Clinical trial NCT04508244: Beta Blocker Use In Traumatic Brain Injury Based On The High-Sensitive Troponin T Status
Official title: Beta Blocker Use In Traumatic Brain Injury Based On The High-Sensitive Troponin T Status: A Randomized Controlled Trial (BBTBBT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Trauma
Brain Injuries
Stress Reaction
Beta Blockers
Troponin
Keywords: propranolol
troponin
biomarkers
myocardial injury
brain injury
trauma
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Lead sponsor: Hamad Medical Corporation
Sponsor class: INDUSTRY
First posted: 2020-08-11
Enrollment: 771
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, double-blinded, placebo-controlled trial
Primary purpose: TREATMENT

Brief summary: Beta blockers (BB) play an important role in protection of end organs that are susceptible for secondary injury by the Traumatic brain injury (TBI)-induced catecholamine surge. However, use of BBs in trauma patients is not yet the standard of care which necessitates clear scientific evidence and justification to be used especially in TBI patients. The BBTBBT study aims to determine whether early administration of propranolol based on the HSTnT status will improve the outcome of mild-to-severe TBI patients. Our primary hypothesis is that BBs are effective in reducing 10 and 30-day mortality in TBI patients.BBs are effective in reducing 10 and 30-day mortality in TBI patients.

Methods/Design: The BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled trial, three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status.

Detailed description: Traumatic brain injury (TBI) accounts for up to 30% of all injury-related deaths \[1\]. It also poses a significant morbidity and economic burden world-wide \[2,3\]. While there has been significant advances in trauma care overall, there are limited medical management options for head injury. Based on retrospective observational studies, TBI is associated with an increased risk of mortality. Some of these studies reported higher rate of mortality in TBI patients who had elevated serum troponin in comparison to those who had normal troponin, even in isolated TBI.

Few studies have evaluated the clinical significance of the release of serum cardiac troponins after trauma \[4-7\]. Some of these studies showed that elevated troponin could reflect the degree of severity of overall body injury, but in particular the severity of thorax trauma regardless of cardiac involvement \[5,6\]. Furthermore, elevated troponins were reported in acute non-traumatic head injury, including acute stroke (≈27%), and subarachnoid hemorrhage (≈20%) \[4, 7\]. However, the precise mechanism of elevated troponin is difficult to be determined due to the multitude of prevailing clinical circumstances which may influence troponin release. Moreover, the clinical significance and prognostic value of elevated troponins levels and immune response remain poorly explored in TBI patients. Earlier studies relied mainly on TnT or TnI and did not examine the newer high-sensitive TnT (HsTnT) which has more sensitivity and shorter time to detect myocardial damage. A recent meta-analysis showed that elevated troponins are commonly seen in critically-ill patients even in the absence of coronary artery disease \[7,8,9\] with a prevalence of 45% studies utilized conventional troponin assays ( TnT and TnI), \[10\] however, this figure reaches 62% with the use of HsTnT \[11, 12\]. From the therapeutic point of view, BBs use was reported to have better survival in blunt TBI patients \[4, 14, 15,16\]. Notably, BBs play an important role in protection of end organs that are susceptible for secondary injury by the TBI-induced catecholamine surge \[4\]. Upon the latter observation, the use of HsTnT test early in TBI cases may allow early stratification and therapy to possibly reduce mortality. However, this assumption needs further support through large clinical trials. Prospective studies that link the release of troponins and mortality in post-TBI patients are lacking. The use of BBs in patients with acute coronary myocardial injury is evidence-based, especially in the very early hours post myocardial injury. However, use of BBs in trauma patients is not yet the standard of care. The use of BBs needs to be clearly justified in TBI patients. Retrospectively, Salim et al \[13\] reported that patients with severe TBI who did not receive BBs had a mortality rate of 36% vs. 24% in those who were receiving BBs (p=0.036). Furthermore, if troponin I was elevated on admission, the hospital mortality increased to 48.5% in patients without BBs therapy vs. 22.4% in those who were using BBs (p=0.026).However, the two groups (with \& without BB) were comparable for mortality, if the admission troponin values were not elevated (p=0.31). In brief, the utmost benefit in survival occurred in BBs use group based on the troponin positivity on admission. However, this study did not explain the specific underlying mechanism of troponin positivity. The BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled trial, three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status. We hypothesized that early administration of BBs has beneficial effect on the 10 and 30-day mortality in patients with mild-to-severe TBI based on the admission HsTnT status.

Eligibility criteria: Inclusion Criteria:

* All adults (≥18 -65 years)
* both genders
* mild-to-severe blunt TBI (head AIS 1-5 and/ GCS 4-15) patients requiring hospital admission

Exclusion Criteria:

* Patients \<18 and\> 65 yrs old
* penetrating trauma
* non-survivable injuries (head AIS=6 \& GCS=3)
* uncontrolled bleeding on arrival to ED
* pregnant women
* prisoners
* patients with heart rate (HR) ≤70, systolic blood pressure (SBP) ≤100 mmHg (or MAP \<70 mmHg) not responding to initial management or required to be maintained on vasopressors on arrival .
* Patients who will undergo hypothermia therapy,
* any penetrating injury to head, thorax or abdomen,
* history of bronchial asthma
* patients posted for emergency surgery during the first 6 hrs.

Primary outcomes:
measure: Mortality
timeFrame: 10 days
measure: Mortality
timeFrame: 30 days
Secondary outcomes:
measure: Duration of hospital stay
timeFrame: 3 months
measure: Functional status
timeFrame: 3 months
Other outcomes:
measure: Injury severity indicators
timeFrame: 48 hours
Locations:
city: Doha
country: Qatar
facility: Hamad General Hospital
Study officials:
affiliation: Hamad Medical Corporation
name: Ayman El-Menyar, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010.
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citation: Mock C, Lormand JD, Goosen J, Joshipura M, Peden M. Guidelines for essential trauma care. Geneva, World Health Organization, 2004. Retrieved from: http://www.who.int/violence_injury_prevention/publications/services/en/guidelines_traumacare.pdf
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citation: Mahmood I, El-Menyar A, Dabdoob W, Abdulrahman Y, Siddiqui T, Atique S, Arumugam SK, Latifi R, Al-Thani H. Troponin T in Patients with Traumatic Chest Injuries with and without Cardiac Involvement: Insights from an Observational Study. N Am J Med Sci. 2016 Jan;8(1):17-24. doi: 10.4103/1947-2714.175188.
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citation: Salim A, Hadjizacharia P, Brown C, Inaba K, Teixeira PG, Chan L, Rhee P, Demetriades D. Significance of troponin elevation after severe traumatic brain injury. J Trauma. 2008 Jan;64(1):46-52. doi: 10.1097/TA.0b013e31815eb15a.
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citation: Ko A, Harada MY, Barmparas G, Thomsen GM, Alban RF, Bloom MB, Chung R, Melo N, Margulies DR, Ley EJ. Early propranolol after traumatic brain injury is associated with lower mortality. J Trauma Acute Care Surg. 2016 Apr;80(4):637-42. doi: 10.1097/TA.0000000000000959.
citation: El-Menyar A, Asim M, Latifi R, Bangdiwala SI, Al-Thani H. Predictive value of positive high-sensitivity troponin T in intubated traumatic brain injury patients. J Neurosurg. 2018 Dec 1;129(6):1541-1549. doi: 10.3171/2017.7.JNS17675. Epub 2018 Jan 5.
citation: El-Menyar A, Goyal A, Latifi R, Al-Thani H, Frishman W. Brain-Heart Interactions in Traumatic Brain Injury. Cardiol Rev. 2017 Nov/Dec;25(6):279-288. doi: 10.1097/CRD.0000000000000167.
citation: El-Menyar A, Asim M, Bahey AA, Chughtai T, Alyafai A, Abdelrahman H, Rizoli S, Peralta R, Al-Thani H. Beta blocker use in traumatic brain injury based on the high-sensitive troponin status (BBTBBT): methodology and protocol implementation of a double-blind randomized controlled clinical trial. Trials. 2021 Dec 7;22(1):890. doi: 10.1186/s13063-021-05872-8.