Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

How and when post intensive care syndrome-family is measured: A scoping review.

OBJECTIVES: Family members of Intensive Care Unit (ICU) patients can experience mental health difficulties. These are collectively described as Post Intensive Care Syndrome-Family (PICS-F). There are no standardised outcome measures to benchmark the impact of PICS-F. This scoping review aimed to map and characterise interventions, outcomes, and outcome instruments related to PICS-F. METHODS: Eight databases were searched in June 2023: Pubmed, CINAHL, Ovid Medline, EMBASE, PsycInfo, AMED, Emcare and Cochrane. The grey literature was also searched. Studies published after 2012 related to PICS-F were included. Search strategy included: (Population) family members of adult ICU patients, (Concept) PICS-F, (Context) ICU settings. Frequency analysis of outcomes was performed, and instruments were mapped to describe the characteristics. RESULTS: Of the identified 4848 records, 46 papers representing 44 unique studies met the inclusion criteria and were retained for analysis. In total, 8008 family members were represented across 15 countries in four continents worldwide. The number of studies reporting PICS-F interventions increased rapidly over the past 12 years and were performed in ICUs treating mixed conditions. Studies were randomised control trials (n = 33), before-and-after design (n = 6) and non-randomised trials (n = 5). A total of 18 outcome instruments were used measuring predominantly anxiety, with complicated grief measured only once. The identified instruments were mostly validated for clinical and disease specific populations but not validated among relatives of ICU patients. CONCLUSION: There is a plethora of instruments measuring PICS-F outcomes. No core outcome set is currently available for PICS-F. To reduce heterogeneity of how PICS-F is measured, a core outcome set with validated measurements is recommended to allow benchmarking and to document the impact of PICS-F interventions. IMPLICATIONS FOR CLINICAL PRACTICE: Recognising PICS-F symptoms and understanding how to assess them could help clinicians to develop interventions to improve family outcomes. Validated instruments are needed to evaluate these interventions.

Exploring the Experiences of Family Members When a Patient Is Admitted to the ICU with a Severe Traumatic Brain Injury: A Scoping Review.

The needs of family members of patients in the intensive care unit (ICU) with a severe traumatic brain injury (TBI) remain unmet. To date, no review has been performed to explore the experiences of relatives of adults who have been admitted to the ICU for treatment of a TBI. The aim of this scoping review is to explore and map the evidence of the experiences of family members when an adult relative is admitted to an ICU with a severe TBI. This review follows a combination of guidelines from Arksey and O'Malley and the Joanna Briggs Institute. Five electronic databases, Medline, Emcare, Embase, CINAHL, and PsycInfo were searched in February 2023, as were a number of grey literature sources. The population, concepts, and context framework were used to define the inclusion and exclusion criteria. From 4077 records, nine studies were retained, which represented seven discrete studies. The experiences of family members were thematically analyzed. The narrative synthesis of findings revealed three themes: communication with the clinical team, uncertainty, and involvement in care. These results offer richness and depth of understanding to clinicians regarding the experiences of families during this traumatic time. This review provides direction for targeted interventions aimed at supporting family members while in the ICU.

Coenzyme Q10 supplementation in traumatic brain injury: a scoping review protocol.

OBJECTIVE: The objective of this review is to map evidence on coenzyme Q10 (CoQ10) use in traumatic brain injury (TBI). INTRODUCTION: Traumatic brain injury is an insult to the brain structure caused by external force and resulting in physiological disruption to brain function. Globally, 60% of all TBIs occur from road traffic accidents. In 2016, the World Health Organization reported that road traffic accidents were among the top 10 leading causes of death. Following the initial brain injury, a secondary injury can occur due primarily to a significant increase in production of free radicals causing oxidative stress, which can dictate the patient's ability to survive. Coenzyme Q10 is known to protect neuronal cells from oxidative stress; the mechanism for this has been examined in studies using rats. This review will examine what is known about CoQ10 in TBI and identify gaps in the literature, which may guide future research. INCLUSION CRITERIA: The review will include both human and animal subjects who have experienced a TBI in the acute/laboratory-controlled setting and where CoQ10 is supplemented. Animal studies will be included. The review will consider experimental and quasi-experimental study designs including randomized controlled trials, non-randomized controlled trials, before and after studies, and interrupted time-series studies. Studies published in English will be considered, with no date restriction. METHODS: Searches will be conducted in the Cochrane Library, MEDLINE, Embase, CINAHL and trial registries. Data will be extracted and presented on details about the population, concept, context, study methods and key findings.