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Cerebral blood flow and vasoresponsivity within and around cerebral contusions

Mark R. McLaughlin and Donald W. Marion

✓ There is increasing evidence that regional ischemia plays a major role in secondary brain injury. Although the cortex underlying subdural hematomas seems particularly vulnerable to ischemia, little is known about the adequacy of cerebral blood flow (CBF) or the vasoresponsivity within the vascular bed of contusions. The authors used the xenon-enhanced computerized tomography (CT) CBF technique to define the CBF and vasoresponsivity of contusions, pericontusional parenchyma, and the remainder of the brain 24 to 48 hours after severe closed head injury in 10 patients: six patients with one contusion and four with two contusions, defined as mixed or high-density lesions on CT scanning. The CBF within the contusions (29.3 ± 16.4 ml/100 g/minute, mean ± standard deviation) was significantly lower than both that found in the adjacent 1-cm perimeter of normal-appearing tissue (42.5 ± 15.8 ml/100 g/minute) and the mean global CBF (52.5 ± 17.5 ml/100 g/minute) (p < 0.004, repeated-measures analysis of variance). A subset of seven patients (10 contusions) also underwent a second Xe-CT CBF study during mild hyperventilation (a PaCO of 24–32 mm Hg). In only two of these 10 contusions was vasoresponsivity less than 1% (range 0%–7.6%); in the rim of normal-appearing pericontusional tissue, it was 0.4% to 9.1%. The authors conclude that CBF within intracerebral contusions is highly variable and is often above 18 ml/100 g/minute, the reported threshold for irreversible ischemia. Intracontusional CBF is significantly reduced relative to surrounding brain parenchyma, and CO2 vasoresponsivity is usually present. In the contusion and the surrounding parenchyma, vasoresponsivity may be nearly three times normal, suggesting hypersensitivity to hyperventilation therapy. Given this possible hypersensitivity and relative hypoperfusion within and around cerebral contusions, these lesions are particularly vulnerable to secondary injury such as that which may be caused by hypotension or aggressive hyperventilation.

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Head Injury and Therapeutic Hypothermia

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Acute regional cerebral blood flow changes caused by severe head injuries

Donald W. Marion, Joseph Darby, and Howard Yonas

✓ To evaluate the changes in cerebral blood flow (CBF) that occur immediately after head injury and the effects of different posttraumatic lesions on CBF, 61 CBF studies were obtained using the xenon-computerized tomography method in 32 severely head-injured adults (Glasgow Coma Scale score (GCS) ≤ 7). The measurements were made within 7 days after injury, 43% in the first 24 hours. During the 1st day, patients with an initial GCS score of 3 or 4 and no surgical mass had significantly lower flows than did those with a higher GCS score or mass lesions (p < 0.05): in the first 1 to 4 hours, those without surgical mass lesions had a mean CBF of 27 cc/100 gm/min, which rose to 44 cc/100 gm/min by 24 hours. Patients without surgical mass lesions who died tended to have a lower global CBF than did those with better outcomes. Mass lesions were associated with a high global CBF and bihemispheric contusions with the lowest flows. By 24 hours after injury, global blood flow increased in groups that originally had low flows and decreased in those with very high initial flows, such that by 36 to 48 hours, most patients had CBF values between 32 and 55 cc/100 gm/min. Lobar, basal ganglion, and brain-stem blood flow values frequently differed by 25% or more from global averages. Brain-stem CBF varied the most but did not correlate with clinical signs of brain-stem dysfunction. Double studies were performed at two different pCO2 values in 10 patients with various posttraumatic lesions, and the CO2 vasoresponsivity was calculated. Abnormal CO2 vasoresponsivity was found with acute subdural hematomas and defuse cerebral swelling but not with epidural hematomas. In patients without surgical mass lesions, the findings suggest that CBF in the first few hours after injury is often low, followed by a hyperemic phase that peaks at 24 hours. Global CBF values vary widely depending on the type of traumatic brain injury, and brain-stem flow is often not accurately reflected by global CBF values. These findings underscore the need to define regional CBF abnormalities in victims of severe head injury if treatment is intended to prevent regional ischemia.

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Cerebral Blood Flow and Vasoresponsivity

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Hyperventilation and Head Injury

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Continuum of the United States military’s traumatic brain injury care: adjusting to the changing battlefield

Rachel Lazarus, Katherine Helmick, Saafan Malik, Emma Gregory, Yll Agimi, and Donald Marion

Over the past 8 years, advances in the US Military Health System (MHS) have led to extensive changes in the way combat casualty care is provided to deployed service members with a traumatic brain injury (TBI). Changes include the application of cutting-edge Clinical Practice Guidelines, use of pioneering technologies, and advances in evacuation procedures. Compared with previous engagements, current operations occur on a much smaller scale, and more frequently in austere environments, such that effective medical support is increasingly challenging. In this paper, the authors describe key aspects of the current continuum of TBI care in the US military, from the point of injury through rehabilitation, with an emphasis on how emerging technologies and evidence-based Clinical Practice Guidelines assist MHS clinicians with providing the best clinical care possible in the changing battlefield.

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The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report

Donald W. Marion, Walter D. Obrist, Patricia M. Earlier, Louis E. Penrod, and Joseph M. Darby

✓ Animal research suggests that moderate therapeutic hypothermia may improve outcome after a severe head injury, but its efficacy has not been established in humans. The authors randomly assigned 40 consecutively treated patients with a severe closed head injury (Glasgow Coma Scale score 3 to 7) to either a hypothermia or a normothermia group. Using cooling blankets and cold saline gastric lavage, patients in the hypothermia group were cooled to 32° to 33°C (brain temperature) within a mean of 10 hours after injury, maintained at that temperature for 24 hours, and rewarmed to 37° to 38°C over 12 hours. Patients in the normothermia group were maintained at 37° to 38°C during this time. Deep-brain temperatures were monitored directly and used for all temperature determinations. Intracranial pressure (ICP), cerebral blood flow (CBF), and cerebral metabolic rate for oxygen (CMRO2) were measured serially for all patients.

Hypothermia significantly reduced ICP (40%) and CBF (26%) during the cooling period, and neither parameter showed a significant rebound increase after patients were rewarmed. Compared to the normothermia group, the mean CMRO2 in the hypothermia group was lower during cooling and higher 5 days after injury. Three months after injury, 12 of the 20 patients in the hypothermia group had moderate, mild, or no disabilities; eight of the 20 patients in the normothermia group had improved to the same degree. Both groups had a similar incidence of systemic complications, including cardiac arrhythmias, coagulopathies, and pulmonary complications. It is concluded that therapeutic moderate hypothermia is safe and has sustained favorable effects on acute derangements of cerebral physiology and metabolism caused by severe closed head injury. The trend toward better outcome with hypothermia may indicate that its beneficial physiological and metabolic effects limit secondary brain injury.

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Dose response to cerebrospinal fluid drainage on cerebral perfusion in traumatic brain–injured adults

Mary E. Kerr, Barbara B. Weber, Susan M. Sereika, Jack Wilberger, and Donald W. Marion


Intracranial hypertension remains a common complication of traumatic brain injury (TBI). Ventriculostomy drainage is a recommended therapy to decrease intracranial pressure (ICP), but little empirical evidence exists to guide treatment. The authors conducted a study to examine systematically the effect of cerebral spinal fluid (CSF) drainage on ICP and indices of cerebral perfusion.


Intracranial pressure, cerebral perfusion pressure (CPP), cerebral blood flow velocity (CBFV), and near-infrared spectroscopy–determined regional cerebral oxygenation (rSO2) were measured in 58 patients (with Glasgow Coma Scale scores ≤ 8) before, during, and after ventriculostomy drainage. Three randomly ordered CSF drainage protocols varied in the volume of CSF removed (1 ml, 2 ml, and 3 ml). Physiological variables were time averaged in 1-minute blocks from baseline to 10 minutes after cessation of ventricular drainage.

There was a significant dose–time interaction for ICP with the three-extraction volume protocol, with incremental decreases in ICP (F [20, 1055] = 6.10; p = 0.0001). There was a significant difference in the CPP depending on the amount of CSF removed (F [2, 1787] = 3.22; p = 0.040) and across time (F [10, 9.58] = 11.9; p = 0.0003) without a significant dose–time interaction. A 3-ml withdrawal of CSF resulted in a 10.1% decrease in ICP and a 2.2% increase in CPP, which were sustained for 10 minutes. There was no significant dose, time or dose–time interaction with CBFV or rSO2.


Cerebrospinal fluid drainage (3 ml) significantly reduced ICP and increased CPP for at least 10 minutes. Analysis of these findings supports the use of ventriculostomy drainage as a means of at least temporarily reducing elevated ICP in patients with TBI.

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Association of time to craniectomy with survival in patients with severe combat-related brain injury

Stacy A. Shackelford, Deborah J. del Junco, Michael C. Reade, Randy Bell, Tyson Becker, Jennifer Gurney, Randall McCafferty, and Donald W. Marion


In combat and austere environments, evacuation to a location with neurosurgery capability is challenging. A planning target in terms of time to neurosurgery is paramount to inform prepositioning of neurosurgical and transport resources to support a population at risk. This study sought to examine the association of wait time to craniectomy with mortality in patients with severe combat-related brain injury who received decompressive craniectomy.


Patients with combat-related brain injury sustained between 2005 and 2015 who underwent craniectomy at deployed surgical facilities were identified from the Department of Defense Trauma Registry and Joint Trauma System Role 2 Registry. Eligible patients survived transport to a hospital capable of diagnosing the need for craniectomy and performing surgery. Statistical analyses included unadjusted comparisons of postoperative mortality by elapsed time from injury to start of craniectomy, and Cox proportional hazards modeling adjusting for potential confounders. Time from injury to craniectomy was divided into quintiles, and explored in Cox models as a binary variable comparing early versus delayed craniectomy with cutoffs determined by the maximum value of each quintile (quintile 1 vs 2–5, quintiles 1–2 vs 3–5, etc.). Covariates included location of the facility at which the craniectomy was performed (limited-resource role 2 facility vs neurosurgically capable role 3 facility), use of head CT scan, US military status, age, head Abbreviated Injury Scale score, Injury Severity Score, and injury year. To reduce immortal time bias, time from injury to hospital arrival was included as a covariate, entry into the survival analysis cohort was defined as hospital arrival time, and early versus delayed craniectomy was modeled as a time-dependent covariate. Follow-up for survival ended at death, hospital discharge, or hospital day 16, whichever occurred first.


Of 486 patients identified as having undergone craniectomy, 213 (44%) had complete date/time values. Unadjusted postoperative mortality was 23% for quintile 1 (n = 43, time from injury to start of craniectomy 30–152 minutes); 7% for quintile 2 (n = 42, 154–210 minutes); 7% for quintile 3 (n = 43, 212–320 minutes); 19% for quintile 4 (n = 42, 325–639 minutes); and 14% for quintile 5 (n = 43, 665–3885 minutes). In Cox models adjusted for potential confounders and immortal time bias, postoperative mortality was significantly lower when time to craniectomy was within 5.33 hours of injury (quintiles 1–3) relative to longer delays (quintiles 4–5), with an adjusted hazard ratio of 0.28, 95% CI 0.10–0.76 (p = 0.012).


Postoperative mortality was significantly lower when craniectomy was initiated within 5.33 hours of injury. Further research to optimize craniectomy timing and mitigate delays is needed. Functional outcomes should also be evaluated.

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Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury

Amy K. Wagner, Dianxu Ren, Yvette P. Conley, Xiecheng Ma, Mary E. Kerr, Ross D. Zafonte, Ava M. Puccio, Donald W. Marion, and C. Edward Dixon


Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3′ variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI.


Sixty-three patients with severe TBI (Glasgow Coma Scale score ≤ 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury.

Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002).


In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.