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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                                                                                                 Review Article 

Non-Selective Beta-Adrenergic Blocker Propranolol: A Life Saving Drug for Hospitalized Patient with Traumatic Brain Injury in Intensive Care Unit

Ashwathi P¹* , Srinivas K² 

¹ Doctor of Pharmacy, Department of Clinical Pharmacy, Neurofoundation Hospital, 3 roads-636009, Tamil Nadu, India

² Doctor of Pharmacy, Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Kumarapalayam-638183, Tamil Nadu, India 

1. INTRODUCTION

Traumatic Brain Injury in Intensive Care Unit

One of the most tremendous causes of mortality worldwide is due to Traumatic brain injury (TBI) commonly in people under the age of forty ¹. All most every case related to trauma results in intracranial harm to the individuals. It is estimated that about 90% of the deaths are from defective income countries².In Patients with severe TBI, it often resulted in a major neurological outcome where trauma is the primary hit which is managed by preventive strategies and the second hit occurs from the complication of primary insult which is accompanied by cerebral edema, ischemia, and hypoxia. It is believed that secondary insult may aggravate the condition through cerebral vasoconstriction and ischemia by adrenergic cyclones induced by primary insult ^{3, 4}. To combat these two traumatic factors international guidelines have made a protocol for better outcomes for traumatized patients through standard management in the intensive care unit (ICU). This is composed of standardized neurointensive care, Neurosurgical interventions, neuro-specific monitoring and, the use of intracranial pressure monitoring ^{5, 6}. Several researchers started focusing on reducing the prevalence of secondary brain injury mainly to improve the quality of life in TBI patients and also few studies from both prospective as well as retrospective data reported that the early use of beta-blockers shows promising results in managing the sympathetic storms^7-10.

Sympathetic Storming in Patients with Traumatic Brain Injury

In the ICU patients with moderate to severe TBI associated with restlessness and agitation are frequently sedated and incubated in order to reduce the workload of the brain. This hyperactive response is called sympathetic storming which occurs in the comatose of Glasgow Coma Scale (GCS ≤ 8) within 24 hours of brain injury or weeks later ^{11, 12}. The cause of sympathetic storming is because of acceleration in sympathetic nervous system activity in charge of the parasympathetic activity in the central nervous system which results in loss of cortical control due to downregulation of autonomic balance in the brain injury ¹³. Where specific alpha-1, alpha-2, beta 1, and beta 2 adrenergic receptors are disturbed which results in response to individual target organs ¹⁴. To understand this condition signs and symptoms should take place back-to-back with a minimum of 1 cycle per day ¹⁵. Heart rate, blood pressure, respiratory rate, temperature, sweating, posturing, and laboratory details are accompanied in TBI patients once the sedatives and narcotics are discontinued in the ICU and this helps us to identify the elevated serum catecholamine in hospitalized patients with TBI ^16-19.

Role of Non-Selective beta-blocker Propranolol in Traumatic Brain Injury

A Non-Selective beta-adrenergic antagonist propranolol, is one of the most customarily used treatments in the case of paroxysmal sympathetic hyperactivity (PSH) to balance the secondary complications. It acts on two types of beta-adrenergic receptors (beta-1 and beta-2) where, beta-1are located in the heart, brain, and kidney and beta -2 in the liver, lungs, skeletal muscles, arterioles, and eyes ²⁰. It has both cardioprotective and neuroprotective effects thereby exerting its action through decreasing the heart rate, stroke volume, and arterial pressure as well as lowering the cerebral blood flow, oxygen, and glucose accumulation by reducing the cerebral metabolism ²¹. Compared to cardio-selective beta-adrenergic blockers, propranolol has the huge advantage in that it has a lipophilic property that can easily penetrate into the blood brain barrier (BBB) and mediates central action by controlling theparoxysms^22-24. As a result, an increase in catecholamines activates an inflammatory process which is harmful in patients with TBI. Implementation of empirical administration of beta-blocking agents within 24 hours of brain injury will decrease sympathetic storming and enhance the patient’s quality of life ²⁵. The aim of this review is to study and analyze the initial use of beta-adrenergic blocking agent propranolol which is used as a lifesaving drug in patients with TBI in various experimental studies.

2. METHODOLOGY

The information was collected from various articles through online search tools like PubMed, Embase, Scopus, and Medline by applying the key formula (“Traumatic Brain Injury” OR “sympathetic storming”) and (“Propranolol” OR “Beta blocking agent In Traumatic Brain Injury” OR” “paroxysmal sympathetic hyperactivity”) and (“Randomized control trials” OR “ Prospective studies” OR “Retrospective studies”) and contents were extracted from the identified articles and correlated according to the need of the study.

3. RESULTS AND DISCUSSION:

1.1 The Outcome and effectiveness of propranolol in TBI

At present, there are several human as well as animal studies on adrenergic agonists/antagonists as the treatment option in patients with TBI and it has been reported that using both drug classes has a protective action against secondary complications²⁶. This is because of the certainty that through negative feedback action, agonistic drug manages the receptor pursuit^27-29 and it upregulates beta-2 adrenergic receptors after the TBI³⁰. Current studies mainly focus on the primary utilization of beta-adrenergic blocking agents and their outcome measures in patients admitted with TBI.

A prospective randomized control trial was conducted by (Hosseinali Khalili et al) ³¹ for the span of eight months in patients with severe TBI. This study was carried out to evaluate the effective outcome of beta-adrenergic blockers in TBI. Around 356 patients were assessed for eligibility out of them 222 were randomized based on inclusion and exclusion criteria of which 18 were declined from the trial and 102 patients were allotted equally to each group. In the intervention arm three of them lost follow-up due to bradycardia and only 99 were taken for analysis in the control arm all 102 were included as they were on continuous duplicate intervention. During the treatment period due to severe extracranial injury, 31 were excluded from the intervention group and 34 from the no-intervention group. Finally, 68(Intervention) and 86 (No Intervention) were in follow-up at the end of the study.

As a result, 18.6% were declared from the no-intervention group compared to the intervention group with a mortality rate of 4.4% in the isolated TBI. From this randomized trial it was concluded that early use of beta-adrenergic blocker propranolol 20mg every 12 hours orally will improve the existence rate and outcome in patients with severe TBI for the period of six months from the time of injury. 

Similarly, the trial conducted by (Ammar and Hussein) ³² was a double-blinded study in which 30 patients (Group A) was undergone treatment with propranolol and the remaining 30 patients (Group B) received a placebo. In the study discussed previously which was undertaken by (Hosseinali Khalili et al)³¹Non-Selective beta-adrenergic blocker Propranolol was given as oral therapy but, in this clinical trial propranolol 1mg was given intravenously within 24 hours of TBI and it was followed for one week every 6 hourlies. The aim of this trial was to analyze the improvement in the elevated serum catecholamines that occur in TBI. From this study it was observed that empirical use of propranolol has reduced serum catecholamine levels in Group A compared to Group B on day seven further, it also improved GCS in the propranolol group and it exhibited statistically significant variation compared to Group B. Comparing the results from the above observational study this clinical trial data clearly shows that the long-term clinical outcome and the mortality rate was not recorded.

1.2 Lund’s concept on the administration of beta-blocker in TBI

The Empirical administration of beta-blocker propranolol and whether it has to be included in the standardized treatment protocol in patients with TBI is still debated in the neuro-intensive care unit (NICU)⁶. According to Brain Trauma Foundation, this therapy is not specifically advised whereas, in Lund’s concept administration of propranolol is recommended to manage brain capacity, O2, and perfusion by controlling the systemic blood pressure (SBP). In addition, extracranial effects induced by TBI are also alleviated with the help of beta-blockade by lowering the sympathetic storming and accumulation of fluids resulting in the devastation of BBB. Various protocols have been formulated from both retrospective as well as animal studies but, none of them introduced Lund’s concept in randomized control trials (RCT). Even though, nowadays this concept is vastly used in huge countries in order to analyze the risks and benefits of the administration of propranolol²⁰.

Several groups from Lund’s concept developed the following cardinal steps to achieve the targeted outcome.1) Lowering the stress by blocking the catecholamines and proving adequate sedation; 2) maintaining normal fluid balance; 3) to maintain cerebral perfusion pressure; 4) restricting cerebral drainage; 5) promoting the adequate use of oxygen and ventilation and 6) early use of nutrition^33-35. To accentuate this, one study used a selective beta-1 blocker, metoprolol to minimize the myocardial contraction as well as an alpha-2 agonist, clonidine to inhibit the catecholamine and produce vasodilatory action. The combined effect of the drugs showed a decrease in hydrostatic pressure and an increase in reabsorption^{36, 37}. The other study identified that the use of propranolol in TBI minimized the risk of death rate with an odds ratio: of 0.54 also, it increased the survival rate in patients with raised cardiac troponins. While differentiating the type of beta-blockers it was observed that non-selective beta-adrenergic blocker propranolol showed reduced mortality and better outcome compared to specific beta-selective blockers³⁸.

1.3 Risks associated with beta-adrenergic blocker in TBI

The only thing that bothered the clinical trial was the side effects associated with patients undergoing treatment with propranolol. The first one is hypotensive incidents and the second concern is bronchoconstriction-induced hypoxia due to the blockade of beta-2 adrenergic blocker and this increases the risk of mortality³⁹. One study reported that no such events had occurred in patients with TBI in the intervention group compared to the control group⁴⁰ and also it has been noted that safety measures and considerations were taken for prudent administration of beta-blockers in a sequence of such adverse drug events by Cruickshank and colleagues⁴¹.Fascinatingly, in the trial conducted by (Hosseinali Khalili et al)³¹ no such hypotensive or hypoxic events had been reported but, only three patients lost follow-up due to lowering heart rate and theysettled with good response at the time of discharge.

On the other side, the case reported by (Mayank Garg et al)⁴²on neurogenic fever (NF) in TBI patients who had undergone treatment with propranolol. NF is usual in Severe TBI and various studies have reported an occurrence rate of 4 to 37 % due to the disruption of temperature points in the hypothalamus.^43,44 A twenty- six-year-old male admitted with complaints of a road traffic accident (RTA) with multiple contusions where taken for a decompressive carniectomy. After his post-operation, he developed a fever and was on supportive treatment with antibiotics and paracetamol. Even though, his temperature was not declined and started propranolol 10mg BID on the seventh day of post-operation assuming it was an NF. On the day-17 of his post-operation, he developed hypothermia. Unexpectedly, the temperature returned to normal on the very next day the drug was stopped. This study concludes that stopping propranolol earlier has helped them to maintain the normal temperature in patients with TBI and it also suggests that future studies must focus on when to stop the drug therapy.

4. CONCLUSION

In general it is known that sympathetic storming is common in patients with TBI admitted to the ICU. The main intension is to rapidly stop the adrenergic cyclones stimulated by the primary complications during the TBI. Various preclinical and clinical studies in the year of 2020 had taken multiple steps to improve the therapeutic outcome but, there is a lack in understanding the modern pathophysiological changes, recognition methods, clinical findings, and interventions which is mandatory to achieve the targeted therapy and this gap has to be kept in consideration for the further clinical trials. The recent studies suggest that using beta-adrenergic blocker propranolol in the hospitalized patients with TBI decreases the elevated catecholamines as well as increases the survival rate. This review concludes from the identified articles that, initial administration of Non-selective beta-adrenergic blocker propranolol is the drug of choice and will continue to be the standard prophylactic pharmacotherapeutic interventions as it reduces the risk of PSH in patients with TBI as well as improves GCS and further RCT are required to evaluate the safety, efficacy, duration of propranolol therapy and impression of these hopeful interventions to improve the quality of life and better clinical outcome following TBI. 

Conflicts of Interest: Authors declare that they have no conflicts of interest.

Funding statement: This review did not receive any funding.

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