Support for nursing science.

BACKGROUND: The mission of the Department of Health and Human Services is to enhance the health and well-being of the American people. It does this by providing oversight for more than 1,000 grant programs across 26 federal agencies at an annual cost of approximately $500 billion. The National Institute of Nursing Research (NINR) at the National Institutes of Health (NIH) is one institute originated to support health care research from a nursing perspective. However, funding of nursing research from federal agencies has remained relatively flat for more than a decade, despite increases in total NIH funding. PURPOSE: The purpose of this report is to describe the types of funding support provided by federal government agencies (including the NIH) to schools of nursing. METHOD: The NIH's Research Portfolio Online Reporting Tool, Expenditures and Results system from 1988 to 2014 was accessed to collect information on the grant recipient institutions as well as the source, number, type, and dollar amounts of grants. DISCUSSION: The funding level and its implications for the future of nursing science are considered.

CT Density Changes with Rapid Onset Acute, Severe, Focal Cerebral Ischemia in Monkeys.

Computerized tomography (CT) is the most often used imaging modality in the evaluation of acute clinical stroke. However, the rapidity with which CT density changes occur after acute, severe, focal ischemia cannot be determined clinically. Even if the time of symptom onset is known, clinical stroke severity is highly variable. We studied the time course of CT density change after severe, rapid onset, acute, focal ischemia as documented by stable xenon CT cerebral blood flow (CBF) in monkeys. Eight monkeys (Macaca mulatta) were subjected to transorbital occlusion of the left posterior cerebral, anterior, middle, and internal carotid arteries to induce focal ischemia. CT density Hounsfield units (HU), CBF by stable xenon CT, arterial blood pressure, and blood gases were measured before occlusion, immediately after occlusion, at 30 min, and hourly for up to 6 h. Occlusion of the cerebral arteries decreased CBF to 8 ± 5 ml/100 g/ min within 15 min postocclusion. At 6 h, CBF was unchanged at 9 ± 4 ml/100 g/ min. CT density within the ischemic core fell from 42 to 38 HU immediately after occlusion (P < 0.05), rose transiently, then fell at 2 h (P < 0.01) and plateaued at 36 ± 5 HU for a total decrease of 4-5 HU between 4 and 6 h poststroke. Changes in CT density lag severe focal ischemia by 2 h. Thus, when CT hypodensity is seen in acute stroke, it is likely 2 h old. It also provides an explanation for the phenomenon of clinical CT mismatch with clinical deficits and normal CT.

Cerebrospinal fluid ferritin level, a sensitive diagnostic test in late-presenting subarachnoid hemorrhage.

The workup of patients with suspected subarachnoid hemorrhage (SAH) presenting late is complicated by a loss of diagnostic sensitivity of computed tomography (CT) brain imaging and cerebrospinal fluid (CSF) bilirubin levels. In this prospective longitudinal study of CSF ferritin levels in SAH, serial CSF samples from 14 patients with aneurysmal SAH requiring extraventricular drainage (EVD) were collected. The control group comprised 44 patients presenting with headache suspicious of SAH. Nine patients underwent a traumatic spinal tap. CSF ferritin levels were significantly higher in the patients with SAH compared with controls (P < .0001). The upper reference range of CSF ferritin is 12 ng/mL, and there was no significant difference between the traumatic and normal spinal taps (mean, 9.0 ng/mL vs 3.9 ng/mL; P = .59). CSF ferritin levels increased after SAH, from an average of 65 ng/mL on day 1 to 1750 ng/mL on day 11 (P < .01). Both the Fisher and Columbia CT scores were significantly correlated with CSF ferritin level. The increase in CSF ferritin level after SAH and possibly may provide additional diagnostic information in patients with suspected SAH who present late to the clinic.

Cerebrospinal fluid apolipoprotein E, calcium and cerebral vasospasm after subarachnoid hemorrhage.

Intracellular calcium (Ca++) regulation of cerebral vessels is impaired after subarachnoid hemorrhage (SAH), making secondary pathways, such as that involving apolipoprotein E, potentially more influential. To evaluate cerebrospinal fluid (CSF) apolipoprotein E and Ca++ levels as biomarkers of cerebral vasospasm, we examined changes in levels over time and apolipoprotein E (APOE) epsilon4 allele presence after SAH in individuals with and without vasospasm. We hypothesized that individuals with low apolipoprotein E levels, increased Ca++ levels and/or at least one copy of the APOE epsilon4 allele would have vasospasm. Daily samples from 50 participants, aged 18-75, with SAH were used to quantify apolipoprotein E and Ca++ levels. Vasospasm was verified using cerebral angiogram and/or elevated transcranial Dopplers in combination with clinical neurologic deterioration. Overall apolipoprotein E levels were higher in individuals with the APOE epsilon4 allele (p = .02) or angiographic vasospasm (p = .01), but there were no differences between individuals with and without symptomatic vasospasm. There were no significant changes in apolipoprotein E levels over time. Individuals with the epsilon4 allele had lower Ca++ levels (p = .02) with trends suggesting a different pattern of change over time (p = .07). CSF Ca++ levels were lower in individuals with symptomatic vasospasm (p < .01). Change in apolipoprotein E and Ca++ levels (p = .006) correlated over time regardless of genotype or vasospasm status. These findings suggest that apolipoprotein E and Ca++ may be interacting after SAH, but this interaction does not appear to influence vasospasm.

Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury.

Presence of the apolipoprotein E (APOE) 4 allele has been associated with increased incidence and faster progression of neurodegenerative diseases, poorer recovery from neurologic insult, and decreased cognitive function in the well-elderly. The specific association between APOE genotype and recovery from severe traumatic brain injury (TBI) is conflicting with many groups finding the APOE 4 allele to be associated with poorer outcome while others have found no association. The purpose of this study was to investigate the association between APOE 4 allele presence and recovery during the two years after injury from severe TBI in light of other potential covariates, such as age, race, gender, hypotension or hypoxia before hospital admission and severity of injury. APOE genotype was determined for 123 subjects with severe TBI. Glasgow outcome score (GOS) and mortality were collected at 3, 6, 12, and 24 months after injury. Results showed individuals improved over the two year period following injury and those with the 4 allele had a slower recovery rate than those without the APOE 4 allele over the two year period. We did not however find significant differences in GOS at individual time points when controlling for other covariates. Our findings suggest that APOE 4 allele presence influences recovery rate from severe TBI independent of other covariates. The findings of this study are unique in that they address not only the relationship between APOE 4 allele presence and outcome from severe TBI, but also describe differences in trajectory of recovery by APOE 4 allele presence.

Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury.

OBJECT: Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3' variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI. METHODS: Sixty-three patients with severe TBI (Glasgow Coma Scale score < or = 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury. Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002). CONCLUSIONS: In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.

Magnesium infusion for vasospasm prophylaxis after subarachnoid hemorrhage.

OBJECT: Despite the application of current standard therapies, vasospasm continues to result in death or major disability in patients treated for ruptured aneurysms. The authors investigated the effectiveness of continous MgSO4 infusion for vasospasm prophylaxis. METHODS: Seventy-six adults (mean age 54.6 years; 71% women; 92% Caucasian) were included in this comparative matched-cohort study of patients with aneurysmal subarachnoid hemorrhage on the basis of computed tomography (CT) findings. Thirty-eight patients who received continuous MgSO4 infusion were matched for age, race, sex, treatment option, Fisher grade, and Hunt and Hess grade to 38 historical control individuals who did not receive MgSO4infusion. Twelve grams of MgSO4 in 500 ml normal saline was given intravenously daily for 12 days if the patient presented within 48 hours of aneurysm rupture. Vasospasm was diagnosed on the basis of digital substraction angiography, CT angiography, and transcranial Doppler ultrasonography, and evidence of neurological deterioration. Symptomatic vasospasm was present at a significantly lower frequency in patients who received MgSO4 infusion (18%) compared with patients who did not receive MgSO4 (42%) (p = 0.025). There was no significant difference in mortality rate at discharge (p = 0.328). A trend toward improved outcome as measured by the modifed Rankin Scale (p = 0.084), but not the Glasgow Outcome Scale (p = 1.0), was seen in the MgSO4 treated group. CONCLUSIONS: Analysis of the results suggests that MgSO4 infusion may have a role in cerebral vasospasm prophylaxis if therapy is initiated within 48 hours of aneurysm rupture.

Identification and quantification of the hydroxyeicosatetraenoic acids, 20-HETE and 12-HETE, in the cerebrospinal fluid after subarachnoid hemorrhage.

PURPOSE: The monohydroxylated metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE), is a potent vasoconstrictor of cerebral microvessels. 20-HETE formation is substantially elevated in the cerebral spinal fluid (CSF) in the rat subarachnoid hemorrhage (SAH) model. The presence of 20-HETE in human CSF has not been demonstrated. Therefore, it was the purpose of this study to determine if HETE metabolites are present in human CSF after SAH. METHODS: CSF samples were collected daily from four SAH patients over 15 days. HETE metabolites were separated by HPLC with identification by ion-trap MS/MS and quantification via single quadrupole MS operating in negative single ion monitoring mode. RESULTS: Two major metabolites were identified as 12-HETE and 20-HETE. 20-HETE maximal concentrations were 2.9 and 0.7 ng/ml at approximately 70 h in the two patients with symptomatic cerebral vasospasm (SV) after SAH. Concentrations of 12-HETE in these patients peaked at 21.9 ng/ml and 2.8 ng/ml. Concentrations of 20-HETE and 12-HETE were non-detectible in the majority of the samples obtained from two matched SAH patients without SV. CONCLUSIONS: This study is the first to demonstrate that 20-HETE and 12-HETE are present in the CSF of SAH patients at physiologically relevant concentrations. Based on this information future prospective studies will allow for the delineation of the role of these metabolites in the pathogenesis of SAH.

A comparison of gastric and rectal CO2 in cardiac surgery patients.

Critical care nurses assess and treat clinical conditions associated with inadequate oxygenation. Changes in regional organ (gut) blood flow are believed to occur in response to a decrease in oxygenation. Although the stomach is a widely accepted monitoring site, there are multiple methodological and measurement issues associated with the gastric environment that limit the accuracy of P CO2 detection. The rectum may provide nurses with an alternative site for monitoring changes in P CO2 without the limitations associated with gastric monitoring. This pilot study used a repeated measures design to examine changes in gastric and rectal P CO2 during elective coronary artery bypass grafting with cardiopulmonary bypass (CPB) and in the immediate 4-hr postoperative period in 26 subjects. The systemic indicators explained little variation in the regional indicators during protocol. A comparison of rectal and gastric P CO2 revealed no statistically significant differences in the direction or magnitude of change over any phase of cardiac surgery (baseline, CPB, post-CPB). A reduction in both rectal and gastric P CO2 occurred during CPB, and both values trended upward during the post-CPB phase. However, poor correlation and agreement was found between the measures of P CO2 at the two sites. Although clinically important, the cause is unclear. Possible explanations include variation in CO2 production between the gastric and rectal site, differences in sensitivity of the two monitoring instruments, or the absence of hemodynamic complications, which limited the extent of change in P CO2. Further investigation using patients with more profound changes in oxygenation are needed to identify response patterns and possible mechanisms.

The effects of admission alcohol level on cerebral blood flow and outcomes after severe traumatic brain injury.

This study examined the relationship between admission serum alcohol level (ETOH) and cerebral blood flow (CBF) and outcomes in the adult traumatic brain injured (TBI) population. We hypothesized that individuals with ETOH > 100 mg/dL will have decreased blood flow on admission and poorer outcomes. Eighty subjects, age 16-65, with severe TBI (Glasgow Coma Score [GCS] 100 mg/dL at the time of admission after a TBI were associated with a decrease in global CBF. Elevated serum ETOH level at time of injury did not, however, impact outcomes.

Qualitative and quantitative detection of mitochondrial heteroplasmy in cerebrospinal fluid using denaturing high-performance liquid chromatography.

Detecting and quantifying generalized mitochondrial heteroplasmy is essential if the field of mitochondrial genetics is to advance in the arena of complex genetic disorders. The majority of techniques used to detect and quantify mitochondrial heteroplasmy focus on a known mutation or polymorphism. The necessity of knowing the mitochondrial DNA (mtDNA) change beforehand means that non-specific heteroplasmy in general cannot be assessed. In this study, we assessed the extent that denaturing high-performance liquid chromatography (dHPLC) could detect and quantify mitochondrial heteroplasmy from cerebrospinal fluid (CSF). Although we used a known polymorphism to assess reliability and sensitivity of this technique, a distinct advantage to using dHPLC for heteroplasmy detection is that the entire fragment is screened for variability and any unique fragments will be detected regardless of the placement or type of change. Our results demonstrate that dHPLC can consistently and reliably detect mitochondrial heteroplasmy in a CSF sample down to 0.01%. In addition, the level of heteroplasmy was consistent with peak height for each homoduplex, giving a reliable method to quantify level of heteroplasmy.

Relationship between apoE4 allele and excitatory amino acid levels after traumatic brain injury.

OBJECTIVE: Apolipoprotein E isoform (E4) has been posited to affect outcomes after central nervous system injury. This project sought to determine the relationship between the apoE4 allele and the recovery of amino acid neurotransmitters (aspartate, glutamate, and lactate/pyruvate ratio [L/P]) following a traumatic brain injury (TBI) after controlling for patient characteristics. DESIGN: This prospective clinical study examined neurotransmitters and L/P within the cerebrospinal fluid and compared the trends by apoE genotypes. SETTING: Adults with TBI were recruited from a neurotrauma intensive care unit within a trauma I university medical center. PATIENTS: Ninety-one patients were enrolled into the study after a severe TBI (Glasgow Coma Scale [GCS] score,

Influence of delaying treatment after symptoms develop from subarachnoid hemorrhage: a preliminary analysis.

Patients experiencing subarachnoid hemorrhage (SAH) symptoms may delay seeking medical attention, not realizing the severity of these symptoms. The purposes of this study were to determine (a) the length of time between the development of SAH symptoms in patients and when treatment was initially sought and (b) whether the delay in hospital admission had an effect on patient outcomes. Inclusion criteria were age (18-75 years) and diagnosis of severe SAH. Consent was obtained on 90 eligible patients admitted to the neurovascular intensive care unit. Outcomes were assessed at 3 months using the Glasgow Outcome Scale (GOS) and Modified Rankin Scale (MRS). Initial time delay, calculated by subtracting the time of initial symptom development from the time of admission to the emergency department (ED), ranged from 0.08 to 103 hours. There was no relationship between the initial time delay and GOS or MRS scores. There was a significant difference between the time to initial ED admission to a trauma ED and to a community ED; patients were admitted within 2.7 hours to a trauma ED admission, compared to 7 hours for a community ED admission. There was a significant relationship between the Hunt and Hess Scale and GOS and between the Hunt and Hess and MRS. There was a significant relationship between the Fisher Grade and GOS and between the Fisher Grade and MRS. This study shows that patients may delay treatment for nearly 7 hours after initial symptoms develop. This suggests that laypersons are not aware of SAH symptoms, thereby delaying ED admission and care. The study also suggests that more severe symptoms upon admission to the ED were related to poorer outcomes. Initial clinical presentation is a useful predictor for SAH outcomes. This study supports the idea that the general public needs to be educated on the symptoms of SAH.

Absence of a diastolic velocity notch does not indicate hyperemia in traumatic brain injured patients without elevated cerebral blood flow velocity.

Elevated blood flow velocity (BFV), measured by transcranial Doppler (TCD), has been associated with hyperemia and cerebral vasospasm. This study examined whether the lack of a diastolic notch within the TCD waveform was associated with relative hyperemia within 5 days after injury in 35 traumatic brain injured (TBI) patients. Hyperemia (avD(O2) of < 4 ml/dL) was present in 16 patients and absent in 19 patients. Two clinicians independently coded TCD waveforms based on the presence of a diastolic notch (88% agreement). There was no significant difference in the presence of a diastolic notch by group; a diastolic notch was present in 57% (11/19) of patients without hyperemia and 81% (13/16) of patients with hyperemia. Sensitivity and specificity of detecting hyperemia using the diastolic notch was 18.7% and 57.9% respectively. The results showed that relative hyperemia was present without an elevation in blood flow velocities, and that the lack of a diastolic notch did not detect the presence of hyperemia in the TBI patient.