Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 1 of 35
1
Traumatic intracerebral hemorrhage: Risk factors associated with progression
SANTIAGO CEPEDA, M.D.1, PEDRO A. GÓMEZ, M.D. Ph.D.1,
ANA MARÍA
CASTAÑO, M.D.1, RAFAEL MARTÍNEZ-PÉREZ, M.D.1, PABLO M. MUNARRIZ, M.D.1, AND ALFONSO LAGARES, M.D. Ph.D.1
1
Department of Neurosurgery, Hospital 12 de Octubre, Universidad Complutense de
Madrid, Spain Corresponding author: Santiago Cepeda, M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 651 035 158. Fax: +34 913 90 80 00. Email: [email protected] Pedro A. Gómez, M.D., Ph.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 659 617 011. Fax: +34 913 90 80 00. Email: [email protected] Ana María Castaño M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 653 369 188 . Fax: +34 913 90 80 00. Email: [email protected]
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 2 of 35
2 Rafael Martínez-Pérez M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 661 939 345 . Fax: +34 913 90 80 00. Email: [email protected] Pablo M. Munarriz M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 649 404 478. Fax: +34 913 90 80 00. Email: [email protected] Alfonso Lagares, M.D., Ph.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 649 803 025. Fax: +34 913 90 80 00. Email: [email protected]. Running title: Progression of traumatic intracerebral hemorrhage Financial and material support: This study was funded by grant no. 2010-007 from the Mutua Madrileña Foundation (Spain). Pedro A. Gómez M.D. Ph.D. Presentation: Portions of this work were presented in abstract form as proceedings at the XIX Congress of the Spanish Society of Neurological Surgery, Cádiz, Spain, May 15, 2014.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 3 of 35
3 ABSTRACT The increase in the volume of a traumatic intracerebral hemorrhage (TICH) is a widely studied phenomenon that has a direct impact on the prognosis of patients. The objective of this study was to identify the risk factors associated with the progression of TICH. We retrospectively analyzed the records of 1970 adult patients older than 15 years who were consecutively admitted after suffering a closed severe traumatic brain injury (TBI) between January 1987 and November 2013 at a single center. Beginning in 2007, patients with moderate TBIs were also included. 782 patients exhibited one or more TICH on the initial CT scan and met the selection criteria. The main outcome variable was the presence or absence of progression of the TICH. Univariate and multivariate statistical analyses were performed. Factors independently associated with the growth of TICH obtained through logistic regression included the following: an initial volume less than 5 cc (OR 2.42, p < 0.001), cisternal compression (OR 1.95, p < 0.001), decompressive craniectomy (OR 2.18, p < 0.001), age (mean 37.67 vs. 42.95 years; odds ratio [OR] 1.01, p < 0.001), falls as mechanism of trauma (OR 1.72, p = 0.001), multiple TICHs (OR 1.56, p = 0.007), and hypoxia (OR 1.56, p = 0.02). TICH progression occurred with a frequency of 63% in our study. We showed that there is a correlation between TICH growth and some variables, such as multiple TICHs, a lower initial volume, acute subdural hematoma, cisternal compression, older patient age, hypoxia, falls, and decompressive craniectomy. Keywords: Contusion, intracerebral hematoma, progressive hemorrhagic injury, traumatic brain injury, traumatic intracerebral hemorrhage.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 35
4 INTRODUCTION Traumatic intracerebral hemorrhage (TICH) occurs in approximately 13 to 35% of patients following a traumatic brain injury (TBI).1,2 The increase in the volume of a TICH is a widely studied phenomenon that has a direct impact on the prognosis of patients. Several authors have reported that an increase in the size of a TICH occurs in approximately 38 to 59% of cases and mainly occurs in the first few hours after head trauma.3,4,5 While most of the TICHs that increase in volume do not require surgical intervention,6,7,8 some cases exist in which the progression of lesions can cause neurological deterioration of the patient or signs of refractory increased intracranial pressure (ICP) or a mass effect on a computed tomography (CT) scan, all of which require surgical evacuation.9 In some studies of TBI, TICHs were the reason for surgery in up to 20% of patients.10,11 This result emphasizes the importance of being able to identify the group of patients who will experience a significant increase in the volume of the traumatic intraparenchymal lesion. Overall, several factors have been recognized as having an association with TICH growth and subsequent neurological deterioration, such as trauma severity, advanced age, multiple lesions, radiological signs (e.g., midline deviation or cisternal compression), and coagulopathy. Some studies3,12,13,14 have attempted to determine the association of various factors with TICH growth. However, the main limitation of these studies was a small sample size; therefore, the conclusions cannot be generalized. The primary objective of this study was to identify a set of factors associated with TICH progression in a large cohort of patients who have suffered severe or moderate TBI.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 5 of 35
5 METHODS Inclusion and exclusion criteria We retrospectively analyzed the records of 1970 adult patients older than 15 years of age who were admitted consecutively after suffering a closed (non-missile) severe TBI, which was defined as a score of ≤8 points on the Glasgow Coma Scale (GCS) after non-surgical resuscitation within the first 48 hours after trauma, between January 1987 and November 2013 at University Hospital 12 de Octubre. Beginning in 2007, patients with moderate TBIs (GCS 9-13) were also included. Patients were included in the study if an assessable initial CT scan was performed on admission and a control CT scan could be evaluated to determine TICH progression or the appearance of new lesions. Therefore, from a total of 1970 patients diagnosed with moderate or severe TBI, 950 patients exhibited one or more TICH on the initial or control CT scan. Of these patients, 168 were excluded due to lack of a control CT scan as a result of death or an immediate neurosurgical procedure, including evacuation of the TICH. The causes of death in this group of patients included the direct effect of TBI in 113 patients and systemic causes and medical complications in 13 patients. Therefore, 782 patients met the selection criteria, and we performed the subsequent analysis using data from this group (Figure 1). Variables assessed We collected radiological, demographic, clinical, and treatment information, which is summarized in Table 1. Data were collected at the bedside in a standardized manner based
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 6 of 35
6 on previous research15,16,17,18 and were also used in the creation of the TBI database of 12 de Octubre Hospital.19 Radiological variables The radiological features analyzed are summarized in Table 1. The initial CT scan was defined as the scan performed immediately after a patient was admitted to the hospital. The control CT was defined as the scan with the worst radiological features. The control CT scan was performed after clinical deterioration or raised ICP and without a scheduled protocol. The time between the head trauma, initial CT, and control CT was recorded. CT scans were classified according to the Marshall classification20 and individual radiological features, including the following: a) traumatic subarachnoid hemorrhage (tSAH), which was defined as the presence of blood in the subarachnoid space either over the convexity or fissures or in the basal cisterns; b) intraventricular blood (IVH), which was categorized as present or absent; c) basal cisterns, which were categorized as normal or abnormal (compressed or absent); d) the presence and type of mass lesions, including epidural hematoma (EDH), acute subdural hematoma (ASH), or traumatic intracerebral hemorrhage (TICH) (TICHs were categorized based on volume into the following groups: 1 - 5 cc, 6 - 10 cc, 11 - 15 cc, 16 - 20 cc, 21 - 25 cc, 26 - 30 cc, 31 - 35 cc, and ≥ 36 cc); and e) midline shifts (MLS) (shifts ≤ 5 mm versus shifts >5 mm). We defined TICHs as traumatic intraparenchymal hemorrhagic lesions with a solid and well defined appearance (hematoma) and fewer well-defined areas of mixed attenuation. Petechial lesions with a classic pattern of diffuse axonal injury (DAI) were excluded.21
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 7 of 35
7 The initial and control volumes of TICH were measured in cubic centimeters. We recorded whether the initial volume was less than or equal to 5 cc, which was used as a dichotomous variable. All CT scans were assessed by two senior neurosurgeons (PAG, AL). TICH volume was estimated by the following formula as suggested by the Surgical Guidelines of the Brain Trauma Foundation: A x B x C / 2 (cm3),22,9 where A, B, and C represent the largest dimensions of the hematoma measured at perpendicular angles to one another. TICHs were classified according to their location and number as single, focal, multiple unilateral, or multiple bilateral hematomas. Treatment variables Patients were classified as operated and non-operated. Surgical procedures were classified as follows: 1) craniotomy: evacuation of the lesion or lobectomy and debridement with bone flap replacement; 2) decompressive craniectomy: removal of the bone flap without evacuation of the TICH; and c) others: elevation of bone fragments, cerebrospinal fluid drainage, and burr hole drilling. Primary endpoint The main outcome variable was the presence or absence of TICH progression. We defined progression as an increase equal or greater than 33% of the initial volume of the TICH or the appearance of a new lesion in a control CT scan. In addition to the main variable, we estimated the change in volume in cubic centimeters from the initial to the control CT scan.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 8 of 35
8 Outcome variable: According Glasgow Outcome Scale (GOS) we classified patients in favorable (GOS score 4 - 5) and unfavorable (GOS score 1 - 3) and we used it as dichotomous variable. All patients had a minimum follow-up of 6 months. Statistical analysis To identify factors associated with TICH growth, a univariate analysis was performed. Univariate comparisons were performed using Student’s t-test for continuous variables and Fisher's exact test for dichotomous variables. Logistic regression analysis was used to estimate the association between the risk factors (i.e., clinical findings, laboratory findings, and neuroimaging characteristics) and the main outcome variable (progression of TICH). The initial examination included a set of 22 potential predictors (Table 2) that were collected at the time of admission; these predictors are consistently referenced in the literature.
3,12,13,14,18,23,24
The relationship between a
predictor and progression was estimated using a crude odds ratio (OR) and R2. P values equal to or less than 0.05 were considered statistically significant. In addition, with the results of the multivariate analysis, we were able to develop a predictive model based on the variables of greatest statistical significance. We used the Nagelkerke R2 value to determine the predictive ability of the model.25 The HosmerLemeshow goodness of fit test was used for the model calibration.26 To evaluate the discrimination of the model, we used the area under the receiver operating characteristic (ROC) curve.27
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 9 of 35
9 We used the model produced by logistic regression to develop a nomogram that creates a simple graphical representation of our statistical predictive model and generates a numerical probability of progression. All statistical analyses were performed with SPSS 22.0 software (IBM, Chicago, IL). The nomogram was created using Orange 2.7 software (University of Ljubljana, Slovenia).
RESULTS Patient characteristics Epidemiological and clinical characteristics are shown in Table 1. A total of 621 (79%) of the patients were male, and 161 (21%) were female. The mean age was 41 years, ranging from 15 to 84 years. The mean time between trauma and admission was 2.8 hours; the mean time was 2.6 hours in the group that demonstrated progression and 3.2 hours in the group that did not exhibit progression. These values were not significantly different between groups. The main mechanism of trauma was traffic accidents (498 (64%) patients), followed by falls (233 (30%) patients) and impact and other mechanisms (51 (6%) patients). The motor scores at admission showed the following distribution: M1: 51 (8%) patients, M2: 68 (11%), M3: 84 (14%), M4: 123 (20%), M5: 192 (32%), and M6: 86 (14%). In 178 (23%) patients, the motor score was not reliable mainly due to the effects of sedation.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 10 of 35
10 The mean time between the trauma and the first CT scan was 2.9 hours, and the mean time between the trauma and the control CT scan was 30.1 hours. Table 2 shows the radiological features of the initial CT scans. According to the Marshall classification, 345 (44%) patients corresponded to type II, 143 (18%) patients corresponded to type III, 22 (3%) patients corresponded to type IV, and 272 (34%) patients corresponded to type V-VI. We observed the presence of tSAH in 611 (78%) patients, IVH in 232 (30%) patients, and skull fracture in 507 (65%) patients. An MLS greater than 5 mm was present in 172 (22%) patients. Compressed or absent cisterns were visualized in 397 (51%) patients. TICHs were the only type of mass lesion in 258 (33%) patients. We also observed the presence of ED in 153 (20%) and ASH in 389 (50%) patients. With respect to the number and location of TICHs, 368 (57%) patients presented a focal TICH, 68 (10%) showed multiple unilateral TICHs, and 213 (33%) showed multiple bilateral TICHs. The mean volume of the TICH on the initial CT scan was 7.29 cc; on the control CT scan, it was 18.18 cc. By classifying the initial TICH volume into groups, we observed that 412 (52.7%) patients presented a volume of less than 5 cc; 229 (29.3%) patients presented a volume of 6 – 10 cc; 74 (9.5) patients presented a volume of 11 – 15 cc; 33 (4.2%) patients presented a volume of 16 – 20 cc; 13 (1.7%) patients presented a volume of 26 – 30 cc; 5
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 11 of 35
11 (0.6%) patients presented a volume of 31 – 35 cc; and 9 (1.2%) patients presented a volume of more than 35 cc. TICH progression was observed in 497/782 (64%) patients. The mean increase in volume was 10.9 cc. In 228 (46%) cases, there was an increase of less than 10 cc; an increase of 11 to 20 cc occurred in 130 (26%) cases; an increase of 21 to 30 cc occurred in 66 (13%) cases; and 73 (15%) patients presented an increase of greater than 30 cc. In 285/782 (36%) patients, the TICH volume remained stable or decreased on the control CT scan (Figure 2). The outcome at six months of follow up was favorable in 285 (36%) patients and unfavorable in 474 (64%) patients. Although the purpose of this study was not to determine the outcome of patients with TICH, we found a significant correlation between progression and an unfavorable outcome (OR 3.6, p
Page 1 of 35
1
Traumatic intracerebral hemorrhage: Risk factors associated with progression
SANTIAGO CEPEDA, M.D.1, PEDRO A. GÓMEZ, M.D. Ph.D.1,
ANA MARÍA
CASTAÑO, M.D.1, RAFAEL MARTÍNEZ-PÉREZ, M.D.1, PABLO M. MUNARRIZ, M.D.1, AND ALFONSO LAGARES, M.D. Ph.D.1
1
Department of Neurosurgery, Hospital 12 de Octubre, Universidad Complutense de
Madrid, Spain Corresponding author: Santiago Cepeda, M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 651 035 158. Fax: +34 913 90 80 00. Email: [email protected] Pedro A. Gómez, M.D., Ph.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 659 617 011. Fax: +34 913 90 80 00. Email: [email protected] Ana María Castaño M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 653 369 188 . Fax: +34 913 90 80 00. Email: [email protected]
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 2 of 35
2 Rafael Martínez-Pérez M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 661 939 345 . Fax: +34 913 90 80 00. Email: [email protected] Pablo M. Munarriz M.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 649 404 478. Fax: +34 913 90 80 00. Email: [email protected] Alfonso Lagares, M.D., Ph.D., Department of Neurosurgery, Hospital 12 de Octubre, Avda de Cordoba s/n, Madrid 28041, Spain. Telephone: +34 649 803 025. Fax: +34 913 90 80 00. Email: [email protected]. Running title: Progression of traumatic intracerebral hemorrhage Financial and material support: This study was funded by grant no. 2010-007 from the Mutua Madrileña Foundation (Spain). Pedro A. Gómez M.D. Ph.D. Presentation: Portions of this work were presented in abstract form as proceedings at the XIX Congress of the Spanish Society of Neurological Surgery, Cádiz, Spain, May 15, 2014.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 3 of 35
3 ABSTRACT The increase in the volume of a traumatic intracerebral hemorrhage (TICH) is a widely studied phenomenon that has a direct impact on the prognosis of patients. The objective of this study was to identify the risk factors associated with the progression of TICH. We retrospectively analyzed the records of 1970 adult patients older than 15 years who were consecutively admitted after suffering a closed severe traumatic brain injury (TBI) between January 1987 and November 2013 at a single center. Beginning in 2007, patients with moderate TBIs were also included. 782 patients exhibited one or more TICH on the initial CT scan and met the selection criteria. The main outcome variable was the presence or absence of progression of the TICH. Univariate and multivariate statistical analyses were performed. Factors independently associated with the growth of TICH obtained through logistic regression included the following: an initial volume less than 5 cc (OR 2.42, p < 0.001), cisternal compression (OR 1.95, p < 0.001), decompressive craniectomy (OR 2.18, p < 0.001), age (mean 37.67 vs. 42.95 years; odds ratio [OR] 1.01, p < 0.001), falls as mechanism of trauma (OR 1.72, p = 0.001), multiple TICHs (OR 1.56, p = 0.007), and hypoxia (OR 1.56, p = 0.02). TICH progression occurred with a frequency of 63% in our study. We showed that there is a correlation between TICH growth and some variables, such as multiple TICHs, a lower initial volume, acute subdural hematoma, cisternal compression, older patient age, hypoxia, falls, and decompressive craniectomy. Keywords: Contusion, intracerebral hematoma, progressive hemorrhagic injury, traumatic brain injury, traumatic intracerebral hemorrhage.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 35
4 INTRODUCTION Traumatic intracerebral hemorrhage (TICH) occurs in approximately 13 to 35% of patients following a traumatic brain injury (TBI).1,2 The increase in the volume of a TICH is a widely studied phenomenon that has a direct impact on the prognosis of patients. Several authors have reported that an increase in the size of a TICH occurs in approximately 38 to 59% of cases and mainly occurs in the first few hours after head trauma.3,4,5 While most of the TICHs that increase in volume do not require surgical intervention,6,7,8 some cases exist in which the progression of lesions can cause neurological deterioration of the patient or signs of refractory increased intracranial pressure (ICP) or a mass effect on a computed tomography (CT) scan, all of which require surgical evacuation.9 In some studies of TBI, TICHs were the reason for surgery in up to 20% of patients.10,11 This result emphasizes the importance of being able to identify the group of patients who will experience a significant increase in the volume of the traumatic intraparenchymal lesion. Overall, several factors have been recognized as having an association with TICH growth and subsequent neurological deterioration, such as trauma severity, advanced age, multiple lesions, radiological signs (e.g., midline deviation or cisternal compression), and coagulopathy. Some studies3,12,13,14 have attempted to determine the association of various factors with TICH growth. However, the main limitation of these studies was a small sample size; therefore, the conclusions cannot be generalized. The primary objective of this study was to identify a set of factors associated with TICH progression in a large cohort of patients who have suffered severe or moderate TBI.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 5 of 35
5 METHODS Inclusion and exclusion criteria We retrospectively analyzed the records of 1970 adult patients older than 15 years of age who were admitted consecutively after suffering a closed (non-missile) severe TBI, which was defined as a score of ≤8 points on the Glasgow Coma Scale (GCS) after non-surgical resuscitation within the first 48 hours after trauma, between January 1987 and November 2013 at University Hospital 12 de Octubre. Beginning in 2007, patients with moderate TBIs (GCS 9-13) were also included. Patients were included in the study if an assessable initial CT scan was performed on admission and a control CT scan could be evaluated to determine TICH progression or the appearance of new lesions. Therefore, from a total of 1970 patients diagnosed with moderate or severe TBI, 950 patients exhibited one or more TICH on the initial or control CT scan. Of these patients, 168 were excluded due to lack of a control CT scan as a result of death or an immediate neurosurgical procedure, including evacuation of the TICH. The causes of death in this group of patients included the direct effect of TBI in 113 patients and systemic causes and medical complications in 13 patients. Therefore, 782 patients met the selection criteria, and we performed the subsequent analysis using data from this group (Figure 1). Variables assessed We collected radiological, demographic, clinical, and treatment information, which is summarized in Table 1. Data were collected at the bedside in a standardized manner based
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 6 of 35
6 on previous research15,16,17,18 and were also used in the creation of the TBI database of 12 de Octubre Hospital.19 Radiological variables The radiological features analyzed are summarized in Table 1. The initial CT scan was defined as the scan performed immediately after a patient was admitted to the hospital. The control CT was defined as the scan with the worst radiological features. The control CT scan was performed after clinical deterioration or raised ICP and without a scheduled protocol. The time between the head trauma, initial CT, and control CT was recorded. CT scans were classified according to the Marshall classification20 and individual radiological features, including the following: a) traumatic subarachnoid hemorrhage (tSAH), which was defined as the presence of blood in the subarachnoid space either over the convexity or fissures or in the basal cisterns; b) intraventricular blood (IVH), which was categorized as present or absent; c) basal cisterns, which were categorized as normal or abnormal (compressed or absent); d) the presence and type of mass lesions, including epidural hematoma (EDH), acute subdural hematoma (ASH), or traumatic intracerebral hemorrhage (TICH) (TICHs were categorized based on volume into the following groups: 1 - 5 cc, 6 - 10 cc, 11 - 15 cc, 16 - 20 cc, 21 - 25 cc, 26 - 30 cc, 31 - 35 cc, and ≥ 36 cc); and e) midline shifts (MLS) (shifts ≤ 5 mm versus shifts >5 mm). We defined TICHs as traumatic intraparenchymal hemorrhagic lesions with a solid and well defined appearance (hematoma) and fewer well-defined areas of mixed attenuation. Petechial lesions with a classic pattern of diffuse axonal injury (DAI) were excluded.21
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 7 of 35
7 The initial and control volumes of TICH were measured in cubic centimeters. We recorded whether the initial volume was less than or equal to 5 cc, which was used as a dichotomous variable. All CT scans were assessed by two senior neurosurgeons (PAG, AL). TICH volume was estimated by the following formula as suggested by the Surgical Guidelines of the Brain Trauma Foundation: A x B x C / 2 (cm3),22,9 where A, B, and C represent the largest dimensions of the hematoma measured at perpendicular angles to one another. TICHs were classified according to their location and number as single, focal, multiple unilateral, or multiple bilateral hematomas. Treatment variables Patients were classified as operated and non-operated. Surgical procedures were classified as follows: 1) craniotomy: evacuation of the lesion or lobectomy and debridement with bone flap replacement; 2) decompressive craniectomy: removal of the bone flap without evacuation of the TICH; and c) others: elevation of bone fragments, cerebrospinal fluid drainage, and burr hole drilling. Primary endpoint The main outcome variable was the presence or absence of TICH progression. We defined progression as an increase equal or greater than 33% of the initial volume of the TICH or the appearance of a new lesion in a control CT scan. In addition to the main variable, we estimated the change in volume in cubic centimeters from the initial to the control CT scan.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 8 of 35
8 Outcome variable: According Glasgow Outcome Scale (GOS) we classified patients in favorable (GOS score 4 - 5) and unfavorable (GOS score 1 - 3) and we used it as dichotomous variable. All patients had a minimum follow-up of 6 months. Statistical analysis To identify factors associated with TICH growth, a univariate analysis was performed. Univariate comparisons were performed using Student’s t-test for continuous variables and Fisher's exact test for dichotomous variables. Logistic regression analysis was used to estimate the association between the risk factors (i.e., clinical findings, laboratory findings, and neuroimaging characteristics) and the main outcome variable (progression of TICH). The initial examination included a set of 22 potential predictors (Table 2) that were collected at the time of admission; these predictors are consistently referenced in the literature.
3,12,13,14,18,23,24
The relationship between a
predictor and progression was estimated using a crude odds ratio (OR) and R2. P values equal to or less than 0.05 were considered statistically significant. In addition, with the results of the multivariate analysis, we were able to develop a predictive model based on the variables of greatest statistical significance. We used the Nagelkerke R2 value to determine the predictive ability of the model.25 The HosmerLemeshow goodness of fit test was used for the model calibration.26 To evaluate the discrimination of the model, we used the area under the receiver operating characteristic (ROC) curve.27
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 9 of 35
9 We used the model produced by logistic regression to develop a nomogram that creates a simple graphical representation of our statistical predictive model and generates a numerical probability of progression. All statistical analyses were performed with SPSS 22.0 software (IBM, Chicago, IL). The nomogram was created using Orange 2.7 software (University of Ljubljana, Slovenia).
RESULTS Patient characteristics Epidemiological and clinical characteristics are shown in Table 1. A total of 621 (79%) of the patients were male, and 161 (21%) were female. The mean age was 41 years, ranging from 15 to 84 years. The mean time between trauma and admission was 2.8 hours; the mean time was 2.6 hours in the group that demonstrated progression and 3.2 hours in the group that did not exhibit progression. These values were not significantly different between groups. The main mechanism of trauma was traffic accidents (498 (64%) patients), followed by falls (233 (30%) patients) and impact and other mechanisms (51 (6%) patients). The motor scores at admission showed the following distribution: M1: 51 (8%) patients, M2: 68 (11%), M3: 84 (14%), M4: 123 (20%), M5: 192 (32%), and M6: 86 (14%). In 178 (23%) patients, the motor score was not reliable mainly due to the effects of sedation.
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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10 The mean time between the trauma and the first CT scan was 2.9 hours, and the mean time between the trauma and the control CT scan was 30.1 hours. Table 2 shows the radiological features of the initial CT scans. According to the Marshall classification, 345 (44%) patients corresponded to type II, 143 (18%) patients corresponded to type III, 22 (3%) patients corresponded to type IV, and 272 (34%) patients corresponded to type V-VI. We observed the presence of tSAH in 611 (78%) patients, IVH in 232 (30%) patients, and skull fracture in 507 (65%) patients. An MLS greater than 5 mm was present in 172 (22%) patients. Compressed or absent cisterns were visualized in 397 (51%) patients. TICHs were the only type of mass lesion in 258 (33%) patients. We also observed the presence of ED in 153 (20%) and ASH in 389 (50%) patients. With respect to the number and location of TICHs, 368 (57%) patients presented a focal TICH, 68 (10%) showed multiple unilateral TICHs, and 213 (33%) showed multiple bilateral TICHs. The mean volume of the TICH on the initial CT scan was 7.29 cc; on the control CT scan, it was 18.18 cc. By classifying the initial TICH volume into groups, we observed that 412 (52.7%) patients presented a volume of less than 5 cc; 229 (29.3%) patients presented a volume of 6 – 10 cc; 74 (9.5) patients presented a volume of 11 – 15 cc; 33 (4.2%) patients presented a volume of 16 – 20 cc; 13 (1.7%) patients presented a volume of 26 – 30 cc; 5
Journal of Neurotrauma Traumatic intracerebral hemorrhage: Risk factors associated with progression (doi: 10.1089/neu.2014.3808) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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11 (0.6%) patients presented a volume of 31 – 35 cc; and 9 (1.2%) patients presented a volume of more than 35 cc. TICH progression was observed in 497/782 (64%) patients. The mean increase in volume was 10.9 cc. In 228 (46%) cases, there was an increase of less than 10 cc; an increase of 11 to 20 cc occurred in 130 (26%) cases; an increase of 21 to 30 cc occurred in 66 (13%) cases; and 73 (15%) patients presented an increase of greater than 30 cc. In 285/782 (36%) patients, the TICH volume remained stable or decreased on the control CT scan (Figure 2). The outcome at six months of follow up was favorable in 285 (36%) patients and unfavorable in 474 (64%) patients. Although the purpose of this study was not to determine the outcome of patients with TICH, we found a significant correlation between progression and an unfavorable outcome (OR 3.6, p
