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The relationship between the blood flow and the marrow cavity pressure of bone Hawk, Hubert Edmund 1971

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THE RELATIONSHIP BETWEEN THE BLOOD FLOW AND THE MARROW CAVITY PRESSURE OF BONE by HUBERT EDMUND HAWK B.A., Case-Western Reserve Un i v e r s i t y , 1960 M.D., Dalhousie University, 1965 F.R.C.S.(C), Royal College of Physicians and Surgeons of Canada, 1970 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of SURGERY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1971. In presenting t h i s t h e s i s in p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree t h a t permission for e x t e n s i v e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . I t i s understood that copying or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n p e r m i s s i o n . Department of The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada \ i ABSTRACT An experimental animal model was developed to study and define the r e l a t i o n s h i p between the blood flow and the marrow c a v i t y pressure of bone. The study was c a r r i e d out i n 24 rabbits and 32 dogs under nembutol anesthesia. A multichannel physiograph was used to record simultaneously the systemic blood pressure, bone blood flow, marrow cavity pressure of bone and time sequence. The systemic blood pressure was measured by cannulating a brach-i a l or c a r o t i d artery. The bone blood flow was measured by cannulating the nutrient vein and /or the nutrient artery. The marrow ca v i t y pressure was measured by i n s e r t i n g a s t e e l cannula through a d r i l l hole i n the cortex into the marrox* cavity. The bones studied were mainly the t i b i a and femur. During the normal control condition, the marrow ca v i t y pressure was found to have a wide range from animal to animal. In the r a b b i t s , the range was from 20 to 60 mm. Hg. (15 to 50 percent of the systemic blood pressure). In the dogs, i t ranged from 40 to 120 mm. Hg. (20 to 90 percent of the systemic blood pressure). However, the systemic blood pressure, intramedullary pressure and nutrient venous outflow were remarkably constant In a c o n t r o l period, therefore, t h e i r changes under experimental conditions were r e a d i l y recordable. Various factors a f f e c t i n g bone c i r c u l a t i o n were studied. I f the femoral vein i s occluded the marrow c a v i t y pressure r i s e s and the nutrient venous outflow increases i n d i c a t i n g venous congestion of bone. Nutrient artery occlusion causes a sharp f a l l i n marrow cavity pressure coupled with a marked decrease i n the nut r i e n t venous outflow. Adrenalin and noradrenalin intravenous infusions produce a f a l l i n marrow cavity pressure coupled with a decreased bone blood flow, despite an elevation i n the systemic blood pressure. Isoproterenol hydrochloride generally causes a f a l l i n the i i systemic blood pressure, widening of the pulse pressure, a f a l l i n the marrow c a v i t y pressure and a decrease i n the nutrient venous outflow. E l e c t -r i c a l sympathetic stimulation produces a f a l l i n the marrow ca v i t y pressure and a decrease i n bone blood flow. Lumbar sympathectomy causes a r i s e i n the marrottf cavity pressure and an increase i n the bone blood flow. S k e l e t a l muscle contraction produces bone venous congestion with e l e v a t i o n of the marrow c a v i t y pressure and increased n u t r i e n t venous outflow. Muscular re l a x a t i o n causes a momentary sharp f a l l i n the marrow ca v i t y pressure to sub c o n t r o l levels before returning to the normal pressure. It i s concluded that the marrow ca v i t y pressure i s bone blood flow dependent and r e f l e c t s w ell the changes i n the hemodynamics of bone. The narrow pressure r i s e s i f the a r t e r i a l blood supply to bone increases or the venous congestion occurs i n bone. The marrow pressure f a l l s i f the a r t e r i a l blood supply to bone decreases or the venous drainage of bone i s f a c i l i t a t e d . TABLE OF CONTENTS i i i PAGE NO. I INTRODUCTION II REVIEW OF LITERATURE A. Vascular Anatomy of Bone B. Nerve Supply of Bone C. Physiology of Bone C i r c u l a t i o n D. Bone Marrow Cavity Pressure I I I MATERIALS AND METHOD A. General Experimental Model B. Experimental Conditions IV RESULTS A. Normal Control Condition B. Experimental Observations 1. E f f e c t of Femoral Artery Occlusion 2. E f f e c t of Nutrient Artery Occlusion 3. E f f e c t of Femoral Vein Occlusion 4. E f f e c t of Low Pressure Tourniquet 5. E f f e c t of Catecholamine Drugs 6. E f f e c t of S c i a t i c and Lumbar Sympathetic E l e c t r i c a l Stimulation 7. E f f e c t of Sympathectomy 8. E f f e c t of Muscle Contraction 32 41 V DISCUSSION 64 VI SUMMARY AND CONCLUSION 69 Iv TABLES PAGE NO. I Summary of Bone Blood Flow Studies - L i t e r a t u r e Review 22 I I Normal Control Marrow Cavity Pressures 42 V FIGURES PAGE NO. 1. Micrograph of a cross section of the dog's femur with India 7 ink perfusion of the medullary and c o r t i c a l vessels. 2. Micrograph of a l o n g i t u d i n a l section of the dog's t i b i a - 8 f i b u l a with India ink perfusion of the medullary and c o r t -i c a l v e s s e l s . 3. Micrograph of the p e r i o s t e a l vessels of the dog t i b i a . 10 4. Micrograph of a cross section of the dog's femur showing 17 medullated nerve i n the marrow c a v i t y . 5. The experimental set-up. 38 6. The normal c o n t r o l t r a c i n g . 44 7. The e f f e c t of femoral artery occlusion. 45 8. The e f f e c t of femoral vein occlusion. 47 9. The e f f e c t of low pressure tourniquet. 49 10. The e f f e c t of adrenalin i . v . i n f u s i o n . 51 11. The e f f e c t of noradrenalin i . v . i n f u s i o n . 52 12. The e f f e c t of isoproterenol hydrochloride i . v . i n f u s i o n . 54 13. The e f f e c t of e l e c t r i c a l stimulation of the lumbar sym- 55 pathetic trunk. 14. The e f f e c t of e l e c t r i c a l s timulation of the lumbar aym- 56 pathetic trunk. 15. The e f f e c t of e l e c t r i c a l stimulation of the s c i a t i c nerve. 58 16. The e f f e c t of lumbar sympathectomy. 59 17. The e f f e c t of te t a n i c muscle contraction. 61 18. The e f f e c t of te t a n i c muscle contraction. 62 19. The e f f e c t of phasic muscle contraction. 63 v i ACKNOWLEDGEMENTS The author wishes to express h i s sincere appreciation to Dr. Sun Shik Shim f or h i s sponsorship of the author's graduate study and research work and f o r h i s t i r e l e s s guidance and advice. The author i s g r a t e f u l to Dr. Frank P. Patterson f o r h i s d i r e c t i o n and encouragement of the authors graduate study. The author, a l s o , would l i k e to express appreciation to Dr. William Yu and Mr. George Leung for t h e i r valuable assistance i n t h i s research work. The author extends many thanks to Mr. Bardolf Paul who prepared the trac i n g s , to Miss B i c k n e l l who a s s i s t e d i n the preparation of the manuscript, and to the s t a f f members of the medical i l l u s t r a t i o n department and the animal research laboratory f o r t h e i r help and co-operation. 1 INTRODUCTION Bone i s a hig h l y s p e c i a l i z e d connective t i s s u e which i s rendered r i g i d by the impregnation of i t s ground substance with calcium s a l t s . Bone i s an important organ not only because of i t s mechanical functions of supporting ligaments and muscles and the surrounding and protecting v i t a l organs, but, al s o , f o r i t s e s s e n t i a l metabolic functions of mineral banking and hemato-p o i e s i s . Since the r i c h vascular system of bone supports these functions, the study of bone c i r c u l a t i o n i s of great importance. There i s a need f o r the development of a u s e f u l method f o r the study of the dynamic p h y s i o l o g i c a l aspects of bone c i r c u l a t i o n . The i n v e s t i g a t i o n of the f u n c t i o n a l properties of the c i r c u l a t i o n of bone i s remarkably d i f -f i c u l t because of the deep c e n t r a l l o c a t i o n and r i g i d structure of bone and the complexity of i t s vascular system. Both the qua n t i t a t i v e and q u a l i t -ative studies of bone c i r c u l a t i o n are hampered by the lack of s u i t a b l e methods of study. The objectives of t h i s research work were: 1) to develop an animal model to study the q u a l i t a t i v e changes i n bone c i r c u l a t i o n under various experimental conditions. 2) to determine the r e l a t i o n s h i p between intramedullary pressure and bone blood flow. This paper w i l l be introduced by a review of the current l i t e r a t u r e dealing with the vascular anatomy of bone, the innervation of bone, the p h y s i o l o g i c a l mechanisms c o n t r o l l i n g bone c i r c u l a t i o n and the marrow ca v i t y pressure studies of bone. This in t r o d u c t i o n w i l l be followed by the materials and method of t h i s study, the r e s u l t s obtained, a discussion of these r e s u l t s and, l a s t l y , a summary and conclusion. 2 REVIEW OF LITERATURE Vascular anatomy of bone Nerve supply of bone Physiology of bone c i r c u l a t i o n Intramedullary pressure of bone. Vascular Anatomy of Bone The r i c h vascular anatomy of bone has been studied by numerous i n v e s t i -gators using gross, microangiographic, microradiographic and v i t a l microscopy techniques. Most studies used i n j e c t i o n materials such as v i n y l p l a s t i c , l atex, India i n k , B e r l i n blue or barium s u l f a t e (micropaque) suspension to 99 demonstrate the vascular channels. Frequently,the Spalteholz technique for c l e a r i n g i n j e c t e d specimens was used which allows the microscopic study of r e l a t i v e l y t h i c k sections bone. Through these methods of study,we have improved our knowledge of the complexity of the vascular arrangement i n bone, the anastomotic connections between the a r t e r i a l i n l e t s to bone, the fi n e vascular anatomy, and the nature of the connections of the s i n u s o i d a l system with a r t e r i e s and veins. 53 58 Langer i n 1876 and Lexer i n 1904 described the c l a s s i c a l o u t l i n e of the anatomy of the blood supply of tubular bones. Regardless of species, tubular bones have three major a r t e r i a l i n l e t s : 1. Epiphyseal - Metaphyseal a r t e r i e s at the ends of the bone, 2. Nutrient a r t e r i e s , usually one or two main a r t e r i e s entering the diaphysis, 3. P e r i o s t e a l a r t e r i e s , multiple branches from the vessels of soft tissues adjacent to the bone covering membrane. Epiphyseal - Metaphyseal A r t e r i e s The ends of the tubular bones receives an abundant blood supply which, i n general, a r i s e from the c i r c u l u s a r t i c u l i vasculosus of Hunter.^ This ci r c u m f e r e n t i a l a r t e r i a l network gives o f f numerous r a d i a l l y oriented vessels which enter the epiphysis and metaphysis l i k e spokes of a wheel. Each spoke i s composed of several a r t e r i e s and t h e i r accompanying v e i n s . T h e s e vessels give o f f many branches at r i g h t angles to form a dense Interlocking vascular network. The a r t e r i a l arcades become smaller and smaller and 106 terminate i n small a r t e r i a l loops beneath the a r t i c u l a r c a r t i l a g e . 36 Holmdahl and Ingelmark studying h i s t o l o g i c specimens from the major j o i n t s of rabbits and man observed i n a l l specimens the existance of d i r e c t contact between the medullary c a v i t y and the basal portion of the a r t i c u l a r c a r t -i l a g e . Two types of vascular contact were described as: 1) Ampulla-like (wide) 30-50 „u i n diameter, 36 2) Canal-like (dendritic) 10-20 ; i i n diameter. 85 Rogers and Gladstone studied the vascular foramina and a r t e r i a l supply of the d i s t a l end of the human femur and grouped these foramina into "area c r i b r o s a Vasorum Femoris" and subdivided t h i s i n t o supracondylar, condylar and intercondylar regions. Their i n j e c t i o n studies, as do Nelson et. a l . ^ o f the proximal and d i s t a l human t i b i a , demonstrate the abundant vascular supply i n these regions. The vascular foramina should be regarded 12 57 as important avenues of a r t e r i a l supply to the whole bone. ' The t o t a l cross s e c t i o n a l area of the epiphysio-metaphyseal a r t e r i e s must exceed many times that of the p r i n c i p a l nutrient a r t e r y . ^ During growth, the epiphysis and metaphysis are separated by an 108 a c t i v e l y d i v i d i n g epiphyseal c a r t i l a g e p l a t e . There i s controversy concerning the vascular connection between the metaphyseal and epiphyseal regions during t h i s period. Vascular channels have been described by some i n v e s t i g a t o r s ^ ^ a n d denied by others.^' Vasculature Adjacent to the Epiphyseal Plate  Epiphyseal Side The epiphyseal a r t e r i e s by progressive branching and anastomosing large c a l i b e r vessels reach the bone plate which covers the growth c a r t i l a g e and cross i t through numerous canals. Once under the p l a t e , these vessels 108 divide i n t o several terminal spurs turning back as large veins. Each terminal vascular expansion supplies an area r e l a t e d to four to ten columns 109 of c a r t i l a g e c e l l s . These vessels never penetrate between the c a r t i l a g e c e l l columns as has been suggested by those in v e s t i g a t o r s f a i l i n g to appreciate the d i v e r s i t y of depth at which the c a r t i l a g e columns begin.^>H2 Metaphyseal Side The majority of vessels reaching the growth p l a t e from the metaphyseal side are the l a s t ramifications of the nutrient a r t e r i a l system supplying 109 the c e n t r a l portion of the p l a t e . The periphery of the plate i s supplied by large p e r f o r a t i n g metaphyseal a r t e r i e s which act as minute nutrient arteries.''' Both nutr i e n t and metaphyseal a r t e r i e s end i n f i n e vessels at the approximate l e v e l of the l a s t trabeculae where they become p a r a l l e l to each other while advancing toward the l a s t hypertrophic c e l l of 7 9 the c a r t i l a g e column. ' A l l vessels turn back at about the same l e v e l , the descending leg of the loop, being i n d i s t i n g u i s h a b l e from the ascending 69 limb, terminates i n a pool of sinusoids. Injected specimens show no d i r e c t contact between the perfused vascular loops and the l a s t hypertrophic c a r t i l a g e c e l l s . ^ This i s now known to be due to the i n t e r p o s i t i o n of blood between the summit of the v e s s e l loops and the l a s t i n t e r c e l l u l a r septum. The sudden collapse of the c a r t i l a g e c e l l w a l l i s thought to cause a vascular burst producing a microhemorrhage."'^' Trueta^ S i a s studied t h i s sequence with the aid of an e l e c t r o n microscope. A c i r c u m f e r e n t i a l artery of small c a l i b e r runs about the periphery of the epiphyseal c a r t i l a g e p l a t e . This vessel receives f i n e branches from the 7 69 p e r i o s t e a l a r t e r i o l e s and connects the metaphyseal-epiphyseal a r t e r i e s . ' Nutrient A r t e r i a l System A l l long bones receive one or more proper nutrient a r t e r i e s . They vary i n number and i n p o s i t i o n from one bone to another as x^ell as one 109 species to another. Nevertheless, the v a r i a t i o n s are small. The 53 58 pioneer studies of Langer and Lexer have been extended by numerous in v e s t i g a t o r s . Laing"^studying the a r t e r i a l supply of the human humerus found a s i n g l e main nutrient artery, usually a branch of the b r a c h i a l artery, 13 i n 28 of 30 specimens and double i n the remaining two cases. C a r r o l l and Laing^^studied the nutrient foramina of the humeral diaphysis and found the foramen of entry v a r i a b l e , most commonly located on the anteromedial 52 aspect at the j u n c t i o n of the middle and lower t h i r d . Laing In an anatomical study of the blood supply the human femoral shaft observed the nutrient a r t e r i e s were branches of p e r f o r a t i n g a r t e r i e s a r i s i n g from the profunda femoris artery. In 11 of 17 c h i l d r e n and four of ten adult femora two n u t r i e n t a r t e r i e s were found and one nutrient artery i n the remaining cases. In a l l cases the n u t r i e n t artery penetrated the cortex i n the region of the l i n e a aspera within the upper two-thirds of the diap-h y s i s . 88 In 328 specimens of the human r a d i i and ulnae, Schulman found 98 percent of bones had a s i n g l e nutrient foramina with the remainder having two foramina. A l l were present i n the proximal h a l f of the diaphysis. Nelson, et. a l . ^ f o u n d the n u t r i e n t artery i n 12 human t i b i a e c o n s i s t e n t l y arose, from the p o s t e r i o r t i b i a l a r t e r y obliquely penetrating the postero-l a t e r a l cortex j u s t d i s t a l to the oblique s a l e a l l i n e of the t i b i a . The explanation f o r the o b l i q u i t y of the nutrient foramina i s not known. The theories of explanation may be divided into four groups: 1. Periosteal: Differential growth rate of bone versus 4 * 3 7 periosteum. 62 2. Muscular: In line with muscular pu l l . 3. Vascular: Differential growth rate of bone versus art e r i a l system. 4. Morpho-genetically determined vascular patterns of bone.^ Upon entering the medullary cavity through the nutrient foramen, usually accompanied by a nutrient vein and nerve, the nutrient artery quickly 9 10 69 109 divides into ascending and descending branches. ' ' ' These branches give off numerous smaller radial branches which supply the adjacent medullary tissue and cortex by piercing the endosteal surface and subdividing into smaller vessels that run in the Haversian canals.(see figures 1 and 2) As the major medullary nutrient vessels approach the bone ends, they are joined by the epiphyseal-metaphyseal vessels. Anastomoses occur between both sets of arteries, forming the medullary a r t e r i a l s y s t e m . ^ From this system branches are given off to the surrounding narrow, cancellous 27 and compact bone, and articular cartilage. Although the epiphyseal-metaphyseal and diaphyseal nutrient arteries principally supply their own areas, following obstruction of one group anastomotic channels of the remaining groups enlarge and the function of the obstructed group is 12 completely taken over. There i s a controversy regarding the extent of the functional vascular continuity across the epiphyseal plate scar in wing a 2,7,57,69,109,110 102 mature bones. However, there i s considerable evidence showing a definite connection between the vessels of these two regions.' Lewis^^is of the opinion that i n the earliest stages of development, the metaphysis is supplied by vessels derived from the nutrient artery. Later metaphyseal arteries progressively take over the supply of i t s peri-7 FIGURE 1. Micrograph of a cross section of the dog's femur with India ink perfusion of the medullary and c o r t i c a l v e s s e l s . Note the numerous r a d i a l l y oriented medullary vessels supplying at l e a s t the inner two thirds of the cortex. FIGURE 2. Micrograph of a longitudinal section of the dog's t i b i a fibula with India ink perfusion of the medullary and cortical vessels Note the numerous medullary vessels piercing the endosteal surface of the cortex. 109 pheral part. Trueta found i n r a b b i t i n j e c t i o n studies over f o u r - f i f t h s of the vessels reaching the growth p l a t e from the metaphysis are the l a s t r a m i f i c a t i o n s of the nutrient artery evenly d i s t r i b u t e d over the c e n t r a l 93 part of the growth p l a t e . Shim and associates found i n adult r a b b i t s , 85 using a Sr clearance technique, that the nutrient artery contributed at l e a s t 46 percent of the normal t o t a l blood supply of the e n t i r e femur, and at l e a s t 71 percent of the normal t o t a l blood flow of the shaft i n c l u d i n g i t s marrow,and 37 percent and 33 percent of the normal blood flow of the upper and lower epiphyseal and metaphyseal areas r e s p e c t i v e l y . P e r i o s t e a l A r t e r i a l System The periosteum of bone has a r i c h vascular supply, the a r t e r i e s with 109 two companion veins forming a continuous vascular net about the bones. Large branches of vessels supplying neighouring muscles, pass on to the fibrous layer of the periosteum and form at i n t e r v a l s several vascular c i r c l e s round the shaft which are i n s e r i e s with the c i r c u l u s a r t i c u l i vasculosus. Longitudinal anastomotic chains are found, also, associated with the borders of the bone, for example the interosreous border of the 69 t i b i a . (see f i g u r e 3) A r i s i n g from the fibrous p e r i o s t e a l v e s s e l s , a c a p i l l a r y network forms i n the osteogenic layer of the periosteum l y i n g r i g h t on the bone surface.^ Brookes and associates^demonstrated that at s i t e s of fleshy muscle attachments the fibrous periosteum i s d e f i c i e n t with the intramuscular and p e r i o s t e a l c i r c u l a t i o n s intimately associated. They suggested the pumping action of muscle may be important i n maintaining a normal c e n t i f u g a l c o r t i c a l blood flow. C o r t i c a l Vessels and Blood Flow Vessels of c o r t i c a l bone are generally simple endothelial tubes of 34 48 approximately 15 ju i n diameter. 5 The o r i g i n s of these vessels are from the p e r i o s t e a l and medullary systems with a f u n c t i o n a l anastomotic 10 FIGURE 3. Micrograph of the periosteal vessel of the dog's t i b i a . Note the numerous horizontally oriented vessels which are given off by the longitudinal periosteal vessels. Each arterial branch is accompanied by two veins. 11 84 communication between them. The vessels tend to be l a r g e r on the endos-7 71 t e a l surface. ' In the i n t e r t r a b e c u l a r spaces of the f o e t a l cortex multiple vessels occur; i n the primary osteones two or three; but the vascular canals of the adult cortex, whether i n the surface bone or secondary osteones, generally contains but a s i n g l e v e s s e l . 1 2 , 7 6 y^ere Haversian canals fuse, then the fused portion may contain more than one 6 v e s s e l . Descriptions of canals normally containing a r t e r i e s , veins and c a p i l l a r i e s are generally not accepted.^ In man the Haversian canals vary from 25 to 125 p i n diamter, averaging 50 ji. Although these canals run l o n g i t u d i n a l l y , they do not run v e r t i c a l l y f o r more than short distance, 86 soon deviating from a s t r a i g h t l i n e . The canals form continuously, anastomosing and ramifying networks. Beneath the a r t i c u l a r c a r t i l a g e at the upper and lower ends of the bone the canals run transversely to the 36 38 long diameter of the bone. ' Near the surface of the bone, Haversian canals communicate with canals of the ground lamella which open to the external surface of the bone. The inner most canals lead i n t o the medullary cavity. Recently the term macrocanalicular system has been used to r e f e r to the system i n demineralized bone which i s composed of Haversian and 38 anastomosing Volkmann spaces. The vascular patterns of c o r t i c a l c a p i l l a r i e s are usually described as being l o n g i t u d i n a l l y oriented with short h o r i z o n t a l limbs l y i n g i n 34 Volkmann's canals. However, a large body of information gathered i s not t o t a l l y In agreement with t h i s description.6*9,11,15,71 T y p i c a l l y c o r t i c a l c a p i l l a r i e s are oblique i n d i s p o s i t i o n . ^ This c o r t i c a l vascular o b l i q u i t y i s i n opposing senses at e i t h e r end of a long bone, the two regions meeting by abrupt d i r e c t i o n a l changes. For example, i n the adult human t i b i a , t h i s change takes place at the i n f e r i o r metaphysis and may be a f a c t o r i n 86 delayed frac ure healing. 12 In discussing the problem of the direction of the cortical blood flow, 9 12 Brookes and associates ' pointed out the unlikelihood of blood passing through the simple cortical vascular channels in two directions (medullary vessels to periosteum and vice versa) and supported the concept of centi-fugal blood flow in the cortex. Nelson and associates^ found that the cortex is mainly supplied by the nutrient medullary system and along, with other investigators,9*64,69,71 c o n s ^ e Y S ^ e periosteal system provides a reserve supply in case of injury to the medullary vesselc. Branemark has visualized the fibular medullary and cortical blood flow in the li v e rabbit and observed capillaries from the marrow arterioles dip into the Haversian canals to supply the endosteal parts of cortical bone then swing back into the marrow to empty into marrow sinusoids. Venous System of Bone Delineation of the anatomy of the venous drainage i s more d i f f i c u l t for venous valves tend to block attempts at retrograde injections of the 53 extraosseous veins. Hoyer, as cited by Langer, showed dye or contrast media injected directly into the medullary cavity would f i l l and demon-strate the intraosseous venous system. There i s a large centrally placed vein in the marrow cavity of long bones.69>109 <j^^B v e n o u s S i n u s i s some ten times wider than the principle 7 69 nutrient artery when distended. ' The central sinus, with a wall two to three cells thick, extends the entire length of the diaphyseal marrow.69,109 The central venous sinus is formed in the metaphyses by the confluence of a rich venous sinusoidal network which tends to parallel the arteries but are more numerous and of larger caliber. These sinusoids anastomose frequently and the peripheral ones are drained by numerous metaphyseal 69 v<iins leaving the bone. The sinusoids have been observed to have essen-t i a l l y two different forms: spindle-shaped and hexagonal shaped sinusoids.^ 13 The hexagonal sinusoids are often drained by more than one venule and the spindle sinusoids o c c a s i o n a l l y have two o u t l e t s . ^ These sinusoids e i t h e r drain d i r e c t l y into the c e n t r a l venous sinus or i n d i r e c t l y i n t o i t s l a r g e r t r i b u t o r i e s . This r i c h network of sinusoids cross the long axis of the bone and i n cross sections of the marrow cavity are seen to converge as spokes of a wheel i n t o the c e n t r a l venous h u b . ^ ' ^ The c e n t r a l venous sinus i s drained by the nutrient v e i n and by the occasional large emissary 7 69 v e i n seen tr a v e r s i n g the cortex. Morgan points out that the nutrient vein leaving bone by the nutrient canal cannot provide outflow for a l l of the blood leaving the bone. Steinback and a s s o c i a t e s 1 ^ intraosseous phlebography studies i n d i c a t e much of the venous drainage occurs at the ends of bones. Vascular Bed of Red Marrow The anatomy and physiology of hematopoietic t i s s u e i s of p a r t i c u l a r i n t e r e s t to the hematologist and the orthopedic surgeon. The d i s t r i b u t i o n 34 of red marrow va r i e s with age. The sinusoids of red marrow have a tv-all one c e l l l a y e r thick. Whether t h i s wall i s c l o s e d ^ or open^' 1 1"* Is an o l d controversy. Most modern workers using i n j e c t i o n techniques deny the open view because of the c l e a r cut d e f i n i t i o n of boundaries obtained. 1^' 108,111 contrary to t h i s , some i n v e s t i g a t o r s ^ ' 1 1 " ' now consider that there is. a r e a l p o s s i b i l i t y of open vessels being present, at l e a s t i n the 57 109 juxta-epiphyseal marrow. ' It i s generally accepted that diapedesis of red c e l l s and p a r t i c u l a t e matter occurs through c a p i l l a r i e s , e s p e c i a l l y growing endothelium and that marrow i s highly phagocytic. 1 1~* W e i s s 1 1 ^ showed that marrow sinusoids are formed by reticuloendothelial" c e l l s which may become motile with a d d i t i o n a l functions such as phagocytosis or cytopoi-e s i s . C e l l s that assume these secondary functions may not be replaced 57 rendering segments of the marrow sinusoids incompetant. Pease observed that the sinusoid w a l l d e f i c i e n c i e s , due to r e t i c u l o e n d o t h e l i a l c e l l s with long protoplasmic processes, were frequently plugged by e r y t h r o b l a s t i c or metamyelocytlccells which he suggests as evidence for an open marrow c i r c u l a t i o n . However, t h e i r r e s u l t s do not i n d i c a t e whole blood extra-vasation i n t o the surrounding stroma, and could be interpreted as demon-s t r a t i n g a mechanism for the passage of blood c e l l s from t h e i r s i t e of 115 formation i n t o the systemic c i r c u l a t i o n . x Non tubular cancellous bones, a l s o , have a general vascular pattern. The vascular anatomy of the scaphoid, talus and femoral head are examples of t h i s group which have been studied.^»70»1H j n g e n e r a i j several nutr i e n t a r t e r i e s penetrate the cortex at d i f f e r e n t s i t e s and begin to branch and subdivide on entering the medullary c a v i t y . ^ They frequently anastomose intraosseously with branches of other nutrient a r t e r i e s . These a r t e r i e s continue to arborize sending branches towards the a r t i c u l a r c a r t i l a g e , c o r t i c a l bone and medullary t i s s u e , e i t h e r following the can-cellous pattern^»^^" or as others believe i n a s p e c i f i c pattern u n i n f l u e -42 need by that of the osseous trabeculae. Near the a r t i c u l a r c a r t i l a g e , intraosseous arcade formation occurs before descrete a r t e r i a l terminals pass to the j u x t a - a r t i c u l a r p l a t e . Sinusoid loops, ampullae and d i g i t -ations are formed which then pass into and possibly beyond the c a l i f i e d 109 c a r t i l a g e . These loops anastomose at t h e i r venous end so that a sinus-o i d network i s formed from which venous r a d i c l e s a r i s e and pass into larger c o l l e c t i n g sinuses. The l a t t e r are drained by veins leaving bone i n 42 a s s o c i a t i o n with an artery. Lymphatic Pathways of Bone The question of lymphatics i n bone i s a neglected one. Although they have been suggested, lymphatic channels have never been anatomically demon-str a t e d i n bone.° Anderson''" placed guaze pledgets soaked with India ink 15' i n t o the medullary c a v i t y of the r a b b i t t i b i a but was unable to show the exis t a n c e of lymphatic channels. However, he d i d show an i n t e r s t i t i a l f l u i d flow from w i t h i n the medullary space of bone through the Haversian canals. This problem r e q u i r e s f u r t h e r study. Nerve Supply of Bone 28 Du Verney i n 1700, p o s t u l a t e d that bone contained nerve f i b e r s when he noted apparent p a i n f u l r e a c t i o n s produced i n animals by the i n t r o -d u ction of an instrument i n t o the marrow c a v i t y opened by the amputation of the limb. 73 O t t o l e n g h i i n 1902, studying the i n n e r v a t i o n of the bone marrow of man, sheep, dog, r a b b i t , guinea p i g and chic k e n , concluded from h i s obser-v a t i o n s t h a t : 1) the bone marrow i s r i c h l y s u p p l i e d w i t h medullated and non-medullated f i b e r s , 2) these nerves form f i n e plexuses i n the w a l l s of the blood v e s s e l s and many r a m i f i c a t i o n s reach the c a p i l l a r i e s , 3) i n the marrow pulp there are many medullated and non-medullated f i b e r s passing e v e n t u a l l y to d i s t a n t v e s s e l s , and 4) the ex i s t a n c e of s p e c i a l nerve endings about independent marrow elements cannot be d e f i n i t e l y determined. Kuntz and R i c h i n s ~ ^ i n 1945 s t u d i e d the nerves of bone marrow from the cat and dog. Some animals i n t h e i r study were three weeks post complete lumbar sympathectomy or had had a s u r g i c a l removal of the s p i n a l g a n g l i a of a l l nerves c o n t r i b u t i n g to the a f f e r e n t i n n e r v a t i o n of one limb. They observed nerves enter the bone marrow v i a n u t r i e n t foramina w i t h the blood v e s s e l s . W i t h i n the marrow, the nerves remain a s s o c i a t e d w i t h the v e s s e l s , excepting s m a l l bundles and i n d i v i d u a l nerve f i b e r s which deviated from the p e r i v a s c u l a r plexuses to pursue independent courses through parenchy-matous t i s s u e . Kuntz, e t . a l . " ^ observed sympathetic f i b e r s are mainly unmyelinated forming l e s s complete plexuses about the blood v e s s e l s , and 16 suggested these f i b e r s , probably did not innervate the bone marrow d i r e c t l y . They observed the afferent f i b e r s are mainly myelinated and give r i s e to loose perivascular plexuses from which some f i b e r s deviate e i t h e r s i n g l y or i n small bundles and appear r e l a t e d to receptors i n the bone marrow. 68 M i l l e r and Kasahara i n 1963, studied the innervation of human and animal bones by methylene blue immersion. They found small myelinated f i b e r s winding about trabeculae of the spongiosa or spread out on the under surface of the a r t i c u l a r c a r t i l a g e . Some f i b e r s were observed to end i n small knob l i k e endings under the periosteum and other f i b e r s from the p e r i o -90 steum entering Volkmann's canals. Sherman i n 1963 using hematoxylin and eosin s t a i n s observed the r i c h nerve supply of bone was usually assoc-i a t e d with a r t e r i a l vessels and that the majority of nerves to be non-myelinated, (see figure 4) Physiology of Bone C i r c u l a t i o n Bone i s a highly vascular organ. However, there i s no d i r e c t q u a n t i t a t i v e r e l a t i o n s h i p between the mere existance of vessels and t h e i r f u n c t i o n a l value to bone. Maintainance of blood c i r c u l a t i o n through bone i s of v i t a l importance f o r osteogenesis, bone growth and remodelling, fracture r e p a i r and the homeostatic functions of hematopoiesis and mineral banking. Understanding the mechanisms and factors c o n t r o l l i n g bone c i r c u l -a t i o n w i l l increase our knowledge of the p h y s i o l o g i c a l functions of bone blood flow, as w e l l as, i t s r o l e i n some path o l o g i c a l st a t e s . In the l i v i n g body, the cardiac output, the tone and capacity of vascular systems, and the amount and q u a l i t y of blood are continuously being changed by many 91 l o c a l and systemic f a c t o r s . Thus the blood flow to various tissues and organs, such as bone, i s i n a constant state of change. 17 FIGURE 4. Micrograph of a cross section of the dogs femur. Hemat-oxylin eosin stain showing a medullated nerve in the marrow cavity. 18 Method of P h y s i o l o g i c a l Study The p h y s i o l o g i c a l study of bone c i r c u l a t i o n may be approached b a s i c a l l y by e i t h e r a quantitative or q u a l i t a t i v e method. The method i s d i r e c t i f based d i r e c t l y on bone blood flow or i n d i r e c t i f based on c r i t e r i a which are presumed to be bone blood flow dependent. 91 Shim out l i n e d the previously used methods of p h y s i o l o g i c a l study of bone c i r c u l a t i o n as follows: I Quantitative Studies A. Direct Methods 1. Cannulation - c o l l e c t i o n measurement 2. A p p l i c a t i o n of electromechanical flow meters B. Indirect Methods 1. Blood ti s s u e exchange mechanism a. Fick p r i n c i p l e b. Radioisotope clearance 2. Indicator - d i l u t i o n p r i n c i p l e a. Radioisotope ( C r ^ \ 1*^) b. Dye (Evans blue) 3. Various occlusion Plethysmography II Q u a l i t a t i v e Studies A. Flow pattern 1. V i t a l microscopy 2. Bone venography B. S e l e c t i v e a r t e r i a l i s o l a t i o n to determine r e l a t i v e importance of a r t e r i e s 1. Destruction or occlusion of c e r t a i n vessels a. Study of d e v i t a l i z e d area b. E f f e c t on fracture healing or bone growth 19 c. Effect on relative isotope uptake 2. Injection of indicators into an artery to observe the area i t sustains. C. Bone hemodynamics 1. Direct methods (cannulation) a. Assessment of relative flow volume change b. Study of arteriovenous blood constituents 2. Indirect methods a. Intramedullary blood pressure b. Intra osseous thermometry c. Oxygen tension of bone d. Radioisotope uptake or clearance from bone D. Alteration of hemodynamics to stimulate growth, fracture repair and bone v i t a l i t y 1. Sympathectomy 2. Arteriovenous f i s t u l a 3. Periosteal stripping 4. Fracture 5. Ligation of a major vein 6. Application of low pressure tourniquets 7. Artery or muscle transplantation to bone. Due to i t s deep central location, r i g i d structure, delicate thin walled sinusoids and numerous periosteal and epiphysio-metaphyseal vessels arising from the vasculature of the surrounding soft tissues, the dynamic study of bone circulation i s d i f f i c u l t without disrupting i t to some extent. Thus the qualitative and quantitative studies of bone blood flow are d i f f i c u l t , with each method having i t s own limitations. 20 Rate of Bone Blood Flow Despite the complex v a s c u l a r i t y of bone i t has frequently been sug-gested that mature bone has a low metabolic demand and requires a r e l a t -86 i v e l y small blood supply. The m u l t i p l i c i t y and complexity of i t s vas-cular pattern and i t s r i g i d a rchitecture makes the use of d i r e c t quantit-45 26 a t i v e methods v i r t u a l l y u n r e l i a b l e . Drinker and Drinker found the flow values quite v a r i a b l e during t h e i r perfusion experiments on the dog t i b i a . Other workers have measured blood flow rates by cannulating one or two u 18,81,95 vessels of long bones. Although d i r e c t methods may be u s e f u l i n animals for the evaluation of r e l a t i v e changes i n bone blood flow, t h i s type of study has l i m i t e d a p p l i c a b i l i t y and does not give a measurement of t o t a l blood flow i n any 91 bone. Due to the l i m i t a t i o n s of d i r e c t measurements, i n d i r e c t methods 29 have been developed. Edholm and associates estimated normal bone blood flow using venous occ l u s i o n plethysmography, but the r a t i o n a l e and v a l i d i t y of such a method to estimate bone blood flow i s questionable. At the present time, v i r t u a l l y a l l i n v e s t i g a t i o n s of the q u a n t i t a t i o n of blood 45 flow involves the use of radioactive tracers and i n d i c a t o r s . The short term clearance of bone seeking radioisotopes from the blood by bone 30 was pioneered by Frederickson, Honour, and Copp, i n 1955, to measure s k e l e t a l blood flow i n the r a t . Their method has been modified and ext-92 93 96 ended by Shim and associates ' ' i n the rabbit and dog, and by Ray 82 115 and co-workers and Weinman and associates, i n the dog. The use of Cr^* tagged red blood c e l l s has been developed on the 119 45 d i l u t i o n p r i n c i p l e by White and S t e i n . Kane and Grim proposed a method u t i l i z i n g bone clearance of c i r c u l a t i n g and Rb^^. They support the use of these isotopes by l i s t i n g the following advantages: 1. The method i s v a l i d a t e d , 2. Requires no surgery near the organ under i n v e s t i g a t i o n , 3. Offers a method of simultaneous study of the s k i n and muscle perfusion, 4. Can be done on unanesthetized animals, and 5. Has an e x t r a c t i o n r a t i o of 93 percent for the primary c i r c u l a t i o n and e f f e c t i v e l y 100 percent at one minute. The l a t t e r exceeds the extraction r a t i o s of S r ^ and C a ^ which have been determined to be 50 to 75 per c e n t . 1 ^ ' 1 1 " ' This may be corrected by 94 using a c o r r e c t i o n f a c t o r . (see Table I) S k e l e t a l Blood Flow The rate of the e n t i r e s k e l e t a l blood flow i n animals has been e s t i -91 mated to be four to ten percent of the r e s t i n g cardiac output. Recently 94 Shim et a l reported the average bone blood flow i n man to be 2.5 ml./min/ 100 grams wet bone and estimated the e n t i r e s k e l e t a l blood flow to be 250 ml./min or f i v e percent of the r e s t i n g cardiac output. Blood Flow Through D i f f e r e n t Regions of Long Bones 97 Shim, Patterson and Copp studied the regional femoral blood flow 85 i n 50 mature rabbits using the Sr bone clearance method. The following regional blood flow rates were measured: Region Rate (ml/min/100 grams wet bone) Femoral Head 18.5-3.6 Trochanteric 10.5 - 3.5 Diaphyseal 7.5 - 1.4 Condylar 12.1 - 3.8 The above data indicates there are s i g n i f i c a n t differences i n the rates of blood flow through various regions i n long bones which supports findings i n anatomical studies and c l i n i c a l experience. In a study of the r e l a t i v e contribution of the three a r t e r i a l systems 22 TABLE I SUMMARY OF BONE BLOOD FLOW STUDIES FLOW AUTHOR YEAR METHOD SPECIES ml/min/100 grams Wet Bone Edholm et a l 2 9 1945 Plethysmo-graphy Human 1.0 Frederickson 1955 et a l 30 Ca 45 Rat 10-30 Cummings 18 1960 Venous C o l l e c t i o n Rabbit Marrow 16.0 Weinman et a l Shim 9 2 Ray 8 2 115 1963 Ca 1963 47 S r 8 5 Sr85 1964 Ca 45 Dog ^Mature /Immature Rabbit Dog \ Mature )Immature 5.6 7.7 16.0 4.9 6.5 Kane and G r i m 4 5 1964 K42 Rb 8^ Dog 12 Copp and Shim 1 7 1965 Sr 85 Rabbit Dog 10 10 White and S t e i n 1 1 9 1965 Cr 5 1RBC Rabbit 16 Shim et a l 9 2 1967 Sr' 85 Rabbit Dog 12.5 13.2 Shim et a l 9 4 1971 Sr 85 Man 2.5 23 41 of dog long bones, Johnson , i n 1927, concluded that the nut r i e n t artery i s responsible f o r the nourishment of the bone marrow and the inner h a l f of the cortex of the shaft; the metaphyseal vessels supply the metaphyses and through anastomoses are able to supply the area of the nutrient artery. The p e r i o s t e a l a r t e r i e s supply the outer h a l f of the cortex. Trueta and Caladias"''"'"^ i n v e s t i g a t i n g the blood supply of the radius of the rabbit using s e l e c t i v e vascular occlusion confirmed Johnson's e a r l i e r work. Other 64 workers have denied the p e r i o s t e a l vessels any r e s p o n s i b i l i t y i n supplying 93 85 the cortex. Shim et a l using the Sr clearance technique studied the femoral blood flow i n 13 adult rabbits d i r e c t l y following l i g a t i o n of one femoral nut r i e n t artery. The nut r i e n t artery was found to contribute at l e a s t 46 percent of the normal t o t a l blood supply of the e n t i r e femur and at l e a s t 71 percent of the normal t o t a l blood flow of the shaft and at l e a s t 37 percent and 33 percent of the normal t o t a l blood flow of the upper and lower epiphyseal-metaphyseal region r e s p e c t i v e l y . Mechanisms C o n t r o l l i n g Bone Blood Flow There i s considerable evidence from data reported that bone c i r c u l -a tion i s regulated or c o n t r o l l e d by four important mechanisms: neural, hormonal, metabolic and mechanical. Neural Control Mechanism H i s t o l o g i c a l studies have shown bone has an abundant nerve supply with the majority of medullated and non-medullated f i b e r s forming f i n e 26 plexuses i n the walls of blood vessels. Drinker and Drinker i n perfusion experiments of the i s o l a t e d dog t i b i a , observed that the blood outflow from bone decreased when the nerve f i b e r s entering the nut r i e n t foramin of the 95 bone were e l e c t r i c a l l y stimulated. Shim and Patterson found a marked decrease of nut r i e n t venous outflow from the rabbit humerus during e l e c t -r i c a l stimulation of the i p s i l a t e r a l c e r v i c a l sympathetic trunk. Herzig 24 and Root^"* and Weiss and Root^"^ found that e l e c t r i c a l stimulation of the d i s t a l ends of cut peripheral nerves to a limb caused a f a l l i n the i n t r a -2 medullary pressure i n the curarized cat antf dog. Azuma observed a f a l l i n the rabbit t i b i a l intramedullary pressure during e l e c t r i c a l stimulation of the lumbar sympathetic trunk and s c i a t i c nerve with F l a x e d i l muscle p a r a l -y s i s . Trotman and K e l l y , u s i n g Rb^^ clearance technique, found a 27 percent increase i n bone blood flow i n the dog hind limb following lumbar sympathectomy, but t h i s increase was not found i n h i s dog experiments nine 61 weeks post lumbar sympathectomy. Lowenstein and associates i n an e a r l i e r dog study using I J - J X Rose Bengal t r a c e r found a 27 percent increase i n the blood turn over rate i n the t i b i a one hour post lumbar sympathectomy and 90 percent higher from one to eight weeks post surgery. Leeds and co-55 workers found a d e f i n i t e increase i n the pressure i n small vessels of 96 sympathectomized extremities. Shim and Patterson measured a f i v e percent to 45 percent increase i n bone blood flow of the rabbit t i b i a , f i b u l a t alus and calcaneus following complete s c i a t i c nerve section. The r e s u l t s of these q u a l i t a t i v e and quantitative experiments i n d i c a t e the presence of a neural mechanism which can produce s i g n i f i c a n t changes i n bone c i r c u l a t i o n . Hormonal Control Mechanism 26 Drinker and Drinker i n t h e i r dog perfusion experiments, u t i l i z i n g the n u t r i e n t artery of the i s o l a t e d t i b i a noted a decrease i n the volume of e f f l u e n t blood from bone when adrenalin was added to the perfusing 54 blood. Larsen observed a temporary f a l l i n the femoral intramedullary pressure i n the dog despite an e l e v a t i o n of the systemic blood pressure following intravenous i n j e c t i o n s of adrenalin hydrochloride and p i t u i t r i n S. Bloomenthal and associates^ found a f a l l i n the femoral marrow cavity pressure i n the dog following intravenous administration of adrenalin which 25 they suggested might be due to d i l a t i o n of a r t e r i o l e s and c a p i l l a r i e s i n the marrow cav i t y . Stein and co-workers 1*^ 1 observed s i m i l a r e f f e c t s following i n t r a v a s c u l a r i n j e c t i o n s of adrenalin, noradrenalin and p i t r e s s i n i n the dog, noting an absence of bleeding from holes d r i l l e d through the t i b i a l cortex into the medullary c a v i t y or a f a l l i n the intramedullary pressure. They interpreted these findings to i n d i c a t e a decrease blood supply to bone probably due to v a s o c o n s t r i c t i o n of the nutrient vessels. Branemark observed i n h i s v i t a l microscopy study of the m i c r o c i r c u l a t i o n of the ra b b i t f i b u l a , that an i n j e c t i o n of adrenalin induced a marked change i n the bone and bone marrow c i r c u l a t i o n . The marrow vessels become con-s t r i c t e d and the marrow cavity i s emptied of blood as when squeezing a 66 sponge. McPherson and associates found intravenous i n j e c t i o n s of adrenalin and noradrenalin increased the blood flow i n the d i s t a l femoral 89 metaphysis of the cat using an intraosseous heated thermocouple. Shaw repeated t h i s study i n the cat measuring the femoral marrow pressure and intramedullary temperature changes with a thermocouple and found adrenalin, noradrenalin and p i t u i t r i n produced a f a l l i n the i n t r a n e d u l l a r y pressure. 91 2 Shim and Azuma confirmed the e f f e c t s of these vasopressor hormones on the intramedullary pressure. The e f f e c t s of adrenalin on bone blood flow was q u a n t i t a t i v e l y 18 92 120 evaluated by Cummings and Shim i n the rabbit,and by Woodhouse i n the dog. They found that a microgram dose of adrenalin could reduce bone blood flow by 25 to 75 percent. Quantitative and q u a l i t a t i v e studies i n d i c a t e that the n a t u r a l l y occuring vasopressor hormones of the body cause v a s o c o n s t r i c t i o n of bone 91 blood vessels and reduce bone blood flow. Shim suggests a close i n t e r -a ction between the neural and the hormonal regulatory mechanisms of bone c i r c u l a t i o n , noting noradrenalin i s produced by the sympathetic nerve 26 endings and adrenalin and p i t r e s s i n i s produced by the neural glands. Metabolic Control Mechanisms The idea that metabolites formed l o c a l l y i n anoxic t i s s u e can produce 40 v a s o d i l a t i o n has been known f o r a long time. John and Warren showed that an increase blood flow was associated with reactive hyperemia i n the dog hind limb. There i s evidence that bone blood flow i s c o n t r o l l e d by chem-i c a l factors such as a c i d metabolites, pH, and oxygen and carbon dioxide concentrations i n the blood at both the l o c a l and systemic l e v e l s . Cummings' i n a study of blood flow through the bone marrow, using a d i r e c t method of c o l l e c t i n g femoral nutrient venous outflow i n the r a b b i t , measured a 20 percent increase i n flow rate when the animal rebreathed expired a i r i n t o a long tube or when breathing gas mixtures e i t h e r low i n oxygen (5 to 10% 0 2 81 i n N2) or high i n C0 2 (10% C0 2 i n O 2 ) . Post and Shoemaker measuring blood c o l l e c t e d from the upper and lower venous drainage systems of the dog femur noted an increase blood flow following an intravenous or i n t r a -120 a r t e r i a l i n j e c t i o n a small amount of hydrochloric a c i d . Woodhouse observed an increase i n the dog humeral nutr i e n t a r t e r i a l flow, using an electromagnetic flowmeter and d i r e c t cannulation of the nutrient a r t e r y , when the animals were made hypoxic or hypercapnic by a l t e r i n g the r e s p i r a t o r gas mixtures, or a c i d o t i c following intravenous or i n t r a a r t e r i a l i n j e c t i o n s 95 of N/15 l a c t i c a c i d . Shim and Patterson observed increased bone blood flow when the rabbit rebreathed a i r i n a paper bag covering i t s mouth and nose producing hypoxia and hypercapnea. The r e f l e x e f f e c t of hypoxia i n increasing the rate of blood flow i s of i n t e r e s t i n view of the fa c t that hypoxic states r e s u l t i n increased a c t i v i t y of the bone marrow and polye-rythemia. Shim and Patterson, also, noted that the nutrient venous outflow volume of the rabbit femur increase two to three times the control rate 95 following release of the femoral artery occlusion. The period of femoral 27 artery occlusion producing intraosseous ischemia with a l o c a l accumulation of a c i d metabolites, f a l l i n pH, hypoxia and increased carbon dioxide con-centration. The reactive bone hyperemia which followed was unresponsive to e l e c t r i c a l stimulation of nerves or to administration of exagenous vaso-98 pressor hormones. Sim and K e l l y studying t i b i a l c i r c u l a t i o n of normal dogs and dogs i n states of low bone remodelling (hypothyroidism and hypo-parathyroidism) and high bone remodelling (hyperparathyroidism and hyper-thyroidism) found a close adjustment of osseous blood flow with remodelling a c t i v i t y . In a d d i t i o n , they found the arteriovenous differences i n oxygen content of t i b i a l blood were the same i n high, normal and low remodelling states. This constant oxygen uptake indicates the importance of a l t e r -g ation i n blood flow to meet bone's n u t r i t i o n a l demands. Brookes observed a d i f f u s e increase i n v a s c u l a r i t y of the c o r t i c a l and cancellous bone and the periosteum i n 25 lower limbs that had been amputated f o r s e n i l e athero-s c l e r o s i s with gangrene. His gross, h i s t o l o g i c a l and r a d i o l o g i c a l studies suggest a long standing v a s o d i l a t i o n and hypervascularity secondary to a chronic ischemia. Mechanical Control Mechanisms (Muscular Contraction E f f e c t ) The d i s t r i b u t i o n of blood to a bone i s c a r r i e d by the l a r g e r a r t e r i e s and t h e i r branches, but the e f f e c t i v e physiologic exchange of n u t r i t i v e and waste substances take place i n the c a p i l l a r y beds. Sur v i v a l of c e l l s , therefore, i s dependent upon the pressure and volume flow i n these c a p i l -33 l a r i e s . Green has shown that the arteriovenous pressure differences between the artery and the vein supplying a c a p i l l a r y network must be at l e a s t 10 mm. Hg. and i n many regions 20 to 40 mm. Hg. before bloCd begins to flow through c a p i l l a r i e s . Variations i n posture produce changes i n the perfusion blood pressure 32 of a limb which seem to be t o t a l l y h ydrostatic or graviometric. These 28 pressures are probably s l i g h t l y a l t e r e d by nervous r e f l e x mechanisms but there remains a d i r e c t c o r r e l a t i o n between the calculated blood pressure and 87 actual blood pressure of a limb. Schemberg et a l have shown inflow into an extremity i s about 35 percent greater when the veins are empty than when 119 they are f u l l . White and Stein observed i n acute experiments that occ-l u s i o n of the femoral vein i n rabbits diminished the rate of t i b i a l blood 31 flow. Geiser and Trueta found that immobilization of the os c a l c i s i n rabbits e i t h e r by d i v i s i o n of the a c h i l l e s tendon or by encasing the rabbits le g i n p l a s t e r c o n s i s t e n t l y produced a severe osteoporosis i n the d i s t a l t i b i a , os c a l c i s and talus by about the f i f t e e n t h day. The osteoporotic bones h i s t o l o g i c a l l y were characterized by marked d i l a t i o n of the sinusoids and veins. Once immobilization was discontinued new and energetic bone deposition occurred with the sudden return of vascular patterns to normal. 31 Geiser et a l suggested the immobilization may i n some way be related to a l t e r e d blood flow secondary to i n h i b i t e d muscle contraction. Trueta"*"^ measuring the t i b i a l marrow cavity pressure i n dogs during e l e c t r i c a l stim-u l a t i o n of the s c i a t i c nerve found a sharp increase i n pressure and an immediate f a l l below co n t r o l intramedullary pressure l e v e l v/ith muscle rela x a t i o n . From these observations, he suggested that muscle a c t i o n plays an important r o l e i n bone c i r c u l a t i o n with muscle contraction and r e l a x -a t i o n s i m i l a r to a pump. The pumping pressure on the venous side can be quite high. The c a l f pump has been shown to overcome a resistance greater than 100 mm. Hg.^ Brookes'*"^ a f t e r studying the osseous vascular patterns i n the r a t , postulated that muscle pump a c t i v i t y at fleshy muscle attach-92 ments was important i n maintaining c o r t i c a l c e n t r i f u g a l blood flow. Shim immobilized one hind limb of the r a b b i t i n a long leg p l a s t e r then measured the bone blood flow ( S r ^ clearance) at one to two weeks and at two months. He found a decreased bone blood flow during the early stages of immobiliz-ation (one - two weeks) but at two months the blood flow of osteoporotic bone had increased s i g n i f i c a n t l y when calculated on a weight b a s i s . Ray et a l 8 ^ i n a s i m i l a r study i n rabbits using i ^ l tagged serum albumin, at periods of one,two, four and eight weeks immobilization, found no changes i n blood volume or rate of flow or i n tiss u e blood volumes, except i n those instances where the cast was too t i g h t and edema had developed. Marrow Cavity Pressure of Bone 54 Larsen i n 1938 was f i r s t to i n s e r t a cannula into the marrow ca v i t y of bone to measure and study the intramedullary pressure. He studied the d i s t a l diaphyseal marrow cavity pressure i n the dog by d r i l l i n g the cortex and t i g h t l y i n s e r t i n g a tapered threaded cannula. Larsen found the femoral intramedullary pressure to be 30 to 40 mm. Hg. with pulse and r e s p i r a t o r y waves of le s s e r magnitude but simultaneous with the c a r o t i d a r t e r i a l pressure. He, a l s o , studied the divergent e f f e c t s of adrenalin and p i t u i -t r i n noting an ele v a t i o n of the systemic blood pressure coupled with a f a l l i n the intramedullary pressure and the p a r a l l e l e f f e c t s of ephedrine and histamine, the former causing an e l e v a t i o n i n both the systemic B.P. and marrow cavity pressure and the l a t t e r decreasing them. In h i s normal s a l i n e marrow i n f u s i o n experiments, Larsen observed i n f u s i o n pressures greater than 77 mm. Hg. produced bone death and sequestration. 44 Kaiser and associates i n 1951, demonstrated a d i r e c t c o r r e l a t i o n betxreen a l t i t u d e and a f a l l i n marroxv cavity pressure i n dogs and experi-mentally confirmed the f a c t that the marrow cavity acts as a semiclosed chamber. They observed a wide range of marrow pressures from 12/8 mm. Hg. to 117/96 mm. Hg. with a mean 52/41 mm. Hg. No c o r r e l a t i o n was found betxreen the systemic blood pressure and intramedullary pressure. Bloom-enthal et al"' i n 1952, studying the marrow cavity pressure i n the dog, 30 confirmed Larsen's observations on the e f f e c t s of adrenalin and found benze-drine produced a consistent e l e v a t i o n of the systemic a r t e r i a l and venous pressures and the intramedullary pressure. 102 Stein and co-workers studying the dog femoral and t i b i a l i n t r a -medullary pressure observed the mean diaphyseal pressure was s i g n i f i c a n t l y higher than the epiphyseal pressure and that occlusion of the femoral artery caused an immediate abrupt f a l l i n both the diaphyseal and epiphyseal pres-sures with a los s of pulse and r e s p i r a t o r y waves. Occlusion of the femoral vein produced a prompt el e v a t i o n i n the intramedullary pressure and no sign-i f i c a n t change i n pulse pressures. S t e i n et al"*"^" and Azuma^ studied the e f f e c t s of adrenalin, noradrenalin, p i t u i t r i n , amphetamine, histamine and a c e t y l c h o l i n e , confirming, i n the main the e a r l i e r observations of Larsen and Bloomenthal. They concluded from the intravenous and i n t r a a r t e r i a l i n j e c t i o n that the major e f f e c t s of adrenalin noradrenalin and p i t r e s s i n on the bone c i r c u l a t i o n i s produced l o c a l l y , independent of the systemic blood pressure and probably due to the v a s o c o n s t r i c t i o n of nutrient vessels. Herzig and Root"*"* and Weiss and Root^"' using the intramedullary pressure to assess bone blood flow i n the cat,studied the o r i g i n of vaso-c o n s t r i c t o r f i b e r s supplying the vessels of the marrow c a v i t y and demon-strated that e l e c t r i c a l stimulation of the peripheral cut end of the abdom-i n a l sympathetic trunk produces a f a l l i n the intramedullary pressure and that u n i l a t e r a l sympathectomy i n decerebrate cats had a higher intramedul-20 l a r y pressure on the denervated side. Cuthbertson and co-workers invest-i g a t i n g the e f f e c t of nutrient artery l i g a t i o n on the intramedullary i n the dog, observed i n every instance an immediate and usually large decrease i n the marrow ca v i t y pressure. However, i n about 50 percent of animals the pressure returned to preocclusion l e v e l s w i t h i n three hours and an addit-i o n a l 40 percent within two to 22 days i n d i c a t i n g the nutrient a r t e r i a l 31 system, although an Important source of intraosseous a r t e r i a l blood, has r e a d i l y a v a i l a b l e anastomoses with the remaining a r t e r i a l systems of the 46 bone. Keck and associate observed that the diaphyseal intramedullary pressure increased with growth of the normal dog and that a femoral a r t e r i o -venous f i s t u l a induced an immediate sharp decrease i n the femoral diaphy-s e a l pressure which then increased over a four month period, more r a p i d l y 89 at f i r s t but never a t t a i n i n g c o n t r o l l e v e l s . Shaw studied the femoral marrow ca v i t y pressure and estimated the marrow blood flow with an i n t r a -osseous heated thermocouple and suggested a d i r e c t c o r r e l a t i o n between bone blood flow and intramedullary pressure. However, Shaw admits to the short-66 comings of intraosseous thermometry. McPherson and co-workers could not corroborate these findings i n an e a r l i e r s i m i l a r study using t h i s method based on heat trans f e r to estimate bone blood flow. Tocantins and a s s o c i a t e s 1 ^ (1940) reported the s t e r n a l intramedul-l a r y pressure i n man ranged from 3.7 to 8.9 mm. Hg. This compares with the human s t e r n a l marrow pressures reported by P e t r a k i s ^ (1954), ranging from 2/0 to 17/15 mmg. Hg. Petrakis found acute leukemic patients had higher marrow ca v i t y pressures with greater pulse pressures than h i s normal group. These observations correlated with an e a r l i e r study i n which Petrakis et a l ^ 8 had demonstrated an increase T!31 clearance rate from the bone marrow of leukemic patients. 67 Miles studied the intramedullary pressure of the femoral head i n more than 30 patients to assess the status of i t s c i r c u l a t i o n and i t s v i a b i l i t y . He found a v a r i a t i o n i n marrow pressures up to 40 to 50 cm. of s a l i n e (3-3.7 mm. Hg.) but suggested more important than the pressure measurement i s the presence or absence of pulse pressure. The absence of pulse pressure i n the femoral head in d i c a t e s avascular necrosis. The use of t h i s i n d i r e c t method of measuring changes i n the marrow 32 cavity pressure to assess blood flow i s based on the assumption that i t reflects well the changes in bone hemodynamics. The validity of this assumption has not been definitely proven to date probably due to a lack of proper study. PURPOSE OF THE STUDY This study has a twofold purpose: 1. To describe a method of simultaneous study of the marrow cavity pressure and blood flow of bone, and 2. To define the nature of the marrow cavity pressure by demonstrating conclusively the close relationship between the bone blood flow and marrow cavity pressure. MATERIALS AND METHOD Animals Twenty four female New Zealand white rabbits, weighing 2 - 3 kilograms, and 32 mongrel dogs, weighing 16 - 33 kilograms were studied. Anaesthesia A l l animals were anaesthetized with intravenous sodium pentobarbitol (30 mg. per kilogram) and maintainance doses were repeated as required. Position A l l animals were placed supine on the operating table with a l l four limbs tied. Skin Preparation The anterior neck, right foreleg, abdomen, and hind limbs were shaved and painted with tincture of zepherin as required. Intravenous Route The external jugular vein or a foreleg vein was used for the admini-33 s t r a t i o n of a l l drugs and f l u i d s during the experiments. A l l animals were given 300 units of heparin per kilogram body weight which was repeated every two hours. A r t e r i a l Cannulation for Systemic Blood Pressure The right common c a r o t i d artery or the righ t b r a c h i a l artery was can-nulated and connected to a E. & M. Bourdon type pressure transducer with a polyethylene tube f i l l e d with a s a l i n e heparin s o l u t i o n . The transducer was connected to one channel of a multi-channel electromechanical recorder (E. & M. Physiograph). Nutrient Vessel Cannulation The c i r c u l a t i o n of the femoral and t i b i a l bones were studied i n both the rabbit and dog. The nut r i e n t vein and/or nutrient artery of the bone was cannulated with a (PE50 or PE60) polyethylene catheter and the flow rate of the vessel continuously measured by pl a c i n g the open end of the tube over a g r i d of a drop counting transducer (E. & M.) which was con-nected to a channel of the electromechanical recorder. Since the s u r g i c a l exposure of the vessels without undue trauma i s e s s e n t i a l to avoid and minimize l o c a l c i r c u l a t o r y disturbance, the techn-iques to expose and cannulate the nut r i e n t vessels of the femur and t i b i a i n the rabbit and the dog w i l l be described. I t must be emphasized that dissections and v e s s e l cannulations be done with utmost care to obtain meaningful r e s u l t s . Rabbit Femoral Nutrient Vessel Dissection and Cannulation The nut r i e n t vessels of the femur are exposed through the femoral t r i a n g l e using a v e r t i c l e 2 cm. i n c i s i o n . As the femoral artery and vein are c a r e f u l l y dissected free of each other, a p a i r of n u t r i e n t vessels are seen running along the l a t e r a l border of the i l i o p s o a s muscle. The nutrient 34 artery i s a branch of the proximal portion of the deep femoral artery and passes down obliquely along the l a t e r a l border of the i l i o p s o a s muscle to reach the nutrient foramen anterior and l a t e r a l to the l e s s e r trochanter of the femur. The nutrient vein usually e x i t s from the femur v i a the nutrient cannal being c l o s e l y associated with the nutrient artery along the l a t e r a l border of the i l i o p s o a s , enters the femoral t r i a n g l e and drains into the deep femoral vein. Cannulation of the nutrient vein i s accomplished by c a r e f u l l y d i s -secting the proximal portion of the nutrient vein free from the nutrient artery and l i g a t i n g the vein proximally. Through a small opening i n the nutrient vein wall a (PE 50 or PE 60) polyethylene tube i s introduced to-ward the bone. The nutrient artery may be cannulated i n a s i m i l a r manner, toward the bone, to study retrograde nutrient a r t e r i a l blood flow through f u n c t i o n a l nutrient a r t e r i a l anastomoses with a r t e r i a l systems of the bone. Cannulation of the T i b i a l Emissary Vein The c e n t r a l venous sinus of the t i b i a i s p a r t i a l l y drained by a large emissary vein which pierces the diaphyseal cortex j u s t below and ante r i o r to the accessory nutr i e n t foramen on the l a t e r a l t i b i a l cortex at the i n f e r i o r t i b i o f i b u l a r junction. An a n t e r o - l a t e r a l i n c i s i o n which i s curved p o s t e r i o r l y at i t s up end i s made over the middle h a l f of the t i b i a . The deep f a s c i a i s i n c i s e d along the l a t e r a l aspect of the ant e r i o r t i b i a l border. The an t e r i o r t i b i a l and extensor digitorum longus muscles are e a s i l y separated and ret r a c t e d from the antero l a t e r a l aspect of the t i b i a . The emissary vein i s seen passing h o r i z o n t a l l y p o s t e r i o r to these muscles and a n t e r i o r to f i b u l a r i s longus and b r e v i s , to pierce the deep f a s c i a and drain into the l a t e r a l saphenous vein. This vein may be cannulated d i r e c t l y or i n d i r e c t l y by i n s e r t i n g a polyethylene (PE 50) catheter into the l a t e r a l saphenous and plac i n g the 35 catheter t i p at the mouth of the emissary vein. The l a t e r a l saphenous vein i s t i e d o f f above and below t h i s l e v e l . Dog Femoral Nutrient Vessel Dissection and Cannulation The nutrient vessels of the femur are exposed through the femoral t r i a n g l e using a two to three inch v e r t i c l e i n c i s i o n beginning j u s t below the mid point to the i n g u i n a l ligament. The deep femoral artery i s i d e n t i -f i e d l y i n g between the quadricepts femoris muscle and the medially l y i n g pectineus. The medial circumflex artery, a terminal branch of the deep femoral a r t e r y , i s then followed passing obliquely across vastus medialis giving muscular branches to i t and the abductor muscle. A f t e r reaching the p o s t e r i o r aspect of the femur i t gives r i s e to the nutrient artery of the femur which enters the nutrient foramen on the p o s t e r i o r aspect of the femur at the j u n c t i o n of the proximal and middle t h i r d s . The small branch which usually runs across the l i n e a aspera to anastomose with the l a t e r a l circumflex artery must be l i g a t e d along with the muscular branches. A l i g a t u r e i s placed about the medial circumflex proximally and a polyethy-lene catheter (PE 50) i s towards the bone to study retrograde nutrient a r t e r i a l flow. The nutrient v e i n which i s c l o s e l y associated with the nutrient artery may be cannulated i n a s i m i l a r manner. T i b i a l Nutrient Vessel Dissection and Cannulation The t i b i a l nutrient vessels were approached through an a n t e r o - l a t e r a l i n c i s i o n over the upper one-half of the t i b i a curving the proximal end of the i n c i s i o n p o s t e r i o r l y . The deep f a s c i a at the anterior t i b i a l border was i n c i s e d and the t i b i a l i s a n t e r i o r , extensor digitorum longus and peroneal muscles are. retracted l a t e r a l l y from the l a t e r a l surface of the t i b i a . The a n t e r i o r t i b i a l vessels are e a s i l y seen proximally and i n the d i s t a l part of the i n c i s i o n are covered by the extensor h a l l u c i s longus 36 muscle. The anterior t i b i a l vessels usually consist of an artery with two accompanying venae comitantes. The nutrient artery usually was found a r i s i n g adjacent to the proximal t h i r d of the t i b i a along with the nutrient vein passing obliquely downwards to enter the posterio l a t e r a l aspect of the t i b i a at the j u n c t i o n of the proximal and middle t h i r d s . The l e v e l of the foramen was v a r i a b l e and occasionally was found at the mid-diaphyseal l e v e l . In about 25 percent of the animals, the nutrient artery x^ as found a r i s i n g from the p o s t e r i o r t i b i a l artery running deep to the f l e x o r h a l l u c i s muscle next to the p o s t e r i o r aspect of the t i b i a entering the n u t r i e n t foramen on the p o s t e r i o r aspect near the l a t e r a l border at the junction of the proximal and middle thirds of the t i b i a . The nutrient artery was e a s i l y exposed i n the l a t t e r p o s i t i o n by i n c i s i n g the interosseous membrane and b l u n t l y separ-ating the f l e x o r h a l l u c i s muscle from the p o s t e r i o r aspect of the t i b i a bringing the artery i n t o view entering the nutrient foramen. The nutrient vessels were e i t h e r cannulated d i r e c t l y or i n d i r e c t l y v i a the a n t e r i o r t i b i a l vessels. Intramedullary Cannulation The intramedullary pressures of the femur, t i b i a and i l i a c crest were studied i n the dog and rabbit. The technique of intramedullary cannulation used i n t h i s study was through a small 1-2 cm. i n c i s i o n or through the i n c i s i o n used for nutrient vessel cannulation. The periosteum and s o f t tissues were c a r e f u l l y cleared away at the desired s i t e of the bone. In the rabbit the cortex was perforated with a 0.118 centimeter diameter d r i l l . The marrow was punctured by the p e r f o r a t i n g d r i l l as i t penetrated the cortex. Several m i l l i l i t e r s of a s a l i n e heparin s o l u t i o n were i n j e c t e d into the medullary cavity to wash out any bone debris. At t h i s point blood ladened with f a t globules with a p u l s a t i l e flow hemorrhaged from the d r i l l hole. A number 18 guage s t e e l cannula was t i g h t l y inserted 37 which was connected to a pressure transducer (E, & M. l i n e a r core transducer) with a polyethylene tube f i l l e d with a heparin s a l i n e s o l u t i o n , care being taken to exclude a l l a i r from t h i s system. The pressure transducer was connected to one channel of the multichannel recorder. In the dog a 0.238 centimeter diameter p e r f o r a t i n g d r i l l was used and a number 13 guage s t e e l cannula t i g h t l y inserted. Thus, the blood flow and the marrow cavity pressure of the same bone, the systemic blood pressure and the time sequence were simultaneously re-corded to define the r e l a t i o n s h i p between bone blood flow and the bone marrow cavity pressure under various experimental conditions. (See Figure 5) Experimental Conditions The experimental conditions studied were: 1. Normal c o n t r o l condition 2. E f f e c t of regional vascular occlusion a. Femoral artery b. Nutrient artery c. Femoral v e i n d. Low pressure tourniquet 3. E f f e c t of catacholamine drugs a. Adrenalin b. Noradrenalin c. Isoproterenol hydrochloride (Isuprel) 4. E f f e c t of e l e c t r i c a l stimulation of nerves a. S c i a t i c nerve b. Lumbar sympathetic trunk 5. Sympathectomy 6. E f f e c t of s k e l e t a l muscle contraction. 38 FIGURE 5. The experimental set-up. The marrow cavity pressure was measured by i n s e r t i n g a s t e e l cannula through a d r i l l hole into the marrow cavity. The bone blood-flow was recorded by cannulation of the nutrient vein or/and artery which was connected to a blood drop counting transducer. The systemic B.P. was measured by cannulating the c a r o t i d artery. In the foreground i s a multiple channel physiograph to record simultaneously these parameters against time. 39 Normal Control Condition Af t e r completing the vascular and intramedullary cannulations, the parameters (nutrient venous outflow and/or nutrient a r t e r i a l retrograde flow, marrow cavity pressure and systemic blood pressure) simultaneously recorded against time were found remarkably constant i n our experimental model. Regional Vascular Occlusion Femoral artery occlusion was accomplished by exposing the femoral arte r y i n the femoral t r i a n g l e and occluding the vessel lumen with a vas- v cular clamp. Nutrient artery occlusion was accomplished by c a r e f u l d i s s e c t i o n of the v e s s e l and applying tension on a s i l k l i g a t u r e looped about the v e s s e l . Femoral vein occlusion W A S accomplished by exposing the femoral vein i n the femoral t r i a n g l e and occluding the v e s s e l lumen with a vascular clamp. L O X J Pressure Tourniquet The lovr pressure tourniquet was an e l a s t i c rubber tube or pneumatic tourniquet placed about the thigh with s u f f i c i e n t pressure to p a r t i a l l y occlude venous return but not a r t e r i a l inflow i n t o the hind limb. Catacholamine Drug Infusion Adrenalin (Epinephrine - B r i t i s h Drug House (Canada). The e f f e c t s of a continuous intravenous i n f u s i o n of adrenalin i n a 1:200,000 to 1:500,000 d i l u t i o n adjusted to d e l i v e r 0.1 to 10.0 micrograms of adrenalin per kilogram body weight per minute were studied i n 12 rabbits and 18 dogs. The i n f u s i o n was given through the external jugular vein for a f i v e minute period. Noradrenalin (Levophed B i t a r t r a t e - Winthrop Laboratories). The e f f e c t s of a continuous intravenous i n f u s i o n of noradrenalin i n a 1:100,000 to 1:250,000 d i l u t i o n adjusted to d e l i v e r 0.1 to 1.0 micrograms of noradrenalin per kilogram body weight per minute were studied i n f i v e rabbits 40 and 15 dogs. The i n f u s i o n was given through the external jugular vein gen-e r a l l y f o r a f i v e minute period. Isoproterenol Hydrochloride (Isuprel - Winthrop Laboratories) The e f f e c t s of a continuous intravenous i n f u s i o n of isoproterenol i n a 1:100,000 to l!250,000 d i l u t i o n adjusted to d e l i v e r 0.1 to 2.0 micrograms of drug per kilogram body weight per minute were studied i n 15 dogs. The i n f u s i o n was given through the external jugular vein generally f o r a f i v e minute period. E l e c t r i c a l Stimulation of Nerves The s c i a t i c nerve and abdominal sympathetic trunk were e l e c t r i c a l l y stimulated with rectangular pulses of 2.0 milliseconds duration, two to 200 pulses per second and f i v e to 60 v o l t s for a f r a c t i o n of a second up to a ten minute duration through a s i l v e r stimulating electrode. The s c i a t i c nerve was exposed i n continuity i n the proximal mid thigh by separating muscle planes i n both the rabbit and dog. The lumbar sympath-e t i c trunk was i s o l a t e d i n t a c t through a transperitoneal approach. In both nerve stimulation experiments a s i l v e r stimulating electrode was c a r e f u l l y placed on the nerve and the retracted surrounding soft tissues were allowed to f a l l gently back into place to prevent dehydration of the nerve. Sympathectomy Following lumbar sympathetic trunk stimulation a two to three segment section of the sympathetic trunk was excised i n f i v e dog experiments. E l e c t r i c a l Stimulation of S k e l e t a l Muscle Sk e l e t a l muscle groups of the hind limb of 15 dogs were stimulated d i r e c t l y with two needle electrodes placed into muscles with a centimeter distance between them. The quadriceps, adductor and t r i c e p s surae muscle groups were stimulated with retangular pulses of 2.0 milliseconds duration two to 200 pulses per second and f i v e to 25 v o l t s f o r a f r a c t i o n of a 41 second up to f i v e minutes duration. RESULTS Normal Control Condition Marrow cavity pressures i n the rabbit and dog showed a wide range of i n d i v i d u a l v a r i a t i o n . No q u a n t i t a t i v e c o r r e l a t i o n was found between the systemic blood pressure and the marrow cavity pressure. Rabbit Intramedullary pressures were studied i n 40 bones i n 24 r a b b i t s , measuring mainly the t i b i a l and le s s frequently the femora], humeral and i l e a l marrow ca v i t y pressures. The intramedullary pressures i n the rabbit ranged from 19 to 62 mm. Hg., with an average of 32.9 mm. Hg. These pres-sures were 14 to 52 percent of the simultaneously measured systemic blood pressure with a mean of 41.3 percent. Dog Intramedullary pressures were studied i n 52 bones i n 32 dogs, meas-uring mainly the t i b i a l (40) and l e s s frequently the femoral (10) and the i l i a l marrow ca v i t y pressures. The dogs intramedullary pressures ranged from 20 to 140 mm. Hg. with a mean of 80.8 mm. Hg. These pressures were 20 to 90 percent of the simultaneously recorded systemic blood pressure with an average of 76.7 percent. (See Table II) P u l s a t i l e waves and re s p i r a t o r y waves i n the intramedullary pressure were observed which cor r e l a t e w e l l with the systemic a r t e r i a l pulse and r e s p i r a t o r y waves. The pulse waves were d i c r o t i c . The r e s p i r a t o r y waves of the marrow ca v i t y pressure of the i l i a c crest were more pronounced than seen i n the long bones, with a decrease i n pressure associated with i n s p i r -a t i o n and an increase associated with e x p i r a t i o n . Occasionally a slow 42 TABLE II ANIMAL AVERAGE SYSTEMIC B.P. (mm.Hg.) MARROW CAVITY PRESSURE (mm.Hg.) PERCENT OF SYSTEMIC B.P. 1 AVERAGE 1 RANGE ! i AVERAGE | RANGE I RABBIT 105/ 80 I 32.9 1 19 to 62 1 1 41.3 ( 14 to 52 i DOG 145/120 ! 80.8 ! 20 to 140 i ! i 46.7 , 20 to 90 NORMAL CONTROL MARROW CAVITY PRESSURES 43 p e r i o d i c undulation of the marrow ca v i t y pressure was observed which was not associated with a change i n the systemic pressure. (See Figure 6) Regional differences of the intramedullary pressure were noted i n a given bone: the diaphyseal marrow cavity pressure was higher than that of the metaphysis i n some cases, and v i c e versa i n other instances. Epiphy-s e a l marrow cavity pressures were not studied. During the c o n t r o l periods, the systemic a r t e r i a l pressure, the i n t r a -medullary pressure and the bone blood flow were found remarkably constant i n our experimental model. Any changes i n these parameters produced during various experimental conditions were r e a d i l y observable. E f f e c t s of Vascular Occlusion 1. Femoral artery occlusion. Occlusion of the femoral artery i n ten rabbits and ten dogs caused an immediate f a l l i n the intramedullary pressure with loss of the pulse and r e s p i r a t o r y waves coupled with a marked decrease of the bone blood flow without changes i n the systemic blood pressure. Femoral artery occlusion produced an average 9 mm. Hg. f a l l i n the marrow cavity pressure i n both the rabbit and the dog with a range of 3 to 20 mm. Hg. The nutrient venous outflow rate f e l l an average 57 percent with a range of 33 to 94 percent of the c o n t r o l flow rate. I f the o c c l u s i o n of the femoral artery was maint-ained f o r more than several minutes (three to f i v e minutes) the bone blood flow and marrow ca v i t y pressure gradually rose toward control l e v e l s but always remained w e l l below t h i s l e v e l . When occlusion was released, these parameters promptly returned to control l e v e l s a f t e r a b r i e f period during which the marrow cavity pressure and bone blood flow overshoot the c o n t r o l values i n d i c a t i n g a reactive hyperemia of bone following an ischemia. (See Figure 7) 2. Nutrient artery occlusion. 44 Control Tracings D O G #27 2 0 0 n 160' 1 2 0 J SYSTEMIC B.P. TIBIAL DIAPHYSEAL I.M.P. « oi 110 lo 1 100 UJ c ? E TIBIAL METAPHYSEAL I.M.P. ™ 100 x 90 E 80 E 70 TIBIAL NUTRIENT VENOUS OUTFLOW 1 1 1 1 1 1 1 1 1 1 1 llllllll! llllillliiiillliiin'tHiiiiniiniiMiitiii i i I 1 I i i i I i I imilii! IIIIIIIIHillllllllllllliilllillllllMIII'll 1 1 ! ! I I I ! ! Time (5 second interval 1 1 1 1 ' 1 1 1 ! •) M i l l ! 1 1 1 FIGURE 6. The normal con t r o l t r a c i n g . The traci n g paper speed was i n i t i a l l y 1.5 cm./min. and then slowed to 0.25 cm./min. Note the reg-u l a r i t y of the parameters being measured and the corresponding pulse and resp i r a t o r y waves i n the systemic B.P. and marrow ca v i t y pressure t r a c -ings. 45 Rabbit X E E tt L_ 3 30-20- ' 10-Femoral Artery Occlusion Release i 1 TIBIAL INTRAMEDULLARY PRESSURE TIBIAL NUTRIENT VENOUS OUTFLOW Femoral Artery Occlusion Release I i Time (5 second intervals) FIGURE 7 . The e f f e c t of femoral artery occlusion. Note that the t i b i a l intramedullary pressure f e l l sharply coupled with a decrease i n the nutrient venous outflow. The e f f e c t i s reproducible. 46 The e f f e c t s of occluding the nutrient artery were studied i n f i v e rabbits and 11 dogs. An immediate f a l l of the intramedullary pressure to an average of 49 percent of control l e v e l s , a loss of the p u l s a t i l e and r e s p i r a t o r y waves coupled with an average 38 percent reduction i n the nut-r i e n t venous outflow was observed immediately following occlusion. I f the nutrient artery occlusion was maintained more than several minutes, the marrow ca v i t y pressure and nutrient venous outflow tended to return toward con t r o l l e v e l s i n d i c a t i n g a f u n c t i o n a l anastomotic c i r c u l a t i o n . On release of the nut r i e n t a r t e r y , an immediate return of the intramedullary pressure bone blood flow to control l e v e l s was observed. The re a c t i v e hyperemia was of a l e s s e r magnitude i f i t occurred at a l l . 3. Femoral vein occlusion. The e f f e c t s of femoral v e i n occlusion were studied i n ten rabbits and ten dogs. Occlusion of the vein caused a rapid e l e v a t i o n i n the medullary c a v i t y pressure coupled with an increased nutrient venous outflow and a decreased nutrient a r t e r i a l retrograde flow. Femoral vein occlusion pro-duced an average e l e v a t i o n of the marrow ca v i t y pressure of 9 mm. Hg i n the rabbit (range 5 to 15 mm. Hg.) and 25 mm. Hg i n the dog (range 3 to 80 mm. Hg.). In the rabbit t h i s was coupled with an average 82 percent increase i n the nutrient venous outflow r a t e , and i n the dog an average 185 percent increase above the co n t r o l flow with a range of 12 to 900 percent. In the dog an average 38 percent reduction was,found i n the nutrient a r t e r i a l retrograde flow with a range of 11 to 85 percent below normal c o n t r o l l e v e l s . (See Figure 8) The changes i n these parameters i n d i c a t e intraosseous venous congestion with decreased bone blood flow. I f the femoral vein occlusion was maintained there was a s l i g h t tendency f o r the marrow cavity pressure and bone blood flow to return toward c o n t r o l l e v e l s . No change was observed i n the systemic blood pressure. Following release of the femoral vein the 47 TIBIAL NUTRIENT ARTERIAL BACKFLOW ' •••I I I I I I M M 1 1 : 1 i — ( — f — i — r TIBIAL NUTRIENT VENOUS OUTFLOW 1 11 111 1 i l| 11 [ l l i l f l i p ^ I I 1 | 1 i I | 1 1 1 |« • Femoral Vein Occlusion '| Time (5 second intervals) FIGURE 8. The e f f e c t of femoral vein occlusion. Note that a marked r i s e of the t i b i a l intramedullary pressure associated with simultaneous congest-ion of the nutrient v e i n and a decrease a r t e r i a l blood supply. 48 intramedullary pressure and blood flow of the bone quickly returned to c o n t r o l l e v e l s . 4. Low pressure tourniquet. In ten rabbits and f i v e dogs a low pressure tourniquet was placed about the thigh while the marrow cavity pressure and blood flow of the t i b i a were being recorded. With oc c l u s i o n of the proximal venous drainage, changes i n the t i b i a l marrow ca v i t y pressure and blood flow were observed which were s i m i l a r but more pronounced than the changes i n the femoral vein experi-ments. Low pressure tourniquet caused an average 18 mm. Hg. r i s e i n marrow ca v i t y pressure i n the rabbit with a 10 to 30 mm. Hg. range. In the dog the average e l e v a t i o n was 29 mm. Hg. with an 18 to 35 mm. Hg. range. The nutrient venous outflow i n both animals was markedly increased by an average 1300 percent above control rates with a range of 200 to 2600 per-cent. (See Figure 9) E f f e c t s of Catacholamine Drugs The e f f e c t s of continuous intravenous Infusion of adrenalin, noradren-a l i n and isoproterenol were studied i n 12 rabbits and 17 dogs. 1. Adrenalin e f f e c t . During an intravenous i n f u s i o n of adrenalin, d e l i v e r i n g 0.1 to 1.0 micrograms per kilogram per minute, the hemodynamic changes observed were s i m i l a r i n the rabbit and dog. The systemic a r t e r i a l pressure was f r e -quently elevated with an increased pulse pressure. A qu a n t i t a t i v e e f f e c t was observed with the e l e v a t i o n of the systemic blood pressure varying d i r e c t l y with the amount of the drug given. The intramedullary pressure, however, co n s i s t e n t l y showed a marked reduction to an average 33 percent below the co n t r o l l e v e l s . The range of the reduction was eight percent to 66 percent below the co n t r o l pressure. A l o s s or reduction of the pulse and r e s p i r a t o r y waves was observed. The nutrient venous outflow rate was 49 TIBIAL NUTRIENT VEIN FLOW ' 1 ' i i M I — I llllllHIIIMIIIIIHHHIHiMHIHIIIIIIimilH"'! I • I • •! 1 — t t Tourniquet at thigh Released Bone Vein Congestion Time (5 second intervals) FIGURE 9. The e f f e c t of low pressure tourniquet. Note the sharp r i s e of the Intramedullary pressure of the t i b i a and the narked congestion of the nutrient vein. 50 decreased to an average 29 percent below the c o n t r o l flow. The range of reduction was ten to 80 percent. I f the adrenalin i n f u s i o n was maintained f o r a ten to 15 minute period the intramedullary pressure and nutrient venous outflow showed a s l i g h t tendency to return to t h e i r control values, but the adrenalin e f f e c t remained throughout i n f u s i o n periods. A f t e r d i s -continuing the i n f u s i o n , the systemic blood pressure, the intramedullary pressure and bone blood flow gradually returned to c o n t r o l values within a f i v e to ten minute period. No d e f i n i t e c o r r e l a t i o n between the dose of adrenalin and i t s e f f e c t on bone blood flow was found. However, the systemic blood pressure was i n c r e a s i n g l y elevated by increasing the dose of the drug. (See Figure 10) 2. Noradrenalin e f f e c t . Noradrenalin infusions produced a s i m i l a r e f f e c t on the systemic a r t e r i a l pressure, the intramedullary pressure and bone blood flow as was observed with the adrenalin i n f u s i o n s . The marrow ca v i t y pressure was reduced an average 21 percent, with a range of s i x to 50 percent below the c o n t r o l pressure. The nutrient venous outflow was reduced an average 20 percent, with a range of f i v e to 70 percent below the c o n t r o l flow l e v e l . The only f a i r l y consistent d i f f e r e n c e noted between the adrenalin and noradrenalin infusions was a higher elevation of the systemic blood pressure and a wider pulse pressure per microgram of noradrenalin than seen i n the adrenalin i n f u s i o n s . (See Figure 11) 3. Isoproterenol hydrochloride e f f e c t . Isoproterenol (Isuprel) infusions caused a decrease i n the systemic a r t e r i a l pressure and a widening of the pulse pressure. A corresponding decrease of the intramedullary pressure to an average 16 percent below the co n t r o l pressure was observed. The range of the intramedullary pressure change was from ten percent above to 48 percent below c o n t r o l marrow ca v i t y 51 Dog TIBIAL NUTRIENT VENOUS OUTFLOW i l l i i l i l l H l l l i i i l l i l l l l H l l l i 111 111 1 1 1 ' 1 1 111 1 1 1 1 1 1 1 1 1 ' 1 1 1 1 1 1 1 ' ' 1 1 1 1 L l 1 1 1 1 m i N i i i i u i i i i D i m i i i n i i i i i H i l l i i i i i i i i i i i i i i M i i n i i i U i l i i n i |' Adrenalin Infusion 0.3^jg/kg./min. *j ; i [ M L 1 1 1 , 1 111 1 1 1 1 , M i. 1111., 11 .111111 i i i: i. i 11111111 i i 1III, ! I i i n i i i i n i i i i i i i i i i i u i i i i i i i i i i i i i i i i i i i i M i n i i i Time |5 second intervals) FIGURE 10. The e f f e c t of adrenalin i . v . i n f u s i o n . Note a profound f a l l of the intramedullary pressure with loss of the pulse and res p i r a t o r y waves associated with a decrease (50%) of the t i b i a l n utrient venous outflow. 52 Dog 2 4 0 T SYSTEMIC B.P 200-£ 120 J £ TIBIAL INTRAMEDULLARY PRESSURE o- 70n 50-30 TIBIAL NUTRIENT VENOUS OUTFLOW MII.IMIIMIIII1I1I M II I I M | I I I I I I 1 I | | |.|-M ! I I I I I I I I l-t I ! i j I I I I I I M I I I I I ! I ! H-H H I I 1 ! 1 ! M i I I i I I I U-H I |« Norodrenalin Infusion 0.3jug/kg./min. *| I;,, 1111 |l| j 11 j 1111111111| | | 11 i; 11 i 11111111,1 i 1111I i i 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Ii t~i I I 1 i 1 1 i 1 1 1 1 I I 1 1 I I 1 1 1 1 1 1 I I 1 1 1 1 1 I I 1 1 1 1 1 1 1 1 1 1 1 M 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Time (5 second intervals) FIGURE 11. The e f f e c t of noradrenalin i n f u s i o n . Note the profound f a l l of the intramedullary pressure and marked decrease of the nutrient venous outflow despite a great r i s e of systemic blood pressure. pressure. The nutrient venous outflow was decreased by an average 25 per-cent below the co n t r o l outflow. The range of venous outflow was from 20 percent above to 90 percent below con t r o l values. These parameters returned to c o n t r o l l e v e l s within a f i v e minute period a f t e r stopping the i n f u s i o n . (See Figure 12) E f f e c t s of E l e c t r i c a l Stimulation of Nerves 1.. Lumbar sympathetic trunk stimulation. E l e c t r i c a l stimulation of the lumbar sympathetic trunk i n 12 dogs produced a rapid f a l l i n the femoral and t i b i a l intramedullary pressure with a los s of the pulse and r e s p i r a t o r y waves. The marrow cavity pressure decreased an average 49 mm. Hg. with a range of 20 to 80 mm. Hg. below cont r o l pressures. This was coupled with a marked reduction i n the bone blood flow, with the nutrient venous outflow slowing to 60 percent of the co n t r o l rate. The range was 15 to 85 percent below con t r o l flow rates. I f stimulation was continued for more than three to f i v e minutes, there was a tendency f o r the marrow ca v i t y pressure and the bone blood flow to return toward c o n t r o l l e v e l s , but always remained w e l l depressed. Only s l i g h t e l e v a t i o n and a l t e r a t i o n of cardiac rhythm was seen i n the systemic a r t e r i a l pressure tra c i n g s . In those animals i n which the intramedullary pressure or bone blood flow was being measured simultaneously i n both hind limbs the stimulation of one lumbar sympathetic trunk produced changes only i n the i p s i l a t e r a l limb. When the sympathetic stimulation was discontinued, the bone blood flow and marrow ca v i t y pressure gradually returned to normal with i n a f i v e to ten minute period, (See Figures 13 and 14) 2. S c i a t i c nerve stimulation. The e f f e c t s of s c i a t i c nerve stimulation on the marrow cavity pressure and blood flow of the t i b i a were studied i n seven rabbits and f i v e dogs. E l e c t r i c a l impulses which were below the somatic nerve threshold did not FIGURE 12. The e f f e c t of isoproterenol i . v . i n f u s i o n . Note the f a l l i n systemic B.P. coupled with the decrease i n intramedullary pressure and nut-r i e n t venous outflow. DOG #25 1/5 2 0 0 -at I 1 5 0 -£ E 1 0 0 -9 0-i O) X 6 0 -£ E 3 0 -S Y S T E M I C B.P. T IB IAL I.M.P. T IB IAL N U T R I E N T V E N O U S O U T F L O W i I i i 11 \ 11 \ 11 u i i u m u i u i n o n I nm T i m e (5 s e c o n d i n t e r v a l s ) H]||J|J!I111!11H[]IM o f f E l e c t r i c a l S t i m u l a t i o n o f L u m b a r S Y M P A T H E T I C C H A I N V o l t s 12 2.0 M s D F r e q . 2 0 0 FIGURE 13. The e f f e c t of e l e c t r i c a l stimulation of the lumbar sympath-e t i c trunk. Note the sharp f a l l i n the t i b i a l intramedullary pressure and the decrease i n the t i b i a l n utrient venous outlfow during lumbar sympath-e t i c trunk stimulation. 56 DOG 200 SYSTEMIC B.P Electrical Lumbar Sympathetic Stimulation l | ! | i | | l | | l | l | l i i | | | | | | | i | i i l l l i | | | I I I M I t ! l l l l l i l ! Time (5 second intervals) Volts 10 MsD 2.0 Freq. 200 FIGURE 14. The e f f e c t of e l e c t r i c a l stimulation of the lumbar sympath-e t i c trunk. Note the simultaneous f a l l of both t i b i a l and femoral marrow cavity pressure despite the systemic blood pressure unchanged. In s i m i l a r experiments a marked decrease i n the bone blood-flow was observed. 57 produce any measurable change i n the t i b i a l blood flow. When slowly i n -creasing the strength (voltage) of the e l e c t r i c a l stimulus, the e x c i t a t i o n of the somatic nerves i s f i r s t apparent producing a tetan i c contraction of the s k e l e t a l muscles below the knee. The muscle contractions produce a sharp e l e v a t i o n of f i v e to 20 mm. Hg. i n the marrow ca v i t y pressure coupled with an increase nutrient venous outflox* and decreased a r t e r i a l retrograde flow. These changes i n d i c a t e intraosseos venous congestion. I f the tetanic contraction i s maintained, the blood flow and marrow cavity pressure of the t i b i a tend to return to cont r o l l e v e l s . When the e l e c t r i c a l stimulation was discontinued, the intramedullary pressure momentarily f e l l sharply below the c o n t r o l pressure then quickly returned to the normal pressure. By increasing the voltage of the stimulus, a more f o r c e f u l muscle contraction was observed producing a b r i e f i n i t i a l r i s e of the marrow ca v i t y pressure and increase venous outflow, followed quickly by a precipitous f a l l of the intramedullary pressure with a marked decrease i n the nutrient venous out-flow. The immediate r i s e of the intramedullary pressure and the increase of venous outflow are due to muscle contraction and the sharp f a l l i s due to e x c i t a t i o n of vasomotor f i b e r s of the s c i a t i c nerve supplying vessels below the knee. No change was observed i n the femoral marrow ca v i t y pressure or the systemic blood pressure. (See Figure 15) E f f e c t of Lumbar Sympathectomy Lumbar sympathectomy studied i n f i v e dogs produced an average 48 per-cent increase In the t i b i a l blood flow and an average 9 mm. Hg. r i s e i n the t i b i a l marrow cavity pressure. The ranges of t i b i a l blood flow and marrow cavity changes were 15 to 110 percent and two to 25 mm. Hg. re s p e c t i v e l y . (See Figure 16) Ef f e c t s of Muscle Contraction The influence of s k e l e t a l muscle contraction on bone c i r c u l a t i o n was 58 DOG TIBIAL NUTRIENT VENOUS OUTFLOW 1 M M I i — i - i i i i nn—•• 1 U M I U M H U I H U M ' ' . t ' I i 1 I > (•', , i • . . . i I . , I t j > > ! ! . , , i Electrical Sciatic Nerve Stimulation 111111 i i i i i i 111 i i i u 11 i i i i i i i u l I i i i I 11111 [ || I111111; i ! u 111 n i i i i i i i M i i Time (1 second intervals) Volts 15 MsD 2.0 Freq. 200 ' FIGURE 15. The e f f e c t of e l e c t r i c a l stimulation of the s c i a t i c nerve. Note the great f a l l of the t i b i a l intramedullary pressure coupled with a marked decrease i n the t i b i a l nutrient venous outflow. The b r i e f i n i t i a l r i s e of the marrow ca v i t y pressure and increased venous outflow are due to muscle contraction. Also note the femoral marrow ca v i t y pressure unchanged. This i s due to the fac t that the s c i a t i c nerve c a r r i e d the vasomotor f i b e r s supplying vessels below the knee. 59 DOG #27 SYSTEMIC B.P. 70-1 RIGHT TIBIAL NUTRIENT VEINOUS OUTFLOW •mmm . » • [• EFFECT OF SYMPATHECTOMY (Rt. Lumbar Trunk) Time (5 second intervals) FIGURE 16. The e f f e c t of lumbar sympathectomy. Note the elev a t i o n of the rig h t t i b i a l intramedullary pressure and increase i n the ri g h t t i b i a l nut-r i e n t venous outflow following r i g h t lumbar sympathectomy. 60 studied i n ten rabbits and 15 dogs by e l e c t r i c a l nerve stimulation or d i r e c t muscle stimulation. Contraction of the quadriceps or adductor muscle groups produced a sharp r i s e i n the marrow cavity pressure and an increase nutrient venous outflow i n the femur and the t i b i a . Quadriceps and adductor muscle contractions caused an average 15 mm. Hg. elevation i n the marrow cavity pressures, with a range of four to 35 mm. Hg. above the control pressures. These marrow cavity pressure changes were coupled with an average 67 per-cent increase i n the nutrient venous outflow. The range of increase was 18 to 140 percent of control flow rates. The contraction of muscles below the knee caused a l t e r a t i o n s i n the t i b i a l c i r c u l a t i o n , but the femoral c i r c u l -a t i o n showed no change. An average 10 mm. Hg. r i s e i n the marrow cavity pressure with a range from three to 30 mm. Hg. above c o n t r o l pressures was observed. The nutrient venous outflow increased an average 48 percent with an 18 to 85 percent range. These intraosseous changes indi c a t e muscle con-t r a c t i o n produces bone venous congestion. With cessation of the stimulus, muscle relaxation frequently was followed by a sudden short l i v e d f a l l of marrow cavity pressure below con t r o l values. Then intramedullary pressure and blood flow of the bone quickly return to normal. (See Figures 17 and 18). Phasic momentary muscle contractions were produced by decreasing the frequency of the stimulating e l e c t r i c a l impulse. These are interspersed by periods of muscle rel a x a t i o n . As shown i n figure 19, muscle contraction produces an immediate el e v a t i o n of the intramedullary pressure and with muscle r e l a x a t i o n there i s a momentary rapid drop of the marrow cavity pressure below control l e v e l s followed by a resumption of c o n t r o l l e v e l s . Phasic muscle contractions occurring every two seconds were studied for a f i v e minute i n t e r v a l i n four dog experiments. The volume of blood obtained from the nutrient venous catheter and the rate of flow, by counting drops, 61 DOG #27 200-i 160-120- 1 SYSTEMIC B.P. TIBIAL DIAPHYSEAL I.M.P. 100-3 CO to I 80 -60- 1 TIBIAL METAPHYSEAL I.M.P. 100-I 80-1 E 60-40-TIBIAL NUTRIENT VENOUS OUTFLOW '.UU1', Time (5 second intervals) I I I ! 11111111 1 1 1 1 • * Quadricepts Electrical Stimulations Volt 12 MsD 2.0 Freq. 200 FIGURE 17. The e f f e c t of tetan i c muscle contraction. E l e c t r i c a l stim-u l a t i o n of the quadriceps muscle. Note the phasic r i s e and f a l l of the marrow ca v i t y pressure due to muscular contraction and rela x a t i o n . Muscle re l a x a t i o n causes a b r i e f f a l l i n the marrow cavity pressure to sub control l e v e l before returning to normal l e v e l . 62 DOG #25 TIBIAL NUTRIENT VENOUS OUTFLOW 111! * 11 L 1 I I I ! W vv f t v • r f Time (5 second intervals) on off - « — i — i —»— - i — « — r - r riTTH - - ^ ~ ^ - _ r -Adductor Muscle Electrical Stimulation Volts 25 MsD 2.0 Freq. 200 FIGURE 18. The e f f e c t of tet a n i c muscle contraction. E l e c t r i c a l stim-u l a t i o n of adductor muscles. Note the r i s e i n the t i b i a l marrow ca v i t y pressure coupled with an increase In the t i b i a l n utrient venous outflow due to intraosseous venous congestion during adductor muscle contraction. 6 3 DOG #34 200 SYSTEMIC B.P. £ 6 120-1 TIBIAL DIAPHYSEAL I.M.P. o> 100-3 • 9 0 " lo E go iu E ? 70 TIBIAL METAPHYSEAL I.M.P 0 110 TIBIAL NUTRIENT VENOUS OUTFLOW I I I I I I I | | I I | | i r i f f i i i r r > . i' Time (5 second intervals) • f • T I T t • T Phasic Quadricepts Electrical Stimulations Volts 12 Freq. 2.0 MsD 2.0 FIGURE 19. The e f f e c t s of phasic, muscle contraction. E l e c t r i c a l stim-u l a t i o n of the quadriceps. Note the phasic r i s e - f a l l of the marrow cavity pressure due to muscle contraction - r e l a x a t i o n . 64 di d not show a s i g n i f i c a n t change from the c o n t r o l f i v e minute period. DISCUSSION The method of simultaneous study of both the blood flow and the marrow cav i t y pressure of the same bone, described i n t h i s paper, i s very useful f o r q u a l i t a t i v e i n v e s t i g a t i o n s of the r e l a t i v e changes of the hemodynamics of the bone. The findings c l e a r l y i n d i c a t e there i s a good c o r r e l a t i o n bet-ween the blood flow and marrow ca v i t y pressure of bone. Observations made during the experimental conditions described, i n d i c a t e that the marrow cav i t y pressure r i s e s i f the a r t e r i a l blood supply to bone increases or venous congestion occurs i n the limb and bone. Conversely, the marrow cav i t y pressure f a l l s i f the blood supply to bone decreases or venous d r a i n -age i s f a c i l i t a t e d . The problem of intramedullary pressure i s complex, but since i t may 54 have p h y s i o l o g i c a l s i g n i f i c a n c e i n the intraosseous c a p i l l a r y c i r c u l a t i o n , 6 47 blood c e l l formation and formation and maintainance of bone, i t deserves c a r e f u l study and i n v e s t i g a t i o n . The factors i n f l u e n c i n g marrow cavity pressure are the inflow of blood through the nutrient v e s s e l s , f u n c t i o n a l intraosseous anastomoses, the volume of the c a p i l l a r y and s i n u s o i d a l beds, the p e r i p h e r a l vascular resistance, the outflow of venous blood and the e x t r a c e l l u l a r f l u i d . From the p h y s i o l o g i c a l point of view, the marrow cavity i s occupied by: the trabecular and fibrous t i s s u e framework; f a t cells;, nerve f i b e r s : developing and adult blood c e l l s ; blood vessels and c i r c u l a t i n g blood; and e x t r a c e l l u l a r f l u i d . A l l of these are incompressible and, except for blood c e l l s and f l u i d , immobile. There i s some evidence to suggest that extra-c e l l u l a r f l u i d i s able to flow along the sheaths and osseous canals of blood , 1 vessels. 65 The intramedullary pressure i n normal bone i s the pressure of blood i n a l o c a l pool of hemorrhage from ruptured intraosseous vessels produced 2 during the placement of an intramedullary cannula. Azuma pointed out that during the d r i l l i n g of the cortex i n t o the marrow cavity and the placement of the cannula i n t o the marrow c a v i t y , the underlying vessels are damaged to a varying extent. Our h i s t o l o g i c a l studies support t h i s view. There-fore, the measurable marrow cavity pressure v a r i e s to some extent by the s i z e and type of vessels ruptured as well as with t h e i r vasomotor action i n the marrow cav i t y . The pressures developed i n the intramedullary cannula may not be the exact normal intramedullary pressure i n these experiments. However, the f l u i d i n the intramedullary cannula i s i n d i r e c t continuity with opened ruptured vessels i n the anticoagulated animal. Therefore, changes i n the marrow ca v i t y pressure should r e f l e c t w e l l the changes i n the hemodymics of bone. The wide v a r i a t i o n of intramedullary pressure observed i n t h i s study 46 are s i m i l a r to those reported by other i n v e s t i g a t o r s . Keck and K e l l y found that diaphyseal intramedullary pressure increased with growth i n 19 t h e i r dog experiments. Cutherbertson et a l did not observe t h i s change i n t h e i r dog studies. The intramedullary pressure has been shown to be 2 102 lower i n the epiphysis as compared to the diaphysis. ' Dickerson and 24 Duthie found intramedullary pressure highest i n the mid. diaphysis i n t h e i r bone a r t e r i a l d i v e rsion experiments i n the dog and suggested that the marrow pressure i n an adult long bone varies i n inverse proportion to the number of venous channels draining that area of bone. In t h i s study a regional difference of intramedullary pressure was observed ( i . e . meta-physis and diaphysis). In some cases the intramedullary pressure of the metaphysis was higher than that of the diaphysis and v i c e versa. 54 Larsen i n 1938 observed constant bone s u b s t i t u t i o n or sequestration 66 following sustained high pressure (77 mm. mercury or greater) intramedul-l a r y s a l i n e i n f u s i o n and concluded that increased intramedullary pressure may be of extreme importance i n the production of massive bone necrosis. This observation appears to have p a r t i c u l a r c l i n i c a l s i g n i f i c a n c e with respect to the bone necrosis i n acute osteomyelitis with the accumulation of inflammatory exudate i n extravascular tissues of bone and marrow pro-ducing pressure pain and ischemia r e s u l t i n g i n bone necrosis. The marrow cavit y , i n a sense, i s a semi-closed chamber surrounded by r i g i d c a l c i f i e d walls and containing tissues which are incompressible and excluding blood and extravascular f l u i d , immobile. Increased marrow cavity pressure due to even intraosseous venous congestion decreases blood supply to bone. Since massive diaphyseal bone necrosis with sequestration r e s u l t s from Ischemia produced p r i m a r i l y by pressure, the fundamental p r i n c i p l e treatment of acute osteomyelitis i s e a r l y decompression of increased medullary c a v i t y pressure before bone death occurs. 72 Nick and associates observed a r i s e i n pressure to about 75 mm.Hg. i n fracture hematoma and suggested t h i s may be an important f a c t o r i n 114 fra c t u r e healing. Wehner studied the intramedullary pressure i n the d i s t a l metaphysis, during closed reaming and n a i l i n g of fractures of the t i b i a and femur i n man. He found the marrow cavity pressure was 9-10 mm. Hg. f i v e to eight days a f t e r the fracture Closed reduction or opening the marrow ca v i t y with an awl caused an increase i n pressure to 20-25 mm. Hg. Insertion of the guide wire into the marrow cavity produced a pressure increase of 40 mm. Hg. During reaming, there was a maximal pressure increase of 120 mm. Hg., greatest when the reamer entered the d i s t a l fragment and was greater with the wide c a l i b e r of reamer. A negative pressure of about 100 mm. Hg. was recorded during the removal of the reamer. On d r i v i n g i n the n a i l no s i g n i f i c a n t e l e v a t i o n of intramedullary pressure was noted. 67 22 Danckwardt-Lilliestrom studying the e f f e c t s of reaming the medullary ca v i t y on diaphyseal bone i n the rabbit and dog concluded the pressure increase i n the medullary c a v i t y , produced during surgery, forced marrow tis s u e i n t o the i n t r a c o r t i c a l canal where i t blocks the i n t r a c o r t i c a l c i r c u l a t i o n producing avascular necrosis i n the endosteal c o r t i c a l bone. 23 In a further study Danckwardt-Lilliestrom and associates found a reduction of the intramedullary pressure during reaming of the medullary cavity decreases considerably the extent of the i n t r a c o r t i c a l vascular damage, as compared to the group of animals i n which no attempt to reduce the i n t r a -medullary pressure during reaming. Considerable evidence has accumulated that suggests bone can act as a c o l l a t e r a l route f o r venous drainage. On the basis of planned experiments 4 and numerous routine i n j e c t i o n s , Batson derived the p h y s i o l o g i c a l concept of the v e r t e b r a l vein system. This system consists of the veins of the head and neck, the veins of the body w a l l and the v a l v e l e s s veins of the extremities, which are a l l mutually continuous with the veins of the v e r t e b r a l column (the true v e r t e b r a l v e i n s ) . S t e i n b a c h " ^ found no e v i d -3 ence intraosseous venous valves. Batson pointed out the function of the v e r t e b r a l vein system and i t s r o l e i n the spread of metastases. Cuthbertson 21 and associates observed c o l l a t e r a l c i r c u l a t i o n through the venous channels of the dog femur investigated with roentgenographic and tr a c e r techniques. In approximately 50 percent of extremities studied by these authors, acute venous obstruction (midthigh low pressure tourniquet) produced c o l l a t e r a l c i r c u l a t i o n as demonstrated by r e v e r s a l of blood flow through small t r i b u t a r i e s of the femoral vein entering the d i s t a l femoral metaphysis, following the c e n t r a l medullary venous sinus, and draining through the normal channels from the proximal end of the femur. In our study, a low pressure tourniquet produced venous congestion of the limb and intraosseous con-gestion. This i s p a r t l y due to the c o l l a t e r a l d i v e rsion flov; of venous blood i n t o the bone from the surrounding s o f t t i s s u e i n the limb. Sk e l e t a l muscle contraction causes phasic e l e v a t i o n of intramedullary pressure due to intraosseous venous congestion. Brookes1"'' postulated that muscle pump a c t i v i t y at fleshy muscle attachments was important to promote c o r t i c a l venous drainage. P r i o r to t h i s , muscle contraction was usually 118 thought to act on large systemic veins. Wells and associates showed the pumping pressure on venous blood to reach 90 mm. Hg. i n the veins of the contracting soleus. A f t e r demonstrating c o r t i c a l c a p i l l a r i e s are i n continuity with the i n t e r f a s i c u l a r venules of the muscle, Brookes''' 1 1 sug-gested that the muscle pump action could d i r e c t l y influence normal bone 107 c i r c u l a t i o n , and maybe an important haemodynamic f a c t o r . Trueta meas-uring t i b i a l marrow cavity pressure i n the dog, found s c i a t i c nerve stim-u l a t i o n causing muscle contraction produced an immediate elevation and a prompt f a l l to co n t r o l l e v e l s with muscle r e l a x a t i o n . He noted a momentary negative intramedullary pressure suggesting a muscle pump. Since s k e l e t a l muscle contraction can cause d i v e r s i o n flow of the so f t t i s s u e venous blood i n t o bone, motions of the limb may cause spread of so f t t i s s u e tumor or i n f e c t i o n d i r e c t l y into l o c a l bone. S k e l e t a l muscle's influence on bone blood flow may have p h y s i o l o g i c a l s i g n i f i c a n c e i n the maintainance of 74 43 normal i n t e g r i t y of bone. Pearse and Morton and McMasters and Roome suggested that l i g a t i o n of the hind limb veins stimulated bone growth. Key and Walt 39, 43, 103 49 16 ton could not confirm t h e i r findings. Other in v e s t i g a t o r s : found an increase weight and length of bone d i s t a l to l i g a t e d 39 veins. Hutchinson and Burdeaux found a 1.04 percent increase i n leg length i n seven of 11 animals, and a 1.45 percent increase i n t i b i a l length a f t e r prolonged a p p l i c a t i o n of tourniquets to legs of young dogs. A number of i n v e s t i g a t o r s ^ 1 ' ^ ' ^ ' 1 ^ have shown evidence to in d i c a t e that 69 chronic introsseous venous congestion produces increased endosteal r e -sorption, decreased endosteal bone formation and increased p e r i o s t e a l bone formation. The fact that sympathetic nerve stimulation and vasopressor drugs such as adrenalin and noradrenalin decrease bone blood flow and lower intramedullary pressure of bone has been observed repeatedly by previous workers. However, no one has conclusively demonstrated as has been done i n t h i s study that the f a l l of the marrow cavity pressure i s due to vasocon-s t r i c t i o n of nut r i e n t vessels and a decreased blood supply to bone. SUMMARY AND CONCLUSIONS 1. An experimental method of simultaneously recording bone blood flow and marrow c a v i t y pressure i s described. 2. The systemic blood pressure, marrow ca v i t y pressure, and nutrient venous outflow are remarkably constant i n a c o n t r o l period, therefore, t h e i r changes under experimental conditions are r e a d i l y r e c o r d i b l e . 3. There are differences of the marrow c a v i t y pressure from region to region i n a given bone, from bone to bone and from animal to animal i n the same and d i f f e r e n t species. Normally the marrow ca v i t y pressure i n the dog ranges from 20 to 90 percent of the systemic a r t e r i a l blood pressure (average 47%) and i n the rabbit 14 to 52 percent of the systemic a r t e r i a l pressure (average 41%). 4. I f the femoral vein i s occluded the marrow cavity pressure r i s e s and the nut r i e n t venous outflow increases i n d i c a t i n g venous congestion of bone. 5. I f the nutrient artery i s occluded, an immediate f a l l i n the marrow cav i t y pressure occurs coupled with a profound decrease i n the nutrient venous outflow. 70 6. Adrenalin and noradrenalin Intravenous infusions generally produce an ele v a t i o n i n the systemic blood pressure and a more constant f a l l i n the marrow cavity pressure coupled with a decrease bone blood flow with an observable nutrient vascular c o n s t r i c t i o n . 7. Isoproterenol hydrochloride generally causes a f a l l i n the systemic a r t e r i a l pressure, widening of the pulse pressure, a f a l l i n the marrow ca v i t y pressure and a decrease i n nutri e n t venous outflow. i 8. Sympathetic stimulation (the lumbar sympathetic trunk and s c i a t i c nerve sympathetic component) causes a f a l l of the marrow cavity pressure and a decrease i n bone blood flow. 9. Lumbar sympathectomy causes a r i s e i n the marrow cavity pressure and an increase i n bone blood flow. 10. S k e l e t a l muscle contraction produces bone venous congestion and e l e -vates the marrow cavity pressure and muscular r e l a x a t i o n causes a momentary f a l l of the marrow ca v i t y pressure to sub-control l e v e l s before returning to the normal pressure. 11. The p h y s i o l o g i c a l and c l i n i c a l s i g n i f i c a n c e s of the bone marrow ca v i t y pressure are discussed. 12. I t i s concluded that the marrow cavity pressure i s bone blood flow dependent and r e f l e c t s w e l l the changes i n the hemodynamics of bone. The marrow pressure r i s e s i f the a r t e r i a l blood supply to bone increases or venous congestion occurs i n bone. The marrow pressure f a l l s i f the a r t e r i a l blood supply to bone decreases or the venous drainage of bone i s f a c i l i t a t e d . 71 BIBLIOGRAPHY  Literature Cited 1. Anderson, D. W.: Studies of Lymphatic Pathways of Bone and Bone Marrow. J. Bone Jt. Surg. (Abst.) 64-A: 716-717, 1960. 2. 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