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Platelet response to acute blood loss: An experimental study
ORIGINAL CONTRIBUTIONS
Platelet Response to Acute Blood Loss: An Experimental Study Robert C. Lim, Jr, MD* James W. Holcroft, MD* Donald D. Trunkey, MD* San Francisco, California
T h e p l a t e l e t c h a n g e s a s s o c i a t e d w i t h a c u t e b l o o d loss w e r e s t u d i e d i n d o g s and baboons. The circulating platelets decreased and aggregability i n c r e a s e d in r e s p o n s e to h e m o r r h a g e . I n t r i n s i c A T P a n d A D P c o n c e n trations and ultrastructural morphology did not change significantly. T h e s e r e s u l t s e x p l a i n , in part, t h e c o a g u l o p a t h y t h a t o c c u r s in t h e t r a u m a v i c t i m in h e m o r r h a g i c s h o c k . B a s e d u p o n t h e s e o b s e r v a t i o n s , the a u t h o r s describe a resuscitative program that includes whole blood and platelet administration. Lim RC Jr, Holcroft JW, Trunkey DD: Platelet response to acute blood loss: an experimental study. JACEP 4: 524-527, November/December 1975. blood,
platelet; blood, clotting, shock, hemorrhagic, shock, hypovolemic. INTRODUCTION
T h e p a t h o p h y s i o l o g y of h e m o r r h a g i c shock s e c o n d a r y to s u d d e n acute blood loss m u s t be elucidated to provide a deeper i n s i g h t into its management in the emergency d e p a r t m e n t . W i t h i m p r o v e m e n t of p r e h o s p i t a l care, more p a t i e n t s i n hemorrhagic shock are reaching the emergency d e p a r t m e n t alive. Aggressive resuscitation has increased the survival rate of these patients but now we are faced with a new c h a l l e n g e - complications of resuscitation. Shock l u n g has been well described but the *Department of Sm'gery and Trauma Center, University of California, San Francisco General Hospital, San Francisco, California 94110. Supported by National Institutes of Health GM #18470. Presented at the Fifth Annual Meeting of UA/EMS in Vancouver, British Columbia, Canada, May 1975.
Page 524 Volume 4 Number 6
u n d e r l y i n g etiology is still controversial. The other dreaded complication of h e m o r r h a g i c shock is a massive bleeding diathesis after resuscitation. In studies of battlefield casualties, a m a r k e d d e r a n g e m e n t in victims' coagulation systems after resuscitation from hemorrhagic shock has been reported. The use of fresh blood has been helpful, in part, in p r e v e n t i n g this problem, l In civilian t r a u m a victims, bleeding problems after resuscit a t i o n with m a s s i v e blood t r a n s f u sions are related largely to platelet dysfunction. It was believed t h a t this bleeding diathesis was related to the infusion of massive a m o u n t s of stored blood. '~Progressive thrombocytopenia was noted with i n c r e a s i n g n u m b e r of whole blood transfusions. Therefore, the p l a t e l e t defect was i n i t i a l l y thought to be secondary to a dilutive effect of massive blood t r a n s f u s i o n s 2 However, more sophisticated tests
have shown t h a t there is not only a deficiency in platelet count, but als0 a deficiency in platelet function. Platelet a g g r e g a t i o n w a s s i g n i f i c a n t l y depressed after t r a n s f u s i o n of 10 units of whole blood. 3 This study attempts to identify defects i n platelet function r e s u l t i n g from acute blood loss before resuscitation is instituted. MATERIALS AND METHODS
T h i r t e e n mongrel dogs of both sexes, weighing 10 to 20 kg, were anesthetized with t h i o p e n t a l sodium, intravenously, i n t u b a t e d and allowed to breathe spontaneously. Maintenance fluid was given intravenously. Large bore catheters were inserted into both femoral arteries, one for continuous m o n i t o r i n g of blood pressure and the other for bleeding and sampling the blood. After control samples were obtained, blood was w i t h d r a w n until a systolic pressure of 50 to 55 mm Hg was achieved. Blood samples were t a k e n i m m e d i a t e l y and 1 hour after h e m m o r h a g e for d e t e r m i n a t i o n of platelet count, plateiet aggregation i n d u c e d by a d e n o s i n e diphosphate (ADP), p l a t e l e t n u c l e o t i d e conceit" t r a t i o n (intrinsic adenosine triph0S" phate [ATP] and ADP) and electron microscopic study of platelet morph" ology. General a n e s t h e s i a was induced i~ 20 female baboons weighing 8 to 15~g after the a n i m a l s were tranqUili~g
November/December i975 .o[~)
~ith phencyclidine (1 mg/kg), administered intramuscularly_ The a n i m a l s were i n t u b a t e d and allowed to b r e a t h e spontaneously. C a t h e t e r i z a t i o n for monitoring blood p r e s s u r e and obtainking blood samples was carried out a s !i~1 the dogs. A f t e r control s a m p l e s I~vere obtained, blood was w i t h d r a w n antil a systolic p r e s s u r e of 50 to 55 m m ;ttg was achieved. Blood s a m p l e s were drawn i m m e d i a t e l y , 10 minutes, 30 minutes, and 1 hour after hemorrhage. ;platelet counts, p l a t e l e t a g g r e g a t i o n induced by A D P and epinephrine, and platelet nucleotide concentration were determined. Then, e l e c t r o n microscopic studies were performed.
l i
Hematocrits were m e a s u r e d by the microtechnique in duplicates. Platelet a g g r e g a t i o n induced by A D P (5 tam) and e p i n e p h r i n e (5 × 10 -4 mg/ ~1) was performed on an aggregome:er (Chronolog), 2 P l a t e l e t nucleotide ~c0ncentrations ( i n t r i n s i c A T P a n d ADP) w e r e m e a s u r e d a c c o r d i n g to It01msen's t e c h n i q u e with the firefly [aciferase system. 4 E m i t t e d light was measured w i t h a b i o m e t e r (Dupont Luminescence B i o m e t e r ) . E l e c t r o n microscopy studies w i t h c i r c u l a t i n g platelet were performed by centrifuging 10 ml of c i t r a t e d whole blood at t00 x g for 15 m i n u t e s to o b t a i n plate'let-richp l a s m a t h a t was t h e n immediitely fixed in 10 ml of l'/e% glutaraldehyde. The p l a t e l e t suspension was :entrifuged at 1000 x g to obtain a llatelet button. It was t h e n embedded Araldite® and sectioned at 700-800 gstrom t h i c k n e s s . A n e l e c t r o n icroscope (RCA) was used to s t u d y lhe sections and to p h o t o g r a p h the latelets.
l l
RESULTS
Dogs: The significant findings are ~umrnarized in Table 1. After hemorrhage the c i r c u l a t i n g p l a t e l e t level !ell p r o g r e s s i v e l y from a m e a n of t76,000 cu m m to 351,000 c u m m ~< 0.05). P l a t e l e t a g g r e g a t i o n inUcedby A D P increased i m m e d i a t e l y '0m a m e a n of 35% to 50% (P<0.01) utthe m e a n r e t u r n e d to control level 1 hour. I n t r i n s i c ATP and A D P acentrations decreased from .7k 18,2 and 5.5 5 3.7 ~,M/1 milan platelets ( tx M/10 ~ p l a t e l e t s ) to LaX 15_2 and 3 9 + 4.0/u M/106 atelets, respectively, after hemor'ager e t u r n i n g t o w a r d control levels •lhour; however, the decreases were
November/December 1975
Table I PLATELET RESPONSE AFTER HEMORRHAGE IN THE DOG* Platelet Test
Count
Control
Immed.
1 Hr.
376+203
364+222
351 +209 (P < 0.05)
35+17
50+24 (P < 0.01)
40+17
(x 10a/mm 3)
Aggregation (%) ADP
(5/~ M) Intrinsic ATP
31.7+18.2 20,3+15.2 26,4+14.3
(/u M/106 platelet) Intrinsic ADP
5.5+3.7
3.9+4.0
4.9+4.6
(p. M/106 platelet) *Mean+SD
not significantly different. Ultrastruct u r a l studies of the c i r c u l a t i n g platelets showed no significant changes at the different t i m e periods after acute bleeding. Baboons: The d a t a are s u m m a r i z e d on Table 2. After h e m o r r h a g e , the circ u l a t i n g p l a t e l e t level fell progress i v e l y f r o m a m e a n of 359,000 to 266,000 c u m m ( P < 0 0 0 1 ) . P l a t e l e t a g g r e g a t i o n i n d u c e d by A D P increased s i g n i f i c a n t l y from 55% to 76%, t h e n r e t u r n e d to c o n t r o l levels by 1 hour. A g g r e g a t i o n induced by epin e p h r i n e s h o w e d no s i g n i f i c a n t change. Intrinsic A T P and ADP concentrations remained essentially unchanged. U l t r a s t r u c t u r a l e v a l u a tion of the c i r c u l a t i n g p l a t e l e t s before and after h e m o r r h a g e at the different periods of observation showed no significant change. H e m a t o c r i t s in both groups were u n c h a n g e d before and after h e m o r r h a g e at t h e different time periods. DISCUSSION
T r a u m a victims in profound hypovolemic shock secondary to acute blood loss d e m a n d q u i c k a n d c o m p e t e n t
r e s u s c i t a t i v e efforts to restore circul a t i n g blood volume and control hemorrhage. T h e r e are v a r y i n g opinions on how to best m a n a g e these patients. The overuse of Ringer's lactate solution h a s been a s s o c i a t e d w i t h p u b m o n a r y edema. S k i l l m a n et aP adv o c a t e u s e of c o l l o i d or a l b u m i n solution to m a i n t a i n oncot~c pressure w i t h i n c i r c u l a t i o n to p r e v e n t pulm o n a r y edema. On the other hand, Holcroft and T r u n k e y ~ showed t h a t the d e g r e e of p u l m o n a r y e d e m a is, in fact, worse in baboons resuscitated with colloid solution compared with crystalloid solution. These conflicting points of view need f u r t h e r study. A n o t h e r e q u a l l y major complication t h a t follows successful resuscitation of p a t i e n t s in h e m o r r h a g i c shock is a generalized bleeding diatbesis. 7,s The massive use of stored blood has been shown to be responsible for the deficiency in a n u m b e r of c o a g u l a t i o n factors. The r e s u l t s of our study indicate t h a t with acute blood loss there is a definite change in p l a t e l e t function, especially when r e s u s c i t a t i v e efforts are delayed. The c i r c u l a t i n g platelet
Volume 4 Number 6 Page 525
counts decrease and p l a t e l e t aggregabllityincreases (Figure). A transient hypercoagulative state exists and i n t r a v a s c u l a r c o a g u l a t i o n occurs. This is reflected by a fall in p l a t e l e t count, t h e p r e s e n c e of c i r c u l a t i n g f i b r i n m o n o m e r c o m p l e x e s a n d a r i s e in fibrin d e g r a d a t i o n products (authors' unpublished observations). These c h a n g e s o c c u r r e d i n d e p e n d e n t l y of massive blood transfusions. With prolonged tissue ischemia, the coagul o p a t h y would become worse. Therefore, m a n a g e m e n t of p a t i e n t s in hypovolemic shock should be directed at p r o m p t and aggressive r e s u s c i t a t i o n to m i n i m i z e t h e d u r a t i o n of poor p e r i p h e r a l perfusion.
Table 2 PLATELET
RESPONSE
Platelet Test
Control
Count
359+ 127
(x 103) (mm 3)
Aggregation ADP
(%)
(5/~ M)
270±87
72+22
47+39
Epinephrine
60'
263_+95 266+108
Intrinsic ADP
(/~ M/10 G platelets) *Mean+SD
PLATELET COUNT x 103
72+20
35--+29
(5 x 10 -4 mg/ml)
(/~ M/106 platelets)
Page 526 Volume 4 Number 6
258+107
30'
624-28
(P < 0.05)(P < 0.001)(P < 0.001) (P < 0.5)
To m a n a g e these patients, we i n s e r t large bore c a t h e t e r s t h r o u g h cutdowns for r a p i d infusion of crystalloid solutions and for central venous p r e s s u r e monitoring. The r a p i d infusion of I to 2 liters of c r y s t a l l o i d solution should b r i n g about a d r a m a t i c response in t h e p a t i e n t ' s v i t a l s i g n s . If t h e p a t i e n t ' s response is t r a n s i e n t or only p a r t i a l , we suspect continued i n t r a a b d o m i n a l or i n t r a t h o r a c i c bleeding. P r o m p t s u r g e r y to control the bleeding while r e s u s c i t a t i v e efforts continue is m a n d a t o r y for successful outcome.
F i n a l l y , if t h e b l e e d i n g d i a t h e s i s after m a s s i v e blood r e p l a c e m e n t is a red blood cell and coagulation deficiency, t h e use of w a r m fresh blood is
10'
76--+21
55+15
Intrinsic ATP
In p a t i e n t s who develop a generalized oozing a f t e r m u l t i p l e t r a n s f u sions, e v a l u a t i o n of t h e h e m o s t a t i c disorder should include the following d e t e r m i n a t i o n s : p a r t i a l thromboplastin time, p r o t h r o m b i n time, p l a t e l e t count, p l a t e l e t function tests, circul a t i n g fibrin m o n o m e r level, fibrinogen level and fibrin d e g r a d a t i o n products p r e s e n t . If a p r i m a r y p l a t e l e t defect exists, 8 to 10 units of p l a t e l e t packs or c o n c e n t r a t e s are a d m i n i s tered. If t h e defect is p r i m a r i l y in the coagulation factors, t h e n fresh frozen p l a s m a is a d m i n i s t e r e d .
Immed.
IN T H E B A B O O N *
(P < 0.01) (P < O.O01)(P < 0.001) (P < 0.01)
Patient Management
After infusion of 2 liters of crystalloid solution, r e p l a c e m e n t of predicted shed blood w i t h whole blood is init i a t e d . I f t h e d e m a n d for b l o o d r e p l a c e m e n t exceeds 8 to 10 units, i d e a l l y all s u b s e q u e n t t r a n s f u s i o n s should be fresh blood; ie, 24 hours old or less.
AFTER HEMORRHAGE
56.64-11.5 51.6+14.9
47.4+19.2
37.1+2.7
62,64-9.6
--
42+._34
50.0+1,7.2 52.2&19.2
47.5+20.1 39.3--+11.7 47.7_+13.7
,oo 300
T i
Or
I
2O0 10C -
100
75
PLATELET AGGREGATION 50 % 25
t
~.ontrol
i 0
i 10
i 20
i 30
i 40
i 50
1 60
MINUTES F i g . Changes in platelet count and aggregation induced by 5 / ~ M A D £ after hemorrhage. (Control = baseline, 0 - immediately after hemorrhage)
November/December 1975 , ~ P
j~dicated- Fresh w a r m blood has all Ihe coagulation factors including the }]~bile factors, viable platelets, and functioning red blood cells to correct 'the global defect t h a t occurs w i t h ~$~ssive whole blood transfusions. !
cONCLUSION With this s e q u e n t i a l resuscitative ~pproach to the hypovolemic patient, 'the period of shock and low flow state ~is minimized. In t u r n , the complicaPti011sof generalized coagulopathy can bbeavoided or lessened.
~PNovember/December 1975
REFERENCES 1. Miller RD, Robbins TO, Tong MJ, et al: Coagulation defects associated with massive blood transfusions. A n n S u r g 174: 794-801, 1971. 2. Lim RC, Jr, Olcott C IV, Robinson AJ, et al: Platelet response and coagulation changes following massive blood replacement. J Trauma 13:577-582, 1973. 3. Krevans JR, Jackson DP: Hemorrhagic disorder following massive whole blood transfusions. J A M A 159:171-177, 1955. 4. Holmsen H, Holmsen I, Bernhardsen A: Microdetermination of ADP and ATP in plasma with the firefly luciferase system. A n a l Biochem 17:456-473, 1966.
5. Skillman JJ, Parikh BM, Tanenbaum BJ: Pulmonary arteriovenous admixture: Improvement with albumin and distress. A m J S u r g 119:440-447, 1970. 6. Holcroft JW, Trunkey DD: Extravascular lung water following hemorrhagic shock in the baboon: Comparison between resuscitation with Ringer's lactate and plasmanate. A n n S u r g 180:408-417, 1974. 7. String T, Robinson AJ, Blaisdell FW: Massive trauma. Arch S u r g 102:406-411, 1971. 8. Ljungqvist U, Bergentz SE, Leandoer L: Platelet adhesiveness and aggregability after acute hemorrhage in the dog. Acta Chir S c a n d (preprint) Feb. 1970.
Volume 4 Number 6 Page 527
Platelet Response to Acute Blood Loss: An Experimental Study Robert C. Lim, Jr, MD* James W. Holcroft, MD* Donald D. Trunkey, MD* San Francisco, California
T h e p l a t e l e t c h a n g e s a s s o c i a t e d w i t h a c u t e b l o o d loss w e r e s t u d i e d i n d o g s and baboons. The circulating platelets decreased and aggregability i n c r e a s e d in r e s p o n s e to h e m o r r h a g e . I n t r i n s i c A T P a n d A D P c o n c e n trations and ultrastructural morphology did not change significantly. T h e s e r e s u l t s e x p l a i n , in part, t h e c o a g u l o p a t h y t h a t o c c u r s in t h e t r a u m a v i c t i m in h e m o r r h a g i c s h o c k . B a s e d u p o n t h e s e o b s e r v a t i o n s , the a u t h o r s describe a resuscitative program that includes whole blood and platelet administration. Lim RC Jr, Holcroft JW, Trunkey DD: Platelet response to acute blood loss: an experimental study. JACEP 4: 524-527, November/December 1975. blood,
platelet; blood, clotting, shock, hemorrhagic, shock, hypovolemic. INTRODUCTION
T h e p a t h o p h y s i o l o g y of h e m o r r h a g i c shock s e c o n d a r y to s u d d e n acute blood loss m u s t be elucidated to provide a deeper i n s i g h t into its management in the emergency d e p a r t m e n t . W i t h i m p r o v e m e n t of p r e h o s p i t a l care, more p a t i e n t s i n hemorrhagic shock are reaching the emergency d e p a r t m e n t alive. Aggressive resuscitation has increased the survival rate of these patients but now we are faced with a new c h a l l e n g e - complications of resuscitation. Shock l u n g has been well described but the *Department of Sm'gery and Trauma Center, University of California, San Francisco General Hospital, San Francisco, California 94110. Supported by National Institutes of Health GM #18470. Presented at the Fifth Annual Meeting of UA/EMS in Vancouver, British Columbia, Canada, May 1975.
Page 524 Volume 4 Number 6
u n d e r l y i n g etiology is still controversial. The other dreaded complication of h e m o r r h a g i c shock is a massive bleeding diathesis after resuscitation. In studies of battlefield casualties, a m a r k e d d e r a n g e m e n t in victims' coagulation systems after resuscitation from hemorrhagic shock has been reported. The use of fresh blood has been helpful, in part, in p r e v e n t i n g this problem, l In civilian t r a u m a victims, bleeding problems after resuscit a t i o n with m a s s i v e blood t r a n s f u sions are related largely to platelet dysfunction. It was believed t h a t this bleeding diathesis was related to the infusion of massive a m o u n t s of stored blood. '~Progressive thrombocytopenia was noted with i n c r e a s i n g n u m b e r of whole blood transfusions. Therefore, the p l a t e l e t defect was i n i t i a l l y thought to be secondary to a dilutive effect of massive blood t r a n s f u s i o n s 2 However, more sophisticated tests
have shown t h a t there is not only a deficiency in platelet count, but als0 a deficiency in platelet function. Platelet a g g r e g a t i o n w a s s i g n i f i c a n t l y depressed after t r a n s f u s i o n of 10 units of whole blood. 3 This study attempts to identify defects i n platelet function r e s u l t i n g from acute blood loss before resuscitation is instituted. MATERIALS AND METHODS
T h i r t e e n mongrel dogs of both sexes, weighing 10 to 20 kg, were anesthetized with t h i o p e n t a l sodium, intravenously, i n t u b a t e d and allowed to breathe spontaneously. Maintenance fluid was given intravenously. Large bore catheters were inserted into both femoral arteries, one for continuous m o n i t o r i n g of blood pressure and the other for bleeding and sampling the blood. After control samples were obtained, blood was w i t h d r a w n until a systolic pressure of 50 to 55 mm Hg was achieved. Blood samples were t a k e n i m m e d i a t e l y and 1 hour after h e m m o r h a g e for d e t e r m i n a t i o n of platelet count, plateiet aggregation i n d u c e d by a d e n o s i n e diphosphate (ADP), p l a t e l e t n u c l e o t i d e conceit" t r a t i o n (intrinsic adenosine triph0S" phate [ATP] and ADP) and electron microscopic study of platelet morph" ology. General a n e s t h e s i a was induced i~ 20 female baboons weighing 8 to 15~g after the a n i m a l s were tranqUili~g
November/December i975 .o[~)
~ith phencyclidine (1 mg/kg), administered intramuscularly_ The a n i m a l s were i n t u b a t e d and allowed to b r e a t h e spontaneously. C a t h e t e r i z a t i o n for monitoring blood p r e s s u r e and obtainking blood samples was carried out a s !i~1 the dogs. A f t e r control s a m p l e s I~vere obtained, blood was w i t h d r a w n antil a systolic p r e s s u r e of 50 to 55 m m ;ttg was achieved. Blood s a m p l e s were drawn i m m e d i a t e l y , 10 minutes, 30 minutes, and 1 hour after hemorrhage. ;platelet counts, p l a t e l e t a g g r e g a t i o n induced by A D P and epinephrine, and platelet nucleotide concentration were determined. Then, e l e c t r o n microscopic studies were performed.
l i
Hematocrits were m e a s u r e d by the microtechnique in duplicates. Platelet a g g r e g a t i o n induced by A D P (5 tam) and e p i n e p h r i n e (5 × 10 -4 mg/ ~1) was performed on an aggregome:er (Chronolog), 2 P l a t e l e t nucleotide ~c0ncentrations ( i n t r i n s i c A T P a n d ADP) w e r e m e a s u r e d a c c o r d i n g to It01msen's t e c h n i q u e with the firefly [aciferase system. 4 E m i t t e d light was measured w i t h a b i o m e t e r (Dupont Luminescence B i o m e t e r ) . E l e c t r o n microscopy studies w i t h c i r c u l a t i n g platelet were performed by centrifuging 10 ml of c i t r a t e d whole blood at t00 x g for 15 m i n u t e s to o b t a i n plate'let-richp l a s m a t h a t was t h e n immediitely fixed in 10 ml of l'/e% glutaraldehyde. The p l a t e l e t suspension was :entrifuged at 1000 x g to obtain a llatelet button. It was t h e n embedded Araldite® and sectioned at 700-800 gstrom t h i c k n e s s . A n e l e c t r o n icroscope (RCA) was used to s t u d y lhe sections and to p h o t o g r a p h the latelets.
l l
RESULTS
Dogs: The significant findings are ~umrnarized in Table 1. After hemorrhage the c i r c u l a t i n g p l a t e l e t level !ell p r o g r e s s i v e l y from a m e a n of t76,000 cu m m to 351,000 c u m m ~< 0.05). P l a t e l e t a g g r e g a t i o n inUcedby A D P increased i m m e d i a t e l y '0m a m e a n of 35% to 50% (P<0.01) utthe m e a n r e t u r n e d to control level 1 hour. I n t r i n s i c ATP and A D P acentrations decreased from .7k 18,2 and 5.5 5 3.7 ~,M/1 milan platelets ( tx M/10 ~ p l a t e l e t s ) to LaX 15_2 and 3 9 + 4.0/u M/106 atelets, respectively, after hemor'ager e t u r n i n g t o w a r d control levels •lhour; however, the decreases were
November/December 1975
Table I PLATELET RESPONSE AFTER HEMORRHAGE IN THE DOG* Platelet Test
Count
Control
Immed.
1 Hr.
376+203
364+222
351 +209 (P < 0.05)
35+17
50+24 (P < 0.01)
40+17
(x 10a/mm 3)
Aggregation (%) ADP
(5/~ M) Intrinsic ATP
31.7+18.2 20,3+15.2 26,4+14.3
(/u M/106 platelet) Intrinsic ADP
5.5+3.7
3.9+4.0
4.9+4.6
(p. M/106 platelet) *Mean+SD
not significantly different. Ultrastruct u r a l studies of the c i r c u l a t i n g platelets showed no significant changes at the different t i m e periods after acute bleeding. Baboons: The d a t a are s u m m a r i z e d on Table 2. After h e m o r r h a g e , the circ u l a t i n g p l a t e l e t level fell progress i v e l y f r o m a m e a n of 359,000 to 266,000 c u m m ( P < 0 0 0 1 ) . P l a t e l e t a g g r e g a t i o n i n d u c e d by A D P increased s i g n i f i c a n t l y from 55% to 76%, t h e n r e t u r n e d to c o n t r o l levels by 1 hour. A g g r e g a t i o n induced by epin e p h r i n e s h o w e d no s i g n i f i c a n t change. Intrinsic A T P and ADP concentrations remained essentially unchanged. U l t r a s t r u c t u r a l e v a l u a tion of the c i r c u l a t i n g p l a t e l e t s before and after h e m o r r h a g e at the different periods of observation showed no significant change. H e m a t o c r i t s in both groups were u n c h a n g e d before and after h e m o r r h a g e at t h e different time periods. DISCUSSION
T r a u m a victims in profound hypovolemic shock secondary to acute blood loss d e m a n d q u i c k a n d c o m p e t e n t
r e s u s c i t a t i v e efforts to restore circul a t i n g blood volume and control hemorrhage. T h e r e are v a r y i n g opinions on how to best m a n a g e these patients. The overuse of Ringer's lactate solution h a s been a s s o c i a t e d w i t h p u b m o n a r y edema. S k i l l m a n et aP adv o c a t e u s e of c o l l o i d or a l b u m i n solution to m a i n t a i n oncot~c pressure w i t h i n c i r c u l a t i o n to p r e v e n t pulm o n a r y edema. On the other hand, Holcroft and T r u n k e y ~ showed t h a t the d e g r e e of p u l m o n a r y e d e m a is, in fact, worse in baboons resuscitated with colloid solution compared with crystalloid solution. These conflicting points of view need f u r t h e r study. A n o t h e r e q u a l l y major complication t h a t follows successful resuscitation of p a t i e n t s in h e m o r r h a g i c shock is a generalized bleeding diatbesis. 7,s The massive use of stored blood has been shown to be responsible for the deficiency in a n u m b e r of c o a g u l a t i o n factors. The r e s u l t s of our study indicate t h a t with acute blood loss there is a definite change in p l a t e l e t function, especially when r e s u s c i t a t i v e efforts are delayed. The c i r c u l a t i n g platelet
Volume 4 Number 6 Page 525
counts decrease and p l a t e l e t aggregabllityincreases (Figure). A transient hypercoagulative state exists and i n t r a v a s c u l a r c o a g u l a t i o n occurs. This is reflected by a fall in p l a t e l e t count, t h e p r e s e n c e of c i r c u l a t i n g f i b r i n m o n o m e r c o m p l e x e s a n d a r i s e in fibrin d e g r a d a t i o n products (authors' unpublished observations). These c h a n g e s o c c u r r e d i n d e p e n d e n t l y of massive blood transfusions. With prolonged tissue ischemia, the coagul o p a t h y would become worse. Therefore, m a n a g e m e n t of p a t i e n t s in hypovolemic shock should be directed at p r o m p t and aggressive r e s u s c i t a t i o n to m i n i m i z e t h e d u r a t i o n of poor p e r i p h e r a l perfusion.
Table 2 PLATELET
RESPONSE
Platelet Test
Control
Count
359+ 127
(x 103) (mm 3)
Aggregation ADP
(%)
(5/~ M)
270±87
72+22
47+39
Epinephrine
60'
263_+95 266+108
Intrinsic ADP
(/~ M/10 G platelets) *Mean+SD
PLATELET COUNT x 103
72+20
35--+29
(5 x 10 -4 mg/ml)
(/~ M/106 platelets)
Page 526 Volume 4 Number 6
258+107
30'
624-28
(P < 0.05)(P < 0.001)(P < 0.001) (P < 0.5)
To m a n a g e these patients, we i n s e r t large bore c a t h e t e r s t h r o u g h cutdowns for r a p i d infusion of crystalloid solutions and for central venous p r e s s u r e monitoring. The r a p i d infusion of I to 2 liters of c r y s t a l l o i d solution should b r i n g about a d r a m a t i c response in t h e p a t i e n t ' s v i t a l s i g n s . If t h e p a t i e n t ' s response is t r a n s i e n t or only p a r t i a l , we suspect continued i n t r a a b d o m i n a l or i n t r a t h o r a c i c bleeding. P r o m p t s u r g e r y to control the bleeding while r e s u s c i t a t i v e efforts continue is m a n d a t o r y for successful outcome.
F i n a l l y , if t h e b l e e d i n g d i a t h e s i s after m a s s i v e blood r e p l a c e m e n t is a red blood cell and coagulation deficiency, t h e use of w a r m fresh blood is
10'
76--+21
55+15
Intrinsic ATP
In p a t i e n t s who develop a generalized oozing a f t e r m u l t i p l e t r a n s f u sions, e v a l u a t i o n of t h e h e m o s t a t i c disorder should include the following d e t e r m i n a t i o n s : p a r t i a l thromboplastin time, p r o t h r o m b i n time, p l a t e l e t count, p l a t e l e t function tests, circul a t i n g fibrin m o n o m e r level, fibrinogen level and fibrin d e g r a d a t i o n products p r e s e n t . If a p r i m a r y p l a t e l e t defect exists, 8 to 10 units of p l a t e l e t packs or c o n c e n t r a t e s are a d m i n i s tered. If t h e defect is p r i m a r i l y in the coagulation factors, t h e n fresh frozen p l a s m a is a d m i n i s t e r e d .
Immed.
IN T H E B A B O O N *
(P < 0.01) (P < O.O01)(P < 0.001) (P < 0.01)
Patient Management
After infusion of 2 liters of crystalloid solution, r e p l a c e m e n t of predicted shed blood w i t h whole blood is init i a t e d . I f t h e d e m a n d for b l o o d r e p l a c e m e n t exceeds 8 to 10 units, i d e a l l y all s u b s e q u e n t t r a n s f u s i o n s should be fresh blood; ie, 24 hours old or less.
AFTER HEMORRHAGE
56.64-11.5 51.6+14.9
47.4+19.2
37.1+2.7
62,64-9.6
--
42+._34
50.0+1,7.2 52.2&19.2
47.5+20.1 39.3--+11.7 47.7_+13.7
,oo 300
T i
Or
I
2O0 10C -
100
75
PLATELET AGGREGATION 50 % 25
t
~.ontrol
i 0
i 10
i 20
i 30
i 40
i 50
1 60
MINUTES F i g . Changes in platelet count and aggregation induced by 5 / ~ M A D £ after hemorrhage. (Control = baseline, 0 - immediately after hemorrhage)
November/December 1975 , ~ P
j~dicated- Fresh w a r m blood has all Ihe coagulation factors including the }]~bile factors, viable platelets, and functioning red blood cells to correct 'the global defect t h a t occurs w i t h ~$~ssive whole blood transfusions. !
cONCLUSION With this s e q u e n t i a l resuscitative ~pproach to the hypovolemic patient, 'the period of shock and low flow state ~is minimized. In t u r n , the complicaPti011sof generalized coagulopathy can bbeavoided or lessened.
~PNovember/December 1975
REFERENCES 1. Miller RD, Robbins TO, Tong MJ, et al: Coagulation defects associated with massive blood transfusions. A n n S u r g 174: 794-801, 1971. 2. Lim RC, Jr, Olcott C IV, Robinson AJ, et al: Platelet response and coagulation changes following massive blood replacement. J Trauma 13:577-582, 1973. 3. Krevans JR, Jackson DP: Hemorrhagic disorder following massive whole blood transfusions. J A M A 159:171-177, 1955. 4. Holmsen H, Holmsen I, Bernhardsen A: Microdetermination of ADP and ATP in plasma with the firefly luciferase system. A n a l Biochem 17:456-473, 1966.
5. Skillman JJ, Parikh BM, Tanenbaum BJ: Pulmonary arteriovenous admixture: Improvement with albumin and distress. A m J S u r g 119:440-447, 1970. 6. Holcroft JW, Trunkey DD: Extravascular lung water following hemorrhagic shock in the baboon: Comparison between resuscitation with Ringer's lactate and plasmanate. A n n S u r g 180:408-417, 1974. 7. String T, Robinson AJ, Blaisdell FW: Massive trauma. Arch S u r g 102:406-411, 1971. 8. Ljungqvist U, Bergentz SE, Leandoer L: Platelet adhesiveness and aggregability after acute hemorrhage in the dog. Acta Chir S c a n d (preprint) Feb. 1970.
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