The optimal time window for the use and dosage of nimodipine for acute massive cerebral infarction: study protocol for a randomized controlled trial

Run-hui Li＊

Department of Neurology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning Province, China

Background

Large cerebral infarctions are also called massive cerebral infarctions and often indicate complete occlusion of the internal carotid artery, middle cerebral artery, or cortical branches. Massive cerebral infarction is a special type of cerebral infarction, and frequently occurs in people older than 60 years of age. Hypertension, diabetes, coronary heart disease, atrial fibrillation, and hyperlipidemia are major risk factors for massive cerebral infarction, which is of high concern because of the large affected area, resulting severe morbidity, and high mortality.

Acute cerebral infarction can cause calcium influx and intracellular calcium overload, promote free radical generation, and lead to brain injury (Horn et al., 2001). Calcium antagonists reduce calcium influx, inhibit free radical generation, and lessen brain injury (Wang and Ma, 2004).Nimodipine is a dihydropyridine calcium channel blocker that selectively affects cerebral vascular smooth muscle,expands cerebral blood vessels, increases cerebral blood flow, has protective effects on ischemic brain damage,and of special benefit, affects cerebral vasospasm-induced ischemic injury. Nimodipine specifically expands small intracranial arteries in the blood-brain barrier and has been recommended to treat cerebral small vessel disease(Gorelick et al., 2011). Nimodipine also has a small effect on peripheral blood vessels and the heart, unclearly affects cerebral steal syndrome, and contributes to the compensation and rehabilitation of neurological function.Nimodipine suppresses platelet aggregation, enhances erythrocyte deformability, decreases blood viscosity, and inhibits thrombosis. Nimodipine has also been shown to have neuroprotective effects on acute cerebral infarction(Long et al., 1998; Nag et al., 1998; Ahmed et al., 2000;Najarian and Traut, 2000; Ildan et al., 2001; Sobrado et al., 2003; Tomassoni et al., 2008). However, few studies have evaluated the therapeutic effect of nimodipine on acute massive cerebral infarction (Table 1), and none used a double-blind randomized controlled design. This study is designed to identify the optimal time window for nimodipine use and dosage.

Methods/design

Study design

This is a double-blind randomized controlled trial. The experiments will be conducted in the Department of Neurology, Central Hospital Affiliated to Shenyang Medical College of China.

Study participants

One hundred patients with acute massive cerebral infarction, hospitalized in the Department of Neurology, Central Hospital Affiliated to Shenyang Medical College of China,will be recruited to participate in the study.

Inclusion criteria

● First onset ≤ 80 years old and no severe complications related to internal diseases

● Conscious or mild disturbance of consciousness with upper and lower limb paralysis on one side and muscle strength in the paralyzed limb grade 0–III

● Computed tomographic (CT) scan that excludes cerebral hemorrhage and previous cerebral infarction (CT scan can reveal early massive infarction)

● Blood pressure above or within the normal range

Exclusion criteria

● Clinical manifestations significantly improved before treatment

● Serious disturbance of consciousness such as drowsiness or coma

● Mild neurological disorders, such as pure sensory disturbances, ataxia, dysarthria, and hemiparesis

● Severe hypotension: systolic blood pressure ＜ 90 mmHg,diastolic blood pressure ＜ 60 mmHg

● Heart rate ＜ 60 beats/min or sinus bradycardia

● Severe heart, brain, or kidney dysfunction, or malignant tumor

Randomization and interventions

Patient randomization will be performed using computerized randomization by a drug administrator. The treatment program for each subject will be generated using a random allocation sequence, and placed in ordered sealed opaque envelopes. When qualified subjects agree to participate, the envelopes will be opened and subjects will receive appropriate treatment measures. The blinded codes will be preserved by the drug administrator and subjects as participants are assigned to treatment and control groups. In accordance with the time of administration after onset, subjects in the treatment group will be divided into four subgroups (＜ 3 hours, 3–6 hours, 6–24 hours, and ＞ 24 hours). Doctors,patients, and assessors will be blinded regarding patient group assignments to avoid measurement bias.

In the control group, subjects will receive 500 mL of physiological saline and 2.0 g/dose citicoline, intravenously,once per day, for 7 consecutive days. In the treatment group and with the same injection timing, subjects will receive 10 mg of nimodipine (Shandong Xinhua Pharmaceutical Co.,Ltd., Zibo, China) in 500 mL of physiological saline in a covered container, intravenously. The initial intravenous rate will be 1–2 drops per minute and gradually increased if systolic blood pressure remains the same. The intravenous drip will be discontinued if systolic blood pressure drops by more than 10 mmHg. The maximum drip rate will be ≤10 drops per minute once per day for 7 days (Wang et al.,2014). During intravenous drug administration, a monitor will be used for blood pressure and heart rate continuous measurements. According to patient’s conditions, subjects in both groups will be medicated to treat dehydration and upper gastrointestinal bleeding, preventing infection, and to maintain water and electrolyte balance. Symptomatic treatment will be conducted in patients with complications,such as coronary heart disease, hypertension, and diabetes.A packet flow chart of the trial is shown in Figure 1.

Outcome measures

Primary outcomes: (1) the National Institutes of Health Stroke Scale (Brott et al., 1989) will be used to evaluate the severity of neurological impairment; (2) cranial CT scan and magnetic resonance imaging will be used to evaluate brain lesions; (3) the Rankin scale (Rankin, 1957) will be used to assess the recovery of neurological impairment;and (4) the Barthel index (Keith et al., 1987) will be used to evaluate the activities of daily living. Secondary outcomes: heart rate and blood pressure. Other outcomes:adverse reactions during medication, such as headache,dizziness, gastrointestinal symptoms, and changes in liver and kidney function. The timing of the outcome assessment is shown in Table 2.

Table 1: Previous studies addressing the treatment of acute massive cerebral infarction using nimodipine

Table 2: Timing of outcome assessment

Figure 1: Flow chart of the trial.

Data management and statistical analysis

It is the responsibility of the researchers to ensure the accuracy of all data entered and recorded in the case-report forms (CRFs) and the database for his or her site. The data will be collected by the researchers onto a paper CRF for subsequent transcription to the electronic CRF.

A unique numeric identifier will be assigned to each patient, which will be entered as electronic data. The researchers will ensure that patient data are kept securely.Both physical and electronic storage of data will protect the security of these data and the confidentiality of participants.Follow-up will be completed by a professional researcher through medical record consultation and telephone contact.The primary and secondary outcome measures will be analyzed according to intention-to-treat principles.

All data will be analyzed using SAS 8.0 software (SAS Institute Inc., Carey, NC, USA). Numeration data will be expressed as percentages, and statistical differences will be compared using the chi-square test. Measurement data will be expressed as the the mean ± SD, and statistical differences between groups will be compared using the paired t-test or those among groups using analysis of variance and the least significant difference test. P ＜ 0.05 will be considered statistically significant.

Ethical considerations and informed consent

This project has obtained the written approval of the Ethics Committee of Central Hospital Affiliated to Shenyang Medical College of China. Investigator or investigatorauthorized personnel will explain the benefits and risks of participating in the study to each patient, patient’s legitimate representative, or notary and witness, and obtain written informed consent. The study is in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.

Discussion

Citicoline given to the control group is a membrane stabilizer, has neuroprotective effects, can promote cerebral metabolism and improve cerebral circulation by reducing cerebral vascular resistance and by increasing cerebral blood flow, contributes to the recovery of cerebral function, and has been extensively used to treat acute cerebral infarction(Alvarez-Sabín and Román, 2013; Nomani and Kamal,2013). Therefore, citicoline will be used as a positive control drug in our study.

Existing studies regarding nimodipine effects in acute massive cerebral infarction are mainly retrospective studies and non-randomized control studies, which cannot rule out the effects of non-drug therapies that may affect the objectivity of the results. These studies also have limitations such as small sample sizes and short-term follow-ups, which may have affected the results. Our proposed double-blind randomized controlled trial is designed to determine the optimal time window for the use and dosage of nimodipine to treat acute massive cerebral infarction and to provide effective evidence for the clinical application of nimodipine.

Trial status

Ongoing and recruiting at time of submission.

Conflicts of interest

None declared.

Author contributions

RHL conceived and designed the trial procedure, wrote the paper and approved the final version of the paper for publication.

Plagiarism check

This paper was screened twice using CrossCheck to verify originality before publication.

Peer review

This paper was double-blinded and stringently reivewed by international expert reviewers.

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