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Postoperative pulmonary embolism
Postoperative Pulmonary Embolism A Prospective Study Utilizing Low Dose Heparin
Edward A. Abernethy, MD, Oklahoma City, Oklahoma James M. Hartsuck, MD, Oklahoma City, Oklahoma
Although pulmonary embolism is one of the most common causes of death in postoperative patients, the high incidence of diagnostic error and the large number of patients required to provide statistical significance have limited our abilities to evaluate prophylactic measures of thromboembolism. Modern diagnostic tests including peripheral 125I fibrinogen scanning, impedence phlebography, venography, pulmonary scanning, and pulmonary angiography have provided the means necessary to evaluate such prophylactic therapies. In a recent clinical study we have shown that the incidence of peripheral thrombosis by fibrinogen scanning is 17 per cent and have confirmed the presence of such thrombi by venography in 79 per cent of these postoperative patients. Moreover, although abnormal pulmonary scans were obtained in over half of these postoperative patients, follow-up scanning indicated that only in the absence of chronic lung disease could significant perfusion defects be expected to improve with follow-up scanning and therefore be considered to be consistent with pulmonary embolism. With this background a prospective study was designed to evaluate the effectiveness of low dose prophylactic heparin in the prevention of peripheral venous thrombosis and the effect of low dose heparin on pulmonary emboli in the postoperative patient.
From the Department of Surgery, University of Okfahoma Health Scfences Center, Oklahoma City, Oklahoma. This investigation was supported in part by grants from the Veterans Administration Hospital. University of Oklahoma Heakh Sciences Center, and Abbott Laboratories. Reprint requests should be addressed to Dr James hf. Hartsuck, Deoartment of Suroerv. P.O. Box 26901. Okfahoma Ckv. Oklahoma 73190. r- Presented at”tf?e’Twenty-Sixth Annual Meeting of the Southwestern Surgical Congress, Monterey, California, April 29 to May 2. 1974.
vofunle 128, Decentbar 1974
Material and Methods One hundred twenty-five patients were evaluated after a major surgical procedure. Patients scheduled for thyroid surgery and smaller operations, such as herniorrhaphy, were excluded because of the low incidence of peripheral thrombosis demonstrated in previous studies. Also, patients with surgery of the extremities and precordial regions were excluded because of known accumulation of fibrinogen in the wound which would interfere with the fibrinogen scanning technic. After acceptance by the patient of the fibrinogen scanning procedure, the patients were randomized prospectively into two groups; one received heparin and the other served es a control. Heparin, 5,000 units subcutaneously, was given two hours prior to surgery and then every twelve hours beginning twenty-four hours postoperatively. It was continued for one week postoperatively or until the patient was fully ambulatory. One hundred microcuries of labeled fibrinogen with a specific activity of 100 MC/ mg were given intravenously on the day preceding surgery. Both extremities were scanned one hour after surgery and daily for the first postoperative week. The fibrinogen values were expressed as a percentage of heart count, and the scans were considered positive when an elevation of more than 20 per cent occurred at a given point and was sustained on two consecutive days. Preparation of the fibrinogen, administration of iodide for thyroid protection, and details of the scanning procedure were the same as those previously reported [I]. Patients with positive fibrinogen scans had bilateral lower extremity venography. In addition to fibrinogen scanning all patients were followed up with serial venous impedence phlebography and 112 of the patients had a standard pulmonary scan with 1311 macroaggregated serum albumin near the end of the first postoperative week. In addition, each patient underwent daily assessment with measurements of the calf made by a trained person to determine clinical evidence of thrombophlebitis.
739
Abernethy and Hartsuck
TABLE I
Positive 1261 Fibrinogen Scans Control Group (Sixty-Two Venog-
Patient
Age (yr)
Surgery
why
Positive Scan
1
56
Splenectomy
(-)
2 day
2
70
Prostatectomy
(-)
3
48
Radical
(+)
ne-
Heparin Group (Sixty-Three
Patients) Clinical Finding
Patient
Age (yr)
Negative
1
76
2 day
Negative
2
79
4 day
Positive
3 4
phrectomy
Venog-
(+)
1 day
Negative
(f)
0,l
Negative
63
Abdominal anew rysmectomy Excision of bladder tumor Splenectomy
(+)
0
Negative
52
Abdominal
0
1
Positive (edema)
20 5% 15 %o I
1QZ
5
0
El
I WARIN
HEPARIN
Figure 1. The incidence of probable pulmonary emboli comparing the control group and the heparin-treated group.
200
I-
175 -
150 -
125 -
loo-
% % 75-
Figure 2. The incidence of deep venous thrombosis by 1251 fibrinogen scanning in the previous study group and the present study group.
740
day
anew
Results
25
0
Clinical Finding
rwny
(edema)
30
=
Positive Scan
Surgery
rysmectomy
!I
Patients)
Of the 125 patients studied with fibrinogen scanning, sixty-three received low dose heparin and sixty-two served as the control group. Four of the patients treated with low dose heparin had evidence of peripheral thrombosis by fibrinogen scanning and three of the control group had positive scans. Venography confirmed the presence of clots in four of six patients with positive fibrinogen scans, and the seventh patient demonstrated clinical findings of phlebitis. Six of the seven positive scans appeared within the first two days postoperatively and the seventh on the third postoperative day. Three of six patients with positive fibrinogen scans were found to have abnormal lung scans consistent with pulmonary emboli. (Table I.) One hundred and twelve patients underwent postoperative pulmonary scanning. Sixty-five of these patients demonstrated abnormalities in pulmonary perfusion. Analysis of the patients without evidence of chronic obstructive pulmonary disease revealed that of twenty-six patients who were not treated with low dose heparin, five were found to have perfusion defects consistent with pulmonary emboli. Twenty-one patients without chronic pulmonary disease received low dose heparin and none of these demonstrated perfusion defects consistent with pulmonary emboli (p < 0.04 such that there is no difference in a chi square test). (Figure 1.) The incidence of peripheral thrombosis by fibrinogen scanning in the sixty-two control patients was 4.8 per cent. This represents a significant reduction from the previous series of 200 patients in which thirty-four patients [I ] were found to have peripheral thrombi. (Figure 2.) This finding of a dramatic reduction in the incidence of peripheral thrombi was unexpected. Although no effort was made to change the management of the
The American Journal ol Surgery
Postoperative Pulmonary Embolism
patients, analysis of these patients reveals significant differences in postoperative patient care, probably as a result of increased awareness of the frequency of peripheral thrombosis diagnosed by the fibrinogen technic. Utilization of elastic stockings has increased from 24.7 to 45.5 per cent. Earlier ambulation and avoidance of sitting have become routine. The early application of elastic support has been emphasized. The technic of fibrinogen scanning has remained constant, the specific activity of the labeled fibrinogen has been monitored, and the wound activity and pattern of accumulation have remained unchanged. Moreover, superficial phlebitis associated with intravenous therapy has invariably demonstrated high fibrinogen activity. There have been no instances of clinical phlebitis in the absence of positive fibrinogen scans. There were no instances in which surgical bleeding appeared to be a complication of the low dose heparin technic. No complications associated with the fibrinogen scanning or low dose heparin regimen were recognized. Comments
Low dose subcutaneous heparin has been advocated as a prophylactic measure to inhibit the incidence of peripheral thrombosis in postoperative patients. The rationale for this therapy is based on the ability of heparin to activate a naturally occurring plasma inhibitor to activated factor X [2]. The heparin must be given preoperatively. Various regimens involving postoperative heparin beginning twelve to twenty-four hours postoperatively and repeated at eight or twelve hour intervals have been advocated. Although surgical bleeding has not been significantly increased with low dose heparin, the earlier and more frequent regimen of low dose heparin administration may be associated with increased bleeding [3]. Kakkar and others [4-d] have reported significant reduction in the incidence of deep venous thrombosis diagnosed by the fibrinogen scanning technic. Other studies have failed to demonstrate a clear-cut value for the low dose heparin especially in high risk patients such as those who have undergone prostatectomy [5] or hip surgery [9]. We were unable to demonstrate a reduction in the incidence of venous thrombosis in our patients by the fibrinogen scanning technic. A dramatic reduction in the incidence of peripheral thrombosis in the control group, presumably as a result of widespread adoption of prophylactic elastic support, earlier ambu-
volume 128,December1974
lation, and avoidance of sitting, was far more striking than the influence of low dose heparin. Also, this finding has been observed in two other studies which have shown that older patients undergoing major surgery were protected from deep vein thrombosis by a combination of physical measures [l&11 1.
However, the incidence of probable pulmonary emboli diagnosed by pulmonary scanning in patients receiving prophylactic low dose heparin did appear to be significantly reduced. None of the patients without chronic lung disease who received low dose heparin demonstrated perfusion defects consistent with pulmonary emboli whereas 19 per cent of the control group demonstrated significant perfusion defects in the absence of chronic pulmonary disease. This incidence of probable pulmonary emboli in the control group is similar to that observed in our previous study which correlated peripheral 1251 fibrinogen scanning with pulmonary scanning and with an incidence of postoperative pulmonary emboli of 14 per cent determined by a comparison of pre- and postoperative lung scans [12]. Our previous studies have indicated that an abnormal lung scan in the presence of chronic obstructive pulmonary disease did not necessarily indicate pulmonary emboli. Conversely, significant perfusion defects in the absence of chronic lung disease did resolve with follow-up scanning and, in a limited series of patients, the presence of these defects was confirmed by pulmonary angiography [I 1. It must be emphasized that these abnormalities in pulmonary scanning were asymptomatic and were not followed by clinically significant pulmonary emboli in untreated patients. Thus, although the incidence of peripheral deep venous thrombosis was significantly reduced by general prophylactic measures, the incidence of probable pulmonary emboli, diagnosed by pulmonary scanning, remained unchanged. Our inability to demonstrate further reduction in the frequency of peripheral thrombosis by prophylactic low dose heparin may be of limited significance in view of the low incidence of peripheral thrombosis in these patients. Low dose heparin did appear to reduce these pulmonary emboli without significant complications. Although other investigators have indicated that the incidence of deep venous thrombosis can be reduced significantly by low dose heparin, there is little evidence that the frequency of pulmonary emboli was altered. This demonstration of an apparent reduction in pulmonary emboli by low dose heparin necessitates continued clinical evaluation.
741
Abernethy and Hartsuck
Summary
A prospective study of pulmonary embolism utilizing low dose heparin in 125 postoperative patients failed to demonstrate a significant reduction in deep venous thrombosis diagnosed by fibrinogen scanning. However, the incidence of probable pulmonary emboli diagnosed by pulmonary scanning in the absence of chronic lung disease appeared to be reduced by the low dose heparin regimen. Acknowledgment: We wish to thank Dr Lazar Greenfield for his support and assistance and Dr Carl W. Smith for his interpretation of the pulmonary scans. The technical support of Rene Jacocks was appreciated.
4.
5.
6.
7.
8.
9.
References 10. 1. Hat-tsuck JM, Greenfield W: Postoperative thromboembolism: A clinical study with 125l fibrinogen and pulmonary scaring. Arch Surg 107: 733, 1973. 2. Yin ET, Wessler S, Stall PJ: Biological properties of the naturally occurring plasma inhibitor to activated factor X. J Biol Chem 246: 3703, 1971. 3. Gallus AS, Hirsh J. Tuttle RJ, Trebilcock R, O’Brien SE, Carroll JJ, Minden JH, Hudecki SM: Small subcutaneous
742
11.
12.
doses of heparin in prevention of venous thrombosis. N Engl J A&d 288: 545.1973. Kakkar VV, Spindler J, Flute PT, Corrigan T, Fossard DP, Crellin RQ, Wessler S, Yin ET: Efficacy of low doses of heparin in prevention Of deep-vein thrombosis after major surgery. Lancer 2: 101, 1972. Williams HT: Prevention of postoperative deep-vein thrombosis with perioperative subcutaneous heparin. Lancer 2: 950, 1972. Kakkar VV, Nicolaides AN, Field ES, Flute PT. Wessler S, Yin ET: Low doses of heparin in prevention of deep vein thrombosis. Lancer 2: 669. 1971. Gordon-Smith IC, LeQuesne LP, Grundy DJ, Newcombe JF. Branmle FJ: Controlled trial of two regimens of subcutaneous heparin in prevention of postoperative deep-vein thrombosis. Lancet 1: 1133, 1972. Nicolaides AN, Desae S, Douglas JN, Fourides G. DuPont PA, Lewis JD, Dodsworth H, Luck RJ, Jamieson CW: Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis after major surgery. Lancet 2: 890, 1972. Evarts CM, Alfiii RJ: Thromboembolism after total hip reconstruction. JAMA 225: 515, 1973. Flanc C, Kakkar VV, Clarke MB: Postoperative deep-vein thrombosis: effect of intensive prophylaxis. Lancer 1: 477, 1969. Tsapogas MJ. Miller R, Peabody RA, Eckert CL: Detection of postoperative venous thrombosis and effectiveness of prophylactic measures. Arch Surg 101: 149, 1970. Allgood RJ, Cook JH, Weedn RJ, Speed HK, Whtcomb WH, Greenfield W: Prospective analysis of pulmonary embolism in the postoperative patient. Surgery 68: 116. 1970.
The American Journal 01 Surgery
Edward A. Abernethy, MD, Oklahoma City, Oklahoma James M. Hartsuck, MD, Oklahoma City, Oklahoma
Although pulmonary embolism is one of the most common causes of death in postoperative patients, the high incidence of diagnostic error and the large number of patients required to provide statistical significance have limited our abilities to evaluate prophylactic measures of thromboembolism. Modern diagnostic tests including peripheral 125I fibrinogen scanning, impedence phlebography, venography, pulmonary scanning, and pulmonary angiography have provided the means necessary to evaluate such prophylactic therapies. In a recent clinical study we have shown that the incidence of peripheral thrombosis by fibrinogen scanning is 17 per cent and have confirmed the presence of such thrombi by venography in 79 per cent of these postoperative patients. Moreover, although abnormal pulmonary scans were obtained in over half of these postoperative patients, follow-up scanning indicated that only in the absence of chronic lung disease could significant perfusion defects be expected to improve with follow-up scanning and therefore be considered to be consistent with pulmonary embolism. With this background a prospective study was designed to evaluate the effectiveness of low dose prophylactic heparin in the prevention of peripheral venous thrombosis and the effect of low dose heparin on pulmonary emboli in the postoperative patient.
From the Department of Surgery, University of Okfahoma Health Scfences Center, Oklahoma City, Oklahoma. This investigation was supported in part by grants from the Veterans Administration Hospital. University of Oklahoma Heakh Sciences Center, and Abbott Laboratories. Reprint requests should be addressed to Dr James hf. Hartsuck, Deoartment of Suroerv. P.O. Box 26901. Okfahoma Ckv. Oklahoma 73190. r- Presented at”tf?e’Twenty-Sixth Annual Meeting of the Southwestern Surgical Congress, Monterey, California, April 29 to May 2. 1974.
vofunle 128, Decentbar 1974
Material and Methods One hundred twenty-five patients were evaluated after a major surgical procedure. Patients scheduled for thyroid surgery and smaller operations, such as herniorrhaphy, were excluded because of the low incidence of peripheral thrombosis demonstrated in previous studies. Also, patients with surgery of the extremities and precordial regions were excluded because of known accumulation of fibrinogen in the wound which would interfere with the fibrinogen scanning technic. After acceptance by the patient of the fibrinogen scanning procedure, the patients were randomized prospectively into two groups; one received heparin and the other served es a control. Heparin, 5,000 units subcutaneously, was given two hours prior to surgery and then every twelve hours beginning twenty-four hours postoperatively. It was continued for one week postoperatively or until the patient was fully ambulatory. One hundred microcuries of labeled fibrinogen with a specific activity of 100 MC/ mg were given intravenously on the day preceding surgery. Both extremities were scanned one hour after surgery and daily for the first postoperative week. The fibrinogen values were expressed as a percentage of heart count, and the scans were considered positive when an elevation of more than 20 per cent occurred at a given point and was sustained on two consecutive days. Preparation of the fibrinogen, administration of iodide for thyroid protection, and details of the scanning procedure were the same as those previously reported [I]. Patients with positive fibrinogen scans had bilateral lower extremity venography. In addition to fibrinogen scanning all patients were followed up with serial venous impedence phlebography and 112 of the patients had a standard pulmonary scan with 1311 macroaggregated serum albumin near the end of the first postoperative week. In addition, each patient underwent daily assessment with measurements of the calf made by a trained person to determine clinical evidence of thrombophlebitis.
739
Abernethy and Hartsuck
TABLE I
Positive 1261 Fibrinogen Scans Control Group (Sixty-Two Venog-
Patient
Age (yr)
Surgery
why
Positive Scan
1
56
Splenectomy
(-)
2 day
2
70
Prostatectomy
(-)
3
48
Radical
(+)
ne-
Heparin Group (Sixty-Three
Patients) Clinical Finding
Patient
Age (yr)
Negative
1
76
2 day
Negative
2
79
4 day
Positive
3 4
phrectomy
Venog-
(+)
1 day
Negative
(f)
0,l
Negative
63
Abdominal anew rysmectomy Excision of bladder tumor Splenectomy
(+)
0
Negative
52
Abdominal
0
1
Positive (edema)
20 5% 15 %o I
1QZ
5
0
El
I WARIN
HEPARIN
Figure 1. The incidence of probable pulmonary emboli comparing the control group and the heparin-treated group.
200
I-
175 -
150 -
125 -
loo-
% % 75-
Figure 2. The incidence of deep venous thrombosis by 1251 fibrinogen scanning in the previous study group and the present study group.
740
day
anew
Results
25
0
Clinical Finding
rwny
(edema)
30
=
Positive Scan
Surgery
rysmectomy
!I
Patients)
Of the 125 patients studied with fibrinogen scanning, sixty-three received low dose heparin and sixty-two served as the control group. Four of the patients treated with low dose heparin had evidence of peripheral thrombosis by fibrinogen scanning and three of the control group had positive scans. Venography confirmed the presence of clots in four of six patients with positive fibrinogen scans, and the seventh patient demonstrated clinical findings of phlebitis. Six of the seven positive scans appeared within the first two days postoperatively and the seventh on the third postoperative day. Three of six patients with positive fibrinogen scans were found to have abnormal lung scans consistent with pulmonary emboli. (Table I.) One hundred and twelve patients underwent postoperative pulmonary scanning. Sixty-five of these patients demonstrated abnormalities in pulmonary perfusion. Analysis of the patients without evidence of chronic obstructive pulmonary disease revealed that of twenty-six patients who were not treated with low dose heparin, five were found to have perfusion defects consistent with pulmonary emboli. Twenty-one patients without chronic pulmonary disease received low dose heparin and none of these demonstrated perfusion defects consistent with pulmonary emboli (p < 0.04 such that there is no difference in a chi square test). (Figure 1.) The incidence of peripheral thrombosis by fibrinogen scanning in the sixty-two control patients was 4.8 per cent. This represents a significant reduction from the previous series of 200 patients in which thirty-four patients [I ] were found to have peripheral thrombi. (Figure 2.) This finding of a dramatic reduction in the incidence of peripheral thrombi was unexpected. Although no effort was made to change the management of the
The American Journal ol Surgery
Postoperative Pulmonary Embolism
patients, analysis of these patients reveals significant differences in postoperative patient care, probably as a result of increased awareness of the frequency of peripheral thrombosis diagnosed by the fibrinogen technic. Utilization of elastic stockings has increased from 24.7 to 45.5 per cent. Earlier ambulation and avoidance of sitting have become routine. The early application of elastic support has been emphasized. The technic of fibrinogen scanning has remained constant, the specific activity of the labeled fibrinogen has been monitored, and the wound activity and pattern of accumulation have remained unchanged. Moreover, superficial phlebitis associated with intravenous therapy has invariably demonstrated high fibrinogen activity. There have been no instances of clinical phlebitis in the absence of positive fibrinogen scans. There were no instances in which surgical bleeding appeared to be a complication of the low dose heparin technic. No complications associated with the fibrinogen scanning or low dose heparin regimen were recognized. Comments
Low dose subcutaneous heparin has been advocated as a prophylactic measure to inhibit the incidence of peripheral thrombosis in postoperative patients. The rationale for this therapy is based on the ability of heparin to activate a naturally occurring plasma inhibitor to activated factor X [2]. The heparin must be given preoperatively. Various regimens involving postoperative heparin beginning twelve to twenty-four hours postoperatively and repeated at eight or twelve hour intervals have been advocated. Although surgical bleeding has not been significantly increased with low dose heparin, the earlier and more frequent regimen of low dose heparin administration may be associated with increased bleeding [3]. Kakkar and others [4-d] have reported significant reduction in the incidence of deep venous thrombosis diagnosed by the fibrinogen scanning technic. Other studies have failed to demonstrate a clear-cut value for the low dose heparin especially in high risk patients such as those who have undergone prostatectomy [5] or hip surgery [9]. We were unable to demonstrate a reduction in the incidence of venous thrombosis in our patients by the fibrinogen scanning technic. A dramatic reduction in the incidence of peripheral thrombosis in the control group, presumably as a result of widespread adoption of prophylactic elastic support, earlier ambu-
volume 128,December1974
lation, and avoidance of sitting, was far more striking than the influence of low dose heparin. Also, this finding has been observed in two other studies which have shown that older patients undergoing major surgery were protected from deep vein thrombosis by a combination of physical measures [l&11 1.
However, the incidence of probable pulmonary emboli diagnosed by pulmonary scanning in patients receiving prophylactic low dose heparin did appear to be significantly reduced. None of the patients without chronic lung disease who received low dose heparin demonstrated perfusion defects consistent with pulmonary emboli whereas 19 per cent of the control group demonstrated significant perfusion defects in the absence of chronic pulmonary disease. This incidence of probable pulmonary emboli in the control group is similar to that observed in our previous study which correlated peripheral 1251 fibrinogen scanning with pulmonary scanning and with an incidence of postoperative pulmonary emboli of 14 per cent determined by a comparison of pre- and postoperative lung scans [12]. Our previous studies have indicated that an abnormal lung scan in the presence of chronic obstructive pulmonary disease did not necessarily indicate pulmonary emboli. Conversely, significant perfusion defects in the absence of chronic lung disease did resolve with follow-up scanning and, in a limited series of patients, the presence of these defects was confirmed by pulmonary angiography [I 1. It must be emphasized that these abnormalities in pulmonary scanning were asymptomatic and were not followed by clinically significant pulmonary emboli in untreated patients. Thus, although the incidence of peripheral deep venous thrombosis was significantly reduced by general prophylactic measures, the incidence of probable pulmonary emboli, diagnosed by pulmonary scanning, remained unchanged. Our inability to demonstrate further reduction in the frequency of peripheral thrombosis by prophylactic low dose heparin may be of limited significance in view of the low incidence of peripheral thrombosis in these patients. Low dose heparin did appear to reduce these pulmonary emboli without significant complications. Although other investigators have indicated that the incidence of deep venous thrombosis can be reduced significantly by low dose heparin, there is little evidence that the frequency of pulmonary emboli was altered. This demonstration of an apparent reduction in pulmonary emboli by low dose heparin necessitates continued clinical evaluation.
741
Abernethy and Hartsuck
Summary
A prospective study of pulmonary embolism utilizing low dose heparin in 125 postoperative patients failed to demonstrate a significant reduction in deep venous thrombosis diagnosed by fibrinogen scanning. However, the incidence of probable pulmonary emboli diagnosed by pulmonary scanning in the absence of chronic lung disease appeared to be reduced by the low dose heparin regimen. Acknowledgment: We wish to thank Dr Lazar Greenfield for his support and assistance and Dr Carl W. Smith for his interpretation of the pulmonary scans. The technical support of Rene Jacocks was appreciated.
4.
5.
6.
7.
8.
9.
References 10. 1. Hat-tsuck JM, Greenfield W: Postoperative thromboembolism: A clinical study with 125l fibrinogen and pulmonary scaring. Arch Surg 107: 733, 1973. 2. Yin ET, Wessler S, Stall PJ: Biological properties of the naturally occurring plasma inhibitor to activated factor X. J Biol Chem 246: 3703, 1971. 3. Gallus AS, Hirsh J. Tuttle RJ, Trebilcock R, O’Brien SE, Carroll JJ, Minden JH, Hudecki SM: Small subcutaneous
742
11.
12.
doses of heparin in prevention of venous thrombosis. N Engl J A&d 288: 545.1973. Kakkar VV, Spindler J, Flute PT, Corrigan T, Fossard DP, Crellin RQ, Wessler S, Yin ET: Efficacy of low doses of heparin in prevention Of deep-vein thrombosis after major surgery. Lancer 2: 101, 1972. Williams HT: Prevention of postoperative deep-vein thrombosis with perioperative subcutaneous heparin. Lancer 2: 950, 1972. Kakkar VV, Nicolaides AN, Field ES, Flute PT. Wessler S, Yin ET: Low doses of heparin in prevention of deep vein thrombosis. Lancer 2: 669. 1971. Gordon-Smith IC, LeQuesne LP, Grundy DJ, Newcombe JF. Branmle FJ: Controlled trial of two regimens of subcutaneous heparin in prevention of postoperative deep-vein thrombosis. Lancet 1: 1133, 1972. Nicolaides AN, Desae S, Douglas JN, Fourides G. DuPont PA, Lewis JD, Dodsworth H, Luck RJ, Jamieson CW: Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis after major surgery. Lancet 2: 890, 1972. Evarts CM, Alfiii RJ: Thromboembolism after total hip reconstruction. JAMA 225: 515, 1973. Flanc C, Kakkar VV, Clarke MB: Postoperative deep-vein thrombosis: effect of intensive prophylaxis. Lancer 1: 477, 1969. Tsapogas MJ. Miller R, Peabody RA, Eckert CL: Detection of postoperative venous thrombosis and effectiveness of prophylactic measures. Arch Surg 101: 149, 1970. Allgood RJ, Cook JH, Weedn RJ, Speed HK, Whtcomb WH, Greenfield W: Prospective analysis of pulmonary embolism in the postoperative patient. Surgery 68: 116. 1970.
The American Journal 01 Surgery