Time-differentiated target temperature management after out-of-hospital cardiac arrest: a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial

BACKGROUND The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome. METHODS The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients. DISCUSSION This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients. TRIAL REGISTRATION NCT01689077.

Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C

BACKGROUND: Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. METHODS: A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. RESULTS: In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. CONCLUSION: Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naive adults with CHC.

Simplest tasks have greatest dual task interference with balance in brain injured adults

Attention difficulties and poor balance are both common sequel following a brain injury. This study aimed to determine whether brain injured adults had greater difficulty than controls in performing a basic balance task while concurrently completing several different cognitive tasks varying in visuo-spatial attentional load and complexity. Twenty brain injured adults and 20 age-, sex- and education level-matched controls performed a balance-only task (step stance held for 30s), five cognitive-only tasks (simple and complex non-spatial, visuo-spatial, and a control articulation task), and both together (dual tasks). Brain injured adults showed a greater centre of pressure (COP) excursion and velocity in all conditions than controls. Brain injured adults also demonstrated greater interference with balance when concurrently performing two cognitive tasks than control subjects. These were the control articulation and the simple non-spatial task. It is likely that distractibility during these simple tasks contributed to an increase in COP motion and interference with postural stability in stance. Performing visuo-spatial tasks concurrently with the balance task did not result in any change in COP motion. Dual task interference in this group is thus unlikely to be due to structural interference. Similarly, as the more complex tasks did not uniformly result in increased interference, a reduction in attentional capacity in the brain injured population is unlikely to be the primary cause of dual task interference in this group. (C) 2004 Elsevier B.V. All rights reserved.

Effect of cooling and re-warming on cerebral and whole body electrical impedance

Cerebral electrical impedance is useful for the detection of cerebral edema following hypoxia in newborn infants. Thus it may be useful for determining neurological outcome or monitoring treatment. Hypothermia is a promising new therapy currently undergoing trials, but will alter impedance measurements. This study aimed to define the relationship between temperature and both cerebral and whole body electrical impedance, and to derive correction factors for adjustment of impedance measurements during hypothermia. In eight anaesthetized 1-2 day old piglets rectal, tympanic and scalp temperatures were monitored continuously. Following baseline readings at a rectal temperature of 39degreesC, piglets were cooled to 32degreesC. Four piglets were re-warmed. Cerebral and whole body impedance were measured at each 0.5degreesC as rectal temperature decreased. There was a strong linear relationship between both cerebral and whole body impedance and each of the temperatures measured. There was no difference in the relationship between impedance and rectal, tympanic or scalp temperatures. The relationship for impedance and rectal temperature was the same during cooling and re-warming. Using the correction factors derived it will be possible to accurately monitor cerebral and whole body fluid distribution during hypothermic treatment.

Language outcomes subsequent to treatment of brainstem tumour in childhood

While the occurrence and management of brainstem tumours in children would not traditionally indicate potential direct structural impact on classical language centres, recent theories have implicated some involvement of the brainstem in a functional language and cognitive neural loop between the cerebellum and the cerebral hemispheres. Thus, the present paper explored the impact of treatment for brainstem tumour on the general and high-level language abilities of six children treated for brainstem tumour, in addition to phonological awareness skills. Group analysis revealed that children treated for brainstem tumour demonstrated intact language and phonological awareness abilities in comparison to an age- and gender-matched control group. Individual analysis revealed only one of six children treated for brainstem tumour revealed evidence of language disturbances, with an additional child demonstrating an isolated mildly reduced score on one phonological awareness task. Language deficits identified in a child treated with a combination of both radiotherapy and chemotherapy were noted in the high-level language area of lexical generation. Findings highlighted that no overt language disturbances were evident in children treated for brainstem tumour. However, further analysis into higher-level language skills in the present study indicated that both general and high-level language abilities require long-term monitoring in this population.

Is the method of signal analysis and test selection important for measuring standing balance in subjects with persistent whiplash?

Dizziness and or unsteadiness, associated with episodes of loss of balance, are frequent complaints in those suffering from persistent problems following a whiplash injury. Research has been inconclusive with respect to possible aetiology, discriminative tests and analyses used. The aim of this pilot research was to identify the test conditions and the most appropriate method for the analysis of sway that may differentiate subjects with persistent whiplash associated disorders (WAD) from healthy controls. The six conditions of the Clinical Test for Sensory Interaction in Balance was performed in both comfortable and tandem stance in 20 subjects with persistent WAD compared to 20 control subjects. The analyses were carried out using a traditional method of measurement, total sway distance, to results obtained from the use of wavelet analysis. Subjects with WAD were significantly less able to complete the tandem stance tests on a firm surface than controls. In comfortable stance, using wavelet analysis, significant differences between subjects with WAD and the control group were evident in total energy of the trace for all test conditions apart from eyes open on the firm surface. In contrast, the results of the analysis using total sway distance revealed no significant differences between groups across all six conditions. Wavelet analysis may be more appropriate for detecting disturbances in balance in whiplash subjects because the technique allows separation of the noise from the underlying systematic effect of sway. These findings will be used to direct future studies on the aeitiology of balance disturbances in WAD. (c) 2004 Elsevier B.V. All rights reserved.

Objective and behavioural assessment of the emergence from post-traumatic amnesia (PTA)

Primary objective: To determine the profile of resolution of typical PTA behaviours and describe new learning and improvements in self-care during PTA. Research design: Prospective longitudinal study monitoring PTA status, functional learning and behaviours on a daily basis. Methods and procedures: Participants were 69 inpatients with traumatic brain injury who were in PTA. PTA was assessed using the Westmead or Oxford PTA assessments. Functional learning capability was assessed using a routine set of daily tasks and behaviour was assessed using an observational checklist. Data was analysed using descriptive statistics. Main outcomes and results: Challenging behaviours that are typically associated with PTA, such as agitation, aggression and wandering resolved in the early stages of PTA and incidence rates of these behaviours were less than 20%. Independence in self-care and bowel and bladder continence emerged later during resolution of PTA. New learning in functional situations was demonstrated by patients in PTA. Conclusions: It is feasible to begin active rehabilitation focused on functional skills-based learning with patients in the later stages of PTA. Formal assessment of typically observed behaviours during PTA may complement memory-based PTA assessments in determining emergence from PTA.

The rapid screen of concussion: An evaluation of the non-word repetition test for use in mTBI research

Primary objectives: (1) To investigate the Nonword Repetition test (NWR) as an index of sub-vocal rehearsal deficits after mild traumatic brain injury (mTBI); (2) to assess the reliability, validity and sensitivity of the NWR; and (3) to compare the NWR to more sensitive tests of verbal memory. Research design: An independent groups design. Methods and procedures: Study 1 administered the NWR to 46 mTBI and 61 uninjured controls with the Rapid Screen of Concussion (RSC). Study 2 compared mTBI, orthopaedic and uninjured participants on the NWR and the Hopkins Verbal Learning Test (HVLT-R). Main outcomes and results: The NWR did not improve the diagnostic accuracy of the RSC. However, it is reliable and indexes sub-vocal rehearsal speed. These findings provide evidence that although the current form of the NWR lacks sensitivity to the impact of mTBI, the development of a more sensitive test of sub-vocal rehearsal deficits following mTBI is warranted.

Plaques and tangles and the pathogenesis of Alzheimer's disease

Since the earliest descriptions, senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the pathological hallmarks of Alzheimer's disease (AD). Consequently, studies of the morphology, distribution, and molecular composition of SP and NFT have played an important role in developing theories as to the pathogenesis of AD; the most important being the 'Amyloid Cascade Hypothesis (ACH)'. Nevertheless, the significance of SP and NFT to the pathogenesis of AD remains controversial. This review examines three questions: 1) is there a relationship between the lesions and the degree of clinical dementia, 2) is the pathogenesis of the NFT linked to that of the SP, and 3) what is the relationship of SP and NFT to the pathogenesis of AD? These questions are discussed with reference to the morphology and molecular composition of SP and NFT, the effects of gene mutations, studies of head injury patients, experimental studies involving brain lesions and transgenes, and the degeneration of specific anatomical pathways. It was concluded that SP and NFT are not closely related to the developing dementia in AD, arise as relatively independent lesions, and may be the products of a degenerative process rather than being their cause.

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis"

The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the "Amyloid Cascade Hypothesis" (ACH) first formulated in 1992. The ACH proposes that the deposition of ß-amyloid (Aß) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

What risk factors are associated with Alzheimer's disease?

A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.

Central Vestibulopathy in a Female Collegiate Basketball Player: A Case Study

We present a unique case of a collegiate athlete who suffered from a mild head injury following a multi-car motor vehicle accident and was later diagnosed with central vestibulopathy.