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A review of progress in understanding the pathophysiology and treatment of brain edema

Anthony Marmarou


Brain edema resulting from traumatic brain injury (TBI) or ischemia if uncontrolled exhausts volume reserve and leads to raised intracranial pressure and brain herniation. The basic types of edema—vasogenic and cytotoxic—were classified 50 years ago, and their definitions remain intact.


In this paper the author provides a review of progress over the past several decades in understanding the pathophysiology of the edematous process and the success and failures of treatment. Recent progress focused on those manuscripts that were published within the past 5 years.


Perhaps the most exciting new findings that speak to both the control of production and resolution of edema in both trauma and ischemia are the recent studies that have focused on the newly described “water channels” or aquaporins. Other important findings relate to the predominance of cellular edema in TBI.


Significant new findings have been made in understanding the pathophysiology of brain edema; however, less progress has been made in treatment. Aquaporin water channels offer hope for modulating and abating the devastating effects of fulminating brain edema in trauma and stroke.

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Effects of tromethamine and hyperventilation on brain injury in the cat

Kazuo Yoshida and Anthony Marmarou

✓ The metabolic brain acidosis after trauma has been thought to be harmful and to contribute to neurological deterioration. Amelioration of the brain acidosis either by systemic buffering agents or by hyperventilation has been proposed as a method of treatment. The objective of this study was to explore with magnetic resonance (MR) spectroscopy the metabolic changes in brain that occur with the use of hyperventilation, THAM (tromethamine; tris[hydroxymethyl]aminomethane), and a combination (THAM and hyperventilation) therapy in experimental fluid-percussion injury.

Brain lactate, brain pH, inorganic phosphate (Pi), and adenosine triphosphate levels were measured by 1H and 31P MR spectroscopy. Arterial and cerebrovenous lactate and water content in brain tissue was determined in 29 cats using the specific gravimetric technique. Following injury, the phosphocreatine (PCr)/Pi ratio, which is an index of cerebral energy depletion, decreased to 76% in four untreated animals, to 79% in 11 THAM-treated animals, to 68% in seven animals receiving hyperventilation, and to 66% in seven animals with combination THAM and hyperventilation therapy. The PCr/Pi ratio returned to a normal level in 8 hours in animals treated with THAM and THAM in combination with hyperventilation. The brain lactate index increased to 157% in the hyperventilation group after trauma. In cats receiving THAM plus hyperventilation, the brain lactate index was reduced to 142%, while the minimum rise of 126% was associated with treatment of THAM alone. In the THAM-treatment and combination-treatment groups, the water content of the white and gray matter was significantly decreased compared with that in untreated cat brains.

Prolonged hyperventilation provided relative ischemia in brain tissue and promoted more production of brain lactate, no recovery of the PCr/Pi ratio, and no decrease in brain edema. On the other hand, administration of THAM decreased production of brain lactate and brain edema and promoted the recovery of cerebral energy dysfunction. It was found that THAM ameliorates the deleterious effects of hyperventilation by minimizing energy disturbance and that it also decreases brain edema. The authors conclude that THAM may be effective in reducing brain tissue acidosis and helpful as a metabolic stabilizing agent following severe head injury.

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Clearance of brain edema and macromolecules through the cortical extracellular space

Kenji Ohata and Anthony Marmarou

✓ The transit routes of fluid and particulate matter through brain tissue remain unclear. The object of this study was to examine the movement of macromolecules through brain tissue to further clarify the clearance pathways of edema proteins as they migrate toward the cortex. For this purpose, albumin solution (20 µl rat albumin diluted to 65 mg/ml with mock cerebrospinal fluid (CSF)) was intracerebrally infused into the caudate putamen, and the migration through brain tissue as well as through the ultrastructure of the cortical surfaces was explored using an immunocytochemical technique. The authors observed immunoreactive product on the glial limitans and pial lining as well as in the extracellular space of the cortical neuropil at 24 hours postinfusion, confirming that the protein had reached the cortical surface.

To confirm the efflux of macromolecules into the subarachnoid CSF, 71,200 D fluorescein isothiocyanatedextran (FITC-dextran 71,200) was infused; cortical surfaces of brains removed en bloc as well as coronal sections were macroscopically observed under ultraviolet illumination at 15 minutes and 24 hours postinfusion. It was observed that infused FITC-dextran 71,200 mainly localized in the cortical white matter and caudate putamen of the infusion site at 15 minutes postinfusion and by 24 hours was distributed in the entire cortex of the infused hemisphere. However, the dynamics of lower-molecular-weight substances was completely different. The spatial distribution of FITC-dextran 4400 diverged upward toward the cortical surface and spread more extensively than FITC-dextran 71,200. These observations were consistent with a diffusion process as the spread of the tracer was dependent upon molecular size. These studies provide compelling evidence that a process other than bulk flow was involved in the spread of macromolecules through the extracellular space of the normal cortical neuropil to sink into the subarachnoid space. It was concluded that the CSF pathway via the extracellular space of the cortical neuropil is a primary route for clearance of extracellular edema proteins to the subarachnoid space and that diffusion is involved in this process.

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Clinical applications of the pressure-volume index in treatment of pediatric head injuries

Kenneth Shapiro and Anthony Marmarou

✓ The pressure-volume index (PVI) technique of assessing neural axis pressure-volume relationships was used as an adjunct to managing 22 children with severe head injuries and a Glasgow Coma Scale score of 8 or less. Ventricular cannulation was used to continuously monitor intracranial pressure (ICP). Actual PVI was measured by bolus injection of fluid and compared with predicted values determined from head circumference and spinal axis length in each patient. In 55% of the children, ICP was below 20 mm Hg at initial monitoring. During the course of monitoring, 86% of the children had ICP's exceeding 20 mm Hg. Reduced PVI (less than 80% of predicted normal) proved to be an accurate indicator of impending intracranial hypertension. The PVI proved to be a useful test for assessing the response to therapies for lowering ICP. This study demonstrates that reduced neural axis compliance accompanies intracranial hypertension following severe head injury in children, and that treatment of reduced neural axis compliance may prevent refractory intracranial hypertension.

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Cation dysfunction associated with cerebral ischemia followed by reperfusion: a comparison of microdialysis and ion-selective electrode methods

Michael F. Stiefel and Anthony Marmarou

Object. Disruption of ionic homeostasis during ischemia is a well-characterized event and is identified by a rise in the concentration of extracellular potassium [K+]e, with a concomitant reduction in the concentration of extracellular sodium [Na+]e. Results of clinical studies in which microdialysis has been used, however, have shown only modest changes in the levels of extracellular ions. The object of this study was to measure [K+]e and [Na+]e by using ion-selective electrodes (ISEs) and to compare these measurements with those obtained using the well-established method of microdialysis.

Methods. Fifteen Sprague—Dawley rats were separated into three groups. Five animals were subjected to a 15-minute period of ischemia, and another five animals to a 60-minute period of ischemia; animals in both of these groups received K+-free microdialysis perfusate. The third group of five rats underwent a 60-minute period of ischemia and received a reduced-Na+ microdialysis perfusate. Transient forebrain ischemia was produced by bilateral carotid artery occlusion combined with hypotension. A custom-fabricated glass Na+ electrode and a flexible plastic K+ and reference electrodes were used to monitor extracellular ion transients. Microdialysis samples were obtained with the aid of a 2-mm microdialysis probe that was perfused with K+-free mock cerebrospinal fluid at a rate of 2 µl/minute.

Baseline measurements of [K+]e and [Na+]e, obtained using ISEs, were 3.41 ± 0.09 mM and 145 ± 7.75 mM, respectively. Ischemia resulted in a rapid accumulation of [K+]e (in animals subjected to 15 minutes of ischemia, the concentration was 41.9 ± 13.7 mM; and in animals subjected to 60 minutes of ischemia, the concentration was 66.9 ± 11.5 mM), with a concomitant decrease in [Na+]e (in animals subjected to 15 minutes of ischemia, the concentration was 71.7 ± 2.9 mM; and in animals subjected to 60 minutes of ischemia, the concentration was 74.7 ± 1.9 mM). A comparison of microdialysis and ISE methods revealed that microdialysis underestimated the [K+]e changes and was insensitive to concomitant [Na+]e alterations that occur during ischemia.

Conclusions. Our results indicate that the flexible ISE is a reliable and accurate tool for monitoring ionic dysfunction that accompanies brain injury.

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Use of magnetic resonance imaging for in vivo measurements of water content in human brain: method and normal values

Panos P. Fatouros and Anthony Marmarou

Object. The authors present a quantitative in vivo magnetic resonance (MR) imaging method and propose its use for the accurate assessment of brain water in humans.

Methods. With this technique, a pure T1-weighted image of a selected brain slice in a patient is generated, and the image is subsequently converted to a pure water image by means of an equation derived from a tissue relaxation model. The image intensity in the resulting water map directly yields absolute measures of water expressed in grams of water per gram of tissue at a given anatomical location. The method has been validated previously in a series of phantom experiments and in an infusion model of brain edema in cats. In this report, the authors evaluate the method by using samples of tissue harvested from patients who underwent surgery for brain tumor removal and apply the technique to a series of normal volunteers, providing average regional brain water content (fw) values for a range of tissues. Application of the method in pathological conditions such as head trauma, tumor, and hydrocephalus allows quantification of regional or global increases in fw that result from edema.

Conclusions. It is now possible to obtain accurate brain water measurements with the anatomical resolution of MR imaging. This permits monitoring of the development and resolution of edema in a variety of clinical circumstances, thus enhancing understanding of the underlying pathophysiological processes.

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Evaluation of brain-stem dysfunction following severe fluid-percussion head injury to the cat

Katsuji Shima and Anthony Marmarou

✓ The degree of brain-stem dysfunction associated with high-level fluid-percussion injury (3.0 to 3.8 atm) was investigated in anesthetized cats. Measurements were made of the animals' intracranial pressure (ICP), pressure-volume index (PVI), far-field brain-stem auditory evoked responses (BAER's), and cerebral blood flow (CBF). The animals were classified into two groups based on the severity of neuropathological damage to the brain stem after trauma: Group 1 had mild intraparenchymal and subarachnoid hemorrhages and Group 2 had severe intraparenchymal and subarachnoid hemorrhages.

The ICP values in Group 1 were insignificantly lower than those in Group 2, while the PVI values in Group 2 were clearly lower (p < 0.05). Immediately after the injury, peaks II, III, and IV of the BAER's demonstrated a transitory and marked suppression. One Group 1 and two Group 2 animals showed the disappearance of peak V. In Group 1, the latencies of peak II, III, and IV gradually increased until 60 to 150 minutes postinjury, then returned to 95% of baseline value at 8 hours; however, the animals in Group 2 showed poor recovery of latencies. Two hours after brain injury, the CBF decreased to 40% of the preinjury measurement in both groups (p < 0.001). In contrast to Group 2, the CBF in Group 1 returned to 86.8% of the preinjury measurement by 8 hours following the injury. Changes in PVI, BAER, and CBF correlated well with the degree of brain-stem injury following severe head injury'- These data indicate that high-level fluid-percussion injury (> 3.0 atm) is predominantly a model of brain-stem injury.

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Ventriculostomy or Subgaleal Shunting?

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A nonlinear analysis of the cerebrospinal fluid system and intracranial pressure dynamics

Anthony Marmarou, Kenneth Shulman, and Roberto M. Rosende

✓ A mathematical model of the cerebrospinal fluid (CSF) system was developed to help clarify the kinetics of the intracranial pressure (ICP). A general equation predicting the time course of pressure was derived in terms of four parameters: the intracranial compliance, dural sinus pressure, resistance to absorption, and CSF formation. These parameters were measured in the adult cat, and the equation was tested by comparing experimental and calculated values of the time course of pressure in response to volume changes. The theoretical and experimental results were in close agreement, and the role of each parameter in governing the dynamic equilibrium of the ICP was determined. From this analysis, dynamic tests were developed for rapid measurement of CSF formation, absorption resistance, and the bulk intracranial compliance. These techniques are applicable to clinical settings, providing data that are useful in characterizing the physiological mechanisms responsible for raised ICP and assessing changes induced by therapy.

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A simple gravimetric technique for measurement of cerebral edema

Anthony Marmarou, Werner Poll, Kenneth Shulman, and Hemmige Bhagavan

✓ A simple method was developed for the laboratory preparation of gradient columns of specific gravity used in measurement of brain-tissue water. By this automated technique, virtually linear and repeatable density gradients were obtained from which values of tissue specific gravity could be determined. The specific gravity of both solid and fresh cortex and white matter from adult cats was measured and converted to units of percent water per gram tissue using conversion factors derived for this purpose and applicable to studies of brain edema.