RESUMO
Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and ß-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, ß-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.
Assuntos
Delírio , Fraturas do Quadril , Humanos , Idoso de 80 Anos ou mais , Glucose/metabolismo , Acetoacetatos , Ácido 3-Hidroxibutírico , Espectrometria de Massas em Tandem , Fraturas do Quadril/complicações , Fraturas do Quadril/cirurgia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Lactatos , Aminoácidos de Cadeia RamificadaRESUMO
BACKGROUND: Hip fracture patients are frail and have a high mortality. We investigated whether the introduction of fast track care reduced the 30-day mortality after hip fractures. METHODS: Fast track hip fracture care was established at our institution in October 2013. Data from the Norwegian Hip Fracture Register and electronic hospital records were merged for 2230 hip fracture patients operated in our department from January 2012 through December 2015. 1090 of these patients were operated before (conventional treatment group) and 1140 patients were operated after the introduction of fast track care (fast track group). Data were analysed by univariate analysis and binary logistic regression. RESULTS: Mortality did not differ significantly between the conventional treatment group and the fast track group at 30 days (7.9% vs. 6.5%), 90 days (13.5% vs. 12.5%) and one year (22.8% vs. 22.8%). Median admission time and time to surgery were significantly shorter in the fast track group than in the conventional treatment group (1.1 h vs. 3.9 h and 23.6 h vs. 25.7 h, both p < 0.0001). The 30-day reoperation rate was significantly lower in the fast track group compared to the conventional treatment group (odds ratio = 0.35 (95% CI: 0.15-0.84), p = 0.019). A composite 30-day outcome (reoperation, surgical site infection and/or death) was significantly less frequent in the fast track group (8.1%) than in the conventional treatment group (10.7%) in unadjusted analysis (p = 0.006), but not after adjusting for age, gender, cognitive impairment and ASA score (odds ratio = 0.85 (95% CI: 0.63-1.16), p = 0.31, 8.0% missing). Reoperations within 1 year, surgical site infections, 30-day readmissions and length of hospital stay did not differ significantly between the conventional treatment group and the fast track group. CONCLUSIONS: Fast track hip fracture care is safe. However, we observed no statistically significant change in 30-day, 90-day or 1-year mortality after the introduction of fast track hip fracture care. TRIAL REGISTRATION: The study was registered retrospectively at ClinicalTrials.gov (Protocol Record 284907 ) 6 December 2016.
Assuntos
Artroplastia de Quadril/métodos , Fraturas do Quadril/cirurgia , Mortalidade Hospitalar , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/efeitos adversos , Feminino , Fraturas do Quadril/mortalidade , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Noruega/epidemiologia , Readmissão do Paciente/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.
Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.
RESUMO
BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTSIn delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (ß 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSIONOur data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDINGNorwegian Health Association and South-Eastern Norway Regional Health Authorities.