THE COAGULATION-FIBRINOLYSIS SYSTEM IN MAN DURING ETHRANE| ANAESTHESIA AND SURGERY
T. OYAMA, ~ M. TAKICUCHI,M. NAGAYAMA,AND M. MAKI
INTRODUCTION THE CIRCULATORYAND RESPIRATORYRESPONSESto Ethrane|
have been studied since 1966, but the effect of Ethrane| on the coagulation-fibrinolysis system has not been published. The present study was undertaken to determine whether an haemorrhagic tendency may occur during surgical operations under F.thrane| anaesthesia in man. METHODS
1. Sub/ec~s Twenty patients, undergoing gynaecological operations (mainly panhysterectomy), were the subjects of the present study. The pre-operative bleeding time, coagulation time, hepatic function and renal function were normal. None of these patients had any severe anaemia and none received a haemostatic agent. The diagnosis, type of surgery, duration of operation and anaesthesia, volume of haemorrhage, and volume of intravenous fluids administered are shown in Table I.
2. Anaesthetic Method Premedication, given in the usual manner, consisted of pentobarbitone 100 mg, meperedine 35 mg, and atropine 0.5 mg. After control blood sampling, the subject started to inhale 2 litres of oxygen and 4 litres of nitrous oxide combined with Ethrane| Concentration of Ethrane| was increased from 0.5 per cent to 2.5 per cent by opening a Fluotec~ vapourizer one notch of calibration after every two or three respirations. After loss of consciousness tracheal intubation was performed with relaxation provided by injection of succinylcholine chloride 40 mg. Anaesthesia was maintained with 2 litres of oxygen and 2 litres of nitrous oxide. The Fluotec | vapourizer was kept at between 1.0 per cent and 2.0 per cent for the maintenance of anaesthesia. Curare was administered when needed. Five hundred ml of low molecular weight dextran was used throughout the procedure. Anaesthesia was maintained for 30 minutes before beginning the operation and during that period a maximum of 100 ml of low molecular dextran was used. When bleeding exceeded 400 ml, whole blood was transfused.
3. Time and Method of Blood Sampling Blood was withdrawn five times; immediately before induction of anaesthesia at 8.30 a.m. (which served as a control), 30 minutes after the start of anaesthesia, From the Department of Anaesthesia, Hirosaki University School of Medicine, Hirosaki, Aomori-Ken, Japan. *Present address: Anaesthesiology Service/ll2A, Veterans Administration Center, Wood (Milwaukee), Wisconsin 53193. 349 Canad. Anaesth. Soc. J., vol. 22, no. 3, May 1975
350
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL TABLE I SURGICALOPERATIONSPERFORMED
Case
Age
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
41 41 44 47 46 48 39 46 50 38 60 40 44 40 41 47 38 66 35 51
Surgical Procedure Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Exploratory laparotomy Panhysterectomy Panhysterectomy Panhysterectomy Hysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Hysterectomy Colpoperineorrhaphy
Mean ~ = hours.
Operating Anaesthesia Blood Blood Time Time Loss Transfusion 2050' 4000 ' 3035' 5037 ' 4~ ' 3~ ' 2055' 4030' 3~ ' 2~ ' 3~ ' 3~ ' 3~ ' 2~ ' 3~ ' 3040, 3~ ' 2~ ' 2008' 1~ ' 3~ '
4~ ' 6015 ' 4~ ' 7025 ' 5~ ' 4~ ' 4005' 5~ ' 3~ ' 3~ ' 3040 ' 4~ ' 4029 ' 3~ ' 4000 ' 4025, 4~ ' 3000' 3000' 2052' 4~ '
345 437 530 970 914 240 400 440 430 180 320 262 160 261 940 350 700 538 244 136 439
0 400 600 800 1000 0 200 400 200 0 0 0 0 0 800 0 680 400 0 0 274
Fluid 1000 1000 1000 1500 1000 1000 1500 1500 1000 500 1500 1000 1000 1000 1000 1000 1000 1000 1000 1000 1075
' = minutes.
30 m i n u t e s a n d 1 h o u r a f t e r b e g i n n i n g the o p e r a t i o n , a n d in t h e r e c o v e r y r o o m w h e n t h e p a t i e n t was fully a w a k e . T h e b l o o d s a m p l e s w e r e t a k e n t h r o u g h an ind w e l l i n g p o l y v i n y l c a t h e t e r into a d i s p o s a b l e p l a s t i c s y r i n g e w h i c h c o n t a i n e d a m i x t u r e of n i n e v o l u m e s of v e n o u s b l o o d a n d o n e v o l u m e of 3.8 p e r c e n t s o d i u m citrate. T h e p l a s m a was s u b i e c t e d to t h e d e t e r m i n a t i o n s t a b u l a t e d b e l o w a n d p a i r e d S t u d e n t t-tests w e r e e m p l o y e d for statistical analysis.
4. Methods of Determinations (a) Platelet count ( Brecher-Cronkete method ) ( b ) Thrombin time (seconds) ( Hougie method ) (c) Partial thromboplastin time ( seconds ) (d) Prothrombin time ( seconds ) ( Quick one-stage method ) ( e ) P l a s m i n o g e n ( x 10 - 3 P.U. ) ( m o d i f i e d M a k i m e t h o d ) ( f ) F i b r i n o g e n ( m g / 1 0 0 ml) ( M a k i m o d i f i c a t i o n of t h e R a t h o f f - M e n z i e m e t h o d ) ( g ) E u g l o b u l i n clot lysis t i m e ( m i n u t e s ).
RESULTS
1. Platelet Count T h e p l a t e l e t c o u n t i m m e d i a t e l y b e f o r e t h e i n d u c t i o n of a n a e s t h e s i a a v e r a g e d 23.5 -+ 1.14 • 104/mm 3 ( - S . E . ) . I t w a s 21.0 - 1.07 • 104/ram 3 30 m i n u t e s a f t e r t h e s t a r t of a n a e s t h e s i a , 23.1 - 1.4, 19.9 -+ 1.63 one h o u r after s t a r t i n g t h e o p e r a t i o n a n d 20.6 -+ 1.0 • 1 0 t / r a m '~ in t h e r e c o v e r y room. Thus, all w e r e w i t h i n t h e n o r m a l r a n g e a n d no a p p r e c i a b l e v a r i a t i o n was n o t e d ( T a b l e I I ).
OYAMA, et al.: COAGULATION-FIBRINOLYSIS SYSTEM
351
TABLE II PLATELET COUNT DURING ETHRANE| ANAESTHESIA AND SURGICAL OPERATION P l a t e l e t C o u n t ( X 1 0 4 / m m 3) Anaesthesia
Operation
Operation
Recovery
Case
Preincubation
(30')
(30')
(1~
Room
3 4 5 6 7
16.8 20.0 22.2 24.6 33.4
17.2 22.0 15.0 25.0 20.0
16.2 20.6 17.6 21.8 34.0
15.0 23.2 15.0 17.0 30.0
21.0 25.0 16.0 11.0 23.0
8 9 10 11 12 13 14 15 17 18 20
15.6 22.0 28.8 20.0 23.6 29.7" 22.6 18.2 24.2 26.4 28.4
19.4 23.4 28.6 19.6 24.0 19.6 12.4 26.6 18.0 19.6 26.2
--29.8 26.0 22.0 -14.0 24.0 24.0 27.2 22.6
18.2 12.8 18.6 20.8 28.0 -18.0 17.4 27.4 18.6 28.8
17.4 21.4 24.2 19.0 19.0 16.2 16.0 20.0 24.0 17.2 28.2
23.5 1.19
21.0 1.07 N.S.
23.1 1.46 N.S.
19.9 1.63 N.S.
20.6 1.00 N.S.
Mean S.E. p ' = minutes.
~ = hours.
N.S. = n o t significant.
2. Coagulation System (a) Thrombin time. Prior to the induction of anaesthesia, the thrombin time averaged 12.2 • 0.40 seconds ( - S . E . ) . It was 12.6 --- 0.56 seconds 30 minutes after the beginning of anaesthesia and thus within the normal range. During the operation ( 30 minutes after incision ) it showed some prolongation ( 14.5 --- 1.25 seconds ), which was not a significant difference. In the recovery room, the thrombin time was 12.7 --- 0.56 seconds, which is a normal level (Table III ). (b) Prothrombin time. Prothrombin time was 13.7 • 0.38 seconds (• before the induction of anaesthesia. It was slightly, but significantly, decreased to 13.3 --- 0.41 seconds 30 minutes after the start of anaesthesia and to 13.2 --- 0.36 seconds 30 minutes after the beginning of operation. Prothrombin times did not change and were within normal range during the operations ( 13.2 --- 13.6 seconds) and in the recovery room ( 13.6 seconds ) ( Table IV). (c) Partial thromboplastin time (P.T.T.). Partial thromboplastin time prior to the induction of anaesthesia was 60.0 • 3.8 seconds ( - S . E . ) . It decreased insignfficantly to 56.7 • 3.06 seconds 30 minutes after the start of anaesthesia but before the operation. P,T.T. further decreased significantly (49.6 • 1.94 seconds, p < 0.001) 30 minutes after the start of operation and returned to the preinduction level (60.3 • 9.3 seconds) one hour after the start of operation. In the recovery room, however, it was again reduced significantly to 47.1 • 2.0 seconds (p < 0.01) ( Table V).
3. Results on the Fibrinolysis System (a) Plasma plasminogen level before the induction of anaesthesia was 16.3 ---
H
Z ,--i
00
? ~. 0
0
0
lu
t-
0 Z
9
I1
Z
0 e-
II
Z
II
0
o
0
0
II
o
e,,
II
Z~ ~
l
~
l
~
~
O
Of-~-
6"
M
0
t"
N
Z
0
Z
GO
OYAMA, et al.: COAGULATION-FIBRINOLYSISSYSTEM
353
TABLE V PARTIAL THROMBOBLASTIN TIME DURING ~THRANE| ANAESTHESIA AND SURGICAL OPERATION Partial Thromboplastin Time (seconds) Case
Preinduction
Anaesthesia (30')
Operation (30')
Operation (1 ~
Recovery Room
3 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20
70.2 56.0 52.0 100.0 70.2 40.8 69.4 58.0 65.0 47.2 57.0 45.6 62.0 33.0 54.8 78.8
64.2 50.0 58.0 84.0 54.2 40.2 84.0 49.0 58.8 54.0 46.0 49.0 50.0 43.0 57.4 55.6
58.8 45.0 51.0 63.0 58.8 35.4 48.0 49.0 50.0 40.8 47.0 46.0 52.8 41.8 43.6 63.0
54.6 44.0 44.4 67.0 54.6 35.0 43.0 37.6 -42.0 47.4 108.0 42.6 46.4 57.4 3.0
41.4 38.6 47.6 68.0 41.4 47.0 39.0 41.6 63.4 44. O 46.0 45.2 44.4 58.0 42.0 46.2
56.7 3.06 N.S.
49.6 1.94 0.001
Mean S.E. p ' = minutes.
60.0 3.89 ~ = hours.
60.3 9.36 N.S.
47.1 2.08 0.01
N.S. = not significant.
0.80 • 10 -8 P.U. (-S.E.). It decreased significantly (p < 0.001) 30 minutes and one hour after the start of operation. In the recovery room it was still significantly decreased to 13.2 - 0.68 • 10 -:~ P.U. ( p < 0.001 ) (Table VI ). (b) The fibrinogen level before the induction of anaesthesia was 248.7 - 14.56 mg/100 ml (---S.E.). It decreased to 224.6 --- 17.43 mg/100 ml 30 minutes after the induction of anaesthesia, this being within normal range but exhibiting a statistically significant decline (p < 0.05). The fibrinogen level decreased gradually and significantly (p < 0.05) during operation, being 216.3 - 19.35 mg/100 ml and 198.1 --- 19.08 mg/100 ml 30 minutes and one hour after the start of operation, respectively. It was further reduced to 181.8 --- 24.96 mg/100 ml in the recovery room ( p < 0.03) ( Table VII ). (c) The euglobulin clot lysis time was 226.7 - 7.9 minutes (+S.E.) before the induction of anaesthesia. It decreased significantly up to 197.4 - 15.84 minutes 30 minutes after the start of anaesthesia. It decreased significantly (p < 0.001) to 101.1 --- 18.03 and 101.0 - 17.04 minutes, respectively, 30 minutes and one hour after the start of operation, but increased to 191.7 - 16.86 minutes in the recovery room, exhibiting the tendency of returning to the control value (Table VIII). DISCUSSION
We administered Ethrane | anaesthesia for 20 gynaecological operations (mostly panhysterectomy) performed by the same surgeons, and examined the coagulationfibrinolysis system during anaesthesia alone and during operation. The platelets were counted and the coagulation system was evaluated by thrombin time, pro-
354
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL TABLE Vl
PLASMA PLASMINOGEN LEVELS DURING ETHRANE~) ANAESTHESIA AND SURGICAL OPERATION Plasma Plasminogen Levels (X10 -s P.U.) Case
Preinduetion
Anaesthesia (30')
Operation (30')
Operation (10)
Recovery Room
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
19.6 25.4 16.1 19.0 12.7 12.4 16.2 17.0 13.9 19.4 22.2 17.0 13.5 16.1 14.9 11.8 10.0 15.1 17.8 15.1
17.5 14.2 16.4 16.2 -11.6 13.7 11.7 12.8 13,5 18.5 15.6 11.8 10.0 7.7 13.1 9.4 12.1 17.8 11,8
16.4 16.0 15.7 16.2 11.1 12.1 12.9 12.6 9.1 15.6 18.4 13.0 11.8 10.8 8.0 9.9 12.6 14.3 18.8 15.8
13.7 14.6 16.3 17.9 9.7 11.0 11.5 11.8 11.1 16.3 17.1 13.1 8.9 8.2 10.5 9.0 13.5 11.3 15.6 12.9
16.0 14.2 15.0 15.9 10.6 8.9 14.6 13.8 11.8 14.3 19.9 12.4 10.3 16,3 8.2 12.4 9.0 11.4 18.0 11.8
16.3 0.80
13.4 0.67 0.01
13.6 0.66 0.001
12.7 0.63 0.001
13.2 0.68 0,001
Mean S.E. 0 = minutes.
~ = hours.
TABLE VII PLASMA FIBRINOGEN LEVELS DURING F_.THRANE~ ANAESTHESIA AND SURGICAL OPERATION Plasma Fibrinogen Levels (mg/100 ml) Case 1 2 3 4 6 7 8 9 10 11 12 13 15 16 17 18 19 20 Mean S.E. p '
=
Anaesthesia (30')
Operation (30')
226 212 260 410 328 270 228 210 245 351 227 172 214 227 163 227 200 306
184 130 352 360 311 329 153 168 192 279 214 177 163 186 144 217 180 304
152 142 386 398 315 279 140 127 156 250 155 179 163 212 158 296 163 222
140 84 416 290 298 214 177 142 202 194 153 -187 246 91 168 147 220
106 --
248.7 14.56
224.6 17.43 0.05
216.3 19.59 0.05
198.1 19.08 0.05
181.8 24.96 0.03
Preinduction
minutes.
~
=
hours.
Operation (1 ~
Recovery Room
322
426 253 230 210 120 -253 91 106 110 191 42 73 130 246
OYAMA, e t
al.:
COAGULATION-FIBRINOLYSIS SYSTEM
355
T A B L E VIII
EUGLOBULIN CLOT LYSIS TIME DURING ~THRANE| ANAESTHESIA AND SURGICAL OPERATION Euglobulin Clot Lysis Time (minutes) Case
Preinduction
Anaesthesia (30')
Operation (30')
Operation (1 ~
Recovery Room
I 2
240 240
60 30
240 240
60 120
180 240
3
240
240
30
240 240 240 240 240 240 240 240 150 240 120 210 240 240 240 -226.7 7.90
240 240 240 240 240 240 240 240 150 240 90 120 180 240 240 240 197.4 15.84 N.S.
5 6 7 8 9 1O 11 12 13 14 15 16 17 18 19 20 Mean S.E. p = minutes.
~ = hours.
30 210 90 180 90 60 120 30 30 30 30 60 120 30 60 240 101.1 18.03 0.001
90 120 240 60 210 120 90 240 30 30 30 30 60 60 30 60 240 101.1 17.04 0.001
30 30 240 240 240 240 240 240 90 150 270 180 240 240 -150 240 191.7 16.86 N.S.
N.S. = not significant.
thrombin time and partial thromboplastin time (P.T.T.). They were maintained practically within normal range. Plasminogen and euglobulin clot lysis times decreased significantly during Ethrane| anaesthesia alone for 30 minutes, and a further reduction was noted during the surgical operation. The fibrinogen level also tended to decrease. These findings suggest that Ethrane| anaesthesia and surgical operation accelerated the activity of the fibrinolytic system in man. The elucidation of this accelerated mechanism is beyond the scope of the present study. Administration of low molecular dextran, 1000 ml, was not found to cause any significant effect on the coagulation and fibrinolysis system in man. 1 We have observed acceleration, both in the coagulation and fibrinolysis systems, tinder halothane anaesthesia, thereby maintaining a balanced haemostatic mechanism." Vanderveen e t al. '~ found mild disturbance in the coagulation system and prolonged bleeding time only during hypothermia. No difference was found in the blood coagulation factors by other methods of anaesthesia or with other anaesthetics. They observed a slight prolongation in the bleeding time and a decline in capillary resistance. Pison e t al. 4 found that the surgical operations increased fibrinolytic activity significantly. Dillon ~ reported that the volume of bleeding during surgical operations under Ethrane| anaesthesia, was as normal as in other ordinary surgical operations. The haemorrhagic diathesis is considered to be induced by abnormalities, platelets, blood vessels, coagulation, and fibrinolysis. The coagulation and fibrinolysis systems are collectively designated as the coagulation-fibrinolysis system. Under normal conditions there is constantly a dynamic equilibrium between the coagu-
356
CANADIAN ANAESTHETISTS"SOCIETYJOURNAL
lation and the fibrinolysis systems. When the equilibrium is upset by various stresses including surgery, anaesthesia, shock, anoxia, a variety of disturbances are produced. When the coagulation system is predominant, thrombus may be formed. Conversely, if the fibrinolytic system is predominant oozing may result in severe haemorrhage. 6 Ethrane| anaesthesia showed a tendency to accelerated plasmin activity and decreased fibrinogen level. This might be interpreted as setting the stage for the development of a haemorrhagic tendency but in fact the changes are not so extensive as to warrant such an interpretation. It may be suggested that both anaesthesia and surgical operation are conducive to acceleration of coagulation and fibrinolysis, but, the haemostatic mechanism tends to keep a balance between coagulation and fibrinolysis and to be in equilibrium. It is common knowledge that a haemorrhagic tendency becomes overt when the factors participating in the haemostatic mechanism are reduced to less than 20 per cent of normal. Therefore, although l~thrane| anaesthesia causes increased fibrinolysis and decreases fibrinogen level, unless the haemostatic mechanisms have been abnormal before operation no decline below the borderline levels can be observed. However, it should be kept in mind that Ethrane| seems to cause more fibrinolysis and a lower level of fibrinogen than is the case with other anaesthetics? The possible need for an antiplasmin agent during operation should also be considered. SUMMARY
The coagulation-fibrinolysis system was studied during Ethrane| anaesthesia and gynaecological operations in 20 patients. No particular change was noted in the platelet counts, which remained within the normal range. In the coagulation system, no appreciable change was observed except for the partial thromboplastin time(P.T.T.) which was si~maificantly shortended, both 30 minutes after the start of operation and in the recovery room when the patient had completely awakened from the anaesthesia. In the fibrinolytic system, the plasminogen level and the fibrinogen level declined significantly. It is considered that the fibrinolytic system is prominently accelerated under Ethrane| anaesthesia, but the haemostatic mechanism works in such a manner that bleeding is controlled. However, ]~thrane| anaesthesia should be avoided or pre-operati'ee administration of an antiplasmic agent recommended for patients with an abnormal haemostatic mechanism. R~svlvr~ 1. Le syst~me coagulation-fibrinolyse a ~t~ ~tudi6 chez 20 patientes au cours d'interventions gynrcologiques, sous anesth~sie ~ l'Ethrane.| 2. Aucune modification particuli~re ne fut trouvre dans la numeration plaquettaire qui est demeurre dans les limites normales. Le coagulogramme n'a pas 6t6 modifir de fa~on apprrciable saul le temps de thromboplastine partiel (P.T.T.) qui
OYAMA, et al.: COAGULATION-FIBRI-NOLYSISSYSTEM
357
6tait diminu6 de fa$on significative, ceci apr~s 30 minutes de chirurgie et apr~s r6veil complet. 3. Pour ce qui est du syst~me fibrinolytique, les taux de plasminog~ne et de fibrinog~ne 6taient diminu6s de fagon significative; le fibrinog~ne en partieulier 6tait abaiss6 de fa~on marqu6e. 4. Nous consid6rons que sous anesth6sie h l'Ethrane, le syst~me fibrinolytique est acc~16r6, mais que les m6eanismes h6mostatiques agissent de telle fagon que l'h~morragie est contr616e. Cependant, chez les patients pr6sentant des troubles de l'h6mostase, on devrait 6viter l'anesth6sie ~ rEthrane '~ moins de leur administrer un agent antifibrinolytique avant l'intervention.
REFERENCES 1. OYAMA,T. Effect of low molecular weight dextran on coagulative-flbrinolytic system in man ( to be published ). 2. OYAMA,T., TAKICUCHI,M., KIMVP,A, K., & MAKL M. Effect of fluothane anesthesia on coagulative-fibrinolyticsystem. Jap. J. Anesthesiol. 16:686-692 (1967). 3. VENDERVEEN,J. L., McGovEaN, J.J., BUNKER,J.P., & GOLDSTEIN',R. Effect of anesthesia on hemostatic mechanism in man. Anesthesiology23:92--100 ( 1962 ). 4. PIsoN, J., BOYAN,C.P., & CLIFFTON,E.E. Fibrinolytic activity in patients during operation. J.A.M.A. 191:1026-1027 (1965). 5. DILLON,J.B., LEBOWITZ,M.H., & BLITT, C.D. Clinical investigation of compound 347 (Ethrane@). Anesth. Analg. 49: 1-1O (1970). 6. RODEIBIQUE,E.M. & WYNANDS,J.E. Blood coagulation and hemostasis. A review. Canad. Anaesth. Soc. J. 14:129-151 (1967).
T. OYAMA, ~ M. TAKICUCHI,M. NAGAYAMA,AND M. MAKI
INTRODUCTION THE CIRCULATORYAND RESPIRATORYRESPONSESto Ethrane|
have been studied since 1966, but the effect of Ethrane| on the coagulation-fibrinolysis system has not been published. The present study was undertaken to determine whether an haemorrhagic tendency may occur during surgical operations under F.thrane| anaesthesia in man. METHODS
1. Sub/ec~s Twenty patients, undergoing gynaecological operations (mainly panhysterectomy), were the subjects of the present study. The pre-operative bleeding time, coagulation time, hepatic function and renal function were normal. None of these patients had any severe anaemia and none received a haemostatic agent. The diagnosis, type of surgery, duration of operation and anaesthesia, volume of haemorrhage, and volume of intravenous fluids administered are shown in Table I.
2. Anaesthetic Method Premedication, given in the usual manner, consisted of pentobarbitone 100 mg, meperedine 35 mg, and atropine 0.5 mg. After control blood sampling, the subject started to inhale 2 litres of oxygen and 4 litres of nitrous oxide combined with Ethrane| Concentration of Ethrane| was increased from 0.5 per cent to 2.5 per cent by opening a Fluotec~ vapourizer one notch of calibration after every two or three respirations. After loss of consciousness tracheal intubation was performed with relaxation provided by injection of succinylcholine chloride 40 mg. Anaesthesia was maintained with 2 litres of oxygen and 2 litres of nitrous oxide. The Fluotec | vapourizer was kept at between 1.0 per cent and 2.0 per cent for the maintenance of anaesthesia. Curare was administered when needed. Five hundred ml of low molecular weight dextran was used throughout the procedure. Anaesthesia was maintained for 30 minutes before beginning the operation and during that period a maximum of 100 ml of low molecular dextran was used. When bleeding exceeded 400 ml, whole blood was transfused.
3. Time and Method of Blood Sampling Blood was withdrawn five times; immediately before induction of anaesthesia at 8.30 a.m. (which served as a control), 30 minutes after the start of anaesthesia, From the Department of Anaesthesia, Hirosaki University School of Medicine, Hirosaki, Aomori-Ken, Japan. *Present address: Anaesthesiology Service/ll2A, Veterans Administration Center, Wood (Milwaukee), Wisconsin 53193. 349 Canad. Anaesth. Soc. J., vol. 22, no. 3, May 1975
350
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL TABLE I SURGICALOPERATIONSPERFORMED
Case
Age
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
41 41 44 47 46 48 39 46 50 38 60 40 44 40 41 47 38 66 35 51
Surgical Procedure Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Exploratory laparotomy Panhysterectomy Panhysterectomy Panhysterectomy Hysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Panhysterectomy Hysterectomy Colpoperineorrhaphy
Mean ~ = hours.
Operating Anaesthesia Blood Blood Time Time Loss Transfusion 2050' 4000 ' 3035' 5037 ' 4~ ' 3~ ' 2055' 4030' 3~ ' 2~ ' 3~ ' 3~ ' 3~ ' 2~ ' 3~ ' 3040, 3~ ' 2~ ' 2008' 1~ ' 3~ '
4~ ' 6015 ' 4~ ' 7025 ' 5~ ' 4~ ' 4005' 5~ ' 3~ ' 3~ ' 3040 ' 4~ ' 4029 ' 3~ ' 4000 ' 4025, 4~ ' 3000' 3000' 2052' 4~ '
345 437 530 970 914 240 400 440 430 180 320 262 160 261 940 350 700 538 244 136 439
0 400 600 800 1000 0 200 400 200 0 0 0 0 0 800 0 680 400 0 0 274
Fluid 1000 1000 1000 1500 1000 1000 1500 1500 1000 500 1500 1000 1000 1000 1000 1000 1000 1000 1000 1000 1075
' = minutes.
30 m i n u t e s a n d 1 h o u r a f t e r b e g i n n i n g the o p e r a t i o n , a n d in t h e r e c o v e r y r o o m w h e n t h e p a t i e n t was fully a w a k e . T h e b l o o d s a m p l e s w e r e t a k e n t h r o u g h an ind w e l l i n g p o l y v i n y l c a t h e t e r into a d i s p o s a b l e p l a s t i c s y r i n g e w h i c h c o n t a i n e d a m i x t u r e of n i n e v o l u m e s of v e n o u s b l o o d a n d o n e v o l u m e of 3.8 p e r c e n t s o d i u m citrate. T h e p l a s m a was s u b i e c t e d to t h e d e t e r m i n a t i o n s t a b u l a t e d b e l o w a n d p a i r e d S t u d e n t t-tests w e r e e m p l o y e d for statistical analysis.
4. Methods of Determinations (a) Platelet count ( Brecher-Cronkete method ) ( b ) Thrombin time (seconds) ( Hougie method ) (c) Partial thromboplastin time ( seconds ) (d) Prothrombin time ( seconds ) ( Quick one-stage method ) ( e ) P l a s m i n o g e n ( x 10 - 3 P.U. ) ( m o d i f i e d M a k i m e t h o d ) ( f ) F i b r i n o g e n ( m g / 1 0 0 ml) ( M a k i m o d i f i c a t i o n of t h e R a t h o f f - M e n z i e m e t h o d ) ( g ) E u g l o b u l i n clot lysis t i m e ( m i n u t e s ).
RESULTS
1. Platelet Count T h e p l a t e l e t c o u n t i m m e d i a t e l y b e f o r e t h e i n d u c t i o n of a n a e s t h e s i a a v e r a g e d 23.5 -+ 1.14 • 104/mm 3 ( - S . E . ) . I t w a s 21.0 - 1.07 • 104/ram 3 30 m i n u t e s a f t e r t h e s t a r t of a n a e s t h e s i a , 23.1 - 1.4, 19.9 -+ 1.63 one h o u r after s t a r t i n g t h e o p e r a t i o n a n d 20.6 -+ 1.0 • 1 0 t / r a m '~ in t h e r e c o v e r y room. Thus, all w e r e w i t h i n t h e n o r m a l r a n g e a n d no a p p r e c i a b l e v a r i a t i o n was n o t e d ( T a b l e I I ).
OYAMA, et al.: COAGULATION-FIBRINOLYSIS SYSTEM
351
TABLE II PLATELET COUNT DURING ETHRANE| ANAESTHESIA AND SURGICAL OPERATION P l a t e l e t C o u n t ( X 1 0 4 / m m 3) Anaesthesia
Operation
Operation
Recovery
Case
Preincubation
(30')
(30')
(1~
Room
3 4 5 6 7
16.8 20.0 22.2 24.6 33.4
17.2 22.0 15.0 25.0 20.0
16.2 20.6 17.6 21.8 34.0
15.0 23.2 15.0 17.0 30.0
21.0 25.0 16.0 11.0 23.0
8 9 10 11 12 13 14 15 17 18 20
15.6 22.0 28.8 20.0 23.6 29.7" 22.6 18.2 24.2 26.4 28.4
19.4 23.4 28.6 19.6 24.0 19.6 12.4 26.6 18.0 19.6 26.2
--29.8 26.0 22.0 -14.0 24.0 24.0 27.2 22.6
18.2 12.8 18.6 20.8 28.0 -18.0 17.4 27.4 18.6 28.8
17.4 21.4 24.2 19.0 19.0 16.2 16.0 20.0 24.0 17.2 28.2
23.5 1.19
21.0 1.07 N.S.
23.1 1.46 N.S.
19.9 1.63 N.S.
20.6 1.00 N.S.
Mean S.E. p ' = minutes.
~ = hours.
N.S. = n o t significant.
2. Coagulation System (a) Thrombin time. Prior to the induction of anaesthesia, the thrombin time averaged 12.2 • 0.40 seconds ( - S . E . ) . It was 12.6 --- 0.56 seconds 30 minutes after the beginning of anaesthesia and thus within the normal range. During the operation ( 30 minutes after incision ) it showed some prolongation ( 14.5 --- 1.25 seconds ), which was not a significant difference. In the recovery room, the thrombin time was 12.7 --- 0.56 seconds, which is a normal level (Table III ). (b) Prothrombin time. Prothrombin time was 13.7 • 0.38 seconds (• before the induction of anaesthesia. It was slightly, but significantly, decreased to 13.3 --- 0.41 seconds 30 minutes after the start of anaesthesia and to 13.2 --- 0.36 seconds 30 minutes after the beginning of operation. Prothrombin times did not change and were within normal range during the operations ( 13.2 --- 13.6 seconds) and in the recovery room ( 13.6 seconds ) ( Table IV). (c) Partial thromboplastin time (P.T.T.). Partial thromboplastin time prior to the induction of anaesthesia was 60.0 • 3.8 seconds ( - S . E . ) . It decreased insignfficantly to 56.7 • 3.06 seconds 30 minutes after the start of anaesthesia but before the operation. P,T.T. further decreased significantly (49.6 • 1.94 seconds, p < 0.001) 30 minutes after the start of operation and returned to the preinduction level (60.3 • 9.3 seconds) one hour after the start of operation. In the recovery room, however, it was again reduced significantly to 47.1 • 2.0 seconds (p < 0.01) ( Table V).
3. Results on the Fibrinolysis System (a) Plasma plasminogen level before the induction of anaesthesia was 16.3 ---
H
Z ,--i
00
? ~. 0
0
0
lu
t-
0 Z
9
I1
Z
0 e-
II
Z
II
0
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0
0
II
o
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II
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l
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GO
OYAMA, et al.: COAGULATION-FIBRINOLYSISSYSTEM
353
TABLE V PARTIAL THROMBOBLASTIN TIME DURING ~THRANE| ANAESTHESIA AND SURGICAL OPERATION Partial Thromboplastin Time (seconds) Case
Preinduction
Anaesthesia (30')
Operation (30')
Operation (1 ~
Recovery Room
3 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20
70.2 56.0 52.0 100.0 70.2 40.8 69.4 58.0 65.0 47.2 57.0 45.6 62.0 33.0 54.8 78.8
64.2 50.0 58.0 84.0 54.2 40.2 84.0 49.0 58.8 54.0 46.0 49.0 50.0 43.0 57.4 55.6
58.8 45.0 51.0 63.0 58.8 35.4 48.0 49.0 50.0 40.8 47.0 46.0 52.8 41.8 43.6 63.0
54.6 44.0 44.4 67.0 54.6 35.0 43.0 37.6 -42.0 47.4 108.0 42.6 46.4 57.4 3.0
41.4 38.6 47.6 68.0 41.4 47.0 39.0 41.6 63.4 44. O 46.0 45.2 44.4 58.0 42.0 46.2
56.7 3.06 N.S.
49.6 1.94 0.001
Mean S.E. p ' = minutes.
60.0 3.89 ~ = hours.
60.3 9.36 N.S.
47.1 2.08 0.01
N.S. = not significant.
0.80 • 10 -8 P.U. (-S.E.). It decreased significantly (p < 0.001) 30 minutes and one hour after the start of operation. In the recovery room it was still significantly decreased to 13.2 - 0.68 • 10 -:~ P.U. ( p < 0.001 ) (Table VI ). (b) The fibrinogen level before the induction of anaesthesia was 248.7 - 14.56 mg/100 ml (---S.E.). It decreased to 224.6 --- 17.43 mg/100 ml 30 minutes after the induction of anaesthesia, this being within normal range but exhibiting a statistically significant decline (p < 0.05). The fibrinogen level decreased gradually and significantly (p < 0.05) during operation, being 216.3 - 19.35 mg/100 ml and 198.1 --- 19.08 mg/100 ml 30 minutes and one hour after the start of operation, respectively. It was further reduced to 181.8 --- 24.96 mg/100 ml in the recovery room ( p < 0.03) ( Table VII ). (c) The euglobulin clot lysis time was 226.7 - 7.9 minutes (+S.E.) before the induction of anaesthesia. It decreased significantly up to 197.4 - 15.84 minutes 30 minutes after the start of anaesthesia. It decreased significantly (p < 0.001) to 101.1 --- 18.03 and 101.0 - 17.04 minutes, respectively, 30 minutes and one hour after the start of operation, but increased to 191.7 - 16.86 minutes in the recovery room, exhibiting the tendency of returning to the control value (Table VIII). DISCUSSION
We administered Ethrane | anaesthesia for 20 gynaecological operations (mostly panhysterectomy) performed by the same surgeons, and examined the coagulationfibrinolysis system during anaesthesia alone and during operation. The platelets were counted and the coagulation system was evaluated by thrombin time, pro-
354
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL TABLE Vl
PLASMA PLASMINOGEN LEVELS DURING ETHRANE~) ANAESTHESIA AND SURGICAL OPERATION Plasma Plasminogen Levels (X10 -s P.U.) Case
Preinduetion
Anaesthesia (30')
Operation (30')
Operation (10)
Recovery Room
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
19.6 25.4 16.1 19.0 12.7 12.4 16.2 17.0 13.9 19.4 22.2 17.0 13.5 16.1 14.9 11.8 10.0 15.1 17.8 15.1
17.5 14.2 16.4 16.2 -11.6 13.7 11.7 12.8 13,5 18.5 15.6 11.8 10.0 7.7 13.1 9.4 12.1 17.8 11,8
16.4 16.0 15.7 16.2 11.1 12.1 12.9 12.6 9.1 15.6 18.4 13.0 11.8 10.8 8.0 9.9 12.6 14.3 18.8 15.8
13.7 14.6 16.3 17.9 9.7 11.0 11.5 11.8 11.1 16.3 17.1 13.1 8.9 8.2 10.5 9.0 13.5 11.3 15.6 12.9
16.0 14.2 15.0 15.9 10.6 8.9 14.6 13.8 11.8 14.3 19.9 12.4 10.3 16,3 8.2 12.4 9.0 11.4 18.0 11.8
16.3 0.80
13.4 0.67 0.01
13.6 0.66 0.001
12.7 0.63 0.001
13.2 0.68 0,001
Mean S.E. 0 = minutes.
~ = hours.
TABLE VII PLASMA FIBRINOGEN LEVELS DURING F_.THRANE~ ANAESTHESIA AND SURGICAL OPERATION Plasma Fibrinogen Levels (mg/100 ml) Case 1 2 3 4 6 7 8 9 10 11 12 13 15 16 17 18 19 20 Mean S.E. p '
=
Anaesthesia (30')
Operation (30')
226 212 260 410 328 270 228 210 245 351 227 172 214 227 163 227 200 306
184 130 352 360 311 329 153 168 192 279 214 177 163 186 144 217 180 304
152 142 386 398 315 279 140 127 156 250 155 179 163 212 158 296 163 222
140 84 416 290 298 214 177 142 202 194 153 -187 246 91 168 147 220
106 --
248.7 14.56
224.6 17.43 0.05
216.3 19.59 0.05
198.1 19.08 0.05
181.8 24.96 0.03
Preinduction
minutes.
~
=
hours.
Operation (1 ~
Recovery Room
322
426 253 230 210 120 -253 91 106 110 191 42 73 130 246
OYAMA, e t
al.:
COAGULATION-FIBRINOLYSIS SYSTEM
355
T A B L E VIII
EUGLOBULIN CLOT LYSIS TIME DURING ~THRANE| ANAESTHESIA AND SURGICAL OPERATION Euglobulin Clot Lysis Time (minutes) Case
Preinduction
Anaesthesia (30')
Operation (30')
Operation (1 ~
Recovery Room
I 2
240 240
60 30
240 240
60 120
180 240
3
240
240
30
240 240 240 240 240 240 240 240 150 240 120 210 240 240 240 -226.7 7.90
240 240 240 240 240 240 240 240 150 240 90 120 180 240 240 240 197.4 15.84 N.S.
5 6 7 8 9 1O 11 12 13 14 15 16 17 18 19 20 Mean S.E. p = minutes.
~ = hours.
30 210 90 180 90 60 120 30 30 30 30 60 120 30 60 240 101.1 18.03 0.001
90 120 240 60 210 120 90 240 30 30 30 30 60 60 30 60 240 101.1 17.04 0.001
30 30 240 240 240 240 240 240 90 150 270 180 240 240 -150 240 191.7 16.86 N.S.
N.S. = not significant.
thrombin time and partial thromboplastin time (P.T.T.). They were maintained practically within normal range. Plasminogen and euglobulin clot lysis times decreased significantly during Ethrane| anaesthesia alone for 30 minutes, and a further reduction was noted during the surgical operation. The fibrinogen level also tended to decrease. These findings suggest that Ethrane| anaesthesia and surgical operation accelerated the activity of the fibrinolytic system in man. The elucidation of this accelerated mechanism is beyond the scope of the present study. Administration of low molecular dextran, 1000 ml, was not found to cause any significant effect on the coagulation and fibrinolysis system in man. 1 We have observed acceleration, both in the coagulation and fibrinolysis systems, tinder halothane anaesthesia, thereby maintaining a balanced haemostatic mechanism." Vanderveen e t al. '~ found mild disturbance in the coagulation system and prolonged bleeding time only during hypothermia. No difference was found in the blood coagulation factors by other methods of anaesthesia or with other anaesthetics. They observed a slight prolongation in the bleeding time and a decline in capillary resistance. Pison e t al. 4 found that the surgical operations increased fibrinolytic activity significantly. Dillon ~ reported that the volume of bleeding during surgical operations under Ethrane| anaesthesia, was as normal as in other ordinary surgical operations. The haemorrhagic diathesis is considered to be induced by abnormalities, platelets, blood vessels, coagulation, and fibrinolysis. The coagulation and fibrinolysis systems are collectively designated as the coagulation-fibrinolysis system. Under normal conditions there is constantly a dynamic equilibrium between the coagu-
356
CANADIAN ANAESTHETISTS"SOCIETYJOURNAL
lation and the fibrinolysis systems. When the equilibrium is upset by various stresses including surgery, anaesthesia, shock, anoxia, a variety of disturbances are produced. When the coagulation system is predominant, thrombus may be formed. Conversely, if the fibrinolytic system is predominant oozing may result in severe haemorrhage. 6 Ethrane| anaesthesia showed a tendency to accelerated plasmin activity and decreased fibrinogen level. This might be interpreted as setting the stage for the development of a haemorrhagic tendency but in fact the changes are not so extensive as to warrant such an interpretation. It may be suggested that both anaesthesia and surgical operation are conducive to acceleration of coagulation and fibrinolysis, but, the haemostatic mechanism tends to keep a balance between coagulation and fibrinolysis and to be in equilibrium. It is common knowledge that a haemorrhagic tendency becomes overt when the factors participating in the haemostatic mechanism are reduced to less than 20 per cent of normal. Therefore, although l~thrane| anaesthesia causes increased fibrinolysis and decreases fibrinogen level, unless the haemostatic mechanisms have been abnormal before operation no decline below the borderline levels can be observed. However, it should be kept in mind that Ethrane| seems to cause more fibrinolysis and a lower level of fibrinogen than is the case with other anaesthetics? The possible need for an antiplasmin agent during operation should also be considered. SUMMARY
The coagulation-fibrinolysis system was studied during Ethrane| anaesthesia and gynaecological operations in 20 patients. No particular change was noted in the platelet counts, which remained within the normal range. In the coagulation system, no appreciable change was observed except for the partial thromboplastin time(P.T.T.) which was si~maificantly shortended, both 30 minutes after the start of operation and in the recovery room when the patient had completely awakened from the anaesthesia. In the fibrinolytic system, the plasminogen level and the fibrinogen level declined significantly. It is considered that the fibrinolytic system is prominently accelerated under Ethrane| anaesthesia, but the haemostatic mechanism works in such a manner that bleeding is controlled. However, ]~thrane| anaesthesia should be avoided or pre-operati'ee administration of an antiplasmic agent recommended for patients with an abnormal haemostatic mechanism. R~svlvr~ 1. Le syst~me coagulation-fibrinolyse a ~t~ ~tudi6 chez 20 patientes au cours d'interventions gynrcologiques, sous anesth~sie ~ l'Ethrane.| 2. Aucune modification particuli~re ne fut trouvre dans la numeration plaquettaire qui est demeurre dans les limites normales. Le coagulogramme n'a pas 6t6 modifir de fa~on apprrciable saul le temps de thromboplastine partiel (P.T.T.) qui
OYAMA, et al.: COAGULATION-FIBRI-NOLYSISSYSTEM
357
6tait diminu6 de fa$on significative, ceci apr~s 30 minutes de chirurgie et apr~s r6veil complet. 3. Pour ce qui est du syst~me fibrinolytique, les taux de plasminog~ne et de fibrinog~ne 6taient diminu6s de fagon significative; le fibrinog~ne en partieulier 6tait abaiss6 de fa~on marqu6e. 4. Nous consid6rons que sous anesth6sie h l'Ethrane, le syst~me fibrinolytique est acc~16r6, mais que les m6eanismes h6mostatiques agissent de telle fagon que l'h~morragie est contr616e. Cependant, chez les patients pr6sentant des troubles de l'h6mostase, on devrait 6viter l'anesth6sie ~ rEthrane '~ moins de leur administrer un agent antifibrinolytique avant l'intervention.
REFERENCES 1. OYAMA,T. Effect of low molecular weight dextran on coagulative-flbrinolytic system in man ( to be published ). 2. OYAMA,T., TAKICUCHI,M., KIMVP,A, K., & MAKL M. Effect of fluothane anesthesia on coagulative-fibrinolyticsystem. Jap. J. Anesthesiol. 16:686-692 (1967). 3. VENDERVEEN,J. L., McGovEaN, J.J., BUNKER,J.P., & GOLDSTEIN',R. Effect of anesthesia on hemostatic mechanism in man. Anesthesiology23:92--100 ( 1962 ). 4. PIsoN, J., BOYAN,C.P., & CLIFFTON,E.E. Fibrinolytic activity in patients during operation. J.A.M.A. 191:1026-1027 (1965). 5. DILLON,J.B., LEBOWITZ,M.H., & BLITT, C.D. Clinical investigation of compound 347 (Ethrane@). Anesth. Analg. 49: 1-1O (1970). 6. RODEIBIQUE,E.M. & WYNANDS,J.E. Blood coagulation and hemostasis. A review. Canad. Anaesth. Soc. J. 14:129-151 (1967).
