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Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury
Journal of Clinical Neuroscience xxx (2016) xxx–xxx
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury Daniel S. Epstein a,b, Biswadev Mitra a,b,c,⇑, Peter A. Cameron a,b,d, Mark Fitzgerald c,e,f, Jeffrey V. Rosenfeld f,g,h a
Emergency and Trauma Centre, The Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia National Trauma Research Institute, Melbourne, VIC, Australia d Emergency Medicine, Hamad Medical Corporation, Doha, Qatar e Trauma Service, The Alfred Hospital, Melbourne, VIC, Australia f Department of Surgery, Monash University, Melbourne, VIC, Australia g Department of Neurosurgery, The Alfred Hospital, Melbourne, VIC, Australia h Department of Surgery, F. Edward Hébert School of Medicine, Uniformed Services University of The Health Sciences (USUHS), Bethesda, MD, USA b c
a r t i c l e
i n f o
Article history: Received 8 August 2015 Accepted 8 November 2015 Available online xxxx Keywords: Blood coagulation Coagulopathy Craniocerebral trauma Injuries Isolated head trauma Traumatic brain injury
a b s t r a c t Acute traumatic coagulopathy (ATC) has been reported in the setting of isolated traumatic brain injury (iTBI) and is associated with poor outcomes. We aimed to evaluate the effectiveness of procoagulant agents administered to patients with ATC and iTBI during resuscitation, hypothesizing that timely normalization of coagulopathy may be associated with a decrease in mortality. A retrospective review of the Alfred Hospital trauma registry, Australia, was conducted and patients with iTBI (head Abbreviated Injury Score [AIS] P3 and all other body AIS <3) and coagulopathy (international normalized ratio P1.3) were selected for analysis. Data on procoagulant agents used (fresh frozen plasma, platelets, cryoprecipitate, prothrombin complex concentrates, tranexamic acid, vitamin K) were extracted. Among patients who had achieved normalization of INR or survived beyond 24 hours and were not taking oral anticoagulants, the association of normalization of INR and death at hospital discharge was analyzed using multivariable logistic regression analysis. There were 157 patients with ATC of whom 68 (43.3%) received procoagulant products within 24 hours of presentation. The median time to delivery of first products was 182.5 (interquartile range [IQR] 115–375) minutes, and following administration of coagulants, time to normalization of INR was 605 (IQR 274–1146) minutes. Normalization of INR was independently associated with significantly lower mortality (adjusted odds ratio 0.10; 95% confidence interval 0.03–0.38). Normalization of INR was associated with improved mortality in patients with ATC in the setting of iTBI. As there was a substantial time lag between delivery of products and eventual normalization of coagulation, specific management of coagulopathy should be implemented as early as possible. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Acquired disorders of coagulation, also termed acute traumatic coagulopathy (ATC), early trauma induced coagulopathy or acute coagulopathy of trauma, have been previously described in the setting of isolated traumatic brain injury (iTBI) [1–4]. The incidence of ATC in the setting of iTBI is estimated to be 8%, using an international normalized ratio (INR) P1.3 as a cut-off associated with higher mortality and adverse outcomes after iTBI [5,6]. However, ⇑ Corresponding author. Tel.: +61 3 9076 2782; fax: +61 3 9076 2699. E-mail address: [email protected] (B. Mitra).
the incidence of this condition has been variably reported depending on the study design and definition of coagulopathy used [1,7–9]. Regardless of definitions, in-hospital mortality in the setting of ATC and iTBI has been reported approaching 50% [2], and an abnormal initial INR, regardless of magnitude, in the setting of iTBI, was associated with poor outcomes [5,10–13]. It is hypothesized that early treatment of coagulopathy may improve outcomes. There are a number of blood products and synthetic agents that have been shown to be efficacious in treating coagulopathy. These include fresh frozen plasma (FFP), platelets, cryoprecipitate [14], factor concentrates [15,16], activated recombinant factor VIIa [17] and tranexamic acid [18]. At the time of
http://dx.doi.org/10.1016/j.jocn.2015.11.024 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
writing there are no current guidelines towards management of ATC in patients with iTBI [4,19]. Among patients who presented to the emergency department with iTBI and ATC, we aimed to describe times to administration of procoagulant agents and normalization of coagulation status. The secondary aim was to determine the association between normalization of INR and in-hospital mortality. This information could form the basis of a prospective trial to determine the impact of early effective treatment of coagulopathy in trauma patients. 2. Methods 2.1. Setting The Alfred Hospital is one of two tertiary adult trauma referral centers in Melbourne, Australia, receiving 57,000 patients a year to the Emergency and Trauma Centre, including 1300 major trauma patients per year. These centers serve a population of 5.5 million in the state of Victoria, Australia. Trauma teams are activated for patients meeting call-out criteria and trauma reception is standardized using algorithms prompted in real time using computer-aided support systems [20,21]. 2.2. Patients and definitions The Alfred Hospital Trauma Registry (ATR) is a trauma epidemiology, injury surveillance and performance-monitoring program that uses a fully integrated TraumaNet system allowing system monitoring for clinical care, education, audit and research in real time. Inclusion criteria to the ATR are all patients with injury severity score >15, intensive care unit (ICU) admission, transfers, death after injury and admission P72 hours after a traumatic mechanism. Patients presenting to hospital with iTBI and ATC between January 2007 and December 2011 were the target population for this study. The accessible population were all adult (age P16 years old) cases in the ATR with Abbreviated Injury Score (AIS) head P3 and all other body AIS <3. Patients with missing data on INR or head injury details were excluded. ATC was defined as an initial INR of P1.3 on presentation to the emergency department, as this value has been shown to be a clinical horizon point in patients with iTBI, where mortality is around 42%. This mortality rate does not seem to increase with increasing INR value [5]. The International Sensitivity Index of thromboplastin used at our institution ranged from 1.03 to 1.09. This provides an indication for applying the results of this study to centers that use prothrombin time as their measure of coagulation. Patients presenting with previously prescribed anticoagulant medication were excluded from the analysis of association between normalization or INR and death. 2.3. Study design A retrospective study using trauma data was conducted. The primary outcome measure was death recorded at hospital discharge. Secondary outcomes included ICU admission and neurosurgical intervention. Immediately on arrival to hospital blood was drawn and tested for a pre-determined panel of laboratory tests [20]. These results were used for the diagnosis of ATC. During the study period, pre-hospital blood, blood product or procoagulant drug administration were not parts of Ambulance Victoria protocol. Time from hospital admission to the administration of coagulants or blood products was calculated, as was the time from admission to INR normalization (INR <1.3). Prothrombinex-VF (CSL Behring, King of Prussia, PA, USA) is the most common coagulation factor concentrate used in our setting and contains factors II, IX and X and a small amount of factor VII.
2.4. Analysis Normally distributed continuous data were reported as mean (with standard deviation), whereas skewed or ordinal data were reported as medians (with interquartile range). The t-test was used to test for a statistically significant difference between two mean values, while the chi-squared test was used to test for a statistically significant difference between two proportions. A p-value of <0.05 was considered statistically significant. To determine the association between normalization of INR and in-hospital mortality, a multivariable logistic regression model was used. Patients who died in the first 24 hours prior to normalization of INR were excluded in order to adjust for survival bias. Variables that demonstrated any association with death (p < 0.10) were entered into a multivariable logistic regression model to determine independent associations. All data were stored and collated using Excel (Microsoft, Redmond, WA, USA) and analyzed using Stata version 12 (StataCorp, College Station, TX, USA). This study was approved by The Alfred Hospital Research and Ethics Committee. 3. Results There were 1718 patients with iTBI identified in the study period. There were 157 patients who met the set criteria for ATC and were included in the study. There were 68 (43.3%) patients who received coagulant products in the first 24 hours (Fig. 1). The median time to delivery of the first product was 182.5 (115–375) minutes and the median time to normalization of INR among patients who received procoagulant agents was 604 (274–1146) minutes. Among patients who did not receive procoagulant agents but achieved normalization of INR, time to normalization of INR was significantly longer at 1517 (605–2613) minutes (p < 0.01). FFP was the most common procoagulant agent used and was administered to 54 patients within 24 hours, with 40 patients receiving FFP in the first 4 hours. Other products administered in the first 24 hours were vitamin K (n = 7), Prothrombinex (n = 35), platelets (n = 14) and cryoprecipitate (n = 9). Table 1 illustrates the binary combination of products administered to patients. There were 53 patients who required neurosurgical intervention, with 28 patients receiving a procoagulant agent: 27 received FFP, four received vitamin K, 15 received Prothrombinex, five received platelets and three received cryoprecipitate prior to surgery. There was no association between neurosurgical intervention and the volume of red blood cell usage (odds ratio [OR] 1.08; 95% confidence interval [CI] 0.94–1.24; p = 0.29). However, a higher proportion of patients undergoing a neurosurgical intervention were administered procoagulant agents (OR 3.25; 95% CI 1.54– 6.88; p < 0.01). There were 26 patients with a history of oral anticoagulant use. Of these, 19 (73.1%) received procoagulant agents and patients on warfarin were at higher odds of receiving procoagulant agents (OR 4.54; 95% CI 1.78–11.58; p = 0.002). Among the subgroup of patients undergoing a neurosurgical intervention (n = 53), 28 patients received a procoagulant and nine of these patients died, while 25 patients did not receive procoagulants and two of these patients died. Administration of a procoagulant agent was associated with higher odds of death (OR 5.45; 95% CI 1.05–28.31; p = 0.04). Among these 53 patients, 40 patients had normalized INR recorded with an outcome of death in four (10.0%) patients, whereas 13 patients did not achieve normalization of INR, with an outcome of death in seven (53.8%). Among patients undergoing neurosurgical intervention, there was a significant univariate association of normalization of INR with lower mortality (OR 0.09; 95% CI 0.02–0.43; p = 0.002). There were 78 (49.7%) patients admitted to the ICU. Admission to the ICU was significantly associated with normalization of INR (OR 2.27; 95% CI 1.19–4.33). Patients admitted to ICU spent 63
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Coagulopathic n=157
Treatment: 68
INR normalised: 45 Mortality (9/45)= 20.0%
No treatment: 89
INR not normalised: 23 Mortality (15/23): 65.2%
INR normalised: 44 Mortality (11/44)=25.0%
Time to INR normalisation: 604 (274-1146) minutes
INR not normalised 45 Mortality (31/45)= 68.9%
Time to INR normalisation: 1517 (605-2613) minutes
Fig. 1. Management and outcomes in patients with isolated traumatic brain injury and acute traumatic coagulopathy. INR = international normalized ratio.
Table 1 Combination of products given to patients with acute traumatic coagulopathy and isolated traumatic brain injury FFP FFP (n = 54) Platelets (n = 14) Cryoprecipitate (n = 9) Prothrombinexa (n = 35) Vitamin K (n = 7)
12 8 24 4
Platelets
Cryoprecipitate
Prothrombinexa
Vitamin K
12
8 3
24 10 4
4 2 0 5
3 10 2
4 0
5
a
CSL Behring, King of Prussia, PA, USA. FFP = fresh frozen plasma.
(21–184) hours in ICU and were mechanically ventilated for 37 (9–135) hours. Mortality rates at hospital discharge are listed in Fig. 1. There were 66 (42.0%) deaths at hospital discharge. Among 89 patients who had achieved normalization of INR, mortality was 22.5%, compared to 67.6% mortality among those who did not have normalization of INR (p < 0.01). There were 18 patients who died in the first 24 hours after presentation to the emergency department. Of these, three patients had achieved normalization of INR prior to death and were retained. For the secondary analysis, the 15 patients who died in the first 24 hours and prior to normalization of INR and a further 24 patients who were on oral anticoagulants were excluded from analysis, with a total of 142 patients retained for determination of the association between normalization of INR and in-hospital mortality (Fig. 2). Demographics and management of patients, together with univariate associations with mortality at hospital discharge, are listed in Table 2. Normalization of INR was independently associated with improved mortality when adjusted for potential confounders (Table 3).
4. Discussion Coagulopathy after iTBI was uncommon but associated with high mortality. Less than half of the patients with ATC received early management specifically directed at coagulopathy. Normalization of INR was faster when a procoagulant agent was administered, however a long time lag between blood product administration and improved INR was observed. Normalization of INR was associated with significantly improved mortality rates at hospital discharge.
Among patients with iTBI, the association between rapid normalization of INR among patients taking oral anticoagulants and improved mortality post-trauma had been previously reported [22]. Evidence-based guidelines for normalization of INR in the setting of vitamin K dependent oral anticoagulants exist [23]. However, the effectiveness of such guidelines in the setting of ATC has not been proven. The pathophysiology of ATC is more complex and reversal of the coagulopathy is therefore likely to be more difficult to achieve. A combination of agents, such as those recommended in massive transfusion protocols, may therefore be required for reversal of ATC secondary to TBI. In this regard, compared to other trauma patients, isolated head injured patients pose specific challenges. The recognition of patients with isolated head injury may be difficult. The Glasgow Coma Scale is the most common clinical tool used to gauge the severity of head injury, but may be unable to reliably identify patients with intracranial hemorrhage [24]. Permissive hypotension is contraindicated in this patient population with small periods of reduced cerebral perfusion associated with worse outcomes [25]. In addition, coagulopathy in the setting of head injury may be augmented by poorly understood chemical reactions and genomic expressions of proteins such as syndecan [26]. This population of patients with isolated head injury was observed to be older. In our setting where most injuries are secondary to blunt trauma, isolated head injuries are most commonly observed after falls. Falls occur more commonly in older patients, with younger patients more commonly presenting to hospital after motor vehicle crashes sustaining injuries to multiple body regions, and were thus excluded from this study. Delays to recognition of ATC and initiation of management add to the above challenges. A median time of 3 hours from
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
All patients with iTBI: 1718
Excluded Normal INR on arrival: 1561
Patients with iTBI and abnomal INR on presentation: 157
Excluded Death within 24 hrs prior to normalisation of INR: 15
Excluded Patient on oral anticoagulant: 24
Included in analysis: 118
Fig. 2. Inclusion of patients with iTBI in analysis of association of normalization of INR and death at hospital discharge. hrs = hours, INR = international normalized ratio, iTBI = isolated traumatic brain injury.
presentation to receiving procoagulant medication was observed. This is most likely secondary to the cumulative delay of clinical assessment, pathology testing, requesting of products, preparation and delivery. In the setting of isolated head injury where hemorrhagic shock is unlikely, most patients do not receive procoagulant medications through a massive transfusion protocol. Previously we had suggested patients at risk with recognizable clinical variables should be considered for empiric treatment. This includes those with more than one variable from the following: age >50 years, irregular pupillary response and shock index >1. These variables are measurable in the pre-hospital setting or at presentation [5]. Improved sensitivity of early recognition may be further achieved through thromboelastography or rotational thromboelastometry, tools that can quickly assess clot strength [27–30]. These were not available in our center during the period of the study. It was noted that a higher proportion of patients were administered procoagulants if undergoing a neurosurgical intervention and likely secondary to preoperative guidelines to control coagulopathy. However, when adjusted for neurosurgical interventions, survival was independently associated with normalization of INR. This study is limited in being a retrospective analysis in a single center. Patients with missing data were excluded and may not have been missing at random. For example, the first recorded vital signs and investigation results were used, but may have been disproportionately missing among patients who died early or appeared too well to have a coagulation profile requested. Actual normalization of INR may have occurred well before the recorded times, which were the times the blood test result was reported. The available data were limited in recording mortality at hospital discharge with longer-term functional outcomes a more accurate measure of outcomes after major trauma [31]. Exclusion of early deaths may adjust for but cannot exclude bias. For example, patients may have been palliatively managed but survived for longer than 24 hours. This could not be deduced from this retrospective study. Furthermore, it is assumed that procoagulant
Table 2 Variables associated with death in hospital among patients with ATC and iTBI Variable
Survived (N = 73)
Death in hospital (N = 45)
OR (95% CI)
p-value
Age, years (SD) Male Blunt trauma Initial INR INR <2.0 INR 2.0–2.9 INR P3.0 ISS Max head AIS Presenting GCS Pre-hospital fluids received Volume of pre-hospital fluids (ml)* Presenting shock index Platelet count (109/L) RBC in 24 h (%) Received procoagulant FFP in 24 h (units) FFP in 4 h (units) Vitamin K Prothrombinexa Platelets Cryoprecipitate Neurosurgical intervention Multiple neurosurgical interventions
59.2 (25.0) 44 (60.3%) 73 (100%)
63.6 (25.9) 32 (71.1%) 43 (95.5%)
1.01 (0.99–1.02) 1.76 (0.78–3.96) – 0.94 (0.60–1.47)
0.36 0.17 – 0.80
44 (60.3%) 24 (32.9%) 5 (6.8%) 21 (17–26) 4 (3–5) 14 (7–15) 12 (16.4%) 1074.9 (791.8) 0.59 (0.17) 199.6 (85.1) 10 (40.7%) 29 (39.7%) 0 (0–1) 0 (0–0) 3 (4.1%) 12 (16.4%) 6 (8.2%) 3 (4.1%) 33 (45.2%) 8 (10.9%)
28 (62.2%) 14 (31.1%) 3 (6.7%) 25 (25–26) 4 (3–4) 13 (10–14) 12 (31.1%) 1039.4 (709.2) 0.61 (0.20) 179.3 (76.0) 8 (41.2%) 15 (33.3%) 0 (0–2) 0 (0–0) 0 (0%) 3 (6.7%) 3 (6.7%) 5 (11.1%) 8 (17.8%) 3 (6.7%)
1.11 (1.03–1.19) 0.5 (0.29–0.85) 1.01 (0.92–1.10) 1.84 (0.75–4.57) 0.99 (0.98–1.01) 2.15 (0.33–14.84) 0.99 (0.98–1.01) 1.44 (0.52–3.98) 0.78 (0.36–1.71) 1.25 (0.99–1.57) 1.32 (0.92–1.91) – 0.43 (0.13–1.48) 1.38 (0.85–2.25) 2.57 (0.68–9.74) 0.33 (0.13–0.85) 0.58 (0.14–2.31)
0.003 0.011 0.88 0.18 0.89 0.52 0.30 0.48 0.54 0.06 0.13 – 0.18 0.19 0.17 0.022 0.44
Data are presented as number (%) unless otherwise indicated. * If received. a CSL Behring, King of Prussia, PA, USA. AIS = Abbreviated Injury Scale, ATC = acute traumatic coagulopathy, CI = confidence interval, FFP = fresh frozen plasma, GCS = Glasgow Coma Scale score, h = hours, INR = international normalized ratio, ISS = Injury Severity Score, iTBI = isolated traumatic brain injury, max = maximum, OR = odds ratio, RBC = red blood cells, SD = standard deviation.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx Table 3 Results of multivariable logistic regression analysis of factors associated with death in hospital among patients with ATC and iTBI Variables entered
Adjusted OR for death (95% CI)
p-value
Normalization of INR Neurosurgical intervention Max head AIS ISS FFP in 24 hours
0.10 0.24 0.57 1.19 1.66
0.001 0.05 0.16 0.003 0.02
(0.03–0.38) (0.06–1.01) (0.25–1.26) (1.06–1.34) (1.08–2.56)
AIS = Abbreviated Injury Scale, ATC = acute traumatic coagulopathy, CI = confidence interval, FFP = fresh frozen plasma, INR = international normalized ratio, ISS = Injury Severity Score, iTBI = isolated traumatic brain injury, max = maximum, OR = odds ratio.
agents were administered to treat coagulopathy and not used empirically for other reasons. The definition of ATC used was close to the normal range of INR, and may have been ignored as being not clinically significant. This may explain the low proportion of patients who received procoagulant agents. However, we have previously demonstrated significant adverse outcome with even ‘‘mild” coagulopathy and this is supported by studies in different populations [5,32]. There are more fundamental problems with the use of INR for the diagnosis of ATC. While cheap and readily available, it was not developed for the diagnosis of traumatic coagulopathy and assesses only a small component of clot formation and provides no information on clot strength. Laboratory INR results may not be available in a reasonable timeframe and point-of-care INR devices have been evaluated to be inaccurate, especially in the presence of ATC [28,33]. Use of AIS (head) as the inclusion criteria provided an accurate estimation of the incidence of ATC among all patients but does not offer clinical applicability. However, clinical severity scores are limited by pre-hospital management such as intubation, sedation, pharmacologic paralysis and intoxication that precludes accurate assessment of neurologic injury severity. It was surprising to observe a higher maximum AIS of the head region to be independently associated with lower mortality. In the subgroup of major trauma patients with coagulopathy, a higher AIS (head) may have selected patients without injuries to other body regions. Another possibility is that higher AIS (head) scores were allocated to patients with a neurosurgically correctable lesion. The Glasgow Coma Scale is the most common clinical measure of head injury severity used but a poor discriminator for less severe TBI, which account for 80–90% of all cases [34,35], while severity measures based on CT scanning cannot be applied in the pre-hospital or immediate resuscitation phases [36]. While usual practice in our institution results in prompt recording of vital signs and collection of blood on arrival, the exact timing was not studied. 5. Conclusions Normalization of INR was significantly associated with improved mortality in patients with ATC in the setting of iTBI. This generates the hypothesis that early correction of coagulopathy may improve outcomes. There was substantial time lag between delivery of products and eventual normalization of coagulation. A prospective trial to determine the impact of specific management of coagulopathy with real time monitoring of coagulopathy is indicated. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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References [1] Epstein DS, Mitra B, O’Reilly G, et al. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: a systematic review and metaanalysis. Injury 2014;45:819–24. [2] Harhangi BS, Kompanje EJ, Leebeek FW, et al. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien) 2008;150:165–75 [discussion 175]. [3] de Oliveira Manoel AL, Neto AC, Veigas PV, et al. Traumatic brain injury associated coagulopathy. Neurocrit Care 2015;22:34–44. [4] Maegele M. Coagulopathy after traumatic brain injury: incidence, pathogenesis, and treatment options. Transfusion 2013;53:28S–37S. [5] Epstein DS, Mitra B, Cameron PA, et al. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: definition, incidence and outcomes. Br J Neurosurg 2014:1–5 [Epub ahead of print]. [6] Zehtabchi S, Soghoian S, Liu Y, et al. The association of coagulopathy and traumatic brain injury in patients with isolated head injury. Resuscitation 2008;76:52–6. [7] Lee TH, Hampton DA, Diggs BS, et al. Traumatic brain injury is not associated with coagulopathy out of proportion to injury in other body regions. J Trauma Acute Care Surg 2014;77:67–72 [discussion 72]. [8] Joseph B, Aziz H, Zangbar B, et al. Acquired coagulopathy of traumatic brain injury defined by routine laboratory tests: which laboratory values matter? J Trauma Acute Care Surg 2014;76:121–5. [9] Franschman G, Greuters S, Jansen WH, et al. Haemostatic and cranial computed tomography characteristics in patients with acute and delayed coagulopathy after isolated traumatic brain injury. Brain Inj 2012;26:1464–71. [10] Lemcke J, Al-Zain F, von der Brelie C, et al. The influence of coagulopathy on outcome after traumatic subdural hematoma: a retrospective single-center analysis of 319 patients. Blood Coagul Fibrinolysis 2014;25:353–9. [11] Wafaisade A, Lefering R, Tjardes T, et al. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocrit Care 2010;12:211–9. [12] Talving P, Benfield R, Hadjizacharia P, et al. Coagulopathy in severe traumatic brain injury: a prospective study. J Trauma 2009;66:55–61 [discussion 61–2]. [13] Juratli TA, Zang B, Litz RJ, et al. Early hemorrhagic progression of traumatic brain contusions: frequency, correlation with coagulation disorders, and patient outcome: a prospective study. J Neurotrauma 2014;31:1521–7. [14] Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth 2014;113:922–34. [15] Huynh TK, Costello JL, Rebuck JA. Optimizing the dose of three-factor prothrombin complex concentrate in traumatic brain injury patients on warfarin therapy. Pharmacotherapy 2014;34:260–4. [16] Joseph B, Amini A, Friese RS, et al. Factor IX complex for the correction of traumatic coagulopathy. J Trauma Acute Care Surg 2012;72:828–34. [17] Brophy GM, Candeloro CL, Robles JR, et al. Recombinant activated factor VII use in critically ill patients: clinical outcomes and thromboembolic events. Ann Pharmacother 2013;47:447–54. [18] Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, et al. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med 2013;13:20. [19] Peiniger S, Nienaber U, Lefering R, et al. Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care 2011;15:R68. [20] Cameron PA, Gabbe BJ, Smith K, et al. Triaging the right patient to the right place in the shortest time. Br J Anaesth 2014;113:226–33. [21] Fitzgerald M, Cameron P, Mackenzie C, et al. Trauma resuscitation errors and computer-assisted decision support. Archiv Surg 2011;146:218–25. [22] Kalina M, Tinkoff G, Gbadebo A, et al. A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy. Am Surg 2008;74:858–61. [23] Tran HA, Chunilal SD, Harper PL, et al. An update of consensus guidelines for warfarin reversal. Med J Aust 2013;198:198–9. [24] Ivascu FA, Howells GA, Junn FS, et al. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma 2005;59:1131–7 [discussion 1137–9]. [25] Lier H, Bottiger BW, Hinkelbein J, et al. Coagulation management in multiple trauma: a systematic review. Intensive Care Med 2011;37:572–82. [26] Johansson PI, Stensballe J, Rasmussen LS, et al. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg 2011;254:194–200. [27] Schochl H, Solomon C, Traintinger S, et al. Thromboelastometric (ROTEM) findings in patients suffering from isolated severe traumatic brain injury. J Neurotrauma 2011;28:2033–41. [28] Davenport R, Manson J, De’Ath H, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011;39:2652–8. [29] Rugeri L, Levrat A, David JS, et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 2007;5:289–95. [30] Kunio NR, Differding JA, Watson KM, et al. Thrombelastography-identified coagulopathy is associated with increased morbidity and mortality after traumatic brain injury. Am J Surg 2012;203:584–8. [31] Mitra B, Gabbe BJ, Kaukonen KM, et al. Long-term outcomes of patients receiving a massive transfusion after trauma. Shock 2014;42:307–12.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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[32] Greuters S, van den Berg A, Franschman G, et al. Acute and delayed mild coagulopathy are related to outcome in patients with isolated traumatic brain injury. Crit Care 2011;15:R2. [33] Mitra B, O’Reilly G, Collecutt M, et al. Prospective comparison of point-of-care international normalised ratio measurement versus plasma international normalised ratio for acute traumatic coagulopathy. Emerg Med Australas 2012;24:363–8.
[34] Saatman KE, Duhaime AC, Bullock R, et al. Classification of traumatic brain injury for targeted therapies. J Neurotrauma 2008;25:719–38. [35] Joseph B, Pandit V, Aziz H, et al. Mild traumatic brain injury defined by Glasgow Coma Scale: is it really mild? Brain Inj 2015;29:11–6. [36] Marshall LF, Maas AI, Marshall SB, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 1998;89:519–25.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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Clinical Study
Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury Daniel S. Epstein a,b, Biswadev Mitra a,b,c,⇑, Peter A. Cameron a,b,d, Mark Fitzgerald c,e,f, Jeffrey V. Rosenfeld f,g,h a
Emergency and Trauma Centre, The Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia National Trauma Research Institute, Melbourne, VIC, Australia d Emergency Medicine, Hamad Medical Corporation, Doha, Qatar e Trauma Service, The Alfred Hospital, Melbourne, VIC, Australia f Department of Surgery, Monash University, Melbourne, VIC, Australia g Department of Neurosurgery, The Alfred Hospital, Melbourne, VIC, Australia h Department of Surgery, F. Edward Hébert School of Medicine, Uniformed Services University of The Health Sciences (USUHS), Bethesda, MD, USA b c
a r t i c l e
i n f o
Article history: Received 8 August 2015 Accepted 8 November 2015 Available online xxxx Keywords: Blood coagulation Coagulopathy Craniocerebral trauma Injuries Isolated head trauma Traumatic brain injury
a b s t r a c t Acute traumatic coagulopathy (ATC) has been reported in the setting of isolated traumatic brain injury (iTBI) and is associated with poor outcomes. We aimed to evaluate the effectiveness of procoagulant agents administered to patients with ATC and iTBI during resuscitation, hypothesizing that timely normalization of coagulopathy may be associated with a decrease in mortality. A retrospective review of the Alfred Hospital trauma registry, Australia, was conducted and patients with iTBI (head Abbreviated Injury Score [AIS] P3 and all other body AIS <3) and coagulopathy (international normalized ratio P1.3) were selected for analysis. Data on procoagulant agents used (fresh frozen plasma, platelets, cryoprecipitate, prothrombin complex concentrates, tranexamic acid, vitamin K) were extracted. Among patients who had achieved normalization of INR or survived beyond 24 hours and were not taking oral anticoagulants, the association of normalization of INR and death at hospital discharge was analyzed using multivariable logistic regression analysis. There were 157 patients with ATC of whom 68 (43.3%) received procoagulant products within 24 hours of presentation. The median time to delivery of first products was 182.5 (interquartile range [IQR] 115–375) minutes, and following administration of coagulants, time to normalization of INR was 605 (IQR 274–1146) minutes. Normalization of INR was independently associated with significantly lower mortality (adjusted odds ratio 0.10; 95% confidence interval 0.03–0.38). Normalization of INR was associated with improved mortality in patients with ATC in the setting of iTBI. As there was a substantial time lag between delivery of products and eventual normalization of coagulation, specific management of coagulopathy should be implemented as early as possible. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Acquired disorders of coagulation, also termed acute traumatic coagulopathy (ATC), early trauma induced coagulopathy or acute coagulopathy of trauma, have been previously described in the setting of isolated traumatic brain injury (iTBI) [1–4]. The incidence of ATC in the setting of iTBI is estimated to be 8%, using an international normalized ratio (INR) P1.3 as a cut-off associated with higher mortality and adverse outcomes after iTBI [5,6]. However, ⇑ Corresponding author. Tel.: +61 3 9076 2782; fax: +61 3 9076 2699. E-mail address: [email protected] (B. Mitra).
the incidence of this condition has been variably reported depending on the study design and definition of coagulopathy used [1,7–9]. Regardless of definitions, in-hospital mortality in the setting of ATC and iTBI has been reported approaching 50% [2], and an abnormal initial INR, regardless of magnitude, in the setting of iTBI, was associated with poor outcomes [5,10–13]. It is hypothesized that early treatment of coagulopathy may improve outcomes. There are a number of blood products and synthetic agents that have been shown to be efficacious in treating coagulopathy. These include fresh frozen plasma (FFP), platelets, cryoprecipitate [14], factor concentrates [15,16], activated recombinant factor VIIa [17] and tranexamic acid [18]. At the time of
http://dx.doi.org/10.1016/j.jocn.2015.11.024 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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writing there are no current guidelines towards management of ATC in patients with iTBI [4,19]. Among patients who presented to the emergency department with iTBI and ATC, we aimed to describe times to administration of procoagulant agents and normalization of coagulation status. The secondary aim was to determine the association between normalization of INR and in-hospital mortality. This information could form the basis of a prospective trial to determine the impact of early effective treatment of coagulopathy in trauma patients. 2. Methods 2.1. Setting The Alfred Hospital is one of two tertiary adult trauma referral centers in Melbourne, Australia, receiving 57,000 patients a year to the Emergency and Trauma Centre, including 1300 major trauma patients per year. These centers serve a population of 5.5 million in the state of Victoria, Australia. Trauma teams are activated for patients meeting call-out criteria and trauma reception is standardized using algorithms prompted in real time using computer-aided support systems [20,21]. 2.2. Patients and definitions The Alfred Hospital Trauma Registry (ATR) is a trauma epidemiology, injury surveillance and performance-monitoring program that uses a fully integrated TraumaNet system allowing system monitoring for clinical care, education, audit and research in real time. Inclusion criteria to the ATR are all patients with injury severity score >15, intensive care unit (ICU) admission, transfers, death after injury and admission P72 hours after a traumatic mechanism. Patients presenting to hospital with iTBI and ATC between January 2007 and December 2011 were the target population for this study. The accessible population were all adult (age P16 years old) cases in the ATR with Abbreviated Injury Score (AIS) head P3 and all other body AIS <3. Patients with missing data on INR or head injury details were excluded. ATC was defined as an initial INR of P1.3 on presentation to the emergency department, as this value has been shown to be a clinical horizon point in patients with iTBI, where mortality is around 42%. This mortality rate does not seem to increase with increasing INR value [5]. The International Sensitivity Index of thromboplastin used at our institution ranged from 1.03 to 1.09. This provides an indication for applying the results of this study to centers that use prothrombin time as their measure of coagulation. Patients presenting with previously prescribed anticoagulant medication were excluded from the analysis of association between normalization or INR and death. 2.3. Study design A retrospective study using trauma data was conducted. The primary outcome measure was death recorded at hospital discharge. Secondary outcomes included ICU admission and neurosurgical intervention. Immediately on arrival to hospital blood was drawn and tested for a pre-determined panel of laboratory tests [20]. These results were used for the diagnosis of ATC. During the study period, pre-hospital blood, blood product or procoagulant drug administration were not parts of Ambulance Victoria protocol. Time from hospital admission to the administration of coagulants or blood products was calculated, as was the time from admission to INR normalization (INR <1.3). Prothrombinex-VF (CSL Behring, King of Prussia, PA, USA) is the most common coagulation factor concentrate used in our setting and contains factors II, IX and X and a small amount of factor VII.
2.4. Analysis Normally distributed continuous data were reported as mean (with standard deviation), whereas skewed or ordinal data were reported as medians (with interquartile range). The t-test was used to test for a statistically significant difference between two mean values, while the chi-squared test was used to test for a statistically significant difference between two proportions. A p-value of <0.05 was considered statistically significant. To determine the association between normalization of INR and in-hospital mortality, a multivariable logistic regression model was used. Patients who died in the first 24 hours prior to normalization of INR were excluded in order to adjust for survival bias. Variables that demonstrated any association with death (p < 0.10) were entered into a multivariable logistic regression model to determine independent associations. All data were stored and collated using Excel (Microsoft, Redmond, WA, USA) and analyzed using Stata version 12 (StataCorp, College Station, TX, USA). This study was approved by The Alfred Hospital Research and Ethics Committee. 3. Results There were 1718 patients with iTBI identified in the study period. There were 157 patients who met the set criteria for ATC and were included in the study. There were 68 (43.3%) patients who received coagulant products in the first 24 hours (Fig. 1). The median time to delivery of the first product was 182.5 (115–375) minutes and the median time to normalization of INR among patients who received procoagulant agents was 604 (274–1146) minutes. Among patients who did not receive procoagulant agents but achieved normalization of INR, time to normalization of INR was significantly longer at 1517 (605–2613) minutes (p < 0.01). FFP was the most common procoagulant agent used and was administered to 54 patients within 24 hours, with 40 patients receiving FFP in the first 4 hours. Other products administered in the first 24 hours were vitamin K (n = 7), Prothrombinex (n = 35), platelets (n = 14) and cryoprecipitate (n = 9). Table 1 illustrates the binary combination of products administered to patients. There were 53 patients who required neurosurgical intervention, with 28 patients receiving a procoagulant agent: 27 received FFP, four received vitamin K, 15 received Prothrombinex, five received platelets and three received cryoprecipitate prior to surgery. There was no association between neurosurgical intervention and the volume of red blood cell usage (odds ratio [OR] 1.08; 95% confidence interval [CI] 0.94–1.24; p = 0.29). However, a higher proportion of patients undergoing a neurosurgical intervention were administered procoagulant agents (OR 3.25; 95% CI 1.54– 6.88; p < 0.01). There were 26 patients with a history of oral anticoagulant use. Of these, 19 (73.1%) received procoagulant agents and patients on warfarin were at higher odds of receiving procoagulant agents (OR 4.54; 95% CI 1.78–11.58; p = 0.002). Among the subgroup of patients undergoing a neurosurgical intervention (n = 53), 28 patients received a procoagulant and nine of these patients died, while 25 patients did not receive procoagulants and two of these patients died. Administration of a procoagulant agent was associated with higher odds of death (OR 5.45; 95% CI 1.05–28.31; p = 0.04). Among these 53 patients, 40 patients had normalized INR recorded with an outcome of death in four (10.0%) patients, whereas 13 patients did not achieve normalization of INR, with an outcome of death in seven (53.8%). Among patients undergoing neurosurgical intervention, there was a significant univariate association of normalization of INR with lower mortality (OR 0.09; 95% CI 0.02–0.43; p = 0.002). There were 78 (49.7%) patients admitted to the ICU. Admission to the ICU was significantly associated with normalization of INR (OR 2.27; 95% CI 1.19–4.33). Patients admitted to ICU spent 63
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Coagulopathic n=157
Treatment: 68
INR normalised: 45 Mortality (9/45)= 20.0%
No treatment: 89
INR not normalised: 23 Mortality (15/23): 65.2%
INR normalised: 44 Mortality (11/44)=25.0%
Time to INR normalisation: 604 (274-1146) minutes
INR not normalised 45 Mortality (31/45)= 68.9%
Time to INR normalisation: 1517 (605-2613) minutes
Fig. 1. Management and outcomes in patients with isolated traumatic brain injury and acute traumatic coagulopathy. INR = international normalized ratio.
Table 1 Combination of products given to patients with acute traumatic coagulopathy and isolated traumatic brain injury FFP FFP (n = 54) Platelets (n = 14) Cryoprecipitate (n = 9) Prothrombinexa (n = 35) Vitamin K (n = 7)
12 8 24 4
Platelets
Cryoprecipitate
Prothrombinexa
Vitamin K
12
8 3
24 10 4
4 2 0 5
3 10 2
4 0
5
a
CSL Behring, King of Prussia, PA, USA. FFP = fresh frozen plasma.
(21–184) hours in ICU and were mechanically ventilated for 37 (9–135) hours. Mortality rates at hospital discharge are listed in Fig. 1. There were 66 (42.0%) deaths at hospital discharge. Among 89 patients who had achieved normalization of INR, mortality was 22.5%, compared to 67.6% mortality among those who did not have normalization of INR (p < 0.01). There were 18 patients who died in the first 24 hours after presentation to the emergency department. Of these, three patients had achieved normalization of INR prior to death and were retained. For the secondary analysis, the 15 patients who died in the first 24 hours and prior to normalization of INR and a further 24 patients who were on oral anticoagulants were excluded from analysis, with a total of 142 patients retained for determination of the association between normalization of INR and in-hospital mortality (Fig. 2). Demographics and management of patients, together with univariate associations with mortality at hospital discharge, are listed in Table 2. Normalization of INR was independently associated with improved mortality when adjusted for potential confounders (Table 3).
4. Discussion Coagulopathy after iTBI was uncommon but associated with high mortality. Less than half of the patients with ATC received early management specifically directed at coagulopathy. Normalization of INR was faster when a procoagulant agent was administered, however a long time lag between blood product administration and improved INR was observed. Normalization of INR was associated with significantly improved mortality rates at hospital discharge.
Among patients with iTBI, the association between rapid normalization of INR among patients taking oral anticoagulants and improved mortality post-trauma had been previously reported [22]. Evidence-based guidelines for normalization of INR in the setting of vitamin K dependent oral anticoagulants exist [23]. However, the effectiveness of such guidelines in the setting of ATC has not been proven. The pathophysiology of ATC is more complex and reversal of the coagulopathy is therefore likely to be more difficult to achieve. A combination of agents, such as those recommended in massive transfusion protocols, may therefore be required for reversal of ATC secondary to TBI. In this regard, compared to other trauma patients, isolated head injured patients pose specific challenges. The recognition of patients with isolated head injury may be difficult. The Glasgow Coma Scale is the most common clinical tool used to gauge the severity of head injury, but may be unable to reliably identify patients with intracranial hemorrhage [24]. Permissive hypotension is contraindicated in this patient population with small periods of reduced cerebral perfusion associated with worse outcomes [25]. In addition, coagulopathy in the setting of head injury may be augmented by poorly understood chemical reactions and genomic expressions of proteins such as syndecan [26]. This population of patients with isolated head injury was observed to be older. In our setting where most injuries are secondary to blunt trauma, isolated head injuries are most commonly observed after falls. Falls occur more commonly in older patients, with younger patients more commonly presenting to hospital after motor vehicle crashes sustaining injuries to multiple body regions, and were thus excluded from this study. Delays to recognition of ATC and initiation of management add to the above challenges. A median time of 3 hours from
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
All patients with iTBI: 1718
Excluded Normal INR on arrival: 1561
Patients with iTBI and abnomal INR on presentation: 157
Excluded Death within 24 hrs prior to normalisation of INR: 15
Excluded Patient on oral anticoagulant: 24
Included in analysis: 118
Fig. 2. Inclusion of patients with iTBI in analysis of association of normalization of INR and death at hospital discharge. hrs = hours, INR = international normalized ratio, iTBI = isolated traumatic brain injury.
presentation to receiving procoagulant medication was observed. This is most likely secondary to the cumulative delay of clinical assessment, pathology testing, requesting of products, preparation and delivery. In the setting of isolated head injury where hemorrhagic shock is unlikely, most patients do not receive procoagulant medications through a massive transfusion protocol. Previously we had suggested patients at risk with recognizable clinical variables should be considered for empiric treatment. This includes those with more than one variable from the following: age >50 years, irregular pupillary response and shock index >1. These variables are measurable in the pre-hospital setting or at presentation [5]. Improved sensitivity of early recognition may be further achieved through thromboelastography or rotational thromboelastometry, tools that can quickly assess clot strength [27–30]. These were not available in our center during the period of the study. It was noted that a higher proportion of patients were administered procoagulants if undergoing a neurosurgical intervention and likely secondary to preoperative guidelines to control coagulopathy. However, when adjusted for neurosurgical interventions, survival was independently associated with normalization of INR. This study is limited in being a retrospective analysis in a single center. Patients with missing data were excluded and may not have been missing at random. For example, the first recorded vital signs and investigation results were used, but may have been disproportionately missing among patients who died early or appeared too well to have a coagulation profile requested. Actual normalization of INR may have occurred well before the recorded times, which were the times the blood test result was reported. The available data were limited in recording mortality at hospital discharge with longer-term functional outcomes a more accurate measure of outcomes after major trauma [31]. Exclusion of early deaths may adjust for but cannot exclude bias. For example, patients may have been palliatively managed but survived for longer than 24 hours. This could not be deduced from this retrospective study. Furthermore, it is assumed that procoagulant
Table 2 Variables associated with death in hospital among patients with ATC and iTBI Variable
Survived (N = 73)
Death in hospital (N = 45)
OR (95% CI)
p-value
Age, years (SD) Male Blunt trauma Initial INR INR <2.0 INR 2.0–2.9 INR P3.0 ISS Max head AIS Presenting GCS Pre-hospital fluids received Volume of pre-hospital fluids (ml)* Presenting shock index Platelet count (109/L) RBC in 24 h (%) Received procoagulant FFP in 24 h (units) FFP in 4 h (units) Vitamin K Prothrombinexa Platelets Cryoprecipitate Neurosurgical intervention Multiple neurosurgical interventions
59.2 (25.0) 44 (60.3%) 73 (100%)
63.6 (25.9) 32 (71.1%) 43 (95.5%)
1.01 (0.99–1.02) 1.76 (0.78–3.96) – 0.94 (0.60–1.47)
0.36 0.17 – 0.80
44 (60.3%) 24 (32.9%) 5 (6.8%) 21 (17–26) 4 (3–5) 14 (7–15) 12 (16.4%) 1074.9 (791.8) 0.59 (0.17) 199.6 (85.1) 10 (40.7%) 29 (39.7%) 0 (0–1) 0 (0–0) 3 (4.1%) 12 (16.4%) 6 (8.2%) 3 (4.1%) 33 (45.2%) 8 (10.9%)
28 (62.2%) 14 (31.1%) 3 (6.7%) 25 (25–26) 4 (3–4) 13 (10–14) 12 (31.1%) 1039.4 (709.2) 0.61 (0.20) 179.3 (76.0) 8 (41.2%) 15 (33.3%) 0 (0–2) 0 (0–0) 0 (0%) 3 (6.7%) 3 (6.7%) 5 (11.1%) 8 (17.8%) 3 (6.7%)
1.11 (1.03–1.19) 0.5 (0.29–0.85) 1.01 (0.92–1.10) 1.84 (0.75–4.57) 0.99 (0.98–1.01) 2.15 (0.33–14.84) 0.99 (0.98–1.01) 1.44 (0.52–3.98) 0.78 (0.36–1.71) 1.25 (0.99–1.57) 1.32 (0.92–1.91) – 0.43 (0.13–1.48) 1.38 (0.85–2.25) 2.57 (0.68–9.74) 0.33 (0.13–0.85) 0.58 (0.14–2.31)
0.003 0.011 0.88 0.18 0.89 0.52 0.30 0.48 0.54 0.06 0.13 – 0.18 0.19 0.17 0.022 0.44
Data are presented as number (%) unless otherwise indicated. * If received. a CSL Behring, King of Prussia, PA, USA. AIS = Abbreviated Injury Scale, ATC = acute traumatic coagulopathy, CI = confidence interval, FFP = fresh frozen plasma, GCS = Glasgow Coma Scale score, h = hours, INR = international normalized ratio, ISS = Injury Severity Score, iTBI = isolated traumatic brain injury, max = maximum, OR = odds ratio, RBC = red blood cells, SD = standard deviation.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx Table 3 Results of multivariable logistic regression analysis of factors associated with death in hospital among patients with ATC and iTBI Variables entered
Adjusted OR for death (95% CI)
p-value
Normalization of INR Neurosurgical intervention Max head AIS ISS FFP in 24 hours
0.10 0.24 0.57 1.19 1.66
0.001 0.05 0.16 0.003 0.02
(0.03–0.38) (0.06–1.01) (0.25–1.26) (1.06–1.34) (1.08–2.56)
AIS = Abbreviated Injury Scale, ATC = acute traumatic coagulopathy, CI = confidence interval, FFP = fresh frozen plasma, INR = international normalized ratio, ISS = Injury Severity Score, iTBI = isolated traumatic brain injury, max = maximum, OR = odds ratio.
agents were administered to treat coagulopathy and not used empirically for other reasons. The definition of ATC used was close to the normal range of INR, and may have been ignored as being not clinically significant. This may explain the low proportion of patients who received procoagulant agents. However, we have previously demonstrated significant adverse outcome with even ‘‘mild” coagulopathy and this is supported by studies in different populations [5,32]. There are more fundamental problems with the use of INR for the diagnosis of ATC. While cheap and readily available, it was not developed for the diagnosis of traumatic coagulopathy and assesses only a small component of clot formation and provides no information on clot strength. Laboratory INR results may not be available in a reasonable timeframe and point-of-care INR devices have been evaluated to be inaccurate, especially in the presence of ATC [28,33]. Use of AIS (head) as the inclusion criteria provided an accurate estimation of the incidence of ATC among all patients but does not offer clinical applicability. However, clinical severity scores are limited by pre-hospital management such as intubation, sedation, pharmacologic paralysis and intoxication that precludes accurate assessment of neurologic injury severity. It was surprising to observe a higher maximum AIS of the head region to be independently associated with lower mortality. In the subgroup of major trauma patients with coagulopathy, a higher AIS (head) may have selected patients without injuries to other body regions. Another possibility is that higher AIS (head) scores were allocated to patients with a neurosurgically correctable lesion. The Glasgow Coma Scale is the most common clinical measure of head injury severity used but a poor discriminator for less severe TBI, which account for 80–90% of all cases [34,35], while severity measures based on CT scanning cannot be applied in the pre-hospital or immediate resuscitation phases [36]. While usual practice in our institution results in prompt recording of vital signs and collection of blood on arrival, the exact timing was not studied. 5. Conclusions Normalization of INR was significantly associated with improved mortality in patients with ATC in the setting of iTBI. This generates the hypothesis that early correction of coagulopathy may improve outcomes. There was substantial time lag between delivery of products and eventual normalization of coagulation. A prospective trial to determine the impact of specific management of coagulopathy with real time monitoring of coagulopathy is indicated. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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References [1] Epstein DS, Mitra B, O’Reilly G, et al. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: a systematic review and metaanalysis. Injury 2014;45:819–24. [2] Harhangi BS, Kompanje EJ, Leebeek FW, et al. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien) 2008;150:165–75 [discussion 175]. [3] de Oliveira Manoel AL, Neto AC, Veigas PV, et al. Traumatic brain injury associated coagulopathy. Neurocrit Care 2015;22:34–44. [4] Maegele M. Coagulopathy after traumatic brain injury: incidence, pathogenesis, and treatment options. Transfusion 2013;53:28S–37S. [5] Epstein DS, Mitra B, Cameron PA, et al. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: definition, incidence and outcomes. Br J Neurosurg 2014:1–5 [Epub ahead of print]. [6] Zehtabchi S, Soghoian S, Liu Y, et al. The association of coagulopathy and traumatic brain injury in patients with isolated head injury. Resuscitation 2008;76:52–6. [7] Lee TH, Hampton DA, Diggs BS, et al. Traumatic brain injury is not associated with coagulopathy out of proportion to injury in other body regions. J Trauma Acute Care Surg 2014;77:67–72 [discussion 72]. [8] Joseph B, Aziz H, Zangbar B, et al. Acquired coagulopathy of traumatic brain injury defined by routine laboratory tests: which laboratory values matter? J Trauma Acute Care Surg 2014;76:121–5. [9] Franschman G, Greuters S, Jansen WH, et al. Haemostatic and cranial computed tomography characteristics in patients with acute and delayed coagulopathy after isolated traumatic brain injury. Brain Inj 2012;26:1464–71. [10] Lemcke J, Al-Zain F, von der Brelie C, et al. The influence of coagulopathy on outcome after traumatic subdural hematoma: a retrospective single-center analysis of 319 patients. Blood Coagul Fibrinolysis 2014;25:353–9. [11] Wafaisade A, Lefering R, Tjardes T, et al. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocrit Care 2010;12:211–9. [12] Talving P, Benfield R, Hadjizacharia P, et al. Coagulopathy in severe traumatic brain injury: a prospective study. J Trauma 2009;66:55–61 [discussion 61–2]. [13] Juratli TA, Zang B, Litz RJ, et al. Early hemorrhagic progression of traumatic brain contusions: frequency, correlation with coagulation disorders, and patient outcome: a prospective study. J Neurotrauma 2014;31:1521–7. [14] Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth 2014;113:922–34. [15] Huynh TK, Costello JL, Rebuck JA. Optimizing the dose of three-factor prothrombin complex concentrate in traumatic brain injury patients on warfarin therapy. Pharmacotherapy 2014;34:260–4. [16] Joseph B, Amini A, Friese RS, et al. Factor IX complex for the correction of traumatic coagulopathy. J Trauma Acute Care Surg 2012;72:828–34. [17] Brophy GM, Candeloro CL, Robles JR, et al. Recombinant activated factor VII use in critically ill patients: clinical outcomes and thromboembolic events. Ann Pharmacother 2013;47:447–54. [18] Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, et al. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med 2013;13:20. [19] Peiniger S, Nienaber U, Lefering R, et al. Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care 2011;15:R68. [20] Cameron PA, Gabbe BJ, Smith K, et al. Triaging the right patient to the right place in the shortest time. Br J Anaesth 2014;113:226–33. [21] Fitzgerald M, Cameron P, Mackenzie C, et al. Trauma resuscitation errors and computer-assisted decision support. Archiv Surg 2011;146:218–25. [22] Kalina M, Tinkoff G, Gbadebo A, et al. A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy. Am Surg 2008;74:858–61. [23] Tran HA, Chunilal SD, Harper PL, et al. An update of consensus guidelines for warfarin reversal. Med J Aust 2013;198:198–9. [24] Ivascu FA, Howells GA, Junn FS, et al. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma 2005;59:1131–7 [discussion 1137–9]. [25] Lier H, Bottiger BW, Hinkelbein J, et al. Coagulation management in multiple trauma: a systematic review. Intensive Care Med 2011;37:572–82. [26] Johansson PI, Stensballe J, Rasmussen LS, et al. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg 2011;254:194–200. [27] Schochl H, Solomon C, Traintinger S, et al. Thromboelastometric (ROTEM) findings in patients suffering from isolated severe traumatic brain injury. J Neurotrauma 2011;28:2033–41. [28] Davenport R, Manson J, De’Ath H, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011;39:2652–8. [29] Rugeri L, Levrat A, David JS, et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 2007;5:289–95. [30] Kunio NR, Differding JA, Watson KM, et al. Thrombelastography-identified coagulopathy is associated with increased morbidity and mortality after traumatic brain injury. Am J Surg 2012;203:584–8. [31] Mitra B, Gabbe BJ, Kaukonen KM, et al. Long-term outcomes of patients receiving a massive transfusion after trauma. Shock 2014;42:307–12.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024
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D.S. Epstein et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
[32] Greuters S, van den Berg A, Franschman G, et al. Acute and delayed mild coagulopathy are related to outcome in patients with isolated traumatic brain injury. Crit Care 2011;15:R2. [33] Mitra B, O’Reilly G, Collecutt M, et al. Prospective comparison of point-of-care international normalised ratio measurement versus plasma international normalised ratio for acute traumatic coagulopathy. Emerg Med Australas 2012;24:363–8.
[34] Saatman KE, Duhaime AC, Bullock R, et al. Classification of traumatic brain injury for targeted therapies. J Neurotrauma 2008;25:719–38. [35] Joseph B, Pandit V, Aziz H, et al. Mild traumatic brain injury defined by Glasgow Coma Scale: is it really mild? Brain Inj 2015;29:11–6. [36] Marshall LF, Maas AI, Marshall SB, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 1998;89:519–25.
Please cite this article in press as: Epstein DS et al. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.11.024