The synapse in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and is a risk factor for dementia later in life. Research into the pathophysiology of TBI has focused on the impact of injury on the neuron. However, recent advances have shown that TBI has a major impact on synapse structure and function through a combination of the immediate mechanical insult and the ensuing secondary injury processes, leading to synapse loss. In this review, we highlight the role of the synapse in TBI pathophysiology with a focus on the confluence of multiple secondary injury processes including excitotoxicity, inflammation and oxidative stress. The primary insult triggers a cascade of events in each of these secondary processes and we discuss the complex interplay that occurs at the synapse. We also examine how the synapse is impacted by traumatic axonal injury and the role it may play in the spread of tau after TBI. We propose that astrocytes play a crucial role by mediating both synapse loss and recovery. Finally, we highlight recent developments in the field including synapse molecular imaging, fluid biomarkers and therapeutics. In particular, we discuss advances in our understanding of synapse diversity and suggest that the new technology of synaptome mapping may prove useful in identifying synapses that are vulnerable or resistant to TBI.

A national survey of clinical practice of surveillance for post-traumatic brain injury hypopituitarism in the United Kingdom and Ireland.

Background: Traumatic brain injury (TBI) is the most common cause of death and disability in young adults in industrialised countries. Post-TBI hypopituitarism (PTHP) is thought to occur in one-third of patients, however the natural history and predictive factors are not fully understood and as such guidelines for surveillance vary. The aim of this study was to assess the variations in current surveillance practices across the Neurosurgery Centres within the United Kingdom.Methods: A questionnaire was developed following discussions with an expert panel and distributed to members of the Society of British Neurosurgeons (SBNS), by email and printed copy, to survey surveillance practices for PTHP. The questionnaire primarily aimed to determine how commonly screening was performed and the clinical parameters used to guide these surveillance practices.Results: There were 45 responders representing Neurosurgery units in regions of England, Scotland and Ireland. The majority of participants (86.7%) considered PTHP to be a problem but only 25% (11/45) routinely screened for PTHP. There was wide variation in the criteria used to determine which patients were screened.Conclusions: Our survey suggests that few Neurosurgeons routinely screen for PTHP and those that do use a wide variation of clinical parameters to guide surveillance practice. A UK-wide prospective cohort study may help identify patients at risk of developing PTHP.

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury.

BACKGROUND: In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. METHODS: We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). RESULTS: We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). CONCLUSIONS: In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).

Revisited: A Systematic Review of Therapeutic Hypothermia for Adult Patients Following Traumatic Brain Injury.

OBJECTIVES: Therapeutic hypothermia has been of topical interest for many years and with the publication of two international, multicenter randomized controlled trials, the evidence base now needs updating. The aim of this systematic review of randomized controlled trials is to assess the efficacy of therapeutic hypothermia in adult traumatic brain injury focusing on mortality, poor outcomes, and new pneumonia. DATA SOURCES: The following databases were searched from January 1, 2011, to January 26, 2018: Cochrane Central Register of Controlled Trial, MEDLINE, PubMed, and EMBASE. STUDY SELECTION: Only foreign articles published in the English language were included. Only articles that were randomized controlled trials investigating adult traumatic brain injury sustained following an acute, closed head injury were included. Two authors independently assessed at each stage. DATA EXTRACTION: Quality was assessed using the Cochrane Collaboration's tool for assessing the risk of bias. All extracted data were combined using the Mantel-Haenszel estimator for pooled risk ratio with 95% CIs. p value of less than 0.05 was considered statistically significant. All statistical analyses were conducted using RevMan 5 (Cochrane Collaboration, Version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). DATA SYNTHESIS: Twenty-two studies with 2,346 patients are included. Randomized controlled trials with a low risk of bias show significantly more mortality in the therapeutic hypothermia group (risk ratio, 1.37; 95% CI, 1.04-1.79; p = 0.02), whereas randomized controlled trials with a high risk of bias show the opposite with a higher mortality in the control group (risk ratio, 0.70; 95% CI, 0.60-0.82; p < 0.00001). CONCLUSIONS: Overall, this review is in-keeping with the conclusions published by the most recent randomized controlled trials. High-quality studies show no significant difference in mortality, poor outcomes, or new pneumonia. In addition, this review shows a place for fever control in the management of traumatic brain injury.

Temperature Variability in a Modern Targeted Temperature Management Trial.

OBJECTIVES: The Eurotherm3235 trial showed that therapeutic hypothermia was deleterious in patients with raised intracranial pressure following traumatic brain injury. We sought to ascertain if increased temperature variability within the first 48 hours, or for 7 days post randomization, were modifiable risk factors associated with poorer outcome. DESIGN: Eurotherm3235 was a multicenter randomized controlled trial. Patients were randomized to receive either therapeutic hypothermia in addition to standard care or the later only. Mean moving range (mr) was used to stratify subjects into tertiles by the variability present in their core temperature within the first 48 hours post randomization and within 7 days post randomization. The primary outcome measure was a collapsed Glasgow Outcome Scale-Extended at 6 months post randomization. The temperature variability effect was estimated with ordinal logistic regression adjusted for baseline covariates and treatment effect. SETTING: Forty-seven critical care units in 18 countries. PATIENTS: Patients enrolled in the Eurotherm3235 trial to either therapeutic hypothermia or control treatments only. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-six patients were included in our study. High level of temperature variability during the first 48 hours was associated with poorer collapsed Glasgow Outcome Scale-Extended. This effect remained statistically significant when only the control arm of the study was analyzed. No statistically significant effect was seen within the first 48 hours in the hypothermia group or within 7 days in either group. CONCLUSIONS: When targeting normothermia, temperature variability may be a statistically significant variable in an ordinal analysis adjusted for baseline covariates.

Cerebral Concussion Primes the Lungs for Subsequent Neutrophil-Mediated Injury.

OBJECTIVES: Mild traumatic brain injury in the form of concussion is extremely common, and the potential effects on pulmonary priming have been underestimated. The aim of this study was to characterize the pulmonary response following mild traumatic brain injury and assess the pulmonary susceptibility to lung injury after a subsequent innocuous pulmonary insult. DESIGN: Experimental in vivo study. SETTING: University research laboratory. SUBJECTS: Male CD1 mice. INTERVENTIONS: We developed a model of concussive traumatic brain injury in mice followed by pulmonary acid microaspiration. To assess the dependent role of neutrophils in mediating pulmonary injury, we specifically depleted neutrophils. MEASUREMENTS AND MAIN RESULTS: Lateral fluid percussion to the brain resulted in neuronal damage and neutrophil infiltration as well as extensive pulmonary interstitial neutrophil accumulation but no alveolar injury. Following subsequent innocuous acid microaspiration, augmented alveolar neutrophil influx led to the development of pulmonary hemorrhage that was reduced following neutrophil depletion. CONCLUSIONS: This model shows for the first time that innocuous acid microaspiration is sufficient to induce neutrophil-mediated lung injury following mild concussion and that the extracranial effects of mild traumatic brain injury have been underestimated.

Mortality Risk Stratification After Traumatic Brain Injury and Hazard of Death With Titrated Hypothermia in the Eurotherm3235Trial.

OBJECTIVES: Hypothermia reduces intracranial hypertension in patients with traumatic brain injury but was associated with harm in the Eurotherm3235Trial. We stratified trial patients by International Mission for Prognosis and Analysis of Clinical Trials in [Traumatic Brain Injury] (IMPACT) extended model sum scores to determine where the balance of risks lay with the intervention. DESIGN: The Eurotherm3235Trial was a randomized controlled trial, with standardized and blinded outcome assessment. Patients in the trial were split into risk tertiles by IMPACT extended model sum scores. A proportional hazard analysis for death between randomization and 6 months was performed by intervention and IMPACT extended model sum scores tertiles in both the intention-to-treat and the per-protocol populations of the Eurotherm3235Trial. SETTING: Forty-seven neurologic critical care units in 18 countries. PATIENTS: Adult traumatic brain injury patients admitted to intensive care who had suffered a primary, closed traumatic brain injury; increased intracranial pressure; an initial head injury less than 10 days earlier; a core temperature at least 36°C; and an abnormal brain CT. INTERVENTION: Titrated Hypothermia in the range 32-35°C as the primary intervention to reduce raised intracranial pressure. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-six patients were available for analysis in the intention-to-treat and 257 in the per-protocol population. The proportional hazard analysis (intention-to-treat and per-protocol populations) showed that the treatment effect behaves similarly across all risk stratums. However, there is a trend that indicates that patients in the low-risk group could be at greater risk of suffering harm due to hypothermia. CONCLUSIONS: Hypothermia as a first line measure to reduce intracranial pressure to less than 20 mm Hg is harmful in patients with a lower severity of injury and no clear benefit exists in patients with more severe injuries.

Proton spectroscopic imaging of brain metabolites in basal ganglia of healthy older adults.

OBJECT: We sought to measure brain metabolite levels in healthy older people. MATERIALS AND METHODS: Spectroscopic imaging at the level of the basal ganglia was applied in 40 participants aged 73-74 years. Levels of the metabolites N-acetyl aspartate (NAA), choline, and creatine were determined in "institutional units" (IU) corrected for T1 and T2 relaxation effects. Structural imaging enabled determination of grey matter (GM), white matter (WM), and cerebrospinal fluid content. ANOVA analysis was carried out for voxels satisfying quality criteria. RESULTS: Creatine levels were greater in GM than WM (57 vs. 44 IU, p < 0.001), whereas choline and NAA levels were greater in WM than GM [13 vs. 10 IU (p < 0.001) and 76 versus 70 IU (p = 0.03), respectively]. The ratio of NAA/cre was greater in WM than GM (2.1 vs. 1.4, p = 0.001) as was that of cho/cre (0.32 vs. 0.16, p < 0.001). A low voxel yield was due to brain atrophy and the difficulties of shimming over an extended region of brain. CONCLUSION: This study addresses the current lack of information on brain metabolite levels in older adults. The normal features of ageing result in a substantial loss of reliable voxels and should be taken into account when planning studies. Improvements in shimming are also required before the methods can be applied more widely.

Reliability of MRSI brain temperature mapping at 1.5 and 3 T.

MRSI permits the non-invasive mapping of brain temperature in vivo, but information regarding its reliability is lacking. We obtained MRSI data from 31 healthy male volunteers [age range, 22-40 years; mean ± standard deviation (SD), 30.5 ± 5.0 years]. Eleven subjects (age range, 23-40 years; mean ± SD, 30.5 ± 5.2 years) were invited to receive four point-resolved spectroscopy MRSI scans on each of 3 days in both 1.5-T (TR/TE = 1000/144 ms) and 3-T (TR/TE = 1700/144 ms) clinical scanners; a further 20 subjects (age range, 22-40 years; mean ± SD, 30.5 ± 4.9 years) were scanned on a single occasion at 3 T. Data were fitted in the time domain to determine the water-N-acetylaspartate chemical shift difference, from which the temperature was estimated. Temperature data were analysed using a linear mixed effects model to determine variance components and systematic temperature changes during the scanning sessions. To characterise the effects of instrumental drift on apparent MRSI brain temperature, a temperature-controlled phantom was constructed and scanned on multiple occasions. Components of apparent in vivo temperature variability at 1.5 T/3 T caused by inter-subject (0.18/0.17 °C), inter-session (0.18/0.15 °C) and within-session (0.36/0.14 °C) effects, as well as voxel-to-voxel variation (0.59/0.54 °C), were determined. There was a brain cooling effect during in vivo MRSI of 0.10 °C [95% confidence interval (CI): -0.110, -0.094 °C; p < 0.001] and 0.051 °C (95% CI: -0.054, -0.048 °C; p < 0.001) per scan at 1.5 T and 3 T, respectively, whereas phantom measurements revealed minimal drift in apparent MRSI temperature relative to fibre-optic temperature measurements. The mean brain temperature at 3 T was weakly associated with aural (R = 0.55, p = 0.002) and oral (R = 0.62, p < 0.001) measurements of head temperature. In conclusion, the variability associated with MRSI brain temperature mapping was quantified. Repeatability was somewhat higher at 3 T than at 1.5 T, although subtle spatial and temporal variations in apparent temperature were demonstrated at both field strengths. Such data should assist in the efficient design of future clinical studies.

A lesson on induction of hypothermia and measurement of efficacy.

Brain injuries caused by stroke are common and costly in human and resource terms. The result of stroke is a cascade of molecular and physiological derangement, cell death, damage and inflammation in the brain. This, together with infection, if present, commonly results in patients having an increased temperature, which is associated with worse outcome. The usual clinical goal in stroke is therefore to reduce temperature to normal, or below normal (hypothermia) to reduce swelling if brain pressure is increased. However, research evidence does not yet conclusively show whether or not cooling patients after stroke improves their longer-term outcome (reduces death and disability). It is possible that complications of cooling outweigh the benefits. Cooling therapy may reduce damage and potentially improve outcome, and head cooling targets the site of injury and may have fewer side effects than systemic cooling, but the evidence base is unclear.

A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury.

INTRODUCTION: Research into therapeutic hypothermia following traumatic brain injury has been characterised by small trials of poor methodological quality, producing variable results. The Cochrane review, published in 2009, now requires updating. The aim of this systematic review is to assess the effectiveness of the application of therapeutic hypothermia to reduce death and disability when administered to adult patients who have been admitted to hospital following traumatic brain injury. METHODS: Two authors extracted data from each trial. Unless stated in the trial report, relative risks and 95% confidence intervals (CIs) were calculated for each trial. We considered P < 0 · 05 to be statistically significant. We combined data from all trials to estimate the pooled risk ratio (RR) with 95% confidence intervals for death, unfavourable outcome, and pneumonia. All statistical analyses were performed using RevMan 5.1 (Cochrane IMS, Oxford, UK) and Stata (Intercooled Version 12.0, StataCorp LP). Pooled RRs were calculated using the Mantel-Haenszel estimator. The random effects model of DerSimonian and Laird was used to estimate variances for the Mantel-Haenszel and inverse variance estimators. RESULTS: Twenty studies are included in the review, while 18 provided mortality data. When the results of 18 trials that evaluated mortality as one of the outcomes were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in mortality and a significant reduction in poor outcome. There was a lack of statistical evidence for an association between use of therapeutic hypothermia and increased onset of new pneumonia. CONCLUSIONS: In contrast to previous reviews, this systematic review found some evidence to suggest that therapeutic hypothermia may be of benefit in the treatment of traumatic brain injury. The majority of trials were of low quality, with unclear allocation concealment. Low quality trials may overestimate the effectiveness of hypothermia treatment versus standard care. There remains a need for more, high quality, randomised control trials of therapeutic hypothermia after traumatic brain injury.

Modest cooling therapies (35ºC to 37.5ºC) for traumatic brain injury.

BACKGROUND: Animal models of traumatic brain injury suggest that induced normothermia (36.5 or 37 ºC), compared to induced hyperthermia (39 ºC), improves histopathological and neurobehavioural outcomes. Observational clinical studies of patients with TBI suggest an association between raised body temperature and unfavourable outcome, although this relationship is inconsistent. OBJECTIVES: To assess the effects of modest cooling therapies (defined as any drug or physical therapy aimed at maintaining body temperature between 35 ºC and 37.5 ºC) when applied to patients in the first week after traumatic brain injury. SEARCH METHODS: The most recent search was run on 23(rd) September 2013. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library (CENTRAL), MEDLINE (OvidSP), Embase (OvidSP), ISI WOS: SCI-EXPANDED (1970) & CPCI-S (1990), PubMed and trials registries together with reference checking. SELECTION CRITERIA: All completed randomised, controlled and placebo-controlled trials published or unpublished, where modest cooling therapies were applied in the first week after traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria to relevant trials. MAIN RESULTS: We were unable to find any randomised controlled trials of modest cooling therapies after traumatic brain injury. AUTHORS' CONCLUSIONS: In order to further explore the preliminary findings provided by animal models and observational clinical studies that suggests there may be a beneficial effect of modest cooling for TBI, randomised trials designed to explore the effect of these interventions on patient-centred outcomes are needed.

The European clinical trials directive and its impact on critical care and emergency research.

PURPOSE OF REVIEW: The European Clinical Trials Directive was issued in 2001 and aimed to simplify and harmonize the regulatory framework of clinical trials throughout Europe, thus stimulating European research. However, significant complexity and inconsistency remains due to disparate interpretation by European Union member states, creating substantial financial and administrative challenges for investigators. RECENT FINDINGS: Critical care research has been particularly impacted by the Directive due to variable and often restrictive consenting procedures for incapacitated patients. Furthermore, the absence of a waiver of consent threatened to put an end to emergency research in Europe. Approval procedures by ethics committees are equally inconsistent, particularly those relating to provision of a single opinion for multicentre trials. This complexity as well as a general increase in administrative and financial burden following the Directive has been widely shown to cause a reduction in clinical trial activity in Europe. SUMMARY: Various changes to the Directive have been called for by clinical researchers from diverse disciplines, including a risk-based approach to ethical approval, insurance, and monitoring; clarification of terms; and a general simplification of administrative procedures to reduce complexity and cost. This widespread advocacy has led to a planned revision of the Directive in 2011.

Aspects of thermoregulation physiology.

PURPOSE OF REVIEW: The review covers the main aspects of thermoregulation physiology and highlights the implications for therapeutic hypothermia trials. Prevention of shivering and other hypothermia side-effects is of key importance because controlling thermoregulatory responses may be essential for demonstrating neuro-protective properties of hypothermia in several pathologic conditions in which its role is still uncertain, such as in traumatic brain injury and stroke. RECENT FINDINGS: Several recommendations and clinical reviews have been produced in the past 2 years about the application and feasibility of therapeutic hypothermia. Many drugs have been tested in healthy volunteers and anaesthetized patients to abolish shivering but the best protocol for managing side-effects has not yet been defined. A possible strategy might be to simultaneously apply physical methods, such as skin warming, and combination drug therapy. Different drug protocols can be applied, depending on the nature of the care setting. SUMMARY: During moderate hypothermia treatment, conducted in an intensive care environment, shivering can be treated with sedatives, opioids (meperidine in particular), and α2-agonists, combined with active skin counter-warming. However, new randomized controlled clinical trials in intensive care patients are required to improve our knowledge regarding this treatment.

High-frequency oscillation as a rescue strategy for brain-injured adult patients with acute lung injury and acute respiratory distress syndrome.

Acute lung injury and acute respiratory distress syndrome (ARDS) occur frequently in brain-injured patients. Single organ dysfunction ventilator strategies result in a conflict between lung protective ventilation and the prevention of secondary neurological insult(s). The objectives of this study were to determine if clinical and physiological benefits of high-frequency oscillatory ventilation (HFOV) exist compared to conventional ventilation and to determine what data there are on the effects of HFOV on cerebral perfusion pressure and intracranial pressure. Systematic review was designed. An optimally sensitive search strategy was used that included; OVID MEDLINE, OVID EMBASE, Cochrane Clinical Trials Register, and hand searching of references of retrieved articles and proceedings of meetings. Study selection includes published randomized controlled trials comparing HFOV with conventional ventilation in adults with ARDS and observational studies of the use of HFOV in adults with ARDS and traumatic brain injury (TBI). Both authors reviewed all trials. A data extraction form was used. In adults with ARDS no mortality benefit has been shown with HFOV, oxygenation improves, arterial partial pressure of CO(2) may increase and there is no change in mean arterial blood pressure. There are few data describing HFOV in adults with TBI. In the small, low quality, studies that have been reported there have not been uncontrollable changes in intracranial pressure. HFOV has not been shown to have any mortality benefit in adults with ARDS. There are insufficient data to clarify the role, or safety, of HFOV in adults with TBI and concurrent ARDS.

Diagnostic importance of pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP. METHODS: A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers. Growth of pathogens at >10(4) colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from "non-VAP". Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves. RESULTS: Seventy-two patients had recoverable lavage-24% had VAP. BALF interleukin-1beta (IL-1beta), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1alpha were significantly higher in the VAP group (all p<0.005). Using a cut-off of 10 pg/ml, BALF IL-1beta generated negative likelihood ratios for VAP of 0.09. In patients with BALF IL-1beta <10 pg/ml the post-test probability of VAP was 2.8%. Using a cut-off value for IL-8 of 2 ng/ml, the positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <10(4) cfu/ml. CONCLUSIONS: BALF IL-1beta and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.

Selenium and glutamine supplements: where are we heading? A critical care perspective.

PURPOSE OF REVIEW: There is considerable interest in glutamine and selenium in critical care as both offer the potential to enhance host defences, through different but complimentary mechanisms and may reduce subsequent infections and mortality. The SIGNET trial (randomized controlled factorial trial) is the largest, critical care study of both supplements. The data have been presented publicly, but the data are not published or available for review and will therefore not be discussed fully in this update. In the present review I will explore the recently available (past 1-2 years) published literature. RECENT FINDINGS: The current literature demonstrates that there are currently insufficient data to enable confident recommendations on the optimal route, timing, duration and dosage of each of these nutritional supplements. The pending results of SIGNET, the largest critical care trial of parenteral nutrition supplemented by glutamine and or selenium promises to clarify some of the current ambiguities and inform future practice. SUMMARY: To be able to confidently establish or refute the hypothesis that either glutamine or selenium alone or in combination improves outcome in critical care requires a well designed prospective randomized controlled trial. To design such a trial we require the optimal dose and duration of the nutritional supplement (balancing efficacy and toxicity, ease of administration and cost) and then conduct an adequately powered trial. Such a trial is still lacking for these two agents. There are some supportive data for selenium but the case is less strong for parenteral glutamine and weakest for enteral glutamine.