Early-Stage Hyperoxia Is Associated with Favorable Neurological Outcomes and Survival after Severe Traumatic Brain Injury: A Post-Hoc Analysis of the Brain Hypothermia Study

Abstract

The effects of hyperoxia on the neurological outcomes of patients with severe traumatic brain injury (TBI) are still controversial. We examined whether the partial pressure of arterial oxygen (PaO₂) and hyperoxia were associated with neurological outcomes and survival by conducting post-hoc analyses of the Brain Hypothermia (B-HYPO) study, a multi-center randomized controlled trial of mild therapeutic hypothermia for severe TBI. The differences in PaO₂ and PaO₂/fraction of inspiratory oxygen (P/F) ratio on the 1st day of admission were compared between patients with favorable (n = 64) and unfavorable (n = 65) neurological outcomes and between survivors (n = 90) and deceased patients (n = 39). PaO₂ and the P/F ratio were significantly greater in patients with favorable outcomes than in patients with unfavorable neurological outcomes (PaO₂: 252 ± 122 vs. 202 ± 87 mm Hg, respectively, p = 0.008; P/F ratio: 455 ± 171 vs. 389 ± 155, respectively, p = 0.022) and in survivors than in deceased patients (PaO₂: 242 ± 117 vs. 193 ± 75 mm Hg, respectively, p = 0.005; P/F ratio: 445 ± 171 vs. 370 ± 141, respectively, p = 0.018). Similar tendencies were observed in subgroup analyses in patients with fever control and therapeutic hypothermia, and in patients with an evacuated mass or other lesions (unevacuated lesions). PaO₂ was independently associated with survival (odds ratio 1.008, p = 0.037). These results suggested that early-stage hyperoxia might be associated with favorable neurological outcomes and survival following severe TBI.

Introduction

Oxygen administration is an essential therapy in critically ill patients; however, oxygen itself may have toxic effects, for example on the retina of premature infants. It is still unclear whether early-stage hyperoxia has beneficial effects on the outcomes of critically ill patients, and the effects of hyperoxia have been discussed in critical care of patients with neurological trauma.^1,2

Although hyperoxia was reported to increase the increased risk of mortality in patients with post cardiac arrest syndrome,^1

–7 the effects of hyperoxia on the neurological outcomes in patients with traumatic brain injury (TBI) are still controversial.^{1,2,8

–12} Several investigators reported that hyperoxia had harmful effects on the outcomes of patients with moderate to severe TBI.^10
–12 By contrast, Asher and coworkers reported that hyperoxia improved survival after discharge in patients with severe TBI.⁸ Therefore, it is necessary to evaluate the effects of hyperoxia on the outcomes of patients with severe TBI.

The Brain Hypothermia (B-HYPO) study was a Japanese multi-center randomized controlled trial (RCT) of mild therapeutic hypothermia (MTH) for severe TBI patients (Glasgow Coma Scale [GCS] score of 4–8).¹³ Although the B-HYPO study revealed no beneficial effects of MTH (32.0–34.0°C) compared with fever control (35.5–37.0°C) in terms of the neurological outcomes, MTH was associated with statistically significantly better neurological outcomes for patients with evacuated hematoma.¹⁴

In the present study, we investigated whether the partial pressure of arterial oxygen (PaO₂) and PaO₂/fraction of inspiratory oxygen (P/F) ratio, and hence hyperoxia, were associated with the neurological outcomes or survival of patients with severe TBI in post-hoc analyses of the B-HYPO study.

Methods

Patients

The association between hyperoxia and the outcomes of patients with severe TBI was examined using data from the B-HYPO study, which was conducted between December 2002 and September 2008 in Japan.¹³ The RCT involved prospective analyses and blinded assessment of the neurological outcomes. The protocol was approved by the institutional review board at each participating hospital, and the trial was registered in the University Hospital Medical Information Network database (UMIN-CTR, No. C000000231) in Japan and in the National Institutes of Health database (ClinicalTrials.Gov, Identifier NCT00134472) in the United States. Briefly, the inclusion criteria were an age of 15–69 years and a GCS score of 4–8. Overall, 150 patients were randomly assigned (2:1 allocation ratio) to either MTH (32.0–34.0 °C) or fever control (35.5–37.0 °C), and intention-to-treat analyses were performed.¹³ After enrollment, informed consent could not be obtained for two patients, seven patients had unstable vital signs before target temperature management (TTM), and the neurological outcomes could not be assessed at 6 months in six patients. Therefore, per-protocol analyses were performed in 135 patients (88 treated with MTH and 47 treated with fever control). The present post-hoc analyses were conducted using data for 129 patients who underwent arterial blood gas analysis on the 1st day of admission.

Treatments and neurological outcomes

All patients were treated according to the guidelines for the management of severe TBI developed by the Japan Society of Neurotraumatology.¹⁵ All treatments were performed as described in our original article.¹³ In brief, cooling was initiated within 2 h after the onset of TBI. Cooling blankets, rapid cold fluid infusion (up to 1000 mL of saline, human plasma products, or dextrose-free plasma expanders) and/or cold gastric lavage were used during the induction phase in both groups. The goal of treatment in both groups was to achieve the target temperature within 6 h after the onset of TBI and to maintain this temperature for ≥72 h, mainly using surface cooling blankets. Thereafter, the temperature was kept at <38°C for 4 days. During this period, PaO₂ and the partial pressure of arterial carbon dioxide (PaCO₂) were maintained at >100 mm Hg and 30–40 mm Hg, respectively.

Data collection and study outcomes

All data, except for CT data, were transmitted to the UMIN center via an Internet-based system. Head CT on admission was classified using the Traumatic Coma Data Bank (TCDB) classification.¹⁶ The Glasgow Outcome Scale (GOS) at 6 months was assessed by a neurosurgeon, neurologist, or emergency physician who was unaware of the patient's treatment method. Moderate disability (MD) or good recovery (GR) was defined as a favorable neurological outcome, whereas severe disability (SD), persistent vegetative state (PVS), or death was defined as an unfavorable neurological outcome. The survival or death of patients at 6 months after admission were also assessed.

In the present post-hoc analyses, we compared PaO₂ and P/F ratio on the first hospital day between patients with favorable and those with unfavorable neurological outcomes and between survivors and patients who died. PaO₂ and P/F ratio were recorded after the patient's physiological parameters had been stabilized, and just before the start of TTM, at a mean ± standard deviation of 5.6 ± 4.6 h after the onset of TBI. We also examined the factors associated with favorable neurological outcomes and survival in patients with severe TBI.

Statistical analysis

Variables are shown as mean ± SD or number (percentage). Univariate analyses were performed using t tests for continuous variables and χ² tests for categorical variables. Multivariable logistic regression was performed with the stepwise variable selection method to identify factors associated with favorable neurological outcomes or survival, and the results are presented as the odds ratio (OR) and the 95% confidence interval (CI). Variables with a p value of <0.10 in univariate analyses were included in the multivariable logistic regression models. Values of p < 0.05 were considered to indicate statistical significance. All analyses were performed using IBM SPSS Statistics for Windows version 22 (IBM SPSS Inc., Chicago, IL).

Results

Patient characteristics

The characteristics of patients on admission (Table 1) and their physiological parameters (Table 2) at 5.6 ± 4.6 h following the onset of TBI are shown for the four groups of patients (i.e., favorable or unfavorable neurological outcomes and for survivors and deceased patients). Patients with favorable neurological outcomes were significantly younger, had significantly higher GCS scores, and had significantly lower Abbreviated Injury Score (AIS) of the head than patients with unfavorable neurological outcomes (Table 1). The survivors were significantly younger and had significantly higher GCS scores than deceased patients (Table 1).

Table 1.

Characteristics of Patients on Admission or at the Start of Temperature Management According to Their Outcome

Subgroup of patients	Favorable neurological outcomes (n = 64)	Unfavorable neurological outcomes (n = 65)	p value	Survivors (n = 90)	Deceased patients (n = 39)	p value
Age	32.6 ± 16.3	47.5 ± 17.4	0.000	36.8 ± 18.1	47.7 ± 17.1	0.002
Sex, male (%)	50 (78.1)	41 (63.1)	0.082	65 (72.2)	26 (66.7)	0.535
GCS	6.2 ± 1.3	5.4 ± 1.3	0.001	6.0 ± 1.4	5.4 ± 1.2	0.035
Unreactive pupil (%)	26 (40.6)	32 (49.2)	0.378	40 (44.4)	18 (46.2)	1.000
TCDB, evacuated mass (%)	22 (34.4)	32 (50.0)	0.107	35 (38.9)	19 (50.0)	0.327
ISS	24.2 ± 8.3	25.8 ± 8.3	0.274	25.2 ± 8.5	24.6 ± 8.1	0.732
AIS (Head)	4.0 ± 0.7	4.4 ± 0.7	0.003	4.2 ± 0.7	4.4 ± 0.7	0.067
AIS (Chest)	1.1 ± 1.4	0.9 ± 1.4	0.360	1.1 ± 1.5	0.6 ± 1.3	0.060

Values are shown as the number (%) or mean ± standard deviation.

GCS, Glasgow coma scale; TCDB, Traumatic Coma Data Bank; ISS, injury Severity Score; AIS, Abbreviated Injury Score.

Table 2.

Physiological Parameters on the 1st Day of Admission

Subgroup of patients	Favorable neurological outcomes (n = 64)	Unfavorable neurological outcomes (n = 65)	p value	Survivors (n = 90)	Deceased patients (n = 39)	p value
Heart rate (bpm)	92 ± 28	90 ± 23	0.644	92 ± 26	89 ± 25	0.553
Mean arterial pressure (mm Hg)	94 ± 18	88 ± 22	0.104	92 ± 19	89 ± 23	0.472
Body temperature (°C)	35.8 ± 1.4	35.3 ± 1.5	0.067	35.7 ± 1.4	35.2 ± 1.6	0.104
Hemoglobin (mg/dL)	13.0 ± 2.2	11.9 ± 2.2	0.009	12.7 ± 2.1	11.9 ± 2.5	0.078
White blood cell count ( × 10³/mm³)	15.1 ± 7.5	13.1 ± 7.3	0.120	15.0 ± 7.3	11.9 ± 7.2	0.032
Platelet count ( × 10³/mm³)	23.4 ± 7.8	20.4 ± 6.7	0.023	22.8 ± 7.3	19.7 ± 7.3	0.032
PaO₂ (mm Hg)	252 ± 122	202 ± 87	0.008	242 ± 117	193 ± 75	0.005
PaCO₂ (mm Hg)	37.6 ± 7.1	35.4 ± 7.5	0.091	36.8 ± 7.6	35.8 ± 7.0	0.455
pH	7.38 ± 0.07	7.40 ± 0.08	0.047	7.38 ± 0.08	7.40 ± 0.07	0.364
Blood glucose (mg/dL)	174 ± 61	184 ± 52	0.320	172 ± 56	195 ± 55	0.043
ICP (mm Hg)	17.9 ± 13.5	30.0 ± 23.9	0.004	18.3 ± 13.5	37.8 ± 26.7	0.000
CPP (mm Hg)	80.1 ± 18.8	63.7 ± 32.9	0.005	78.3 ± 20.6	56.5 ± 36.7	0.008

Values are shown as the mean ± standard deviation.

PaO₂, partial pressure of arterial oxygen; PaCO₂, partial pressure of arterial carbon dioxide; ICP, intracranial pressure; CPP, cerebral perfusion pressure.

Hemoglobin, platelet count, PaO₂, and cerebral perfusion pressure (CPP) were significantly higher, whereas pH and intracranial pressure (ICP) were significantly lower in patients with favorable neurological outcomes than in patients with unfavorable neurological outcomes (Table 2). The white blood cell count, platelet count, PaO₂, and CPP were significantly higher, and blood glucose and ICP were significantly lower in survivors than in deceased patients (Table 2).

PaO₂ and P/F ratio on the first day in patients with severe TBI

PaO₂ and P/F ratio in the four groups of patients are shown in Table 3. PaO₂ and P/F ratio were significantly greater in patients with favorable neurological outcomes than in patients with unfavorable neurological outcomes (PaO₂: 252 ± 122 vs. 202 ± 87 mm Hg, respectively, p = 0.008, P/F ratio: 455 ± 171 vs. 389 ± 155, respectively, p = 0.022; Table 3). PaO₂ and P/F ratio were also significantly greater in survivors than in deceased patients (PaO₂: 242 ± 117 vs. 193 ± 75 mm Hg, respectively, p = 0.005; P/F ratio: 445 ± 171 vs. 370 ± 141 mm Hg, respectively, p = 0.018; Table 3). In addition, there was no patient with PaO₂ < 60 mm Hg.

Table 3.

PaO₂ and P/F Ratio in Favorable and Unfavorable Outcome Groups or Survival and Death Groups at Stabilized Stage on the 1st Day

Subgroup of patients	Favorable neurological outcomes	Unfavorable neurological outcomes	p value	Survivors	Deceased patients	p value
All patients, n	64	65		90	39
PaO₂ (mm Hg)	252 ± 122	202 ± 87	0.008	242 ± 117	193 ± 75	0.005
P/F ratio	455 ± 171	389 ± 155	0.022	445 ± 171	370 ± 141	0.018
Fever control, n	25	20		36	9
PaO₂ (mm Hg)	241 ± 94	183 ± 69	0.027	226 ± 89	171 ± 72	0.097
P/F ratio	431 ± 172	373 ± 161	0.273	429 ± 162	318 ± 152	0.072
Therapeutic hypothermia, n	39	45		54	30
PaO₂ (mm Hg)	260 ± 137	210 ± 93	0.060	253 ± 132	199 ± 75	0.043
P/F ratio	471 ± 171	394 ± 156	0.034	455 ± 177	385 ± 136	0.065
Evacuated mass lesions, n	22	32		35	19
PaO₂ (mmHg)	252 ± 110	203 ± 82	0.065	241 ± 109	190 ± 58	0.029
P/F ratio	495 ± 150	363 ± 145	0.002	461 ± 155	335 ± 136	0.005
Other lesions, n	42	32		55	19
PaO₂ (mm Hg)	253 ± 129	201 ± 93	0.059	243 ± 123	194 ± 91	0.119
P/F ratio	435 ± 179	415 ± 164	0.640	434 ± 181	405 ± 145	0.519

Data were recorded when the patients' physiological parameters had stabilized on the first hospital day, at 5.6 ± 4.6 h after traumatic brain injury, just before starting targeted temperature management. Data are shown as the mean ± standard deviation. The subgroup “other lesions” included patients with diffuse injury I, II, III, or IV, or unevacuated mass lesions according to the Traumatic Coma Data Bank classification. The evacuated mass lesion and other lesion subgroups comprised 128 patients because the intracranial lesion type was not reported for one patient.

PaO₂, partial pressure of arterial oxygen; P/F ratio; partial pressure of arterial oxygen/fraction of inspiratory oxygen.

We then subdivided patients into the following subgroups: fever control, therapeutic hypothermia, evacuated mass lesions, and other patients (which included patients with diffuse injury I, II, III, or IV, and unevacuated mass lesions according to the TCDB classification). The differences in PaO₂ and P/F between patients with favorable and those with unfavorable neurological outcomes, or between survivors and deceased patients (Table 3) in the four subgroups of patients (i.e., fever control, therapeutic hypothermia, evacuated mass lesions, and other patients) were consistent with those observed in all patients (Table 3). PaO₂ in the fever control subgroup (241 ± 94 vs. 183 ± 69 mm Hg, respectively, p = 0.027), the P/F ratio in the therapeutic hypothermia subgroup (471 ± 171 vs. 394 ± 156, respectively, p = 0.034) and the P/F ratio in the evacuated mass lesion subgroup (495 ± 150 vs. 363 ± 145, respectively, p = 0.002) were significantly greater in patients with favorable neurological outcomes than in patients with unfavorable neurological outcomes (Table 3). PaO₂ in the therapeutic hypothermia subgroup (253 ± 132 vs. 199 ± 75 mmHg, respectively, p = 0.043), PaO₂ in the evacuated mass lesion subgroups (241 ± 109 vs. 190 ± 58 mm Hg, respectively, p = 0.029), and the P/F ratio in the evacuated mass lesion subgroup (461 ± 155 vs. 335 ± 136, respectively, p = 0.005) were significantly greater in survivors than in deceased patients (Table 3).

Factors associated with favorable neurological outcomes and survival

The following variables were included in the multivariable logistic regression model to identify factors associated with favorable neurological outcomes: age, sex, head AIS, GCS, body temperature, ICP, CPP, hemoglobin, platelet count, PaO₂, P/F ratio, PaCO₂, and sodium (Na). Age (OR 0.970, 95% CI 0.944–0.996, p = 0.025), GCS (OR 1.452, 95% CI 1.027–20.53, P = 0.035), and ICP (OR 0.970, 95% CI 0.943–0.998, p = 0.035) were independently associated with favorable neurological outcomes in this model (Table 4).

Table 4.

Factors Associated with Favorable Neurological Outcomes and Survival

	OR	95% CI
Favorable neurological outcomes
Age	0.970	0.944–0.996
GCS	1.452	1.027–20.53
ICP	0.970	0.943–0.998
Survival
PaO₂	1.008	1.000–1.015
Blood glucose	0.992	0.983–1.000
ICP	0.956	0.929–0.986

OR, odds ratio; CI, confidence interval; GCS, Glasgow coma scale; ICP, intracranial pressure; PaO₂, partial pressure of arterial oxygen.

With survival as the outcome variable, the following variables were included in the multivariable logistic regression model: age, head AIS, chest AIS, GCS, ICP, CPP, white blood cell count, hemoglobin, platelet count, PaO₂, P/F ratio, and blood glucose. PaO₂ (OR 1.008, 95% CI 1.000–1.015, p = 0.037), blood glucose (OR 0.992, 95% CI 0.983–1.000, p = 0.045), and ICP (OR 0.956, 95% CI 0.929–0.986, p = 0.003) were independently associated with survival in this model (Table 4).

Discussion

The pathophysiology of patients with TBI varies considerably. In addition to their original brain injury, patients may experience secondary events such as elevated cerebral metabolic rate of oxygen caused by post-traumatic pyrexia,¹⁷ reduced O₂ transport to the brain caused by hemorrhage, reduced CPP caused by elevated ICP and brain edema,¹⁸ regional ischemia/reperfusion injury, and hyperglycemia-related brain damage,¹⁹ particularly during the early stage of the TBI. In the present analyses of the B-HYPO study, we used data obtained on the first hospital day (5.6 ± 4.6 h after the onset of TBI), at which time the patients' physiological parameters had stabilized and PaO₂ and P/F ratio had been measured.

We found that in the total cohort, PaO₂ and P/F ratio were greater in patients with favorable neurological outcomes and in survivors than patients with unfavorable neurological outcomes and deceased patients, respectively (Table 3). These results were particularly evident in patients with an evacuated mass lesion (Table 3). Further, PaO₂ was independently associated with survival in patients with TBI (OR 1.008, 95% CI 1.000–1.015, Table 4). These results indicate that hyperoxia on the first hospital day might have beneficial effects on the neurological outcomes of patients with severe TBI.

Our results showing that hyperoxia was associated with favorable outcomes of patients with severe TBI are consistent with those reported elsewhere. Asher and coworkers reported that hyperoxia during the first 72 h after severe TBI was associated with survival after discharge, and that the PaO₂ threshold was between 250 and 486 mmHg.⁸ In our study, the mean PaO₂ on the first hospital day was 252 mm Hg in patients with favorable neurological outcomes and 242 mm Hg in survivors (Table 3). However, some investigators reported that hyperoxia was associated with worse neurological outcomes in patients with TBI.^10
–12 Therefore, some discordance exists between those reports and our results. Rincon and coworkers¹⁰ and Raj and coworkers⁹ analyzed ventilated patients with moderate to severe TBI. Body temperature was not controlled in those studies. The mean temperature of the patients at intensive care unit (ICU) admission was high, being 38.2 ± 0.9 °C in the study by Rincon and coworkers,¹⁰ and only 8% of 1116 patients underwent therapeutic hypothermia in the study by Raj and coworkers.⁹ Because the cerebral metabolic rate of oxygen is increased by 7% for each 1.0°C increase in temperature,²⁰ the brain and other organs might be damaged as a consequence of elevated core body temperatures, rather than elevated PaO₂. In the present study, the core body temperature was kept at 32.0–34.0°C (MTH) or 35.5–37.0°C (fever control) under brain-oriented intensive care for ≥72 h after admission.

TBI is associated with heterogeneous lesions, including hematoma, contusion, and diffuse brain injury, which might introduce differences in the regional microcirculation of the brain. The microcirculation is very important in severe TBI, especially around the lesions, where the regional microcirculation might be disturbed by elevated regional tissue pressure and the overall ICP (Tables 2 and 4). In the present study, hemoglobin was significantly higher in patients with favorable neurological outcomes than in patients with unfavorable neurological outcomes (13.0 ± 2.2 vs. 11.9 ± 2.2 mg/dL, p = 0.009; Table 2). Accordingly, the O₂ carrying capacity with the brain microcirculation was greater in patients with good rheology (a hemoglobin concentration of 13 mg/dL is associated with adequate blood viscosity). This is supported by the adequate cardiac output in the B-HYPO study, with a cardiac index of 3.3 ± 1.1 L/m²/min in the fever control group and 3.3 ± 1.4 L/m²/min in the therapeutic hypothermia group.¹³

In post cardiac arrest patients, it was reported in two observational studies that hyperoxia was associated with increased mortality risk.^3,7 However, PaO₂ was >300 mm Hg in one study,³ and was much higher than the PaO₂ in survivors in the present study. Elmer and coworkers⁶ reported that moderate or probable hyperoxia (PaO₂ of 100–300 mm Hg) was associated with increased survival following hospital discharge and was associated with improved organ function at 24 h, whereas severe hyperoxia (PaO₂ > 300 mm Hg) was associated with decreased survival after discharge in patients hospitalized for cardiac arrest. These differences may be the result of pathophysiologic differences between TBI and post cardiac arrest.

Among patients with an evacuated mass lesion, PaO₂ was significantly greater in survivors than in deceased patients (241 ± 109 vs. 190 ± 58 mm Hg, p = 0.029; Table 3), and tended to be greater in patients with favorable neurological outcomes than in patients with unfavorable neurological outcomes (252 ± 110 vs. 203 ± 82 mm Hg, p = 0.065; Table 3). Evacuated mass lesions are thought to cause ischemia/reperfusion injury as a result of tissue compression and subsequent removal of the hematoma.²¹ Our previous experimental study revealed that early-stage hyperoxia suppressed superoxide anion radical generation, oxidative stress, early inflammation, and endothelial injury in the acute phase of forebrain ischemia/reperfusion injury in rats.²² In our previous study, the mean PaO₂ ranged from 240 to 345 mm Hg in the hyperoxia group, similar to the mean PaO₂ in patients with favorable neurological outcomes and survivors in the present study (252 and 242 mm Hg, respectively; Table 3). These mechanisms might contribute to the beneficial effects of moderate hyperoxia in patients with TBI and evacuated mass or post cardiac arrest.

There might be another interpretation of higher PaO₂ in patients with favorable neurological outcomes and in survivors. In the present study, the P/F ratio just before TTM on the 1st day was significantly higher in patients with favorable neurological outcomes and in survivors than in the other groups of patients as was PaO₂ (Table 3). The lower P/F ratio in patients with unfavorable neurological outcomes and in deceased patients may be caused by the presence of pulmonary edema and a low O₂ exchange capacity, which might be related to the elevated ICP (favorable vs. unfavorable neurological outcomes: 17.9 vs. 30.0 mm Hg; survivors vs. deceased patients: 18.3 vs. 37.8 mm Hg; Table 2) without a reduction in pulmonary ventilation, as indicated by PaCO₂ (favorable vs. unfavorable neurological outcomes: 37.6 vs. 35.4 mm Hg; survivors vs. deceased patients: 36.8 vs. 35.8 mmHg; Table 2). Although the AIS score of the chest was not significantly different between patients with favorable and those with unfavorable neurological outcomes or between survivors and deceased patients, it was reported that acute lung injury might be caused by TBI,^23

–26 or by an abrupt and extreme increase in ICP.^25,26 In the present study, the mean P/F ratio was lowest in deceased patients (370 ± 141; Table 3) and P/F ratio on the second and the fourth hospital days was not significantly different between patients with favorable and those with unfavorable outcome or between survivors and deceased patients, respectively (Tables S1 and S2) (see online supplementary material at http://www.liebertpub.com).

This suggests that there might be a small number of patients with acute lung injury caused by elevated ICP, and this might be one of the reasons that lower PaO₂ was observed in patients with unfavorable neurological outcomes and in deceased patients. However, this concern could not be resolved in this post-hoc analysis of the B-HYPO study. Therefore, prospective randomized trials are needed to verify the effects of hyperoxia on the outcomes of patients with severe TBI and to measure regional brain tissue oxygen tension around the occupied lesion such as subdural hematoma.

In the present study, PaO₂ in patients with unfavorable neurological outcomes and deceased patients was also higher than the normal range (Table 3). In the B-HYPO study, the total rates of poor outcome and mortality were 51.4% and 31.0%, respectively.¹³ These rates were similar to the results of other RCTs.^27,28 However, it was still unclear whether hyperoxia itself caused harm to the patients with severe TBI or not. Accordingly, this is one of the subjects to be resolved in the future study.

There are some limitations to the present study. First, PaO₂ was recorded just before the start of TTM on the first hospital day, which limits the number of recorded values, although the physiological parameters, including blood gases, had been stabilized to their best levels at that time. Second, the definition of hyperoxia differed among researchers. Brenner and coworkers evaluated hyperoxia and determined the average PaO₂ over 24 h after hospital admission.¹¹ Davis and coworkers defined hyperoxia as PaO₂ of >487 mm Hg.¹² Third, because we conducted post-hoc analyses of the B-HYPO study,¹³ prospective randomized trials are needed to verify the effects of hyperoxia on the outcomes of patients with severe TBI.

Conclusion

In conclusion, early-stage hyperoxia was associated with favorable neurological outcomes and survival without harmful effects in patients with severe TBI. Prospective studies are needed to verify the effects of hyperoxia and the optimal duration of hyperoxia in the context of improving neurological outcomes.

Footnotes

Acknowledgments

This study was supported by research project grants from the Japanese Ministry of Health, Labor and Welfare (H-14-shinkin-005, H-15-shinkin-001, and H-16-shinkin-001) and by the Japanese Human Science Association, 2002–2004.

Author Disclosure Statement

This study was conducted under financial support from the Japanese Ministry of Health, Labor and Welfare and the Japanese Human Science Association. These agencies were not involved in any decisions related to study design or publication of the results. No competing financial interests exist.

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Supplementary Material

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Early-Stage Hyperoxia Is Associated with Favorable Neurological Outcomes and Survival after Severe Traumatic Brain Injury: A Post-Hoc Analysis of the Brain Hypothermia Study

Abstract

Introduction

Methods

Patients

Treatments and neurological outcomes

Data collection and study outcomes

Statistical analysis

Results

Patient characteristics

PaO2 and P/F ratio on the first day in patients with severe TBI

Factors associated with favorable neurological outcomes and survival

Discussion

Conclusion

Footnotes

Acknowledgments

Author Disclosure Statement

References

Supplementary Material

PaO₂ and P/F ratio on the first day in patients with severe TBI