those with clear evidence of sepsis (>14; enclosed sepsis form-appendix). This selection criterion is based on the modification48 of the sepsis score system developed by Brewer and Koterba47 as sepsis scores of >11 showed low specificity/sensitivity in foals with demonstrated sepsis. The control group (healthy foals, n=20) will be foals of less than one week of age with no evidence of disease based on clinical exam, CBC, chemistry profile, fibrinogen and serum IgG concentrations (>800 mg/dl). We predict that most foals will be <48 h old. Differentiating between septic and non-septic foals will be important to determine whether changes in these endocrine factors are associated with severity of sepsis and mortality. Obtaining this number of foals will not be a problem. OSU admits ~60 septic foals/year while HDM and RR admit about 600 foals/year (combined). Foals of all breeds will be included. Foals treated with antimicrobials will be included. Foals treated with plasma, crystalloid fluids, or glucocorticoids prior to admission will be excluded. Sampling and sample processing: Blood samples (20 ml total) will be collected on admission via aseptic venipuncture or directly after sterile placement of an intravenous catheter before any treatment is initiated. This will be done when blood samples for routine laboratory diagnostics are collected. Removing this additional volume of blood will not be harmful to these foals. The owner/trainer will be asked for permission (owner consent form-appendix). Blood will be collected into plain (10 ml) and ice cold (10 ml) EDTA/aprotinin tubes. Aprotinin is a protease inhibitor, important to increase peptide hormone stability. After centrifugation, plasma and serum samples will be stored in 250 μl and 500 μl aliquots at -80 degrees C until analysis. Clinical evaluation and laboratory analysis: Clinical information will be retrieved from the medical records, foal examination form, and sepsis score sheet (enclosed-appendix). Collection of the clinical and laboratorial information from these institutions will be responsibility of the resident/graduate and summer students. Hemogram, blood chemistry, IgG, and fibrinogen will be processed on admission. All hormones will be determined in our laboratory.