Humbert G. Sullivan

Vascular permeability alterations to horseradish peroxidase in experimental brain injury.

Protein uptake and transport within the brain stem vasculature of mechanically brain injured cats was studied by means of both light and electron microscopy utilizing intravenously injected horseradish peroxidase as the protein tracer. In animals sustaining low grade head injuries not of sufficient intensity to elicit either microscopic, intraparenchymal hemorrhages or subtle, neuropathological responses, peroxidase extravasation was noted both in the vascular walls and in the surrounding parenchyma of the ventromedial aspect of the brain stem. At the ultrastructural level as early as 3 min after brain injury, occasional arterioles, venules and capillaries displayed peroxidase leakage. In serial sections large endothelial segments of these vessels revealed the peroxidase reaction product within numerous vesicles which often shared continuity with tubular and vacuolar profiles. Such vesicular activity apparently moved the peroxidase from the luminal surface to extrude it into the basal lamina. From the perivascular basal lamina, the reaction product flooded the interstices of the surrounding brain stem parenchyma where occasional neural, glial and pericytic elements incorporated the peroxidase within coated invaginations, vesicles, tubules and vacuoles. In that protein leakage was consistently observed despite the apparent integrity of both the endothelial tight junctions and their cell membranes, it is concluded that the vesicular transport of horseradish peroxidase across the endothelia of the brain stem vasculature represents a possible mechanism of blood-brain barrier dysfunction in mechanical brain injury.

Complete cerebral ischemia

SummaryNeuronal, astrocytic, and oligodendrocytic elements in several brain loci of the cat were examined at the light and electron microscopic level immediately after periods of complete cerebral ischemia (CCI) uncomplicated by post-ischemic recirculation. Such CCI episodes ranged from 1.5–25 min duration and were methodically produced in a cat model employing rigorous physiological controls. Subsequent to these CCI insults, morphological alterations occurred in a homogeneous manner within each cell type of all loci examined; however, variation in the temporal onset and magnitude of alterations among the various cell types was observed. With brief ischemic insults all cell nuclei demonstrated pronounced nuclear alterations, while their cytoplasmic organelles displayed minimal change. Chromatin clumping and nucleolar condensation were observed in both neurons and glia subsequent to 1.5–5 min of CCI, respectively. With increasing durations of CCI such changes were more dramatic and conspicuous alterations of the cytoplasmic organelles were observed. On the basis of extensive morphological analyses the present study illustrates that nuclear alterations are the first to occur subsequent to CCI. The homogeneity of neuronal involvement seen subsequent to CCI uncomplicated by post-ischemic recirculation is inconsistent with the “selective vulnerability” purported to occur by others. The significance of this inconsistency remains to be assessed; yet, the suggestion is advanced that post-ischemic recirculation may be a factor in the genesis of such vulnerability.

A new paradigm for staging pedicle screw-based spinal procedures: rationale, feasibility, safety, and efficacy.

OBJECT The aims of this study were to present the rationale for and the evolution of a staged, two-procedure paradigm for spinal surgery requiring pedicle screw instrumentation, and to evaluate the feasibility, safety, and efficacy of the technique. METHODS The rationale for the new algorithm is presented for consideration in the form of unproven hypotheses subject to verification by subsequent studies. The first stage of the two-staged algorithm, performed in an interventional radiology (IR) setting, involves percutaneous placement of either headless pedicle screws or K-wire fragment placeholders of the trajectory for pedicle screws. The second stage, performed days or weeks later, involves open surgical completion of instrumentation placement and other surgical objectives. The techniques for IR percutaneous K-wire fragment and percutaneous screw placement evolved over the duration of the study. Instrumentation was placed in 126 pedicles in 25 patients. Efficacy was equated to the accuracy of screw placement, which was evaluated using computed tomography (CT). Algorithms incorporating correction for metal artifact were developed to determine deviation of the screws and K-wire fragments from proper position. Over 1500 measurements were made to evaluate K-wire fragment and screw position in the 116 instrumented pedicles for which CT data were available. RESULTS Accuracy of placement (relative to both cortical and pedicle breaches or to only pedicle breaches) was 98 to 100% for K-wire fragments, 96 to 98% for screws following K-wire fragments, and 100% for percutaneous screws. The only adverse consequence of pedicle screw placement by this method was one infection that occurred 8 months postoperatively. CONCLUSIONS The staged, two-procedure paradigm for pedicle screw placement proved, within the limits of this study, to be feasible, safe, and effective; therefore, the unproven rationale behind the new paradigm merits further evaluation in a larger cohort of patients with randomized, matched controls.

Effect of pressure on cerebrospinal fluid absorption in cats, baboons, and humans: comparison of the linear and logarithmic models.

: To circumvent time constraints inherent in indicator clearance measurements of cerebrospinal fluid absorption, investigators have used the relationship between CSF pressure at steady state and the rate of infusion of mock CSF, in both patients and experimental animals, to evaluate the bulk absorption rate of CSF. This latter approach required mathematical model of the effect of CSF pressure on CSF bulk flow. Two such models--a fixed resistance and a variable resistance model of CSF flow through arachnoid villi--have been used in both clinical and laboratory settings. In this study, the relationship between steady state CSF pressure and mock CSF infusion rate was assessed using both mathematical models. We studied two patients, three cats, and seven baboons. Values of CSF outflow resistance calculated according to both models as well as other parameters of CSF bulk flow estimated on the basis of both models were all in the range expected from other studies. The data from these experiments do not provide justification for preferring one model over the other. Depending on the experimental or clinical situation, some of the assumptions behind both models may not be valid. Multiple direct measurements of the rates of CSF absorption and formation over a wide range of CSF pressures in individual subjects will be necessary to validate either the variable or the fixed resistance model or to suggest a more appropriate model. Until such information is available, it is probably reasonable to use both approaches for the analysis of mock CSF infusion data. CSF bulk flow parameters calculated on the basis of either the variable or the fixed resistance model should never be taken as absolute, but should be evaluated critically in the context of the clinical or experimental situation.

Effect of Pressure on Cerebrospinal Fluid Absorption in Cats, Baboons, and Humans

To circumvent time constraints inherent in indicator clearance measurements of cerebrospinal fluid absorption, investigators have used the relationship between CSF pressure at steady state and the rate of infusion of mock CSF, in both patients and experimental animals, to evaluate the bulk absorption rate of CSF. This latter approach required mathematical model of the effect of CSF pressure on CSF bulk flow. Two such models--a fixed resistance and a variable resistance model of CSF flow through arachnoid villi--have been used in both clinical and laboratory settings. In this study, the relationship between steady state CSF pressure and mock CSF infusion rate was assessed using both mathematical models. We studied two patients, three cats, and seven baboons. Values of CSF outflow resistance calculated according to both models as well as other parameters of CSF bulk flow estimated on the basis of both models were all in the range expected from other studies. The data from these experiments do not provide justification for preferring one model over the other. Depending on the experimental or clinical situation, some of the assumptions behind both models may not be valid. Multiple direct measurements of the rates of CSF absorption and formation over a wide range of CSF pressures in individual subjects will be necessary to validate either the variable or the fixed resistance model or to suggest a more appropriate model. Until such information is available, it is probably reasonable to use both approaches for the analysis of mock CSF infusion data. CSF bulk flow parameters calculated on the basis of either the variable or the fixed resistance model should never be taken as absolute, but should be evaluated critically in the context of the clinical or experimental situation.

Improvements in the technique of spinal subarachnoid recirculatory perfusion

With 14C-labeled dextran as the tracer, studies of the original configuration of spinal recirculatory perfusion and the original model for data analysis demonstrated that this approach does not yield acceptable accuracy in determining cerebrospinal fluid (CSF) formation (Fcsf) and absorption (Acsf) rates. A significant component of this error was due to the fact that the method of data analysis used originally is not based on a realistic mathematical model of the system. A more realistic mathematical model resulted in two simultaneous differential equations that did not have simple analytical solutions and, therefore, could not be used easily for data analysis. By computer simulation, a comparison of the more realistic model with the original model demonstrated that, under ideal conditions, there was a 10% error inherent in the original data analysis method. In the experimental setting, the magnitude of this inherent error is probably 20%. There were three other major problems with the original system: (a) one could not tell when enough data had been collected to ensure convergence of the data analysis algorithm; (b) calibration of the syringe pump in the external circuit was not accurate for short infusion periods; and (c) the presence of the syringe in the external circuit unnecessarily lengthened the period of nonhomogeneous mixing. A new system configuration and new data analysis methods have been developed. In the new system, the syringe is removed from the external circuit and intracranial pressure is controlled by infusion from a separate reservoir where the pressure head is maintained at any desired level by feedback control. Spectrophotometry is used to measure tracer concentration in the external circuit. Data collection and analysis are fully automated under computer control so that, during an experimental run, the investigators are updated at 1- to 2-second intervals as to the convergence of the data analysis routine. Data analysis methods for the new system are superior to previous methods because the models are realistic and no extrapolation is required. In addition, all of the data during the initial period of nonhomogeneous mixing are used to calculate Fcsf and Acsf. With the new system and a simple phantom of the CSF system, the mean error in finding Acsf was 1.7 +/- 1.2% for 27 determinations covering a wide range of absorption rates. Fcsf could be determined to within 0.001 ml/minute. In up to six sequential pressure plateaus, the magnitude of error did not increase with each subsequent run.(ABSTRACT TRUNCATED AT 400 WORDS)