Relative Bradycardia With Hypertension in Traumatic Brain Injury: A Marker for Mortality?

Transcription

1 Relative Bradycardia With Hypertension in Traumatic Brain Injury: A Marker for Mortality? The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Accessed Citable Link Terms of Use Subramanian, Melanie Relative Bradycardia With Hypertension in Traumatic Brain Injury: A Marker for Mortality?. Doctoral dissertation, Harvard Medical School. January 8, :01:01 PM EST This article was downloaded from Harvard University's DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at (Article begins on next page)

2 Table of Contents 1. Title Page page 1 2. Abstract page 1 3. Glossary of abbreviations page 3 4. Acknowledgments page 4 5. Introduction page 5 6. Methods page 7 7. Results page 8 8. Discussion page 9 9. Limitations page Conclusion page Figure 1: CT-imaging findings of select primary TBI-types. page Table 1: Glasgow coma scale page Table 2: Study inclusion an dexclusion criteria page Table 3: Glasgow outcome scale page Figure 2: Selection of study population page Table 4a: Demographic Information among hypertensive patients with TBI page 19 Table 4b: Injury Burden among hypertensive patients with TBI page 19 Table 4c: Clinical Presentation of hypertensive patients with TBI page 20 Table 4d: Clinical management in the ED of hypertensive patients with TBI page 20 Table 4e: Outcomes of hypertensive patients with TBI page Table 5: Univariate analysis of primary/secondary outcomes (RB vs. Non-RB groups) page Table 6: Multivariate analysis of primary/secondary outcomes (including RB group) page Table 7: Univariate analysis of primary/secondary outcomes (TB vs. Non-RB groups) page Table 8: Multivariate analysis of primary/secondary outcomes (including TB group) page References page 25 2

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4 Glossary of Abbreviations Abbreviation Term AIS Abbreviated Injury Score ARDS Acute Respiratory Distress Syndrome BPM Beats Per Minute CBP Cerebral Blood Flow CPP Cerebral Perfusion Pressure DNR Do Not Resuscitate ED Emergency Department EDSBP Emergency Department Systolic Blood Pressure (initial presenting pressure) GCS Glasgow Coma Scale GOS Glasgow Outcome Scale HLOS Hospital Length-of-stay HR Heart Rate ICP Intracranial Pressure ILOS Intensive Care Unit Length of Stay ISS Injury Severity Score MAP Mean Arterial Pressure Non-RB Non-Relative Bradycardia (patients who presented with initial heart rate>90) NTDB National Trauma Database PEG Percutaneous Endoscopic Gastrostomy RB Relative Bradycardia SBP Systolic Blood Pressure TB True Bradycardia TBI Traumatic Brain Injury 4

5 Acknowledgments I would like to thank Dr. Marc de Moya for serving as my project mentor and principal investigator. He was incredibly supportive of my involvement in his lab and with this project. He provided the necessary project guidance and supervision throughout the completion of this project. I would also like to thank Dr. Ali Mejaddam, one of the former trauma lab research fellows. He provided the day-to-day guidance on project details. He had a significant contribution in the project design, and was the individual responsible for teaching me about the principles of clinical research design and data processing. He also had direct oversight of required work associated with Scholars in Medicine. I would also like to thank Dr. Yuchiaou Chang for assistance with statistical processing. Finally, I would like to thank Dr. Gordon Strewler for serving as my Scholars in Medicine mentor. He has been supportive as not only a research mentor, but also as my Cannon Society Master during the past 4 years. 5

6 Section I. Introduction Traumatic brain injury (TBI) is a leading cause of death in patients under 45 years of age (Rutland-Brown et al., 2006). In the United States, TBI affects upwards of 1.5 million people and causes greater than 50,000 deaths annually. Among patients severe TBI, mortality rate can range between 30 and 50% (Sosin et al., 1996). Nationally, falls are the leading cause (approximately 40%) of TBI-related hospitalizations or death. Motor vehicle accidents are the major cause of TBI-related fatalities among younger populations (ages years), while falls are the leading cause of TBI-related fatalities among persons greater than 65 years of age (CDC 2015). For survivors, the socioeconomic impact of TBI can be staggering. In the United States alone, lifetime medical costs can exceed $9 billion, with greater than $51 billion in lost productivity (Rutland-Brown et al., 2006). Given the significant impact that TBI has on morbidity, mortality, and quality of life, improving the understanding of TBI pathophysiology and clinical management are trop priorities. TBI can be classified by primary and secondary injury type (Figure 1). Primary TBI occurs at the time of injury, and is directly related to the forces impacted on the skull and underlying intracranial tissues (Andriessen et al., 2010). Such forces constitute direct blunt or penetrating impact and acceleration/deceleration injuries. Primary injuries can affect the scalp (scalp laceration), skull base (skull fracture), vasculature (subdural/epidural hematomas, subarachnoid hemorrhage, intraparenchymal hemorrhage, intraventricular hemorrhage), and parenchyma (cerebral contusion, diffuse axonal injury). TBI severity has classically been defined by the Glasgow Coma Scale (GCS), where GCS 13-15, GCS 9-12, and GCS 8 correspond to mild, moderate, and severe injury, respectively (Table 1). Secondary injuries occur within 24 hours of the initial insult and often are systemic consequences that are a result of autoregulation failure (Ghajar 2000). Secondary injuries, including hypoxemia, hypotension, and elevated ICP, can be more difficult to manage but can exact serious consequences on neurological outcomes. Multiple studies have documented that association between hypoxemia in severe TBI patients and increased mortality. One study analyzing prospectively collected data from the Traumatic Coma Data Bank (TCDB) identified hypoxemia in 22.4% of patients that arrived in the emergency department, and these patients faired worse in terms of morbidity and mortality (Chestnut et al., 1993). The relationship between hypotension (systolic blood pressure [SBP]<90 mm Hg) and increased mortality in TBI patients is well documented. In the prospectively collected TCDB database, a single pre-hospital occurrence of hypotension was among the five most powerful predictors of mortality outcome, and was independent of age, GCS, or pupillary reflex response (Marmarou et al., 1991). Similarly, hypotension has been shown to be associated with an eight times increased likelihood of mortality (Manley et al., 2001). As such, there are level II recommendations by the Brain Trauma Foundations to monitor blood pressure and avoid SBP< 90 mm Hg (Brain Trauma Foundation, 2007). 6

7 Systolic blood pressure can contribute to the ability of cerebral tissues to prevent ischemia by maintenance of cerebral perfusion pressure (CPP). Cerebral perfusion pressure is defined as the mean arterial pressure (MAP)- the intracranial pressure (ICP). CPP is vital for maintaining adequate cerebral blood flow (CBF), which in turn is necessary for ensuring optimal oxygenation of tissues. While there is no supported optimal target for CPP, general consensus supports that CPP should stay above 50 mm Hg to reduce the risk of cerebral ischemia and cytotoxic edema (Brain Trauma Foundation 2007). There is no evidence to support targeting CPP to exceed 70 mm Hg, and elevated levels have even been correlated to increased incidence of ARDS (Robertson et al., 1999). Current guidelines emphasize focusing management in treating CPP components of ICP (maintain ICP< 20 mm Hg) and MAP (avoidance of systemic hypotension). While the association between TBI, hypotension, and mortality has been well demonstrated, recent literature has suggested that the relationship is more nuanced. Zafar et al. (2011) studied the relationship between initial emergency department SBP (ED SBP) and mortality in patients with moderate to severe TBI and noted a bimodal relationship. Patients with ED SBP<120 mm Hg and patients with EDSBP 140 mm Hg were 2.7 times and 1.6 times more likely to die, respectively. This suggested that hypertension could potentially be a clinical predictor of mortality, while EDSBP ranges between 120 and 140 mm Hg was associated with a protective effect. The causes for these observations remain to be elucidated, and the role of heart rate was not investigated in their study. Among trauma patients, presenting heart rate has been studied in its correlation to morbidity and mortality. Relative bradycardia (RB), or the inability to mount a tachycardic response in the setting of trauma-induced hypotension, has been associated with increased mortality (Barriot et al., 1987). While the exact pathophysiology is not well understood, it is considered to be a preterminal event. Ley et al. (2009) conducted a retrospective study examining the incidence and outcomes of RB in hypotensive trauma patients. They determined that RB was associated with mortality in all subgroups (p<0.0001) except for patients >55 (years of age and those with GCS>12. The relationship between heart rate and mortality is not well understood in hypertensive TBI patients. Knowledge of this relationship could have important clinical implications for the intensive care management of TBI patients. The goal of this project is to characterize the relationship between heart rate and mortality in hypertensive patients with moderate to severe TBI (GCS<13). Specifically, we aim to 1) Determine if relative bradycardia is associated with increased mortality compared to tachycardia in hypertensive patients with TBI 2) Examine if any relationships exist between heart rate and secondary outcome measures, such as neurological function, hospital length of stay, ICU length of stay, and the need for tracheostomy. 7

8 We hypothesize that RB will demonstrate a similar effect among hypertensive TBI patients, and will be associated with higher mortality and neurological outcomes. Current guidelines suggest that treatment of hypertension should be avoided unless MAP exceeds 120 mmhg, as high SBP may help maintain cerebral blood flow (Helmy et al., 2007). However, if there are specific indicators among hypertensive TBI patients that suggest that the benefit of cerebral blood flow may be outweighed by other factors, then treatment of hypertension may be warranted. Knowledge of heart rate -related outcomes will be useful in guiding the care and management of TBI patients and improving survival rates. Currently, there is no published literature on the effects of heart rate on mortality in hypertensive TBI patients. In a relevant study on the effects of emergency department length of stay on the outcomes of TBI patients at Massachusetts General Hospital, admission SBP showed a similar bimodal relationship of mortality compared to previous literature (Mejaddam et al., 2013). Additionally, the study showed that among hypertensive patients, RB was associated with higher mortality compared to tachycardia (66% vs. 53%; p =0.35). However, the finding was not statistically significant, which may be a result of small study sample size (n=224). Conducting a study with a larger sample size is necessary to determine if the effect did indeed represent a true relationship. As an extension of the studies conducted by Zafar et al., this study will consist of a retrospective observational analysis specifically on hypertensive TBI patients. The principal investigator, Dr. Marc de Moya, contributed to the conceptual origin of the project. Dr. Ali Mejaddam, the research fellow directing the project, also contributed to the study design, IRB project approval, as well as aspects of the data collection. My role was to contribute to the study design, assist with the IRB process, design the data collection tools, and perform data collection, data analysis, and reporting. Dr. Yuchiao Chang, the department s in-house statistician, assisted with data analysis and statistics. The results of this analysis will better guide protocols for treatment and stabilization of hypertensive TBI patients. Section 2. Methods We conducted a retrospective cohort study of trauma patients admitted to the Massachusetts General Hospital between January 1, 2001 and September 30, Massachusetts General Hospital is a designated level I trauma center. We identified trauma patients utilizing the electronic registry maintained by the MGH Division of Trauma, Emergency Surgery, and Critical Care. All adult patients (age 18years) with moderate or severe TBI on ED presentation were included for analysis. TBI was defined by presence of intracranial blood on CT imaging with associated International Classification of Diseases- 9 th Rev codes of , , or Mild, moderate, and severe TBI classifications were based on GCS classifications of 3-8, 9-12, and 13-15, respectively. Patients were excluded if they were hospital transfers, were DNR or comfort-measures-only in the ED, were dead on arrival, had preexisting moderate or severe dementia, or were admitted for a spontaneous, non-traumatic fall(table 2). 8

9 Demographic and clinical data including age, sex, ethnicity, mechanism of injury, presenting emergency department SBP and heart rate, trauma labs, pre-admission use of anticoagulants or antiplatelets, injury severity score (ISS), abbreviated injury score (AIS), TBI type (hemorrhage, contusion, diffuse axonal injury, midline shift), pupillary reflex, intubation or tracheostomy use, use of ED ICP monitoring, use of hyperosmolar/hypertonic therapy, use of antihypertensives, blood product transfusions, hospital and intensive care length-of-stay, and discharge disposition were recorded. The primary outcome measured in this study was in-hospital mortality. Secondary outcomes included neurologic function as measured by the Glasgow Outcome Scale (GOS) (Table 3) hospital length of stay (HLOS), intensive care length of stay (ICU LOS), and need for tracheostomy. Heart rate was dichotomized into RB, or relative bradycardia (HR 90 bpm), and non-rb (HR>90 bpm) groups. Demographics, injury burden, clinical presentation, clinical management, and primary and secondary outcomes were reported for the overall study population and additionally compared between RB and non- RB groups. Additionally, the RB group was further divided to examine patients who presented with TB, or true bradycardia (HR 60 bpm). Descriptive statistics were reported by mean percentages, standard deviations, ranges, odds ratios (OR), and 95% confidence intervals (CI). To assess differences in the primary and secondary outcome groups, categorical variables were analyzed using chi-squared or Fischer s exact tests. Numeric variables were compared by the student t test or Wilcoxon s rank sum tests whenever appropriate. Additionally, analysis was repeated using heart rate as a continuous variable. Univariate and multivariable logistic regression was used to assess factors related to the risk of in-hospital mortality. All factors that were significant with a p value <0.2 on univariate analysis were entered into the logistic regression to identify independent predictors of in-hospital mortality and Glasgow Outcome Scale. P values <0.05 were considered statistically significant. All statistical analysis was performed using SPSS version 22.0, and Microsoft Excel. Section 3: Results Of all TBI patients screened, 490 presented with GCS<13. Fifty-three patients were removed based on the existing exclusion criteria. Of the included 437 patients, 223 were found to be hypertensive (SBP 140). The remaining 214 patients were either normotensive or hypotensive at ED presentation. Among the hypertensive TBI patients, 108 patients (48.4%) had RB, while 115 (51.6%) patients were in the non- RB group. Further division of the RB group into subgroups HR<60 bpm and HR bpm contained 21 (19.4%) patients and 87 (80.6%) patients, respectively (Figure 2). The study group was relatively young (43.1±19.7 years) and predominantly male (80.3%). The most common mechanism of injury was sustaining a fall (31.4%), followed by motor vehicle accident (24.7%), and pedestrian stuck (16.6%). Subarachnoid hemorrhage (70.9%), intraparenchymal hemorrhage 9

10 (67.3%) and subdural hemorrhage (65.0%) were the most commonly reported TBI types. In terms of injury severity, mean ISS was 29±9, and mean GCS was 6.1±3.6 (Table 4a-4d). Total in-hospital mortality was 31%. Initial heart rate was significantly lower among hypertensive patients that did not survive (n=69) compared to patients that did (86±26 vs. 96±23, p<0.01). On univariate analysis, RB had significantly higher mortality rate (p<0.05) and worse neurologic outcomes in Glasgow Outcome Scale (p<0.001) (Table 5). RB and non-rb groups showed no difference in HLOS, ILOS, tracheostomy requirement, or percutaneous endoscopic gastrostomy (PEG) placement. Although on univariate analysis RB was associated with higher mortality, this relationship was not found on multivariable logistic regression analysis. Age, midline shift, absence of pupillary reflex changes, ISS, hyperosmolar therapy usage, and packed red blood cell transfusions were noted to be significant predictors of mortality (Table 6). When subjected to multivariate logistic regression analysis, RB was no longer significant. When the RB group was further divided to examine the sub-group TB (HR 60) and HR 60-90, a stronger correlation was noted. TB was strongly associated with increased mortality rates in univariate analysis (p<0.001). Additionally, it was correlated to worse GOS scores (p<0.02) (Table 7). As in the case of the RB group, TB was not found to be associated with increased HLOS, ICU LOS, or need for PEG or tracheostomy. When subjected to multivariate regression, TB was an independent predictor of mortality, along with the additional predictors of age, midline shift, absence of pupillary reflex, ISS, hyperosmolar therapy usage, and blood transfusions in the ED. Patients with HR between were not correlated to increased mortality. There was no protective effect demonstrated by having an initial HR in this range either (95% CI = 0.77, 12.2, p=0.113). Patients with TB (HR 60) were 6.85 times more likely to die (95% CI =1.76, 26.3, p=0.006) (Table 8). Section 4. Discussion Although the pathophysiology underlying TBI remains complex and poorly characterized to date, identifying clinical indicators that can be used quickly and efficiently to identify patients at risk of further decline is important in the trauma setting. This study aimed to identify vital sign clinical indicators that were predictors of mortality, and to better understand their relationship in TBI patients. Currently, hypotension and hypoxemia are well-studied clinical indicators suggestive of increased mortality risk. There is sufficient evidence demonstrating increased mortality in hypotensive or hypoxic TBI patients that avoidance of these two has been incorporated into level II and level III Brain Trauma Foundation Guidelines, respectively (2007). However, more recent studies have suggested that the role of SBP in TBI patients is much more nuanced. Zafar et al. (2011) examined TBI patients registered in the NTDB with the goal of seeing whether there was an increase in mortality at presenting ED SBP 90 (which is listed in the Brain Trauma Foundation Management Guidelines, 3 rd ed.), or whether the true inflection point was higher. Looking at 10

11 7,238 patients with TBI, Zafar et al. actually identified two inflection points: one occurred for ED SBP<120 and the other was ED SBP 140. Patients with SBP<120 were 2.7 times more likely to die (95% CI 2.13, 3.48, p<0.001) compared to patients with SBP 120 and <140. Patients with SBP 140 were 1.6 times more likely to die (95% CI 1.32, 1.96, p<0.001) compared to patients with SBP 120 and <140. These findings suggested a protective effect associated with 120 ED SBP <140. While a more refined association was made between SBP and mortality, corresponding heart rate was unfortunately not examined. Previous studies have attempted to examine the role of initial HR in trauma patients, with a subset of literature focusing on the correlation between RB and mortality. The exact role of RB is contested. RB has typically been viewed as a preterminal event, with many suggesting that it represents a failure in autoregulation to allow sufficient systemic perfusion. There have been several proposed theories over the year as to the cause of RB. Barriot et al. (1987) suggested that RB could occur after rapid and severe hemorrhage. They proposed that patients suffering from extreme hemorrhage typically exhibited an appropriate sympathetic response. However, they may exhibit a concurrent and equally strong parasympathetic response that does not allow for reflexive tachycardia. Snyder et al. (1989) suggested that RB was a result of a parasympathetic mechanism triggered by hemorrhage into the intraperitoneal cavity. Oberg et al. (1972) have reported that RB may in fact be a vagally-mediated reflex. In response to acute hemorrhage, RB may occur after an initial tachycardic response, and was proposed to allow for greater diastolic filling and thus preservation of stroke volume. This vagally mediated mechanism may originate from mechanoreceptors in the left ventricle. They studied induced hemorrhage in cats with subsequent cooling or severing the vagal nerves. Blood pressure was unaffected but the cats failed to demonstrate bradycardia. Two important studies highlighted the relationship of RB to outcomes in trauma patients. However, their findings were conflicting. Demetriades et al. (1998) performed a retrospective analysis of 10,833 trauma patients. Among those that were hypotensive, overall mortality was higher in the non-rb group compared to the RB group (29.2% vs. 21.7%, p-0.047). RB was actually found to be protective among subgroups with more serious injury patterns (ISS 16, AIS chest score 3, or AIS abdomen score 3). Ley et al. (2009) demonstrated a more ominous correlation between RB and mortality. In a retrospective study of 7,123 hypotensive trauma patients registered the Los Angeles County Trauma System database, they identified RB in 44% of the study population. Those with RB had significantly higher mortality (30.1% vs. 22.6%, p<0.0001). In fact, RB had a higher mortality among all subgroups except older patients (age>55 years) and those with less severe TBI (GCS 12). While RB was shown to be an independent predictor of mortality on logistic regression analysis, this was likely disproportionately due 11

12 to patients with TB. Further subgroup analysis of the RB group divided into HR<60 and HR60-90 showed mortality rates of 62.4% and 9.7%, respectively. Compared to the studies above, this study focused on a much more narrow population (TBI-specific patients with demonstrated hypertension on arrival). Overall mortality was 31%. Independent predictors of mortality included age, presence of midline shift, abnormal pupillary reflex, ISS, use of hyperosmolar therapy, and RBC transfusion in the ED. Many of these variables are progressive clinical findings in patients who may have significantly elevated ICP or herniation. Interestingly, RB was suggestive of increased mortality in univariate analysis, but not on multivariate analysis. Similar to a pattern demonstrated by Ley et al., TB was a strong independent predictor of mortality. In terms of secondary outcomes, RB and TB were correlated to more severe GOS, but not increased HLOS, ICU LOS, tracheotomy use, or PEG placement. Compared to all-comer trauma patients, it is difficult to postulate the physiological mechanism of HR in TBI-specific patients. In the trauma patient, the clinical risk experienced is often hypotension (typically due to hemorrhage). It would be a natural response for HR to rise in an effort to maintain sufficient cardiac output and perfusion to vital organ systems. A loss of this reflex suggests an inability to maintain homeostasis by any of the proposed mechanisms described previously. Thus, it is more obvious why RB is often viewed as deleterious in the trauma patient without significant TBI. In the TBI patient (not considering polytrauma scenarios), the risk is not necessarily hypotension. Rather, it may be inadequate CPP. CPP can be compromised when the patient is hypotensive, and thus cannot maintain adequate CBF. Additionally, CPP can be compromised in the setting of hypertension due to intracranial hypertension, vasogenic edema, and increasing ICP (Zafar et al., 2011). The physiologic role of heart rate in the latter situation is less straightforward. It is possible that the presenting heart rate is part of a neural reflex mechanism or a consequence of autonomic dysregulation from the injury insult itself. We determined that RB was not associated with mortality in hypertensive TBI patients, but patients with TB were 6.85 times more likely to die compared to non-rb patients. It is possible that this finding was indicative of an early Cushing reflex process, where bradycardia and severe hypertension are noted in patients at risk for brainstem herniation. However, the average HLOS was 10.9 days, which is considerably longer than one would expect for a patient with signs of impending herniation. Going forward, it may be more useful to identify ongoing HR and BP measures in the context of more intermediate indicators of prognosis: CPP and ICP. Understanding how BP and HR vary in patients with a variety of different perfusion pressures and intracranial pressures could be very useful not only in predicting outcomes, but also in directing clinical management. However, performing a study of such nature could be difficult given that guidelines for continuous ICP monitoring are not liberalized. 12

13 Section 5. Limitations There are several important limitations in this study. As this is a retrospective observational study, there are limitations to the interpretation of the data, and causation cannot be determined. Additionally, the analysis was limited to the number of TBI trauma patients in the registry, which can directly affect the power of these findings. Finally, the study only collected information on patients admitted to MGH Emergency Department. MGH is a large Level I trauma center with several referring hospitals within its trauma network. However, it is possible that the demographic of patients that are refereed to MGH may not be generalizable to a broader TBI population. Finally, this study took into account exogenous factors that could affect both blood pressure and bleeding risk (use of anticoagulation and antihypertensive agents). However, there was no survey of whether patients were on agents that could have affected their presenting HR (beta blockers or other rate-control agents). Finally, we did not perform subgroup analysis of RB stratified by age (younger vs. older patients). There is no published literature to verify a difference in vital sign response to TBI among different age groups. However, it is certainly possible that age could affect the neural mechanisms used to respond to TBI, and age was found in the study to be an independent predictor of mortality. Section 6. Conclusions Previous literature has described a bimodal distribution of SBP (SBP<120 and SBP>140) and mortality in patients with moderate to severe TBI. Among hypertensive patients, those with RB exhibited higher mortality rates compared to non-rb patients. True bradycardia showed higher mortality rates compared to non-rb patients as well. However, only TB was identified as an independent predictor of mortality. The combination of hypertension and bradycardia in moderate and severe TBI patients can predict greater likelihood of mortality. 13

14 Primary TBI Contact forces (blunt penetrating) - Cerebral contusion - Intracranial hemorrhage - Epidural - Subdural - Subarachnoid - Cerebral laceration Secondary TBI Hypoxemia Hypotension Acceleration/deceleration forces - Diffuse axonal injury - Intracranial hemorrhage Cerebral Edema Figure 1: Classification of TBI. Primary TBI is the immediate results of forces directed on the brain, including blunt/penetrating contact forces and acceleration/deceleration forces. Secondary TBI are often the results of systemic physiologic characteristics, which can worsen primary TBI outcomes. 14

15 Table 1: Glasgow Coma Scale Behavior Response Score Eye opening response Spontaneously To speech To pain No response Best verbal response Best motor response Total score Oriented to time, place, person Confused Inappropriate words Incomprehensible sounds No response Obeys commands Moves to localized pain Flexion withdrawal form pain Abnormal flexion (decorticate) Abnormal extension (decerebrate) No response GCS is often used to classify severity of traumatic brain injury. GCS 13-15, 9-12, and 3-8 are associated with mild, moderate, and severe TBI respectively

16 Table 2. Study Inclusion and Exclusion Criteria Inclusion Criteria Age 18 years Diagnosis of TBI, as evidenced by the presence of intracranial blood on computed tomography and ICD- 9 code Hypertension on presentation to ED (SBP 140 mmhg) GCS 13 upon arrival to the ED Admission to ICU or OR Exclusion Criteria Mechanism of injury was from fall from standing Dementia Transfer from outside hospital Dead on arrival to the ED DNR or CMO in the ED 16

17 Table 3. Glasgow Outcome Scale (GOS) Level Term Definition 1 Dead No life 2 Vegetative state Unaware of self and environment 3 Severe disability Unable to live independently 4 Moderate disability Able to live independently 5 Mild disability Able to return to work/school *In this study, GOS is used as a secondary outcome. It is divided into groups GOS 1-3, and GOS

18 Figure 2: Selection of study population groups. *Note: tachycardia is referred to as Non- RB in the text. 18

19 Table 4a. Demographic Information among hypertensive patients with TBI Total Dead (n=69) Alive (n=154) p Age 43.1± ±22 39±17 <0.001 Male, n (%) 179(80.3) 51(73.9) 128(83.1) 0.03 Race, n (%) Caucasian Hispanic African American Other 168(75.3) 24(10.8) 13(5.8) 5(2.2) 50(72.4) 4(5.8) 3(4.3) 3(4.3) 118(76.6) 20(13.0) 10(6.5) 2(1.3) Mechanism of Injury, n (%) Motor vehicle accident Fall Pedestrian struck Motorcycle accident Assault Other Anticoagulation/antiplatelet, n(%) Warfarin Antiplatelet Statin 55(24.7) 70(31.4) 37(16.6) 16(7.2) 29(13) 14(6.3) 11(4.9) 14(6.3) 14(6.3) 13(18.8) 27(39.1) 14(20.2) 5(7.24) 4(5.8) 6(8.7) 5(7.2) 8(11.6) 6(8.7) 42(27.3) 43(27.9) 23(14.9) 11(7.1) 27(17.5) 8(5.2) 6(3.9) 6(3.9) 8(5.2) Table 4b: Injury Burden among hypertensive patients with TBI. Total Dead (n=69) Alive (n=154) p- value Traumatic Brain Injury Type, n(%) Epidural hematoma Subdural hematoma Subarachnoid hemorrhage Intraparenchymal hemorrhage Intraventricular hemorrhage Diffuse axonal injury 39(17.5) 145(65.0) 158(70.9) 150(67.3) 43(19.3) 52(23.3) 9(8.7) 60(87.0) 56(81.2) 42(60.9) 20(29.0) 19 (27.5) 30(19.5) 85(55.2) 102(66.2) 108(70.1) 23(14.9) 33(21.4) 0.24 < Present Pupillary reflex, n(%) 163(73.1) 30(18.4) 133(86.4) < Midline shift, n(%) 72(32.3) 41(59.4) 31(20.1) < Intubation, n(%) 0.42 None Prehospital ED Post- ED 14(6.3) 88(39.5) 113(50.7) 8(3.6) 6(6.67) 31(44.9) 30(43.5) 2(2.9) 8(5.2) 57(37.0) 83(53.9) 6(3.9) ISS, mean±std 29.0±9 32.6± ±9.5 < AIS head, mean±std 4.4± ± ± AIS abdomen, mean±std 0.48± ± ± AIS chest, mean±std 1.3± ± ± AIS extremities, mean±std 0.73± ± ±

20 Table 4c: Clinical Presentation of hypertensive patients with TBI Total Dead (n=69) Alive (n=154) p GCS, mean±std 6± ± ± GCS motor, mean±std 2.8± ± ± Initial HR, mean±std 93± ± ± Highest recorded SBP in ED, mean±std 182.6± ± ± Glucose mean±std 173.2± ± ± Hemoglobin, mean±std 14.0± ± ± Sodium, mean±std 138.7± ± ± INR, mean±std 1.3± ± ± Table 4d: Clinical management in the ED of hypertensive patients with TBI Total Dead (n=69) Alive (n=154) Hyperosmolar therapy, n(%) 87(39.0) 44(63.7) 43(27.9) < Vasopressors, n(%) 14(6.3) 9(13.0) 5(3.2) Antihyertensive agents, n(%) 100(44.8) 71(46.1) 29(42.0) 0.57 ICP monitor, n(%) 55(24.7) 18(26.0) 37(24.0) 0.74 Blood products, n(%) 36(16.1) 22(31.9) 14(9.1) < Table 4e. Outcomes of hypertensive patients with TBI Total Dead (n=69) Alive (n=154) p HLOS, mean±std 16± ± ± ICU LOS, mean±std 7±7 6.2± ± PEG placement, n(%) 61(27.3) 16(23.2) 45(29.2) 0.35 Tracheostomy, n(%) 56(25.1) 14(20.3) 42(7.8)

21 Table 5. Univariate analysis of primary/secondary outcomes (RB vs. Non- RB groups) HR 90 HR>90 p Mortality, n(%) (37.9) (25.0) GOS 1-3, n(%) (57.3) (88.3) <0.001 HLOS, mean±std 14.7± ± ICU LOS, mean±std 6.4± ± Tracheostomy, n(%) (27.2) (23.3) PEG, n(%) (30.1) (25.0)

22 Table 6. Multivariate analysis of primary/secondary outcomes (including RB group) Multivariable Logistic Regression Analysis of Hypertensive TBI and Mortality Variable Odds Ratio 95% CI p HR Age <0.001 Midline shift Pupillary reflex <0.001 Injury severity score (ISS) Hyperosmolar therapy Blood transfusions in ED

23 Table 7. Univariate analysis of primary/secondary outcomes (TB vs. Non- RB groups) HR 60 (n=21) HR>90 (n=115) p Mortality, n(%) 15 (71.4) 29 (25.0) <0.001 GOS 1-3, n(%) 15 (71.8) 102 (88.3) HLOS, mean±std 10.9± ± ICU LOS, mean±std 5.7± ± Tracheostomy, n(%) 5.0 (23.8) 29 (25.2) 0.89 PEG, n(%) 5.88 (28.6) (27.2)

24 Table 8. Multivariate analysis of primary/secondary outcomes (including TB group) Multivariable Logistic Regression Analysis of Hypertensive TBI and Mortality* Variable Odds Ratio 95% CI p HR between HR< Age <0.001 Midline shift Pupillary reflex <0.001 Injury severity score (ISS) Hyperosmolar therapy Blood transfusions in ED * Regression performed using HR>90 as a reference group 24

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