Beta-blockers in Traumatic Brain Injury

INTRODUCTION

The catecholamines as outcome markers in an isolated TBI study (the COMA-TBI study)¹ have described in a prospective multicenter cohort that TBI patients demonstrated a characteristic pattern of catecholamine release into the peripheral blood over the first 24 hours of injury, which is depicted by a substantial release of Epi and NE in the moments following the trauma (Fig. 1). Patients demonstrated a large peak of catecholamine levels on hospital admission followed by a continuous decrease thereafter.

It is well described that TBI leads to instantaneous and intense activation of sympathetic nervous system with a huge release of both central and peripheral catecholamines.^1,2 This adaptive phenomenon is fundamental for survival, as a single episode of systolic blood pressure (SBP) below 90 mm Hg doubles mortality.³ Recently, additional information emerged showing that blood pressure threshold associated with outcome is even higher after TBI.⁴ The brain trauma foundation, therefore, changed its recommendations to “maintaining SBP at ≥100 mm Hg for patients 50–69 years old or at ≥110 mm Hg or above for patients 15–49 or over 70 years old may be considered to decrease mortality and improve outcomes.”⁵ These recommendations were revised from previous guidelines⁶ due to new evidence arising from a large class II retrospective cohort of moderate to severe TBI patients, which included almost 16,000 patients. Patients were grouped into three age groups as mentioned above, and the results suggested that a cutoff of SBP %3C;110 mm Hg should be considered as hypotension in moderate to severe TBI population .⁴ These results are corroborated by other studies,^7–9 which also support the decision of the Brain Trauma Foundation to change the hypotension thresholds.

On the contrary, sympathetic nervous system overactivation, through the release of catecholamine and stimulation of α and β adrenoreceptors, might produce hypermetabolism, protein catabolism, muscle wasting, and increase cardiac and cerebral metabolic rate of oxygen.^10–12 Additionally, several studies showed a significant association between high catecholamine levels and worse clinical outcomes, such as longer duration of mechanical ventilation and hospital stay, increased myocardial damage, endocrine abnormalities, and unfavorable long-term functional outcome.^13–15

In an effort to counterbalance the catecholamine surge, several observational studies have shown that β-blockage may improve outcome. However, these results require further evaluation in a well-designed multicenter randomized clinical trial. Therefore, this article provides a comprehensive review on the association between catecholamines and the pathophysiology of secondary brain injury after TBI, as well as the potential role of β-blockage after severe TBI.

SEARCH STRATEGY

A systematic review using MEDLINE, EMBASE, and Google Scholar was performed from inception to April 30, 2019. Eligible articles that described the association between catecholamine levels and outcome, as articles that tested the use of β-blockers after TBI were, searched. The terms “traumatic brain injury” (All Fields) AND “catecholamine” (All Fields) returned 62 articles. Additionally, three recent meta-analyses in this topic were analyzed and their reference lists were scrutinized. Also, the authors own article database was used to retrieve additional articles.

EARLY SYMPATHETIC HYPERACTIVITY AND THE EFFECTS WITHIN AND OUTSIDE THE BRAIN

Systemic complications after TBI are common and affect negatively overall outcome, increasing the rates of morbidity and mortality.^16,17 Zygun et al.¹⁶ described the effects of non-neurological complications in a cohort of severe TBI. Out of 209 consecutive patients included in the study, 185 (89%) developed at least one non-neurologic organ dysfunction. The respiratory system was the most common system affected (23%), followed by the cardiovascular system (18%), and the coagulation (4%). The effect of one and two organ failures was significantly associated with mortality (i.e., 40% and 47%, respectively). These systemic complications may result from direct effect of acute brain injury or as a side effect of therapy employed to optimize cerebral blood flow or to treat increased intracranial pressure.¹⁷

The massive catecholamine surge is one of the main theories implicated in the development of cerebral and systemic complications, which includes changes in the brain itself, and non-neurological organ failures, including the heart, the lungs, the immune, and coagulation systems (Table 1).

ARE β-BLOCKERS PROTECTIVE AFTER TBI?

Because increased catecholamine levels play a pivotal role in the progression of secondary brain injury, and it is also associated with the development of systemic complications, after TBI, the use of β-blockers in this scenario has been postulated for decades. Experimental models of propranolol administration, a nonspecific β-blocker that crosses the BBB, have been shown in a dose-dependent fashion to improve cerebral perfusion and glucose metabolism, while decreasing cerebral hypoxia. Additionally, β-blockage interrupts the β-adrenergic signaling pathway, which decreases the oxidative and inflammatory stresses, increasing vasodilation, and reducing the heart remodeling. In humans, several meta-analyses, which included mainly observational studies, revealed that the use of β-blockers after TBI is associated with significant lower mortality rates.³²

BIOLOGICAL PLAUSIBILITY—THE COMA TBI STUDY

The COMA-TBI study was a multicenter prospective study that evaluated the association between peripheral catecholamine levels and functional outcome after moderate to severe blunt TBI. A total of 174 patients were included in three-level 1 trauma centers across North America. Patients had their peripheral blood collected to measure Epi and NE levels at admission (baseline) and every 6 hours thereafter in the first 24 hours post-injury. The study demonstrated that raised peripheral catecholamine levels on hospital admission, especially Epi, were independently associated with unfavorable functional outcome (extended Glasgow Outcome Scale (GOSE) 5–8) and mortality after isolated TBI.¹ Patients displayed a characteristic pattern of catecholamine release into the peripheral blood over the first 24 hours of injury, which was depicted by a substantial release in the moments following the trauma (i.e., a large peak of catecholamine levels on hospital admission) followed by a gradual decrease thereafter (Fig. 1). These catecholamine levels were consistently higher in the TBI patients when compared to healthy volunteers.¹ More importantly, elevated catecholamine levels on hospital admission were independently associated with unfavorable long-term functional outcome (Fig. 2). These findings add biological plausibility to the possible benefit of β-blockage after TBI.

RELATIONSHIP BETWEEN HIGH CATECHOLAMINE LEVELS AND WORSE OUTCOMES AFTER TBI

TBI patients are commonly found to display signs of increased sympathetic nervous system activity, such as hypertension and tachycardia. Likewise, some studies showed that exogenous administration of NE rises the consumption of oxygen, and also increases the respiratory rate, lactic acid production, and blood glucose.

There are several mechanisms that may be implicated in the complex interaction between the sympathoadrenal activation and the brain, which may explain the unfavorable outcome after TBI (Table 2):

• Epi injection during cardiopulmonary resuscitation has deleterious consequences on cerebral microvascular blood flow^33,34 because it decreases cortical microcirculatory blood flow, which worsens the intensity of cerebral ischemia during cardiopulmonary resuscitation,³⁴ and also after the return of spontaneous circulation.³³
• Sympathoadrenal activation mediates the systemic inflammatory response,³⁵ and the development of coagulopathy and endotheliopathy.²⁴ Endothelial damage/dysfunction, mostly glycocalyx disruption resulted from sympathoadrenal activation, is the main driver of coagulopathy and endotheliopathy in this clinical scenario.²⁴
• High circulating catecholamine levels are independently associated with these biomarkers of inflammation, endotheliopathy, and coagulopathy in the first 24 hours after brain injury. These biomarkers of coagulopathy and endotheliopathy are associated with unfavorable outcome in isolated TBI patients.
• Increased cardiac demand—the heart can be negatively affected through different mechanisms after acute brain injury, as described above in the section “Early Sympathetic Hyperactivity and the Effects within and outside the Brain”
• Hypermetabolism, protein catabolism, and muscle wasting—in other clinical scenarios associated with sympathoadrenal overactivation, such as multiple trauma and severe burn, increased sympathetic system activity is associated with hypermetabolism, altered lipid, and protein metabolism, which cause muscle wasting and loss of lean body mass.^10–12
• Augmented intracapillary hydrostatic pressure and the development of vasogenic cerebral edema—this topic will be further discussed below in the Lund Protocol section.

ASSOCIATION BETWEEN β-BLOCKERS USE AND OUTCOME

We performed a systematic review using MEDLINE, EMBASE, and Google Scholar. Eligible articles that tested the use of β-blockers after TBI were searched. Only one complete randomized clinical trial was found. The authors randomized 114 hemodynamically stable patients (intervention: 56, control: 58) to receive atenolol (10 mg intravenously four times a day for 3 days followed by 100 mg orally once a day for 4 days) vs placebo.³⁶ Nine patients (30%) in the placebo group vs two patients (7.4%) in the atenolol group displayed myocardial isoenzyme of creatine kinase (CKMB) levels greater than 3% of total creatine kinase (CK), which is compatible with acute myocardial injury. No patient in the atenolol group vs 16.7% of patients in the placebo group had CKMB levels greater than 6% of total CK, which may be compatible with acute myocardial infarction. Therefore, the use of atenolol was associated with lower likelihood of cardiac events, such as supraventricular tachycardia or ST-segment changes; however, the study was not powered to detect differences in mortality.

Another single-center randomized clinical trial³⁷ tested the adrenergic blockage by the use of propranolol (1 mg intravenously every 6 hours for 7 days) + clonidine (0.1 mg per tube every 12 hours for 7 days), started within 48 hours post-injury vs placebo. The recruitment has been completed, but the study results have not yet been published. According to the results exhibited in the website of ClinicalTrial.gov (Trial Registration: NCT01322048), patients randomized to adrenergic blockage had reduced plasma levels of NE as measured on day 8 compared with the placebo group [median (interquartile range): 962 pg/mL (508–1471) in the propranolol group vs 714 (391–1257)]. Additionally, mortality was lower in the intervention group [5/21 (23.81%) in the propranolol group vs 8/26 (30.77%) in the placebo].³⁷

Several other cohorts reported the association between the use of β-blocker and mortality (Table 3). Interestingly, most of the cohorts that evaluated the impact of β-blockage showed lower adjusted odds of mortality. These studies were combined in different manners in three meta-analyses. The first meta-analysis by Alali et al. included the randomized trial described above plus 8 cohorts.³⁸ The 8 retrospective cohorts contained n = 4,782 patients and “demonstrated that exposure to β-blockers after TBI was associated with a reduction in the adjusted odds of in-hospital mortality by 65% (pooled adjusted odds ratio 0.35; 95% CI 0.27–0.45).” The same author updated this meta-analysis, which included one additional cohort. The authors found that the “exposure to β-blockers after TBI was associated with a reduction in in-hospital mortality (pooled OR 0.39, 95% CI: 0.27–0.56; I² 1/4 65%, p < 0.00001)” .³⁹ Finally, Chen et al. performed a systematic review and meta-analysis that included 13 cohorts with a total of 15,734 cases. Once again β-blocker use was associated with reduced odds of in-hospital mortality (OR 0.33; 95% CI 0.27–0.40; p < 0.001). However, in this last meta-analysis, the use of β-blocker was associated with higher rates of adverse events, such as increased infection (OR 2.01; 95% CI 1.50–2.69; p < 0.001), longer length of stay (MD = 7.40; 95% CI = 4.39, 10.41; p < 0.001), ICU stay (MD = 3.52; 95% CI = 1.56, 5.47; p < 0.001), and longer period of ventilator support (MD = 2.70; 95% CI = 1.81, 3.59; p < 0.001).⁴⁰

ASSOCIATION BETWEEN β-BLOCKER USE AND FUNCTIONAL OUTCOME

One matched case–control study described the association of β-blocker and functional outcome. Ahl et al.⁴¹ were the first to study the association between the use of β-blockers and the long-term functional outcome, including the development of posttraumatic depression. In a retrospective-matched case–control study, the authors included 76 TBI patients who received a β-blocker started within 48 hours of hospital admission and continued until discharge. The cases were matched with 76 pairs using the propensity score. The risk of unfavorable long-term functional outcome, defined as a Glasgow outcome scale ≤3, was more than two-fold in the control group (OR 2.44, 95% CI 1.01–6.03, p = 0.03). Also, β-blocker cases had a shorter length hospital of stay (18.0 vs 26.8 days, p < 0.01). This is the only study that describes the association between β-blocker use and functional outcome after TBI.

The same group of authors describes the association between β-blocker use and the development of posttraumatic depression.⁴² Eighty patients received β-blocker and were matched with 80 pairs by propensity matching. Twenty-six patients (33%) in the non β-blocker group developed posttraumatic depression vs only 14 (18%) in the β-blocker group (p = 0.04). Also, preadmission β-blocker use was associated with a reduced risk of depression.⁴³

THERAPY OF VASOGENIC CEREBRAL EDEMA BASED ON HEMODYNAMIC PRINCIPLES FOR BRAIN VOLUME REGULATION—THE LUND PROTOCOL

Other proposed mechanism of brain injury due to sympathoadrenal activation is the increase in the hydrostatic capillary pressure, which leads to the transcapillary fluid extravasation and the formation of interstitial cerebral edema.⁴⁴

Medical therapy to control elevated intracranial pressure include (1) tracheal intubation with ventilation to achieve normocapnia, (2) sedation + analgesia to achieve a calm/motionless state, (3) cerebrospinal fluid drainage through an external ventricular drain, (4) hyperosmolar therapy (i.e., mannitol or hypertonic saline), and, (5) finally, the rescue therapies such as hyperventilation to induce hypocapnia, induced hypothermia, decompressive craniectomy, and metabolic suppression with barbiturate-induced coma.⁴⁵ However, all those described therapies are associated with adverse effects.^46–48 Additionally, promising rescue interventions such as induced hypothermia⁴⁷ and decompressive craniectomy⁴⁸ did not result in outcomes better than medical therapy alone. Actually, in the RESCUEicp Trial, decompressive craniectomy was associated with higher rates of unfavorable functional outcome than medical therapy.⁴⁸

Because medical therapy to control intracranial pressure is associated with adverse effects and may impact negatively outcome, Asgeirsson et al.⁴⁹ developed a clinical protocol to prevent/treat traumatic brain edema based on the theory that hydrostatic capillary pressure and colloid osmotic pressure are fundamentally involved in transcapillary fluid extravasation and the formation of interstitial cerebral edema. Hydrostatic capillary pressure was decreased by the use of an alfa₂ agonist and a β₁-blocker (i.e., clonidine and metoprolol, respectively). Additionally, the authors added dihydroergotamine as a precapillary vasoconstrictor to reduce even further the hydrostatic capillary pressure, and also to reduce intracranial blood volume. Out of 11 comatose patients with predicted unfavorable functional outcome, 2 died (18%), while 9 patients (82%) survived with good recovery or moderate disability. This was one of the first descriptions of the use of β-blocker in the management of severe TBI, with promising results.⁴⁹

DOES THE TYPE OF β-BLOCKER MATTER?

The pharmacokinetic and pharmacodynamics of each specific β-blockers, especially regarding their ability to cross the BBB, should be taken into consideration when choosing the appropriate agent. For example, propranolol is a nonselective β-blocker that crosses the BBB, with enteral and intravenous formulation. Interestingly, Schroeppel⁵⁰ in a retrospective cohort study found that patients who received β-blockers had a higher mortality rates (13% vs 6%, p < 0.001); however, mortality was lower in patients who received propranolol (3% vs 15%, p = 0.002). These results have been replicated by Ley et al., who showed in a prospective multicenter observational study in 15 trauma centers in North America that propranolol might be superior to other beta blockers.

Unfortunately, most of the cohort studies described in Table 2 did not have a specific protocol regarding the type or dose of β-blocker. Some exception needs to be commented: (1) the randomized trial by Cruickshank et al. discussed above used atenolol 10 mg IV QID for 3 days followed by 100 mg PO once a day for 4 days; (2) the Lund Protocol described the association of thiopentone (0.5–3 mg/kg/hour) adjusted to a delta-wave pattern on the EEG with continuous infusion of metoprolol (max. 0.3 mg/kg per 24 hour) and clonidine (max. 8.0 mg/kg per 24 hour); (3) other studies used propranolol in different ways, such as Patel et al. [propranolol (1 mg intravenously every 6 hour for 7 days) + clonidine (0.1 mg per tube every 12 hours for 7 days), within 48 hours post-injury] or Murray et al. (propranolol 1 mg intravenous every 6 hours starting within 12 hours of ICU admission for a minimum of 48 hours).

CONCLUSION

Catecholamine surge after TBI is common and β-blockage has shown promising results. There is an important signal from several meta-analysis showing a significant reduction in mortality by the use of β-blocker after TBI. However, important uncertainty remains in the field, which needs to be answered, such as the best type (e.g., selective vs nonselective) and the regimen of ß-blocker to be used (i.e., dose, moment of treatment initiation, and duration). High catecholamine levels after TBI is associated with worse outcome, and the use of β-blocker may reduce mortality and improve long-term outcome; however, these benefits must be adequately evaluated in a large multicenter clinical trial. Additionally, cardiac biomarkers may be used to stratify patients at higher risk that may benefit more by the use of β-blockers.

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