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The association of coagulopathy and traumatic brain injury in patients with isolated head injury
Resuscitation (2008) 76, 52—56
available at www.sciencedirect.com
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CLINICAL PAPER
The association of coagulopathy and traumatic brain injury in patients with isolated head injury夽 Shahriar Zehtabchi ∗, Samara Soghoian, Yiju Liu, Kristin Carmody, Lekha Shah, Brian Whittaker, Richard Sinert Department of Emergency Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, United States Received 24 April 2007; accepted 18 June 2007
KEYWORDS Coagulation; Brain injury; International normalized ratio; Trauma
Summary The emergence of prothrombotic agents (e.g. activated factor VII) to treat traumatic brain injury (TBI) requires a better understanding of the association of coagulopathy with isolated head injury (IHI). Objective: To investigate the association of IHI and coagulopathy. Methods: Prospective, observational study in an urban level I trauma center. Inclusion criteria: Adult (≥13 years of age) patients with IHI. Exclusion criteria: patients with known coagulopathies or on anticoagulant therapy. Predictor Variables: TBI (head abbreviated injury severity score >2, or brain hematoma on CT scan), age, gender, mechanism of injury, Glasgow Coma Score (GCS), and loss of consciousness (LOC). Outcome variables: coagulopathy defined as elevated International Normalized Ratio (INR > 1.3) or activated partial thromboplastin time (PTT) greater than 34 s. We divided IHI subjects into two groups of patients with and without TBI. Statistical Analysis: Fisher’s exact test and Mann—Whitney U were used to compare data where appropriate (alpha: 0.05, two-tailed). Results: From July 2005 to December 2006, 276 patients with IHI were studied. The median age was 35 years (interquartile range: 25—52) with a 79% male predominance and 88% blunt trauma. Eight percent (95% CI, 5—12%) of patients had coagulopathy. The rate of coagulopathy in TBI patients (17%) was significantly higher than non-TBI patients (6%) (11% difference, 95% CI, 3—20%]. The relative risk of coagulopathy in TBI patients was 2.9 (95% CI, 1.3—6.6). Conclusion: Coagulopathy as defined by elevated INR and/or PTT is associated with TBI after isolated head injury. © 2007 Elsevier Ireland Ltd. All rights reserved.
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at 10.1016/j.resuscitation.2007.06.024. ∗ Corresponding author at: Department of Emergency Medicine, State University of New York, Downstate Medical Center, Box: 1228, 450 Clarkson Ave., Brooklyn, NY 11203, United States. E-mail address: [email protected] (S. Zehtabchi).
0300-9572/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2007.06.024
Coagulopathy in traumatic brain injury
Introduction The emergence of prothrombotic agents (e.g. activated factor VII) to treat patients with Traumatic Brain Injury (TBI) requires a better understanding of the association of coagulopathy with isolated head injury. Primary brain damage occurs at the time of impact and cannot be modified. Improving the outcome of brain injury patients mainly depends on minimizing the secondary brain insults.1,2 Such secondary insults include cerebral edema, increased intracerebral pressure, infection, hypoxia, and coagulopathy. The potential to treat and thereby avoid or mitigate secondary cerebral insults from disordered coagulation underscores the importance of verifying the association of brain injury and coagulopathy. The brain tissue contains large amounts of thromboplastin. This substance is released in high concentration into the blood stream after physical trauma to the parenchyma, causing disturbance in coagulation processes. In addition, damaged cerebral endothelium activates platelets as well as clotting cascades to produce intravascular thrombosis and depletion of coagulation factors.3 Coagulopathy may affect the outcome of brain injury independent of provoking a bleeding diathesis. Autopsy studies and some animal models suggest that ischemia from intravascular microthrombosis and the deposition of fibrin on endothelial surfaces lead to impaired oxygen exchange and hence accentuate the secondary insult to the brain.3,4 The incidence of various forms of coagulopathy following isolated head injury varies widely based on the definition of coagulopathy in different studies and has been reported in up to 90% of TBI patients.1,3,5 We designed this prospective observational study to estimate the incidence of coagulopathy in patients with traumatic brain injury. We tested the null hypothesis is that there would be no difference in incidence of coagulopathy in patients with or without TBI.
Methods From July 2005 to December 2006 we conducted a prospective, observational study at Kings County Hospital Center (KCHC). KCHC is an academic level I trauma center in Brooklyn, New York that receives approximately 150,000 emergency department visits and 1600 trauma admissions annually. The joint institutional review boards (IRB) of KCHC and State University of New York, Downstate Medical Center approved the study and waived the informed consent requirement. We enrolled prospectively a convenience sample of adult trauma patients (age ≥ 13, the age cut-off for adult trauma in our institution) who sustained head injury and required imaging studies as part of their diagnostic work-up. The attending emergency medicine physician determined the need for imaging to rule out traumatic brain injury (TBI) following significant head trauma. Patients with obvious clinical signs of extracranial injuries or those who were found to have such injuries after extensive trauma workup (CT Scans, serial hematocrit measurements, diagnostic peritoneal lavage, Laparotomy, etc., where indicated),
53 were excluded. Therefore, data analysis was performed on patients with isolated head injury only. Patients with known coagulation disorders and those on anticoagulant therapy were excluded. Trained data abstractors (academic associates, medical student volunteers) enrolled a convenience sample of trauma patients. Academic associates recorded demographic data, triage vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, pulse oxymetry, and temperature), mechanism of injury, and presence or absence of loss of consciousness (LOC) following the injury. Glasgow Coma Score (GCS) was also documented upon patients’ arrival to the emergency department. Arterial blood gas analysis, serum albumin, liver function tests, platelet counts, and serum calcium levels were measured for all patients. Transfusion of red blood cells and other blood products were recorded. Prothrombin Time (PT) (s) and Activated Partial Thromboplastin Time (APTT) (s) were measured by Blood Coagulation System® CA-7000 (DadeBehring, Deerfield, Illinois). The International Normalized Ratio (INR) was calculated and reported by the same machine and was used as a surrogate for PT to account for institutional variability in the measurement of this marker. An attending neuroradiologist confirmed all official head CT reports. Upon completion of trauma work-up, the head Abbreviated Injury severity scores (AISS) were calculated. AIS was graded according to the 1990 revision of the Abbreviated Injury Scale.6 This scoring system is commonly used to estimate the Injury Severity Score (ISS), an acceptable methodology for classification of severity of injury in trauma patients. Only the highest AIS in each region (head in our study) was considered in the final scoring.
Predictor variables Age, sex, mechanism of injury, systolic and diastolic blood pressure at triage, heart rate, hypoxia (Pulse oxymetry < 95%), temperature, GCS, LOC, and Traumatic Brain Injury (TBI). TBI was defined by: a head AISS > 2 and/or any intracranial hematoma (cerebral contusion; subarachnoid, subdural, or epidural hemorrhages) seen on head CT. These criteria have been previously validated in identifying patients with TBI.7—9 Head injury patients were divided into two categories of TBI and non-TBI.
Outcome variable Coagulopathy, was defined as an elevated INR greater than 1.3 (the upper limit of normal in our institution) or an elevated APTT greater than 34 s. APTT greater than 34 s has been defined in the literature as an indicator of coagulopathy.2 Interval data were presented as medians with 25—75% interquartile range (IR). Mann—Whitney U test was used to compare interval data. Categorical data were presented as ratios with 95% confidence intervals (CI). Fisher’s Exact test was used to compare categorical data. All statistical tests were two-tailed. Calculations were done using SPSS for Windows, Rel. 11.0, 1997. SPSS Inc., Chicago.
54
S. Zehtabchi et al.
A sample size analysis established that we needed 16 patients in each group in order to observe a 20% TBI risk in patients (data retrieved from our previous study) with isolated head injury. This number will provide 82% power for the study (two-tailed, alpha: 0.05).
were intoxicated (serum ethanol levels >100 mg/dl). None of the coagulopathic patients received any form of blood transfusion. In-hospital mortality was reported in 6 patients only, who all belonged to TBI group. None of these patients had coagulopathy.
Results Discussion A total of 276 patients with isolated head injury were enrolled. The median age of the study cohort was 35 years old (IR: 25—52). The sample population consisted of 218 males (79%) and 58 females (22%). Fifty-two patients (19%) had TBI. A total of 33 patients (12%) sustained penetrating trauma and 243 (88%) sustained blunt trauma. Among TBI patients, head CT revealed cerebral contusions (n = 16), subdural hemorrhages (n = 7), subarachnoid hemorrhages (n = 14), epidural hemorrhages (n = 19), skull fractures (n = 7), facial bone fractures (n = 8), intra-parenchymal hemorrhage (n = 3), intra-ventricular hemorrhage (n = 2), and cervical spine fractures/dislocations (n = 1). Coagulopathy (INR > 1.3 and/or PTT > 34) was observed in 22 patients (8%, 95% CI, 5—12%). Table 1 presents a comparison of baseline variables among the two study groups (TBI versus non-TBI). The rate of coagulopathy was significantly higher in TBI patients (17.3% versus 5.8%, difference between the proportions: 11%, 95% CI, 3.3—19.7%). The relative risk of coagulopathy in TBI patients compared to non-TBI patients was 2.9 (95% CI, 1.3—6.6). In coagulopathic patients, the abnormal INR ranged from 1.4 to 2.2 and the abnormal PTT levels ranged from 34.9 to 54.8. Among these patients, 19 had elevated INR, 5 had elevated PTT, and 2 patients had both values elevated. Review of data for coagulopathic patients (n = 22) revealed that none of the enrolled patients had any evidence of acidosis, hypothermia, abnormal serum albumin, or serum calcium abnormalities. Only 2 patients (1 TBI and 1 non-TBI) had elevated liver function tests and thrombocytopenia which were not evident in their previous emergency department visits. Both patients
Table 1
A growing body of literature demonstrates that coagulation derangement contributes to the secondary insults that complicate the care of victims of traumatic brain injury. Common coagulation variables such as PT, PTT, Fibrin Degradation Products (FDP), D-dimer, platelet counts, and specific molecular markers such as von Willebrand factor, antithrombin, protein C, and prothrombin fraction 1 + 2, among others, have been investigated to delineate the pathophysiology of post-traumatic coagulopathy better. The incidence of coagulopathy in isolated head injury varies between 15 and 90%.2,5,10,11 We speculate that the wide range of reported prevalence for coagulopathy in TBI patients originates from the diversity of injury severities, the different sensitivities of the clotting tests used, and the different times at which coagulation was tested after injury in different studies. Our study aimed to evaluate prospectively the relationship between coagulopathy and traumatic brain injury using laboratory studies that are performed routinely in the emergency evaluation of trauma patients. In this study spanning over 18 months, we enrolled a large number (276) of patients with isolated head injury. All of our predictor variables in the study were obtained from routine emergency department evaluation of a head injured patient at triage. This point of separation from previous studies is important; using clinical variables at presentation and common laboratory investigations, emergency clinicians are able to make decisions on test results that are available in a reasonable time frame. The other point of departure in our study is the employment of INR as an indicator of coagulopathy. Various types of thromboplastin are prepared commercially and various
Comparison of baseline variables in head injury patients with and without Traumatic Brain Injury (TBI)
Age (year) Gender Mechanism SBP DBP HR Temperature Hypoxiac LOC GCS Coagulopathya
No TBIa (n = 52)
TBIa (n = 224)
Differenceb (95% CI)
34 (24—49) 80% Male 86% Blunt 134 (123—147) 76 (66—86) 89 (80—100) 98 (97.8—98.8) 9% 60% 15 (15—15) 6% (3—10%)
41 (27—58) 79% Male 98% Blunt 131 (117—150) 80 (68—88) 93 (81—105) 98 (97.7—98.7) 15% 53% 15 (12—15) 17% (8—30%)
−4 (−10 to 1) 1% (−11 to 13%) −12% (−18 to −6%) 2 (−5 to 8) −3 (−7 to 2) −4 (−9 to 2) −0.2 (−0.6 to 0.2) 6.5% (−4 to 17%) 7% (−8 to 22%) 0 (0—11) 11% (3—20%)
Abbreviations: TBI, traumatic brain injury; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; CI, confidence interval; GCS, glascow coma scale. a Values represent median (interquartile range) for continuous data and proportions (95% CI) for categorical data. b Differences between medians for continuous data and differences between proportions for categorical date. c Defined as pulse oxymetry <95%.
Coagulopathy in traumatic brain injury ways of reporting exists for the PT. Unlike the reporting of APTT, the INR system has been implemented successfully to standardize the PT. The World Health Organization designed a batch of human brain thromboplastin in 1977 as the international reference preparation (IRP) for thromboplastin. In 1982, based on the assumption that a linear relationship exists between the logarithm of the PT obtained with the IRP and test thromboplastins, a calibration system was proposed. This system standardized the reporting of the PT by converting the PT ratio observed with the local thromboplastin into an international normalized ratio (INR).12 To our knowledge, this is the first study that employs the laboratory calculation of INR to detect coagulopathy in isolated head injury. With our methodology, we were able to detect coagulopathy (17%, 95% CI, 8—30%) in isolated head injured patients who suffered from TBI (relative risk: 2.9, 95% CI, 1.3—6.6). This correlation between TBI and coagulopathy is similar to the study by Carrick et al., who employed PT and PTT measurement to detect coagulopathy, and found coagulopathy in 21% of TBI.1 With an increasing number of proposed treatment options for trauma-related coagulopathy, the need to understand the relationship between coagulopathy and brain injury becomes more pressing. May et al.13 demonstrated a correlation between low GCS score and coagulopathy and recommended empiric treatment with fresh frozen plasma for all patients presenting with a GCS score less than 7. More recently, following their success in treating hemorrhagic stroke and multiple trauma victims, prothrombotic agents such as activated factor VII are emerging as a promising pharmacological option for patients with traumatic brain injury.14—16 Although our study does not include measures of clinical outcome, there is a significant body of evidence in the literature that the development of coagulopathy in patients with traumatic brain injury is an important indicator of poor prognosis. Laboratory abnormalities consistent with coagulopathy or DIC are independently correlated to an increased risk of mortality in patients with moderate to severe traumatic brain injury.2,5,10,17,18,19 Stein et al.5 found that elevated markers of coagulation was correlated to the extent of tissue injury seen on cerebral computed tomography (CT) after head injury. Additionally, the risk of delayed intracranial hemorrhage represented by new or progressive lesions on CT was 31% among patients with normal coagulation profiles on admission, but rose to 85% if at least one marker of coagulation was abnormal.
Limitations We were not able to test the correlation of coagulopathy in TBI patients to mortality. This originated from the small number of mortalities in our study cohort. It is probable that since we enrolled a convenience sample of head trauma patients, patients who were more critically ill had a more expedited disposition from the emergency department (e.g. transfer to the operating room) or died shortly after emergency department arrival and therefore escaped our research pool. Therefore, our study could be subject to sampling bias.
55 The definition of coagulopathy is not standardized. Even though we used the previously reported cut-offs for abnormal PTT and institutional cut-off for abnormal INR as indicators of coagulopathy, patients with such abnormal values may not necessarily represent all patients with clinically significant coagulopathy.
Conclusion The increased risk of coagulopathy in patients with traumatic brain injury, as demonstrated in our study, lends further support to the practice of testing and following the markers of coagulation in emergency department patients with isolated head injury. Further studies should be directed at the potential for therapeutic interventions in this subset of TBI patients.
Conflict of interest No conflict of interest is reported by any of the authors.
References 1. Carrick MM, Tyroch AH, Youens CA, Handley T. Subsequent development of thrombocytopenia and coagulopathy in moderate and severe head injury: support for serial laboratory examination. J Trauma 2005;58:725—9, discussion 729—730. 2. Olson JD, Kaufman HH, Moake J, et al. The incidence and significance of hemostatic abnormalities in patients with head injuries. Neurosurgery 1989;24:825—32. 3. Kaufman HH, Hui KS, Mattson JC, et al. Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury. Neurosurgery 1984;15:34—42. 4. Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care 2004;1(4):479—88. 5. Pondaag W. Disseminated intravascular coagulation related to outcome in head injury. Acta Neurochir Suppl (Wien) 1979;28:98—102. 6. Association for the Advancement of Automotive Medicine. The Abbreviated Injury Scale, 1990 Revision. Des Plaines, IL: Association for the Advancement of Automotive Medicine; 1990. 7. Demetriades D, Kuncir E, Murray J, Velmahos GC, Rhee P, Chan L. Mortality prediction of head Abbreviated Injury Score and Glasgow Coma Scale: analysis of 7,764 head injuries. J Am Coll Surg 2004;199:216—22. 8. Alvarez M, Nava JM, Rue M, Quintana S. Mortality prediction in head trauma patients: performance of Glasgow Coma Score and general severity systems. Crit Care Med 1998;26:142—8. 9. Signorini DF, Andrews PJ, Jones PA, Wardlaw JM, Miller JD. Predicting survival using simple clinical variables: a case study in traumatic brain injury. J Neurol Neurosurg Psychiatry 1999;66:20—5. 10. Murshid WR, Gader AG. The coagulopathy in acute head injury: comparison of cerebral versus peripheral measurements of haemostatic activation markers. Br J Neurosurg Aug 2002;16:362—9. 11. Becker S, Schneider W, Kreuz W, Jacobi G, Scharrer I, NowakGottl U. Post-trauma coagulation and fibrinolysis in children suffering from severe cerebro-cranial trauma. Eur J Pediatr Dec 1999;158 Suppl 3:S197—202. 12. WHO Expert Committee on Biological Standardisation. Guidelines for thromboplastins and plasma used to control oral anticoagulant therapy. WHO Tech. Rep. Series, vol. 889. WHO
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14.
15.
16.
S. Zehtabchi et al. Expert Committee on Biological Standardisation; 1999. pp. 64—93. May AK, Young JS, Butler K, Bassam D, Brady W. Coagulopathy in severe closed head injury: is empiric therapy warranted? Am Surg Mar 1997;63:233—6, discussion 236—237. Dutton RP, McCunn M, Hyder M, et al. Factor VIIa for correction of traumatic coagulopathy. J Trauma 2004;57:709—18, discussion 718—709. Morenski JD, Tobias JD, Jimenez DF. Recombinant activated factor VII for cerebral injury-induced coagulopathy in pediatric patients. Report of three cases and review of the literature. J Neurosurg 2003;98:611—6. Park P, Fewel ME, Garton HJ, Thompson BG, Hoff JT. Recombinant activated factor VII for the rapid correction of
coagulopathy in nonhemophilic neurosurgical patients. Neurosurgery 2003;53:34—8, discussion 38—39. 17. Vavilala MS, Dunbar PJ, Rivara FP, Lam AM. Coagulopathy predicts poor outcome following head injury in children less than 16 years of age. J Neurosurg Anesthesiol 2001;13: 13—8. 18. Kearney TJ, Bentt L, Grode M, Lee S, Hiatt JR, Shabot MM. Coagulopathy and catecholamines in severe head injury. J Trauma 1992;32:608—11, discussion 611—602. 19. Kumura E, Sato M, Fukuda A, Takemoto Y, Tanaka S, Kohama A. Coagulation disorders following acute head injury. Acta Neurochir (Wien) 1987;85:23—8.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/resuscitation
CLINICAL PAPER
The association of coagulopathy and traumatic brain injury in patients with isolated head injury夽 Shahriar Zehtabchi ∗, Samara Soghoian, Yiju Liu, Kristin Carmody, Lekha Shah, Brian Whittaker, Richard Sinert Department of Emergency Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, United States Received 24 April 2007; accepted 18 June 2007
KEYWORDS Coagulation; Brain injury; International normalized ratio; Trauma
Summary The emergence of prothrombotic agents (e.g. activated factor VII) to treat traumatic brain injury (TBI) requires a better understanding of the association of coagulopathy with isolated head injury (IHI). Objective: To investigate the association of IHI and coagulopathy. Methods: Prospective, observational study in an urban level I trauma center. Inclusion criteria: Adult (≥13 years of age) patients with IHI. Exclusion criteria: patients with known coagulopathies or on anticoagulant therapy. Predictor Variables: TBI (head abbreviated injury severity score >2, or brain hematoma on CT scan), age, gender, mechanism of injury, Glasgow Coma Score (GCS), and loss of consciousness (LOC). Outcome variables: coagulopathy defined as elevated International Normalized Ratio (INR > 1.3) or activated partial thromboplastin time (PTT) greater than 34 s. We divided IHI subjects into two groups of patients with and without TBI. Statistical Analysis: Fisher’s exact test and Mann—Whitney U were used to compare data where appropriate (alpha: 0.05, two-tailed). Results: From July 2005 to December 2006, 276 patients with IHI were studied. The median age was 35 years (interquartile range: 25—52) with a 79% male predominance and 88% blunt trauma. Eight percent (95% CI, 5—12%) of patients had coagulopathy. The rate of coagulopathy in TBI patients (17%) was significantly higher than non-TBI patients (6%) (11% difference, 95% CI, 3—20%]. The relative risk of coagulopathy in TBI patients was 2.9 (95% CI, 1.3—6.6). Conclusion: Coagulopathy as defined by elevated INR and/or PTT is associated with TBI after isolated head injury. © 2007 Elsevier Ireland Ltd. All rights reserved.
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at 10.1016/j.resuscitation.2007.06.024. ∗ Corresponding author at: Department of Emergency Medicine, State University of New York, Downstate Medical Center, Box: 1228, 450 Clarkson Ave., Brooklyn, NY 11203, United States. E-mail address: [email protected] (S. Zehtabchi).
0300-9572/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2007.06.024
Coagulopathy in traumatic brain injury
Introduction The emergence of prothrombotic agents (e.g. activated factor VII) to treat patients with Traumatic Brain Injury (TBI) requires a better understanding of the association of coagulopathy with isolated head injury. Primary brain damage occurs at the time of impact and cannot be modified. Improving the outcome of brain injury patients mainly depends on minimizing the secondary brain insults.1,2 Such secondary insults include cerebral edema, increased intracerebral pressure, infection, hypoxia, and coagulopathy. The potential to treat and thereby avoid or mitigate secondary cerebral insults from disordered coagulation underscores the importance of verifying the association of brain injury and coagulopathy. The brain tissue contains large amounts of thromboplastin. This substance is released in high concentration into the blood stream after physical trauma to the parenchyma, causing disturbance in coagulation processes. In addition, damaged cerebral endothelium activates platelets as well as clotting cascades to produce intravascular thrombosis and depletion of coagulation factors.3 Coagulopathy may affect the outcome of brain injury independent of provoking a bleeding diathesis. Autopsy studies and some animal models suggest that ischemia from intravascular microthrombosis and the deposition of fibrin on endothelial surfaces lead to impaired oxygen exchange and hence accentuate the secondary insult to the brain.3,4 The incidence of various forms of coagulopathy following isolated head injury varies widely based on the definition of coagulopathy in different studies and has been reported in up to 90% of TBI patients.1,3,5 We designed this prospective observational study to estimate the incidence of coagulopathy in patients with traumatic brain injury. We tested the null hypothesis is that there would be no difference in incidence of coagulopathy in patients with or without TBI.
Methods From July 2005 to December 2006 we conducted a prospective, observational study at Kings County Hospital Center (KCHC). KCHC is an academic level I trauma center in Brooklyn, New York that receives approximately 150,000 emergency department visits and 1600 trauma admissions annually. The joint institutional review boards (IRB) of KCHC and State University of New York, Downstate Medical Center approved the study and waived the informed consent requirement. We enrolled prospectively a convenience sample of adult trauma patients (age ≥ 13, the age cut-off for adult trauma in our institution) who sustained head injury and required imaging studies as part of their diagnostic work-up. The attending emergency medicine physician determined the need for imaging to rule out traumatic brain injury (TBI) following significant head trauma. Patients with obvious clinical signs of extracranial injuries or those who were found to have such injuries after extensive trauma workup (CT Scans, serial hematocrit measurements, diagnostic peritoneal lavage, Laparotomy, etc., where indicated),
53 were excluded. Therefore, data analysis was performed on patients with isolated head injury only. Patients with known coagulation disorders and those on anticoagulant therapy were excluded. Trained data abstractors (academic associates, medical student volunteers) enrolled a convenience sample of trauma patients. Academic associates recorded demographic data, triage vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, pulse oxymetry, and temperature), mechanism of injury, and presence or absence of loss of consciousness (LOC) following the injury. Glasgow Coma Score (GCS) was also documented upon patients’ arrival to the emergency department. Arterial blood gas analysis, serum albumin, liver function tests, platelet counts, and serum calcium levels were measured for all patients. Transfusion of red blood cells and other blood products were recorded. Prothrombin Time (PT) (s) and Activated Partial Thromboplastin Time (APTT) (s) were measured by Blood Coagulation System® CA-7000 (DadeBehring, Deerfield, Illinois). The International Normalized Ratio (INR) was calculated and reported by the same machine and was used as a surrogate for PT to account for institutional variability in the measurement of this marker. An attending neuroradiologist confirmed all official head CT reports. Upon completion of trauma work-up, the head Abbreviated Injury severity scores (AISS) were calculated. AIS was graded according to the 1990 revision of the Abbreviated Injury Scale.6 This scoring system is commonly used to estimate the Injury Severity Score (ISS), an acceptable methodology for classification of severity of injury in trauma patients. Only the highest AIS in each region (head in our study) was considered in the final scoring.
Predictor variables Age, sex, mechanism of injury, systolic and diastolic blood pressure at triage, heart rate, hypoxia (Pulse oxymetry < 95%), temperature, GCS, LOC, and Traumatic Brain Injury (TBI). TBI was defined by: a head AISS > 2 and/or any intracranial hematoma (cerebral contusion; subarachnoid, subdural, or epidural hemorrhages) seen on head CT. These criteria have been previously validated in identifying patients with TBI.7—9 Head injury patients were divided into two categories of TBI and non-TBI.
Outcome variable Coagulopathy, was defined as an elevated INR greater than 1.3 (the upper limit of normal in our institution) or an elevated APTT greater than 34 s. APTT greater than 34 s has been defined in the literature as an indicator of coagulopathy.2 Interval data were presented as medians with 25—75% interquartile range (IR). Mann—Whitney U test was used to compare interval data. Categorical data were presented as ratios with 95% confidence intervals (CI). Fisher’s Exact test was used to compare categorical data. All statistical tests were two-tailed. Calculations were done using SPSS for Windows, Rel. 11.0, 1997. SPSS Inc., Chicago.
54
S. Zehtabchi et al.
A sample size analysis established that we needed 16 patients in each group in order to observe a 20% TBI risk in patients (data retrieved from our previous study) with isolated head injury. This number will provide 82% power for the study (two-tailed, alpha: 0.05).
were intoxicated (serum ethanol levels >100 mg/dl). None of the coagulopathic patients received any form of blood transfusion. In-hospital mortality was reported in 6 patients only, who all belonged to TBI group. None of these patients had coagulopathy.
Results Discussion A total of 276 patients with isolated head injury were enrolled. The median age of the study cohort was 35 years old (IR: 25—52). The sample population consisted of 218 males (79%) and 58 females (22%). Fifty-two patients (19%) had TBI. A total of 33 patients (12%) sustained penetrating trauma and 243 (88%) sustained blunt trauma. Among TBI patients, head CT revealed cerebral contusions (n = 16), subdural hemorrhages (n = 7), subarachnoid hemorrhages (n = 14), epidural hemorrhages (n = 19), skull fractures (n = 7), facial bone fractures (n = 8), intra-parenchymal hemorrhage (n = 3), intra-ventricular hemorrhage (n = 2), and cervical spine fractures/dislocations (n = 1). Coagulopathy (INR > 1.3 and/or PTT > 34) was observed in 22 patients (8%, 95% CI, 5—12%). Table 1 presents a comparison of baseline variables among the two study groups (TBI versus non-TBI). The rate of coagulopathy was significantly higher in TBI patients (17.3% versus 5.8%, difference between the proportions: 11%, 95% CI, 3.3—19.7%). The relative risk of coagulopathy in TBI patients compared to non-TBI patients was 2.9 (95% CI, 1.3—6.6). In coagulopathic patients, the abnormal INR ranged from 1.4 to 2.2 and the abnormal PTT levels ranged from 34.9 to 54.8. Among these patients, 19 had elevated INR, 5 had elevated PTT, and 2 patients had both values elevated. Review of data for coagulopathic patients (n = 22) revealed that none of the enrolled patients had any evidence of acidosis, hypothermia, abnormal serum albumin, or serum calcium abnormalities. Only 2 patients (1 TBI and 1 non-TBI) had elevated liver function tests and thrombocytopenia which were not evident in their previous emergency department visits. Both patients
Table 1
A growing body of literature demonstrates that coagulation derangement contributes to the secondary insults that complicate the care of victims of traumatic brain injury. Common coagulation variables such as PT, PTT, Fibrin Degradation Products (FDP), D-dimer, platelet counts, and specific molecular markers such as von Willebrand factor, antithrombin, protein C, and prothrombin fraction 1 + 2, among others, have been investigated to delineate the pathophysiology of post-traumatic coagulopathy better. The incidence of coagulopathy in isolated head injury varies between 15 and 90%.2,5,10,11 We speculate that the wide range of reported prevalence for coagulopathy in TBI patients originates from the diversity of injury severities, the different sensitivities of the clotting tests used, and the different times at which coagulation was tested after injury in different studies. Our study aimed to evaluate prospectively the relationship between coagulopathy and traumatic brain injury using laboratory studies that are performed routinely in the emergency evaluation of trauma patients. In this study spanning over 18 months, we enrolled a large number (276) of patients with isolated head injury. All of our predictor variables in the study were obtained from routine emergency department evaluation of a head injured patient at triage. This point of separation from previous studies is important; using clinical variables at presentation and common laboratory investigations, emergency clinicians are able to make decisions on test results that are available in a reasonable time frame. The other point of departure in our study is the employment of INR as an indicator of coagulopathy. Various types of thromboplastin are prepared commercially and various
Comparison of baseline variables in head injury patients with and without Traumatic Brain Injury (TBI)
Age (year) Gender Mechanism SBP DBP HR Temperature Hypoxiac LOC GCS Coagulopathya
No TBIa (n = 52)
TBIa (n = 224)
Differenceb (95% CI)
34 (24—49) 80% Male 86% Blunt 134 (123—147) 76 (66—86) 89 (80—100) 98 (97.8—98.8) 9% 60% 15 (15—15) 6% (3—10%)
41 (27—58) 79% Male 98% Blunt 131 (117—150) 80 (68—88) 93 (81—105) 98 (97.7—98.7) 15% 53% 15 (12—15) 17% (8—30%)
−4 (−10 to 1) 1% (−11 to 13%) −12% (−18 to −6%) 2 (−5 to 8) −3 (−7 to 2) −4 (−9 to 2) −0.2 (−0.6 to 0.2) 6.5% (−4 to 17%) 7% (−8 to 22%) 0 (0—11) 11% (3—20%)
Abbreviations: TBI, traumatic brain injury; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; CI, confidence interval; GCS, glascow coma scale. a Values represent median (interquartile range) for continuous data and proportions (95% CI) for categorical data. b Differences between medians for continuous data and differences between proportions for categorical date. c Defined as pulse oxymetry <95%.
Coagulopathy in traumatic brain injury ways of reporting exists for the PT. Unlike the reporting of APTT, the INR system has been implemented successfully to standardize the PT. The World Health Organization designed a batch of human brain thromboplastin in 1977 as the international reference preparation (IRP) for thromboplastin. In 1982, based on the assumption that a linear relationship exists between the logarithm of the PT obtained with the IRP and test thromboplastins, a calibration system was proposed. This system standardized the reporting of the PT by converting the PT ratio observed with the local thromboplastin into an international normalized ratio (INR).12 To our knowledge, this is the first study that employs the laboratory calculation of INR to detect coagulopathy in isolated head injury. With our methodology, we were able to detect coagulopathy (17%, 95% CI, 8—30%) in isolated head injured patients who suffered from TBI (relative risk: 2.9, 95% CI, 1.3—6.6). This correlation between TBI and coagulopathy is similar to the study by Carrick et al., who employed PT and PTT measurement to detect coagulopathy, and found coagulopathy in 21% of TBI.1 With an increasing number of proposed treatment options for trauma-related coagulopathy, the need to understand the relationship between coagulopathy and brain injury becomes more pressing. May et al.13 demonstrated a correlation between low GCS score and coagulopathy and recommended empiric treatment with fresh frozen plasma for all patients presenting with a GCS score less than 7. More recently, following their success in treating hemorrhagic stroke and multiple trauma victims, prothrombotic agents such as activated factor VII are emerging as a promising pharmacological option for patients with traumatic brain injury.14—16 Although our study does not include measures of clinical outcome, there is a significant body of evidence in the literature that the development of coagulopathy in patients with traumatic brain injury is an important indicator of poor prognosis. Laboratory abnormalities consistent with coagulopathy or DIC are independently correlated to an increased risk of mortality in patients with moderate to severe traumatic brain injury.2,5,10,17,18,19 Stein et al.5 found that elevated markers of coagulation was correlated to the extent of tissue injury seen on cerebral computed tomography (CT) after head injury. Additionally, the risk of delayed intracranial hemorrhage represented by new or progressive lesions on CT was 31% among patients with normal coagulation profiles on admission, but rose to 85% if at least one marker of coagulation was abnormal.
Limitations We were not able to test the correlation of coagulopathy in TBI patients to mortality. This originated from the small number of mortalities in our study cohort. It is probable that since we enrolled a convenience sample of head trauma patients, patients who were more critically ill had a more expedited disposition from the emergency department (e.g. transfer to the operating room) or died shortly after emergency department arrival and therefore escaped our research pool. Therefore, our study could be subject to sampling bias.
55 The definition of coagulopathy is not standardized. Even though we used the previously reported cut-offs for abnormal PTT and institutional cut-off for abnormal INR as indicators of coagulopathy, patients with such abnormal values may not necessarily represent all patients with clinically significant coagulopathy.
Conclusion The increased risk of coagulopathy in patients with traumatic brain injury, as demonstrated in our study, lends further support to the practice of testing and following the markers of coagulation in emergency department patients with isolated head injury. Further studies should be directed at the potential for therapeutic interventions in this subset of TBI patients.
Conflict of interest No conflict of interest is reported by any of the authors.
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