Cryogenic Injury Research Articles

Early hemodynamic changes at the microcirculatory level and effects of mannitol following focal cryogenic injury

Changes in cerebral blood flow due to infusion of hyperosmolar solutions are of considerable importance in states of raised intracranial pressure. The present study was aimed to evaluate the effects of mannitol on the cerebral microcirculation, in a model of vasogenic brain edema. A right fronto-parietal craniotomy was performed in 30 adult Sprague-Dawley rats. Vasogenic edema was produced by placing dry-ice over the dura for 1 min. The cortical blood flow was monitored for 120 min using a laser-Doppler flowmeter (Perimed, Stockholm, Sweden), and graphics were recorded using a personal computer. Animals were randomly divided into three groups: group 1 (control group) received no mannitol; group 2 was treated with a bolus injection of 20% mannitol (1 mg kg-1); group 3 received the same dose over a 30 min infusion. Mean blood pressure, temperature, and respiratory rate were continuously monitored. At the end of the procedure, an intravenous injection of Evan's blue 2% was given. Results were compared by using repeated measures of analysis of variance and a two-sample t-test at each time. After the production of a cryogenic injury, we found a marked decrease in the cerebral blood flow, whereas mannitol partially reversed that effect. There was not significant difference between groups 2 and 3; however, there was a significant difference between mannitol and control groups after 15 min. During the early phase of vasogenic edema, early use of mannitol did not increase the blood flow, but stabilized it, preventing further decrease. Laser-Doppler flowmetry is a valuable method for continuous estimation of hemodynamic changes in the cerebral microcirculation.

U83836E reduces secondary brain injury in a rabbit model of cryogenic trauma.

Oxygen-derived free radicals have been implicated in secondary brain injury after head trauma. Although oxygen-free radicals may be derived from multiple sources, the activation and accumulation of neutrophils in areas of brain injury is a potential source of deleterious inflammatory mediators, including free radicals, which may exacerbate the primary insult. Neutrophils may also impede the cerebral microcirculation by congestion and occlusion of postcapillary venules. The lazaroid U83836E is a potent-free radical scavenger that inhibits lipid peroxidation. U83836E was studied in a cryogenic model of cerebral injury in pretreatment paradigm. Fifteen rabbits received a unilateral cryogenic brain lesion. Six animals received U83836E, and nine animals received vehicle only. Arterial blood gases, hematocrit, temperature, and mean arterial pressure were controlled in physiologic range throughout the experiment. Intracranial pressure was continuously monitored. Lesion size was determined by triphenyltertrazolium chloride staining and planimetric image analysis. Neutrophil aggregation and oxygen-free radical generation was assessed in whole blood by impedance aggregometry and simultaneous luminol-mediated chemiluminescence, respectively. Myeloperoxidase assay was used to determine neutrophil accumulation within the brain. Elevations in intracranial pressure from baseline values were significantly greater in the untreated (control) animals at all time points (p < 0.0001). Mean lesion size (% hemisphere +/- SEM) was significantly reduced in animals receiving U83836E (4.41 +/- 0.64, n = 6) when compared with controls (15.09 +/- 2.28, n = 9, p < 0.001). A reduction in both the release of oxygen-free radicals and in neutrophil aggregation following the cryogenic injury in the U83836E animals correlated with a smaller lesion volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Isoflurane, Fentanyl, Thiopental, and alpha-Chloralose on Formation of Brain Edema Resulting from a Focal Cryogenic Lesion

The objective of this study was to analyze the effects of various anesthetics on the formation of brain edema resulting from a focal cryogenic lesion.Thirty rabbits (six per group) were anesthetized with isoflurane (1 minimum alveolar anesthetic concentration [MAC] 2.1 vol%), fentanyl (bolus 5 micro gram/kg; infusion rate 1.0-0.5 micro gram centered dot kg-1 centered dot min-1), thiopental (32.5 mg centered dot kg-1 centered dot h-1), or alpha-chloralose (50 mg/kg). Control animals (sham operation, no lesion) received alpha-chloralose (50 mg/kg). Regional cerebral blood flow (rCBF) in perifocal brain tissue was measured by H2-clearance. Animals anesthetized with isoflurane required support of arterial pressure by angiotensin II (0.15 micro gram centered dot kg-1 centered dot min-1). Six hours after trauma the animals were killed. Formation of brain edema was studied by specific gravity of cortical gray matter, white matter, hippocampus, caudate nucleus, putamen, and thalamus. Brain tissue samples were collected at multiple sites close to and distant from the lesion. Mean arterial pressure, arterial PCO2 and PO2, hematocrit, body temperature, and blood glucose were not different between groups during the posttraumatic course (except for an increased arterial pressure with alpha-chloralose compared to thiopental 4-6 h after trauma). The specific gravity of cortical gray matter was significantly reduced up to a distance of 6 mm from the center of the lesion in animals anesthetized with isoflurane, thiopental, or alpha-chloralose and up to 9 mm in animals given fentanyl. In white matter, vasogenic edema extended up to 12 mm from the lesion focus in animals anesthetized with fentanyl, thiopental, or alpha-chloralose. In isoflurane-anesthetized animals, white matter samples in all regions were similar to control. The specific gravity in hippocampus, caudate nucleus, putamen, or thalamus was not altered as compared to the controls. rCBF studied before cryogenic injury had a range of 37-44 mL centered dot 100 g-1 centered dot min-1, except in animals given fentanyl (i.e., 59.9 mL centered dot 100 g-1 centered dot min-1). During the first 3 h after trauma, animals given fentanyl had significantly higher rCBF values than animals with thiopental or the controls. At 4-6 h after trauma, rCBF was decreased in animals with fentanyl or thiopental as compared to the baseline level, although differences were not observed between groups. Regression analyses of data from all experimental groups do not reveal a relationship between the formation of posttraumatic brain edema and mean arterial pressure or rCBF. We conclude that isoflurane anesthesia attenuates cerebral edema from a standard cerebral lesion as compared to fentanyl, thiopental, or alpha-chloralose. (Anesth Analg 1995;80:1108-15)

Cryogenic spinal cord injury induces astrocytic gene expression of insulin-like growth factor I and insulin-like growth factor binding protein 2 during myelin regeneration.

To study injury-induced astrocytic responses associated with regrowth of axons and regeneration of myelin, the method of Collins and colleagues was used to make focal cryogenic lesions in spinal cords of adult rats (Collins et al.: J Neuropathol Exp Neurol 45: 742-757, 1986). The duration of cryogenic injury (CI), the size of the cryode, and its temperature were chosen to destroy all myelin sheaths and axons without producing cavities or hemorrhages. Messenger RNA and peptide distributions of insulin-like growth factor I (IGF-I), IGF-I receptor (IGFR-I), IGF binding protein 2 (IGFBP-2), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP) were studied 3-56 days after CI by in situ hybridization and immunocytochemistry. At 3 days, vimentin-positive, GFAP-negative astrocyte-like cells in the lesion expressed IGF-I mRNA and peptide and 7 days after CI, both were expressed by typical GFAP-positive, hypertrophic astrocytes, many of which also were vimentin-positive. Levels of IGF-I, IGFBP-2, and GFAP mRNA and peptide were higher in lesion astrocytes after 14 days. They attained maximum levels at 21-28 days before declining to near control levels at 56 days. Decreasing relative levels of oligodendroglial MBP mRNA were found in and around lesions 7-14 days after CI; subsequently, rising levels accompanied remyelination. At 28 and 56 days after CI, some transferrin-positive, oligodendroglia-like cells also were immunostained by anti-IGFR-I. Our findings suggest that early astrocytic production of IGF-I and IGFBP-2 may be involved in the myelin regeneration which occurs in this model of spinal cord injury.

Colloid infusion after brain injury: effect on intracranial pressure, cerebral blood flow, and oxygen delivery.

We sought to determine the effects of colloid osmotic pressure on cerebral edema formation after brain injury. We hypothesized that an increase in plasma oncotic pressure accompanying a colloid infusion would be associated with a decrease in intracranial pressure and increases in cerebral blood flow and oxygen delivery when compared with isotonic crystalloid. Prospective, laboratory study. University surgical research laboratory. Adult swine, both genders. Cryogenic brain injury with intravenous fluid infusion of either lactated Ringer's solution or 6% dextran-70 in normal saline. The effect of this intervention was monitored for 24 hrs. Mean arterial pressure, central venous pressure, intracranial pressure, hemoglobin concentration, plasma oncotic pressure, serum osmolality, cerebral blood flow, and specific gravity of cortical biopsies. Cryogenic injury significantly increased the cortical water content and the intracranial pressure and significantly decreased the cerebral blood flow and oxygen delivery (p < .05). Dextran infusion significantly increased the colloid oncotic pressure. There were no differences between the lactated Ringer's solution and dextran groups in intracranial pressure, cerebral oxygen delivery, or cortical water content after 24 hrs. Colloid infusion after a focal cryogenic injury does not increase cerebral oxygen delivery or reduce either cerebral edema formation or intracranial pressure when compared with lactated Ringer's solution. Colloid is not superior to isotonic crystalloid in the management of isolated brain injury.

Real‐time confocal microscopy of keratocyte activity in wound healing after cryoablation in rabbit corneas

AbstractA modified tandem scanning confocal microscope was used for real‐time in vivo examination of the rabbit cornea following a cryogenic injury. The corneas of New Zealand white rabbits were frozen with a probe that had been cooled by immersion in liquid nitrogen, effectively destroying keratocytes in a central 5 mm diameter zone throughout the total thickness of the cornea. In these eyes, keratocyte repopulation and corneal stromal wound healing proceeded similarly to that which occurs after epikeratophakia, a refractive surgical procedure designed to change the curvature and optical power of the cornea. In epikeratophakia, a cryolathed donor corneal stroma lenticule is sutured onto the bare stroma of the recipient cornea. The collagen tissue lenticule is repopulated by keratocytes (corneal fibroblasts) that migrate in from the host cornea. In our study, the confocal microscope permitted sequential, noninvasive examination of the corneal stroma in the treated animals. Necrosis of the keratocytes, followed by activation of the remaining viable cells in the corneal periphery, was observed in the first 2 to 3 days after cryo injury. A fine stromal fibrous network was seen to develop; in three eyes, this network progressed to the development of a retrocorneal fibrous membrane and dense stromal fibrosis, both of which resulted in significant loss of corneal clarity. Our results suggest that the confocal microscope may be a valuable tool to provide much needed information on wound healing processes at the cellular level after corneal surgery and injury.

Role of the basement membrane in neurogenesis and repair of injury in the central nervous system.

Although remarkable progress has been made during the last two decades concerning the biosynthesis, expression and assembly of extracellular matrix (ECM) macromolecules in nonneural cells, we are still far from a complete understanding of the role and function of the ECM and the basement membrane (BM) in the central nervous system (CNS). With the aid of correlative light and electron microscopic, Golgi and immunohistochemical studies of the developing neural tube of both early human fetus and mouse, we have shown that the establishment of the pial-glial barrier (PGB) is one of the earliest histogenetic events in neurogenesis. This is accomplished by coordinated interaction among the processes of radial glia, various ECM components, and mesenchymal cells at the pial surface, with the formation of a BM that tightly abuts the glia limitans. The PGB and the BM appear to be critical to the migration and final positioning of neurons and to the differentiation of the laminar cortical pattern within the developing neopallium. This hypothesis is further supported by our study of the brain of a human newborn infant in whom multiple sites of disruption of the BM and PGB resulted in abnormal neuronal migration and massive ectopia of neurons within the subarachnoid space, with abnormal cortical lamination. Finally, studies of the experimental cryogenic injury to the neonatal rat cerebrum have shown that the final positioning of neurons within the developing cortical plate appears to depend largely on the reconstitution of the BM and PGB, which presumably provide crucial positional signals for migrating neurons. Also, one of the essential reparative features seen following cryogenic injury to the adult rat cerebrum is an orderly and dynamic interaction between various ECM components and neural cells, resulting in the formation of the BM.

Dynamics of posttraumatic brain swelling following a cryogenic injury in rats.

For evaluation of novel therapeutic regimens against brain edema in experimental models, it is important to know the temporal profile of edema formation. Since development of brain swelling and edema following a cryogenic injury is poorly documented in rats, these parameters have been investigated in this study. 17 Sprague-Dawley rats were used. Three rats (controls) were sham-operated. Their brains were removed 15 min after sham-operation. In all other animals a right parietal cryogenic lesion was applied in ketamine-xylazine anesthesia. Systemic blood pressure was monitored during the perioperative period. Brains were removed in defined intervals following cryogenic injury (0.25, 0.5, 1, 3, 6, 12, 24, and 72 h; n = 3 each). Hemispheres were then separated and weighed for determination of brain swelling, dried and weighed again. Cerebral water content was calculated as the difference of hemispheric wet- and dry-weight. Posttraumatic hemispheric swelling reached its maximum (7.9 +/- 0.4%) as early as 12 h post trauma. During the first hour after injury, brain swelling showed a steep, linear increase to 3.9%, i.e. swelling amounted to 50% of its maximum within one hour. 6 h post trauma swelling was 5.7%. After 12 h brain swelling started to decline. 72 h post cryogenic injury, 6.1% hemispheric swelling were found. Development of brain swelling was paralleled by a linear increase in brain water content of the lesioned hemisphere. The maximum of hemispheric water content was seen 24 h post trauma. In non-lesioned hemispheres only a marginal transient increase in cerebral water content was observed. edema has to be considered when planning therapeutic protocols.

Biomechanical characteristics of brain edema: the difference between vasogenic-type and cytotoxic-type edema.

Some of the basic biomechanical properties of edematous brain tissue have yet to be clarified. Therefore we measured regional tissue compliance and swelling isotropy/anisotropy in cat brain during development of vasogenic-type and cytotoxic-type edema. In vasogenic-type edema induced by cryogenic injury, the edematous white matter showed an increase of regional tissue compliance (indentation method), which paralleled the increase in the regional tissue water content (gravimetry). Swelling of the white matter due to edema was anisotropic, in which expansion transverse to the neuronal fibers caused by their dissociation was 91.1%, whereas longitudinal expansion was 2.3%. In cytotoxic-type edema induced by cerebral ischemia for 3 h, regional tissue compliance was decreased in the area suffering energy failure, which was visualized as an area of reduced succinic dehydrogenase activity. The ischemic gray matter showed isotropic swelling, and morphologically, prominent swelling of neuroglial cells. These marked differences in basic biomechanical properties between vasogenic-type and cytotoxic-type edema should be taken into account when analyzing the mechanism of edema-mediated tissue injury.

Real-time confocal microscopy of keratocyte activity in wound healing after cryoablation in rabbit corneas

A modified tandem scanning confocal microscope was used for real-time in vivo examination of the rabbit cornea following a cryogenic injury. The corneas of New Zealand white rabbits were frozen with a probe that had been cooled by immersion in liquid nitrogen, effectively destroying keratocytes in a central 5 mm diameter zone throughout the total thickness of the cornea. In these eyes, keratocyte repopulation and corneal stromal wound healing proceeded similarly to that which occurs after epikeratophakia, a refractive surgical procedure designed to change the curvature and optical power of the cornea. In epikeratophakia, a cryolathed donor corneal stroma lenticule is sutured onto the bare stroma of the recipient cornea. The collagen tissue lenticule is repopulated by keratocytes (corneal fibroblasts) that migrate in from the host cornea. In our study, the confocal microscope permitted sequential, noninvasive examination of the corneal stroma in the treated animals. Necrosis of the keratocytes, followed by activation of the remaining viable cells in the corneal periphery, was observed in the first 2 to 3 days after cryo injury. A fine stromal fibrous network was seen to develop; in three eyes, this network progressed to the development of a retrocorneal fibrous membrane and dense stromal fibrosis, both of which resulted in significant loss of corneal clarity. Our results suggest that the confocal microscope may be a valuable tool to provide much needed information on wound healing processes at the cellular level after corneal surgery and injury.

Early changes of blood-brain barrier and superoxide scavenging activity in rat cryogenic brain injury.

Cryogenic brain injury results in blood-brain barrier (BBB) disruption which may be mediated in part by oxygen free radicals. In this study, sequential changes of BBB and endogenous superoxide scavenging activity were investigated in brains subjected to cryogenic injury. 92 male Wistar rats were sacrificed at 15, 30 minutes, 1, 2, 3, 4, 6, 24 and 48 hours after the lesion. The extent of BBB disruption was determined by quantitative assessment of Evans blue (EB) uptake based on extraction from tissue using dimethylformamide. Determination of endogenous superoxide scavenging activity in the injured brain was performed by electron spin resonance spectrometry using a spin trapping agent. Superoxide scavenging activity was significantly decreased within one hour after the injury relative to normal rat brain (p < 0.05, student's t test) persisting for at least 6 hours. The EB content in the lesioned hemisphere was significantly increased within one hour after the injury relative to the normal rat brain (p < 0.01) and continued to increase for 24 hours. In conclusion, early changes of BBB and endogenous superoxide scavenging activity in rat cryogenic injured brain indicate that BBB may be an early target for oxygen free radicals in cryogenic brain injury.

Growth kinetics of a primary brain tissue necrosis from a focal lesion.

Secondary brain damage, such as brain edema or impairment of the cerebral microcirculation may evolve from tissue necrosis of the brain induced by trauma or ischemia. This laboratory has provided novel information on the secondary increase of a primary brain tissue necrosis resulting from a focal lesion. We have presently investigated more closely the growth kinetics of this process during 24 h after trauma. Rats were subjected to a standardized focal freezing injury of the brain. Area and volume of the resulting necrosis were quantitatively assessed by morphometry after different periods of survival (i.e., 5 min, 3, 6, 12, 18 and 24 h after trauma). The maximal area of necrosis increased by 45% (p < 0.001) during the posttraumatic observation period. Growth of necrosis after trauma was not limited to the early period, but continued between 12 and 24 h, amounting then to 29% (p < 0.05). The volume of necrosis calculated on the basis of histological serial sections was also observed to increase by 45%. The current findings confirm that a primary brain tissue lesion induced by a standard cryogenic injury, studied as model of a contusion focus in severe head injury, is subjected to secondary growth within a period of 24 h after trauma, longer periods of survival were not investigated yet. Quantification of lesion growth makes possible not only to study underlying mechanisms, but also of whether this process can be therapeutically inhibited.

A Focal Cryogenic Brain Lesion Does Not Reduce the Minimum Alveolar Concentration for Halothane in Rats

A focal cortical cryogenic brain injury has been reported to reduce the brain pentobarbital concentrations needed to prevent movement in response to pain in rats. This occurred despite any apparent behavioral changes in the awake animals. To determine whether this was true with other anesthetics, the authors determined the minimum alveolar concentration (MAC) for halothane in normothermic, normocarbic ventilated Sprague-Dawley rats previously subjected to a freezing injury of the parietal cortex. Injury was produced in halothane-anesthetized rats by applying a cold (-70 degrees C), 4-mm-diameter brass rod to the exposed dura for 5 or 15 s. Animals then were studied 3 days after injury, a time when cerebral metabolism in the ipsilateral hemisphere reaches a minimum. Minimum alveolar concentration was determined using a tail-clamp stimulus, combined with end-tidal anesthetic sampling. In addition, exploratory activity was measured by the open field test just before MAC determination, and spontaneous nocturnal motility was monitored by an electronic motion sensor during the night before testing. In normal animals subjected only to preparatory surgery, MAC was 1.10 +/- 0.07% (mean +/- SD). Almost identical values were found in rats subjected to 5- and 15-s cryogenic injuries (1.11 +/- 0.07% and 1.08 +/- 0.06%, respectively). There were no intergroup differences in open field test results or in spontaneous nocturnal activity. These results indicate that a focal cortical brain injury that has no obvious neurologic or behavioral effects in the awake rat does not alter halothane requirements.

Effects of cryothermia during cold cardioplegia on epicardial and intramural coronary arteries

Cryosurgery is playing an increasingly important role in the surgical treatment of various supraventricular and ventricular tachyarrhythmias. The short-term and long-term effects of cryogenic injury on epicardial and intramural coronary arteries were studied in 22 dogs. Transmural cryolesions encompassing a posterolateral branch of the circumflex coronary artery were produced in the inferior left ventricular wall during extracorporeal circulation and cold cardioplegic arrest. The mean epicardial cryolesion area ± standard deviation was 10.4 ± 1.8 cm 2. The mean epicardial coronary artery diameter ± standard deviation measured 1.2 ± 0.4 mm. At 6 hours, no important structural changes were noted in any of 6 dogs. At 48 hours, 1 of 2 epicardial coronary arteries showed recent thrombus. At 1, 3, and 6 months, the epicardial coronary arteries were occluded due to thrombosis and intimal hyperplasia in 13 of 14 dogs. A limited degree of recanalization was observed. At all follow-up intervals, the intramural coronary arteries exhibited a histologic pattern similar to that of the epicardial coronary arteries. It is concluded that the exposure of major epicardial coronary arteries to cryoinjury during cold cardioplegic arrest should be avoided where possible.

The Effects of Fentanyl and Sufentanil on Intracranial Pressure and Cerebral Blood Flow in Rabbits with an Acute Cryogenic Brain Injury

The cerebrovascular response to the administration of equipotent doses of fentanyl and sufentanil was evaluated in New Zealand white rabbits following cryogenic brain injury. In a preliminary study consisting of 10 animals, it was documented that the cerebral blood flow response to alterations in the PaCO2 remained intact in this model of brain injury. Subsequently, 28 rabbits were anesthetized with 1.5% halothane in oxygen, paralyzed with pancuronium, and mechanically ventilated. A cryogenic lesion was created over the left hemisphere. One hour later, the intracranial pressure had risen to a mean value of 15 mm Hg. Baseline measurements were then made of monitored variables, which included heart rate, mean arterial pressure, central venous pressure, intracranial pressure, temperature, and arterial blood gases. Global cerebral blood flow was measured utilizing a hydrogen clearance technique. The animals were then randomized to receive an infusion of fentanyl (N = 9, 200 microg/kg), sufentanil (N = 10, 20 microg/kg), or an equal volume of normal saline (N = 9) by i.v. infusion over 5 min. At the conclusion of the opioid infusions, repeated measurements of hemodynamic variables and intracranial pressure were recorded for 15 min and a second cerebral blood flow measurement was made. There were no significant differences in mean arterial pressure, heart rate, central venous pressure, intracranial pressure, cerebral blood flow, or blood gas values between the three groups prior to the administration of fentanyl, sufentanil, or normal saline. At the conclusion of the 5 min infusion, the intracranial pressure had increased by approximately 5 mm Hg in all three groups. The mean arterial pressure decreased to a similar degree in the fentanyl and sufentanil groups and was significantly lower than the mean arterial pressure in the saline group. Although the cerebral perfusion pressure decreased in all three groups, cerebral blood flow was not significantly affected. These results suggest that there is no significant difference in the effects of fentanyl vs. sufentanil on mean arterial pressure, intracranial pressure, or cerebral blood flow in this model of acute brain injury and elevated intracranial pressure.

Capillary NMDA receptors regulate blood-brain barrier function and breakdown

Polyamines and their regulatory synthetic enzyme ornithine decarboxylase (ODC) have been implicated in blood-brain barrier (BBB) breakdown following cryogenic injury. ODC activation and BBB breakdown are prevented by MK-801, indicating involvement of NMDA receptors. Studies in isolated rat cerebral capillaries supports the presence of NMDA receptors linked to ODC. NMDA (1–50 μM) stimulated capillary uptake of horseradish peroxidase, 2-deoxy-[ 14C]glucose, and 45Ca in a receptor-, concentration-, polyamine- and Ca 2+-dependent manner. We suggest that NMDA receptors may couple capillary transport of nutrients to glutamate-mediated neuronal excitation, and when overstimulated disrupt normal BBB function.

Focal brain injury results in severe cerebral ischemia despite maintenance of cerebral perfusion pressure.

Severe head injury often causes an increase in intracranial pressure (ICP) and decreases in cerebral blood flow (CBF) and cerebral oxygen delivery (CO2del). To determine if this reduction in CBF and CO2del would produce cerebral ischemia and if this reduction would be abrogated by maintaining global cerebral perfusion pressure (CPP), we studied CPP, ICP, CBF, CO2del, cerebral oxygen extraction ratio (CO2ER), and cortical water content (CWC) in a porcine model of focal cryogenic brain injury. Fifteen mature swine were randomized to two groups. The experimental group (n = 7) had a brain lesion and was studied for 24 hours. The control group (n = 8) was instrumented only. Cryogenic injury significantly increased ICP and decreased CBF and CO2del compared with controls. There were no significant differences in CPP between the groups for the entire experiment, and the CPP was well above the ischemic threshold. The CO2ER significantly increased in the first three hours after brain injury. However, CO2ER in experimental animals tended to decrease 12 hours after brain injury and was not significantly different from that in controls. Cryogenic injury significantly increased the CWC in the lesioned hemisphere. These data indicate that focal brain injury results in persistent ischemia despite the normalization of CPP, suggesting that a significant increase in cerebral vascular resistance (CVR) occurs after brain injury. We conclude that in addition to maintenance of CPP, intervention to reduce CVR may be important in the management of brain injury.

Reduced latency of the visual evoked cortical response following cryogenic injury to the cerebral cortex--a neuroexcitatory phenomenon.

Changes in the latency of visual cortical evoked responses (VER) were studied in rats subjected to cryogenic injury of the cerebral cortex. Four hours after cold injury the animals revealed a significant reduction of VER latency, which lasted approximately one week, with maximal reduction in latency occurring after 3 days. A potential role of excitotoxic amino acids in this phenomenon was tested by direct application of glutamate to the exposed cerebral cortex of the control rat and by administration of MK-801, antagonist of the NMDA receptor, in rats subjected previously to cryogenic injury and displaying a significant reduction in the VER latency. The direct application of glutamate to the cortex resulted in a decrease of the VER latency similar in magnitude to that observed after cold injury and this effect could repeatedly be demonstrated after washing out the initial application of the glutamate. The administration of MK-801 in animals subjected previously to cryogenic injury produced, within 5 minutes, reversion of reduced VER latencies. The maximal prolongation of latency occurred 30 min after MK-801 administration and reached in some cases latency values greater than in controls. Reduced latencies, corresponding to those observed originally, reappeared within 2 to 4 hours. Our studies suggest that the described reductions in the VER latencies are related to cortical areas of hyperexcitation due to excessive release of neuroexcitatory transmitters.

Decreased visual evoked cortical response latency associated with cerebral ischaemia in the gerbil.

The observation of Xu et al. concerning reduction in latency of the visual evoked responses (VER) following cortical cryogenic injury, prompted us to ascertain whether similar VER changes could be demonstrable after ischaemic brain injury, especially, since both conditions have in common involvement of neuroexcitatory mechanisms. In our study, the Mongolian gerbils, which were subjected to 10 min bilateral carotid occlusion ischaemia, revealed decreased latency of the VER, with the peak of latency reduction between 4 and 7 h. An almost immediate decrease in VER latency was observed when glutamate was directly applied to the pial surface of the brain. These observations indicate that the reduction of VER latency may be related to neuroexcitation induced by release of excitatory amino acids, the latter constituting a widespread phenomenon, concomitant with brain injuries of various aetiologies.

Intravenous fluid tonicity: effect on intracranial pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury

An investigation into the role of intravenous fluid tonicity in determining intracranial pressure (ICP) after brain injury is described. The authors compare the results of infusion of a hypotonic fluid (Ringer's lactate, 270 mOsm/liter) to those of a hypertonic fluid (hypertonic sodium lactate, 500 mOsm/liter) in a porcine model of focal cryogenic brain injury. Hemodynamic parameters (ICP, regional cerebral blood flow (CBF), and oxygen delivery) and serum osmolarity were measured every 3 hours for 24 hours after injury. At sacrifice, the water content of the lesioned and nonlesioned cortex was determined by specific gravity. The cryogenic injury produced a significant increase in ICP and a significant decrease in CBF in all experimental groups. Maintenance infusion of hypertonic sodium lactate for 24 hours resulted in significantly lower ICP, higher CBF and oxygen delivery, and higher serum osmolarity than Ringer's lactate infusion. Cortical water content in the area of the lesion was similar in both groups, but in the uninjured hemisphere it was significantly lower in the hypertonic group. These data suggest that hypertonic maintenance fluid improves intracranial compliance by dehydrating uninjured cortex. Improved CBF in the hypertonic group may be due to dehydration of cerebrovascular endothelium and erythrocytes. By reducing ICP and improving CBF, hypertonic fluid administration may thus reduce secondary brain injury after head trauma.