Efficacy of Concurrent Utilization of Mannitol and Nimodipine in Treating Hypertensive Intracerebral Hemorrhage and Its Effects on Neurological Function

Abstract

Background:

The goal of this study was to retrospectively appraise the efficacy of the combined therapy comprising mannitol and nimodipine for hypertensive intracerebral hemorrhage (HICH) and its impact on neurological function.

Methods:

The study subjects encompassed 100 individuals with HICH who were admitted to the hospital from May 2021 to 2023 and were categorized into a control group and an observation group, with 50 individuals comprising each group. Intravenous mannitol infusion was administered to the control group, while the observation group received nimodipine injection in combination with mannitol, followed by a course of oral nimodipine tablets. Both groups of patients were treated for 3 months. A comparative analysis was performed to assess the clinical efficacy, neurological function, hematoma volume, serum inflammatory cytokine levels, hemodynamic parameters, and incidence of adverse reactions across the 2 groups.

Results:

A remarkably higher overall response rate of 92.00% was observed in the treatment group as opposed to 74.00% in the control group, with both groups exhibiting noteworthy reductions in National Institutes of Health Stroke Scale scores post-treatment, and the reduction being more pronounced in the treatment group (P < .05). Post-treatment, both groups exhibited decreases in hematoma volume and edema area, with the reduction in the observation group being notably more significant than in the control group (P < .05). Post-treatment, there was an upsurge in cerebral blood flow and blood flow velocity, coupled with a reduction in peripheral resistance and critical pressure in both groups. The observation group displayed higher blood flow velocity and lower peripheral resistance and critical pressure than the control group (P < .05). No notable distinction was observed in the overall incidence of adverse reactions between the groups (P > .05).

Conclusion:

The concurrent administration of mannitol and nimodipine in HICH presents substantial advantages, including enhanced clinical efficacy, improved neurological function, decreased hematoma volume, and regulation of hemodynamic parameters. This treatment approach has shown significant efficacy and is worthy of widespread promotion and application in clinical practice.

Main Points

• Therapeutic potential of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo) in traumatic brain injury (TBI): The study highlights that BMSC-Exo has significant therapeutic effects on TBI by promoting neural regeneration and reducing inflammation.

• Mechanism via Extracellular Signal-Regulated Kinase (ERK) signaling pathway: The research demonstrates that BMSC exosomes regulate the ERK/P-ERK signaling pathway, which is crucial for cell proliferation and survival, playing a key role in the recovery of neural function after TBI.

• Regulation of β-catenin and cyclinD-1: BMSC-Exo upregulates β-catenin and downregulates cyclinD-1, both of which are involved in cell proliferation and differentiation, indicating that exosomes help control neuronal cell cycles and improve brain tissue recovery.

• Novel strategy for TBI treatment: The findings suggest that BMSC-derived exosomes could be a promising nanotherapeutic agent for inhibiting neuroinflammatory responses in TBI, offering a new strategy for clinical applications in TBI treatment.

Introduction

Often stemming from long-term hypertension, hypertensive intracerebral hemorrhage (HICH) is a prevalent and serious cerebrovascular ailment, substantially affecting patients’ quality of life with its high incidence and mortality rates.^1-3 The pathogenesis of HICH is a complex multifactorial process involving factors such as vascular wall damage, arteriosclerosis, elevated blood pressure, and dysregulation of cerebral vascular autoregulation.² The interplay of these factors increases the fragility of cerebral blood vessels, raising the risk of intracerebral hemorrhage and potentially leading to abnormalities in cerebral hemodynamics.² Treatment for HICH involves acute-phase interventions like surgical procedures and vigilant monitoring, followed by rehabilitation programs, pharmacological management, and complication prevention measures for long-term recovery and improved outcomes.⁴ A multidisciplinary approach incorporating prompt acute care, tailored rehabilitation, medication regimens, and complication management is essential in optimizing outcomes for patients with HICH.⁵ Currently, treatment strategies for HICH primarily comprise surgical intervention and pharmaceutical treatments.^4,5 Surgical intervention is usually employed to actively manage the expansion of hematomas and mitigate brain tissue damage. Nevertheless, not all patients are suitable candidates for surgical procedures, thus emphasizing the pivotal role of drug therapy in such cases.

Widely utilized in the management of diverse cerebrovascular ailments, mannitol serves as an osmotic diuretic, functioning to regulate intracranial pressure, enhance cerebral blood perfusion and oxygenation, decrease brain edema, and bolster cerebral blood flow. In this manner, it plays a pivotal role in safeguarding brain cells.^6-8 Nimodipine, identified as a calcium channel blocker, operates by expanding cerebral blood vessels and enhancing cerebral circulation, as research indicates.^9,10 Moreover, studies have revealed nimodipine’s capacity to ameliorate cerebral blood supply, mitigate cerebral ischemic and hypoxic damage, and afford a level of protection for neurological function.¹¹ Gan et al¹² have revealed that nimodipine combined with atorvastatin calcium could significantly improve the microinflammation and oxidative stress levels in patients with cerebral vasospasm after subarachnoid hemorrhage. However, research on mannitol plus nimodipine in treating HICH is limited. The combined application of mannitol and nimodipine can complement each other, reducing intracranial pressure, improving brain edema, increasing cerebral blood flow, and providing neuroprotective effects, collectively enhancing the therapeutic outcomes. By synergistically utilizing the mechanisms of both drugs, this combined therapy may improve treatment efficacy, reduce neurological damage following HICH, and promote patient recovery.

Considering the important functions of mannitol and nimodipine in treating HICH, this study seeks to explore the effectiveness of the combined therapy of mannitol and nimodipine for HICH treatment, as well as its influence on neurological function. The goal was to substantiate, via clinical observation and comparative research, that the combination therapy of mannitol and nimodipine is more adept at improving clinical symptoms, facilitating hematoma absorption, and eliciting favorable effects on neurological function in individuals with HICH, in comparison to the use of mannitol or nimodipine independently.

Material and Methods

Data Source

From May 2021 to 2023, the hospital admitted 100 individuals diagnosed with HICH for whom a retrospective study was conducted. The study was approved by the Ethics Committee of Wujin Hospital Affiliated With Jiangsu University (Approval no.: 2021-010). The cohort consisted of 66 males (66%) and 34 females (34%), ranging in age from 45 to 79 years and was segregated into a control group and an observation group, with 50 individuals allocated to each group. The baseline characteristics of the control group were 34 males (68%) and 16 females (32%), with a mean age of (65.72 ± 8.12) years. The observation group consisted of 33 males (66%) and 17 females (34%), with a mean age of (66.13 ± 8.64) years. The 2 groups exhibited comparable baseline features. Informed consent was obtained from all patients or their families.

Inclusion criteria: confirmed diagnosis of HICH through cranial computed tomography or magnetic resonance imaging; history of hypertension; confirmation of hematoma located in the internal capsule or basal ganglia through histological examination; onset time within 48 hours and hematoma volume between 8 and 40 mL.

Exclusion criteria: spontaneous intracerebral hemorrhage; severe visceral diseases or coagulation disorders; presence of brain tumors or cerebral arterial or venous malformations.

All patients received bed rest upon admission and were given oxygen inhalation, monitoring of vital signs, correction of electrolyte and acid-base imbalances, and nutritional support for the brain. Patients in the control group were treated with intravenous infusion of mannitol injection (Shanghai Baitie Medical Products Co., Ltd., Approval no.: National Medical Products Administration H20003300, specification: 100 mL : 20 g) at a dose of 0.25-2.0 g/kg, administered over 30-60 minutes, 2-3 times per day for 10 days. Patients in the observation group received nimodipine injection (Bayer Health Care Co., Ltd., Approval no.: H20181106, specification: 50 mL : 10 mg) in addition to mannitol based on the control group’s treatment. Starting from day 11, patients received oral administration of nimodipine tablets (Guangdong South Pharmaceutical Group Co., Ltd., Approval no.: National Medical Products Administration H44025019, specification: 20 mg × 50 tablets) at a dose of 60 mg once daily, 2 times per day. Both groups of patients were treated for 3 months.

Observational Indexes and Efficacy Evaluation Criteria

Comparative analysis was conducted between the 2 groups for clinical efficacy, neurological function, hematoma volume, serum inflammatory cytokine levels, hemodynamic parameters, and the frequency of adverse reactions.

1. The clinical efficacy was evaluated after 3 months of treatment. The efficacy was classified as follows: markedly effective: clear consciousness, National Institutes of Health Stroke Scale (NIHSS) score reduction >75%, hematoma volume reduction >10 mL; effective: improvement in consciousness, NIHSS score reduction >25%, hematoma volume reduction >5 mL; ineffective: no remarkable improvement in consciousness, NIHSS score, or hematoma volume.¹³ The overall response rate was calculated as (markedly effective cases + effective cases) / total cases × 100%.

2. The evaluation of neurological function involved comparing changes in NIHSS scores prior to and after 3 months of treatment, where a higher score denoted more pronounced neurological deficits.

3. The alterations in hematoma volume and edema area were evaluated pre- and post-treatment, with hematoma volume calculated using the formula: volume = π/6 × length × width × edema area/hemorrhage area.

4. The differences in cerebral blood flow, blood flow velocity, peripheral resistance, and critical pressure before and after treatment were observed and assessed.

5. Both groups were observed and compared for the incidence of adverse reactions, such as transient hypotension, diarrhea, rash, and dizziness.

Statistical Methods

Utilizing SPSS 25.0 (IBM SPSS Corp.; Armonk, NY, USA) software, all the data underwent analysis. Measurement data were normally distributed and expressed as mean ± SD. Comparisons between groups were performed using independent sample t-tests, and within-group comparisons were done using paired t-tests. Count data were analyzed utilizing the chi-square test, with significance set at P < .05.

Results

Clinical Efficacy

In the observation group (n = 50), 56.00% showed a “Markedly effective” response, 36.00% were “Effective,” and 8.00% were “Ineffective,” resulting in an overall response rate of 92.00%. On the other hand, in the control group (n = 50), 38.00% were “Markedly effective,” 36.00% were “Effective,” and 26.00% were “Ineffective,” leading to an overall response rate of 74.00%. Accordingly, a marked difference was observed, with the effective rate of 92.00% in the observation group being substantially higher than the control group’s rate of 74.00% (P < .05) (Table 1).

Table 1.

Curative Effect in the 2 Groups [n (%)]

Group (n)	Markedly Effective	Effective	Ineffective	Overall Response Rate
Observation (50)	28 (56.00)	18 (36.00)	4 (8.00)	46 (92.00)
Control (50)	19 (38.00)	18 (36.00)	13 (26.00)	37 (74.00)
P	.071	>.999	.017	.017

Neurological Function

Prior to treatment, no notable difference in the NIHSS scores between groups was identified (P > .05). Following treatment, both groups experienced a substantial reduction in NIHSS scores, and the decrease was more notable in the observation group (P < .05) (Table 2).

Table 2.

Pulmonary Function of the 2 Groups Before and After Treatment

Group (n)	NIHSS
	Before	After
Observation (50)	22.56 ± 3.89	12.72 ± 2.20*
Control (50)	23.60 ± 3.55	16.64 ± 2.41*
P	.166	<.001

*Signifies a notable disparity post-treatment as compared to pre-treatment.

Hematoma Volume and Edema Area

Following treatment, both groups exhibited reductions in hematoma volume and edema area as opposed to pre-treatment, with the observation group demonstrating smaller hematoma volume and edema area than the control group (P < .05) (Figure 1).

Figure 1.

Hematoma volume and edema area of the patients prior to and following treatment. (A) Hematoma volume of the patients prior to and following treatment. (B) Edema area of the patients prior to and following treatment. ***P < .001.

Hemodynamic Parameters

Following treatment, both groups exhibited enhanced cerebral blood flow and blood flow velocity, along with reduced peripheral resistance and critical pressure relative to pre-treatment. Furthermore, the observation group demonstrated higher blood flow velocity and lower peripheral resistance and critical pressure than the control group (P < .05). There was no statistically remarkable distinction in blood flow volume between groups (P > .05) (Table 3). Table 4 presents a comparison between the observation group and the control group based on percent change. The results indicate significant differences between the 2 groups in variables such as blood flow, blood flow velocity, peripheral resistance, and critical pressure. The observation group shows higher median percent changes in blood flow and blood flow velocity, while peripheral resistance and critical pressure exhibit lower median percent changes. All P-values for the comparisons are less than .001, demonstrating statistical significance in these differences.

Table 3.

Hemodynamic Parameters Comparisons Within the Group Before and After Treatment

		Before	After	P
Blood flow (cm/s)	Observation (n = 50)	10.79 ± 2.46	14.80 ± 2.95	<.001
	Control (n = 50)	11.51 ± 2.20	13.02 ± 2.75	.003
Blood flow velocity (mL/s)	Observation (n = 50)	6.60 ± 1.32	7.33 ± 1.13	.004
	Control (n = 50)	6.39 ± 1.40	8.44 ± 1.34	<.001
Peripheral resistance (Pa·s /mL)	Observation (n = 50)	1679.37 ± 254.41	1367.42 ± 228.15	<.001
	Control (n = 50)	1757.43 ± 289.91	1530.10 ± 237.59*	<.001
Critical pressure (kPa)	Observation (n = 50)	9.66 ± 1.38	7.14 ± 1.28	<.001
	Control (n = 50)	9.82 ± 1.21	8.48 ± 1.35	<.001

Table 4.

Comparisons of Hemodynamic Parameters Between the Groups According to Percent Change [percent change (%)=((after-before)/before)*100]

	Percent Change According to Baseline		P
	Observation (%) (Median (Min-Max))	Control (%) (median (Min-Max))
Blood flow (cm/s)	50.16 (−1.60 to 96.88)	14.82 (−41.37 to 110.27)	<.001
Blood flow velocity (mL/s)	12.33 (−33.33 to 66.45)	38.51 (−18.79 to 93.24)	<.001
Peripheral resistance (Pa·s /mL)	−17.55 (−46.57 to 21.32)	−15.26 (−44.94 to 56.73)	<.001
Critical pressure (kPa)	−24.51 (−63.33 to 17.54)	−11.18 (−50.00 to 30.66)	<.001

Adverse Reactions

The overall incidence of adverse reactions did not display a substantial difference between groups (P > .05) (Table 5).

Table 5.

Adverse Reactions in the 2 Groups [n (%)]

Group (n)	Transient Hypotension	Diarrhea	Dizziness	Rash	Total Adverse Reactions
Observation (50)	2 (4.00)	2 (4.00)	1 (2.00)	1 (2.00)	6 (12.00)
Control (50)	2 (4.00)	1 (2.00)	3 (6.00)	1 (2.00)	7 (14.00)
P	>.999	>.999	.610	>.999	>.999

Discussion

Hypertensive intracerebral hemorrhage is a prevalent cerebrovascular ailment typically observed among middle-aged and elderly demographics. It is recognized for its high incidence, mortality, and disability rates. In recent times, the surge in HICH prevalence has positioned it as a menace to individuals’ physical and mental wellness and life security, comparable to coronary heart disease and cancer.^14,15 High-dose mannitol administration has been associated with causing renal function damage in patients, as indicated by clinical evidence.¹⁶ Conversely, achieving optimal therapeutic effects with low-dose mannitol can be difficult. Consequently, a combination of appropriate mannitol doses with other medications is often recommended to enhance clinical effectiveness and ensure medication safety.¹⁷ Nimodipine, a calcium channel blocker, effectively inhibits the influx of Ca²⁺ into cells, thereby reducing smooth muscle contraction. It also decreases the release of free fatty acids and oxygen radicals, which helps alleviate vasospasm. Additionally, nimodipine improves cerebral tissue blood circulation and enhances cerebral tissue tolerance to hypoxia.¹⁶ Its importance is pronounced in shielding neurons and enhancing brain neural function.¹⁸

The study’s findings revealed a markedly higher overall response rate of 92.00% in the observation group compared to 74.00% in the control group, reflecting a remarkable difference (P < .05). This indicates that the combined therapy of mannitol and nimodipine surpasses the sole use of mannitol in terms of overall efficacy for HICH. A meta-analysis conducted by Chen et al¹⁹ has revealed significant clinical efficacy of nimodipine combined with edaravone in the treatment of hypertensive cerebral hemorrhage, which also supports the conclusion that combined treatment with nimodipine can provide higher efficacy in hypertensive cerebral hemorrhage. Unquestionably, before treatment, no notable disparity in the NIHSS scores was evident between groups. Nonetheless, following treatment, the reduction in the NIHSS scores was notably more substantial in the observation group than in the control group, signaling a more positive impact on improving neurological function from the concurrent administration of mannitol and nimodipine.

Clinical investigations have indicated that hematoma has a direct detrimental effect on brain tissue and surrounding secondary tissue, leading to primary pathological changes in HICH and substantially impacting patient mortality and neurological impairment. Therefore, early hematoma clearance and the reduction of intracranial hypertension are essential in improving the prognosis of HICH patients.^20,21 Post-treatment, both groups experienced decreases in volume and area, with the observation group demonstrating substantially smaller volume and area than the control group (P < .05), and both decreased compared to pre-treatment. This underscores the noteworthy impact of the combined therapy of mannitol and nimodipine in reducing hematoma volume and edema area. The results indicate that the combination treatment of mannitol and nimodipine can effectively promote the absorption of hematoma. The synergistic effect of mannitol and nimodipine enhances collateral circulation blood flow supply, facilitating hematoma absorption.²² Simultaneously, by dilating cerebral blood vessels to increase blood perfusion, the combination improved brain tissue hypoxia and ischemia.²³ The main objectives of clinical treatment for HICH are to promote hematoma absorption and neurological function recovery. The combined treatment of mannitol and nimodipine in the management of HICH demonstrates significant efficacy in hematoma clearance. This therapeutic approach helps alleviate intracranial hypertension caused by hematomas, reducing pressure on brain tissue and nerves while effectively enhancing cerebral blood circulation. By promoting hematoma absorption, this treatment holds promise in reducing brain tissue edema and inflammatory responses, thereby aiding in the protection of nerve cells from further damage. Furthermore, the therapy can mitigate brain tissue hypoxia and ischemia, facilitating the recovery and restoration of neurological function.²² In conclusion, the comprehensive treatment strategy involving the combined use of mannitol and nimodipine exhibits noteworthy efficacy in HICH patients, offering significant clinical relevance for improving patient outcomes and neurological recovery.

The diagnostic and treatment value of cerebral hemodynamic parameters in cerebrovascular diseases is notable, often offering higher accuracy in the disease’s initial stages compared to imaging studies.²⁴ In this study, increased cerebral blood flow and blood flow velocity were identified in both groups, alongside reduced peripheral resistance and critical pressure following treatment. In addition, the observation group exhibited notably higher blood flow velocity and lower peripheral resistance and critical pressure in comparison to the control group. No noteworthy disparity was found in blood flow volume between the 2 groups. Lastly, the collective occurrence of adverse reactions did not notably vary between the observation and control groups, underscoring that the combination of the 2 drugs did not elevate the frequency of drug-related adverse reactions, implying satisfactory safety. However, the concurrent use of mannitol and nimodipine in treating HICH may pose potential risks, including drug interactions, individual variations, uncertainty in treatment outcomes, and considerations regarding long-term safety. Therefore, it is essential to cautiously assess these risks and closely monitor patient responses when using them to ensure treatment effectiveness and patient safety.

In summary, the outcomes of this study uphold the superior effectiveness of the combined therapy of mannitol and nimodipine in ameliorating clinical efficacy, neurological function, as well as diminishing hematoma volume and edema area in HICH. This treatment approach has shown significant efficacy and is worthy of widespread promotion and application in clinical practice.

Nevertheless, this study possesses some limitations. Firstly, due to the limited sample size, the representativeness of the results obtained may be constrained. To enhance the persuasiveness of the study, it is necessary to further expand the sample size in future research. Secondly, the observation period of this study was relatively short. Considering that recovery from HICH typically requires a longer duration, subsequent studies should prolong the follow-up period to observe the long-term recovery of patients. Moreover, as this study was conducted as a retrospective study at a single center, potential biases may be introduced and the representativeness of the sample may be somewhat limited. To improve the accuracy of the research findings, future considerations could involve conducting further multicenter, large-scale, double-blind randomized controlled trials. Moreover, exploring the combined use of mannitol with other medications and investigating the potential mechanisms of hemodynamic changes using imaging techniques are also worth investigating.

Funding Statement

The authors declared that this study has received no financial support.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.