Frailty assessment and risk prediction by GRACE score in older patients with acute myocardial infarction.

BACKGROUND: Risk prediction after myocardial infarction is often complex in older patients. The Global Registry of Acute Coronary Events (GRACE) model includes clinical parameters and age, but not frailty. We hypothesised that frailty would enhance the prognostic properties of GRACE. METHODS: We performed a prospective observational cohort study in two independent cardiology units: the Royal Infirmary of Edinburgh, UK (primary cohort) and the South Yorkshire Cardiothoracic Centre, Sheffield, UK (external validation). The study sample included 198 patients ≥65 years old hospitalised with type 1 myocardial infarction (primary cohort) and 96 patients ≥65 years old undergoing cardiac catheterisation for myocardial infarction (external validation). Frailty was assessed using the Clinical Frailty Scale (CFS). The GRACE 2.0 estimated risk of 12-month mortality, Charlson comorbidity index and Karnofsky disability scale were also determined for each patient. RESULTS: Forty (20%) patients were frail (CFS ≥5). These individuals had greater comorbidity, functional impairment and a higher risk of death at 12 months (49% vs. 9% in non-frail patients, p < 0.001). The hazard of 12-month all-cause mortality nearly doubled per point increase in CFS after adjustment for age, sex and comorbidity (Hazard Ratio [HR] 1.90, 95% CI 1.47-2.44, p < 0.001). The CFS had good discrimination for mortality by Receiver Operating Characteristic (ROC) curve analysis (Area Under the Curve [AUC] 0.81, 95% CI 0.72-0.89) and enhanced the GRACE estimate (AUC 0.86 vs. 0.80 without CFS, p = 0.04). At existing GRACE thresholds, the CFS resulted in a Net Reclassification Improvement (NRI) of 0.44 (95% CI 0.28-0.60, p < 0.001), largely through reductions in risk estimates amongst non-frail patients. Similar findings were observed in the external validation cohort (NRI 0.46, 95% CI 0.23-0.69, p < 0.001). CONCLUSIONS: The GRACE score overestimated mortality risk after myocardial infarction in these cohorts of older patients. The CFS is a simple guided frailty tool that may enhance prediction in this setting. These findings merit evaluation in larger cohorts of unselected patients. TRIAL REGISTRATION: Clinicaltrials.gov; NCT02302014 (November 26th 2014, retrospectively registered).

Early brain temperature elevation and anaerobic metabolism in human acute ischaemic stroke.

Early after acute ischaemic stroke, elevation of brain temperature might augment tissue metabolic rate and conversion of ischaemic but viable tissue to infarction. This might explain the observed link between pyrexia, severe stroke and poor outcome. We tested this hypothesis by measuring brain temperature and lactate concentration with multi-voxel magnetic resonance spectroscopic imaging across the acute ischaemic stroke lesion and normal brain as determined on diffusion imaging. We compared patterns of lactate concentration (reported in 'institutional units') and temperature elevation in diffusion lesion core, potential penumbra, ipsilateral and contralateral normal brain and with stroke severity. Amongst 40 patients with moderate to severe acute stroke imaged up to 26 h after onset, lactate concentration was highest in the ischaemic lesion core (42 versus 26 units in potential penumbra, P < 0.05), whereas temperature was highest in the potential penumbra (37.7 versus 37.3 degrees C in lesion core, P < 0.05). Neither sub-regional temperature nor lactate concentration correlated with stroke severity. With increasing time after stroke, ipsilateral brain temperature did not change, but contralateral hemisphere temperature was higher in patients scanned at later times; lactate remained elevated in the lesion core, but declined in potential penumbral and ipsilateral normal tissue at later times. We conclude that early brain temperature elevation after stroke is not directly related to lactate concentration, therefore augmented metabolism is unlikely to explain the relationship between early pyrexia, severe stroke and poor outcome. Early brain temperature elevation may result from different mechanisms to those which raise body temperature after stroke. Further studies are required to determine why early brain temperature elevation is highest in potential penumbral tissue.

Reproducibility of GABA measurements using 2D J-resolved magnetic resonance spectroscopy.

We determined the reproducibility of GABA (gamma-aminobutyric acid) measurements using 2D J-resolved magnetic resonance spectroscopy (MRS) on a clinical 1.5-T MR imaging scanner. Two-dimensional J-resolved spectra were acquired in vitro across five GABA concentrations using a volume head coil and a 5-in. surface coil. Additional spectra using a sixth GABA phantom with a very low concentration and from a healthy volunteer were recorded in the 5-in. surface coil only. In each case, the 3.01-ppm GABA resonance was quantified; for comparison, the peak integrals of choline (3.2 ppm) and creatine (3.03 ppm) were recorded. At a physiological concentration (1.2 mM), in vitro GABA measurement was significantly more reproducible in the surface coil than in the volume coil (P=.005), with coefficients of variation (CVs) being less than 16% with the surface coil and up to 68% with the volume head coil. At the smallest concentration of in vivo GABA reported using other spectroscopy techniques (0.8 mM) and detected only using the surface coil, the CV for GABA was 23% and was less than 10% for choline and creatine, which compare favorably with results from published studies. In vivo, the CV for GABA measurement was 26%, suggesting that 2D J-resolved MRS would be suitable for detecting physiological changes in GABA, similar to those reported using other methods.

Measurement of regional brain temperature using proton spectroscopic imaging: validation and application to acute ischemic stroke.

A magnetic resonance proton spectroscopic imaging (SI) technique was developed to measure regional brain temperatures in human subjects. The technique was validated in a homogeneous phantom and in four healthy volunteers. Simulations and calculations determined the theoretical measurement precision as approximately +/-0.3 degrees C for individual 1-ml voxels. In healthy volunteers, repeated measurements on individual voxels had an S.D. = 1.2 degrees C. In a clinical study, 40 patients with acute ischemic stroke were imaged within 26 h (mean, 10 h) of onset. Temperatures were highest in the region that appeared abnormal (i.e., ischemic) on diffusion-weighted imaging (DWI) compared with a normal-appearing brain. The mean temperature difference between the DWI "lesion" area and the "normal brain" was 0.17 degrees C [P < 10(-3); range, 2.45 degrees C (hotter)-2.17 degrees C (cooler)]. Noninvasive temperature measurement by SI has sufficient precision to be used in studies of pathophysiology in stroke and in other brain disorders and to monitor therapies.

Phase 2 Randomised Controlled Trial and Feasibility Study of Future Care Planning in Patients with Advanced Heart Disease.

Future Care Planning (FCP) rarely occurs in patients with heart disease until close to death by which time the potential benefits are lost. We assessed the feasibility, acceptability and tested a design of a randomised trial evaluating the impact of FCP in patients and carers. 50 patients hospitalised with acute heart failure or acute coronary syndrome and with predicted 12 month mortality risk of >20% were randomly allocated to FCP or usual care for 12 weeks upon discharge and then crossed-over for the next 12 weeks. Quality of life, symptoms and anxiety/distress were assessed by questionnaire. Hospitalisation and mortality events were documented for 6 months post-discharge. FCP increased implementation and documentation of key decisions linked to end-of-life care. FCP did not increase anxiety/distress (Kessler score -E 16.7 (7.0) vs D 16.8 (7.3), p = 0.94). Quality of life was unchanged (EQ5D: E 0.54(0.29) vs D 0.56(0.24), p = 0.86) while unadjusted hospitalised nights was lower (E 8.6 (15.3) vs D 11.8 (17.1), p = 0.01). Qualitative interviews indicated that FCP was highly valued by patients, carers and family physicians. FCP is feasible in a randomised clinical trial in patients with acute high risk cardiac conditions. A Phase 3 trial is needed urgently.

Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study.

BACKGROUND: There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate gamma-aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA concentrations, fluctuates across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder (PMDD) and that a menstrual cycle phase-dependent abnormality in brain GABA concentrations in women diagnosed as having PMDD would reflect altered central response to circulating gonadal and neuroactive steroids. METHODS: Fourteen healthy menstruating women and 9 women diagnosed as having PMDD were recruited from a women's behavioral health research program located at a university-based medical center. The women underwent serial proton magnetic resonance spectroscopic measurements of occipital cortex GABA levels across the menstrual cycle (primary outcome measure) and had blood drawn for gonadal hormone and neurosteroid levels determined on each scan day (secondary outcome measure). RESULTS: There was a significant group x phase interaction with most of the finding explained by the reduction in cortical GABA levels during the follicular phase in those with PMDD compared with healthy controls. Cortical GABA levels declined across the menstrual cycle in healthy women, whereas women with PMDD experienced an increase in cortical GABA levels from the follicular phase to the mid luteal and late luteal phases. Significant between-group differences in the relationship between hormones and GABA were observed for estradiol, progesterone, and allopregnanolone. CONCLUSIONS: These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.

The neuronal nitric oxide synthase inhibitor, TRIM, as a neuroprotective agent: effects in models of cerebral ischaemia using histological and magnetic resonance imaging techniques.

Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)-weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.

Identifying community based chronic heart failure patients in the last year of life: a comparison of the Gold Standards Framework Prognostic Indicator Guide and the Seattle Heart Failure Model.

OBJECTIVE: To assess the clinical utility of the Gold Standards Framework Prognostic Indicator Guide (GSF) and the Seattle Heart Failure Model (SHF) to identify patients with chronic heart failure (CHF) in the last year of life. DESIGN, SETTING AND PATIENTS: An observational cohort study of 138 community based ambulatory patients with New York Heart Association (NYHA) class III and IV CHF managed by a specialist heart failure nursing team. MAIN OUTCOME MEASURES: 12 month mortality, and sensitivity and specificity of GSF and SHF. RESULTS: 138 CHF patients with NYHA class III and IV symptoms were identified from a population of 368 ambulatory CHF patients. 119 (86%) met GSF criteria for end of life care. The SHF model identified six (4.3%) patients with a predicted life expectancy of 1 year or less. At the 12 month follow-up, 43 (31%) patients had died. The sensitivity and specificity for GSF and SHF in predicting death were 83% and 22%, and 12% and 99%, respectively. Receiver operator characteristic analysis of SHF revealed a C index of 0.68±0.05 (95% CI 0.58 to 0.77). Chronic kidney disease (serum creatinine ≥140 µmol/l) was a strong univariate predictor of 12 month mortality, with a sensitivity of 56% and specificity of 72%. CONCLUSIONS: Neither the GSF nor the SHF accurately predicted which patients were in the last year of life. The poor prognostic ability of these models highlights one of the barriers to providing timely palliative care in CHF.

Identifying acute coronary syndrome patients approaching end-of-life.

BACKGROUND: Acute coronary syndrome (ACS) is common in patients approaching the end-of-life (EoL), but these patients rarely receive palliative care. We compared the utility of a palliative care prognostic tool (Gold Standards Framework (GSF)) and the Global Registry of Acute Coronary Events (GRACE) score, to help identify patients approaching EoL. METHODS AND FINDINGS: 172 unselected consecutive patients with confirmed ACS admitted over an eight-week period were assessed using prognostic tools and followed up for 12 months. GSF criteria identified 40 (23%) patients suitable for EoL care while GRACE identified 32 (19%) patients with ≥ 10% risk of death within 6 months. Patients meeting GSF criteria were older (p = 0.006), had more comorbidities (1.6 ± 0.7 vs. 1.2 ± 0.9, p = 0.007), more frequent hospitalisations before (p = 0.001) and after (0.0001) their index admission, and were more likely to die during follow-up (GSF+ 20% vs GSF- 7%, p = 0.03). GRACE score was predictive of 12-month mortality (C-statistic 0.75) and this was improved by the addition of previous hospital admissions and previous history of stroke (C-statistic 0.88). CONCLUSIONS: This study has highlighted a potentially large number of ACS patients eligible for EoL care. GSF or GRACE could be used in the hospital setting to help identify these patients. GSF identifies ACS patients with more comorbidity and at increased risk of hospital readmission.

The effect of tight glycaemic control, during and after cardiac surgery, on patient mortality and morbidity: A systematic review and meta-analysis.

BACKGROUND: Hyperglycaemia is a common occurrence during cardiac surgery, however, there remains some uncertainty surrounding the role of tight glycaemic control (blood glucose <180 mg/dL) during and/or after surgery. The aim of this study was to systematically review the literature to determine the effects of tight versus normal glycaemic control, during and after cardiac surgery, on measures of morbidity and mortality. METHOD: The literature was systematically reviewed, based on pre-determined search criteria, for clinical trials evaluating the effect of tight versus normal glycaemic control during and/or after cardiac surgery. Each paper was reviewed by two, independent reviewers and data extracted for statistical analysis. Data from identified studies was combined using meta-analysis (RevMan5®). The results are presented either as odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: A total of seven randomised controlled trials (RCTs) were identified in the literature, although not all trials could be used in each analysis. Tight glycaemic control reduced the incidence of early mortality (death in ICU) (OR 0.52 [95% CI 0.30, 0.91]); of post-surgical atrial fibrillation (odds ratio (OR 0.76 [95%CI 0.58, 0.99]); the use of epicardial pacing (OR 0.28 [95%CI 0.15, 0.54]); the duration of mechanical ventilation (mean difference (MD) -3.69 [95% CI -3.85, -3.54]) and length of stay in the intensive care unit (ICU) (MD -0.57 [95%CI -0.60, -0.55]) days. Measures of the time spent on mechanical ventilation (I2 94%) and time spent in ICU (I2 99%) both had high degrees of heterogeneity in the data. CONCLUSION: The results from this study suggest that there may be some benefit to tight glycaemic control during and after cardiac surgery. However, due to the limited number of studies available and the significant variability in glucose levels; period of control; and the reporting of outcome measures, further research needs to be done to provide a definitive answer on the benefits of tight glycaemic control for cardiac surgery patients.

A systematic review of brain metabolite changes, measured with 1H magnetic resonance spectroscopy, in healthy aging.

BACKGROUND: (1)H MR spectroscopy (MRS) can identify metabolite abnormalities in age-related, neurological diseases. However, there is little information on how metabolites change with healthy aging. METHODS: We systematically reviewed the literature on MRS, from 1980 to 2006, for studies where healthy young subjects (<60 years) were compared to healthy older subjects (>60 years). We extracted metabolite data reported as "no change", "increase" or "decrease" for each metabolite by brain region and, where data were available, meta-analysed mean metabolite concentrations (mM) for young versus old subjects. RESULTS: Eighteen studies met the inclusion criteria (total n=703 subjects, 284 >60 years old). Most data came from the frontal region, and reported "no change" in older subjects; however, a meta-analysis revealed a decrease in frontal NAA (p=0.05) and increases in parietal choline (p=0.003) and creatine (p<0.001). DISCUSSION: These data suggest that NAA may decrease and choline and creatine increase with age. Therefore, more data are needed from older subjects to characterise age effects better and ratios in older subjects should be interpreted with caution.

Measurement of brain temperature with magnetic resonance spectroscopy in acute ischemic stroke.

OBJECTIVE: Pyrexia is associated with poor outcome after stroke, but the temperature changes in the brain after stroke are poorly understood. We used magnetic resonance spectroscopic imaging (water-to-N-acetylaspartate frequency shift) to measure cerebral temperature noninvasively in stroke patients. METHODS: We performed magnetic resonance diffusion, perfusion (diffusion- and perfusion-weighted imaging), and magnetic resonance spectroscopic imaging, compared temperatures in tissues as defined by the diffusion-weighted imaging appearance (definitely abnormal, possibly abnormal and immediately adjacent normal-appearing brain, and normal brain), and tested associations with lesion and patient characteristics. RESULTS: Among 40 patients, temperature was higher in possibly abnormal (37.63 degrees C) than in definitely abnormal tissue (37.30 degrees C; p < 0.001) or in normal-appearing brain (ipsilateral, 37.16 degrees C; contralateral, 37.22 degrees C; both p < 0.001). Ischemic lesion temperature increased before normal brain temperature. Higher temperatures occurred in lesions that were large, had diffusion/perfusion-weighted imaging mismatch, had reduced cerebral blood flow, and in clinically severe strokes. Only 1 of 25 patients with ischemic lesion temperature greater than 37.5 degrees C was pyrexial. INTERPRETATION: Temperature is elevated in acutely ischemic brain. More work is required to determine whether raised temperature results from ischemic metabolic reactions, impaired heat exchange from reduced cerebral blood flow, or early inflammatory cell activity (or a combination of these), but magnetic resonance spectroscopic imaging could be used in studies of temperature after brain injury and to monitor interventions.