Implementing diffusion-weighted MRI for body imaging in prospective multicentre trials: current considerations and future perspectives.

For body imaging, diffusion-weighted MRI may be used for tumour detection, staging, prognostic information, assessing response and follow-up. Disease detection and staging involve qualitative, subjective assessment of images, whereas for prognosis, progression or response, quantitative evaluation of the apparent diffusion coefficient (ADC) is required. Validation and qualification of ADC in multicentre trials involves examination of i) technical performance to determine biomarker bias and reproducibility and ii) biological performance to interrogate a specific aspect of biology or to forecast outcome. Unfortunately, the variety of acquisition and analysis methodologies employed at different centres make ADC values non-comparable between them. This invalidates implementation in multicentre trials and limits utility of ADC as a biomarker. This article reviews the factors contributing to ADC variability in terms of data acquisition and analysis. Hardware and software considerations are discussed when implementing standardised protocols across multi-vendor platforms together with methods for quality assurance and quality control. Processes of data collection, archiving, curation, analysis, central reading and handling incidental findings are considered in the conduct of multicentre trials. Data protection and good clinical practice are essential prerequisites. Developing international consensus of procedures is critical to successful validation if ADC is to become a useful biomarker in oncology. KEY POINTS: • Standardised acquisition/analysis allows quantification of imaging biomarkers in multicentre trials. • Establishing "precision" of the measurement in the multicentre context is essential. • A repository with traceable data of known provenance promotes further research.

Diffusion MRI in early cancer therapeutic response assessment.

Imaging biomarkers for the predictive assessment of treatment response in patients with cancer earlier than standard tumor volumetric metrics would provide new opportunities to individualize therapy. Diffusion-weighted MRI (DW-MRI), highly sensitive to microenvironmental alterations at the cellular level, has been evaluated extensively as a technique for the generation of quantitative and early imaging biomarkers of therapeutic response and clinical outcome. First demonstrated in a rodent tumor model, subsequent studies have shown that DW-MRI can be applied to many different solid tumors for the detection of changes in cellularity as measured indirectly by an increase in the apparent diffusion coefficient (ADC) of water molecules within the lesion. The introduction of quantitative DW-MRI into the treatment management of patients with cancer may aid physicians to individualize therapy, thereby minimizing unnecessary systemic toxicity associated with ineffective therapies, saving valuable time, reducing patient care costs and ultimately improving clinical outcome. This review covers the theoretical basis behind the application of DW-MRI to monitor therapeutic response in cancer, the analytical techniques used and the results obtained from various clinical studies that have demonstrated the efficacy of DW-MRI for the prediction of cancer treatment response. Copyright © 2016 John Wiley & Sons, Ltd.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Spiral T1 Spin-Echo for Routine Postcontrast Brain MRI Exams: A Multicenter Multireader Clinical Evaluation.

BACKGROUND AND PURPOSE: Spiral MR imaging has several advantages compared with Cartesian MR imaging that can be leveraged for added clinical value. A multicenter multireader study was designed to compare spiral with standard-of-care Cartesian postcontrast structural brain MR imaging on the basis of relative performance in 10 metrics of image quality, artifact prevalence, and diagnostic benefit. MATERIALS AND METHODS: Seven clinical sites acquired 88 total subjects. For each subject, sites acquired 2 postcontrast MR imaging scans: a spiral 2D T1 spin-echo, and 1 of 4 routine Cartesian 2D T1 spin-echo/TSE scans (fully sampled spin-echo at 3T, 1.5T, partial Fourier, TSE). The spiral acquisition matched the Cartesian scan for scan time, geometry, and contrast. Nine neuroradiologists independently reviewed each subject, with the matching pair of spiral and Cartesian scans compared side-by-side, and scored on 10 image-quality metrics (5-point Likert scale) focused on intracranial assessment. The Wilcoxon signed rank test evaluated relative performance of spiral versus Cartesian, while the Kruskal-Wallis test assessed interprotocol differences. RESULTS: Spiral was superior to Cartesian in 7 of 10 metrics (flow artifact mitigation, SNR, GM/WM contrast, image sharpness, lesion conspicuity, preference for diagnosing abnormal enhancement, and overall intracranial image quality), comparable in 1 of 10 metrics (motion artifacts), and inferior in 2 of 10 metrics (susceptibility artifacts, overall extracranial image quality) related to magnetic susceptibility (P < .05). Interprotocol comparison confirmed relatively higher SNR and GM/WM contrast for partial Fourier and TSE protocol groups, respectively (P < .05). CONCLUSIONS: Spiral 2D T1 spin-echo for routine structural brain MR imaging is feasible in the clinic with conventional scanners and was preferred by neuroradiologists for overall postcontrast intracranial evaluation.

Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project.

BACKGROUND AND PURPOSE: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors. MATERIALS AND METHODS: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity. RESULTS: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%). CONCLUSIONS: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.

Diffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors.

BACKGROUND: A surrogate marker for treatment response that can be observed earlier than comparison of sequential magnetic resonance imaging (MRI) scans, which depends on relatively slow changes in tumor volume, may improve survival of brain tumor patients by providing more time for secondary therapeutic interventions. Previous studies in animals with the use of diffusion MRI revealed rapid changes in tumor water diffusion values after successful therapeutic intervention. METHODS: The present study examined the sensitivity of diffusion MRI measurements in orthotopic rat brain tumors derived from implanted rat 9L glioma cells. The effectiveness of therapy for individual brain cancer patients was evaluated by measuring changes in tumor volume on neuroimaging studies conducted 6--8 weeks after the conclusion of a treatment cycle. RESULTS: Diffusion MRI could detect water diffusion changes in orthotopic 9L gliomas after doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) that resulted in as little as 0.2 log cell kill, a measure of tumor cell death. Mean apparent diffusion coefficients in tumors were found to be correlated with and highly sensitive to changes in tumor cellularity (r =.78; two-sided P =.041). The feasibility of serial diffusion MRI in the clinical management of primary brain tumor patients was also demonstrated. Increased diffusion values could be detected in human brain tumors shortly after treatment initiation. The magnitude of the diffusion changes corresponded with clinical outcome. CONCLUSIONS: These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.

Evaluating changes in tumor volume using magnetic resonance imaging during the course of radiotherapy treatment of high-grade gliomas: Implications for conformal dose-escalation studies.

OBJECTIVE: To determine whether changes in tumor volume occur during the course of conformal 3D radiotherapy of high-grade gliomas by use of magnetic resonance imaging (MRI) during treatment and whether these changes had an impact on tumor coverage. METHODS AND MATERIALS: Between December 2000 and January 2004, 21 patients with WHO Grades 3 to 4 supratentorial malignant gliomas treated with 3D conformal radiotherapy (median dose, 70 Gy) were enrolled in a prospective clinical study. All patients underwent T1-weighted contrast-enhancing and T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging at approximately 1 to 2 weeks before radiotherapy, during radiotherapy (Weeks 1 and 3), and at routine intervals thereafter. All MRI scans were coregistered to the treatment-planning CT. Gross tumor volume (GTV Pre-Rx) was defined from a postoperative T1-weighted contrast-enhancing MRI performed 1 to 2 weeks before start of radiotherapy. A second GTV (GTV Week 3) was defined by use of an MRI performed during Week 3 of radiotherapy. A uniform 0.5 cm expansion of the respective GTV, PTV (Pre-Rx), and PTV (Week 3) was applied to the final boost plan. Dose-volume histograms (DVH) were used to analyze any potential adverse changes in tumor coverage based on Week 3 MRI. RESULTS: All MRI scans were reviewed independently by a neuroradiologist (DGH). Two patients were noted to have multifocal disease at presentation and were excluded from analysis. In 19 cases, changes in the GTV based on MRI at Week 3 during radiotherapy were as follows: 2 cases had an objective decrease in GTV (> or =50%); 12 cases revealed a slight decrease in the rim enhancement or changes in cystic appearance of the GTV; 2 cases showed no change in GTV; and 3 cases demonstrated an increase in tumor volume. Both cases with objective decreases in GTV during treatment were Grade 3 tumors. No cases of tumor progression were noted in Grade 3 tumors during treatment. In comparison, three of 12 Grade 4 tumors had tumor progression, based on MRI obtained during Week 3 of radiotherapy. Median increase in GTV (Week 3) was 11.7 cc (range, 9.8-21.3). Retrospective DVH analysis of PTV (Pre-Rx) and PTV (Week 3) demonstrated a decrease in V(95%)(PTV volume receiving 95% of the prescribed dose) in those 3 cases. CONCLUSIONS: Routine MR imaging during radiotherapy may be essential in ensuring tumor coverage if highly conformal radiotherapy techniques such as stereotactic boost and intensity-modulated radiotherapy are used in dose-escalation trials that utilize smaller treatment margins.

Growth kinetics and treatment response of the intracerebral rat 9L brain tumor model: a quantitative in vivo study using magnetic resonance imaging.

We report the use of magnetic resonance imaging (MRI) for in situ tumor growth rate studies of experimental intracranial 9L tumors. T2-weighted spin-echo coronal magnetic resonance images of rat brains with 9L tumors were obtained every 2 days beginning at 8-11 days postimplantation using a 7 tesla MRI system. Tumors were clearly delineated in the images as a hyperintense region with a relatively well-demarcated border and minimal peritumoral edema. Tumor volumes from individual slices were summed together to yield the total tumor volume. The accuracy of this methodology for volumetric determination was verified by MRI phantom studies. Tumor growth rates determined from sequential MRI measurements of tumor volumes were quantitated in terms of volumetric doubling time. Tumor doubling times were found to range from 50 to 81 h, with an average of 66 +/- 8 h (n = 10). Intracranial 9L tumors were found to grow exponentially over the entire life span of the animal, allowing treated animals to serve as their own controls since the volumetric doubling time could be determined from three to four MRI scans before treatment administration. The intracerebral tumor growth delay following a single injection of 1, 3-bis(2-chloroethyl)-1-nitrosourea (13.3 mg/kg i.p.) allowed for noninvasive determination of in vivo log cell kill. A 2.0 +/- 0.2 (n = 3) log cell kill from 1,3-bis(2-chloroethyl)-1-nitrosourea treatment was found from post-treatment MRI volume measurements. These results demonstrate that MRI provides a powerful and sensitive method for assessing the growth and treatment response of intracranial 9L tumors in the rat.

Monitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging.

Quantitative magnetic resonance imaging was performed to evaluate water diffusion and relaxation times, T1 and T2, as potential therapeutic response indicators for brain tumors using the intracranial 9L brain tumor model. Measurements were localized to a column that intersected tumor and contralateral brain and were repeated at 2-day intervals before and following a single injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (13.3 mg/kg). Tumor growth was measured using T2-weighted magnetic resonance imaging to determine the volumetric tumor doubling time (Td) before (Td = 64 +/- 13 h, mean +/- SD, n = 16) and after (Td = 75 +/- 9 h, n = 4) treatment during exponential regrowth. Apparent diffusion coefficient of untreated tumors was independent of tumor volume or growth time, whereas relaxation times increased during early tumor growth. Diffusion displayed the strongest treatment effect and increased before tumor regression by 55% 6-8 days following treatment. Changes in relaxation times were also significant with increases of 16% for T1 and 27% for T2. Diffusion and relaxation times returned to pretreatment levels by 12 days after treatment. Histological examination supports the model that the observed increase in diffusion reflects an increase of extracellular space following treatment. Furthermore, the subsequent apparent diffusion coefficient decrease is a result of viable tumor cells that repopulate this space at a rate dependent on the surviving tumor cell fraction and recurrent tumor doubling time. Serial tumor volume measurements allowed determination of log cell kill of 1.0 +/- 0.3 (n = 4). These results suggest that diffusion measurements are sensitive to therapy-induced changes in cellular structure and may provide an early noninvasive indicator of treatment efficacy.

Magnetic resonance imaging in cancer research.

Non-invasive assessment of antineoplastic response and correlation of the location, magnitude and duration of transgene expression in vivo would be particularly useful for evaluating cancer gene therapy protocols. This review presents selected examples of how magnetic resonance (MR) has been used to assess therapeutic efficacy by non-invasive quantitation of cell kill, to detect a therapeutic response prior to a change in tumour volume and to detect spatial heterogeneity of the tumour response and quantitate transgene expression. In addition, applications of the use of bioluminescence imaging (BLI) for the evaluation of treatment efficacy and in vivo transgene expression are also presented. These examples provide an overview of areas in which imaging of animal tumour models can contribute towards improving the evaluation of experimental therapeutic agents.

Optimizing three-dimensional gadolinium-enhanced magnetic resonance angiography. Original investigation.

RATIONALE AND OBJECTIVES: This primarily theoretical work examines three-dimensional gadolinium-enhanced magnetic resonance angiography f8p4Gd-MRA) with the goal of understanding how to achieve the best possible images with respect to signal to noise ratio (SNR) and k-space induced artifacts. Patient variables, contrast injection schemes, and pulse sequence parameters are considered for this purpose. METHODS: A theoretical analysis, including computer simulation, describes how contrast material injection profiles influence 3D Gd-MRA images, both in terms of intravascular signal and resultant artifacts. Further theoretical analysis of the spoiled gradient refocused pulse sequence describes how to maximize SNR. Clinical imaging complements computer modeling. RESULTS: Equations were derived relating contrast injection parameters and pulse sequence variables to SNR and artifacts. For present imaging equipment, administering contrast material over a duration of 60% to 80% of the total imaging time and using fractional echo techniques gives the best SNR without significantly sacrificing image quality. CONCLUSIONS: Three-dimensional Gd-MRA can be tailored to a specific clinical situation and imaging system through the use of proper breath-holding, bolus timing, Gd administration, and pulse sequence design.

Multiphase-multistep gadolinium-enhanced MR angiography of the abdominal aorta and runoff vessels.

RATIONALE AND OBJECTIVES: To optimize three-dimensional gadolinium magnetic resonance angiography (3D-Gd-MRA) of the aorta and runoff vessels by addressing fundamentally different requirements for temporal and spatial resolution in a single semiautomated examination. METHODS: The technique was designed to obtain pure arterial-phase 3D-Gd-MR angiograms with adequate spatial resolution for each station while avoiding incomplete enhancement due to delayed filling vessels as well as venous overlay. During gadolinium-chelate infusion, a breath-held multiphase 3D-Gd-MRA scan was initiated in the aorta by automatic triggering, followed by automatic table movement. The acquisition was tailored to the vessels of interest by tilting of the 3D volumes. A spatial resolution of 1.7 x 1.2 x 0.8 mm in the calves was achieved by use of elliptical-centric k-space reordering. Signal-to-noise ratio was maximized with a 12-element peripheral vascular coil. Twelve patients with peripheral vascular disease were studied. RESULTS: In cases of aortic occlusive disease (n = 2), dissections (n = 3), or aneurysms (n = 4), substantially delayed fill-in of reconstituted arteries, false lumens, or aneurysmal segments occurred, which was detected only on the later 3D-Gd-MRA phase. High-resolution arterial-phase scans in the calves were obtained, with only one case of substantial venous overlay. Correlation to digital subtraction angiography revealed excellent agreement of pathological findings. CONCLUSIONS: Multiphase-multistep 3D-Gd-MRA reduces the limitations of standard 3D-Gd-MRA techniques with respect to anatomic coverage, spatial resolution, and nonuniform arterial vessel enhancement.

Magnetic resonance angiography with gadomer-17. An animal study original investigation.

RATIONALE AND OBJECTIVES: Our purpose was to investigate a "blood pool" contrast agent for abdominal and thoracic MR angiography by comparison with standard ionic and nonionic gadolinium-based contrast agents, which redistribute into the extracellular fluid compartment. METHODS: Abdominal and thoracic MR angiography was performed in three adult dogs using a three-dimensional spoiled gradient echo pulse sequence before and after intravenous administration of one of three gadolinium-based contrast agents (gadopentetate dimeglumine, gadobutrol, and gadomer-17). Each compound was tested at five different doses in all three dogs. Quantitative analysis of signal-to-noise ratio (SNR) was performed in the aorta, inferior vena cava (IVC), liver, spleen, kidney (medulla and cortex), fat, and muscle. RESULTS: Gadomer-17 improved visualization of vascular anatomy at doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg with three-fold greater aorta SNR during the arterial phase and more than four-fold greater aorta and IVC SNR during the equilibrium phase, in comparison with gadopentetate dimeglumine and gadobutrol at equal doses. CONCLUSIONS: Gadomer-17 is a promising contrast agent for both arterial phase and equilibrium phase MR angiography.

In vivo MR determination of water diffusion coefficients and diffusion anisotropy: correlation with structural alteration in gliomas of the cerebral hemispheres.

PURPOSE: To determine whether a relationship exists between water diffusion coefficients or diffusion anisotropy and MR-defined regions of normal or abnormal brain parenchyma in patients with cerebral gliomas. METHODS: In 40 patients with cerebral gliomas, diffusion was characterized in a single column of interest using a motion-insensitive spin-echo sequence that was applied sequentially at two gradient strength settings in three orthogonal directions. Apparent diffusion coefficients (ADCs) were derived for the three orthogonal axes at 128 points along the column. An average ADC and an index of diffusion anisotropy (IDA = diffusion coefficientmax-min/diffusionmean) was than calculated for any of nine MR-determined regions of interest within the tumor or adjacent parenchyma. RESULTS: In cerebral edema, mean ADC (all ADCs as 10(-7) cm2/s) was 138 +/- 24 (versus 83 +/- 6 for normal white matter) with mean IDA of 0.26 +/- 0.14 (versus 0.45 +/- 0.17 for normal white matter). Solid enhancing central tumor mean ADC was 131 +/- 25 with mean IDA of 0.15 +/- 0.10. Solid enhancing tumor margin mean ADC was 131 +/- 25, with IDA of 0.25 +/- 0.20. Cyst or necrosis mean ADC was 235 +/- 35 with IDA of 0.07 +/- 0.04. CONCLUSION: In cerebral gliomas ADC and IDA determinations provide information not available from routine MR imaging. ADC and IDA determinations allow distinction between normal white matter, areas of necrosis or cyst formation, regions of edema, and solid enhancing tumor. ADCs can be quickly and reliably characterized within a motion-insensitive column of interest with standard MR hardware.

Flow-enhanced magnetic resonance imaging.

A new technique for detecting blood flow in magnetic resonance imaging is proposed. This technique is tailored to enhance areas containing flow while suppressing static and nonsignal areas with the objective of optimizing the contrast of vascularized tumors. Unlike flow phase imaging, in-plane flow directionality (parallel versus antiparallel to applied flow gradient) is removed by the proposed method to reduce phase cancellation of flow signals. This signal loss is apt to occur in instances of complicated vascularity patterns consisting of many small vessels having multiple flow directions. The new flow-enhanced imaging method is compared to flow phase imaging by computer simulation of simple objects containing many small vessels. The results indicate that flow-enhanced imaging yields significantly greater detectability of regions of complicated small-vessel patterns than phase imaging.

Linear motion correction in three dimensions applied to dynamic gadolinium enhanced breast imaging.

Quantitative analysis of dynamic gadolinium-DTPA (diethylenetriamine pentaacetic acid) enhanced magnetic resonance imaging (MRI) is emerging as a highly sensitive tool for detecting malignant breast tissue. Three-dimensional rapid imaging techniques, such as keyhole MRI, yield high temporal sampling rates to accurately track contrast enhancement and washout in lesions over the course of multiple volume acquisitions. Patient motion during the dynamic acquisitions is a limiting factor that degrades the image quality, particularly of subsequent subtraction images used to identify and quantitatively evaluate regions suggestive of malignancy. Keyhole imaging is particularly sensitive to motion since datasets acquired over an extended period are combined in k-space. In this study, motion is modeled as set of translations in each of the three orthogonal dimensions. The specific objective of the study is to develop and implement an algorithm to correct the consequent phase shifts in k-space data prior to offline keyhole reconstruction three-dimensional (3D) volume breast MR acquisitions.

Automated analysis of multiple performance characteristics in magnetic resonance imaging systems.

As with other digital imaging systems in heavy medical use, it is desirable with magnetic resonance imaging (MRI) to obtain extensive, rigorous system performance measures from a small set of images of one or two relatively simple test objects. Digital analysis of the parallel square rod (PSR) test object introduces digital image system self-evaluation to MRI and extends automated image evaluation to include rigorous measures throughout the imaging volume rather than just average measures over the image. Precise comparisons with theory and between systems can be performed as well as quality control and corrections for nonuniformities. The PSR test object consists of an 18 X 18 X 36 cm rectangular acrylic container enclosing 60 parallel square acrylic rods running the entire length. The inter-rod space is filled with a liquid or gel that produces strong, tissuelike signals in MRI and high contrast relative to the rods for computed tomography (CT). For profiles of slice thickness and separation, the rods are tilted in the test object to intersect the image plane at a 45 degree angle when the test object sides are parallel and perpendicular to the image plane. The test object itself is rotated 6-12 degrees about its major axis so that the sides of the rods make a small angle to the rows and columns of pixels. This allows digital sampling at finer spacing than the pixels for determination of edge response functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats.

There have been few investigations of brain edema formation after intracerebral hemorrhage (ICH), despite the fact that mass effect and edema are important clinical complications. The present study was designed to investigate the time course for the formation and resolution of brain edema and to determine how changes in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability are temporally related to edema formation following ICH. Anesthetized adult rats received a sterile injection of 100 microliters of autologous blood into the caudate nucleus. Water and ion contents were measured immediately, at 4 and 12 hours, and daily to Day 7 (10 time points, six rats at each time) after experimental ICH. The water content of the ipsilateral basal ganglia increased progressively (p < 0.002) over the first 24 hours, then remained constant until after Day 5, when the edema began to resolve. Edema was most severe in the tissue immediately surrounding the hemorrhage; however, it was also present in the ipsilateral cortex, the contralateral cortex, and the basal ganglia. Measurements of local CBF (using [14C]-iodoantipyrine) and BBB permeability (using [3H]-alpha-aminoisobutyric acid) were obtained in separate groups of six to eight rats at various time intervals between 1 and 48 hours after ICH. Cerebral blood flow was reduced to 50% of control at 1 hour, returned to control values by 4 hours, but then decreased to less than 50% of control between 24 and 48 hours after ICH. The BBB permeability increased significantly prior to the occurrence of significant edema in the tissue surrounding the clot. However, BBB permeability in the more distant structures remained normal despite the development of edema. These results demonstrate a time course for the formation and resolution of brain edema following ICH similar to that observed during focal ischemia. Brain edema forms in the immediate vicinity of the clot as a result of both BBB disruption and the local generation of osmotically active substances and then spreads to adjacent structures. While local ischemia, due to the mass effect of the hemorrhage, may play a role in producing cytotoxic and vasogenic edema, the release of toxic substances from the clot should also be considered. Since edema is nearly maximal by 24 hours after ICH, therapy directed at reducing edema formation must be instituted within the 1st day.

Intracerebral infusion of thrombin as a cause of brain edema.

Purified thrombin from an exogenous source is a hemostatic agent commonly used in neurosurgical procedures. The toxicity of thrombin in the brain, however, has not been examined. This study was performed to assess the effect of thrombin on brain parenchyma, using the formation of brain edema as an indicator of injury. Ten microliters of test solution was infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later, and the extent of brain edema and ion content were measured. Concentrations of human thrombin as low as 1 U/microliter resulted in a significant increase in brain water content. Rats receiving 10 U/microliters had a mortality rate of 33% compared to no mortality in the groups receiving smaller doses. Thrombin-induced brain edema was inhibited by a specific and potent thrombin inhibitor, hirudin. A medical grade of bovine thrombin commonly used in surgery also caused brain edema when injected at a concentration of 2 U/microliters. Edema formation was prevented by another highly specific thrombin inhibitor, N alpha-(2-Naphthalenesulfonylglycyl)-4-DL-phenylalaninepiperidid e (alpha-NAPAP). Thrombin-induced brain edema was accompanied by increases in brain sodium and chloride contents and a decrease in brain potassium content. Changes in brain ions were inhibited by both hirudin and alpha-NAPAP, corresponding to the inhibition of brain water accumulation. This study shows that thrombin causes brain edema when infused into the brain at concentrations as low as 1 U/microliter, an amount within the range of concentrations used for topical hemostasis in neurosurgery.

Thrombin-soaked gelatin sponge and brain edema in rats.

Previous work from this laboratory has shown that injection of thrombin into rat basal ganglia causes brain edema. This study investigates the effect on rat brain of thrombin-soaked gelatin sponge (used for intraoperative hemostasis in clinical situations) at a concentration similar to that used in humans. Three models were developed to evaluate this effect. In the first model, a gelatin sponge soaked with vehicle or thrombin (100 U/cm3) was placed on the intact pia of the right frontal lobe in rats without cortical lesions. In the second model, frontal cortex was excised (3 mm3) and the exposed brain was cauterized with electrocoagulation. Gelatin sponge was soaked with vehicle or thrombin (1000, 100, 10, or 1 U/cm3) and placed in the lesion site. In the third model, hirudin, a specific thrombin antagonist, was added to the thrombin-soaked gelatin sponge and placed in a similar cortical lesion to determine if the observed effects were specific to thrombin. The dose-response range for thrombin was determined qualitatively by magnetic resonance (MR) imaging and quantitatively by brain edema formation 24 hours after exposure. We found no edema in the cortically intact rats. The rats given cortical lesions developed significant edema when subjected to 1000, 100, and 10 U/cm3 thrombin as seen on MR imaging and at 100 and 10 U/cm3 thrombin as revealed by wet/dry weight and ion studies of brain tissue. Topical hirudin prevented thrombin-induced edema. It is concluded that thrombin-soaked gelatin sponges cause or enhance significant brain edema in rats at concentrations typically used for human neurosurgery.