eiph: rational approach to therapy

EIPH: RATIONAL APPROACH TO THERAPY

Christine King BVSc, MACVSc, MVetClinStud

Over the years the many and var- ied methods of treating or preventing exercise-induced pulmonary hemorrhage (EIPH) in horses have been based on the various theories of the etiopathogenesis of the condition. When it was thought that a clotting defect was in- volved, procoagulants such a vitamin K, oxalic and malonic acids, and conju- gated estrogens were used? On the basis that underlying small airway disease contributed to EIPH, anti-inflammatory agents, bronchodilators, and water vapor therapy have been advocated, e Although the current rationale for the use of furosemide is still being debated, its initial use apparently pre- ceded the identification of the lung as the site of hemorrhage, 3 and its contin- ued use may have been based on the drug's ability to improve ventilation in humans with pulmonary edema, z

As John Pascoe wrote, "The diver- sity of these agents attests to the pau- city of our knowledge about EIPH, the inventiveness of the prescribers, and the general frustration experienced by clinicians and horsemen in coping with this problem. ''2 To date, there is no consensus on the etiology or pathogen- esis of EIPH - even the actual site of hemorrhage is still in question. Is the hemorrhage from alveolar capillaries

Author's address: 1410 C N. Harrison Ave., Cary, NC 27513

chial artery proliferation? Could it be that both capillary beds are similarly at risk during exercise? Is there some underlying structural or functional defect, or does hemorrhage occur simply as a result of "mechanical" failure of capillary and alveolar membranes under the extreme pressures which occur during exercise in horses?

THEORIES ON ETIOPATHOGENESIS

Small Airway Disease In an impressively comprehensive

series of papers, O'Callaghan et al. reported the clinical, 4 gross postmor- tem, s latex infusion, 6 CT, 7 radio- graphic, 8 scintigraphic, 9 and microscopic findings 1° from a group of ma- ture Thoroughbred racehorses with a history of EIPH. They concluded that bronchiolitis (possibly of viral etiology) initiates inflammatory and fibrotic changes in the lung tissue, and proliferation of bronchial vessels in affected areas? 1 With latex perfusion, it was estimated that up to 22% of the total lung volume was dominated by bronchial arterialization in these horses. 6 The authors suggested that hemorrhage during exercise occurred from the bronchial neovascular tissue because new vessels lack normal vascular control, and are therefore more prone to rupture under pressure? 1 They also proposed that bronchiolitis may cause reduced air flow in affected areas of the lung, which could result in shearing and tear- ing of lung tissue and vessels at the junction of the underventilated area and adjacent areas of normal or compensa- tory over-ventilation? °

In those studies, however, bron-

gross evidence of EIPH; the cranial and ventral portions of the lung were mi- croscopically normal? ° If, as postulated by O'Callaghan et al., the ubiqui- tous global distribution of EIPH is explained by the similarly universal presence of a respiratory virus or an aller- gen, 11 why does the agent affect only a very discrete (and amazingly uniform) region of the lung?

While not disputing their findings, there may be another way of interpret- ing the changes documented by O'Callaghan et al. The presence of free red blood ceils and their phagocytosis by alveolar macrophages may set in motion the chain of events which results in bronchiolitis, interstitial fibro- sis (if the condition persists or recurs), vascular proliferation in areas of inflammation and tissue destruction, and hemorrhage from these areas during exercise? 2 Thus, we could ask the age- old "chicken and egg" conundrum: which came first, the hemorrhage or the inflammation? If hemorrhage initi- ated the inflammation, what caused the hemorrhage?

Stress Failure of Pulmonary Capillaries

Several of the ultrastructural (trans- mission electron microscope) findings in lungs from horses with a history of EIPH are consistent with pulmonary capillary rupture: red blood cells in the alveolar wall interstitium and alveolar space, interstitial edema, and breaks in the capillary walls that are plugged with cell elements (platelets and cyto- plasmic extensions of leukocytes)? a

The mean pulmonary artery pressure in resting horses is about 40 mmHg; la'14 during strenuous exercise this can increase to about 120

Volume 15, Number 1, 1995 7

mmHg, 13,14 with peak pressures reaching values of 170 mmHg during sys- tole. 14 Estimates of mean pulmonary capillary pressure during exercise are in the order of 80-95 mmHg, 13'15'16 although these values may be underes- timating the capillary pressure during certain phases of the breathing cycle, 13 and during rapid acceleration.15 A study using anesthetized rabbits found that their pulmonary capillaries ruptured when the capillary pressure exceeded 40 mmHg; studies in dogs have shown that pulmonary capillaries are damaged when the capillary pressure exceeds 70 mmHg.13 (Incidentally, EIPH has been reported in racing greyhounds. 13) Ex- trapolating from these data, it is reason- able to hypothesize that equine pulmonary capillaries may be at risk of rup- turing under the extreme pulmonary arterial and capillary pressures which occur during strenuous exercise.

At first glance, the dorsocaudal location of EIPH lesions could argue against the stress failure theory. It would be expected that gravitational forces result in lower capillary pressures in the most dorsal lung regions; however, there is some evidence that pulmonary blood flow is particularly high in the dorsocaudal lung because of a lower intrinsic vascular resistance in this region. la Furthermore, the dorsocaudal area of the lung experiences the largest drops in pleural pressure during gallop- ing because (1) it is the furthest from the nares, and (2) displacement of the diaphragm caused by the movement of the abdominal contents, and increased by ground impacting forces, results in greater transient pressure changes in the dorsocaudal area of the lung. 13,14 This translates to higher pulmonary capillary pressures, particularly during inspiration.

Anastomoses between the termi- nal parts of the bronchial arteries and the pulmonary capillaries have been documented in apparently normal horse lungs. 6 The purpose of these "short- circuits" is not known, although they

may ensure oxygenation of interstitial and alveolar cells when ventilation and, hence, perfusion, is low (e.g. at rest). 6 During strenuous exercise the mean systemic arterial pressure in horses can exceed 240 mmHg (up from a mean of around 100 mmHg at rest).13 Assuming that bronchial arterial pressure corre- spondingly increases, the increase in blood flow through bronchopulmonary anastomoses could expose the pulmonary capillaries to even greater pressures during exercise. By the same to- ken, the new vessels seen in areas of bronchial vascular proliferation may also be more prone to rupture under the systemic arterial pressures occurring during exercise.

What isn't explained by this theory is the presence of bronchiolitis, unless we accept the hypothesis that hemorrhage into the airway initiates bron- chiolar inflammation, and the conse- quent vascular and interstitial changes known to occur with EIPH. The bronchial vascular proliferation may also be stimulated by ruptured vessels and other tissue damage.

Hemosta t ic Dysfunct ion Exercise results in an increase in

the number of circulating platelets, but a decrease in platelet responsiveness to ADP, one of the initiators of platelet aggregation in vivo. 17,18 Bayly et al. postulated that this reduction in platelet function may be due to the release of prostacyclin (PGI z - a vasodilator and a potent inhibitor of platelet aggregation). 17 This is supported by the findings of Birks et al., who reported a moderate increase in the stable metabolite of PGI z during and immediately after exercise. 19 They also found an increase in thromboxane B z (TXB 2, the stable metabolite of TXA 2 - a potent stimulator of platelet aggregation, and a vasoconstrictor) 15 minutes after exercise. The authors suggested that the increase in TXB z was in response to vascular sheer stress. 19 It could be that PGI2-mediated vasodilation and inhi-

bition of platelet aggregation ensures optimal blood flow during exercise, and TXAe-mediated platelet aggregation and vasoconstriction ensures adequate hemostasis (and possibly redis- tribution of blood flow) after exercise.

Johnstone et al. found that at rest the platelets from horses with a history of EIPH were less responsive (both in rate and degree) to several natural initiators of aggregation (ADP, collagen, and platelet activating factor), when compared with normal horses, la Dur- ing exercise, however, the reduction in ptatelet responsiveness was similar for both groups of horses? a The reason(s) for the difference in resting platelet function between normal horses and those with EIPH is open to speculation. Reducing platelet responsiveness may be a means of maintaining adequate blood flow through affected capillary beds, by preventing the recruitment of circulating platelets onto existing platelet clumps; alternatively, the alteration in platelet function may simply be an incidental effect of vascular or inflammatory changes secondary to EIPH. No matter what its purpose, it is conceivable that the sluggish platelet response may impair platelet plugging of damaged vessels, thereby contributing to, or exacerbating blood loss during EIPH episodes. 17'1a

There do not appear to be any consistent changes in coagulation times or fibrinolytic indices with exercise in horses. Bayly et al. reported a slight reduction in thrombin time after exercise, 17 whereas Johnstone et al. found no such change in thrombin time. 18 They did, however, see a trend toward an increase in partial thromboplastin time and a decrease in prothrombin time after exercise, which was more marked in horses with a history of EIPH. 18 These changes were quite small, and were not observed in the study by Bayly et al.; however, they do raise some interesting questions about the activity of the coagulation system in horses with EIPH.

8 JOURNAL OF EQUINE VETERINARY SCIENCE

VETERINARY REVIEW

C U R R E N T T H E R A P I E S

Furosemide Furosemide is a loop diuretic - it

achieves its diuretic effect by blocking chloride absorption in the loop of Henle. a° The direct effects are diuresis and hypochloremia. Diuresis occurs within 15 to 30 minutes of intravenous administration, and results in about a 10% reduction in plasma volume, which is essentially restored by 4 hours post- administration, el Hypochloremia con- tributes to a mild metabolic alkalosis (the plasma pH and bicarbonate concentration, and hence the buffering ca- pacity rise) which persists during exercise 4 hours after furosemide administration, al

The potential benefits of a reduction in plasma volume include a decrease in body weight (of the same magnitude as the fluid loss), and a reduction in blood pressure (particularly important in the pulmonary microcir- culation). 21 The potential drawbacks of reduced plasma volume are an increase in blood viscosity (which may reduce blood flow through capillary beds, and consequently alter gas exchange and tissue oxygenation) aa and a reduction in venous return to the heart, which may lead to reduced cardiac filling pressures and impaired circulatory function. al However, because fluid com- partment shifts and absorption of water from the colon restore the plasma volume to normal within about 4 hours (whether or not the horse was permitted to drink during that time), a these factors are not likely to affect cardiovascular function during exercise if furosemide is given 4 hours before a race.

Furosemide also has some "indirect" effects on the cardiovascular system that appear to be independent of its diuretic effect. Furosemide apparently s t imula tes the produc t ion of a "prostanoid" (possibly PGEa) by the kidney. 2° An increase in the concentration ofPGE 2 in the renal vein following

furosemide administration has been reported, z° although it is possible that the substance is a mediator which stimu- lates PGE a production in vascular en- dothelium throughout the body. 2° This hypothesis is supported by the time lag between furosemide administration (and diuresis) and the onset of vascular changes. Changes in vascular resistance and blood pressure during exercise are negligible at one hour post intravenous furosemide, 22 and yet are marked at about 4 hours after furosemide administration. 16 It has been postulated that the substance is a prostaglandin (or at least an arachidonic acid metabolite) because its effects may be blocked by cyclo-oxygenase inhibitors (e.g. flunixin, phenylbutazone), 2°'23'a4 although a recent study in strenuously exercising horses showed no such inhibition of the vascular effects of furosemide by flunixin. 2s

The "indirect" effects of furosemide are wide-reaching:

(a) vasodilation - furosemide increases venous compliance and reduces the vasoconstrictive response of arterial vessels to sympathetic stimula- tion. a°'a4 The net result in the pulmonary circulation is a reduction in vascular resistance, both at rest and during exercise. 16 Furosemide reduces the mean pulmonary arterial and venous pressures by 10 and 18 mmHg (respec- tively)? 6 and mean aortic pressure by 10-15 mmHg during strenuous exercise. 22 One study estimated that furosemide reduced the pulmonary capillary pressure by 14 mmHg (from 79 to 65 mmHg) during strenuous exercise.16 It is conceivable that this may reduce the potential for stress failure of the pulmonary capillaries. On the same note, assuming that the lower mean aortic pressure results in a lower bronchial arterial pressure during exercise, furosemide may reduce the potential for stress failure of the neovascular bronchial vessels, as well as reducing pressure through the bronchopulmonary anastomoses. Despite these

changes in systemic and pulmonary pressures, heart rate, oxygen consump- tion and cardiac output during exercise are unaffected by furosemide administration, as is blood flow to the respiratory and locomotory muscles; a6

(b) bronchodilation- in horses with chronic obstructive pulmonary disease (COPD), furosemide increases dynamic compliance and reduces airway resistance, starting 15 minutes after intravenous administration and peaking about 4-5 hours later, a4 This effect may be useful in horses with small airway disease;

(c) "normalizes" platelet responsiveness during and immediately after exercise. The improvement in platelet responsiveness appears to be greatest in horses with a history of epistaxis, although the mechanism(s) is not yet known. 27 (Bayly et al. suggested that furosemide may inhibit PGI 2 production through an increase in cyclic AMP. 27) This may have significant benefit in limiting the severity of hemorrhage during or immediately after an episode of EIPH.

In a study by Sweeney et al., furosemide apparently improved race times both in horses with endoscopic evidence of EIPH (blood in the trachea following a race), and in horses with no endoscopic evidence of EIPH. 3 How- ever, administration of furosemide 4 hours prior to a race failed to prevent hemorrhage in 61.5 % of EIPH-positive horses, and it did not prevent 25% of EIPH-negative horses from develop- ing EIPH during the study, z The authors concluded that furosemide may enhance performance through factors unrelated to pulmonary hemorrhage.

Bronchodilators The most clinically applicable and

widely used bronchodilators are the beta-2 agonists, such as clenbuterol, albuterol and terbutaline. They exert their effects at beta-2 receptors in smooth muscle, although at higher doses beta-1 receptors may also be stimu-


lated, with a resultant increase in heart rate, and the development of skeletal muscle tremors and excitation. 28 The bronchodilatory effects of these compounds have been well demonstrated in humans 28 and in horses with COPD. 2°,24 However, no changes in airway compliance or resistance have been shown in normal horses, either at rest or during exercise. 29 There is some evidence that beta-2 agonists inhibit the antigen-induced release of histamine, leukotrienes and other inflammatory mediators; they may also enhance mucociliary function, reduce microvascular permeabil- ity, and inhibit phospholipase A2. 2a These actions could be of some impor- tance in inflammatory airway disease. If small airway disease (inflamed bronchial mucosa , mucus plugs, bronchoconstriction) predisposes to, or initiates EIPH, there is some rational basis for the use of beta-2 agonists in horses with EIPH.

Beta-2 agonists may also have some clinically important vascular effects. In anesthetized horses clenbuterol causes a reduction in total peripheral resistance and pulmonary vascular resistance. 3° This reduction in pulmonary arterial and venous resistance has also been demonstrated in conscious calves following intravenous isoprot- erenol (a non-selective beta agonist). 31 An increase in mean pulmonary arterial pressure (despite a drop in heart rate and cardiac output) following the use of the beta-blocker propranolol in horses, is evidence that there are beta- dilatory receptors in the pulmonary vasculature. 22 Clenbuterol also causes an increase in bronchial arterial flow in the conscious horse, despite a decrease in systemic blood pressure; this implies that the drug causes bronchial arterial vasodilation. 32 Whether these effects on the systemic and pulmonary circulation are great enough to cause significant changes in bronchial and pulmonary arterial pressures (and, hence, the potential for stress failure of capillaries) during exercise in horses remains

to be determined. Speculation and anecdotal reports

of improved performance in racehorses have stimulated research into the effects of these drugs in exercising horses. Despite variations in protocol, the re- suits from several different centers are remarkably similar: clenbuterol has no significant effects on lower airway mechanics, gas exchange, or cardiovascular and metabolic responses during exercise. 29,33,34 One group found a slight increase in arterial pH at near- maximal exercise, 34 but this was not the case in other studies. In another study clenbuterol failed to prevent 2 of 5 horses from experiencing EIPH. 33

Aspi r in Recently, Mahony et al. reported

the presence of spontaneous echogenic contrast during routine echo-cardio-

35 graphyinhorses. In investigating this further, they found that contrast particles were more prevalent and more numerous in racehorses (compared with broodmares and young horses), and that racing caused a marked increase in the number of particles for at least 2 days. The greatest concentration of particles was seen in a horse with a history of EIPH and poor race performance. The injection of platelet activating factor in one horse resulted in a dramatic increase in contrast particles, and the appearance of platelet and platelet-neutrophil aggregates on a peripheral blood smear; this led the authors to conclude that the contrast particles were platelet clumps. They cited studies in experimental animals in which transfu- sion of blood containing platelet or platelet-leukocyte aggregates caused alveolar hemorrhage, and they com- mented that aspirin reduced the number of contrast particles, reduced the incidence of EIPH during racing, and improved pe r fo rmance in some

35 horses. No data were provided to sup- port these statements, however. On the surface, the conclusions of this study appear to be in conflict with the find-

ings of the previously cited studies, in which all horses showed a reduction in platelet responsiveness with exercise, and horses with EIPH also had less responsive platelets at rest. However, this may be an oversimplification of a complex process, and could be like comparing apples with oranges in a very dynamic fruit salad.

While other NSAIDs reversibly inhibit the activity ofcyclo-oxygenase, and, therefore, prostaglandin, prostacyclin and thromboxane synthesis, aspirin permanently blocks thromboxane production (and, hence, an important mechanism ofplatelet aggregation) for the remaining life-span of the platelet (about 10 days). 36 Platelets are about 10 times more sensitive to the effects of aspirin than are other cells, so the antithrombotic effect of aspirin can be achieved at a much lower dose than is required for an antipyretic or analgesic effect. 36 Furthermore, a low dose "spares" prostacyclin, because a higher dose is needed to block PGI 2 than is needed to block thromboxane production. 36 The "optimal" oral antithrombotic dose in humans is between 0.5 and 4 mg/kg once a day. 36

Cambridge et al. studied the antithrombotic effects of aspirin in horses, and found that a single intravenous bolus of 4 mg/kg increased the bleeding time for 4 hours, reduced the serum TXB 2 concentration for 6 days, and suppressed collagen-induced platelet aggregation for 48 hours. 37 At a higher dose (12 mg/kg) the bleeding time was increased for 48 hours, although the serum TXB2 concentration and suppression of collagen-induced platelet aggregation were the same as for the lower dose. 37 The suppression of collagen-induced platelet aggregation may have significant clinical implications in EIPH because exposure of subendo- thelial collagen is an important physi- ological stimulus for platelet adhesion and clumping following vascular damage. 37 Thus, aspirin could be expected to worsen hemorrhage from damaged


vessels during an episode of EIPH, although more information is needed on the effects of aspirin in horses with EIPH before such statements are valid.

Anti f ibr inolyt ics Drugs which prevent the break-

down of f ibrin deposits (antifibrinolytics) have been used in an attempt to limit or prevent EIPH in horses. Such drugs include aminocaproic acid (Amicar ®) and tranexamic acid (Cyklokapron®; this drug is marketed for veterinary use in Australia as Vasolamin S®). These drugs are used in human medicine to control bleeding during and after cardiac surgery, and in certain hemostatic disorders including hemophilia, despite the lack of controlled studies to demon- strate their efficacy. 38 The indications for their use are very specific: they are only advocated when a diagnosis of hyperfibrinolysis (excessive breakdown of fibrin clots, leading to hemorrhage) is made. 38 These compounds are apparently ineffective when bleeding is caused by vascular damage .38 Although tranexamic acid is 5 to 10 times more potent than aminocaproic acid, both drugs act by competitively inhibiting the activation of plasminogen to plas- min, the enzyme which degrades fibrin clots, fibrinogen and other procoagulant plasma proteins. 30 One of the side effects of these compounds is thrombus formation 38 (- tranexamic acid has ac- tually been used to induce pulmonary emboli in dogs, for the purpose of study- ing pulmonary hypertension39).

In humans, exercise causes an increase in fibrinolytic activity at moderate and heavy exercise intensities. 17 However, there is no evidence that this occurs in horses, even during strenuous exercise ;17.18 and, given that horses have a propensity to develop thrombi (probably due to an insufficiency of the fibrinolytic system, rather than excessive activation of the coagulation path- ways), 4° there is little to recommend the use of these drugs in this species.

Preventing the normal dissolution of fibrin clots in the lung may lead to vessel occlusion and local changes in blood flow, which may increase the flow (and pressure) in adjacent capillary beds, making them more prone to stress failure. On the other hand, stabi- lizing fibrin clots may prevent hemorrhage from a damaged vessel during the next bout of exercise. Anecdotal reports which claim that these drugs reduce the incidence of epistaxis in horses could be misleading at best, and until studies addressing the efficacy and safety of these drugs in horses are undertaken, their use cannot be sanc- tioned.

C O N C L U S I O N S

Until the etiopathogenesis of EIPH is clear, therapy will continue to be empirical, based on supposition of the underlying cause(s) of the condition. New therapies are constantly being tried by veterinarians and trainers, in the hope of stumbling upon a universally effective means of preventing EIPH. However, given the obviously complex pathophysiology, and probably multifactorial etiology of the condition, the best we may hope for is some- thing which limits the extent of hemorrhage and irreversible changes in the lung, while allowing the horse to continue its athletic career. At this time, furosemide appears to be the drug which comes closest to fulfilling these goals, although its practical benefits are still debated. Perhaps a combination of furosemide and the reduction in the fre- quency of strenuous exercise would be a more rational approach to limiting the effects of EIPH in horses.

R E F E R E N C E S

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Proceedings. Am Assoc Equine Pract. 1980;26"435-440.

2. Pascoe JR: Exercise-induced pulmonary hemorrhage. In: Beech J (ed). Equine Respiratory Disorders. USA: Lea & Febiger, 1991 ;237-252.

3. Sweeney CR, Soma LR, Maxson AD, Thompson JE, Holcombe S J, Spencer PA: Effects of furosemide on the racing times of Thoroughbreds. Am J Vet Res 1990;51:772-778.

4. O'Callaghan MW, Pascoe JR, Tyler WS, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. I. Clinical profile of horses. Eq Vet J 1987;19:384-388.

5. O'Callaghan MW, Pascoe JR, Tyler WS, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. II. Gross lung pathology. Eq Vet J 1987;19:389-393.

6. O'Callaghan MW, Pascoe JR, Tyler WS, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. III. Subgross findings in lungs subjected to latex perfusions of the bronchial and pulmonary arteries. Eq Vet J 1987;19:394-404.

7. O'Callaghan MW, Pascoe JR, Tyler WS, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. IV. Changes in the bronchial circulation demonstrated by C. T. scanning and microradiography. Eq Vet J 1987;19:405-410.

8. O'Callaghan MW, Pascoe JR, O'Brien TR, Hornof W J, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. VI. Radiological/pathological correlations. Eq Vet J 1987;19:419-422.

9. O'Callaghan MW, Hornof W J, Fisher PE, Pascoe JR: Exercise-induced pulmonary haemorrhage in the horses: results of a detailed clinical, post mortem and imaging study. VII. Venti lat ion/ perfusion scintigraphy in horses with EIPH. Eq Vet J 1987;19:423-427.

10. O'Callaghan MW, Pascoe JR, Tyler WS, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. V. Microscopic observations. Eq Vet J 1987;19:411-418.

11. O'Callaghan MW, Pascoe JR, Tyler WS, Mason DK: Exercise-induced pulmonary haemorrhage in the horse: results of a detailed clinical, post mortem and imaging study. VIII. Conclusions and implications. Eq Vet J 1987;19:428-434.

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Vet J 1994;26:441-447. 13. West JB, Mathieu-Costello O,

Jones JH, Birks EK, Logemann RB, Pascoe JR, Tyler WS: Stress failure of pulmonary capillaries in racehorses with exercise- induced pulmonary hemorrhage. J Appl Physiol 1993;75:1097-1109.

14. Erickson BK, Erickson HH, Coffman JR: Pulmonary artery, aortic and oesophageal pressure changes during high intensity treadmill exercise in the horse: a possible relation to exercise-induced pulmonary haemorrhage. Eq Vet J 1990;(suppl.)9:47-52.

15. Manohar M: Pulmonary vascular pressures of Thoroughbreds increase rapidly and to a higher level with rapid onset of high-intensity exercise than slow onset. Eq Vet J 1994;26:496-499.

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Frusemide attenuates the exercise-induced rise in pulmonary capillary blood pressure in horses. Eq Vet J 1994;26:51-54.

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18. Johnstone IB, Viel L, Crane S, Whiting T: Hemostatic studies in racing Standardbred horses with exercise-induced pulmonary hemorrhage. Hemostatic parameters at rest and after moderate exercise. Can J Vet Res 1991 ;55:101-106.

19. Birks EK, Giri SN, Li C, Jones JH: Effects of exercise on plasma concentrations of prostaglandins and thromboxane B 2. In: Persson SGB, Lindholm A, Jeffcott LB (eds). Equine Exercise Physiology 3. Proceedings. 3rd ICEEP. Davis, CA: ICEEP Publications, 1991 ;374-379.

20. Broadstone RV, Derksen F J, Robinson NE: Pulmonary effects of fu rosemide. Proceedings. Am Assoc Equine Pract. 1990;36:189-191.

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22. Erickson BK, Erickson HH, Coffman JR: Pulmonary artery and aortic pressure changes during high intensity treadmill exercise in the horse: effect of frusemide and phentolamine. Eq Vet J 1992;24:215-219.

23. Olsen SC, Coyne CP, Lowe BS, Pelletier N, Raub EM, Erickson HH: Influence of cyclooxygenase inhibitors on furosemide-induced hemodynamic effects during exercise in horses. Am J Vet Res 1992;53:1562-1567.

24. Rubie S, Robinson NE, Stoll M, Broadstone RV, Derksen F J: Flunixin meglumine blocks frusemide-induced bronchodilatation in horses with chronic obstructive pulmonary disease. Eq Vet J 1993;25:138-142.

25. Manohar M: Pulmonary vascular pressures of strenuously exercising Thoroughbreds after administration of flunixin meglumine and furosemide. Am J Vet Res 1994;55:1308-1312.

26. Manohar M: Furosemide and systemic circulation during severe exercise. In: Gillespie JR, Robinson NE (eds), Equine Exercise Physiology 2. Proceedings. 2nd ICEEP. Davis, CA: ICEEP Publications, 1987;132-146.

27. Bayly WM, Meyers KM, Keck MT, Huston L J, Grant BD: Effects of furosemide on exercise-induced alterations in haemostasis in Thoroughbred horses exhibiting post-exercise epistaxis. In: Snow DH, Persson SGB, Rose RJ (eds). Equine Exercise Physiology. Proceedings. 1st iCEEP. Cambridge, UK: Granta Editions,

1983;64-70. 28. Hoffman BB, Lefkowitz R J:

Catecholamines and sympathomimetic drugs. In: Goodman Gillman A, Rail TW, Nies AS, Taylor P (eds). The Pharma- cological Basis of Therapeutics. NY: Pergamon Press Inc, 1991 ;187-220.

29. Slocombe RF, Covelli G, BaylyWM: Respiratory mechanics of horses during stepwise treadmill exercise tests, and the effect of clenbuterol pretreatment on them. Aust Vet J 1992;69:221-225.

30. Dodam JR, Moon RE, Olson NC, Exposito A J, Fawcett TA, Huang YC, Theil DR, Camporesi E, Swanson CR: Effects of clenbuterol hydrochloride on pulmonary gas exchange and hemodynamics in anesthetized horses. (Abstr.) Am J Vet Res 1993;54:776-782.

31. Greenlees K J, Gamble R, Eyre P: Adrenoceptor function in the bovine pulmonary circulation. (Abstr.) Can J Physiol Pharmacol 1986;64:689-693.

32. Sanders EA, Gleed RD, Hackett RP, Dobson A: Action of sympathomimetic drugs on the bronchial circulation of the horse. (Abstr.) Experim Physiol 1991; 76:301-304.

33. Rose R J, Evans DL: Cardiorespiratory effects of clenbuterol in fit Thoroughbred horses during a maximal exercise test. In: Gillespie JR, Robinson NE(eds). Equine Exercise Physiology 2. Proceedings. 2nd ICEEP. Davis, CA: ICEEP Publications, 1987;117-131.

34. Kallings P, Ingvast-Larsson C, Persson S, Appelgren LE, Forster H J, Rominger KL: Clenbuterol plasma concentrations after repeated oral administration and its effects on cardiorespiratory and blood lactate responses to exercise in healthy Standardbred horses. J Vet Pharmacol Therap 1991 ;14:243-249.

35. Mahony C, Rantanen NW, DeMichael JA, Kincaid B: Spontaneous echocardiographic contrast in the Thoroughbred: high prevalence in racehorses and a characteristic abnormality in bleeders. Eq Vet J 1992;24:129-133.

36. Roth GJ, Calverley DC: Aspirin, platelets, and thrombosis: theory and practice. Blood 1994;83:885-898.

37. Cambridge H, Lees P, Hooke RE, Russell CS: Antithrombotic actions of aspirin in the horse. Eq Vet J 1991 ;23:123- 127.

38. 47th Physicians' Desk Reference. Dowd AL (ed). Medical Economics Data, NJ. 1993; 1185, 1223.

39. Moser KM, Cantor JP, Olman M, Villespin I, Graif JL, Konopka R, Marsh J J, Pedersen C: Chronic pulmonary thromboembolism in dogs treated with tranexamic acid. (Abstr.) Circulation 1991 ;83:1371 - 1379.

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eiph: rational approach to therapy

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