What is the approach to using beta (beta blockers) in patients with traumatic brain injury (TBI)?

Beta Blockers in Traumatic Brain Injury

In adults with acute traumatic brain injury requiring ICU admission, beta blockers should be administered during hospitalization to reduce mortality, with propranolol being the preferred agent. 1

Mortality Benefit

The Eastern Association for the Surgery of Trauma (EAST) guideline provides a conditional recommendation for the use of in-hospital beta blockers in adults with acute TBI based on a systematic review and meta-analysis. 1 The evidence demonstrates:

• Beta blocker exposure after TBI is associated with a 61% reduction in in-hospital mortality (pooled OR 0.39,95% CI: 0.27–0.56, p<0.00001) based on 9 studies encompassing 2,005 treated patients and 6,240 controls. 1

• More recent multicenter prospective data from 2,252 patients across 15 trauma centers confirmed this benefit, showing beta blockers were independently associated with lower mortality (adjusted OR 0.35, p<0.001). 2

• A 2023 meta-analysis of 13,244 patients from 17 studies corroborated the mortality benefit (RR 0.8,95% CI 0.68 to 0.94). 3

Mechanism and Rationale

Beta blockers work by blunting the hyperadrenergic state that occurs after TBI. 1 Acute TBI triggers:

• Elevated local norepinephrine levels due to disrupted blood-brain barrier 1
• Increased cerebral metabolic rate for oxygen and glucose 1
• Exacerbation of ischemia and metabolic crisis in injured brain tissue with defective autoregulation 1

Agent Selection: Propranolol Preferred

Propranolol is superior to other beta blockers for TBI patients. 2 The evidence shows:

• Propranolol demonstrated better outcomes compared to other beta blockers (adjusted OR 0.51, p=0.010; adjusted HR 0.50, p=0.003). 2

• Propranolol's advantages include nonselective beta-receptor inhibition and ability to cross the blood-brain barrier, allowing direct central nervous system effects. 4

• In the EAST guideline cohort, 60% of patients received metoprolol only, 33% received propranolol only, with smaller numbers receiving both or atenolol. 1

Timing and Dosing

Beta blockers should be initiated within 24 hours of admission. 4, 2 Implementation details:

• Most patients (56.3%) in the multicenter trial received their first dose by hospital day 1. 2

• Early propranolol dosing protocol: 1 mg intravenous every 6 hours, initiated within 24 hours of admission. 4

• Treatment should continue for at least 48 hours and typically throughout the hospital stay (>24 hours to >48 hours documented in studies). 1

• Dosing should be guided by heart rate (>60 bpm), systolic blood pressure (≥100 mmHg), and mean arterial pressure (>70 mmHg). 5

Target Population

Beta blockers are recommended for patients with moderate-to-severe TBI requiring ICU admission (Glasgow Coma Scale <13). 1, 6 The intervention applies to:

• Adult patients aged ≥16-18 years 1
• Blunt trauma patients with head Abbreviated Injury Scale scores 3-5 4, 2
• Patients admitted to ICU where cardiovascular monitoring is feasible 1

Functional Outcomes

The evidence on functional outcomes is mixed and represents a significant knowledge gap:

• No studies in the EAST guideline examined functional outcome or quality of life measures. 1

• A 2023 TRACK-TBI study of 450 patients found no difference in 6-month Glasgow Outcome Scale-Extended scores between beta blocker and non-beta blocker groups (OR 0.86,95% CI 0.48-1.53). 6

• However, a 2023 meta-analysis showed functional benefit at longer-term follow-up (OR 1.75,95% CI 1.09 to 2.8) but not at hospital discharge. 3

Safety Considerations and Contraindications

The recommendation is conditional on avoiding symptomatic bradycardia and hypotension, which are associated with poor TBI outcomes. 1 Critical safety points:

• Beta blockers are negative inotropes that can induce bradycardia and hypotension, both harmful in TBI populations. 1

• Cardiopulmonary complications were more likely in beta blocker recipients (RR 1.94,95% CI 1.69 to 2.24). 3

• Infectious complications were also increased (RR 2.36,95% CI 1.42 to 3.91). 3

• Avoid in patients with systolic blood pressure <90-100 mmHg or heart rate <60 bpm. 5, 4

• Contraindications include bronchospasm risk and congestive heart failure. 1

Biomarker Effects

Recent trial data demonstrates beta blockers reduce inflammatory markers after TBI. 5 Specifically:

• Propranolol administration showed significant temporal reduction in IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 hours post-injury (p=0.001). 5

• Greatest reductions occurred in patients with positive high-sensitivity troponin T, indicating potential role in modulating post-TBI inflammation. 5

Evidence Quality and Limitations

The quality of evidence is very low, consisting primarily of observational studies with risk of selection bias. 1 Important caveats:

• No high-quality randomized controlled trials exist; most evidence comes from retrospective cohort studies. 1

• The EAST guideline explicitly states this is a conditional (weak) recommendation due to very low evidence quality. 1

• Optimal dose, specific agent selection, titration targets, and treatment duration remain undefined. 1

• The mortality benefit could be influenced by unmeasured confounding despite adjusted analyses. 1

Clinical Implementation Algorithm

1. Identify eligible patients: Adults ≥16 years with moderate-severe TBI (GCS <13) requiring ICU admission 1, 6

2. Exclude contraindications: Systolic BP <100 mmHg, heart rate <60 bpm, bronchospasm, decompensated heart failure 5, 4

3. Initiate propranolol within 24 hours: Start 1 mg IV every 6 hours 4, 2

4. Monitor continuously: Maintain heart rate >60 bpm, systolic BP ≥100 mmHg, MAP >70 mmHg 5

5. Continue throughout hospitalization: Minimum 48 hours, typically for duration of ICU stay 1, 4

6. Discontinue if: Symptomatic bradycardia, hypotension requiring intervention, or bronchospasm develops 1