ORIGINAL ARTICLE
Does traumatic brain injury increase the risk for venous thromboembolism in polytrauma patients? Evan J. Valle, MD, Robert M. Van Haren, MD, MSPH, Casey J. Allen, MD, Jassin M. Jouria, MD, M. Ross Bullock, MD, PhD, Carl I. Schulman, MD, PhD, Nicholas Namias, MD, Alan S. Livingstone, MD, and Kenneth G. Proctor, PhD, Miami, Florida
Trauma is a major risk factor for venous thromboembolism (VTE). Traumatic brain injury (TBI) is generally considered to further increase the VTE risk, which should prompt routine thromboprophylaxis. However, the associated risk for intracranial hemorrhage often delays anticoagulants. We test the hypothesis that TBI associated with polytrauma results in a higher rate of VTE than polytrauma without TBI. METHODS: From August 2011 to June 2013, a prospective observational trial with informed consent was performed in 148 intensive care unit (ICU) patients with a Greenfield Risk Assessment Profile score of 10 or greater. RESULTS: Demographics, Greenfield Risk Assessment Profile scores, the incidence of polytrauma, and mortality were similar, but TBI patients had worse Injury Severity Scores (ISS) (32 vs. 22), longer ICU lengths of stay (21 days vs. 12 days), more hypercoagulable thromboelastogram values on admission (94% vs. 79%), more received unfractionated heparin prophylaxis (65% vs. 36%), and the prophylaxis start date was more than a day later (all p G 0.05). Nevertheless, the VTE rate with TBI was similar to that without TBI (25% vs. 26%, p = 0.507). Furthermore, VTE occurred at similar time points after ICU admission with and without TBI. In both groups, about 30% of the VTEs were detected within 2 days of ICU admission and 50% of the VTEs occurred within 10 days of admission despite chemical and mechanical thromboprophylaxis. CONCLUSION: In complex polytrauma patients who survived to ICU admission and who were prescreened for high VTE risk, TBI did not further increase the risk for VTE. The most likely explanation is that no single risk factor is necessary or sufficient for VTE development, especially in those who routinely receive chemical and mechanical thromboprophylaxis. (J Trauma Acute Care Surg. 2014;77: 243Y250. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Epidemiologic study, level III. KEY WORDS: Thromboelastography; coagulopathy; heparin; intensive care unit. BACKGROUND:
T
raumatic brain injury (TBI) is a leading cause of death and disability in both civilian and military populations.1Y4 Proper management is especially difficult when complex polytrauma is superimposed on TBI.5Y7 In general, patients hospitalized with trauma or TBI have increased risks for both bleeding and venous thromboembolism (VTE). Additional relative risk factors are hypercoagulability, age, lower extremity fractures, indwelling catheters, and blood product transfusions.8Y11 These factors have been compiled into the Greenfield Risk Assessment Profile (RAP) and have provided the foundations for current thromboprophylaxis strategies.12Y15 There is no absolute definition of high VTE risk, and most agree that thromboprophylaxis is necessary in polytrauma patients with or without TBI. However, there is considerable
Submitted: January 16, 2014, Revised: March 11, 2014, Accepted: March 14, 2014. From the Dewitt-Daughtry Family Department of Surgery, Divisions of Trauma and Surgical Critical Care, and Department of Neurosurgery, University of Miami Miller School of Medicine, Ryder Trauma Center, Miami, Florida. This study was presented at the 9th Annual Academic Surgical Congress, February 4Y6, 2014, in San Diego, California. Address for reprints: Kenneth G. Proctor, PhD, Dewitt-Daughtry Family Department of Surgery, Divisions of Trauma and Surgical Critical Care, University of Miami Miller School of Medicine, Ryder Trauma Center, 1800 NW 10th Ave, Miami, FL 33136; email: [email protected]. DOI: 10.1097/TA.0000000000000307
uncertainty about the prophylaxis modality (pharmacologic or mechanical) and about the optimal agent, dose, timing, and duration.16Y18 In a series of studies, we have identified coagulation changes and VTE risk factors in high-risk surgical and trauma patients.19Y24 We now test the hypothesis that TBI associated with polytrauma results in a higher rate of VTE than polytrauma without TBI.
PATIENTS AND METHODS This was an institutional review boardYapproved, prospective, observational trial with informed consent. All patients admitted to the intensive care unit (ICU) of the Level I Ryder Trauma Center at Jackson Memorial Hospital/University of Miami from August 2011 until June 2013 were eligible. Exclusions were those who were pregnant, incarcerated, younger than 18 years, and/or with delayed presentation due to transfer. All patients were screened with RAP,12 which assigns a numerical VTE risk score on the basis of age, medical history, iatrogenic factors, and injury-related factors. Those with an indwelling catheter and an RAP score of 10 or greater upon admission to the ICU were asked to participate in the trial. If consent was obtained, serial bilateral lower extremity venous Doppler ultrasound (VDU) and serial blood samples for coagulation analysis using thromboelastography (TEG)
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were performed. Repeat VDU and blood samples were obtained weekly for those who remained in the ICU; however, in this current study, only admission TEG values were evaluated. Patients who died, those who were transferred to the floor, or those with VTE on initial VDU did not undergo repeat VDU or TEG. VDU evaluated the deep venous system of the lower extremities from the ankle to the inguinal ligament. Deep venous thrombosis (DVT) was defined as an abnormality seen on VDU such as the presence of dilated, noncompressible veins or intraluminal shadows consistent with thrombosis. The DVTs were catalogued as being either above the knee or below the knee. Pulmonary embolism (PE) was defined as a filling defect detected on a computed tomography (CT) pulmonary angiogram, which was ordered only on the basis of clinical suspicion such as the onset of abrupt and unexplained hypoxia, hypotension, tachycardia, or any combination of the aforementioned. No institutional-based guidelines exist for obtaining CT pulmonary angiograms in the ICU; however, evidence-based guidelines are followed.16 The primary outcome was VTE, defined as either PE or DVT in the ankle to the groin, including thrombus in the soleus and gastrocnemius veins. There was no specific protocol for treatment of asymptomatic or symptomatic VTE, but the practice among our group of experienced trauma surgeons is relatively consistent. The general treatment strategy is to administer full therapeutic anticoagulation for 3 months to 6 months in the absence of contraindications and the placement of inferior vena cava (IVC) filters in those patients with contraindication to chemical anticoagulation according to evidence-based guidelines.16 During the course of this study, the chemical thromboprophylaxis protocol at this institution changed three times. Heparin (5,000 U subcutaneous TID) was the standard when the study started; however, a transition was made to dalteparin (5,000 U subcutaneous daily) and then finally to enoxaparin (30 mg subcutaneous BID). Blood (6ml) was drawn from indwelling radial arterial catheters, peripherally inserted central catheters, or central venous catheters into two vacuum-sealed tubes containing sodium citrate. After 15 minutes, an aliquot of blood (340 KL) was transferred to the TEG (Thromboelastograph Hemostasis Analyzer Model 5000 System, Braintree, MA) and reconstituted using 20 KL of CaCl2. TEG was performed on native whole blood samples with no activation material. Each TEG sample was run in duplicate and averaged to ensure an accurate result. TEG parameters included reaction time (R), k-time (K), alpha angle (>), maximum amplitude (MA), and G-value (G). R is the time between initiation of the test and the initial fibrin formation and represents the enzymatic portion of coagulation. K is the time needed to reach 20-mm clot strength and represents clot kinetics. > is the measure of the TEG tracing’s slope and represents fibrin cross-linking. MA is the measure of the overall clot strength and represents platelet aggregation. G is a measure of clot strength. In this present study, hypercoagulability was defined by values outside the standard reference ranges, specifically as R of less than 9 minutes, K of less than 2 minutes, > of greater than 58 degrees, or MA of greater than 64 mm. 244
TBI was defined by the presence of subdural hemorrhage, epidural hemorrhage, focal contusion, or diffuse axonal injury on CT. Polytrauma was defined by the Abbreviated Injury Scale (AIS) score in two or more body regions. The sample size was estimated based on the assumptions that the incidence of VTE in TBI patients ranges from 25% to 35%, depending on whether prophylaxis is used or contraindicated because of intracranial hemorrhage,9,16 and that the incidence of VTE in the general trauma population ranges from a low of 6%17,18 to about 25% in patients prescreened with RAP of greater than 10.19 Accordingly, the minimum group size is n = 20 and the maximum group size is n = 114 to detect a difference in VTE rates between TBI and trauma, with an > of 0.05 and a power of 0.80. Data were analyzed using SPSS version 21.0 (IBM Corporation, Armonk, NY). If values were normally distributed, data are reported as mean T SD. If values were not normally distributed, data are reported as median (interquartile range). Independent data were compared with the Student’s t test and the Mann-Whitney U-test for parametric and nonparametric data, respectively. Categorical data were compared with the W2 test or the Fisher’s exact test.
RESULTS Figure 1 shows that there were 741 trauma ICU admissions that were screened between August 2011 and June 2013; a total of 170 were consented and 148 were enrolled. Patients were not enrolled because of RAP of less than 10, refusal to participate in the study, lack of a designated proxy, or no indwelling catheter from which to draw blood. About half of the study population had TBI and half had no TBI, but the majority in both groups had polytrauma, as defined by an AIS score in more than one body region. The demographics were as follows: age, 47 years T 19 years; male,
Figure 1. CONSORT diagram showing patients who were screened, consented, and enrolled. Patients were not enrolled because of RAP score of less than 10, refusal to participate in the study, lack of a designated proxy, or no indwelling catheter from which to draw blood. CVC, central venous catheter. * 2014 Lippincott Williams & Wilkins
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received chemical thromboprophylaxis, 71 (55%) received subcutaneous heparin, 54 (42%) received dalteparin, and 4 (3%) received therapeutic anticoagulation with a heparin drip. Only one patient received enoxaparin. IVC filters were placed in 8 of the non-TBI patients within a median (interquartile range) of 2 days (4 days) and in 14 of the TBI patients within a median (interquartile range) of 7 days (10 days). One IVC filter in the non-TBI group and two IVC filters in the TBI group were placed because of contraindications to chemical anticoagulation. In addition, mechanical prophylaxis was used in 126 patients (86%). Both chemical and mechanical prophylaxis were used in 108 patients (73%). Only one patient in the non-TBI cohort had both chemical and mechanical thromboprophylaxis withheld because of contraindications. Contraindications to mechanical prophylaxis were complex lower extremity fractures that required external fixation with hardware or bilateral lower extremity amputations. Contraindications to chemical thromboprophylaxis were continued progression of intracranial hemorrhage, postoperative bleeding, and anemia. There was no significant difference in VTE rates with heparin or dalteparin thromboprophylaxis (23% vs.
Figure 2. Cumulative total VTE versus time in those with and without TBI.
78%; blunt mechanism of injury, 76%; Injury Severity Score (ISS), 27 T 11; ICU days, 16 (22); and mortality, 14%. VTE was detected in 26% (n = 38) of patients and occurred a median (interquartile range) of 10 days (14 days) after admission. Thirty-one of the VTEs were DVTs, 7 in the upper extremity, which were symptomatic and not detected in the VDU screening protocol; 23 above the knee; and 1 below the knee, which was located in the lesser saphenous vein. The remaining seven VTEs were PEs. One DVTwas discovered at the time PE was detected. Figure 2 shows that VTE occurred at similar time points during the ICU length of stay (LOS) with or without TBI. In both groups, about 30% of the VTEs were detected within 2 days of ICU admission. Most of the VTEs were DVTs (n = 31, 82%), and the remaining were PEs (n = 7, 18%). Of the PE patients, two had DVT as well, one discovered at the same time as the PE and the other approximately 9 weeks before the PE. In this particular subset, four patients (66%) in the non-TBI group and three patients (60%) in the TBI group were hypercoagulable on initial TEG screening ( p = 0.500). Figure 3 A and B shows the distribution of chemical thromboprophylaxis and therapeutic anticoagulation for both the non-TBI and TBI groups, respectively. For the overall population, the median (interquartile range) time until drug initiation was 2 days (2 days) after admission. In those who
Figure 3. Distribution and type of chemical prophylaxis or therapeutic anticoagulation. Chem, chemical; iv, intravenous; sq, subcutaneous.
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22%, p=0.571) or between thromboprophylaxis and no thromboprophylaxis (23% vs. 28%, p = 0.425), but the study was not powered to detect either of these effects (see Discussion). The median (interquartile range) time from initial hospital admission to initial TEG was 1.2 days (0.6 days). Most (i.e., 86%) of the patients were hypercoagulable, defined by at least one TEG value outside the reference range. R was decreased in 78%, K was decreased in 55%, > was increased in 74%, and MA was increased in 29%. The population’s values were R, 7.1 minutes (3.1 minutes); K, 1.9 minutes (0.8 minutes); >, 61.1 degrees T 9.4 degrees; and MA, 60 mm T 7mm. There was no significant difference in VTE rates between the patients who were hypercoagulable on admission compared with those who were not hypercoagulable (25% vs. 30%, p = 0.401). All patients in the TBI group had an AIS score (head) of greater than 2, plus head CT changes including 52 patients (76%) with subarachnoid hemorrhage, 24 (35%) with intraventricular hemorrhage, 22 (32%) with intraparenchymal hemorrhage, 19 (29%) with nonspecific intracranial hemorrhage, 20 (29%) with subdural hemorrhage, 6 (9%) with epidural hemorrhage, and 4 (6%) with diffuse axonal injury. An AIS score (head) of greater than 3 occurred in 59 (87%) of the TBI group. VTE was not solely encountered in the 87% with an AIS score (head) of greater than 3; however, five (55%) of the remainder who did not have an AIS score (head) of greater than 3 had VTE. Specifically, there were five total VTEs in this group, four DVTs and one PE, which was discovered simultaneously with one of the DVTs. An intracranial pressure monitor was placed in 46% (n = 31) of these TBI patients. Craniotomy or craniectomy was performed in 38% (n = 26) of the TBI patients. There were a total of 12 craniectomies and 14 craniotomies described in the operative reports. In the non-TBI group, there were six patients (8%) who had a Glasgow Coma Scale (GCS) score of less than 8. Low GCS score was attributed to hemorrhagic shock, combativeness, or seizure/unconsciousness rather than to TBI because there were no head CT changes. All these patients were intubated in the field or required intubation shortly after arrival because of inability to protect their airways. Table 1 shows that demographics, RAP scores, and incidence of polytrauma were similar in TBI versus no TBI. The TBI group had a greater incidence of blunt trauma (99% vs. 58%, p G 0.001), had higher ISS (32 vs. 22, p G 0.001), was more hypercoagulable (94% vs. 79%, p = 0.005), and had longer ICU LOS (21 days vs. 12 days, p = 0.007). The mortality rate was numerically higher (18% vs. 9%), but the apparent difference did not reach statistical significance ( p = 0.076). The patients in the TBI group received more unfractionated heparin (65% vs. 36%, p = 0.004) and less dalteparin than the non-TBI group (20% vs. 53%, p G 0.001). There were more missed doses of chemical thromboprophylaxis in the TBI group within the first 2 weeks of enrollment as well (2 vs. 7, p G 0.001). The TBI patients also had their VTE prophylaxis withheld a median (interquartile range) of 1 day longer than those patients without TBI (3 days [1 day] vs. 2 days [2 days], p = 0.010). Nevertheless, neither the VTE rate (24% vs. 26%, p = 0.507) nor the distribution of VTE between above the knee, below the knee, upper extremity, and PE differed between the TBI and no TBI groups. 246
TABLE 1. Characteristics of Trauma ICU Patients With and Without TBI Non-TBI (n = 80) Age Male Blunt mechanism Polytrauma RAP ISS Hypercoagulable Heparin prophylaxis Dalteparin No VTE prophylaxis ICU LOS, d VTE rate Above knee DVT Below knee DVT Upper extremity DVT PE IVC filter Mortality TEG values R, min K, min >, degrees MA, mm G, dyne/cm2 Laboratory values PT, s INR aPTT, s Platelets, 103/KL
49 T 19 76% 58% 69% 14 T 3 22 T 10 79% 36% 53% 10% 12 (19) 26% 10 (48%) 1 (4%) 4 (19%) 6 (29%) 8 (10%) 9% 7.2 (3.3) 2.1 (1.1) 58.9 T 10.7 57.7 T 6.9 7,158 T 2,050 12.0 (1.9) 1.0 (0.2) 25.8 (7.0) 232 T 98
TBI (n = 68) 45 T 18 81% 99% 76% 15 (6) 32 T 11 94% 65% 20% 15% 21 (22) 25% 13 (76%) 0 (0%) 3 (18%) 1 (6%) 14 (21%) 18% 7.1 (3.0) 1.8 (0.7) 63.6 T 6.9 61.9 T 6.6 8,545 T 2,344 11.5 (1.9) 1.0 (0.2) 27.1 (6.0) 242 T 64
p 0.259 0.495 G0.001 0.345 0.122 G0.001 0.005 0.004 G0.001 0.350 0.007 0.507 0.0691 V 0.624 0.0823 0.0579 0.076 0.213 0.001 0.002 G0.001 G0.001 0.98 0.093 0.116 0.441
aPTT, activated partial thromboplastin time; INR, international normalized ratio; PT, prothrombin time. Boldface indicates statistical significance.
Using multiple logistic regression, TBI was the only significant variable predicting hypercoagulability among all variables of the RAP score. Nevertheless, neither TBI nor any other single RAP score variable significantly predicted VTE in the regression model (data not shown). There were multiple iatrogenic and injury-related risk factors favoring VTE development in the non-TBI patients (Table 2). These included four or more transfusions in the first 24 hours after admission (81% vs. 60%, p = 0.003), more surgical procedures longer than 2 hours (64% vs. 46%, p = 0.027), more repair of major vascular injury (45% vs. 21%, p = 0.002), and more complex lower extremity fracture (45% vs. 25%, p = 0.011). Inflammation from multiple trips to the operating room and infection could have also contributed to the risk for VTE. Fifteen patients (10%) had positive blood culture results, seven in the non-TBI group (of which two were associated with VTE) and eight in the TBI group (of which three were associated with VTE). None of these apparent differences were statistically significant. However, there were a total of four patients (one in the non-TBI group and three in the TBI group) who had * 2014 Lippincott Williams & Wilkins
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TABLE 2. Risk Factors of VTE in Trauma ICU Patients With and Without TBI RAP variables Obesity (BMI 9 30 kg/m2) Malignancy Abnormal coagulation History of VTE Femoral line 94 transfusions in 24 h OR 9 2 h Vascular injury AIS score chest 9 2 AIS score abdomen 9 2 AIS score head 9 2 GCS score G 8 Lower extremity fracture Pelvic fracture Spinal cord injury Age 40Y59 y Age 60Y75 y Age 9 75 y Additional risk factors Central line Central/PICC line Arterial line PPX, % Days to PPX Days to first VDU Switched PPX Mechanical PPX Missed doses of chemical PPX*
Non-TBI (n = 80)
TBI (n = 68)
p
40% 4% 64% 1% 20% 81% 64% 45% 53% 44% 3% 8% 45% 39% 9% 28% 24% 11%
24% 0% 50% 0% 18% 60% 46% 21% 51% 41% 100% 71% 25% 46% 1% 32% 21% 6%
0.043 0.161 0.092 0.547 0.776 0.003 0.027 0.002 0.901 0.752 G0.001 G0.001 0.011 0.401 0.056 0.520 0.645 0.271
70% 71% 95% 90 2 (2) 1 (1) 26% 79% 2 (6)
59% 63% 94% 85 3 (1) 1 (1) 16% 90% 7 (7)
0.156 0.299 0.531 0.247 0.010 0.934 0.161 0.064 G0.001
*First 2 weeks of study enrollment. OR, operative intervention; PICC, peripherally inserted central catheter; PPX, thromboprophylaxis.
a positive blood culture result before the occurrence of VTE. Finally, three patients (all in the TBI group) had positive blood culture results before VTE occurrence and were hypercoagulable on initial TEG. Both groups had a median (interquartile range) of 2 (2) operations during their LOS ( p = 0.144). To address the possibility that the non-TBI cohort achieved an RAP of 10 or greater simply because of the aforementioned factors, and effectively created dissimilar groups, all TBI patients were excluded who had an RAP score of less than 10 if their TBI was ignored. This resulted in 17 patients being excluded from the TBI group (n = 51). In this subset, the VTE rate was 26%, which was equal to the VTE rate of the non-TBI patients.
DISCUSSION This is the sixth in a recent series of studies from our group on hypercoagulability in various populations of surgical patients.19Y24 To our knowledge, this is the first study to examine VTE rates in complex trauma patients with superimposed TBI
recovering in the ICU. It should be emphasized that this study population is by no means representative of trauma patients in general. Only a small fraction of the sickest trauma patients are admitted to the ICU, and fewer than 20% of ICU admissions met our definition of high VTE risk (i.e., RAP score 9 10). The major new findings are that, relative to those with no TBI, trauma patients with TBI had worse ISS, had longer LOS, and were more hypercoagulable on admission (all p G 0.05). Fewer received chemical VTE prophylaxis, almost twice as many received unfractionated heparin as low-molecularweight heparin (LMWH) prophylaxis, the prophylaxis start date was more than 1 day later, and more had missed doses (all p G 0.05). Nevertheless, the VTE rate with TBI was similar to that without TBI (24% vs. 26%, p = 0.507). Despite some differences in experimental design, the VTE rate we observed in high-risk trauma patients is remarkably similar to that observed by others. Denson et al.9 evaluated 5,787 trauma patients and deemed 539 (9%) as high risk for VTE. The incidence of VTE determined with surveillance VDU in patients with isolated TBI (88, 16%) was 25%, excluding those with pelvic fracture, lower extremity fracture, and spinal cord injury with paralysis.9 In this present study, the VTE rate was also 25%; 741 trauma ICU admissions were screened and 148 (20%) met criteria as high risk for VTE (i.e., RAP score 9 10 incorporates risk factors such as fractures and spinal cord injury). One major difference is that the mean time to thromboprophylaxis was 14.2 days in the Denson et al. study versus 2 days in this present study. We recently concluded that hypercoagulability (at least on ICU admission) was neither necessary nor sufficient for VTE development.21 The results from this present study confirm and extend that idea. We now report that TBI was the most important variable predicting admission hypercoagulability among all variables of the RAP score, but neither hypercoagulability nor TBI was associated with higher VTE rates. Furthermore, using multiple logistic regression, no other combination of risk factors was highly correlated with VTE risk. In retrospect, this lack of correlation is probably not surprising. Every patient in our study population was already prescreened with RAP,12,13 and those are the same variables used in our regression analysis. We also observed no significant difference in VTE rates between heparin and dalteparin thromboprophylaxis (23% vs. 22%, p = 0.571) or between chemical anticoagulation and mechanical thromboprophylaxis in trauma patients with contraindications for chemical anticoagulation (23% vs. 28%, p = 0.425). Both of these results are almost certainly Type II statistical errors. This study was in no way powered to detect either of those effects. Assuming the same VTE rate, the same distribution of treatments, and the same contraindications for thromboprophylaxis in Figure 2 in this high-risk ICU population, the sample size would have had to be about 2,000 patients to detect an effect of heparin versus dalteparin and about 20,000 patients to detect an effect of a drug versus sequential compression devices. Another possible explanation for the lack of observed difference in the VTE rate between the two subgroups is the almost universal use of mechanical prophylaxis at our
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institution. Ginzburg et al.18 conducted a prospective randomized trial in 442 patients who received thromboprophylaxis with either an intermittent pneumatic compression device or LMWH and serial VDU. They concluded that mechanical thromboprophylaxis is both safe and effective in trauma patients relative to LMWH.18 In this present study, mechanical prophylaxis was used in 126 patients (86%). Both chemical and mechanical prophylaxis were used in 108 patients (73%). The pathogenesis of VTE has traditionally been summarized by the Virchow triad, which includes endothelial injury, venous stasis, and hypercoagulability. Greenfield et al.12 incorporated these and additional risk factors in developing the trauma RAP score. Our data showed multiple iatrogenic and injury-related risk factors favoring VTE development in both TBI (Table 1) and non-TBI polytrauma patients (all p G 0.05) who survived to ICU admission, including obesity, more transfusions, longer operative intervention, twice as many vascular repairs, and lower extremity fractures (Table 2). In a meta-analysis of 34 studies, Harhangi et al.25 showed an overall prevalence of coagulopathy of 33% in TBI patients and that coagulopathy after TBI was related to both mortality and unfavorable outcome. In this present study, 86% of the patients were hypercoagulable, defined by at least one TEG value outside the reference range, but there was no significant difference in VTE rates between the patients who were and who were not hypercoagulable on admission (25% vs. 30%, p = 0.401). Coagulopathy and high VTE rates have also been demonstrated in other surgical patient populations.18Y27 It is logical to predict that the risk for VTE would increase when TBI is accompanied by polytrauma and/or coagulopathy, but the data did not cooperate. We interpret our findings, in conjunction with other recent evidence, that, like hypercoagulability, TBI is only one of the many risk factors that are critical in the development of VTE.28,29 Table 2 compares the TBI group with the nonTBI group by the RAP score risk factors. There were significantly more patients in the non-TBI group who required more than four transfusions in 24 hours, there were more operative interventions that lasted longer than 2 hours, there were more vascular injuries with ligation or repair, there were more AIS scores (head) of greater than 2, and there were more lower extremity fractures. Although the TBI group was more hypercoagulable, these other factors contributed sufficiently to the non-TBI group so that the presence of TBI did not increase the rate of VTE. There is no consensus regarding the optimal timing and type of VTE prophylaxis for TBI patients.16,30 Our institutional practice is to initiate chemical thromboprophylaxis once the bleeding from TBI has stabilized. The state of the art was recently reviewed by Phelan et al.31 They pointed out that, despite the frequency and morbidity of VTE after TBI, there is no national standard of care to guide the use of thromboprophylaxis.31 Progress in the field has been slow because of legitimate fears of iatrogenic propagation of intracranial hemorrhage. Furthermore, virtually all patients are classified in a binary fashion as having the presence or the absence of intracranial blood.31 This methodology does not account for the fact that smaller injury patterns stabilize more rapidly and thus may 248
be able to safely tolerate earlier initiation of thromboprophylaxis than larger injury patterns.31 For this reason, Phelan et al.32 developed an algorithm that stratifies TBI patients into low, moderate, and high risk for spontaneous injury progression and tailors a prophylaxis regimen to each arm. The Delayed Versus Early Enoxaparin Prophylaxis I study was a double-blind, placebo-controlled, randomized pilot trial on the low-risk arm.32 The data showed that TBI progression rates after starting enoxaparin in small, stable injuries 24 hours after injury are similar to those of placebo and are subclinical.32 These data are important but cannot be directly compared with our present results because our patients were preselected with AIS scores of greater than 2 and high DVT risk and because of the fact that TBI was classified in a binary fashion as either present or absent (based on CT findings). The Vanderbilt group conducted a retrospective cohort study in 669 TBI patients receiving early (0Y72 hours) or late (972 hours) VTE prophylaxis.33 They found no differences in proximal DVT, PE, ISS, age, and pelvic and/or long bone fractures and concluded that early VTE prophylaxis does not increase the rate of intracranial hemorrhage progression in hemodynamically stable patients with TBIs.33 These data are important but cannot be directly compared with our present results because virtually all the patients in our study met their definition of ‘‘early thromboprophylaxis’’ (i.e., start within 72 hours) and because unfractionated heparin, rather than LMWH, was used. There are several limitations to this observational, singlecenter study. It must be re-emphasized that the results cannot be generalized to all trauma patients because of at least three fundamental biases. First, the relatively high VTE rate can be attributed, in part, to the fact that the entire ICU study population was preselected as high risk, with RAP scores of 10 or greater (selection bias). Only a fraction of trauma patients, in general, are sick enough to require ICU admission, and only a fraction of ICU patients met the eligibility criteria for this study. Furthermore, patients without preexisting venous or arterial catheters were excluded to avoid venipuncture. We previously demonstrated that the presence of indwelling catheters contributes to hypercoagulability,34 but obviously, many trauma patients do not have invasive catheters. The VTE rate in trauma patients in general is probably about 5%,12Y15 but in this preselected population, the VTE rate was about five times higher. Second, the high VTE rate can also be attributed to weekly VDU (surveillance bias). We previously observed that only about half of VTEs in high-risk trauma patients are symptomatic;19,21 in this present study, we counted both symptomatic and asymptomatic VTE. Third, there is a possibility of survival bias. The apparent difference in mortality rates between the TBI and non-TBI groups was not statistically different (18% vs. 9%, p = 0.076). However, a severely injured patient with TBI superimposed on VTE risk factors such as more than four transfusions in 24 hours, complex lower extremity fractures, vascular injuries, and prolonged operative interventions would have had a low likelihood of survival, and this would have concomitantly decreased the observed VTE rate in the TBI group. * 2014 Lippincott Williams & Wilkins
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Thus, we cannot rule out a Type II error, due to small sample size, for the lack of difference in VTE rates between TBI and non-TBI. Finally, another limitation concerns the interpretation of hypercoagulability in the TBI group. This was based on TEG samples, but this was not confirmed by prothrombin time, activated partial thromboplastin time, international normalized ratio, or platelet counts. All these values could have been altered by events in the course of the hospital stay. In summary, the most likely explanation for these observations is that no single risk factor is necessary or sufficient for VTE development, especially in those who routinely receive mechanical and/or chemical thromboprophylaxis. This supports the conclusion that, in complex polytrauma patients who survived to ICU admission and who were prescreened for high VTE risk, TBI did not further increase the risk for VTE. More studies are needed to further evaluate the role of TBI superimposed on trauma on VTE risk. Lastly, we can recommend that more vigilant VTE surveillance should be considered in these high-risk trauma populations. About 50% of the VTEs were discovered within the first 10 days of admission, and knowledge as to the presence of VTE is valuable in the treatment of the critically ill. AUTHORSHIP E.J.V. is directly responsible for all aspects of this study. He participated in the collection, analysis, and interpretation of data and drafting and revision of the manuscript, figures, and tables. C.J.A., R.M.V.H., and J.M.J. participated in the experimental design; collection of data; and revision of the manuscript, figures, and tables. M.R.B., C.I.S., N.N., and A.S.L. were medically responsible for the patients in this study; treatments were administered at their discretion. In addition, they participated in the experimental design, interpretation of the data, critical review, and revision of the manuscript. K.G.P. had overall responsibility for the study, including conception and experimental design; analysis and interpretation of data; drafting and revision of the manuscript, figures, and tables; statistical expertise and evaluation; obtaining funding for this project; and supervision.
ACKNOWLEDGMENT We thank Ronald J. Manning, RN, BSN, MPH, who serves as our clinical coordinator and research manager, and the nurses, students, residents, and fellows who rotated through the trauma ICU for their cooperation.
DISCLOSURE This study was supported in part by Grants #N140610670 from the Office of Naval Research and #09078015 from the US Army Medical Research & Materiel Command.
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3. Robertson CS, Valadka AB, Hannay HJ, Contant CF, Gopinath SP, Cormio M, Uzura M, Grossman RG. Prevention of secondary ischemic insults after severe head injury. Crit Care Med. 1999;27(10):2086Y2095. 4. Robertson C. Treatment of secondary ischemic insults after traumatic brain injury. Crit Care Med. 2000;28(9):3358Y3359. 5. Lamberty GJ, Nakase-Richardson R, Farrell-Carnahan L, McGarity S, Bidelspach D, Harrison-Felix C, Cifu DX. Development of a traumatic brain injury model system within the Department of Veterans Affairs polytrauma system of care. J Head Trauma Rehabil. 2014 MayYJun: 29(3):E1Y7. 6. Andruszkow H, Probst C, Gru¨n O, Krettek C, Hildebrand F. Does additional head trauma affect the long-term outcome after upper extremity trauma in multiple traumatized patients: is there an additional effect of traumatic brain injury? Clin Orthop Relat Res. 2013;471(9):2899Y2905. 7. Bullock MR, Povlishock JT. Guidelines for the management of severe traumatic brain injury. Editor’s commentary. J Neurotrauma. 2007;24 (Suppl 1):2 p preceding S1. Erratum in: J Neurotrauma. 2008;25(3): 276Y278. 8. Mohseni S, Talving P, Lam L, Chan LS, Ives C, Demetriades D. Venous thromboembolic events in isolated severe traumatic brain injury. J Emerg Trauma Shock. 2012;5(1):11Y15. 9. Denson K, Morgan D, Cunningham R, Nigliazzo A, Brackett D, Lane M, Smith B, Albrecht R. Incidence of venous thromboembolism in patients with traumatic brain injury. Am J Surg. 2007;193(3):380Y383; discussion 383Y384. 10. Kahn SR, Morrison DR, Cohen JM, Emed J, Tagalakis V, Roussin A, Geerts W. Interventions for implementation of thromboprophylaxis in hospitalized medical and surgical patients at risk for venous thromboembolism. Cochrane Database Syst Rev. 2013;7:CD008201. 11. Harr JN, Moore EE, Chin TL, Ghasabyan A, Gonzalez E, Wohlauer MV, Banerjee A, Silliman CC, Sauaia A. Platelets are dominant contributors to hypercoagulability after injury. J Trauma Acute Care Surg. 2013;74(3): 756Y762; discussion 762Y765. 12. Greenfield LJ, Proctor MC, Rodriguez JL, Luchette FA, Cipolle MD, Cho J. Posttrauma thromboembolism prophylaxis. J Trauma. 1997;42(1): 100Y103. 13. Gearhart MM, Luchette FA, Proctor MC, Lutomski DM, Witsken C, James L, Davis K Jr, Johannigman JA, Hurst JM, Frame SB. The risk assessment profile score identifies trauma patients at risk for deep vein thrombosis. Surgery. 2000;128(4):631Y640. 14. Haut ER, Chang DC, Pierce CA, Colantuoni E, Efron DT, Haider AH, Cornwell EE 3rd, Pronovost PJ. Predictors of posttraumatic deep vein thrombosis (DVT): hospital practice versus patient factorsVan analysis of the National Trauma Data Bank (NTDB). J Trauma. 2009;66(4): 994Y999; discussion 999Y1001. 15. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma. 2002;53(1):142Y164. 16. Singh S, Haut ER, Brotman DJ, Sharma R, Chelladurai Y, Shermock KM, Kebede S, Stevens KA, Prakasa KR, Shihab HM, et al. Pharmacologic and Mechanical Prophylaxis of Venous Thromboembolism Among Special Populations. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013. Report No.: 13-EHC082-1. AHRQ Comparative Effectiveness Reviews. http://www.ncbi.nlm.nih.gov/books/NBK148555/ accessed March 13, 2014. 17. Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with low-molecular weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996;335(10):701Y707. 18. Ginzburg E, Cohn SM, Lopez J, Jackowski K, Brown M, Hameed SM. Randomized clinical trial of intermittent pneumatic compression and low molecular weight heparin in trauma. Br J Surg. 2003;90(11):1338Y1344. 19. Thorson CM, Ryan ML, Van Haren RM, Curia E, Barrera JM, Guarch GA, Busko AM, Namias N, Livingstone AS, Proctor KG. Venous thromboembolism after trauma: a never event?. Crit Care Med. 2012;40(11): 2967Y2973. 20. Ryan ML, Van Haren RM, Thorson CM, Andrews DM, Perez EA, Neville HL, Sola JE, Proctor KG. Trauma-induced hypercoagulability in
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Does traumatic brain injury increase the risk for venous thromboembolism in polytrauma patients? Evan J. Valle, MD, Robert M. Van Haren, MD, MSPH, Casey J. Allen, MD, Jassin M. Jouria, MD, M. Ross Bullock, MD, PhD, Carl I. Schulman, MD, PhD, Nicholas Namias, MD, Alan S. Livingstone, MD, and Kenneth G. Proctor, PhD, Miami, Florida
Trauma is a major risk factor for venous thromboembolism (VTE). Traumatic brain injury (TBI) is generally considered to further increase the VTE risk, which should prompt routine thromboprophylaxis. However, the associated risk for intracranial hemorrhage often delays anticoagulants. We test the hypothesis that TBI associated with polytrauma results in a higher rate of VTE than polytrauma without TBI. METHODS: From August 2011 to June 2013, a prospective observational trial with informed consent was performed in 148 intensive care unit (ICU) patients with a Greenfield Risk Assessment Profile score of 10 or greater. RESULTS: Demographics, Greenfield Risk Assessment Profile scores, the incidence of polytrauma, and mortality were similar, but TBI patients had worse Injury Severity Scores (ISS) (32 vs. 22), longer ICU lengths of stay (21 days vs. 12 days), more hypercoagulable thromboelastogram values on admission (94% vs. 79%), more received unfractionated heparin prophylaxis (65% vs. 36%), and the prophylaxis start date was more than a day later (all p G 0.05). Nevertheless, the VTE rate with TBI was similar to that without TBI (25% vs. 26%, p = 0.507). Furthermore, VTE occurred at similar time points after ICU admission with and without TBI. In both groups, about 30% of the VTEs were detected within 2 days of ICU admission and 50% of the VTEs occurred within 10 days of admission despite chemical and mechanical thromboprophylaxis. CONCLUSION: In complex polytrauma patients who survived to ICU admission and who were prescreened for high VTE risk, TBI did not further increase the risk for VTE. The most likely explanation is that no single risk factor is necessary or sufficient for VTE development, especially in those who routinely receive chemical and mechanical thromboprophylaxis. (J Trauma Acute Care Surg. 2014;77: 243Y250. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Epidemiologic study, level III. KEY WORDS: Thromboelastography; coagulopathy; heparin; intensive care unit. BACKGROUND:
T
raumatic brain injury (TBI) is a leading cause of death and disability in both civilian and military populations.1Y4 Proper management is especially difficult when complex polytrauma is superimposed on TBI.5Y7 In general, patients hospitalized with trauma or TBI have increased risks for both bleeding and venous thromboembolism (VTE). Additional relative risk factors are hypercoagulability, age, lower extremity fractures, indwelling catheters, and blood product transfusions.8Y11 These factors have been compiled into the Greenfield Risk Assessment Profile (RAP) and have provided the foundations for current thromboprophylaxis strategies.12Y15 There is no absolute definition of high VTE risk, and most agree that thromboprophylaxis is necessary in polytrauma patients with or without TBI. However, there is considerable
Submitted: January 16, 2014, Revised: March 11, 2014, Accepted: March 14, 2014. From the Dewitt-Daughtry Family Department of Surgery, Divisions of Trauma and Surgical Critical Care, and Department of Neurosurgery, University of Miami Miller School of Medicine, Ryder Trauma Center, Miami, Florida. This study was presented at the 9th Annual Academic Surgical Congress, February 4Y6, 2014, in San Diego, California. Address for reprints: Kenneth G. Proctor, PhD, Dewitt-Daughtry Family Department of Surgery, Divisions of Trauma and Surgical Critical Care, University of Miami Miller School of Medicine, Ryder Trauma Center, 1800 NW 10th Ave, Miami, FL 33136; email: [email protected]. DOI: 10.1097/TA.0000000000000307
uncertainty about the prophylaxis modality (pharmacologic or mechanical) and about the optimal agent, dose, timing, and duration.16Y18 In a series of studies, we have identified coagulation changes and VTE risk factors in high-risk surgical and trauma patients.19Y24 We now test the hypothesis that TBI associated with polytrauma results in a higher rate of VTE than polytrauma without TBI.
PATIENTS AND METHODS This was an institutional review boardYapproved, prospective, observational trial with informed consent. All patients admitted to the intensive care unit (ICU) of the Level I Ryder Trauma Center at Jackson Memorial Hospital/University of Miami from August 2011 until June 2013 were eligible. Exclusions were those who were pregnant, incarcerated, younger than 18 years, and/or with delayed presentation due to transfer. All patients were screened with RAP,12 which assigns a numerical VTE risk score on the basis of age, medical history, iatrogenic factors, and injury-related factors. Those with an indwelling catheter and an RAP score of 10 or greater upon admission to the ICU were asked to participate in the trial. If consent was obtained, serial bilateral lower extremity venous Doppler ultrasound (VDU) and serial blood samples for coagulation analysis using thromboelastography (TEG)
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were performed. Repeat VDU and blood samples were obtained weekly for those who remained in the ICU; however, in this current study, only admission TEG values were evaluated. Patients who died, those who were transferred to the floor, or those with VTE on initial VDU did not undergo repeat VDU or TEG. VDU evaluated the deep venous system of the lower extremities from the ankle to the inguinal ligament. Deep venous thrombosis (DVT) was defined as an abnormality seen on VDU such as the presence of dilated, noncompressible veins or intraluminal shadows consistent with thrombosis. The DVTs were catalogued as being either above the knee or below the knee. Pulmonary embolism (PE) was defined as a filling defect detected on a computed tomography (CT) pulmonary angiogram, which was ordered only on the basis of clinical suspicion such as the onset of abrupt and unexplained hypoxia, hypotension, tachycardia, or any combination of the aforementioned. No institutional-based guidelines exist for obtaining CT pulmonary angiograms in the ICU; however, evidence-based guidelines are followed.16 The primary outcome was VTE, defined as either PE or DVT in the ankle to the groin, including thrombus in the soleus and gastrocnemius veins. There was no specific protocol for treatment of asymptomatic or symptomatic VTE, but the practice among our group of experienced trauma surgeons is relatively consistent. The general treatment strategy is to administer full therapeutic anticoagulation for 3 months to 6 months in the absence of contraindications and the placement of inferior vena cava (IVC) filters in those patients with contraindication to chemical anticoagulation according to evidence-based guidelines.16 During the course of this study, the chemical thromboprophylaxis protocol at this institution changed three times. Heparin (5,000 U subcutaneous TID) was the standard when the study started; however, a transition was made to dalteparin (5,000 U subcutaneous daily) and then finally to enoxaparin (30 mg subcutaneous BID). Blood (6ml) was drawn from indwelling radial arterial catheters, peripherally inserted central catheters, or central venous catheters into two vacuum-sealed tubes containing sodium citrate. After 15 minutes, an aliquot of blood (340 KL) was transferred to the TEG (Thromboelastograph Hemostasis Analyzer Model 5000 System, Braintree, MA) and reconstituted using 20 KL of CaCl2. TEG was performed on native whole blood samples with no activation material. Each TEG sample was run in duplicate and averaged to ensure an accurate result. TEG parameters included reaction time (R), k-time (K), alpha angle (>), maximum amplitude (MA), and G-value (G). R is the time between initiation of the test and the initial fibrin formation and represents the enzymatic portion of coagulation. K is the time needed to reach 20-mm clot strength and represents clot kinetics. > is the measure of the TEG tracing’s slope and represents fibrin cross-linking. MA is the measure of the overall clot strength and represents platelet aggregation. G is a measure of clot strength. In this present study, hypercoagulability was defined by values outside the standard reference ranges, specifically as R of less than 9 minutes, K of less than 2 minutes, > of greater than 58 degrees, or MA of greater than 64 mm. 244
TBI was defined by the presence of subdural hemorrhage, epidural hemorrhage, focal contusion, or diffuse axonal injury on CT. Polytrauma was defined by the Abbreviated Injury Scale (AIS) score in two or more body regions. The sample size was estimated based on the assumptions that the incidence of VTE in TBI patients ranges from 25% to 35%, depending on whether prophylaxis is used or contraindicated because of intracranial hemorrhage,9,16 and that the incidence of VTE in the general trauma population ranges from a low of 6%17,18 to about 25% in patients prescreened with RAP of greater than 10.19 Accordingly, the minimum group size is n = 20 and the maximum group size is n = 114 to detect a difference in VTE rates between TBI and trauma, with an > of 0.05 and a power of 0.80. Data were analyzed using SPSS version 21.0 (IBM Corporation, Armonk, NY). If values were normally distributed, data are reported as mean T SD. If values were not normally distributed, data are reported as median (interquartile range). Independent data were compared with the Student’s t test and the Mann-Whitney U-test for parametric and nonparametric data, respectively. Categorical data were compared with the W2 test or the Fisher’s exact test.
RESULTS Figure 1 shows that there were 741 trauma ICU admissions that were screened between August 2011 and June 2013; a total of 170 were consented and 148 were enrolled. Patients were not enrolled because of RAP of less than 10, refusal to participate in the study, lack of a designated proxy, or no indwelling catheter from which to draw blood. About half of the study population had TBI and half had no TBI, but the majority in both groups had polytrauma, as defined by an AIS score in more than one body region. The demographics were as follows: age, 47 years T 19 years; male,
Figure 1. CONSORT diagram showing patients who were screened, consented, and enrolled. Patients were not enrolled because of RAP score of less than 10, refusal to participate in the study, lack of a designated proxy, or no indwelling catheter from which to draw blood. CVC, central venous catheter. * 2014 Lippincott Williams & Wilkins
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received chemical thromboprophylaxis, 71 (55%) received subcutaneous heparin, 54 (42%) received dalteparin, and 4 (3%) received therapeutic anticoagulation with a heparin drip. Only one patient received enoxaparin. IVC filters were placed in 8 of the non-TBI patients within a median (interquartile range) of 2 days (4 days) and in 14 of the TBI patients within a median (interquartile range) of 7 days (10 days). One IVC filter in the non-TBI group and two IVC filters in the TBI group were placed because of contraindications to chemical anticoagulation. In addition, mechanical prophylaxis was used in 126 patients (86%). Both chemical and mechanical prophylaxis were used in 108 patients (73%). Only one patient in the non-TBI cohort had both chemical and mechanical thromboprophylaxis withheld because of contraindications. Contraindications to mechanical prophylaxis were complex lower extremity fractures that required external fixation with hardware or bilateral lower extremity amputations. Contraindications to chemical thromboprophylaxis were continued progression of intracranial hemorrhage, postoperative bleeding, and anemia. There was no significant difference in VTE rates with heparin or dalteparin thromboprophylaxis (23% vs.
Figure 2. Cumulative total VTE versus time in those with and without TBI.
78%; blunt mechanism of injury, 76%; Injury Severity Score (ISS), 27 T 11; ICU days, 16 (22); and mortality, 14%. VTE was detected in 26% (n = 38) of patients and occurred a median (interquartile range) of 10 days (14 days) after admission. Thirty-one of the VTEs were DVTs, 7 in the upper extremity, which were symptomatic and not detected in the VDU screening protocol; 23 above the knee; and 1 below the knee, which was located in the lesser saphenous vein. The remaining seven VTEs were PEs. One DVTwas discovered at the time PE was detected. Figure 2 shows that VTE occurred at similar time points during the ICU length of stay (LOS) with or without TBI. In both groups, about 30% of the VTEs were detected within 2 days of ICU admission. Most of the VTEs were DVTs (n = 31, 82%), and the remaining were PEs (n = 7, 18%). Of the PE patients, two had DVT as well, one discovered at the same time as the PE and the other approximately 9 weeks before the PE. In this particular subset, four patients (66%) in the non-TBI group and three patients (60%) in the TBI group were hypercoagulable on initial TEG screening ( p = 0.500). Figure 3 A and B shows the distribution of chemical thromboprophylaxis and therapeutic anticoagulation for both the non-TBI and TBI groups, respectively. For the overall population, the median (interquartile range) time until drug initiation was 2 days (2 days) after admission. In those who
Figure 3. Distribution and type of chemical prophylaxis or therapeutic anticoagulation. Chem, chemical; iv, intravenous; sq, subcutaneous.
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22%, p=0.571) or between thromboprophylaxis and no thromboprophylaxis (23% vs. 28%, p = 0.425), but the study was not powered to detect either of these effects (see Discussion). The median (interquartile range) time from initial hospital admission to initial TEG was 1.2 days (0.6 days). Most (i.e., 86%) of the patients were hypercoagulable, defined by at least one TEG value outside the reference range. R was decreased in 78%, K was decreased in 55%, > was increased in 74%, and MA was increased in 29%. The population’s values were R, 7.1 minutes (3.1 minutes); K, 1.9 minutes (0.8 minutes); >, 61.1 degrees T 9.4 degrees; and MA, 60 mm T 7mm. There was no significant difference in VTE rates between the patients who were hypercoagulable on admission compared with those who were not hypercoagulable (25% vs. 30%, p = 0.401). All patients in the TBI group had an AIS score (head) of greater than 2, plus head CT changes including 52 patients (76%) with subarachnoid hemorrhage, 24 (35%) with intraventricular hemorrhage, 22 (32%) with intraparenchymal hemorrhage, 19 (29%) with nonspecific intracranial hemorrhage, 20 (29%) with subdural hemorrhage, 6 (9%) with epidural hemorrhage, and 4 (6%) with diffuse axonal injury. An AIS score (head) of greater than 3 occurred in 59 (87%) of the TBI group. VTE was not solely encountered in the 87% with an AIS score (head) of greater than 3; however, five (55%) of the remainder who did not have an AIS score (head) of greater than 3 had VTE. Specifically, there were five total VTEs in this group, four DVTs and one PE, which was discovered simultaneously with one of the DVTs. An intracranial pressure monitor was placed in 46% (n = 31) of these TBI patients. Craniotomy or craniectomy was performed in 38% (n = 26) of the TBI patients. There were a total of 12 craniectomies and 14 craniotomies described in the operative reports. In the non-TBI group, there were six patients (8%) who had a Glasgow Coma Scale (GCS) score of less than 8. Low GCS score was attributed to hemorrhagic shock, combativeness, or seizure/unconsciousness rather than to TBI because there were no head CT changes. All these patients were intubated in the field or required intubation shortly after arrival because of inability to protect their airways. Table 1 shows that demographics, RAP scores, and incidence of polytrauma were similar in TBI versus no TBI. The TBI group had a greater incidence of blunt trauma (99% vs. 58%, p G 0.001), had higher ISS (32 vs. 22, p G 0.001), was more hypercoagulable (94% vs. 79%, p = 0.005), and had longer ICU LOS (21 days vs. 12 days, p = 0.007). The mortality rate was numerically higher (18% vs. 9%), but the apparent difference did not reach statistical significance ( p = 0.076). The patients in the TBI group received more unfractionated heparin (65% vs. 36%, p = 0.004) and less dalteparin than the non-TBI group (20% vs. 53%, p G 0.001). There were more missed doses of chemical thromboprophylaxis in the TBI group within the first 2 weeks of enrollment as well (2 vs. 7, p G 0.001). The TBI patients also had their VTE prophylaxis withheld a median (interquartile range) of 1 day longer than those patients without TBI (3 days [1 day] vs. 2 days [2 days], p = 0.010). Nevertheless, neither the VTE rate (24% vs. 26%, p = 0.507) nor the distribution of VTE between above the knee, below the knee, upper extremity, and PE differed between the TBI and no TBI groups. 246
TABLE 1. Characteristics of Trauma ICU Patients With and Without TBI Non-TBI (n = 80) Age Male Blunt mechanism Polytrauma RAP ISS Hypercoagulable Heparin prophylaxis Dalteparin No VTE prophylaxis ICU LOS, d VTE rate Above knee DVT Below knee DVT Upper extremity DVT PE IVC filter Mortality TEG values R, min K, min >, degrees MA, mm G, dyne/cm2 Laboratory values PT, s INR aPTT, s Platelets, 103/KL
49 T 19 76% 58% 69% 14 T 3 22 T 10 79% 36% 53% 10% 12 (19) 26% 10 (48%) 1 (4%) 4 (19%) 6 (29%) 8 (10%) 9% 7.2 (3.3) 2.1 (1.1) 58.9 T 10.7 57.7 T 6.9 7,158 T 2,050 12.0 (1.9) 1.0 (0.2) 25.8 (7.0) 232 T 98
TBI (n = 68) 45 T 18 81% 99% 76% 15 (6) 32 T 11 94% 65% 20% 15% 21 (22) 25% 13 (76%) 0 (0%) 3 (18%) 1 (6%) 14 (21%) 18% 7.1 (3.0) 1.8 (0.7) 63.6 T 6.9 61.9 T 6.6 8,545 T 2,344 11.5 (1.9) 1.0 (0.2) 27.1 (6.0) 242 T 64
p 0.259 0.495 G0.001 0.345 0.122 G0.001 0.005 0.004 G0.001 0.350 0.007 0.507 0.0691 V 0.624 0.0823 0.0579 0.076 0.213 0.001 0.002 G0.001 G0.001 0.98 0.093 0.116 0.441
aPTT, activated partial thromboplastin time; INR, international normalized ratio; PT, prothrombin time. Boldface indicates statistical significance.
Using multiple logistic regression, TBI was the only significant variable predicting hypercoagulability among all variables of the RAP score. Nevertheless, neither TBI nor any other single RAP score variable significantly predicted VTE in the regression model (data not shown). There were multiple iatrogenic and injury-related risk factors favoring VTE development in the non-TBI patients (Table 2). These included four or more transfusions in the first 24 hours after admission (81% vs. 60%, p = 0.003), more surgical procedures longer than 2 hours (64% vs. 46%, p = 0.027), more repair of major vascular injury (45% vs. 21%, p = 0.002), and more complex lower extremity fracture (45% vs. 25%, p = 0.011). Inflammation from multiple trips to the operating room and infection could have also contributed to the risk for VTE. Fifteen patients (10%) had positive blood culture results, seven in the non-TBI group (of which two were associated with VTE) and eight in the TBI group (of which three were associated with VTE). None of these apparent differences were statistically significant. However, there were a total of four patients (one in the non-TBI group and three in the TBI group) who had * 2014 Lippincott Williams & Wilkins
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TABLE 2. Risk Factors of VTE in Trauma ICU Patients With and Without TBI RAP variables Obesity (BMI 9 30 kg/m2) Malignancy Abnormal coagulation History of VTE Femoral line 94 transfusions in 24 h OR 9 2 h Vascular injury AIS score chest 9 2 AIS score abdomen 9 2 AIS score head 9 2 GCS score G 8 Lower extremity fracture Pelvic fracture Spinal cord injury Age 40Y59 y Age 60Y75 y Age 9 75 y Additional risk factors Central line Central/PICC line Arterial line PPX, % Days to PPX Days to first VDU Switched PPX Mechanical PPX Missed doses of chemical PPX*
Non-TBI (n = 80)
TBI (n = 68)
p
40% 4% 64% 1% 20% 81% 64% 45% 53% 44% 3% 8% 45% 39% 9% 28% 24% 11%
24% 0% 50% 0% 18% 60% 46% 21% 51% 41% 100% 71% 25% 46% 1% 32% 21% 6%
0.043 0.161 0.092 0.547 0.776 0.003 0.027 0.002 0.901 0.752 G0.001 G0.001 0.011 0.401 0.056 0.520 0.645 0.271
70% 71% 95% 90 2 (2) 1 (1) 26% 79% 2 (6)
59% 63% 94% 85 3 (1) 1 (1) 16% 90% 7 (7)
0.156 0.299 0.531 0.247 0.010 0.934 0.161 0.064 G0.001
*First 2 weeks of study enrollment. OR, operative intervention; PICC, peripherally inserted central catheter; PPX, thromboprophylaxis.
a positive blood culture result before the occurrence of VTE. Finally, three patients (all in the TBI group) had positive blood culture results before VTE occurrence and were hypercoagulable on initial TEG. Both groups had a median (interquartile range) of 2 (2) operations during their LOS ( p = 0.144). To address the possibility that the non-TBI cohort achieved an RAP of 10 or greater simply because of the aforementioned factors, and effectively created dissimilar groups, all TBI patients were excluded who had an RAP score of less than 10 if their TBI was ignored. This resulted in 17 patients being excluded from the TBI group (n = 51). In this subset, the VTE rate was 26%, which was equal to the VTE rate of the non-TBI patients.
DISCUSSION This is the sixth in a recent series of studies from our group on hypercoagulability in various populations of surgical patients.19Y24 To our knowledge, this is the first study to examine VTE rates in complex trauma patients with superimposed TBI
recovering in the ICU. It should be emphasized that this study population is by no means representative of trauma patients in general. Only a small fraction of the sickest trauma patients are admitted to the ICU, and fewer than 20% of ICU admissions met our definition of high VTE risk (i.e., RAP score 9 10). The major new findings are that, relative to those with no TBI, trauma patients with TBI had worse ISS, had longer LOS, and were more hypercoagulable on admission (all p G 0.05). Fewer received chemical VTE prophylaxis, almost twice as many received unfractionated heparin as low-molecularweight heparin (LMWH) prophylaxis, the prophylaxis start date was more than 1 day later, and more had missed doses (all p G 0.05). Nevertheless, the VTE rate with TBI was similar to that without TBI (24% vs. 26%, p = 0.507). Despite some differences in experimental design, the VTE rate we observed in high-risk trauma patients is remarkably similar to that observed by others. Denson et al.9 evaluated 5,787 trauma patients and deemed 539 (9%) as high risk for VTE. The incidence of VTE determined with surveillance VDU in patients with isolated TBI (88, 16%) was 25%, excluding those with pelvic fracture, lower extremity fracture, and spinal cord injury with paralysis.9 In this present study, the VTE rate was also 25%; 741 trauma ICU admissions were screened and 148 (20%) met criteria as high risk for VTE (i.e., RAP score 9 10 incorporates risk factors such as fractures and spinal cord injury). One major difference is that the mean time to thromboprophylaxis was 14.2 days in the Denson et al. study versus 2 days in this present study. We recently concluded that hypercoagulability (at least on ICU admission) was neither necessary nor sufficient for VTE development.21 The results from this present study confirm and extend that idea. We now report that TBI was the most important variable predicting admission hypercoagulability among all variables of the RAP score, but neither hypercoagulability nor TBI was associated with higher VTE rates. Furthermore, using multiple logistic regression, no other combination of risk factors was highly correlated with VTE risk. In retrospect, this lack of correlation is probably not surprising. Every patient in our study population was already prescreened with RAP,12,13 and those are the same variables used in our regression analysis. We also observed no significant difference in VTE rates between heparin and dalteparin thromboprophylaxis (23% vs. 22%, p = 0.571) or between chemical anticoagulation and mechanical thromboprophylaxis in trauma patients with contraindications for chemical anticoagulation (23% vs. 28%, p = 0.425). Both of these results are almost certainly Type II statistical errors. This study was in no way powered to detect either of those effects. Assuming the same VTE rate, the same distribution of treatments, and the same contraindications for thromboprophylaxis in Figure 2 in this high-risk ICU population, the sample size would have had to be about 2,000 patients to detect an effect of heparin versus dalteparin and about 20,000 patients to detect an effect of a drug versus sequential compression devices. Another possible explanation for the lack of observed difference in the VTE rate between the two subgroups is the almost universal use of mechanical prophylaxis at our
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institution. Ginzburg et al.18 conducted a prospective randomized trial in 442 patients who received thromboprophylaxis with either an intermittent pneumatic compression device or LMWH and serial VDU. They concluded that mechanical thromboprophylaxis is both safe and effective in trauma patients relative to LMWH.18 In this present study, mechanical prophylaxis was used in 126 patients (86%). Both chemical and mechanical prophylaxis were used in 108 patients (73%). The pathogenesis of VTE has traditionally been summarized by the Virchow triad, which includes endothelial injury, venous stasis, and hypercoagulability. Greenfield et al.12 incorporated these and additional risk factors in developing the trauma RAP score. Our data showed multiple iatrogenic and injury-related risk factors favoring VTE development in both TBI (Table 1) and non-TBI polytrauma patients (all p G 0.05) who survived to ICU admission, including obesity, more transfusions, longer operative intervention, twice as many vascular repairs, and lower extremity fractures (Table 2). In a meta-analysis of 34 studies, Harhangi et al.25 showed an overall prevalence of coagulopathy of 33% in TBI patients and that coagulopathy after TBI was related to both mortality and unfavorable outcome. In this present study, 86% of the patients were hypercoagulable, defined by at least one TEG value outside the reference range, but there was no significant difference in VTE rates between the patients who were and who were not hypercoagulable on admission (25% vs. 30%, p = 0.401). Coagulopathy and high VTE rates have also been demonstrated in other surgical patient populations.18Y27 It is logical to predict that the risk for VTE would increase when TBI is accompanied by polytrauma and/or coagulopathy, but the data did not cooperate. We interpret our findings, in conjunction with other recent evidence, that, like hypercoagulability, TBI is only one of the many risk factors that are critical in the development of VTE.28,29 Table 2 compares the TBI group with the nonTBI group by the RAP score risk factors. There were significantly more patients in the non-TBI group who required more than four transfusions in 24 hours, there were more operative interventions that lasted longer than 2 hours, there were more vascular injuries with ligation or repair, there were more AIS scores (head) of greater than 2, and there were more lower extremity fractures. Although the TBI group was more hypercoagulable, these other factors contributed sufficiently to the non-TBI group so that the presence of TBI did not increase the rate of VTE. There is no consensus regarding the optimal timing and type of VTE prophylaxis for TBI patients.16,30 Our institutional practice is to initiate chemical thromboprophylaxis once the bleeding from TBI has stabilized. The state of the art was recently reviewed by Phelan et al.31 They pointed out that, despite the frequency and morbidity of VTE after TBI, there is no national standard of care to guide the use of thromboprophylaxis.31 Progress in the field has been slow because of legitimate fears of iatrogenic propagation of intracranial hemorrhage. Furthermore, virtually all patients are classified in a binary fashion as having the presence or the absence of intracranial blood.31 This methodology does not account for the fact that smaller injury patterns stabilize more rapidly and thus may 248
be able to safely tolerate earlier initiation of thromboprophylaxis than larger injury patterns.31 For this reason, Phelan et al.32 developed an algorithm that stratifies TBI patients into low, moderate, and high risk for spontaneous injury progression and tailors a prophylaxis regimen to each arm. The Delayed Versus Early Enoxaparin Prophylaxis I study was a double-blind, placebo-controlled, randomized pilot trial on the low-risk arm.32 The data showed that TBI progression rates after starting enoxaparin in small, stable injuries 24 hours after injury are similar to those of placebo and are subclinical.32 These data are important but cannot be directly compared with our present results because our patients were preselected with AIS scores of greater than 2 and high DVT risk and because of the fact that TBI was classified in a binary fashion as either present or absent (based on CT findings). The Vanderbilt group conducted a retrospective cohort study in 669 TBI patients receiving early (0Y72 hours) or late (972 hours) VTE prophylaxis.33 They found no differences in proximal DVT, PE, ISS, age, and pelvic and/or long bone fractures and concluded that early VTE prophylaxis does not increase the rate of intracranial hemorrhage progression in hemodynamically stable patients with TBIs.33 These data are important but cannot be directly compared with our present results because virtually all the patients in our study met their definition of ‘‘early thromboprophylaxis’’ (i.e., start within 72 hours) and because unfractionated heparin, rather than LMWH, was used. There are several limitations to this observational, singlecenter study. It must be re-emphasized that the results cannot be generalized to all trauma patients because of at least three fundamental biases. First, the relatively high VTE rate can be attributed, in part, to the fact that the entire ICU study population was preselected as high risk, with RAP scores of 10 or greater (selection bias). Only a fraction of trauma patients, in general, are sick enough to require ICU admission, and only a fraction of ICU patients met the eligibility criteria for this study. Furthermore, patients without preexisting venous or arterial catheters were excluded to avoid venipuncture. We previously demonstrated that the presence of indwelling catheters contributes to hypercoagulability,34 but obviously, many trauma patients do not have invasive catheters. The VTE rate in trauma patients in general is probably about 5%,12Y15 but in this preselected population, the VTE rate was about five times higher. Second, the high VTE rate can also be attributed to weekly VDU (surveillance bias). We previously observed that only about half of VTEs in high-risk trauma patients are symptomatic;19,21 in this present study, we counted both symptomatic and asymptomatic VTE. Third, there is a possibility of survival bias. The apparent difference in mortality rates between the TBI and non-TBI groups was not statistically different (18% vs. 9%, p = 0.076). However, a severely injured patient with TBI superimposed on VTE risk factors such as more than four transfusions in 24 hours, complex lower extremity fractures, vascular injuries, and prolonged operative interventions would have had a low likelihood of survival, and this would have concomitantly decreased the observed VTE rate in the TBI group. * 2014 Lippincott Williams & Wilkins
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Thus, we cannot rule out a Type II error, due to small sample size, for the lack of difference in VTE rates between TBI and non-TBI. Finally, another limitation concerns the interpretation of hypercoagulability in the TBI group. This was based on TEG samples, but this was not confirmed by prothrombin time, activated partial thromboplastin time, international normalized ratio, or platelet counts. All these values could have been altered by events in the course of the hospital stay. In summary, the most likely explanation for these observations is that no single risk factor is necessary or sufficient for VTE development, especially in those who routinely receive mechanical and/or chemical thromboprophylaxis. This supports the conclusion that, in complex polytrauma patients who survived to ICU admission and who were prescreened for high VTE risk, TBI did not further increase the risk for VTE. More studies are needed to further evaluate the role of TBI superimposed on trauma on VTE risk. Lastly, we can recommend that more vigilant VTE surveillance should be considered in these high-risk trauma populations. About 50% of the VTEs were discovered within the first 10 days of admission, and knowledge as to the presence of VTE is valuable in the treatment of the critically ill. AUTHORSHIP E.J.V. is directly responsible for all aspects of this study. He participated in the collection, analysis, and interpretation of data and drafting and revision of the manuscript, figures, and tables. C.J.A., R.M.V.H., and J.M.J. participated in the experimental design; collection of data; and revision of the manuscript, figures, and tables. M.R.B., C.I.S., N.N., and A.S.L. were medically responsible for the patients in this study; treatments were administered at their discretion. In addition, they participated in the experimental design, interpretation of the data, critical review, and revision of the manuscript. K.G.P. had overall responsibility for the study, including conception and experimental design; analysis and interpretation of data; drafting and revision of the manuscript, figures, and tables; statistical expertise and evaluation; obtaining funding for this project; and supervision.
ACKNOWLEDGMENT We thank Ronald J. Manning, RN, BSN, MPH, who serves as our clinical coordinator and research manager, and the nurses, students, residents, and fellows who rotated through the trauma ICU for their cooperation.
DISCLOSURE This study was supported in part by Grants #N140610670 from the Office of Naval Research and #09078015 from the US Army Medical Research & Materiel Command.
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