Participants recruitment

A total of 121 children with viral myocarditis received and treated in Xingtai People’s Hospital from June 2019 to January 2022 were randomly divided into two groups, which were the control group (N = 60) and the traditional Chinese medicine group (N = 61). The diagnostic criteria of Western medicine were based on the diagnostic criteria of viral myocarditis (revised draft) issued in 2000. ¹⁴ The detailed criteria were as follows: (1) cardiac insufficiency, cardiogenic shock, or cardio-cerebral syndrome; (2) cardiac enlargement (one of the manifestations of X-ray and echocardiography); (3) ECG changes; (4) elevated creatine kinase myocardial isoenzyme or positive cardiac troponin (cTnI or cTnT). A clinical diagnosis of myocarditis can be made on the basis of 2 clinical criteria. Viral myocarditis can be diagnosed if the patient’s endocardium, myocardium, pericardium, or pericardiocentesis fluid is positive for viral nucleic acid or specific virus antibodies. The diagnostic criteria of Chinese medicine referred to the guiding principles for Clinical Research of New Drugs of traditional Chinese medicine formulated by the Ministry of Health of the People’s Republic of China. ¹⁵ The diagnostic basis of traditional Chinese medicine syndrome type included (1) palpitation, fatigue, dizziness, shortness of breath, upset and insomnia, hot heart in hands and feet; (2) chest tightness, chest pain, dry oropharynx; (3) red tongue, less fur, and thin or knot pulse. The cardiac function was documented according to the NYHA cardiac function classification. ^{Reference Caraballo, Desai and Mulder16}

The inclusion criteria were as follows: (1) age within 2–14 years old, (2) good compliance and clear medical records; (3) diagnosis with viral myocarditis according to clinical symptoms and laboratory tests or imaging tests. The exclusion criteria were as follows: (1) complicated with other heart diseases; (2) with malignant tumours; (3) suffering from serious liver and kidney diseases; (4) could not adhere to oral traditional Chinese medicine.

Ethics statement and informed consent

The researcher introduced the experimental objectives and experimental procedures. All children and their guardians were aware of the study and signed the informed consent after being fully aware of the possible risks and benefits. These experiments were approved by the Ethics Committee of Xingtai People’s Hospital and in accordance with the Declaration of Helsinki 1975. The clinical trials fully followed the requirements of good clinical practice. ¹⁷

Randomisation and blinding

The independent statistician generated a random allocation table, and patients with viral myocarditis were given random numbers. The patients obtained traditional Chinese medicine with respective number labelling. The statistician did not participate in any other processes, including patient collection, pharmacy, packaging, distribution, index determination, et cetera.

An independent researcher was responsible for decocting Yangxin Huoxue Jiedu and labelling the drug packages. This researcher did not participate in any other trials. Other researchers and all patients were only told the code. Only the principal investigator knows the complete treatment allocations. The distribution result will not be disclosed unless the patient has serious adverse events and reactions.

Components of the Yangxin Huoxue Jiedu recipe

The prescriptions for the Yangxin Huoxue Jiedu recipe are shown in Table 1. The dosage of one day and the potential effects of each traditional Chinese medicine material are also shown in Table 1. The medicinal materials were all provided by the traditional Chinese medicine pharmacy of Xingtai People’s Hospital. All the herbs in the Yangxin Huoxue Jiedu recipe were soaked in water for 30 min. The prescription herbs were decocted twice, and then, the residue was filtered. The decoctions were combined and concentrated to 400 ml, named one dose. Half dose (200 ml) was packaged in a separate container.

Table 1. The main components of YHJ decoction.

YHJ = Yangxin Huoxue Jiedu, a traditional Chinese medicine.

Placebo was manufactured on the basis of traditional Chinese medicine dilution, as described previously. ^{Reference Yap, Loo and Zheng18} The placebo is a decoction made of 5% Yangxin Huoxue Jiedu decoction, ingredient (starch), bittering agent, and colouring agent to ensure the similar visual feature, taste characteristics, smell sense, transparency, and turbidity to Yangxin Huoxue Jiedu decoction. This preparation method of placebo is a routine avenue, and the placebo is similar in nature to the traditional Chinese medicine but did not have pharmacological effects. ^{Reference Wang, Wang and Jia19} The specification of the placebo was 200 ml. The placebo was also prepared by the traditional Chinese medicine pharmacy of Xingtai People’s Hospital.

Management to patients

The patients in the control group were placebo and routine treatment, while those in the traditional Chinese medicine group were given Yangxin Huoxue Jiedu therapy and routine treatment. The routine treatment was symptomatic treatment according to the actual situation of the patients, including anti-virus treatment and anti-infection management. In addition, it also included nutritional guidance, oxygen support, and basic nursing. Drug options included antibiotic therapy, ribavirin, coenzyme Q10, and vitamin C. Antiviral therapy was administered with Wellbutrin at 15 mg/kg daily for 7 days of observation therapy. Improvement of myocardial metabolism was treated with coenzyme Q10 (20 mg each time, 3 times daily) and vitamin C (1 each time, twice daily) for 14 days. Penicillin was injected intramuscularly 2.5 × 104 U/ (kg-d) twice/d according to the condition. Intravenous gamma globulin 2 g/kg was administered intravenously in divided doses over 2–3 days.

The patients in the traditional Chinese medicine group were required to take the half dose (200 ml) twice in the morning and evening of one day. The patients in the control group received a 200 ml placebo in the same way as that of traditional Chinese medicine group.

Specimen obtain

The fasting venous blood of 5 ml of the two groups of patients was collected before and after a course of 14-day treatment and centrifuged for 5 min at 3000 r per minute. The upper serum was taken and deposited in the medical refrigerator at −80°C.

Diagnostic tests in patients with viral myocarditis

All children received routine electrocardiogram, 24-hour Holter ECG monitoring, and echocardiogram before treatment. Routine electrocardiograms were examined using an ECG-9130P 12-lead synchronised electrocardiograph (Nippon Kohden, Tokyo, Japan). A tracing speed of 25 mm per second was established to ensure that the baseline of the ECG recorded during the tracing period was stable, and the images were clear and free of interference. The ECG was monitored for 60s in the resting state of the patients, and the results were recorded. Dynamic electrocardiography was performed using a 300-4A dynamic electrocardiograph (DMS, Nevada, USA). Using high-quality electrodes special for dynamic electrocardiography, fastening the wires and electrodes, electrode sheets are correctly pasted, the conductive adhesive is evenly applied to the middle position of the electrode sheets, and all the electrode sheets need to be directly pasted on the skin of ribs and sternum. The results were automatically transmitted to the analysis system to analyse the results of 24h dynamic ECG examination. Arrhythmias mainly include sinus tachycardia, ST segment changes, and others including ventricular presystole, atrial presystole, atrioventricular block, paroxysmal supraventricular tachycardia, et cetera.

Echocardiography was performed with an HP77020AC ultrasound system from Hewlett-Packard. The left ventricular end-diastolic dimension, left ventricular end-systolic dimension, interventricular septal thickness, left ventricular ejection fraction, and cardiac enlargement (a chamber diameter or cardiothoracic ratio > 0.5 ^{Reference Park, Chon, Na, Lee and Choi20} ) were assessed by M-mode echocardiography. The measurements were repeated three times, and the average value was taken.

Curative effect standard

According to the changes in the myocardial enzyme spectrum, an electrocardiogram, and clinical symptoms, the curative outcome was estimated. The normal myocardial enzyme and electrocardiogram examination results and total disappearance of symptoms and signs mean the recovery effect of patients. When the symptoms and signs of patients obviously improved or basically disappeared, partial recovery of laboratory examination, which means excellent effect. The effectiveness was on behalf of recovery of more than one symptom or auxiliary examination. The ineffective meant no improvement in the main symptoms and examination. All these effects of Yangxin Huoxue Jiedu were distinguished by referring to the guiding principles for Clinical Research of New Drugs of traditional Chinese medicine.

Estimation of laboratory indicators

The changes of myocardial enzyme spectrum were revealed in all patients with viral myocarditis, including creatine kinase, creatine kinase myocardial isoenzyme, aspartate aminotransferase, lactic dehydrogenase, and hydroxybutyrate dehydrogenase. The serum cardiac troponin I, and brain natriuretic peptide of children with viral myocarditis were evaluated by immunoturbidimetry. ELISA method was used to detect inflammatory and oxidative factors, including serum interleukin-6, interleukin-8, tumour necrosis factor-α, and superoxide dismutase. The operation was carried out in strict accordance with the reagent instructions (Boster, Wuhan, China). The detection of malondialdehyde was performed based on the kit reference from Jisskang Biotechnology (Qingdao, China).

Safety assessment

During the study, the patient’s liver, renal function, electrolytes, analysis of blood, and urine analysis were examined. The adverse drug reactions and medical events of patients during treatment were recorded according to the requirements of the Administrative Measures for Adverse Drug Reaction Monitoring Reports. ²¹

Statistical analysis

SPSS Statistics 20.0 and GraphPad software 7.04 were used for statistical analysis. The measurement data are expressed by mean ± standard deviation, and the differences within and between groups were compared by t-test. The counting data were exhibited by n (%), and χ² test was used. The difference was statistically significant (p < 0.05).