Effects of Dl-3-n-butylphthalide on neurological function, hemodynamics and Hcy concentration in cerebral hemorrhage: a systematic review and meta-analysis

Background Dl-3-n-Butylphthalide (NBP) has emerged as a potential therapeutic agent for cerebral hemorrhage, despite not being included in current guideline recommendations. Investigating the underlying physiological and pathological mechanisms of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment remains a critical area of research. Objective This review aims to evaluate the efficacy of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment and elucidate its potential biological mechanisms, thereby providing evidence to support treatment optimization. Methods A comprehensive search of seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang Database) was conducted for studies published up to September 2023. Screening and data extraction were performed by a team of researchers. The Cochrane collaboration tool was utilized for risk bias assessment, and Revman 5.3 along with Stata 17.0 were employed for statistical analysis. Outcomes We searched 254 literature, and 19 were included in this meta-analysis. The results showed that Dl-3-n-Butylphthalide improved the clinical efficacy rate (RR = 1.25, 95% CI 1.19–1.31; p = 0.00), quality of life (MD = 13.93, 95% CI: 11.88–15.98; p = 0.000), increased cerebral blood flow and velocity, reduced cerebral edema volume, Hcy concentration, and did not have obvious adverse reactions (RR = 0.68, 95% CI: 0.39–1.18; p = 0.10). Conclusion This meta-analysis is the first to demonstrate the potential of Dl-3-n-Butylphthalide in treating cerebral hemorrhage. It suggests that Dl-3-n-Butylphthalide may alleviate clinical symptoms by modulating neurological function and improving hemodynamics. Our findings provide robust evidence for incorporating Dl-3-n-Butylphthalide into cerebral hemorrhage treatment strategies, potentially guiding future clinical practice and research. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=355114, Identifier CRD42022355114.


Introduction
Cerebral hemorrhage, a severe form of stroke, is categorized into non-traumatic and traumatic types.It typically manifests with sudden local neurological dysfunction and potential elevations in intracranial pressure.Clinical symptoms often include nausea, vomiting, headache, increased blood pressure, and cognitive impairment (Hwang et al., 2023;Romero and Rojas-Serrano, 2023).Non-traumatic intracerebral hemorrhage (ICH) primarily results from ruptured arterial vessels, frequently occurring in the basal ganglia or thalamic regions.The predominant cause is cerebral small vessel diseases (CSVD), affecting small arteries.Conditions such as cerebral amyloid angiopathy (CAA) and hypertensive arteriosclerosis are common examples (DeSimone et al., 2017;Gil-Garcia et al., 2022).Approximately 20% of ICH cases arise from other etiologies, including arteriovenous malformations, spongiomas, or fistulas (Sallinen et al., 2020).ICH constitutes about 20% of all stroke incidents and remains a significant cause of morbidity and mortality globally, with mortality rates reaching up to 50% (Poon et al., 2014;Hemphill et al., 2015).The incidence of ICH varies regionally, with the Global Burden of Disease Study reporting that 80% of global brain hemorrhages occur in low-and middle-income countries (Krishnamurthi et al., 2014).By 2050, the incidence is projected to increase by 35.2%.The aging population trend suggests that the proportion of cerebral hemorrhage patients over 80 years will rise by 2.5 times (Steiner et al., 2016).Traumatic intracerebral hemorrhage results from external head impacts, often leading to contusions in the frontal and temporal lobes.Concurrently, patients may exhibit neuroimaging signs of traumatic subarachnoid hemorrhage, epidural hematoma, subdural hematoma, or skull fractures (Cepeda et al., 2015).
Early hematoma expansion is a prevalent and grave complication in cerebral hemorrhage patients, often indicating a dismal prognosis (Chen et al., 2015).To mitigate hematoma growth, clinicians administer hemostatic agents such as tranexamic acid, recombinant activated factor VII (rFVIIa), and prothrombin complex concentrate (PCC).However, these treatments minimally impact the improvement of clinical symptoms and lack sufficient evidence to demonstrate effects on functional outcomes or mortality reduction (Steiner and Bsel, 2010;Garg and Biller, 2019).The "mass effect," inflammatory responses, and iron-induced secondary damage (Jiang et al., 2020) necessitate medical interventions targeting secondary injury.These include anti-inflammatory agents (Ironside et al., 2021) and iron chelating agents (Ramadhan et al., 2023).Surgical evacuation of the hematoma represents a therapeutic approach for cerebral hemorrhage.Yet, current evidence scarcely supports that surgery or pharmacological treatment substantially decreases mortality or morbidity associated with cerebral hemorrhage (Wilkinson et al., 2018a;Wilkinson et al., 2018b;de Oliveira Manoel, 2020).Therefore, exploring novel methods to enhance neuroinflammation management and neural function recovery post-cerebral hemorrhage is imperative.
In mitigating adverse neurological outcomes and mortality among cerebral hemorrhage patients, prompt diagnosis and swift implementation of suitable interventions are vital (Rabinstein, 2017).Despite extensive clinical research in recent years investigating optimal treatment strategies for cerebral hemorrhage, including Western medicine and surgical approaches, definitive evidence-based medical guidance for managing this condition remains elusive.Enhancing patient survival and quality of life continues to present significant challenges, underscoring the urgent necessity for novel therapeutic agents to augment current clinical outcomes (Al-Kawaz et al., 2020;Gil-Garcia et al., 2022;Magid-Bernstein et al., 2022;Sheth, 2023).
NBP, commonly known as butylphthalide, is an organic compound derived from celery oil.In 2002, the China Food and Drug Administration (CFDA) approved NBP for the treatment of cerebral infarction (Wang et al., 2018).Numerous studies have identified NBP as a promising neuroprotective agent, effective in treating heart failure, ischemic stroke, Parkinsonism syndrome, Alzheimer's disease, and other neurologic disorders associated with cognitive dysfunction (Qiu et al., 2018;Wang et al., 2018;Gao et al., 2019;Li et al., 2022;Hu et al., 2023).Previous metaanalyses highlight NBP's role in cerebrovascular disease treatment, including reducing inflammation, mitigating oxidative stress, and enhancing vascular endothelial function (Liu et al., 2023).Its neuroprotective effects in cerebrovascular diseases, corroborated by extensive animal studies, are attributed to a range of biomolecular mechanisms (Cheng et al., 2019;Liu et al., 2021;Chen X. et al., 2022a;Gao et al., 2022).Tu et al. (2020) discovered that NBP may mitigate neurological impairment following localized cerebral hemorrhage by fostering neovascularization near the hemorrhage site.NBP can diminish brain cell apoptosis, safeguard neuronal cells, and repair neurological function, primarily through the upregulation of UBIAD1 expression.However, there has been limited investigation into the therapeutic potential of this compound in experimental models of hemorrhagic stroke (Pi et al., 2021).
To our knowledge, no meta-analysis has specifically addressed the efficacy of NBP in treating cerebral hemorrhage.This study serves as a reference for clinicians considering NBP as a therapeutic option for this condition.

Literature screening and data extraction
We imported the retrieved literature into EndNote 20.1 and excluded those not meeting the eligibility criteria.Two researchers, C-C G and Y-G W, independently reviewed the titles and abstracts to identify studies suitable for analysis.Concurrently, all full texts meeting the inclusion criteria were downloaded and independently assessed.Researchers C-C G and Y-Q M utilized Excel 2021 to collate and organize the baseline characteristics of the selected studies, which included the first author, publication year, sample size, region, study design, participants' gender and age, blood loss, intervention types, treatment duration, and outcomes.The results were cross-verified, and any discrepancies were resolved through discussion between the parties involved.If necessary, a third researcher (Y-Q M) was available to assist in resolving any disagreements.

Quality evaluation
Two researchers, Y-G W and C-C G, evaluated the quality of the included studies utilizing the Revman5.3Risk of Bias assessment tool.The assessment criteria encompassed random sequence generation, allocation concealment, blinding (including implementer and participant blinding, as well as outcome evaluator blinding), incomplete outcome data, selective reporting, and other potential sources of bias.Based on this quality assessment, the risk levels were categorized as "low risk," "high risk," or "unclear risk."In cases of disagreement, the two researchers engaged in discussions, and a third researcher, X-X L, intervened as necessary to make a final determination.

Statistical analysis
The meta-analysis was conducted using Stata 17.0 software.Overall parameter estimates were presented as 95% confidence intervals (95% CI), with p-values less than 0.05 indicating statistical significance.( 1) The I 2 test was employed to assess heterogeneity among studies.A fixed-effect model was applied when heterogeneity was low (p > 0.1, I 2 < 50%).In contrast, a random-effects model was chosen in cases of high heterogeneity (p < 0.1, I 2 > 50%).(2) The effect size for binary variables was measured using Relative Risk (RR), and Mean Difference (MD) for continuous variables.Standardized Mean Difference (SMD) was utilized when the included studies employed different measurement instruments, whereas Weighted Mean Difference (WMD) was used otherwise.

Sensitivity analysis
To assess the stability and reliability of the outcome indicators, sensitivity analysis was conducted.In instances of high heterogeneity, a Galbraith plot was utilized to identify the sources of significant heterogeneity in each study.

Meta-regression analysis
Meta-regression analysis was conducted on variables such as age, sex, and route of administration in studies comprising more than ten reports, to determine their correlation with the effect size.

Publication bias
If the funnel plot exhibits asymmetry or the Egger test indicates publication bias (p < 0.05), it becomes necessary to assess the stability and reliability of the outcome indicators.In such cases, the "Trim and Fill" method is employed to estimate the combined effect size while adjusting for publication bias.

Results of literature search
A comprehensive computer search yielded 254 studies.After the exclusion of 70 duplicates, the titles, abstracts, and full texts of the remaining 184 articles were meticulously reviewed.Studies that failed to meet the inclusion criteria were subsequently excluded.Ultimately, 19 studies qualified for inclusion.The detailed retrieval process is illustrated in Figure 1.

Literature quality evaluation
A total of seven studies (Jia et al., 2017;Qian et al., 2017;Han et al., 2021;Qian, 2021;Huang et al., 2022;Shi and Chen, 2022;Chen et al., 2023) employed the random number table method for participant allocation.Nine studies (Wang Y. et al., 2021a;Liu et al., 2018;Pang et al., 2010;hongli, 2019;Chen et al., 2018;Lin, 2021;Guo and Liao, 2022;fang, 2017;Ji and Zhou, 2017) only specified the use of "random" without further detail.One study (yan et al., 2021) allocated participants according to different treatment groups.Another study (fang and yixin, 2021) used a lottery system for grouping, and one study (yang et al., 2020) divided participants based on odd and even numbers.None of the studies exhibited evidence of selective reporting.One study (Liu et al., 2018) provided detailed information on patient dropouts and missed follow-ups, including the primary reasons for these occurrences.These aspects are illustrated in Figure 2, 3.

Incidence of adverse reactions
Five studies (Wang Y. et al., 2021a;Han et al., 2021;Lin, 2021;Huang et al., 2022;Shi and Chen, 2022) investigated the incidence of adverse reactions, such as nausea and vomiting.Two of these studies (Lin, 2021; Shi and Chen, 2022) reported statistical differences in comparisons before and after treatment between groups, suggesting that NBP may reduce the incidence of adverse reactions.However, three other studies (Wang Y. et al., 2021a;Han et al., 2021;Huang et al., 2022) found that NBP did not significantly decrease adverse reactions.In the meta-analysis, which included five eligible studies with a total of 613 participants, the results indicated no statistically significant difference in adverse outcomes (RR = 0.68, 95% CI: 0.39-1.18;p = 0.17; Q (4) = 7.83; p = 0.10, I 2 = 48.89).These findings are illustrated in Figure 5.
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Sensitivity analysis (NIHSS, ADL score, hemodynamic indexes)
A Galbraith map was utilized for sensitivity analysis to identify the sources of high heterogeneity in the NIHSS score.This analysis revealed that two studies (Guo and Liao, 2022;fang and yixin, 2021) fell outside the 95% CI, suggesting they might be anomalies contributing to the heterogeneity, as depicted in Figure 13A.Excluding two studies (Guo and Liao, 2022;fang and yixin, 2021) from the analysis, the NIHSS score remained statistically significant (SMD = −1.29,95% CI -1.72 to −0.85; p < 0.0001), and heterogeneity was notably reduced (p = 0.000; I 2 = 88%).In the ADL score heterogeneity analysis, the study (Shi and Chen, 2022) was identified as not within the 95% CI, potentially indicating a source of heterogeneity, as shown in Figure 13B.Removal of study (Shi and Chen, 2022) maintained the statistical significance of the ADL score (MD = 15.03,95% CI 14.02 to 16.04; p < 0.0001), with a significant reduction in heterogeneity (p = 0.34; I 2 = 12%).Sensitivity analysis of mean blood flow, as illustrated in Figure 13C, did not reveal specific sources of heterogeneity.Regarding mean blood flow velocity, sensitivity analysis indicated that the statistical significance persisted even after the exclusion of study (Han et al., 2021) (SMD = 1.37, 95% CI 1.10 to 1.64; p < 0.0001), with a substantial reduction in heterogeneity (p = 0.27, I 2 = 23%), as shown in Figure 13D.

Meta-regression analysis
The results of meta-analysis of clinical efficacy showed that the effect size was not significantly correlated with age, gender, and drug dosage form (p > 0.05).
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Publication bias
Given the requirement of a minimum of 10 original studies for funnel plot analysis, this approach was applied exclusively to clinical efficacy rates.Subsequently, an Egger test was conducted, revealing a statistically significant difference (p < 0.01), indicating publication bias in clinical remission rates.To address this, a "trim and filling" method was employed to estimate the adjusted combined effect size for publication bias.The adjusted combined effect size was found to remain statistically significant (p < 0.01), aligning with the unadjusted findings.In conclusion, the publication bias in clinical efficiency Meta-analysis of incidence of adverse reactions.Meta-analysis of NIHSS score.
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Findings analysis
To our knowledge, this is the inaugural systematic review and meta-analysis investigating the clinical efficacy and outcomes of NBP in cerebral hemorrhage patients.The findings indicate that NBP markedly enhances clinical efficacy, cerebral blood flow, and velocity, facilitates neurological function recovery, ameliorates symptoms of cerebral edema, and attenuates the inflammatory response.Furthermore, the use of NBP in treating cerebral hemorrhage was not associated with significant adverse reactions.Consequently, NBP can be considered a viable therapeutic option for cerebral hemorrhage treatment.
This study reveals that NBP enhances clinical efficacy in patients with cerebral hemorrhage, contributing to reductions in both the NIHSS score and the ADL score.Furthermore, NBP was found to promote neurological recovery and elicit a greater clinical response than conventional treatment.These findings align with the experimental results reported by Zhao et al. (Zhao et al., 2017), which indicated that continuous NBP administration for 21 days post-traumatic brain injury (TBI) significantly improved sensorimotor recovery in adult male mice.Our meta-analysis corroborates the ability of NBP to notably improve patient living  Meta-analysis results of the MCBF.capabilities.Correspondingly, Lv et al. (Lv et al., 2021) reported that a combination of NBP with modified mandatory exercise therapy markedly enhanced daily living abilities in patients with cerebral hemorrhage, echoing our observations.NBP has been effective in alleviating symptoms of cerebral hemorrhage by reducing Hcy concentrations.Multiple studies have identified Hcy as a biomarker for predicting cerebral hemorrhage, categorizing it as an independent predictor (Zhang et al., 2022).Consequently, Hcy was chosen as one of the main indicators in this study.Xu et al. reported that Hcy levels can be instrumental in assessing the progression and prognosis of cerebral hemorrhage.Their research indicated that higher serum Hcy concentrations in patients are associated with larger cerebral hemorrhage volumes, which is crucial for timely assessment of the condition's progression and prognosis (Xu et al., 2022).In this studies, a positive correlation was found between Hcy concentration and the severity of cerebral hemorrhage.Our findings confirm that NBP significantly reduces Hcy concentrations.
SP, a neuropeptide of the tachykinin family, is widely distributed in the central and peripheral nervous systems, respiratory system, and intestinal tract.It exhibits proinflammatory effects upon binding to its receptors.In cerebral hemorrhage patients, SP may play a key role in hematoma enlargement, perihematoma edema, Meta-analysis of the MBFV.
Frontiers in Pharmacology frontiersin.organd neuroinflammatory responses (Lorente et al., 2020;Wang et al., 2020).Animal model studies have shown that inflammation can lead to neuronal death, blood-brain barrier disruption, and neurological deficits post-ICH in rats (Zhu et al., 2018;Chen S. et al., 2022b).Our results indicated that NBP significantly increases SP concentration.
Potentially by blocking SP's binding to its receptor, thus reducing inflammation and edema in brain tissue.The rise in peripheral SP level might be a feedback regulation after the inhibition of the SP receptor, consistent with the conclusions of Wang et al. (Wang haibo et al., 2021b).However, the specific mechanism requires further exploration.
Perihematoma edema is a principal contributor to the high morbidity and mortality associated with intracranial hemorrhage.The edema volume often surpasses that of the original hematoma, potentially increasing intracranial pressure or leading to hydrocephalus, thereby causing neurological deterioration and even death (Mehdiratta et al., 2008).Persistent or expanding edema can further impede cerebral blood supply, disrupt the intracellular environment of nerve cells, and exacerbate nerve cell damage (Gong et al., 2015;Wang et al., 2016).Animal experimental studies have demonstrated that NBP significantly enhances neurological function and mitigates symptoms of Meta-analysis of Hcy concentration.

FIGURE 12
Meta-analysis of SP concentration.
Frontiers in Pharmacology frontiersin.org13  Frontiers in Pharmacology frontiersin.org14 Ma et al. 10.3389/fphar.2024.1360932cerebral edema in rats experiencing cerebral hemorrhage (Huang et al., 2021).These findings are consistent with our own observations.The monitoring and regulation of hemodynamic parameters are critical in cerebral hemorrhage management (Jurgen et al., 2021).Cerebral vasospasm, commonly observed in subarachnoid hemorrhage patients, is intricately linked to the reduction in blood flow velocity and volume, potentially impairing the body's capacity for autoregulation of these parameters.Experimental studies have indicated that alterations in cerebral blood flow (CBF) correlate with the capacity for oxygen delivery.Cerebral hypoperfusion and inadequate oxygen delivery can result in brain tissue injury (Prunell et al., 2004;Muench et al., 2007).Lennihan L et al. demonstrated that increasing CBF and enhancing microcirculation can mitigate brain tissue damage (Lennihan et al., 2000;Qiu et al., 2019).The meta-analysis results of this study suggest that NBP may enhance cerebral blood flow and velocity, which could be a key mechanism in restoring cerebral nerve function deficits.However, due to limited sample sizes, extensive evidence is still required for confirmation.Our metaanalysis observed that the improvement in cerebral hemorrhage adverse effects by NBP was marginally lower than that reported in the retrospective study by Lv et al. (Lv et al., 2021).In this study, the improvement in adverse effects was less pronounced with NBP, but did not exacerbate the adverse effects.

Limitations
This study acknowledges five limitations in the evidence presented.Firstly, the majority of the included studies originated from China, with all cases involving Chinese patients, introducing potential regional publication bias.Further international clinical trials are warranted.Secondly, the assessment of evidence quality revealed that only seven studies in the meta-analysis reported random sequence generation, and none implemented blinding for subjects and clinicians or reported on it.This aspect necessitates optimization in clinical trial design and may significantly impact the quality of the literature.Thirdly, due to publication bias in clinical response rates, the "trim and filling" method was employed to estimate the adjusted combined effect size.However, this approach, based on the principle of symmetry and the inclusion of hypothetical small-sample studies, warrants cautious interpretation of clinical response rate results.Importantly, the interventions in the control groups of the included studies were all conventional Western medical treatments viewed as placebo therapy was not involved in the control groups and most of the studies did not have a follow-up period, which may expensively result in a waste of research Finally, while efforts were made to encompass a comprehensive range of studies, the exclusion of grey literature might have led to the omission of crucial literature.
This review process is subject to two main limitations.Firstly, the scope of our study predominantly focused on evaluating the clinical efficacy, neurological function, quality of life, and blood indices of NBP in cerebral hemorrhage patients.It did not extensively delve into the occurrence of adverse events linked to the prognosis of cerebral hemorrhage.This limitation stems from the absence of clinical trials concerning NBP that investigate prognosisrelated adverse outcomes.Secondly, the studies incorporated in our analysis were characterized by small sample sizes.Future research should encompass a substantial number of multicenter, randomized, double-blind controlled trials with larger samples to substantiate the efficacy of NBP and elucidate its specific biomolecular mechanisms.

Conclusion
In conclusion, our study demonstrates that NBP effectively enhances clinical response rates, neurological function, and quality of life, while reducing cerebral blood flow and velocity in cerebral hemorrhage patients.Additionally, NBP exhibits minimal side effects and may ameliorate brain injury and clinical symptoms by diminishing inflammatory responses and Hcy concentrations.This review substantiates that timely administration of NBP can improve clinical symptoms in the cerebral hemorrhage population.The findings aim to shed light on NBP's potential targets in treating cerebral hemorrhage and provide valuable insights for clinicians, medical institutions, and intervention strategists dealing with cerebral hemorrhage.

FIGURE 1 Flow
FIGURE 1Flow chart of literature screening.

FIGURE 7
FIGURE 7Meta-analysis of ADL score.

FIGURE 14 (
FIGURE 14 (A) Funnel plot of clinical efficacy, (B) Trim and filling figure of meta-analysis of clinical efficiency.

TABLE 1
Baseline characteristics of the included studies.

TABLE 1 (
Continued) Baseline characteristics of the included studies.