Mark H. Zornow

Changes in Extracellular Concentrations of Glutamate, Aspartate, Glycine, Dopamine, Serotonin, and Dopamine Metabolites After Transient Global Ischemia in the Rabbit Brain

Although considerable evidence supports a role for excitatory amino acids in the pathogenesis of ischemic neuronal injury, few in vivo studies have examined the effect of increasing durations of ischemia on the extracellular concentrations of these agents. Recently, other neurotransmittiers (e.g., glycine and doparaine) have been implicated in the mechanism of ischemic neuronal injury. Accordingly, this study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, glycine concentrations in the hippocampus, and dopamine, serotonin, and dopamine metabolites in the caudate nucleus with varying durations (5, 10, or 15 minutes) of transient global cerebral ischemia as evidence to support their pathogenetic roles. Microdialysis was used to sample the brains extracellular space before, during, and after the ischemic period. Glutamate and aspartate concentrations in the dialysate increased from baseline by 1‐, 5‐, and 13‐fold and by 4‐, 9‐, and 31‐fold, respectively, for the three ischemic durations. The concentrations returned to baseline rapidly after reperfusion. The peak concentrations of glutamate and aspartate were significantly higher with increasing ischemic duration. Dopamine concentrations increased by approximately 700‐fold in response to all three ischemic durations and returned to baseline within 10 min of reperfusion. Glycine, in contrast, increased during ischemia by a mean of 4‐fold, but remained elevated throughout the 80‐min period of reperfusion. The final concentrations of glycine were significantly higher than baseline levels (p = 0.0002, Mann‐Whitney test). That glutamate and aspartate concentrations in the hippocampus co‐vary with the duration of global ischemia is taken as supportive evidence of their pathogenetic role in ischemic neuronal injury. The observation that dopamine concentrations increased independently of ischemic duration indicates a maximal release with only S min of ischemia and suggests that dopamines role in the incremental injury seen with increasing ischemic duration is limited to prolonged high concentrations rather than increasing peak levels as seen with glutamate and aspartate. The sustained elevation of glycine concentrations after ischemia may explain the ability of excitatory amino acids to produce delayed toxicity in the reperfusion phase, as glycine has been shown to facilitate glutamates activity at the N‐ methyl‐D‐aspartate receptor.

Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine.

Background:Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action. This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine. Methods:One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor–blinded, parallel group, active-controlled, Phase IIIa trial. Anesthesia was induced and maintained with propofol and an opioid. Neuromuscular transmission was blocked and tracheal intubation facilitated with 1.2 mg/kg rocuronium or 1 mg/kg succinylcholine. Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration. Neuromuscular function was monitored by acceleromyography. The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T1) to 10%. Results:One hundred and ten patients received study treatment. Mean times to recovery of T1 to 10% and T1 to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively), as compared with the succinylcholine group (7.1 and 10.9 min, respectively; all P < 0.001). Timed from sugammadex administration, the mean time to recovery of T1 to 10%, T1 to 90%, and the train-of-four (T4/T1) ratio to 0.9 was 1.2, 2.9, and 2.2 min, respectively. Reoccurrence of the block was not observed. There were no serious adverse events related to study treatments. Conclusion:Reversal of profound high-dose rocuronium-induced neuromuscular block (1.2 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine.

Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits.

We subjected 10 New Zealand White rabbits to 10 minutes of global cerebral ischemia under either normothermic (37 degrees C) or moderately hypothermic (29 degrees C) conditions. Hippocampal concentrations of glutamate, aspartate, and glycine were monitored using in vivo microdialysis. Outcome was assessed by both neurological and neuropathologic criteria. Hypothermia afforded nearly complete protection from ischemic injury. Ischemia-induced increases in the concentrations of glutamate, aspartate, and glycine in the normothermic group (3, 12, and 3 times baseline) were strikingly attenuated in the hypothermic group. In addition, the prolonged postischemic elevation of glycine levels seen in the normothermic group was absent in the hypothermic group. These results suggest that the neuroprotective properties of hypothermia may reside, in part, in their ability to prevent increases in the extracellular concentrations of amino acids that enhance the activity of the N-methyl-D-aspartate receptor complex.

The effects of sevoflurane on cerebral blood flow, cerebral metabolic rate for oxygen, intracranial pressure, and the electroencephalogram are similar to those of isoflurane in the rabbit

The effects of 0.5 and 1.0 MAC end-tidal concentrations of sevo-flurane on intracranial pressure, cerebral metabolic rate for oxygen, cerebral blood flow, and the electroencephalogram were compared to those of equi-MAC concentrations of isoflurane in rabbits anesthetized with morphine-nitrous oxide. At 1.0 MAC end-tidal level, both sevoflurane and isoflurane caused a significant reduction in cerebral metabolic rate for oxygen of about 50%. Neither anesthetic caused a significant change in global cerebral blood flow or cortical cerebral blood flow during either 0.5 or 1.0 MAC administration. However, both sevoflurane and isoflurane caused small but significant increases in intracranial pressure during 0.5 MAC and 1.0 MAC administration. The electroencephalogram of animals anesthetized with 1.0 MAC of either anesthetic demonstrated a burst suppression pattern with no evidence of spike or seizure activity. The data suggest that the effects of sevofluranc on cerebral blood flow, cerebral metabolic rate for oxygen, intracranial pressure, and the electroencephalogram are indistinguishable from those of equivalent concentrations of isoflurane in the rabbit.

Dexmedetomidine, an α2-adrenergic agonist, decreases cerebral blood flow in the isoflurane-anesthetized dog

The purpose of this study was to examine the effects of dexmedetomidine, an α2-adrenergic agonist, on cerebral blood flow and metabolic rate in dogs anesthetized with 0.64% isoflurane. After intubation and institution of mechanical ventilation, arterial, venous, pulmonary artery, and sagittal sinus catheters were inserted. Measurements of cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRo2), mean arterial pressure, cardiac output, and blood gas tensions were made at various levels of isoflurane anesthesia (0.64%, 1.9%, and 2.8%), after the administration of 10 μg/kg of dexmedetomidine (a dose that has been shown to reduce anesthetic requirements in dogs by >90%) and finally after 0.3 mg/kg of the α2-adrenergic antagonist idazoxan. Despite an increase in arterial pressure, dexmedetomidine caused a marked reduction (>45%, P < 0.05) in CBF when compared with all preceding concentrations of isoflurane. The administration of dexmedetomidine had no effect on the CMRo2. The electroencephalogram showed a loss of high-frequency activity in a pattern similar to that seen with 1.90% isoflurane. Administration of dexmedetomidine was associated with a 57% decrease in cardiac output (to 0.89 L/min). Administration of idazoxan (an α2-adrenergic antagonist) resulted in an increase in cardiac output and a reversal of the electroencephalogram effects. This experiment indicates that 10 μg/kg of dexmedetomidine in isoflurane-anesthetized dogs is associated with a profound decrease in CBF and cardiac output in the face of an unaltered CMRo2. Despite the large reduction in the CBF/CMRo2 ratio, there was no evidence of global cerebral ischemia.

Effect of a hypertonic lactated Ringer's solution on intracranial pressure and cerebral water content in a model of traumatic brain injury.

There has recently been an increased interest in the use of hypertonic solutions for fluid resuscitation of trauma victims. In this study, we examined the acute cerebral effects of a hypertonic lactated Ringers solution (measured osmolality = 469 mOsm/kg) in an animal model of traumatic brain injury. Following the production of a cerebral cryogenic lesion, eight New Zealand white rabbits were randomized to undergo hemodilution with either lactated Ringers (measured osmolality = 254 mOsm/kg) or hypertonic lactated Ringers. Over the course of the experiment the lactated Ringers group required significantly more fluid than the hypertonic group to maintain stable central venous and mean arterial pressure (245 +/- 5 ml vs. 132 +/- 20 ml; p less than 0.0001). Osmolality increased in the hypertonic group by 13.5 +/- 3.3 mOsm/kg whereas it decreased in the lactated Ringers group by 5.5 +/- 2.6 mOsm/kg. Intracranial pressure increased in both groups over the course of the experiment but the increase in pressure was greater in the lactated Ringers group than the hypertonic group (9.5 +/- 2.4 mm Hg vs. 1.7 +/- 1.5 mm Hg; p less than 0.001). Brain water content was significantly increased in the region of the lesion as assayed by both the wet/dry weight method and cortical specific gravity determinations, but there was no difference between the two treatment groups. Water content of the nonlesioned hemisphere was significantly less in the hypertonic group. This study suggests that hypertonic saline solutions may be useful for the resuscitation of hypovolemic patients with localized brain injury.

The Acute Cerebral Effects of Changes in Plasma Osmolality and Oncotic Pressure

Although it is generally accepted that a decrease in plasma oncotic pressure may result in the formation of peripheral edema, the effect of a hypo-oncotic state on brain water content is less well known. Therefore, utilizing the technique of hollow-fiber plasma-pheresis to manipulate plasma composition, the authors examined the effects of acute changes in either plasma osmolality or colloid oncotic pressure on the EEG, regional cerebral blood flow, intracranial pressure, and brain tissue specific gravity (as a measure of cerebral water content) in anesthetized, neurologically normal New Zealand white rabbits. Animals in which either osmolality or oncotic pressure was decreased by plasma replacement with an appropriate solution were compared with a group of control animals in which both of these variables were maintained constant. Animals in which plasma osmolality was decreased by 13 ± 6 mOsm/kg (from a baseline value of 295 ± 5 mOsm/kg) showed evidence of a significant increase in cortical water content (≈0.5%), whereas a 65% reduction in oncotic pressure (from 20 ± 2 mmHg to 7 ± 1 mmHg) failed to produce any change. There were no significant differences in mean arterial pressure, central venous pressure, regional cerebral blood flow, or the EEG between any of the groups. Although intracranial pressure increased in all groups, the largest increase (8.1 ± 4.4 mmHg) occurred in those animals whose osmolality was reduced. The increase in intracranial pressure in animals rendered hypo-oncotic was no different front the “control‘’ group (2.4 ± 0.9 mmHg vs. 3.0 ± 1.5 mmHg). This study suggests that an acute fall in oncotic pressure does not promote an increase in cerebral water content in the non-injured brain. Unlike peripheral tissues, the presence of the blood-brain barrier with its small pore size and limited permeability may serve to enhance the importance of osmolality and minimize the role of oncotic pressure in determining water movement between the vasculature and brain tissue.

Effects of hypothermia or anesthetics on hippocampal glutamate and glycine concentrations after repeated transient global cerebral ischemia.

BackgroundThe search for cerebroprotective pharmacologic interventions has been based on the assumption that reducing the cerebral metabolic rate may enhance the cerebral tolerance for ischemic episodes. Recently, evidence has accumulated implicating excitatory amino acids (e.g., glutamate) as mediators of ischemic brain injury. We investigated the effects of mild hypothermia (32° C), pentobarbital, isoflurane, and propofol on hippocampal extracellular concentrations of glutamate and glycine after repeated global ischemia. MethodsNew Zealand white rabbits were initially anesthetized with halothane in oxygen. Brain epidural temperature was reduced by external cooling in the hypothermia group to 32° C (n = 5). A burst-suppressed electroencephalogram pattern was achieved in the other groups with isoflurane (n = 7), pentobarbital (n = 6), or propofol (n = 6). Halothane-anesthetized rabbits (1% inspired) served as the control group (n = 5). In all groups, two global cerebral ischemic episodes (each 7.5 min) were produced by a combination of neck tour niquet inflation and induction of systemic hypotension. Perlischemic hippocampal glutamate and glycine concentrations were estimated using in vivo microdialysis and high-performance liquid chromatography (two-way analysis of variance, P < 0.05). ResultsGlutamate concentrations were similar in the five groups during the baseline period. Hypothermia (32° C) was associated with significantly lower concentrations of glutamate during both the first and second ischemic periods when compared with all other groups. Although there were no differences in glycine concentrations among groups during the first ischemic episode, glycine concentrations were significantly lower in the hypothermic group compared with the control, isoflurane, and pentobarbital groups during the second episode of cerebral ischemia. Glycine concentrations also were lower in the propofol group when compared to the isoflurane and pentobarbital groups. ConclusionsHypothermia (32° C) attenuates ischemia-induced increases in both glutamate and glycine concentrations after repeated global cerebral ischemia. Propofol attenuated glycine increases in a manner similar to that of hypothermia but did not attenuate ischemia-induced glutamate increases. There were no differences in hippocampal glutamate or glycine concentrations for animals receiving isoflurane, halothane, or pentobarbital.

Preservation of evoked potentials in a case of anterior spinal artery syndrome.

A case of anterior spinal artery syndrome is presented for which there are neurologic, electrophysiologic, and pathologic correlations. Ten days prior to her death, a 52-year-old hypertensive female developed severe chest pain and lower extremity weakness. A diagnosis of aortic dissection resulting in an anterior spinal artery syndrome was made. Intraoperative posterior tibial somatosensory evoked potentials demonstrated normal morphology and latencies. Autopsy revealed an infarction of the anterior portion of the thoraco-lumbar spinal cord with preservation of the posterior columns. This case demonstrates that severe spinal cord injury can exist in the presence of preserved somatosensory evoked potentials.

MK-801, an Excitatory Amino Acid Antagonist, Does Not Improve Neurologic Outcome Following Cardiac Arrest in Cats

The excitatory amino antagonist MK-801 was administered to cats following resuscitation from cardiac arrest to evaluate its effect on neurologic and neuropathology outcome in a clinically relevant model of complete cerebral ischemia. In 29 cats studied, cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was successfully performed in 21 cats. Four animals underwent a sham arrest. MK-801 or placebo was administered in a blinded, randomized manner. Beginning at 5 min post resuscitation (PR), MK-801 330 μg/kg over 2 min followed by 73 μg/kg/h for 10 h or the same volume of placebo was administered. Resuscitated animals remained paralyzed and sedated in an intensive care setting for 24–30 h PR. Neurologic examinations were performed at 2, 4, and 7 days PR by observers blinded to the treatment groups. Seventeen cats were entered into data analysis (nine MK-801-treated and eight placebo-treated). MK-801-treated animals had a significantly greater neurologic deficit score (NDS) rank (0 = normal, 100 = brain death) 2 days PR (mean rank 12.1 vs. 5.6; p = 0.008). This difference is most likely due to ongoing sedative actions of MK-801. There were no significant differences in NDS rank at 4 (10.3, MK-801 vs. 7.5, placebo) and 7 (9.6, MK-801 vs. 8.3, placebo) days PR. There were no significant differences in frontal cortex, hippocampus, occipital cortex, or cerebellar neuropathology between groups. Sham-arrested cats had normal neurologic and neuropathologic evaluations. In the circumstance of complete cerebral ischemia as employed in the current study, MK-801 had no beneficial effect upon neurologic or neuropathologic outcome.