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Effects of Conjugated Estrogens and Aminocaproic Acid on Reducing Exercise-Induced Pulmonary Hemorrhage
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1. Introduction
Established treatments for exercise-induced pulmonary hemorrhage (EIPH) include the nasal strip and furosemide. Although these abrogate the degree of EIPH measured after exercise, they have not been able to completely eliminate EIPH. Progress to abolition of EIPH has been hampered by the complex multifactorial etiology of EIPH as well as the limited sensitivity and quantitative ability of some techniques used in detecting changes in the severity of EIPH as a result of treatment. Both aminocaproic acid (ACA) and conjugated estrogens [a] have been considered potential treatments for EIPH by means of their putative effect on blood coagulation during exercise. We hypothesized that neither ACA nor PRE would show a reduction in EIPH because of evidence in the current literature that coagulation deficits are actually not manifested in exercising horses. Despite the lack of rigorous scientific testing and evidence for effectiveness against EIPH, many treatments including conjugated estrogens and anti-fibrinolytics (i.e., the ACA Amicar) are used on the racetrack. This provides a timely and compelling rationale for the present investigation.
2. Materials and Methods
To investigate if PRE and/or ACA can reduce EIPH, six Thoroughbreds were run at progressively increasing speeds on a 6°inclined treadmill [b] from 4 m/s to fatigue (in 1 m/s x 1-min increments) after being treated with 0.9% saline (placebo), PRE (25 mg), or ACA [c] (5 gm) at 2-wk intervals in a randomized crossover design. During each run, pulmonary arterial pressure, pulmonary gas exchange, heart rate, respiratory rate, arterial blood gases, plasma lactate, and time to fatigue were measured. Coagulation variables were evaluated at rest and during maximal exercise. The severity of EIPH and inflammation were quantified by enumeration of red blood cells (RBCs)/ml and white blood cells (WBCs)/ml in bronchoalveolar lavage fluid (BALF) 30 - 60 min post-exercise. Data were analyzed with a statistical package [d] using a three-period crossover design with horse and run as random effects and treatment as a fixed effect; a Least-Square Means post-hoc test was used to determine where differences existed. Significance was concluded at the p≤0.05 level.
3. Results
No alterations were shown in coagulation variables at rest or during maximal exercise for either treatment. The severity of EIPH was not reduced by either treatment (PL = 3.8±1.7x106 RBC/ml BALF; ACA = 4.6±3.2x106 RBC/ml BALF; PRE = 2.4±1.2x106 RBC/ml BALF; p = 0.12). However, inflammation was acutely ameliorated as evidenced by a decrease in WBC in the BALF (PL = 5.9±0.9x105 WBC/ml BALF; ACA = 4.4±0.9x105 WBC/ml BALF; PRE = 4.2±0.4x105 WBC/ml BALF; both p<0.05). The only maximal exercise and metabolic variables affected by treatment were a trend for decreased time to fatigue (PL = 720± 27 s; ACA = 709±24 s; PRE = 726±28 s; p = 0.09 for PL vs. ACA) and a reduction in plasma lactate (PL = 19.5±3.0 mmol/l; ACA = 14.7±1.0 mmol/l; and PRE = 17.6±2.5 mmol/l; p<0.05 for PL vs. ACA) after administration of ACA.
4. Discussion
The current investigation directly refutes anecdotal reports from the racetrack regarding the beneficial effects of using PRE and ACA as adjunct bleeder race-day medications for controlling EIPH by enhanced coagulation. However, a potential benefit of both ACA and PRE is the modest reduction in WBC concentrations in the BALF, which indicates the opportunity for mitigating the effects of pulmonary inflammation after intense exercise. In addition, larger scale studies among heavy bleeders may be warranted, because only two of six horses bled substantially in the current study; four of six of those horses were lighter bleeders. Further consideration of the data suggests that PRE may show significant reductions in EIPH when larger groups of bleeders are tested (n > 24 if the current study population is representative of all horses), potentially through anti-inflammatory effects and strengthening collagen in the blood-gas barrier. In contrast to PRE, ACA showed no potential to decrease EIPH. It was, in fact, contraindicated by the research, because when administered before maximal exercise, it was detrimental to performance.
The authors would like to thank the following people for their help in completing this project: Dr. James Higgins for help with statistical analysis and Tami Lightfoot, Kate Taylor, Megan Rice, Ann Molloy, Melia Mattke, Melissa Fund, Kally Bowen, Emily Langenegger, Coy Macy, Dustie McClain, and Megan Walters for helping with data collection and the training of the horses. Funding was provided by the American Association of Equine Practitioners, Grayson Jockey Club Research Foundation, and the Racing Medication and Testing Consortium.
Footnotes
a. Premarin, Wyeth Pharmaceuticals, Madison, NJ 07940.
b. Sato Incorporated, Vÿarsÿangsvägen 13, 5-74143 Knivsta, Uppsala, Sweden.
c. Hospira Pharmaceuticals, Lake Forest, IL 60045.
d. Statistical Analysis System (SAS) Program 9.1.2., SAS Institute, Cary, NC 27513-2414.
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