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Bone circulation in hemorrhagic shock. Yu, William Yan 1971-12-31

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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 in  OF SCIENCE  the Department of SURGERY  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA March, 1971  In  presenting  this  an a d v a n c e d  degree  the L i b r a r y  shall  I  f u r t h e r agree  for  scholarly  by h i s of  this  written  thesis at  the U n i v e r s i t y  make  it  It  f i n a n c i a l gain  of  /^AA^JI^LSJ  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, C a n a d a  Date  by  Columbia  shall  the  requirements  B r i t i s h Columbia, for  I agree  r e f e r e n c e and copying of  this  that  not  copying  or  for  that  study. thesis  t h e Head o f my D e p a r t m e n t  is understood  permission.  Department  of  for extensive  p u r p o s e s may be g r a n t e d  for  fulfilment of  freely available  that permission  representatives. thesis  in p a r t i a l  or  publication  be a l l o w e d w i t h o u t my  i ABSTRACT  Bone c i r c u l a t i o n mongrel dogs.  i n Hemorrhagic Shock was  studied in 35 male  The term hemorrhagic shock i s defined i n this  thesis  as persistent profound hypotensive syndrome, due to acute hemorrhage of more than one t h i r d 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 i n a stepwise manner u n t i l the maintaining l e v e l of 30 - 35 mmHg i s 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 intramedullary pressure of t i b i a . When one t h i r d of estimated blood volume was  removed, the bone  blood flow through the nutrient vessel decreased to 22*5 + 3'47. of control l e v e l .  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 f i f t e e n minutes to s i x hours a f t e r hemorrhage resulted i n a complete or p a r t i a l recovery of the control systemic blood pressure as well as the control rate of bone blood flow and the control l e v e l of intramedullary pressure of bone.  The curve showing relationship between the changes i n bone blood flow and the systemic blood pressure i s 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. observations:  (1)  This was  substantiated by the following  The severity of decrease i n 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 a l t e r s the pressure-flow curve of bone c i r c u l a t i o n i n chock to a linear pattern which indicates that the drug blocks the bone vasoc o n s t r i c t i n g mechanism(s).  It i s concluded that bone blood flow decreases i n hemorrhagic shock and i s not merely due to a decrease i n c i r c u l a t o r y blood volume, but also due to sympathetic and catecholamine hormonal vasoconstrictor mechanisms.  iii TABLE OF CONTENTS Page I II  INTRODUCTION AND PURPOSE OF STUDY  1  REVIEW OF LITERATURE  2  BONE CIRCULATION  2  Anatomy - Vascular supply of bone .  2  Nerve supply of bone  8  Physiology of Bone C i r c u l a t i o n  10  Methods of study  10  Rate of bone blood flow  15  Rate of e n t i r e s k e l e t a l blood flow.  18  The r e g u l a t i o n mechanisms of bone blood flow  . 18  Neural Control  18  Hormonal Control  19  Metabolic Control  20  SHOCK  ,  20  Definition  20  H i s t o r i c a l aspect  22  Abnormal p h y s i o l o g i c a l aspect of shock  25  Regional c i r c u l a t i o n i n shock  30  T o t a l p e r i p h e r a l resistance Coronary c i r c u l a t i o n  ±  n  shock ...  30 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 III  IV  MATERIALS AND METHODS  34  General set-up  34  Study of bone blood flow  36  Transperitoneal lumbar sympathectomy  36  Use of d i b e n z y l i n e (phenoxybenzamine)  37  Induction and s u s t a i n i n g of hemorrhagic shock ....  37  RESULTS  38  I II  III IV V  Acute hemorrhage  38  E f f e c t of one t h i r d of estimated blood volume loss  38  E f f e c t of prolonged hemorrhage  38  E f f e c t of r e - i n f u s i o n of l o s t blood  39  R e l a t i o n s h i p between bone blood flow and systemic a r t e r i a l pressure  VI  39  E f f e c t of e l e c t r i c a l s t i m u l a t i o n of lumbar sympathetic chain  VII  VIII IX V  E f f e c t of lumbar  39 sympathectomy  A.  Before induction of hemorrhagic shock ..  39  B.  A f t e r induction of hemorrhagic shock ...  40  E f f e c t of epinephrine and norepinephrine ....  41  E f f e c t of d i b e n z y l i n e (phenoxybenzamine)  41  ....  DISCUSSION  42  V a l i d i t y of experimental methods  44  I  44  Parameters used i n measuring bone c i r c u l a t i o n . A. B.  D i r e c t cannulation - c o l l e c t i o n method .  44  Intramedullary pressure as an Index of bone blood flow  44  Page V  DISCUSSION (cont'd) II  V a l i d i t y of the hemorrhagic shock model  DISCUSSION ON RESULTS  46  I  Acute hemorrhage  46  E f f e c t of one t h i r d blood volume loss  47  Prolonged hemorrhage  48  Re-infusion of l o s t blood  48  II III! IV V  R e l a t i o n s h i p between bone blood flow and systemic B.P  VI  VII  VIII IX  49  E f f e c t of e l e c t r i c a l s t i m u l a t i o n of lumbar sympathetic chain  50  E f f e c t of lumbar sympathectomy  50  A.  Before induction of hemorrhage . .  B.  E f f e c t of lumbar sympathectomy  i n shock.  E f f e c t of catecholamines  VII IX  50 51 52  E f f e c t of dibenzyline on bone blood flow i n hemorrhagic shock  VI  44  52  SUGGESTED FUTURE STUDIES  54  1.  Bone and marrow blood volume  54  2.  Ischemic e f f e c t on bone marrow i n shock  54  3.  Pathogenesis of f a t embolism  54  4.  Metabolic aspect of bone c i r c u l a t i o n i n shock  55  SUMMARY  55  CONCLUSION  57  BIBLIOGRAPHY  61  vi TABLES Page I  RELATIONSHIP BETWEEN PERCENTAGE CHANGE IN SYSTEMIC BLOOD PRESSURE AND BONE BLOOD FLOW  II  EFFECT OF LUMBAR SYMPATHECTOMY ON BONE BLOOD FLOW IN SHOCK  III  58.  59  EFFECT OF DIBENZYLINE ON BONE CIRCULATION IN SHOCK ... 60  vii 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 n u t r i e n t and p e r i o s t e a l vessels  2  2a  Micrograph of a s a g i t t a l section of dog's t i b i a with I n d i a ink i n j e c t i o n , demonstrating d i s t r i b u t i o n s of n u t r i e n t a r t e r i a l branches  2b  3  Micrograph of the p e r i o s t e a l vessels of the dog's t i b i a  4  Micrograph of transverse section of bone, with H & E s t a i n , demonstrating nerves of bone marrow  2c  8a  5  General set-up i n experiment  34a  6  The "Bleeding R e s e r v o i r " used i n experiment  35a  7  The e f f e c t s of acute hemorrhage  38a  8  The e f f e c t s of removal of one t h i r d of estimated blood volume  9 10  „  The e f f e c t s of r e - i n f u s i o n of l o s t blood.,..;  38b 39a  Graph to show the percentage changes of bone blood flow, with respect to percentage changes i n systemic blood pressure i n hemorrhagic shock  11  The e f f e c t s of e l e c t r i c a l s t i m u l a t i o n of lumbar sympathetic chain  12  39d  The e f f e c t of sympathectomy on bone blood flow i n shock  14  , 39c  The e f f e c t s of sympathectomy on bone c i r c u l a t i o n before hemorrhage  13  39b  The e f f e c t s of epinephrine (adrenalin) i n f u s i o n  40a 41a  viii Page 15  The e f f e c t s of norepinephrine  (noradrenalin)  infusion 16  41b  The e f f e c t of dibenzyline (phenoxybenzamine) on bone c i r c u l a t i o n i n shock  41c  ix ACKNOWLEDGEMENTS To Dr. S. S. Shim, my teacher deepest g r a t i t u d e .  and sponsor, I wish to extend my  He has i n t r o d u c e d  and has shown me the s y s t e m a t i c s c i e n t i f i c problem.  the a r t o f r e s e a r c h  approach to the s o l u t i o n o f a  He has made many v a l u a b l e s u g g e s t i o n s  shown remarkable t o l e r a n c e t o the ignorance beginner.  to me,  and has  and n a i v e t y o f a  The p r i n c i p l e s and methods f o r s t u d y i n g bone c i r c u l a t i o n ,  a field  i n which Dr. S. S. Shim has won i n t e r n a t i o n a l r e c o g n i t i o n ,  provide  the b a s i s o f t h i s  study.  My s i n c e r e thanks go t o Dr. F. P. P a t t e r s o n , Head o f the D i v i s i o n of Orthopaedics, arranged  f o r h i s constant  t h i s year  encouragement.  of r e s e a r c h as p a r t of my t r a i n i n g ;  which I have enjoyed an e x c e l l e n t e d u c a t i o n a l  I would l i k e A.  He has k i n d l y a year i n  experience.  to extend my thanks to Dr. W. G. Trapp and Dr.  I . Munro f o r a l l o w i n g me to use t h e i r equipment i n the study o f  shock, and t o Dr. P. J . Moloney f o r the s u p p l y o f D i b e n z y l i n e , i s p r i m a r i l y intended  f o r h i s research  which  i n renal transplantation.  Dr. H. E . Hawk, my s e n i o r c o l l e a g u e , has c o n t i n u a l l y bombarded me w i t h i n t e l l e c t u a l s t i m u l a t i o n and has r e f i n e d some o f the techniques and  i n t h i s study.  The t e c h n i c a l a s s i s t a n c e o f Mr. G. Leung  the s t a f f o f the Animal Research L a b o r a t o r y  B r i t i s h Columbia i s w e l l  appreciated.  o f the U n i v e r s i t y o f  x Mr.  B a r d o l f Paul and  the  Department of the Vancouver  s t a f f of  the M e d i c a l  G e n e r a l H o s p i t a l have k i n d l y  and photographed a l l the f i g u r e s i n t h i s  L a s t , but not l e a s t , who  has k i n d l y typed t h i s  my  Illustration  study.  thanks a r e due  thesis.  framed  to Miss Judy R e i d ,  1. INTRODUCTION AND PURPOSE OF STUDY  Shock i s one o f the most e x t e n s i v e l y s t u d i e d  conditions  in clinical  as w e l l as l a b o r a t o r y medicine, w i t h an almost i n e x h a u s t i b l e 72, references  and many e x c e l l e n t monographs  this  i n depth.  field  Regional c i r c u l a t i o n  105, 139, 159 covering  i n shock, i n c l u d i n g e v a l u a t i o n o f b l o o d  mechanism o f c o n t r o l , and f u n c t i o n a l i n t e g r i t y organs such as coronary 70,  pulmonary splanchnic studied. different  108, 123  26,  42, 112, 123  , renal  1, 69, 123, 127  and a d r e n a l s  responses o f v a r i o u s  to l a c k o f study.  of various  , hepatic  54, 71, 75, 97  i n d i c a t e s that  26, 123  ,  have been  59  i s known about the bone c i r c u l a t i o n  study on bone c i r c u l a t i o n  ,  there a r e d i s t i n c t l y  v a s c u l a r beds i n shock  A review of l i t e r a t u r e  flow,  systems and  26, 45, 123  , cerebral  26, 65, 123, 125, 126  Available information  However, l i t t l e  l i s t of  failed  i n shock due  to d i s c l o s e a  previous  i n shock.  Purpose o f Study The questions  a i m o f t h i s t h e s i s i s to f i n d out the answers to b a s i c 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 a r e brought about, and comparison w i t h other in and  shock.  r e g i o n a l and organ  I t i s hoped t h a t t h i s study w i l l r a i s e  stimulate  future  studies.  further  circulations questions  REVIEW OF LITERATURE  BONE CIRCULATION Anatomy  V a s c u l a r s u p p l y o f bone Nerve supply o f bone  Physiology  Methods o f study o f bone c i r c u l a t i o n Rate of bone b l o o d  flow  Rate o f e n t i r e s k e l e t a l b l o o d  flow  C o n t r o l mechanisms  SHOCK Definition Historical  aspect  Abnormal p h y s i o l o g i c a l  aspect  N e u r a l , hormonal, m e t a b o l i c Regional c i r c u l a t i o n  aspects  i n shock  V a s c u l a r S u p p l y of Bone 89 Langer  (1876) appeared  v a s c u l a r anatomy o f bone.  t o be the p i o n e e r i n s t u d y i n g the g e n e r a l  Lexer, K u l i g a and Turk (1904), as c i t e d by  37 Laing  , i n j e c t e d the a r t e r i a l systems o f newborn and a d u l t  with a mercury-turpentine  emulsion,  cadavera  f o l l o w e d by s t e r e o s c o p i c r a d i o g r a p h s  of the specimen, and was a b l e t o g i v e a d e t a i l e d d e s c r i p t i o n o f the v a s c u l a r s u p p l y o f the femur.  They found evidence  a r t e r i a l systems s u p p l y i n g a l l long bones; and m e t a p h y s i o - e p i p h y s e a l  systems.  o f three main  namely, p e r i o s t e a l ,  nutrient,  2a. FIGURE 1  Micrograph of a transverse section of a dog's femur with India Ink injection. I t shows the r e l a t i v e contributions of n u t r i e n t and p e r i o s t e a l a r t e r i e s . The bone marrow and inner two t h i r d s are supplied by nutrient a r t e r y , and outer t h i r d by the p e r i o s t e a l a r t e r i e s . Note r a d i a l arrangement of branches of n u t r i e n t a r t e r y .  2b. FIGURE 2  Micrograph of s a g i t t a l section of a dog's t i b i a with India Ink i n j e c t i o n . I t shows d i s t r i b u t i o n s of n u t r i e n t a r t e r i a l branches i n the marrow c a v i t y (central portion). Note that there are many l o n g i t u d i n a l vessels (contained i n the Haversian canals) and some transversely running vessels ( v i a Volkmann's canals).  2c. FIGURE 3  P e r i o s t e a l vessels of a dog's t i b i a s h a f t . The dark vessels are veins and l i g h t e r ones are a r t e r i e s . Note that there i s a 'trio-arrangement', the a r t e r y i n the centre and the veins on each s i d e .  Micro angiographic study of bone was  carried out by Barclay ^.  Materials, such as v i n y l p l a s t i c , India ink, B e r l i n blue, or f i n e l y 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 i n the talus of man, Nelson i n the human t i b i a , Brookes i n tubular bone in 16 17 rats , long bones in the human foetus , and in r a b b i t s ' femur and tibiofibula  1 5  .  A l l authors  tend to agree that the nutrient artery, a f t e r entering  the diaphyseal cortex, divides into ascending and descending branches which have further r a d i a l l y oriented branches to the cortex.  The ends  of the bones are supplied by the epiphyseal and the metaphyseal a r t e r i e s , which enter the epiphysis and metaphysis through small foramina.  After  entering the substance of bone, the a r t e r i e s 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 i n small c a p i l l a r y loops beneath the a r t i c u l a r c a r t i l a g e . observed by Nelson et a l  1X1  Such arrangements have been  i n the human t i b i a and Rogers and Gladstone  12  in the d i s t i l end of the human femur. The p e r i o s t e a l system forms an abundant vascular network, and can e a s i l y be observed i n the periosteum It has been pointed out by Nelson  this  of long bones, such as the t i b i a .  , of the prevalence of a t r i o  arrangement of vessels, i n which each one of the a r t e r i a l twigs  was  accompanied by two veins, i n the t i b i a . 14 Branemark  , with a special illumination device, was able to  v i s u a l i z e the marrow of f i b u l a of the rabbit, and observed i t s structure  and  f u n c t i o n i n the microscope without i n t e r f e r i n g w i t h  f u n c t i o n o f the organ. the  The v e s s e l c a l i b e r was n o t i c e d t o v a r y  activity.  Arteriole  10 u  Capillary  3 u  Sinusoid  15 - 60 u  Venule  12 u  flow r a t i o between the a r t e r i o l e and the s i n u s o i d was estimated  be a p p r o x i m a t e l y 10:1, a f i g u r e c l o s e to that d e r i v e d corrosive preparations  The  shaped, sometimes more or  T h i s rhythmic a c t i v i t y  by K n i s e l y  85  i n spleen.  Foa  i s somewhat s i m i l a r to 47  , by measuring changes  i n volume o f bone marrow, suggested t h a t the b e h a v i o r marrow was v e r y  injection-  They showed a rhythmic f u n c t i o n w i t h a l t e r n a t i n g  d i l a t i o n and emptying. described  from  to  o f the v a s c u l a r bed.  s i n u s o i d s a r e sometimes s p i r a l l e d  less hexagonal.  that  with  f u n c t i o n a l s t a t e o f the marrow, and a rough average i n a marrow  of " o r d i n a r y "  The  the normal  s i m i l a r to the s p l e e n ;  o f the bone  and proposed t h a t the bone  marrow c i r c u l a t i o n may a c t u a l l y be r e g u l a t e d by s p h i n c t e r s s i m i l a r to those o f the venous s i n u s o i d s .  In s t u d y i n g  the i n n e r v a t i o n by d i r e c t o b s e r v a t i o n  o f the marrow  m i c r o c i r c u l a t i o n , Branemark commented that the marrow v e s s e l s become c o n s t r i c t e d , and the marrow i s emptied o f b l o o d as when squeezing a sponge, d u r i n g a d r e n a l i n e  injection.  Another o b s e r v a t i o n  was the r i c h  anastomoses and a t y p i c a l course o f marrow c a p i l l a r i e s d i p p i n g compacta, and then t u r n i n g back a g a i n  i n t o the  i n t o the marrow s i n u s o i d s .  5. Venous Drainage Long bones have a central venous sinus.  The  capacity of the  venous system i s estimated to be s i x to eight times that of a r t e r i a l 39  system  .  The  transverse  sinusoids of the marrow drain d i r e c t l y  into the central venous sinus or into larger t r i b u t a r i e s 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 s p i r a l course around the straight central vein and pulsations i n the artery were assumed to be a driving force propelling the blood i n the thin wall vein, which cannot drive the blood forward by  itself.  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 p a r a l l e l to the a r t e r i e s and arteries.  leave the bone i n very close proximity to the 111 In the c o r t i c a l bone of human t i b i a  entering  , a vein accompanying  a r a d i a l l y arranged branch of the nutrient artery has been shown to drain into the central nutrient sinus. Relative Importance of Three A r t e r i a l Systems of Long Bone 79  Johnson  , by i n t e r f e r i n g with two out of the three sources of blood  supply of t i b i a i n dog,  concluded that the nutrient artery was  important source, being responsible  for the nourishment of the marrow as  well as the inner h a l f of the cortex, and was v i a b i l i t y of the entire shaft.  capable of maintaining  the  The metaphysial a r t e r i e s supported the  metaphysial regions, and were capable of nourishing nutrient artery.  the most  partly the area of  The periosteal a r t e r i e s , being the least important  supplied approximately  The  relative  the o u t e r h a l f of the c o r t e x .  importance  of the n u t r i e n t a r t e r y was  a l s o demonstrated  34 by K i s t l e r  , who  observed n e c r o s i s of the marrow and  some areas of the  c o r t e x a f t e r i n d u c t i o n of embolism w i t h p a r t i c u l a t e carbon nutrient a r t e r i a l  system, by i n j e c t i n g i n t o the femoral  i n the  artery.  74 Huggins and Wiege  found marrow i n f a r c t i o n  the femoral n u t r i e n t a r t e r y i n the  f o l l o w i n g l i g a t i o n of  rabbit.  48 F o s t e r , K e l l y and Watts  noted, by c u t t i n g the n u t r i e n t v e s s e l s  of the femur, t o g e t h e r w i t h s t r i p p i n g of i t s periosteum,  i t was  in-  v a r i a b l y f o l l o w e d by e x t e n s i v e i n f a r c t i o n of bone and o f bone marrow i n young, r a p i d l y growing r a b b i t s .  Impairment i n the r a t e of  c i r 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 i n l o n g i t u d i n a l growth was  found.  In animals approaching  the o p e r a t i o n produces v a r i a b l e r e s u l t s .  maturity,  These workers a l s o  emphasized t h a t l o s s of both e n d o s t e a l and p e r i o s t e a l b l o o d causes  delay  a complete i n f a r c t i o n of c o r t i c a l bone.  supply  I f the source of e i t h e r  one o f these b l o o d s u p p l i e s remained, f o c i o f v i a b l e c o r t e x p e r s i s t e d . By measuring the i n t r a m e d u l l a r y p r e s s u r e o f bone b e f o r e and  after  l i g a t i o n of the n u t r i e n t a r t e r y of t i b i a and humerus i n dogs, 30 Cuthbertson,  Siris  these bones f e l l  and G i l f i l l a n  immediately  found  the i n t r a m e d u l l a r y p r e s s u r e i n  and p r o f o u n d l y , but i n the m a j o r i t y of  cases, i t r e t u r n e d to p r e - o c c l u s i o n l e v e l s w i t h i n hours to Collateral circulations,  both e x t r a - o s s e o u s , and  days.  i n t r a - o s s e o u s , were  a p p a r e n t l y r e s p o n s i b l e f o r the r e s t o r a t i o n of i n t r a m e d u l l a r y p r e s s u r e . 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  v e r y much d i s p u t e d .  Johnson  79  believed they supply the outer h a l f of cortex.  De Marneffe  99  , as  136 cited by Shim  , believed that i n the rat, guinea-pig and rabbit  the nutrient artery was mainly responsible  for bone marrow n u t r i t i o n ,  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 p e r i o s t e a l a r t e r i a l supply was n e g l i g i b l e i n 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 s i t u a t i o n , such as i n a fracture, revascularisation from the periosteum help  to  r e i n s t i t u t e the endisteal c i r c u l a t i o n . 150 Trueta and Cavadias  , by s e l e c t i v e interruption of two of the three  sources of blood to rabbits' radius, demonstrated that the nutrient artery i s the main vessel to supply to the shaft of the radius, and i s responsible  f o r at least the i r r i g a t i o n of the whole of the marrow and  the inner two-thirds or three-quarters of i t s cortex.  The p e r i o s t e a l  vessels supplied the outer part of cortex and kept that part of the bone a l i v e i f the nutrient c i r c u l a t i o n had been suppressed. The metaphysial vessels alone are incapable of maintaining the marrow and deep h a l f of the cortex a l i v e , but a f t e r their union with the epiphysial vascular network following the fusion of the growth plate, enough blood flow i s provided to the nutrient artery through i t s d i s t i l branches to maintain the v i a b i l i t y of marrow and bone.  Simple d i v i s i o n  of nutrient artery does not cause any s i g n i f i c a n t e f f e c t on the v i a b i l i t y of the marrow.  In the young, the compensatory c i r c u l a t i o n comes from  p e r i o s t e a l , 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 c i r c u l a t o r y Strontium-85, studied the rates and r e g i o n a l d i s t r i b u t i o n s of the n u t r i e n t a r t e r i a l blood flow as w e l l as the rates of blood supply by the other a r t e r i a l systems of the femur i n the r a b b i t The rate of the n u t r i e n t a r t e r i a l blood supply was studied by evaluating the rate of reduction of bone blood flow immediately a f t e r l i g a t i o n of the n u t r i e n t a r t e r y .  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 d i a p h y s i s , w i t h i n f i v e minutes a f t e r l i g a t i o n of the n u t r i e n t a r t e r y From these data, i t was deduced that the n u t r i e n t a r t e r y supplies about 50% of the t o t a l blood supply of the e n t i r e femur, about 707„ of t o t a l blood flow of the s h a f t , 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 q u a n t i t a t i v e study 79  (1927), Trueta  corresponded with the q u a l i t a t i v e f i n d i n g s of Johnson and Cavadias (1964), and many others mentioned above. Nerve Supply of Bone According to Drinker and Drinker  36  , and Sherman  130  , Gros  62  , a  French anatomist, was the f i r s t one to demonstrate the presence of a nerve, which accompanied the n u t r i e n t a r t e r y i n t o the horse's femur and gave o f f twigs to the periosteum.  With more r e f i n e d techniques,  i n c l u d i n g s t a i n i n g with gold c h l o r i d e , osmic a c i d , or picrocarmine,  3a.  FIGURE 4  Micrograph of t r a n s v e r s e s e c t i o n o f bone, w i t h H & E s t a i n . I t sh the presence o f nerve bundles, i n c l o s e p r o x i m i t y to the n u t r i e n t v e s s e l s of bone.  and  then c r u s h i n g s m a l l b i t s of marrow, V a r i o t and  nerves which v a r i e d from 10 - 100  154  Remy  illustrated  miera i n diameter.  113 Ottolenghi  d e s c r i b e d t h r e e main groups of nerve  fibres,  w i t h i n the marrow c a v i t y : 1.  those which p e n e t r a t e and  the w a l l s of the  arterioles  form d e l i c a t e p l e x i f o r m networks between  a d v e n t i t i a and  the  the media;  2.  those which surround  3.  those which terminate  the  capillaries;  between the c e l l s of  the  parenchyma. The  vasomotor nature  „ experimentally  o f nerves of bone i s w e l l documented  . 3, by v a r i o u s authors  36,  presence of p a i n f i b r e s i s supported  by  L  47,  73,  135,  161  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  the nerve endings terminate Even though De  Castro  f i b r e s terminating  34  i s l i t t l e and  claimed  i n a r i n g on  o s t e o i d t i s s u e , and H u r r e l l  76  The  the common c l i n i c a l  that puncture o f the bone marrow, many bone tumors, and cause p a i n .  .  observations  osteomyelitis to where and  yet c o n f l i c t i n g  i n the  how  literature.  to have i d e n t i f i e d sympathetic nerve the p r o t o p l a s m of the o s t e o b l a s t s i n  b e l i e v e d t h a t nerve f i b r e s  extend 104  between bone l a m e l l a e , more r e c e n t s t u d i e s by M i l l e r et a l methylene b l u e immersion technique c a l c i f i e d bone, c o u l d not  on t h i n s e c t i o n s of f r e s h under-  s u b s t a n t i a t e such o b s e r v a t i o n s .  workers found the e p i p h y s i a l and m e t a p h y s i a l s m a l l mammals and  the s h a f t marrow by  foramen.  The  latter  ends of long bones both i n  i n humans to be s u p p l i e d by s m a l l m y e l i n a t e d  unmyelinated nerve f i b r e s and  using  from p e r i o s t e a l and  joint  and  capsular tissues,  f i b r e s e n t e r i n g the bone through the n u t r i e n t  Though i t i s b e l i e v e d t h a t some nerve f i b r e s e n t e r  c o r t e x through volkmann's c a n a l s , the exact  course  and  the bone  disposition  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 a r t i c u l a r cartilage are 86  Kuntz and Richins  demonstrated.  and M i l l e r  104  observed the presence of nerve  fibres i n 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 f i b r e s , 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 i n 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 i n tissue  incorporated i n the vessel wall, although the afferent nerve fibres are also found i n close association with the vascular structure. types of delicate arborizing structures suggestive of nerve  Various endings  86 have been described  .  Exact role of each, however, i s not completely  104 known yet Physiology of Bone C i r c u l a t i o n Methods of Study A comprehensive and concise c l a s s i f i c a t i o n of existing methods of 137 studying of bone c i r c u l a t i o n i s given by Shim 1.  Quantitative Studies:A.  Direct Methods r, -. • . 31, 29 167 ( I ) Cannulation - c o l l e c t i o n measurement ( i i ) Application of electromechanical flow meter  Indirect Methods (i)  Blood - tissue exchange mechanism. (a)  Fick's P r i n c i p l e  (b)  Radioisotope  25, 53, 132, (ii)  134  clearance  Indicator - d i l u t i o n p r i n c i p l e . 51 (a)  Radioisotope  (b)  Dye  (  163 Cr  42 K  86  148  Rb  )  (Evans blue) 40  (iii)  Venous occlusion plethysmography  Qualitative Studies:A.  Flow Pattern 14 (i)  V i t a l microscopy  (ii)  Bone venography  31, B.  145  Selective a r t e r i a l i s o l a t i o n to determine r e l a t i v e importance of a r t e r i e s (i)  Destruction or occlusion of certain 48, 79, 84, 96, 136,  150  vessels (a)  Study of d e v i t a l i z e d area.  (b)  E f f e c t on fracture healing or bone growth.  (c) (ii)  E f f e c t on r e l a t i v e isotope uptake.  Injection of indicators into an artery to 29 observe the area i t sustains  C.  Bone Hemodynamics (i)  Direct methods (cannulation). (a) (b)  Assessment of r e l a t i v e flow-volume 36, 135 changes Study of arteriovenous blood constituent.  (ii)  I n d i r e c t methods. 3, 67, 91, 144 (a) (b) (c) (d)  Intramedullary blood pressure 110 Intraosseous thermometry 166 Oxygen tension of bone Radioisotope uptake by or clearance 88, 152 from bone  A l t e r a t i o n of hemodynamics to stimulate growth, fracture r e p a i r , 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) L i g a t i o n of a major v e i n (vi)  A r t e r y or muscle p e d i c l e t r a n s p l a n t a t i o n _ to . bone 13, 51  Of a l l the c u r r e n t l y a v a i l a b l e q u a n t i t a t i v e and q u a l i t a t i v e methods, there are advantages as w e l l as l i m i t a t i o n s .  The p h y s i o l o g i c a l study  of bone c i r c u l a t i o n i s d i f f i c u l t due to the deep l o c a t i o n and r i g i d s t r u c t u r e , together with the numerous intraosseous as w e l l as extraosseous vessels forming complex anastomosis. The c a n n u l a t i o n - c o l l e c t i o n 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 t h i s study i n evaluating bone c i r c u l a t i o n . The use of d i r e c t cannulation of n u t r i e n t vessels of bone as an index of bone blood flow dated back to 1916, when Drinker and Drinker perfused an i s o l a t e d t i b i a of dog through the n u t r i e n t a r t e r y with a  36  13. pump.  They demonstrated the existence of vasomotor nerves to the  marrow, evidenced by decreasing blood flow through the cannula following e l e c t r i c a l stimulation of the nerve to bone marrow and i n j e c t i o n 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 e a r l i e r work. marrow was  their  The rate of flow of the perfusing blood from the  recorded, but no attempt was made to relate this to either  the weight of the tissue or i t s haemopoietic 29 Cumming  activity.  , assuming that the nutrient artery entering the femoral  shaft supplied a l l the marrow except a very small amount i n 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. i n the rabbit.  He also observed a 20% increase in the rate of blood flow through the bone marrow during the period of rebreathing. effect.  Hypoxia had  similar  Epinephrine decreased venous outflow. 135  Shim and Patterson  cannulated the nutrient vessels of femur  and humerus in the rabbit, and t i b i a i n the dog. blood through the canula was connected  The outflowing  introduced to a drop counting device  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 i s very  useful for q u a l i t a t i v e investigations of the r e l a t i v e changes of the hemodynamics of bone, but not a method of measurement of the t o t a l rate of blood flow through a given bone, as i t i s obvious that the measurement of blood flow through any one or two vessels of a bone would not give a t o t a l measurement since there are many a r t e r i e s and veins other  than the cannulated vessels.  They demonstrated the usefulness of  their method. Intramedullary Pressure 91 Larsen metaphysis,  , i n 1933,  inserted a s t e e l cannula into d i s t a l  while studying diaphyseal necrosis, and observed  femoral the  intramedullary pressure to be 30 - 40 mrriHg. and showed fluctuations related to a r t e r i a l pulsation. 12 Bloomenthal et a l  , while studying fat embolism, observed changes  in intramedullary pressure with pain s t i m u l i , nervous stimulation, to reflexes, to changes i n blood volume, and to a number of drugs.  They  regarded the intramedullary pressure as measured by the cannula, apparently a fusion of a r t e r i a l and venous pressure i s dependent upon the i n f l u x of blood from the artery and i t s return through the venous drainage. 103 Miles  measured pressure i n the femoral heads of over t h i r t y  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 i s s i g n i f i c a n t l y greater than the pulse pressure i n the epiphysis i n the same bone. 129 Shaw  , used heated thermocouple to measure bone blood flow, and  reported the d i r e c t relationship between intramedullary pressure and bone blood flow.  The v a l i d i t y of using a thermocouple to measure bone blood  flow i s , however, open to discussion.  15. Azuma  3  performed h i s t o l o g i c a l  i n t r a m e d u l l a r y p r e s s u r e , and found  s t u d i e s o f bone used f o r measuring t h a t the cannula a c t u a l l y  some venous s i n u s e s , a r t e r i a l s and v e n u l e s , with emerged i n an a r t i f i c i a l  ruptured  the t i p s  blood p o o l , and the i n t r a m e d u l l a r y p r e s s u r e  d i d n o t appear to r e p r e s e n t p r e s s u r e o f venous s i n u s e s .  T h i s view  67 was  supported  by Hawk and Shim  , and p r o b a b l y e x p l a i n e d  range o f i n t r a m e d u l l a r y p r e s s u r e recorded and  Shim, by measuring bone blood  v e s s e l s , and recorded  the wide  even i n the same bone.  f l o w by d i r e c t c a n n u l a t i o n o f n u t r i e n t  i n t r a m e d u l l a r y p r e s s u r e i n the same bone,  t h a t the i n t r a m e d u l l a r y p r e s s u r e  Hawk  concluded  i s bone blood flow dependent and  r e f l e c t s w e l l the changes i n the hemodynamics o f bone.  In this  thesis,  t h e r e f o r e , the methods used f o r e v a l u a t i o n of bone c i r c u l a t i o n i n hemorrhagic shock a r e the above methods of Hawk and Shim. Rate o f Bone Blood The  Flow  d i r e c t methods by c a n n u l a t i n g n u t r i e n t v e s s e l s o f bone a r e n o t  r e l i a b l e i n measurement o f a b s o l u t e r a t e o f bone blood f l o w as d i s c u s s e d 40 before.  Edholm e t a l  a p p l i e d venous o c c l u s i o n plethysmography to measure  bone b l o o d f l o w i n Paget's d i s e a s e , b u t the v a l i d i t y o f t h e i r method i s very doubtful. o t h e r than  T h i s method, o f n e c e s s i t y , i g n o r e s the r i c h supply o f v e s s e l s , the main n u t r i e n t a r t e r i e s w h i c h . c o n t r i b u t e to the c i r c u l a t i o n o f 110  the l o n g bones.  Thermocouples had been used by M c P h ^ s o n e t a l  method o n l y gave q u a l i t a t i v e i n f o r m a t i o n r a t h e r than q u a n t i t a t i v e .  , but t h i s There  a r e many l i m i t a t i o n s to the use o f heated thermocouples to measure blood flow. The thermocouple probe can sample o n l y a l i m i t e d amount o f t i s s u e and may o n l y r e f l e c t a p u r e l y l o c a l change i n blood flow.  Presence  of a  9 c l o t around the probe decreases  i t s sensitivity.  p o i n t e d o u t " t h e r e i s no standard  Bill  80 , as c i t e d by Kane  type o f 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 i s b l i n d l y introduced".  Matumoto and Mizuno  100  , according to Shim  137  i n d i r e c t method based on clearance of a radiopaque  , developed an dye;  the dye i s  injected into bone and using a theoretical exponential c o r r e l a t i v e curve, the clearance rate i s converted to blood flow of bone. The bone seeking c h a r a c t e r i s t i c s of various isotopes of calcium <u i andA strontium have been u t« -i- -l, i• z e dA uby many workers  24,  25,  53,  118,  132  as an indicator of bone blood flow.  Shim  132  , Copp and Shim  24  , described a method for quantitative  33 method using Sr  .  In 10 dogs they injected a non-diffusible plasma 85  dye (T-1824) and Sr  into the nutrient artery of t i b i a and i n the  next five minutes recovered 907= of the plasma dye and only 217« of the Sr  85  * from cannulated femoral vein.  the Sr  i n blood flowing through bone, compared to 907 removal of  diodrast by kidney. Sr  This indicated removal of 767> of o  They concluded that the i n i t i a l clearance of  should give a useful measure of bone blood flow and found this to  be 9 - 12 mm/min/lOOgrm of fresh weight of d i f f e r e n t bones i n adult 118 dogs and rabbits. Their method was considered v a l i d by Ray , and 153, 160, 163, 164 other workers gave comparable r e s u l t s , with d i f f e r e n t methods and isotopes. 138 Recently Shim et a l  measured the bone blood flow of various  bones i n the lower extremity i n a 26 year old man just before a highthigh amputation for osteogenic sarcoma of d i s t i l femoral using ^ S r clearance technique.  metaphysis,  The estimated bone blood flow was  2*5 c.c./min./100 gr. of wet bone i n human.  17.  SUMMARY OF LITERATURE REVIEW ON THE RATE OF BONE BLOOD FLOW Author  Year  Edholm et a l Frederizkson et al  Species  Flow ml/min.100 Sr.  1945 Plethysmography  Human  1- 0  1955  Ca  Rat  10 - 30  1957  45 Ca  Dog  2- 5 - 5-8  Cumming  1960  Venous C o l l e c t i o n  Rabbit (marrow)  41 - 51  Barnes et a l  1961  87 Sr  Human  1- 25  H o l l i n g et a l  1961 Plethysmography 85 1963 Sr  Dog  5-8 - 7-7  Rabbit  16-0  Dog  5- 6 mature  Copp  Shim  1963  Method  4 5  47  Ca  Weiman et a l  Ray  7'7 immature 1964  45 Ca  1964  Kane and Grim  1964  4 2  White and Stein  1965  5 1  Copp and Shim  1965  8 5  Sr  Rabbit) Dog )  9-12  Dog  12  C r RBC  Rabbit  16  Sr  Rabbit and Dog  10  Rat  10  Dog and Rabbit  13-2/12-5  Human  2- 43  K,  8 5  86  18 1965 1967  Shim et a l Shim et a l  4-9 mature 6- 5 immature  Copp and Shim  Van Dyke et a l  Dog  1971  8 5  F Sr  85 Sr  Rb  18. Rate o f 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 o f i n d i r e c t method o f bone c l e a r a n c e o f a c i r c u l a t i n g bone s e e k i n g r a d i o i s o t o p e , and assuming the t o t a l s k e l e t a l weight  to be a percentage  o f t o t a l body weight  (15% i n  138 human  ), the s k e l e t a l b l o o d flow e s t i m a t e d as percentage o f 138 r e s t i n g c a r d i a c output i s summarised i n the f o l l o w i n g t a b l e :  Author  Species  Percentage o f Resting Cardiac Output  Van Dyke e t a l  Rat  4- 3  Shim, Copp and P a t t e r s o n  Rabbit  7'1 + 2-3  Shim, Copp and P a t t e r s o n  Dog  7- 3  Ray, Aovadrand  Dog  3- 5 - 9-4  Galante  Weinman e t a l  Dog  Shim e t a l  +3-0  - mature  5- 0 - 7-0  - puppy  8- 0 - 10-0  Man  4- 7 - 6-3  The R e g u l a t i o n Mechanisms o f Bone Blood Flow Although n o t c o m p l e t e l y understood, t h a t bone b l o o d c i r c u l a t i o n  there i s accumulating  evidence  i s c o n t r o l l e d by n e u r a l , hormonal as w e l l  as m e t a b o l i c mechanisms.  Evidence The workers  f o r a N e u r a l C o n t r o l Mechanism  presence o f nerves 62,  recognised  113, 130, 154  i n bone have been demonstrated  by many  , and t h e i r vasomotor n a t u r e i s a l s o  well  3, 36, 47, 73, 135, 161  D r i n k e r and D r i n k e r isolated tibia  36  , by c a n n u l a t i o n o f the n u t r i e n t a r t e r y o f the  of the dog, demonstrated  the bone when the nerve  fibres  decrease o f b l o o d o u t f l o w  from  to the bone were s t i m u l a t e d e l e c t r i c a l l y .  19. Sympathetic Patterson  nerve trunk stimulation i n the rabbit by Shim and  135  had similar e f f e c t .  Weiss and Root  161  stimulated the  peripheral end of the cut s c i a t i c nerve and observed reduced marrow 3 pressure i n the t i b i a i n five cats.  Azuma  made similar observations  in the rabbit. 42 86 Using radioactive K and Rb to estimate bone blood flow by 148 f r a c t i o n a l d i s t r i b u t i o n of radioactive isotopes, Trotman and K e l l y demonstrated a 27% increase i n blood flow to the t i b i a i n the anaesthetised dog following lumbar sympathectomy.  E f f e c t , however,  disappeared completely nine x<?eeks l a t e r . 133 85 Shim et a l  , using  Sr clearance method, demonstrated the rate  of bone blood flow i n the side of s c i a t i c nerve section was generally increased by f i v e to f o r t y - f i v e percent i n the t i b i a , f i b u l a , talus and calcaneus.  A l l the above d i r e c t and indirect methods are suggestive  of a neural mechanism of control i n bone c i r c u l a t i o n . Evidence for a Hormonal Control Mechanism 36 Drinker and Drinker  observed decrease bone blood outflow i n the 12 dog's isolated t i b 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 i n the intramedullary pressure of bone following the administration 144 of epinephrine and norepinephrine i n experimental animals.  Stein  131 and Shim  observed a decrease i n , or arrest of, bone bleeding following  epinephrine infusion i n the dog. 29 Quantitative estimation by Cumming  132 , Shim  i n the rabbit, and  166 Woodhouse  i n the dog showed epinephrine reduced bone blood flow.  Shim  13 2  showed with 2 - 4  microgram/kg/min of intravenous  epinephrine i n f u s i o n , blood flow to t i b i a and humerus was  reduced  by 74 - 81%. Evidence f o r a Metabolic Control Mechanism There i s strong evidence that bone blood flow i s c o n t r o l l e d by metabolic factors such as a c i d metabolites, pH and oxygen and dioxide both at systemic and l o c a l l e v e l s .  carbon  Thus with rebreathing of  expired a i r , or a gas mixture low i n oxygen and high i n carbon d i o x i d e , Cumming 29 , Shim and Patterson 135 , were able to demonstrate an increase of blood outflow through the n u t r i e n t v e i n i n r a b b i t s . 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 a c i d , resulted  i n an increase of n u t r i e n t a r t e r i a l outflow, measured with e l e c t r o magnetic flowmeter by Woodhouse  .  Reactive hyperemia of bone a f t e r  femoral a r t e r i a l o c c l u s i o n was unabolished by e l e c t r i c a l s t i m u l a t i o n of nerve, or exogenous vasopressor Patterson *35_  drugs, was a l s o reported by Shim and  Their observations suggest that the metabolic c o n t r o l  mechanism maybe the most potent of the three control mechanisms mentioned above. SHOCK Definition I t i s very f r u s t r a t i n g to admit a subject so i n t e n s i v e l y studied as shock has no u n i v e r s a l l y 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 specificity.  The work has been used i n a number of d i f f e r e n t senses -  for example, as a c l i n i c a l d e s c r i p t i o n - by Cannon  or Weil  .  l a t t e r r e f e r r e d to shock as a d e s c r i p t i v e term used by c l i n i c i a n s to  The  21. denote a syndrome characterized by prostration and hypotension, and usually i s accompanied by p a l l o r , coldness and moistness of the skin, and collapse of, s u p e r f i c i a l veins, a l t e r a t i o n 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 c i r c u l a t o r y f a i l u r e " .  ,  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, i n that the word shock has been used i n a single and consistent sense, but the d e f i n i t i o n i s so loose as to lack c l a r i t y . "shock" i s no more exact than "fever",  Perhaps  but i t describes a group of  c l i n i c a l symptoms which require immediate attention i n order to improve blood flow.  The common thread in a l l form of shock i s an inadequate  c i r c u l a t i o n with diminished blood flow to tissue, r e s u l t i n g i n c e l l hypoxia and i t s seguelae ^.  Hardaway ^  4  defined shock as "inadequate  c a p i l l a r y perfusion due to any of many causes", and i s probably the most accepted one at present time, as i t describes the f i n a l common pathway of the shock syndrome. No a r b i t r a r y l i m i t or single parameter, either c l i n i c a l , physiological or laboratory, used alone, i s adequate to define shock. Where i s the l i n e 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 s i m i l a r i t y , but d i f f e r i n g in important details  .  Perhaps 20  we can be comforted by the philosophical approach of Cannon  (1923),  "It seems to me that, i n such a complex as shock, d e f i n i t i o n i s not a prime r e q u i s i t e .  The important matter i s to obtain a careful description  of the observed f a c t s " . H i s t o r i c a l 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 i l l n e s s 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, f i n a l sinking of v i t a l i t y , nervous shock, and violent mental emotion".  He attempted to c l a s s i f y  shock into those following s u r g i c a l operations and i n j u r i e s , and shock a r i s i n g from mental causes. Gross, according to Simone  described shock as  "a rude  unhinging machinery of l i f e " , as perhaps the most sagacious d e f i n i t i o n at  that time.  In the remainder of the 19th century, the term "shock"  was used very loosely. the  Pain and mental agitation were regarded upon  primary aetiology of shock. 28 Crile  i n i t i a t e d experimental studies i n animals in 1899.  He  ,  23. demonstrated and  that the h e a r t i s capable o f pumping b l o o d s u p p l i e d to i t ,  i m p l i c a t e d t h a t d y s f u n c t i o n o f the vasomotor c e n t r e and  the  p e r i p h e r a l c i r c u l a t i o n are the p o s s i b l e p h y s i o l o g i c a l e x p l a n a t i o n s in  shock.  68 Henderson  i n 1910  p o i n t e d out the important r e l a t i o n s h i p between  venous r e t u r n , c a r d i a c output and a r t e r i a l p r e s s u r e . 165 Wiggers in  1950,  era.  renowned monograph:  1  remained  The  P h y s i o l o g y o f Shock, p u b l i s h e d  the major r e f e r e n c e to the accomplishments o f t h a t  e x p e r i m e n t a l model o f hemorrhagic  a c l a s s i c a l model i n l a b o r a t o r y study of A s s o c i a t e d w i t h each major war  shock he d e s i g n e d , i s s t i l l  shock.  or c o n f l i c t  t h e r e was  i n c e n t i v e to b e t t e r c a r e , t o g e t h e r w i t h enthusiasm  on  u s u a l l y more  experimental  7 studies. of  During World War  wound shock f o l l o w i n g  animals.  The  I, B a y l i s s and  l a c e r a t i o n and  Cannon  s t u d i e d the  effect  c r u s h i n g o f muscle i n e x p e r i m e n t a l  s y s t e m i c 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 t i s s u e breakdown, without a p p r o p r i a t e a t t e n t i o n importance  of f l u i d  l o s s and  to  infection.  83 Keith  developed  the method of measuring  b l o o d volume by  dye  d i l u t i o n technique and began to r e a l i s e the volume d e p l e t i o n i n wound shock. The  interest  w o r l d wars.  The  i n s t u d y i n g shock p r o b a b l y d e c l i n e d r o l e of l o c a l t i s s u e f l u i d  t r a u m a t i c i n j u r y was  r e a l i s e d by B l a l o c k  d e f i c i e n c y o f the a d r e n a l c o r t e x i n shock was  i n between the  l o s s e s i n t o l o c a l areas of The  possible  investigated.  functional 147  During the Second World War,  there was  renewed  i n t e r e s t , with  emphasis on the importance of volume depletion, i n f e c t i o n and failure.  Shock was  renal  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 i n  cardiac output in r e l a t i o n to f l u i d loss in patients, and opened a new  thus  era for investigation of shock.  After the Second World War, of blood flow and  studies began to focus on  evaluation  the functional i n t e g r i t y of various systems and organs.  The blood supply, mechanism of control of regional c i r c u l a t i o n , including cerebral, pulmonary, hepatic, renal have been extensively studied.  Hole of micro c i r c u l a t i o n , association with slugging, or  embolic occlusion was  also brought into notice.  In the Korean c o n f l i c t , the syndrome of o l i g u r i c renal f a i l u r e following shock, was  a major cause of death.  In the recent Vietnam c o n f l i c t , improved therapeutic measures made i t possible to maintain l i f e inconsistent x^ith s u r v i v a l only a decade ago.  Also with improved diagnostic tools, i t became possible  to demonstrate respiratory and c i r c u l a t o r y function better than ever before.  A new  syndrome, referred to at various  lung, non-infectious  times as the shock  congestive a t e l e c t a s i s , the adult equivalent  the respiratory distress syndrome of the newborn, the pulmonary equivalent  of acute tubular necrosis, or post traumatic  lung,  was  brought into focus  The  changes i n the subcellular l e v e l , such as a l t e r a t i o n s of  mitochondria  35,  102  , lysosomal  disruption  8  , nuclear ribonucleic  of  acid synthesis  92  o f v a r i o u s organs i n shock, a r e c u r r e n t t o p i c s of  medical research.  Abnormal P h y s i o l o g i c a l A s p e c t s  of Shock  Hemorrhagic shock i s the e x p e r i m e n t a l model used t h e r e f o r e our d i s c u s s i o n w i l l  in this  study,  be mostly on t h i s type of shock.  abnormal changes i n shock a r e innumerable,  but we w i l l attempt  The to d i s c u s s  them under:  A.  Neural  Aspects  B.  Hormonal A s p e c t s  C.  Metabolic Aspects  Knowing t h a t c o n t r o l of bone b l o o d c i r c u l a t i o n i s b a s i c a l l y r e l a t e d n e u r a l , hormonal and m e t a b o l i c mechanisms, we hope to c o r r e l a t e  with  the  abnormal p h y s i o l o g i c a l a s p e c t s i n shock, w i t h the changes i n bone blood c i r c u l a t i o n i n shock.  Neural  Aspects  In hemorrhagic shock, hypovolemia,  or decreased  effective  c i r c u l a t i n g b l o o d volume s t i m u l a t e the autonomic nervous system. Hypovolemia c o u l d be due  to e x t e r n a l or i n t e r n a l hemorrhage o r  s e q u e s t r a t i o n of f l u i d or v a s c u l a r p o o l i n g . i s decreased,  f o l l o w e d by decrease  Venous r e t u r n to the h e a r t  i n c a r d i a c output w i t h decreased  b l o o d p r e s s u r e which s t i m u l a t e b a r o r e c e p t o r s and f o r c e of c o n t r a c t i o n . Blood  Thus the sympathetic  flow to the s k i n , s k e l e t a l muscles,  arterial  i n c r e a s e h e a r t r a t e and  nervous system i s  kidneys and  alarmed.  s p l a n c h n i c bed i s  economized by both a r t e r i a l and venous v a s o c o n s t r i c t i o n i n o r d e r to r e d i s t r i b u t e b l o o d to more v i t a l organs,  particularly  the h e a r t and  brain.  I t i s generally accepted  that as blood is l o s t , the cardiovascular  system adjusts to accommodate the smaller volume and that, i n i t i a l l y , this adjustment i s mediated by the vasomotor nerve aided along by an increase of plasma l e v e l of catecholamines, vasomotor tone  115  .  Page and A b e l l  114  resulting i n increase  studied the caliber of blood  vessels through micro windows placed i n rabbits' ears and i n the mesentery.  Vasoconstriction was  shock by various means.  shown regularly in early stages of  Moderate vasodilation only occurs shortly 55  before death.  Gernandt  demonstrated efferent impulses i n 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 a f t e r hemorrhage, a further drop of a r t e r i a l  pressure  with sectioning of the sinus nerves. Hormonal Aspects Hormones are b i o l o g i c a l l y active substances discharged  by  glandular tissues into the c i r c u l a t i o n and are transported to tissues where they regulate the rates of important metabolic processes.  The  hormones are s t r u c t u r a l l y 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 a l  , by cannulation of adrenal vein and  c o l l e c t i n g the adrenal venous blood. photofluorometric method.  The  Catecholamines were measured by  level i n dogs twenty-four hours a f t e r  operation, more l i k e l y to represent values to be expected in the normal intact dogs, are i n 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. catecholamines  secretion.  Barbiturate anaesthesia  lowered  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  i n the adrenal vein blood.  The increase was due  primarily and i n i t i a l l y to an increase i n concentration rather than norepinephrine i n the adrenal venous blood.  Early retransfusion of  the lost blood or blood substitute immediately and d r a s t i c a l l y  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 t o t a l blood volume decrease, the average concentration of epinephrine increased from 1-0 to 7*8 u g / l i t r e of plasma, and norepinephrine increased from 2*5 to 3*6 ^ i g / l i t r e of plasma. Adrenal Corticosteroid Secretion Graded hemorrhage resulted i n depletion of adrenal ascorbic acid in rats, suggestive of c o r t i c o i d 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 i n increased secretion of 17- Hydroxycorticosteroid.  Some workers ^ '  secretion of c o r t i c o i d steroid unchanged or decreased.  reported  Such 50, 157  discrepancy i s explained by the fact that the l a t t e r group of workers subjected the animals to a profound degree of hypotension, with very marked decrease of adrenal blood flow.  The calculated secretion rate  i s lowered even though there i s increase of steroids i n adrenal venous  blood  157  .  Hume and Nelson  75  showed that the adrenal cortex i s  capable of maintaining high l e v e l s of c o r t i c o i d s e c r e t i o n even i n severe shock, i n s p i t e 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 c o r t i c o i d output i s reduced.  Reinfusion of l o s t blood r e s u l t e d i n r a p i d return of 54, 75  s e c r e t i o n of c o r t i c o i d s t e r o i d s to c o n t r o l l e v e l s  '  .  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 perfusion.  the already poor c o r t i c a l  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 f u n c t i o n a l damage.  Mack et a l  suggested  that the s e n s i t i v i t y of the adrenal cortex to a d r e n o c o r t i c o t r o p i c hormone i n hemorrhagic shock was not a l t e r e d , based on t h e i r studies i n hypophysectomised dogs, given exogenous ACTH, and then subjected to hemorrhage.  In such hypophysectomised animals, there was a decrease of  adrenal c o r t i c o s t e r o i d s e c r e t i o n s , which could be restored to normal l e v e l s with systemic or l o c a l i n f u s i o n of s a l i n e i n t o lumboadrenal artery.  From such s t u d i e s , i t would appear the i n t e g r i t y of the  hypothalamus, with i n t a c t ACTH s e c r e t i o n , i s important f o r the increase of c o r t i c o s t e r o i d s e c r e t i o n i n shock. Aldosterone Aldosterone acts p r i m a r i l y 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. i s retained and potassium s e c r e t i o n i n urine i s increased.  Sodium  This hormone  i n f a c t regulates cardiac output by increasing the end d i a s t o l i c volume  and c o n s e q u e n t l y  the s t r o k e volume.  In a d d i t i o n , a l d o s t e r o n e  p o t e n t i a t e s the v a s o c o n s t r i c t o r a c t i v i t y of n o r e p i n e p h r i n e peripheral resistance.  Increase of a l d o s t e r o n e output 44,  in  and  increases  i n dogs and  man  46  acute hemorrhage have been demonstrated  .  Mulrow  and  107 Ganong  confirmed  t h i s , and  demonstrated  a mechanism independent o f the p i t u i t a r y  i n hypophysectomised  dogs,  s t i m u l a t i o n i s present i n  a l d o s t e r o n e s e c r e t i o n i n hemorrhage. Angiotensin A n g i o t e n s i n , s e c r e t e d i n response glomerular  cells  to r e l e a s e of r e n i n from the j u x t a -  of the k i d n e y s , produces i n c r e a s e d a l d o s t e r o n e s e c r e t i o n .  A n t i d i u r e t i c hormone, r e l e a s e d by p o s t e r i o r p i t u i t a r y , reabsorbs water i n ' :  excess  of s o l u t e by d i s t i l  convoluted  hormones i n shock a r e b e l i e v e d to be  6, Metabolic  tubules. i n c r e a s e d ^'  s e c r e t i o n s of  both  .  159  Aspects  There i s a g e n e r a l p a t t e r n o f m e t a b o l i c metabolites not  The  specific  changes, i n v o l v i n g almost a l l  so f a r s t u d i e d , c h a r a c t e r i s t i c of the shock syndrome, but to i t .  In recent years  the b i o c h e m i c a l a l t e r a t i o n s t h a t  occur as shock p r o g r e s s e s , a r e o f t e n a s c r i b e d to h y p o x i a , r e s u l t i n g decrease  and  inadequate  tissue perfusion.  a e r o b i c o x i d a t i o n through t r a n s p o r t system and  later  decreased  the Kreb's t r i c a r b o x y l i c a c i d c y c l e and  an i n c r e a s e i n anaerobic  Meyerhoff pathway, i s observed. i n i t i a l l y , but  C e l l hypoxia,  g l y c o l y s i s by  L a c t a t e and pyruvate both  l a c t a t e i n c r e a s e s more than pyruvate.  a c i d m e t a b o l i t e s produce m e t a b o l i c  acidosis.  Blood  from  the  electr  the Embden increase Increased  pH and carbon  dioxide  CO content  f a l l and  i n more profound  p  2 may  be decreased  shock, decrease  by pulmonary v e n t i l a t i o n .  i n pulmonary f u n c t i o n may  r e s p i r a t o r y a c i d o s i s , superimposed on a m e t a b o l i c  acidosis.  Later,  result in Early  development of azotemia r e f l e c t s an increased metabolic  turnover  of c e r t a i n t i s s u e proteins with an increased t i s s u e breakdown, and a decrease i n urine output.  F a l l i n serum sodium c h l o r i d e , a r i s e  i n serum potassium, and a reduced u r i n a r y e x c r e t i o n of sodium, c h l o r i d e and water are c h a r a 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 P e r i p h e r a l Resistance Total p e r i p h e r a l resistance  = Mean A r t e r i a l Pressure Cardiac Output  49 Fowler and Franch  showed questionable decrease of t o t a l p e r i p h e r a l  r e s i s t a n c e , by bleeding dogs a t 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 190%.  , however, showed the t o t a l peripheral r e s i s t a n c e increased by 165 V a r i a b i l i t y of f i n d i n g s was noted by Wiggers  Coronary C i r c u l a t i o n The coronary flow i n humans may be estimated with reasonable 10, 38, 60, 122  accuracy  by the use of n i t r o u s oxide i n h a l a t i o n method A p p l i c a t i o n of F i c k ' 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 r a t e .  Coronary  flow and coronary resistance are g r e a t l y decreased, though the coronary 42 flow f r a c t i o n of cardiac output i s increased  .  Coronary flow i s  g e n e r a l l y greater, and the r e s i s t a n c e generally l e s s than can be 112 accounted f o r , by a simple d e c l i n e i n a r t e r i a l blood  pressure  With the use of electromagnetic flowmeters which were c h r o n i c a l l y  31. implanted on the l e f t coronary artery as well as the aorta and 61 various systemic a r t e r i e s  , the experiments confirmed  previous  findings - the coronary c i r c u l a t i o n shows a decreased vascular resistance during hemorrhagic shock. Cerebral C i r c u l a t i o n i n Shock 146  Stone et a l  measured cerebral blood flow i n volunteers  subjected to hemorrhage, using nitrous oxide method.  Hemorrhage  of 20 - 387. of blood volume, resulted i n decrease of cerebral blood flow, but cerebral vascular resistance also decreased.  Hyperventilation  led to respiratory a l k a l o s i s , decrease i n a r t e r i a l C02 and cerebral vasoconstriction.  Intravenous morphia improved cerebral blood flow,  by depressing respiratory and restored Co^ tension to normal l e v e l s . 45 Fazekas et a l  found the cerebral vascular resistance was  not 123  s i g n i f i c a n t l y altered i n patients i n shock .  Rutherford et a l  ,  with the use of labelled microspheres, demonstrated a 567. decrease of cerebral vascular resistance i n early shock, and a 167. increase i n 2 (3 late shock.  Corday and Williams  ,with photoelectric dropmeter i n  dogs, demonstrated an increase of cerebral vascular resistance as blood pressure was  lowered.  The considerable differences of opinion i n the  l i t e r a t u r e are probably due to difference i n techniques employed, and p a r t l y r e f l e c t the variations i n the experimental conditions and 26 d i f f e r e n t species of test animals  Renal C i r c u l a t i o n i n Shock Renal blood flow estimated by PAH clearances d i f f e r e d from those 124, 126 obtained by a d i r e c t method  .  In dogs bleeding to drop the  a r t e r i a l blood pressure to 60 mmHg. d i r e c t renal flow measurement was 417, of control, while clearance was  zero, because of anuria  32. p r e s e n t a t t h i s l e v e l of blood p r e s s u r e .  D i r e c t measurement by  124 Selkurt graded  suggested  t h a t the r e d u c t i o n i n r e n a l blood  hemorrhage was  g r e a t e r than produced by reduced  a r t e r i a l p r e s s u r e , which a l s o suggests has  occurred.  flow i n a head of  that a c t i v e v a s o c o n s t r i c t i o n  R e s u l t s of Corday and W i l l i a m s  marked i n c r e a s e of r e n a l r e s i s t a n c e i n shock.  26  a l s o demonstrated 59  Green and  Kepchar  s t a t e d t h a t b l o o d i s shunted  away from the kidneys more than  any  o t h e r organs i n shock.  kidneys are h i g h l y r e a c t i v e and  also  The  123 n o r m a l l y r e c e i v e a h i g h share (20%) of c a r d i a c output. Rutherford demonstrated minimal change of v a s c u l a r r e s i s t a n c e i n e a r l y stages of shock, and  an 80% i n c r e a s e i n l a t e hemorrhagic shock i n dogs.  125 Selkurt  plotted  the response  of blood flow to p r o g r e s s i v e decrement  of e f f e c t i v e p e r f u s i o n p r e s s u r e by l o w e r i n g the a r t e r i a l applying a o r t i c T h i s was  compression,  i n a study of " p r e s s u r e - f l o w "  the same i n the i n t a c t as i n the  denervated  Hemorrhage appeared to a b o l i s h the c o n c a v i t y of the  flow r e l a t i o n s h i p .  T h i s suggests  pressure  t h a t the r e n a l 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 rather  relationship.  concave to the p r e s s u r e a x i s i n a range of 14 to 117 mmHg..  R e s u l t s were e s s e n t i a l l y kidney.  pressure  factors  than by n e u r a l mechanism.  S p l a n c h n i c 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 s t a n d a r d i s e d hemorrhagic shock, S e l k u r t 127 et a l  observed  t h a t the s p l a n c h n i c v a s c u l a r r e s i s t a n c e d i d not  increase s i g n i f i c a n t l y during hypotension, t r a n s f u s i o n , there was the m e s e n t e r i c  and  that f o l l o w i n g  a phase of marked r e d u c t i o n , p a r t i c u l a r l y i n 94 component. Levy demonstrated no i n c r e a s e of  s p l a n c h n i c r e s i s t a n c e d u r i n g hemorrhage, though i n f u s i o n of n o r e p i n e p h r i n e d u r i n g hemorrhage r e s u l t e d  i n double  the  resistance.  69 , with r a d i o i s o t o p e t e c h n i q u e , demonstrated a 38»47o  Henly e t a l decrease  i n p o r t a l b l o o d f l o w i n Wiggers' graduated  hemorrhage.  120 Reynell et a l  r e p o r t e d t h a t , a f t e r an acute hemorrhage,  s p l a n c h n i c blood f l o w decreased and  i n p r o p o r t i o n to c a r d i a c o u t p u t ,  t h a t s p l a n c h n i c v a s c u l a r r e s i s t a n c e rose o n l y 24%  whereas the t o t a l p e r i p h e r a l r e s i s t a n c e r o s e 90%  above c o n t r o l ,  above c o n t r o l .  123 Rutherford et a l  , with l a b e l l e d microsphere,  i n c r e a s e of s p l a n c h n i c  demonstrated a marked  ( p o r t a l v e i n ) r e s i s t a n c e , though the h e p a t i c  ( a r t e r i a l ) r e s i s t a n c e a c t u a l l y decreased. S k i n and Muscle C i r c u l a t i o n i n Shock 57 Green, Cosby and Lewis before a r t e r i a l  p r e s s u r e changed, and  a o r t i c mean p r e s s u r e f e l l v a s c u l a r r e s i s t a n c e i s due discharge.  reported skin c i r c u l a t i o n  to 60  - 80  partially  s k i n blood f l o w stopped mmHg.  The  i n c r e a s e of  to augmented  However, under s i m i l a r e x p e r i m e n t a l  muscle a r t e r y lumen was  decreased  often dilated.  c o n d i t i o n s , the  I n f o r m a t i o n about muscle  Dale and  showed s m a l l doses of e p i n e p h r i n e caused denervated  skin  sympathetic  32, c i r c u l a t i o n i n shock i s fragmentary.  when  33  Richards  v a s o d i l a t i o n i n the  muscles of the c a t ' s h i n d limb.  The  a c t i o n of e p i n e p h r i n e  19 i n a p i e c e of smooth muscle can be b i p h a s i c both v a s o d i l a t i o n and v a s o d i l a t i o n a r e due  .  I t i s probable  v a s o c o n s t r i c t i o n phases of the. i n i t i a l  that  transient  to a d i r e c t b i p h a s i c a c t i o n of e p i n e p h r i n e on  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 b e f o r e v a s o c o n s t r i c t i o n , and i n any  given  i n f u s i o n o f e p i n e p h r i n e , the degrees  vaso-  of the v a s o d i l a t i o n and  the  c o n s t r i c t i o n are usually equal.  Norepinephrine  given i n t r a -  a r t e r i a l l y , i n animals or man, constricts muscle vessels i n a l l 162 e f f e c t i v e doses . I f i t i s given intravenously i n animals, the constrictor action may be overcome by use of systemic blood 23 pressure  , or by r e f l e x vasodilation of the sympathetic  nerve  5 origin . In skin c i r c u l a t i o n , both epinephrine and norepinephrine given subcutaneously or by slow intravenous infusion, caused severe blood flow reduction  5 , 41 ' .  I t i s reasonable to assume that skin  c i r c u l a t i o n and muscle c i r c u l a t i o n may behave d i f f e r e n t l y i n shock. 123 Rutherford et a l  , with labelled microsphere,  demonstrated that  vascular resistance of lower extremity markedly increased i n shock, with 186% and 108% i n early and late stages qf shock respectively. This, however, would represent the o v e r a l l change i n vascular r e s i s tance i n the skin, muscle and bone i n the lower extremity. To sum up, there i s evidence that various organs' vascular beds behave d i s t i n c t l y d i f f e r e n t i n shock, and neurohormonal and metabolic factors play important roles. though i t i s generally agreed  Much controversy s t i l l that blood i s shunted  exists,  i n shock to the  myocardium and brain from other regions such as kidneys, skin and splanchnic c i r c u i t s . MATERIALS AND METHODS General Set Up (Figure 5) 35 male mongrel dogs weighing 8 - 3 3 study.  kilograms were used i n this  Sodium pentobarbitol (nembutal) 30 mg/kg was given i n t r a -  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 r i g h t b r a c h i a l a r t e r y was cannulated to measure systemic blood pressure, T i b i a l n u t r i e n t a r t e r y or v e i n 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 i n the multichannel Physiograph. The r i g h t common c a r o t i d a r t e r y was cannulated and connected to the "Bleeding Reservoir".  repeated every two to three hours. and the abdomen were shaved.  The extremities, anterior chest,  The right brachial artery was  cannulated  with a large polyethylene tube and connected to a pressure transducer, and the blood pressure was physiograph.  continuously recorded i n the multi-channel  The right external jugular vein was  the central venous pressure continuously.  cannulated to monitor  The right common carotid  artery was also cannulated with a polyethylene tube and was to the bleeding reservoir.  (Figure 6).  It has a two-litre p l a s t i c bag,  containing 200 n l heparinised saline, and connected v i a rubber tubing with a three-way tap.  connected  to the venous system  The p l a s t i c bag i s placed i n a  water-cylinder and any inflow of blood into the p l a s t i c bag w i l l displace water i n the cylinder and amount of water displacement in another graduated cylinder.  i s recorded  Thus the amount of bleeding volume  can be read i n this graduated cylinder.  The hydrostatic pressure  in the p l a s t i c bag i s controlled by the l e v e l of water in the graduated cylinder.  Three electrodes, the l e v e l of which are adjustable, are so  designed that their tips just dip into the water in the graduated cylinder, and any further changes i n l e v e l of water w i l l r e s u l t in automatic adjustment  of the water height of the graduated cylinder by  an e l e c t r i c motor.  Sodium n i t r i t e i s added to saturate the water i n  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 i n the solution. predetermined  With this apparatus  the animals can be bled to a  l e v e l of blood pressure, and a r t i f i c i a l l y maintained at  such l e v e l for a considerable time.  Intravenous medications and  replacement were given v i a l e f t forearm vein.  During surgical  procedure, slow l.V. saline and Dextran replacement maintain a constant central venous pressure.  were given to  fluid  FIGURE 6  The "Bleddin^ Reservoir" used i n Experiment. Blood volume l o s t was measured by changes i n the volume i n the graduated c y l i n d e r . The l e v e l of systemic blood pressure i n the animal was c o n t r o l l e d 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 t i p s of the electrodes just emerged i n t o the sodium n i t r i t e s o l u t i o n i n the graduated c y l i n d e r .  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 extended  .  Skin i n c i s i o n  from three inches below the knee to two inches above the  ankle i n 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 s e l f - r e t a i n i n g 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 . area.  The nutrient vein can usually be found i n the same  Muscular branches of the anterior t i b i a l vessels were a l l  l i g a t e d , and the main vessel was catheter (PE 50 to 90). of  the t i b i a was  then cannulated with a polyethylene  Thus the nutrient a r t e r i a l or venous outflow  then measured by a drop counting device, and continuously  recorded i n the physiograph. Bone Marrow Cavity Pressure The subcutaneous anteromedial surface of the t i b i a was i n s e r t i o n of cannula.  chosen for  A steel d r i l l , with a diameter of 0*093 i n , was  inserted from this anteromedial surface near the diaphysis, followed by a No. 13 gauge steel cannula inserted into the medullary cavity. cannula was connected  to a pressure transducer with a polyethylene tube  f i l l e d with heparinised saline. in the physiograph.  The  The pressure was continuously recorded  I t i s important to prevent any gas bubble i n the  tubings, i n order to have sensitive recording.  Transperitoneal Lumbar Sympathectomy In f i v e dogs, the r i g h t lumbar sympathetic  trunk was i d e n t i f i e d v i a  a midline i n c i s i o n , with transperitoneal approach.  E l e c t r i c a l stimulation  with voltage 12, and frequency 200/sec, was applied i n each case to  37. c o n f i r m the anatomy, by o b s e r v a t i o n of the e f f e c t of s t i m u l a t i o n on these  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  tibia.  In  f i v e dogs , b i l a t e r a l c a n n u l a t i o n of t i b i a l n u t r i e n t v e s s e l s  c a r r i e d o u t , and  subsequently  observe the e f f e c t of  subjected  of D i b e n z y l i n e  sympathectomy. 56  (Phenoxybenzamine)  This alpha-receptor venously  b l o c k i n g agent, was  g i v e n i n f o u r dogs,  a t a dosage of 2 mg/kg over a p e r i o d of a t l e a s t one  a l p h a - r e c e p t o r b l o c k i n g e f f e c t was dosage of 0>3  was  to the shock procedure to  22, Use  electrical  t e s t e d by e p i n e p h r i n e  - 1 ug/kg/min, and by lumbar sympathetic  s t i m u l a t i o n i n each animal  before  the animal  was  intra-  hour.  The  infusion, at a  chain  subjected  electric  to hemorrhagic  shock. I n d u c t i o n and Prior  S u s t a i n i n g of Hemorrhagic Shock  to s h o c k i n g  the a n i m a l s ,  the systemic blood p r e s s u r e ,  r a t e , r e s p i r a t o r y r a t e , c e n t r a l venous p r e s s u r e , bone blood measured by number of drops per u n i t time, and were a l l r e c o r d e d .  They served  hemorrhage w a s done by b l e e d i n g to about 25  estimated All  - 5- ml/min., and  at this  A f t e r one  stage of  to one  into  pressure  I n d u c t i o n of  the r e s e r v o i r ,  t h i r d of e s t i m a t e d  blood  adjusted  volume, 169  animals  i n the c o n t r o l phase were r e p e a t e d l y experimentation.  t h i r d of blood volume was  dropped s i g n i f i c a n t l y . and  the c o n t r o l v a l u e s .  che animals  f l o w as  intramedullary  as 87« of the t o t a l body weight of the. i n d i v i d u a l  the parameters recorded  recorded  as  pulse  b l e d , the systemic  At t h i s s t a g e , f u r t h e r b l e e d i n g was  blood  pressure  inducted,  the l e v e l s of the e l e c t r o d e s i n the b l e e d i n g r e s e r v o i r were a d j u s t e d  to lower the systemic  blood p r e s s u r e  step by s t e p , 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 a t a r a t e 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 c e n t r a l venous pressure a l s o gradually f e l l and  so d i d the intramedullary pressure. II  E f f e c t of One Third of Estimated Blood Volume Loss (Figure 8) Control  One Third Blood Volume Loss  Systemic B.P.  100/!, (150.5 + 5.8 mmHg.) standard error  55-2 + 5-1% standard error (range 30 - 80%)  Bone Blood Flow  100%  22'5 + 3-4% standard error (range 8 - 45%)  Intramedullary Pressure  55 + 8-2 mmHg. (25 - 130 mmHg.)  Not recordable  Pulse Rate  88 + 9'6/min. standard e r r o r  112 + 10-2min. standard error  Respiratory Rate  3-8 + 1-2/min. standard error  8*2 + 1-5/min. standard error  Central Venous Pressure  4-2 + 0-8 cm H0 standard error  - 1-2 + 0-3 cm H„0 standard error (range - 3 to + I cm H 0)  2  III  2  E f f e c t of Prolonged Hemorrhage In a l l dogs, the systemic blood pressure was brought down stepwise  by 10 - 15 mmHg., and kept steady f o r \ - h hour, and eventually maintained around 30 - 35 mmHg., u n t i l eventually a l l the animals exsanguinated. duration of experiment v a r i e d from four hours to eighteen hours.  The  During  t h i s time, bone blood flow remained decreased and the intramedullary  38a. FIGURE 7  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 i n central venous pressure, t i b i a l intramedullary pressure and t i b i a l nutrient a r t e r i a l retrograde flow, which was measured by a mechanical dropmeter. Each v e r t i c a l stroke represents one drop of blood.  FIGURE 8  DOG  #12b  Hemorragic Shock [Vz blood volume loss) B. P. 50-  £  Of  2  C. V.P.  O  CN  E  o.  05 X E E  TIBIAL IMP 20100-  BONE BLOOD (Tibial Nutrient Arterial Retrograde Flow)  The E f f e c t s of Acute Blood Loss with one t h i r d of estimated blood volume removed. Note the f a l l of systemic blood pressure and c e n t r a l 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 n u t r i e n t a r t e r i a l retrograde flow, a l s o decreased.  39. pressure of bone f e l l to unrecordable IV  level.  E f f e c t of Re-infusion of Lost Blood (Figure 9) When lost blood was re-infused into the dogs, f i f t e e n minutes to  six hours a f t e r induction of hemorrhage, at a rate of about 50 min.,  - 100  ml/  the systemic blood pressure, central venous pressure, t i b i a l  intramedullary pressure and bone blood flow were f u l l y or p a r t i a l l y returned to control values. animal was V  The longer the duration i n which the  i n shock, the less complete was  the recovery  observed.  Relationship between Bone Blood Flow and Systemic A r t e r i a l Pressure (Figure 10) In ten dogs, the percentage  f a l l of systemic blood pressure  plotted against the percentage decrease of bone blood flow.  was  The  curve  is not a straight l i n e , but rather an exponential one with concavity towards the flow axis.  VI  The curve intercepts the pressure axis at  E f f e c t of E l e c t r i c a l Stimulation of Lumbar Sympathetic (Figure 11) Right lumbar sympathetic  chain of five dogs was  Chain  i d e n t i f i e d , and  e l e c t r i c a l stimulation with voltage of 12v, and frequency of 200 second was applied i n each.  157o.  per  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 i n a l l f i v e dogs. VII  E f f e c t of Lumbar Sympathectomy A.  Before Induction of Hemorrhagic Shock (Figure  Sympathectomy of right lumbar trunk was  performed i n five dogs,  in which b i l a t e r a l cannulation of nutrient vessels was During the s u r g i c a l procedure,  compression  12)  carried out.  of the i n f e r i o r vena cava  caused a r i s e of intramedullary pressure of both l e f t and right  tibia,  FIGURE 9  DOG #12c Recovery Stage of Hemorragic Shock by Transfusion of Lost Blood  150-i  10050-  0  1  C.v.p.  10-  1 4-  CO  x  TIBIAL IMP  203 10 J  BONE BLOOD FLOW (Tibial Nutrient Arterial Retrograde Flow) i I I I i I i i i ij | !i!  l l  i — r  Re-i  nfusion i  ||  Time (5 second intervals)  The Effects of Re--infusion of Lost Blood, 6 hours a f t e r 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 i n systemic blood pressure i n hemorrhagic shock.  FIGURE 11  DOG #25 SYSTEMIC B.P  3CH TIBIAL NUTRIENT VENOUS OUTFLOW  Illllllliiiilium i i iiiu u i\  mi'.niiiUKi'iiiiuutmuii i i \ i  off  on  11  iHii u \  \in  111  Time (5 second intervals)  •ft  Electrical Stimulation of Lumbar SYMPATHETIC CHAIN Volts 12 2.0 MsD Freq. 200  The E f f e c t s 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 n u t r i e n t venous outflow were demonstrated.  39d. FIGURE 12  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 o f Sympathectomy o f R i g h t Lumbar Trunk on Bone Blood Flow. Compression on the i n f e r i o r vena cava d u r i n g s u r g i c a l procedure, r e s u l t e d i n venous c o n g e s t i o n , with i n c r e a s e of i n t r a m e d u l l a r y p r e s s u r e o f both t i b i a , and r i g h t t i b i a l n u t r i e n t venous o u t f l o w . Note the i n c r e a s e o f r i g h t t i b i a l i n t r a m e d u l l a r y p r e s s u r e , 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 n u t r i e n t venous o u t f l o w was a l s o s i g n i f i c a n t l y i n c r e a s e d a f t e r sympathectomy.  40. but i t was coupled with an increase of nutrient venous outflow indicating bone venous congestion. effect.  This was purely a mechanical  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 t i b i a i n four of the f i v e dogs.  B. In  After Induction of Hemorrhagic Shock the same five dogs, bone blood flow was studied a f t e r induction  of hemorrhagic shock.  The bone blood flow as measured by d i r e c t  cannulation on both sides was compared and plotted as percentage change i n respect to percentage change of systemic blood pressure (Figure 13). In a l l five dogs, there was s i g n i f i c a n t l y less decrease i n percentage of bone blood flow i n 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„ l e v e l of the control pressure, and persisted u n t i l the systemic blood pressure f e l l to 30% l e v e l of the control.  The difference i n percentage of  bone blood flow between sympathectomised and control side ranged 10 - 30 percent with an average of 16 percent.  from  Control studies were  carried out i n two dogs, i n which b i l a t e r a l 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 i n the right and l e f t side i n these two animals was p r a c t i c a l l y the same on both sides, well within 57« range of difference from each other.  FIGURE 13  EFFECT OF SYMPATHECTOMY ON BONE CIRCULATION IN SHOCK (Average for 5 Dogs)  10090-)  o Sympathectomy • Intoct  o •  80 70 60 H 50 40 302010-  0  10  20  30  40  50  60  70  80  90  100  % SYSTEMIC BP.  The E f f e c t of Sympathectomy on Bone Blood Flow in Shock. The upper curve represents the bone blood flow i n the sympathectomised side, with the control (nerve intact) side represented by the lower curve. There i s less decrease of bone blood flow in the sympathectomised side compared with the control.  VIII E f f e c t of Epinephrine and Norepinephrine Infusion of epinephrine at a rate of 0-3 pag/kg/min. resulted in s l i g h t increase of s y s t o l i c blood pressure and s l i g h t increase of pulse pressure, abrupt f a l l i n 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 h a l f  to two minutes a f t e r 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  E f f e c t 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 i n each animal was  confirmed by epinephrine infusion at a rate of 0*3 ^ig/kg/min., i n which case the t i b i a l nutrient venous outflow d i d not show any decrease On e l e c t r i c a l stimulation of the lumbar sympathetic trunk, the i p s i 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 p a r t i a l 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 r e l a t i o n -  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.  41a. FIGURE 14  jf  Adrenalin Infusion 0.3^jg/kg./nnm.  *|  |j1 1 1 1 1 1 1 1 1 1 1 | | 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 i 1 1 1 1 | 1 1 1 1 1 1 [ 111111111111111IIMII ii i111111111I11111111111i1111111111111111111111111i11111111111111111 i Time |5 second intervals]  The E f f e c t s of Epinephrine (adrenalin) Infusion on Bone Blood Flow. Note the abrupt f a l l i n 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.  41b. FIGURE 15  Dog  240' SYSTEMIC 200-  120 "  ^^^^^^1^^  J  ,„  TIBIAL INTRAMEDULLARY PRESSURE  5030-  TIBIAL NUTRIENT VENOUS OUTFLOW i-Hill  |'  11111 ll I 1111 | ! 1111 | I 1111  Norodrenalin Infusion 0.3^jg/kg./min.  ! I  111  i1 ' i I II  1 1 M i IHMMi 11II11' 11' H IIII l|M | i ! ' 111 M 111  *|  1 1 1i1 1 1 1 1 ' | 11111111111111111111II1111111111111111111111111111111111111 n 111IIII111 n 1111111111111111111 II 1111111 i 111111111 i 111 l l 1111111 Time (5 second intervals)  The E f f e c t s 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 s l i g h t 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)  t  V  Y  V /  A  t /  A  10  20  30  40  50  60  70  80  90  -i  100  % SYSTEMIC B.P.  The E f f e c t of Dibenzyline (phenoxybenzamine) on Bone C i r c u l a t i o n in Shock. Note the linear relationship between the systemic blood pressure and bone blood flow.  DISCUSSION The purpose of this study, as mentioned before, i s to find out the fundamental changes i n bone hemodynamics, mechanisms whereby such changes are brought about, and to compare with other regional c i r c u l a t i o n i n 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 i n the systemic c i r c u l a t i o n . i s known or studied on bone c i r c u l a t i o n i n shock.  However, l i t t l e In our survey,  no previous study on bone c i r c u l a t i o n i n shock was found i n the l i t e r a t u r e , and the purpose of the present study i s to carry out such a work.  The l i t e r a t u r e on bone c i r c u l a t i o n 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 q u a l i t a t i v e l y , and the control mechanisms involved i n bone circulation.  The nerve supply of bone has been demonstrated by many  62, 113, 130, 1154 . , workers and the vasomotor nature i s well known workers 3, 36, 47, 73, 135, 161 Humoral mechanisms involved i n bone J  u  3, 12, 36, c i r c u l a t i o n are also supported by the studies of many workers 129, 132, 144, 166 are also demonstrated  Ketabolic factors influencing bone c i r c u l a t i o n 29, 135, 167  The current concept of shock was reviewed.  I t would appear that 64  decreased c a p i l l a r y perfusion of tissue suggested by Hardaway  is  perhaps the generally accepted description of the term 'shock , i n 1  the l i g h t of our present knowledge.  Decreased tissue perfusion i s  the f i n a l outcome pathway of the shock syndrome, and i s the fundamental  43. pathophysiology i n the pathogenesis of shock.  The neural aspect  of alarming the sympathetic nervous system for r e d i s t r i b u t i o n of blood by a r t e r i a l and venous c o n s t r i c t i o n to the central c i r c u l a t i o n , p a r t i c u l a r l y the heart and brain, i s discussed.  Evidence for increase  55, 90, 114 vasomotor tone i s reviewed . Hormonal output, involving 98, 156 52, 54, 75 catecholamines , adrenal corticosteroid , aldosterone  44, 46, 107  been reported.  and renin-angiotensin secretion  6, 159  , have  The metabolic aspects secondary to c e l l u l a r hypoxia  i n shock, include metabolic acidosis, lactate and pyruvate acid accuromulation, azotemia, hyponatraemia and hyperkalemia, are recognised. The regional and various organs' blood flow i n shock are reviewed. , . 42, 61, 112 , , . , . Coronary c i r c u l a t i o n and cerebral c i r c u l a t i o n  123  >  1 4 7  are  p r e f e r e n t i a l l y perfused, and their vascular resistance usually decreases m  u . A , i • i „. 26, 59, 123, 124 . , . shock as opposed to renal c i r c u l a t i o n and skin  circulation ^ . circulation  In other vascular beds, notably splanchnic  69, 94, 120, 123,  i n the l i t e r a t u r e .  127  , there i s considerable controversy  Pooling of blood i n the splanchnic bed with marked  distention of the. l i v e r i s a prominent feature i n the dog and the rat in shock.  A muscular sphincter l i k e structure i s present i n the region  of the e f f l u e n t hepatic vein which i s highly sensitive to vasoactive product, and this structure i s thought to be responsible for congestion ?1 of l i v e r during shock Knowing that neural, hormonal and metabolic changes occur i n shock, and knowing that bone c i r c u l a t i o n i s affected by neural, hormonal and metabolic factors, i t i s most interesting to find out the changes of hemodynamics i n bone c i r c u l a t i o n i n shock, and evaluation of various mechanisms by which such changes are effected.  44.  V a l i d i t y of Experimental Methods I  Parameters Used i n Measuring Bone C i r c u l a t i o n A.  D i r e c t Cannulation - Collection Method  Cannulation of nutrient vessel, either vein or artery of t i b i a as 135  described by Shim and Patterson  , was used i n 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  i s useful for q u a l i t a t i v e investigations of the r e l a t i v e changes of the 135  hemodynamics of bone with reasonable degree of accuracy nutrient vascular system i s widely distributed throughout  , since the the long bone -  a representative vascular system of long bone. B. Intramedullary Pressure as an Index of Bone Blood Flow Since Larsen  91  started to measure intramedullary pressure i n dogs'  d i s t a l femoral metaphysis,  i t s close relationship with bone hemodynamics 12  3  has been implied by many workers  '  103  '  129  '  Clinically 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 i s bone blood flow dependent, and, r e f l e c t s well the changes i n the hemodynamics of bone.  The volume of  blood inside the bone i s also reflected by intramedullary pressure. Therefore, intramedullary pressure i s a v a l i d parameter i n evaluation of bone hemodynamics. II  V a l i d i t y of the Hemorrhagic Shock Model  From the point of view of obtaining v a l i d data, the animal preparation  45. should mimic the conditions encountered i n human situations. models generally f a l l into two categories:  Experimental  (a) those i n which a fixed  volume of blood i s withdrawn, regardless of changes i n blood pressure, and  (b) those i n which enough blood i s withdrawn to lower the mean  a r t e r i a l pressure to c e r t a i n predetermined l e v e l s , either once or repeatedly i n 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 a r t e r i a l pressure to 50 mmHg. for ninety minutes, then at 30 mmHg. for f o r t y - f i v e minutes, followed by re-infusion at a rate of 50 ml/min.  A r b i t r a r y aspects of the method as noted i n 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 r e l a t i v e l y stable hemorrhaged preparation i s provided for a period of  several hours and can be reproducible i n any laboratory.  However,  one of the disadvantages of the Wigger method i s that the animal i s suddenly plunged into late or i r r e v e r s i b l e shock;  this state i s 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 s u f f i c i e n t to maintain the blood pressure at a predetermined value.  This  experimental s i t u a t i o n d i f f e r s 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. generally lowers the systemic blood pressure to 55*2 +5*1%  This  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 r e l a t i v e l y stable blood pressure at each step for k, - h hour, u n t i l 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 u n t i l the animals exsanguinated.  This model appears  more mimic to c l i n i c a l situations, and bears s i m i l a r i t y to the model 140 used by Shoemaker et a l all  .  The preparation can be reproducible as  the procedures were s p e c i f i e d .  DISCUSSION ON RESULTS I  Acute Hemorrhage  By hemorrhaging at the rate s p e c i f i e d , we observed the gradual f a l l of intramedullary, with gradual o b l i t e r a t i o n of the normal f l u c t u a t i o n associated with a r t e r i a l pulsation. a r t e r i a l outflow decreased. of  Nutrient venous or  Both parameters are q u a l i t a t i v e measures  bone hemodynamics, indicating a decrease of bone c i r c u l a t i o n i n 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 c i r c u l a t i o n .  The skeleton, i n  addition to being hemopoietic organs, also acts as stores of blood. Structures such as spleen and l i v e r i n the dog and cat add to the 21 47 active c i r c u l a t i o n as much as 307 of existing blood volume . Foa , by measuring changes i n volume of bone marrow, suggested that the o  behaviour of the bone marrow was very similar to the spleen. 14 Branemark  a c t u a l l y observed the l i v i n g marrow i n the f i b u l a of the  r a b b i t , and reported a rhythmic a c t i v i t y with alternating d i l a t i o n and emptying of the marrow sinusoids, very similar to those described by Knisely ^ observed of  i n the spleen.  During epinephrine i n j e c t i o n , Branemark  ^  the marrow vessels became constricted and the marrow emptied  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,  pressure  '  '  129  '  the decrease observed during shock i s most  l i k e l y associated with decrease of the blood volume inside the marrow due to vasoconstriction i n early stages and followed by a decreased blood supply to bone.  This i s quite contrary to pooling of blood i n  the splanchnic c i r c u l a t i o n observed total skeletal blood flow was  i n the dog and rat i n shock.  The  estimated i n dogs as 7*3 + 3*0% of the 132  resting cardiac output by Shim, Copp and Patterson  .  Little  knowledge of the volume of blood inside the bone marrow i s available. Knowing that there are 205 bones i n the human body, the volume may considerable.  be  Further studies i n this area are required before any  quantitative estimation i s j u s t i f i e d . II  E f f e c t of One Third Blood Volume Loss  When one third of the estimated blood volume i s l o s t , the systemic blood pressure f e l l level.  to 55-2 +5-1 98  Manger et a l  % (range 30 - 80%) of the control  reported after approximately one third of total  blood volume loss i n dogs, the mean a r t e r i a l 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  medullary pressure invariably f e l l  +3*4% of control l e v e l .  to unrecordable l e v e l .  Intra-  The bone  c i r c u l a t i o n decreased markedly with the s p e c i f i c amount of hemorrhage.  48. I t i s d i f f i c u l t to compare quantitatively the changes of bone c i r c u l a t i o n with other regional c i r c u l a t i o n i n shock, because the methods of inducing shock and the methods of assessing blood flow are d i f f e r e n t . 123 However, Rutherford et a l  ,immediately  a f t e r bleeding i n  dogs to lower the systemic blood pressure to 40 mmHg., measured regional blood flow of various organs by labelled microspheres, as percentage of myocardium 70%,  control groups' values: hepatic ( a r t e r i a l ) 64%,  cerebral 867,,, renal  splanchnic (portal vein) 29%,  and lower extremity 13%,.  417o,  bronchial  25%,  In the coronary and cerebral c i r c u l a t i o n , 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 i n vascular resistance. were made i n coronary  and cerebral  Similar observations c i r c u l a t i o n s by  others. On the other hand, a marked decrease of blood flow, out of 26,  124  proportion to reduction of a r t e r i a l pressure, was noticed i n renal  57 and skin  circulation.  It would appear that bone c i r c u l a t i o n i n shock  behaves more l i k e the l a t t e r group of regional c i r 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, u n t i l the dogs eventually  IV  exsanguinated.  Re-infusion of Lost Blood  This varied from f i f t e e n minutes to s i x hours after induction of hemorrhage.  Re-infusion of l o s t blood resulted i n p a r t i a l or complete  ,  49. r e c o v e r y of the c o n t r o l l e v e l s of systemic blood p r e s s u r e , i n t r a m e d u l l a r y p r e s s u r e , and  bone blood f l o w .  I t was  tibial  observed  the l o n g e r the d u r a t i o n of the shock, the l e s s complete was  that  the  recovery  observed.  V  The  R e l a t i o n s h i p between Bone Blood Flow and ( F i g u r e 10) curve o b t a i n e d was  the f l o w a x i s .  Systemic  B.P.  an e x p o n e n t i a l one w i t h c o n c a v i t y towards  I t must be noted  t h a t the s y s t e m i c blood p r e s s u r e i s not  e x a c t l y the p e r f u s i n g p r e s s u r e a t the l e v e l of r e g i o n a l c i r c u l a t i o n of bone, although  the s y s t e m i c blood p r e s s u r e i s c l o s e l y r e l a t e d or p r o p o r t i o n a l  to the p e r f u s i n g p r e s s u r e .  In o r d e r it  to i n t e r p r e t  i s necessary  the curve of f l o w and p r e s s u r e  to understand  the r e s i s t a n c e and  relationship,  c a p a c i t a n c e phenomena  58 i n v a s c u l a r beds. b l o o d flow and  Green e t a l  expressed  p r e s s u r e i n a c i r c u l a t o r y bed n  the r e l a t i o n s h i p  between  as  F = c x P where  F = f l o w i n ml/min. c = a  constant  n = an exponent having a v a l u e between 1 and 3 The  lowest v a l u e of n and  h i g h e s t value of c were found  at  "low  93 vasomotor tone" and f i n d i n g s and  v i c e versa.  demonstrated  Levy *and Share  have confirmed  t h a t w i t h maximal d i l a t i o n induced  minute p e r i o d of i s c h e m i a and  by a ten  subsequent p e r f u s i o n w i t h hypoxic blood i n  the dog's h i n d limb, a l i n e a r r e l a t i o n s h i p between F and indicating  these  the v a l u e of n i s 1.  P was  obtained,  50. By l o c a l perfusion of nutrient artery i n canine t i b i a , without shocking the animals and maintaining a constant systemic blood pressure, 81 Kato et a l  demonstrated a l i n e a r relationship between perfusion  pressure and measured bone blood flow rate.  This was  interpreted as  no s i g n i f i c a n t change i n the peripheral resistance under such  experimental  conditions. The flow and pressure curve i n 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 i s as follows: F = c P therefore  n  log F = log c + n log P.  By p l o t t i n g the graph of log F against log P, a straight l i n e i s obtained, and the slope represents n.  In our study, n was  found to be  2-4,  i n d i c a t i n g presence of vasomotor bone. VI  E f f e c t of E l e c t r i c a l 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, decrease of bone c i r c u l a t i o n due to an increase of sympathetic  indicating  activity.  The presence of nerves i n the bone has been documented by various workers  113, 130, 154  documented 3  VII  , , , ana their vasomotor nature was also well  3, 36, 47, 73, 135,  #  161  E f f e c t of Lumbar Sympathectomy A.  Before Induction of Hemorrhage  Sympathectomy of r i g h t lumbar trunk, performed i n f i v e dogs, resulted in an increase of nutrient venous outflow ranging from 15 - 110 percent 148 above control value i n acute experiment.  Trotman and Kelly  demonstrated a 27% increase i n bone blood flow to the t i b i a i n the 133 anaesthetised dog following lumbar sympathectomy, while Shim et a l showed a 5 - 45 percent increase  in blood flow of bones i n the leg and  foot i n rabbits a f t e r s c i a t i c nerve section, sympathetic  fibres below the knee.  X v h i c h  carries most of the  The increase of bone blood flow  a f t e r sympathectomy, which was also observed i n this study, indicates the presence of vasomotor control of bone. B.  E f f e c t of Lumbar Sympathectomy i n Shock  In f i v e dogs, a f t e r lumbar sympathectomy on right side was performed and leaving the l e f t side intact, hemorrhagic shock was induced.  The  decrease of bone blood flow on the sympathectomised side was correspondingly 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 i n the control side, occurring already i n the early stage of hemorrhage.  This implies that  the sympathetic discharge occurs r a p i d l y to loss of blood volume.  The  average difference i n the percentage of bone blood flow betxveen sympathectomised and control was 16'IT,.  To compare the bone blood flow i n the right and l e f t sides without sympathectomy, two experiments 57. difference throughout Such experiments were performed,  were performed which showed less than  the whole range of systemic blood pressure.  are s t a t i s t i c a l l y not s i g n i f i c a n t , because only two but the results agree with the work of Trotman and  148 Kelly  , who demonstrated no s i g n i f i c a n t difference i n bone blood flow  in both sides i n s i x dogs used as control.  52. V I I I E f f e c t of Catecholamines  (Figures 14 and 15)  The ' r e s t i n g 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 i n the plasma concentration of catecholamine, p r i m a r i l y of epinephrine with less norepinephrine. When % to 1/3 of the blood volume i s depleted, the output of epinephrine was 0.14 - 0-88 ^g/kg/iain. and norepinephrine was 0*04 - 0-12 156 mg/kg/min.  98 .  Manger  reported the l e v 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 a t the dosage of 0-3 ^ig/kg/min. was i n f u s e d , 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 l e 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 a f f e c t e d by epinephrine i n shock.  Nore-  pinephrine a t the dose of 0-3 ug/kg/min. resulted i n e l e v a t i o n of systemic blood pressure due to i t s generalized v a s o c o n s t r i c t i o n 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 e f f e c t on bone c i r c u l a t i o n was not c o n s i s t e n t . IX  E f f e c t of Dibenzyline on Bone Blood Flow i n Hemorrhagic Shock 22,56  Dibenzyline (phenoxybenzamine)  '  produces a prolonged and  e f f e c t i v e blockage of alpha-adrenergic receptors.  I t does neither  produce the c h a r a c t e r i s t i c blockage by a l t e r i n g the f u n c t i o n of adrenergic nerves nor the b a s i c response mechanisms of e f f e c t o r 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 c l o s e l y r e l a t e d  compounds and i s considered to be an interaction with s p e c i f i c tissue receptors.  Responses to c i r c u l a t i n g catecholamines are inhibited more  e f f e c t i v e l y than those to mediator released l o c a l l y at nerve endings. Blockage e f f e c t i s r e l a t i v e l y slow and mild i n f i r s t one to two hours a f t e r drug administration, but the effect i s 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 o f f the vasomotor tone.  Under the  dibenzyline medication, the hemorrhagic shock induction did not produce concave bone blood flow-pressure r e l a t i o n curve; was a linear one (Figure 16).  instead, the r e l a t i o n  This was interpreted as no s i g n i f i c a n t  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 d i l a t e d by ten minute period of ischaemia and subsequent perfusion with hypoxic blood, and this 81 a linear flow-pressure relationship.  Kato et a l  produced  also demonstrated  a linear relationship between flow and perfusing pressure by l o c a l l y perfusing the canine t i b 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 i n 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 c i r c u l a t i o n in shock. As Trueta interpreted, the blood i n the sinusoids was removed away to replace the loss by the 47 systemic c i r c u l a t i o n . 14 Branemark  .  This was also the impression of Foa  and  However, l i t t l e quantitative studies of the volume of  blood inside the bone marrow i s available, and to assess the contribution of blood from bone c i r c u l a t i o n to the e f f e c t i v e c i r c u l a t o r y volume i n shock i s a pure conjecture. 2.  Future study i s necessary.  Ischemic E f f e c t on Bone Marrow j  n  Sb^^pk  The injurious effect of shock on various organs - such as acute tubular neurosis i n kidneys, myocardial i n f a r c t i o n , Sheehan's syndrome in p i t u i t a r y , are well recognised.  We demonstrated the s i g n i f i c a n t  decrease i n bone blood flow in shock. occur i n the bone?  Can similar injurious effect  The answer to this question has to be given by  more refined h i s t o l o g i c a l or biochemical techniques with future studies in this area. 3.  Pathogenesis of Fat Embolism  Trauma and hypovolemic  shock have been implicated i n the pathogenesis  117 of fat embolism  .  Bone marrow i s r i c h i n f a t .  By studying the  composition of nutrient venous outflow i n shock, i t i s possible to bring more l i g h t to the possible association of pathogenesis of fat embolism to shock.  55. 4.  Metabolic Aspect of Bone C i r c u l a t i o n i n Shock  Metabolic f a c t o r s , such as changes i n pH, hypoxia, hypercapnia, and accummulacion of d i f f e r e n t metabolites,such as l a c t i c and pyruvatic a c i d s , are present i n hemorrhagic  shock.  Even though the e f f e c t of  some factors i n f l u e n c i n g bone c i r c u l a t i o n has been studied. 29 Hypercapnia and hypoxia increase bone blood flew  135 ' " , parental 157  l a c t i c acid also increases n u t r i e n t a r t e r i a l outflow  , and r e a c t i v e  hyperemia of bone a f t e r femoral a r t e r i a l o c c l u s i o n was unabolished by e l e c t r i c a l s t i m u l a t i o n or exogenous  vasopressin  .  But q u a n t i t a t i v e  studies of a combination of the various metabolic factors i n shock are not available. SUMMARY  Bone c i r c u l a t i o n i n hemorrhagic mongrel dogs.  shock was studied i n t h i r t y - f i v e male  The term shock i s defined i n t h i s thesis as p e r s i s t e n t  profound hypotensive syndrome, due to acute hemorrhage of more than one t h i r d of blood volume. The method of i n d u c t i o n of shock consisted of removal of one  third  of estimated blood volume (87 of body weight) at a rate of 25 - 50 n  ml/min., and subsequently dropping the systemic pressure i n a stepwise manner u n t i l the maintaining l e v e l of 30 - 35 mmHg. was reached.  The  c e n t r a l venous pressure, pulse and r e s p i r a t o r y 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 n u t r i e n t vein or a r t e r y , and (2) recording the bone marrow c a v i t y pressure of t i b i a .  When one t h i r d  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 i n v a r i a b l y f e l l to unrecordable l e v e l a f t e r one t h i r d 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, a f t e r hemorrhage r e s u l t e d i n p a r t i a l or complete recovery of the c o n t r o l l e v e l s of systemic blood pressure as w e l l as bone blood flow and intramedullary pressure of bone. The curve showing r e l a t i o n s h i p between changes i n bone blood flow and systemic blood pressure was an exponential one with concavity towards the flow a x i s .  The presence of increased p e r i p h e r a l r e s i s t a n c e of bone  during hemorrhagic shock was deduced. 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 a r t e r y or vein with lumbar sympathectomy on. one side showed a correspondingly l e s s decrease (average 16*1%) of bone blood flow on the sympathectomised side i n hemorrhagic shock. Dibenzyline (phenoxybenzamine) a l t e r e d the pressure-flow r e l a t i o n curve to a l i n e a r pattern i n bone c i r c u l a t i o n i n shock. These observations i n d i c a t e 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 a c t i v e vasomotor control mechanisms responsible for the reduction i n bone blood flow.  These mechanisms are neural  (sympathetic) and hormonal (catecholamine).  CONCLUSION Hemorrhagic shock i n dogs decreases bone c i r c u l a t i o n , as measured by bone blood flow and intradmedullary pressure.  The decrease of bone c i r c u l a t i o n persists as long as eighteen hours and recovers p a r t i a l l y or completely the normal rate of flow i f the lost blood i s re-infused.  The relationship of changes i n 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 c i r c u l a t i o n i n shock is demonstrated:  sympathetic  stimulation decreases bone  c i r c u l a t i o n and sympathectomy decreases  the vasomotor  response i n bone c i r c u l a t i o n in shock.  The role of catecholamines demonstrated:  on bone c i r c u l a t i o n i n shock i s  epinephrine and norepinephrine  infusion  decreases bone c i r c u l a t i o n . Dibenzyline (phenoxybenzamine), an alpha-receptor blocking drug, blocks the bone vasoconstriction action in shock. This indicates the bone vasomotor system has alpha-receptors. Bone c i r c u l a t i o n decreases i n shock, not only due to decreased perfusing pressure and c i r c u l a t i n g 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 Dogs  95  90  85  80  75  70  65  60  55  50  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  8 100  92  83.5  76.5  68  59  50.5  42.5  36.5  31  10 100  95  83  74.5  66  54.5  40  29  25  12 100  80  65  61  54  51  46  41  14 100  91.5  83.5  74  68.5  61.5  55  38.5  15 100  86  72.5  60  24.5  10  8  4.5  4  3.5  3  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  34 100  76  68  59  51.5  42  36.5  30  23  18.5  87.6  77.2  67.6  55.2  45.5  38.2  35.7.  27.4  24.1  45  40  35  30  25  20  -  -  -  -  -  -  25.5  12  2  -  -  -•  26.5  22.5  15  9  5  -  -  22  17.5  13  7  5  36  30.5  25  25  23  20  16  13  10  36  32.5  28.5.  22.5  16  10  4  -  -  1.5  1  -  -  -  -  -  -  -  -  32.5  25  -  -  -  -  14  10.5  8  -  -  -  -  20.4  15.3  11  4 .9  3.0  1.3  1.3  7  /o Bone Blood Flow  Mean  S.E. . Mean + S.E.  2  -  9.5  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  87.6 +5.7  77.2 +3.6  67.6 +4.1  55.2 +5.6  45.5 +5.9  38.2 +5.5  35.2 +4.2  27.4 +4.7  24.1 +4.3  20.4 +3.9  15.3 +3.8  11 +3.0  4 .9 +1 .9  3.0 +1.6  -  TABLE I I  Nerve Intact  Bone Blood Flow  M « -  e a n  S  +  EFFECT OF LUMBAR SYMPATHECTOMY ON BONE BLOOD FLOW IN SHOCK % Systemic Blood P r e s s u r e 100  95  90  85  80  75  100  75  58  40  25  14.5  100  98  96  88  72.5  57  51  45  43  100  88  78  67  56  45  36  29  100  82  62  40  39.5  38.5  37.5  100  82  64  43.5  41.5  39  85.0  71.6  55.5  46.9  38.8  100  + 3.9 +  E  Sympathectomised  Mean + S.E.  70  65  60  55  5  4  50  45  40  40.5  38  33  25.5  22.5  18  14  10.5  36.5  36.5  36.5  36.5  36.5  36.5  31.5  26.5  36  34  27  14  34  30.2  26.8  22.6  19.1  16.6  14.0  7.4  5.3  9.5  6.5  7.3 + 3.1 + 8.0 + 6.9 + 6.7 + 6.4 + 4 . 5 + 7.2 +  8  35  5.5  7*7 + 7.6 + 7.3 + 6.2 +  100  93  86  78  58  17.5  12  100  97  94.5  90  84  78  69  60  57  53  50  43  36.5  100  90  80  71  62  53  47  42  37  31  24  19.5  18.5  17.5  100  94  87  84.5  73  68  57  51  51  51  51  51  50  53  100  94  89  85  77  71  65  59  51  38.5  31  22  12  100 +  8.5  6.5  4.5  30  5.3  -  6.5  9.5  53 -  93.6 87.3 81.7 70.8 57.5 50.0 44.1 40.5 35.6 31.2 27.1 23.4 15.4 13.0 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  EFFECT OF DIBENZYLINE ON BONE CIRCULATION IN SHOCK  TABLE I I I  7» Systemic Blood Pressure  S.E.  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  + 0  +  6.2  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  0  30  61. 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