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The Therapy and Prophylaxis of Venous Thrombosis and Pulmonary Embolism
THE THERAPY AND PROPHYLAXIS OF VENOUS THROMBOSIS AND PULMONARY EMBOLISM GORDON A. DONALDSON, M.D., F.A.C.S." OVER the past five years the literature on the subject of thrombophlebitis and embolism has become voluminous. This enthusiasm has been shared in by surgeon, pbstetrician and internist alike, and it is just becoming evident that the measures, both therapeutic and prophylactic, which have followed in the wake of this interest are producing results. At the Massachusetts General Hospital in 1925, there were three deaths from massive fatal pulmonary embolus following every 1000 operations. 1 Ten years ago, with the introduction of more careful attention to the position of the patient on the operating table, active and passive leg exercises postoperatively, encouraged deep breathing, routine elevation of the foot of the bed to speed venous return, and finally earlier ambulation, the incidence of fatal embolism had dropped to one death in 800 operations. In 1945, twenty years after Davis' observations, there were nine proven fatal emboli following 9765 operations. This ratio of slightly less than one to one thousand was maintained in 1946, when there were nine deaths after 9969 operative procedures. It is noteworthy that this reduction in mortality of 66 per cent over a twenty-year period has occurred in the face of several hostile factors. Chief among these has been the increasing age of hospital patients. It has been adequately demonstrated that age greatly influences the incidence of postoperative pulmonary embolism. In a previous report,2 it was found that patients in the sixth decade of life were most susceptible, and this has been adequately corroborated by others. In the fifteen year period from 1930, the mean age of patients admitted to the Massachusetts General Hospital has· risen from 36 years 3 months to 42 years 3 months, an increase of six years. Again, it.is obvious that the magnitude of the operative procedure has a direct bearing on the incidence of phlebitis. The relatively recent developmentof modern anesthesia resources, technical operative facilities, and better understanding of preoperative and postoperative care have combined to extend the surgical horizon ,considerably. Finally, from the time of Trousseau, 3 the association of thrombophlebitis and malignant disease has been recognized. This development of phlebitis in the presence of cancer has come to be known as "Trousseau's sign." "Assistant Surgeon, Massachusetts General Hospital; Assistant in Surgery, Harvard Medical. School, Boston. 1037
1038
GORDON A. DONALDSON
In 1930 patients with malignant disease comprised JO.3 per cent of total surgical admissions to the hospital, whereas in 1945 this figure had risen to 16.5 per cent. It is thus evident that any measures which have lessened the incidence of embolism in recent years have done so against steadily increasing obstacles. The importance of the tibial veins and their tributaries below the level of the knee as the source of most pulmonary emboli has now become well established. Adequate support for this contention comes from the pathologist and clinician. In the last decade, pathologists have shown that where postmortem examination of the legs is thoroughly made, ante mortem thrombosis .is found in the deep veins of the calf in over 50 per cent of all cases.4 , 5 In the older individual the incidence rises. In 200 routine autopsies performed in an old folks' home, the deep veins of the legs were found thrombosed premortally in 90 per cent of the cases. Much of this thrombosis, of course, was the result of enforced bed rest, and in no sense the cause of death. In a second series of cases, Hunter and his associates 6 indicated that recumbency is the greatest single factor in thrombus formation. In a group of patients exercised systematically until shortly before death, only 18 per cent exhibit thromboses at autopsy as opposed to 53 per cent when exercise was not emphasized. Simpson's observations further incriminate the leg veins. Pulmonary embolism was strikingly increased in elderly persons, cared for in London bomb-proof shelters, who reclined in chairs for long hours with pressure on the calf and popliteal vein. On the clinical side, pulmonary emboli, arising from the leg veins as a source, are becoming recognized by symptoms and signs often regarded in the past as indicative of primary disease of the heart or lungs or as an inconsequential digestive disturbance. A single symptom in itself is not sufficient to make the diagnosis, but often enough calls attention to the presence of other obscure signs which give added evidence of the presence of vascular pathology. At the Massachusetts General Hospital,2 59 per cent of patients presented leg signs as first indication of thromboembolic disease; and of these fJl per cent showed leg swelling, 61 per cent tenderness over the tibial vessels, and 42 per cent a positive Homans' sign. The remaining 41 per cent presented chest symptoms as first indication of disease. We have come to put great reliance on the appearance of the clinical chart. Any patient who, otherwise convalescing smoothly, suddenly develops a simultaneous rise in temperature, pulse and respiration is suspected of harboring phelebitis or of having a subclinical pul'monary embolus until proven otherwise. In a small series of cases, 81 per cent of charts considered suitable for study demonstrated this positive "Allen sign." It has become evident that the picture' of deep leg vein thrombosis
.'~
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1039
is not constant. We believe that the extremes of acute thrombophlebitis on the one hand, and "bland thrombosis" of Homans or "phlebothrombosis" of Ochsner and DeBakey on the other, are expressions of an identical process. Between them are all gradations, the picture at the moment depending on the extent of involvement of vein intima in the inflammatory process. Most often the inflammatory reaction is an aseptic one, and the extent of endothelial damage is dependent on such factors as the degree of local anoxia and general alterations in the cellular and fluid constituents of the blood which tend to increase clotting proficiency. At one extreme is found diffuse swelling, tender~ ness, warmth and pain in the calf on dorsiflexion of the foot. The superficial veins over the ankle and forefoot are distended, and there is a leukocytosis, elevated sedimentation rate, and fever. Here the clot is firmly adherent to the vein wall over some distance and the likelihood of a large, death-producing embolus is slight. This type, if it does not kill by several repeated smaller emboli, enforces a prolonged hospital stay and results in a permanently impaired leg due to valvular destruction. The gradations of the bland, asymptomatic thromboses are many. Minimal swelling of the ankle, local areas of point tenderness, a sense of firmness in the tissue of the calf, slight fullness of the long saphenous vein at the ankle, associated with mild systemic reaction indicate that the clot coagulum is adherent to only a small area of vessel intima. Propagation is chiefly cephalward, and when the thrombus does free itself a long column of clot is liberated to the right heart and pulmonary arteries. THERAPY The many reports on the effectiveness of one form of treatment against another tend to be misleading. In fact; the therapeutic procedures available today should be used, depending on the case at hand, to supplement one another, rather than be considered as rival forms of therapy. Rational treatment of established thromboembolic disease may take one or more of three forms; the use of anticoagulant drugs, lumbar sympathetic procaine block, or deep vein interruption. The use of heparin and dicumarol is based primarily on the prevention of the extension of thrombosis until such time as the established coaguluf!1 becomes more strongly organized to itself and to the vessel wall, and until the patient is adequately ambulatory to insure a vigorous venous flow. Lumbar sympathetic block, on the other hand, rapidly and effectively increases venous return by interrupting reflex arterial spasm resulting from the irritating venous inflammatory process. The disappearance of leg swelling and pain is often dramatic, as the normal arteriovenous gradient is regained. Finally, deep vein interruption properly performed above the level of the thrombus precludes the
1040
GORDON A. DONALDSON
possibility of further propagation of fatal embolism. All three forms of therapy reduce the period of convalescence; mitigate the sequelae of untreated thrombosis, and lower the incidence of fatal embolism. In some instances, it is obvious all three may be employed to advantage ' on the same patient. Homans 8 was the first clinician to call attention to the feasibility of interruption of the femoral vein in the groin to prevent pulmonary infarction. The method has found many enthusiastic advocates in this country. From 1939 to January 1947 at the Massachusetts General Hospital, there have been 1692 patients who have been subjected to femoral vein interruption, representing a total of 3185 vein operations (Table 1). It is worthy of note here, that in not a single instance has TABLE 1 1587 PATIENTS Massachusetts General Hospital, 1937-1946
FEMORAL VEIN INTERRUPTION IN
Patients
1937."""""", .. 1938"" , . . . . . . . . . . . 1939"""" , ....... 1940""" , . . . . . . . . . 1941""""""", , 1942.,.,., ' ......... 1943 ... ............ . 1944 ... ............. 1945 .. ,.,.,.,., ..... 1946 ... " .... " .. , ..
Total .. " ....... , ...
1 0 8 5 51 137 165 280 392 548
-1587
Veins
Unilateral Interruption
1 0 8 15 55 211 299 554 781 1091
100,0% ,0% 100,0% 100,0% 92,1% 46.0% 19.0% 2.1% 0.8% 0.9%
--
I
Bilateral Interruption ,0% ,0% ,0% ,0% 7,9% 54.0% 81.0% 97.9% 99.2% 99.1%
3005
a patient lost life or limb as a result of the procedure. One hundred and five of these cases were operated upon in treatment of the sequelae of an old phlegmasia, and will not be discussed further in this paper. Approximately two-thirds of the group have been treated for acute thromboembolic disease, the remaining patients re:F>resenting interruptions done as a prophylactic measure (Table 2). In those patients treated for acute disease, the results have been most gratifying. In the first place, it has been noted that usually there is a relatively rapid subsidence of fever and swelling, the average length of time to normal temperature chart being four and one-haH days. It has become possible to discharge patients from the hospital at an earlier date, resulting in a great saving of needed beds. The amount of residual edema of the legs has not been disturbing and
I Ii
1041
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
unless such factors as cardiac incompetency or malnutrition are present, swelling is not permanent. Its severity and persistence are directly proportional to the extent the phlebitic process is allowed to attain before interruption is done. In the past two years, earlier diagnosis has been the rule; and with prope~ after-care in the form of elevation and supportive bandages, ankle edema has not been bothersome. In TABLE 2 INCIDENCE OF THERAPEUTIC AND PROPHYLACTIC FEMORAL VEIN INTERRUPTION IN 1587 CASES
Massachusetts General Hospital, 1937 to January 1947 Therapeutic
Prophylactic
Total
o~ 9 0
202 165 280 392 548
-~
1937-1942 ......... 1943 .............. 1944 .............. 1945 .............. 1946 .............. Total. ...........
202 150 208 214 259
-1033
0 15 72 178 289
-554
26% 45% 53%
--
1587
the occasional case eihibiting a spread of the inflammatory process in the leg vein tributaries after interruption, lumbar block with or without dicumarol has controlled both pain and swelling. In the older group, because of altered electrolytes, cardiac Incompetency, inadequate venous structures, or lymphatic sclerosis, vesper edema, dependent on osmotic and hydrostatic factors, has persisted as long as TABLE 3 1587 CASES Massachusetts General Hospital, 1937-1946 Incidence of sepsis. . . . . . . . . . . . . . . . . . . . . . . 13 0.8% Incidence of hemorrhage. . . . . . . . . . . . . . . . . 9 0.6% 26 Incidence of lymphorrhea. . . . . . . . . . . . . . . . 1.6% 2 Incidence of postphlebitic ulcer .. , . . . . . . . . 0.1% Incidence of pulmonary infarct. . . . . . . . . . . . 63 4.0% 6* Incidence of fatal embolism. . . . . . . . . . . . . . . 0.4% * Five of these cases were iIi. the therapeutic group. COMPLICATIONS OF FEMORAL VEIN INTERRUPTJON IN
six months. Two in the group of 1033 patients carry postphlebitic ulcers. It is difficult to evaluate what eHect vein interruption has had on the life history of tvese lesions in view of the work of Buxton and Coller9 on the~ use o£'rthis procedure in the treatment of the postphlebitic syn4i"ome. S,ubsequent pulmonary emboli have been encountered in 4; per cent· of cases, necessitating the use of supplemental dictnnarol. It is of interest that practically kIl of this group who
1042
GORDON A. DONALDSON
suffered subsequent emboli had been subjected to vein interruption because of a previous pulmonary infarction. Five patients in the group of 1033 therapeutic interruptions succumbed to proven subsequent emboli. In none of these earlier cases was anticoagulant therapy used as an adjunct. Four of the five had had pulmonary infarctions prior to interruption, resulting in a lowered pulmonary reserve so that lesser subsequent emboli were adequate to cause death (Table 3). It would be helpful if, in each case of early deep venous thrombosis, the morbidity or mortality could be known. This is difficult to evaluate because from different areas of the country come various statistics. In our own clinic, Miller and RogerslO prior to 1929 found seven deaths in 206 cases of thrombophlebitis. One hundred and three of these cases were of spontaneous origin, the remaining 50 per cent being postoperative. Welch and Faxon l l in a later study found the death rate to be almost identical, the ratio of fatal embolism to phlebitis being one in twenty-five. Three-fifths of their cases of deep phlebitis followed operation or trauma. In 1946, with present day therapeutic measures fairly well established, the ratio of autopsy proven fatal embolism to clinical thrombophlebitis had fallen to 1 in 130. There were two failures in 259 cases of thromboembolic disease. One hundred fifty-two cases, or essentially three-fifths of the total again, occurred following operation or trauma, and each of the fatalities occurred in this group. In these surgical cases the ratio remains 1 to 76, or a mortality of 1.3 per cent. That this figure reflects the true picture is borne out by statistics of 1945 in which there were two fatalities in 214 instances of phlebitis. Operation and trauma contributed 136 of these cases and were responsible for both deaths. Ochsner and DeBakey12 feel safe in the continued use of procaine sympathetic block. This has proved effective in their southern climate. Bauer's13 results in Sweden with the use of repeated intravenous aqueous heparin are impressive. He has reduced the incidence of fatal embolism in all cases of clinical thrombosis, of both medical and surgical origin, from 18 per cent to 1.4 per cent in the Mariestad Hospital. The experience of Barker and his co-workers14 with dicumarol and of Loewe, Rosenblatt and Hirsh15 with heparin in Pitkins' menstruum are encouraging. Evans and Boller16 report two fatalities from embolism in 127 cases of postoperative phlebitis following the combined use of both heparin and dicumarol, occasionally resorting to femoral vein interruption when indicated. With the judicious use of one or more of these agents of therapy available, it is not out of reason to suppose that fatalities in the presence of recognized thrombophlebitis or pulmonary infarction may be eliminated. At the Massachusetts General Hospital therapeutic femoral vein interruption has proved to be highly effective. In the future, with 'the adjuncts of lumbar sympathetic block and dicumarol to con-
1
1
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1043
trol the occasional case in which the acute phlebitic process spreads throughout the leg, and the more astute use of anticoagulants to control the 4 per cent of postinterruption emboli, functionally normal legs should be preserved and mortality from this disease should be elim"inated. PROPHYLAXIS
. The results in therapy noted above represent a great advance in the prevention of pulmonary embolism once a warning venous accident has occurred in the form of venous thrombosis or a benign pulmonary embolus. In spite of this progress, it remains that death may occur from sudden and unheralded pulmonary embolism. It is in an effort to eliminate such events that prophylactic measures have been elaborated. Over the past two years this basic incidence of embolism from unrecognized bland or phlebothrombosis has been attacked at the Massachusetts General Hospital in a controlled group of patients by the routine prophylactic use, as indicated, or dicumarol or femoral vein interruption. Sudden massive embolism under the age of 40 years is unusual. There have been four such cases in our clinic over the past six years, and these have occurred chiefly on the Medical Services. That bland thrombosis may develop in this younger group, partcularly as the result of trauma, is stressed by Hamilton and Angevine 17 who report ninety-nine such fatalities in soldiers under the age of 40. Certainly in civilian life it may be considered a relatively rare postoperative complication. In those patients over 40 years of age, three factors are of great importance. One is the actual age of the patient. In our series from 1940 to 1947, the highest incidence of sudden massive embolism occurred in the seventh and eighth decades, each contributing twenty-one deaths. These age groups compare with those reported by Evans and Boller16 who found over a similar six-year period a total of fifty-two fatalities, seventeen of these occurring in the sixth and fourteen in the seventh decades of life. The nature of the primary illness is also of significance. Debilitated patients, those suffering from cancer, intestinal obstruction and general old age are prone to develop bland thrombi in their leg veins as the result of venous stasis. Finally, the initial operative procedure must be considered. VeaP8 has demonstrated convincingly the surprising frequency of fatal embolism following low thigh amputation. Here, particularly, the entire length of the superficial femoral vein lies quiescent, as a nidus for thrombus formation. By the simple expedient of prophylactic vein interruption, Veal has been able to lower the mortality in comparable groups of patients from 42.1 per cent to 11.5 per cent. Patients with fractures about the hip region offer opportunity of a similar proportion. Because of medicolegal intervention autopsy proof of embolism is often lacking, but the clinical
1044
GORDON A. DONALDSON
picture is no less graphic. In our clinic we have grown to respect and fear the group of patients with cancer of the gastrointestinal tract, esophagus, stomach, colon and rectum. Prostatic surgery carries a relatively high risk, and only less so small bowel obstruction, pelvic tumors, breast cancer and biliary tract disease, In an attempt to formulate a program which would be both effective and practically applicable to the hospital laboratory, a control study was carried out at the Massachusetts General Hospital. The plan. entailed combining the use of prophylactic dicumaroland prophylactic vein interruption, and the study was continued over the years 1945 and 1946. The two identical Surgical Services in the General Hospital itself made ideal controls. The East Surgical Service under Arthur W. Allen sponsored the experiment, and the West Surgical Service under E. D. Churchill and L. S. McKittrick cooperated as the control. Following major surgery on the East Service, dicumarol was administered prophylactically to the middle age group, aged 40 to 65, and those older were routinely subjected to prophylactic femoral vein interruption. Reported subarachnoid, gastrointestinal, and renal accidents subsequent to the use of anticoagulants in the arteriosclerotic, elderly people, particularly in the presence of hypertension, led us to prefer vein interruption as less dangerous. The age limit of 65 was somewhat flexible. In instances where the incidence of phlebothrombosis was known to be high, as after thigh amputation and resections of the rectum or stomach, femoral vein interruption was preferred to the use of dicumarol in some patients younger than 65. Except for an occasional unavoidable prophylactic interruption, the West Surgical Service obligingly served as a control, reservirig the therapeutic procedure for thosfil patients who developed recognizable thromboembolic phenomena. That these two Service groups, were admirably suited for comparison can be seen from the admission data in Table 5. That dicumarol is a specific liver poison cannot beoveremphasiied. It probably interferes with the synthesis of fibrinogen as well as prothrombin, and accidents following its earlier, inadequately controlled use are reported. 19 Over the past year, however, added experience by cardiologists as well as surgeons has increased respect for its dangers and confidence in its use. Future adverse reports should be rare. In our clinic, we have been conservative in that only 200 mg. has been given as an initial dose, and this has been repeated only if a satisfactory response was not evident after forty-eight hours. In all cases initial prothrombin levels have been determined before administration of the drug, and subsequent blood values have been measured every fortyeight hours. Allowing for the known hypoprothrombinemia immediately following anesthesia and operation,20 200 mg. has been withheld until the first postoperative day. The maximum rise in prothrombin time occurs three to four days thereafter. Those patients requiring a longer
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1045
period of strict bed rest are given an additional 200 mg. before the expected fall in prothrombin time has resulted. As might be expected, depending on liver competency, the prothrombin response to dicumarol has been markedly variable. In an occasional case, the increase in prothrombin time after only 200 mg. has been frightening; and we have been tempered in our earlier enthusiasm to increase the size and frequency of dosage. It is a good general rule, that when the prothrombin time response is twice the "normal reading," the prothrombin content of the blood is reduced to 30 per cent of normal and serious bleeding may ensue. 21 Certain individuals, on the other hand, respond poorly to this dosage. Rarely, however, has phlebitis developed in such cases; and it is our distinct TABLE 4 CONTRAINDICATIONS TO DICUMAROL THERAPY
Of 1299 patients between the ages of 40 and 65 who were admitted to the East Surgical Service of the Massachusetts General Hospital from January 1, 1945 to January 1, 1947, 223 (17.2 per CIlnt) received dicumarol. In the remaining 1076 patients, dicumarol 'ras contraindicated for the following reasons: Hospitalized for minor procedures AdInission for study, no operation Liver disease Hypertension Cht'.st cases Plasma prothrombin found above 25 seconds Hyperthyroidism . Excessive bleeding at operation Diabetes Arthritics taking aspirin.
impression that changes in blood constituents are eHected which are not detected by our present admittedly crude laboratory methods. We have had no evidence of toxicity and no deaths from hemorrhage. One patient in the group bled from an ileotransverse colostomy suture line and received a transfusion. Other bleeding episodes have been trivial. In the event of an unexpected sensitivity to the drug, transfusion or massive doses of vitamin K will lower the prothrombin time in a matter of hours. The results in the middle age group treated with dicumatol as outlined above have been striking, both in point of lowering the incidence of thrombophlebitis and preventing phlebothrombosis and massive pulmonary embolism. During the years 1945 and 1946 in 1299 admissions in this age group eligible for dicumarol there have been nine instances of thrombophlebitis as against an incidence of forty-five cases in the control series. Only four of these nine actually received dicumarol, the remaining five presenting one or more contraindications to its use. In this same dicumarol-h'eated group there was no instance of phlebothrombosis resulting in fatal embolism. The con-
1046
GORDON A. DONALDSON
trol group, on the other hand, contributed three such fatalities in the same period. In the older patients, because it was felt that superficial femoral vein interruption held fewer hazards than the use of dicumarol, all patients subjected to major surgery were prophylactically ligated. This procedure was done in some cases, particularly those in which the patient had been bedridden at home or who had a prolonged course of preoperative study, prior to major surgery. In others it was feasible to interrupt the veins at the time of operation, and in the majority "prophylaxis" was accomplished within forty-eight hours after operation. Actually, due to the temporary venous congestion in TABLE 5 INCIDENCE OF POSTOPERATIVE PHLEBITIS AND FATAl. EMBOLISM IN THE PROPHYLACTIC-TREATED AND THE CONTROL GROUPS
Magsachusetts General Hospital. 1945-1946
III East Service I II (DicumaroI40-64; 1-39 yrs. 40-64yrs. 65+ yrs. Total Vein Interrup0 223 tion 65+) Prophylactic dicumarol. 0 223 181 Prophylactic interruption 1 35 217 9* 26 Postoperative phlebItis .. 9 8t 0 Fatal embolism ........ 0 0 0 497 Admissions ............. 1136 1299 West Service (Control) 0 Prophylactic dicumarol. 0 0 0 .') 14 19 Prophylactic interruption 0 45 17 Postoperative phlebitis .. 71 9 0 3 6 3 Fatal embolsim ........ 1280 453 Admissions ............. 1163
* Five of the 9 did not receive dicumarol because of "contraindications"; 3 of the remaining 4 failed to obtain a satisfactory rise in prothrombin time, and should have received additional dicumarol. t Four of the 8 developed phlebitis, requiring vein interruption, before prophylactic nterruption had been done.
the pelvis following superficial femoral vein interruption, it is advisable to postpone the procedure until forty-eight hours have elapsed following a Wertheim or Miles operation. Although most fatal emboli occur approximately ten days after operation, we feel uncomfo~table if more than forty-eight hours elapse, particularly in individuals who have been bedridden preoperatively. One hundred eighty-one such prophylactic interruptions have been done on this admittedly vulnerable group without a single death. Again in the control group, three patients succumbed from a proven embolus (Table 5). These measures have not been limited to the ward patients on the East Surgical Service. Although all of the members of the staf¥are not convinced of the value of prophylaxis, many of the orthope~ic,
,r.
,1 ~l
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1047
genitourinary, gynecologic and private service patients have been treated. As of January 1, 1947, there had been a total of 247 patients treated with dicumarol and 554 prophylactic femoral vein interruptions. The complications encountered following dicumarol in this small group is evident in Table 6. TABLE 6 247 PATIENTS Massachusetts General Hospital, 1945-1946 Minor bleeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 9 Major bleeding·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 Phlebitist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5 Pulmonary infarctt. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 7 Fatal pulmonary embolus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 0 • Requiring vitamin K and transfusion. t Requiring femoral vein interruption. COMPLICATIONS OF PROPHYLACTIC DICUMAROL IN
The vein interrupted in each instance has been the superficial femoral. Of the 554 patients undergoing this procedure, fifteen have developed clinical phlebitis in one leg or the other, a,s measured by findings other than swelling; namely, pain, tenderness, dorsiflexion discomfort, or a general systemic response. In this group of 554 there has been one postinterruption fatal embolus, proven at autopsy. This patient was an obese 63 year old woman with a large ventral hernia. Two days after hernioplasty, vein interruption was done. Thirteen days later, a left middle lobe infarct was demonstrated by x-ray. Sudden death ensued two days thereafter. This misfortune occurred in 1945, and since then we have adopted two measures which would have been of value. The superficial femoral vein should be tied with care, flush with the profunda so as to leave no nidus for thrombus formation. There was a 3 cm. nidus in the above case. Secondly, today she would be given heparin and dicumarol, following her initial warning pulmonary infarct. We feel that this patient demonstrates further that given a normal pulmonary circulation, the short profunda and common femoral vessel thrombi cause death by repeated insults to the lung, rather than harboring a single thrombus large enough to produce a sudden fatal result. The value of prophylactic interruption becomes more tangible when cases so treated are compared with a like group drawn in sequence from our hospital files (Table 7). The records have been consecutive. Age, sex, disease, operative procedure, and service in the hospital, whether public or private, have been matched as accurately as possible. Under these limitations it has been necessary to search as far back as 1939 and 1941 respectively for comparable hip fractures and leg amputations. Prophylactic vein interruptions were practically universal in both these groups from 1943 to the present. The remain-
lO48
GORDON A. DONALDSON
ing series were in addition matched year by year. The findings arc corroborated by a group of amputations collected by Veal, 18 and support a similar, overlapping series reported earlier.22 TABLE 7 COMPARATIVE INCIDENCE OF POSTOPERATIVE THROMBOSIS AND EMBOLISM
Older Age Group of Patients
I ~U:i:f 1 - - - - - , - - - - 1 - - - - - ; - - - With Prophylactic Vein Interruption
Without Prophylactic Vein Interruption
.
Each Group
Fractures hip region .................. .
~:ict;,=ti~~·... ::::::·:::.:
:::::: Colon operations ..................... .
Small bowel obstructiop. ............... . Cbolecystectomay ................... .. Resection rectum ••.................... Hernioplasty ........................ . Pelvic Burgery ....................... . Prostatectomy ....................... . Radical mastectomy. . . . . . . . . . . . . . . .. Heart disease .••••....................
A~'1=~~;,:·.::::::::::::::: ... :::
114 57 59
62
9 38 32 28 26 '17 18 21 10 8 8 6 6 4
Phlebitis
Fatal Embolus
Phlebitis
Fatal Embolus
3
o o
20 2
10*
o
2 I I
o
2 I
o o o o 1 o o o
o o o o o 1 o o o o o o
7 4 3 1
5 5 1
5
1 1 1
7
3
1
2 2
I
o o
1
4 1
o o o
o
1
o o o
o o
o 1 o 2
o
Mr:.:u~:..~:.·.::::::::::::::::::::: :
2
16
o
o
o 1
o o o
Total............................. .
554
15
63
30
Study cases .......................... . E80pbagectomy ................ . Common duct exploration ............. . Resection pancress ................... . Leg abscess, leg fracture. neck dissection. each .............................. . Lung abscess. peritonitis. popliteal aueu-
o
3
2
o
II (I
* Because of medicolegal jurisdiction. autopsy was not poBSible i~l all deaths following hip t~actures. TECHNIC OF OPERATIONS
'"
The operation of femoral vein interruption should not be considered too lightly. Although we have had no serious complications following the procedure in our own group, instances of loss of an extremity are reported in the literature.23 • 24 In the poorly nourished, thin individual the technical procedure is relatively simple, requiring perhaps thirty or forty minutes. In the short, stout patient, vein interruption may be time-consuming and hazardous. Venous anomalies in the area are frequent, and preliminary acquaintance with the region should be had by precept or by autopsy experience, before undertaking the procedure. Although reported elsewhere,24 certain details of the technic are worthy of emphasis: The patient should lie in 'slightly reverse· Trendelenburg position to give increased local positive venous pressure. Infarcts during the manipulation of the vein have not occurred, but- this- precautionary
"I
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
..
I
1049
measure is employed. One per cent procaine anesthesia is adequate. The skin incision is strictly vertical, parallel with major blood and lymph vessels, from the groin crease distally for a distance of 8 to 10 cm, The pulsating femoral artery in the groin crease gives an excellent guide, regardless of obesity. Subsequent incisions are carefully. maintained i~ a vertical dissection, thus making it possible to displace the main femoral lymphatic vessels and nodes medially, without entering them. Transverse and oblique incisions are to be avoided as there ineVitably is injury to lymphatic structures, resulting in postoperative lymph edema of the leg and lymph drainage from the wound'. The medial margin of the sartorius muscle next makes an excellent guide to the underlying femoral sheath. The entire sheath is carefully retracted laterally without baring the artery itself, thus exposing the vein which lies more posteriorly than medially -at this level. Before grasping the vein, the fossa through which the profunda escapes is first identified. Unnecessary injury to the common femoral vessel is thus avoided. Several landmarks are helpful. In the normal subject, the bifurcation of the common femoral should lie in the middle of the wound, if properly made. In most indiivduals a bulge can be detected just below this level, indicating the site of a valve in the superficial vein. This valve lies within 1 to 2 cm. of the actual bifurcation, and is almost constantly present. Finally with· careful blunt scissors dissection, a definite fossa will be found posteriorly through which the profunda femoris runs in a slightly medial direction. Above and lateral to the vein, the profunda artery can often be felt running parallel to it. Exposure of the upper 2 cm. of vein to be interrupted is _sufficient. In spite _of the presence of one or more heavy muscular branches entering directly posteriorly, it is possible with the aid of a right angle clamp to pass No. 00 chromic guy ligatures about the superficial vein, between the levels of profunda femoris and posterior muscular branches. A transverse incision in the anterior half of the vein is made. Any clot present may be removed with forceps and caref1.dly applied suction, and it is always desirable to remove as much thrombus from above and below as possible. Thrombi which have been present for a day or two' at this level, as foreshadowed by early swelling of the thigh, are often difficult to remove completely. Following aspiration, the vein is completely divided between clamps, and the proximalligature is carefully placed flush with the entrance of the profunda branch. For safety sake, the cut vein ends are further secured with stitch ligat~es dist~l to the original ties. _. In ~closure of the wound it is important to make an accurate three layer" approximation of deep fascia, superficial fascia and skin. Escape of soine lymph into the wound is inevitable, and lymph cyst or transient lymphorrhea sometimes occurs. Care must be exercised not to
1050
GORDON A. DONALDSON
include in interrupted ligatures the femoral nerve which lies deep to the deep fascia, and the medial or anterior femoral cutaneous nerves.~ lying deep to the superficial fascia. After a change of instruments and gloves, a similar procedure is carried out on the other leg. As· the diagnosis of thrombophlebitis in the last year or two has been made earlier, fewer thrombi have been encountered at operation. If the process has extended to involve the profunda as determined by palpation of the vein, a similar guy ligature technic is used to explore this vessel. In those patients on whom it is not possible to establish free retrograde bleeding through the common femoral, we have come to feel that supplemental anticoagulant therapy in the form of heparin and dicumarol should be used until the patient is fully ambulatory. Intervention at the iliac or inferior vena caval level in comparison is unnecessarily hazardous and carries a disturbing morbidity and a forbidding mortality.25 Vena cava ligation in our clinic is now reserved for patients presenting septic emboli, the source of which is, or has extended, above the femoral level.
REFERENCES 1. Davis, Lincoln: Quoted by A. W. Allen in "Vascular Disease," Chapter VI, Nelson Loose-leaf Medicine, 4:531-:.580, 1931. 2. Allen, A. W.,Linton, R. R. and Donaldson, G. A.: Thrombosis and Embolism. Ann. Surg., 118:728, 1943. 3. Trousseau, A., cited by Sproul, E. E.: Carcinoma and Venous Thrombosis: . The Frequency of Association of Carcinoma in the Body or Tail of the Pancreas with Multiple Venous Thrombosis. Am. J. Cancer, 84:566-585, 1938 4. Neumann, R: Ursprungszentren und Entwicklungsformen der Bein-Thrombose. Arch. Path. Anat., 801:708-735, 1938. 5. Hunter, W. C., Sneeden, V. D., Robertson, T. D. and Snyder, G. A. C.: Thrombosis of Deep Veins of the Leg: Its Clinical Significance as Exernplilled in 351 Autopsies. Arch. Int. Med., 68:1-17, 1941. 6. Hunter, W. C., Krygier, J. J., Kennedy, J. C. and Sneeden, V. D.: Etiology and Prevention of Thrombosis of Deep Leg Veins: Study of 400 Cases. Surgery, 17:178-190, 1945. 7. Simpson, K. I.: Shelter Deaths from Pulmonary Embolism. Lancet, 2:744, 1940. 8. Homans, John: Thrombosis of the Deep Veins of the Lower Leg Causing Pulmonary Embolism. New England J. Med., 211:993-997, 1934. 9. Buxton, R. W. and Coller, F. A.: Surgical Treatment of Long Standing Deep Phlebitis of the Leg: Supplementary Report. Surgery, 18:663-669, 1945. 10. Miller, R. H. and Rogers, H.: Postoperative Embolism and Phlebitis. J.A.M.A., 98:1452, 1929. 1l. Welch, C. E. and Faxon, H. H.: Thrombophlebitis and Pulmonary Embolism. J.A.M.A., 117:1502-1508, 1941. 12. Ochsner, A. and DeBakey, M.: Therapeutic Considerations of Thrombophlebitis and Phlebothrombosis. New England J. Med., 225:207-227, 1941. 13. Bauer, G.: Heparin Therapy in Acute Deep Venous Thrombosis. J.A.M.A., 181:196-203, 1946. 14. Barker, N. W., Croner, H. E., Hum, M. and Waugh, J. M.: Use of Dicumarol
I
I
"
VENOUS TlffiOMBOti18 AND PULMONARY EMBOLISM
15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25.
1051
in Prevention of Postoperative Thrombosis and Embolism with Special Reference to Dosage and Safe Administration. Surgery, 17:207-217, 1945. Loewe, L., Rosenblatt, P. and Hirsh, E.: Venous Thrombo-embolic Disease. J.A.M.A., 130:386-393, 1946. Evans, J. A. and Boller, R. J.: The Prevention of Postoperative Pulmonary Embolism. New England J. Med., 236:392-397, 1947. Hamilton, T. R. and Angevine, D. M.: Fatal Pulmonary Embolism in One Hundred Battle Casualties. The Military Surgeon, 99:456-458, 1946. Veal, J. R.: The Prevention of Pulmonary Complications Following Thigh Amputations by High Ligation of the Femoral Vein. J.A.M.A., 121:240-244, 1943. Shevlin, E. L. and Lederer, M.: Uncontrollable Hemorrhage after Dicumarol Therapy, with Autopsy Findings. Ann. Int. Med., 21:332-342, 1944. Richards, R. K.: Influence of Fever upon the Action of Dicumarol. Science, 97:313-314, 1943. Stewart, John D.: Personal communication. Allen, A. W.: Interruption of the Deep Veins of the Lower Extremities in the Prevention and Treatment of Thrombosis and Embolism. Surg., Gyn. & Obst. (In press). Dennis, C.: Disaster Following Femoral Vein Ligation for Thrombophlebitis: Relief by Fasciotomy: Clinical Case of Renal Impairment Following Crush Injury. SUrgery, 17:264-269, 1945. Allen, A. W., Linton, R. R. and Donaldson, G. A.: Venous Thrombosis and Pulmonary Embolism. J.A.M.A., 1947. (In press.) Read before the Surgical Section, A.M.A., San Francisco, July 3, 1946. Moses, W. R.: Ligation of the Inferior Vena Cava or Iliac Veins: a Report of Thirty-six Operations. New England J. Med., 235:1-7, 1946.
1038
GORDON A. DONALDSON
In 1930 patients with malignant disease comprised JO.3 per cent of total surgical admissions to the hospital, whereas in 1945 this figure had risen to 16.5 per cent. It is thus evident that any measures which have lessened the incidence of embolism in recent years have done so against steadily increasing obstacles. The importance of the tibial veins and their tributaries below the level of the knee as the source of most pulmonary emboli has now become well established. Adequate support for this contention comes from the pathologist and clinician. In the last decade, pathologists have shown that where postmortem examination of the legs is thoroughly made, ante mortem thrombosis .is found in the deep veins of the calf in over 50 per cent of all cases.4 , 5 In the older individual the incidence rises. In 200 routine autopsies performed in an old folks' home, the deep veins of the legs were found thrombosed premortally in 90 per cent of the cases. Much of this thrombosis, of course, was the result of enforced bed rest, and in no sense the cause of death. In a second series of cases, Hunter and his associates 6 indicated that recumbency is the greatest single factor in thrombus formation. In a group of patients exercised systematically until shortly before death, only 18 per cent exhibit thromboses at autopsy as opposed to 53 per cent when exercise was not emphasized. Simpson's observations further incriminate the leg veins. Pulmonary embolism was strikingly increased in elderly persons, cared for in London bomb-proof shelters, who reclined in chairs for long hours with pressure on the calf and popliteal vein. On the clinical side, pulmonary emboli, arising from the leg veins as a source, are becoming recognized by symptoms and signs often regarded in the past as indicative of primary disease of the heart or lungs or as an inconsequential digestive disturbance. A single symptom in itself is not sufficient to make the diagnosis, but often enough calls attention to the presence of other obscure signs which give added evidence of the presence of vascular pathology. At the Massachusetts General Hospital,2 59 per cent of patients presented leg signs as first indication of thromboembolic disease; and of these fJl per cent showed leg swelling, 61 per cent tenderness over the tibial vessels, and 42 per cent a positive Homans' sign. The remaining 41 per cent presented chest symptoms as first indication of disease. We have come to put great reliance on the appearance of the clinical chart. Any patient who, otherwise convalescing smoothly, suddenly develops a simultaneous rise in temperature, pulse and respiration is suspected of harboring phelebitis or of having a subclinical pul'monary embolus until proven otherwise. In a small series of cases, 81 per cent of charts considered suitable for study demonstrated this positive "Allen sign." It has become evident that the picture' of deep leg vein thrombosis
.'~
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1039
is not constant. We believe that the extremes of acute thrombophlebitis on the one hand, and "bland thrombosis" of Homans or "phlebothrombosis" of Ochsner and DeBakey on the other, are expressions of an identical process. Between them are all gradations, the picture at the moment depending on the extent of involvement of vein intima in the inflammatory process. Most often the inflammatory reaction is an aseptic one, and the extent of endothelial damage is dependent on such factors as the degree of local anoxia and general alterations in the cellular and fluid constituents of the blood which tend to increase clotting proficiency. At one extreme is found diffuse swelling, tender~ ness, warmth and pain in the calf on dorsiflexion of the foot. The superficial veins over the ankle and forefoot are distended, and there is a leukocytosis, elevated sedimentation rate, and fever. Here the clot is firmly adherent to the vein wall over some distance and the likelihood of a large, death-producing embolus is slight. This type, if it does not kill by several repeated smaller emboli, enforces a prolonged hospital stay and results in a permanently impaired leg due to valvular destruction. The gradations of the bland, asymptomatic thromboses are many. Minimal swelling of the ankle, local areas of point tenderness, a sense of firmness in the tissue of the calf, slight fullness of the long saphenous vein at the ankle, associated with mild systemic reaction indicate that the clot coagulum is adherent to only a small area of vessel intima. Propagation is chiefly cephalward, and when the thrombus does free itself a long column of clot is liberated to the right heart and pulmonary arteries. THERAPY The many reports on the effectiveness of one form of treatment against another tend to be misleading. In fact; the therapeutic procedures available today should be used, depending on the case at hand, to supplement one another, rather than be considered as rival forms of therapy. Rational treatment of established thromboembolic disease may take one or more of three forms; the use of anticoagulant drugs, lumbar sympathetic procaine block, or deep vein interruption. The use of heparin and dicumarol is based primarily on the prevention of the extension of thrombosis until such time as the established coaguluf!1 becomes more strongly organized to itself and to the vessel wall, and until the patient is adequately ambulatory to insure a vigorous venous flow. Lumbar sympathetic block, on the other hand, rapidly and effectively increases venous return by interrupting reflex arterial spasm resulting from the irritating venous inflammatory process. The disappearance of leg swelling and pain is often dramatic, as the normal arteriovenous gradient is regained. Finally, deep vein interruption properly performed above the level of the thrombus precludes the
1040
GORDON A. DONALDSON
possibility of further propagation of fatal embolism. All three forms of therapy reduce the period of convalescence; mitigate the sequelae of untreated thrombosis, and lower the incidence of fatal embolism. In some instances, it is obvious all three may be employed to advantage ' on the same patient. Homans 8 was the first clinician to call attention to the feasibility of interruption of the femoral vein in the groin to prevent pulmonary infarction. The method has found many enthusiastic advocates in this country. From 1939 to January 1947 at the Massachusetts General Hospital, there have been 1692 patients who have been subjected to femoral vein interruption, representing a total of 3185 vein operations (Table 1). It is worthy of note here, that in not a single instance has TABLE 1 1587 PATIENTS Massachusetts General Hospital, 1937-1946
FEMORAL VEIN INTERRUPTION IN
Patients
1937."""""", .. 1938"" , . . . . . . . . . . . 1939"""" , ....... 1940""" , . . . . . . . . . 1941""""""", , 1942.,.,., ' ......... 1943 ... ............ . 1944 ... ............. 1945 .. ,.,.,.,., ..... 1946 ... " .... " .. , ..
Total .. " ....... , ...
1 0 8 5 51 137 165 280 392 548
-1587
Veins
Unilateral Interruption
1 0 8 15 55 211 299 554 781 1091
100,0% ,0% 100,0% 100,0% 92,1% 46.0% 19.0% 2.1% 0.8% 0.9%
--
I
Bilateral Interruption ,0% ,0% ,0% ,0% 7,9% 54.0% 81.0% 97.9% 99.2% 99.1%
3005
a patient lost life or limb as a result of the procedure. One hundred and five of these cases were operated upon in treatment of the sequelae of an old phlegmasia, and will not be discussed further in this paper. Approximately two-thirds of the group have been treated for acute thromboembolic disease, the remaining patients re:F>resenting interruptions done as a prophylactic measure (Table 2). In those patients treated for acute disease, the results have been most gratifying. In the first place, it has been noted that usually there is a relatively rapid subsidence of fever and swelling, the average length of time to normal temperature chart being four and one-haH days. It has become possible to discharge patients from the hospital at an earlier date, resulting in a great saving of needed beds. The amount of residual edema of the legs has not been disturbing and
I Ii
1041
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
unless such factors as cardiac incompetency or malnutrition are present, swelling is not permanent. Its severity and persistence are directly proportional to the extent the phlebitic process is allowed to attain before interruption is done. In the past two years, earlier diagnosis has been the rule; and with prope~ after-care in the form of elevation and supportive bandages, ankle edema has not been bothersome. In TABLE 2 INCIDENCE OF THERAPEUTIC AND PROPHYLACTIC FEMORAL VEIN INTERRUPTION IN 1587 CASES
Massachusetts General Hospital, 1937 to January 1947 Therapeutic
Prophylactic
Total
o~ 9 0
202 165 280 392 548
-~
1937-1942 ......... 1943 .............. 1944 .............. 1945 .............. 1946 .............. Total. ...........
202 150 208 214 259
-1033
0 15 72 178 289
-554
26% 45% 53%
--
1587
the occasional case eihibiting a spread of the inflammatory process in the leg vein tributaries after interruption, lumbar block with or without dicumarol has controlled both pain and swelling. In the older group, because of altered electrolytes, cardiac Incompetency, inadequate venous structures, or lymphatic sclerosis, vesper edema, dependent on osmotic and hydrostatic factors, has persisted as long as TABLE 3 1587 CASES Massachusetts General Hospital, 1937-1946 Incidence of sepsis. . . . . . . . . . . . . . . . . . . . . . . 13 0.8% Incidence of hemorrhage. . . . . . . . . . . . . . . . . 9 0.6% 26 Incidence of lymphorrhea. . . . . . . . . . . . . . . . 1.6% 2 Incidence of postphlebitic ulcer .. , . . . . . . . . 0.1% Incidence of pulmonary infarct. . . . . . . . . . . . 63 4.0% 6* Incidence of fatal embolism. . . . . . . . . . . . . . . 0.4% * Five of these cases were iIi. the therapeutic group. COMPLICATIONS OF FEMORAL VEIN INTERRUPTJON IN
six months. Two in the group of 1033 patients carry postphlebitic ulcers. It is difficult to evaluate what eHect vein interruption has had on the life history of tvese lesions in view of the work of Buxton and Coller9 on the~ use o£'rthis procedure in the treatment of the postphlebitic syn4i"ome. S,ubsequent pulmonary emboli have been encountered in 4; per cent· of cases, necessitating the use of supplemental dictnnarol. It is of interest that practically kIl of this group who
1042
GORDON A. DONALDSON
suffered subsequent emboli had been subjected to vein interruption because of a previous pulmonary infarction. Five patients in the group of 1033 therapeutic interruptions succumbed to proven subsequent emboli. In none of these earlier cases was anticoagulant therapy used as an adjunct. Four of the five had had pulmonary infarctions prior to interruption, resulting in a lowered pulmonary reserve so that lesser subsequent emboli were adequate to cause death (Table 3). It would be helpful if, in each case of early deep venous thrombosis, the morbidity or mortality could be known. This is difficult to evaluate because from different areas of the country come various statistics. In our own clinic, Miller and RogerslO prior to 1929 found seven deaths in 206 cases of thrombophlebitis. One hundred and three of these cases were of spontaneous origin, the remaining 50 per cent being postoperative. Welch and Faxon l l in a later study found the death rate to be almost identical, the ratio of fatal embolism to phlebitis being one in twenty-five. Three-fifths of their cases of deep phlebitis followed operation or trauma. In 1946, with present day therapeutic measures fairly well established, the ratio of autopsy proven fatal embolism to clinical thrombophlebitis had fallen to 1 in 130. There were two failures in 259 cases of thromboembolic disease. One hundred fifty-two cases, or essentially three-fifths of the total again, occurred following operation or trauma, and each of the fatalities occurred in this group. In these surgical cases the ratio remains 1 to 76, or a mortality of 1.3 per cent. That this figure reflects the true picture is borne out by statistics of 1945 in which there were two fatalities in 214 instances of phlebitis. Operation and trauma contributed 136 of these cases and were responsible for both deaths. Ochsner and DeBakey12 feel safe in the continued use of procaine sympathetic block. This has proved effective in their southern climate. Bauer's13 results in Sweden with the use of repeated intravenous aqueous heparin are impressive. He has reduced the incidence of fatal embolism in all cases of clinical thrombosis, of both medical and surgical origin, from 18 per cent to 1.4 per cent in the Mariestad Hospital. The experience of Barker and his co-workers14 with dicumarol and of Loewe, Rosenblatt and Hirsh15 with heparin in Pitkins' menstruum are encouraging. Evans and Boller16 report two fatalities from embolism in 127 cases of postoperative phlebitis following the combined use of both heparin and dicumarol, occasionally resorting to femoral vein interruption when indicated. With the judicious use of one or more of these agents of therapy available, it is not out of reason to suppose that fatalities in the presence of recognized thrombophlebitis or pulmonary infarction may be eliminated. At the Massachusetts General Hospital therapeutic femoral vein interruption has proved to be highly effective. In the future, with 'the adjuncts of lumbar sympathetic block and dicumarol to con-
1
1
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1043
trol the occasional case in which the acute phlebitic process spreads throughout the leg, and the more astute use of anticoagulants to control the 4 per cent of postinterruption emboli, functionally normal legs should be preserved and mortality from this disease should be elim"inated. PROPHYLAXIS
. The results in therapy noted above represent a great advance in the prevention of pulmonary embolism once a warning venous accident has occurred in the form of venous thrombosis or a benign pulmonary embolus. In spite of this progress, it remains that death may occur from sudden and unheralded pulmonary embolism. It is in an effort to eliminate such events that prophylactic measures have been elaborated. Over the past two years this basic incidence of embolism from unrecognized bland or phlebothrombosis has been attacked at the Massachusetts General Hospital in a controlled group of patients by the routine prophylactic use, as indicated, or dicumarol or femoral vein interruption. Sudden massive embolism under the age of 40 years is unusual. There have been four such cases in our clinic over the past six years, and these have occurred chiefly on the Medical Services. That bland thrombosis may develop in this younger group, partcularly as the result of trauma, is stressed by Hamilton and Angevine 17 who report ninety-nine such fatalities in soldiers under the age of 40. Certainly in civilian life it may be considered a relatively rare postoperative complication. In those patients over 40 years of age, three factors are of great importance. One is the actual age of the patient. In our series from 1940 to 1947, the highest incidence of sudden massive embolism occurred in the seventh and eighth decades, each contributing twenty-one deaths. These age groups compare with those reported by Evans and Boller16 who found over a similar six-year period a total of fifty-two fatalities, seventeen of these occurring in the sixth and fourteen in the seventh decades of life. The nature of the primary illness is also of significance. Debilitated patients, those suffering from cancer, intestinal obstruction and general old age are prone to develop bland thrombi in their leg veins as the result of venous stasis. Finally, the initial operative procedure must be considered. VeaP8 has demonstrated convincingly the surprising frequency of fatal embolism following low thigh amputation. Here, particularly, the entire length of the superficial femoral vein lies quiescent, as a nidus for thrombus formation. By the simple expedient of prophylactic vein interruption, Veal has been able to lower the mortality in comparable groups of patients from 42.1 per cent to 11.5 per cent. Patients with fractures about the hip region offer opportunity of a similar proportion. Because of medicolegal intervention autopsy proof of embolism is often lacking, but the clinical
1044
GORDON A. DONALDSON
picture is no less graphic. In our clinic we have grown to respect and fear the group of patients with cancer of the gastrointestinal tract, esophagus, stomach, colon and rectum. Prostatic surgery carries a relatively high risk, and only less so small bowel obstruction, pelvic tumors, breast cancer and biliary tract disease, In an attempt to formulate a program which would be both effective and practically applicable to the hospital laboratory, a control study was carried out at the Massachusetts General Hospital. The plan. entailed combining the use of prophylactic dicumaroland prophylactic vein interruption, and the study was continued over the years 1945 and 1946. The two identical Surgical Services in the General Hospital itself made ideal controls. The East Surgical Service under Arthur W. Allen sponsored the experiment, and the West Surgical Service under E. D. Churchill and L. S. McKittrick cooperated as the control. Following major surgery on the East Service, dicumarol was administered prophylactically to the middle age group, aged 40 to 65, and those older were routinely subjected to prophylactic femoral vein interruption. Reported subarachnoid, gastrointestinal, and renal accidents subsequent to the use of anticoagulants in the arteriosclerotic, elderly people, particularly in the presence of hypertension, led us to prefer vein interruption as less dangerous. The age limit of 65 was somewhat flexible. In instances where the incidence of phlebothrombosis was known to be high, as after thigh amputation and resections of the rectum or stomach, femoral vein interruption was preferred to the use of dicumarol in some patients younger than 65. Except for an occasional unavoidable prophylactic interruption, the West Surgical Service obligingly served as a control, reservirig the therapeutic procedure for thosfil patients who developed recognizable thromboembolic phenomena. That these two Service groups, were admirably suited for comparison can be seen from the admission data in Table 5. That dicumarol is a specific liver poison cannot beoveremphasiied. It probably interferes with the synthesis of fibrinogen as well as prothrombin, and accidents following its earlier, inadequately controlled use are reported. 19 Over the past year, however, added experience by cardiologists as well as surgeons has increased respect for its dangers and confidence in its use. Future adverse reports should be rare. In our clinic, we have been conservative in that only 200 mg. has been given as an initial dose, and this has been repeated only if a satisfactory response was not evident after forty-eight hours. In all cases initial prothrombin levels have been determined before administration of the drug, and subsequent blood values have been measured every fortyeight hours. Allowing for the known hypoprothrombinemia immediately following anesthesia and operation,20 200 mg. has been withheld until the first postoperative day. The maximum rise in prothrombin time occurs three to four days thereafter. Those patients requiring a longer
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1045
period of strict bed rest are given an additional 200 mg. before the expected fall in prothrombin time has resulted. As might be expected, depending on liver competency, the prothrombin response to dicumarol has been markedly variable. In an occasional case, the increase in prothrombin time after only 200 mg. has been frightening; and we have been tempered in our earlier enthusiasm to increase the size and frequency of dosage. It is a good general rule, that when the prothrombin time response is twice the "normal reading," the prothrombin content of the blood is reduced to 30 per cent of normal and serious bleeding may ensue. 21 Certain individuals, on the other hand, respond poorly to this dosage. Rarely, however, has phlebitis developed in such cases; and it is our distinct TABLE 4 CONTRAINDICATIONS TO DICUMAROL THERAPY
Of 1299 patients between the ages of 40 and 65 who were admitted to the East Surgical Service of the Massachusetts General Hospital from January 1, 1945 to January 1, 1947, 223 (17.2 per CIlnt) received dicumarol. In the remaining 1076 patients, dicumarol 'ras contraindicated for the following reasons: Hospitalized for minor procedures AdInission for study, no operation Liver disease Hypertension Cht'.st cases Plasma prothrombin found above 25 seconds Hyperthyroidism . Excessive bleeding at operation Diabetes Arthritics taking aspirin.
impression that changes in blood constituents are eHected which are not detected by our present admittedly crude laboratory methods. We have had no evidence of toxicity and no deaths from hemorrhage. One patient in the group bled from an ileotransverse colostomy suture line and received a transfusion. Other bleeding episodes have been trivial. In the event of an unexpected sensitivity to the drug, transfusion or massive doses of vitamin K will lower the prothrombin time in a matter of hours. The results in the middle age group treated with dicumatol as outlined above have been striking, both in point of lowering the incidence of thrombophlebitis and preventing phlebothrombosis and massive pulmonary embolism. During the years 1945 and 1946 in 1299 admissions in this age group eligible for dicumarol there have been nine instances of thrombophlebitis as against an incidence of forty-five cases in the control series. Only four of these nine actually received dicumarol, the remaining five presenting one or more contraindications to its use. In this same dicumarol-h'eated group there was no instance of phlebothrombosis resulting in fatal embolism. The con-
1046
GORDON A. DONALDSON
trol group, on the other hand, contributed three such fatalities in the same period. In the older patients, because it was felt that superficial femoral vein interruption held fewer hazards than the use of dicumarol, all patients subjected to major surgery were prophylactically ligated. This procedure was done in some cases, particularly those in which the patient had been bedridden at home or who had a prolonged course of preoperative study, prior to major surgery. In others it was feasible to interrupt the veins at the time of operation, and in the majority "prophylaxis" was accomplished within forty-eight hours after operation. Actually, due to the temporary venous congestion in TABLE 5 INCIDENCE OF POSTOPERATIVE PHLEBITIS AND FATAl. EMBOLISM IN THE PROPHYLACTIC-TREATED AND THE CONTROL GROUPS
Magsachusetts General Hospital. 1945-1946
III East Service I II (DicumaroI40-64; 1-39 yrs. 40-64yrs. 65+ yrs. Total Vein Interrup0 223 tion 65+) Prophylactic dicumarol. 0 223 181 Prophylactic interruption 1 35 217 9* 26 Postoperative phlebItis .. 9 8t 0 Fatal embolism ........ 0 0 0 497 Admissions ............. 1136 1299 West Service (Control) 0 Prophylactic dicumarol. 0 0 0 .') 14 19 Prophylactic interruption 0 45 17 Postoperative phlebitis .. 71 9 0 3 6 3 Fatal embolsim ........ 1280 453 Admissions ............. 1163
* Five of the 9 did not receive dicumarol because of "contraindications"; 3 of the remaining 4 failed to obtain a satisfactory rise in prothrombin time, and should have received additional dicumarol. t Four of the 8 developed phlebitis, requiring vein interruption, before prophylactic nterruption had been done.
the pelvis following superficial femoral vein interruption, it is advisable to postpone the procedure until forty-eight hours have elapsed following a Wertheim or Miles operation. Although most fatal emboli occur approximately ten days after operation, we feel uncomfo~table if more than forty-eight hours elapse, particularly in individuals who have been bedridden preoperatively. One hundred eighty-one such prophylactic interruptions have been done on this admittedly vulnerable group without a single death. Again in the control group, three patients succumbed from a proven embolus (Table 5). These measures have not been limited to the ward patients on the East Surgical Service. Although all of the members of the staf¥are not convinced of the value of prophylaxis, many of the orthope~ic,
,r.
,1 ~l
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
1047
genitourinary, gynecologic and private service patients have been treated. As of January 1, 1947, there had been a total of 247 patients treated with dicumarol and 554 prophylactic femoral vein interruptions. The complications encountered following dicumarol in this small group is evident in Table 6. TABLE 6 247 PATIENTS Massachusetts General Hospital, 1945-1946 Minor bleeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 9 Major bleeding·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 Phlebitist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5 Pulmonary infarctt. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 7 Fatal pulmonary embolus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 0 • Requiring vitamin K and transfusion. t Requiring femoral vein interruption. COMPLICATIONS OF PROPHYLACTIC DICUMAROL IN
The vein interrupted in each instance has been the superficial femoral. Of the 554 patients undergoing this procedure, fifteen have developed clinical phlebitis in one leg or the other, a,s measured by findings other than swelling; namely, pain, tenderness, dorsiflexion discomfort, or a general systemic response. In this group of 554 there has been one postinterruption fatal embolus, proven at autopsy. This patient was an obese 63 year old woman with a large ventral hernia. Two days after hernioplasty, vein interruption was done. Thirteen days later, a left middle lobe infarct was demonstrated by x-ray. Sudden death ensued two days thereafter. This misfortune occurred in 1945, and since then we have adopted two measures which would have been of value. The superficial femoral vein should be tied with care, flush with the profunda so as to leave no nidus for thrombus formation. There was a 3 cm. nidus in the above case. Secondly, today she would be given heparin and dicumarol, following her initial warning pulmonary infarct. We feel that this patient demonstrates further that given a normal pulmonary circulation, the short profunda and common femoral vessel thrombi cause death by repeated insults to the lung, rather than harboring a single thrombus large enough to produce a sudden fatal result. The value of prophylactic interruption becomes more tangible when cases so treated are compared with a like group drawn in sequence from our hospital files (Table 7). The records have been consecutive. Age, sex, disease, operative procedure, and service in the hospital, whether public or private, have been matched as accurately as possible. Under these limitations it has been necessary to search as far back as 1939 and 1941 respectively for comparable hip fractures and leg amputations. Prophylactic vein interruptions were practically universal in both these groups from 1943 to the present. The remain-
lO48
GORDON A. DONALDSON
ing series were in addition matched year by year. The findings arc corroborated by a group of amputations collected by Veal, 18 and support a similar, overlapping series reported earlier.22 TABLE 7 COMPARATIVE INCIDENCE OF POSTOPERATIVE THROMBOSIS AND EMBOLISM
Older Age Group of Patients
I ~U:i:f 1 - - - - - , - - - - 1 - - - - - ; - - - With Prophylactic Vein Interruption
Without Prophylactic Vein Interruption
.
Each Group
Fractures hip region .................. .
~:ict;,=ti~~·... ::::::·:::.:
:::::: Colon operations ..................... .
Small bowel obstructiop. ............... . Cbolecystectomay ................... .. Resection rectum ••.................... Hernioplasty ........................ . Pelvic Burgery ....................... . Prostatectomy ....................... . Radical mastectomy. . . . . . . . . . . . . . . .. Heart disease .••••....................
A~'1=~~;,:·.::::::::::::::: ... :::
114 57 59
62
9 38 32 28 26 '17 18 21 10 8 8 6 6 4
Phlebitis
Fatal Embolus
Phlebitis
Fatal Embolus
3
o o
20 2
10*
o
2 I I
o
2 I
o o o o 1 o o o
o o o o o 1 o o o o o o
7 4 3 1
5 5 1
5
1 1 1
7
3
1
2 2
I
o o
1
4 1
o o o
o
1
o o o
o o
o 1 o 2
o
Mr:.:u~:..~:.·.::::::::::::::::::::: :
2
16
o
o
o 1
o o o
Total............................. .
554
15
63
30
Study cases .......................... . E80pbagectomy ................ . Common duct exploration ............. . Resection pancress ................... . Leg abscess, leg fracture. neck dissection. each .............................. . Lung abscess. peritonitis. popliteal aueu-
o
3
2
o
II (I
* Because of medicolegal jurisdiction. autopsy was not poBSible i~l all deaths following hip t~actures. TECHNIC OF OPERATIONS
'"
The operation of femoral vein interruption should not be considered too lightly. Although we have had no serious complications following the procedure in our own group, instances of loss of an extremity are reported in the literature.23 • 24 In the poorly nourished, thin individual the technical procedure is relatively simple, requiring perhaps thirty or forty minutes. In the short, stout patient, vein interruption may be time-consuming and hazardous. Venous anomalies in the area are frequent, and preliminary acquaintance with the region should be had by precept or by autopsy experience, before undertaking the procedure. Although reported elsewhere,24 certain details of the technic are worthy of emphasis: The patient should lie in 'slightly reverse· Trendelenburg position to give increased local positive venous pressure. Infarcts during the manipulation of the vein have not occurred, but- this- precautionary
"I
VENOUS THROMBOSIS AND PULMONARY EMBOLISM
..
I
1049
measure is employed. One per cent procaine anesthesia is adequate. The skin incision is strictly vertical, parallel with major blood and lymph vessels, from the groin crease distally for a distance of 8 to 10 cm, The pulsating femoral artery in the groin crease gives an excellent guide, regardless of obesity. Subsequent incisions are carefully. maintained i~ a vertical dissection, thus making it possible to displace the main femoral lymphatic vessels and nodes medially, without entering them. Transverse and oblique incisions are to be avoided as there ineVitably is injury to lymphatic structures, resulting in postoperative lymph edema of the leg and lymph drainage from the wound'. The medial margin of the sartorius muscle next makes an excellent guide to the underlying femoral sheath. The entire sheath is carefully retracted laterally without baring the artery itself, thus exposing the vein which lies more posteriorly than medially -at this level. Before grasping the vein, the fossa through which the profunda escapes is first identified. Unnecessary injury to the common femoral vessel is thus avoided. Several landmarks are helpful. In the normal subject, the bifurcation of the common femoral should lie in the middle of the wound, if properly made. In most indiivduals a bulge can be detected just below this level, indicating the site of a valve in the superficial vein. This valve lies within 1 to 2 cm. of the actual bifurcation, and is almost constantly present. Finally with· careful blunt scissors dissection, a definite fossa will be found posteriorly through which the profunda femoris runs in a slightly medial direction. Above and lateral to the vein, the profunda artery can often be felt running parallel to it. Exposure of the upper 2 cm. of vein to be interrupted is _sufficient. In spite _of the presence of one or more heavy muscular branches entering directly posteriorly, it is possible with the aid of a right angle clamp to pass No. 00 chromic guy ligatures about the superficial vein, between the levels of profunda femoris and posterior muscular branches. A transverse incision in the anterior half of the vein is made. Any clot present may be removed with forceps and caref1.dly applied suction, and it is always desirable to remove as much thrombus from above and below as possible. Thrombi which have been present for a day or two' at this level, as foreshadowed by early swelling of the thigh, are often difficult to remove completely. Following aspiration, the vein is completely divided between clamps, and the proximalligature is carefully placed flush with the entrance of the profunda branch. For safety sake, the cut vein ends are further secured with stitch ligat~es dist~l to the original ties. _. In ~closure of the wound it is important to make an accurate three layer" approximation of deep fascia, superficial fascia and skin. Escape of soine lymph into the wound is inevitable, and lymph cyst or transient lymphorrhea sometimes occurs. Care must be exercised not to
1050
GORDON A. DONALDSON
include in interrupted ligatures the femoral nerve which lies deep to the deep fascia, and the medial or anterior femoral cutaneous nerves.~ lying deep to the superficial fascia. After a change of instruments and gloves, a similar procedure is carried out on the other leg. As· the diagnosis of thrombophlebitis in the last year or two has been made earlier, fewer thrombi have been encountered at operation. If the process has extended to involve the profunda as determined by palpation of the vein, a similar guy ligature technic is used to explore this vessel. In those patients on whom it is not possible to establish free retrograde bleeding through the common femoral, we have come to feel that supplemental anticoagulant therapy in the form of heparin and dicumarol should be used until the patient is fully ambulatory. Intervention at the iliac or inferior vena caval level in comparison is unnecessarily hazardous and carries a disturbing morbidity and a forbidding mortality.25 Vena cava ligation in our clinic is now reserved for patients presenting septic emboli, the source of which is, or has extended, above the femoral level.
REFERENCES 1. Davis, Lincoln: Quoted by A. W. Allen in "Vascular Disease," Chapter VI, Nelson Loose-leaf Medicine, 4:531-:.580, 1931. 2. Allen, A. W.,Linton, R. R. and Donaldson, G. A.: Thrombosis and Embolism. Ann. Surg., 118:728, 1943. 3. Trousseau, A., cited by Sproul, E. E.: Carcinoma and Venous Thrombosis: . The Frequency of Association of Carcinoma in the Body or Tail of the Pancreas with Multiple Venous Thrombosis. Am. J. Cancer, 84:566-585, 1938 4. Neumann, R: Ursprungszentren und Entwicklungsformen der Bein-Thrombose. Arch. Path. Anat., 801:708-735, 1938. 5. Hunter, W. C., Sneeden, V. D., Robertson, T. D. and Snyder, G. A. C.: Thrombosis of Deep Veins of the Leg: Its Clinical Significance as Exernplilled in 351 Autopsies. Arch. Int. Med., 68:1-17, 1941. 6. Hunter, W. C., Krygier, J. J., Kennedy, J. C. and Sneeden, V. D.: Etiology and Prevention of Thrombosis of Deep Leg Veins: Study of 400 Cases. Surgery, 17:178-190, 1945. 7. Simpson, K. I.: Shelter Deaths from Pulmonary Embolism. Lancet, 2:744, 1940. 8. Homans, John: Thrombosis of the Deep Veins of the Lower Leg Causing Pulmonary Embolism. New England J. Med., 211:993-997, 1934. 9. Buxton, R. W. and Coller, F. A.: Surgical Treatment of Long Standing Deep Phlebitis of the Leg: Supplementary Report. Surgery, 18:663-669, 1945. 10. Miller, R. H. and Rogers, H.: Postoperative Embolism and Phlebitis. J.A.M.A., 98:1452, 1929. 1l. Welch, C. E. and Faxon, H. H.: Thrombophlebitis and Pulmonary Embolism. J.A.M.A., 117:1502-1508, 1941. 12. Ochsner, A. and DeBakey, M.: Therapeutic Considerations of Thrombophlebitis and Phlebothrombosis. New England J. Med., 225:207-227, 1941. 13. Bauer, G.: Heparin Therapy in Acute Deep Venous Thrombosis. J.A.M.A., 181:196-203, 1946. 14. Barker, N. W., Croner, H. E., Hum, M. and Waugh, J. M.: Use of Dicumarol
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VENOUS TlffiOMBOti18 AND PULMONARY EMBOLISM
15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25.
1051
in Prevention of Postoperative Thrombosis and Embolism with Special Reference to Dosage and Safe Administration. Surgery, 17:207-217, 1945. Loewe, L., Rosenblatt, P. and Hirsh, E.: Venous Thrombo-embolic Disease. J.A.M.A., 130:386-393, 1946. Evans, J. A. and Boller, R. J.: The Prevention of Postoperative Pulmonary Embolism. New England J. Med., 236:392-397, 1947. Hamilton, T. R. and Angevine, D. M.: Fatal Pulmonary Embolism in One Hundred Battle Casualties. The Military Surgeon, 99:456-458, 1946. Veal, J. R.: The Prevention of Pulmonary Complications Following Thigh Amputations by High Ligation of the Femoral Vein. J.A.M.A., 121:240-244, 1943. Shevlin, E. L. and Lederer, M.: Uncontrollable Hemorrhage after Dicumarol Therapy, with Autopsy Findings. Ann. Int. Med., 21:332-342, 1944. Richards, R. K.: Influence of Fever upon the Action of Dicumarol. Science, 97:313-314, 1943. Stewart, John D.: Personal communication. Allen, A. W.: Interruption of the Deep Veins of the Lower Extremities in the Prevention and Treatment of Thrombosis and Embolism. Surg., Gyn. & Obst. (In press). Dennis, C.: Disaster Following Femoral Vein Ligation for Thrombophlebitis: Relief by Fasciotomy: Clinical Case of Renal Impairment Following Crush Injury. SUrgery, 17:264-269, 1945. Allen, A. W., Linton, R. R. and Donaldson, G. A.: Venous Thrombosis and Pulmonary Embolism. J.A.M.A., 1947. (In press.) Read before the Surgical Section, A.M.A., San Francisco, July 3, 1946. Moses, W. R.: Ligation of the Inferior Vena Cava or Iliac Veins: a Report of Thirty-six Operations. New England J. Med., 235:1-7, 1946.