Normobaric Hyperoxia in Patients With Acute Stroke: Enhancing Neuroprotection Through Inhibition of Inflammation

Abstract

Background

Inflammatory response is an important pathological and physiological mechanism in the occurrence and development of acute ischemic stroke. This study investigated the effects of normobaric hyperoxia on the inflammatory response in acute ischemic stroke and explored the role of inflammation in stroke‐induced brain injury.

Methods

This secondary analysis of the OPENS (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke) trial, included 86 acute ischemic stroke patients with anterior circulation large vessel occlusion: 43 received normobaric hyperoxia (10 L/min, 100% oxygen for 4 hours) with endovascular thrombectomy, and 43 received endovascular thrombectomy alone. Inflammatory markers were measured at different time points (admission, 24 hours, 7 days), and National Institutes of Health Stroke Scale score and cerebral infarction volume were also recorded. The main outcome measures were serum CRP (C‐reactive protein) levels, peripheral blood leukocyte count, neutrophil count, and neutrophil‐to‐lymphocyte ratio. Correlation analysis was used to analyze the relationship between inflammatory markers and stroke.

Results

The results showed that the normobaric hyperoxia group had significantly lower levels of inflammatory markers compared with the control group at 24 hours (P<0.05). Early correlation analysis (within 24 hours) showed a significant positive association between 24‐hour inflammatory marker levels and early neurological function scores (National Institutes of Health Stroke Scale) as well as early infarct volume (assessed at 24–48 hours).

Conclusions

Normobaric hyperoxia attenuates early postthrombectomy inflammation, as evidenced by reduced CRP, neutrophil counts, and neutrophil‐to‐lymphocyte ratio. These inflammation markers were significantly associated with acute stroke severity and infarct volume.

Registration

URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03620370.

Nonstandard Abbreviations and Acronyms

AIS

acute ischemic stroke

EVT

endovascular thrombectomy

NBO

normobaric hyperoxia

NIHSS

National Institutes of Health Stroke

NLR

neutrophil‐to‐lymphocyte ratio

OPENS

Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke

Clinical Perspective.

What Is New?

• Adjunctive normobaric hyperoxia therapy significantly attenuates early inflammation (CRP [C‐reactive protein], neutrophils, neutrophil‐to‐lymphocyte ratio) after endovascular thrombectomy, revealing a novel neuroprotective mechanism and a distinct time‐dependent rise in CRP peaking at 24 hours.

• Higher levels of these inflammatory markers (CRP, neutrophil‐to‐lymphocyte ratio) are correlated with increased stroke severity and larger infarct volume.

What Are the Clinical Implications?

• Normobaric hyperoxia represents a safe, low‐cost adjunct therapy that may improve outcomes by reducing inflammation, with CRP and neutrophil‐to‐lymphocyte ratio serving as practical biomarkers for clinical monitoring.

Acute ischemic stroke (AIS) is a serious health condition that has become the leading cause of morbidity and death, particularly in China, due to the aging population. ¹ Although the advent of thrombolysis and endovascular treatment has significantly improved the prognosis of AIS, there is still a considerable gap in achieving desired outcomes. ² , ³ Therefore, it is crucial for researchers to continue exploring the pathogenesis of AIS and develop targeted therapeutic approaches based on specific injury mechanisms. Current studies highlight the key role of inflammatory responses in the pathophysiology of brain injury in acute ischemic stroke. ⁴ , ⁵ White blood cells, particularly neutrophils, play a central role in the inflammatory response, with CRP (C‐reactive protein) as a prominent inflammatory marker. Inflammation leads to an elevation in peripheral blood leukocyte count and subsequent leukocyte infiltration, exacerbating local tissue accumulation and intensifying brain tissue damage. ⁶ CRP, a significant marker of acute stress response, demonstrates a rapid surge in serum concentration during tissue injury, ischemia, and hypoxia, reflecting the severity of damage. ⁷ Multiple studies have demonstrated that serum CRP levels and peripheral blood leukocyte counts, especially neutrophil counts, increase in patients with AIS, and these inflammatory markers are closely associated with the severity and prognosis of AIS. ⁸ , ⁹ , ¹⁰ However, the inflammatory response following endovascular thrombectomy in patients with stroke remains unclear, as some reports suggest that the procedure itself can lead to vascular endothelial injury and inflammation. ¹¹ This study aims to investigate the levels of serum CRP and the elevation of peripheral blood leukocytes and neutrophils in patients undergoing endovascular thrombectomy, while also exploring the potential for normobaric oxygen (NBO) treatment to alleviate the inflammatory response in these patients. The findings of this study will provide crucial theoretical evidence regarding the neuroprotective role of NBO in AIS and offer strong support for its clinical application.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Design

The data for this study came from the OPENS (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke) trial. The study design and main outcomes, including efficacy and safety evaluations, have been previously published. ¹² The OPENS trial was a single‐center randomized controlled study that included 86 patients with acute anterior circulation large‐vessel occlusion who underwent endovascular thrombectomy between 2018 and 2019 at the emergency stroke center of Xuanwu Hospital. These patients were randomly assigned to the NBO group or the control group. Patients in the NBO group received immediate oxygen inhalation via a nonrebreather mask at a flow rate of 10 L/min with 100% oxygen for 4 hours, while the control group received room air inhalation. Following randomization, NBO was promptly initiated in the emergency department and maintained for 4 consecutive hours. This duration comprehensively encompassed the preprocedure, intraprocedure, and postprocedure phases of endovascular thrombectomy (EVT).

Study Protocol Approval, Clinical Registration, and Informed Consent

The OPENS study protocol and all data collection were approved by the Ethics Committee of Xuanwu Hospital, and informed consent was obtained from all patients before the start of the study. The trial was registered at http://www.clinicaltrials.gov, with the registration number NCT03620370.

Inclusion and Exclusion Criteria

To be eligible for participation in the study, patients had to meet the inclusion and exclusion criteria specified in the OPENS‐1 study. Specifically, they needed to have indications for EVT for acute large‐vessel occlusion in the anterior circulation, as well as indications for oxygen therapy. Additionally, they had to provide written consent to join the study and cooperate in completing the follow‐up procedures.

Study Treatment Strategy

All patients were randomly assigned to groups at a ratio of 1:1, divided into the NBO combined with EVT group (NBO+EVT group) and the pure EVT group. Patients enrolled in the NBO+EVT group immediately received oxygen inhalation through an oxygen reservoir mask with the oxygen flow rate set at 10 L/min. They continued to inhale oxygen for 4 hours and received EVT treatment simultaneously. Patients in the pure EVT group, on the other hand, inhaled room air and underwent EVT treatment concurrently. Except for the difference in the oxygen inhalation protocol, all other intervention measures were the same for the 2 groups. The oxygen inhalation process for the NBO+EVT group spanned the entire process before, during, and after the EVT treatment.

Data Collection

Baseline Data

Age, sex, past medical history, stroke risk factors, Alberta Stroke Program Early Computed Tomography Score and National Institutes of Health Stroke Scale (NIHSS) score at admission were collected.

Clinical Assessment Data

Clinical evaluation data included NIHSS score at 24 hours and 7 days, cerebral infarction volume at 24 to 48 hours, and other important clinical indicators.

Blood Sample Data Collection

We collected baseline, 24‐hour, and 7‐day serum CRP levels. The specific detection method involved extracting 2 mL of venous blood from patients at different time points according to the OPENS study protocol. The blood samples were left to stand at room temperature for 2 hours and then centrifuged. The supernatant was aliquoted into Eppendorf tubes and stored at −80 °C until serum testing. The centrifuge parameters were set at 3000 rpm, 145 000g, and 10 minutes. The serum CRP levels were measured using a commercially available ELISA kit (USCN, Wuhan, China). We collected baseline and 24‐hour peripheral blood cell counts. We obtained venous blood samples using EDTA anticoagulant tubes at patient admission and 24 hours after enrollment. The samples were analyzed in the Xuanwu Hospital Hematology Laboratory using a whole blood cell automatic counter to obtain white blood cell count, neutrophil count, and the neutrophil‐to‐lymphocyte ratio (NLR).

The mean follow‐up values of inflammatory markers were designated as the primary analysis. Additionally, 24‐hour inflammatory marker changes from baseline were also documented.

Clinical Outcome Assessment

The primary end point measure recorded according to the OPENS study protocol was the 24‐ to 48‐hour infarction volume. Cerebral infarction volume was calculated using magnetic resonance/diffusion‐weighted imaging. The appropriate window level, window width, and infarction edge were defined to accurately delineate the contours of each infarct. The total infarct volume was calculated by summing the volumes of the infarcts in each slice. Two independent physicians assessed the infarct volume in a blinded manner to eliminate bias. Infarct volume ≥30 mL was classified as moderate to large cerebral infarction, while infarct volume <30 mL was considered small‐area cerebral infarction. Neurological function scores at baseline and 24 hours were also collected. These scores were evaluated by trained neurologists who were unaware of the interventions. Two physicians reviewed the data to ensure accuracy. The disease was classified according to the NIHSS score, with a score≥10 indicating severe stroke and a score<10 indicating mild stroke.

Statistical Analysis

The statistical analysis was conducted using SPSS 26.0 software (IBM Corp., Armonk, NY). Continuous data were presented as mean±SD, while nonnormally distributed data were presented as median with interquartile range (IQR). The Mann–Whitney U test and linear regression analysis were used to compare the levels of serum CRP, peripheral blood leukocyte count, neutrophil count, and NLR between the NBO group and the control group. After conducting a multiple linear regression analysis with adjustment for age, sex, baseline NIHSS, intravenous thrombolysis use, and occluded vessel location, the adjusted regression coefficient (B value) and its 95% CI were derived. Pearson correlation analysis was performed to assess the correlation between serum CRP levels, peripheral blood leukocyte count, neutrophil count, NLR, NIHSS score, and infarction volume. As a secondary analysis, receiver operating characteristic curves were used to explore and describe the trend of the relationship between markers and disease severity/infarct volume, and their cutoff values were for reference only. Optimal cutoffs were determined by maximizing Youden’s index. A P value <0.05 was considered statistically significant.

Results

Baseline Characteristics

A total of 86 patients were included in the study, with 43 in the NBO group and 43 in the control group. The mean age was 62.0±11.7 years in the NBO group, with 31 men and 12 women, and 64.0±9.9 years in the control group, with 29 men and 14 women. The baseline characteristics of the 2 groups were described in detail in our previous study. ¹²

NBO Significantly Reduces Serum CRP Levels in Patients Undergoing Thrombectomy

We found no significant difference in baseline serum CRP levels between the 2 groups (6.68 [IQR, 3.47–12.99] versus 6.84 [IQR, 3.12–12.97], P=0.122). However, at 24 hours, the NBO group had significantly lower levels compared with the control group (7.77 [IQR, 4.35–14.57] versus 10.93 [IQR, 5.67–22.95]; adjusted value, −8.81 [95% CI, −16.11 to −1.52]; P=0.019). Interestingly, the difference in serum CRP levels from baseline to 24 hours was significantly lower in the NBO group compared with the control group (1.57 [IQR, 0.46–3.07] versus 2.92 [IQR, 1.14–7.16]; adjusted value, −5.99 [95% CI, −10.07 to −1.92]; P=0.005). However, at 7 days, there was no significant difference in serum CRP levels between the 2 groups (4.78 [IQR, 2.45–8.73] versus 5.61 [IQR, 2.12–9.73]; P=0.306). Additionally, found that serum CRP levels gradually increased over time, reaching the highest detected level at 24 hours during this study, and then gradually decreased to normal levels (Table 1, Figure 1).

Table 1.

Comparison in Serum CRP Levels and Peripheral WBC Counts Between the 2 Groups

Variable	NBO+EVT group (n=43)	EVT group (n=43)	Adjusted value (95% CI)‡	P value
Serum CRP levels (mg/L)
Baseline (IQR)	6.68 (3.47 to 12.99)	6.84 (3.12 to 12.97)	−2.82 (−6.41 to 0.77)	0.122
24 h after randomization (IQR)	7.77 (4.35 to 14.57)	10.93 (5.67 to 22.95)	−8.81 (−16.11 to −1.52)	0.019
Serum CRP levels shift* (IQR)	1.57 (0.46 to 3.07)	2.92 (1.14 to 7.16)	−5.99 (−10.07 to −1.92)	0.005
7 d after randomization (IQR)	4.78 (2.45 to 8.73)	5.61 (2.12 to 9.73)	−1.27 (−3.71 to 1.18)	0.306
WBC counts (109/L)
Baseline (IQR)	7.59 (6.45 to 8.98)	7.63 (6.70 to 9.18)	−0.33 (−1.25 to 0.60)	0.481
24 h after randomization (IQR)	8.43 (7.21 to 9.62)	9.07 (8.17 to 11.36)	−0.98 (−2.25 to 0.28)	0.125
WBC counts shift† (IQR)	0.96 (0.76 to 1.73)	1.49 (1.06 to 2.62)	−0.68 (−1.19 to −0.18)	0.009
Neutrophil count (109/L)
Baseline (IQR)	5.48 (4.68 to 7.04)	5.92 (4.82 to 7.63)	−9.86 (−2.18 to 0.45)	0.194
24 h after randomization (IQR)	6.63 (5.76 to 8.55)	7.88 (6.73 to 10.42)	5.69 (5.11 to 6.26)	< 0.001
NLR
Baseline (IQR)	7.87 (5.33 to 10.20)	8.54 (4 to 12.89)	−1.73 (−3.88 to 0.42)	0.113
24 h after randomization (IQR)	9.12 (6.26 to 12.05)	11.00 (9.28 to 14.88)	−2.64 (−5.27 to −0.02)	0.042

Data are expressed as median and interquartile range. CRP indicates C‐reactive protein; EVT, endovascular thrombectomy; IQR, interquartile range; NBO, normobaric hyperoxia; NLR, neutrophil‐to‐lymphocyte ratio; and WBC, white blood cell.

^*Serum CRP level shift was equal to the difference between the 24‐h serum CRP levels and the baseline serum CRP levels at admission.

^† WBC counts shift was equal to 24‐h WBC counts minus baseline WBC counts.

^‡ Adjusted for age, sex, baseline National Institutes of Health Stroke Scale, intravenous thrombolysis use, and occluded vessel location.

Figure 1. Serum CRP levels within 1 week.

The findings revealed a time‐dependent increase in serum CRP levels, peaking at 24 hours and subsequently declining toward normal levels. At the 24‐hour mark, the NBO+EVT group exhibited significantly lower serum CRP levels compared with the EVT group (7.77 [4.35–14.57] vs 10.93 [5.67–22.95], P=0.019). CRP indicates C‐reactive protein; EVT, endovascular thrombectomy; and NBO, normobaric hyperoxia.

NBO Significantly Reduces Peripheral Blood Leukocyte Count, Neutrophil Count, and NLR in Patients Undergoing Thrombectomy

Peripheral blood results showed that at baseline, both groups had leukocyte count, neutrophil count, and NLR levels above the normal range, but there was no significant difference between the 2 groups. However, at 24 hours, there were significant differences in neutrophil count (6.63 [IQR, 5.76–8.55] versus 7.88 [IQR, 6.73–10.42]; adjusted value, 5.69 [95% CI, 5.11–6.26]; P<0.001) and NLR (9.12 [IQR, 6.26–12.05] versus 11.00 [IQR, 9.28–14.88]; adjusted value, −2.64 [95% CI, −5.27 to −0.02]; P=0.042) between the 2 groups, while there was no significant difference in leukocyte count (P>0.05). Notably, we observed that the difference in 24‐hour white blood cell count from baseline was significantly lower in the NBO group compared with the control group (0.96 [IQR, 0.76–1.73] versus 1.49 [IQR, 1.06–2.62]; adjusted value, −0.68 [95% CI, −1.19 to −0.18]; P=0.009), see Table 1.

Correlation of Inflammatory Markers With Neurological Scores and Infarct Volume

To evaluate the relationship between inflammatory markers and clinical outcomes, Pearson correlation analysis revealed significant positive associations (all P<0.001). Both 24‐hour serum CRP levels and CRP changes from baseline showed strong correlations with 24‐hour NIHSS scores (r=0.6, r=0.528), NIHSS score changes (r=0.636, r=0.634), and 24‐ to 48‐hour infarct volumes (r=0.681, r=0.581). Similarly, 24‐hour white blood cell counts, neutrophil counts, and NLR values demonstrated consistent positive correlations with these clinical parameters (range, r=0.342–0.597), with neutrophil counts showing the strongest associations. Detailed correlation coefficients and significance levels are presented in Table 2.

Table 2.

Pearson Correlation Analysis of CRP, WBC Counts, Neutrophil Counts, NLR, and 24 Hours NIHSS Scores or Infarct Volume in Included Patients (n=86)

Variable	24‐h NIHSS		△NIHSS*		Infarct volume
	r value	P value	r value	P value	r value	P value
24‐h CRP	0.6	<0.001	0.636	<0.001	0.681	<0.001
CRP shift	0.528	<0.001	0.634	<0.001	0.581	<0.001
24‐h WBC counts	0.413	<0.001	0.342	<0.001	0.534	<0.001
24‐h neutrophil counts	0.511	<0.001	0.47	<0.001	0.597	<0.001
24 h‐NLR	0.591	<0.001	0.424	<0.001	0.513	<0.001

CRP indicates C‐reactive protein; NIHSS, National Institutes of Health Stroke Scale; NLR, neutrophil‐to‐lymphocyte ratio; and WBC, white blood cell.

^*△NIHSS means change in NIHSS score from baseline to 24 h.

The Correlation Between Serum CRP and Peripheral White Blood Cell Count, Neutrophil Count, and NLR

This study further revealed that serum CRP levels exhibited a significant positive correlation with peripheral white blood cell count (r=0.582, P<0.001), neutrophil count (r=0.61, P<0.001), and NLR (r=0.539, P<0.001), as depicted in Figure 2.

Figure 2. The correlation between serum CRP and peripheral blood white blood cell count, neutrophil count, and NLR.

The results showed that serum CRP levels were significantly correlated with peripheral white blood cell count (A) (r=0.582, P<0.001, neutrophil count (B) (r=0.61, P<0.001), and NLR (C) r=0.539, P<0.001). CRP indicates C‐reactive protein; and NLR, neutrophil‐to‐lymphocyte ratio.

Exploratory Analysis

Receiver operating characteristic analysis showed that 24‐hour CRP >8.85 mg/L and 24‐hour NLR >9.32 were associated with 24‐hour disease severity (NIHSS ≥10) at 24 hours after a stroke (area under the curve=0.86 [95% CI, 0.77–0.94]; P<0.001; area under the curve=0.69 [95% CI, 0.55–0.83]; P=0.017), while 24‐hour CRP >9.4 mg/L and 24‐hour NLR >11.2 were associated with moderate to large infarctions (infarct volume ≥30 mL) at 24 to 48 hours after a stroke (area under the curve=0.76 [95% CI, 0.64–0.88]; P=0.001; AUC=0.77 [95% CI, 0.64–0.91]; P=0.001). These exploratory results require further validation (Figures S1 and S2).

Discussion

The study presents preliminary data on the short‐term effects of NBO on inflammatory markers. It provides compelling evidence that in patients with stroke undergoing thrombectomy, administration of NBO is associated with significant reductions in serum CRP, peripheral neutrophil count, NLR, and total white blood cell count within 24 hours. The study revealed dynamic changes in serum CRP levels over time and establishes a correlation between 24‐hour serum CRP levels, peripheral blood white blood cell count, neutrophil count, NLR, and 24‐ to 48‐hour NIHSS scores and infarct volume. Moreover, Pearson analysis revealed that these markers were significantly correlated with neurological deficits and infarct volume, which provides evidence for NBO improving prognosis through anti‐inflammatory mechanisms.

Ischemic Stroke and Inflammatory Response

In recent years, growing evidence has highlighted the crucial role of the inflammatory response in cerebral ischemic injury. ¹³ Neutrophils, in particular, have been implicated in promoting postischemic inflammation. They contribute to tissue perfusion limitation by causing vascular occlusion, releasing matrix metalloproteinases that disrupt the blood–brain barrier, and generating reactive oxygen species. ¹⁴ , ¹⁵ , ¹⁶ It is important to note that this inflammatory response is not limited to the initial ischemic injury but can also be exacerbated in patients undergoing mechanical thrombectomy due to the endothelial damage caused by the procedure.

Several studies have shown that the peak white blood cell count is closely associated with stroke volume and clinical outcomes at 12 months in patients who did not receive endovascular treatment. ¹⁷ Likewise, a study by Huber et al demonstrated that elevated white blood cell count and serum CRP levels can serve as indicators for evaluating outcomes after thrombectomy. ¹⁸ Our study aligns with these findings, as we observed a strong correlation between serum CRP levels, white blood cell count, and infarct volume. Moreover, we found an even stronger correlation between neutrophil count and NLR and clinical outcomes, suggesting that these factors may be more sensitive predictors of prognosis. These findings established threshold values for serum CRP, white blood cell count, neutrophil count, and NLR, which can provide a rough assessment of disease severity and infarct volume. This further enhances the quantification of clinical outcome evaluations.

Time Dependence of the Inflammatory Response

The timing of recanalization after cerebral ischemia is a well‐established independent risk factor for clinical outcomes following thrombectomy. ¹⁹ Moreover, the inflammatory response following cerebral ischemia is known to be time‐dependent, with different stages of ischemia potentially reflected by varying white blood cell counts. However, Huber’s study did not find a correlation between the duration of cerebral ischemia treatment and the initial white blood cell count. ¹⁸ In our study, we observed a significant increase in neutrophil count at 24 hours compared with baseline. Unfortunately, we did not assess the neutrophil count between 48 and 72 hours, which is typically when neutrophils reach their peak and rapidly decline in most models. ¹³ Nonetheless, we did observe changes in serum CRP, an inflammatory marker, at different time points. Serum CRP levels increased from baseline, peaked at 24 hours, and returned to normal levels by 1 week. These dynamic changes reflect the progression of cerebral ischemic injury within the first week.

Mechanisms of Oxygen Therapy in Inhibiting the Inflammatory Response

The use of anti‐inflammatory strategies in the treatment of ischemic stroke is promising because they have a wider therapeutic window compared with current reperfusion strategies. ¹³ Animal studies suggest that interventions aimed at reducing leukocyte infiltration may have a beneficial effect in mitigating the progression of ischemic brain injury. However, clinical trials using antileukocyte drugs have not shown significant benefits. ²⁰ At present, there are limited reports on the effects of oxygen therapy on the inflammatory response. Benson’s study demonstrated that 90 minutes of hyperbaric oxygen treatment inhibited the synthesis of interleukin‐l. The study concluded that hyperbaric oxygen exposure transiently suppresses stimulus‐induced proinflammatory cytokine production and steady‐state RNA levels. ²¹ Current studies have shown that various cytokines could upregulate the expression of matrix metalloproteinase‐9 during the inflammatory response. However, matrix metalloproteinase‐9 not only appears as a downstream product of the inflammatory response, but also plays a positive feedback role on many proinflammatory factors. It acts as an important “regulator” of the inflammatory response. Our preliminary experiments indicate that NBO protects the blood–brain barrier by reducing the matrix metalloproteinase‐9–occludin pathway. ²² This suggests that NBO may have an inhibitory effect on the inflammatory response. This study demonstrated that NBO can reduce the peripheral blood white blood cell count, neutrophil count, NLR, and serum CRP levels in patients undergoing thrombectomy. This clinical evidence provides direct validation of the role of NBO in inhibiting the inflammatory response and establishes a foundation for understanding the neuroprotective effects of NBO through its anti‐inflammatory properties. However, further research is necessary to confirm the specific mechanisms by which NBO inhibits the inflammatory response from various perspectives.

Study Limitations

This study has several limitations that should be acknowledged. First, the sample size was small, and the study was conducted at a single center, which may introduce bias and limit the generalizability of the findings. Second, inflammatory marker assessment was restricted to 24 hours with limited markers, hindering precise prognostic threshold determination. Expanding to 48‐/72‐hour time points and broader marker panels would enhance comprehensiveness. Third, unmonitored infection‐related events (eg, pneumonia, urinary tract infections) could confound inflammatory marker interpretations, necessitating systematic infection surveillance in future trials. Notably, the absence of long‐term follow‐up data (eg, modified Rankin Scale scores) limits clinical relevance evaluation. While early CRP/NLR reductions suggest anti‐inflammatory effects, their association with functional outcomes remains unclear. Future studies should prioritize long‐term neurological recovery and patient‐centered outcomes to bridge mechanistic findings with clinical benefit. Finally, the receiver operating characteristic analyses conducted were used solely to generate research hypotheses. Due to the limitation of sample size, their performance is insufficient to support the development of predictive models. Meanwhile, cross‐validation was not performed, also due to sample size constraints. Therefore, these research findings still need to be further validated in larger‐scale cohort studies.

Clinical Application and Future Research Directions

The identification of CRP, neutrophil count, and NLR as early prognostic markers informs clinical practice by enabling risk stratification. Integration of these biomarkers into acute stroke triage protocols could identify high‐risk patients for enhanced monitoring or tailored interventions. For example, CRP >8.85 mg/L or NLR >9.32 at 24 hours after EVT may predict severe neurological deficits or large infarcts, prompting early anti‐inflammatory or neuroprotective strategies aligned with precision medicine.

NBO’s anti‐inflammatory effects position it as a low‐cost adjunct to EVT, particularly in resource‐limited settings. Prioritizing NBO for patients with elevated baseline inflammation may mitigate secondary injury. Future trials should explore biomarker‐tailored NBO protocols (eg, adjusting oxygen duration/flow on the basis of serial CRP/NLR) to optimize efficacy.

Translating Findings Into Patient Management

Incorporating inflammatory biomarkers into clinical workflows could revolutionize post‐EVT care:

1. Early risk stratification: Electronic health records may integrate CRP/NLR thresholds to alert clinicians for high‐risk patients, facilitating timely rehabilitation or secondary prevention.

2. Therapeutic decision making: Patients exceeding biomarker cutoffs may benefit from combined NBO and immunomodulatory agents (eg, interleukin‐1 inhibitors), a hypothesis warranting validation in randomized controlled trials.

3 Resource allocation: In settings with limited neuroimaging, CRP/NLR could serve as surrogate markers for infarct volume, guiding bed allocation or interhospital transfer decisions.

Future Research Directions

While this study establishes proof of concept, critical steps are needed for clinical translation:

1. Multicenter validation: Prospective studies in diverse, large cohorts are essential to confirm generalizability, including long‐term outcome associations (eg, 90‐day modified Rankin Scale).

2. Mechanistic exploration: Elucidating NBO’s effects on specific inflammatory pathways (eg, neutrophil extracellular traps, cytokine networks) will refine its role in neuroprotection.

3. Combination therapies: Trials evaluating NBO alongside targeted anti‐inflammatory drugs (eg, colchicine, canakinumab) may enhance neuroprotection and reduce reperfusion injury.

These priorities bridge inflammation and stroke care, advancing evidence‐based, personalized postthrombectomy strategies.

Conclusions

In conclusion, our study provides evidence that NBO may effectively reduce the inflammatory response in patients with acute ischemic stroke undergoing thrombectomy. This is supported by the significant reductions in serum CRP levels, peripheral blood white blood cell count, neutrophil count, and NLR. The inflammatory response mitigation by NBO may represent a key mechanism underlying its neuroprotective effect.

Sources of Funding

This work was partially supported by grants from National Natural Science Foundation of China (82360783); the Natural Science Foundation of Shandong Province, China (ZR2024MH081); 2025 Gansu Provincial Support Program for Young Doctors in Universities (25CXGA097); and 2025 Gansu Province Science and Technology Program Funding Project (2025QB‐009).

Disclosures

None.

Supporting information

Figures S1–S2