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Update in mild traumatic brain injury
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Review
Update in mild traumatic brain injury夽 María Dolores Freire-Aragón, Ana Rodríguez-Rodríguez, Juan José Egea-Guerrero ∗ UGC de Medicina Intensiva, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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Article history: Received 21 April 2017 Accepted 1 May 2017 Available online xxx Keywords: Mild traumatic brain injury Intracranial lesion Head computed tomography Brain injury biomarkers
a b s t r a c t There has been concern for many years regarding the identification of patients with mild traumatic brain injury (TBI) at high risk of developing an intracranial lesion (IL) that would require neurosurgical intervention. The small percentage of patients with these characteristics and the exceptional mortality associated with mild TBI with IL have led to the high use of resources such as computerized tomography (CT) being reconsidered. The various protocols developed for the management of mild TBI are based on the identification of risk factors for IL, which ultimately allows more selective indication or discarding both the CT application and the hospital stay for neurological monitoring. Finally, progress in the study of brain injury biomarkers with prognostic utility in different clinical categories of TBI has recently been incorporated by several clinical practice guidelines, which has allowed, together with clinical assessment, a more accurate prognostic approach for these patients to be established. ˜ S.L.U. All rights reserved. © 2017 Elsevier Espana,
Actualización en el traumatismo craneoencefálico leve r e s u m e n Palabras clave: Traumatismo craneoencefálico leve Lesión cerebral Tomografía axial computarizada craneal Biomarcadores de lesión cerebral
˜ Durante anos ha existido preocupación por la identificación de pacientes con traumatismo craneoencefálico (TCE) leve en alto riesgo de presentar lesión intracraneal (LI) subsidiaria de intervención neu˜ porcentaje de pacientes de estas características, y la mortalidad excepcional roquirúrgica. El pequeno ligada al TCE leve con LI, han llevado a reconsiderar la elevada utilización de recursos como la tomografía craneal (TC). Los diversos protocolos desarrollados para el manejo del TCE leve se basan en la identificación de factores de riesgo de presentar LI, lo que finalmente permite indicar o descartar selectivamente tanto la solicitud de TC como la estancia hospitalaria para la vigilancia neurológica. Finalmente, el avance realizado en el estudio de biomarcadores de lesión cerebral con utilidad de carácter pronóstico, en diferentes categorías clínicas del TCE, ha sido recientemente incorporado por diversas guías de práctica clínica, lo que ha permitido, junto con la valoración clínica, una estimación pronóstica más exacta para estos pacientes. ˜ S.L.U. Todos los derechos reservados. © 2017 Elsevier Espana,
Introduction Traumatic brain injury (TBI) represents a major public health problem worldwide. Epidemiological studies show high variability in their results, with a crude incidence rate ranging from 47.3 to 849 cases per 100,000 inhabitants/year for all ages and severity types.1 Specifically, mild TBI constitutes 70–90% of all cases.2
夽 Please cite this article as: Freire-Aragón MD, Rodríguez-Rodríguez A, EgeaGuerrero JJ. Actualización en el traumatismo craneoencefálico leve. Med Clin (Barc). 2017. http://dx.doi.org/10.1016/j.medcli.2017.05.002 ∗ Corresponding author. E-mail address: [email protected] (J.J. Egea-Guerrero).
Currently, this process is a health priority due to several key facts. First, it has a high incidence, estimated at 224 cases per 100,000 inhabitants. Second, it causes many emergency department visits. Third, there is a lack of specific symptomatology that allows the identification of those patients at risk of developing an intracranial lesion (IL), which causes a high consumption of resources and complementary tests.3 Several protocols and clinical practice guidelines have been developed in recent years aimed at the early identification of patients who may present IL after mild TBI. These protocols attempt to weight the risk factors and thus the indication of neuroimaging tests or hospital observation. Compliance with these guidelines would make it possible to balance health costs and reduce ionizing radiation in patients with very low IL probability.4 In fact, only
˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,
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7–10% of patients with mild TBI have tomographic findings after trauma and less than 1% require neurosurgical intervention, with death being a very rare outcome (0.1%).5 The objective of the present review is to address the management of adult patients with mild TBI considering conventional risk factors, such as advanced age, anticoagulant (AC)/antiplatelet intake, as well as indication of neuroimaging studies, need of neurosurgical assessment and the recent introduction of brain injury biomarkers to discriminate patients with a true risk of having IL. Initial management of mild traumatic brain injury In general, TBI does not have a universal definition; additionally, there are several denominations published to define mild TBI, which sometimes makes the standardized management of this pathology more complicated.6 The score reached on the Glasgow Coma Scale (GCS) has been used without changes for the last 4 decades to assess the conscious level impairment following a TBI, and is one of the most relevant prognostic indicators in this pathology.7 Classically, the mild TBI category includes patients with a score of 13–15. However, a tendency adopted by many authors is to exclude patients with 13 points from the “mild” category, given the high anomaly percentage in cranial computed tomography (CT), as well as their clinical and prognostic progression, which is closer to moderate TBI. This difference of criteria adopted to define mild TBI has been, perhaps, one of the most important biases in the comparison of the different published series.8,9 The information derived from an adequate case history and physical examination allows the identification of certain risk factors for IL and is the basis of renowned clinical decision protocols that prompt the CT indication. However, the lack of specificity of the accompanying symptoms, coupled with the absence of conclusive evidence for individual risk factors, somehow explains the discrepancies found in the different guidelines designed for the management of this pathology.10–12 The presence of primary or acquired coagulopathy, posttraumatic neurological deterioration or the presence of clinical cranial fracture signs are widely recognized as high risk factors for IL association.10,13 However, we find variable considerations for other factors. In this sense, the recently revised Scandinavian guidelines recognize an insufficient predictive capacity for age (>65 years) or antiplatelet as individual risk factors for IL. Within the lesion mechanisms considered by some guidelines, having an accident has proven to be a higher risk factor for IL association.14 In relation to symptomatology referred by the patient, the loss of consciousness, or suspicion of the same, is a risk factor in itself.10 However, other symptoms such as headache, nausea or amnesia have shown, in some series, a low capacity to predict the presence of IL. It is worth mentioning the recent inclusion of patients with a shunt for the treatment of hydrocephalus as a specific group of patients at risk.10 Finally, the presence of cranial fracture has shown a 5-times-higher association with the existence of IL requiring a neurosurgical intervention versus the subgroup of mild TBI without fracture.13 Indication of initial cranial CT and scheduled cranial CT to monitor progression The availability of cranial CT in most centres, coupled with the practice of a somewhat defensive medicine for a normally benign process, has been responsible for the exponential increase in the use of CT scans in mild TBI. The corresponding increase in costs, associated with the risk of cancer due to radiological exposure, as
well as the low frequency with which an IL requiring intervention is detected, have led to question its indication.15 The usefulness of CT in the early management of moderate and severe TBI is well established.10–12 However, the variability in its application shown for mild TBI has led to the development of protocols that identify cases which could actually involve an IL.10–12 Specifically, patients with a GCS score of 15 points, without other risk factors, should be discharged from hospital without CT or observation, with family support, and ensuring specific recommendations. In a recent systematic review, which compares the diagnostic accuracy of different clinical decision protocols, it was observed that both Canadian CT Head Rule (CCHR) as well as the New Orleans Criteria (NOC) have a good negative odds ratio (OR) (0.04 and 0.08, respectively) and diagnostic accuracy to detect patients at low risk of requiring neurosurgical intervention (CCHR: OR of 0.05; NOC: OR of 0.7).14 Previously, the analysis of the subgroup of patients with a 15-point GCS score after a TBI had shown a high sensitivity (100%) for both protocols, although CCHR had a greater specificity versus the NOC, both for detection (50.6% versus 12.7%) as well as to predict the need for neurosurgical intervention (76.3% versus 12.1%, respectively).16 A second problem to be considered, which is an issue still without consensus, is the indication of a cranial CT to monitor progression in patients in whom the existence of an IL after mild TBI has been confirmed.17 Although the presence of some lesions has not necessarily demonstrated an increase in morbidity and mortality, a large number of examinations are finally carried out in order to rule out progression of intracranial bleeding and obtain radiological evidence which could help to plan the patient’s transfer to centres with neurosurgical services, hospital admission or strengthen the discharge decision.18 In a recent meta-analysis, it was observed that scheduled CT scans leads to management changes in only a minority of patients (9.6–11.4%), including cases with tomographic evidence of IL progression. For example, in the mild TBI subgroup (GCS of 13–15 points), treatment strategy only changed in 2.3–3.9% of the cases.17 The type of IL should be an element that determines the indication of a progression control CT. There are lesions such as convexity subarachnoid haemorrhage, laminar subdural hematomas (SDH) or small volume hematomas (<4–7 mm), as well as small single convexity contusions, where other factors should reinforce the decision to repeat imaging tests. Among them, we could highlight the patient’s own progression and clinical condition, the presence of coagulopathies or other blood dyscrasias that favour the progression of IL or the timing of trauma.19 The possible occurrence of late bleeding in anticoagulated patients or, less frequently, in patients with shunts for the treatment of hydrocephalus deserves a special consideration after a normal initial CT.20 Although the management protocol varies between centres, performing follow-up CT scans after a first normal imaging study or admission for observation during 24 h would not allow the detection of the small number of cases that present bleeding beyond the first 24 h after trauma, its indication being widely questioned.21 In the group of anticoagulated patients, the reported incidence of bleeding within the 24 h after trauma following a normal initial CT scan is very low (0.6%), with cases of sub-therapeutic AC levels having been reported.22,23 Considering current evidence, the risk of late bleeding is low enough to allow discharge with specific recommendations. However, particular aspects such as the high-energy injury mechanism, associated antiplatelet therapy or an excessive level of AC (INR > 3) should be considered in an individualized way when deciding the management strategy. Special mention should be made of patients treated with new oral ACs (dabigatran, apixaban, among others). For this subgroup, considered in risk, there are no updated recommendations in the guidelines.24
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Mild traumatic brain injury in older adults This group of adults does not have a standard definition and generally involves people aged 60–65 years or over. Treatment of TBI in patients older than 65 years of age has increased in the last years.25 Advances in the field of medicine, better prehospital care, coupled with an increase in population life expectancy, may explain the change in the epidemiology of trauma. In these cases, worse functional results associated with TBI have been observed for all severity groups, which leads to an increase in health expenditure.26 The age-specific physiological change association, together with individual comorbidities – more frequent with advanced age – make the elderly a frailer population after a TBI. In this group, more than 70% of the patients presented previous comorbidities, which could explain longer hospital stays, as well as a lower score on the GCS or Disability Rating Scale.27 Falling from one’s own height has been identified as one of the most frequent lesion mechanisms in this subgroup (60–82%). In a mortality analysis, it was found to be the cause of death in 77% of patients over 65 years of age with mild TBI, and SDH was the most frequently identified LI (86%).28 Despite the development of fall prevention guidelines and different local implementation plans, standardized hospitalization rates secondary to falls have increased up to 8.4% per year.29 AC and antiplatelet therapy based on recommendations for the prevention of cardiovascular and cerebral ischaemic events (quite frequent in this patient subpopulation), is likely to play a role in the increased hospitalization rate due to IL secondary to TBI, mainly for SDH (42.9%).30 Up to 80% of TBI in those over 65 years of age are considered clinically mild. The elderly may have a lower baseline response associated with an attention deficit or a mobility or auditory/visual function impairment, something that may be considered by clinicians as “pseudo-normal”, which may associate an underestimation in the determination of the TBI’s clinical severity. We recognize that there are patients with underlying cognitive disorders, comorbidities or under treatment with medications that affect the sensorium, in whom distinguishing mild and moderate forms of TBI during the initial care phase is difficult. In this sense, an easy-to-apply dichotomous decision model has been proposed, based on the level of alertness (alert/non-alert) and motor function (obeys orders/does not obey), but still pending validation.31 On the other hand, age-associated cerebral atrophy occasionally allows for a “symptom-free window” where certain significant ILs may not have clinical expression. This may explain how some mild TBI initially go unnoticed and over the course of the days they need emergency care in their progression as moderate or even severe TBI. A mechanism which has been traditionally proposed for late acute SDH is the greater vulnerability of the cerebral veins draining in the dural sinuses when a TBI occurs, since the increase of subdural space in the presence of atrophy causes greater elongation and length.32 Age also affects the relationship between GCS and anatomic severity in TBI. Patients who are 65 years of age or older have a better GCS score than younger ones for similar severity injuries.33 GCS is a better predictor of mortality for patients under 55 years of age than for the over 60 years of age subgroup, where it has not been shown to predict differences in mortality between moderate and severe TBI.34 Among the reasons proposed to justify the absence of detected difference in mortality are the presence of comorbidities and physiological changes typical of the biological age that would hinder the response to aggression, as well as a trend towards a more conservative treatment in this population.35 However, in view of the functional and cognitive outcomes of recent studies in older adults with TBI – similar to younger age groups when aggressive measures are applied –, and in
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contrast to the generalized trend of a more conservative management, the need to identify the subgroup of patients who could benefit from neurosurgical treatment, multimodal neuromonitorization and admission to an intensive care unit has increased.36
Characteristics of the antiplatelet and anticoagulated patient The current recommendations in the prevention of ischaemic events according to clinical practice guidelines, as well as the management of coronary patients are largely responsible for the increase in population under AC and antiplatelet therapy. AC association with vitamin K antagonists (mainly warfarin), or with new ACs in patients with a TBI, is a well-established risk factor for the presence of IL along with other variables such as the low energy mechanism, the initial IL progression and the patient’s own morbidity.37 Rapid reversal of the anticoagulant effect using prothrombin complex concentrate and, to a lesser extent, fresh frozen plasma or vitamin K has been shown to reduce the haemorrhagic progression of IL and its mortality.38 On the other hand, there is growing concern about the introduction of new ACs (direct thrombin inhibitors/direct factor Xa inhibitors) with attractive advantages over warfarin for monitoring or interactions, but with the drawback of a lack of antidote allowing a rapid reversal of its effect following trauma.24 However, there is evidence of a lower rate of traumatic IL in patients treated with dabigatran (direct thrombin inhibitor), compared with warfarin, which has been supported by studies in animal models.39,40 The progression of IL has been associated with coagulation parameter disorders. Coagulopathy and abnormal fibrinolysis associated with severe TBI is well documented, although its mechanism is not fully understood.41 A statistically significant association between prothrombin time, INR and d-dimer levels and the risk of IL progression after trauma has been observed.42 In mild TBI, Suehiro et al. have identified certain abnormalities in coagulation and fibrinolysis studies as predictors of increased IL and the need for neurosurgery.43 Despite the undoubted usefulness of having extensive coagulation and fibrinolysis studies, including the possibility of implementing thromboelastometry, there is currently insufficient scientific evidence to recommend or justify the costs that would be incurred in a pathology as prevalent as mild TBI. In relation to antiplatelet therapy and its association with LI after mild TBI, studies to date have not allowed it to be established as an individual risk factor. On the one hand, we find works like Fabri et al. which establish an association between acetylsalicylic acid (ASA) and the presence of IL after mild TBI.44 Likewise, clopidogrel has been identified as a risk factor for IL occurrence requiring neurosurgical intervention, re-bleeding episodes, and a greater need for blood product transfusion.45 Although several authors have suggested an association of antiplatelet therapy in patients with traumatic IL and mortality, others, however, have not shown an increase in unfavourable outcomes.46 In a recent meta-analysis, there is only a slight increased risk of death between the use of antiplatelet therapy and TBI, with no statistical significance.47 Some of the risk factors suggested to explain the differences found in these studies are heterogeneity in severity or injury mechanism, as well as inclusion in the antiplatelet group only due to previous patient history, without considering the actual adherence to the treatment nor the degree of inhibition of platelet activity measured through functionality tests. We know that antiplatelet treatment does not work equally in all patients and we have studies that have shown resistance to ASA or clopidogrel ranging from 1 to 45%.48
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In the case of antiplatelet therapy, there is no antidote capable of reversing its activity since the enzymatic block occurs irreversibly. However, to date, routine platelet transfusion in patients with IL is not recommended.49 Regardless of the antiplatelet therapy, the platelet count itself has been associated with a greater progression of IL and the need for surgery after the TBI. A count below 135,000 platelets in patients undergoing treatment with ASA or clopidogrel has been identified as a predictor of clinical and radiological worsening following TBI.50 Ultimately, in the presence of an IL in the context of mild TBI, in a patient under antiplatelet therapy, it would be extremely useful to have immediate platelet function tests that allow knowing the predictable risk and establishing therapeutic measures in an individualized way. We believe it is appropriate to emphasize that although these tests cannot be urgently requested in most centres, the risk-benefit ratio, both for the temporary suspension of the antiplatelet treatment and for the rare indication of platelet transfusion, should be mainly dependent on the assessment of the characteristics of the IL (volume/distribution/location) in routine clinical practice, as well as the pathology that motivated the antiplatelet treatment.
Need for transfer of mild traumatic brain injury for neurosurgical assessment Usually, the presence of IL after a TBI requires assessment by a neurosurgeon, with or without transfer to trauma centres that have this specialty. In those patients who are clinically classified as having a moderate or severe level of severity (regardless of the need for surgical intervention), the referral indication is well established.51 However, the concern about a possible unfavourable progression in patients with IL after suffering a mild TBI occasionally forces the transfer of patients to other centres in search of specialized assessment without considering real risk groups and IL characteristics, as previously discussed (type, size, location). This fact has been increased in recent years due to the greater detection of IL as a consequence of a more widespread use of CT scans. It is evident that a proper selection in the number of consultations performed by neurosurgery would improve cost-opportunity for patients with TBI. The need for surgical intervention in mild TBI is less than 1%. Higher figures in recent studies (up to 8%) could be explained by the absence of exclusion of AC or antiplatelet patients, and a more liberal definition of “neurosurgical intervention”.52 Given the concern for a more efficient use of hospital resources, management protocols that include “non-transfer” criteria are starting to emerge, although pending validation.53 It has been suggested that certain groups of patients with mild TBI and GCS of 15 points – mainly without AC/antiplatelet therapy or without coagulopathy or platelet function disorder –, and low risk IL, can be managed in centres with no neurosurgical specialty in a safe and efficient way. Lesions considered to be at low risk of progression and requiring neurosurgical intervention are: minimal convexity subarachnoid haemorrhage, intraparenchymal haematoma or haemorrhagic contusion in a single site, SDH or epidural, all less than or equal to 4 mm in size. The progression of the IL in follow-up CT in these protocols has been shown to be low (5–7%), with no need for surgical intervention.53 The implementation analysis of one of these protocols has demonstrated a reduction in scheduled follow-up CT scans, as well as a decrease in the overall hospital costs, which, besides being safe, are also cost-effective.54 As in any medical evaluation, finding an IL on a CT scan plays a significant role in the decision to refer the patient, but it is not the only one. IL characteristics as well as the existence of other associated extracranial lesions, personal history and
comorbidities, should be weighed to establish an individualized management plan.
Usefulness of brain injury biomarkers in mild traumatic brain injury In the last 30 years, we have witnessed a breakthrough in the study of brain injury biomarkers. The characteristics of these are largely conditioned by the presence of the blood–brain barrier. Although biomarker determination in brain tissue itself or in cerebrospinal fluid is useful, its invasive nature limits its use.55 The main brain injury biomarkers studied are: S100B protein, glial fibrillary acidic protein, Tau protein, amyloid beta protein, myelin basic protein, creatine kinase brain isoenzyme and neuron specific enolase.55 More recently, studies on ubiquitin carboxy-terminal hydrolase L1, spectrin breakdown products and neurofilament light chain have been incorporated. Of these, only a few have shown sufficient diagnostic or prognostic accuracy to be used in TBI’s risk stratification. Among them, neuro specific enolase or S100B protein have shown good correlation with clinical severity and prognostic prediction.56 To date, the most studied biomarker in this field is the S100B protein, which has been widely validated as a brain injury marker and, therefore, with a prognostic value in different TBI clinical categories.5,57 Its utility to discriminate patients with mild TBI with low risk of IL has been documented in numerous studies and incorporated into clinical practice guidelines for the management of TBI.10 Discussion on the existence of extracranial sources of S100B protein, such as adipose tissue or bone, which could cover-up its concentration, remains active especially in cases of traumatic injury associated with TBI.5,58 Regardless of the above, the existence of some extracranial source for this protein should not be an inconvenience for its determination, when its main virtue relies on an excellent sensitivity and a negative predictive value (100%), and it is used to discriminate the mild TBI with no IL subgroup of patients.57,59 The characteristics of the test, with a high sensitivity, allow reducing the number of patients who should receive a cranial CT scan. However, we must recognize that it has low specificity, so a value above the cut-off point of 0.10 g/l has no clinical significance.5,59 Another biomarker recently emerging in mild TBI is the glial fibrillary acidic protein (GFAP). Compared with the S100B protein, there are studies that have shown higher cerebral specificity and better ability to predict IL when associated with extracranial lesions.60
Conclusions The management of mild TBI is a challenge for health systems. The availability of CT in most centres represents a diagnostic tool of indisputable utility, but its liberal use has led to increased health costs, exposure to ionizing radiation of a population at very low risk, as well as increased detection of IL that sometimes have little clinical significance and do not require any type of intervention or neurosurgical assessment. Several clinical decision protocols that identify patients at high risk for IL, which have been widely validated, allow to standardize the management and guide the indication of CT. However, further studies are needed to validate the promising protocols for the management of patients with very low-risk IL in non-neurosurgical centres that have been presented as safe and cost-effective. Finally, we hope that in the not too distant future we will have a panel of biomarkers that will allow, together with clinical assessment, the establishment of a more accurate diagnostic and
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prognostic approach for patients with mild TBI in the emergency department.
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Conflict of interest The authors declare no conflict of interest.
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Acknowledgements
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The authors wish to thank Prof. Murillo-Cabezas for the detailed reading of the article, as well as his contributions during the review of the same.
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Prehosp Emerg Care. 2015;19:202–12. Doherty DL. Posttraumatic cerebral atrophy as a risk factor for delayed acute subdural hemorrhage. Arch Phys Med Rehabil. 1988;69:542–4. Salottolo K, Levy AS, Slone DS, Mains CW, Bar-Or D. The effect of age on Glasgow Coma Scale score in patients with traumatic brain injury. JAMA Surg. 2014;149:727–34. Linn S, Levi L, Grunau PD, Zaidise I, Zarka S. Effect measure modification and confounding of severe head injury mortality by age and multiple organ injury severity. Ann Epidemiol. 2007;17:142–7. McIntyre A, Mehta S, Aubut J, Dijkers M, Teasell RW. Mortality among older adults after a traumatic brain injury: a meta-analysis. Brain Inj. 2013;27:31–40. Lau D, El-Sayed AM, Ziewacz JE, Jayachandran P, Huq FS, Zamora-Berridi GJ, et al. Postoperative outcomes following closed head injury and craniotomy for evacuation of hematoma in patients older than 80 years. J Neurosurg. 2012;116:234–45. Claudia C, Claudia R, Agostino O, Simone M, Stefano G. Minor head injury in warfarinized patients: indicators of risk for intracranial hemorrhage. J Trauma. 2011;70:906–9. Ivascu FA, Howells GA, Junn FS, Bair HA, Bendick PJ, Janczyk RJ. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma. 2005;59:1131–7. Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43:1511–7. Schaefer JH, Leung W, Wu L, van Cott EM, Lok J, Whalen M, et al. Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation. J Cereb Blood Flow Metab. 2014;34:870–5. Laroche M, Kutcher ME, Huang MC, Cohen MJ, Manley GT. Coagulopathy after traumatic brain injury. Neurosurgery. 2012;70:1334–45. Zhang D, Gong S, Jin H, Wang J, Sheng P, Zou W, et al. Coagulation parameters and risk of progressive hemorrhagic injury after traumatic brain injury: a systematic review and meta-analysis. Biomed Res Int. 2015:261825. Suehiro E, Koizumi H, Fujiyama Y, Yoneda H, Suzuki M. Predictors of deterioration indicating a requirement for surgery in mild to moderate traumatic brain injury. Clin Neurol Neurosurg. 2014;127:97–100. Fabbri A, Servadei F, Marchesini G, Stein SC, Vandelli A. Predicting intracranial lesions by antiplatelet agents in subjects with mild head injury. J Neurol Neurosurg Psychiatry. 2010;81:1275–9. Wong DK, Lurie F, Wong LL. The effects of clopidogrel on elderly traumatic brain injured patients. J Trauma. 2008;65:1303–8. Bonville DJ, Ata A, Jahraus CB, Arnold-Lloyd T, Salem L, Rosati C, et al. Impact of preinjury warfarin and antiplatelet agents on outcomes of trauma patients. Surgery. 2011;150:861–8. Batchelor JS, Grayson A. A meta-analysis to determine the effect of preinjury antiplatelet agents on mortality in patients with blunt head trauma. Br J Neurosurg. 2013;27:12–8. Ben-Dor I, Kleiman NS, Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy. Am J Cardiol. 2009;104:227–33. Nishijima DK, Zehtabchi S, Berrong J, Legome E. Utility of platelet transfusion in adult patients with traumatic intracranial hemorrhage and preinjury antiplatelet use: a systematic review. J Trauma Acute Care Surg. 2012;72:1658–63. Joseph B, Pandit V, Meyer D, Butvidas L, Kulvatunyou N, Khalil M, et al. The significance of platelet count in traumatic brain injury patients on antiplatelet therapy. J Trauma Acute Care Surg. 2014;77:417–21.
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51. Mendelow AD, Timothy J, Steers JW, Lecky F, Yates D, Bouamra O, et al. Management of patients with head injury. Lancet. 2008;372:685–7. 52. Tierney KJ, Nayak NV, Prestigiacomo CJ, Sifri ZC. Neurosurgery intervention in patients with mild traumatic brain injury and its effect on neurological outcomes. J Neurosurg. 2016;124:538–45. 53. Joseph B, Friese RS, Sadoun M, Aziz H, Kulvatunyou N, Pandit V, et al. The BIG (brain injury guidelines) project: defining the management of traumatic brain injury by acute care surgeons. J Trauma Acute Care Surg. 2014;76:965–9. 54. Joseph B, Pandit V, Haider AA, Kulvatunyou N, Zangbar B, Tang A, et al. Improving hospital quality and costs in nonoperative traumatic brain injury: the role of acute care surgeons. JAMA Surg. 2015;150:866–72. 55. Gordillo-Escobar E, Egea-Guerrero JJ, Rodríguez-Rodríguez A, Murillo-Cabezas F. Utilidad de los biomarcadores en el pronóstico del traumatismo craneoencefálico grave. Med Intensiva. 2016;40:105–12. 56. Rodríguez-Rodríguez A, Egea-Guerrero JJ, Gordillo-Escobar E, EnamoradoEnamorado J, Hernández-García C, Ruiz de Azúa-López Z, et al. S100B and
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neuron-specific enolase as mortality predictors in patients with severe traumatic brain injury. Neurol Res. 2016;38:130–7. Undén J, Romner B. Can low serum levels of S100B predict normal CT findings after minor head injury in adults? An evidence-based review and meta-analysis. J Head Trauma Rehabil. 2010;25:228–40. Pham N, Fazio V, Cucullo L, Teng Q, Biberthaler P, Bazarian JJ, et al. Extracranial sources of S100B do not affect serum levels. PLoS ONE. 2010;5:e12691. Biberthaler P, Linsenmeier U, Pfeifer KJ, Kroetz M, Mussack T, Kanz KG, et al. Serum S-100B concentration provides additional information for the indication of computed tomography in patients after minor head injury: a prospective multicenter study. Shock. 2006;25:446–53. Papa L, Silvestri S, Brophy GM, Giordano P, Falk JL, Braga CF, et al. GFAP out-performs S100 in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J Neurotrauma. 2014;31:1815–22.
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Review
Update in mild traumatic brain injury夽 María Dolores Freire-Aragón, Ana Rodríguez-Rodríguez, Juan José Egea-Guerrero ∗ UGC de Medicina Intensiva, Hospital Universitario Virgen del Rocío, Sevilla, Spain
a r t i c l e
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Article history: Received 21 April 2017 Accepted 1 May 2017 Available online xxx Keywords: Mild traumatic brain injury Intracranial lesion Head computed tomography Brain injury biomarkers
a b s t r a c t There has been concern for many years regarding the identification of patients with mild traumatic brain injury (TBI) at high risk of developing an intracranial lesion (IL) that would require neurosurgical intervention. The small percentage of patients with these characteristics and the exceptional mortality associated with mild TBI with IL have led to the high use of resources such as computerized tomography (CT) being reconsidered. The various protocols developed for the management of mild TBI are based on the identification of risk factors for IL, which ultimately allows more selective indication or discarding both the CT application and the hospital stay for neurological monitoring. Finally, progress in the study of brain injury biomarkers with prognostic utility in different clinical categories of TBI has recently been incorporated by several clinical practice guidelines, which has allowed, together with clinical assessment, a more accurate prognostic approach for these patients to be established. ˜ S.L.U. All rights reserved. © 2017 Elsevier Espana,
Actualización en el traumatismo craneoencefálico leve r e s u m e n Palabras clave: Traumatismo craneoencefálico leve Lesión cerebral Tomografía axial computarizada craneal Biomarcadores de lesión cerebral
˜ Durante anos ha existido preocupación por la identificación de pacientes con traumatismo craneoencefálico (TCE) leve en alto riesgo de presentar lesión intracraneal (LI) subsidiaria de intervención neu˜ porcentaje de pacientes de estas características, y la mortalidad excepcional roquirúrgica. El pequeno ligada al TCE leve con LI, han llevado a reconsiderar la elevada utilización de recursos como la tomografía craneal (TC). Los diversos protocolos desarrollados para el manejo del TCE leve se basan en la identificación de factores de riesgo de presentar LI, lo que finalmente permite indicar o descartar selectivamente tanto la solicitud de TC como la estancia hospitalaria para la vigilancia neurológica. Finalmente, el avance realizado en el estudio de biomarcadores de lesión cerebral con utilidad de carácter pronóstico, en diferentes categorías clínicas del TCE, ha sido recientemente incorporado por diversas guías de práctica clínica, lo que ha permitido, junto con la valoración clínica, una estimación pronóstica más exacta para estos pacientes. ˜ S.L.U. Todos los derechos reservados. © 2017 Elsevier Espana,
Introduction Traumatic brain injury (TBI) represents a major public health problem worldwide. Epidemiological studies show high variability in their results, with a crude incidence rate ranging from 47.3 to 849 cases per 100,000 inhabitants/year for all ages and severity types.1 Specifically, mild TBI constitutes 70–90% of all cases.2
夽 Please cite this article as: Freire-Aragón MD, Rodríguez-Rodríguez A, EgeaGuerrero JJ. Actualización en el traumatismo craneoencefálico leve. Med Clin (Barc). 2017. http://dx.doi.org/10.1016/j.medcli.2017.05.002 ∗ Corresponding author. E-mail address: [email protected] (J.J. Egea-Guerrero).
Currently, this process is a health priority due to several key facts. First, it has a high incidence, estimated at 224 cases per 100,000 inhabitants. Second, it causes many emergency department visits. Third, there is a lack of specific symptomatology that allows the identification of those patients at risk of developing an intracranial lesion (IL), which causes a high consumption of resources and complementary tests.3 Several protocols and clinical practice guidelines have been developed in recent years aimed at the early identification of patients who may present IL after mild TBI. These protocols attempt to weight the risk factors and thus the indication of neuroimaging tests or hospital observation. Compliance with these guidelines would make it possible to balance health costs and reduce ionizing radiation in patients with very low IL probability.4 In fact, only
˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,
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7–10% of patients with mild TBI have tomographic findings after trauma and less than 1% require neurosurgical intervention, with death being a very rare outcome (0.1%).5 The objective of the present review is to address the management of adult patients with mild TBI considering conventional risk factors, such as advanced age, anticoagulant (AC)/antiplatelet intake, as well as indication of neuroimaging studies, need of neurosurgical assessment and the recent introduction of brain injury biomarkers to discriminate patients with a true risk of having IL. Initial management of mild traumatic brain injury In general, TBI does not have a universal definition; additionally, there are several denominations published to define mild TBI, which sometimes makes the standardized management of this pathology more complicated.6 The score reached on the Glasgow Coma Scale (GCS) has been used without changes for the last 4 decades to assess the conscious level impairment following a TBI, and is one of the most relevant prognostic indicators in this pathology.7 Classically, the mild TBI category includes patients with a score of 13–15. However, a tendency adopted by many authors is to exclude patients with 13 points from the “mild” category, given the high anomaly percentage in cranial computed tomography (CT), as well as their clinical and prognostic progression, which is closer to moderate TBI. This difference of criteria adopted to define mild TBI has been, perhaps, one of the most important biases in the comparison of the different published series.8,9 The information derived from an adequate case history and physical examination allows the identification of certain risk factors for IL and is the basis of renowned clinical decision protocols that prompt the CT indication. However, the lack of specificity of the accompanying symptoms, coupled with the absence of conclusive evidence for individual risk factors, somehow explains the discrepancies found in the different guidelines designed for the management of this pathology.10–12 The presence of primary or acquired coagulopathy, posttraumatic neurological deterioration or the presence of clinical cranial fracture signs are widely recognized as high risk factors for IL association.10,13 However, we find variable considerations for other factors. In this sense, the recently revised Scandinavian guidelines recognize an insufficient predictive capacity for age (>65 years) or antiplatelet as individual risk factors for IL. Within the lesion mechanisms considered by some guidelines, having an accident has proven to be a higher risk factor for IL association.14 In relation to symptomatology referred by the patient, the loss of consciousness, or suspicion of the same, is a risk factor in itself.10 However, other symptoms such as headache, nausea or amnesia have shown, in some series, a low capacity to predict the presence of IL. It is worth mentioning the recent inclusion of patients with a shunt for the treatment of hydrocephalus as a specific group of patients at risk.10 Finally, the presence of cranial fracture has shown a 5-times-higher association with the existence of IL requiring a neurosurgical intervention versus the subgroup of mild TBI without fracture.13 Indication of initial cranial CT and scheduled cranial CT to monitor progression The availability of cranial CT in most centres, coupled with the practice of a somewhat defensive medicine for a normally benign process, has been responsible for the exponential increase in the use of CT scans in mild TBI. The corresponding increase in costs, associated with the risk of cancer due to radiological exposure, as
well as the low frequency with which an IL requiring intervention is detected, have led to question its indication.15 The usefulness of CT in the early management of moderate and severe TBI is well established.10–12 However, the variability in its application shown for mild TBI has led to the development of protocols that identify cases which could actually involve an IL.10–12 Specifically, patients with a GCS score of 15 points, without other risk factors, should be discharged from hospital without CT or observation, with family support, and ensuring specific recommendations. In a recent systematic review, which compares the diagnostic accuracy of different clinical decision protocols, it was observed that both Canadian CT Head Rule (CCHR) as well as the New Orleans Criteria (NOC) have a good negative odds ratio (OR) (0.04 and 0.08, respectively) and diagnostic accuracy to detect patients at low risk of requiring neurosurgical intervention (CCHR: OR of 0.05; NOC: OR of 0.7).14 Previously, the analysis of the subgroup of patients with a 15-point GCS score after a TBI had shown a high sensitivity (100%) for both protocols, although CCHR had a greater specificity versus the NOC, both for detection (50.6% versus 12.7%) as well as to predict the need for neurosurgical intervention (76.3% versus 12.1%, respectively).16 A second problem to be considered, which is an issue still without consensus, is the indication of a cranial CT to monitor progression in patients in whom the existence of an IL after mild TBI has been confirmed.17 Although the presence of some lesions has not necessarily demonstrated an increase in morbidity and mortality, a large number of examinations are finally carried out in order to rule out progression of intracranial bleeding and obtain radiological evidence which could help to plan the patient’s transfer to centres with neurosurgical services, hospital admission or strengthen the discharge decision.18 In a recent meta-analysis, it was observed that scheduled CT scans leads to management changes in only a minority of patients (9.6–11.4%), including cases with tomographic evidence of IL progression. For example, in the mild TBI subgroup (GCS of 13–15 points), treatment strategy only changed in 2.3–3.9% of the cases.17 The type of IL should be an element that determines the indication of a progression control CT. There are lesions such as convexity subarachnoid haemorrhage, laminar subdural hematomas (SDH) or small volume hematomas (<4–7 mm), as well as small single convexity contusions, where other factors should reinforce the decision to repeat imaging tests. Among them, we could highlight the patient’s own progression and clinical condition, the presence of coagulopathies or other blood dyscrasias that favour the progression of IL or the timing of trauma.19 The possible occurrence of late bleeding in anticoagulated patients or, less frequently, in patients with shunts for the treatment of hydrocephalus deserves a special consideration after a normal initial CT.20 Although the management protocol varies between centres, performing follow-up CT scans after a first normal imaging study or admission for observation during 24 h would not allow the detection of the small number of cases that present bleeding beyond the first 24 h after trauma, its indication being widely questioned.21 In the group of anticoagulated patients, the reported incidence of bleeding within the 24 h after trauma following a normal initial CT scan is very low (0.6%), with cases of sub-therapeutic AC levels having been reported.22,23 Considering current evidence, the risk of late bleeding is low enough to allow discharge with specific recommendations. However, particular aspects such as the high-energy injury mechanism, associated antiplatelet therapy or an excessive level of AC (INR > 3) should be considered in an individualized way when deciding the management strategy. Special mention should be made of patients treated with new oral ACs (dabigatran, apixaban, among others). For this subgroup, considered in risk, there are no updated recommendations in the guidelines.24
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Mild traumatic brain injury in older adults This group of adults does not have a standard definition and generally involves people aged 60–65 years or over. Treatment of TBI in patients older than 65 years of age has increased in the last years.25 Advances in the field of medicine, better prehospital care, coupled with an increase in population life expectancy, may explain the change in the epidemiology of trauma. In these cases, worse functional results associated with TBI have been observed for all severity groups, which leads to an increase in health expenditure.26 The age-specific physiological change association, together with individual comorbidities – more frequent with advanced age – make the elderly a frailer population after a TBI. In this group, more than 70% of the patients presented previous comorbidities, which could explain longer hospital stays, as well as a lower score on the GCS or Disability Rating Scale.27 Falling from one’s own height has been identified as one of the most frequent lesion mechanisms in this subgroup (60–82%). In a mortality analysis, it was found to be the cause of death in 77% of patients over 65 years of age with mild TBI, and SDH was the most frequently identified LI (86%).28 Despite the development of fall prevention guidelines and different local implementation plans, standardized hospitalization rates secondary to falls have increased up to 8.4% per year.29 AC and antiplatelet therapy based on recommendations for the prevention of cardiovascular and cerebral ischaemic events (quite frequent in this patient subpopulation), is likely to play a role in the increased hospitalization rate due to IL secondary to TBI, mainly for SDH (42.9%).30 Up to 80% of TBI in those over 65 years of age are considered clinically mild. The elderly may have a lower baseline response associated with an attention deficit or a mobility or auditory/visual function impairment, something that may be considered by clinicians as “pseudo-normal”, which may associate an underestimation in the determination of the TBI’s clinical severity. We recognize that there are patients with underlying cognitive disorders, comorbidities or under treatment with medications that affect the sensorium, in whom distinguishing mild and moderate forms of TBI during the initial care phase is difficult. In this sense, an easy-to-apply dichotomous decision model has been proposed, based on the level of alertness (alert/non-alert) and motor function (obeys orders/does not obey), but still pending validation.31 On the other hand, age-associated cerebral atrophy occasionally allows for a “symptom-free window” where certain significant ILs may not have clinical expression. This may explain how some mild TBI initially go unnoticed and over the course of the days they need emergency care in their progression as moderate or even severe TBI. A mechanism which has been traditionally proposed for late acute SDH is the greater vulnerability of the cerebral veins draining in the dural sinuses when a TBI occurs, since the increase of subdural space in the presence of atrophy causes greater elongation and length.32 Age also affects the relationship between GCS and anatomic severity in TBI. Patients who are 65 years of age or older have a better GCS score than younger ones for similar severity injuries.33 GCS is a better predictor of mortality for patients under 55 years of age than for the over 60 years of age subgroup, where it has not been shown to predict differences in mortality between moderate and severe TBI.34 Among the reasons proposed to justify the absence of detected difference in mortality are the presence of comorbidities and physiological changes typical of the biological age that would hinder the response to aggression, as well as a trend towards a more conservative treatment in this population.35 However, in view of the functional and cognitive outcomes of recent studies in older adults with TBI – similar to younger age groups when aggressive measures are applied –, and in
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contrast to the generalized trend of a more conservative management, the need to identify the subgroup of patients who could benefit from neurosurgical treatment, multimodal neuromonitorization and admission to an intensive care unit has increased.36
Characteristics of the antiplatelet and anticoagulated patient The current recommendations in the prevention of ischaemic events according to clinical practice guidelines, as well as the management of coronary patients are largely responsible for the increase in population under AC and antiplatelet therapy. AC association with vitamin K antagonists (mainly warfarin), or with new ACs in patients with a TBI, is a well-established risk factor for the presence of IL along with other variables such as the low energy mechanism, the initial IL progression and the patient’s own morbidity.37 Rapid reversal of the anticoagulant effect using prothrombin complex concentrate and, to a lesser extent, fresh frozen plasma or vitamin K has been shown to reduce the haemorrhagic progression of IL and its mortality.38 On the other hand, there is growing concern about the introduction of new ACs (direct thrombin inhibitors/direct factor Xa inhibitors) with attractive advantages over warfarin for monitoring or interactions, but with the drawback of a lack of antidote allowing a rapid reversal of its effect following trauma.24 However, there is evidence of a lower rate of traumatic IL in patients treated with dabigatran (direct thrombin inhibitor), compared with warfarin, which has been supported by studies in animal models.39,40 The progression of IL has been associated with coagulation parameter disorders. Coagulopathy and abnormal fibrinolysis associated with severe TBI is well documented, although its mechanism is not fully understood.41 A statistically significant association between prothrombin time, INR and d-dimer levels and the risk of IL progression after trauma has been observed.42 In mild TBI, Suehiro et al. have identified certain abnormalities in coagulation and fibrinolysis studies as predictors of increased IL and the need for neurosurgery.43 Despite the undoubted usefulness of having extensive coagulation and fibrinolysis studies, including the possibility of implementing thromboelastometry, there is currently insufficient scientific evidence to recommend or justify the costs that would be incurred in a pathology as prevalent as mild TBI. In relation to antiplatelet therapy and its association with LI after mild TBI, studies to date have not allowed it to be established as an individual risk factor. On the one hand, we find works like Fabri et al. which establish an association between acetylsalicylic acid (ASA) and the presence of IL after mild TBI.44 Likewise, clopidogrel has been identified as a risk factor for IL occurrence requiring neurosurgical intervention, re-bleeding episodes, and a greater need for blood product transfusion.45 Although several authors have suggested an association of antiplatelet therapy in patients with traumatic IL and mortality, others, however, have not shown an increase in unfavourable outcomes.46 In a recent meta-analysis, there is only a slight increased risk of death between the use of antiplatelet therapy and TBI, with no statistical significance.47 Some of the risk factors suggested to explain the differences found in these studies are heterogeneity in severity or injury mechanism, as well as inclusion in the antiplatelet group only due to previous patient history, without considering the actual adherence to the treatment nor the degree of inhibition of platelet activity measured through functionality tests. We know that antiplatelet treatment does not work equally in all patients and we have studies that have shown resistance to ASA or clopidogrel ranging from 1 to 45%.48
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In the case of antiplatelet therapy, there is no antidote capable of reversing its activity since the enzymatic block occurs irreversibly. However, to date, routine platelet transfusion in patients with IL is not recommended.49 Regardless of the antiplatelet therapy, the platelet count itself has been associated with a greater progression of IL and the need for surgery after the TBI. A count below 135,000 platelets in patients undergoing treatment with ASA or clopidogrel has been identified as a predictor of clinical and radiological worsening following TBI.50 Ultimately, in the presence of an IL in the context of mild TBI, in a patient under antiplatelet therapy, it would be extremely useful to have immediate platelet function tests that allow knowing the predictable risk and establishing therapeutic measures in an individualized way. We believe it is appropriate to emphasize that although these tests cannot be urgently requested in most centres, the risk-benefit ratio, both for the temporary suspension of the antiplatelet treatment and for the rare indication of platelet transfusion, should be mainly dependent on the assessment of the characteristics of the IL (volume/distribution/location) in routine clinical practice, as well as the pathology that motivated the antiplatelet treatment.
Need for transfer of mild traumatic brain injury for neurosurgical assessment Usually, the presence of IL after a TBI requires assessment by a neurosurgeon, with or without transfer to trauma centres that have this specialty. In those patients who are clinically classified as having a moderate or severe level of severity (regardless of the need for surgical intervention), the referral indication is well established.51 However, the concern about a possible unfavourable progression in patients with IL after suffering a mild TBI occasionally forces the transfer of patients to other centres in search of specialized assessment without considering real risk groups and IL characteristics, as previously discussed (type, size, location). This fact has been increased in recent years due to the greater detection of IL as a consequence of a more widespread use of CT scans. It is evident that a proper selection in the number of consultations performed by neurosurgery would improve cost-opportunity for patients with TBI. The need for surgical intervention in mild TBI is less than 1%. Higher figures in recent studies (up to 8%) could be explained by the absence of exclusion of AC or antiplatelet patients, and a more liberal definition of “neurosurgical intervention”.52 Given the concern for a more efficient use of hospital resources, management protocols that include “non-transfer” criteria are starting to emerge, although pending validation.53 It has been suggested that certain groups of patients with mild TBI and GCS of 15 points – mainly without AC/antiplatelet therapy or without coagulopathy or platelet function disorder –, and low risk IL, can be managed in centres with no neurosurgical specialty in a safe and efficient way. Lesions considered to be at low risk of progression and requiring neurosurgical intervention are: minimal convexity subarachnoid haemorrhage, intraparenchymal haematoma or haemorrhagic contusion in a single site, SDH or epidural, all less than or equal to 4 mm in size. The progression of the IL in follow-up CT in these protocols has been shown to be low (5–7%), with no need for surgical intervention.53 The implementation analysis of one of these protocols has demonstrated a reduction in scheduled follow-up CT scans, as well as a decrease in the overall hospital costs, which, besides being safe, are also cost-effective.54 As in any medical evaluation, finding an IL on a CT scan plays a significant role in the decision to refer the patient, but it is not the only one. IL characteristics as well as the existence of other associated extracranial lesions, personal history and
comorbidities, should be weighed to establish an individualized management plan.
Usefulness of brain injury biomarkers in mild traumatic brain injury In the last 30 years, we have witnessed a breakthrough in the study of brain injury biomarkers. The characteristics of these are largely conditioned by the presence of the blood–brain barrier. Although biomarker determination in brain tissue itself or in cerebrospinal fluid is useful, its invasive nature limits its use.55 The main brain injury biomarkers studied are: S100B protein, glial fibrillary acidic protein, Tau protein, amyloid beta protein, myelin basic protein, creatine kinase brain isoenzyme and neuron specific enolase.55 More recently, studies on ubiquitin carboxy-terminal hydrolase L1, spectrin breakdown products and neurofilament light chain have been incorporated. Of these, only a few have shown sufficient diagnostic or prognostic accuracy to be used in TBI’s risk stratification. Among them, neuro specific enolase or S100B protein have shown good correlation with clinical severity and prognostic prediction.56 To date, the most studied biomarker in this field is the S100B protein, which has been widely validated as a brain injury marker and, therefore, with a prognostic value in different TBI clinical categories.5,57 Its utility to discriminate patients with mild TBI with low risk of IL has been documented in numerous studies and incorporated into clinical practice guidelines for the management of TBI.10 Discussion on the existence of extracranial sources of S100B protein, such as adipose tissue or bone, which could cover-up its concentration, remains active especially in cases of traumatic injury associated with TBI.5,58 Regardless of the above, the existence of some extracranial source for this protein should not be an inconvenience for its determination, when its main virtue relies on an excellent sensitivity and a negative predictive value (100%), and it is used to discriminate the mild TBI with no IL subgroup of patients.57,59 The characteristics of the test, with a high sensitivity, allow reducing the number of patients who should receive a cranial CT scan. However, we must recognize that it has low specificity, so a value above the cut-off point of 0.10 g/l has no clinical significance.5,59 Another biomarker recently emerging in mild TBI is the glial fibrillary acidic protein (GFAP). Compared with the S100B protein, there are studies that have shown higher cerebral specificity and better ability to predict IL when associated with extracranial lesions.60
Conclusions The management of mild TBI is a challenge for health systems. The availability of CT in most centres represents a diagnostic tool of indisputable utility, but its liberal use has led to increased health costs, exposure to ionizing radiation of a population at very low risk, as well as increased detection of IL that sometimes have little clinical significance and do not require any type of intervention or neurosurgical assessment. Several clinical decision protocols that identify patients at high risk for IL, which have been widely validated, allow to standardize the management and guide the indication of CT. However, further studies are needed to validate the promising protocols for the management of patients with very low-risk IL in non-neurosurgical centres that have been presented as safe and cost-effective. Finally, we hope that in the not too distant future we will have a panel of biomarkers that will allow, together with clinical assessment, the establishment of a more accurate diagnostic and
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prognostic approach for patients with mild TBI in the emergency department.
22.
Conflict of interest The authors declare no conflict of interest.
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Acknowledgements
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The authors wish to thank Prof. Murillo-Cabezas for the detailed reading of the article, as well as his contributions during the review of the same.
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