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Background and Purpose: Cardiac arrest and resuscitation in immature piglets result in a delayed increase in blood-brain barrier permeability. We tested the hypothesis that pretreatment with oxygen radical scavengers reduces postischemic permeability., Methods: Permeability was assessed by measuring the plasma-to-brain transfer coefficient of the small amino acid, alpha-aminoisobutyric acid, in 2- to 3-week-old anesthetized piglets. Three groups were studied: (1) a nonischemic time control group (n = 5), (2) an ischemia group (n = 8) pretreated with 5 mL of polyethylene glycol vehicle, and (3) an ischemia group (n = 8) pretreated with polyethylene glycol conjugated to superoxide dismutase (10,000 U/kg) and to catalase (20,000 U/kg). The ischemia protocol consisted of 8 minutes of ventricular fibrillation, 6 minutes of cardiopulmonary resuscitation, defibrillation, and 4 hours of spontaneous circulation., Results: The mean +/- SEM of the transfer coefficient of alpha-aminoisobutyric acid in cerebrum was (in microL/g per minute): 1.54 +/- 0.37 in the nonischemic group, 2.04 +/- 0.26 in the ischemia group treated with vehicle, and 1.29 +/- 0.25 in the ischemia group treated with oxygen radical scavengers. Postischemic values with scavenger treatment were significantly lower than those with vehicle treatment in cerebrum, cerebellum, medulla and cervical spinal cord., Conclusions: Pretreatment with oxygen radical scavengers reduces postischemic blood-brain barrier permeability by a small amino acid. These data are consistent with oxygen radical-mediated dysfunction of cerebral endothelium in a pediatric model of cardiopulmonary resuscitation.

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 After 2 hours of ischemia, the suture was withdrawn, and rats were allowed to survive for 3 days.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.

Background and Purpose: Epinephrine administration during cardiopulmonary resuscitation increases cerebral blood flow by increasing arterial pressure. We tested whether potential beta-adrenergic effects of epinephrine directly influence cerebral blood flow and oxygen consumption independently of raising perfusion pressure., Methods: Four groups of seven anesthetized dogs were subjected to 8 minutes of fibrillatory arrest followed by 6 minutes of chest compression, ventricular defibrillation, and 4 hours of spontaneous circulation. Cerebral perfusion pressure was increased to approximately equivalent ranges during resuscitation by either 1) epinephrine infusion, 2) epinephrine infusion after pretreatment with the lipophilic beta-adrenergic antagonist pindolol, 3) infusion of the alpha-adrenergic agonist phenylephrine, or 4) descending aortic balloon inflation without pressor agents., Results: We found no difference in cerebral blood flow, oxygen extraction, or oxygen consumption during chest compression among groups. After ventricular defibrillation, depressed levels of cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potential amplitude were not different among groups., Conclusions: We detected no evidence that after 8 minutes of complete ischemia, epinephrine administration during resuscitation substantially influences cerebral blood flow or cerebral oxygen consumption independent of its action of raising arterial pressure or or that epinephrine has a negative impact on immediate metabolic or electrophysiological recovery attributable to its beta-adrenergic activity.

We investigated blood-brain barrier permeability in 2-3-week-old anesthetized pigs during and after cardiopulmonary resuscitation. We assessed permeability by tissue uptake of radiolabeled aminoisobutyric acid, after correcting for plasma counts in tissue with radiolabeled inulin. Among 14 regions examined, the transfer coefficient of aminoisobutyric acid in nonischemic control animals ranged from 0.0018 +/- 0.0001 ml/g/min in diencephalon to 0.0049 +/- 0.0003 ml/g/min in cervical spinal cord. After 8 minutes of cardiac arrest followed by either 10 or 40 minutes of continuous sternal compression, there was no increase in the transfer coefficient. Likewise, during the immediate period after ventricular defibrillation, there was no increase in transfer coefficient despite the brief, transient hypertension. However, after 8 minutes of arrest, 6 minutes of cardiopulmonary resuscitation, and 4 hours of spontaneous circulation, the transfer coefficient was significantly increased by 59-107% in 10 of 11 regions rostral to the pons. Plasma volume in tissue measured by inulin was not elevated, suggesting that the increased transfer coefficient was not due to increased surface area. Thus, after an 8-minute period of complete ischemia, the blood-brain barrier remains intact during and immediately after resuscitation despite large vascular pressure fluctuations. However, in contrast to previous work on adult dogs, immature pigs are prone to a delayed increase in permeability, thereby allowing circulating substances greater access to the brain.

Blood-brain barrier integrity during cardiopulmonary resuscitation may be important because of the potential effects of adrenergic agonists administered during arrest on cerebral metabolism and the cerebral vasculature. As an index of blood-brain barrier permeability to small molecules, we measured the brain uptake of [14C]alpha-aminoisobutyric acid during a 10-minute period in 25 anesthetized dogs. To correct for the amount of carbon-14 label in the plasma space, we administered [3H] inulin 2 minutes before death. The mean transfer coefficient in 14 brain regions of five control dogs ranged from 0.002 to 0.007 ml/g/min. After 8 (n = 15) or 15 (n = 5) minutes of cardiac arrest, external chest compression was instituted to maintain aortic blood pressure above 60 mm Hg. The transfer coefficient was not elevated during chest compression (n = 10), immediately following defibrillation (n = 5), or 4 hours after resuscitation (n = 5); in some brain regions the transfer coefficient decreased. However, the decrease in the transfer coefficient was proportional to the decrease in the cerebral plasma volume as measured by the ratio of the [3H]inulin concentration in the tissue to that in the plasma. Thus, it is unlikely that a decrease in capillary surface area masked an increase in blood-brain barrier permeability. Therefore, we found no evidence of blood-brain barrier disruption during or after cardiopulmonary resuscitation in dogs. Despite the large phasic increases in sagittal sinus pressure associated with external chest compression, concurrent increases in cerebrospinal fluid pressure apparently protect the microcirculation from increased transmural pressure.