|Year : 2018 | Volume
| Issue : 1 | Page : 15-20
Role of early propranolol in weaning from mechanical ventilator in severe traumatic brain injury patients
Tamer Habib1, Ahmed Sabry2, Ahmed El-Beheiry3, Islam Ahmed4
1 Department of Critical Care Medicine, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
2 Department of Neurosurgery, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Radiodiagnosis and Interventional Radiology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
4 Department of Clinical Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
|Date of Web Publication||24-Jan-2018|
Agami, Aelxandria, 21575
Source of Support: None, Conflict of Interest: None
Background Traumatic brain injury (TBI) is responsible for up to 30% of all injury-related deaths. The majority of patients with severe TBI require mechanical ventilation (MV). To date, no pharmacologic agent has been developed to improve outcomes in TBI. The primary aim of this prospective study was to investigate whether early use of low-dose propranolol within 24 h in patients with severe TBI can affect their weaning from MV or not.
Patients and methods This study was carried out on 340 adult patients with severe TBI randomly assigned to two groups. The early propranolol after traumatic brain injury (EPAT) group (102) received propranolol 40 mg twice daily within 24 h from admission. The non-EPAT group (238) did not receive any β blockers.
Results EPAT patients showed lower duration of MV (7.74 vs. 11.14 days, P=0.0013). The length of stay in ICU was lower in the EPAT group (10.62 vs. 14.13 days, P=0.003), but there was no statistically significant difference in mortality between the two groups studied (P=0.392).
Conclusion Early use of propranolol does not increase episodes of bradycardia or hypotension. Early propranolol after TBI can be used safely and may be associated with decreased days on MV and ICU length of stay.
Keywords: β-blockers, critical, mechanical ventilation, neurology, propranolol, traumatic brain injury
|How to cite this article:|
Habib T, Sabry A, El-Beheiry A, Ahmed I. Role of early propranolol in weaning from mechanical ventilator in severe traumatic brain injury patients. Res Opin Anesth Intensive Care 2018;5:15-20
|How to cite this URL:|
Habib T, Sabry A, El-Beheiry A, Ahmed I. Role of early propranolol in weaning from mechanical ventilator in severe traumatic brain injury patients. Res Opin Anesth Intensive Care [serial online] 2018 [cited 2018 Jun 25];5:15-20. Available from: http://www.roaic.eg.net/text.asp?2018/5/1/15/223837
| Background|| |
Traumatic brain injury (TBI) is defined as a noncongenital, nondegenerative damage to the intracranial tissue, probably leading to lasting or short-term deficiency of cognitive, psychosocial and physical functions, coupled with a decreased or an altered level of consciousness . Trauma remains a main public health crisis, responsible for over six million deaths and thrice as many disabled patients worldwide yearly. TBI is an important factor in this area across all age strata . TBI is responsible for up to 30% of all injury-related deaths . Young individuals and males (15–30 years) are at a higher risk of severe TBI and road traffic accidents lead the list of causes of TBI-related mortality . Guidelines for the management of TBI emphasize the role of prevention of secondary injury from hypoxemia and hypoperfusion  and from damage because of excitatory neurotransmitters, catecholamine surge, and the inflammatory cascade .
To date, no pharmacologic agent has been developed to improve outcomes in TBI . All strategies focus on the prevention of secondary injury from ischemic insults to the injured brain. The majority of patients with severe TBI require intubation and mechanical ventilation (MV). Although MV is life-saving, if managed incorrectly, it may exacerbate secondary injury and worsen outcomes . The optimal approach to ventilatory support facilitates neurologic recovery by reducing secondary injury and also decreases the risk for ventilator-induced lung injury.
Severe TBI is characterized by a marked increase in intracranial pressure (ICP) and heightened sympathetic nervous system (central nervous system) fluxes marked by spiking elevations in plasma catecholamine (epinephrine and norepinephrine) levels. Patients with multiple injuries and persistent coma have markedly increased plasma levels of catecholamine . β-Adrenergic receptor blockers may interrupt the cascade of immune and inflammatory changes associated with injury. Several retrospective studies show that β-blocker exposure in TBI is associated with a reduction in mortality ,,,,. Despite these positive findings, early β blockade use is not routine because of concerns that risks of hypotension or bradycardia events may increase secondary brain injury.
Murine models have shown that catecholamine blockade with early β-adrenergic receptor inhibition may increase cerebral perfusion, decrease cerebral hypoxia and edema, and improve neurologic recovery ,,,. Several large retrospective reviews of patients who received β-blockers before TBI report improved outcomes ,,,. Propranolol may be the ideal agent because of its nonselective inhibition and its lipophilic ability to penetrate the blood–brain barrier . Propranolol decreases heart rate and myocardial oxygen demand and blood pressure (BP). Two small observational clinical trials suggest that early low-dose propranolol can be administered safely and might improve outcomes after TBI or severe trauma ,.
The primary aim of this prospective study was to investigate whether early use of low-dose propranolol within 24 h in patients with severe TBI can affect their weaning from MV or not.
| Patients and methods|| |
After ethical approval for this clinical trial (IRB No: 00007589 FWA no.: 00015712) was obtained from the Local Committee of Ethics in the Faculty of Medicine of Alexandria University and the Department of Critical Care, informed consent was obtained from the next of kin. This prospective controlled study was carried out on MV patients admitted to the critical care department with a diagnosis of severe TBI between the 1 February 2016 and 1 January 2017. Alexandria Main University Hospital is the only tertiary referral trauma center serving a geographical area covering four governorates (Alexandria, Marsa Matrouh, El-Beheira, and Kafr El-Sheikh) with an estimated population of 14 million individuals.
Randomly selected patients of both sexes (except pregnant women) with severe TBI were enrolled if ranged in age from 18 to 64 years, with Glasgow coma scale (GCS) of 8 or less, and with injury detected on computed tomography (CT) of the brain. However, we excluded all patients with heart diseases, cardiac dysrhythmia, allergy to propranolol, contraindication to enteral feeding, penetrating brain injuries, pre-existing brain dysfunction, impending brain herniation, craniectomy or craniotomy, spinal cord injuries, myocardial injury, and severe liver disease. Any patient on intravenous vasopressors at any time of the study was also excluded. We also excluded all patients with mild TBI [head abbreviated injury scale (AIS) <3] and nonsurvivable TBI (head AIS=6).
All enrolled patients who completed the study (n=340) were assigned randomly to two groups. The early propranolol after traumatic brain injury (EPAT) group (102) received propranolol 40 mg tablet twice daily through an orogastric or a nasogastric tube plus conventional treatment. The non-EPAT group (238) only received conventional treatment without propranolol or any other β-blocker.
All enrolled patients were assessed within 24 h of admission; the following was documented at enrollment: personal data including, demographics, and previous medical and drug history; complete clinical examination including the GCS, the regional AIS score, the injury severity score, BP (mmHg), temperature (°C), pulse (beats/min), and respiratory rate (cycles/min). CT of the brain without contrast, the Marshall CT classification, and the Rotterdam CT score were calculated.
All routine laboratory investigations were performed including complete blood count, serum sodium (mEq/l), serum potassium (mEq/l), serum creatinine (mg/dl), serum urea (mg/dl), random blood sugar (mg/dl), alanine aminotransferase (U/l), aspartate aminotransferase (U/l), and total bilirubin (mg/dl). Also, a standard 12-lead ECG was performed for all enrolled patients.
The EPAT group was administered propranolol within 24 h from admission. Doses of propranolol were held when patients developed bradycardia (HR less than 60 beats/min) or hypotension (mean arterial pressure less than 80 mmHg). Conventional treatment included a standard sedative regimen, which was midazolam or propofol. Sedation interruption was performed twice daily according to our hospital protocol. Analgesics as opioids were allowed as prescribed by the attending senior resident. For both groups, GCS was measured every 12 h and CT brain was repeated when needed. Vital signs including mean arterial pressure, pulse rate, respiratory rate, and temperature were measured every 4 h. The targeted primary outcome of this study was the number of days on a MV.
Data were entered into an electronic spreadsheet and statistical package (version 24, IBM, Egypt) was used for statistical analyses. Descriptive statistics were reported as raw percentages or mean and SD. A Student’s t-test or Mann–Whitney U-test was used when appropriate to compare the means for parametric or nonparametric data, respectively. A χ2-test or Fisher’s exact test was performed for comparison of categorical variables. P value of less than 0.05 was considered statistically significant.
| Results|| |
Over the 11-month study period, 3219 patients were confirmed to have TBI on imaging. 2879 patients were excluded. After exclusions, 340 patients remained in the study population. Early propranolol was administered within the first 24 h from admission to 30% (102/340) of patients (EPAT) and the other patients (non-EPAT), 238, only received traditional treatment without any β blockers.
In terms of patient characteristics, the mean age of the patients in the EPAT group was 44.61 years whereas the mean age of the patients in the non-EPAT group was 46.60 years, with no significant difference (P=0.061). There was a predominance of men than women in the both groups, but there was no significant difference between the two groups (P=0.06). The EPAT group showed a slightly lower GCS (5.12 vs. 5.99, P=0.001), lower head AIS (3.17 vs. 3.64, P=0.0013), and higher admission HR (96.36 vs. 87.29, P=0.0021) ([Table 1]).
|Table 1 Comparison between the two groups studied in terms of characteristic features|
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In terms of the type of TBI, there were significant differences between the two groups studied in favor of any type of TBI. Subdural hematoma was the most frequently occurring type of TBI in both groups: 31.4 and 32.8% of patients in the EPAT group and the non-EPAT group, respectively (P=0.692) ([Table 2]). There were no significant differences between the two groups in the Marshall CT classification or the Rotterdam CT score ([Table 3]).
|Table 3 Comparison between the two groups studied according to computed tomography brain|
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In terms of the intervention for ICP, our results did not show any significant differences between the two groups, except in craniotomy or craniectomy: 27 (26.47%) in the EPAT group and 82 (34.45%) in the non-EPAT group (P<0.05) ([Table 4]). Also, there were no significant differences between the two groups studied in the complications observed in ICU. Our results showed no difference in ventilator-associated complications such as incidence of acute respiratory distress syndrome (P=0.2) or ventilator-associated pneumonia (P=0.7) ([Table 5]).
|Table 4 Comparison between the two groups studied according to interventions|
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|Table 5 Comparison between the two groups studied according to complications|
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In terms of the patients’ follow-up for events of bradycardia and hypotension episodes, these events were more prevalent in the EPAT group, but with statistically significant differences ([Table 6]). In terms of our main study outcome, EPAT patients showed lower durations of MV (7.74 vs. 11.14 days, P=0.0013). The length of stay in the ICU was lower in the EPAT group (10.62 vs. 14.13 days, P=0.003), but there was no statistically significant difference in mortality between the two groups studied (P=0.392) ([Table 7] and [Figure 1]).
|Table 7 Comparison between the two groups studied in terms of the outcomes|
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| Discussion|| |
The majority of patients with severe TBI require MV, although the exact incidence is poorly defined. Indications for the initiation of MV in these patients can be classified into four main categories: neurologic, pulmonary, airway, and miscellaneous causes. Depressed mental status remains a common indication for MV in TBI. The general guidance involves intubation of a patient with a GCS less than or equal to 8 or for whom protection of the airway is not possible . Patients with increased ICP or status epilepticus also typically require MV. A number of pulmonary conditions usually complicate TBI, including aspiration, pneumonia, volume overload from resuscitation with fluids and blood products, hemothorax or pneumothorax, and venous thromboembolism.
Acute respiratory distress syndrome may be precipitated by trauma, aspiration, fat embolism, or transfusion-related acute lung injury. Neurogenic pulmonary edema (NPE) is a complication that is reported to occur in ∼20% of TBI patients . The pathogenesis of NPE is not well understood, but it is believed that increases in ICP lead to the activation of the sympathetic nervous system and release of catecholamines, which result in cardiopulmonary dysfunction leading to rapid onset of pulmonary edema ,. The onset of NPE may be early (minutes to hours) or delayed (12–24 h) after the brain insult . In addition to direct insults, TBI increases cellular metabolism, leading to increased oxygen utilization and carbon dioxide production . Also, metabolic acidosis of shock results in increased work of breathing for carbon dioxide clearance. These increases in metabolic demands, especially when combined with primary or secondary lung injury, may lead to hypercapnic respiratory failure .
β-Blockers after trauma are usually administered for control of BP, heart rate ,, or resumption of home medications . Few studies have examined the use of β-blockers as empiric treatment after TBI . When an indication for treatment was evaluated, outcomes were better when propranolol was compared with other β-blockers started for therapeutic or resumption purposes .
Ko et al.  studied the use of early propranolol in moderate to severe 440 TBI patients and mortality. The results showed a statistically significant decrease in MV days in patients who received propranolol. This result supports the results found in this study. However, we failed to find a difference in mortality that was reported by Ko et al. . Murry et al.  carried out a small prospective study of early propranolol administration in moderate to severe TBI patients. Jason and his colleagues found no differences in mortality unlike our study. However, they did not report any results on the duration of MV. Their results showed that no complications were associated with the use of early propranolol administration.
| Conclusion|| |
Although bradycardia and hypotensive events may occur after TBI, early use of propranolol does not increase their number or severity and does not increase the risk of other complications. Early propranolol after TBI may be associated with decreased duration of MV and ICU length of stay. Early propranolol may not decrease mortality in ICU. Additional large studies are required to establish a clear correlation with mortality.
This research was partially supported by the head of the critical care department Professor Dr Taysser Zaytoun. The authors thank the colleagues from Alexandria Main University Hospital, who provided their insights and expertise, which greatly benefited the research.
Ahmed Sabry performed the literature search and wrote the first draft of this paper. Tamer Habib contributed to the interventions and data collection. Ahmed El-Beheiry supplied us with all radiology consultations. Islam Ahmed contributed to statistical analysis and checked the administration of the study drugs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]