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Bone circulation in hemorrhagic shock. 1971

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BONE CIRCULATION IN HEMORRHAGIC SHOCK by WILLIAM YAN YU ' M.B.B.S., Honours, University of Hong Kong, 1966 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the Department of SURGERY We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA March, 1971 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced deg ree a t the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t he 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 r e f e r e n c e and s t u d y . I f u r t h e r ag ree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Depar tment o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r 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 g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Depar tment o f /^AA^JI^LSJ The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8, Canada Date i ABSTRACT Bone circulation in Hemorrhagic Shock was studied in 35 male mongrel dogs. The term hemorrhagic shock is defined in this thesis as persistent profound hypotensive syndrome, due to acute hemorrhage of more than one third of blood volume. The method of induction of shock consisted of removal of one third of estimated blood volume (87o of body weight) at a rate of 25 - 50 ml/min, and subsequently dropping the systemic blood pressure in a stepwise manner until the maintaining level of 30 - 35 mmHg is reached. The central venous pressure, pulse and respiratory rates were also recorded. Bone circulation was studied by (1) recording the blood flow through a cannula inserted into the t i b i a l nutrient vein or artery and (2) recording the intramedullary pressure of t i b i a . When one third of estimated blood volume was removed, the bone blood flow through the nutrient vessel decreased to 22*5 + 3'47. of control level. The decreased bone blood flow persisted as long as the hemorrhagic shock was maintained for 4 - 1 8 hours. The decreased bone blood flow was also evidenced by a profound and persistent f a l l of the intramedullary pressure of bone. Reinfusion into the animal of lost blood within fifteen minutes to six hours after hemorrhage resulted in a complete or partial recovery of the control systemic blood pressure as well as the control rate of bone blood flow and the control level of intramedullary pressure of bone. The curve showing relationship between the changes in bone blood flow and the systemic blood pressure is an exponential one with concavity towards the flow axis. This indicates that bone has a vasomotor control mechanism of increasing peripheral resistance during hemorrhagic shock. This was substantiated by the following observations: (1) The severity of decrease in bone blood flow on the side of lumbar sympathectomy was much milder (16% less) compared to the side of the intact sympathetic nerve; (2) Dibenzyline (phenoxybenzamine) a sympatholytic drug or alpha-receptor blocking agent alters the pressure-flow curve of bone circulation in chock to a linear pattern which indicates that the drug blocks the bone vaso- constricting mechanism(s). It is concluded that bone blood flow decreases in hemorrhagic shock and is not merely due to a decrease in circulatory blood volume, but also due to sympathetic and catecholamine hormonal vasoconstrictor mechanisms. i i i TABLE OF CONTENTS Page I INTRODUCTION AND PURPOSE OF STUDY 1 II REVIEW OF LITERATURE 2 BONE CIRCULATION 2 Anatomy - Vascular supply of bone . 2 Nerve supply of bone 8 Physiology of Bone Circulation 10 Methods of study 10 Rate of bone blood flow 15 Rate of entire skeletal blood flow. 18 The regulation mechanisms of bone blood flow . 18 Neural Control 18 Hormonal Control 19 Metabolic Control 20 SHOCK , 20 Defi n i t i o n 20 H i s t o r i c a l aspect 22 Abnormal physiological aspect of shock 25 Regional c i r c u l a t i o n i n shock 30 Total peripheral resistance 30 Coronary c i r c u l a t i o n ± n shock ... 3 0 Cerebral c i r c u l a t i o n i n shock 31 Renal c i r c u l a t i o n i n shock 31 Splanchnic c i r c u l a t i o n i n shock ... 32 Skin and muscle c i r c u l a t i o n i n shock 33 iv Page I I I MATERIALS AND METHODS 34 General set-up 34 Study of bone blood flow 36 Transperitoneal lumbar sympathectomy 36 Use of dibenzyline (phenoxybenzamine) 37 Induction and sustaining of hemorrhagic shock .... 37 IV RESULTS 38 I Acute hemorrhage 38 II Effect of one th i r d of estimated blood volume loss 38 I I I Effect of prolonged hemorrhage 38 IV Effect of re-infusion of lost blood 39 V Relationship between bone blood flow and systemic a r t e r i a l pressure 39 VI Effect of e l e c t r i c a l stimulation of lumbar sympathetic chain 39 VII Effect of lumbar sympathectomy A. Before induction of hemorrhagic shock .. 39 B. After induction of hemorrhagic shock ... 40 VIII Effect of epinephrine and norepinephrine .... 41 IX Effect of dibenzyline (phenoxybenzamine) .... 41 V DISCUSSION 42 V a l i d i t y of experimental methods 44 I Parameters used i n measuring bone c i r c u l a t i o n 44 . A. Direct cannulation - c o l l e c t i o n method . 44 B. Intramedullary pressure as an Index of bone blood flow 44 Page V DISCUSSION (cont'd) I I V a l i d i t y of the hemorrhagic shock model 44 DISCUSSION ON RESULTS 46 I Acute hemorrhage 46 I I Effect of one t h i r d blood volume loss 47 III! Prolonged hemorrhage 48 IV Re-infusion of l o s t blood 48 V Relationship between bone blood flow and systemic B.P 49 VI Effect of e l e c t r i c a l stimulation of lumbar sympathetic chain 50 VII Effect of lumbar sympathectomy 50 A. Before induction of hemorrhage . . 50 B. Effect of lumbar sympathectomy i n shock. 51 VIII Effect of catecholamines 52 IX Effect of dibenzyline on bone blood flow i n hemorrhagic shock 52 SUGGESTED FUTURE STUDIES 54 1. Bone and marrow blood volume 54 2. Ischemic effect on bone marrow in shock 54 3. Pathogenesis of fat embolism 54 4. Metabolic aspect of bone c i r c u l a t i o n i n shock 55 VI SUMMARY 55 VII CONCLUSION 57 IX BIBLIOGRAPHY 61 v i TABLES Page I RELATIONSHIP BETWEEN PERCENTAGE CHANGE IN SYSTEMIC BLOOD PRESSURE AND BONE BLOOD FLOW 58. II EFFECT OF LUMBAR SYMPATHECTOMY ON BONE BLOOD FLOW IN SHOCK 59 I I I EFFECT OF DIBENZYLINE ON BONE CIRCULATION IN SHOCK ... 60 v i i FIGURES Page 1 Micrograph of a transverse section of a dog's t i b i a with India ink i n j e c t i o n , demonstrating nutrient and periosteal vessels 2a 2 Micrograph of a s a g i t t a l section of dog's t i b i a with India ink i n j e c t i o n , demonstrating distri b u t i o n s of nutrient a r t e r i a l branches 2b 3 Micrograph of the periosteal vessels of the dog's t i b i a 2c 4 Micrograph of transverse section of bone, with H & E st a i n , demonstrating nerves of bone marrow 8a 5 General set-up i n experiment 34a 6 The "Bleeding Reservoir" used i n experiment 35a 7 The effects of acute hemorrhage 38a 8 The effects of removal of one th i r d of estimated blood volume „ 38b 9 The effects of re-infusion of lost blood.,..; 39a 10 Graph to show the percentage changes of bone blood flow, with respect to percentage changes i n systemic blood pressure i n hemorrhagic shock 39b 11 The effects of e l e c t r i c a l stimulation of lumbar sympathetic chain , 39c 12 The effects of sympathectomy on bone c i r c u l a t i o n before hemorrhage 39d 13 The effect of sympathectomy on bone blood flow i n shock 40a 14 The effects of epinephrine (adrenalin) infusion 41a v i i i Page 15 The effects of norepinephrine (noradrenalin) infusion 41b 16 The effect of dibenzyline (phenoxybenzamine) on bone c i r c u l a t i o n i n shock 41c i x ACKNOWLEDGEMENTS To Dr. S. S. Shim, my teacher and sponsor, I wish to extend my deepest gratitude. He has introduced the art of research to me, and has shown me the systematic approach to the so l u t i o n of a s c i e n t i f i c problem. He has made many valuable suggestions and has shown remarkable tolerance to the ignorance and naivety of a beginner. The p r i n c i p l e s and methods for studying bone c i r c u l a t i o n , a f i e l d i n which Dr. S. S. Shim has won i n t e r n a t i o n a l recognition, provide the basis of this study. My sincere thanks go to Dr. F. P. Patterson, Head of the D i v i s i o n of Orthopaedics, for h i s constant encouragement. He has k i n d l y arranged t h i s year of research as part of my t r a i n i n g ; a year i n which I have enjoyed an excellent educational experience. I would l i k e to extend my thanks to Dr. W. G. Trapp and Dr. A. I. Munro for allowing me to use t h e i r equipment i n the study of shock, and to Dr. P. J . Moloney for the supply of Dibenzyline, which i s p r i m a r i l y intended f o r h i s research i n renal transplantation. Dr. H. E. Hawk, my senior colleague, has continually bombarded me with i n t e l l e c t u a l stimulation and has re f i n e d some of the techniques i n th i s study. The technical assistance of Mr. G. Leung and the s t a f f of the Animal Research Laboratory of the U n i v e r s i t y of B r i t i s h Columbia i s well appreciated. Mr. Bardolf Paul and the s t a f f Department of the Vancouver General and photographed a l l the figures i n Last, but not least, my thanks who has k i n d l y typed this t h e s i s . x of the Medical I l l u s t r a t i o n Hospital have k i n d l y framed this study. are due to Miss Judy Reid, 1. INTRODUCTION AND PURPOSE OF STUDY Shock i s one of the most extensively studied conditions i n c l i n i c a l as well as laboratory medicine, with an almost inexhaustible l i s t of 72, 105, 139, 159 references and many excellent monographs covering this f i e l d i n depth. Regional c i r c u l a t i o n i n shock, including evaluation of blood flow, mechanism of con t r o l , and functional i n t e g r i t y of various systems and 26, 42, 112, 123 26, 45, 123 organs such as coronary , cerebral , 70, 108, 123 26, 65, 123, 125, 126 26, 123 pulmonary , renal , hepatic , 1, 69, 123, 127 54, 71, 75, 97 splanchnic and adrenals have been studied. A v a i l a b l e information indicates that there are d i s t i n c t l y 59 d i f f e r e n t responses of various vascular beds i n shock However, l i t t l e i s known about the bone c i r c u l a t i o n i n shock due to lack of study. A review of l i t e r a t u r e f a i l e d to d i s c l o s e a previous study on bone c i r c u l a t i o n i n shock. Purpose of Study The aim of th i s thesis i s to f i n d out the answers to basic questions regarding bone c i r c u l a t i o n i n shock, such as fundamental changes i n bone hemodynamics, mechanisms whereby such changes are brought about, and comparison with other regional and organ c i r c u l a t i o n s i n shock. I t i s hoped that this study w i l l r a i s e further questions and stimulate future studies. REVIEW OF LITERATURE BONE CIRCULATION Anatomy Vascular supply of bone Nerve supply of bone Physiology Methods of study of bone c i r c u l a t i o n Rate of bone blood flow Rate of en t i r e s k e l e t a l blood flow Control mechanisms SHOCK D e f i n i t i o n H i s t o r i c a l aspect Abnormal p h y s i o l o g i c a l aspect Neural, hormonal, metabolic aspects Regional c i r c u l a t i o n i n shock Vascular Supply of Bone 89 Langer (1876) appeared to be the pioneer i n studying the general vascular anatomy of bone. Lexer, Kuliga and Turk (1904), as c i t e d by 37 Laing , in j e c t e d the a r t e r i a l systems of newborn and adult cadavera with a mercury-turpentine emulsion, followed by stereoscopic radiographs of the specimen, and was able to give a de t a i l e d d e s c r i p t i o n of the vascular supply of the femur. They found evidence of three main a r t e r i a l systems supplying a l l long bones; namely, p e r i o s t e a l , nutrient, and metaphysio-epiphyseal systems. FIGURE 1 2a. Micrograph of a transverse section of a dog's femur with India Ink in j e c t i o n . I t shows the r e l a t i v e contributions of nutrient and periosteal a r t e r i e s . The bone marrow and inner two thirds are supplied by nutrient artery, and outer th i r d by the periosteal a r t e r i e s . Note r a d i a l arrangement of branches of nutrient artery. FIGURE 2 2b. Micrograph of s a g i t t a l section of a dog's t i b i a with India Ink in j e c t i o n . I t shows distributions of nutrient a r t e r i a l branches i n the marrow cavity (central portion). Note that there are many longitudinal vessels (contained i n the Haversian canals) and some transversely running vessels (via Volkmann's canals). FIGURE 3 2c. Periosteal vessels of a dog's t i b i a shaft. The dark vessels are veins and lighter ones are a r t e r i e s . Note that there i s a 'trio-arrangement', the artery i n the centre and the veins on each side. Micro angiographic study of bone was carried out by Barclay ^. Materials, such as vinyl plastic, India ink, Berlin blue, or finely divided barium sulphate (micropaque), are the most commonly used 149 contrast media. This method was used by Trueta and Harrison in studying the vascular anatomy of the femoral head, Haliburton in the talus of man, Nelson in the human ti b i a , Brookes in tubular bone in 16 17 rats , long bones in the human foetus , and in rabbits' femur and tibiofibula 1 5 . A l l authors tend to agree that the nutrient artery, after entering the diaphyseal cortex, divides into ascending and descending branches which have further radially oriented branches to the cortex. The ends of the bones are supplied by the epiphyseal and the metaphyseal arteries, which enter the epiphysis and metaphysis through small foramina. After entering the substance of bone, the arteries branch into a r t e r i a l arcades resembling the arcades of the mesentery of the bowel. These vascular arcades become smaller and smaller, and terminate in small capillary loops beneath the articular cartilage. Such arrangements have been 1X1 12 observed by Nelson et a l in the human tibia and Rogers and Gladstone in the d i s t i l end of the human femur. The periosteal system forms an abundant vascular network, and this can easily be observed in the periosteum of long bones, such as the t i b i a . It has been pointed out by Nelson , of the prevalence of a trio arrangement of vessels, in which each one of the ar t e r i a l twigs was accompanied by two veins, in the t i b i a . 14 Branemark , with a special illumination device, was able to visualize the marrow of fibula of the rabbit, and observed i t s structure and function i n the microscope without i n t e r f e r i n g with the normal function of the organ. The vessel c a l i b e r was noticed to vary with the functional state of the marrow, and a rough average i n a marrow of "ordinary" a c t i v i t y . A r t e r i o l e 10 u C a p i l l a r y 3 u Sinusoid 15 - 60 u Venule 12 u The flow r a t i o between the a r t e r i o l e and the sinusoid was estimated to be approximately 10:1, a figure close to that derived from i n j e c t i o n - corrosive preparations of the vascular bed. The sinusoids are sometimes s p i r a l l e d shaped, sometimes more or less hexagonal. They showed a rhythmic function with a l t e r n a t i n g d i l a t i o n and emptying. This rhythmic a c t i v i t y i s somewhat s i m i l a r to 85 47 that described by Knisely i n spleen. Foa , by measuring changes i n volume of bone marrow, suggested that the behavior of the bone marrow was very s i m i l a r to the spleen; and proposed that the bone marrow c i r c u l a t i o n may a c t u a l l y be regulated by sphincters s i m i l a r to those of the venous sinusoids. In studying the innervation by d i r e c t observation of the marrow mi c r o c i r c u l a t i o n , Branemark commented that the marrow vessels become constricted, and the marrow i s emptied of blood as when squeezing a sponge, during adrenaline i n j e c t i o n . Another observation was the r i c h anastomoses and a t y p i c a l course of marrow c a p i l l a r i e s dipping into the compacta, and then turning back again into the marrow sinusoids. 5. Venous Drainage Long bones have a central venous sinus. The capacity of the venous system is estimated to be six to eight times that of a r t e r i a l 39 system . The transverse sinusoids of the marrow drain directly into the central venous sinus or into larger tributaries and then 18 into the central venous sinus . The veins of bone are thin-walled. 66 14 Hashimoto , according to Branemark , observed that the nutrient artery pursues a spiral course around the straight central vein and pulsations in the artery were assumed to be a driving force propelling the blood in the thin wall vein, which cannot drive the blood forward by i t s e l f . Intra-osseous phlebography indicated that much of the venous drainage 31 145 leaves the long bones at the bone ends . Epiphysial ends of long bene are drained by thin-walled vessels, which are parallel to the arteries and leave the bone in very close proximity to the entering 111 arteries. In the cortical bone of human tibia , a vein accompanying a radially arranged branch of the nutrient artery has been shown to drain into the central nutrient sinus. Relative Importance of Three Arterial Systems of Long Bone 79 Johnson , by interfering with two out of the three sources of blood supply of tibi a in dog, concluded that the nutrient artery was the most important source, being responsible for the nourishment of the marrow as well as the inner half of the cortex, and was capable of maintaining the v i a b i l i t y of the entire shaft. The metaphysial arteries supported the metaphysial regions, and were capable of nourishing partly the area of nutrient artery. The periosteal arteries, being the least important supplied approximately the outer h a l f of the cortex. The r e l a t i v e importance of the nutrient a r t e r y was also demonstrated 34 by K i s t l e r , who observed necrosis of the marrow and some areas of the cortex a f t e r induction of embolism with p a r t i c u l a t e carbon i n the nutr i e n t a r t e r i a l system, by i n j e c t i n g into the femoral a r t e r y . 74 Huggins and Wiege found marrow i n f a r c t i o n following l i g a t i o n of the femoral nutrient a r t e r y i n the r a b b i t . 48 Foster, K e l l y and Watts noted, by cutting the nutrient vessels of the femur, together with s t r i p p i n g of i t s periosteum, i t was i n - v a r i a b l y followed by extensive i n f a r c t i o n of bone and of bone marrow in young, r a p i d l y growing r a b b i t s . Impairment i n the rate of cir c u m f e r e n t i a l growth accompanied c o r t i c a l i n f a r c t i o n , but no delay i n l o n g i t u d i n a l growth was found. In animals approaching maturity, the operation produces v a r i a b l e r e s u l t s . These workers also emphasized that loss of both endosteal and p e r i o s t e a l blood supply causes a complete i n f a r c t i o n of c o r t i c a l bone. If the source of e i t h e r one of these blood supplies remained, f o c i of v i a b l e cortex persisted. By measuring the intramedullary pressure of bone before and a f t e r l i g a t i o n of the nutrient a r t e r y of t i b i a and humerus i n dogs, 30 Cuthbertson, S i r i s and G i l f i l l a n found the intramedullary pressure i n these bones f e l l immediately and profoundly, but in the majority of cases, i t returned to pre-occlusion levels within hours to days. C o l l a t e r a l c i r c u l a t i o n s , both extra-osseous, and intra-osseous, were apparently responsible for the r e s t o r a t i o n of intramedullary pressure. 79 The r o l e of p e r i o s t e a l a r t e r i e s was very much disputed. Johnson 99 believed they supply the outer half of cortex. De Marneffe , as 136 cited by Shim , believed that in the rat, guinea-pig and rabbit the nutrient artery was mainly responsible for bone marrow nutrition, while the periosteal a r t e r i a l supply mainly the cortex through the 2 haversian and volkmann canals. On the other extreme, Anseroff , Brookes and Harrison MacNab ^ and McAuley believed that the periosteal a r t e r i a l supply was negligible in normal situations, and that the nutrient artery supplied the whole marrow, and the entire 96 cortex, other than the metaphyses. However, MacNab stated the v i t a l importance of periosteal system under abnormal situation, such as in a fracture, revascularisation from the periosteum help to reinstitute the endisteal circulation. 150 Trueta and Cavadias , by selective interruption of two of the three sources of blood to rabbits' radius, demonstrated that the nutrient artery is the main vessel to supply to the shaft of the radius, and is responsible for at least the irrigation of the whole of the marrow and the inner two-thirds or three-quarters of it s cortex. The periosteal vessels supplied the outer part of cortex and kept that part of the bone alive i f the nutrient circulation had been suppressed. The metaphysial vessels alone are incapable of maintaining the marrow and deep half of the cortex alive, but after their union with the epiphysial vascular network following the fusion of the growth plate, enough blood flow is provided to the nutrient artery through its d i s t i l branches to maintain the v i a b i l i t y of marrow and bone. Simple division of nutrient artery does not cause any significant effect on the v i a b i l i t y of the marrow. In the young, the compensatory circulation comes from periosteal, while i n adults from the metaphysial-epiphysial vascular network. Their findings are e s s e n t i a l l y the same as those of 79 Johnson 136 Recently, Shim, Copp and Patterson , by using a method of bone clearance of circu l a t o r y Strontium-85, studied the rates and regional distri b u t i o n s of the nutrient a r t e r i a l blood flow as well as the rates of blood supply by the other a r t e r i a l systems of the femur i n the rabbit The rate of the nutrient a r t e r i a l blood supply was studied by evaluating the rate of reduction of bone blood flow immediately after l i g a t i o n of the nutrient artery. They reported a 46% reduction of t o t a l blood supply to femur, 377o decrease i n upper epiphysial-metaphysial, and 33% decrease i n lower epiphysial-metaphysial region, and 717„ decrease i n the diaphysis, within five minutes after l i g a t i o n of the nutrient artery From these data, i t was deduced that the nutrient artery supplies about 50% of the t o t a l blood supply of the entire femur, about 707„ of t o t a l blood flow of the shaft, 377» of the t o t a l blood flow of the upper epiphysis and metaphysis and 33% of t o t a l blood flow of the lower epiphysis and metaphysis of the femur. Their quantitative study 79 corresponded with the q u a l i t a t i v e findings of Johnson (1927), Trueta and Cavadias (1964), and many others mentioned above. Nerve Supply of Bone 36 130 62 According to Drinker and Drinker , and Sherman , Gros , a French anatomist, was the f i r s t one to demonstrate the presence of a nerve, which accompanied the nutrient artery into the horse's femur and gave off twigs to the periosteum. With more refined techniques, including staining with gold chloride, osmic acid, or picrocarmine, 3a. FIGURE 4 Micrograph of transverse section of bone, with H & E s t a i n . I t sh the presence of nerve bundles, i n close proximity to the nutrient vessels of bone. 154 and then crushing small b i t s of marrow, Variot and Remy i l l u s t r a t e d nerves which varied from 10 - 100 miera i n diameter. 113 Ottolenghi described three main groups of nerve f i b r e s , within the marrow c a v i t y : 1. those which penetrate the walls of the a r t e r i o l e s and form d e l i c a t e plexiform networks between the a d v e n t i t i a and the media; 2. those which surround the c a p i l l a r i e s ; 3. those which terminate between the c e l l s of the parenchyma. The vasomotor nature of nerves of bone i s well documented „ L . 3, 36, 47, 73, 135, 161 experimentally by various authors . The presence of pain f i b r e s i s supported by the common c l i n i c a l observations that puncture of the bone marrow, many bone tumors, and osteomyelitis cause pain. The d e t a i l e d h i s t o l o g i c a l d e s c r i p t i o n as to where and how the nerve endings terminate i s l i t t l e and yet c o n f l i c t i n g i n the l i t e r a t u r e . 34 Even though De Castro claimed to have i d e n t i f i e d sympathetic nerve f i b r e s terminating i n a r i n g on the protoplasm of the osteoblasts i n 76 osteoid t i s s u e , and H u r r e l l believed that nerve f i b r e s extend 104 between bone lamellae, more recent studies by M i l l e r et a l using methylene blue immersion technique on t h i n sections of fresh under- c a l c i f i e d bone, could not substantiate such observations. The l a t t e r workers found the e p i p h y s i a l and metaphysial ends of long bones both i n small mammals and i n humans to be supplied by small myelinated and unmyelinated nerve f i b r e s from p e r i o s t e a l and j o i n t capsular tissues, and the shaft marrow by f i b r e s entering the bone through the nutrient foramen. Though i t i s believed that some nerve f i b r e s enter the bone cortex through volkmann's canals, the exact course and d i s p o s i t i o n of 10. these fibres has not been determined. Small myelinated fibres wind about the trabeculae of the spongiosa or spread out on the undersurface of the articular cartilage are demonstrated. 86 104 Kuntz and Richins and Miller observed the presence of nerve fibres in marrow parenchyma apparently not ending at blood vessels. The former group of workers, by removal of the spinal ganglia of a l l the nerves contributing to the afferent innervation of one limb three weeks previously, to insure degeneration of the afferent fibres, so that only the sympathetic fibres remained intact, demonstrated that the perivascular plexuses appear to be less abundant and less complex than in sections of the normally innervated marrow. Those nerve fibres in the parenchyma which exhibit no obvious relationship to blood vessels, apparently disappeared, together with the degeneration of the afferent nerve fibres. Sympathetic fibres were exclusively found in tissue incorporated in the vessel wall, although the afferent nerve fibres are also found in close association with the vascular structure. Various types of delicate arborizing structures suggestive of nerve endings 86 have been described . Exact role of each, however, is not completely 104 known yet Physiology of Bone Circulation Methods of Study A comprehensive and concise classification of existing methods of 137 studying of bone circulation is given by Shim 1. Quantitative Studies:- A. Direct Methods r, -. • . 31, 29 ( I ) Cannulation - collection measurement 167 ( i i ) Application of electromechanical flow meter Indirect Methods (i) Blood - tissue exchange mechanism. (a) Fick's Principle 25, 53, 132, 134 (b) Radioisotope clearance ( i i ) Indicator - dilution principle. 51 163 42 86 148 (a) Radioisotope ( Cr K Rb ) (b) Dye (Evans blue) 40 ( i i i ) Venous occlusion plethysmography Qualitative Studies:- A. Flow Pattern 14 (i) Vital microscopy 31, 145 ( i i ) Bone venography B. Selective a r t e r i a l isolation to determine relative importance of arteries (i) Destruction or occlusion of certain 48, 79, 84, 96, 136, 150 vessels (a) Study of devitalized area. (b) Effect on fracture healing or bone growth. (c) Effect on relative isotope uptake. ( i i ) Injection of indicators into an artery to 29 observe the area i t sustains C. Bone Hemodynamics (i) Direct methods (cannulation). (a) Assessment of relative flow-volume 36, 135 changes (b) Study of arteriovenous blood constituent. ( i i ) Indirect methods. 3, 67, 91, 144 (a) Intramedullary blood pressure 110 (b) Intraosseous thermometry 166 (c) Oxygen tension of bone (d) Radioisotope uptake by or clearance 88, 152 from bone Alt e r a t i o n of hemodynamics to stimulate growth, fracture repair, and bone v i t a l i t y 133, 148 ( i ) Sympathectomy 78, 82, 101 ( i i ) Arteriovenous f i s t u l a 168 ( i i i ) Periosteal stripping ,. s 168 (iv) Fracture 77, 82, 116 (v) Ligation of a major vein (vi) Artery or muscle pedicle transplantation _ . 13, 51 to bone Of a l l the currently available quantitative and q u a l i t a t i v e methods, there are advantages as well as l i m i t a t i o n s . The physiological study of bone c i r c u l a t i o n i s d i f f i c u l t due to the deep location and r i g i d structure, together with the numerous intraosseous as well as extra- osseous vessels forming complex anastomosis. The cannulation-collection method of measurement of bone blood flow, and the intramedullary pressure as an index of bone hemodynamics, w i l l be further discussed, as these two methods are used i n this study in evaluating bone c i r c u l a t i o n . The use of direct cannulation of nutrient vessels of bone as an 36 index of bone blood flow dated back to 1916, when Drinker and Drinker perfused an isolated t i b i a of dog through the nutrient artery with a 13. pump. They demonstrated the existence of vasomotor nerves to the marrow, evidenced by decreasing blood flow through the cannula following electrical stimulation of the nerve to bone marrow and injection of 37 epinephrine. In 1922, Drinker, Drinker and Lund published the results of extensive experiments using perfusion and dye injection techniques in dogs, cats, guinea-pigs, and rabbits, and confirmed their earlier work. The rate of flow of the perfusing blood from the marrow was recorded, but no attempt was made to relate this to either the weight of the tissue or i t s haemopoietic activity. 29 Cumming , assuming that the nutrient artery entering the femoral shaft supplied a l l the marrow except a very small amount in the epiphyses at either end of the bone, estimated the mean rate of blood flow through bone marrow to be 0*51 ml/g wet tissue/min. in the rabbit. He also observed a 20% increase in the rate of blood flow through the bone marrow during the period of rebreathing. Hypoxia had similar effect. Epinephrine decreased venous outflow. 135 Shim and Patterson cannulated the nutrient vessels of femur and humerus in the rabbit, and tibia in the dog. The outflowing blood through the canula was introduced to a drop counting device connected to a multiple channel electronic-mechanical recorder. They demonstrated the constancy of the bone blood flow by this method, with a standard error of less than 57„. They emphasized this method is very useful for qualitative investigations of the relative changes of the hemodynamics of bone, but not a method of measurement of the total rate of blood flow through a given bone, as i t is obvious that the measure- ment of blood flow through any one or two vessels of a bone would not give a total measurement since there are many arteries and veins other than the cannulated vessels. They demonstrated the usefulness of their method. Intramedullary Pressure 91 Larsen , in 1933, inserted a steel cannula into distal femoral metaphysis, while studying diaphyseal necrosis, and observed the intramedullary pressure to be 30 - 40 mrriHg. and showed fluctuations related to arterial pulsation. 12 Bloomenthal et a l , while studying fat embolism, observed changes in intramedullary pressure with pain stimuli, nervous stimulation, to reflexes, to changes in blood volume, and to a number of drugs. They regarded the intramedullary pressure as measured by the cannula, apparently a fusion of ar t e r i a l and venous pressure is dependent upon the influx of blood from the artery and its return through the venous drainage. 103 Miles measured pressure in the femoral heads of over thirty individuals following femoral neck fractures, and noticed fluctuation related to a r t e r i a l pulsation, and the absence of which was often followed by avascular necrosis of the femoral head. 143 Stein et a l observed the intramedullary pressure as well as pulse pressure of the diaphysis is significantly greater than the pulse pressure in the epiphysis in the same bone. 129 Shaw , used heated thermocouple to measure bone blood flow, and reported the direct relationship between intramedullary pressure and bone blood flow. The validity of using a thermocouple to measure bone blood flow i s , however, open to discussion. 15. 3 Azuma performed h i s t o l o g i c a l studies of bone used for measuring intramedullary pressure, and found that the cannula a c t u a l l y ruptured some venous sinuses, a r t e r i a l s and venules, with the tip s emerged i n an a r t i f i c i a l blood pool, and the intramedullary pressure did not appear to represent pressure of venous sinuses. This view 67 was supported by Hawk and Shim , and probably explained the wide range of intramedullary pressure recorded even i n the same bone. Hawk and Shim, by measuring bone blood flow by d i r e c t cannulation of nutri e n t vessels, and recorded intramedullary pressure i n the same bone, concluded that the intramedullary pressure i s bone blood flow dependent and r e f l e c t s well the changes i n the hemodynamics of bone. In this t h e s i s , therefore, the methods used for evaluation of bone c i r c u l a t i o n i n hemorrhagic shock are the above methods of Hawk and Shim. Rate of Bone Blood Flow The d i r e c t methods by cannulating n u t r i e n t vessels of bone are not r e l i a b l e i n measurement of absolute rate of bone blood flow as discussed 40 before. Edholm et a l applied venous occlusion plethysmography to measure bone blood flow i n Paget's disease, but the v a l i d i t y of the i r method i s very doubtful. This method, of necessity, ignores the r i c h supply of vessels, other than the main n u t r i e n t a r t e r i e s which.contribute to the c i r c u l a t i o n of 110 the long bones. Thermocouples had been used by McPh^son et a l , but th i s method only gave q u a l i t a t i v e information rather than quantitative. There are many l i m i t a t i o n s to the use of heated thermocouples to measure blood flow. The thermocouple probe can sample only a lim i t e d amount of tissue and may only r e f l e c t a purely l o c a l change i n blood flow. Presence of a 9 80 c l o t around the probe decreases i t s s e n s i t i v i t y . B i l l , as cited by Kane , pointed out "there i s no standard type of r e l a t i o n s h i p between the thermal conductivity and the flow in any tissue into which the probe is blindly introduced". 100 137 Matumoto and Mizuno , according to Shim , developed an indirect method based on clearance of a radiopaque dye; the dye is injected into bone and using a theoretical exponential correlative curve, the clearance rate is converted to blood flow of bone. The bone seeking characteristics of various isotopes of calcium A <- u « - - - , • A u i 24, 25, 53, 118, 132 and strontium have been uti l i z e d by many workers as an indicator of bone blood flow. 132 24 Shim , Copp and Shim , described a method for quantitative 3 3 method using Sr . In 10 dogs they injected a non-diffusible plasma 85 dye (T-1824) and Sr into the nutrient artery of tibia and in the next five minutes recovered 907= of the plasma dye and only 217« of the 85 * Sr from cannulated femoral vein. This indicated removal of 767> of the Sr in blood flowing through bone, compared to 907o removal of diodrast by kidney. They concluded that the i n i t i a l clearance of Sr should give a useful measure of bone blood flow and found this to be 9 - 12 mm/min/lOOgrm of fresh weight of different bones in adult 118 dogs and rabbits. Their method was considered valid by Ray , and 153, 160, 163, 164 other workers gave comparable results, with different methods and isotopes. 138 Recently Shim et al measured the bone blood flow of various bones in the lower extremity in a 26 year old man just before a high- thigh amputation for osteogenic sarcoma of d i s t i l femoral metaphysis, using ^ S r clearance technique. The estimated bone blood flow was 2*5 c.c./min./100 gr. of wet bone in human. 17. SUMMARY OF LITERATURE REVIEW ON THE RATE OF BONE BLOOD FLOW Author Edholm et a l Frederizkson et a l Copp Cumming Barnes et a l Holling et a l Shim Weiman et a l Ray Year Method 1945 Plethysmography 1955 4 5Ca 45 1957 Ca 1960 Venous Collection 1961 1963 1963 87 Sr 1961 Plethysmography 85 Sr 47 Ca 45 1964 Ca Copp and Shim 1964 8 5 S r Kane and Grim 1964 4 2K, 8 6Rb White and Stein 1965 5 1 C r RBC Copp and Shim 1965 8 5 S r 18 Van Dyke et a l 1965 F Shim et a l 1967 8 5 S r Shim et a l 85 1971 Sr Species Human Rat Dog Rabbit (marrow) Human Dog Rabbit Dog Dog Rabbit) Dog ) Dog Rabbit Rabbit and Dog Rat Dog and Rabbit Human Flow ml/min.- 100 Sr. 1- 0 10 - 30 2- 5 - 5-8 41 - 51 1- 25 5-8 - 7-7 16-0 5- 6 mature 7'7 immature 4-9 mature 6- 5 immature 9 - 1 2 12 16 10 10 13-2/12-5 2- 43 18. Rate of E n t i r e S k e l e t a l Blood Flow With the a p p l i c a t i o n of i n d i r e c t method of bone clearance of a c i r c u l a t i n g bone seeking radioisotope, and assuming the t o t a l s k e l e t a l weight to be a percentage of t o t a l body weight (15% in 138 human ), the s k e l e t a l blood flow estimated as percentage of 138 r e s t i n g cardiac output i s summarised in the following table: Author Van Dyke et a l Shim, Copp and Patterson Shim, Copp and Patterson Ray, Aovadrand Galante Weinman et a l Shim et a l Species Rat Rabbit Dog Dog Dog - mature - puppy Man Percentage of Resting Cardiac Output 4- 3 7'1 + 2-3 7- 3 +3-0 3- 5 - 9-4 5- 0 - 7-0 8- 0 - 10-0 4- 7 - 6-3 The Regulation Mechanisms of Bone Blood Flow Although not completely understood, there i s accumulating evidence that bone blood c i r c u l a t i o n i s co n t r o l l e d by neural, hormonal as well as metabolic mechanisms. Evidence for a Neural Control Mechanism The presence of nerves i n bone have been demonstrated by many 62, 113, 130, 154 workers recognised , and t h e i r vasomotor nature i s also well 3, 36, 47, 73, 135, 161 36 Drinker and Drinker , by cannulation of the nutrient a r t e r y of the i s o l a t e d t i b i a of the dog, demonstrated decrease of blood outflow from the bone when the nerve f i b r e s to the bone were stimulated e l e c t r i c a l l y . 19. Sympathetic nerve trunk stimulation in the rabbit by Shim and 135 161 Patterson had similar effect. Weiss and Root stimulated the peripheral end of the cut sciatic nerve and observed reduced marrow 3 pressure in the tibia in five cats. Azuma made similar observations in the rabbit. 42 86 Using radioactive K and Rb to estimate bone blood flow by 148 fractional distribution of radioactive isotopes, Trotman and Kelly demonstrated a 27% increase in blood flow to the tibia in the anaesthetised dog following lumbar sympathectomy. Effect, however, disappeared completely nine x<?eeks later. 133 85 Shim et a l , using Sr clearance method, demonstrated the rate of bone blood flow in the side of sciatic nerve section was generally increased by five to forty-five percent in the tibi a , fibula, talus and calcaneus. A l l the above direct and indirect methods are suggestive of a neural mechanism of control in bone circulation. Evidence for a Hormonal Control Mechanism 36 Drinker and Drinker observed decrease bone blood outflow in the 12 dog's isolated tib i a when epinephrine was perfused. Bloomenthal , 144 129 67 3 Stein , Shaw , Hawk and Shim , and Azuma , also observed a f a l l in the intramedullary pressure of bone following the administration 144 of epinephrine and norepinephrine in experimental animals. Stein 131 and Shim observed a decrease in, or arrest of, bone bleeding following epinephrine infusion in the dog. 29 132 Quantitative estimation by Cumming , Shim in the rabbit, and 166 Woodhouse in the dog showed epinephrine reduced bone blood flow. 13 2 Shim showed with 2 - 4 microgram/kg/min of intravenous epinephrine infusion, blood flow to t i b i a and humerus was reduced by 74 - 81%. Evidence for a Metabolic Control Mechanism There i s strong evidence that bone blood flow i s controlled by metabolic factors such as acid metabolites, pH and oxygen and carbon dioxide both at systemic and l o c a l l e v e l s . Thus with rebreathing of expired a i r , or a gas mixture low i n oxygen and high i n carbon dioxide, 29 135 Cumming , Shim and Patterson , were able to demonstrate an increase of blood outflow through the nutrient vein i n rabbits. Intravenous or i n t r a - a r t e r i a l i n j e c t i o n of /15 l a c t i c acid, resulted in an increase of nutrient a r t e r i a l outflow, measured with electro- magnetic flowmeter by Woodhouse . Reactive hyperemia of bone after femoral a r t e r i a l occlusion was unabolished by e l e c t r i c a l stimulation of nerve, or exogenous vasopressor drugs, was also reported by Shim and Patterson *35_ Their observations suggest that the metabolic control mechanism maybe the most potent of the three control mechanisms mentioned above. SHOCK Defi n i t i o n I t i s very frustrating to admit a subject so intensively studied as shock has no universally acknowledged d e f i n i t i o n . Sometimes the use of the term "shock" has been c r i t i c i z e d because of i t s lack of s p e c i f i c i t y . The work has been used i n a number of different senses - for example, as a c l i n i c a l description - by Cannon or Weil . The l a t t e r referred to shock as a descriptive term used by c l i n i c i a n s to 21. denote a syndrome characterized by prostration and hypotension, and usually is accompanied by pallor, coldness and moistness of the skin, and collapse of, superficial veins, alteration of mental status, and suppression of formation of urine. The term "shock" has also been used as a description of some 119 underlying disturbance - for example, Blalock, as cited by Reeves , defined shock as "peripheral circulatory failure". It has also been used as the causation of some underlying disturbance - for example, hemorrhagic shock, anaphyllactic shock and endotoxin shock, etc., attempting to relate the cause to the condition. Confusion has thus arisen, in that the word shock has been used in a single and consistent sense, but the definition is so loose as to lack c l a r i t y . Perhaps "shock" is no more exact than "fever", but i t describes a group of c l i n i c a l symptoms which require immediate attention in order to improve blood flow. The common thread in a l l form of shock is an inadequate circulation with diminished blood flow to tissue, resulting in c e l l hypoxia and i t s seguelae ^. Hardaway ^ 4 defined shock as "inadequate capillary perfusion due to any of many causes", and is probably the most accepted one at present time, as i t describes the final common pathway of the shock syndrome. No arbitrary limit or single parameter, either c l i n i c a l , physiological or laboratory, used alone, is adequate to define shock. Where is the line of demarcation between "Hypotension" and "Hemorrhagic shock", or "Toxaemia" and "Endotoxin shock"? "Shock" w i l l remain a useful term, provided we regard i t as a 22. generic one and use i t to define a group or class of conditions having 142 a basic similarity, but differing in important details . Perhaps 20 we can be comforted by the philosophical approach of Cannon (1923), "It seems to me that, in such a complex as shock, definition is not a prime requisite. The important matter is to obtain a careful description of the observed facts". Historical Aspect The c l i n i c a l syndrome, which we c a l l shock, has been given a variety of names, without knowing what exactly i t means. According to Simone , this corresponds to the Latin word "conlapsus", used by a Iloman playwright two thousand years ago, with reference, to illness in Conlapsa membra, when Dido, Queen of Carthage, whose love had been thwarted by Aeneas, f e l l as i f l i f e l e s s . The present day medical concept of shock was brought into light by 106 Morris , who offered the following terms for the word shock: Sudden v i t a l depression, great venous depression, fi n a l sinking of v i t a l i t y , nervous shock, and violent mental emotion". He attempted to classify shock into those following surgical operations and injuries, and shock arising from mental causes. Gross, according to Simone described shock as "a rude unhinging machinery of l i f e " , as perhaps the most sagacious definition at that time. In the remainder of the 19th century, the term "shock" was used very loosely. Pain and mental agitation were regarded upon the primary aetiology of shock. 28 Crile initiated experimental studies in animals in 1899. He 23. demonstrated that the heart i s capable of pumping blood supplied to i t , and implicated that dysfunction of the vasomotor centre and the peripheral c i r c u l a t i o n are the possible p h y s i o l o g i c a l explanations in shock. 68 Henderson i n 1910 pointed out the important r e l a t i o n s h i p between venous return, cardiac output and a r t e r i a l pressure. 165 Wiggers 1 renowned monograph: Physiology of Shock, published i n 1950, remained the major reference to the accomplishments of that era. The experimental model of hemorrhagic shock he designed, i s s t i l l a c l a s s i c a l model i n laboratory study of shock. Associated with each major war or c o n f l i c t there was usually more incentive to better care, together with enthusiasm on experimental 7 studies. During World War I, B a y l i s s and Cannon studied the e f f e c t of wound shock following l a c e r a t i o n and crushing of muscle i n experimental animals. The systemic e f f e c t s of these i n j u r i e s were a t t r i b u t e d to the c i r c u l a t i o n of tissue breakdown, without appropriate attention to importance of f l u i d loss and i n f e c t i o n . 83 Keith developed the method of measuring blood volume by dye d i l u t i o n technique and began to r e a l i s e the volume depletion i n wound shock. The i n t e r e s t i n studying shock probably declined in between the world wars. The r o l e of l o c a l tissue f l u i d losses into l o c a l areas of traumatic i n j u r y was r e a l i s e d by Blalock The possible functional 147 d e f i c i e n c y of the adrenal cortex i n shock was investigated. During the Second World War, there was renewed interest, with emphasis on the importance of volume depletion, infection and renal failure. Shock was explained more in hemodynamic terms, such as blood flow, resistance and effectiveness of perfusion. With the application 27 of cardiac catheterisation, Cournand confirmed a reduction in cardiac output in relation to fl u i d loss in patients, and thus opened a new era for investigation of shock. After the Second World War, studies began to focus on evaluation of blood flow and the functional integrity of various systems and organs. The blood supply, mechanism of control of regional circulation, including cerebral, pulmonary, hepatic, renal have been extensively studied. Hole of micro circulation, association with slugging, or embolic occlusion was also brought into notice. In the Korean conflict, the syndrome of oliguric renal failure following shock, was a major cause of death. In the recent Vietnam conflict, improved therapeutic measures made i t possible to maintain l i f e inconsistent x^ith survival only a decade ago. Also with improved diagnostic tools, i t became possible to demonstrate respiratory and circulatory function better than ever before. A new syndrome, referred to at various times as the shock lung, non-infectious congestive atelectasis, the adult equivalent of the respiratory distress syndrome of the newborn, the pulmonary equivalent of acute tubular necrosis, or post traumatic lung, was brought into focus The changes in the subcellular level, such as alterations of 35, 102 8 mitochondria , lysosomal disruption , nuclear ribonucleic 92 a c i d synthesis of various organs i n shock, are current topics of medical research. Abnormal Ph y s i o l o g i c a l Aspects of Shock Hemorrhagic shock i s the experimental model used i n t h i s study, therefore our discussion w i l l be mostly on this type of shock. The abnormal changes i n shock are innumerable, but we w i l l attempt to discuss them under: A. Neural Aspects B. Hormonal Aspects C. Metabolic Aspects Knowing that control of bone blood c i r c u l a t i o n i s b a s i c a l l y related with neural, hormonal and metabolic mechanisms, we hope to co r r e l a t e the abnormal p h y s i o l o g i c a l aspects i n shock, with the changes in bone blood c i r c u l a t i o n i n shock. Neural Aspects In hemorrhagic shock, hypovolemia, or decreased e f f e c t i v e c i r c u l a t i n g blood volume stimulate the autonomic nervous system. Hypovolemia could be due to external or i n t e r n a l hemorrhage or sequestration of f l u i d or vascular pooling. Venous return to the heart i s decreased, followed by decrease i n cardiac output with decreased a r t e r i a l blood pressure which stimulate baroreceptors and increase heart rate and force of contraction. Thus the sympathetic nervous system i s alarmed. Blood flow to the skin, s k e l e t a l muscles, kidneys and splanchnic bed i s economized by both a r t e r i a l and venous vasoconstriction i n order to r e d i s t r i b u t e blood to more v i t a l organs, p a r t i c u l a r l y the heart and brain. It is generally accepted that as blood is lost, the cardiovascular system adjusts to accommodate the smaller volume and that, i n i t i a l l y , this adjustment is mediated by the vasomotor nerve aided along by an increase of plasma level of catecholamines, resulting in increase 115 114 vasomotor tone . Page and Abell studied the caliber of blood vessels through micro windows placed in rabbits' ears and in the mesentery. Vasoconstriction was shown regularly in early stages of shock by various means. Moderate vasodilation only occurs shortly 55 before death. Gernandt demonstrated efferent impulses in the splanchnic nerve of cats increased markedly when the animals were bled just as they did during asphyxia. Denervation eliminates this response 90 Landgren demonstrated a heavy chemoreceptor discharge due to stagnant hypoxia, and that after hemorrhage, a further drop of ar t e r i a l pressure with sectioning of the sinus nerves. Hormonal Aspects Hormones are biologically active substances discharged by glandular tissues into the circulation and are transported to tissues where they regulate the rates of important metabolic processes. The hormones are structurally polypeptides, aromatic amides, or steroids. Catecholamines The 'resting secretion' of adrenal medulla of dogs, under anaesthesia, recovered from anaesthesia and twenty-four hours later, 155 was estimated by Walker et al , by cannulation of adrenal vein and collecting the adrenal venous blood. Catecholamines were measured by photofluorometric method. The level in dogs twenty-four hours after operation, more likely to represent values to be expected in the normal intact dogs, are in the order of 0*001 ug/kg/min. Immobilization 27. alone has very l i t t l e effect on secretion, though the output was increased, when complicated by excitement and struggling, or when pain or discomfort was involved. Barbiturate anaesthesia lowered catecholamines secretion. Tissue trauma,including fracture of the long bones, increases secretion of the catecholamines. Blood loss produced an immediate and marked increase in concentration of catecholamines in the adrenal vein blood. The increase was due primarily and i n i t i a l l y to an increase in concentration rather than norepinephrine in the adrenal venous blood. Early retransfusion of the lost blood or blood substitute immediately and drastically reduced 156 the catecholamines output . When 1/4 to 1/3 of blood volume was depleted, the output of epinephrine was 0*14 - 0*88 ug/kg/min and norepinephrine was 0"04 - 0*12 ug/kg/min . Other workers ^ reported that with 1/3 of the total blood volume decrease, the average concentration of epinephrine increased from 1-0 to 7*8 ug/litre of plasma, and norepinephrine increased from 2*5 to 3*6 ^ig/litre of plasma. Adrenal Corticosteroid Secretion Graded hemorrhage resulted in depletion of adrenal ascorbic acid in rats, suggestive of corticoid steroid secretion from adrenal may 95 52, 54, 75 have occurred . Many workers reported hemorrhage accompanied by moderate a r t e r i a l hypotension have resulted in increased secretion of 17- Hydroxycorticosteroid. Some workers ^ ' reported secretion of corticoid steroid unchanged or decreased. Such 50, 157 discrepancy is explained by the fact that the latter group of workers subjected the animals to a profound degree of hypotension, with very marked decrease of adrenal blood flow. The calculated secretion rate is lowered even though there is increase of steroids in adrenal venous 157 75 blood . Hume and Nelson showed that the adrenal cortex i s capable of maintaining high levels of c o r t i c o i d secretion even i n severe shock, i n spite of market reduced adrenal blood flow, but when the mean s y s t o l i c blood pressure i s reduced below 35 mmHg, the adrenal blood flow may become so low that the minute co r t i c o i d output i s reduced. Reinfusion of lost blood resulted i n rapid return of 54, 75 secretion of c o r t i c o i d steroids to control levels ' . Herman et a l suggested shunting of blood from the adrenal cortex d i r e c t l y to the adrenal medulla, and thus accentuate the already poor c o r t i c a l perfusion. Their study suggested that a flow of greater than 1 ml/min allows adequate perfusion of the adrenal cortex to prevent such shunting 97 and to protect against functional damage. Mack et a l suggested that the s e n s i t i v i t y of the adrenal cortex to adrenocorticotropic hormone i n hemorrhagic shock was not altered, based on their studies in hypophysectomised dogs, given exogenous ACTH, and then subjected to hemorrhage. In such hypophysectomised animals, there was a decrease of adrenal corticosteroid secretions, which could be restored to normal levels with systemic or l o c a l infusion of saline into lumboadrenal artery. From such studies, i t would appear the i n t e g r i t y of the hypothalamus, with intact ACTH secretion, i s important for the increase of corticosteroid secretion in shock. Aldosterone Aldosterone acts primarily on the transport of sodium i n c e l l s of the renal tubules and sweat glands. Sodium reabsorption i s increased with an exchange of potassium for sodium i n the d i s t a l tubules. Sodium i s retained and potassium secretion i n urine i s increased. This hormone in fact regulates cardiac output by increasing the end d i a s t o l i c volume and consequently the stroke volume. In a d d i t i o n , aldosterone potentiates the vasoconstrictor a c t i v i t y of norepinephrine and increases peripheral resistance. Increase of aldosterone output in dogs and man 44, 46 in acute hemorrhage have been demonstrated . Mulrow and 107 Ganong confirmed t h i s , and demonstrated in hypophysectomised dogs, a mechanism independent of the p i t u i t a r y stimulation i s present in aldosterone secretion in hemorrhage. Angiotensin Angiotensin, secreted in response to release of renin from the juxta- glomerular c e l l s of the kidneys, produces increased aldosterone secretion. A n t i d i u r e t i c hormone, released by posterior p i t u i t a r y , reabsorbs water in :' excess of solute by d i s t i l convoluted tubules. The secretions of both hormones in shock are believed to be increased ^' . 6, 159 Metabolic Aspects There i s a general pattern of metabolic changes, involving almost a l l metabolites so far studied, c h a r a c t e r i s t i c of the shock syndrome, but not s p e c i f i c to i t . In recent years the biochemical a l t e r a t i o n s that occur as shock progresses, are often ascribed to hypoxia, r e s u l t i n g from decrease and inadequate tissue perfusion. C e l l hypoxia, decreased aerobic oxidation through the Kreb's t r i c a r b o x y l i c acid cycle and the e l e c t r transport system and an increase i n anaerobic g l y c o l y s i s by the Embden - Meyerhoff pathway, i s observed. Lactate and pyruvate both increase i n i t i a l l y , but l a t e r lactate increases more than pyruvate. Increased acid metabolites produce metabolic a c i d o s i s . Blood pH and carbon dioxide CO content f a l l and p 2 may be decreased by pulmonary v e n t i l a t i o n . Later, in more profound shock, decrease in pulmonary function may r e s u l t in r e s p i r a t o r y a c i d o s i s , superimposed on a metabolic a c i d o s i s . Early development of azotemia r e f l e c t s an increased metabolic turnover of certain tissue proteins with an increased tissue breakdown, and a decrease i n urine output. F a l l i n serum sodium chloride, a r i s e i n serum potassium, and a reduced urinary excretion of sodium, chloride and water are chara c t e r i s t i c . Regional C i r c u l a t i o n i n Shock Total Peripheral Resistance Total peripheral resistance = Mean A r t e r i a l Pressure Cardiac Output 49 Fowler and Franch showed questionable decrease of total peripheral resistance, by bleeding dogs at 50 ml/min. to systemic blood pressure of 35 mmHg. and measuring cardiac output by Fick's P r i n c i p l e . Reynell 120 et a l , however, showed the to t a l peripheral resistance increased by 165 190%. V a r i a b i l i t y of findings was noted by Wiggers Coronary Circulation The coronary flow i n humans may be estimated with reasonable accuracy 10, 38, 60, 122 by the use of nitrous oxide inhalation method Application of Fick's P r i n c i p l e with radioisotopes such as or R b ^ uptake by myocardium i s another method of accuracy. Standardised oligemic shock i n dogs i s characterised during the hypotensive phase by a decrease i n cardiac output, systemic blood pressure, stroke volume, and by an increase i n heart rate. Coronary flow and coronary resistance are greatly decreased, though the coronary 42 flow f r a c t i o n of cardiac output i s increased . Coronary flow i s generally greater, and the resistance generally less than can be 112 accounted f o r , by a simple decline i n a r t e r i a l blood pressure With the use of electromagnetic flowmeters which were chronically 31. implanted on the l e f t coronary artery as well as the aorta and 61 various systemic arteries , the experiments confirmed previous findings - the coronary circulation shows a decreased vascular resistance during hemorrhagic shock. Cerebral Circulation in Shock 146 Stone et al measured cerebral blood flow in volunteers subjected to hemorrhage, using nitrous oxide method. Hemorrhage of 20 - 387. of blood volume, resulted in decrease of cerebral blood flow, but cerebral vascular resistance also decreased. Hyperventilation led to respiratory alkalosis, decrease in arterial C02 and cerebral vasoconstriction. Intravenous morphia improved cerebral blood flow, by depressing respiratory and restored Co^ tension to normal levels. 45 Fazekas et al found the cerebral vascular resistance was not 123 significantly altered in patients in shock . Rutherford et al , with the use of labelled microspheres, demonstrated a 567. decrease of cerebral vascular resistance in early shock, and a 167. increase in 2 (3 late shock. Corday and Williams ,with photoelectric dropmeter in dogs, demonstrated an increase of cerebral vascular resistance as blood pressure was lowered. The considerable differences of opinion in the literature are probably due to difference in techniques employed, and partly reflect the variations in the experimental conditions and 26 different species of test animals Renal Circulation in Shock Renal blood flow estimated by PAH clearances differed from those 124, 126 obtained by a direct method . In dogs bleeding to drop the arterial blood pressure to 60 mmHg. direct renal flow measurement was 417, of control, while clearance was zero, because of anuria 32. present at this l e v e l of blood pressure. Direct measurement by 124 Selkurt suggested that the reduction i n renal blood flow i n a graded hemorrhage was greater than produced by reduced head of a r t e r i a l pressure, which also suggests that active v a s o constriction 26 has occurred. Results of Corday and Williams also demonstrated 59 marked increase of renal resistance i n shock. Green and Kepchar stated that blood i s shunted away from the kidneys more than any other organs i n shock. The kidneys are highly reactive and also 123 normally receive a high share (20%) of cardiac output. Rutherford demonstrated minimal change of vascular resistance i n early stages of shock, and an 80% increase i n l a t e hemorrhagic shock i n dogs. 125 Selkurt plotted the response of blood flow to progressive decrement of e f f e c t i v e perfusion pressure by lowering the a r t e r i a l pressure applying a o r t i c compression, i n a study of "pressure-flow" r e l a t i o n s h i p . This was concave to the pressure axis i n a range of 14 to 117 mmHg.. Results were e s s e n t i a l l y the same i n the i n t a c t as i n the denervated kidney. Hemorrhage appeared to abolish the concavity of the pressure flow r e l a t i o n s h i p . This suggests that the renal hemodynamic i s l a r g e l y c o n t r o l l e d by c i r c u l a t i n g blood volume and humoral factors rather than by neural mechanism. Splanchnic C i r c u l a t i o n i n Shock Considerable controversy e x i s t s i n the l i t e r a t u r e on this subject. Using B r i s t l e flowmeter i n a standardised hemorrhagic shock, Selkurt 127 et a l observed that the splanchnic vascular resistance did not increase s i g n i f i c a n t l y during hypotension, and that following transfusion, there was a phase of marked reduction, p a r t i c u l a r l y i n 94 the mesenteric component. Levy demonstrated no increase of splanchnic resistance during hemorrhage, though i n f u s i o n of norepinephrine during hemorrhage resulted i n double the resistance. 69 Henly et a l , with radioisotope technique, demonstrated a 38»47o decrease i n p o r t a l blood flow i n Wiggers' graduated hemorrhage. 120 Reynell et a l reported that, a f t e r an acute hemorrhage, splanchnic blood flow decreased i n proportion to cardiac output, and that splanchnic vascular resistance rose only 24% above c o n t r o l , whereas the t o t a l peripheral resistance rose 90% above co n t r o l . 123 Rutherford et a l , with l a b e l l e d microsphere, demonstrated a marked increase of splanchnic (portal vein) resistance, though the hepatic ( a r t e r i a l ) resistance a c t u a l l y decreased. Skin and Muscle C i r c u l a t i o n i n Shock 57 Green, Cosby and Lewis reported skin c i r c u l a t i o n decreased before a r t e r i a l pressure changed, and skin blood flow stopped when a o r t i c mean pressure f e l l to 60 - 80 mmHg. The increase of skin vascular resistance i s due p a r t i a l l y to augmented sympathetic discharge. However, under s i m i l a r experimental conditions, the muscle a r t e r y lumen was often d i l a t e d . Information about muscle 32, 33 c i r c u l a t i o n i n shock i s fragmentary. Dale and Richards showed small doses of epinephrine caused v a s o d i l a t i o n i n the denervated muscles of the cat's hind limb. The a c t i o n of epinephrine 19 i n a piece of smooth muscle can be biphasic . I t i s probable that both v a s o d i l a t i o n and vasoconstriction phases of the. i n i t i a l transient v a s o d i l a t i o n are due to a d i r e c t biphasic a c t i o n of epinephrine on the smooth muscle coat of the a r t e r i o l e of the s k e l e t a l muscle. Vaso- d i l a t i o n i n v a r i a b l y comes before vasoconstriction, and i n any given i n f u s i o n of epinephrine, the degrees of the v a s o d i l a t i o n and vaso- constriction are usually equal. Norepinephrine given intra- a r t e r i a l l y , in animals or man, constricts muscle vessels in a l l 162 effective doses . If i t is given intravenously in animals, the constrictor action may be overcome by use of systemic blood 23 pressure , or by reflex vasodilation of the sympathetic nerve 5 origin . In skin circulation, both epinephrine and norepinephrine given subcutaneously or by slow intravenous infusion, caused severe 5 , 41 blood flow reduction ' . It is reasonable to assume that skin circulation and muscle circulation may behave differently in shock. 123 Rutherford et al , with labelled microsphere, demonstrated that vascular resistance of lower extremity markedly increased in shock, with 186% and 108% in early and late stages qf shock respectively. This, however, would represent the overall change in vascular resis- tance in the skin, muscle and bone in the lower extremity. To sum up, there is evidence that various organs' vascular beds behave distinctly different in shock, and neurohormonal and metabolic factors play important roles. Much controversy s t i l l exists, though i t is generally agreed that blood is shunted in shock to the myocardium and brain from other regions such as kidneys, skin and splanchnic circuits. MATERIALS AND METHODS General Set Up (Figure 5) 35 male mongrel dogs weighing 8 - 3 3 kilograms were used in this study. Sodium pentobarbitol (nembutal) 30 mg/kg was given intra- venously for anaesthesia. The animals were a l l intubated but allowed to breath spontaneously. Heparin 300 l.U/kg was given, and 34a. FIGURE 5 General Set up i n Experiment. The dog was under nembutal anaesthesia. The right brachial artery was cannulated to measure systemic blood pressure, T i b i a l nutrient artery or vein was cannulated to measure bone blood flow. Cannula inserted into the t i b i a to measure the intramedullary pressure of bone. Results were recorded in the multichannel Physiograph. The right common carotid artery was cannulated and connected to the "Bleeding Reservoir". repeated every two to three hours. The extremities, anterior chest, and the abdomen were shaved. The right brachial artery was cannulated with a large polyethylene tube and connected to a pressure transducer, and the blood pressure was continuously recorded in the multi-channel physiograph. The right external jugular vein was cannulated to monitor the central venous pressure continuously. The right common carotid artery was also cannulated with a polyethylene tube and was connected to the bleeding reservoir. (Figure 6). It has a two-litre plastic bag, containing 200 nl heparinised saline, and connected to the venous system via rubber tubing with a three-way tap. The plastic bag is placed in a water-cylinder and any inflow of blood into the plastic bag w i l l displace water in the cylinder and amount of water displacement is recorded in another graduated cylinder. Thus the amount of bleeding volume can be read in this graduated cylinder. The hydrostatic pressure in the plastic bag is controlled by the level of water in the graduated cylinder. Three electrodes, the level of which are adjustable, are so designed that their tips just dip into the water in the graduated cylinder, and any further changes in level of water w i l l result in automatic adjustment of the water height of the graduated cylinder by an electric motor. Sodium n i t r i t e is added to saturate the water in the graduated cylinder, for f a c i l i t a t i o n of conduction of e l e c t r i c i t y in the solution. With this apparatus the animals can be bled to a predetermined level of blood pressure, and a r t i f i c i a l l y maintained at such level for a considerable time. Intravenous medications and fl u i d replacement were given via lef t forearm vein. During surgical procedure, slow l.V. saline and Dextran replacement were given to maintain a constant central venous pressure. FIGURE 6 The "Bleddin^ Reservoir" used i n Experiment. Blood volume lost was measured by changes i n the volume i n the graduated cylinder. The l e v e l of systemic blood pressure i n the animal was controlled by the height of the electrodes. The height of the graduated cylinder was continously adjusted by an e l e c t r i c motor, to maintain the tips of the electrodes just emerged into the sodium n i t r i t e solution i n the graduated cylinder. 36. Study of Bone Blood Flow The bone blood flow was studied by cannulating the t i b i a l nutrient 135 vessels, as described by Shim and Patterson . Skin incision extended from three inches below the knee to two inches above the ankle in the anterolateral aspect of leg was made. The interval between t i b i a l i s anterior muscle and the anterolateral surface of the shaft was held open by a self-retaining retractor. The nutrient artery usually arises from the anterior t i b i a l artery above the middle of the shaft of t i b i a . The nutrient vein can usually be found in the same area. Muscular branches of the anterior t i b i a l vessels were a l l ligated, and the main vessel was then cannulated with a polyethylene catheter (PE 50 to 90). Thus the nutrient a r t e r i a l or venous outflow of the tibia was then measured by a drop counting device, and continuously recorded in the physiograph. Bone Marrow Cavity Pressure The subcutaneous anteromedial surface of the tibia was chosen for insertion of cannula. A steel d r i l l , with a diameter of 0*093 in, was inserted from this anteromedial surface near the diaphysis, followed by a No. 13 gauge steel cannula inserted into the medullary cavity. The cannula was connected to a pressure transducer with a polyethylene tube f i l l e d with heparinised saline. The pressure was continuously recorded in the physiograph. It is important to prevent any gas bubble in the tubings, in order to have sensitive recording. Transperitoneal Lumbar Sympathectomy In five dogs, the right lumbar sympathetic trunk was identified via a midline incision, with transperitoneal approach. Electrical stimulation with voltage 12, and frequency 200/sec, was applied in each case to 37. confirm the anatomy, by observation of the e f f e c t of e l e c t r i c a l stimulation on the bone c i r c u l a t i o n of the i p s i l a t e r a l t i b i a . In these f i v e dogs , b i l a t e r a l cannulation of t i b i a l n u t r i e n t vessels was ca r r i e d out, and subsequently subjected to the shock procedure to observe the e f f e c t of sympathectomy. 22, 56 Use of Dibenzyline (Phenoxybenzamine) This alpha-receptor blocking agent, was given i n four dogs, i n t r a - venously at a dosage of 2 mg/kg over a period of at l e a s t one hour. The alpha-receptor blocking e f f e c t was tested by epinephrine i n f u s i o n , at a dosage of 0>3 - 1 ug/kg/min, and by lumbar sympathetic chain e l e c t r i c stimulation i n each animal before the animal was subjected to hemorrhagic shock. Induction and Sustaining of Hemorrhagic Shock Prior to shocking the animals, the systemic blood pressure, pulse r a t e , r e s p i r a t o r y rate, central venous pressure, bone blood flow as measured by number of drops per unit time, and intramedullary pressure were a l l recorded. They served as the control values. Induction of hemorrhage was done by bleeding che animals into the r e s e r v o i r , adjusted to about 25 - 5- ml/min., and to one t h i r d of estimated blood volume, 169 estimated as 87« of the t o t a l body weight of the. i n d i v i d u a l animals A l l the parameters recorded i n the control phase were repeatedly recorded at this stage of experimentation. A f t e r one t h i r d of blood volume was bled, the systemic blood pressure dropped s i g n i f i c a n t l y . At this stage, further bleeding was inducted, and the l e v e l s of the electrodes i n the bleeding reservoir were adjusted to lower the systemic blood pressure step by step, 10 - 15 mmHg. each time. 38. Eventually, the systemic blood pressure was lowered and maintained at about 30 - 35 mmHg., u n t i l the animal died. RESULTS I Acute Hemorrhage (Figure 7) When the dogs were bled at a rate of 25 - 50 ml/min., there was a gradual f a l l of the systemic blood pressure and corresponding decrease i n bone blood flow. The central venous pressure also gradually f e l l and so did the intramedullary pressure. I I Effect of One Third of Estimated Blood Volume Loss (Figure 8) Control One Third Blood Volume Loss Systemic B.P. 100/!, 55-2 + 5-1% standard error (150.5 + 5.8 (range 30 - 80%) mmHg.) standard error Bone Blood Flow 100% 22'5 + 3-4% standard error (range 8 - 45%) Intramedullary Pressure 55 + 8-2 mmHg. Not recordable (25 - 130 mmHg.) Pulse Rate 88 + 9'6/min. 112 + 10-2min. standard error standard error Respiratory Rate 3-8 + 1-2/min. 8*2 + 1-5/min. standard error standard error Central Venous Pressure 4-2 + 0-8 cm - 1-2 + 0-3 cm H„0 standard error H20 (range - 3 to + I cm H 20) standard error I I I Effect of Prolonged Hemorrhage In a l l dogs, the systemic blood pressure was brought down stepwise by 10 - 15 mmHg., and kept steady for \ - h hour, and eventually maintained around 30 - 35 mmHg., u n t i l eventually a l l the animals exsanguinated. The duration of experiment varied from four hours to eighteen hours. During this time, bone blood flow remained decreased and the intramedullary FIGURE 7 38a. DOG #12a Induction of Hemorragic Shock B.P. a. a. TIBIAL IMP BONE BLOOD FLOW (Tibial Nutrient Arterial Retrograde Flow) Hemorrage beginsj Time (5 second intervals) The Induction of Hemorrhagic Shock. Note the f a l l of systemic blood pressure, gradual decline in central venous pressure, t i b i a l intramedullary pressure and t i b i a l nutrient ar t e r i a l retrograde flow, which was measured by a mechanical dropmeter. Each vertical stroke represents one drop of blood. FIGURE 8 DOG # 1 2 b Hemorragic Shock [Vz blood volume loss) £ 5 0 - O CN Of 2 E o. 05 X E E B. P. C. V.P. TIBIAL IMP 2 0 - 1 0 - 0 - BONE BLOOD (Tibial Nutrient Arterial Retrograde Flow) The Effects of Acute Blood Loss with one th i r d of estimated blood volume removed. Note the f a l l of systemic blood pressure and central venous pressure. The t i b i a l intramedullary pressure f e l l to unrecordable level,. Bone blood flow, measured by t i b i a l nutrient a r t e r i a l retrograde flow, also decreased. 39. pressure of bone f e l l to unrecordable level. IV Effect of Re-infusion of Lost Blood (Figure 9) When lost blood was re-infused into the dogs, fifteen minutes to six hours after induction of hemorrhage, at a rate of about 50 - 100 ml/ min., the systemic blood pressure, central venous pressure, t i b i a l intramedullary pressure and bone blood flow were ful l y or partially returned to control values. The longer the duration in which the animal was in shock, the less complete was the recovery observed. V Relationship between Bone Blood Flow and Systemic Arterial Pressure (Figure 10) In ten dogs, the percentage f a l l of systemic blood pressure was plotted against the percentage decrease of bone blood flow. The curve is not a straight line, but rather an exponential one with concavity towards the flow axis. The curve intercepts the pressure axis at 157o. VI Effect of El e c t r i c a l Stimulation of Lumbar Sympathetic Chain (Figure 11) Right lumbar sympathetic chain of five dogs was identified, and electrical stimulation with voltage of 12v, and frequency of 200 per second was applied in each. An abrupt and immediate drop of t i b i a l intramedullary pressure of the same side, coupled with decrease of bone blood flow were observed repeatedly in a l l five dogs. VII Effect of Lumbar Sympathectomy A. Before Induction of Hemorrhagic Shock (Figure 12) Sympathectomy of right lumbar trunk was performed in five dogs, in which bilateral cannulation of nutrient vessels was carried out. During the surgical procedure, compression of the inferior vena cava caused a rise of intramedullary pressure of both le f t and right ti b i a , FIGURE 9 150-i 100- 50-1 DOG #12c Recovery Stage of Hemorragic Shock by Transfusion of Lost Blood C.v.p. 0 10- 1 4- CO x TIBIAL IMP 203 10J BONE BLOOD FLOW (Tibial Nutrient Arterial Retrograde Flow) l l i I I I i I i i i i j | ! i ! | | i — r Re-i nfusion i Time (5 second intervals) The Effects of Re--infusion of Lost Blood, 6 hours after hemorrhag shock. Note the recovery of systemic blood pressure, central venous pressure, t i b i a l intramedullary pressure, and bone blood flow. 39b. FIGURE 1 0 Graph to Shov the Percentage Changes of Bone Blood Flow, with respect to percentage changes in systemic blood pressure in hemorrhagic shock. FIGURE 11 DOG #25 SYSTEMIC B.P 3CH TIBIAL NUTRIENT VENOUS OUTFLOW Illllllliiiilium i i m i ' . n i i i U K i ' i i i i u u t m u i i i i \ i i i i u u i \ 11 i H i i u \ \ i n 111 on • f t off Time (5 second intervals) Electrical Stimulation of Lumbar SYMPATHETIC CHAIN Volts 12 2.0 MsD Freq. 200 The Effects of E l e c t r i c a l Stimulation of Lumbar Sympathetic Chain. An abrupt decrease of t i b i a l intramedullary pressure, and t i b i a l nutrient venous outflow were demonstrated. FIGURE 12 39d. DOG #27 SYSTEMIC B.P. 704 RIGHT TIBIAL NUTRIENT VEINOUS OUTFLOW EFFECT OF SYMPATHECTOMY (Rt. Lumbar Trunk) Time (5 second intervals) The E f f e c t s of Sympathectomy of Right Lumbar Trunk on Bone Blood Flow. Compression on the i n f e r i o r vena cava during s u r g i c a l procedure, resu l t e d i n venous congestion, with increase of intramedullary pressure of both t i b i a , and r i g h t t i b i a l n utrient venous outflow. Note the increase of r i g h t t i b i a l intramedullary pressure, as opposed to the l e f t , which remained unchanged, a f t e r r i g h t lumbar sympathectomy. The r i g h t t i b i a l nutrient venous outflow was also s i g n i f i c a n t l y increased a f t e r sympathectomy. 40. but i t was coupled with an increase of nutrient venous outflow indicating bone venous congestion. This was purely a mechanical effect. After sympathectomy of right lumbar trunk, obvious increase of right t i b i a l nutrient venous outflow, ranging from 15 - 110 percent, was observed, with an increase of intramedullary pressure of right tibia in four of the five dogs. B. After Induction of Hemorrhagic Shock In the same five dogs, bone blood flow was studied after induction of hemorrhagic shock. The bone blood flow as measured by direct cannulation on both sides was compared and plotted as percentage change in respect to percentage change of systemic blood pressure (Figure 13). In a l l five dogs, there was significantly less decrease in percentage of bone blood flow in the sympathectomised side as compared to the control side which has intact lumbar sympathetic nerve. This effect was already obvious when systemic blood pressure f e l l to the 907„ level of the control pressure, and persisted until the systemic blood pressure f e l l to 30% level of the control. The difference in percentage of bone blood flow between sympathectomised and control side ranged from 10 - 30 percent with an average of 16 percent. Control studies were carried out in two dogs, in which bilateral cannulation of nutrient vessels was performed, without sympathectomy of either side, and subsequently underwent the same hemorrhage procedure. The percentage change of bone blood flow in the right and le f t side in these two animals was practically the same on both sides, well within 57« range of difference from each other. FIGURE 13 100- 90-) 80 70 60 H 50 40 30- 20- 10- EFFECT OF SYMPATHECTOMY ON BONE CIRCULATION IN SHOCK (Average for 5 Dogs) o o Sympathectomy • • Intoct 0 10 20 30 40 50 60 70 80 90 100 % SYSTEMIC BP. The Effect of Sympathectomy on Bone Blood Flow in Shock. The upper curve represents the bone blood flow in the sympathec- tomised side, with the control (nerve intact) side represented by the lower curve. There is less decrease of bone blood flow in the sympathectomised side compared with the control. VIII Effect of Epinephrine and Norepinephrine Infusion of epinephrine at a rate of 0-3 pag/kg/min. resulted in slight increase of systolic blood pressure and slight increase of pulse pressure, abrupt f a l l in t i b i a l intramedullary pressure, and a persistent decrease of t i b i a l nutrient venous outflow by about 307„. The above parameters returned to control levels within half to two minutes after the infusion was stopped (Figure 14). Infusion of norepinephrine at a rate of 0-3 ̂ ig/kg/min. resulted in quite similar effects (Figure 15). IX Effect of Dibenzyline (Phenoxybenzamine) In four dogs, dibenzyline (phenoxybenzamine) was given with the dosage of 2 mg/kg body weight intravenously over a period of over one hour. The alpha-receptor blocking effect in each animal was confirmed by epinephrine infusion at a rate of 0*3 ̂ ig/kg/min., in which case the t i b i a l nutrient venous outflow did not show any decrease On ele c t r i c a l stimulation of the lumbar sympathetic trunk, the ipsi l a t e r a l t i b i a l intramedullary pressure and bone blood flow decreased to a lesser extent, than would be expected i f dibenzyline were not given, indicating a partial blockage of the sympathetic discharge with this dosage of the drug. The four dogs were subsequently subjected to hemorrhage as described above. The percentage change of bone blood flow and systemic blood pressure were plotted (Figure 16). A linear relation- ship between bone blood flow and systemic blood pressure was demonstrated. This indicates that neural control of bone vasomotor mechanisms has been blocked by dibenzyline. FIGURE 14 41a. jf Adrenalin Infusion 0.3^jg/kg./nnm. *| | j 11111111111||111111111111111111111111i1111|111111 [ 111111111111111IIMIiIi i111111111I11111111111i1111111111111111111111111i11111111111111111 i Time |5 second intervals] The Effects of Epinephrine (adrenalin) Infusion on Bone Blood Flow. Note the abrupt f a l l in t i b i a l intramedullary pressure, and decrease of t i b i a l nutrient venous outflow. Prompt return to control levels occurred when infusion was stopped. FIGURE 15 41b. Dog 240' 200- 120 J SYSTEMIC ̂ ^^^^^1^^ " , „ TIBIAL INTRAMEDULLARY PRESSURE 50- 30- TIBIAL NUTRIENT VENOUS OUTFLOW i-Hill 11111 ll I 1111 | ! 1111 | I 1111 ! I 111 i 1 ' i I I I 1  M i IHMMi 11II11' 11' H IIII l|M | i ! ' 11 M 111 |' Norodrenalin Infusion 0.3^jg/kg./min. *| 111 i 111'| 11111111111111111111II1111111111111111111111111111111111111 n 111III111 n 1111111111111111111 I I 1111111 i 111111111 i 111 l l 1111111 Time (5 second intervals) The Effects of Norepinephrine (noradrenalin) Infusion. Systemic blood pressure increased because of generalized vasoconstriction. Note the f a l l of t i b i a l intramedullary pressure and slight decrease of t i b i a l nutrient venous outflow. FIGURE 16 EFFECT OF DIBENZYLINE ON BONE BLOOD FLOW IN HAEMORRHAGIC SHOCK (Average and Standard Error for 4 Dogs) V V t Y / A / t A -i 10 20 30 40 50 60 70 80 90 100 % SYSTEMIC B.P. The Effect of Dibenzyline (phenoxybenzamine) on Bone Circulation in Shock. Note the linear relationship between the systemic blood pressure and bone blood flow. DISCUSSION The purpose of this study, as mentioned before, is to find out the fundamental changes in bone hemodynamics, mechanisms whereby such changes are brought about, and to compare with other regional circulation in shock. Trueta commented upon profuse bleeding produced the collapse of intraosseous pressure, and this was interpreted as being caused by emptying of the sinusoids and veins to replace the loss in the systemic circulation. However, l i t t l e is known or studied on bone circulation in shock. In our survey, no previous study on bone circulation in shock was found in the literature, and the purpose of the present study is to carry out such a work. The literature on bone circulation has been reviewed with special emphasis on the anatomical aspect of blood supply of bone, i t s innervation, methods of study of bone blood flow, both quantitatively and qualitatively, and the control mechanisms involved in bone circulation. The nerve supply of bone has been demonstrated by many 62, 113, 130, 1 workers 3, 36, 47, 73, 135, 161 54 J u . , workers and the vasomotor nature is well known Humoral mechanisms involved in bone 3, 12, 36, circulation are also supported by the studies of many workers 129, 132, 144, 166 are also demonstrated Ketabolic factors influencing bone circulation 29, 135, 167 The current concept of shock was reviewed. It would appear that 64 decreased capillary perfusion of tissue suggested by Hardaway is perhaps the generally accepted description of the term 'shock1, in the light of our present knowledge. Decreased tissue perfusion is the final outcome pathway of the shock syndrome, and is the fundamental 43. pathophysiology in the pathogenesis of shock. The neural aspect of alarming the sympathetic nervous system for redistribution of blood by arterial and venous constriction to the central circulation, particularly the heart and brain, is discussed. Evidence for increase 55, 90, 114 vasomotor tone is reviewed . Hormonal output, involving 98, 156 52, 54, 75 catecholamines , adrenal corticosteroid , 44, 46, 107 6, 159 aldosterone and renin-angiotensin secretion , have been reported. The metabolic aspects secondary to cellular hypoxia in shock, include metabolic acidosis, lactate and pyruvate acid accuromulation, azotemia, hyponatraemia and hyperkalemia, are recognised. The regional and various organs' blood flow in shock are reviewed. , . 42, 61, 112 , , . , . 1 2 3> 1 4 7 Coronary circulation and cerebral circulation are preferentially perfused, and their vascular resistance usually decreases u . A , i • i „. 26, 59, 123, 124 . , . m shock as opposed to renal circulation and skin circulation ^ . In other vascular beds, notably splanchnic 69, 94, 120, 123, 127 circulation , there is considerable controversy in the literature. Pooling of blood in the splanchnic bed with marked distention of the. liver is a prominent feature in the dog and the rat in shock. A muscular sphincter like structure is present in the region of the effluent hepatic vein which is highly sensitive to vasoactive product, and this structure is thought to be responsible for congestion ?1 of liver during shock Knowing that neural, hormonal and metabolic changes occur in shock, and knowing that bone circulation is affected by neural, hormonal and metabolic factors, i t is most interesting to find out the changes of hemodynamics in bone circulation in shock, and evaluation of various mechanisms by which such changes are effected. 44. Validity of Experimental Methods I Parameters Used in Measuring Bone Circulation A. Direct Cannulation - Collection Method Cannulation of nutrient vessel, either vein or artery of tibia as 135 described by Shim and Patterson , was used in this experiment. Knowing the vascular anatomy of bone, with the three separate systems. of the nutrient, periosteal and epiphysial-metaphysial vessels with numerous intraosseous and extraosseous anastomoses, this method cannot be used to measure the total blood flow of a given bone. However, i t is useful for qualitative investigations of the relative changes of the 135 hemodynamics of bone with reasonable degree of accuracy , since the nutrient vascular system is widely distributed throughout the long bone - a representative vascular system of long bone. B. Intramedullary Pressure as an Index of Bone Blood Flow 91 Since Larsen started to measure intramedullary pressure in dogs' distal femoral metaphysis, i t s close relationship with bone hemodynamics 3 12 103 129 has been implied by many workers ' ' ' C l i n i c a l l y intra- medullary pressure has been used to correlate with v i a b i l i t y of femoral head after femoral neck fracture * <^. Hawk and Shim by measuring intramedullary pressure and bone blood flow simultaneously, concluded that the intramedullary pressure is bone blood flow dependent, and, reflects well the changes in the hemodynamics of bone. The volume of blood inside the bone is also reflected by intramedullary pressure. Therefore, intramedullary pressure is a valid parameter in evaluation of bone hemodynamics. II Validity of the Hemorrhagic Shock Model From the point of view of obtaining valid data, the animal preparation 45. should mimic the conditions encountered in human situations. Experimental models generally f a l l into two categories: (a) those in which a fixed volume of blood is withdrawn, regardless of changes in blood pressure, and (b) those in which enough blood is withdrawn to lower the mean arter i a l pressure to certain predetermined levels, either once or repeatedly in stepwise fashion. After bleeding a percentage of predetermined blood 128 volumes, i t was found that the residual volume varies considerably Such a method does not generally produce predictable and consistent 165 results. The Western Reserve method, or Wiggers msthod , consists of lowering the arterial pressure to 50 mmHg. for ninety minutes, then at 30 mmHg. for forty-five minutes, followed by re-infusion at a rate of 50 ml/min. Arbitrary aspects of the method as noted in various modifications of this method, are Che levels of hypotension (35 - 70 mmHg.) and the percentage take-up from the reservoir to the 128 animal accepted as end point (15 - 30% of blood volume ). Shoemaker, 140 Walker and Moore commented on the advantage of Wiggers method as that a relatively stable hemorrhaged preparation is provided for a period of several hours and can be reproducible in any laboratory. However, one of the disadvantages of the Wigger method is that the animal is suddenly plunged into late or irreversible shock; this state is then a r t i f i c i a l l y prolonged by the gradual return of the shed-blood at a rate sufficient to maintain the blood pressure at a predetermined value. This experimental situation differs remarkably from the usual course of hemorrhagic shock. The method we adopted consisted of removal of one third of estimated blood volume (8% of body weight) at a rate of 25 - 50 ml/min. This generally lowers the systemic blood pressure to 55*2 +5*1% of the i n i t i a l 46. blood pressure, considerably higher than that of standard Wiggers' procedure. We then brought the systemic blood pressure down further in a stepwise manner, and maintaining a relatively stable blood pressure at each step for k, - h hour, until the systemic B.P. f e l l to 30 - 35 mmHg. We attempted to show the events occurring from the very beginning of hemorrhage until the animals exsanguinated. This model appears more mimic to c l i n i c a l situations, and bears similarity to the model 140 used by Shoemaker et a l . The preparation can be reproducible as a l l the procedures were specified. DISCUSSION ON RESULTS I Acute Hemorrhage By hemorrhaging at the rate specified, we observed the gradual f a l l of intramedullary, with gradual obliteration of the normal fluctuation associated with ar t e r i a l pulsation. Nutrient venous or art e r i a l outflow decreased. Both parameters are qualitative measures of bone hemodynamics, indicating a decrease of bone circulation in 151 hemorrhage. Trueta observed a profuse bleeding was associated with a marked f a l l of intramedullary pressure. He thought that the sinusoids and veins of bone are emptied with the blood being removed to replace the loss by the systemic circulation. The skeleton, in addition to being hemopoietic organs, also acts as stores of blood. Structures such as spleen and liver in the dog and cat add to the 21 47 active circulation as much as 307o of existing blood volume . Foa , by measuring changes in volume of bone marrow, suggested that the behaviour of the bone marrow was very similar to the spleen. 14 Branemark actually observed the living marrow in the fibula of the rabbit, and reported a rhythmic activity with alternating dilation and emptying of the marrow sinusoids, very similar to those described by Knisely ^ in the spleen. During epinephrine injection, Branemark ^ observed the marrow vessels became constricted and the marrow emptied of blood as though i t was squeezed, similar to that of a sponge when squeezed. With the present knowledge of nature of intramedullary 3, 12, 103, 129 pressure ' ' ' the decrease observed during shock is most li k e l y associated with decrease of the blood volume inside the marrow due to vasoconstriction in early stages and followed by a decreased blood supply to bone. This is quite contrary to pooling of blood in the splanchnic circulation observed in the dog and rat in shock. The total skeletal blood flow was estimated i n dogs as 7*3 + 3*0% of the 132 resting cardiac output by Shim, Copp and Patterson . L i t t l e knowledge of the volume of blood inside the bone marrow is available. Knowing that there are 205 bones in the human body, the volume may be considerable. Further studies in this area are required before any quantitative estimation is justified. II Effect of One Third Blood Volume Loss When one third of the estimated blood volume is lost, the systemic blood pressure f e l l to 55-2 +5-1 % (range 30 - 80%) of the control 98 level. Manger et al reported after approximately one third of total blood volume loss in dogs, the mean arterial pressure f e l l by a range of 55 - 81%. The rate of bleeding was varied from extremely rapid (138 - 217 ml/min.) to slow (5 - 12 ml/min.). Bone blood flow decreased to 22-5 +3*4% of control level. Intra- medullary pressure invariably f e l l to unrecordable level. The bone circulation decreased markedly with the specific amount of hemorrhage. 48. It is d i f f i c u l t to compare quantitatively the changes of bone circulation with other regional circulation in shock, because the methods of inducing shock and the methods of assessing blood flow are different. 123 However, Rutherford et al ,immediately after bleeding in dogs to lower the systemic blood pressure to 40 mmHg., measured regional blood flow of various organs by labelled microspheres, as percentage of control groups' values: myocardium 70%, cerebral 867,,, renal 417o, hepatic (arterial) 64%, splanchnic (portal vein) 29%, bronchial 25%, and lower extremity 13%,. In the coronary and cerebral circulation, the shares of cardiac output i n early shock were actually found to have increased, though the absolute amount of flow was decreased with a proportional decrease in vascular resistance. Similar observations were made in coronary and cerebral circulations by others. On the other hand, a marked decrease of blood flow, out of 26, 124 proportion to reduction of arterial pressure, was noticed in renal , 57 and skin circulation. It would appear that bone circulation in shock behaves more like the latter group of regional cir c u i t . III Prolonged Hemorrhage A l l the parameters remained low during prolonged hemorrhage, and the duration lasted four hours to eighteen hours, until the dogs eventually exsanguinated. IV Re-infusion of Lost Blood This varied from fifteen minutes to six hours after induction of hemorrhage. Re-infusion of lost blood resulted in partial or complete 49. recovery of the control l e v e l s of systemic blood pressure, t i b i a l intramedullary pressure, and bone blood flow. I t was observed that the longer the duration of the shock, the less complete was the recovery observed. V Relationship between Bone Blood Flow and Systemic B.P. (Figure 10) The curve obtained was an exponential one with concavity towards the flow axis. I t must be noted that the systemic blood pressure i s not exactly the perfusing pressure at the l e v e l of regional c i r c u l a t i o n of bone, although the systemic blood pressure i s c l o s e l y r e l a t e d or proportional to the perfusing pressure. In order to i n t e r p r e t the curve of flow and pressure r e l a t i o n s h i p , i t i s necessary to understand the resistance and capacitance phenomena 5 8 i n vascular beds. Green et a l expressed the r e l a t i o n s h i p between blood flow and pressure i n a c i r c u l a t o r y bed as n F = c x P where F = flow i n ml/min. c = a constant n = an exponent having a value between 1 and 3 The lowest value of n and highest value of c were found at "low 93 vasomotor tone" and vice versa. Levy *and Share have confirmed these findings and demonstrated that with maximal d i l a t i o n induced by a ten minute period of ischemia and subsequent perfusion with hypoxic blood i n the dog's hind limb, a l i n e a r r e l a t i o n s h i p between F and P was obtained, i n d i c a t i n g the value of n i s 1. 50. By local perfusion of nutrient artery in canine t i b i a , without shocking the animals and maintaining a constant systemic blood pressure, 81 Kato et al demonstrated a linear relationship between perfusion pressure and measured bone blood flow rate. This was interpreted as no significant change in the peripheral resistance under such experimental conditions. The flow and pressure curve in our study would suggest an increase of vascular resistance as judged by the shape of the curve. The method to calculate the value of n is as follows: F = c P n therefore log F = log c + n log P. By plotting the graph of log F against log P, a straight line is obtained, and the slope represents n. In our study, n was found to be 2-4, indicating presence of vasomotor bone. VI Effect of Electrical Stimulation of Lumbar Sympathetic Chain An abrupt and immediate drop of t i b i a l intramedullary pressure, together with a marked decrease of bone blood flow, was observed, indicating decrease of bone circulation due to an increase of sympathetic activity. The presence of nerves in the bone has been documented by various 113, 130, 154 , # , workers , ana their vasomotor nature was also well 3 3, 36, 47, 73, 135, 161 documented VII Effect of Lumbar Sympathectomy A. Before Induction of Hemorrhage Sympathectomy of right lumbar trunk, performed in five dogs, resulted in an increase of nutrient venous outflow ranging from 15 - 110 percent 148 above control value in acute experiment. Trotman and Kelly demonstrated a 27% increase in bone blood flow to the tibia in the 133 anaesthetised dog following lumbar sympathectomy, while Shim et a l showed a 5 - 45 percent increase in blood flow of bones in the leg and foot in rabbits after sciatic nerve section, X v h i c h carries most of the sympathetic fibres below the knee. The increase of bone blood flow after sympathectomy, which was also observed in this study, indicates the presence of vasomotor control of bone. B. Effect of Lumbar Sympathectomy in Shock In five dogs, after lumbar sympathectomy on right side was performed and leaving the left side intact, hemorrhagic shock was induced. The decrease of bone blood flow on the sympathectomised side was corres- pondingly less than the control (Figure 13). The difference was apparent, and maximal when the systemic blood pressure was between 75 - 357o, indicating the presence of more vasoconstriction in the control side, occurring already in the early stage of hemorrhage. This implies that the sympathetic discharge occurs rapidly to loss of blood volume. The average difference in the percentage of bone blood flow betxveen sympathectomised and control was 16'IT,. To compare the bone blood flow in the right and left sides without sympathectomy, two experiments were performed which showed less than 57. difference throughout the whole range of systemic blood pressure. Such experiments are s t a t i s t i c a l l y not significant, because only two were performed, but the results agree with the work of Trotman and 148 Kelly , who demonstrated no significant difference in bone blood flow in both sides in six dogs used as control. 52. VIII Effect of Catecholamines (Figures 14 and 15) The 'resting l e v e l ' of catecholamine was estimated by Walker 155 et a l to be i n the order of O'OOl ug/kg/min. Blood loss produced an immediate and marked increase in the plasma concentration of catecholamine, primarily of epinephrine with less norepinephrine. When % to 1/3 of the blood volume i s depleted, the output of epine- phrine was 0.14 - 0-88 ̂ g/kg/iain. and norepinephrine was 0*04 - 0-12 156 98 mg/kg/min. . Manger reported the lev e l of epinephrine increased from 1-0 to 7'8 pg/L of plasma, and norepinephrine increased from 2-5 - 3«6 jig/L of plasma. When epinephrine at the dosage of 0-3 ̂ ig/kg/min. was infused, an abrupt f a l l i n t i b i a l intramedullary pressure and decrease of bone blood flow were observed. The above, dosage of epinephrine corresponds to the range of epinephrine le v e l i n blood when 1/3 of estimated blood volume was removed by other workers J^' . This suggests for an evidence that bone blood flow i s also affected by epinephrine i n shock. Nore- pinephrine at the dose of 0-3 ug/kg/min. resulted i n elevation of systemic blood pressure due to i t s generalized vasoconstriction e f f e c t , f a l l of intramedullary pressure, and a less obvious decrease i n bone blood flow. With smaller doses of norepinephrine, the effect on bone c i r c u l a t i o n was not consistent. IX Effect of Dibenzyline on Bone Blood Flow i n Hemorrhagic Shock 22,56 Dibenzyline (phenoxybenzamine) ' produces a prolonged and effective blockage of alpha-adrenergic receptors. I t does neither produce the charac t e r i s t i c blockage by a l t e r i n g the function of adrenergic nerves nor the basic response mechanisms of effector c e l l s , but rather i t appears to act s p e c i f i c a l l y for catecholamines and closely related compounds and is considered to be an interaction with specific tissue receptors. Responses to circulating catecholamines are inhibited more effectively than those to mediator released locally at nerve endings. Blockage effect is relatively slow and mild in f i r s t one to two hours after drug administration, but the effect is very persistent. When dibenzyline was administered intravenously at the dosage of 2 mg/kg over a period of one hour, the systemic blood pressure dropped from control 140 mmHg. to 105 mmHg. (average for four dogs). This seems partly due to the drug action of l i f t i n g off the vasomotor tone. Under the dibenzyline medication, the hemorrhagic shock induction did not produce concave bone blood flow-pressure relation curve; instead, the relation was a linear one (Figure 16). This was interpreted as no significant increase of vascular resistance after dibenzyline was administered, and the decrease of bone blood flow became proportional to decrease of the perfusing pressure. 93 Similar observations were made by Levy and Share . The hind limb vascular bed of the dog was maximally dilated by ten minute period of ischaemia and subsequent perfusion with hypoxic blood, and this produced 81 a linear flow-pressure relationship. Kato et a l also demonstrated a linear relationship between flow and perfusing pressure by locally perfusing the canine tib i a , without exciting the neurohormonal mechanisms and thus maintaining a constant peripheral resistance. A l l the above information supports our interpretation that catecholamine reduces bone blood flow in hemorrhagic shock through vasoconstriction action. 54. SUGGESTED FUTURE STUDIES 1. Bone and Marrow Blood Volume In our present study we deduced decrease of volume of blood inside the marrow, coincided with decrease of intramedullary pressure 151 and decrease of bone circulation in shock. As Trueta interpreted, the blood in the sinusoids was removed away to replace the loss by the 47 systemic circulation. This was also the impression of Foa and 14 Branemark . However, l i t t l e quantitative studies of the volume of blood inside the bone marrow is available, and to assess the contribution of blood from bone circulation to the effective circulatory volume in shock is a pure conjecture. Future study is necessary. 2. Ischemic Effect on Bone Marrow j n Sb̂ p̂k The injurious effect of shock on various organs - such as acute tubular neurosis in kidneys, myocardial infarction, Sheehan's syndrome in pituitary, are well recognised. We demonstrated the significant decrease in bone blood flow in shock. Can similar injurious effect occur in the bone? The answer to this question has to be given by more refined histological or biochemical techniques with future studies in this area. 3. Pathogenesis of Fat Embolism Trauma and hypovolemic shock have been implicated in the pathogenesis 117 of fat embolism . Bone marrow is rich in fat. By studying the composition of nutrient venous outflow in shock, i t is possible to bring more light to the possible association of pathogenesis of fat embolism to shock. 55. 4. Metabolic Aspect of Bone Circulation i n Shock Metabolic factors, such as changes i n pH, hypoxia, hypercapnia, and accummulacion of different metabolites,such as l a c t i c and pyruvatic acids, are present i n hemorrhagic shock. Even though the effect of some factors influencing bone c i r c u l a t i o n has been studied. 29 135 Hypercapnia and hypoxia increase bone blood flew ' " , parental 157 l a c t i c acid also increases nutrient a r t e r i a l outflow , and reactive hyperemia of bone after femoral a r t e r i a l occlusion was unabolished by e l e c t r i c a l stimulation or exogenous vasopressin . But quantitative studies of a combination of the various metabolic factors in shock are not available. SUMMARY Bone c i r c u l a t i o n i n hemorrhagic shock was studied i n t h i r t y - f i v e male mongrel dogs. The term shock i s defined i n this thesis as persistent profound hypotensive syndrome, due to acute hemorrhage of more than one third of blood volume. The method of induction of shock consisted of removal of one third of estimated blood volume (87n of body weight) at a rate of 25 - 50 ml/min., and subsequently dropping the systemic pressure i n a stepwise manner u n t i l the maintaining level of 30 - 35 mmHg. was reached. The central venous pressure, pulse and respiratory rates were also recorded. Bone c i r c u l a t i o n was studied by (1) recording the blood flow through a cannula inserted into the t i b i a l nutrient vein or artery, and (2) recording the bone marrow cavity pressure of t i b i a . When one third of the estimated blood volume was removed, the bona blood flow decreased to 22*4 + 3*4 % of control l e v e l . 56. The duration of hemorrhagic shock varied from four hours to eighteen hours, and hone blood flow was decreased persistently. Intramedullary pressure of t i b i a invariably f e l l to unrecordable lev e l after one third of blood volume was removed. Re-infusion of l o s t blood, f i f t e e n minutes to s i x hours, after hemorrhage resulted i n p a r t i a l or complete recovery of the control levels of systemic blood pressure as well as bone blood flow and intramedullary pressure of bone. The curve showing relationship between changes i n bone blood flow and systemic blood pressure was an exponential one with concavity towards the flow axis. The presence of increased peripheral resistance of bone during hemorrhagic shock was deduced. B i l a t e r a l cannulation of t i b i a l nutrient artery or vein with lumbar sympathectomy on. one side showed a correspondingly less decrease (average 16*1%) of bone blood flow on the sympathectomised side i n hemorrhagic shock. Dibenzyline (phenoxybenzamine) altered the pressure-flow r e l a t i o n curve to a linear pattern i n bone c i r c u l a t i o n i n shock. These observations indicate that the bone c i r c u l a t i o n decreased i n hemorrhagic shock, and apart from the decreased c i r c u l a t i n g blood volume, there are active vasomotor control mechanisms responsible for the reduction in bone blood flow. These mechanisms are neural (sympathetic) and hormonal (catecholamine). CONCLUSION Hemorrhagic shock in dogs decreases bone circulation, as measured by bone blood flow and intradmedullary pressure. The decrease of bone circulation persists as long as eighteen hours and recovers partially or completely the normal rate of flow i f the lost blood is re-infused. The relationship of changes in bone blood flow and systemic blood pressure indicates that vasomotor control mechanisms play a role in shock to increase bone vascular resistance. The role of nervous control of bone circulation in shock is demonstrated: sympathetic stimulation decreases bone circulation and sympathectomy decreases the vasomotor response in bone circulation in shock. The role of catecholamines on bone circulation in shock is demonstrated: epinephrine and norepinephrine infusion decreases bone circulation. Dibenzyline (phenoxybenzamine), an alpha-receptor blocking drug, blocks the bone vasoconstriction action in shock. This indicates the bone vasomotor system has alpha-receptors. Bone circulation decreases in shock, not only due to decreased perfusing pressure and circulating blood volume, but also due to neural and hormonal active vasomotor control mechanisms. TABLE I RELATIONSHIP BETWEEN PERCENTAGE CHANGE IN SYSTEMIC BLOOD PRESSURE AND BONE BLOOD FLOW % Sy stemic B.P. 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 Dogs 5 100 88.5 78 66 55 44 32.5 24 18 17 16.5 - - - - - - 6 100 92 84 76.5 68.5 61 54 50.5 47.5 42.5 35 25.5 12 2 - - -• 7 8 100 92 83.5 76.5 68 59 50.5 42.5 36.5 31 26.5 22.5 15 9 5 - - /o Bone 10 100 95 83 74.5 66 54.5 40 29 25 22 17.5 13 9.5 7 5 -Blood Flow 12 100 80 65 61 54 51 46 41 36 30.5 25 25 23 20 16 13 10 14 100 91.5 83.5 74 68.5 61.5 55 38.5 36 32.5 28.5. 22.5 16 10 4 - - 15 100 86 72.5 60 24.5 10 8 4.5 4 3.5 3 2 1.5 1 - - - 28 100 77 58.5 41.5 24 14.6 9 6 5 4 - - - - - - - 32 100 98 96 87.5 72.5 57.1 51 45.5 43 40 38 32.5 25 - - - - 34 100 76 68 59 51.5 42 36.5 30 23 18.5 14 10.5 8 - - - - Mean 87.6 77.2 67.6 55.2 45.5 38.2 35.7. 27.4 24.1 20.4 15.3 11 4 .9 3.0 1.3 S.E. . 5.7 3.6 4.1 5.6 5.9 5.5 4.2 4.7 4.3 3.9 3.8 3.0 1 .9 1.6 1.3 Mean + 87.6 77.2 67.6 55.2 45.5 38.2 35.2 27.4 24.1 20.4 15.3 11 4 .9 3.0 S.E. +5.7 +3.6 +4.1 +5.6 +5.9 +5.5 +4.2 +4.7 +4.3 +3.9 +3.8 +3.0 +1 .9 +1.6 TABLE II Nerve Intact Bone M e a n + Blood S « E - Flow EFFECT OF LUMBAR SYMPATHECTOMY ON BONE BLOOD FLOW IN SHOCK % Systemic Blood Pressure Sympath- ectomised Mean + S.E. 100 100 1 0 0 1 00 1 00 100 9 5 7 5 9 8 8 8 8 2 8 2 9 0 5 8 9 6 78 6 2 6 4 8 5 8 0 4 0 2 5 8 8 7 2 . 5 5 7 67 5 6 7 5 7 0 65 6 0 1 4 . 5 9 . 5 6 . 5 5 4 5 5 1 3 6 4 5 2 9 5 5 5 0 4 4 3 4 0 . 5 3 8 2 2 . 5 1 8 1 4 4 5 4 0 3 5 3 0 3 3 2 5 . 5 1 0 . 5 8 5 . 5 4 0 3 9 . 5 3 8 . 5 3 7 . 5 3 6 . 5 3 6 . 5 3 6 . 5 3 6 . 5 3 6 . 5 3 6 . 5 3 1 . 5 2 6 . 5 4 3 . 5 4 1 . 5 3 9 3 6 3 4 27 1 4 100 8 5 . 0 7 1 . 6 5 5 . 5 4 6 . 9 3 8 . 8 3 4 3 0 . 2 2 6 . 8 2 2 . 6 1 9 . 1 1 6 . 6 1 4 . 0 7 . 4 5 . 3 + 3 . 9 + 7 . 3 + 3 . 1 + 8 . 0 + 6 . 9 + 6 . 7 + 6 . 4 + 4 . 5 + 7 . 2 + 7 * 7 + 7 . 6 + 7 . 3 + 6 . 2 + 5 . 3 100 9 3 8 6 7 8 5 8 100 9 7 9 4 . 5 9 0 8 4 100 9 0 8 0 7 1 62 100 9 4 8 7 8 4 . 5 7 3 1 0 0 9 4 89 8 5 77 1 7 . 5 12 8 . 5 6 . 5 4 . 5 - 78 6 9 6 0 57 5 3 5 0 5 3 47 4 2 3 7 3 1 2 4 68 5 7 5 1 5 1 5 1 5 1 7 1 6 5 5 9 5 1 3 8 . 5 3 1 4 3 3 6 . 5 - 1 9 . 5 1 8 . 5 1 7 . 5 9 . 5 5 1 5 0 5 3 5 3 2 2 1 2 6 . 5 - 1 0 0 9 3 . 6 8 7 . 3 8 1 . 7 7 0 . 8 5 7 . 5 5 0 . 0 4 4 . 1 4 0 . 5 3 5 . 6 3 1 . 2 2 7 . 1 2 3 . 4 1 5 . 4 1 3 . 0 + 1.1 + 2 . 3 + 3 . 3 + 4 . 8 + 1 0 . 8 + 1 0 . 2 + 9 . 4 + 9 . 1 + 8 . 7 + 9 . 4 + 9 . 0 + 9 . 1 + 5 . 6 + 1 0 . 1 TABLE I I I EFFECT OF DIBENZYLINE ON BONE CIRCULATION IN SHOCK 7» Systemic Blood Pressure 100 95 90 85 80 75 70 65 60 55 50 45 40 35 100 95 90.5 85.5 76.5 63 50 36.5 34 8 5 0 0 0 100 92 84 76 68 60 51 45 38 28 25 12 4 0 100 88 78 72 . 66 53 48 44 28 19 14 5 0 0 100 91 82 73 66 59.5 53.5 46.5 42 39 35.3 29 21 0 100 91.5 83.6 76.1 69.1 57.4 49.6 44.0 35.5 23.5 19, 11.5 6.2 0 30 S.E. + 0 + 1.4 + 2.9 + 2.8 + 2.7 + 2.9 + 1.5 -I- 2.6 + 2.9 + 6.6 + 6.5 + 6.3 + 5.0 61. 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