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There are many causes of acute myelopathy including multiple sclerosis, systemic disease (SD), and acute spinal cord compression (SCC). SCC should be among the first potential causes considered given the significant permanent loss of neurologic function commonly associated with SCC. This impairment can occur over a short period of time, and may be avoided through rapid and acute surgical intervention. Patients with SCC typically present with a combination of motor and sensory dysfunction that has a distribution referable to a spinal level. Bowel and bladder dysfunction and neck or back pain may also be part of the clinical presentation, but are not uniformly present. Because interventions are critically time-sensitive, the recognition and treatment of SCC was chosen as an ENLS protocol.

We have developed a piglet model to assess chemotherapy administration directly into the fourth ventricle as a potential treatment for medulloblastoma and other malignant posterior fossa tumors. The objective of this study was to assess safety and pharmacokinetics after methotrexate infusions into the fourth ventricle. Catheters were inserted into the fourth ventricle and lumbar cistern in five piglets. Two milligrams of Methotrexate (MTX) was infused into the fourth ventricle on five consecutive days. Safety was assessed by neurological examination, 4.7 T MRI, and post-mortem pathological analysis. MTX levels in serum and cerebrospinal fluid (CSF) were measured, and area under the concentration-time curve (AUC) was calculated for CSF samples. No neurological deficits were caused by MTX infusions. One piglet died from complications of anesthesia induction for MRI scanning. MRI scans showed accurate catheter placement without signal changes in the brainstem or cerebellum. One piglet had asymptomatic ventriculomegaly. Pathological analysis demonstrated meningitis and choroid plexitis consisting predominantly of CD-3 positive T-lymphocytes in all piglets and a small focal area of subependymal necrosis in one. In all piglets, mean peak MTX level in fourth ventricular CSF exceeded that in lumbar CSF by greater than five-fold. Serum MTX levels were undetectable or negligible. Statistically significant differences between fourth ventricle and lumbar AUC were detected at peaks (P = 0.01) and at all collection time points (P = 0.01) but not at troughs (P = 0.36). MTX can be infused into the fourth ventricle without clinical or radiographic evidence of damage. An inflammatory response without clinical correlate is observed. Significantly higher peak MTX levels are observed in the fourth ventricle than in the lumbar cistern.

We hypothesize that infusion of chemotherapeutic agents directly into the fourth ventricle potentially may play a role in treating malignant posterior fossa brain tumors. Accordingly, we used a piglet model developed in our laboratory to test the safety of etoposide infusions into the fourth ventricle and to study the pharmacokinetics associated with these infusions. In 5 piglets, closed-tip silicone catheters were inserted into the fourth ventricle and lumbar cistern. Five consecutive daily infusions of etoposide (0.5 mg) were administered via the fourth ventricle catheter. Serum and CSF from both catheters were sampled for measurement of etoposide level by reversed-phase high performance liquid chromatography (HPLC). For CSF samples, area under the concentration-time curve (AUC) was calculated. Piglets underwent daily neurological examinations, a 4.7 Tesla MRI scan, and then were sacrificed for post-mortem brain examination. No neurological deficits or signs of meningitis were caused by intraventricular chemotherapy infusions. MRI scans showed catheter placement within the fourth ventricle but no signal changes in the brain stem or cerebellum. In all piglets, the mean fourth ventricular CSF peak etoposide level exceeded the mean peak lumbar etoposide levels by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC were noted at peaks (DeltaAUC = 3384196 ng h/ml with 95%CI: 1758625, 5009767, P = 0.0044) and at all collection time points (DeltaAUC = 1422977 ng h/ml with 95%CI: 732188, 2113766, P = 0.0046) but not at troughs (DeltaAUC = -29546 ng h/ml (95%CI: -147526, 88434.2, P = 0.5251). Serum etoposide was absent at two and four hours after intraventricular infusions in all animals. Pathological analysis demonstrated meningitis, choroid plexitis, and ependymitis in the fourth and occasionally lateral ventricles. Etoposide can be infused directly into the fourth ventricle without clinical or radiographic evidence of damage. Autopsy examination revealed ventriculitis and meningitis which did not have a clinical correlate. Etoposide does not distribute evenly throughout CSF spaces after administration into the fourth ventricle, and higher peak CSF levels are observed in the fourth ventricle than in the lumbar cistern.

Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (308 degree C), normothermia (378 degree C), or hyperthermia (398 degree C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase ( JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120 min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24 h after injury. Our findings showed that only JNK activation at 15 min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.

Object: The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets., Methods: A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion., Results: All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 microg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation., Conclusions: Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.

Background: Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets., Methods: The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM)., Results: A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM., Conclusion: The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques.

Background/aims: Children born small for gestational age (SGA) are at increased risk for short stature and type 2 diabetes mellitus as a result of growth hormone (GH) resistance and insulin resistance. The mechanisms of multiple hormone resistance remain unclear. This study was designed to investigate the relationship between GH resistance and insulin resistance in non-catch-up growth (NCU-SGA) rats, and how their signaling pathways are related based on their crosstalk on the insulin receptor substrate-1 phosphatidylinositol 3'-kinase (IRS-1-PI3K) pathway., Methods: NCU-SGA rat model was developed by restricting prenatal food intake in pregnant dams. Activated levels of IRS-1 and Akt in liver protein extracts were compared between NCU-SGA and age- and sex-matched controls born appropriate for gestational age rats at baseline, after insulin stimulation, and after pretreatment with AG490 (GH-JAK2 pathway inhibitor) followed by insulin stimulation., Results: GH secretion was positively related to markedly increased insulin levels in NCU-SGA rats. There was no difference of IRS-1 phosphorylation in response to insulin between two groups, however, insulin-stimulated Akt phosphorylation was attenuated in NCU-SGA rats compared to appropriate for gestational age rats. Pretreatment with AG490 restored the Akt response to insulin demonstrated by significantly increased Akt phosphorylation., Conclusion: GH plays a role in inducing insulin resistance via signaling crosstalk with insulin at the level of PI3K/Akt in NCU-SGA rats., (Copyright 2008 S. Karger AG, Basel.)

Objective: To investigate the effects of Snoezelen therapy on physiological, cognitive and behavioural changes in children recovering from severe traumatic brain injury (TBI)., Methods: An observational study was conducted to assess the physiological, cognitive and behavioural changes of children recovering from severe TBI while receiving Snoezelen therapy. Fifteen subjects completed the pre- and post-Snoezelen treatment measurements computed over 10 consecutive sessions. Physiological, cognitive and behavioural measures were administered. Data was collected prospectively on each session in the Snoezelen room and were analysed by calculating the difference between pre- and post-treatment measurements for each Snoezelen session., Results: Results revealed significant changes on physiological measures. Heart rates decreased for each subject in each treatment session and were found to be significant (p = 0.032). Muscle tone was decreased in all the affected extremities (right upper extremity p = 0.009, left upper extremity p = 0.020, right lower extremity p = 0.036 and left lower extremity p = 0.018). Agitation levels decreased over time and the overall cognitive outcome measures showed significant improvement when comparing the beginning of treatment with the end., Conclusion: This study revealed a beneficial use of Snoezelen therapy with children recovering from severe brain injury. However, there continues to be a critical need for evidenced-based research for this patient population and others in this multi-sensory environment.

Positron emission tomography (PET) with [18F] fluoro-deoxy-glucose (FDG) provides information about glucose metabolism and is used to measure tissue glucose kinetics in the brain. The recent interest in hybrid SPECT/PET systems emerged as a practical approach to reduce the high cost of purchasing a dedicated ring-detector PET system. We have implemented interpolation methods for processing the projection data that could potentially reduce artifacts when reconstructing a dynamic imaging sequence in a PET study from a dual-head rotating SPECT/PET system. The computer simulations predict that parameter estimates from the dedicated PET system will be superior to results using the rotating camera system. However, the rotating camera system using projection interpolation may approach the accuracy of the dedicated PET system if the data noise is below 20%.

Objective: To measure the effect of pre-ischemic administration of intraluminal epidermal growth factor on the changes in intestinal permeability induced by 30 mins of superior mesenteric artery occlusion, followed by 2 hrs of reperfusion., Design: Prospective, randomized, placebo-controlled experimental study., Setting: University basic science research laboratory., Subjects: Healthy, young, adult, male Sprague-Dawley rats., Interventions: A 10-cm segment of small intestine was isolated and studied in situ in rats that were anesthetized with fentanyl and mechanically ventilated. Intestinal ischemia-reperfusion injury was induced by temporary occlusion of the superior mesenteric artery for 30 mins, followed by 2 hrs of reperfusion. Three groups were studied: time controls with a sham operation, saline-treated ischemia-reperfusion, and epidermal growth factor-treated ischemia-reperfusion. Epidermal growth factor, 100 ng/min, was infused intraluminally, beginning 30 mins before and continued until 40 mins after ischemia., Measurements and Main Results: Intestinal permeability was measured for each 10-min time period by using chromium-labeled EDTA. Histopathologic injury was assessed by light microscopy. After superior mesenteric artery occlusion, intestinal permeability increased approximately ten-fold and was sustained for 2 hrs of reperfusion in saline-treated rats. Pretreatment with epidermal growth factor significantly reduced the permeability changes during reperfusion by >60% compared with saline-treated animals (p <.05). Histopathologic sections revealed apparently more extensive loss of epithelial cells and mucosal disruption in saline-treated intestine compared with epidermal growth factor-treated intestine., Conclusion: Pre-ischemic administration of intraluminal epidermal growth factor significantly protects against intestinal ischemia-reperfusion injury.

Objective: Measure the fraction of inspired oxygen (F(IO(2))) in infants receiving supplemental oxygen via nasal cannula and identify clinical variables that affect F(IO(2))., Methods: Hypopharyngeal gas samples were obtained from 20 infants receiving oxygen via nasal cannula at flows between 0 and 4 L/min. F(IO(2)) was calculated using the alveolar gas equation and measurements of partial pressure of oxygen in the samples and the barometric pressure., Results: F(IO(2)) increased as oxygen flow was increased. F(IO(2)) exceeded safe levels (> 60%) in two thirds of samples when the oxygen flow was 2 L/min or higher. Tachypnea (respiratory rate > 40 breaths/min) was associated with lower F(IO(2))., Conclusion: Infants receiving oxygen via nasal cannula at > or = 2 L/min may be at risk for hyperoxic lung injury. Therefore, we recommend using the lowest possible oxygen flow needed to maintain normoxia in infants requiring prolonged oxygen therapy via nasal cannula.

Alterations in cerebral autoregulation and cerebrovascular reactivity after traumatic brain injury (TBI) may increase the susceptibility of the brain to secondary insults, including arterial hypotension. The purpose of this study was to evaluate the consequences of mild hemorrhagic hypotension on hemodynamic and histopathologic outcome after TBI. Intubated, anesthetized male rats were subjected to moderate (1.94 to 2.18 atm) parasagittal fluid-percussion (FP) brain injury. After TBI, animals were exposed to either normotension (group 1: TBI alone, n = 6) or hypotension (group 2: TBI + hypotension, n = 6). Moderate hypotension (60 mm Hg/30 min) was induced 5 minutes after TBI or sham procedures by hemorrhage. Sham-operated controls (group 3, n = 7) underwent an induced hypotensive period, whereas normotensive controls (group 4, n = 4) did not. For measuring regional cerebral blood flow (rCBF), radiolabeled microspheres were injected before, 20 minutes after, and 60 minutes after TBI (n = 23). For quantitative histopathologic evaluation, separate groups of animals were perfusion-fixed 3 days after TBI (n = 22). At 20 minutes after TBI, rCBF was bilaterally reduced by 57% +/- 6% and 48% +/- 11% in cortical and subcortical brain regions, respectively, under normotensive conditions. Compared with normotensive TBI rats, hemodynamic depression was significantly greater with induced hypotension in the histopathologically vulnerable (P1) posterior parietal cortex (P < 0.01). Secondary hypotension also increased contusion area at specific bregma levels compared with normotensive TBI rats (P < 0.05), as well as overall contusion volume (0.96 +/- 0.46 mm(3) vs. 2.02 +/- 0.51 mm(3), mean +/- SD, P < 0.05). These findings demonstrate that mild hemorrhagic hypotension after FP injury worsens local histopathologic outcome, possibly through vascular mechanisms.

Central administration of interleukin-1 beta (IL-1 beta) increases cerebral blood flow (CBF) and body temperature, in part, through the production of prostaglandins. In previous studies, the temporal relationship between these effects of IL-1 beta have not been measured. In this study, we hypothesized that the increase in CBF occurs before any change in brain or body temperature and that the cerebrovascular and thermoregulatory effects of IL-1 beta would be attenuated by inhibiting the production of nitric oxide (NO). Adult male rats received 100 ng intracerebroventricular (icv) injection of IL-1 beta, and cortical CBF (cCBF) was measured by laser-Doppler in the contralateral cerebral cortex. A central injection of IL-1 beta caused a rapid increase in cCBF to 133 +/- 12% of baseline within 15 min and to an average of 137 +/- 12% for the remainder of the 3-h experiment. Brain and rectal temperature increased by 0.4 +/- 0.2 and 0.5 +/- 0.2 degrees C, but not until 45 min after IL-1 beta administration. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg iv) completely prevented the changes in cCBF and brain and rectal temperature induced by IL-1 beta. L-Arginine (150 mg/kg iv) partially reversed the effects of L-NAME and resulted in increases in both cCBF and temperature. These findings suggest that the vasodilatory effects of IL-1 beta in the cerebral vasculature are independent of temperature and that NO plays a major role in both the cerebrovascular and thermoregulatory effects of centrally administered IL-1 beta.

OBJECTIVE: To test the hypothesis that cerebral and other regional organ blood flow would be maintained during partial liquid ventilation (PLV) in an animal model of acute lung injury during different ventilation strategies. DESIGN: A prospective, randomized study. SETTING: Animal research facility. SUBJECTS: Sixteen piglets, 2 to 4 wks of age. INTERVENTIONS: Severe lung injury was induced in infant piglets by repeated saline lavage and high tidal volume ventilation. Animals were then randomized to either conventional volume-controlled ventilation or PLV. MEASUREMENTS AND MAIN RESULTS: Organ blood flow was determined in both groups using radiolabeled microspheres under four conditions: high mean airway pressure, Paw; high Paco(2), high Paw; normal Paco(2); low Paw, high Paco(2); low Paw, normal Paco(2). There were no differences in cerebral blood flow during conventional ventilation and PLV, regardless of ventilation strategy. CONCLUSIONS: These results suggest in an acute lung injury model, PLV does not affect cerebral blood flow or other regional organ blood flow over a range of airway pressures.

OBJECTIVE: The most severe form of generalized junctional epidermolysis bullosa, the Herlitz variant, is associated with a number of extracutaneous manifestations. We report on a 45-day-old infant with laryngotracheobronchial mucosa involvement who underwent successful tracheal extubation after 10 days of orotracheal intubation and mechanical ventilatory support. Issues regarding airway management and mechanical ventilatory support in the pediatric intensive care unit are discussed.

Using infant piglets, we studied the effects of nonspecific inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME; 3 mg/kg) on vascular pressures, regional blood flow, and cerebral metabolism before 8 min of cardiac arrest, during 6 min of cardiopulmonary resuscitation (CPR), and at 10 and 60 min of reperfusion. We tested the hypotheses that nonspecific NO synthase inhibition 1) will attenuate early postreperfusion hyperemia while still allowing for successful resuscitation after cardiac arrest, 2) will allow for normalization of blood flow to the kidneys and intestines after cardiac arrest, and 3) will maintain cerebral metabolism in the face of altered cerebral blood flow after reperfusion. Before cardiac arrest, L-NAME increased vascular pressures and cardiac output and decreased blood flow to brain (by 18%), heart (by 36%), kidney (by 46%), and intestine (by 52%) compared with placebo. During CPR, myocardial flow was maintained in all groups to successfully resuscitate 24 of 28 animals [P value not significant (NS)]. Significantly, L-NAME attenuated postresuscitation hyperemia in cerebellum, diencephalon, anterior cerebral, and anterior-middle watershed cortical brain regions and to the heart. Likewise, cerebral metabolic rates of glucose (CMRGluc) and of lactate production (CMRLac) were not elevated at 10 min of reperfusion. These cerebral blood flow and metabolic effects were reversed by L-arginine. Flows returned to baseline levels by 60 min of reperfusion. Kidney and intestinal flow, however, remained depressed throughout reperfusion in all three groups. Thus nonspecific inhibition of NO synthase did not adversely affect the rate of resuscitation from cardiac arrest while attenuating cerebral and myocardial hyperemia. Even though CMRGluc and CMRLac early after resuscitation were decreased, they were maintained at baseline levels. This may be clinically advantageous in protecting the brain and heart from the damaging effects of hyperemia, such as blood-brain barrier disruption.

Objectives: To test the hypothesis that selective brain cooling could be performed in an infant model of cardiac arrest and resuscitation without changing core temperature and to study its acute effects on regional organ blood flow, cerebral metabolism, and systemic hemodynamics., Design: Prospective, randomized, controlled study., Setting: Research laboratory at a university medical center., Subjects: Fourteen healthy infant piglets, weighing 3.5 to 6.0 kg., Interventions: piglets were anesthetized and mechanically ventilated, and had vascular catheters placed. Parietal cortex (superficial brain), caudate nucleus (deep brain), esophageal, and rectal temperatures were monitored. All animals underwent 6 mins of cardiac arrest induced by ventricular fibrillation, 6 mins of external cardiopulmonary resuscitation (CPR), defibrillation, and 2 hrs of reperfusion. Normal core temperature (rectal) was regulated in all animals. In seven control animals (group 1), brain temperature was not manipulated. In seven experimental animals (group 2), selective brain cooling was begin during CPR, using a cooling cap filled with -30 degrees C solution. Selective brain cooling was continued for 45 mins of reperfusion after which passive rewarming was allowed. Regional blood flow (microspheres) and arterial and sagittal sinus blood gases were measured prearrest, during CPR, and at 10 mins, 45 mins, and 2 hrs of reperfusion., Measurements and Main Results: Rectal temperature did not change over time in either group. In group 1, brain temperature remained constant except for a decrease of 0.6 degrees C at 10 mins of reperfusion. In group 2, superficial and deep brain temperatures were lowered to 32.8 +/- 0.7 (SEM) degrees C and 34.9 +/- 0.4 degrees C, respectively, by 15 mins of reperfusion. Superficial and deep brain temperatures were further lowered to 27.8 +/- 0.8 degrees C and 31.1 +/- 0.3 degrees C, respectively, at 45 mins of reperfusion. Both temperatures returned to baseline by 120 mins. Cerebral blood flow was not different between groups at any time point, although there was a trend for higher flow in group 2 at 10 mins of reperfusion (314% of baseline) compared with group 1 (230% of baseline). Cerebral oxygen uptake was lower in group 2 than in group 1 (69% vs. 44% of baseline, p=.02) at 45 mins of reperfusion. During CPR, aortic diastolic pressure was lower in group 2 than in group 1 (27 +/- 1 vs. 23 +/- 1 mm Hg, p = .007). Myocardial blood flow during CPR was also lower in group 2 (80 +/- 7 vs. 43 +/- 7 mL/min/100 g, p=.002). Kidney and intestinal blood flows were reduced during CPR in both groups; however, group 2 animals also had lower intestinal flow vs. group 1 at 45 and 120 mins of reperfusion., Conclusions: Selective brain cooling by surface cooling can be achieved rapidly in an infant animal model of cardiac arrest and resuscitation without changing core temperature. Brain temperatures known to improve neurologic outcome can be achieved by this technique with minimal adverse effects. Because of its ease of application, selective brain cooling may prove to be an effective, inexpensive method of cerebral resuscitation during pediatric CPR.

High-frequency ventilation is indicated when acute hypoxemic respiratory failure is associated with an ongoing air leak. This report describes the successful use of high-frequency oscillatory ventilation in a child with pulmonary contusions and traumatic pulmonary pseudocysts who experienced severe air leak syndrome on conventional mechanical ventilation.

This study examined the early microvascular and neuronal consequences of cardiac arrest and resuscitation in piglets. We hypothesized that early morphological changes occur after cardiac arrest and reperfusion, and that these findings are partly caused by post-resuscitation hypertension. Three groups of normothermic piglets (37.5 degrees - 38.5 degrees C) were investigated: group 1, non-ischemic time controls; group 2, piglets undergoing 8 min of cardiac arrest by ventricular fibrillation, 6 min of cardiopulmonary resuscitation (CPR) and 4 h of reperfusion; and group 3, non-ischemic hypertensive controls, receiving 6 min of CPR after only 10 s of cardiac arrest followed by 4-h survival. Immediately following resuscitation, acute hypertension occurred with peak systolic pressure equal to 197 +/- 15 mm Hg usually lasting less than 10 min. In reacted vibratome sections, isolated foci of extravasated horseradish peroxidase were noted throughout the brain within surface cortical layers and around penetrating vessels in group 2. Stained plastic sections of leaky sites demonstrated variable degrees of tissue injury. While many sections were unremarkable except for luminal red blood cells and leukocytes, other specimens contained abnormal neurons, some appearing irreversibly injured. The number of vessels containing leukocytes was higher in group 2 than in controls (3.8 +/- 0.6% vs 1.4 +/- 0.4% of vessels, P < 0.05). Evidence for irreversible neuronal injury was only seen in group 2. Endothelial vacuolization was higher in groups 2 and 3 than in group 1 (P < 0.05). Ultrastructural examination of leaky sites identified mononuclear and polymorphonuclear leukocytes adhering to the endothelium of venules and capillaries only in group 2. The early appearance of luminal leukocytes in ischemic animals indicates that these cells may contribute to the genesis of ischemia reperfusion injury in this model. In both groups 2 and 3 endothelial cells demonstrated vacuolation and luminal discontinuities with evidence of perivascular astrocytic swelling. Widespread microvascular and neuronal damage is present as early as 4 h after cardiac arrest in infant piglets. Hypertension appears to play a role in the production of some of the endothelial changes.

Background and Purpose: Previous in vitro and in vivo studies of the effects of nitric oxide synthase inhibition in the central nervous system have yielded conflicting results concerning the role of nitric oxide in the events that lead to ischemic injury. In this study, we tested the hypothesis that preischemic inhibition of nitric oxide synthase increases infarct volume after reversible focal cerebral ischemia in rats., Methods: NG-nitro-L-arginine methyl ester hydrochloride 15 mg/kg IV or an equivalent volume of saline was administered to adult Wistar rats 15 minutes before middle cerebral artery occlusion by the intraluminal suture method. After 2 hours of ischemia, the suture was withdrawn, and rats were allowed to survive for 3 days. Areas of infarction in 10 hematoxylin-eosin-stained sections were measured and used to determine infarct volume., Results: Administration of NG-nitro-L-arginine methyl ester hydrochloride increased hemispheric infarct volume by 137% over control (60.9 +/- 30.5 to 144.3 +/- 19.6 mm3, P < .05; mean +/- SEM). Cortical and subcortical infarct volumes were increased by 176% (33.8 +/- 21.9 to 93.3 +/- 15.2 mm3, P < .05) and 103% (25.1 +/- 9.4 to 51.0 +/- 5.5 mm3, P < .03), respectively., Conclusions: Nitric oxide synthase inhibition increases infarct volume and decreases the variability of the response to middle cerebral artery occlusion in Wistar rats, a strain that is normally resistant to focal cerebral ischemic injury owing to extensive collateralization. The mechanism of the deleterious effect of nitric oxide synthase inhibition likely involves a more severe degree of blood flow reduction during and after middle cerebral artery occlusion, primarily by preventing the vasodilatory response of collateral vessels to proximal middle cerebral artery occlusion. Maintenance of nitric oxide synthase activity during and after focal cerebral ischemia appears to minimize ischemic injury.

Background and Purpose: We tested the hypothesis that fructose-1,6-bisphosphate, when administered 10 minutes before the end of 2 hours of reversible middle cerebral artery occlusion, reduces ischemia-reperfusion injury and infarct volume measured after a 3-day survival period in rats., Methods: After 1 hour and 50 minutes of middle cerebral artery occlusion by the intraluminal suture method, fructose-1,6-bisphosphate, 500 mg/kg in group 1 and 350 mg/kg in group 2 (or an equivalent volume of 1.8% saline as placebo in each group), was given intravenously for a period of 15 minutes to fasted adult Sprague-Dawley rats. After 2 hours of ischemia, the suture was withdrawn and the rats allowed to survive for 3 days. The areas of infarction in 10 hematoxylin-eosin-stained coronal sections of the brain were measured and used to calculate infarct volume., Results: In group 1, fructose-1,6-bisphosphate decreased total cerebral hemispheric infarct volume by 43% (from 199.6 +/- 11.2 to 114.2 +/- 35.8 mm3, P < .04; mean +/- SEM). Cerebral cortical and subcortical infarct volumes were decreased by 46% (from 137.3 +/- 7.5 to 74.1 +/- 28.6 mm3, P < .04) and 36% (from 62.3 +/- 5.1 to 40.0 +/- 8.3 mm3, P < .04), respectively. In group 2, fructose-1,6-bisphosphate had no effect on infarct volume in rats that developed mild intraischemic hyperthermia, but in rats kept normothermic during ischemia, fructose-1,6-bisphosphate reduced subcortical infarct volume from 53.7 +/- 8.1 to 18.4 +/- 8.0 mm3 (P < .03)., Conclusions: Fructose-1,6-bisphosphate improves functional neurological outcome and reduces infarct volume after reversible middle cerebral artery occlusion in rats.

To evaluate the effect of selective brain cooling on cortical cerebral blood flow, we reduced brain temperature in nitrous oxide anesthetized adult rats using a high speed fan while keeping rectal temperature at 37-38 degrees C. During selective brain cooling, cortical cerebral blood flow, as measured by laser-Doppler flowmetry, increased to 215 +/- 26% (mean +/- SE) of baseline at a cortical brain temperature of 30.9 +/- 0.5 degrees C and a rectal temperature of 37.5 +/- 0.1 degrees C. During rewarming, as brain temperature increased, cortical cerebral blood flow decreased. The cerebral vasodilatory response to hypothermia may explain its protective effects during and after cerebral ischemia.

Background and Purpose: Studies of the cerebroprotective effects of selective brain cooling have failed to show amelioration of ischemic injury in the cerebral cortex. This study was designed to test the hypothesis that mild-to-moderate selective brain cooling initiated after the onset of global brain ischemia in rats protects the cerebral cortex and improves neurological outcome., Methods: Global forebrain ischemia for 30 minutes in 27 fasted adult male Wistar rats was achieved by bilateral carotid occlusion and hypotension. In group 1, brain temperature, measured in the temporalis muscle, was maintained at 37-38 degrees C throughout the experiment. In group 2, brain temperature fell spontaneously during ischemia to 34.7 +/- 0.1 degrees C and rose spontaneously to 36-37 degrees C after 10 minutes of recirculation. In group 3, brain temperature was lowered with ice packs placed around the head after 15 minutes of ischemia to 24.1 +/- 0.9 degrees C by the end of ischemia, maintained at 30.0 +/- 1.0 degrees C for the first hour of recirculation, then allowed to rise to 36-37 degrees C., Results: Seven-day survival was 0% (0 of 6) in group 1, 73% (8 of 11) in group 2, and 100% (6 of 6) in group 3. Severity of neuronal damage was less in group 2 than in group 1 in the cortex (p < 0.05) and hippocampal CA1 (p < 0.05) and CA3 regions (p < 0.05). Group 3 had less neuronal damage than group 2 in both cortex (p < 0.02) and striatum (p < 0.02). Furthermore, postischemic weight loss was less and neurobehavioral scores were significantly higher in group 3., Conclusions: This study shows that selective brain cooling increases survival from prolonged global ischemia and reduces neuronal injury in the cerebral cortex as well as the striatum and hippocampus.