Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study

Background:

Severe traumatic brain injury often leads to death from withdrawal of life-sustaining therapy, although prognosis is difficult to determine.

Methods:

To evaluate variation in mortality following the withdrawal of life-sustaining therapy and hospital mortality in patients with critical illness and severe traumatic brain injury, we conducted a two-year multicentre retrospective cohort study in six Canadian level-one trauma centres. The effect of centre on hospital mortality and withdrawal of life-sustaining therapy was evaluated using multivariable logistic regression adjusted for baseline patient-level covariates (sex, age, pupillary reactivity and score on the Glasgow coma scale).

Results:

We randomly selected 720 patients with traumatic brain injury for our study. The overall hospital mortality among these patients was 228/720 (31.7%, 95% confidence interval [CI] 28.4%–35.2%) and ranged from 10.8% to 44.2% across centres (χ² test for overall difference, p < 0.001). Most deaths (70.2% [160/228], 95% CI 63.9%–75.7%) were associated with withdrawal of life-sustaining therapy, ranging from 45.0% (18/40) to 86.8% (46/53) (χ² test for overall difference, p < 0.001) across centres. Adjusted odd ratios (ORs) for the effect of centre on hospital mortality ranged from 0.61 to 1.55 (p < 0.001). The incidence of withdrawal of life-sustaining therapy varied by centre, with ORs ranging from 0.42 to 2.40 (p = 0.001). About one half of deaths that occurred following the withdrawal of life-sustaining therapies happened within the first three days of care.

Interpretation:

We observed significant variation in mortality across centres. This may be explained in part by regional variations in physician, family or community approaches to the withdrawal of life-sustaining therapy. Considering the high proportion of early deaths associated with the withdrawal of life-sustaining therapy and the limited accuracy of current prognostic indicators, caution should be used regarding early withdrawal of life-sustaining therapy following severe traumatic brain injury.Traumatic brain injury is the leading cause of death and disability among patients younger than 45 years of age, with mortality rates ranging from 30% to 40%.^1–3 Moreover, the impact of traumatic brain injury on quality of life among survivors is tremendous, with up to 30% of patients acquiring major neurologic sequelae.Although few studies have compared mortality among centres in global trauma populations,^4,5 overall mortality and variation in mortality, specifically for patients with critical illness and traumatic brain injury, are less well described. Because patients with severe traumatic brain injury lack capacity for making medical decisions, relatives and medical teams must frequently estimate patients’ preferences for treatment, including life support. Decisions to withdraw life-sustaining therapies are usually based on perceptions of unfavourable prognosis for meaningful neurologic recovery.^6–8 However, there are relatively few accurate and useful prediction tools to inform such estimates of prognosis. Therefore, prognostication is often based on clinicians’ impressions and past experiences. The subjective nature of neuroprognostication may lead to variability in the incidence of death associated with the withdrawal of life-sustaining therapy. With the recent advent of programs for organ donation following cardiovascular death, potential variability in mortality and withdrawal of life-sustaining therapy among patients with severe traumatic brain injury would be of major importance from a medicolegal perspective. The ethical debate surrounding organ donation following cardiovascular death having recently reached a public hearing⁹ highlights the need to improve our understanding of withdrawal of life-sustaining therapy for this specific population of patients.We hypothesized that hospital mortality varies across centres and that this may be explained, at least in part, by variability in the rate of withdrawal of life-sustaining therapy. We conducted a multicentre cohort study in six Canadian level-one trauma centres to investigate and compare rates of death associated with withdrawal of life-sustaining therapy among patients with severe traumatic brain injury.     

CT follow-up and clinical outcome in severe traumatic brain injury patients

Determining a patient's prognosis after severe traumatic brain injury remains difficult and complex. The purpose of the present study was following up patients with severe traumatic brain injury by correlating their clinical outcome and sequential computer tomography (CT) findings. We investigated 51 patients who survived the first year following an accident. All patients underwent successive CT examinations within a maximum period of 2 years. The patients' outcomes depended on the underlying brain damage and are presented by the Glasgow Outcome Scale. Based on the investigated data we concluded that the worst outcomes were experienced by patients with initial massive cerebral edema, extensive subdural hematoma and intraventricular hemorrhage, followed by stroke as subacute CT finding and cerebral atrophy as chronic finding visible at follow-up CT scans. The majority of lesions identified by CT scan were found in the frontal lobes, basal ganglia, and temporal lobes. We suggest that CT examination still represents a simple and useful tool in attempting to predict the clinical outcome in patients with severe traumatic brain injury.     

Peculiarities of disorders of brain bioelectrical activity spatial-time organization in patients with different consciousness depression after severe head injury

Specific changes of bioelectrical brain activity was found in 27 patients with different level of posttraumatic consciousness depression by the methods of crosscorrelation, coherence and factor analysis of EEG. The changes of activity of morphofunctional systems of intracerebral integrations were revealed partially by decreasing of unspecific activity from brainstem structures reflected with increasing of slow wave activity and decreasing of EEG coherence in alpha- and beta-range. Depression of system organization of interconnections of bioelectrical brain activity in frontal and occipital regions of both hemispheres was also detected, and testified about decreasing of intercortical and thalamocortical brain system action under brain dislocation. The changes of integrative brain system activity, provides interhemispheric interaction, had the specific characted. Our results propose a "facilitation" of activity of system, providing "direct" interhemispheric connections through corpus callosum and other commissural tracts of telencephalon as a sequel of mesodiencephalon structures depression with steady reciprocal, antiphase relations of slow weve activity in symmetrical areas of hemispheres in coma II patients. The data of our research had shown no complete disintegration of system brain activity in coma II patients in spite of consciousness and brainstem reflexes depression.     

Impact of chronic smoking on traumatic brain microvascular injury: An in vitro study

Traumatic brain injury (TBI) is a major reason of cerebrovascular and neurological damage. Premorbid conditions such as tobacco smoking (TS) can worsen post-TBI injuries by promoting vascular endothelial impairments. Indeed, TS-induced oxidative stress (OS) and inflammation can hamper the blood-brain barrier (BBB) endothelium. This study evaluated the subsequence of chronic TS exposure on BBB endothelial cells in an established in vitro model of traumatic cell injury. Experiments were conducted on confluent TS-exposed mouse brain microvascular endothelial cells (mBMEC-P5) following scratch injury. The expression of BBB integrity–associated tight junction (TJ) proteins was assessed by immunofluorescence imaging (IF), Western blotting (WB) and quantitative RT-PCR. We evaluated reactive oxygen species (ROS) generation, the nuclear factor 2–related (Nrf2) with its downstream effectors and several inflammatory markers. Thrombomodulin expression was used to assess the endothelial haemostatic response to injury and TS exposure. Our results show that TS significantly decreased Nrf2, thrombomodulin and TJ expression in the BBB endothelium injury models while increased OS and inflammation compared to parallel TS-free cultures. These data suggest that chronic TS exposure exacerbates traumatic endothelial injury and abrogates the protective antioxidative cell responses. The downstream effect was a more significant decline of BBB endothelial viability, which could aggravate subsequent neurological impairments.     

Severe traumatic brain injury after the assault with an axe handle

Traumatic brain injuries represent a major cause of death and disability. We present a case of a 47-year-old patient who sustained a severe brain injury after being assaulted with a handle of an axe. The patient underwent numerous surgeries by various specialists during several months. Following a few failed attempts to cover the skull defects, the vacuum-assisted closure system had been utilized with great success in healing of her complex head wound. Traumatic brain injury requires great effort and collaboration in order to rehabilitate people to the most independent level of functioning possible.     

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy

Abstract

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker’s limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.     

Platelet-rich plasma-derived scaffolds increase the benefit of delayed mesenchymal stromal cell therapy after severe traumatic brain injury

Background

Cell therapy using mesenchymal stromal cells (MSCs) offers new perspectives in the treatment of traumatic brain injury (TBI). The aim of the present study was to assess the impact of platelet-rich plasma scaffolds (PRPS) as support of MSCs in a delayed phase after severe TBI in rats.

EEGgui: a program used to detect electroencephalogram anomalies after traumatic brain injury

Background

Identifying and quantifying pathological changes in brain electrical activity is important for investigations of brain injury and neurological disease. An example is the development of epilepsy, a secondary consequence of traumatic brain injury. While certain epileptiform events can be identified visually from electroencephalographic (EEG) or electrocorticographic (ECoG) records, quantification of these pathological events has proved to be more difficult. In this study we developed MATLAB-based software that would assist detection of pathological brain electrical activity following traumatic brain injury (TBI) and present our MATLAB code used for the analysis of the ECoG.

Methods

Software was developed using MATLAB(?) and features of the open access EEGLAB. EEGgui is a graphical user interface in the MATLAB programming platform that allows scientists who are not proficient in computer programming to perform a number of elaborate analyses on ECoG signals. The different analyses include Power Spectral Density (PSD), Short Time Fourier analysis and Spectral Entropy (SE). ECoG records used for demonstration of this software were derived from rats that had undergone traumatic brain injury one year earlier.

Results

The software provided in this report provides a graphical user interface for displaying ECoG activity and calculating normalized power density using fast fourier transform of the major brain wave frequencies (Delta, Theta, Alpha, Beta1, Beta2 and Gamma). The software further detects events in which power density for these frequency bands exceeds normal ECoG by more than 4 standard deviations. We found that epileptic events could be identified and distinguished from a variety of ECoG phenomena associated with normal changes in behavior. We further found that analysis of spectral entropy was less effective in distinguishing epileptic from normal changes in ECoG activity.

Conclusion

The software presented here was a successful modification of EEGLAB in the Matlab environment that allows detection of epileptiform ECoG signals in animals after TBI. The code allows import of large EEG or ECoG data records as standard text files and uses fast fourier transform as a basis for detection of abnormal events. The software can also be used to monitor injury-induced changes in spectral entropy if required. We hope that the software will be useful for other investigators in the field of traumatic brain injury and will stimulate future advances of quantitative analysis of brain electrical activity after neurological injury or disease.

     

Association of iron metabolism markers,socioeconomic and lifestyle factors with endometriosis: A cross-sectional study

BackgroundEvidence on the link between iron metabolism markers and endometriosis is limited. We aimed to investigate the associations of iron metabolism markers, including serum ferritin level and transferrin saturation, with endometriosis.MethodsThis study involved 6551 participants from the National Health and Nutrition Examination Survey (NHANES). Univariable and multivariable logistic regression analyses were used to examine the linear relationships between iron metabolism markers and endometriosis. Furthermore, restricted cubic splines were used to identify the non-linear dose-response associations.ResultsUnivariable analysis showed that the factors associated with endometriosis included age, race, education level, and smoking status. In multivariable model, compared with lowest quartile, highest quartile of serum ferritin level was positively associated with endometriosis (OR: 2.11, 95% confidence intervals [CI]: 1.31, 3.40, P = 0.004), and third quartile of transferrin saturation positively associated with endometriosis (OR: 1.55, 95% CI: 1.05, 2.29, P = 0.033). The restricted cubic splines showed the non-linear (inverted U-shape) associations between serum ferritin level and transferrin saturation and endometriosis (all P for non-linear＜0.01), indicating that the ORs of endometriosis increased with serum ferritin level and transferrin saturation up to the turning point and thereafter the ORs of endometriosis did not significantly increase with the increasing serum ferritin and transferrin saturation.ConclusionsOur findings suggests that serum ferritin level and transferrin saturation were positively associated with endometriosis. Serum ferritin and transferrin saturation may be an important marker for endometriosis. Future prospective and longitudinal studies are necessary to better understand these findings.     

Prognostic value of copeptin: one-year outcome in patients with traumatic brain injury

High plasma copeptin level has been associated with one-month mortality after traumatic brain injury. However, not much is known regarding its relation with long-term outcome. Thus, we investigated the ability of copeptin to predict 1-year outcome in patients with traumatic brain injury. One hundred and six healthy controls and 106 patients with acute severe traumatic brain injury were included. Plasma samples were obtained on admission. Its concentration was measured by enzyme-linked immunosorbent assay. Forty-eight patients (45.3%) suffered from unfavorable outcome (Glasgow Outcome Scale score of 1-3) and 31 patients (29.2%) died in 1 year after traumatic brain injury. Upon admission, plasma copeptin level in patients was substantially higher than that in healthy controls. A forward stepwise logistic regression selected plasma copeptin level as an independent predictor for 1-year unfavorable outcome and mortality of patients. A receiver operating characteristic curve analysis showed plasma copeptin level predicted 1-year unfavorable outcome and mortality obviously. The predictive value of the copeptin concentration was thus similar to that of Glasgow Coma Scale score for the prediction of unfavorable outcome and mortality after 1 year. In a combined logistic-regression model, copeptin improved the area under curve of Glasgow Coma Scale score for the prediction of unfavorable outcome and mortality after 1 year, but the differences were not significant. Thus, copeptin level is a useful, complementary tool to predict functional outcome and mortality 1 year after traumatic brain injury.     

Burying our mistakes: Dealing with prognostic uncertainty after severe brain injury

Prognosis after severe brain injury is highly uncertain, and decisions to withhold or withdraw life-sustaining treatment are often made prematurely. These decisions are often driven by a desire to avoid a situation where the patient becomes ‘trapped’ in a condition they would find unacceptable. However, this means that a proportion of patients who would have gone on to make a good recovery, are allowed to die. I propose a shift in practice towards the routine provision of aggressive care, even in cases where the probability of survival and acceptable recovery is thought to be low. In conjunction with this shift, I argue in favour of a presumption towards withdrawing life-sustaining treatment, including artificial nutrition and hydration, when it becomes clear that a patient will not recover to a level that would be acceptable to them. I then respond to three potential objections to this proposal.     

Acoustic thermometry of the patient brain with traumatic brain injury

Non-invasive deep brain acoustic thermometry is carried out for two patients at Burdenko Neurosurgery Institute. This method is based on the measurements of the own thermal acoustic radiation of the investigated object. These two patients have got the brain injury. Some of their skull bones are absent. Infrared thermometry was also used to measure the surface temperature of the forehead skin. On the basis of the experimental data the temperatures deep within the brain were reconstructed. The values for the two patients are equal to 37.3 ± 0.7 and 37.0 ± 0.3°C.     

Hypolipoproteinemia and hyperinflammatory cytokines in serum of severe and moderate traumatic brain injury (TBI) patients

Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta], interleukin-6 [IL-6] and interleukin-8 [IL-8]), and causes metabolic alterations in the early, post-traumatic state, either in the brain or/and the systemic circulation. The metabolic changes involve carbohydrates, proteins and lipids. We focused on the serum lipid profile, the impact of trauma on lipoproteins, and their subsequent effects, on inflammation. We investigated the role of cytokines and serum lipids, in patient outcome, reviewing 30-day mortality and the Glasgow Coma Scale (GCS). A total of 75 patients with severe or moderate TBI (GCS 相似文献   

Association between serum cholesterol and eating behaviours during early childhood: a cross-sectional study

Background:

Modifiable behaviours during early childhood may provide opportunities to prevent disease processes before adverse outcomes occur. Our objective was to determine whether young children’s eating behaviours were associated with increased risk of cardiovascular disease in later life.

Methods:

In this cross-sectional study involving children aged 3–5 years recruited from 7 primary care practices in Toronto, Ontario, we assessed the relation between eating behaviours as assessed by the NutriSTEP (Nutritional Screening Tool for Every Preschooler) questionnaire (completed by parents) and serum levels of non–high-density lipoprotein (HDL) cholesterol, a surrogate marker of cardiovascular risk. We also assessed the relation between dietary intake and serum non-HDL cholesterol, and between eating behaviours and other laboratory indices of cardiovascular risk (low-density lipoprotein [LDL] cholesterol, apolipoprotein B, HDL cholesterol and apoliprotein A1).

Results:

A total of 1856 children were recruited from primary care practices in Toronto. Of these children, we included 1076 in our study for whom complete data and blood samples were available for analysis. The eating behaviours subscore of the NutriSTEP tool was significantly associated with serum non-HDL cholesterol (p = 0.03); for each unit increase in the eating behaviours subscore suggesting greater nutritional risk, we saw an increase of 0.02 mmol/L (95% confidence interval [CI] 0.002 to 0.05) in serum non-HDL cholesterol. The eating behaviours subscore was also associated with LDL cholesterol and apolipoprotein B, but not with HDL cholesterol or apolipoprotein A1. The dietary intake subscore was not associated with non-HDL cholesterol.

Interpretation:

Eating behaviours in preschool-aged children are important potentially modifiable determinants of cardiovascular risk and should be a focus for future studies of screening and behavioural interventions.Modifiable behaviours during early childhood may provide opportunities to prevent later chronic diseases, in addition to the behavioural patterns that contribute to them, before adverse outcomes occur. There is evidence that behavioural interventions during early childhood (e.g., ages 3–5 yr) can promote healthy eating.¹ For example, repeated exposure to vegetables increases vegetable preference and intake,² entertaining presentations of fruits (e.g., in the shape of a boat) increase their consumption,³ discussing internal satiety cues with young children reduces snacking,⁴ serving carrots before the main course (as opposed to with the main course) increases carrot consumption,⁵ and positive modelling of the consumption of healthy foods increases their intake by young children.^6,7 Responsive eating behavioural styles in which children are given access to healthy foods and allowed to determine the timing and pace of eating in response to internal cues with limited distractions, such as those from television, have been recommended by the Institute of Medicine.⁸Early childhood is a critical period for assessing the origins of cardiometabolic disease and implementing preventive interventions.⁸ However, identifying behavioural risk factors for cardiovascular disease during early childhood is challenging, because signs of disease can take decades to appear. One emerging surrogate marker for later cardiovascular risk is the serum concentration of non–high-density lipoprotein (HDL) cholesterol (or total cholesterol minus HDL cholesterol).^9–12 The Young Finn Longitudinal Study found an association between non-HDL cholesterol levels during childhood (ages 3–18 yr) and an adult measure of atherosclerosis (carotid artery intima–media thickness), although this relation was not significant for the subgroup of younger female children (ages 3–9 yr).^10,11 The Bogalusa Heart Study, which included a subgroup of children aged 2–15 years, found an association between low-density lipoprotein (LDL) cholesterol concentration (which is highly correlated with non-HDL cholesterol) and asymptomatic atherosclerosis at autopsy.¹² The American Academy of Pediatrics recommends non-HDL cholesterol concentration as the key measure for screening for cardiovascular risk in children.⁹ Serum non-HDL cholesterol concentration is the dyslipidemia screening test recommended by the American Academy of Pediatrics for children aged 9–11 years.⁹ Cardiovascular risk stratification tools such as the Reynold Risk Score (www.reynoldsriskscore.org) and the Framingham Heart Study coronary artery disease 10-year risk calculator (www.framinghamheartstudy.org/risk) for adults do not enable directed interventions when cardiovascular disease processes begin — during childhood.The primary objective of our study was to determine whether eating behaviours at 3–5 years of age, as assessed by the NutriSTEP (Nutritional Screening for Every Preschooler) questionnaire,^13,14 are associated with non-HDL cholesterol levels, a surrogate marker of cardiovascular risk. Our secondary objectives were to determine whether other measures of nutritional risk, such as dietary intake, were associated with non-HDL cholesterol levels and whether eating behaviours are associated with other cardiovascular risk factors, such as LDL cholesterol, apolipoprotein B, HDL cholesterol and apoliprotein A1.     

Association between high voltage overhead transmission lines and mental health: a cross-sectional study

We examined the association between residential proximity to 60 Hz high voltage (22-500 kV) overhead transmission lines (HVOTLs) and mental health (MH). The subjects were 223 mothers with a mean age of 37 years. The distance from the subject's residence to the closest HVOTL was measured on a map. MH status was assessed by the SF-36 Health Survey, which was scored on a 0-100 point scale, and an individual with a score of 52 points or less was defined as having poor MH. Logistic regression models were used to examine the association between the distance from the subjects' residence to the closest HVOTL and MH status. The prevalence of poor MH was 15%. Among the 223 subjects, 10 lived within 100 m of a HVOTL. The adjusted odds ratios (OR) for poor MH among those who lived 101-300 m or within 100 m from HVOTL were 1.29 (95% confidence interval (CI): 0.35-10.13) and 1.87 (95% CI: 0.35-10.13), respectively, against the reference category (300+ m). MH status was not significantly associated with the distance between the subject's residence and the closest HVOTL.     

Association between folate metabolism polymorphisms and breast cancer: a case-control study

We investigated the association between methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthetase (MTR A2756G), and methionine synthase reductase (MTRR A66G) polymorphisms involved in folate pathway and breast cancer risk, and the interaction between these polymorphisms and tobacco and alcohol consumption. Furthermore, we evaluated the association between these polymorphisms and clinicopathological variables. This case-control study included 606 Brazilian women, comprising 128 patients with breast cancer and 478 controls. MTHFR and MTR polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and MTRR polymorphisms using real-time PCR. Age ≥50 years (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.65-4.26; p<0.001) and alcohol consumption (OR: 1.76; 95% CI: 1.0-2.85; p=0.021) were associated with an increased risk of breast cancer. For MTHFR A1298C, we observed a reduced risk of developing breast cancer in the codominant model (genotype CC-OR: 0.22; 95% CI: 0.06-0.74; p=0.014), recessive model (OR: 0.22; 95% CI: 0.07-0.76 p=0.004), and log-additive model (OR: 0.70; 95% CI: 0.49-0.98; p=0.035). Women aged ≥50 years and those who are alcohol consumers had increased susceptibility to breast cancer, and MTHFR A1298C modulated the risk for this disease. This is the first study to evaluate the association between polymorphisms in folate metabolism and breast cancer in the northwest region of São Paulo State, Brazil.     

Association between the behavioral and neurochemical effects of amphetamine: Hemispheric asymmetry study

Effects of amphetamine on concentrations of dopamine, norepinephrine and serotonin in several monoamine-containing cell body and terminal regions were examined left and right separately in rats. Results suggest that amphetamine reduced the L-R asymmetry of most of these measures, and this effect is more significant in the cell body than in the terminal regions. Behaviorally, amphetamine also decreased L-R asymmetry of the spontaneous turning behavior in rats and this latter effect is most closely associated with the reductions of dopamine and norepinephrine asymmetries in the substantia nigra and reduction of norepinephrine asymmetry in the locus coeruleus.