J Neurosurg 49:378-381, 1978
Deep vein thrombosis and low-dose heparin prophylaxis in neurosurgical patients DARIO CERRATO, M.D., CESARE ARIANO, B.Sc., AND
FOLCO FIACCHINO, M.D.
Departments of Clinical Investigation and Anaesthesiology, and Intensive Care Unit, "'C. Besta" Neurological Institute, Milan, Italy ~" By the use of l~q-labeled fibrinogen test, the incidence of postoperative deep vein thrombosis (DVT) and the effectiveness of prophylactic low-dose heparin treatment were investigated in 110 patients who underwent elective neurosurgical procedures. Fifty patients were appointed randomly to a control group and 50 to a heparin group (10 patients were excluded since they had DVT before surgery). The incidence of DVT was reduced from 34% in the control group to 6% in the heparin group (p < 0.005). No statistically significant differences were observed in transfusion requirements, postoperative hemoglobin concentration, and the occurrence of postoperative hematomas between the two groups. Positive correlation was observed between DVT and motor deficit (p < 0.05). Preoperative assessment of patients' sensitivity to the standard 5000-unit dose of heparin was performed in all treated patients and is thought an important factor in improving the safety of heparin prophylaxis. KEY WORDS 9 deep vein thrombosis 9 low-dose heparin 12q-fibrinogen test plasma beparin concentration
9
I
N the international trial on thrombo- and to test the effectiveness of heparin embolic complications after major prophylaxis. surgical procedures, n the 12q-labeled Clinical Material and Methods fibrinogen test ra2 revealed the occurrence of postoperative deep vein thrombosis (DVT) in Assessment of Deep Vein Thrombosis 24.6% of 667 control patients and in 7.7% of Deep vein thrombosis was investigated by 625 heparin-treated patients. Neurosurgical procedures were not considered in that trial. the fibrinogen test using a Pitman 235 isotope In 1975, Joffe TM reported the results obtained localization monitor.* Radioactive fibrinfrom 23 neurosurgical patients, and found ogen,t I00 ~Ci, was given to each patient 24 DVT in 43% of them. In his reply to doubts hours before operation. At the same time, expressed by Coppola, 5 Joffe 9 stated that a distinction should be made between "clinical" and "isotopic" DVT diagnosis. The purpose *Pitman 235 isotope localization monitor of our present study was to use the fibrinogen manufactured by D. A. Pitman, Ltd., Mill Works, test in patients undergoing elective intra- Jessamy Road, Weybridge, Surrey, England. cranial surgical procedures in order to intRadioactive fibrinogen obtaihed from Radiovestigate the incidence of postoperative DVT chemical Center, Amersham, England. 378
J. Neurosurg. / Volume 49 / September, 1978
Low-dose heparin prophylaxis sodium or potassium iodide treatment was started. Scanning was done before induction of anesthesia, at the conclusion of the operation, and each day thereafter for at least 8 days. The presence of DVT was determined by the methods of Kakkar, et al., TM Browse, 2 and Roberts. la tratibnt tropuliTtion The series included 110 patients, all over 40 years of age, who were to undergo elective intracranial surgical procedures. To ascertain the real incidence of postoperative DVT, we excluded 10 of these patients who had a positive fibrinogen test before operation? The study was then completed in 100 patients: 50 were randomized to a control group (Group A), and 50 to a heparin group (Group B). The two groups were well matched (Tables 1-3). Heparin Treatment All patients were preoperatively evaluated by prothrombin time, partial thromboplastin time (PTT), thrombin time (TT), and plasma fibrinogen and platelets count. Group B patients were then given 5000 units of calcium heparin subcutaneously. This was considered to be a safe prophylactic dose if the patient's plasma heparin concentration was less than 0.18 units/ml 3 hours after administration? Otherwise, a lower dose was given and the patient's plasma heparin concentration was tested again after 3 hours? ,4 Once established, the safe prophylactic dose was given 2 hours before surgery and every 8 hours thereafter for at least 7 days. Results
Occurrence o f Deep Vein Thrombosis The incidence of postoperative DVT was 34% in the control group and 6% in the treated group (p < 0.005) (Table 4). A positive correlation was observed in control patients between t h r o m b o s i s and m o t o r deficit (p < 0.05). There were no differences in the transfusion requirements in the two groups (Table 5). Postoperative hemoglobin concentration was lower in the treated group, but the difference was not statistically significant (Table 6). Three postoperative hematomas were observed, one in the control group and two in the treated group (Table 2). J. Neurosurg. / Volume 49 / September, 1978
TABLE 1 Comparison of Groups A and B Factors
Group A
Group B
age (yrs) sex male female weight (kg) height (cm) preop hospital days
51 ~- 7
53 • 9
27 23 66 • 11 166 =~ 7 14 • 9
24 26 66 • I1 166 • 8 16 • 9
TABLE 2 Operations performed in Groups A and B Operation
Group A
Group B
14 9 3 1 0 8 1 0 4
17 13 2 0 2 5 0 1 2
3* 1 I 4 0 1
4 2* 0 1" 1 0
supratentorial lesions meningiomas gliomas angiomas pituitary adenomas craniopharyngiomas arterial aneurysms cavernous angiomas arachnoid cysts metastatic tumors subtentorial lesions gliomas hemangioblastomas chemodectomas neurinomas metastatic tumors epidermoid tumors
*One patient had a postoperative hematoma.
TABLE 3 Distribution of risk factors in untreated and treated patients* No. of Risk Factors
Group A
Group B
2
36
3 4
11 3
39 9 2
*Risk factors include age, surgery, previous myocardial infarction, previous pulmonary embolism, chronic bronchitis, taking contraceptive pills, previous lower limb fractures, varicose veins, varicose ulcers, healed varicose ulcers, and malignant disease, p = not significant. 379
D. Cerrato, C. Ariano and F. Fiacchino TABLE 4 Deep vein thrombosis ( D VT) diagnosed by 1251-labeledfibrinogen test Incidence test performed patients with DVT patients with bilateral DVT limbs with DVT paretic limbs paretic limbs with DVT
Group A
Group B
50 17 (34 ~o)*
50 3 (6 7o)*
3 20 42t 13t
2 5 45 4
*p < 0.005. tp < 0.05.
Heparin Treatment
The standard regime of 5000 units was administered to 46 patients. Average values of PTT, TT, and plasma heparin concentration before and after heparin treatment are listed in Table 7. A lower dose (3750 units) was used in four patients because the heparin plasma concentration was higher than 0.18 units/ml (range 0.18 to 0.21 units/ml), and because of abnormal values of P T T and/or TT. Discussion
TABLE 5 Blood transfusion requirements during surgery* Transfusion Requirements (units)
Group A
Group B
25 12 7 2 1 3
22 15 3 3 3 4
0
1
2 3 4 >4
*p = not significant.
TABLE 6 Postoperative hemoglobin concentration: comparison with preoperative value (gm 7o)* Day After Surgery
Group A
Group B
1st day 7th day
-0.4 -4- 1.6 --0.6 ~: 1.2
--0.8 • 1.4 --0.7 ~: 1.3
*p = not significant.
Our results in neurosurgical patients agree with those reported in general surgery. 11 The incidence of postoperative DVT is high and its prevention is possible by the use of prophylactic heparin t r e a t m e n t . N e u r o surgical patients seem to be particularly prone to this complication? ~ The possible factors that could predispose them to develop DVT more frequently than other surgical patients include the positive correlation between t h r o m b o s i s and m o t o r deficit 14 (Table 4). It should be remembered that 10 patients who exhibited DVT before operation (eight with DVT in the paretic limb or limbs) were n o t considered in our study. The prophylactic role of heparin treatment was well demonstrated in our patients by the reduction to 6% of the postoperative DVT. After treating 150 neurosurgical patients, Barnett, et al., ~ recently reported that "minidose heparin therapy can be used safely and without fear of increased intracranial or intraspinal bleeding." Our data confirm this assumption. No differences were observed in our treated and untreated patients so far as surgical complications, transfusion requirements, and postoperative hematomas are concerned. Nevertheless, the tendency (not statistically significant) for treated
TABLE 7 Tests of blood coagulation obtained in 50 heparin-treated patients* Test
Normal Range
Before Heparin
After Heparin
PTT (seconds) PT ratio thrombin time (seconds) plasma fibrinogen (gm/liter) platelet count/liter plasma heparin (units/ml)
23-39 0.9-1.1 up to 22 1-4 140--440 • 109
28 :~ 5 1.02 • 0.1 18 • 2 2.45 • 0.85 258 • 73 X l0 g
29 ~ 5 19 • 3 0.05 =~ 0.03
*Data are given as mean values ~- SD. PTT = partial thromboplastin time; PT = prothrombin time. 380
J. Neurosurg. / Volume 49 / September, 1978
Low-dose heparin prophylaxis patients to have a lower hemoglobin postoperatively, and the occurrence of four cases of unsafe plasma heparin concentrations must be kept in mind. "Minor bleeding" or "wound hematomas" such as occurred in treated patients of the International Trial 11 could be very dangerous in neurosurgery. We think that the preoperative assessment of the patients' sensitivity to the standard dose of heparin could be important in improving the safety of heparin prophylaxis. From the practical point of view, the detection of DVT in the paretic limbs of neurosurgical patients may be relevant in respect to their early mobilization. Acknowledgments
We are deeply grateful to Professors G. Morello and V. Borroni for criticism and advice. References
I. Barnett HG, Clifford JR, Llewellyn RC: Safety of mini-dose heparin administration for ncurosurgical patients. J Neurosurg 47:27-30, 1977 2. Browse NL: The 225I fibrinogen uptake test. Arch Surg 104:160-163, 1972 3. Brozovid M, Stirling Y, Klenerman L, et al: Subcutaneous heparin and postoperative thromboembolism. Lancet 2:99-100, 1974 (Letter) 4. Cooke ED, Lloyd MJ, Bowcock SA, et al" Monitoring during low-dose heparin prophylaxis. N Engl J Med 294:1066-1067, 1976 (Letter)
J. Neurosurg. / Volume 49 / September, 1978
5. Coppola AR: Deep vein thrombosis. J Neurosurg 43:510-511, 1975 (Letter) 6. Denson KWE, Bonnar J: The measurement of heparin. A method based on the potentiation of anti-factor Xa. Thromb Diath Haemorrh 30:471-479, 1973 7. Flanc C, Kakkar VV, Clarke MB: The detection of venous thrombosis of the legs using 125I-labelled fibrinogen. Br J Surg 55:742-747, 1968 8. Heatley RV, Hughes LE, Morgan A, et al: Preoperative or postoperative deep-vein thrombosis? Lancet 1:437-439, 1976 9. Joffe SN: Deep vein thrombosis. J Neurosurg 43:511, 1975 (Letter) 10. Joffe SN: Incidence of postoperative deep vein thrombosis in neurosurgical patients. J Neurosnrg 42:201-203, 1975 11. Kakkar VV, Corrigan TP, Fossard DP (Coordinators): Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 2:45-51, 1975 12. Kakkar VV, Nicolaides AN, Renney JTG, et al: 12SI-labelled fibrinogen test adapted for routine screening of deep vein thrombosis. Lancet 1:540-542, 1970 13. Roberts VC: Fibrinogen uptake scanning for diagnosis of deep vein thrombosis: a plea for standardization. Br Med J 3:455-458, 1975 14. Warlow C, Ogston D, Douglas AS: Venous thrombosis following strokes. Lancet 1:1305-1306, 1972 Address reprint requests to: Dario Cerrato, M.D., Neurological Institute of Milan, Via Celoria l l, 20133 Milano, Italy.
38
Deep vein thrombosis and low-dose heparin prophylaxis in neurosurgical patients DARIO CERRATO, M.D., CESARE ARIANO, B.Sc., AND
FOLCO FIACCHINO, M.D.
Departments of Clinical Investigation and Anaesthesiology, and Intensive Care Unit, "'C. Besta" Neurological Institute, Milan, Italy ~" By the use of l~q-labeled fibrinogen test, the incidence of postoperative deep vein thrombosis (DVT) and the effectiveness of prophylactic low-dose heparin treatment were investigated in 110 patients who underwent elective neurosurgical procedures. Fifty patients were appointed randomly to a control group and 50 to a heparin group (10 patients were excluded since they had DVT before surgery). The incidence of DVT was reduced from 34% in the control group to 6% in the heparin group (p < 0.005). No statistically significant differences were observed in transfusion requirements, postoperative hemoglobin concentration, and the occurrence of postoperative hematomas between the two groups. Positive correlation was observed between DVT and motor deficit (p < 0.05). Preoperative assessment of patients' sensitivity to the standard 5000-unit dose of heparin was performed in all treated patients and is thought an important factor in improving the safety of heparin prophylaxis. KEY WORDS 9 deep vein thrombosis 9 low-dose heparin 12q-fibrinogen test plasma beparin concentration
9
I
N the international trial on thrombo- and to test the effectiveness of heparin embolic complications after major prophylaxis. surgical procedures, n the 12q-labeled Clinical Material and Methods fibrinogen test ra2 revealed the occurrence of postoperative deep vein thrombosis (DVT) in Assessment of Deep Vein Thrombosis 24.6% of 667 control patients and in 7.7% of Deep vein thrombosis was investigated by 625 heparin-treated patients. Neurosurgical procedures were not considered in that trial. the fibrinogen test using a Pitman 235 isotope In 1975, Joffe TM reported the results obtained localization monitor.* Radioactive fibrinfrom 23 neurosurgical patients, and found ogen,t I00 ~Ci, was given to each patient 24 DVT in 43% of them. In his reply to doubts hours before operation. At the same time, expressed by Coppola, 5 Joffe 9 stated that a distinction should be made between "clinical" and "isotopic" DVT diagnosis. The purpose *Pitman 235 isotope localization monitor of our present study was to use the fibrinogen manufactured by D. A. Pitman, Ltd., Mill Works, test in patients undergoing elective intra- Jessamy Road, Weybridge, Surrey, England. cranial surgical procedures in order to intRadioactive fibrinogen obtaihed from Radiovestigate the incidence of postoperative DVT chemical Center, Amersham, England. 378
J. Neurosurg. / Volume 49 / September, 1978
Low-dose heparin prophylaxis sodium or potassium iodide treatment was started. Scanning was done before induction of anesthesia, at the conclusion of the operation, and each day thereafter for at least 8 days. The presence of DVT was determined by the methods of Kakkar, et al., TM Browse, 2 and Roberts. la tratibnt tropuliTtion The series included 110 patients, all over 40 years of age, who were to undergo elective intracranial surgical procedures. To ascertain the real incidence of postoperative DVT, we excluded 10 of these patients who had a positive fibrinogen test before operation? The study was then completed in 100 patients: 50 were randomized to a control group (Group A), and 50 to a heparin group (Group B). The two groups were well matched (Tables 1-3). Heparin Treatment All patients were preoperatively evaluated by prothrombin time, partial thromboplastin time (PTT), thrombin time (TT), and plasma fibrinogen and platelets count. Group B patients were then given 5000 units of calcium heparin subcutaneously. This was considered to be a safe prophylactic dose if the patient's plasma heparin concentration was less than 0.18 units/ml 3 hours after administration? Otherwise, a lower dose was given and the patient's plasma heparin concentration was tested again after 3 hours? ,4 Once established, the safe prophylactic dose was given 2 hours before surgery and every 8 hours thereafter for at least 7 days. Results
Occurrence o f Deep Vein Thrombosis The incidence of postoperative DVT was 34% in the control group and 6% in the treated group (p < 0.005) (Table 4). A positive correlation was observed in control patients between t h r o m b o s i s and m o t o r deficit (p < 0.05). There were no differences in the transfusion requirements in the two groups (Table 5). Postoperative hemoglobin concentration was lower in the treated group, but the difference was not statistically significant (Table 6). Three postoperative hematomas were observed, one in the control group and two in the treated group (Table 2). J. Neurosurg. / Volume 49 / September, 1978
TABLE 1 Comparison of Groups A and B Factors
Group A
Group B
age (yrs) sex male female weight (kg) height (cm) preop hospital days
51 ~- 7
53 • 9
27 23 66 • 11 166 =~ 7 14 • 9
24 26 66 • I1 166 • 8 16 • 9
TABLE 2 Operations performed in Groups A and B Operation
Group A
Group B
14 9 3 1 0 8 1 0 4
17 13 2 0 2 5 0 1 2
3* 1 I 4 0 1
4 2* 0 1" 1 0
supratentorial lesions meningiomas gliomas angiomas pituitary adenomas craniopharyngiomas arterial aneurysms cavernous angiomas arachnoid cysts metastatic tumors subtentorial lesions gliomas hemangioblastomas chemodectomas neurinomas metastatic tumors epidermoid tumors
*One patient had a postoperative hematoma.
TABLE 3 Distribution of risk factors in untreated and treated patients* No. of Risk Factors
Group A
Group B
2
36
3 4
11 3
39 9 2
*Risk factors include age, surgery, previous myocardial infarction, previous pulmonary embolism, chronic bronchitis, taking contraceptive pills, previous lower limb fractures, varicose veins, varicose ulcers, healed varicose ulcers, and malignant disease, p = not significant. 379
D. Cerrato, C. Ariano and F. Fiacchino TABLE 4 Deep vein thrombosis ( D VT) diagnosed by 1251-labeledfibrinogen test Incidence test performed patients with DVT patients with bilateral DVT limbs with DVT paretic limbs paretic limbs with DVT
Group A
Group B
50 17 (34 ~o)*
50 3 (6 7o)*
3 20 42t 13t
2 5 45 4
*p < 0.005. tp < 0.05.
Heparin Treatment
The standard regime of 5000 units was administered to 46 patients. Average values of PTT, TT, and plasma heparin concentration before and after heparin treatment are listed in Table 7. A lower dose (3750 units) was used in four patients because the heparin plasma concentration was higher than 0.18 units/ml (range 0.18 to 0.21 units/ml), and because of abnormal values of P T T and/or TT. Discussion
TABLE 5 Blood transfusion requirements during surgery* Transfusion Requirements (units)
Group A
Group B
25 12 7 2 1 3
22 15 3 3 3 4
0
1
2 3 4 >4
*p = not significant.
TABLE 6 Postoperative hemoglobin concentration: comparison with preoperative value (gm 7o)* Day After Surgery
Group A
Group B
1st day 7th day
-0.4 -4- 1.6 --0.6 ~: 1.2
--0.8 • 1.4 --0.7 ~: 1.3
*p = not significant.
Our results in neurosurgical patients agree with those reported in general surgery. 11 The incidence of postoperative DVT is high and its prevention is possible by the use of prophylactic heparin t r e a t m e n t . N e u r o surgical patients seem to be particularly prone to this complication? ~ The possible factors that could predispose them to develop DVT more frequently than other surgical patients include the positive correlation between t h r o m b o s i s and m o t o r deficit 14 (Table 4). It should be remembered that 10 patients who exhibited DVT before operation (eight with DVT in the paretic limb or limbs) were n o t considered in our study. The prophylactic role of heparin treatment was well demonstrated in our patients by the reduction to 6% of the postoperative DVT. After treating 150 neurosurgical patients, Barnett, et al., ~ recently reported that "minidose heparin therapy can be used safely and without fear of increased intracranial or intraspinal bleeding." Our data confirm this assumption. No differences were observed in our treated and untreated patients so far as surgical complications, transfusion requirements, and postoperative hematomas are concerned. Nevertheless, the tendency (not statistically significant) for treated
TABLE 7 Tests of blood coagulation obtained in 50 heparin-treated patients* Test
Normal Range
Before Heparin
After Heparin
PTT (seconds) PT ratio thrombin time (seconds) plasma fibrinogen (gm/liter) platelet count/liter plasma heparin (units/ml)
23-39 0.9-1.1 up to 22 1-4 140--440 • 109
28 :~ 5 1.02 • 0.1 18 • 2 2.45 • 0.85 258 • 73 X l0 g
29 ~ 5 19 • 3 0.05 =~ 0.03
*Data are given as mean values ~- SD. PTT = partial thromboplastin time; PT = prothrombin time. 380
J. Neurosurg. / Volume 49 / September, 1978
Low-dose heparin prophylaxis patients to have a lower hemoglobin postoperatively, and the occurrence of four cases of unsafe plasma heparin concentrations must be kept in mind. "Minor bleeding" or "wound hematomas" such as occurred in treated patients of the International Trial 11 could be very dangerous in neurosurgery. We think that the preoperative assessment of the patients' sensitivity to the standard dose of heparin could be important in improving the safety of heparin prophylaxis. From the practical point of view, the detection of DVT in the paretic limbs of neurosurgical patients may be relevant in respect to their early mobilization. Acknowledgments
We are deeply grateful to Professors G. Morello and V. Borroni for criticism and advice. References
I. Barnett HG, Clifford JR, Llewellyn RC: Safety of mini-dose heparin administration for ncurosurgical patients. J Neurosurg 47:27-30, 1977 2. Browse NL: The 225I fibrinogen uptake test. Arch Surg 104:160-163, 1972 3. Brozovid M, Stirling Y, Klenerman L, et al: Subcutaneous heparin and postoperative thromboembolism. Lancet 2:99-100, 1974 (Letter) 4. Cooke ED, Lloyd MJ, Bowcock SA, et al" Monitoring during low-dose heparin prophylaxis. N Engl J Med 294:1066-1067, 1976 (Letter)
J. Neurosurg. / Volume 49 / September, 1978
5. Coppola AR: Deep vein thrombosis. J Neurosurg 43:510-511, 1975 (Letter) 6. Denson KWE, Bonnar J: The measurement of heparin. A method based on the potentiation of anti-factor Xa. Thromb Diath Haemorrh 30:471-479, 1973 7. Flanc C, Kakkar VV, Clarke MB: The detection of venous thrombosis of the legs using 125I-labelled fibrinogen. Br J Surg 55:742-747, 1968 8. Heatley RV, Hughes LE, Morgan A, et al: Preoperative or postoperative deep-vein thrombosis? Lancet 1:437-439, 1976 9. Joffe SN: Deep vein thrombosis. J Neurosurg 43:511, 1975 (Letter) 10. Joffe SN: Incidence of postoperative deep vein thrombosis in neurosurgical patients. J Neurosnrg 42:201-203, 1975 11. Kakkar VV, Corrigan TP, Fossard DP (Coordinators): Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 2:45-51, 1975 12. Kakkar VV, Nicolaides AN, Renney JTG, et al: 12SI-labelled fibrinogen test adapted for routine screening of deep vein thrombosis. Lancet 1:540-542, 1970 13. Roberts VC: Fibrinogen uptake scanning for diagnosis of deep vein thrombosis: a plea for standardization. Br Med J 3:455-458, 1975 14. Warlow C, Ogston D, Douglas AS: Venous thrombosis following strokes. Lancet 1:1305-1306, 1972 Address reprint requests to: Dario Cerrato, M.D., Neurological Institute of Milan, Via Celoria l l, 20133 Milano, Italy.
38
