Recovery of cerebral blood flow and energy state in piglets after hypothermic circulatory arrest versus recovery after low-flow bypass.

A miniature piglet model that replicates clinical hypothermic (14 degrees C nasopharyngeal) circulatory arrest and low-flow (50 ml/kg per minute) bypass was used to study carotid blood flow with electromagnetic flow probe, cerebral blood flow by microsphere injection, cerebral metabolic rate by arteriovenous oxygen and glucose extractions, lactate production by cerebral arteriovenous difference, and cerebral edema. Data from five animals that underwent circulatory arrest and five animals that underwent low-flow bypass (aged 28.8 +/- 0.4 [mean +/- standard error of the mean] days) were analyzed. The duration of circulatory arrest and low-flow bypass was 1 hour. In a parallel study with the same animal model, phosphorus 31 magnetic resonance spectroscopy was used to assess cerebral phosphocreatine, nucleoside triphosphate (adenosine triphosphate), and intracellular pH. Five animals (aged 31.8 +/- 1.1 days) underwent circulatory arrest, and five underwent low-flow bypass. A brief phase of hyperemic carotid blood flow was seen immediately after the onset of reperfusion in the circulatory arrest group but not in the low-flow group. In the circulatory arrest and low-flow bypass groups, cerebral blood flow (percentage of baseline 71.2% +/- 8.3% and 69.1% +/- 5.8%, respectively), cerebral oxygen consumption (45.6% +/- 10.0%, 44.5% +/- 7.6%), and cerebral glucose consumption (31.5% +/- 30.7%, 83.5% +/- 24.2%) remained depressed after 45 minutes of reperfusion and rewarming to normothermia. However, after 3 more hours of pulsatile normothermic reperfusion, cerebral oxygen consumption and cerebral glucose consumption had returned to baseline. Phosphocreatine, adenosine triphosphate, and pH were maintained at or above baseline levels throughout low-flow bypass and throughout 3 hours of normothermic reperfusion. In contrast, both phosphocreatine and adenosine triphosphate became undetectable 32 +/- 3.7 minutes after onset of circulatory arrest. During and early after circulatory arrest, pH decreased to a minimum of 6.506 +/- 0.129 at 40 minutes after reperfusion. After 3 hours of normothermic reperfusion, phosphocreatine and adenosine triphosphate recovered to 98.6% +/- 9.0% and 90.1% +/- 13.5% of baseline, respectively, and pH was 7.087 +/- 0.051, similar to baseline (7.1755 +/- 0.041). In the low-flow bypass group, the disparity between the depressed level of cerebral oxygen consumption and normal high-energy phosphate levels may reflect incomplete cerebral rewarming or decreased energy consumption. In the circulatory arrest group, the parallel recovery of oxygen consumption and high-energy phosphates eventually achieving baseline levels suggests that the degree of hypothermia used provides adequate protection for acute cerebral recovery after 1 hour of circulatory arrest.(ABSTRACT TRUNCATED AT 400 WORDS)

Profound, reversible energy loss in the hypoxic immature rat brain.

The goal of this study was to compare the effects of oxygen deprivation on cellular energy state and pH in the developing and adult rat brain. Relative quantities of phosphocreatine (PC), inorganic phosphorus (P(i)), and nucleoside triphosphates (NTP), and intracellular pH, were determined using in vivo 31P NMR spectroscopy at different postnatal ages (postnatal day (P) 2-6, P9-13, P16-20, P23-27) in the hypoxic rat brain (7 min, 4% O2). While a significant increase in P(i) was seen at all ages during hypoxia, a severe but reversible reduction in concentrations of PC (80-100% decrease) and NTP (40-50% decrease) was observed only at P9-13. This dramatic response was not seen in older (> P16) or younger (< P6) animals. These latter groups responded with moderate decreases in brain PC (50-60% decrease) and NTP (20-40% decrease). In addition, the youngest animals showed much less intracellular brain acidosis than the other age groups. The transient period of development during which the brain exhibits heightened susceptibility to hypoxic energy failure coincides with known changes in brain energy production pathways and susceptibility to hypoxia-induced excitability.

Creatine kinase-catalyzed reaction rate in the cyanide-poisoned mouse brain.

Brain creatine kinase (CK)-catalyzed phosphorus flux from phosphocreatine (PC) to ATP was measured in vivo in young adult mice made reversibly hypoxic by injection of cyanide. Phosphorus spectra and saturation transfer measurements of CK-catalyzed flux were acquired using a high-field (8.45 T) nuclear magnetic resonance (NMR) spectrometer. After low cyanide doses (1-3 mg/kg of body weight), there were no measurable changes in brain pH or in concentrations of PC, the nucleoside triphosphates (including ATP), and Pi. The CK-catalyzed phosphorus flux increased about 75% after the low cyanide dose. Higher doses (4-6 mg/kg) produced a transient 30-40% decrease in PC concentration, doubling of Pi, and a 0.2 unit decrease in pH. The CK-catalyzed phosphorus flux decreased 50-80% after the higher cyanide doses. This decrease in phosphorus flux was present long after reactant concentrations returned to precyanide values. It is proposed that the increase in brain CK-catalyzed phosphorus flux with the lower cyanide doses is due to an increase in ADP concentration. The large, prolonged decrease in CK-catalyzed reaction rate in the moderately poisoned brain may be due to loss of activity of the mitochondrial CK isoform.

Maturational increase in mouse brain creatine kinase reaction rates shown by phosphorus magnetic resonance.

In-vivo phosphorus fluxes in the reaction catalyzed by creatine kinase (CK) were measured in brains of mice from 3 to 40 days of age using high-field (8.45 T) phosphorus magnetic resonance and the saturation transfer technique. This technique gives the ratio of chemical flux to reactant concentration directly and allows the calculation of pseudo-rate constants for the forward direction from PC to ATP (kf) and for the reverse direction (kr). The spin-lattice relaxation times (T1) for phosphocreatine (PC) and for the nucleoside triphosphate (NTP) nuclei, estimated by the progressive saturation technique, did not change during this age period. The PC concentration doubled relative to the NTP concentration over the first month of life. The kf and the flux of phosphorus nuclei in the forward direction increased 2- to 3-fold in the very narrow time period from 12 to 15 days of age. Brain phosphorus flux from PC to ATP thus increased 4- to 6-fold in the first month of life. An increase at least that large occurred in the reverse direction, but the kr could not be measured consistently in the younger animals using the saturation transfer technique. Phosphorus fluxes were equal in the forward and reverse directions in the mature brain. The capacity to increase rates of glycolysis and tissue respiration in response to increased energy demand appears in the same narrow age period as the increase in CK-catalyzed reaction rates in the developing rodent brain. We propose that these coincident changes in brain energy metabolism reflect the maturation of mechanisms for coupling cell energy production to rapid changes in energy requirements.