NMR-Spectroscopic Investigation of Cerebral Reanimation After Prolonged Ischemia

Abstract

The severity of brain injury following interruption of blood flow depends on a number of ischemic and post-ischemic variables. The most important ischemic variables are the duration of ischemia, the amount of residual blood flow, the type and depth of anesthesia, brain glucose content and temperature. Among the post-ischemic factors the no-reflow phenomenon, edema and a variety of biochemical disturbances are of particular importance. Due to the complex interaction of these factors irreversible brain injury usually occurs after less than 10 min cerebrocirculatory arrest in normothermia. However, the safe ischemia time of the brain can be substantially extended when appropriate therapeutic measures are used to alleviate post-ischemic injury. NMR-spectroscopy is particularly suited for the analysis of this process. Recording of ³¹P, ¹H and ¹⁹F spectra allow the continuous non-invasive assessment of such basic parameters as brain energy state, tissue pH, the content of lactate and blood flow (using Freon-23 as an inert tracer). In addition, information is obtained about changes in the content of phosphomonoesters and -diesters, glutamate, glutamine, aspartate and N-acetyl aspartate. These measurements can be combined with in vivo electrophysiological and post-mortem biochemical investigations for the further refinement of functional/metabolic monitoring.

We have used this approach to study the potentials of postischemic resuscitation after one hour complete ischemia of the normothermic cat brain. The following results were obtained:

• 1) Cerebrocirculatory arrest caused a suppression of EEG within 15 sec, complete depletion of ATP, and phosphocreatine in less than 10 min, a rise of lactate to about 70% of its maximum value during this interval, and a decrease of pH to between 5.31 and 6.70. After longer ischemia times little further changes occurred.

• 2) Recirculation of the brain after one hour complete ischemia in normothermia resulted in complete recovery of ATP, CrP, lactate and tissue pH in 30%, in partial recovery of the energy metabolism in 53%, and in no recovery in 17% of cats.

• 3) Recovery did not depend on pH, lactate or residual blood flow during ischemia but it was critically determined by the speed of ATP resynthesis after ischemia. Complete recovery occurred only when ATP and CrP began to reappear within 5 min and, returned to more than 50% within 20 min after the onset of recirculation; recovery was always incomplete when these intervals were longer.

• 4) The NMR data correlated with invasive measurements in most but not all animals. In particular, dissociations occurred at low pH and low metabolite levels where NMR either underestimated or overestimated the actual tissue values.

We conclude that recovery of brain metabolism after prolonged ischemia is less sensitive to pH than generally assumed but requires fast blood reperfusion and rapid post-ischemic restoration of energy state. The implications for therapeutic interventions and the monitoring of these interventions by NMR will be discussed.