Efficacy of hyperbaric oxygen combined with dual antiplatelet therapy in elderly patients with acute cerebral infarction and its impact on nerve factors

Abstract

Objective

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We aimed to ascertain the efficacy of hyperbaric oxygen therapy (HBOT) combined with dual antiplatelet therapy (DAPT) in elderly patients with acute cerebral infarction (ACI) and its impact on nerve factors.

Methods

A total of 122 patients were randomly assigned (1:1) to either the observation group or the control group. Patients in the control group received DAPT, And those in the observation group received HBOT combined with DAPT. Treatment was administered in 3 consecutive daily sessions starting from the date of admission. All patients were evaluated for efficacy after treatment. Before and after treatment, the National Institutes of Health Stroke Scale (NIHSS), and the Chinese Stroke Scale (CSS) were assessed; the levels of serum neuron-specific enolase (NSE) and plasma β-amyloid-42 (Aβ-42), hemorheology indices (whole blood viscosity and plasma viscosity), coagulation indicators [activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and fibrinogen (Fbg)], and inflammatory factor [matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and C-reactive protein (CRP)] were measured; the Barthel Index (BI) scores were recorded.

Results

After treatment, the observation group exhibited higher total effective rate, longer APTT, PT and TT, and higher BI score compared to the control group (all P < 0.05), while lower NIHSS, CSS scores, lower levels of NSE, Aβ-42, and Fbg, lower whole blood viscosity, plasma viscosity, MMP-9, IL-6 and CRP compared to the control group (all P < 0.05).

Conclusion

HBOT combined with DAPT can enhance efficacy, ameliorate neurologic impairments, enhance the effect of thrombolysis, reduce inflammatory response, and improve activities of daily living in elderly patients with ACI.

Introduction

Acute cerebral infarction (ACI), a subtype of cerebrovascular accident, results from abrupt arterial narrowing or complete blockage within the cerebral vasculature, precipitating hypoperfusion of brain tissue and subsequent neuronal injury due to oxygen-glucose deprivation [1]. This pathophysiological cascade may culminate in irreversible cerebral ischemia, severe neurological deficits, or even mortality [1]. Globally, the prevalence of cerebral infarction exceeds 50 million cases, with approximately 45% of survivors experiencing persistent disability, including motor dysfunction, cognitive decline, or aphasia [1]. The current therapeutic approach for ACI primarily focuses on symptomatic management, including volume expansion, intracranial pressure reduction, anticoagulation therapy, and management of underlying comorbidities [2]. However, evolving lifestyle patterns have contributed to increasingly complex and multifactorial ACI pathogenesis, rendering conventional treatment strategies progressively less effective [2].

Currently, thrombolysis and antiplatelet aggregation therapy are commonly employed in the management of ACI. Promoting neurological recovery is a critical therapeutic objective for ACI patients [2]. Globally, the most frequently prescribed antiplatelet agents include low-dose aspirin, clopidogrel, and dipyridamole [3]. The standard dual antiplatelet therapy (DAPT) regimen for ACI involves aspirin combined with clopidogrel [2]. Compared to monotherapy, DAPT more effectively prevents secondary ischemic stroke when administered for < 90 days [4]. Intensified DAPT may represent a promising strategy for reducing recurrent cerebral infarction risk following cerebrovascular interventions [5]. However, while DAPT may offer superior efficacy in stroke prevention among elderly populations, it is also associated with an elevated risk of bleeding complications [6]. Age-related factors can alter the risk-benefit balance of therapeutic approaches, with older adults generally exhibiting heightened susceptibility to adverse effects of antithrombotic agents [7].

As a non-invasive therapeutic modality, hyperbaric oxygen therapy (HBOT) has shown considerable promise in the management of ACI [8]. HBOT is a Mature therapy for the treatment of a wide range of diseases. It is the inhalation of 100% oxygen in a pressure vessel at a pressure higher versus atmospheric pressure (1 atmosphere absolute = 101 kPa). In general, treatment is implemented at a pressure of 202 kPa to 282.8 kPa for 1 to 2 h per day, depending on the indication [9]. By creating a hyperbaric, oxygen-enriched environment, HBOT effectively elevates plasma-dissolved oxygen levels and arterial oxygen partial pressure [10]. Recently, it has been adopted to ameliorate cognition, quality of life and neurological health after traumatic brain injury and stroke [11]. This has opened up new ways for older adults, including the therapy of neurological and neurodegenerative disorders, as well as enhancing brain metabolism and cognition in patients with mild cognitive impairment [11]. Data available indicate that HBO serves as a feasible therapeutic option for brain injury [12, 13] and plays a role in neuroprotection [14]. However, current research on the synergistic effects and underlying mechanisms of combined HBOT and DAPT remains limited, underscoring the novelty of this study. DAPT inhibits platelet aggregation and reduces thrombotic risk through the synergistic action of aspirin and P2Y12 receptor antagonists (e.g., clopidogrel) [15], thereby mitigating recurrent cerebral infarction. Nevertheless, DAPT does not directly address oxygen deprivation in ischemic regions. HBOT, by elevating arterial oxygen partial pressure and enhancing oxygen diffusion and utilization in tissues and cells, alleviates tissue hypoxia [16]. For stroke patients, the hyperbaric conditions of HBOT maximize oxygen delivery to compromised brain regions [16]. Given these mechanisms, the combined use of HBOT and DAPT in elderly patients with ACI may yield synergistic therapeutic benefits. This study aims to investigate the efficacy of HBOT combined with DAPT in elderly patients with ACI. We hypothesize that this combination therapy will enhance neurological recovery, augment thrombolytic efficacy, and improve daily living activities in this population.

Materials and methods

Ethics statement

The study was approved by the Ethics Committee of Cangzhou Central Hospital (approval number: 2023-138-02), and followed the tenets of the Declaration of Helsinki. All patients were aware of the study content and volunteered to participate.

Trial design

This study was a randomized controlled trial designed to evaluate the efficacy of HBOT combined with DAPT in elderly patients with ACI and its impact on nerve factors.

Recruitment

The elderly patients with ACI admitted to the Department of Neurology of Cangzhou Central Hospital from June 2023 to December 2024 were recruited. Individuals were eligible to participate in the study after meeting all of the following inclusion criteria: ① patients who met the diagnostic criteria of Chinese guidelines for the diagnosis And treatment of acute ischemic stroke 2018 [17]; ② those aged ≥ 60 years old; ③ those with the first onset of disease, and the onset of disease from the treatment time ≤ 72 h; ④ those who were conscious, with stabilized vital signs, And whose condition had not progressed within 48 h of hospitalization; and ⑤ those who had normal swallowing function and were capable of cooperating with the clinical treatment. The exclusion criteria were as follows: ① patients with cerebral infarction caused by rheumatic heart disease, metabolic disorder, tumor, parasites or trauma; ② those with severe abnormalities of renal and hepatic functions; ③ those with active bleeding, coagulation disorders and history of ulcers; ④ those who cannot tolerate HBOT or who were allergic to aspirin and clopidogrel; ⑤ those with incomplete clinical data or follow-up data.

Random grouping

Eligible subjects were randomly assigned to either the control group or the observation group at a 1:1 ratio using computer-generated random numbers produced by the Microsoft Excel ‘RAND’ function, ensuring equal distribution of patients between groups. The randomization sequence was sealed in sequentially numbered, opaque envelopes and stored in a double-locked cabinet. Randomization was conducted by an independent researcher not involved in enrollment. Following the assignment, envelopes were re-stored separately in the double-locked cabinet. Allocation concealment was maintained until trial completion.

Blind method

The individuals responsible for outcome assessment and data analysis remained unaware of the treatment assignments throughout the study. Specifically, the assessor input data into a Microsoft Excel spreadsheet after data collection had been completed, without any knowledge of which treatment group the data belonged to. Subsequently, all entered data were encoded with corresponding identifiers and stripped of any extraneous details. The blinding was only lifted after the data analysis had been finished.

Treatment methods

The control group received DAPT. Conventional treatments such as Lipid regulation, improvement of microcirculation, And nutrition of nerves were executed, And symptomatic treatment was given to patients with combined diabetes and hypertension. On this basis, patients were given aspirin 100 mg/d (Bayer HealthCare Co., Ltd., Beijing, China, batch number: BTA6040), clopidogrel 75 mg/d (Sanofi Pharmaceutical Co., Ltd., Hangzhou, China, batch number: 0904138).

The observation group was given DAPT combined with HBOT. On top of DAPT, patients were given HBOT [18], which was carried out in a large pressurized oxygen chamber with Mask oxygen inhalation, And the therapeutic pressure was set at 0.2 MPa. After entering the chamber, patients were pressurized for 15–20 min, and after stabilizing the pressure, they were given Mask inhalation of pure oxygen for 30 min, then rested for 10 min. Afterwards, patients were given Mask inhalation of pure oxygen for 30 min, And then left the chamber after 15–20 min of gradual decompression. The treatment was administered once daily, with each treatment session lasting 60 min of oxygen inhalation. A Full therapeutic course comprised 10 consecutive days of treatment (10 sessions). From the time of hospital admission, patients received a total of 3 complete courses, amounting to 30 HBOT sessions And 1,800 cumulative minutes of oxygen exposure.

Outcome measurement

Clinical efficacy

After the treatment, the efficacy judgment of both groups of patients was executed. Functional impairment was assessed using the “Clinical Neurological Deficit Scale” (revised by the Fourth National Academic Conference on Cerebrovascular Diseases in China) [19]. Clinical efficacy evaluation criteria: (1) basic cure: 91%−100% reduction in functional deficit score; (2) notable progress: 46%−90% reduction in functional deficit score; (3) progress: 18%−45% reduction in functional deficit score; (4) ineffectiveness: 0–17% reduction in functional deficit score. The clinical efficacy rate was calculated using the following formula: (number of “basic cure” patients + number of “notable progress” patients + number of “progress” patients)/total number of patients × 100% [20].

Patients’ neurologic impairment scores

The National Institutes of Health Stroke Scale (NIHSS) score [21] was employed to assess the neurologic impairments of the patients in both groups before And after treatment. The NIHSS score involved 11 assessment items: levels of gaze, visual field, consciousness, facial palsy, upper Limb And lower Limb locomotor ability, ataxia, sensation, speech, neglect, And dysarthria, with a total score of 42 points. The higher the score, the more severe the neurologic impairment. Before and after treatment, the China Stroke Scale (CSS) score [22] was adopted to test the neurologic impairments of both groups. The CSS score involved 8 items: level of consciousness, ability to gaze, facial palsy, speech, walking ability, upper Limb muscle strength, lower limb muscle strength And hand muscle strength, with a total score of 45 points. According to the score, the results were categorized into mild impairment (0–15 points), moderate impairment (16–30 points) and serious impairment (16–30 points), and the higher the score, the worse the neurological function and the more serious the condition.

Patient’s neurological function

Before and after treatment, the serum neuron-specific enolase (NSE) and β-amyloid-42 (Aβ−42) levels were compared in both groups. Peripheral venous blood (5 mL) was collected from each patient and distributed into tubes with or without anticoagulant. After centrifugation, supernatants were collected as serum or plasma. Serum NSE and plasma Aβ−42 levels were tested by the enzyme-linked immunosorbent assay (ELISA). The NSE kit was provided by Shanghai Jihe Biotechnology Co., Ltd. (Shanghai, China) and the Aβ−42 kit was provided by SenBeiJia Biological Technology Co., Ltd. (Nanjing, China). According to the instructions of the kits, the related operation was strictly implemented.

Patients’ hemorheology and coagulation function indices

Before and after treatment, the automatic hemorheological analyzer was applied to measure the changes in hemorheology indices, including whole blood viscosity and plasma viscosity in both groups; patients’ venous early morning fasting blood 5 mL was gathered; and CA-55 hemocoagulation instrument was employed. The coagulation method [23] was performed to test activated partial thrombin time (TT), prothrombin time (PT), and thromboplastin time (APTT), and the thrombin method was adopted to determine fibrinogen (Fbg).

Patients’ inflammatory factor levels

Before and after treatment, rerum inflammatory factor index levels were compared in both groups; patients’ fasting venous blood 5 mL was gathered from all patients, And centrifuged at 3000 g for 15 min at 4 ℃. The serum was separated, and ELISA was utilized to assess matrix metalloproteinase-9 (MMP-9), C-reactive protein (CRP), and interleukin-6 (IL-6). The reagents were provided by Ningbo MedicalSystem Biotechnology Co., Ltd. (Zhejiang, China). All the operations were implemented in strict conformity to the instructions of the reagents.

Patients’ recovery

The Barthel index (BI) was employed to assess the ability to implement activities of daily Living in both groups before And after treatment. The BI index scores were assessed as a total score of 0−100, with a score of > 60 regarded as good And with mild dysfunction, a score of 41–60 showing moderate dysfunction, a score of 21–40 indicating severe dysfunction, and a score of < 20 indicating total disability, with complete dependence on others for activities of daily living. The higher the score, the better the ability to implement activities of daily living.

Statistics

GraphPad Prism 6.0 software (Graph Pad Inc., La Jolla, CA, USA) And SPSS 24 software (IBM Corporation, Armonk, USA) were applied, and the experimental data were first assessed for normal and homogeneity of variance test. If the test was consistent with homogeneity of variance and normal distribution, the measurement data were exhibited as the mean ± standard deviation (± s), the Student’s t-test was measured for two-by-two comparisons, and the paired t-tests were implemented for comparisons of the same group before and after treatment. Numeration data were described as (%) and analyzed by the χ² test. Cohen’s d effect sizes were calculated. The test level was α = 0.05, and P < 0.05 was regarded as indicative of significant differences.

Results

Baseline characteristics of participants

A total of 155 patients were screened, And 33 patients were excluded. Finally, a total of 122 patients were included in the Full Analysis set. The 122 patients were randomly divided into the observation group (n = 61) and the control group (n = 61) (Fig. 1). Baseline characteristics were compared between groups, revealing no statistically significant differences (P > 0.05) in gender, age, or history of hypertension/diabetes mellitus (Table 1).

Fig. 1

A flowchart indicating study design

Table 1 Comparative analysis results of baseline characteristics between the two groups of patients [(± s), n (%)]

HBOT combined with DAPT can improve the efficacy of ACI in the elderly

The overall effective rate of clinical treatment of patients in the observation group was higher versus that of patients in the control group (P < 0.05) (OR = 0.335, 95% CI = 0.120 ~ 0.932) (Table 2), indicating that HBOT combined with DAPT in elderly patients with ACI has better efficacy.

Table 2 Comparative analysis results of therapeutic efficacy between the two groups of patients after treatment [n (%)]

HBOT combined with DAPT can reduce neurologic impairments in elderly patients with ACI

NIHSS, CSS scores and NSE, Aβ−42 levels were diminished in the two groups after treatment, and those in the observation group were lower versus those in the control group after treatment (P < 0.05) (NIHSS scores: Cohen’s d = 0.610, 95% CI = 1.211 ~ 4.658; CSS scores: Cohen’s d = 1.392, 95% CI = 4.565 ~ 7.730; NSE: Cohen’s d = 1.976, 95% CI = 4.298 ~ 6.203; Aβ−42: Cohen’s d = 2.297, 95% CI = 9.908 ~ 13.572) (Fig. 2), suggesting that HBOT combined with DAPT can ameliorate the patients’ conditions and facilitate the recovery of neurological function in elderly patients with ACI.

Fig. 2

Comparative analysis of NIHSS/CSS scores and NSE/Aβ−42 levels between the control group and observation group pre- and post-treatment. Note: A: Comparison of NIHSS scores between the two groups of patients before and after treatment; B: Comparison of CSS scores between the two groups of patients before and after treatment; C: Comparison of serum NSE levels between the two groups of patients before and after treatment; D: Comparison of serum Aβ−42 levels between the two groups of patients before and after treatment. CSS, Chinese Stroke Scale; NIHSS, National Institutes of Health Stroke Scale; NSE, Neuron-specific enolase; Aβ−42, β-amyloid-42

HBOT combined with DAPT in elderly patients with ACI has better thrombolytic effects

After treatment, APTT, PT, and TT of the two groups were higher in contrast with before treatment, and whole blood viscosity, plasma viscosity, and Fbg levels were lower versus before treatment (P < 0.05). After treatment, the observation group exhibited higher APTT, PT, and TT in comparison with the control group (APTT: Cohen’s d = −1.424, 95% CI = −3.586~−2.119; PT: Cohen’s d = −0.378, 95% CI = −0.942~−0.009; TT: Cohen’s d = −0.688, 95% CI = −3.829~−1.154) (Fig. 3CDE), and lower whole blood viscosity, plasma viscosity, and Fbg levels (whole blood viscosity: Cohen’s d = 1.247, 95% CI = 0.635 0.809; Fbg: Cohen’s d = 2.278, 95% CI = 1.042 ~ 1.427) compared with the control group (P < 0.05) (Fig. 3ABF), implying that HBOT combined with DAPT is beneficial in decreasing the level of coagulation factors and blood viscosity in elderly patients with ACI and promoting the thrombolysis effect.

Fig. 3

Comparative analysis of hemorheological parameters (whole blood viscosity, plasma viscosity) and coagulation function (APTT, PT, TT, Fbg) between groups pre- and post-treatment Note: A: Comparison of whole blood viscosity between the two groups of patients before and after treatment; B: Comparison of plasma viscosity between the two groups of patients before and after treatment; C: Comparison of APTT level between the two groups of patients before and after treatment; D: Comparison of PT level between the two groups of patients before and after treatment; E: Comparison of TT level between the two groups of patients before and after treatment; F: Comparison of Fbg level between the two groups of patients before and after treatment. APTT, Thromboplastin time; PT, Prothrombin time; TT, Thrombin time; Fbg, Fibrinogen

HBOT combined with DAPT can lessen the levels of vasoactive factors and inflammatory factors in patients

The levels of MMP-9, CRP and IL-6 were decreased in both groups after treatment, and the levels of all factors in the observation group were lower versus those in the control group after treatment (P < 0.05) (MMP-9: Cohen’s d = 0.983, 95% CI = 17.631 ~ 37.250; CRP: Cohen’s d = 1.353, 95% CI = 9.005 ~ 15.376; IL-6: Cohen’s d = 3.147, 95% CI = 9.449 ~ 11.870) (Fig. 4ABC), suggesting that HBOT combined with DAPT can lessen the inflammatory response of patients with ACI and help neovascularization.

Fig. 4

Comparative analysis of MMP-9, inflammatory markers (IL-6, CRP), and BI between groups pre- and post-treatment Note: A: Comparison of MMP-9 level between the two groups of patients before and after treatment; B: Comparison of IL-6 level between the two groups of patients before and after treatment; C: Comparison of CRP level between the two groups of patients before and after treatment; D: Comparison of BI scores between the two groups of patients before and after treatment. MMP-9, Matrix metalloproteinase-9; IL-6, Interleukin-6; CRP, C-reactive protein (CRP); BI, Barthel index

HBOT combined with DAPT can improve the ability of daily living activities of elderly patients with ACI

The BI in both groups increased after treatment, and that in the observation group was higher than in the control group (P < 0.05) (Cohen’s d = −0.598, 95% CI = −12.791~−2.914) (Fig. 4D), indicating that HBOT combined with DAPT can enhance the activity of daily living ability of elderly patients with ACI.

Discussion

Our results further substantiated the hypothesis that HBOT combined with DAPT can enhance the therapeutic efficacy for elderly patients with ACI, improve neurological deficits, augment the thrombolytic effect, mitigate inflammatory responses, and elevate patients’ daily living abilities.

A study shows that DAPT with aspirin And clopidogrel or ticagrelor for 21–30 days is more available than antiplatelet therapy alone in patients with high-risk transient ischaemic attack or mild acute noncardioembolic ischemic stroke [24]. In patients with cerebral infarction due to intracranial arterial stenosis, a combination of clopidogrel and aspirin may be needed to prevent subsequent ischemic attacks [25]. Arslanturk et al.‘s report also indicates that, compared with monotherapy, DAPT significantly reduces short-term ischemic complications following carotid artery stenting [26]. Additionally, it has been reported that DAPT is effective in early secondary prevention for patients with acute ischemic stroke of mild severity and those at high risk of transient ischemic attacks [27].

HBOT is a medical technology with great promise that delivers oxygen to the targeted tissues at high pressures to raise the dissolved oxygen amount in the blood. In both normal and injured tissues, the hyperoxia produced by HBOT is conducive to anti-inflammation, promotion of angiogenesis through vascular endothelial proliferation, enhancement of fibroblast activity, increase in macrophage and lymphocyte activity, and bactericidal effects for wound repair [28]. HBO is considered a possible treatment for brain injuries, which can be neuroprotective by modulating the neuroinflammatory response [14]. A study in An Animal model of ischemic brain injury demonstrated that 14-day And 21-day HBO interventions significantly reduced infarct volume, elevated Akt phosphorylation levels and antioxidant enzyme activity, and improved motor performance [12]. Some data confirm that HBO intervention can successfully raise the nerve growth factor expression level and reduce systemic oxidative stress in patients with craniocerebral injury [13]; HBOT may exert neuroprotective effects on traumatic brain injury by regulating inflammatory pathways, providing support for its clinical application [14].

Our study demonstrated that the observation group receiving DAPT combined with HBOT demonstrated superior efficacy in terms of neurological deficits, thrombolytic effect, inflammatory response, and patient’s ability to perform daily activities in elderly patients with ACI, in comparison with the control group receiving only DAPT. From the findings, when HBOT was combined with DAPT, it may produce synergistic effects and enhance therapeutic effects. In terms of the underlying mechanisms, the synergistic effect of HBOT and DAPT may involve multiple pathways. Regarding oxygen metabolism, HBOT expands the oxygen diffusion radius by elevating the partial pressure of oxygen in the blood [10], potentially directly improving the energy supply to the ischemic penumbra. Meanwhile, DAPT maintains vascular patency by inhibiting platelet aggregation [2, 29], providing a structural basis for oxygen delivery. In terms of hemorheology, HBOT may reduce blood viscosity by regulating fluid balance and indirectly modulate Fbg levels by inhibiting inflammatory factors such as IL-6. DAPT further improves hemodynamics through its antiplatelet effects, creating a synergistic interaction between the two therapies. In the context of neuroprotection, as demonstrated in previous studies [30], the improvement of hypoxic metabolism by HBOT and the optimization of microcirculation by DAPT collectively promote neurological recovery. However, the mechanisms underlying the synergistic effect of HBO-DAPT are preliminary speculations. Future studies should incorporate mechanistic biomarkers to further discuss and validate these mechanisms.

When comparing our HBOT protocol with the prior one [17], both use 0.2 MPa but differ in design: the prior approach employs two 30-min oxygen sessions with a 5-min air break and rapid decompression, focusing on short-term oxygenation. Our protocol uses a staged method—two 30-min oxygen sessions with a 10-min rest interval—and reduces barotrauma risk via slower pressurization/depressurization (15–20 min each). Notably, we uniquely combine HBOT with DAPT, enabling a multimodal strategy for thrombotic and hypoxic injuries, unlike the prior oxygenation-only approach.

It is noteworthy that this study has certain limitations. Firstly, the study sample size was not rigorously calculated, which may introduce selection bias and affect the generalizability of the study results. Secondly, the lack of long-term follow-up data may prevent a comprehensive assessment of the long-term efficacy and safety of HBOT combined with DAPT. Additionally, although this study proposed multiple potential mechanisms for the synergistic effect of HBOT and DAPT, these mechanisms remain speculative and require further evaluation and validation.

Conclusion

To sum up, HBOT combined with DAPT can markedly enhance the efficacy of elderly ACI, ameliorate patients’ neurological deficits, enhance the thrombolytic effect, reduce the inflammatory response, and improve the patient’s daily activity ability. This provides some data support for the treatment of elderly ACI. From a clinical perspective, this combined treatment regimen offers a new therapeutic option for elderly patients with ACI. Elderly ACI patients face greater treatment challenges due to factors such as declining physical function and multiple comorbidities. HBOT combined with DAPT has shown certain positive effects, which are expected to improve the prognosis of these patients, enhance their quality of life, and reduce the burden on families and society. Given the limitations of this study, more large-sample, multicenter studies, high-quality are needed in the future to validate the efficacy and safety of HBOT combined with DAPT further in the treatment of ACI. Long-term follow-up data should also be included, and the potential mechanisms of action of HBOT combined with DAPT should be explored. At the same time, uniform standards for treatment protocols need to be developed to improve the reliability and comparability of study results.