Wil M. Chew

Nicardipine reduces ischemic brain injury. Magnetic resonance imaging/spectroscopy study in cats.

We investigated whether the calcium channel entry blocker nicardipine would reduce ischemic brain damage in barbiturate-anesthetized cats subjected to permanent unilateral occlusion of the middle cerebral artery. The evolution of cerebral injury was assessed in vivo in 24 cats by a combination of proton magnetic resonance imaging and phosphorus-31 magnetic resonance spectroscopy for 5 hours following occlusion. Immediately thereafter, the volume of histochemically ischemic brain tissue was determined planimetrically in triphenyl tetrazolium chloride-stained serial coronal sections. Nicardipine was initially administered as an intravenous bolus injection of 10 mg/kg/hr 15 minutes before or 15 minutes after occlusion, followed by continuous infusion at 8 mg/kg/hr for the 5 hours of the experiment. Compared with untreated controls, cats that received nicardipine before or after occlusion showed a significant reduction in the extent of edema in the ipsilateral cerebral cortex, internal capsule, and basal ganglia. The results of phosphorus-31 magnetic resonance spectroscopy studies suggest that nicardipine may protect against cerebral ischemic damage by an action on cellular metabolic processes that preserve high-energy phosphates during the ischemic period.

Comparison of initial biodistribution patterns of Gd-DTPA and albumin-(Gd-DTPA) using rapid spin echo MR imaging.

The initial biodistribution patterns of gadolinium-diethylenetria-minepentaacetic acid (Gd-DTPA), an extracellular fluid contrast agent, and human serum albumin, paramagnetically labeled with 19 Gd-DTPA groups and used as an intravascular agent, were compared in the brain, heart, liver, and major mediastinal vessels of rats. Repeated 4 s spin echo images acquired after injection of 0.2 mmol/kg Gd-DTPA demonstrated a maximum enhancement between 15 and 25 s of 57% in brain, 307% in heart, 220% in liver, 83% in subcutaneous tissue, and 380% in slowly flowing blood in mediastinal vascular structures. In the following 55 s there was a continuous decrease (average 45%) in signal intensity in each tissue except brain. Albumin-(Gd-DTPA), injected at a four times lower molar dose (0.045 mmol/kg) with respect to Gd-DTPA, demonstrated maximal enhancement of brain by 34%, heart by 237%, liver by 186%, and blood in mediastinal vessels by 325%. Gadolinium-DTPA, which rapidly diffuses from the small vessels into the interstitial space, was noted to accumulate in solid tissues and subsequently to be partially eliminated within 70 s of administration. Signal enhancement achieved with albumin-(Gd-DTPA) remained at a constant level over the 70 s observation period. These data further support the notion that albumin-(Gd-DTPA), due to its predominantly intravascular distribution, might be applied advantageously for the assessment of perfusion and blood-volume disorders.

Magnetic resonance imaging of myocardial infarction using albumin-(Gd-DTPA), a macromolecular blood-volume contrast agent in a rat model.

Magnetic resonance (MR) contrast enhancement of acute myocardial infarction was studied in rats using albumin-(Gd-DTPA), a paramagnetic macromolecule with prolonged intravascular retention after intravenous injection. Histologic examination and distribution measurements of radiolabeled microspheres confirmed induction of regional myocardial infarction after ligation of the left coronary artery. ECG-gated spin-echo images at 2.0 Tesla, employing short, T1-weighted pulse sequence settings, demonstrated time-persistent and significant (P less than .05) enhancement of normal myocardium (66%) and an even greater enhancement of the infarcted area (100%), for as long as 60 minutes after injection of 160 mg/kg albumin-(Gd-DTPA). The contrast difference between normal and infarcted myocardium was increased significantly (P less than .05) after administration of albumin-(Gd-DTPA). The prolonged enhancing effects of albumin-(Gd-DTPA) on MR images are useful for evaluating regional differences in blood volume and capillary integrity between normal and infarcted myocardium.

An In Vivo 19F Nuclear Magnetic Resonance Study of Isoflurane Elimination from the Rabbit Brain

19F nuclear magnetic resonance spectroscopy was performed at 2.0 Tesla to evaluate the washout of isoflurane from the adult rabbit brain after 90 min of anesthesia. This investigation reconciles previous in vivo NMR studies of others, which observed a slow anesthetic washout, with invasive non-NMR studies that found a rapid washout, as predicted by perfusion-limited models of anesthetic uptake and elimination. Two NMR surface coil experiments were performed: in the first, a 1-cm surface coil was placed directly over the exposed dura to be certain that the washout was observed only from the brain; in the second, a 3-cm coil was placed noninvasively over the intact scalp to emulate previous NMR experiments. As in previous NMR experiments, a slow washout of isoflurane was observed with the large coil. The NMR signal that is observed with the large coil cannot be attributed solely to brain tissue. Fat surrounding the brain contributes significantly to the fluorine NMR spectra that are observed with the 3-cm coil, and its contributions lengthen the apparent washout time. A rapid washout of isoflurane from the rabbit brain was observed with the small coil, whose signal unambiguously arises only from brain tissue. The observed rapid washout is consistent with previous invasive biochemical measurements of anesthetic washout from the brain.

An in vivo study of halothane uptake and elimination in the rat brain with fluorine nuclear magnetic resonance spectroscopy

A recent NMR study reported the elimination of halothane from the brain of rabbits to be ten times slower than expected, based on known anesthetic solubility and cerebral blood flow. The authors conducted a study in five rats using fluorine nuclear magnetic resonance (NMR) spectroscopy to see if major pharmacokinetic discrepancies are associated with the uptake, maintenance, and elimination of halothane from the brain. The rats underwent a 60-min period of halothane anesthesia. They employed a spatially selective NMR spectroscopy technique known as surface coil “depth-pulsing” to assure that the fluorine NMR signals originated in brain tissue, and not in the scalp, muscle, adipose tissue, and bone marrow that surround the brain. After the inspired anesthetic concentration was decreased to zero, the amplitude of the fluorine NMR signal decreased to 40% of its maximum value within 34 ± 8.0 minutes (n = 5), rather than after 7 h as in the recent study, where the fluorine signal may have contained substantial contributions from metabolites tissues outside the brain. Fluorine was barely detectable in all of the animals 90 min after stopping the administration of halothane. The authors results are in agreement with model calculations the several other investigations.

Spin-echo fluorine magnetic resonance imaging at 2 T: In vivo spatial distribution of halothane in the rabbit head

Spin-echo 19F magnetic resonance imaging was performed at 2.0 T to explore the in vivo spatial distribution of halothane in the rabbit head. Because the halothane concentration is low in vivo, and because the measured relaxation times of the 19F resonance peak for halothane were T1 approximately equal to 1.0 sec and T2 approximately equal to 3.5-65 msec, 1-3-h imaging times were required (TR = 1 sec, TE = 9 msec) in order to obtain adequate images with a 64 X 256 raw data matrix and a 20-mm slice thickness. With this technique, halothane was primarily detected in lipophilic regions of the rabbit head, but little or no halothane was observed in brain tissue. Because T2 was shorter in brain tissue than in surrounding fat, a shorter TE than we could obtain is needed for optimal spin-echo imaging of brain halothane.

In vivo sodium-23 magnetic resonance surface coil imaging: Observing experimental cerebral ischemia in the rat

Sodium-23 magnetic resonance imaging can be used to detect and assess experimental cerebral ischemia in the rat. An imaging technique utilizing a surface coil is described to produce sodium magnetic resonance images of good quality and resolution within 10 min. A novel method of hemispheric occlusion showed edema in the right brain of the rat head within 3 hr after injury. The edema was especially pronounced by 12 hr with effects in the right brain, eye and surrounding muscle evident.

In situ brain metabolism

As an understanding of cerebral metabolism and circulation may have practical consequences for the treatment of brain injury and for surgery, a considerable body of knowledge has been gathered on the subject over a period of a t least twenty years.’-* Probably the most striking aspect of the subject is its complexity. The interplay of biochemical and physiological events when cerebral ischemia and hypoxia occur has still not been elucidated. Ischemia, i.e., either partial or total restriction of cerebral blood flow, presents the major medical problem of stroke. Hypoxia (low oxygen levels with normal cerebral blood flow) poses a concern during pulmonary failure, anesthetic malfeasance, and in high altitudes. The effects of ischemia and hypoxia are not identical. These cerebral insults exert various interrelated effects on morphological structure, function, and chemistry that are not simply reversed with reperfusion or restoration of oxygen. Since N M R spectroscopy has the potential for following some metabolic processes noninvasively, there has been some effort made to develop N M R as a technology to examine cerebral metabolism. Much is known about the mechanism of injury associated with cerebral ischemia. Gross physiological problems include brain edema, increased intracranial pressure, microcirculatory compromise, and post-ischemic recirculation problems, such as the “no-reflow” phenomenon and “loss of reperfusion” syndrome. Biochemical and in tracellular physiological aspects include low intracellular pH; the calcium-induced arachidonic acid cascade, excitotoxins, preischemic glucose excess, and oxygenderived free radical toxicity. Although much is known, optimum clinical stratagems for “brain protection” and “brain resuscitation” remain to be developed. It is suspected that much of the injury secondary to ischemia occurs during reperfusion and that an optimum regimen for reperfusion has yet to be developed. Many patients must also tolerate unavoidable periods of cerebral ischemia during surgery. Regulation of cellular energy metabolism and the consequences of lack of regulation are central to the problems of ischemia and hypoxia. The important factors fur regulation have been r e ~ i e w e d . ~ ATP is the bridge between the metabolic reactions that produce energy (glycolysis in the cytosol and oxidative phosphorylation in the mitochondria) and the energy-requiring functions of the cell including biosynthesis (gluconeogenesis, lipogenesis, protein synthesis, and nucleic acid synthesis), muscle contraction, and ion transport (to maintain ion gradients across cell membranes, transepithelial transport, and nerve conduction). The vast majority of ATP is produced