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PHYSIOLOGY OF BLOOD CIRCULATION

In: Blood Vessles and Lymphatics In Organ Systems

by D.W. Lennox and D.S. Hungerford

This material has been published in Blood Vessels and Lymphatics in Organ Systems, edited by David I. Abramson and Philip B. Dorbin, the only definitive repository of the content that has been certified and accepted after peer review. Copyright and all rights therein are retained by Elsevier Science (USA). This material may not be copied or reposted without explicit permission.

Copyright 1984, Elsevier Science (USA). All rights reserved.


Besides biomechanically providing a rigid framework for protecting vital organs and for the attachment of muscle and ligament, bone also possesses a remarkable capacity to modify its structure and function in response to injury, growth, aging, neoplasm, metabolic derangement, infection, surgery, and neurohumoral factors. Of utmost importance in maintaining the varied responsiveness of bone is the existence of a highly responsive system of bone blood flow to deliver necessary nutrients, cells, and possibly chemical mediators.

Although at the present time there is no clinically useful technique for the direct measurement of bone blood flow in human subjects, a number of procedures are available for this purpose in experimental animals. Several of these are considered in the following discussion.

1. METHODS OF STUDYING BONE BLOOD FLOW

a. Direct method: Direct measurement of total bone blood flow is nearly impossible due to the multiple afferent and efferent channels involved. Cumming (1960) used a direct technique to study flow to the rabbit femur, by cannulating the superficial femoral vein (having previously ligated the deep femoral and circumflex veins) and measuring flow from the cannulated vessel, considering this to represent femoral flow. A similar methodology was reported earlier by Drinker and Drinker (1916). Such an approach has more utility in investigating gross changes in circulation in response to any of a number of interventions than in determining precise values for blood flow.

b. Indirect methods: A number of indirect procedures exist for the study of blood flow in bone, one of which is red blood cell (RBC) labeling. White et al. (1964) utilized 51Cr-tagged red cells for this purpose. The technique consists of injecting tagged red cells intravenously, and, after an appropriate time to permit mixing, blood is sampled to establish a reference radioactivity level per volume collected. The animal is then sacrificed and the bones under investigation are fixed, weighted, sectioned, and measured for radioactivity. Circulating red cell volume is then calculated and expressed as volume per net weight of specimen. This method assumes that the hematocrit in bone blood is the same as that in the blood sample.

A second approach, the radioisotope clearance method, consists of the use of both non-bone-seeking isotopes to assess bone blood flow. With the non-bone-seeking isotopic method, a given amount of radioisotope is injected into the bone to be studied and the radioactivity level is followed over time. Rapid clearance is evidenced by a rapid diminution in radioactivity, which is considered to be proportional to blood flow. Isotopes such as Na131I have been employed for this purpose. Since the procedure is an invasive one, it is subject to artefacts produced by the injecting trocar. With the bone-seeking isotopic method, either 86Rb (Kane, 1968), 45Ca, or 85Sr is employed to estimate lower limb blood flow.

With the use of the substances mentioned above, flow estimates are based upon the Fick principle. For example, in the case of 85Sr the amount of the isotope fixed in bone in a given time is divided by the arteriovenous concentration difference in order to calculate flow. The flow value generated by such an approach is less then the true value since the extraction ratio for 85SR is less than unity (Shim et al., 1971).

The use of tracer microspheres is a relatively new method for measuring bone blood flow in experimental animals, the value of which has not been fully established. It employs 15 µm microspheres labeled with any of a number of different isotopes, including 125I, 85Sr, 46Sc, 141Ce, and 95Nb. The availability of several different isotopes and their separability by spectroscopy create the possibility for repeated measurements in one animal. Arterial reference samples are obtained just prior to and for several minutes following the intracardiac microsphere injection. At the conclusion of the experiment, the animal is sacrificed and the bone cleaned and counted in a gamma counter. Microspheres are trapped in the bone microcirculation in numbers proportional to flow. The technique allows for analysis of flow to various anatomic regions of bone, as well as for overall bone blood flow. Although the method appears to be applicable to many studies with experimental animals, its validity in states of fracture healing, growth, or necrosis has not been established (Gross et al., 1981). Tothill and MacPherson (1980) have emphasized that due to removal of some microspheres in preosseous capillaries, the microsphere technique has limited applicability as standard in determining extraction ratios. (For details of the technique, its assumptions, and discussion of the validity and applicability of the method, see Gross et al., 1979, 1981.)

2. BLOOD FLOW TO BONE

Recent measurements made with the microsphere technique indicate a heterogeneous pattern of flow to bone and bone marrow. In the anesthetized dog, low flow rates were reported for compact bone (2 ml/min/100 gm) in humeral and femoral diaphysis) and much higher values for hematopoietic cancellous bone and hematopoietic marrow (18-30 ml/min/100 gm) (Gross et al., 1981). Morris and Kelly (1980) found similar values for compact and cancellous blood flow in the dog but recommended that, for optimal microsphere technique, the animal should be conscious with the reference catheter in the aorta. Whiteside et al. (1977a), utilizing the hydrogen washout technique, measured epiphyseal cancellous bone blood flow in the rabbit and found that for cancellous bone, the flow was 0.129 + 0.015 ml/min/ml, with the corresponding value for cortical bone being 0.069 ± 0.002 ml/min/ml.

3. SKEKETAL BLOOD FLOW

Estimates of total skeletal blood flow vary widely. Figures as high as 27.5% of cardiac output have been proposed (Brookes, 1967). Wootton et al. (1976b) found bone blood flow to be 4.1 ml/min/100 gm in eight normal male volunteers using an 18F isotope technique. Shim et al. (1971) reported a reading of 2.4 ml/min/100 gm for man with an 85Sr clearance method, a value similar to that previously found by Van Dvke et al. (1965). With the microsphere technique, Gross et al. (1981) estimated total skeletal blood flow in the dog to represent 11% of cardiac output. An earlier report by Shim et al. (1967) noted a rate of 7.3 ± 3.0% of cardiac output. Morris and Kelly (1980) estimated the percentage of cardiac output to bone tissue in the conscious dog to be 9.6% in the mature animal and 10.3% in the immature one. Of interest was their finding that in the mature animal, approximately 2% was flow to cortical bone and 8% to cancellous bone, whereas, in the immature dog, 7% was flow to cortical bone and 4% to cancellous bone. Such results were attributed to the fact that although cortical bone represents 80% of the skeleton by weight, its surface area is roughly equivalent to less voluminous cancellous bone; moreover, in the immature animal, appositional growth is greater, with possible shunting to cortical bone.

4. ALTERED PHYSIOLOGIC PARATMETERS AND BONE BLOOD FLOW

Although it seems reasonable to assume that bone blood flow, constituting a significant portion of overall cardiac output, should respond and be sensitive to altered physiologic parameters, it is only recently that this expectation has gained experimental confirmation.

a. Response to hemorrhage: Syftestad and Boelkins (1980) subjected conscious rabbits to nonfatal reversible hemorrhage and analyzed the effects on marrow, bone, and a number of other tissues, utilizing the radioactive microsphere technique. There was no evidence for immediate shunting of blood from bone to marrow, but an increase in marrow blood flow did occur 16 hr after hemorrhage. This response was interpreted as a possible preparatory mechanism for increased erythropoietic activity.

In a related experiment, Gross et al. (1979) induced hypotension in the dog by arterial hemorrhage and followed changes in bone blood flow. The response to this state was a marked increase in vascular resistance and a decreased bone and marrow blood flow.

b. Response to exercise: In the dog, exercise induced by treadmill markedly increased blood flow to exercising skeletal muscles (Gross et al., 1979), and, at the same time, vascular resistance in bone rose significantly and flow, both to bone and marrow, diminished. During exercise, nonexercising muscle (temporalis) exhibited increased vascular resistance.

c. Response to hypoxia: In the dog, systemic arterial hypoxia was found to reduce blood flow to bone and marrow and raise vascular resistance in skeletal muscle (Gross et al., 1979). However, Adachi et al. (1976) had previously found no change under similar conditions. The differences in results may reflect variation in anesthesia technique or level of hypoxia.

d. Response to aging: MacPherson and Tothill (1978) presented evidence for increased bone blood flow to the tibia, fibula, femur, pelvis, humerus, radius, ulna, and scapula with increase in age and weight of rats.

e. Response to growth: McInnis et al. (1977) reported a positive correlation between bone blood flow and percent of new bone formation in a standardized tibial defect in the dog. The finding that cortical bone blood flow is higher in the immature than in the mature animal (Pasternak et al., 1966; Morris and Kelly, 1980) may be related to greater appositional growth and more extensive bone remodeling (Lee, 1964; Vanderhoeft et al., 1962). Whiteside et al. (1977b) noted a positive correlation between bone blood flow and osteoblastic activity in the rabbit tibia.

f. Summary: Blood flow to bone and marrow is responsive to altered physiology. Vessels to bone and marrow appear to be involved in the overall circulatory adjustment to hypotension, hypoxia, and exercise. Neurohumoral factors also produce alterations in blood flow to bone. (For a discussion of neurohumoral factors, see Section C.)

References

  1. Adachi, H., Strauss, H.W., Ochi, H., and Wagner, H.N. (1976). The effect of hypoxia on the regional distribution of cardiac output in the dog. Circ. Res. 39, 314-319.
  2. Brookes, M. (1967). Blood flow rates in compact and cancellous bone, and bone marrow. J. Anat. 101, 533-541.
  3. Cumming, J.D. (1960). A method for studying the rate of blood flow through the bone marrow of a rabbit's femur. J. Physiol. (London) 152, 39-40.
  4. Drinker, C.K., and Drinker, K.R. (1916). A method for maintaining an artificial circulation through the tibia of the dog, with a demonstration of the vasomotor control of the marrow vessels. Am. J. Physiol. 40, 511-521.
  5. Gross, P.M., Heistad, D.D., and Marcus, M.L. (1979). Neurohumeral regulation of blood flow to bone and marrow. Am. J. Physiol. 237, H440-H448.
  6. Gross, P.M., Marcus, M.L., and Heistad, D.D. (1981). Measurement of blood flow to bone and marrow in experimental animals by means of the microsphere technique. J. Bone Jt. Surg. Am. Vol. 63-A, 1028-1031.
  7. Kane, W.J. (1968). The determination of blood flow to tissues of the human leg. J. Bone Jt. Surg. Am. Vol. 50-A, 1070 (abstr.).
  8. Lee, W.R. (1964). Appositional bone formation in canine bone: A quantitative microscopic study using tetracycline markers. J. Anat. 98, 665-677.
  9. McInnis, J.C., Robb, R.A., and Kelly, P.J. (1977). Relationship of bone blood flow, mineral deposition, and endosteal new bone formation in healing canine tibial defects. Orthoped. Trans. 2, 162 (abstr.).
  10. Macpherson, J.N., and Tothill, P. (1978). Bone blood flow and age in the rat. Clin. Sci. Mol. Med. 54, 111-113.
  11. Morris, M., and Kelly, P.J. (1980). Use of tracer microspheres to measure bone blood flow in conscious dogs. Calcif. Tissue Int. 32, 69-76.
  12. Pasternak, N.S., Kelly, P.J., and Owen, C.A., Jr. (1966). Estimation of oxygen consumption, and carbon dioxide production and blood flow of bone in growing and mature dogs. Mayo Clin. Proc. 41, 831-835.
  13. Shim, S.S., Copp, D.H., and Patterson, F.P. (1967). An indirect method of bone-blood flow measurement based on the bone clearance of a circulating bone-seeking radioisotope. J. Bone. Jt. Surg. Am. Vol. 49-A, 693-702.
  14. Shim, S.S., Mokkhavesa, S., McPherson, G.D., and Schweigel, J.F. (1971). Bone and skeletal blood flow in man measured by a radioisotopic method. Can. J. Surg. 14, 38-41.
  15. Syftestad, G.T., and Boelkins, J.N. (1980). Effect of hemorrhage on blood flow to marrow and osseous tissue in conscious rabbits. Am. J. Physiol. 238, H360-H364.
  16. Tothill, P., and MacPherson, J.M. (1980). Limitations of radioactive microspheres as tracers for bone blood flow and extraction ratio studies. Calcif. Tissue In. 31, 261-265.
  17. Vanderhoeft, P.J., Kelly, P.J., and Peterson, L.F.A. (1962). Determination of growth rates in canine bone by means of tetracycline-labeled patterns. Lab. Invest. 11, 714-726.
  18. Van Dyke, D., Anger, H.O., Yano, Y., and Bozzini, C. (1965). Bone blood flow shown with 18F and the position camera. Am. J. Physiol. 209, 65-70.
  19. White, N.B., Ter-Pogossian, M.M., and Stein, A.H. (1964). A method to determine the rate of blood flow in long bone and selected soft tissues. Surg. Gynecol. Obstet. 119, 535-540.
  20. Whiteside, L.A., Lesker, P.A., and Simmons, D.J. (1977a). Measurement of regional bone and bone marrow blood flow in the rabbit using the hydrogen washout technique. Clin. Orthop. Relat. Res. 122, 340-346.
  21. Whiteside, L.A., Simmons, D.J., and Lesker, P.A. (1977b). Comparison of regional blood flow in areas with differing osteoblastic activity in the rabbit tibia. Clin. Orthop. Relat. Res. 124, 267-269.
  22. Wootton, R., Reeve, J., and Veall, N. (1976b). The clinical measurement of skeletal blood flow. Clin. Sci. Mol. Med. 50, 261-268.

PHYSIOLOGY OF BLOOD CIRCULATION

In: Blood Vessels And Lymphatics In Organ Systems

by D.W. Lennox and D.S. Hungerford This material has been published in Blood Vessels and Lymphatics in Organ Systems, edited by David I. Abramson and Philip B. Dorbin, the only definitive repository of the content that has been certified and accepted after peer review. Copyright and all rights therein are retained by Elsevier Science (USA). This material may not be copied or reposted without explicit permission.

Copyright 1984, Elsevier Science (USA). All rights reserved.