Beta-Blocker Therapy in Severe Traumatic Brain Injury: A Prospective Randomised Controlled trial

Hosseinali Khalili. World J Surgery 2020; 44:1844-1853. https://doi.org/10.1007/s00268-020-05391-8

Clinical Question

• In patients with severe traumatic brain injury, does the administration of Beta-Blockade, compared with standard care alone, improve in-hospital mortality?

Background

• The main aim of neurocritical in the management of traumatic brain injury is to mitigate the burden of secondary brain injury. The brain trauma foundation guidelines advocate augmenting blood pressure to maintain cerebral perfusion in the context of raised intracranial pressure whilst the Lund protocol aims to reduce cerebral hydrostatic pressure to avoid cerebral oedema
• Severe traumatic brain injury is the predominant cause of death and disability after trauma, and any potentially effective treatments to reduce mortality and disability should be explored
• Multiple observational cohort studies and retrospective matched case control studies have indicated that B-blockade is associated with a survival benefit and reduction in disability after severe traumatic brain injury. It is hypothesised that the benefit is caused by a reduction in the adrenergic effects of the initial insult thereby reducing secondary vasoconstriction and ischaemia

Design

• Prospective Single Centre Randomised Controlled Trial
• Unblinded and no placebo in control arm as funding not available
• Consent sought from patients or next of kin
• Power calculation showed that 210 patients were needed to detect a 65% relative risk reduction with a significance level of 5% assuming a event rate of 20% in the control group
• Randomised by random number generator at 24 hours
• Patients with an isolated severe head injury (as opposed to poly-trauma) were determined as a specified sub-group for analysis
• Association between B-blocker therapy and in hospital survival, GOS-E at discharge and 6 months was evaluated using Poisson regression models
• Registered at Iranian Registry of Clinical Trials
• Modified intention to treat analysis (excluded patients who received b-blocker and developed bradycardia (n=3) or hypotension, or refused to continue treatment

Setting

• Conducted in the neurosurgical intensive care in the Emtiaz Trauma Hospital in Shiraz, Iran
• Patients recruited between December 1 2017 until August 31 2018

Population

• Inclusion:
  • Patients over 18 years old with blunt head trauma and an intracranial injury with an Abbreviated Injury Scale (AIS) score of 3-5 (evaluated by a neurosurgeon and radiologist within 24 hours of admission)
  • Admitted to neuro-intensive care unit (main NICU admission criteria are severe TBI detected on admission CT or GCS <12)
  • Haemodynamically stable at 24 hours after admission (BP>100, not requiring vasopresor or blood transfusion, and allowed to start enteral feeding)
• Exclusion:
  • Extracranial injury requiring surgery within first 24 hours (laparotomy, sternotomy, pelvic packing, long bone fracture fixation, surgery for spinal cord injury)
  • Patients already on B-blocker therapy
  • Persistent shock (SBP<100mmHg, base deficit >4 or oliguria) at 24 hours after admission
  • Patients transferred from another hospital
• 356 patients were assessed for eligibility, and after exclusion or lack of consent 222 patients were randomised. 102 were allocated to intervention arm (3 lost to follow up, 3 treatment discontinued due to bradycardia). 120 were allocated to the control arm
• Comparing baseline characteristics of beta-blocker vs. control group – no significant differences:
  • Male: 87% vs. 86%
  • Age: 37 vs. 39
  • Hypertension: 9% vs. 11%
  • Diabetes: 4% vs. 7.5%
  • GCS <=8: 33% vs. 41%
  • Head AIS >=4: 63% vs. 66%
  • ISS >=16: 83% vs. 74%
  • Epidural haemorrhage: 34% vs. 37%
  • Subdural haemorrhage: 37% vs. 47%
  • Subarachoid haemorrhage: 35% vs 38%

Intervention

• B-blocker and routine care
  • Propranolol 20mg orally 12 hourly by mouth or NG
    • Given for 10 days or until hospital discharge whichever was first
    • Observed for at least 24 hours with continuous BP monitoring in ICU
    • Patients with bradycardia (<50 bpm) or Hypotension (<100mmHg) were excluded from further analysis

Control

• Routine NICU care (not defined)

Outcome

• Primary outcome: In-hospital mortality – no significant difference (b-blocker vs. control group)
  • 8.1% (n=8) vs. 16.7% (n=20), p=0.058
  • After adjustment for all clinical variables – no significant difference
    • adjusted incidence rate ratios (IRR) 0.6 (95% C.I. 0.3-1.2), p=0.2
  • No significant difference in survival to hospital discharge in primary study gro
• Secondary outcomes: comparing b-blocker vs. control group – no significant differences
  • Good functional outcome (GOS-E >=5) at:
    • Discharge:
      • 72.4% vs. 66.7%, p=0.36
      • After adjustment for all clinical variables
        • Adjusted IRR 1.0 (95% C.I. 0.9-1.2), p=0.8
  • 6 months:
    • 86.5% vs. 77.5%, p=0.09
    • After adjustment for all clinical variables
      • Adjusted IRR 1.1 (95% C.I. 0.9-1.2), p=0.3
• Pre-specified sub-group analysis: Isolated severe TBI (n=154), comparing b-blocker (n=68) vs. control group (n=86)
  • In-hospital mortality – significantly reduced in b-blocker group
    • 4.4% vs. 18.6%, p=0.012
    • Poisson regression analysis: control group had significantly increased mortality rate
      • Adjusted IRR 3.1 (95% C.I. 1.1-8.9), p=0.037
  • Good functional outcome at:
    • Discharge – no significant difference
      • 77.9% vs. 65.1%, p=0.08
    • 6 months – significantly reduced in b-blocker group
      • 92.3% vs. 79.1%, p=0.04

Authors’ Conclusions

• The results of the trial show that the use of early oral propranolol in patients suffering isolated severe traumatic brain injury lead to improved survival and better functional outcome up to 6 months following injury. This provides support for the routine administration of beta-blocker therapy as part of a standardised neuro-intensive care protocol.

Strengths

• Pragmatic RCT
• Important clinical question
• Relevant patient outcomes (mortality and morbidity short term and longer term)

Weaknesses

• Single Centre RCT
• Small patient numbers (especially in final sub group analysis)
• Not blinded/No placebo
• Results only statistically significant after examination of predetermined sub-group
• Routine care not specified
• Other interventions used in severe TBI not recorded (osmotic therapy, thiopentone coma, hypothermia which may have differed between groups)
• Patients who experienced side effects from b-blockers were excluded from analysis. Authors report that all of these patients had good functional outcome at discharge
• Study performed in Iran only. This limits external validity to other healthcare settings

The Bottom Line

• There is increasing evidence that propranolol may improve patient centred outcomes in patients with isolated severe traumatic brain injury
• I will consider starting propranolol in all cardiovascular stable patients with isolated severe TBI, but I will wait for further larger studies or a prospective multi-centre RCT before using it for all patients, or as part of a standard TBI protocol

External Links

• [article] Beta-Blocker Therapy in Severe Traumatic Brain Injury: A Prospective Randomized Controlled Trial

Metadata

Summary author: Joel Swindin – @JSwindin
Summary date: 31/8/2020
Peer-review editor: @davidslessor

Photo by: Lisaleo at Morguefile.com