Effectiveness and safety of Qidong Huoxue decoction (芪冬活血饮) in treatment of acute lung injury and acute respiratory distress syndrome: a randomized, controlled trial

Abstract

OBJECTIVE:

To evaluate the efficacy of Qidong Huoxue decoction (芪冬活血饮，QDHX) in treating acute lung injury and acute respiratory distress syndrome (ALI/ARDS) when used as an adjunctive treatment.

METHODS:

ALI/ARDS patients admitted to our medical intensive care unit were randomly allocated to the control group or the QDHX group and received standard therapy. The QDHX group received QDHX (50 mL per day for 14 d) orally or via a gastric tube. The primary outcome was measured according to Traditional Chinese Medicine (TCM) syndrome scores, with partial pressure of oxygen/fraction of inspired oxygen (PaO₂/FiO₂) levels as the secondary outcome.

RESULTS:

A total of 73 patients completed the study (36 in the TCM and 37 in the conventional group), and their records were analyzed. After 14-d treatment, the TCM group showed a significant decrease in TCM syndrome scores (P < 0.05) and increased PaO₂/FiO₂ levels (P < 0.05). The therapeutic effect of integrated Chinese and western medicine was more significant than that of Western Medicine alone. No serious side effects were observed.

CONCLUSIONS:

Our study results show that QDHX in combination with conventional drug therapy can significantly reduce some clinical symptoms in patients with ALI/ARDS.

1. INTRODUCTION

First described in 1967, acute respiratory distress syndrome (ARDS) is a cascading process that develops from acute lung injury (ALI).¹ ALI/ARDS is an acute, diffuse, inflammatory lung condition that results in increased pulmonary vascular permeability, increased lung weight, and loss of ventilating lung tissue.² The prevalence of ARDS accounts for 10.4% of intensive care unit (ICU) admissions and 4% of all hospitalizations; the mortality rate in some patients is as high as 60%, with an approximate 40% mortality rate overall.³ Although there have been many advances in the understanding of ALI/ARDS, treatment by Western Medicine still mainly consists of symptom management.

Traditional Chinese Medicine (TCM) has been used in clinical practice for more than 2000 years. Characterized by a holistic view and syndrome differentiation, it has shown unique advantages in the prevention, treatment, and rehabilitation of various diseases as well as in health care in general.⁴ Many efforts have been made by doctor of TCM to find natural therapies that can effectively treat symptoms such as asthma and chest tightness for centuries. ALI/ARDS is the disease name based on modern medicine studies while there is not same name in TCM. According to TCM theory, ALI/ARDS belongs to the category of diseases such as “dyspnea”.⁵ Adding to TCM’s long history of treatment for ARDS, great progress has also been made in recent years.^6,⇓,⇓-9 For example, Qidong Huoxue (芪冬活血饮，QDHX) is a Chinese herbal medicine used for the treatment of ALI/ARDS. An empirical formula composed of Huangqi (Radix Astragali Mongolici), Maidong (Radix Ophiopogonis Japonici), Danggui (Radix Angelicae Sinensis), Huzhang (Radix Polygoni Cuspidati), and Dahuang (Radix Et Rhizoma Rhei Palmati), QDHX was developed by Prof. CAI, a well-known doctor in Zhejiang Province, based on the basic theory of TCM treatment for ALI/ARDS. Prof. CAI focused on the ALI/ARDS’s TCM pathologic basis of ‘deficiency, heat, stasis’, followed the treatment principle of clearing heat and toxicity, removing stasis and purging Fu, nourishing Qi and Yin, emphasized on treating lung and bowel together, cared of spleen and stomach. QDHX has the functions of clearing heat and toxicity, removing stasis and purging Fu, nourishing Qi and Yin. Studies have shown that QDHX reduces the secretion of inflammatory factors, regulates the balance between anti-inflammatory and pro-inflammatory factors, reduces acidosis, increases the partial pressure of oxygen (PaO₂), decreases the partial pressure of carbon dioxide (PaCO₂), alleviates edema and bleeding in the alveolar septum, and acts as an antioxidant.^10,⇓-12 However, few clinical trials have examined the efficacy of TCM for ALI/ARDS. In this study, we aimed to evaluate the effectiveness and safety of QDHX on the symptoms and quality of life of patients with ALI/ARDS, as an adjunctive therapy to western medical standard treatment.

2. METHODS

2.1. Study design

This prospective, randomized controlled trial was conducted at the Second Affiliated Hospital of Zhejiang Chinese Medical University from June 2016 to January 2021. Ninety patients were assigned to the experimental groups using a table of computer-generated random numbers. According to the order of admission, the patients were randomly allocated to one of two groups: the control group and the TCM herb group.

2.2. Ethical considerations

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (No. 2016-17), in line with the guidelines of the Declaration of Helsinki, and was registered in the Clinical Trial Registry of China (ChiCTR2100050170). All participants signed informed consent to participate in the study.

2.3. Inclusion/exclusion criteria

The inclusion criteria were as follows: (a) diagnosed with ALI/ARDS according to The Berlin Definition published in 2012 and conformed to the TCM syndrome of heat toxin stasis and deficiency of both Qi and Yin; (b) admitted to our hospital for treatment and mechanical ventilation; (c) aged between 18 and 85 years; (d) without tumor or autoimmune disease; (e) did not participate in clinical studies of any other drugs within 1 month; and (f) volunteered to participate in this trial and signed the informed consent form.¹³ The exclusion criteria were as follows: (a) patients with pulmonary edema due to hypoproteinemia owing to liver or kidney disease or malnutrition, cardiogenic pulmonary edema, acute pulmonary embolism, reconstructive pulmonary edema, pulmonary edema due to tumor compression or pulmonary fibrosis, pulmonary edema due to upper airway obstruction, or any medical history that, according to the investigator's judgment, could interfere with test results or increase the patient's risk of treatment; (b) patients with QDHX allergy or an intolerance; (c) pregnant or lactating women; (d) psychiatric patients; or (e) patients who were participating in clinical trials of other drugs.

2.4. Intervention

According to guidelines for the treatment of ALI/ARDS, all participates received general standard treatment such as active treatment of primary disease, infection control, mechanical ventilation, prevention and treatment of complications, administration of sedative, corrected water-electrolyte disturbance and acid-base imbalance, nutritional support, airway management and so on. In addition, TCM group received QDHX formula. All herbs were obtained from qualified suppliers in Zhejiang Province, China, and the formula was manufactured by the Pharmaceutical Department of Chinese Herbal Medicine of the Second Affiliated Hospital of Zhejiang Chinese Medical University. TCM groups received 50 mL of QDHX per day for 14 d using a gastric tube (experimental group). The investigators were trained beforehand and were provided with a printed standardized protocol and case report form. Clinical assessments, adverse events assessments and safety examinations were made at 7th, 14th after enrollment.

2.5. Randomization, blinding, and data quality

After subjection to rigorous inclusion and exclusion criteria, patients were randomly allocated to either the QDHX experimental group or the control group in a 1 ∶1 ratio. Randomization with a computer-generated random number table ensured as far as possible that the two groups had the same number of participants. The investigators were blinded to the treatment assignment, and the patients remained blinded to the treatment assignment throughout the study. Data were monitored for accuracy.

2.6. Outcomes

The primary endpoint was the TCM syndrome score on the 14th day of hospitalization. The secondary endpoints included PaO₂/FiO₂ (fraction of inspired oxygen) levels. TCM syndrome scores were taken from TCM theory based on the quantitative assessment of the symptoms of each ALI/ARDS patient’s system, in line with the guidelines for clinical research of new drugs of TCM issued in 2002,¹⁴ and were in line with preliminary investigations and research results. The key points of the score include the patient’s TCM symptoms such as gasping for breath, chest tightness, shortness of breath, cyanosis of lips, irritability, cough, aversion to cold, fever, fatigue, appetite, tongue and pulse (supplementary Table 1). The total score was 58 points, and the lowest was 0 points, with higher scores indicating greater disease severity. TCM diagnoses in all participants were made by the same physician.

2.7. Safety assessment

The safety evaluations were conducted at baseline, treatment for 1week and treatment for 2 weeks, including the report of serious adverse events and laboratory results such as creatinine, liver function and so forth.

2.8. Sample size estimation

No clinical trial existed on the efficacy of QDHX decoction in treating ALI/ARDS, but according to our previous clinical observation, QDHX decoction was shown effectiveness of treating patients with ALI/ARDS. The TCM syndrome scores of patients which received Western Medicine treatment were estimated to be 25 ± 5. And the patients which received TCM combined with western medicine treatment were observed to have lower TCM syndrome scores. Average difference between the two groups were 6. The power of test was at 90% and the shedding rate at 20%. According to formula below, the sample size for each group was calculated to be 40, and thus 80 cases were needed for this case.

$n=\frac{\left(\mathrm{Z}_{\alpha}+\mathrm{Z}_{\beta}\right)^{2} * 2 \sigma^{2}}{\delta^{2}}$

2.9. Statistical analysis

Continuous data are reported as statistical means and standard deviations for normally and as medians and quantiles for non-normally distributed data; categorical data are reported as frequencies and percentages. Shapiro-Wilk test was used for testing normality. Comparisons were performed with independent-samples t-tests, Fisher’s exact test, Mann-Whitney U-test, or χ² tests, as appropriate. The missing values percentage was lower than 2% and missing values were corrected using a mean value imputation. And there were no missing values in primary or secondary endpoints. Correlation analysis was done using Spearson Correlation Analysis method. The P-values were two-sided at a significance level of 0.05. Data were analyzed with R (version 4.02, R Foundation for Statistical Computing, Vienna, Austria).

3. RESULTS

3.1. Baseline characteristics

A total of 90 patients with ALI/ARDS participated in the study, 49 of whom were randomly allocated to the conventional group and 41 to the TCM herb groups. Seventeen patients discontinued the study after randomization, 12 of whom were in the conventional group and five in the TCM group. Ultimately, 73 patients completed the study, and their records were analyzed. The demographic characteristics and clinical information of the two groups were comparable. Among the 73 patients, 36 patients were randomized to the TCM herb and 37 to the conventional group. TCM syndrome scores and PaO₂/FiO₂ level at different time point between two groups were shown in Figure 1. There were no significant differences at baseline (Table 1).

Figure 1. TCM syndrome scores and PaO₂/FiO₂ levels.

A1: TCM syndrome scores on the 1st day; A2: TCM syndrome scores on the 7th day; A3: TCM syndrome scores on the 14h day; B1: PaO₂/FiO₂ levels on the 1st day; B2: PaO₂/FiO₂ levels on the 7th day; B3: PaO₂/FiO₂ levels on the 14th day; C: TCM syndrome scores on the 1st, 7th, and 14th day for the TCM treatment group and the conventional group; D: PaO2/FiO2 levels on the 1st, 7th, and 14th day for the TCM treatment group and the conventional group. The TCM group (n = 36) and conventional group (n = 37) received general standard treatment. In addition, TCM groups received 50 mL of QDHX per day for 14 d. TCM: Traditional Chinese Medicine; PaO₂: oxygen tension; FiO₂: fraction of inspired oxygen; crt: Conventional group; trt: Traditional Chinese Medicine group; QDHX: Qidong Huoxue decoction. All data is presented in the form of bar charts and scatter plots.

Table 1.

Baseline clinical characteristics

Item	Overall (n = 73)	TCM group (n = 36)	Conventional group (n = 37)	P value
Sex [F/M, n (%)]	25/48 (34.2/65.8)	11/25 (30.6/69.4)	14/23 (37.8/62.2)	0.624
Age	73.00 (66.00, 81.00)	74.50 (68.00, 85.00)	70.00 (63.00, 80.00)	0.068
TCM syndrome scores	29.21 (9.01)	30.86 (8.80)	27.59 (9.03)	0.122
HGB (g/L)	109.00 (84.00, 125.00)	110.50 (91.00, 133.00)	104.00 (78.00, 123.00)	0.235
WBC (109/L)	9.80 (6.91, 16.00)	9.80 (7.47, 12.60)	9.90 (6.40, 16.90)	0.783
PLT (109/L)	160.00 (110.00, 230.00)	166.50 (133.50, 230.00)	147.00 (105.00, 199.00)	0.206
CRP (mg/L)	65.30 (32.00, 119.00)	81.12 (44.32, 141.77)	53.68 (20.90, 111.00)	0.077
D-D (mg/L)	3.38 (1.73, 6.46)	3.36 (1.90, 6.49)	3.67 (1.12, 6.46)	0.804
PCT (µg/L)	0.31 (0.13, 1.30)	0.26 (0.12, 1.79)	0.38 (0.14, 1.04)	0.749
Murray score	1.50 (1.00, 2.00)	1.62 (1.25, 2.00)	1.50 (1.00, 2.00)	0.493
APACHE II	17.00 (12.00, 24.00)	17.00 (12.75, 24.00)	17.00 (12.00, 22.00)	0.715
PaO2/FiO2	187.00 (153.00, 232.00)	192.50 (158.50, 240.50)	180.00 (145.00, 224.00)	0.110

Notes: the TCM group and conventional group received general standard treatment. In addition, TCM groups received 50 mL of QDHX per day for 14 d. TCM: Traditional Chinese Medicine; HGB: hemoglobin; WBC: white blood cell; PLT: blood platelet; CRP: C-reactive protein; D-D: D-dimer; PCT: procalcitonin; APACHE II: Acute Physiology and Chronic Health Evaluation II; PaO₂/FiO₂: oxygen tension/fraction of inspired oxygen. The continuous variables are presented as median (Q1, Q3), and categorical variables are presented as numbers and percentages. Student t-test was used for comparison analysis.

3.2. Primary outcomes

Compared with the control group, TCM syndrome scores of TCM herb group decreased significantly at day 14 (P < 0.001). And there were no statistically significant differences between two groups at day 7 (P > 0.05) (Table 2, Figure 2). TCM syndrome scores decreased compared with baseline in both groups at various time points.

Table 2.

Comparison of TCM clinical syndromes in TCM group and Conventional group ($\bar{x}±s$)

Time	TCM group (n = 36)	Conventional group (n = 37)	t value	P value
Baseline	31±9	28±9	－1.57	0.122
After 7 d treatment	20±6	23±8	1.47	0.148
After 14 d treatment	11±4	20±8	5.73	< 0.001

Notes: the TCM group and conventional group received general standard treatment. In addition, TCM groups received 50 mL of QDHX per day. TCM: Traditional Chinese Medicine. Student t-test was used for comparison analysis.

Figure 2. Comparison between the TCM herb and control groups after treatment of 7 and 14 d.

A: comparison of TCM Syndrome Score between the TCM herb and control groups after treatment of 7 and 14 d; B: comparison of PaO₂/FiO₂ between the TCM herb and control groups after treatment of 7 and 14 d. TCM: Traditional Chinese Medicine; crt: conventional group; trt: TCM group. QDHX: Qidong Huoxue decoction; PaO₂/FiO₂: oxygen tension/fraction of inspired oxygen. The TCM group and conventional group received general standard treatment. In addition, TCM groups received 50 mL of QDHX per day for 14 d. Student t-test and one-way analysis of variance were used for comparison analysis. ^aP > 0.05, vs conventional group; ^bP < 0.0001 vs conventional group; ^cP < 0.01, vs conventional group;

3.3. Secondary outcomes

Compared with the control group, PaO₂/FiO₂ level of TCM herb group at day 7 was not significant, and after 14 d of treatment was significantly higher than that of the control group, and the difference was statistically significant (P = 0.006) (Table 3, Figure 2). Spearman correlation analyses showed that TCM symptom scores on day 14 were positively correlated with APACHE Ⅱ and Murray scores on day 7, with procalcitonin and Murray scores on day 14, and with hemoglobin levels on day 14, and negatively correlated with hemoglobin levels on day 7 and the oxygenation index on day 14 (Figure 3).

Table 3.

Comparison of PaO₂/FiO₂ levels in TCM group and conventional group (IQR)

Time	TCM group (n = 36)	Conventional group (n = 37)	W value	P value
Baseline	192.50 (158.50, 240.50)	180.00 (145.00, 224.00)	521	0.110
After 7 d treatment	255.50 (179.50, 327.25)	230.00 (168.00, 323.00)	660	0.947
After 14 d treatment	332.50 (239.25, 378.25)	250.00 (180.00, 313.00)	418.5	0.006

Notes: the TCM group and conventional group received general standard treatment. In addition, TCM groups received 50 mL of QDHX per day. The data are presented as median (Q1, Q3). TCM: Traditional Chinese Medicine; QDHX: Qidong Huoxue decoction; PaO₂/FiO₂: oxygen tension/fraction of inspired oxygen; IQR: interquartile range. Wilcoxon Rank Sum Test was used for comparison analysis.

Figure 3. Spearman correlation analysis.

TCM: Traditional Chinese Medicine; HGB: hemoglobin; WBC: white blood cell; PLT: blood platelet; CRP: C-reactive protein; D-D: D-dimer; PCT: procalcitonin; APACHE II: Acute Physiology and Chronic Health Evaluation II; PaO₂/FiO₂: oxygen tension/fraction of inspired oxygen.

3.4. Adverse events and safety analysis

No serious adverse events were observed in two groups. We checked laboratory tests such as creatinine, BUN, platelet, D-dimer, ALT, AST levels in each group. And results were shown in Supplementary Figure 1.

4. DISCUSSION

ARDS is a clinical syndrome characterized by pulmonary edema and diffuse pulmonary interstitial inflammation caused by damage to alveolar epithelial cells and capillary endothelial cells.¹⁵ ARDS is an important cause of admission to ICUs and a leading cause of ICU deaths. Currently, there is no specific treatment for ARDS, and its economic burden is an urgent global concern.¹⁶ Any treatment that can reduce patient’s symptoms is encouraged.

In china, TCM formulations are commonly and widely used to treat different diseases including common emergency severe syndrome. Although there is no record of ALI/ARDS in TCM ancient books, the clinical symptoms caused by ALI/ARDS have been recognized for a long time. As Ling Shu informed us, patient with lung disease usually was puffing hard with flared nostrils. In TCM theories, ALI/ARDS caused by various inducements, such as six exogenous pathogenic factors, epidemic toxin, injury, postpartum, febrile disease, blood loss, carbuncle, which were consistent with its etiology in the view of western medicine. The pathogenesis of ALI/ARDS are mainly due to the process that evil poisons invade the lung, enter the body and transform heat, burn fluid into phlegm, phlegm heat obstructs the lung, and the lung Qi stagnates and reverses, and finally leading to disease state. Based on the above characteristics, many TCM herb decoctions have been reported to be proven effective such as Dachengqi decocation,¹⁷ Jiawei Xuanbai Chengqi Tang,¹⁸ Chaiqin Chengqi decoction,¹⁹ Baofei Jiejiong mixture,²⁰ etc. Some scholars have explored the internal mechanism of TCM for ARDS/ALI treatment from the perspective of modern medicine. They have found TCM exerts therapeutic effect through multiple pathways that are highly related to ARDS.^{21,⇓,⇓,⇓,⇓-26}

QDHX decoction has been used for over 30 years to effectively treat ALI/ARDS.²⁷ The ingredients of QDHX decoction play different roles in the theory of TCM. Combination of Dahuang (Radix Et Rhizoma Rhei Palmati) and Huzhang (Radix Polygoni Cuspidati) can clear away heat and relieve the toxin, remove stasis and relax the bowels. Combination of Huangqi (Radix Astragali Mongolici) and Maidong (Radix Ophiopogonis Japonici) can nourish Qi and Yin, tonify Qi and promote fluid production. Combination of Huangqi (Radix Astragali Mongolici) and Danggui (Radix Angelicae Sinensis) can tonify Qi and promote blood circulation with an important synergistic effect in the theory of “Qi generates blood”. This formula has the characteristics of dispelling evil without harming the right and strengthening the right without retaining evil. Its effects are consistent with the pathogenesis of ALI/ARDS.

Although QDHX decoction has been used clinically for many years, there is still lack of high-quality evidence-based trials. This study makes up this vacancy and leads to high credibility of QDHX’s clinical effectiveness. To ensure quality, the researchers participating in the trial were consistent and had experience with clinical trials and the necessary skills and qualifications; before the clinical trial, the participating clinicians carefully studied the clinical trial plan and implemented various technical indicators. Our findings that QDHX in combination with western medical treatment can significantly reduce some clinical symptoms, will offer a new treatment option for patients with ALI/ARDS. In addition, the incidence of adverse events showed no difference between the two groups. The clinical findings are also supported by the results of previous laboratory tests showing that QDHX reduces the secretion of inflammatory factors, regulates the balance between anti-inflammatory and pro-inflammatory factors, alleviates acidosis, increases PaO₂, decreases PaCO₂, alleviates alveolar septal edema and bleeding, and acts as an antioxidant.^10,⇓-12 This study also has some limitations. First, we did not set the follow-up period and period may be extended. Second, a larger sample size will be required to validate results. Third, our study involved a Chinese population only. Briefly, with the increasing use of TCM throughout the world, multi-center, long-term, large-scale, and methodologically sound trials are warranted.

In conclusion, the TCM and Western Medicine treatment groups showed an advantage over the control group in relieving clinical symptoms and syndromes associated with ALI/ARDS and showed increased PaO₂/FiO₂ levels. Applying TCM herbs during standard treatment according to the official guidelines may be an inexpensive, safe, and efficient way to help ALI/ARDS patients.

5. SUPPORTING INFORMATION

Supporting data to this article can be found online at http://journaltcm.cn.

Funding Statement

Supported by Zhejiang Province Traditional Chinese Medicine Science and Technology Plan: the Study on Clinical Effects of Qidong Huoxue decoction in the Treatment of Acute Lung Injury (No.2017ZZ008)