EXERCISE-INDUCED PULMONARY HAEMORRHAGE A GLOBAL REVIEW OF RECENT FINDINGS

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1 EXERCISE-INDUCED PULMONARY HAEMORRHAGE A GLOBAL REVIEW OF RECENT FINDINGS Dr. David Marlin, Centre for Equine Studies, Animal Health Trust, Newmarket General Background: Between 1997 and March 2001 a search of the literature for the keywords EIPH or exerciseinduced pulmonary haemorrhage reveals around 40 publications in this area. To try to describe the current areas and themes of research, publications fell into 4 broad areas as follows: (1) Effects of EIPH on performance (2 publications); (2) EIPH & Furosemide/Lasix (22 publications); (3) Detection and or quantification of EIPH (4 publications); Investigation of mechanisms or pathogenesis of EIPH (12 publications). The publications on furosemide could be further divided into studies in which the occurrence of EIPH following treatment was either recorded or quantified (5 publications) and those in which the study was linked to EIPH (primarily mechanisms of action in relation to pulmonary vascular pressures) but in which EIPH occurrence was not reported (17 publications). The 40 publications came from 14 different groups, although 4 groups were responsible for half of the total number of publications. The highest number of publications in the last 4 years was in 1999 (15 publications), followed by 1998 (10 publications), 2000 (9 publications), 1997 (3) and so far only 1 publication in The peak in publications in 1999 is most likely due to the publication of the Proceedings of the 5 th International Conference on Equine Exercise Physiology held in Japan in 1998 as a supplement to the Equine Veterinary Journal. Although EIPH has been reported to occur in horses, ponies, racing camels, greyhound dogs and maximally exercised human athletes, perhaps not surprisingly nearly all publications have been in veterinary or equine veterinary journals. Quantification of EIPH: An important question as far as the aetiology of EIPH is concerned has been to know what area of lung is involved in haemorrhage and how the progression of EIPH occurs. Post mortem 1

2 studies have demonstrated that in nearly all horses the damage initially occurs in the very tips of the right and left dorsal-caudal lung and progresses in a cranial direction. As a result, a greater potential area for bleeding is recruited due to the shape of the diaphragmatic lobes. Whilst endoscopic scoring of the amount of blood in the trachea min after exercise has been a technique used in research and is the most widely used approach to confirm the occurrence of EIPH and assess its severity in clinical practice, the limitations have long been recognised. For example, the relationship between the true amount of haemorrhage within the lung and the volume seen in the trachea following exercise is still unclear. McKane (Roberts and Erickson, 1999) reported that instillation of 200 ml of autologous blood divided between the left and right lung before exercise gave a similar appearance to a grade 2 out of 5 visual score of haemorrhage in the trachea post-exercise. After a severe (grade 4 or 5 out of 5) haemorrhage or after a bout of epistaxis, increased numbers of haemosiderophages may be seen in tracheal wash and BAL for many weeks afterwards but the volume of blood involved in the original haemorrhage cannot be inferred. It can also be difficult to assess from which side of the lung haemorrhage has originated simply on the basis of post-race or post-exercise endoscopy. (Hillidge, 1986) reported that in a 601 out of 840 horses that had endoscopic evidence of EIPH post-racing, the origin of the haemorrhage (i.e. left or right lung) could not be determined in 144 horses. (Hillidge, Lane and Whitlock, 1985) and Hillidge, 1986) reported a trend for both racing Apaloosa horses and racing Thoroughbreds, respectively, to bleed more from the right than the left lung based on visual observation during post-exercise endoscopy. Whilst an important observation, this simple approach may be misleading. For example, if the origin of haemorrhage on the right was more cranial than on the left, this may give the appearance at the carina of more blood originating from that side. Similarly, post mortem examination often shows that the areas of damage are often symmetrical as far as left and right sides are concerned. However, recent experience in our own laboratory using left and right lung BAL following exercise does suggest that horses bleed predominantly more from either one side or the other and that this pattern of difference tends to be maintained over time, although this is not confined more to the right side (Brown, Roberts, Marlin and Schroter, unpublished). It is therefore possible that with further 2

3 refinement, investigation and description, the BAL technique for quantifying EIPH may contribute to answering questions such as this. Radiography is only likely to provide evidence of the progression of EIPH in an individual horse in the case of severe, repeated episodes of haemorrhage and is of limited use in the horse that has an average degree of EIPH for its age. Similarly, until now the application of techniques such as scintigraphy has generally been disappointing as far as demonstrating areas of tissue damaged as a result of previous EIPH or for demonstration of the region of current haemorrhage following exercise (Votion et al., 1999). As an improvement to simple endoscopic scoring of blood in the trachea post-exercise, more recently a number of groups have begun to investigate the use of red cell counts in bronchoalveolar lavage fluid (Meyer et al., 1998; Lester et al., 1999) as an indication of the severity of haemorrhage. However, a number of fundamental questions remain to be resolved including, the precise region lavaged and whether this is dependent on the size of endoscope or BAL catheter used (i.e. airway level at which the endoscope or BAL catheter wedges) and the reproducibility of counts in the same horse over time. The area of lavage can be demonstrated by using radiography (McKane and Rose, 1993) and or scintigraphy (see below) and indicates that even with a relatively large diameter endoscope (12 mm) the wedge takes place in a relatively distal segment of lung. (Figure 1) Figure 1: From left: (a) Lateral radiographic image of the left lung showing dorso-caudal placement of a wedged 12 mm diameter endoscope; (b) Lateral scintigraphic image of the left lung following instillation of 50 ml of saline containing Technitium [ 99m Tc] via the wedged endoscope as shown in (a) (the two small areas of high activity in the top of each image are external position markers); (c) Image of pulmonary vascular bed to show lung border obtained immediately following image shown in (b) by injection of Tc-MAA into the jugular vein (Votion et al., 1999). 3

4 The red appearance of a post-exercise BAL can often be quite dramatic. Although the cell counts per unit volume of BAL fluid are often very high, we must not lose sight of the fact that a count of 50,000 RBC/ul BAL (or 50 x 10 6 RBC/ml BAL) with a circulating red cell count of 20 x RBC/litre during exercise would only equate to a volume of ul peripheral blood/ul BAL or 375 ul of blood in 150 ml of recovered BAL fluid (based on an instillation volume of 2 x 100 ml aliquots and assuming 75% recovery). (Figure 2) Figure 2: Appearance of 150 ml of 0.9% saline with (from left to right) volumes of 0, 50, 100, 250 and 1000 ul of resting venous blood added. The blood sample had a RBC count of around 10 x cells/litre, giving counts of approximately 0, 3.3, 6.7, 17 and 67 x 10 6 RBC/ml BAL (equivalent to 0, 3300, 6700, 17,000 and 67,000 RBC/ul BAL ). 4

5 Mechanisms of EIPH: The most commonly accepted theory as to the cause of EIPH is pulmonary capillary stress failure as proposed by West and colleagues in a series of studies over the last decade. One might argue that pulmonary capillary stress failure is simply a description of what occurs rather than encompassing a mechanism. However, there is no doubt that studies by a number of authors and groups have clearly demonstrated that during intense exercise the combination of a relatively thin blood gas barrier required to support a high maximal oxygen uptake and the high pulmonary capillary transmural pressures as a result of both high vascular and highly negative alveolar (airway) pressures place a tremendous stress on the gas exchange surface. In 1999, Schroter and colleagues (Schroter et al., 1998; Schroter et al., 1999) published two theoretical papers proposing that the actual mechanism of pulmonary capillary disruption was due to localised shear stress within the pulmonary tissue resulting from loading (compression) of the chest by the forelimbs. However, these theories currently remain untested. Relationship between Pulmonary Artery and Airway Pressures to Transmural Pressures and EIPH: A logical extension of the pulmonary capillary stress failure theory of West and colleagues would be that any factors increasing either the airway or vascular components of transmural pressure should increase the frequency or severity of haemorrhage or decrease the threshold for onset. As far as the vascular component, (Manohar and Goetz, 1996) reported that the magnitude of the increases in right atrial, pulmonary arterial, capillary, and venous pressures during intense exercise were not different between horses showing post-exercise endoscopic evidence of EIPH and those which did not. However, (Poole et al., 2000) have more recently demonstrated that the severity of EIPH can be changed independently from parallel changes in pulmonary artery pressures. Thus, if there is a threshold for transmural pressure at which haemorrhage occurs based on both in vitro (Birks et al., 1997) and in vivo data (Langsetmo et al., 2000), is the likelihood of this being reached related more to variance between horses in the airway component of transmural pressure than the vascular component? As far as experimentally induced laryngeal hemiplegia (primarily an inspiratory obstruction) is concerned however, induction did not increase mean transmural pulmonary artery pressure compared with control 5

6 (Jackson et al., 1997). The same group (Hackett et al., 1999) also reported that dorsal displacement (a primarily expiratory obstruction) increased mean pulmonary artery pressure but not transmural pulmonary artery pressure. In summary, whilst it is clear that high transmural pressures result in pulmonary haemorrhage, the vascular and airway contributions in generating the required pressures to in vivo remain unclear. Intensity of Exercise Required to Cause EIPH: Whitwell and Greet first reported in 1984 that in a sample of 191 Thoroughbred horses in full training in Newmarket (this would imply galloping twice weekly), haemosiderophages were present in all tracheal wash samples. The implication, providing of course that previous endoscopy had not produced any haemorrhage during the actual process of tracheal wash sampling, was that all horses when galloping have some degree of pulmonary haemorrhage at some time. It has generally been believed, based on anecdotal reports, that EIPH is most commonly associated with intense work, whether at high-speeds during training, racing and in competition or as a result of pulling very heavy draught loads. However, a recent study by (Oikawa, 1999) based on post mortem examination of the lungs of young Thoroughbred racehorses aged 18-2 months suggests that lesions consistent with previous EIPH occur following training at speeds as low as m/s. Efficacy of Furosemide in Preventing or Reducing the Severity of EIPH: Furosemide is almost certainly the most widely used treatment for EIPH. Whilst in the USA its use is permitted during both training and racing, in the UK its use is mainly restricted to during training in horses experiencing severe EIPH. Furosemide has been used as a treatment for EIPH for many years on the basis that the most commonly accepted explanation for EIPH is pulmonary capillary stress failure due to high pulmonary capillary transmural pressures. The efficacy of furosemide in reducing pulmonary vascular pressures during exercise has been extensively demonstrated, however, evidence for its efficacy in preventing EIPH has been lacking. For example, Manohar and colleagues reported in 1997 that whilst furosemide at 1 and 1.5 mg/kg significantly reduced pulmonary capillary pressure during intense treadmill exercise (14.2 m/s 6

7 3.5% incline), the incidence of EIPH was the same in control and both furosemide treatment sessions. Of course, it is possible that rather than prevention of EIPH as a result of furosemide treatment we should perhaps instead be looking for a reduction severity either based on endoscopic grading or BAL red blood cell counts. (Lester et al., 1999) demonstrated a reduction in peak mean pulmonary artery pressure during maximal exercise in the field and a significant decrease in BAL RBC count, compared with control, as a result of administration of 250mg furosemide i.v. 30 min before exercise. Interestingly, administration of 250 mg furosemide i.v. in the same horses 240 min before exercise failed to decrease peak mean PAP or BAL RBC count following exercise compared with the control session. The reduction in BAL RBC count following treatment with furosemide has also been recently replicated by (Kindig et al., 2000). Other Approaches to Treating EIPH: Nasal dilator strips to improve nasal airflow for human athletes and for the relief of snoring have been available for a number of years. An equine nasal dilator strip has recently been introduced (FLAIR strip, CNS Inc). The rationale for its development and introduction is that the tissue overlying the area between the nostril and the nasomaxillary notch is relatively unsupported and collapses inwards during inspiration at high flow rates. As highly negative airway pressures as a result of increased upper airway resistance could increase the airway component of transmural pressure, the hypothesis is that this could increase severity of EIPH. A study on the efficacy of the nasal dilator strip for reducing EIPH indicated a significant mean reduction in BAL RBC count of 33% compared with control and a 6% decrease in oxygen uptake and carbon dioxide production (McDonough et al., 2000). A second study from the same group confirmed these findings, but indicated that furosemide had a considerably greater efficacy than the nasal dilator strip (Kindig et al., 2000). Questions: Whilst a great deal of effort has been directed to trying to understand the cause of EIPH with a view to preventing or reducing either its severity or occurrence in individual horses, we still have 7

8 many inconsistencies, gaps in our knowledge and contradictions. Some questions for the future might include: Is there a right and left lung difference in the severity of haemorrhage and if so, can this help to explain more about the aetiology of EIPH? In the field, practitioners and trainers often report that the occurrence or severity of EIPH over time is highly variable either during training or racing. Why is this the case? Again, is it simply a limitation of endoscopic scoring or even if the amount of blood in the trachea does relate closely to the volume of haemorrhage most of the time, can the volume present at any one time (i.e. the time of observation) be influenced by whether the horses puts its head down, coughs, etc. Why is the are of haemorrhage in the dorsal caudal lung and why does it have the characteristic pattern of progression? Why don t horses bleed in ventral regions where pulmonary vascular pressures should be higher at least based on purely gravitational influences? How does the region of haemorrhage vary from one exercise session to the next? Is it the same area that is repeatedly damaged or is there a random pattern of damage in which a previously damaged area may or may not be involved in the next bout of haemorrhage? Almost all of the physiological measurements made in research studies measure global pulmonary or cardiovascular variables. What is the relationship between global and local (i.e. where the haemorrhage actually occurs) physiological changes? Can we apply techniques of investigation that enable us to make measurements closer to the actual site of haemorrhage? Of course, there may well be important limitations in terms of the calibre of blood vessels and airways as we move from central regions of the lung towards the periphery. References: 1. Birks, E.K., Mathieu-Costello, O., Fu, Z., Tyler, W.S. and West, J.B. (1997) Very high pressures are required to cause stress failure of pulmonary capillaries in thoroughbred racehorses. J Appl Physiol. 82(5), Hackett, R.P., Ducharme, N.G., Ainsworth, D.M., Erickson, B.K., Erb, H.N., Soderholm, L.V. Jr. and Thorson, L.M. (1999). Effects of extrathoracic airway obstruction on 8

9 intrathoracic pressure and pulmonary artery pressure in exercising horses. Am J Vet Res, 60:4, Hillidge, C.J., Lane, T.J. and Whitlock, T.W. (1985) Exercise-induced pulmonary hemorrhage in the racing Appaloosa horse. J Equine Vet Sci, 5:6, Hillidge, C.J. (1986) Predisposition for right lung involvement in equine exercise-induced pulmonary haemorrhage. Br Vet J, 142:3, Jackson, J.A., Ducharme, N.G., Hackett, R.P., Rehder, R.S., Ainsworth, D.M., Shannon, K.J., Erickson, B.K., Erb, H.N., Jansson, N., Soderholm, L.V. and Thorson, L.M. (1997) Effects of airway obstruction on transmural pulmonary artery pressure in exercising horses. Am J Vet Res, 58:8, Kindig, C.A., Erickson, H., McDonough, P. and Poole, D.C. (2000) Efficacy of nasal strip and furosemide in mitigating equine exercise-induced pulmonary haemorrhage (EIPH). Proceedings of the 18 th Symposium of the Comparative Respiratory Society, November 6-9, 2000, Melbourne, Australia. p Langsetmo, I., Fedde, M.R., Meyer, T.S. and Erickson, H.H. (2000) Relationship of pulmonary arterial pressure to pulmonary haemorrhage in exercising horses. EquineVet J, 32: 5, Lester, G., Clark, C., Rice, B., Steible-Hartless, C. and Vetro-Widenhouse, T. (1999) Effect of timing and route of administration of furosemide on pulmonary hemorrhage and pulmonary arterial pressure in exercising Thoroughbred racehorses. Am J Vet Res 60:1, McDonough, P., Kindig, C.A, Poole, D.C., Rush, B.R. and Erickson, H.H. (2000) Equine nasal strip reduces bleeding in racehorses. Proceedings of the 18 th Symposium of the Comparative Respiratory Society, November 6-9, 2000, Melbourne, Australia. p McKane, S.A. and Rose, R.J. (1993) Radiographic determination of the location of a blindly passed bronchoalveolar lavage catheter. Equine Vet Edu. 5:6, Manohar, M. and Goetz, T.E. (1996) Pulmonary vascular pressures of exercising thoroughbred horses with and without endoscopic evidence of EIPH. J Appl Physiol. 81:4,

10 12. Manohar, M., Goetz, T.E., Sullivan, E. and Griffin, R. (1997) Pulmonary vascular pressures of strenuously exercising Thoroughbreds after administration of varying doses of frusemide. Equine Vet J, 29: 4, Meyer, T.S., Fedde, M.R., Gaughan, E.M., Langsetmo, I. and Erickson, H.H. (1998) Quantification of exercise-induced pulmonary haemorrhage with bronchoalveolar lavage. Equine Vet J, 30:4, Oikawa, M. (1999) Exercise-induced haemorrhagic lesions in the dorsocaudal extremities of the caudal lobes of the lungs of young thoroughbred horses. J Comp Pathol,121(4): Poole, D.C., Kindig, C.A., McDonough, P., Ramsel C. and Erickson, H.H. (2000) Independence of exercise-induced pulmonary hemorrhage (EIPH) and pulmonary artery pressure. Proceedings of the 18 th Symposium of the Comparative Respiratory Society, November 6-9, 2000, Melbourne, Australia. p Roberts, C.A. and Erickson, H.H. (1999) Exercise-induced pulmonary haemorrhage workshop. Equine Vet J, suppl. 30, Schroter, R.C., Marlin, D.J. and Denny, E. (1998) Exercise-induced pulmonary haemorrhage (EIPH) in horses results from locomotory impact-induced trauma - a novel, unifying concept. Equine Vet J, 30(3), Schroter, R.C., Leeming, A., Denny, E., Bharath, A. and Marlin, D.J. (1999) Modelling impact-initiated wave transmission through lung parenchyma in relation to the aetiology of exercise-induced pulmonary haemorrhage. Equine Vet J (Suppl. 30), Votion, D.M., Roberts, C.A., Marlin, D.J. and Lekeux, P.M. (1999) Feasibility of scintigraphy in exercise-induced pulmonary haemorrhage detection and quantification: preliminary studies. Equine Vet J (Suppl. 30), Whitwell, K.E. and Greet, T.R.C. (1984) Collection and evaluation of tracheobronchial washes in the horse. Equine Vet J, 16:6,