Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT

Background Traumatic brain injury (TBI) is a major cause of disability and death in young adults worldwide. It results in around 1 million hospital admissions annually in the European Union (EU), causes a majority of the 50,000 deaths from road traffic accidents and leaves a further ≈10,000 people severely disabled. Objective The Eurotherm3235 Trial was a pragmatic trial examining the effectiveness of hypothermia (32–35 °C) to reduce raised intracranial pressure (ICP) following severe TBI and reduce morbidity and mortality 6 months after TBI. Design An international, multicentre, randomised controlled trial. Setting Specialist neurological critical care units. Participants We included adult participants following TBI. Eligible patients had ICP monitoring in place with an ICP of > 20 mmHg despite first-line treatments. Participants were randomised to receive standard care with the addition of hypothermia (32–35 °C) or standard care alone. Online randomisation and the use of an electronic case report form (CRF) ensured concealment of random treatment allocation. It was not possible to blind local investigators to allocation as it was obvious which participants were receiving hypothermia. We collected information on how well the participant had recovered 6 months after injury. This information was provided either by the participant themself (if they were able) and/or a person close to them by completing the Glasgow Outcome Scale – Extended (GOSE) questionnaire. Telephone follow-up was carried out by a blinded independent clinician. Interventions The primary intervention to reduce ICP in the hypothermia group after randomisation was induction of hypothermia. Core temperature was initially reduced to 35 °C and decreased incrementally to a lower limit of 32 °C if necessary to maintain ICP at < 20 mmHg. Rewarming began after 48 hours if ICP remained controlled. Participants in the standard-care group received usual care at that centre, but without hypothermia. Main outcome measures The primary outcome measure was the GOSE [range 1 (dead) to 8 (upper good recovery)] at 6 months after the injury as assessed by an independent collaborator, blind to the intervention. A priori subgroup analysis tested the relationship between minimisation factors including being aged < 45 years, having a post-resuscitation Glasgow Coma Scale (GCS) motor score of < 2 on admission, having a time from injury of < 12 hours and patient outcome. Results We enrolled 387 patients from 47 centres in 18 countries. The trial was closed to recruitment following concerns raised by the Data and Safety Monitoring Committee in October 2014. On an intention-to-treat basis, 195 participants were randomised to hypothermia treatment and 192 to standard care. Regarding participant outcome, there was a higher mortality rate and poorer functional recovery at 6 months in the hypothermia group. The adjusted common odds ratio (OR) for the primary statistical analysis of the GOSE was 1.54 [95% confidence interval (CI) 1.03 to 2.31]; when the GOSE was dichotomised the OR was 1.74 (95% CI 1.09 to 2.77). Both results favoured standard care alone. In this pragmatic study, we did not collect data on adverse events. Data on serious adverse events (SAEs) were collected but were subject to reporting bias, with most SAEs being reported in the hypothermia group. Conclusions In participants following TBI and with an ICP of > 20 mmHg, titrated therapeutic hypothermia successfully reduced ICP but led to a higher mortality rate and worse functional outcome. Limitations Inability to blind treatment allocation as it was obvious which participants were randomised to the hypothermia group; there was biased recording of SAEs in the hypothermia group. We now believe that more adequately powered clinical trials of common therapies used to reduce ICP, such as hypertonic therapy, barbiturates and hyperventilation, are required to assess their potential benefits and risks to patients. Trial registration Current Controlled Trials ISRCTN34555414. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 45. See the NIHR Journals Library website for further project information. The European Society of Intensive Care Medicine supported the pilot phase of this trial.

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Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury

Journal of Neurosurgery ◽

10.3171/2009.12.jns09689 ◽

2010 ◽

Vol 113 (3) ◽

pp. 564-570 ◽

Cited By ~ 99

Author(s):

Roukoz Chamoun ◽

Dima Suki ◽

Shankar P. Gopinath ◽

J. Clay Goodman ◽

Claudia Robertson

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Intracranial Pressure ◽

Mortality Rate ◽

Functional Outcome ◽

Excitatory Amino Acid ◽

Demographic Data ◽

Cerebral Microdialysis ◽

Factors Affecting

Object Authors of several studies have implied a key role of glutamate, an excitatory amino acid, in the pathophysiology of traumatic brain injury (TBI). However, the place of glutamate measurement in clinical practice and its impact on the management of TBI has yet to be elucidated. The authors' objective in the present study was to evaluate glutamate levels in TBI, analyzing the factors affecting them and determining their prognostic value. Methods A prospective study of patients with severe TBI was conducted with an inclusion criterion of a Glasgow Coma Scale score ≤ 8 within 48 hours of injury. Invasive monitoring included intracranial pressure measurements, brain tissue PO2, jugular venous O2 saturation, and cerebral microdialysis. Patients received standard care including mass evacuation when indicated and treatment of elevated intracranial pressure values. Demographic data, CT findings, and outcome at 6 months of follow-up were recorded. Results One hundred sixty-five patients were included in the study. Initially high glutamate values were predictive of a poor outcome. The mortality rate was 30.3% among patients with glutamate levels > 20 μmol/L, compared with 18% among those with levels ≤ 20 μmol/L. Two general patterns were recognized: Pattern 1, glutamate levels tended to normalize over the monitoring period (120 hours); and Pattern 2, glutamate levels tended to increase with time or remain abnormally elevated. Patients showing Pattern 1 had a lower mortality rate (17.1 vs 39.6%) and a better 6-month functional outcome among survivors (41.2 vs 20.7%). Conclusions Glutamate levels measured by microdialysis appear to have an important role in TBI. Data in this study suggest that glutamate levels are correlated with the mortality rate and 6-month functional outcome.

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Statistical analysis plan for early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury – a randomised clinical feasibility trial

10.21203/rs.2.468/v3 ◽

2019 ◽

Author(s):

Christian Gunge Riberholt ◽

Christian Gluud ◽

Janus Christian Jakobsen ◽

Christian Ovesen ◽

Jesper Mehlsen ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Statistical Analysis ◽

Brain Injury ◽

Adverse Events ◽

Severe Traumatic Brain Injury ◽

Standard Care ◽

Statistical Analysis Plan ◽

Feasibility Trial ◽

Early Mobilisation ◽

Head Up Tilt

Abstract Background: Early mobilisation on a tilt table with stepping versus standard care may be beneficial for patients with severe brain injury, but data from randomised clinical trials are lacking. Methods: This detailed statistical analysis plan describes the analyses of data collected in a randomised clinical feasibility trial for early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury. Primary feasibility outcomes are the proportion of included participants who were randomised out of all screened patients; the proportion of participants allocated to the experimental intervention who received at least 60% of the planned exercise sessions; and safety outcomes such as adverse events and reactions and serious adverse events and reactions. Exploratory clinical outcomes are suspected unexpected serious adverse reactions; and functional outcomes as assessed by Coma Recovery Scale – Revised at four weeks; Early Functional Ability Scale and Functional Independence Measure at three months. The description includes the statistical analyses including use of multiple imputation and Trial Sequential Analysis. Conclusions: The present statistical analysis plan serves to minimise potential trial reporting bias and selective P hacking and to improve transparency. This trial will inform the feasibility of a potential future multicentre randomised clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT02924649. Registered on 3 October 2016.

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A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury

Journal of Neurosurgery ◽

10.3171/2013.2.jns121468 ◽

2013 ◽

Vol 118 (6) ◽

pp. 1317-1328 ◽

Cited By ~ 81

Author(s):

Sarah B. Rockswold ◽

Gaylan L. Rockswold ◽

David A. Zaun ◽

Jiannong Liu

Keyword(s):

Clinical Trial ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Intracranial Pressure ◽

Clinical Outcome ◽

Severe Traumatic Brain Injury ◽

Standard Care ◽

Cerebral Metabolism ◽

Control Group ◽

Normobaric Hyperoxia

Object Preclinical and clinical investigations indicate that the positive effect of hyperbaric oxygen (HBO2) for severe traumatic brain injury (TBI) occurs after rather than during treatment. The brain appears better able to use baseline O2 levels following HBO2 treatments. In this study, the authors evaluate the combination of HBO2 and normobaric hyperoxia (NBH) as a single treatment. Methods Forty-two patients who sustained severe TBI (mean Glasgow Coma Scale [GCS] score 5.7) were prospectively randomized within 24 hours of injury to either: 1) combined HBO2/NBH (60 minutes of HBO2 at 1.5 atmospheres absolute [ATA] followed by NBH, 3 hours of 100% fraction of inspired oxygen [FiO2] at 1.0 ATA) or 2) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Intracranial pressure, surrogate markers for cerebral metabolism, and O2 toxicity were monitored. Clinical outcome was assessed at 6 months using the sliding dichotomized Glasgow Outcome Scale (GOS) score. Mixed-effects linear modeling was used to statistically test differences between the treatment and control groups. Functional outcome and mortality rates were compared using chi-square tests. Results There were no significant differences in demographic characteristics between the 2 groups. In comparison with values in the control group, brain tissue partial pressure of O2 (PO2) levels were significantly increased during and following combined HBO2/NBH treatments in both the noninjured and pericontusional brain (p < 0.0001). Microdialysate lactate/pyruvate ratios were significantly decreased in the noninjured brain in the combined HBO2/NBH group as compared with controls (p < 0.0078). The combined HBO2/NBH group's intracranial pressure values were significantly lower than those of the control group during treatment, and the improvement continued until the next treatment session (p < 0.0006). The combined HBO2/NBH group's levels of microdialysate glycerol were significantly lower than those of the control group in both noninjured and pericontusional brain (p < 0.001). The combined HBO2/NBH group's level of CSF F2-isoprostane was decreased at 6 hours after treatment as compared with that of controls, but the difference did not quite reach statistical significance (p = 0.0692). There was an absolute 26% reduction in mortality for the combined HBO2/NBH group (p = 0.048) and an absolute 36% improvement in favorable outcome using the sliding dichotomized GOS (p = 0.024) as compared with the control group. Conclusions In this Phase II clinical trial, in comparison with standard care (control treatment) combined HBO2/NBH treatments significantly improved markers of oxidative metabolism in relatively uninjured brain as well as pericontusional tissue, reduced intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. There was significant reduction in mortality and improved favorable outcome as measured by GOS. The combination of HBO2 and NBH therapy appears to have potential therapeutic efficacy as compared with the 2 treatments in isolation. Clinical trial registration no.: NCT00170352 (ClinicalTrials.gov).

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Early, specialist vocational rehabilitation to facilitate return to work after traumatic brain injury: the FRESH feasibility RCT

Health Technology Assessment ◽

10.3310/hta22330 ◽

2018 ◽

Vol 22 (33) ◽

pp. 1-124 ◽

Cited By ~ 8

Author(s):

Kate Radford ◽

Chris Sutton ◽

Tracey Sach ◽

Jain Holmes ◽

Caroline Watkins ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cost Effectiveness ◽

Brain Injury ◽

Technology Assessment ◽

Work Ability ◽

Self Efficacy ◽

Clinical Effectiveness ◽

Health Technology ◽

Face To Face

BackgroundUp to 160,000 people incur traumatic brain injury (TBI) each year in the UK. TBI can have profound effects on many areas of human functioning, including participation in work. There is limited evidence of the clinical effectiveness and cost-effectiveness of vocational rehabilitation (VR) after injury to promote early return to work (RTW) following TBI.ObjectiveTo assess the feasibility of a definitive, multicentre, randomised controlled trial (RCT) of the clinical effectiveness and cost-effectiveness of early, specialist VR plus usual care (UC) compared with UC alone on work retention 12 months post TBI.DesignA multicentre, feasibility, parallel-group RCT with a feasibility economic evaluation and an embedded mixed-methods process evaluation. Randomisation was by remote computer-generated allocation.SettingThree NHS major trauma centres (MTCs) in England.ParticipantsAdults with TBI admitted for > 48 hours and working or studying prior to injury.InterventionsEarly specialist TBI VR delivered by occupational therapists (OTs) in the community using a case co-ordination model.Main outcome measuresSelf-reported RTW 12 months post randomisation, mood, functional ability, participation, work self-efficacy, quality of life and work ability. Feasibility outcomes included recruitment and retention rates. Follow-up was by postal questionnaires in two centres and face to face in one centre. Those collecting data were blind to treatment allocation.ResultsOut of 102 target participants, 78 were recruited (39 randomised to each arm), representing 39% of those eligible and 5% of those screened. Approximately 2.2 patients were recruited per site per month. Of those, 56% had mild injuries, 18% had moderate injuries and 26% had severe injuries. A total of 32 out of 45 nominated carers were recruited. A total of 52 out of 78 (67%) TBI participants responded at 12 months (UC,n = 23; intervention,n = 29), completing 90% of the work questions; 21 out of 23 (91%) UC respondents and 20 out of 29 (69%) intervention participants returned to work at 12 months. Two participants disengaged from the intervention. Face-to-face follow-up was no more effective than postal follow-up. RTW was most strongly related to social participation and work self-efficacy. It is feasible to assess the cost-effectiveness of VR. Intervention was delivered as intended and valued by participants. Factors likely to affect a definitive trial include deploying experienced OTs, no clear TBI definition or TBI registers, and repatriation of more severe TBI from MTCs, affecting recruitment of those most likely to benefit/least likely to drop out.LimitationsTarget recruitment was not reached, but mechanisms to achieve this in future studies were identified. Retention was lower than expected, particularly in UC, potentially biasing estimates of the 12-month RTW rate.ConclusionsThis study met most feasibility objectives. The intervention was delivered with high fidelity. When objectives were not met, strategies to ensure feasibility of a full trial were identified. Future work should test two-stage recruitment and include resources to recruit from ‘spokes’. A broader measure covering work ability, self-efficacy and participation may be a more sensitive outcome.Trial registrationCurrent Controlled Trials ISRCTN38581822.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 33. See the NIHR Journals Library website for further project information.

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Early Orthostatic Exercise by Head-Up Tilt With Stepping vs. Standard Care After Severe Traumatic Brain Injury Is Feasible

Frontiers in Neurology ◽

10.3389/fneur.2021.626014 ◽

2021 ◽

Vol 12 ◽

Author(s):

Christian Gunge Riberholt ◽

Markus Harboe Olsen ◽

Christian Baastrup Søndergaard ◽

Christian Gluud ◽

Christian Ovesen ◽

...

Keyword(s):

Clinical Trial ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Adverse Events ◽

Severe Traumatic Brain Injury ◽

Standard Care ◽

Randomized Clinical Trials ◽

Neurointensive Care ◽

Control Group ◽

Neurointensive Care Unit

Background: Intensive rehabilitation of patients after severe traumatic brain injury aims to improve functional outcome. The effect of initiating rehabilitation in the early phase, in the form of head-up mobilization, is unclear.Objective: To assess whether early mobilization is feasible and safe in patients with traumatic brain injury admitted to a neurointensive care unit.Methods: This was a randomized parallel-group clinical trial, including patients with severe traumatic brain injury (Glasgow coma scale <11 and admission to the neurointensive care unit). The intervention consisted of daily mobilization on a tilt-table for 4 weeks. The control group received standard care. Outcomes were the number of included participants relative to all patients with traumatic brain injury who were approached for inclusion, the number of conducted mobilization sessions relative to all planned sessions, as well as adverse events and reactions. Information on clinical outcome was collected for exploratory purposes.Results: Thirty-eight participants were included (19 in each group), corresponding to 76% of all approached patients [95% confidence interval (CI) 63–86%]. In the intervention group, 74% [95% CI 52–89%] of planned sessions were carried out. There was no difference in the number of adverse events, serious adverse events, or adverse reactions between the groups.Conclusions: Early head-up mobilization is feasible in patients with severe traumatic brain injury. Larger randomized clinical trials are needed to explore potential benefits and harms of such an intervention.Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02924649]. Registered on 3rd October 2016.

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The role of ICP monitoring in meningitis

Neurosurgical FOCUS ◽

10.3171/2017.8.focus17419 ◽

2017 ◽

Vol 43 (5) ◽

pp. E7 ◽

Cited By ~ 10

Author(s):

Areej Tariq ◽

Pedro Aguilar-Salinas ◽

Ricardo A. Hanel ◽

Neeraj Naval ◽

Mohamad Chmayssani

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Intracranial Pressure ◽

Mortality Rate ◽

Intracranial Hypertension ◽

Clinical Outcomes ◽

Icp Monitoring ◽

Review Of The Literature ◽

Cns Infections

Intracranial pressure (ICP) monitoring has been widely accepted in the management of traumatic brain injury. However, its use in other pathologies that affect ICP has not been advocated as strongly, especially in CNS infections. Despite the most aggressive and novel antimicrobial therapies for meningitis, the mortality rate associated with this disease is far from satisfactory. Although intracranial hypertension and subsequent death have long been known to complicate meningitis, no specific guidelines targeting ICP monitoring are available. A review of the literature was performed to understand the pathophysiology of elevated ICP in meningitis, diagnostic challenges, and clinical outcomes in the use of ICP monitoring.

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Hypertonic saline reduces cumulative and daily intracranial pressure burdens after severe traumatic brain injury

Journal of Neurosurgery ◽

10.3171/2014.10.jns132545 ◽

2015 ◽

Vol 122 (1) ◽

pp. 202-210 ◽

Cited By ~ 61

Author(s):

Halinder S. Mangat ◽

Ya-Lin Chiu ◽

Linda M. Gerber ◽

Marjan Alimi ◽

Jamshid Ghajar ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Intracranial Pressure ◽

Mortality Rate ◽

Hypertonic Saline ◽

New York State ◽

Mortality Rates ◽

Icp Monitoring ◽

Severe Tbi ◽

The Mean

OBJECT Increased intracranial pressure (ICP) in patients with traumatic brain injury (TBI) is associated with a higher mortality rate and poor outcome. Mannitol and hypertonic saline (HTS) have both been used to treat high ICP, but it is unclear which one is more effective. Here, the authors compare the effect of mannitol versus HTS on lowering the cumulative and daily ICP burdens after severe TBI. METHODS The Brain Trauma Foundation TBI-trac New York State database was used for this retrospective study. Patients with severe TBI and intracranial hypertension who received only 1 type of hyperosmotic agent, mannitol or HTS, were included. Patients in the 2 groups were individually matched for Glasgow Coma Scale score (GCS), pupillary reactivity, craniotomy, occurrence of hypotension on Day 1, and the day of ICP monitor insertion. Patients with missing or erroneous data were excluded. Cumulative and daily ICP burdens were used as primary outcome measures. The cumulative ICP burden was defined as the total number of days with an ICP of > 25 mm Hg, expressed as a percentage of the total number of days of ICP monitoring. The daily ICP burden was calculated as the mean daily duration of an ICP of > 25 mm Hg, expressed as the number of hours per day. The numbers of intensive care unit (ICU) days, numbers of days with ICP monitoring, and 2-week mortality rates were also compared between the groups. A 2-sample t-test or chi-square test was used to compare independent samples. The Wilcoxon signed-rank or Cochran-Mantel-Haenszel test was used for comparing matched samples. RESULTS A total of 35 patients who received only HTS and 477 who received only mannitol after severe TBI were identified. Eight patients in the HTS group were excluded because of erroneous or missing data, and 2 other patients did not have matches in the mannitol group. The remaining 25 patients were matched 1:1. Twenty-four patients received 3% HTS, and 1 received 23.4% HTS as bolus therapy. All 25 patients in the mannitol group received 20% mannitol. The mean cumulative ICP burden (15.52% [HTS] vs 36.5% [mannitol]; p = 0.003) and the mean (± SD) daily ICP burden (0.3 ± 0.6 hours/day [HTS] vs 1.3 ± 1.3 hours/day [mannitol]; p = 0.001) were significantly lower in the HTS group. The mean (± SD) number of ICU days was significantly lower in the HTS group than in the mannitol group (8.5 ± 2.1 vs 9.8 ± 0.6, respectively; p = 0.004), whereas there was no difference in the numbers of days of ICP monitoring (p = 0.09). There were no significant differences between the cumulative median doses of HTS and mannitol (p = 0.19). The 2-week mortality rate was lower in the HTS group, but the difference was not statistically significant (p = 0.56). CONCLUSIONS HTS given as bolus therapy was more effective than mannitol in lowering the cumulative and daily ICP burdens after severe TBI. Patients in the HTS group had significantly lower number of ICU days. The 2-week mortality rates were not statistically different between the 2 groups.

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Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases

Journal of Neurosurgery ◽

10.3171/jns.2000.93.4.0546 ◽

2000 ◽

Vol 93 (4) ◽

pp. 546-549 ◽

Cited By ~ 201

Author(s):

Ji-Yao Jiang ◽

Ming-Kun Yu ◽

Cheng Zhu

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mortality Rate ◽

Severe Traumatic Brain Injury ◽

Mild Hypothermia ◽

Body Temperatures ◽

Content Type ◽

Hypothermia Group ◽

Fine Print

Object. The goal of this study was to investigate the protective effects of long-term (3–14 days) mild hypothermia therapy (33–35°C) on outcome in 87 patients with severe traumatic brain injury (TBI) (Glasgow Coma Scale score ≤ 8).Methods. In 43 patients assigned to a mild hypothermia group, body temperatures were cooled to 33 to 35°C a mean of 15 hours after injury and kept at 33 to 35°C for 3 to 14 days. Rewarming commenced when the individual patient's intracranial pressure (ICP) returned to the normal level. Body temperatures in 44 patients assigned to a normothermia group were maintained at 37 to 38°C. Each patient's outcome was evaluated 1 year later by using the Glasgow Outcome Scale. One year after TBI, the mortality rate was 25.58% (11 of 43 patients) and the rate of favorable outcome (good recovery or moderate disability) was 46.51% (20 of 43 patients) in the mild hypothermia group. In the normothermia group, the mortality rate was 45.45% (20 of 44 patients) and the rate of favorable outcome was 27.27% (12 of 44 patients) (p < 0.05). Induced mild hypothermia also markedly reduced ICP (p < 0.01) and inhibited hyperglycemia (p < 0.05). The rates of complication were not significantly different between the two groups.Conclusions. The data produced by this study demonstrate that long-term mild hypothermia therapy significantly improves outcomes in patients with severe TBI.

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