Journal of Neuro-Oncology 14: 11%125,1992. © 1992KluwerAcademic Publishers. Printedin the Netherlands. Clinical Study
Postoperative venous thromboembolism and brain tumors: part I. Clinical profile
Raymond Sawaya, Mario Zuccarello, Magdy Elkalliny and Hiroshi Nishiyama Departments of Neurosurgery (R.S., M.Z., M.E.) and Nuclear Medicine (H.N.), University of Cincinnati and V.A.M.C., Cincinnati, Ohio 45221, USA
Key words." anticoagulation, brain tumor, fibrinogen scan, prophylaxis, venous thrombosis Abstract
Forty-six patients who underwent surgery for brain tumors were studied prospectively with 125I labeled Fibrinogen leg scans to detect postoperative venous thrombosis. The incidence of thrombosis was 72% for meningioma patients, 60% for glioblastoma patients, and 20% for brain metastasis patients. Correlation between the occurrence of venous thrombosis and the various clinical factors thought to be responsible for the high incidence of thrombosis generally failed to show statistical significance. This finding, along with the marked variation in the incidence of venous thrombosis between the different brain tumor groups, strongly suggests that biological factors play a more important role than clinical factors in determining which brain tumor patient will suffer a postoperative thrombotic event.
A direct association between malignancies and thromboembolic complications has been well established, but the occurrence of these complications in patients with brain tumors has not received sufficient attention. Wetzel et al. reviewed a series of 6,065 neurosurgical patients [1] and found a 3% incidence of fatal postoperative pulmonary emboli; however, patients with brain tumors were not specifically identified [1]. In an autopsy study involving 334 patients with primary intracranial neoplasms, the incidence of venous thrombosis was 27.5%, statistically significantly different from the 17% incidence for a control neurosurgical group [2]. Several clinical studies have confirmed a high incidence of postoperative thrombophlebitis in neurosurgical patients [3-9], but brain tumor patients have rarely been studied separately. In another study, Ruff & Posner reported [10] that of 268 consecutive patients with malignant glioma, 36% developed clinical signs of systemic venous thrombosis. Choucair et al. [11], in their
series of 715 patients, identified a 4% risk of venous thromboembolism after 6 weeks of the craniotomy. In none of these studies were the patients evaluated prospectively. We undertook this study with the hope of specifically identifying clinical risk factors and reliably estimating the incidence of postoperative clots detectable by 125I-labeled fibrinogen scans in patients with the three most common brain tumors [12, 13].
Materials and methods
Forty-six male patients operated on for glioblastoma, meningioma, or brain metastasis at the V.A.M.C. in Cincinnati were included in this study. Clinical data obtained preoperatively included patient age, side of the lesion, duration of symptoms, Karnofsky score, ambulatory status, and the presence of paresis.
120 CT scan data included the size of the mass measured according to the formula Volume =
plethysmography were used whenever confirmation of the venous thrombosis was judged necessary. Prophylactic measures against venous thromboembolism, other than leg wrapping and early ambulation, whenever feasible, were not employed in any of the patients. Statistical analysis of the data was done using standard computerized software and included calculations of the mean, standard error of the mean, and correlation coefficients. Analysis of variance was used for group comparisons. The significance level was at P = 0.05.
( A x B x C) 6
where A, B, and C represent the three longest axes of the mass; and the presence and degree of peritumoral brain edema, graded from 0 to 5 with 0 representing no edema and 5 severe edema. Other clinical data included duration of surgery and estimated blood loss. The general medical status of the patients was comparable among the glioblastoma and the metastasis groups and slightly less affected in the meningioma group. There were no instances of liver failure. Antibiotics (cephalosporin) were given perioperatively to all patients for a duration of 24 hours. Steroids (Dexamethasone) was administered to all patients (16 mg daily) beginning prior to surgery and continuing for a variable number of days depending on the extent of brain edema. All patients were studied one day perioperatively with 125I fibrinogen leg scanning after proper suppression of thyroid gland function [12, 14]. Scans were continued daily for at least 7 days, and when scans were positive, patients were reinjected with 12sI fibrinogen to evaluate any indication of thrombus spread. Venography and/or impedance
Results
Clinical data by tumor type Clinical data are summarized in Table 1. The following differences among the three groups of brain tumor patients were noted: duration of symptoms was more prolonged in the meningioma group; percentage of patients with paretic limbs was highest in the glioblastoma group; tumor size was smallest in the metastasis group, which also had the greatest degree of brain edema; and duration of surgery and estimated blood loss were significantly higher in the meningioma group.
Table 1. Summary of clinical data Clinical characteristic
Total
By group Meningioma
Glioblastoma
Age (years) Side of tumor (% right) Duration of symptoms (days) Karnofsky score (0-100) Ambulatory status (%) Paresis (% of patients) Size of mass (cm 3) Edema score (0-5) Steroid treatment (days) Anesthesia time (minutes) Estimated blood loss (ml)
Number
Mean
SEM
46 46 43 43 44 44 37 36 18 44 27
62.43 1.07 56.5 117.83 21.41 66.04 3.12 68.18 59.09 39.64 2.50 0.25 13.52 4.60 278.13 19.79 333.88 68.42
Mean
SEM
59.60 2.23 40 118.28 32.26 59.28 4.85 53 80 56.84 7.68 2.14 0.34 9.83 2.41 235.00 26.73 281.85 40.01
(N) Mean 15 15 14 14 15 15 14 14 6 14 8
SEM
63.54 1.71 81 239.00 62.27 77.00 5.97 90 30 48.36 16.05 1.55 0.41 3.00 1.08 396.00 48.84 725.00 252.23
Metastasis (N) Mean 11 11 10 10 10 10 9 9 3 11 6
SEM
63.95 1.50 55 53.73 13.77 65.26 4.91 68 57 16.84 5.79 3.53 0.40 20.66 9.17 241.21 20.37 185.76 20.11
P (N) 20 20 19 19 19 19 14 13 9 19 13
0.18 0.19 0.001 0.10 0.16 0.04 0.006 0.003 0.31 0.001 0.003
121 Fibrinogen scan data:
Incidence
of Thrombosis
100
Forty-five percent of the patients had fibrinogen scan evidence of venous thrombosis occurring after craniotomy. The diagnosis was confirmed by other methods in 44% of the patients when judged necessary because of the spread of the thrombi and/or prior to initiation of therapy. One third of the patients had no symptoms associated with the thrombotic event, and all patients with negative scans were studied for at least 7 days following craniotomy. The incidence of venous thrombosis differed markedly among the groups (Fig. 1). The highest rate was in the meningioma group (72%) followed by the glioblastoma group (60%). The metastasis group had a surprisingly low rate of thrombosis (20%) compared with the other two groups. There were no noticeable differences among the three groups with regard to the remaining fibrinogen scan data (Table 2). Approximately 40% of the patients with a positive scan received treatment for thrombosis. The decision to treat was influenced by the evidence of proximal spread of the thrombi and/or the presence of thrombi in the large proximal venous system of the lower extremities. The treatment consisted of either standard anticoagulation therapy or vena cava filter based on the proximity of the thrombotic event to the time of craniotomy. Two patients died of thromboembolic complications. The first was a patient with glioblastoma who died suddenly on the
T
SEM 0.005
P 75
Percent 50
25
GBM
MNG
METS
Fig. 1. G B M , g l i o b l a s t o m a ; M E T S , m e t a s t a s i s ; M N G , men i n g i o m a ; S E M = s t a n d a r d e r r o r of the m e a n ; T E C , t h r o m b o e m b o l i c c o m p l i c a t i o n . I n c i d e n c e of v e n o u s t h r o m b o s i s by b r a i n t u m o r group. T h e a s t e r i s k r e p r e s e n t s the g r o u p t h a t is statistically significantly d i f f e r e n t from the others.
second postoperative day from a massive pulmonary embolism, and the second was a patient with a frontal convexity meningioma who died on the twelfth postoperative day from mesenteric thrombosis and total infarction of the bowels.
Correlation data Specific preoperative clinical parameters were correlated with the occurrence of venous thromboembolism (Table 3). There was no significant correlation between the occurrence of a thrombotic event and any of the frequently cited 'risk factors', name-
Table 2. S u m m a r y of 125I f i b r i n o g e n scan d a t a By group Total Number D u r a t i o n of s c a n n i n g (days) P o s i t i v e scan ( % ) Days positive Diagnosis confirmed (%) Symptoms present (%) S p r e a d of t h r o m b i ( % ) Treatment initiated (%)
44 46 19 18 18 20 17
Glioblastoma Mean
SEM
Mean
Meningioma
SEM
N
Mean
Metastasis
Sere
N
Mean
P
SEM
N
8.88
0.47
8.57
0.76
14
10.50
0.90
10
8.50
0.77
20
0.39
45.65 4.63
0.76
60 4.75
1.12
15 8
72 5.14
1.58
11 7
20 3.50
1.25
20 4
0.005 0.75
44.44 66.66 35.00
-
50 50 25
-
6 6 8
50 75 50
-
8 8 8
25 75 25
-
4 4 4
0.71 0.61 0.56
41.17
-
40
-
5
50
-
8
25
-
4
0.74
122 ly age, Karnofsky score, ambulatory status, presence of paretic limbs, and duration of surgery. Patients with prolonged duration of symptoms tended to have a higher incidence of thromboembolism. Similarly, patients with larger tumors were more likely to suffer a thromboembolic complication.
Venous thrombosis within tumor groups
Because of differences in specific clinical parameters noted among the three tumor groups (Table 1), a comparison within each tumor group was made with regard to the occurrence or lack of occurrence of venous thromboembolism. The results again indicated no statistically significant differences in the occurrence of thromboembolism within the groups for any of the following parameters: age, Karnofsky score, ambulatory status, or duration of surgery (Table 4). Overall, however, older patients tended to have a higher incidence of venous thrombosis. Patients with a brain metastasis and venous thrombosis tended to have a longer duration of symptoms, a lower Karnofsky score, a lower ambulatory status, and a higher percentage of limb paresis (Table 4, Figs 2, 3). Interestingly, patients with glioblastoma and venous thrombosis tended to have a higher Karnofsky score and were less likely to have paretic limbs (Table 4, Fig. 3). Meningioma patients with venous thrombosis had the same duration of surgery as those without thrombosis but tended to have fewer paretic limbs,
larger tumors, more peritumoral edema, and greater blood loss (Table 4, Fig. 3).
Discussion
The incidence of venous thrombosis as demonstrated by the 125I fibrinogen scan is considered reliable: the test is well established, technically easy, and highly sensitive, and thrombosis has been documented in every patient with a positive scan who has undergone venography [12, 14]. In addition, the duration of leg scanning in our study was long enough to detect the great majority of venous thrombi occurring postoperatively. It is conceivable that in a few instances, patients may have suffered from venous thrombosis in sites of the body other than the veins of the lower extremities; such events, however, are not frequent enough to affect the results of this study [15]. The marked variability in the incidence of venous thrombosis among the various tumor types was an unexpected finding. Moreover, analysis of the results with regard to the major risk factors generally identified in neurosurgical patients failed to predict the likelihood of thrombosis [9]. The high incidence of venous thrombosis in the meningioma group could have been explained on the basis of a longer duration of surgery, as demonstrated in Table 1; however, correlative analysis failed to indicate any statistical significance for this parameter, and a comparison within the meningioma group also did not demonstrate any significant
Table 3. Correlation coefficient data venous thrombosis vs clinical p a r a m e t e r Parameter
N
R
P
Age Side of t u m o r D u r a t i o n of sy mp toms Karnofsky
46 46 43 43
0.13 0.009 0.25 - 0.03
0.38 0.94 0.09 0.82
A m b u l a t o r y status
44
- 0.19
0.21
Paresis Size Edema A n e s t h e s i a Time E s t i m a t e d blood loss
44 37 36 44 27
- 0.11 0.34 - 0.22 0.14 0.31
0.45 0.03 0.18 0.34 0.11
123 • No TEC [] TEC
m No TEC
i00
[] TEC SEM : 0.04
100
Percent Ambulatory
Percent
5O
Paretie
50
m
GBM
MNG
METS
GBM
Fig. 2. Differences in ambulatory status of patients within each
MNG
METS
Fig. 3. Percentage of patients with paretic limbs within each brain tumor group. The asterisks represent the groups that are statistically significantly different.
brain tumor group.
difference in duration of surgery (Table 4). In several instances, a paradoxical result was found; e.g., as shown in Fig. 3, glioblastoma and meningioma patients suffering a thrombotic event were less likely to have a paretic limb than were those patients within the same group who had a negative fibrinogen scan. The duration of symptoms did correlate positively with thrombosis (P = 0.09), and as shown in Table 4, this appears to apply to both groups with malignant brain tumors. Such a finding may suggest that for intraaxial masses, longer periods of growth may be associated with a greater degree of cerebral disturbance and release of thrombogenic
material. This same hypothesis may apply to benign extraaxial tumors because the tumors associated with venous thrombosis in that group caused almost twice as much edema as those tumors without associated thrombosis (Table 4). Brain edema, however, was not a factor for the other two tumor groups. The results of this study suggest that the occurrence of thrombotic complications is specifically related to the type of tumor and, therefore, is biologically determined and that clinical parameters such as paresis, lack of ambulation, and duration of surgery are non-determinant factors, at least dur-
Table 4. Results by group and TEC Parameter
Glioblastoma TEC-
Mean Age (years) 57.33 Duration of 91.40 symptoms (days) Karnofsky score 56.00
Meningioma TEC+
SEM
TEC-
Metastasis TEC+
TEC-
Mean
SEM
Mean
SEM
Mean
SEM
4.18 21.88
61.11 133.22
2.57 49.19
59.33 303.33
4.97 203.00
65.12 211.42
1.34 44.73
9.79
61.11
5.63
80.00
11.54
75.71
11.68 0,54
57.81 2.12
10.88 0.47
33.60 1.00
27.11 0.57
44.76
246.87
34.67
376.66
100.00
275.00
47.87
375.00
Mean
P TEC+
SEM
Mean
SEM
63.56 38.06
1.84 11.41
65.50 112.50
1.50 40.85
0.32 0.01
7.51
67.33
5.56
57.50
11.08
0.37
55.75 1.83
20.94 0.54
16.98 3.50
6.25 0.43
9.00 3.66
6.00 0.33
0.04 0.04
84.12
404.37
62.43
254.53
23.96
191.25
26.95
0.01
225.00
900.00
346.41
186.50
23.89
183.33
44.09
0.01
(0-100)
Tumor size (cm3) 55.55 Edema score 2.16 (0-5)
Anesthesia time 219.16 (minutes) Blood loss(ml) 300.00
124 ing the immediate perioperative period. Such a conclusion should stimulate interest in studying the tumor tissue for a better understanding of the pathogenetic mechanisms involved (see Part III). The clinical implications of our findings are of utmost importance because of the serious consequences of venous thromboembolism. The fact that patients with meningioma have such a high incidence of thrombosis, for instance, is worth emphasizing because of the benign nature of the tumor and the high potential for cure. As pointed out in a previous review of this topic, the association between brain tumors and venous thromboembolism has not received systematic attention, and most clinical studies of meningiomas fail to identify venous thromboembolism as a significant source of morbidity and mortality ]16]. It is imperative that prophylactic measures be taken in the perioperative period to minimize this risk. Several publications documenting the usefulness of deep venous thrombosis prophylaxis in neurosurgical patients have appeared in the past decade [6, 17-21]; however, no publication has specifically identified brain tumor patients in sufficient numbers to permit prediction of how well prophylactic measures work in this subset of high-risk patients. The reluctance of neurosurgeons to use subcutaneous heparin has led to interest in pneumatic compression boot devices, which have been shown to facilitate blood flow in the lower extremity veins and to enhance systemic fibrinolysis [22]. It is conceivable that a single method (i.e., subcutaneous heparin or pneumatic compression boots) may not be sufficient to significantly reduce the risk of thrombosis and that a combination of measures will be required. Further studies are necessary before this concern can be put to rest. Once identified, the management of venous thromboembolism depends on the location and extent of the thrombi and on the length of time since craniotomy. Large thrombi in the proximal venous system and/or pulmonary embolism must be treated promptly. Full anticoagulation of brain tumor patients has been considered generally safe, although there are no data on how soon after craniotomy anticoagulation can be initiated [23]. Anecdotal experiences suggest that anticoagulation may
be safe as early as 24 hours after craniotomy. However, experimental data in rats suggest an increased risk of intracerebral hemorrhage if anticoagulation therapy is initiated during the first 7 postoperative days [24]. Placement of a vena cava umbrella, on the other hand, carries a low risk when properly performed, but it does not help reduce the occurrence or sequelae of lower extremity thrombophlebitis [23, 25, 26]. In summary, venous thromboembolism represents a frequent and serious complication in brain tumor patients. Biological factors appear to be more significant than clinical factors in determining the likelihood of occurrence of this highly threatening complication. The efficacy of prophylactic measures needs to be studied in this group of patients, and most important a high level of vigilance must be maintained throughout the perioperative period so that effective therapy can be initiated as soon as it is necessary [27].
Acknowledgements This work was made possible by a grant from the Veterans Administration. Data was managed and analyzed using the GCRC Data Management and Analysis System at the University of Cincinnati General Clinical Research Center (Grant No. MO1 RR00068) supported by the Division of Research Resources of the National Institutes of Health. This work was presented in part at the Congress of Neurological Surgeons in Seattle, Washington, in September 1988. We thank Pat Short and Saundra K. Eversole for secretarial assistance.
References 1. Wetzel N, Anderson MC, Sheilds TW: Pulmonary embolism as a cause of death in the neurosurgical patient. J Neurosurg 17: 664-668, 1960 2. Kayser-Gatchalian MC, Kayser K: Thrombosis and intracranial tumors. J Neurol 209: 217-224, 1975 3. Blabey RG, Weil R, III, Santuli TV: Iliofemoral thrombophlebitis associated with central nervous system pathology. Am J Surg 130: 315-316, 1975
125 4. Joffe SN: Incidence of postoperative deep vein thrombosis in neurosurgical patients. J Neurosurg 42: 201-203, 1975 5. Sjoberg HE, Blomback M, Granberg PO: Thromboembolic complications, heparin treatment and increase in coagulation factors in cushing's syndrome. Acta Med Scand 199: 95-98, 1976 6. Barnett HG, Clifford Jr, Llewellyn RC: Safety of mini-dose heparin administration for neurosurgical patients. J Neurosurg 47: 2%30, 1977 7. Valladares JB, Hankinson J: Incidence of lower extremity deep vein thrombosis in neurosurgical patients. Neurosurgery 6: 138-141, 1980 8. Brisman R, Mendell J: Thromboembolism and brain tumors. J Neurosurg 38: 337-338, 1983 9. Swann KW, Black PM: Deep vein thrombosis and pulmonary emboli in neurosurgical patients: A review. J Neurosurg 61: 1055-1062, 1984 10. Ruff RL, Posner JB: The incidence of systemic venous thrombosis and the risk of anticoagulation in patients with malignant gliomas. Am Neurol Assoc 106: 223-226, 1981 11. Choucair AK, Silver P, Levin VA: Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism. J Neurosurg 66: 35%358, 1987 12. Kakkar VV: Deep vein thrombosis detection and prevention. Circulation 51: 8-19, 1975 13. Clayton JK, Anderson JA, McNicol GP: Preoperative prediction of postoperative deep vein thrombosis. Brit Med J 2: 910-912, 1976 14. Browse NL, Clapham WF, Croft DN, Jones D J, Thomas ML, Williams JO: Diagnosis of established deep vein thrombosis with the lzsI Fibrinogen uptake test. Brit Med J 4: 325-328, 1971 15. Sundqvist SB, Hedner U, Kullenberg HKE, Bergentz SE: Deep venous thrombosis of the arm: A study of coagulation and fibrinolysis. Bri Med J 283: 265-267, 1981 16. Sawaya R, DeCourten-Myers G, Copeland B: Massive preoperative pulmonary embolism and suprasellar brain tumor: Case report and review of the literature. Neurosurgery 15: 566-571, 1984 17. Turpie AGG, Gallus AS, Beattie WS, Hirsh J: Prevention of venous thrombosis in patients with intracranial disease
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27.
by intermittent pneumatic compression of the calf. Neurology 27: 435-438, 1977 Cerrato D, Ariano C, Riacchino F: Deep vein thrombosis and low-dose heparin prophylaxis in neurological patients. J Neurosurg 49: 378-381, 1978 Skillman J J, Collins REC, Coe NP, Shapiro RM, Salzman EW: Prevention of deep vein thrombosis in neurosurgical patients: A controlled, randomized trial of external pneumatic compression boots. Surgery 83: 354-358, 1978 Powers SK, Edwards SB: Prophylaxis of thromboembolism in the neurosurgical patient: A review. Neurosurgery 10: 509-513, 1982 Consensus conference prevention of venous thrombosis and pulmonary embolism. JAMA 256: 744-749, 1986 Allenby F, Boardman L, Pflug JJ, Calnau JS: Effects of external pneumatic intermittent compression on fibrinolysis in man. Lancet 2: 1412-1414, 1973 Swann KW, Black PM, Baker MF: Management of symptomatic deep venous thrombosis and pulmonary embolism on a neurosurgical service. J Neurosurg 64: 563-567, 1986 Schaible KL, Smith LJ, Fessler RG, Raichlin JR, Brown FD, Mullau S: Evaluation of the risks of anticoagulation therapy following experimental craniotomy in the rat. J Neurosurg 63: 959-962, 1985 Kakkar VV, Howe CT, Flanc C, Clarke MB: Natural history of postoperative deep-vein thrombosis. Lancet 2: 230233, 1969 Olin J, Young JR, Graor RA, Ruschhaupt WF, Beven EG, Bay JW: Treatment of deep vein thrombosis and pulmonary emboli in patients with primary and metastatic brain tumors. Arch Intern Med 147: 2177-2179, 1987 Di Ricco G, Marini C, Rindi M, Ravelli V, Lutzemberger L, Tusini G, Giuntini C: Pulmonary embolism in neurosurgical patients: Diagnosis and treatment. J Neurosurg 60: 972-975, 1984
Address for offprints: R. Sawaya, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Box 064, Houston, TX 77030, USA
Postoperative venous thromboembolism and brain tumors: part I. Clinical profile
Raymond Sawaya, Mario Zuccarello, Magdy Elkalliny and Hiroshi Nishiyama Departments of Neurosurgery (R.S., M.Z., M.E.) and Nuclear Medicine (H.N.), University of Cincinnati and V.A.M.C., Cincinnati, Ohio 45221, USA
Key words." anticoagulation, brain tumor, fibrinogen scan, prophylaxis, venous thrombosis Abstract
Forty-six patients who underwent surgery for brain tumors were studied prospectively with 125I labeled Fibrinogen leg scans to detect postoperative venous thrombosis. The incidence of thrombosis was 72% for meningioma patients, 60% for glioblastoma patients, and 20% for brain metastasis patients. Correlation between the occurrence of venous thrombosis and the various clinical factors thought to be responsible for the high incidence of thrombosis generally failed to show statistical significance. This finding, along with the marked variation in the incidence of venous thrombosis between the different brain tumor groups, strongly suggests that biological factors play a more important role than clinical factors in determining which brain tumor patient will suffer a postoperative thrombotic event.
A direct association between malignancies and thromboembolic complications has been well established, but the occurrence of these complications in patients with brain tumors has not received sufficient attention. Wetzel et al. reviewed a series of 6,065 neurosurgical patients [1] and found a 3% incidence of fatal postoperative pulmonary emboli; however, patients with brain tumors were not specifically identified [1]. In an autopsy study involving 334 patients with primary intracranial neoplasms, the incidence of venous thrombosis was 27.5%, statistically significantly different from the 17% incidence for a control neurosurgical group [2]. Several clinical studies have confirmed a high incidence of postoperative thrombophlebitis in neurosurgical patients [3-9], but brain tumor patients have rarely been studied separately. In another study, Ruff & Posner reported [10] that of 268 consecutive patients with malignant glioma, 36% developed clinical signs of systemic venous thrombosis. Choucair et al. [11], in their
series of 715 patients, identified a 4% risk of venous thromboembolism after 6 weeks of the craniotomy. In none of these studies were the patients evaluated prospectively. We undertook this study with the hope of specifically identifying clinical risk factors and reliably estimating the incidence of postoperative clots detectable by 125I-labeled fibrinogen scans in patients with the three most common brain tumors [12, 13].
Materials and methods
Forty-six male patients operated on for glioblastoma, meningioma, or brain metastasis at the V.A.M.C. in Cincinnati were included in this study. Clinical data obtained preoperatively included patient age, side of the lesion, duration of symptoms, Karnofsky score, ambulatory status, and the presence of paresis.
120 CT scan data included the size of the mass measured according to the formula Volume =
plethysmography were used whenever confirmation of the venous thrombosis was judged necessary. Prophylactic measures against venous thromboembolism, other than leg wrapping and early ambulation, whenever feasible, were not employed in any of the patients. Statistical analysis of the data was done using standard computerized software and included calculations of the mean, standard error of the mean, and correlation coefficients. Analysis of variance was used for group comparisons. The significance level was at P = 0.05.
( A x B x C) 6
where A, B, and C represent the three longest axes of the mass; and the presence and degree of peritumoral brain edema, graded from 0 to 5 with 0 representing no edema and 5 severe edema. Other clinical data included duration of surgery and estimated blood loss. The general medical status of the patients was comparable among the glioblastoma and the metastasis groups and slightly less affected in the meningioma group. There were no instances of liver failure. Antibiotics (cephalosporin) were given perioperatively to all patients for a duration of 24 hours. Steroids (Dexamethasone) was administered to all patients (16 mg daily) beginning prior to surgery and continuing for a variable number of days depending on the extent of brain edema. All patients were studied one day perioperatively with 125I fibrinogen leg scanning after proper suppression of thyroid gland function [12, 14]. Scans were continued daily for at least 7 days, and when scans were positive, patients were reinjected with 12sI fibrinogen to evaluate any indication of thrombus spread. Venography and/or impedance
Results
Clinical data by tumor type Clinical data are summarized in Table 1. The following differences among the three groups of brain tumor patients were noted: duration of symptoms was more prolonged in the meningioma group; percentage of patients with paretic limbs was highest in the glioblastoma group; tumor size was smallest in the metastasis group, which also had the greatest degree of brain edema; and duration of surgery and estimated blood loss were significantly higher in the meningioma group.
Table 1. Summary of clinical data Clinical characteristic
Total
By group Meningioma
Glioblastoma
Age (years) Side of tumor (% right) Duration of symptoms (days) Karnofsky score (0-100) Ambulatory status (%) Paresis (% of patients) Size of mass (cm 3) Edema score (0-5) Steroid treatment (days) Anesthesia time (minutes) Estimated blood loss (ml)
Number
Mean
SEM
46 46 43 43 44 44 37 36 18 44 27
62.43 1.07 56.5 117.83 21.41 66.04 3.12 68.18 59.09 39.64 2.50 0.25 13.52 4.60 278.13 19.79 333.88 68.42
Mean
SEM
59.60 2.23 40 118.28 32.26 59.28 4.85 53 80 56.84 7.68 2.14 0.34 9.83 2.41 235.00 26.73 281.85 40.01
(N) Mean 15 15 14 14 15 15 14 14 6 14 8
SEM
63.54 1.71 81 239.00 62.27 77.00 5.97 90 30 48.36 16.05 1.55 0.41 3.00 1.08 396.00 48.84 725.00 252.23
Metastasis (N) Mean 11 11 10 10 10 10 9 9 3 11 6
SEM
63.95 1.50 55 53.73 13.77 65.26 4.91 68 57 16.84 5.79 3.53 0.40 20.66 9.17 241.21 20.37 185.76 20.11
P (N) 20 20 19 19 19 19 14 13 9 19 13
0.18 0.19 0.001 0.10 0.16 0.04 0.006 0.003 0.31 0.001 0.003
121 Fibrinogen scan data:
Incidence
of Thrombosis
100
Forty-five percent of the patients had fibrinogen scan evidence of venous thrombosis occurring after craniotomy. The diagnosis was confirmed by other methods in 44% of the patients when judged necessary because of the spread of the thrombi and/or prior to initiation of therapy. One third of the patients had no symptoms associated with the thrombotic event, and all patients with negative scans were studied for at least 7 days following craniotomy. The incidence of venous thrombosis differed markedly among the groups (Fig. 1). The highest rate was in the meningioma group (72%) followed by the glioblastoma group (60%). The metastasis group had a surprisingly low rate of thrombosis (20%) compared with the other two groups. There were no noticeable differences among the three groups with regard to the remaining fibrinogen scan data (Table 2). Approximately 40% of the patients with a positive scan received treatment for thrombosis. The decision to treat was influenced by the evidence of proximal spread of the thrombi and/or the presence of thrombi in the large proximal venous system of the lower extremities. The treatment consisted of either standard anticoagulation therapy or vena cava filter based on the proximity of the thrombotic event to the time of craniotomy. Two patients died of thromboembolic complications. The first was a patient with glioblastoma who died suddenly on the
T
SEM 0.005
P 75
Percent 50
25
GBM
MNG
METS
Fig. 1. G B M , g l i o b l a s t o m a ; M E T S , m e t a s t a s i s ; M N G , men i n g i o m a ; S E M = s t a n d a r d e r r o r of the m e a n ; T E C , t h r o m b o e m b o l i c c o m p l i c a t i o n . I n c i d e n c e of v e n o u s t h r o m b o s i s by b r a i n t u m o r group. T h e a s t e r i s k r e p r e s e n t s the g r o u p t h a t is statistically significantly d i f f e r e n t from the others.
second postoperative day from a massive pulmonary embolism, and the second was a patient with a frontal convexity meningioma who died on the twelfth postoperative day from mesenteric thrombosis and total infarction of the bowels.
Correlation data Specific preoperative clinical parameters were correlated with the occurrence of venous thromboembolism (Table 3). There was no significant correlation between the occurrence of a thrombotic event and any of the frequently cited 'risk factors', name-
Table 2. S u m m a r y of 125I f i b r i n o g e n scan d a t a By group Total Number D u r a t i o n of s c a n n i n g (days) P o s i t i v e scan ( % ) Days positive Diagnosis confirmed (%) Symptoms present (%) S p r e a d of t h r o m b i ( % ) Treatment initiated (%)
44 46 19 18 18 20 17
Glioblastoma Mean
SEM
Mean
Meningioma
SEM
N
Mean
Metastasis
Sere
N
Mean
P
SEM
N
8.88
0.47
8.57
0.76
14
10.50
0.90
10
8.50
0.77
20
0.39
45.65 4.63
0.76
60 4.75
1.12
15 8
72 5.14
1.58
11 7
20 3.50
1.25
20 4
0.005 0.75
44.44 66.66 35.00
-
50 50 25
-
6 6 8
50 75 50
-
8 8 8
25 75 25
-
4 4 4
0.71 0.61 0.56
41.17
-
40
-
5
50
-
8
25
-
4
0.74
122 ly age, Karnofsky score, ambulatory status, presence of paretic limbs, and duration of surgery. Patients with prolonged duration of symptoms tended to have a higher incidence of thromboembolism. Similarly, patients with larger tumors were more likely to suffer a thromboembolic complication.
Venous thrombosis within tumor groups
Because of differences in specific clinical parameters noted among the three tumor groups (Table 1), a comparison within each tumor group was made with regard to the occurrence or lack of occurrence of venous thromboembolism. The results again indicated no statistically significant differences in the occurrence of thromboembolism within the groups for any of the following parameters: age, Karnofsky score, ambulatory status, or duration of surgery (Table 4). Overall, however, older patients tended to have a higher incidence of venous thrombosis. Patients with a brain metastasis and venous thrombosis tended to have a longer duration of symptoms, a lower Karnofsky score, a lower ambulatory status, and a higher percentage of limb paresis (Table 4, Figs 2, 3). Interestingly, patients with glioblastoma and venous thrombosis tended to have a higher Karnofsky score and were less likely to have paretic limbs (Table 4, Fig. 3). Meningioma patients with venous thrombosis had the same duration of surgery as those without thrombosis but tended to have fewer paretic limbs,
larger tumors, more peritumoral edema, and greater blood loss (Table 4, Fig. 3).
Discussion
The incidence of venous thrombosis as demonstrated by the 125I fibrinogen scan is considered reliable: the test is well established, technically easy, and highly sensitive, and thrombosis has been documented in every patient with a positive scan who has undergone venography [12, 14]. In addition, the duration of leg scanning in our study was long enough to detect the great majority of venous thrombi occurring postoperatively. It is conceivable that in a few instances, patients may have suffered from venous thrombosis in sites of the body other than the veins of the lower extremities; such events, however, are not frequent enough to affect the results of this study [15]. The marked variability in the incidence of venous thrombosis among the various tumor types was an unexpected finding. Moreover, analysis of the results with regard to the major risk factors generally identified in neurosurgical patients failed to predict the likelihood of thrombosis [9]. The high incidence of venous thrombosis in the meningioma group could have been explained on the basis of a longer duration of surgery, as demonstrated in Table 1; however, correlative analysis failed to indicate any statistical significance for this parameter, and a comparison within the meningioma group also did not demonstrate any significant
Table 3. Correlation coefficient data venous thrombosis vs clinical p a r a m e t e r Parameter
N
R
P
Age Side of t u m o r D u r a t i o n of sy mp toms Karnofsky
46 46 43 43
0.13 0.009 0.25 - 0.03
0.38 0.94 0.09 0.82
A m b u l a t o r y status
44
- 0.19
0.21
Paresis Size Edema A n e s t h e s i a Time E s t i m a t e d blood loss
44 37 36 44 27
- 0.11 0.34 - 0.22 0.14 0.31
0.45 0.03 0.18 0.34 0.11
123 • No TEC [] TEC
m No TEC
i00
[] TEC SEM : 0.04
100
Percent Ambulatory
Percent
5O
Paretie
50
m
GBM
MNG
METS
GBM
Fig. 2. Differences in ambulatory status of patients within each
MNG
METS
Fig. 3. Percentage of patients with paretic limbs within each brain tumor group. The asterisks represent the groups that are statistically significantly different.
brain tumor group.
difference in duration of surgery (Table 4). In several instances, a paradoxical result was found; e.g., as shown in Fig. 3, glioblastoma and meningioma patients suffering a thrombotic event were less likely to have a paretic limb than were those patients within the same group who had a negative fibrinogen scan. The duration of symptoms did correlate positively with thrombosis (P = 0.09), and as shown in Table 4, this appears to apply to both groups with malignant brain tumors. Such a finding may suggest that for intraaxial masses, longer periods of growth may be associated with a greater degree of cerebral disturbance and release of thrombogenic
material. This same hypothesis may apply to benign extraaxial tumors because the tumors associated with venous thrombosis in that group caused almost twice as much edema as those tumors without associated thrombosis (Table 4). Brain edema, however, was not a factor for the other two tumor groups. The results of this study suggest that the occurrence of thrombotic complications is specifically related to the type of tumor and, therefore, is biologically determined and that clinical parameters such as paresis, lack of ambulation, and duration of surgery are non-determinant factors, at least dur-
Table 4. Results by group and TEC Parameter
Glioblastoma TEC-
Mean Age (years) 57.33 Duration of 91.40 symptoms (days) Karnofsky score 56.00
Meningioma TEC+
SEM
TEC-
Metastasis TEC+
TEC-
Mean
SEM
Mean
SEM
Mean
SEM
4.18 21.88
61.11 133.22
2.57 49.19
59.33 303.33
4.97 203.00
65.12 211.42
1.34 44.73
9.79
61.11
5.63
80.00
11.54
75.71
11.68 0,54
57.81 2.12
10.88 0.47
33.60 1.00
27.11 0.57
44.76
246.87
34.67
376.66
100.00
275.00
47.87
375.00
Mean
P TEC+
SEM
Mean
SEM
63.56 38.06
1.84 11.41
65.50 112.50
1.50 40.85
0.32 0.01
7.51
67.33
5.56
57.50
11.08
0.37
55.75 1.83
20.94 0.54
16.98 3.50
6.25 0.43
9.00 3.66
6.00 0.33
0.04 0.04
84.12
404.37
62.43
254.53
23.96
191.25
26.95
0.01
225.00
900.00
346.41
186.50
23.89
183.33
44.09
0.01
(0-100)
Tumor size (cm3) 55.55 Edema score 2.16 (0-5)
Anesthesia time 219.16 (minutes) Blood loss(ml) 300.00
124 ing the immediate perioperative period. Such a conclusion should stimulate interest in studying the tumor tissue for a better understanding of the pathogenetic mechanisms involved (see Part III). The clinical implications of our findings are of utmost importance because of the serious consequences of venous thromboembolism. The fact that patients with meningioma have such a high incidence of thrombosis, for instance, is worth emphasizing because of the benign nature of the tumor and the high potential for cure. As pointed out in a previous review of this topic, the association between brain tumors and venous thromboembolism has not received systematic attention, and most clinical studies of meningiomas fail to identify venous thromboembolism as a significant source of morbidity and mortality ]16]. It is imperative that prophylactic measures be taken in the perioperative period to minimize this risk. Several publications documenting the usefulness of deep venous thrombosis prophylaxis in neurosurgical patients have appeared in the past decade [6, 17-21]; however, no publication has specifically identified brain tumor patients in sufficient numbers to permit prediction of how well prophylactic measures work in this subset of high-risk patients. The reluctance of neurosurgeons to use subcutaneous heparin has led to interest in pneumatic compression boot devices, which have been shown to facilitate blood flow in the lower extremity veins and to enhance systemic fibrinolysis [22]. It is conceivable that a single method (i.e., subcutaneous heparin or pneumatic compression boots) may not be sufficient to significantly reduce the risk of thrombosis and that a combination of measures will be required. Further studies are necessary before this concern can be put to rest. Once identified, the management of venous thromboembolism depends on the location and extent of the thrombi and on the length of time since craniotomy. Large thrombi in the proximal venous system and/or pulmonary embolism must be treated promptly. Full anticoagulation of brain tumor patients has been considered generally safe, although there are no data on how soon after craniotomy anticoagulation can be initiated [23]. Anecdotal experiences suggest that anticoagulation may
be safe as early as 24 hours after craniotomy. However, experimental data in rats suggest an increased risk of intracerebral hemorrhage if anticoagulation therapy is initiated during the first 7 postoperative days [24]. Placement of a vena cava umbrella, on the other hand, carries a low risk when properly performed, but it does not help reduce the occurrence or sequelae of lower extremity thrombophlebitis [23, 25, 26]. In summary, venous thromboembolism represents a frequent and serious complication in brain tumor patients. Biological factors appear to be more significant than clinical factors in determining the likelihood of occurrence of this highly threatening complication. The efficacy of prophylactic measures needs to be studied in this group of patients, and most important a high level of vigilance must be maintained throughout the perioperative period so that effective therapy can be initiated as soon as it is necessary [27].
Acknowledgements This work was made possible by a grant from the Veterans Administration. Data was managed and analyzed using the GCRC Data Management and Analysis System at the University of Cincinnati General Clinical Research Center (Grant No. MO1 RR00068) supported by the Division of Research Resources of the National Institutes of Health. This work was presented in part at the Congress of Neurological Surgeons in Seattle, Washington, in September 1988. We thank Pat Short and Saundra K. Eversole for secretarial assistance.
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Address for offprints: R. Sawaya, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Box 064, Houston, TX 77030, USA
