Method for identifying neuronal cells suffering zinc toxicity by use of a novel fluorescent sensor.

During excitotoxic brain damage, injured neurons accumulate an anomalous, pathological burden of weakly bound, rapidly exchangeable Zn(2+) that diffusely fills the soma, nucleus and proximal dendrites. Mounting evidence indicates that this Zn(2+) is a major contributing factor in the subsequent demise of the damaged neurons. Thus, identifying, imaging, and characterizing zinc-filled cells have become essential steps in understanding excitotoxicity. Here we demonstrate that a new fluorescent stain for zinc can rather selectively and quite vividly label zinc-filled neurons in frozen histologic sections. The method is more sensitive and selective than the existing stain TSQ, and simpler than the Timm-Danscher silver staining techniques. A previously unobserved population of apparently injured cells in the dentate gyrus has been discovered with the new reagent. Whereas cells viewed in situ in normal, healthy tissue virtually never display any perikaryal staining by histochemical methods for zinc, injured cells stain intensely for zinc in culture, acute slice preparations and in tissue harvested in vivo. Thus, the presence of rapidly-exchangeable, "stainable" perikaryal zinc may be taken as an indicator of cell injury.

Cerebral pressure autoregulation is intact and is not influenced by hypothermia after traumatic brain injury in rats.

In head-injured patients and experimental traumatic brain injury (TBI), important cerebrovascular abnormalities include decreases in cerebral blood flow (CBF) and impairment of cerebral pressure autoregulation. We evaluated CBF and pressure autoregulation after fluid percussion injury (FPI) and hypothermia in rats with the hypothesis that hypothermia would ameliorate changes in posttraumatic CBF. Male Sprague-Dawley rats, intubated and mechanically ventilated, were prepared for parasagittal FPI (1.8 atm) and laser Doppler CBF flow (LDF) measurement. The abdominal aorta was cannulated for rapid removal and reinfusion of blood. Baseline autoregulatory testing in all groups consisted of LDF measurements at normothermia and a mean arterial pressure (MAP) of 100 mm Hg, followed by randomly ordered changes of MAP to 80, 60, and 40 mm Hg. Animals were then randomized to one of five groups: normothermic control without FPI; normothermia with FPI; hypothermic control (32 degrees C) without FPI; hypothermia initiated before FPI; and hypothermia initiated immediately after FPI injury. For each group, a complete, randomly ordered autoregulatory sequence was performed at 30 and 60 min after FPI or sham TBI. In a second study, rats were prepared identically, maintained at normothermic temperatures and autoregulation was tested before and after TBI using a set of randomly ordered levels of hypotension or using progressive reductions in MAP (i.e., 80, 60, 40 mm Hg) with the hypothesis that the technical manner and timing of decreasing of the blood pressure would effect CBF after TBI. Due to high acute mortality, the group in which hypothermia was induced before FPI was excluded from the analysis. At baseline, autoregulation was similar in all groups. There was no change in CBF or autoregulation in the normothermic control group at 30 and 60 min. In the other groups at 30 and 60 min, there was a similar, statistically significant decrease in absolute CBF (i.e., a decrease of 27-57% of baseline values), but pressure autoregulation was intact except at the lowest blood pressure tested at 60 min, where there was a slight improvement in the hypothermic group. Thus, in these experiments, absolute CBF decreased with hypothermia and FPI, while neither hypothermia nor FPI significantly altered autoregulation. In the second study, autoregulatory function was not different before TBI when comparing random and sequential blood pressure changes, but, when comparing the groups after TBI at the 60 mm Hg blood pressure level, CBF was significantly lower in the sequential group than in the random order group. This suggests that the mechanism of creating hypotension, whether random or sequential, significantly affects the measurement of CBF and autoregulation after TBI in rats.

Percutaneous venovenous perfusion-induced systemic hyperthermia for lung cancer: a phase I safety study.

BACKGROUND: Veno-venous perfusion-induced systemic hyperthermia (VV-PISH) homogeneously raises core body temperature potentially improving outcomes from metastatic lung cancer. METHODS: Patients (n = 10) with stage IV lung cancer, received VV-PISH (>or= 42 degrees C to or= 70. Time to target temperature was 47 +/- 2 minutes, as electrolytes remained normal, without patient or circuit complications. Extubation occurred between 6 and 18 hours. Hospital stay was 4.6 +/- 1.1 days; median length-of-survival after hyperthermia was 271 days. For concurrent controls (n = 16, stage IV lung cancer), median length-of-survival from time of diagnosis to death was 96 days, but for the VV-PISH patients it was significantly longer at 450 days (p < 0.05). All patients returned to pretreatment status following treatment and died from progression of lung cancer. CONCLUSIONS: Venovenous perfusion-induced systemic hyperthermia is safe, technically feasible, and achieves target temperature. Survival may be enhanced in stage IV lung cancer.

Anesthetic management of traumatic brain injury.

The management of TBI remains an important and frustrating component of the practice of anesthesiology and critical care medicine. The difficulties in management of TBI as well as the poor response rates to medical therapy after TBI are not new. The following passage appeared in the introductory chapter of a text on TBI from 1897: "The manner of treatment is of importance in only a minority of cases, since many subjects of intracranial injury are fated to die whatever measures may be adopted for their relief, and a still greater number are destined to recover though left entirely to the resources of nature. It is probable that in by far the larger proportion of cases in which the issue is determined by treatment it is met in the initial stage, and by insuring restoration from primary shock" [111]. Although secondary insults from factors such as hypotension, hypoxemia, and hyperventilation increase morbidity and mortality, data are not yet available to indicate whether scrupulous prevention and prompt treatment of secondary injuries will reduce morbidity and mortality. In addition, no specific intervention to date has improved overall long-term outcome. With ongoing research, perhaps active interventions will become available. Until that time, thoughtful and careful attention to physiologic management provides the greatest opportunity for a good outcome.