JOURNAL
OF SURGICAL
RESEARCH
26, 33-44 (1979)
An Experimental
Model of Pulmonary
ANDRE DURANCEAU, M.D., GLYN G. JAMIESON, WALTER G. WOLFE, M.D., AND DAVID Department
of Surgery, Duke University
Medical
Embolism
M.D., ROBERT H. JONES, M.D.’ C. SABISTON, JR., M.D.
Center, Durham,
North Carolina
27710
Submitted for publication March 18, 1978 Previous experimental studies have contributed to the diagnosis and management of pulmonary embolism in patients. However, most experimental techniques to produce pulmonary embolism used material with a structure and composition quite unlike the pulmonary emboli which occur in patients. This report describes a method to induce pulmonary embolism by using a subcutaneously implanted prosthetic graft for thrombus formation. Dogs were prepared by anastomosis of the graft from the distally ligated carotid artery to the proximally ligated femoral artery to provide initial blood flow which led to gradual graft occlusion by laminar deposition of fibrin and blood elements. Seven of 10 animals examined developed a large quantity of formed thrombus within the graft 5 days following implantation. A subsequent intravenous administration of a quantity of 0.2 g/kg of animal weight produced a massive pulmonary embolus which caused hemodynamic alterations in all 36 animals studied and proved lethal in four. Pulmonary embolism was induced in 20 dogs and the systemic arterial pressure, pulmonary arterial pressure, pulmonary arterial blood flow, left atria1 pressure, static and dynamic lung compliance were observed for a 2-hr period. One group of 10 dogs was subjected to pulmonary embolism using fresh autologous blood clot, and the other group of 10 dogs was subjected to formed thrombus obtained by gradual occlusion of a prosthetic graft anastomosed to the carotid and femoral arteries and placed subcutaneously. Neither group of animals demonstrated significant alterations of systemic blood pressure. However, two animals died and two other animals developed significant hypotension in the group of 10 animals subjected to formed thrombus pulmonary embolism. None of the animals subjected to autologous blood clot developed significant hypotension. The pulmonary artery pressure increased in animals subjected to clot but returned to control values within 60 min. A much larger increase in pulmonary artery pressure was observed following embolism using formed thrombus and the pulmonary artery pressure remained elevated for the duration of study. Pulmonary mean blood flow did not change significantly in dogs subjected to clot but decreased significantly for a 60-min period in dogs subjected to formed thrombus. Left atria1 pressure increased and static and dynamic compliance decreased significantly in dogs subjected to formed thrombus embolism, but no significant changes occurred in dogs which received fresh blood clot. This study documented significant differences in hemodynamic and ventilatory alterations induced by material with different mechanical properties. In addition, these observations indicate that the approach to inducing pulmonary embolism using thrombus recovered from a subcutaneous graft represents a useful experimental technique for evaluation of pulmonary embolism.
Pulmonary embolism remains a major clinical problem despite recent advances in diagnosis and management [ 131.Experimental studies of the physiologic alterations associated with pulmonary embolism have contributed greatly to an understanding of this common disorder. External ligation or intraluminal balloon occlusion of pulmonary arteries provides an experimental setting of 1 Howard Hughes Medical Investigator.
obstruction to pulmonary blood flow somewhat similar to pulmonary embolism. In addition, experimental pulmonary embolism has been produced with a variety of foreign substances, an approach which permits introduction of a controlled number of emboli of known size. However, the alterations induced in animals by these approaches often differ from those associated with pulmonary embolism in patients and observations made by these experiments using intravenously 33
0022-4804/79/010033-12$01.00/O Copyright 0 1979 by Academic Press. Inc. All rights of reproduction in any form reserved.
34
JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY Carotid Artery
1979
perimental pulmonary embolism induced with fresh clot and with formed thrombus in the dog. The experimental model described permits studies which closely simulate pulmonary embolism in patients. METHODS
FIG. 1. Anastomosis of a prosthetic graft between the distally occluded common carotid artery and proximally occluded common femoral artery provided a site for thrombus formation by gradual graft occlusion. Blood flow produced layering of platelets and fibrin resulting in a thrombus with mechanical characteristics similar to pulmonary emboli in patients.
administered foreign substances have limited application to patient situations. Experimental studies of pulmonary embolism with fresh autologous blood clot more closely resemble the clinical setting of pulmonary embolism. However, fresh blood clot and layered thrombus which forms in the veins of patients demonstrate different mechanical and humoral characteristics. The physiologic alterations associated with pulmonary embolism result primarily from mechanical obstruction of the pulmonary arteries and emboli with different physical characteristics may induce a quite different physiologic response in the pulmonary circulation. This study reports a technique of thrombus production which provides embolic material with characteristics similar to venous thrombi recovered from patients. Intravenous administration of a standard dose of this embolic material produces physiologic alterations typical of pulmonary embolism in patients. This study compares the physiologic alterations associated with ex-
General anesthesia was induced in mongrel dogs with sodium pentobarbital, and the animals were maintained on positive pressure ventilation using an endotracheal tube. An oblique incision was made in the left neck for isolation of the common carotid artery. A vertical incision in the left inguinal region provided exposure of the common femoral artery. Using vascular clamps for temporary occlusion, a IO-mm woven Dacron straight prosthesis (USCI-DeBakey graft) was anastomosed to the left common femoral artery in an end-to-side configuration using 5-O arterial suture. The graft was then filled with blood which was permitted to clot. A subcutaneous tunnel was developed along the left thoracoabdominal wall to join the inguinal and neck incisions. All clot was expressed from the graft prior to passing it through the subcutaneous tunnel. Vascular clamps were placed on the common carotid artery for temporary occlusion to permit anastomosis of the graft to this vessel in an end-to-side configuration using a 5-O arterial suture. The common carotid artery was ligated distal to the site of graft origin and the left common femoral artery was ligated proximal to the site of graft insertion to permit brisk blood flow through the prosthesis (Fig. 1). In addition to general supportive care, antibiotics were administered to prevent graft infection. Grafts were inserted in 36 adult dogs with an average weight of 17 kg. The duration of blood flow through grafts was carefully monitored in 10 animals by daily observation of the graft pulse and by serial arteriograms at times ranging from 2 hr to 5 days following graft insertion. After a 3- to 5-day period, the animals were again anesthetized, and the incisions were opened. The carotid
DURANCEAU
ET
AL.:
EXPERIMENTAL
A
' I-IOcm-
PULMONARY
35
EMBOLISM
I
FIG. 2. (A) This thrombus removed from the subcutaneous graft demonstrates the typical gross appearance of the material when removed from the graft. (B) This postmortem photograph following intravenous administration of thrombus demonstrates the intact embolus in the left main pulmonary artery of the dog.
artery proximal to anastomosis and the femoral artery distal to anastomosis were ligated, and the graft was removed with small segments of the carotid and femoral arteries attached. The graft was opened longitudinally, and the thrombus was inspected, photographed, and weighed. The volume of thrombus which proved ideal to induce massive but sublethal pulmonary embolism was 0.2 g/kg of animal weight. This amount of thrombus was placed in saline and aspirated into a rigid piece of plastic tubing which had an internal diameter just larger than the thrombus. A plunger fitted to the tubing aided introduction of the clot from the plastic tubing which was inserted into the left internal jugular vein. Pulmonary arterial pressure, pulmonary blood flow, and
systemic pressure were recorded before and after introduction of the embolus. Physiologic alterations were carefully studied in a group of 10 dogs during experimental pulmonary embolism induced by formed thrombus. A second group of 10 dogs was subjected to pulmonary embolism with fresh blood clot. Autologous clot was prepared by introducing 50 ml of venous blood mixed with 30 units of bovine thrombin into polyethylene tubes with a lo-mm diameter. Clotting occurred rapidly and incubation of the clot at room temperature for 90 min permitted clot retraction. Serum was decanted from the fresh clots which were retained in normal saline until use. Included in the group of dogs studied with fresh autologous clot were five dogs which underwent graft inser-
36
JOURNAL
OF SURGICAL
RESEARCH:
VOL.
26, NO. 1, JANUARY
1979
FIG. 3. These photomicrographs were all made at 40x magnification. (A) The histologic appearance of this pulmonary embolus recovered from the lung of a patient shows layering of fibrin and platelets with enmeshed erythrocytes and leukocytes distributed throughout the embolus. (B) Blood clot formed by coagulation of stagnated blood shows no order to the blood elements. (C) This thrombus produced in the dog using the technique described in this study has a histologic appearance similar to emboli recovered from the lungs of patients. (D) This thrombus formed in a dog illustrates well the layering of fibrin and platelets during the formation of thrombus within the graft.
DURANCEAU
ET AL.: EXPERIMENTAL
PULMONARY
EMBOLISM
37
38
JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY
1979
A. 1’12
I3.
cm
I-7cm-
I
4 FIG. 4. (A) This 4-g segment of thrombus was used for an experimental pulmonary embolus in a dog. (B) The embolus recovered from the pulmonary artery at the completion of the experiment weighed 4.4 g. The embolus is folded on itself and has a dull, white glaze on the surface representing fibrin deposition. (C) This histologic section of the embolus demonstrates the original thrombus folded on itelf (included between arrows). The layer of material overlying the original thrombus consists mainly of platelets which were deposited upon the embolus in situ in the lungs.
tion and removal to exclude the possibility that changes resulting from this initial procedure might alter subsequent hemodynamic measurements. The remainder of studies
using fresh clot were in animals without a previous operative procedure. In preparation for experimental pulmonary embolism, a large-bore polyethylene
DURANCEAU
ET AL.: EXPERIMENTAL
cannula was inserted into the right femoral artery for continuous monitoring of systemic blood pressure. Using a left thoracotomy, a large bore polyethylene catheter was inserted into the left atrium through the left atria1 appendage and lead through the chest wall. A catheter was inserted directly into the main pulmonary artery and a Micron RC 1000 electromagnetic flow probe of appropriate size was placed about the artery. The thoracotomy was closed and an intrapleural tube was connected to underwater seal drainage. During the course of the experiment 500 to 1000 ml of normal saline was administered intravenously at a constant flow rate. All pressure measurements were obtained using Statham P23DB pressure transducers and continuously monitored on a HewlettPackard 7700 eight-channel recorder. The flowmeter signal passed through a dc amplifier, and mean pulmonary blood flow was continuously recorded on the HewlettPackard instrument. Calibration of flow measurements was validated by comparison with direct determination of saline flow through a rubber tube. In addition to continuous monitoring of systemic, left atria], and pulmonary pressures and pulmonary blood flow, endotracheal pressure was also monitored using a small catheter introduced through the endotracheal tube. Hemodynamic and ventilatory measurements were obtained during a stable control period following which the embolus was introduced through the previously exposed external jugular vein. Autologous clot or formed thrombus in a weighed amount of 0.2 g/kg of animal weight was suspended in saline as an intact embolus and placed in a rigid plastic tube with an internal diameter just greater than 10 mm. A plunger was adapted to the plastic tubing to aid introduction of the clot into the vein. Hemodynamic measurements were made continuously during introduction of the embolus and for a 120-min period following embolism. Using a calibrated fixed-volume respirator, static and dynamic pulmonary
PULMONARY
39
EMBOLISM
compliance measurements were obtained at -40, -5, 5, 20, 40, 60, 90, and 120 min relative to the time of pulmonary embolism. Endotracheal pressure was determined immediately before and after cessation of air flow at tidal volumes of 100, 200, 300, 400, and 500 ml. The dynamic and static compliance at each of these volumes was calculated, and mean values of the five readings were compared. In both groups of 10 dogs, one dog died or was sacrificed 20 min following embolism, three dogs died or were sacrificed 60 min after embolism, and six dogs died or were sacrificed 120min following embolism. Each animal was systemically heparinized at the conclusion of study, and following sacrifice the heart and lungs were removed en bloc. The right atrium and ventricle were opened and examined for thrombus. The main pulmonary artery and all branches with sufficient size to be examined by gross dissection were opened, and the distribution of thrombus was recorded. The total quantity of embolic material recovered from the heart and lungs was weighed. From the continuously recorded hemodynamic data, mean pulmonary pressure and flow, mean left atria1 pressure, and systemic pressure were determined at -40, -5, 5, 20, 40, 60, 90, 160,
I
Systolic L
I--------"
Y
.--_
80 i--------~~~~-.~~-------t---t 60 40'
-40
I
1
t -5+5 20 P"lmnr~Lmb~s
40
a
--ii ----g 60
Thrombus ClOl 90
120
MllVJkS
FIG. 5. Although four dogs developed systemic hypotension following pulmonary embolism with formed thrombus, no statistically significant change occurred in systemic pressure in either of the two total groups studied. The mean and one standard deviation is plotted for all numeric data. Comparisons for significance are made between individual observations and control values using Student’s paired t test.
40
JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY 30
0’
-40
c
4
-5 t 5 20 PuimmryErnbdui
1
40
60
90
120
thlutes
FIG. 6. Mean pulmonary artery pressure increased abruptly following pulmonary embolism with fresh clot, but returned to a value similar to the control at 60 min following the embolus. A larger increase occurred in mean pulmonary artery pressure following administration of formed thrombus, and the pressure remained elevated for the duration of study.
and 120min relative to the time of pulmonary embolism. Pulmonary vascular resistance was calculated from mean pulmonary pressure and blood flow at each time interval. A statistical analysis of data was performed within and between groups using a two-tailed Student’s t test, and probabilities were quoted as percentages. RESULTS
All animals survived graft insertion. In the group of 10 dogs studied by arteriography , the graft remained patent for more than 24 hr in all but one animal. An arteriogram performed 2 hr after graft insertion in this animal confirmed early occlusion. Five days after insertion all grafts were removed, and seven of the remaining nine grafts were occluded at this time. The two animals without graft occlusion demonstrated a thick fibrin sleeve lining the interior of the graft without thrombus formation. In animals with thrombosed grafts, the formed thrombus occluding the graft was easily separated from the graft fabric. The thrombus which formed near the carotid inflow end of the graft commonly demonstrated the best layering of thrombus whereas the distal portion of the graft frequently contained uniform clot without structure. The gross ap-
1979
pearance of the thrombus harvested from the graft was similar to thrombus material recovered from veins of patients with thrombophlebitis (Fig. 2A). Sufficient formed thrombus was present in all dogs with occluded grafts to provide a single intact embolus in the desired amount of 0.2 g/kg of animal weight. Although clot fragmentation occasionally occurred, the mechanical properties of the clot most commonly caused it to remain intact during passage through the right heart and into the lungs (Fig. 2B). This amount of embolus proved fatal in four of 36 animals studied. Pulmonary embolism of this magnitude was sufficient to significantly increase pulmonary artery pressure in all dogs studied. Histologic examination of material recovered from pulmonary arteries of patients who succumb to pulmonary embolism typically demonstrates the thrombus to be organized in layers of fibrin with enmeshed platelets and red cells. Interspersed with organized regions may be areas of less organized clot which commonly appear as aggregates of red blood cells (Fig. 3A). Fresh clot formed in the absence of blood flow does not demonstrate an organized arrangement, but all blood components are distributed in a random uniform fashion (Fig. 3B). Histologic examination of thrombus formed in grafts implanted in dogs shows
‘*O-
FIG. 7. Mean pulmonary blood flow measured with an electromagnetic flow probe remained relatively constant following fresh clot administration. Pulmonary blood flow decreased significantly for a I-hr period following experimental pulmonary embolus with formed thrombus.
DURANCEAU
ET AL.:
EXPERIMENTAL
PULMONARY
EMBOLISM
41
a structure suggesting sequential layering of platelets, fibrin, and blood cells which appears quite similar to the structure of human thrombus recovered from the pulmonary artery at postmortem examination (Figs. 3C and D). ---Thrambus clot The average percentage by weight of rex PC01 covered embolic material in the 10 animals which received fresh clot was 26.6 t 12.8%, J 01’ 1 and in 10 dogs which received autologous 90 120 20 40 60 -40 -5t5 P"I.o"m, Embola Mi""k thrombus it was 60.3 t 18.2%. In five dogs, the weight of thrombus recovered after FIG. 9. The left atria1 mean pressure increased sigsacrifice was less than the amount adminis- nificantly following pulmonary embolism induced with tered. Although incomplete recovery of thrombus. No significant changes occurred following thrombus due to fragmentation and pas- fresh clot embolism. sage into small pulmonary arteries could not always be excluded, the decrease in throm- potension. Although some animals debus weight provided evidence of partial veloped systemic hypotension, the systemic lysis of the thrombus when the thrombus systolic and diastolic blood pressure did not remained intact. However, in two animals change significantly in either group followthe thrombus increased in weight due to in ing embolism with thrombus or fresh clot situ thrombus formation around the embolus (Fig. 5). Pulmonary embolism increased in the pulmonary artery. In these animals, pulmonary artery pressure in both groups, new fibrin and platelet deposition on the and the magnitude of increase was sigembolus could be observed histologically and nificantly greater in the thrombus group by the gross appearance of the thrombus compared to the clot group (Fig. 6). Within 60 min after embolism, the pulmonary artery (Fig. 4). Death resulted in two of 10 dogs sub- pressure returned to a level which was simjected to pulmonary embolism with formed ilar to the baseline value in the group with thrombus, and two other dogs developed embolism induced by fresh clot. Although systemic hypotension. All 10 dogs survived blood pressure decreased during the first autologous blood clot embolism without hy- hour after embolism in dogs receiving thrombi, the pulmonary artery pressure remained significantly elevated over control PULMONARYVASCULAR RESISTANCE values throughout the period of study. Pulmonary blood flow decreased significantly in dogs receiving thrombus and remained significantly below control values for a 60min interval. Pulmonary blood flow did not significantly decrease in dogs following pulmonary embolism with fresh clot (Fig. 7). Calculation of pulmonary vascular resistance from pulmonary blood flow and pressure 120 -40 -5t 5 20 40 60 90 PYlmmq tnPs,u, measurements reflected the alterations obMl""lW served in pulmonary arterial pressure and FIG. 8. The pulmonary vascular resistance inflow measurements in the two groups. Pulcreased transiently following administration of autolmonary vascular resistance remained sigogous clot. A more pronounced increase was susnificantly elevated for only a 20-min period tamed for the duration of study in the group of dogs with pulmonary embolism induced by formed thrombus. in dogs receiving clot whereas the pulmo-----lhrombur
o-’
42
JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY
1979
the pulmonary artery. Guyton et al. [9] used a plastic loop passed around the pulmonary artery of dogs to constrict the vessel in a closed chest preparation. Simple ligation of lobar pulmonary arteries has also been used to evaluate the hemodynamics of acute pul-----Thromb”r monary arterial obstruction [7]. Intraluminal -Clot balloon-tipped catheters have been introduced in animals and in man to evaluate I I1 I 40 60 90 120 -5t5 20 O -40 the physiologic response to acute pulPvlnonor"Embll Minutes monary arterial obstruction [ 11. A variety of emoblic material has been FIG. 10. Static compliance of the lung decreased significantly following thrombus administration, but re- administered intravenously in laboratory mained unchanged with pulmonary embolism induced animals to simulate alterations associated by fresh clot. with pulmonary embolism. Although dogs have been the most commonly used animal, nary vascular resistance remained elevated cats, rats, sheep, and goats have also been for the entire period of study in animals re- employed. The list of foreign substances ceiving formed thrombus (Fig. 8). Pulmo- used as experimental embolic material innary vascular resistance was approximately cludes rubber tubing filled with fluid [lo], three times greater in animals subjected to seeds [16], glass beads [2], plastic spheres thrombus embolism compared to those sub[ 151, lycopodium spores [ 161, starch granjected to fresh clot emoblism. ules [21], barium sulfate [lo], and lead The left atria1 pressure was not sig- phosphate in agar gel [3]. nificantly altered by pulmonary embolism In the present study, no animals deusing fresh clot (Fig. 9). Pulmonary em- veloped systemic hypotension following bolism with thrombus caused an elevation autologous blood clot pulmonary embolism, of the atria1 pressure which returned to con- but two dogs died and two other dogs betrol values after a 60-min interval. Formed came hypotensive following pulmonary thrombus caused a significant decrease in embolism with formed thrombus. This obboth static and dynamic lung compliance servation suggests that autologous thrombus (Figs. 10 and ll), but no change occurred induces a much more severe hemodynamic in pulmonary compliance following intro- insult to the pulmonary circulation than a duction of fresh clot. 60
STATIC COMPLIANCE
l
PCOI
DISCUSSION
60
DYNAMIC COMPLIANCE
Between the years of 1846 and 1856 Ru5 40dolph Virchow performed a series of experiz ments confirming the basic mechanism of 8 pulmonary emoblism [23]. He introduced a variety of foreign substances into the veins of dogs and recovered this material from the lungs at postmortem examination. FolI OL’ c ’ lowing those initial observations, a wide 90 120 -40 -515 20 40 60 P"l.cw~ Enlo,", variety of approaches have evolved for MlllUkS study of this common disorder. Cohnheim FIG. 11. A transient increase occurred in dy[4] observed the right ventricular response namic lung compliance following clot embolism, but to acute pulmonary artery obstruction in the decrease in compliance persisted throughout the study dog by slowly tightening a ligature around in the dons treated with formed thrombus.
DURANCEAU
ET AL.: EXPERIMENTAL
similar weight of autologous fresh blood clot. In addition, all alterations observed following autologous blood clot pulmonary embolism proved more transient than corresponding alterations in the group with thrombus embolism. Acute changes following pulmonary embolism are partially resolved by a variety of homeostatic mechanisms of the right heart and pulmonary circulation. However, the abruptness and magnitude of resolution of physiologic alterations following embolism with fresh clot suggests that much of the return toward normal function results from early fragmentation and lysis of the clot. The fact that only about 27% of the weight of the initial fresh clot could be recovered from the lungs compared to 60% of the formed thrombus administered provides further evidence of rapid lysis of this material. Experimental studies of acute hemodynamic alterations following pulmonary embolism with fresh clot have previously documented early resolution of altered hemodynamics which may result primarily from clot lysis [18]. Conclusions regarding the acute hemodynamic response following pulmonary embolism in patients would require use of an experimental model utilizing material similar to venous thrombi. Hemodynamic observations in 10 dogs subjected to experimental pulmonary embolism using formed thrombus indicate that mechanical blockage of the pulmonary arteries elevated pulmonary vascular resistance. increased right ventricular work partially compensated for the increased resistance by increasing pulmonary arterial pressure. However, pulmonary blood flow decreased significantly with massive pulmonary embolism and the cardiac output also decreased. Increased systemic peripheral resistance prevented hypotension in a majority of animals. However, the decreased coronary blood flow associated with decreased cardiac output produced mild left ventricular failure as evidenced by the increase in left atria1 mean pressure. Pulmonary embolism represents a com-
PULMONARY
EMBOLISM
43
mon clinical problem and experimental study of the disorder requires an experimental model which causes changes similar to those occurring in patients. Marked differences were observed in this study between alterations induced by similar quantities of autologous fresh blood clot and formed thrombus suggesting that clinical application of experimental studies utilizing fresh blood clot may not prove valid. REFERENCES 1. Brofman, B. L., Charms, B. L., Kohn, P. M., Elder, J. Newman, R, and Rizika, M. Unilateral pulmonary artery occlusion in man. .I. Thorac. Surg. 34: 206-227, 1957. 2. Caro, C. G., and Harrison, G. K. Observations on pulse wave velocity and pulsatile blood pressure in human pulmonary circulation. C/in. Sci. 23: 317-329, 1962. 3. Cate, W. R., Jr., Light, R. A., Daniel, R. A., Jr., and Edwards, W. H. Role of the autonomic nervous system in the control of the pulmonary vascular bed; I. Experimental pulmonary embolism. Surg. Forum 4: 190-197, 1953. 4. Cohnheim, J. F. Lectures on Genera/ Pathology. London: The New Sydenham Society, 1889. Pp. 50-52. 5. Daley, R., Wade, J. D., Maraist, F., and Bing, R. J. Pulmonary hypertension in dogs induced by the injection of lycopodium spores into the pulmonary artery. Amer. .I. Physiol. 164: 380, 1951. 6. Dexter, L., and Smith, G. T. Quantitative studies of pulmonary embolism. Amer. J. Med. Sci. 247: 641-648, 1964. 7. Ebert, P. A., Allgood, R. J.. Jones, H. W., III, and Sabiston, D. C., Jr. Hemodynamics during pulmonary artery occlusion. Surgery 62: 18-24, 1967. 8. Gurewich, V., Cohen, M. L., and Thomas, D. P. Humoral factors in massive pulmonary embolism: An experimental study. Amer. Heart J. 76: 784-794, 1968. 9. Guyton, A. C., Lindsey, A. W., and Gilluly, J. The limits of right ventricular compensation following acute increase in pulmonary circulatory resistance. Circ. Res. 2: 326-332, 1954. 10. Halmagyi, D. F. J., and Colebatch, H. J. H. Cardiorespiratory effects of experimental lung embolism. J. C&n. Invest. 40: 1785, 1961. 11. Hara, M., and Smith, J. R. Experimental observations on embolism of pulmonary lobar arteries. J. Thorac. Surg. IS: 536-542, 1949. 12. Heimbecker, R. O., Keon, W. J., and Richards, K. U. Massive pulmonary embolism. Arch. Surg. 107: 740-746, 1973.
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JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY
13. Jones, R. H., and Sabiston, D. C., Jr. Pulmonary embolism. Surg. Clin. North Amer. 56: 891-907, 1976. 14. Just-Viera, J. O., Oster, W. F., and Yeager, G. H. Recurrent pulmonary embolism. J. Thorac. Cardiovasc.
Surg. 52: 282-291,
1%6.
15. Lewin, R. J., Cross, C. E., Rieben, P. A., and Salisbury, P. F. Stretch reflexes from the main pulmonary artery to the systemic circulation. Circ. Res. 9: 585-588, l%l. 16. Megibow, R. S., Katz, L. N., and Steinitz, F. S. Dynamic changes in experimental pulmonary embolism. Surgery 11: 19-32, 1942. 17. Olsson, P., Swedenborg, J., and Lindquist, 0. Effects of slow defibrinogenation on the canine lung. J. Trauma 14: 325, 1974. 18. Puckett, C. L., Gervin, A. S., Rhodes, G. R., and Silver, D. Role of platelets and serotonin in acute massive pulmonary embolism. Surg. Gynecol. Obstet. 137: 618, 1973.
19. Puckett, C. L., Robinson, A. E., Gervin, A. S., Rhodes, G. R., and Silver, D. Microradiographic
1979
characterization of broncho-constriction after pulmonary embolism. J. Surg. Res. 14: 165. 20. Sabiston, D. C., Jr., Marshall, R., Dunnill, M. I., and Alison, P. R. Experimental pulmonary embolism. Description of a method utilizing large venous thrombi. Surgery 52: 9, 1%2. 21. Singer, D., Salzman, P. W., Rivera-Estrada, C., Pick, R., and Katz, L. N. Hemodynamic alterations following miliary pulmonary embolization in relation to the pathogenesis of the consequent diffuse edema. Amer. J. Physiol. 191: 437-442, 1957. 22. Stein, M., Tanabe, G., Calm, M., and Thomas, V. P. Pulmonary responses to macro and microembolic. In A. A. Sassahara, and M. Stein, (Eds.), Pulmonary
Embolic
Disease a Symposium.
New
York: Grune & Stratton, 1965. 23. Virchow, R. Die Cellularpathologie. Berlin: Hirschwald, 1859. P. 444. 24. Wessler, S., Freiman, D. G., Ballon, J. D., Katz, J. H., Wolff, R., and Wolf, E. Experimental pulmonary embolism with serum-induced thrombi. Amer. J. Pathol. 38: 89-101, 1961.
OF SURGICAL
RESEARCH
26, 33-44 (1979)
An Experimental
Model of Pulmonary
ANDRE DURANCEAU, M.D., GLYN G. JAMIESON, WALTER G. WOLFE, M.D., AND DAVID Department
of Surgery, Duke University
Medical
Embolism
M.D., ROBERT H. JONES, M.D.’ C. SABISTON, JR., M.D.
Center, Durham,
North Carolina
27710
Submitted for publication March 18, 1978 Previous experimental studies have contributed to the diagnosis and management of pulmonary embolism in patients. However, most experimental techniques to produce pulmonary embolism used material with a structure and composition quite unlike the pulmonary emboli which occur in patients. This report describes a method to induce pulmonary embolism by using a subcutaneously implanted prosthetic graft for thrombus formation. Dogs were prepared by anastomosis of the graft from the distally ligated carotid artery to the proximally ligated femoral artery to provide initial blood flow which led to gradual graft occlusion by laminar deposition of fibrin and blood elements. Seven of 10 animals examined developed a large quantity of formed thrombus within the graft 5 days following implantation. A subsequent intravenous administration of a quantity of 0.2 g/kg of animal weight produced a massive pulmonary embolus which caused hemodynamic alterations in all 36 animals studied and proved lethal in four. Pulmonary embolism was induced in 20 dogs and the systemic arterial pressure, pulmonary arterial pressure, pulmonary arterial blood flow, left atria1 pressure, static and dynamic lung compliance were observed for a 2-hr period. One group of 10 dogs was subjected to pulmonary embolism using fresh autologous blood clot, and the other group of 10 dogs was subjected to formed thrombus obtained by gradual occlusion of a prosthetic graft anastomosed to the carotid and femoral arteries and placed subcutaneously. Neither group of animals demonstrated significant alterations of systemic blood pressure. However, two animals died and two other animals developed significant hypotension in the group of 10 animals subjected to formed thrombus pulmonary embolism. None of the animals subjected to autologous blood clot developed significant hypotension. The pulmonary artery pressure increased in animals subjected to clot but returned to control values within 60 min. A much larger increase in pulmonary artery pressure was observed following embolism using formed thrombus and the pulmonary artery pressure remained elevated for the duration of study. Pulmonary mean blood flow did not change significantly in dogs subjected to clot but decreased significantly for a 60-min period in dogs subjected to formed thrombus. Left atria1 pressure increased and static and dynamic compliance decreased significantly in dogs subjected to formed thrombus embolism, but no significant changes occurred in dogs which received fresh blood clot. This study documented significant differences in hemodynamic and ventilatory alterations induced by material with different mechanical properties. In addition, these observations indicate that the approach to inducing pulmonary embolism using thrombus recovered from a subcutaneous graft represents a useful experimental technique for evaluation of pulmonary embolism.
Pulmonary embolism remains a major clinical problem despite recent advances in diagnosis and management [ 131.Experimental studies of the physiologic alterations associated with pulmonary embolism have contributed greatly to an understanding of this common disorder. External ligation or intraluminal balloon occlusion of pulmonary arteries provides an experimental setting of 1 Howard Hughes Medical Investigator.
obstruction to pulmonary blood flow somewhat similar to pulmonary embolism. In addition, experimental pulmonary embolism has been produced with a variety of foreign substances, an approach which permits introduction of a controlled number of emboli of known size. However, the alterations induced in animals by these approaches often differ from those associated with pulmonary embolism in patients and observations made by these experiments using intravenously 33
0022-4804/79/010033-12$01.00/O Copyright 0 1979 by Academic Press. Inc. All rights of reproduction in any form reserved.
34
JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY Carotid Artery
1979
perimental pulmonary embolism induced with fresh clot and with formed thrombus in the dog. The experimental model described permits studies which closely simulate pulmonary embolism in patients. METHODS
FIG. 1. Anastomosis of a prosthetic graft between the distally occluded common carotid artery and proximally occluded common femoral artery provided a site for thrombus formation by gradual graft occlusion. Blood flow produced layering of platelets and fibrin resulting in a thrombus with mechanical characteristics similar to pulmonary emboli in patients.
administered foreign substances have limited application to patient situations. Experimental studies of pulmonary embolism with fresh autologous blood clot more closely resemble the clinical setting of pulmonary embolism. However, fresh blood clot and layered thrombus which forms in the veins of patients demonstrate different mechanical and humoral characteristics. The physiologic alterations associated with pulmonary embolism result primarily from mechanical obstruction of the pulmonary arteries and emboli with different physical characteristics may induce a quite different physiologic response in the pulmonary circulation. This study reports a technique of thrombus production which provides embolic material with characteristics similar to venous thrombi recovered from patients. Intravenous administration of a standard dose of this embolic material produces physiologic alterations typical of pulmonary embolism in patients. This study compares the physiologic alterations associated with ex-
General anesthesia was induced in mongrel dogs with sodium pentobarbital, and the animals were maintained on positive pressure ventilation using an endotracheal tube. An oblique incision was made in the left neck for isolation of the common carotid artery. A vertical incision in the left inguinal region provided exposure of the common femoral artery. Using vascular clamps for temporary occlusion, a IO-mm woven Dacron straight prosthesis (USCI-DeBakey graft) was anastomosed to the left common femoral artery in an end-to-side configuration using 5-O arterial suture. The graft was then filled with blood which was permitted to clot. A subcutaneous tunnel was developed along the left thoracoabdominal wall to join the inguinal and neck incisions. All clot was expressed from the graft prior to passing it through the subcutaneous tunnel. Vascular clamps were placed on the common carotid artery for temporary occlusion to permit anastomosis of the graft to this vessel in an end-to-side configuration using a 5-O arterial suture. The common carotid artery was ligated distal to the site of graft origin and the left common femoral artery was ligated proximal to the site of graft insertion to permit brisk blood flow through the prosthesis (Fig. 1). In addition to general supportive care, antibiotics were administered to prevent graft infection. Grafts were inserted in 36 adult dogs with an average weight of 17 kg. The duration of blood flow through grafts was carefully monitored in 10 animals by daily observation of the graft pulse and by serial arteriograms at times ranging from 2 hr to 5 days following graft insertion. After a 3- to 5-day period, the animals were again anesthetized, and the incisions were opened. The carotid
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' I-IOcm-
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I
FIG. 2. (A) This thrombus removed from the subcutaneous graft demonstrates the typical gross appearance of the material when removed from the graft. (B) This postmortem photograph following intravenous administration of thrombus demonstrates the intact embolus in the left main pulmonary artery of the dog.
artery proximal to anastomosis and the femoral artery distal to anastomosis were ligated, and the graft was removed with small segments of the carotid and femoral arteries attached. The graft was opened longitudinally, and the thrombus was inspected, photographed, and weighed. The volume of thrombus which proved ideal to induce massive but sublethal pulmonary embolism was 0.2 g/kg of animal weight. This amount of thrombus was placed in saline and aspirated into a rigid piece of plastic tubing which had an internal diameter just larger than the thrombus. A plunger fitted to the tubing aided introduction of the clot from the plastic tubing which was inserted into the left internal jugular vein. Pulmonary arterial pressure, pulmonary blood flow, and
systemic pressure were recorded before and after introduction of the embolus. Physiologic alterations were carefully studied in a group of 10 dogs during experimental pulmonary embolism induced by formed thrombus. A second group of 10 dogs was subjected to pulmonary embolism with fresh blood clot. Autologous clot was prepared by introducing 50 ml of venous blood mixed with 30 units of bovine thrombin into polyethylene tubes with a lo-mm diameter. Clotting occurred rapidly and incubation of the clot at room temperature for 90 min permitted clot retraction. Serum was decanted from the fresh clots which were retained in normal saline until use. Included in the group of dogs studied with fresh autologous clot were five dogs which underwent graft inser-
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FIG. 3. These photomicrographs were all made at 40x magnification. (A) The histologic appearance of this pulmonary embolus recovered from the lung of a patient shows layering of fibrin and platelets with enmeshed erythrocytes and leukocytes distributed throughout the embolus. (B) Blood clot formed by coagulation of stagnated blood shows no order to the blood elements. (C) This thrombus produced in the dog using the technique described in this study has a histologic appearance similar to emboli recovered from the lungs of patients. (D) This thrombus formed in a dog illustrates well the layering of fibrin and platelets during the formation of thrombus within the graft.
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A. 1’12
I3.
cm
I-7cm-
I
4 FIG. 4. (A) This 4-g segment of thrombus was used for an experimental pulmonary embolus in a dog. (B) The embolus recovered from the pulmonary artery at the completion of the experiment weighed 4.4 g. The embolus is folded on itself and has a dull, white glaze on the surface representing fibrin deposition. (C) This histologic section of the embolus demonstrates the original thrombus folded on itelf (included between arrows). The layer of material overlying the original thrombus consists mainly of platelets which were deposited upon the embolus in situ in the lungs.
tion and removal to exclude the possibility that changes resulting from this initial procedure might alter subsequent hemodynamic measurements. The remainder of studies
using fresh clot were in animals without a previous operative procedure. In preparation for experimental pulmonary embolism, a large-bore polyethylene
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cannula was inserted into the right femoral artery for continuous monitoring of systemic blood pressure. Using a left thoracotomy, a large bore polyethylene catheter was inserted into the left atrium through the left atria1 appendage and lead through the chest wall. A catheter was inserted directly into the main pulmonary artery and a Micron RC 1000 electromagnetic flow probe of appropriate size was placed about the artery. The thoracotomy was closed and an intrapleural tube was connected to underwater seal drainage. During the course of the experiment 500 to 1000 ml of normal saline was administered intravenously at a constant flow rate. All pressure measurements were obtained using Statham P23DB pressure transducers and continuously monitored on a HewlettPackard 7700 eight-channel recorder. The flowmeter signal passed through a dc amplifier, and mean pulmonary blood flow was continuously recorded on the HewlettPackard instrument. Calibration of flow measurements was validated by comparison with direct determination of saline flow through a rubber tube. In addition to continuous monitoring of systemic, left atria], and pulmonary pressures and pulmonary blood flow, endotracheal pressure was also monitored using a small catheter introduced through the endotracheal tube. Hemodynamic and ventilatory measurements were obtained during a stable control period following which the embolus was introduced through the previously exposed external jugular vein. Autologous clot or formed thrombus in a weighed amount of 0.2 g/kg of animal weight was suspended in saline as an intact embolus and placed in a rigid plastic tube with an internal diameter just greater than 10 mm. A plunger was adapted to the plastic tubing to aid introduction of the clot into the vein. Hemodynamic measurements were made continuously during introduction of the embolus and for a 120-min period following embolism. Using a calibrated fixed-volume respirator, static and dynamic pulmonary
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compliance measurements were obtained at -40, -5, 5, 20, 40, 60, 90, and 120 min relative to the time of pulmonary embolism. Endotracheal pressure was determined immediately before and after cessation of air flow at tidal volumes of 100, 200, 300, 400, and 500 ml. The dynamic and static compliance at each of these volumes was calculated, and mean values of the five readings were compared. In both groups of 10 dogs, one dog died or was sacrificed 20 min following embolism, three dogs died or were sacrificed 60 min after embolism, and six dogs died or were sacrificed 120min following embolism. Each animal was systemically heparinized at the conclusion of study, and following sacrifice the heart and lungs were removed en bloc. The right atrium and ventricle were opened and examined for thrombus. The main pulmonary artery and all branches with sufficient size to be examined by gross dissection were opened, and the distribution of thrombus was recorded. The total quantity of embolic material recovered from the heart and lungs was weighed. From the continuously recorded hemodynamic data, mean pulmonary pressure and flow, mean left atria1 pressure, and systemic pressure were determined at -40, -5, 5, 20, 40, 60, 90, 160,
I
Systolic L
I--------"
Y
.--_
80 i--------~~~~-.~~-------t---t 60 40'
-40
I
1
t -5+5 20 P"lmnr~Lmb~s
40
a
--ii ----g 60
Thrombus ClOl 90
120
MllVJkS
FIG. 5. Although four dogs developed systemic hypotension following pulmonary embolism with formed thrombus, no statistically significant change occurred in systemic pressure in either of the two total groups studied. The mean and one standard deviation is plotted for all numeric data. Comparisons for significance are made between individual observations and control values using Student’s paired t test.
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JOURNAL OF SURGICAL RESEARCH: VOL. 26, NO. 1, JANUARY 30
0’
-40
c
4
-5 t 5 20 PuimmryErnbdui
1
40
60
90
120
thlutes
FIG. 6. Mean pulmonary artery pressure increased abruptly following pulmonary embolism with fresh clot, but returned to a value similar to the control at 60 min following the embolus. A larger increase occurred in mean pulmonary artery pressure following administration of formed thrombus, and the pressure remained elevated for the duration of study.
and 120min relative to the time of pulmonary embolism. Pulmonary vascular resistance was calculated from mean pulmonary pressure and blood flow at each time interval. A statistical analysis of data was performed within and between groups using a two-tailed Student’s t test, and probabilities were quoted as percentages. RESULTS
All animals survived graft insertion. In the group of 10 dogs studied by arteriography , the graft remained patent for more than 24 hr in all but one animal. An arteriogram performed 2 hr after graft insertion in this animal confirmed early occlusion. Five days after insertion all grafts were removed, and seven of the remaining nine grafts were occluded at this time. The two animals without graft occlusion demonstrated a thick fibrin sleeve lining the interior of the graft without thrombus formation. In animals with thrombosed grafts, the formed thrombus occluding the graft was easily separated from the graft fabric. The thrombus which formed near the carotid inflow end of the graft commonly demonstrated the best layering of thrombus whereas the distal portion of the graft frequently contained uniform clot without structure. The gross ap-
1979
pearance of the thrombus harvested from the graft was similar to thrombus material recovered from veins of patients with thrombophlebitis (Fig. 2A). Sufficient formed thrombus was present in all dogs with occluded grafts to provide a single intact embolus in the desired amount of 0.2 g/kg of animal weight. Although clot fragmentation occasionally occurred, the mechanical properties of the clot most commonly caused it to remain intact during passage through the right heart and into the lungs (Fig. 2B). This amount of embolus proved fatal in four of 36 animals studied. Pulmonary embolism of this magnitude was sufficient to significantly increase pulmonary artery pressure in all dogs studied. Histologic examination of material recovered from pulmonary arteries of patients who succumb to pulmonary embolism typically demonstrates the thrombus to be organized in layers of fibrin with enmeshed platelets and red cells. Interspersed with organized regions may be areas of less organized clot which commonly appear as aggregates of red blood cells (Fig. 3A). Fresh clot formed in the absence of blood flow does not demonstrate an organized arrangement, but all blood components are distributed in a random uniform fashion (Fig. 3B). Histologic examination of thrombus formed in grafts implanted in dogs shows
‘*O-
FIG. 7. Mean pulmonary blood flow measured with an electromagnetic flow probe remained relatively constant following fresh clot administration. Pulmonary blood flow decreased significantly for a I-hr period following experimental pulmonary embolus with formed thrombus.
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a structure suggesting sequential layering of platelets, fibrin, and blood cells which appears quite similar to the structure of human thrombus recovered from the pulmonary artery at postmortem examination (Figs. 3C and D). ---Thrambus clot The average percentage by weight of rex PC01 covered embolic material in the 10 animals which received fresh clot was 26.6 t 12.8%, J 01’ 1 and in 10 dogs which received autologous 90 120 20 40 60 -40 -5t5 P"I.o"m, Embola Mi""k thrombus it was 60.3 t 18.2%. In five dogs, the weight of thrombus recovered after FIG. 9. The left atria1 mean pressure increased sigsacrifice was less than the amount adminis- nificantly following pulmonary embolism induced with tered. Although incomplete recovery of thrombus. No significant changes occurred following thrombus due to fragmentation and pas- fresh clot embolism. sage into small pulmonary arteries could not always be excluded, the decrease in throm- potension. Although some animals debus weight provided evidence of partial veloped systemic hypotension, the systemic lysis of the thrombus when the thrombus systolic and diastolic blood pressure did not remained intact. However, in two animals change significantly in either group followthe thrombus increased in weight due to in ing embolism with thrombus or fresh clot situ thrombus formation around the embolus (Fig. 5). Pulmonary embolism increased in the pulmonary artery. In these animals, pulmonary artery pressure in both groups, new fibrin and platelet deposition on the and the magnitude of increase was sigembolus could be observed histologically and nificantly greater in the thrombus group by the gross appearance of the thrombus compared to the clot group (Fig. 6). Within 60 min after embolism, the pulmonary artery (Fig. 4). Death resulted in two of 10 dogs sub- pressure returned to a level which was simjected to pulmonary embolism with formed ilar to the baseline value in the group with thrombus, and two other dogs developed embolism induced by fresh clot. Although systemic hypotension. All 10 dogs survived blood pressure decreased during the first autologous blood clot embolism without hy- hour after embolism in dogs receiving thrombi, the pulmonary artery pressure remained significantly elevated over control PULMONARYVASCULAR RESISTANCE values throughout the period of study. Pulmonary blood flow decreased significantly in dogs receiving thrombus and remained significantly below control values for a 60min interval. Pulmonary blood flow did not significantly decrease in dogs following pulmonary embolism with fresh clot (Fig. 7). Calculation of pulmonary vascular resistance from pulmonary blood flow and pressure 120 -40 -5t 5 20 40 60 90 PYlmmq tnPs,u, measurements reflected the alterations obMl""lW served in pulmonary arterial pressure and FIG. 8. The pulmonary vascular resistance inflow measurements in the two groups. Pulcreased transiently following administration of autolmonary vascular resistance remained sigogous clot. A more pronounced increase was susnificantly elevated for only a 20-min period tamed for the duration of study in the group of dogs with pulmonary embolism induced by formed thrombus. in dogs receiving clot whereas the pulmo-----lhrombur
o-’
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the pulmonary artery. Guyton et al. [9] used a plastic loop passed around the pulmonary artery of dogs to constrict the vessel in a closed chest preparation. Simple ligation of lobar pulmonary arteries has also been used to evaluate the hemodynamics of acute pul-----Thromb”r monary arterial obstruction [7]. Intraluminal -Clot balloon-tipped catheters have been introduced in animals and in man to evaluate I I1 I 40 60 90 120 -5t5 20 O -40 the physiologic response to acute pulPvlnonor"Embll Minutes monary arterial obstruction [ 11. A variety of emoblic material has been FIG. 10. Static compliance of the lung decreased significantly following thrombus administration, but re- administered intravenously in laboratory mained unchanged with pulmonary embolism induced animals to simulate alterations associated by fresh clot. with pulmonary embolism. Although dogs have been the most commonly used animal, nary vascular resistance remained elevated cats, rats, sheep, and goats have also been for the entire period of study in animals re- employed. The list of foreign substances ceiving formed thrombus (Fig. 8). Pulmo- used as experimental embolic material innary vascular resistance was approximately cludes rubber tubing filled with fluid [lo], three times greater in animals subjected to seeds [16], glass beads [2], plastic spheres thrombus embolism compared to those sub[ 151, lycopodium spores [ 161, starch granjected to fresh clot emoblism. ules [21], barium sulfate [lo], and lead The left atria1 pressure was not sig- phosphate in agar gel [3]. nificantly altered by pulmonary embolism In the present study, no animals deusing fresh clot (Fig. 9). Pulmonary em- veloped systemic hypotension following bolism with thrombus caused an elevation autologous blood clot pulmonary embolism, of the atria1 pressure which returned to con- but two dogs died and two other dogs betrol values after a 60-min interval. Formed came hypotensive following pulmonary thrombus caused a significant decrease in embolism with formed thrombus. This obboth static and dynamic lung compliance servation suggests that autologous thrombus (Figs. 10 and ll), but no change occurred induces a much more severe hemodynamic in pulmonary compliance following intro- insult to the pulmonary circulation than a duction of fresh clot. 60
STATIC COMPLIANCE
l
PCOI
DISCUSSION
60
DYNAMIC COMPLIANCE
Between the years of 1846 and 1856 Ru5 40dolph Virchow performed a series of experiz ments confirming the basic mechanism of 8 pulmonary emoblism [23]. He introduced a variety of foreign substances into the veins of dogs and recovered this material from the lungs at postmortem examination. FolI OL’ c ’ lowing those initial observations, a wide 90 120 -40 -515 20 40 60 P"l.cw~ Enlo,", variety of approaches have evolved for MlllUkS study of this common disorder. Cohnheim FIG. 11. A transient increase occurred in dy[4] observed the right ventricular response namic lung compliance following clot embolism, but to acute pulmonary artery obstruction in the decrease in compliance persisted throughout the study dog by slowly tightening a ligature around in the dons treated with formed thrombus.
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similar weight of autologous fresh blood clot. In addition, all alterations observed following autologous blood clot pulmonary embolism proved more transient than corresponding alterations in the group with thrombus embolism. Acute changes following pulmonary embolism are partially resolved by a variety of homeostatic mechanisms of the right heart and pulmonary circulation. However, the abruptness and magnitude of resolution of physiologic alterations following embolism with fresh clot suggests that much of the return toward normal function results from early fragmentation and lysis of the clot. The fact that only about 27% of the weight of the initial fresh clot could be recovered from the lungs compared to 60% of the formed thrombus administered provides further evidence of rapid lysis of this material. Experimental studies of acute hemodynamic alterations following pulmonary embolism with fresh clot have previously documented early resolution of altered hemodynamics which may result primarily from clot lysis [18]. Conclusions regarding the acute hemodynamic response following pulmonary embolism in patients would require use of an experimental model utilizing material similar to venous thrombi. Hemodynamic observations in 10 dogs subjected to experimental pulmonary embolism using formed thrombus indicate that mechanical blockage of the pulmonary arteries elevated pulmonary vascular resistance. increased right ventricular work partially compensated for the increased resistance by increasing pulmonary arterial pressure. However, pulmonary blood flow decreased significantly with massive pulmonary embolism and the cardiac output also decreased. Increased systemic peripheral resistance prevented hypotension in a majority of animals. However, the decreased coronary blood flow associated with decreased cardiac output produced mild left ventricular failure as evidenced by the increase in left atria1 mean pressure. Pulmonary embolism represents a com-
PULMONARY
EMBOLISM
43
mon clinical problem and experimental study of the disorder requires an experimental model which causes changes similar to those occurring in patients. Marked differences were observed in this study between alterations induced by similar quantities of autologous fresh blood clot and formed thrombus suggesting that clinical application of experimental studies utilizing fresh blood clot may not prove valid. REFERENCES 1. Brofman, B. L., Charms, B. L., Kohn, P. M., Elder, J. Newman, R, and Rizika, M. Unilateral pulmonary artery occlusion in man. .I. Thorac. Surg. 34: 206-227, 1957. 2. Caro, C. G., and Harrison, G. K. Observations on pulse wave velocity and pulsatile blood pressure in human pulmonary circulation. C/in. Sci. 23: 317-329, 1962. 3. Cate, W. R., Jr., Light, R. A., Daniel, R. A., Jr., and Edwards, W. H. Role of the autonomic nervous system in the control of the pulmonary vascular bed; I. Experimental pulmonary embolism. Surg. Forum 4: 190-197, 1953. 4. Cohnheim, J. F. Lectures on Genera/ Pathology. London: The New Sydenham Society, 1889. Pp. 50-52. 5. Daley, R., Wade, J. D., Maraist, F., and Bing, R. J. Pulmonary hypertension in dogs induced by the injection of lycopodium spores into the pulmonary artery. Amer. .I. Physiol. 164: 380, 1951. 6. Dexter, L., and Smith, G. T. Quantitative studies of pulmonary embolism. Amer. J. Med. Sci. 247: 641-648, 1964. 7. Ebert, P. A., Allgood, R. J.. Jones, H. W., III, and Sabiston, D. C., Jr. Hemodynamics during pulmonary artery occlusion. Surgery 62: 18-24, 1967. 8. Gurewich, V., Cohen, M. L., and Thomas, D. P. Humoral factors in massive pulmonary embolism: An experimental study. Amer. Heart J. 76: 784-794, 1968. 9. Guyton, A. C., Lindsey, A. W., and Gilluly, J. The limits of right ventricular compensation following acute increase in pulmonary circulatory resistance. Circ. Res. 2: 326-332, 1954. 10. Halmagyi, D. F. J., and Colebatch, H. J. H. Cardiorespiratory effects of experimental lung embolism. J. C&n. Invest. 40: 1785, 1961. 11. Hara, M., and Smith, J. R. Experimental observations on embolism of pulmonary lobar arteries. J. Thorac. Surg. IS: 536-542, 1949. 12. Heimbecker, R. O., Keon, W. J., and Richards, K. U. Massive pulmonary embolism. Arch. Surg. 107: 740-746, 1973.
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13. Jones, R. H., and Sabiston, D. C., Jr. Pulmonary embolism. Surg. Clin. North Amer. 56: 891-907, 1976. 14. Just-Viera, J. O., Oster, W. F., and Yeager, G. H. Recurrent pulmonary embolism. J. Thorac. Cardiovasc.
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15. Lewin, R. J., Cross, C. E., Rieben, P. A., and Salisbury, P. F. Stretch reflexes from the main pulmonary artery to the systemic circulation. Circ. Res. 9: 585-588, l%l. 16. Megibow, R. S., Katz, L. N., and Steinitz, F. S. Dynamic changes in experimental pulmonary embolism. Surgery 11: 19-32, 1942. 17. Olsson, P., Swedenborg, J., and Lindquist, 0. Effects of slow defibrinogenation on the canine lung. J. Trauma 14: 325, 1974. 18. Puckett, C. L., Gervin, A. S., Rhodes, G. R., and Silver, D. Role of platelets and serotonin in acute massive pulmonary embolism. Surg. Gynecol. Obstet. 137: 618, 1973.
19. Puckett, C. L., Robinson, A. E., Gervin, A. S., Rhodes, G. R., and Silver, D. Microradiographic
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characterization of broncho-constriction after pulmonary embolism. J. Surg. Res. 14: 165. 20. Sabiston, D. C., Jr., Marshall, R., Dunnill, M. I., and Alison, P. R. Experimental pulmonary embolism. Description of a method utilizing large venous thrombi. Surgery 52: 9, 1%2. 21. Singer, D., Salzman, P. W., Rivera-Estrada, C., Pick, R., and Katz, L. N. Hemodynamic alterations following miliary pulmonary embolization in relation to the pathogenesis of the consequent diffuse edema. Amer. J. Physiol. 191: 437-442, 1957. 22. Stein, M., Tanabe, G., Calm, M., and Thomas, V. P. Pulmonary responses to macro and microembolic. In A. A. Sassahara, and M. Stein, (Eds.), Pulmonary
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Disease a Symposium.
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York: Grune & Stratton, 1965. 23. Virchow, R. Die Cellularpathologie. Berlin: Hirschwald, 1859. P. 444. 24. Wessler, S., Freiman, D. G., Ballon, J. D., Katz, J. H., Wolff, R., and Wolf, E. Experimental pulmonary embolism with serum-induced thrombi. Amer. J. Pathol. 38: 89-101, 1961.
