Introduction: papers from the National Institutes of Health State-of-the-Science Conference on Improving End-of-Life Care.

A 1997 Institute of Medicine report cited growing public concern about the quality of care in the U.S. health care system for persons at the end of life. The National Institute of Nursing Research (NINR), the lead Institute at the National Institutes of Health for end-of-life research, has conducted a number of public forums to gather information and to assist in identifying research priorities. The complexity of biomedical research requires new methods of discovery, and scientists must use a broad approach and explore new models of team science. In December 2004, NINR and the NIH Office of Medical Applications of Research, along with many co-sponsors, held an interdisciplinary State-of-the-Science Conference on Improving End-of-Life Care. The conference panel identified many gaps in our current state of knowledge and provided suggestions for future research directions. This supplement presents papers from a distinguished group of scientists with a wide range of backgrounds who participated in this state-of-the-science conference.

Evidence for a 'paravascular' fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space.

The protein tracer, horseradish peroxidase (HRP), was infused into the lateral cerebral ventricles or subarachnoid space of anesthetized cats and dogs after insertion of a cisternal cannula to permit drainage of cerebrospinal fluid (CSF) and tracer solution. The intracerebral distribution of the tracer was then determined by light microscopy of serial brain sections after postinfusion intervals of 4 min-2 h. For the localization of HRP, sections were incubated with diaminobenzidine (DAB) or the much more sensitive chromogen, tetramethylbenzidine (TMB). The TMB reaction showed a consistent 'paravascular' distribution of tracer reaction product, within the perivascular spaces (PVS) around large penetrating vessels and in the basal laminae around capillaries, far beyond the termination of the PVS. After infusion of HRP over 4 min, arterioles were surrounded by the tracer, but capillaries and venules were usually less densely demarcated; by 6 min, however, the intraparenchymal microvasculature was outlined in toto throughout the forebrain and brainstem. Electron microscopy of sections incubated in DAB after 10 or 20 min HRP circulation confirmed the paravascular location of the reaction product, which was also dispersed throughout the extracellular spaces (ECS) of the adjacent parenchyma. Our results demonstrate that solutes in the CSF have access to the ECS throughout the neuraxis within minutes via fluid pathways paralleling the intraparenchymal vasculature. The rapid paravascular influx of HRP could be prevented by stopping or diminishing the pulsations of the cerebral arteries by aortic occlusion or by partial ligation of the brachiocephalic artery. The exchange of solutes between the CSF and the cerebral ECS has generally been attributed to diffusion, however, HRP enters the neuraxis along the intraparenchymal microvasculature far more rapidly than can be explained on this basis. This apparent convective tracer influx may be facilitated by transmission of the pulsations of the cerebral arteries to the microvasculature. We postulate that a fluid circulation through the CNS occurs via paravascular pathways.

Focal cerebral edema impedes convective fluid/tracer movement through paravascular pathways in cat brain.

Cerebral blood vessels are accompanied by longitudinal paravascular fluid pathways that communicate with the subarachnoid space. After infusion into the subarachnoid space, the tracer protein, HRP, distributes throughout the brain with such rapidity as to suggest that the paravascular fluid transport system serves to flush the entire brain parenchyma. However, it was found that the tracer is largely excluded from regions of experimental vasogenic brain edema as well as from remotely situated white matter in the cold-lesioned hemisphere. The results suggest that the persistence and spread of vasogenic edema may be related to an impairment or disruption of the normal paravascular fluid transport system of the brain.

Rapid solute transport throughout the brain via paravascular fluid pathways.

Solutes in CSF have rapid access to ECS throughout the CNS (within 5-10 min). This occurs by solute/fluid influx through PVS around penetrating arteries, followed by longitudinal spread along the BL of capillaries to reach venules and veins. These paravascular pathways can be demonstrated light-microscopically by infusion of the tracer protein, HRP, into SAS and the subsequent localization of this probe molecule in brain sections using the sensitive histochemical method based on TMB. This unidirectional tracer/fluid movement along the intraparenchymal vascular network, with accompanying spread into the cerebral interstitium, appears to be facilitated by the pulsation of penetrating arterioles within their PVS with each cardiac contraction.

Physiologic parameters of the Cushing reflex.

The effects of increased intracranial pressure and blood gas tensions on systemic blood pressure were examined in this study. Intracranial pressure was raised hydrostatically and blood gas tensions, blood pressure, and respiration were monitored in anesthetized dogs. Small gradual increments in intracranial pressure resulted in increased cerebral venous carbon dioxide tension, followed by increased respiration, a gradual rise in blood pressure, and finally an increase in heart rate. The results of this study indicate that blood pressure changes appear to be determined by alterations in carbon dioxide tension following increases in intracranial pressure; small increases in intracranial pressure elicit a cluster of physiologic responses, all directed toward stabilization of local cerebral carbon dioxide tension.

Experimental cerebral vasospasm: resolution by chlorpromazine.

Vasospasm of the cat basilar artery was produced by electrical, mechanical, or chemical stimuli or by subarachnoid hemorrhage. The vasospasm induced by these stimuli was relieved by the topical application of chlorpromazine to the vascular wall. Chlorpromazine appears to be a nonspecific vasoparalytic agent. Unlike previously used substances, it is effective in resolving vasospasm caused by mechanical as well as chemical irritation.

Quality of life for transplantation patients: National Institute of Nursing Research Spring Science Work Group.

Quality of life for transplantation patients offers many opportunities for basic science and clinical researchers, ranging from biological and behavioral investigations to clinical interventions and population studies. Specific topics of interest for the field of transplantation research that have immediate application to studies of quality of life include signs and symptoms of chronic illness, biobehavioral risk factors for disease, functional disabilities, patient outcomes, adherence to treatment, care delivery, roles of families and caregivers, strategies of stress management, special needs of children and high-risk patients, health promotion and education, and long-term care. These topics offer investigators a unique opportunity to develop and apply integrated prevention and treatment strategies and to contribute valuable insights and skills to multidisciplinary research teams needed for quality-of-life studies of transplantation patients.

Cerebral venous blood gas tensions in elevated intracranial pressure.

Cerebral venous blood gas tensions were correlated with elevated intracranial pressure in spontaneously breathing dogs lightly anesthetized with nitrous oxide/halothane. Intracranial pressure was elevated by infusion of artificial cerebrospinal fluid into a lateral ventricle. Respiration and blood pressure were monitored. The results of these experiments indicate that cerebral venous carbon dioxide tension is increased in association with elevation in intracranial pressure. Moreover, it appears that cerebral venous pCO2 is effectively regulated at a mean of about 52 mm Hg over a wide range of intracranial pressure.

Increasing nursing postdoctoral opportunities: National Institute of Nursing Research Spring Science Work Group.

On May 1-2, 2000, the National Institute of Nursing Research (NINR) hosted a Spring Science Work Group on Increasing Nursing Postdoctoral Opportunities. The work group met at the National Institutes of Health (NIH) in Bethesda and was chaired by Dr Patricia A. Grady, director, and Dr Hilary D. Sigmon, program director, NINR. The purpose of the meeting was to identify ways to increase postdoctoral opportunities for nurse researchers. The work group considered the gaps and strengths currently present in postdoctoral education and suggested strategies and collaborative approaches for future initiatives. As biomedicine and behavioral science enter the 21st century, nurse scientists have critical roles to play in basic laboratory studies, translational research, clinical investigations, care delivery, and outcome evaluations. To fulfill these roles and to meet the growing need for well-trained nurse scientists in complex, multidisciplinary research, the "pipeline" of postdoctoral nurse researchers must be strengthened.