Progression of traumatic intracerebral hemorrhage: a prospective observational study.Narayan RK1, Maas AI, Servadei F, Skolnick BE, Tillinger MN, Marshall LF; Traumatic Intracerebral Hemorrhage Study Group.Collaborators (36)Author information AbstractABSTRACT Preliminary evidence has shown that intracerebral hemorrhages, either spontaneous (sICH) or traumatic (tICH) often expand over time. An association between hemorrhage expansion and clinical outcomes has been described for sICH. The intent of this prospective, observational study was to characterize the temporal profile of hemorrhage progression, as measured by serial computed tomography (CT) scanning, with the aim of better understanding the natural course of hemorrhage progression in tICH. There was also a desire to document the baseline adverse event (AE) profile in this patient group. An important motive for performing this study was to set the stage for subsequent studies that will examine the role of a new systemic hemostatic agent in tICH. Subjects were enrolled if they had tICH lesions of at least 2 mL on a baseline CT scan obtained within 6 h of a head injury. CT scans were repeated at 24 and 72 h. Clinical outcomes and pre-defined AEs were documented. The data showed that 51% of the subjects demonstrated an increase in tICH volume, and that most of the increase occurred early. In addition, larger hematomas exhibited the greatest expansion. Thromboembolic complications were identified in 13% of subjects. This study demonstrates that tICH expansion between the baseline and 24-h CT scans occurred in approximately half of the subjects. The earlier after injury that the initial CT scan is obtained, the greater is the likelihood that the hematoma will expand on subsequent scans. The time frame during which hemorrhagic expansion occurs provides an opportunity for early intervention to limit a process with adverse prognostic implications.2008 Jun;25(6):629-39. doi: 10.1089/neu.2007.0385.

Traumatic Intraparenchymal HemorrhageWhat Is It?

Traumatic Intraparenchymal hemorrhage is bleeding into the tissue of the brain caused by trauma to the head. This type of bleeding can cause a hematoma which expands inside the brain, pushing aside adjacent brain tissue and compressing it. The term intraparenchymal basically means "within the brain tissue". It distinguishes the hemorrhage from bleeding that can occur outside of the brain such as subarachnoid hemorrhage, subdural hematoma and epidural hematoma.Some people use the term intraparenchymal hemorrhage to describe other types of injury and/or bleeding into the brain tissue itself as well, such as a cerebral contusion.Intraparenchymal bleeding, or intracerebral hemorrhage, can also occur spontaneously, without trauma, in the setting of poorly-controlled, high blood pressure. This type of bleeding be discussed elsewhere.

What Types of Symptoms Are Typical?The presentation of a brain injury patient varies dramatically depending on patient and injury factors. An intraparenchymal hemorrhage rarely occurs alone, most of these patients have other brain injury as well. Therefore, their symptoms cannot always be attributed to any one pathology and rather are the sum of all their injuries. Theoretically, the hematoma in the brain can cause injury and dysfunction of that part of the brain, causing some specific neurological symptom. These symptoms would vary considerably depending on where in the brain the hemorrhage occurred. If big enough, these hematomas can contribute to increased pressure inside the head which can occur after trauma. With all these variables, it is hard and inappropriate to generalize.

How Is The Diagnosis Typically Made?As with other traumatic injuries, this type of bleeding can typically be seen on a CT scan. Most patients with head injury, after initial stabilization and assessment, will undergo this type of study. Bleeding within the brain can clearly be seen on CT and evaluated for location, size, compression of adjacent brain, concurrent injuries and other factors.

What Are Some Common Treatments?The treatment of head trauma can be very complex depending on the specific patient and their injury characteristics. Whether an intraparenchymal hemorrhage requires specific treatment depends on the clinical condition of the patient as well as the location and size of the hematoma. While smaller hemorrhage often require no specific treatment other than the standard treatment of any trauma victim, very large hematomas may require surgical removal. This is highly variable and the treatment plan of any one patient should be discussed with that patient's personal physicians.2006 Apr;58(4):647-56; discussion 647-56.Acute traumatic intraparenchymal hemorrhage: risk factors for progression in the early post-injury period.Chang EF1, Meeker M, Holland MC.Author information AbstractOBJECTIVE: To characterize the natural course of traumatic intraparenchymal contusions and hematomas (IPHs) and to identify risk factors for IPH progression in the acute post-injury period.METHODS: A retrospective analysis was performed on a prospective observational database containing 113 head trauma patients exhibiting 229 initially nonoperated acute IPHs. The main outcome variable was radiographic evidence of IPH progression on serially obtained head computed tomographic (CT) scans. Secondary outcomes included the actual amount of IPH growth and later surgical evacuation. Univariate and multivariate analyses (using a generalized estimate equation) were applied to both demographic and initial radiographic features to identify risk factors for IPH progression and surgery.RESULTS: Overall, 10 IPHs (4%) shrank, 133 (58%) remained unchanged, and 86 (38%) grew between the first and second head CT scan. IPH progression was independently associated with the presence of subarachnoid hemorrhage (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.12-2.3), presence of a subdural hematoma (OR, 1.94; 95% CI, 1.1-3.43), and initial size (OR, 1.11; 95% CI, 1.02-1.21, for each cm volume). Size of initial IPH proportionately correlated with the amount of subsequent growth (linear regression, P < 0.001). Worsened Glasgow Coma Score between initial and follow-up head CT scan (OR, 8.6; 95% CI, 1.5-50), IPH growth greater than 5 cm (OR, 7.3; 95% CI, 1.6-34), and effacement of basal cisterns on initial CT scan (OR, 9.0; 95% CI, 1.5-52) were strongly associated with late surgical evacuation.CONCLUSION: A large proportion of IPHs progress in the acute post-injury period. IPHs associated with subarachnoid hemorrhage, a subdural hematoma, or large initial size should be monitored carefully for progression with repeat head CT imaging. Effacement of cisterns on the initial head CT scan was strongly predictive of failure of nonoperative management, thereby leading to surgical evacuation. These findings should be important factors in the understanding and management of IPH.Republished in Neurosurgery. 2007 Jul;61(1 Suppl):222-30; discussion 230-1. Neuroanatomy and Traumatic Brain Injury

The human brain is the most complex, mystifying, and elegant object in the known universe. Our brains are responsible for virtually every aspect of our functioning from controlling hair growth to the origins of the universe. The human brain is truly a remarkable organ. It is estimated that the human brain contains over 100 billion neurons and several times that number in supportive cells. Each neuron, in addition, assesses between 30,000 and 50,000 branches which connect to both itself and other neurons. Thus, in one cubic millimeter of particle tissues there are literally billions of synapses or connection points between neurons. Furthermore, to support this complex system of neuronal connections the vascular system must function at a highly complex level in order to supply oxygenated blood to each of the neuronal cells. Thus, the vascular system in the human brain and the neurons it serves form a complex and interrelated matrix of extremely delicate vessels. The sensitivity and complexity of such a system leaves one to easily comprehend the results of high velocity impact injury to such a delicate system. Any stretching, compression, twisting, or other physical forces to the brain have the potential to negatively impact these delicate, physical structures. And this does not even address the changes which take place at a metabolic or chemical level. As noted by Bigler (2001) in describing the complexity of the human brain and the effects of trauma on that structure, complex systems achieve complex functions only with efficient, well integrated, and fast recruitment of constituent parts, followed by a rapid response. Anything that disrupts this complex system, even subtly, will render the system less efficient and prone to errors in processing and responding.

To further expand on this concept let us look at the individual neuro cell. Each cell in the brain has a specified length, width, and breadth and is held in position by other cells. As such, consistent with the physical constraints inherent in any component, the cell has limited elasticity. In other words, as with almost anything, neuro cells are limited in the amount they can be stretched, twisted, rotated, or compressed before there is an associated negative result. And the human brain is subjected to such physical motion damage may be identified using neuroimaging techniques such as computerized tomography (ct), magnetic resonance (mr), single photon emission computed tomography (spect), and magneto encephalography (mag). It is important to remember, however, that the entire brain is affected by such physical forces. Thus, when a legion is identified by any of the above methods it is erroneous to conclude that the brain has been subjected to damage in only that area identified by the imaging study. Thus, damage to the brain is always beyond just the visually identified legion. In essence, brain injuries resulting from traumatic forces are often diffuse in nature rather than specific to localized areas. Differences in brain injury, thus, should be viewed on a continuum ranging from minimal damage to a few selected neurons to progressively greater damage involving more neuronal injury.

Diffuse axonal injury has been described as a term involving injury to the cerebrial white matter of the brain. Neurons are comprised of a cell body, an axon or long trunk, and dendrites or connective branches. DAI identifies injury to the axonal section of the neurons. Three levels of DAI have been identified. Grade 1 represents wide spread non-specific axonal damage without focal abnormalities. Grade 2 incorporates the injuries in grade 1 but also includes focal abnormalities. Grade 3 again assumes levels 1 and 2 and includes brain stem injury. Very mild DAI has been objectively identified on autopsy as a result of a trauma involving as little as 60 seconds recorded loss of consciousness. Onset of DAI occurs anywhere from 6 to 72 hours following injury. And delayed cell death can occur for as long as up to one month post injury. Researchers have suggested that neuronal death can continue to occur for up to 3 years post injury!

The brain has been found to be most vulnerable if it is moved laterally. That is, trauma that occurs from a side impact has been found to result in the greatest degree of wide spread axonal damage.

Three stages of axonal injury have been suggested. In stage 1 a rapidly stretched axon which does not tear can undergo biochemical changes that may be transient. Studies have found that a minimum of a 5% increase in axon length from its resting length is sufficient to produce a transient disruption of the membrane of the neuron. This results in the neuron being unable to fire. Neuronal function may fully return within minutes after such an injury. Stage 2 axonal injury results from a 5 to 10% increase in axonal length resulting in swelling and enlargement of the injured axon resulting in disruption of neuronal functioning. Stage 3 occurs with a 15% or greater stretching and results in a high likelihood of permanent damage. With such a level of injury the neuron is believed to be unable to self-repair. Stage 4 injury in which stretching is in excess of 20% of the resting length produces immediate and irreversible damage.

In addition to neuronal injury as a result of physical forces impacting the human brain, the vascular system can also be compromised given the delicate lattice work of blood vessels supplying the billions of neurons in the brain any injury to the vascular system resulting in damage to that system can have a profound impact on the ability of that system to deliver nutrients to neurons. Swelling and compromised blood flow drop resulting in a reduction of glucose and oxygen delivery below the need the energy demands of the neuronal cells. With such a drop in glucose and oxygen there is a corresponding metabolic response in the neuron. This finding has been demonstrated most readily with SPECT and MAG imaging. The result of reduced glucose and oxygen delivery to neurons results in neuronal death and can be demonstrated by reduced brain volume. Experimental studies of even mild TBI have demonstrated hemorrhagic contusions at the gray-white matter interface.

*** studies have found that mild cases of TBI which include simple concussions, typically do not demonstrate depictable abnormalities using traditional MR imaging techniques. This does not mean, however, that there is an absence of injury to the brain. In fact, a recent series of articles published in the Journal of the American Medical Association demonstrated that concussion can produce mild but persistent neurocognitive deficits despite the absence of complete cell death resulting from such injuries. It is considered that a concussion can result in a disruption in the efficiency of the neurofunctioning of the brain. This finding clashes with other researchers who have consistently found in their studies that persistent post-concussion symptomatology is more likely due to psychological rather than neurologic injury. It has been suggested by other researchers, however, that as greater sophistication develops in the area of neuroimaging that argument will be found to be untenable.

In conclusion, the complexity of the human brain cannot be understated and the extent to which that delicate structure can be negatively impacted as a result of trauma should not be minimized. Most confident assessing such injury should involve sophisticated neuroimaging techniques and neuropsychological and comprehensive and sophisticated neuropsychological testing conducted by a well-trained and experienced Neuropsychologist.

Immediate and Delayed Traumatic Intracranial Hemorrhage in Patients with Head Trauma and Pre-Injury Warfarin or Clopidogrel UseDaniel K. Nishijima, MD, MAS,1 Steven R. Offerman, MD,2 Dustin W. Ballard, MD,3 David R. Vinson, MD,4 Uli K. Chettipally, MD, MPH,5 Adina S. Rauchwerger, MPH,6 Mary E. Reed, DrPH,6 and James F. Holmes, MD, MPH1, for the Clinical Research in Emergency Services and Treatment (CREST) NetworkAuthor information Copyright and License information The publisher's final edited version of this article is available at Ann Emerg MedSee other articles in PMC that cite the published article.Go to:AbstractStudy ObjectivePatients on warfarin or clopidogrel are considered at increased risk for traumatic intracranial hemorrhage (tICH) following blunt head trauma. The prevalence of immediate tICH and the cumulative incidence of delayed tICH in these patients, however, are unknown.MethodsA prospective, observational study at two trauma centers and four community hospitals enrolled emergency department (ED) patients with blunt head trauma and pre-injury warfarin or clopidogrel use from April 2009 through January 2011. Patients were followed for two weeks. The prevalence of immediate tICH and the cumulative incidence of delayed tICH were calculated from patients who received an initial cranial computed tomography (CT) in the ED. Delayed tICH was defined as tICH within two weeks following an initially normal CT scan and in the absence of repeat head trauma.ResultsA total of 1,064 patients were enrolled (768 warfarin patients [72.2%] and 296 clopidogrel patients [27.8%]). There were 364 patients [34.2%] from Level 1 or 2 trauma centers and 700 patients [65.8%] from community hospitals. One thousand patients received a cranial CT scan in the ED. Both warfarin and clopidogrel groups had similar demographic and clinical characteristics although concomitant aspirin use was more prevalent among patients on clopidogrel. The prevalence of immediate tICH was higher in patients on clopidogrel (33/276, 12.0%; 95% confidence interval [CI] 8.4-16.4%) than patients on warfarin (37/724, 5.1%; 95%CI 3.6-7.0%), relative risk 2.31 (95%CI 1.48-3.63). Delayed tICH was identified in 4/687 (0.6%; 95%CI 0.2-1.5%) patients on warfarin and 0/243 (0%; 95%CI 0-1.5%) patients on clopidogrel.ConclusionWhile there may be unmeasured confounders that limit intergroup comparison, patients on clopidogrel have a significantly higher prevalence of immediate tICH compared to patients on warfarin. Delayed tICH is rare and occurred only in patients on warfarin. Discharging patients on anticoagulant or antiplatelet medications from the ED after a normal cranial CT scan is reasonable but appropriate instructions are required as delayed tICH may occur.Go to:INTRODUCTIONBackgroundThe use of anticoagulant and antiplatelet medications, specifically warfarin and clopidogrel, is steadily increasing in the population.1-3 Prior studies suggest patients on either of these medications are at increased risk for traumatic intracranial hemorrhage (tICH) following blunt head trauma, but the risk in a large, generalizable cohort is unknown.4-6ImportanceThe majority of patients with tICH are identified on initial cranial computed tomographic (CT) scan. Limited data, however, suggest patients on warfarin are at increased risk for delayed tICH (tICH diagnosed within two weeks of injury following an initially normal cranial CT).7-9 This concern is highlighted by the not uncommon practice of reversing patients on warfarin following head trauma despite a normal cranial CT.10 The potential risk for both immediate and delayed tICH has generated guidelines recommending routine cranial CT imaging and hospital admission for neurological observation in head-injured patients taking warfarin.11-14 These recommendations, however, are not informed by rigorous, prospective, multicenter studies identifying the prevalence and incidence of immediate tICH and delayed tICH in patients on warfarin.The evidence supporting an increased risk of tICH in patients on clopidogrel is more limited,11 despite this drug being one of the most commonly prescribed worldwide.15 Although small retrospective studies suggest an increased risk of tICH and mortality in head trauma patients on clopidogrel,6,16,17 current guidelines do not explicitly recommend routine CT imaging for these patients after blunt head trauma.11-13 In addition, the risk of delayed tICH in patients on clopidogrel is entirely unknown.Goals of This InvestigationKnowledge of the true prevalence and incidence of immediate and delayed tICH in patients on warfarin or clopidogrel would allow clinicians to make evidence-based decisions regarding their initial patient evaluation and disposition. Therefore, we assessed the prevalence and incidence of immediate and delayed tICH in patients with blunt head trauma taking either warfarin or clopidogrel. Warfarin and clopidogrel cohorts were compared. We hypothesized that the prevalence for immediate tICH is similar between patients on clopidogrel and those on warfarin and that the cumulative incidence of delayed tICH in both groups is < 1%.Go to:METHODSStudy DesignThis is a prospective, observational, multicenter study conducted at two trauma centers and four community hospitals in Northern California. The study was approved by the Institutional Review Boards at all sites.Setting and Selection of ParticipantsAdult ( 18 years old) emergency department (ED) patients with blunt head trauma and pre-injury warfarin or clopidogrel use (within the previous seven days) were enrolled. We defined blunt head trauma as any blunt head injury regardless of loss of consciousness (LOC) or amnesia. We excluded patients with known injuries transferred from outside facilities, as their inclusion would falsely inflate the prevalence of tICH. Additionally, patients with concomitant warfarin and clopidogrel use were excluded.Data CollectionThe treating ED faculty physicians recorded patient history and medication use, injury mechanism, and clinical exam, including initial Glasgow Coma Scale score (GCS) and evidence of trauma above the clavicles (defined as trauma to the face, neck, or scalp) on a standardized data form prior to cranial CT (if obtained). Imaging studies were obtained at the discretion of the treating physician and not dictated by study protocol. At each site, approximately 10% of patients (non-randomly selected) had a separate, independent faculty physician assessment that was masked to and completed within 60 minutes of the initial assessment to evaluate the reliability of pre-selected clinical variables. Data on patients eligible but not enrolled (failures of the study screening process) during ED evaluation were abstracted from their medical records to assess for enrollment bias.Outcome MeasuresImmediate tICH was defined as the presence of any intracranial hemorrhage or contusion as interpreted by the faculty radiologist on the initial cranial CT scan. Patients without a cranial CT during initial ED evaluation were excluded from the immediate tICH calculation. Delayed tICH was defined as tICH on cranial CT scan, occurring within 14 days after an initial normal CT scan and in the absence of repeat head trauma. Neurosurgical intervention was defined as the use of intracranial pressure monitor or brain tissue oxygen probe, placement of burr hole, craniotomy/craniectomy, intraventricular catheter, or subdural drain, or the use of mannitol or hypertonic saline.Follow UpPatients were admitted to the hospital at the discretion of the ED physician. Patients with normal cranial CT scans and therapeutic international normalized ratio (INR) levels are not reversed at the participating centers. Electronic medical records (EMR) were reviewed in a standardized fashion by research coordinators and site investigators to assess INR results, CT scan results, ED disposition, and hospital course. Patients admitted to the hospital for at least 14 days were evaluated for the presence of delayed tICH through review of the EMR. Patients discharged from the ED or admitted to the hospital for less than 14 days received a consented, standardized telephone survey at least 14 days after the index ED visit. The 14-day follow up was deemed sufficient to identify clinically important delayed tICH.8,18,19 Repeat cranial imaging was obtained at the discretion of the patients treating physicians. If patients were unable to be contacted by telephone survey or the EMR, the Social Security Death Index was reviewed to evaluate for death.20Statistical AnalysisData were compared using STATA for Windows, Rel. 10.0 2007 (STATA Corp College Station, TX, USA). Normally distributed continuous data were reported as the mean standard deviations (SDs), and ordinal or non-normally distributed continuous data described as the median with interquartile (25-75%) ranges (IQR). For primary, stratified, and sensitivity analyses, proportions and relative risks were presented with 95% confidence intervals (CI). Categorical data were compared with chi-square test or Fishers exact test in cases of small cell size. Inter-rater reliability of independent variables recorded by initial and second physicians was reported as percent agreement.To ensure that differences in outcome between cohorts were not secondary to differences in injury severity, we performed both stratified and sensitivity analyses. We compared the following strata: patients 65 years old or older, patients with minor head injury (GCS scores 13-15), patients with an initial GCS score of 15, patients with a ground level fall, patients with physical evidence of trauma above the clavicles, patients without concomitant aspirin use, and patients evaluated at a community hospital. In addition we stratified the analyses by degree of anticoagulation (INR 1.3 and INR 2.0). Sensitivity analyses were conducted assuming those patients without an initial cranial CT (1) had immediate tICH and (2) did not have tICH. Finally, we compared the cumulative incidence of delayed tICH assuming all patients lost to follow up had a delayed tICH.Role of the Funding SourceThe sponsors of the study had no role in study design, data collection and analysis, or manuscript preparation. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication.Go to:RESULTSCharacteristics of Study SubjectsBetween April 2009 and January 2011, 1101 patients were enrolled (83.3% of all eligible patients) (Figure). Comparison of patients enrolled and those eligible but not enrolled demonstrated similar characteristics (age, gender, medication use, ED cranial CT, and hospital admission) and outcomes (immediate tICH, neurosurgical intervention, and in-hospital mortality). Reasons for failures of the study screening process were unknown. Thirty-seven patients were excluded (25 transferred patients and 12 patients with concomitant clopidogrel and warfarin use), leaving 1064 patients for data analysis. Of the 1064 patients, 768 patients (72.2%) were taking warfarin and 296 patients (27.8%) were taking clopidogrel. There were 364 patients (34.2%) from two American College of Surgeons designated Level 1 or 2 trauma centers and 700 patients (65.8%) from four community hospitals. The most common mechanism of injury was a ground level fall (n=887, 83.3%) followed by direct blow (n=59, 5.6%) and motor vehicle collision (n=51, 4.8%).

Figure 1Flow of Patients in StudyThe majority (n=932, 87.6%) of patients had a GCS of 15 and 752 (70.7%) patients had physical examination findings of head trauma above the clavicles. The primary indication for warfarin and clopidogrel use was atrial fibrillation (543/768, 70.7%) and coronary artery disease (158/296, 53.4%), respectively. Most patients reported taking their medication less than 24 hours prior to injury (warfarin group 660/768, 85.9%; clopidogrel group 252/296, 85.1%). In patients on warfarin, 603/768 (78.5%) had an INR measurement on initial evaluation in the ED (median INR 2.5; IQR 2.0-3.3). The majority of these patients (576/603, 95.5%) had an elevated INR ( 1.3) and 458/603 (76.0%) had an INR ( 2.0).One thousand of the 1064 (94.0%; 95% CI 92.4-95.3%) received a cranial CT during initial ED evaluation. Hospitalization rates were similar for those on warfarin (271/768, 35.3%) and on clopidogrel (93/296, 31.4%). Patient clinical characteristics were similar in both groups, except for headache, concomitant aspirin use, and evidence of trauma to the neck and scalp laceration, which were more common in the clopidogrel group (Table 1).

Table 1Demographic and Clinical Characteristics of the Study PopulationMain ResultsImmediate tICH Seventy of the 1000 patients had immediate tICH on ED CT scan. The prevalence of immediate tICH was higher in patients on clopidogrel (33/276, 12.0%; 95% CI 8.4-16.4%) than on warfarin (37/724, 5.1%; 95% CI 3.6-7.0%), relative risk = 2.31 (95% CI 1.48-3.63), p