Intrapulmonary Clotting and Fibrinolysis During Abdominal Aortic Aneurysm Surgery GERALD A. McLOUGHLIN, M.D., GENE A. GRINDLINGER, M.D., JONAH MANNY, M.D., C. ROBERT VALERI, M.D., BOGUSLAW LIPINSKI, PH.D., JOHN A. MANNICK, M.D., HERBERT B. HECHTMAN, M.D.
Intravascular clotting and fibrinolysis (C and F) are events which often accompany major surgical trauma. Their role in inducing cardiopulmonary failure is debated and prompted this study of 13 patients undergoing elective AAA. Following intubation, anesthesia and pressure breathing fibrinolytic activity (FA) in arterial blood exceeded that in mixed venous blood (p < 0.001) indicating pulmonary secretion of proteolytic activity. Fibrinogen, plasminogen and fibrin degradation products (FDPs) were normal. During surgery, fibrinogen and plasminogen fell (p < 0.001) while nonplasmin mediated FA and FDPs rose (p < .001). Despite heparinization (5000 U IV) aortic clamping (avg 56 min) led to evidence of C and F within the lungs. Arterial fibrinogen was 33.2 mg/ml lower than mixed venous blood (p < 0.01) and plasminogen was 0.47 Sherry units lower (p < 0.001). Soluble fibrin monomer appeared in arterial blood (p < 0.01). At the same time nonplasmin mediated FA was consumed within the lungs (p < 0.01) and FDPs were produced (44.6 lig/ml higher in arterial blood, p < 0.001). Similar changes were noted after aortic declamping. The transient 5.3 ml/cm H20 fall in dynamic compliance was unrelated to C and F. Pulmonary vascular resistance and arterial pressure were unchanged. During wound closure intrapulmonary C and F ceased. Postoperatively (6 h), the physiologic shunt of 15.1% was similar to tbe preoperative value of 13.3%. All C and F factors returned to normal except FDPs which remained elevated. An average of0.2 U blood was given prior to aortic clamping and 3.1 U during clamping. Neither the volume nor the type of blood (7 patients received washed RBCs) influenced pulmonary C and F. The results show that pressure breathing will alter pulmonary metabolism from clearance to secretion of fibrinolytic activity. Surgery leads to systemic C and F while intrapulmonary C and F is triggered by aortic clamping despite IV heparin. Delayed functional consequences of C and F are possible. Immediate postoperative effects are not apparent.
clotting and fibrinolysis are events which often accompany critical illness and are considered by some investigators to D ISSEMINATED INTRAVASCULAR
Reprint requests Herbert B. Hechtman, M.D., Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Mass. 02115. Supported in part by NIGMS Grant #GM24891-02, the U.S. Army Med. Research and Development Command Contract #DAMD-17-78-C-8026, the Brigham Surgical Group, Inc., and The Trauma Research Foundation. Submitted for publication: February 28, 1979.
From the Department of Surgery, Peter Bent Brigham Hospital, and Harvard University School of Medicine, Boston Massachusetts
play a causal role in the development of multisystems organ failure including nonhydrostatic pulmonary edema.12 DIC may be stimulated by sepsis, trauma as well as major surgery.38 Whether or not these hematologic events lead to pulmonary endothelial cell damage, edema and organ failure is debated.7 Abdominal aortic aneurysm (AAA) surgery results in a prolonged period of lower torso ischemia. This is considered to be a trigger for intravascular clotting and subsequent microembolization after aortic declamping.23 The hypoxia that often accompanies AAA surgery has been related to these events. This is a study of clotting and fibrinolysis and their relationship to cardiopulmonary function during elective AAA surgery. Methods A series of 13 consecutive patients who were to undergo elective AAA repair formed the study group. On the evening prior to surgery all patients had arterial and flow directed 7 French pulmonary arterial (Instrumentation Laboratory, Lexington, MA) catheters inserted. An infusion of 1500 ml Ringers lactate and 75 g albumin was given overnight. During surgery, blood and fluid were administered by the anesthesiologist according to clinical criteria. Patients were randomized so that they received either liquid stored whole blood or washed red cells. Autotransfusions were used as a supplementary source of blood which was usually administered at the time of wound closure. All blood was given through a 40 ,u Pall filter (Pall Corp., Glenn Cove, NY). Each patient received 5000 u Heparin IV just prior to application of the infrarenal aortic clamp. The average time of aortic occlusion was 56.4 + 10.4 min
0003-4932/79/1100/0623 $00.90 © J. B. Lippincott Company
623
McLOUGHLIN AND OTHERS
624 TABLE 1. Blood Utilization
Study Period Autotransfused Washed RBCs Whole blood Total Mean
30 min
Aortic Clamp
Release
1 2 3 0.2
1 17 13 31 2.4
1 5 3 9 0.7
Ann.
Surg. a November 1979
eight) from the ratio tidal volume/peak inspiratory pressure minus end expiratory pressure.
Closure 4 3 8 15
1.2
6h 2 3 5 0.4
24 h 1 4 5 0.4
(mean SD). The entire operative procedure lasted 4.11 0.24 hrs. Postoperatively, patients were kept intubated and were maintained on mechanical ventilatory assistance. In our institution this represents routine care following AAA surgery. All patients were gradually weaned from the ventilator and extubated between 24 and 36 hours postoperatively. Studies were conducted during 10 time periods: 1) preoperatively, 2) following intubation, 3) 30 minutes after skin incision, 4) 30 minutes after aortic clamping, 5) two to three minutes following aortic declamping, 6) wound closure, 7) six hours postoperatively, 8) 24 hours postoperatively, 9) four hours after extubation, and 10) 48 hours postoperatively. The following measurements were performed at each time interval unless otherwise noted. ±
±
Hemodynamics Complete studies were done during periods one through six. Central venous (CVP), mean pulmonary arterial (MPAP), pulmonary arterial wedge (PAWP) and mean arterial (MAP) pressures were measured with standard strain gauge transducers. The values were taken at end exhalation. Pulse rate was measured from the arterial wave form. Cardiac outputs (CO) were performed in triplicate using the thermodilution technique (Instrumentation Laboratory, Model 601). Pulmonary vascular resistance (PVR) was calculated from the ratio MPAP-PAWP/CO where pressures are in mm Hg and CO is in ml/sec. Pulmonary Function Mixed venous and arterial blood samples were analyzed for Po2, PCO2, and pH using standard Clark and Severinghaus electrodes (Instrumentation Laboratory, Model 813). Hemoglobin and per cent saturation were measured spectrophoto'metrically (Instrumentation Laboratory, Model 282) and the physiologic shunt fraction (OS/I4T) calculated. These measurements were only done preoperatively and six hours postoperatively at an FI02 of 0.2 and 0.3, respectively. Effective dynamic compliance was measured when patients were intubated (time periods two through
Clotting and Fibrinolysis Plasmafibrinogen was estimated by the gravimetric method of Hickman. 15 Plasma plasminogen was measured by the caseinolytic method.' Soluble fibrin monomer complexes were measured using serial dilutions of protamine sulfate mixed with equal volumes of citrated plasma. 10 These assays of fibrin monomer were conducted only at the time of clamp release. Fibrin Degradation Products (FDPs) were measured by a modified tanned red cell hemagglutination technique of Mersky.2' Fibrinolytic activity was assayed using the method of Moroz.22 The two components of this activity, plasmin/ plasminogen mediated and non-plasmin mediated were separated. Total fibrinolytic activity was measured by preparing euglobulin fractions4 from EDTA treated plasma and then incubating with plasminogen enriched 1251-fibrin. The results are expressed as qg fibrin lysed. In order to measure nonplasmin mediated activity, plasminogen and plasmin were removed from a second aliquot of test plasma. This was done by affinity chromatography using cyanobromide activated 1-Lysine Sepharose 4B.6 The ability of the column to completely remove plasminogen was confirmed by the failure of urokinase to activate the eluate when applied to heated fibrin plates. Similarly, plasmin was passed through the column. The removal of plasmin (Sigma, St. Louis, MO) was confirmed by testing the eluate on heated fibrin plates. Euglobulin fractions were prepared from the plasminogen/plasmin depleted serum and then incubated with plasminogen depleted '251-fibrin. The results are again expressed as vqg fibrin lysed. This value subtracted from total fibrinolytic activity yields plasminogen/plasmin mediated activity. All data is presented as the mean + one standard deviation. Statistics make use of the Student's t-test for paired samples as well as simple correlation analysis. Results All 13 patients underwent uneventful abdominal aortic aneurysmectomy and had uncomplicated postoperative courses. Each patient received an average of 5.2 units of blood; 4.2 units were given intraoperatively (Table 1). Similar volumes of red cells were given to patients designated to receive washed red cells or whole blood. Five patients received autotransfusions of small volumes of blood, the majority being given at the time of wound closure.
Vol. 190 * No. S
625
CLOTTING AND FIBRINOLYSIS TABLE 2. Cardiopulmonary Function
Pre-Op Intubate 30' Aortic Clamp Release Close 6h
CI /min M2
MAP (mmHg)
Pulse (min-')
2.43 .57 2.64 ± .61 2.54+ .80 2.34+ .64 2.56+ .60 2.49+ .75 * 3.05+ .45J
97 18 110 ± 25 109 23 110±281k 94± 27J 103 12 92 16
67 74 + 79 70 72 68 82
9 15 25 17 17
141** 16f
MPAP (mmHg) 14.4 17.5 17.7 17.1 16.5 15.6 16.8
3.0]** + 3.1 4.8 5.2 6.1 ± 3.2 ± 4.2
PAWP (mmHg)
PVR (mmHg -sec/ml)
6.1 4.61** 10.3 ± 3.4f 11.2 4.2 11.6±5.4 10.8 4.9 9.0± 3.8 7.4± 3.4
.10 .04 .09 + .03 .09 +.05 .08± .04 .07 .05 .09 .06 .10 .03
EDC
(mi/cm H20)
(S/(T (%) 13.3
+
7.5
39 ± 13 35 + 7 35± 9 30+ 9} 36± 15.1 ± 5.8
Results are mean + SD. Asterisks refer to significant differences between adjacent study periods: *p < .05, **p < .01. The last three time periods (24 h, extubate and 48 h) are not presented since the data are incomplete. The abbreviations are: cardiac index (CI);
mean arterial pressure (MAP); mean pulmonary arterial pressure (MPAP); pulmonary arterial wedge pressure (PAWP); pulmonary vascular resistance (PVR); effective dynamic compliance (EDC) and physiologic shunt (Qs/QT).
Cardiopulmonary Function Following intubation and pressure breathing, MPAP and PAWP rose (Table 2, p < 0.01). The average amount of end expiratory pressure resulting from the anesthesia circuitry was 2.3 cm H20. There was hemodynamic stability until release of the aortic clamp when MAP fell 16 mmHg (p < 0.05). At the same time, effective dynamic compliance (EDC) fell (p < 0.01). During closure EDC returned toward normal (p < 0.01). Six hours postoperatively the cardiac index rose 0.56 I/min. M2 (p < 0.05). This was due to a rise in pulse rate from 68 to 82 (p < 0.01). Pulmonary vascular resistance and the physiologic shunt were unchanged. End expiratory pressure was not applied in the postoperative period.
Clotting and Fibrinolysis After 30 minutes of surgery fibrinogen levels had fallen by 69 mg/dl (Fig. 1, p < 0.001), plasminogen was reduced by 0.88 Sherry units (Fig. 2, p < 0.001) and FDPs had risen from 0.9 to 68.5 ug/ml (Fig. 3, p < 0.001). Following aortic clamping, fibrinogen and plasminogen levels in mixed venous blood decreased further (p < 0.001). An even greater decrease in arterial fibrinogen (p < 0.001) and plasminogen levels (p < 0.001) was noted. The decrease in fibrinogen of 33 mg/dl and in plasminogen of 0.47 Sherry units across the lungs was significant (p < 0.01 and p < 0.001, respectively). On the other hand, the levels of FDPs in mixed venous blood increased by a further 25 ,g/ml (p < 0.05) and in arterial blood by a further 71 Ag/ml
o--o Artery FIG. 1. Thirty minutes into the surgical procedure fibrinogen levels show significant decreases compared to the levels during intubation (p < 0.001 by paired t-test). During aortic clamping and declamping the difference between arterial and mixed venous fibrinogen levels is evidence of intrapulmonary clotting. The sharp postoperative recovery of fibrinogen suggests that had measurements been conducted beyond 48 hours an overshoot would have been observed. Asterisks refer to differences between pulmonary and systemic arterial blood.
Lu11
600O
Pulmonary Artery T SD ** p
Intravascular clotting and fibrinolysis (C and F) are events which often accompany major surgical trauma. Their role in inducing cardiopulmonary failure is debated and prompted this study of 13 patients undergoing elective AAA. Following intubation, anesthesia and pressure breathing fibrinolytic activity (FA) in arterial blood exceeded that in mixed venous blood (p < 0.001) indicating pulmonary secretion of proteolytic activity. Fibrinogen, plasminogen and fibrin degradation products (FDPs) were normal. During surgery, fibrinogen and plasminogen fell (p < 0.001) while nonplasmin mediated FA and FDPs rose (p < .001). Despite heparinization (5000 U IV) aortic clamping (avg 56 min) led to evidence of C and F within the lungs. Arterial fibrinogen was 33.2 mg/ml lower than mixed venous blood (p < 0.01) and plasminogen was 0.47 Sherry units lower (p < 0.001). Soluble fibrin monomer appeared in arterial blood (p < 0.01). At the same time nonplasmin mediated FA was consumed within the lungs (p < 0.01) and FDPs were produced (44.6 lig/ml higher in arterial blood, p < 0.001). Similar changes were noted after aortic declamping. The transient 5.3 ml/cm H20 fall in dynamic compliance was unrelated to C and F. Pulmonary vascular resistance and arterial pressure were unchanged. During wound closure intrapulmonary C and F ceased. Postoperatively (6 h), the physiologic shunt of 15.1% was similar to tbe preoperative value of 13.3%. All C and F factors returned to normal except FDPs which remained elevated. An average of0.2 U blood was given prior to aortic clamping and 3.1 U during clamping. Neither the volume nor the type of blood (7 patients received washed RBCs) influenced pulmonary C and F. The results show that pressure breathing will alter pulmonary metabolism from clearance to secretion of fibrinolytic activity. Surgery leads to systemic C and F while intrapulmonary C and F is triggered by aortic clamping despite IV heparin. Delayed functional consequences of C and F are possible. Immediate postoperative effects are not apparent.
clotting and fibrinolysis are events which often accompany critical illness and are considered by some investigators to D ISSEMINATED INTRAVASCULAR
Reprint requests Herbert B. Hechtman, M.D., Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Mass. 02115. Supported in part by NIGMS Grant #GM24891-02, the U.S. Army Med. Research and Development Command Contract #DAMD-17-78-C-8026, the Brigham Surgical Group, Inc., and The Trauma Research Foundation. Submitted for publication: February 28, 1979.
From the Department of Surgery, Peter Bent Brigham Hospital, and Harvard University School of Medicine, Boston Massachusetts
play a causal role in the development of multisystems organ failure including nonhydrostatic pulmonary edema.12 DIC may be stimulated by sepsis, trauma as well as major surgery.38 Whether or not these hematologic events lead to pulmonary endothelial cell damage, edema and organ failure is debated.7 Abdominal aortic aneurysm (AAA) surgery results in a prolonged period of lower torso ischemia. This is considered to be a trigger for intravascular clotting and subsequent microembolization after aortic declamping.23 The hypoxia that often accompanies AAA surgery has been related to these events. This is a study of clotting and fibrinolysis and their relationship to cardiopulmonary function during elective AAA surgery. Methods A series of 13 consecutive patients who were to undergo elective AAA repair formed the study group. On the evening prior to surgery all patients had arterial and flow directed 7 French pulmonary arterial (Instrumentation Laboratory, Lexington, MA) catheters inserted. An infusion of 1500 ml Ringers lactate and 75 g albumin was given overnight. During surgery, blood and fluid were administered by the anesthesiologist according to clinical criteria. Patients were randomized so that they received either liquid stored whole blood or washed red cells. Autotransfusions were used as a supplementary source of blood which was usually administered at the time of wound closure. All blood was given through a 40 ,u Pall filter (Pall Corp., Glenn Cove, NY). Each patient received 5000 u Heparin IV just prior to application of the infrarenal aortic clamp. The average time of aortic occlusion was 56.4 + 10.4 min
0003-4932/79/1100/0623 $00.90 © J. B. Lippincott Company
623
McLOUGHLIN AND OTHERS
624 TABLE 1. Blood Utilization
Study Period Autotransfused Washed RBCs Whole blood Total Mean
30 min
Aortic Clamp
Release
1 2 3 0.2
1 17 13 31 2.4
1 5 3 9 0.7
Ann.
Surg. a November 1979
eight) from the ratio tidal volume/peak inspiratory pressure minus end expiratory pressure.
Closure 4 3 8 15
1.2
6h 2 3 5 0.4
24 h 1 4 5 0.4
(mean SD). The entire operative procedure lasted 4.11 0.24 hrs. Postoperatively, patients were kept intubated and were maintained on mechanical ventilatory assistance. In our institution this represents routine care following AAA surgery. All patients were gradually weaned from the ventilator and extubated between 24 and 36 hours postoperatively. Studies were conducted during 10 time periods: 1) preoperatively, 2) following intubation, 3) 30 minutes after skin incision, 4) 30 minutes after aortic clamping, 5) two to three minutes following aortic declamping, 6) wound closure, 7) six hours postoperatively, 8) 24 hours postoperatively, 9) four hours after extubation, and 10) 48 hours postoperatively. The following measurements were performed at each time interval unless otherwise noted. ±
±
Hemodynamics Complete studies were done during periods one through six. Central venous (CVP), mean pulmonary arterial (MPAP), pulmonary arterial wedge (PAWP) and mean arterial (MAP) pressures were measured with standard strain gauge transducers. The values were taken at end exhalation. Pulse rate was measured from the arterial wave form. Cardiac outputs (CO) were performed in triplicate using the thermodilution technique (Instrumentation Laboratory, Model 601). Pulmonary vascular resistance (PVR) was calculated from the ratio MPAP-PAWP/CO where pressures are in mm Hg and CO is in ml/sec. Pulmonary Function Mixed venous and arterial blood samples were analyzed for Po2, PCO2, and pH using standard Clark and Severinghaus electrodes (Instrumentation Laboratory, Model 813). Hemoglobin and per cent saturation were measured spectrophoto'metrically (Instrumentation Laboratory, Model 282) and the physiologic shunt fraction (OS/I4T) calculated. These measurements were only done preoperatively and six hours postoperatively at an FI02 of 0.2 and 0.3, respectively. Effective dynamic compliance was measured when patients were intubated (time periods two through
Clotting and Fibrinolysis Plasmafibrinogen was estimated by the gravimetric method of Hickman. 15 Plasma plasminogen was measured by the caseinolytic method.' Soluble fibrin monomer complexes were measured using serial dilutions of protamine sulfate mixed with equal volumes of citrated plasma. 10 These assays of fibrin monomer were conducted only at the time of clamp release. Fibrin Degradation Products (FDPs) were measured by a modified tanned red cell hemagglutination technique of Mersky.2' Fibrinolytic activity was assayed using the method of Moroz.22 The two components of this activity, plasmin/ plasminogen mediated and non-plasmin mediated were separated. Total fibrinolytic activity was measured by preparing euglobulin fractions4 from EDTA treated plasma and then incubating with plasminogen enriched 1251-fibrin. The results are expressed as qg fibrin lysed. In order to measure nonplasmin mediated activity, plasminogen and plasmin were removed from a second aliquot of test plasma. This was done by affinity chromatography using cyanobromide activated 1-Lysine Sepharose 4B.6 The ability of the column to completely remove plasminogen was confirmed by the failure of urokinase to activate the eluate when applied to heated fibrin plates. Similarly, plasmin was passed through the column. The removal of plasmin (Sigma, St. Louis, MO) was confirmed by testing the eluate on heated fibrin plates. Euglobulin fractions were prepared from the plasminogen/plasmin depleted serum and then incubated with plasminogen depleted '251-fibrin. The results are again expressed as vqg fibrin lysed. This value subtracted from total fibrinolytic activity yields plasminogen/plasmin mediated activity. All data is presented as the mean + one standard deviation. Statistics make use of the Student's t-test for paired samples as well as simple correlation analysis. Results All 13 patients underwent uneventful abdominal aortic aneurysmectomy and had uncomplicated postoperative courses. Each patient received an average of 5.2 units of blood; 4.2 units were given intraoperatively (Table 1). Similar volumes of red cells were given to patients designated to receive washed red cells or whole blood. Five patients received autotransfusions of small volumes of blood, the majority being given at the time of wound closure.
Vol. 190 * No. S
625
CLOTTING AND FIBRINOLYSIS TABLE 2. Cardiopulmonary Function
Pre-Op Intubate 30' Aortic Clamp Release Close 6h
CI /min M2
MAP (mmHg)
Pulse (min-')
2.43 .57 2.64 ± .61 2.54+ .80 2.34+ .64 2.56+ .60 2.49+ .75 * 3.05+ .45J
97 18 110 ± 25 109 23 110±281k 94± 27J 103 12 92 16
67 74 + 79 70 72 68 82
9 15 25 17 17
141** 16f
MPAP (mmHg) 14.4 17.5 17.7 17.1 16.5 15.6 16.8
3.0]** + 3.1 4.8 5.2 6.1 ± 3.2 ± 4.2
PAWP (mmHg)
PVR (mmHg -sec/ml)
6.1 4.61** 10.3 ± 3.4f 11.2 4.2 11.6±5.4 10.8 4.9 9.0± 3.8 7.4± 3.4
.10 .04 .09 + .03 .09 +.05 .08± .04 .07 .05 .09 .06 .10 .03
EDC
(mi/cm H20)
(S/(T (%) 13.3
+
7.5
39 ± 13 35 + 7 35± 9 30+ 9} 36± 15.1 ± 5.8
Results are mean + SD. Asterisks refer to significant differences between adjacent study periods: *p < .05, **p < .01. The last three time periods (24 h, extubate and 48 h) are not presented since the data are incomplete. The abbreviations are: cardiac index (CI);
mean arterial pressure (MAP); mean pulmonary arterial pressure (MPAP); pulmonary arterial wedge pressure (PAWP); pulmonary vascular resistance (PVR); effective dynamic compliance (EDC) and physiologic shunt (Qs/QT).
Cardiopulmonary Function Following intubation and pressure breathing, MPAP and PAWP rose (Table 2, p < 0.01). The average amount of end expiratory pressure resulting from the anesthesia circuitry was 2.3 cm H20. There was hemodynamic stability until release of the aortic clamp when MAP fell 16 mmHg (p < 0.05). At the same time, effective dynamic compliance (EDC) fell (p < 0.01). During closure EDC returned toward normal (p < 0.01). Six hours postoperatively the cardiac index rose 0.56 I/min. M2 (p < 0.05). This was due to a rise in pulse rate from 68 to 82 (p < 0.01). Pulmonary vascular resistance and the physiologic shunt were unchanged. End expiratory pressure was not applied in the postoperative period.
Clotting and Fibrinolysis After 30 minutes of surgery fibrinogen levels had fallen by 69 mg/dl (Fig. 1, p < 0.001), plasminogen was reduced by 0.88 Sherry units (Fig. 2, p < 0.001) and FDPs had risen from 0.9 to 68.5 ug/ml (Fig. 3, p < 0.001). Following aortic clamping, fibrinogen and plasminogen levels in mixed venous blood decreased further (p < 0.001). An even greater decrease in arterial fibrinogen (p < 0.001) and plasminogen levels (p < 0.001) was noted. The decrease in fibrinogen of 33 mg/dl and in plasminogen of 0.47 Sherry units across the lungs was significant (p < 0.01 and p < 0.001, respectively). On the other hand, the levels of FDPs in mixed venous blood increased by a further 25 ,g/ml (p < 0.05) and in arterial blood by a further 71 Ag/ml
o--o Artery FIG. 1. Thirty minutes into the surgical procedure fibrinogen levels show significant decreases compared to the levels during intubation (p < 0.001 by paired t-test). During aortic clamping and declamping the difference between arterial and mixed venous fibrinogen levels is evidence of intrapulmonary clotting. The sharp postoperative recovery of fibrinogen suggests that had measurements been conducted beyond 48 hours an overshoot would have been observed. Asterisks refer to differences between pulmonary and systemic arterial blood.
Lu11
600O
Pulmonary Artery T SD ** p
