Edwin M. Nemoto

Global brain ischemia: a reproducible monkey model.

We developed a monkey model of 16 minutes global brain ischemia (GBI) resulting in reproducible, severe, permanent functional neurologic deficit with long term (7 days) postischemic (PI) survival made possible by standardized intensive care with 24 hour coverage by trained personnel. Quantitated neurologic deficit (ND) and brain histopathological examinations were developed. Fifteen minutes GBI resulted in rapid recovery within12--24 hours PI without residual neurologic sequelae. Twenty minutes GBI caused severe neurologic deficit and within 4 days PI, a delayed Cushing response eventually leading to cardiac arrest. Sixteen minutes GBI resulted in severe neurologic deficit (monkeys unable to sit, stand, walk, or feed themselves), but with long term survival. Brain histopathological analyses revealed a combination of cortical and brainstem lesions. Severest changes were observed in the occipital (calcarine) cortex with less severe damage in the frontal and temporal regions. Oculomotor nuclei and medial longitudinal fasciculus in the midbrain were regularly affected. With this model we can test the efficacy of promising therapies in terms of clinically relevant variables.

Regional low-flow perfusion provides somatic circulatory support during neonatal aortic arch surgery

BACKGROUNDnRegional low-flow perfusion has been shown to provide cerebral circulatory support during neonatal aortic arch operations. However, its ability to provide somatic circulatory support remains unknown.nnnMETHODSnFifteen neonates undergoing arch reconstruction with regional perfusion were studied. Three techniques were used to assess somatic perfusion: abdominal aortic blood pressure, quadriceps blood flow (near-infrared spectroscopy), and gastric tonometry.nnnRESULTSnTwelve patients required operation for hypoplastic left heart syndrome, and 3 required arch reconstruction with a biventricular repair. There was one death (7%). Abdominal aortic blood pressure was higher (12+/-3 mm Hg versus 0+/-0 mm Hg), and quadriceps blood volumes (5+/-24 versus -17+/-26) and oxygen saturations (57+/-25 versus 33+/-12) were greater during regional perfusion than during deep hypothermic circulatory arrest (p < 0.05). During rewarming, the arterial-gastric mucosal carbon dioxide tension difference was lower after circulatory arrest than after regional perfusion (-3.3+/-0.3 mm Hg versus 7.8+/-7.6 mm Hg, p < 0.05).nnnCONCLUSIONSnRegional low-flow perfusion provides somatic circulatory support during neonatal arch surgical procedures. Support of the subdiaphragmatic viscera should improve the ability of neonates to survive the postoperative period.

Loss of Cell Ion Homeostasis and Cell Viability in the Brain: What Sodium MRI Can Tell Us

This chapter demonstrates the use of sodium magnetic resonance imaging (MRI) as a noninvasive, in vivo means to assess metabolic changes that ensue from loss of cell ion homeostasis due to cell death in the brain. The chapter is organized in two sections. In the first section, the constraints imposed on the imaging methods by the nuclear magnetic resonance (NMR) properties of the sodium ion are discussed and strategies for avoiding their potential limitations are addressed. The second section illustrates the use of sodium MRI for monitoring focal brain ischemia in permanent and temporary primate models of endovascular middle cerebral artery occlusion.

Cerebrovascular Reserve in Patients With Carotid Occlusive Disease Assessed by Stable Xenon-Enhanced CT Cerebral Blood Flow and Transcranial Doppler

Background and Purpose— Cerebrovascular reserve (CVR) by both transcranial Doppler ultrasonography (TCD) and quantitative cerebral blood flow (CBF) can identify subgroups of patients at increased risk for stroke. A direct comparison of CVR measurements obtained with both technologies in patients with cerebrovascular occlusive disease is lacking. Methods— CVRs before and after acetazolamide administration (1 g IV) were measured by TCD insonation of the middle cerebral artery (MCA) and CBF obtained with stable xenon CT (Xe/CT) in 38 patients with carotid occlusive disease. Sensitivity/specificity calculations were based on 2 Xe/CT MCA values: an average over 4 levels and the level with the lowest percent change in CBF. Compromised CVR was defined as no reactivity or a decrease in reactivity. Results— Using the analysis of the systolic TCD, we found that velocity changes compared with the average Xe/CT MCA CVR showed a sensitivity of 33%, specificity of 90.6%, positive predictive value of 54.5%, and negative predictive value of 80%. The sensitivity of TCD compared with the lowest Xe/CT CBF CVR was 35.5%, specificity and positive predictive values were 100%, and negative predictive value was 66.7%. The index of validity was between 72% and 76%. Conclusions— TCD is much less sensitive than Xe/CT CBF in identifying patients with compromised CVR. This may be a result of the inability of TCD to identify patients with compromised reserves when their MCA blood flow comes from collateral sources. The lack of correlation between TCD and Xe/CT CBF for identifying patients with compromised CVR should be considered when stroke risk assessments are made by TCD.

Identification of Hemodynamic Compromise by Cerebrovascular Reserve and Oxygen Extraction Fraction in Occlusive Vascular Disease

Cerebrovascular reserve (CVR) and oxygen extraction fraction (OEF) are used to identify hemodynamic compromise in symptomatic patients with carotid occlusive vascular disease, but evidence suggests that they are not equivalent. The authors studied the relationship between CVR and OEF to evaluate their equivalence and stages of hemodynamic compromise. Symptomatic patients (N = 12) with carotid occlusion were studied by stable xenon–computed tomography CBF after intravenous acetazolamide administration for CVR, followed within 24 hours by positron emission tomography (PET) for OEF. Middle cerebral artery territories were analyzed by hemisphere and level. Hemispheric subcortical white matter infarctions were graded with magnetic resonance imaging. Both hemispheric and level analysis of CVR and OEF showed a significant (P = 0.001), negative linear relationship [CVR (%) = −1.5 (OEF) + 83.4, (r = −0.57, P = 0.001, n = 24]. However, 37.5% of the hemispheres showed compromised CVR but normal OEF and were associated (P = 0.019) with subcortical white matter infarction. CMRO2 was elevated in stage II hemodynamic compromise (CVR < 10%, OEF > 50%). CVR and OEF showed a significant negative linear relationship in stage II hemodynamic compromise but revealed hemispheres in hemodynamic compromise by CVR but normal OEF that were associated with subcortical white matter infarction.

Barbiturate Attenuation of Brain Free Fatty Acid Liberation During Global Ischemia

Abstract: To find a biochemical basis for the increased tolerance of the brain to anoxia during barbiturate anesthesia, we studied whole‐brain free fatty acids (FFA) at various times after decapitation of awake and pentobarbital‐anesthetized rats. Post‐decapitation, the brains were kept at 37°C for 1 to 60 min before freezing in liquid N2. Nonischemic brains were frozen in liquid N2, using a rapid sampling technique. Whole‐brain arachidonic, stearic, oleic, linoleic, and palmitic acids were quantitated by gas‐liquid chromatography. In unanesthetized, nonischemic brain, total FFA was 1226 ± 121 nmol/g brain (n= 12) and was unaffected by pentobarbital anesthesia (1126 ± 86 nmol/g brain, n= 11), except for a reduction in arachidonic acid. Total FFA in unanesthetized and pentobarbital‐anesthetized rats transiently declined between 0 and 1 min of ischemia, and then rose linearly for up to 60 min, with consistently lower values in pentobarbital‐treated rats, the greatest attenuation being that of arachidonic and stearic acid liberation. Brain FFA liberation during global ischemia is the first known biochemical variable directly correlated with the duration (i.e., severity) of global ischemia. The attenuation of brain FFA liberation and especially of arachidonic and stearic acids may be the biochemical basis of barbiturate attenuation of ischemic brain injury.

Cerebrovascular and cerebrometabolic effects of intracarotid infused platelet-activating factor in rats

Platelet-activating factor has been implicated in a variety of disease processes including ischemic brain injury and endotoxic shock, but its effects on cerebral blood flow (CBF) and metabolism in normal brain have not been described. The effects of platelet-activating factor on global CBF (hydrogen clearance) and the global cerebral metabolic rate for oxygen (CMRO2) were studied in halothane-N2O anesthetized Wistar rats. Hexadecyl-platelet-activating factor infused into the right carotid artery (67 pmol/min) for 60 min decreased mean arterial pressure (MAP) from 122 ±4 (x ± SEM) to 77 ± 6 mm Hg and CBF from 159 ± 12 to 116 ± 14 ml/100 g/min (p < 0.002). In contrast, CMRO2 increased from 9.7 ± 0.9 to 11.7 ± 1.1 ml/100 g/min after 15 min (p < 0.05). In controls rendered similarly hypotensive by blood withdrawal and infused with the platelet-activating factor vehicle, CMRO2 was unchanged, whereas CBF transiently decreased then returned to baseline at 60 min. These cerebrovascular and cerebrometabolic effects of PAF are reminiscent of and may be relevant to hypoperfusion and hypermetabolism observed after global brain ischemia and in endotoxic shock.

Reassessment of Brain Free Fatty Acid Liberation During Global Ischemia and Its Attenuation by Barbiturate Anesthesia

Abstract: We previously reported that whole‐brain free fatty acids (FFA) rose almost linearly for up to 1 h after decapitation of unanesthetized rats and was significantly attenuated by pentobarbital anesthesia. However, our values for total FFA and arachidonic, stearic, oleic, and palmitic acids were severalfold higher than those obtained by previous investigators. Based upon the suggestion that this may be due to FFAs released from di‐ and triglycerides in the quantitation of FFAs, we have now analyzed and improved our procedures for TLC separation of FFA and reassessed the accumulation of FFA in whole brain during decapitation ischemia in unanesthetized and pentobarbital‐anesthetized rats. FFA levels in whole brain after 0.5 min of ischemia were one‐half to one‐ fourth the levels previously reported after 1 min of ischemia. The rise in FFA between 0.5 and 60 min of ischemia was 9‐fold for total FFA, and between 7 and 12‐fold for each of the FFAs quantitated. Pentobarbital significantly attenuated the rise of all FFAs with, however, greater effects on oleic and palmitic acids than previously reported.

Increased hepatic platelet activating factor (PAF) and PAF receptors in carbon tetrachloride induced liver cirrhosis

Background and aims: The liver is a major site for the synthesis and actions of platelet activating factor (PAF), a potent hepatic vasoconstrictor and systemic vasodilator. As PAF is implicated in portal hypertension and hyperdynamic circulation associated with liver cirrhosis, we characterised changes in the hepatic PAF system in experimental cirrhosis. Methods: In rats made cirrhotic by carbon tetrachloride (CCl4) administration for eight weeks, we determined hepatic levels of PAF and its cognate receptor, and the effects of PAF and PAF antagonist (BN52021) on portal and arterial pressure. Results: Compared with control rats, cirrhotic rats had higher hepatic PAF levels, higher apparent hepatic efflux of PAF, and higher PAF levels in arterial blood (p<0.01, p<0.01, p<0.05, respectively). Relative to controls, cirrhotic livers had elevated hepatic PAF receptors (by mRNA and protein levels and [3H]PAF binding), higher (p<0.01) baseline hepatic portal pressure, and an augmented (pu200a=u200a0.03) portal pressure response to PAF infusion (1 μg/kg). Portal infusion of BN52021 (5 mg/kg) showed that elevated endogenous PAF was responsible for 23% of the cirrhotic portal pressure increase but made no contribution to systemic hypotension. Finally, increased PAF receptor density was observed in the contractile perisinusoidal stellate cells isolated from cirrhotic livers relative to those from control livers. Conclusions: In cirrhosis, increased hepatic release of PAF elevates systemic PAF; in combination with upregulated hepatic PAF receptors in stellate cells, this contributes to portal hypertension.

Measurement of cytochrome oxidase redox state by near infrared spectroscopy.

Although near infrared spectroscopy (NIRS) is primarily used to probe changes in oxyhaemoglobin (HbO2) and deoxyhaemoglobin (dHb) concentrations, it has long been realised that there is a significant oxygen-concentration dependent near infrared signal from the mitochondrial enzyme cytochrome c oxidase. In this paper we discuss the origins of this near infrared (NIR) signal, the possible factors affecting its intensity and its likely physiological and clinical significance. This paper complements our recent review on this subject1.