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Research Article - (2021) Volume 12, Issue 3

The Effect of Hyperoxia in Traumatic Brain Injury Patients in the Intensive Care Unit of a Tertiary Care Center

Sarah Alromaih, Hind Alshabanat, Nosaiba Alshanqiti, Almaha Aldhuwaihy, Sarah Abdullah Almohanna, Muna Alqasem, Fatmah Othman and Raymond M. Khan*

King Saud bin Abdulaziz University for Health Sciences, Collage of Medicine, Riyadh, Saudi Arabia

*Corresponding Author:
Khan RM
King Saud bin Abdulaziz University for Health Sciences
Collage of Medicine
Riyadh, Saudi Arabia
Tel: + 9668112479
E-mail: [email protected]

Received Date: February 02, 2021; Accepted Date: March 12, 2021; Published Date: March 19, 2021

Citation: Alromaih S, Alshabanat H, Alshanqiti N, Aldhuwaihy A, Almohanna SA, et al. (2021) The Effect of Hyperoxia in Traumatic Brain Injury Patients in the Intensive Care Unit of a Tertiary Care Center. J Neurol Neurosci Vol.12 No.3:359.

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Abstract

Background: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality globally. Currently, the association between hyperoxia and outcomes in patients with TBI remains debatable. We assessed the effect of hyperoxia on the neurological outcomes and survival of critically ill patients with moderate-severe TBI.

Methods: This was a retrospective cohort study of all adults with moderatesevere TBI admitted to the ICU between 1st January 2016 and 31st December 2019 who required invasive mechanical ventilation. We noted ABGs performed with the first 3 hours of intubation, then 6-12 hours and 24-48 hours. The patients were divided into two categories: normoxia (PaO2 60-99 mmHg) and hyeroxia (PaO2 >100 mmHg). Multivariable logistic regression was performed to assess predictors of hospital mortality and good neurologic outcome (Glasgow outcome score [GOS] ≥ 4). In a second analysis the patients were divided into survivors and non-survivors.

Results: The study included 308 patients: 23.4% (n=72) in normoxia group and 76.6% (n=236) in hyeroxia group. Hyperoxia was not associated with increased hospital (43% vs. 18%, p=0.20) mortality. Further, the hospital discharge GCS (10 ± 5 vs. 11 ± 4, p=0.10) and GOS (3 ± 1 vs. 3 ± 1, p=0.35) were similar. In multivariable logistic regression analysis, hyperoxia was not associated with increased mortality (adjusted odds ratio [aOR] 0.99, 95% CI 0.99-1.00, p=0.11). PaO2 within different ranges was also not associated with mortality: 100-200 mmHg: aOR 0.60, 95% CI 0.29-1.52; 201-300 mmHg: aOR 0.66, 95% CI 0.29-1.52; 301-400 mmHg: aOR 0.80, 95% CI 0.31-2.09; and >400 mmHg: aOR 0.39, 95% CI 0.14-1.08; reference: PaO2 60-99 mmHg. The Kaplan-Meier survival curve for normoxia verses hyperoxia showed no significant difference for all-cause mortality. In the survivors verse nonsurvivors analysis, the PaO2 were (median, IQT) 199 mmHg (111-329) and 165 mmHg (84-252), respectively.

Conclusion: Hyperoxia (PaO2 >100 mmHg) was not associated with increased mortality or poor neurological outcomes (determined by GOS) in moderatesevere TBI patients.

Keywords

Hyperoxia; Traumatic brain injury; Mortality; Neurological outcomes; Intensive care; Mechanical ventilator.

Introduction

Traumatic brain injury (TBI) is a major cause of death, morbidity and economic burden globally, with more than 13 million people estimated to live with disabilities related to TBI in Europe and USA [1]. However, the magnitude of this problem may be even greater than envisioned, as a significant number of patients survive hospitalization but ultimately succumb to complications of their injuries [2]. Thus, clear individualized approach considering the pathophysiological diversity of TBI is of vital importance.

The primary injury in TBI cannot be reversed, hence, current management strategies and research are focused on preventing secondary insults by avoiding hypotension and hypoxia, thus maintaining appropriate cerebral blood flow and oxygen delivery [3]. Immediately following TBI, the metabolic demand of the brain increases, but oxygen delivery may decrease due to a reduction of CBF, increased ICP, and decreased oxygen diffusion caused by capillary endothelium edema, secondary to the neuroinflammatory response [4]. This oxygen deficiency forces conversion to anaerobic metabolism, leading to depletion of cellular ATP, calcium influx, release of excitatory neurotransmitters and mediators of programed cell death [5]. Hyperoxia in acute brain injury reverses the anaerobic state, with increased brain tissue PaO2, reduced lactate pyvurate ratio, increased cytochrome C oxidase and cerebral metabolic rates [6]. Thus, there is a paradigm shift in some clinicians to accept hyperoxia (PaO2 >100 mmHg or 13.3 kPa) in order to improve oxygen delivery [7]. However, oxygen resuscitation frequently exceeds physiological requirement and toxicity may ensue as elevated PaO2 induces vasoconstriction and reduces cardiac output, which may impair blood flow, paradoxically lowering the delivery of oxygen [8]. Also, exposure to high fractions of inspired oxygen may amplify the production of oxygen free radicals, resulting in neuronal injury via calcium influx causing excitotoxic damage or oxidative damage to the electron transport chain leading to decrease ATP production and subsequent activation of apoptotic pathways [9- 11].

The clinical relationship between hyperoxia and outcome in patients with TBI remains controversial, with published studies having mixed results and thus there is no consensus on the ideal PaO2 target in TBI. A retrospective study in patients with severe TBI showed that hyperoxia (PaO2> 487 mmHg/64.9 kPa) was associated with decreased survival (OR: 0.50, 95% CI 0.36-0.71; p < 0.001) [12]. Similar findings were obtained in a multicenter study among mechanically ventilated patients suffering from TBI, where hyperoxia (PaO2> 300 mmHg) within 24 hours after admission was independently associated with higher in-hospital mortality (OR: 1.5, 95% CI 1.02-2.4; P=0.04) [13]. Brenner and associates, in a logistic regression model showed that mortality (OR, 1.56; 95% CI, 1.18-2.07; P=0.002) and hospital length of stay (OR, 0.74; 95% CI, 0.58-1.13; P=0.01) were significantly worse for hyperoxic (PaO2>200 mmHg/26.7 kPa) patients [14]. On the other hand, Raj and associates found in patients with moderate-to-severe TBI that hyperoxia (PaO2>100 mmHg/13.3 kPa) was not predictive of 6-month mortality [15]. Russell, et al. observed among their patients with TBI that PaO2 was not related to increased mortality (OR 1.27, 95% CI 0.72 - 2.25) [2]. Likewise, Fujita and colleagues, found that PaO2 was significantly greater in patients with favorable outcomes than in patients with unfavorable neurological outcomes (PaO2: 252 ± 122 vs. 202 ± 87 mm Hg, p = 0.008), and PaO2 was independently associated with survival following severe TBI [16]. Finally, in a large multicenter cohort of TBI patients, hyperoxia in the first 24 hours after ICU admission was not independently associated with greater in-hospital mortality [17].

This disparity in findings is witnessed in two meta-analyses using the same studies, but yielding different conclusions. Damiani, et al. claims that hyperoxia may be associated with increased mortality in patients with TBI, while Helmerhorst, et al. found that hyperoxia was not independently associated with increased mortality [18]. In a more recent meta-analysis, Ni and colleagues showed that hyperoxia was not associated with worse mortality in TBI patients [19].

Significant clinical ambiguity still exists in regard to the benefit or harm of hyperoxia in TBI patients. This uncertainty paired with the immense burden of TBI in the Kingdom of Saudi Arabia and lack of data in our patient population has led us to perform a retrospective cohort study to investigate if hyperoxia in the first 24 hours of admission would affect the outcomes of moderatesevere TBI patients. We believe that this data could yield vital information needed to optimally manage our patients and it may add some clarity to the haziness encircling hyperoxia that still exists today.

Research Methodology

Parents and setting

This was a retrospective cohort study of all consecutive adult patients with moderate-sever TBI who were admitted to the Intensive Care Unit (ICU) at King Abdulaziz Medical City, a 1000- bed tertiary care center in Riyadh, Saudi Arabia. The critical care units were covered by board-certified intensivists with onsite coverage 24 hr/day and a nurse-to-patient ratio of 1:1. The hospital was accredited by Joint Commission International and had active Trauma and Neurosurgical teams. We included all adult patients (>18 years) admitted to ICU after TBI and a GCS ≤ 12, from 1st January 2016 to 31st December 2019. Patients were all intubated, on a mechanical ventilator with arterial blood gas (ABG) done within 20 minutes of being intubated and, repeated 3-6, 12-24, and 48 hours after intubation. We excluded patients who were admitted in ICUs for less than 72 hours, those with labeled no code, comfort care, supportive care or brain dead, or with incomplete medical records. The Institutional Review Board and of the Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia, approved this study and waived the requirement for informed consent (RYD-19-419812-59135).

Data collection

A list was generated of all patients admitted to the ICU that fulfill the inclusion criteria. Data were obtained from the computer chart for the analysis. These data included demographic characteristics, source of ICU admission, the severity of illness on ICU admission assessed by Injury Severity Score (ISS), Revised Trauma Score (RTS), Shock Index (SI), and The International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) in TBI –core model (using age, motor function and pupil response), admission and discharge Glasgow coma score (GCS), laboratory parameters, ABGs results, computerized tomography (CT) findings, and the therapeutic intervention. The PaO2 on intubation and within 3-6, 12-24, and 48 hours, the corresponding fraction of inspired oxygen (FiO2), and Positive End Expiratory Pressures (PEEP) were documented. For the PaO2 level, patients were categorized into normoxia (PaO2 60-99 mmHg) and hyperoxia (PaO2 >100 mmHg) groups depending on their ABG findings within 3 hours of intubation. Data on study outcomes were collected for each patient that includes: ICU and hospital mortality, hospital length of stay (measured in days), tracheostomy, and. Glasgow Outcome Score (GOS) at hospital discharge day.

Study design

In this study, we analyzed the data in two different approaches. In the first analysis, patients were categorized into in normoxia (PaO2 60-99 mmHg) and hyeroxia (PaO2 >100 mmHg) groups depending on their arterial blood gas (ABG) findings within 3 hours of intubation. We examined for predictors of outcome (mortality and neurological status). We also examined if hyperoxia may have an effect on subgroups and if different ranges of PaO2 (PaO2: 50- 99 mmHg, 100-200 mmHg, 201-300 mmHg, 301-400 mmHg and >400 mmHg) may influence outcomes. In the second analysis, the patients were divided into survivors and non-survivors depending on their mortality outcome, and their characteristics were examined.

Statistical analysis

The patient’s demographic and clinical data were presented as means (standard deviations SD) for the continuous variables if normally distributed, otherwise median and interquartile range(IQR) were used, where the categorical variables were presented as frequencies and percentages. We compared the baseline characteristics between normoxia and hyperoxia patients using Chi-squared (or Fisher’s exact test if indicated), and Student t-test or ANOVA for continuous variables. In the multivariable logistic regression analysis for the predictors of hospital mortality and neurologic outcome (GOS ≥ vs. < 4), the following variables were entered in the model: age, Injury Severity Score, arrival Glasgow Coma Scale [GCS], systolic blood pressure > 90 mmHg, and the presence of midline shift > 5 mm on brain CT. The results were presented as an odds ratio (OR) with a 95% confidence interval (95% CI) with a p-value < 0.05 was considered statistically significant.

A Kaplan-Meier survival curve was carried out to demonstrate the probability of survival over time for hyperoxia and normoxia patients. All analyses were done with the Stata 12 software system (StataCorp L.P., College Station, TX).

Results

The baseline characteristics of the cohort are presented in Table 1. The patients were predominately young males, with a vast majority being admitted from the emergency department. There were some significant differences between the normoxia and hyperoxia groups. Hyperoxic patients had significantly lower central venous pressure, creatinine, positive end-expiratory pressure, partial pressure of carbon dioxide and RBC transfusions, but higher rates of isolated head injury.

Variables All Normoxia Hyperoxia p-value
 (n=308)  (n=72)  (n=236)
Age (years), median (IQR) 28 (23-36) 30 (11) 31 (12) 0.59
Male Gender, N (%) 292 (94.8) 70 ± 97 222 ± 94 0.37
Weight, kg (mean ± SD) 68 ± 16 70 (17) 67 ± 14 0.1
IDBW, kg (mean ± SD) 65 ± 6 64 ± 6 65 ± 6 0.7
Markers of Severity, (mean ± SD)
Injury Severity Score 29 ± 7 31 ± 7 29 ± 7 0.11
Revised Trauma Score 5.3 ± 1 5.3 ± 1 5.3 ± 1 0.93
Shock Index 0.86 ± 0.3 0.8 ± 0.3 0.8 ± 0.3 0.32
IMPACT mortality 27.9 ± 18 29 ± 18 27 ± 17 0.47
Vital signs at admission, (mean ± SD)
MAP, mmHg 94 ± 22 91 ± 23 95 ± 22 0.18
Heart rate, beats/min 104 ± 28 108 ± 29 103 ± 27 0.19
Respiratory rate, breaths/min 24 ± 7 24 ± 7 24 ± 6 0.73
Oxygen saturation, % 95 ± 8 92 ± 13 96 ± 6 0.002
Temperature, ?C 36.6 ± 0.6 36 ± 0.7 36.7 ± 0.6 0.3
CVP, mmHg 10.6 ± 4.5 12 ± 5 10 ± 4 0.012
Arrival GCS, N (%)
GCS 9-12 56 (18.1) 61 (84) 191 (80) 0.46
GCS ≤ 8 252 (81.8) 11 (15) 45 (19)  
Laboratory parameters, (mean ± SD)
Hemoglobin, gm/L 138 ± 24 138 ± 26 138 ± 24 0.92
Platelets, 109/L 271 ± 90 266 ± 104 273 ± 86 0.58
Sodium, mmol/L 139 ± 4 140 ± 4 139 ± 4 0.17
Creatinine, umol/L (median,IQR) 81 (71-96) 84 (73-104) 80 (70-95) 0.006
Lactic Acid, mmol/L (median,IQR) 2.4 (1.4-3.9) 3 (1.9-4.2) 2.2 (1.3-3.7) 0.32
AST, U/l (median,IQR) 62 (36-122) 93 (59-149) 55 (34-103) 0.023
ALT,U/L (median,IQR) 43 (25-84) 72 (40-118) 37 (24-79) 0.02
Respiratory and ventilator parameters, (mean ± SD)
Tidal volume per IDBW, mL/kg 6.5 ± 0.7 6.6 ± 0.6 6.5 ± 0.8 0.22
FiO2, % 0.8 ± 0.2 0.8 ± 0.2 0.7 ± 0.2 0.26
pH 7.2 ± 0.08 7.2 ± 0.09 7.3 ± 0.08 0.002
PaCO2, mmHg 43 ± 9 44 ± 10 42 ± 8 0.08
PaO2, mmHg (median, IQR) 194 (105-308) 81 (71-92) 246 (162-357) <0.001
PaO2/FiO2 ratio, (median, IQR) 267 (147-433) 91 (78-141) 343 (216-466) <0.001
CT Head Findings, N (%)
Isolated Head Injury 96 (31.1) 13 (18) 83 (35) 0.006
Epidural Hematoma 26 (8.4) 7 (9) 19 (8) 0.78
Subdural Hematoma 125 (40) 27 (37) 98 (41) 0.54
Subarachnoid hemorrhage 115 (37.3) 27 (37) 88 (37) 0.97
Intraparenchymal Hemorrhage/Contusion 151 (49) 34 (47) 38 (52) 0.72
Intraventricular Hemorrhage 46 (14.9) 12 (16) 34 (14) 0.63
Cerebral Edema 106 (34) 26 (36) 80 (33) 0.72
Midline Shift ≥ 5 mm 42 (13.6) 9 (12) 33 (13) 0.74
No bleeding on CT 50 (16) 11 (15) 39 (16) 0.8
Management, N (%)
Blood product transfusions
PRBC 114 (37) 34 (47) 81 (34) 0.04
Fresh Frozen Plasma 66 (82) 18 (90) 48 (80) 0.31
Platelets 49 (79) 13 (86) 36 (76) 0.4
Tranexamic acid, N (%) 95 (30) 26 (36) 70 (29) 0.62
ICP Monitoring, N (%) 54 (15) 14 (19) 39 (15) 0.76
Hypertonic saline, N (%) 174 (55) 57 (52) 134 (56) 0.57
Head injury protocol, N (%) 225 (72) 52 (72) 173 (72) 0.96

SD: Standard Deviation; IMPACT: International Mission for Prognosis and Analysis of Clinical Trials; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; GCS: Glasgow Come Scale; AST: Aspartate Transaminase; ALT: Alanine Transaminase; IDBW: Ideal Body Weight; FiO2: Fraction of Inspired Oxygen; PEEP: Positive End-Expiratory Pressure; PaCO2: Partial Pressure of Carbon Dioxide; PaO2: Partial Pressure of Oxygen; PaO2/FiO2: Ratio of arterial oxygen partial pressure to fractional inspired oxygen; ICP: Intracranial Pressure.

Table 1: Baseline characteristics of normoxia (PaO2 60-100 mmHg) and hyperoxia (PaO2 >100 mmHg).

Table 2 describes the clinical outcome of our cohort. Hyperoxia was not associated with a prolonged ICU or hospital length of stay or duration of mechanical ventilator. Additionally, hyperoxia was not associated with increased hospital stay (18.2% vs. 25.0%, P=0.2) Further, the hospital discharge GCS (10 ± 5 vs. 11 ± 4, P=0.1) and Glasgow outcome scores (3 ± 1 vs. 3 ± 1, P=0.35) were similar in hyperoxia and normoxia groups, respectively.

Variables All Normoxia Hyperoxia p-value
N=308 n=72 n=236
Duration on mechanical ventilator, days (mean ± SD) 10 ± 7 11 ± 6 10 ± 7 0.28
ICU Length of stay, days (mean ± SD) 15 ± 11 19 ± 17 13 ± 9 <0.001
Hospital length of stay, days (median, IQR) 26 (11-59) 28 (10-67) 24 (11-55) 0.44
Tracheostomy, N (%) 98 (31.8) 29 (40.2) 69 (29.2) 0.07
ICU discharge GCS, (mean ± SD) 8 ± 4 7 ± 4 9 ± 4 0.02
Hospital discharge GCS, (mean ± SD) 11 ± 4 11 ± 4 10 ± 5 0.1
Hospital discharge GOS, (mean ± SD) 3 ± 1 3 ± 1 3 ± 1 0.35
Hospital mortality, N (%) 61 (19.8) 18 (25.0) 43 (18.2) 0.2

SD: Standard Deviation; IQR: Interquartile Range; ICU: Intensive Care Unit; N: Patient Number; %: Patient Percentage; GCS: Glasgow Coma Scale; GOS: Glasgow Outcome Score.

Table 2: Clinical outcomes in normoxia and hyperoxia.

The unadjusted outcomes for different PaO2 ranges in the first 3 hours of intubation are presented in Figure 1A. Compared to a PaO2 of 60-99 mmHg, there is no significant difference in hospital mortality or good neurological outcome (Glasgow outcome score ≥ 4) in any of the categories (100-200 mmHg, 201-300 mmHg, 301-400 mmHg, and >400 mmHg). In our multivariable logistic regression analysis, midline shift ≥ 5mm was an independent predictor of mortality (OR: 0.19; 95% CI: 0.09-0.41, p <0.001), while hyperoxia was not associated with increased mortality (OR 0.62, 95% CI 0.30-1.25, P=0.18). In subgroups analysis for hospital admission GCS <9, isolated TBI, initiation of HIP and PF ratio within first 3 hours >300, there were no significant differences in both mortality and neurological outcomes between the groups (Table 3).

Figure

Figure 1: (A) Association between PaO2 and hospital mortality in an unadjusted analysis. (B) Kaplan-Meier survival curve for normoxia vs. hyperoxia.

PaO2 ranges Total Hospital Mortality Hospital Discharge GOS ≥ 4
N (%) OR 95% CI OR 95% CI
60-99 mmHg 69 (22.4) Reference Reference
100-200 mmHg 91 (29.5) 0.6 0.29-1.52 0.86 0.44-1.67
201-300 mmHg 63 (20.4) 0.66 0.29-1.52 0.65 0.30-1.36
301-400 mmHg 35 (11.6) 0.8 0.31-2.09 0.5 0.19-1.27
>400 mmHg 49 (15.9) 0.39 0.14-1.08 1.55 0.73-3.28

N: number; %: percentage; OR: Odds Ratio; CI: Confidence Interval; GOS: Glasgow Outcome Score.

Table 3: Significantly different parameters (p<0.05) compared with normal.

Survivor verses non-survivors analysis is presented in Table 4. Non-survivors had higher markers of severity (Injury Severity Score, Revised Trauma Score and IMPACT mortality), and significantly lower oxygen saturation, temperature, and platelets. Further, non-survivors had lower median partial pressure of oxygen (165 mmHg, IQR 84-252 vs. 199 mmHg, IQR 111-329) and partial pressure to fractional inspired oxygen ratio (205 mmHg, IQR 112-337 vs. 299 mmHg, IQR 160-451) compared to survivors. Additionally, the frequency of hyperoxia (PaO2>100 mmHg) was similar in survivors and non-survivors (77% vs. 70%, P=0.2, respectively).

Variables All Survivors Non-survivors p-value
 (N=309)  (N=235)  (N=73)
Age, years (median IQR) 28 (23-36) 31 (12) 30 (11) 0.36
Male Gender, N (%) 292 (94.8) 236 (95.5) 56 (91.8) 0.23
IDBW, kg (mean ± SD) 65 ± 6 65 ± 6 64.7 ± 7 0.713
Markers of Severity, (mean ± SD)
Injury Severity Score 29 ± 7 29.5 ± 7 31.2 ± 7 0.03
Revised Trauma Score 5.3 ± 1.1 5.4 ± 1.1 4.7 ± 1.0 <0.001
IMPACT mortality 27.9 ± 17.8 24.4 ± 15.7 42.0 ± 19.4 <0.001
Vital signs at admission, (mean ± SD)
MAP, mmHg 94 ± 27.5 94 ± 21 93 ± 27 0.88
Heart rate, beats/min 105 ± 28 105 ± 26 101 ± 34 0.27
Respiratory rate, breaths/min 24 ± 7 24 ± 6 23 ± 7 0.64
Oxygen saturation, % 96 ± 9 96 ± 7 91 ± 12 <0.001
Temperature, °C 36.7 ± 0.7 36.7 ± 0.6 36.4 ± 0.8 <0.001
Arrival GCS, N (%)
GCS 9-12 56 (18) 52 (21.1) 4 (6.5) 0.009
GCS ≤ 8 252 (82) 195 (78.9) 57 (39)  
Laboratory Parameters, (mean ± SD)
Hemoglobin, gm/L 138 ± 25 139 ± 22 134 ± 32 0.13
Platelets, 109/L 272 ± 87 278 ± 88 245 ± 93 0.009
Creatinine, umol/L (median,IQR) 81 (71-960) 80 (71-95) 84 (74-96) 0.84
Lactic Acid, mmol/L (median,IQR) 2.5 (1.5-4) 2.3 (1.3-3.8) 2.9 (1.9-4.7) 0.04
Respiratory Parameters, (mean ± SD)
Tidal volume per IDBW, mL/kg   6.5 ± 0.7 6.4 ± 0.7 0.18
FiO2, %   0.7 (0.2) 0.8 (0.2) 0.03
PaO2, mmHg (median,IQR) 194 (105-308) 199 (111-329) 165 (84-252) 0.04
PaO2/FiO2 ratio, (median,IQR) 267 (147-433) 299 (160-451) 205 (112-337) 0.02
Hyperoxia- PaO2>100 mmHg, N (%) 236 (76) 193 (87) 43 (70) 0.2
CT Head Findings, N (%)
Isolated Head Injury 96 (31) 73 (29.5) 23 (38) 0.21
Intraparenchymal Hemorrhage/Contusion 151 (49) 123 (49) 28 (46) 0.58
Midline Shift ≥ 5mm 42 (14) 21 (8.5) 21 (34) <0.001
No findings on CT 50 (16) 46 (18) 4 (6) 0.02
Management, N (%)
Tranexamic acid, N (%) 95 (31) 65 (26) 30 (49) 0.007
ICP Monitoring, N (%) 54 (17.5) 38 (14) 16 (25) 0.24
Hypertonic saline, N (%) 203 (67) 165 (53) 38 (56) 0.69
Head injury protocol, N (%) 215 (70) 162 (69) 53 (85) 0.08

SD: Standard Deviation; IMPACT: International Mission for Prognosis and Analysis of Clinical Trials; MAP: Mean Arterial Pressure; GCS: Glasgow Come Scale; IDBW: Ideal Body Weight; FiO2: Fraction of inspired Oxygen; PaO2: Partial Pressure of Oxygen; PaO2/FiO2: Ratio of Arterial Oxygen Partial Pressure to fractional inspired oxygen; ICP: Intracranial Pressure.

Table 4: Significantly (p<0, 05) different parameters.

The Kaplan-Meier curve (Figure 1B) compared the survival rates between the hyperoxia and normoxia groups. The log-rank test (p=0.06) indicated a no statistically significant difference between the groups for all-cause mortality.

Discussion

This retrospective study of moderate-severe TBI patients, suggests that hyperoxia (PaO2 >100 mmHg) in the first 3 hours of admission was not an independent predictor of hospital mortality or unfavorable neurological outcomes. In analyzing different ranges of PaO2 none of the categories contribute to increased mortality or poor neurological outcomes. Further, in our survivors' verse non-survivors analysis, hyperoxia was not associated with nonsurvival; rather survivors had a higher median PaO2.

Comparing to previous literature

Supplemental oxygen therapy remains the cornerstone of many resuscitation protocols [17]. However, this frequently results in oxygen levels that exceed the patient physiological requirements. Substantial evidence suggests that elevated PaO2 may increase the formation of reactive oxygen species in the neuronal tissue via the mitochondrial oxidoreductive process, which may enhance oxidative and nitrosative stress, thereby favoring the induction of apoptotic neuronal death and necrosis, potentially contributing to poor neurological outcomes [2]. Further, supraphysiological levels of oxygen can cause cerebral vasoconstriction resulting in decreased cerebral blood flow (CBF), paradoxically lowering delivery of oxygen and other important substrates to the cerebral tissue [8]. Conversely, clinical studies suggest that supplemental oxygen seems to possess the potential to rescue threatened neurons after brain injury, and it is known to prolong the safe apnea time [20].

The metabolic demand of the brain increases immediately following TBI, but oxygen delivery may decrease due to a reduction of CBF, increased ICP, and decreased oxygen diffusion caused by capillary endothelium edema, secondary to the neuroinflammatory response [4]. This oxygen deficit forces conversion to anaerobic metabolism, resulting in depletion of cellular ATP. This crisis results in inadequate ATP needed for normal Na+/K+ ATPase pump function, leading to calcium influx, the release of excitatory neurotransmitters, and mediators of programmed cell death [5]. Hyperoxia has been associated with improvements in intracranial pressure, brain tissue oxygenation, lactate concentration, and lactate pyruvate ratio (creating a more aerobic metabolic profile) in TBI [21]. Ghosh et al. showed that hyperoxia in acute brain injury resulted in increased brain tissue PaO2, reduced lactate pyruvate ratio, increased cytochrome c oxidase, and cerebral metabolic rates [6].

This friend-foe dichotomy of oxygen therapy has made it challenging to ascertain the optimal targets for both SpO2 and PaO2 in TBI patients. A large meta-analysis found increased rates of mortality for patients with oxygen saturation greater than 96% compared to 94-96%, but only one RCT on trauma patients was included and it showed no effects of liberal oxygen [22]. A recent meta-analysis by Ni et al. found that hyperoxia did not contribute to higher mortality in patients with TBI (OR 1.23, 95% CI 0.91-1.67; P=0.19), stroke (OR 1.02, 95% CI 0.76-1.36; P=0.91), post-cardiac surgery (OR 1.06, 95% CI 0.78-1.44; P=0.69) or mechanical ventilation (OR 1.23, 95% CI 0.99-1.54; P=0.06), but was associated with higher mortality in post-cardiac arrest patients (OR 1.30, 95% CI 1.08-1.57; P=0.03) [19].

The results of our study are consistent with others, suggesting no association between hyperoxia and mortality or neurological outcome in TBI patient [2,15-17]. Raj et al. using the Finnish Intensive Care Consortium database of mechanically ventilated patients with moderate-to-severe TBI, found no independent relationship between hyperoxia (PaO2>100 mmHg) and 6-month mortality (OR 0.88, 95% CI, 0.63-1.22; P=0.43) [15]. In patients with severe TBI, Russell and associates observed that hyperoxia in the first 24 hours of intubation was not associated with increased mortality (OR 1.27 95% CI 0.72-2.25; P=0.41) [2]. While, Fujita et al. in a Post-hoc analysis of data from the Brain Hypothermia study, revealed that PaO2 was higher in survivors and those with favorable neurological outcomes as measured by GOS than in non-survivors and those with unfavorable outcomes (PaO2: 242 vs. 193 mmHg, p=0.022 and PaO2: 252 vs. 202 mmHg, P=0.008- respectively) [16]. Further, O’Brian et al. found in 24,148 TBI patients that hyperoxia was not independently associated with greater in-hospital mortality in any group (OR 0.99, 95% CI, 0.84- 1.13-GCS <9; OR 1.01 95% CI 0.67-1.51-GCS 9-12; OR 1.1 95% CI, 0.75-1.63-GCS > 12) [17]. Recent data from a French registry of 5912 patients, observed that early hyperoxia in trauma patients was associated with reduced adjusted in-hospital mortality (OR 0.59 95% CI 0.50–0.70; p<0.0001) [20].

On the other hand, in patients with severe TBI Davis et al. found that extreme hyperoxia (PaO2 ≥ 487 mmHg) was associated with increased mortality (OR 0.50, 95% CI, 0.36-0.71, <0.001) [12]. However, this study used an arbitrarily high PaO2 as a threshold and only included the first PaO2 measurement in their regression analysis models. Brenner et al. in a single-center retrospective study, showed that hyperoxia (PaO2>200 mmHg) was associated with increased hospital length of stay (OR 0.75, 95% CI, 0.60-0.94) and mortality (OR 1.5, 95% CI 1.15-1.97; p=0.003), and decreased GCS (OR 1.52, 95% CI, 1.18-1.96; P=0.001) [14]. Although this study used the mean PaO2 from ABGs in the first 24 hours, it included non-mechanically ventilated patients, which may introduce biases, as it is possible that patients not on mechanical ventilation had less severe TBI and thus less likely to be hyperoxic. Rincon and colleagues, in a multicenter cohort study of ventilated TBI patents found in a multivariate analysis that hyperoxia (PaO2 ≥ 300 mmHg) was independently associated with higher inhospital mortality (OR 1.5, 95% CI 1.02-2.4; P=0.04) [13]. This study used only the “worst” PaO2 which may be misleading as we found in our study that many patients may have an elevated PaO2 immediately post-intubation, but this did not persist in subsequent ABGs repeated 1-3 hours later.

In a randomized pilot study comparing FiO2 of 0.7 (PaO2 mean ± SD: 218 ± 92 mmHg) and FiO2 of 0.4 (PaO2 mean ± SD: 124 ± 42 mmHg), the higher fraction of FiO2 was not associated with blood concentrations of markers of oxidative stress (reactive oxygen species-ROS), inflammation (interleukin 6-Il6), neurological injury (neuron-speci?c enolase-NSE), mortality (p=1.0) or poor neurological outcome (P=0.58) as measured by Extended Glasgow outcome scale [23].

Furthermore, the combination of hyperbaric and normobaric hyperoxia in the treatment of severe TBI has been associated with improved markers of oxidative stress, 26% absolute reduction in mortality (P=0.048), and 36% improvement in favorable outcome (p=0.024) [24]. This suggests that hyperoxia may contribute to increased oxygen delivery to brain tissue and protect against secondary ischemic damage [5].

Our subgroup analysis for patients with arrival GCS ≤ 8 and isolated TBI revealed that hyperoxia was not associated with increased hospital mortality or poor neurological outcomes. Analogous findings were reported by O’Brian et al. in that hyperoxia was not identified as an independent risk factor for mortality in isolated TBI (OR: 1.21, 95% CI 0.90-1.64) or those with GCS <9 (OR 0.99, 95% CI, 0.84-1.13) [17]. Furthermore, different ranges of PaO2 (50- 99 mmHg, 100-200 mmHg, 201-300 mmHg, 301-400 mmHg, and >400 mmHg) were not associated with worse clinical outcomes.

This study did not find an exact threshold for either the SpO2 or PaO2 in TBI patients; however, it suggests that a moderately aggressive approach to maintaining PaO2 above 100 mmHg does not seem to be harmful and may prevent episodes of hypoxia, which is known to be associated with increased mortality in TBI [25,26]. Hence, any theoretical disadvantage caused by increased free radicle and oxygen toxicity may be outweighed by the beneficial effect of improved tissue oxygenation, thus avoiding hypoxia.

Strength and Limitations

This study has several strengths including the use of a relatively large well-designed database to extract patients with moderatesevere TBI as the data were collected by trained collectors and have been validated. We included only patients receiving mechanical ventilation, with multiple ABGs with the first 48 hours of intubation, ensuring that the cohort had a significant injury and remained hyperoxic for several hours. We used validated markers for severity of illness, which allowed us to calculate adjusted mortality risk with varying PaO2 categories. We also performed analysis in multiple subgroups to further substantiate our findings. Lastly, we used Glasgow outcome sores to evaluate neurological outcomes. Regardless of this However, we acknowledge several limitations to this study. Firstly, this was a single-centered study of mostly male patients, thus generalization of our findings should be cautious. Secondly, this was an observational study, in which we did not collect information on other factors that could influence the analysis such as unmeasured confounder. Third, due to the retrospective nature of the study we were unable to assess long-term neurological outcome and our GOS was done at hospital discharge. Finally, TBI encompasses a number of unique pathologies (e.g., SDH, SAH, diffuse axonal injury) and that although no differences were evident in isolated TBI and GCS ≤ 8, it is highly conceivable that hyperoxia may impact each injury sub-type differently.

Conclusion

Our data revealed that hyperoxia (PaO2 >100 mmHg) was not associated with increased mortality or poor neurological outcomes (determined by GOS) in moderate-severe TBI patients. Further, our analysis did not reveal any PaO2 range 100-200 mmHg, 201-300 mmHg, 301-400 mmHg, and >400 mmHg) for which outcomes were affected. Thus, currently the exact target for SaO2 and PaO2 in TBI remains unclear, and requires clear evidence from well-designed randomized control studies.

Ethics Approval and Consent

The Institutional Review Board and of the Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia, approved this study and waived the requirement for informed consent.

Acknowledgement

We thank Dr. Bibi Shalimar Yamin, PhD, St. Johns University, New York, USA for reviewing and editing the manuscript.

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