Albuterol combined with tiotropium bromide to improve the conditions and pulmonary functions of patients with acute exacerbation of chronic obstructive pulmonary disease

Abstract

We aimed to explore the clinical efficacy and effects of albuterol combined with tiotropium bromide on pulmonary functions of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). 72 patients with AECOPD were divided into a combination treatment group (n = 38, albuterol + tiotropium bromide) and the control group (n = 34, routine treatment). Efficacy, incidence of adverse reactions, results of blood gas analysis, pulmonary function indices, time to improve clinical symptoms, St. George's respiratory questionnaire (SGRQ), and British Medical Research Council (MMRC) scores were compared between the two groups. The overall response rate was significantly higher, and the time to improve coughing was significantly shorter, in the combination treatment group compared with controls (p < 0.05). After treatment, both groups achieved a marked rise in PaO₂, forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio, and peak expiratory flow (PEF) (p < 0.05), which was more dominant with combination therapy. The reduction in PaCO₂ was more obvious in the combination therapy group. The combination of albuterol and tiotropium bromide is an effective treatment for patients with AECOPD and functions by improving conditions and pulmonary functions without raising the incidence of adverse reactions.

KEYWORDS:

• Albuterol and tiotropium bromide in combination
• acute exacerbation of chronic obstructive pulmonary disease
• efficacy
• prognosis

Introduction

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common but progressively developing pulmonary disease characterized by airflow limitation and persistent decline in pulmonary function (PF). Patients with severe AECOPD are likely to experience respiratory failure and heart failure (Kiser and Vandivier 2015; Tan et al. 2017). With middle-aged and senior populations as the major targets, the disease is associated with a high incidence and case fatality rate as well as difficulties in treatment (Jing et al. 2016; Liu et al. 2017). So far, the clinical treatments for AECOPD have focused on improving PF, blood oxygen levels, and mitigating clinical symptoms (Tan et al. 2017; Morantes-Caballero and Fajardo Rodriguez 2019). Therefore, to find an appropriate clinical treatment to improve PF, pneumodynamics, and blood gas indices of AECOPD patients has become a major focus of pulmonary research (Yohannes et al. 2017; Heys et al. 2018).

Glucocorticoids, oxygen therapy, and bronchiectasia are usually adopted in the clinical treatment of AECOPD (Yao et al. 2017). Albuterol is a selective receptor agonist with some effect on preventing and improving symptoms caused by airflow limitation (Allen et al. 2016). When used alone, however, the drug is not likely to be effective in patients with chronic obstructive pulmonary disease (COPD): in particular, AECOPD (Wolfe and Silvestri 2016; Jacobson et al. 2017). Tiotropium bromide, an anticholinergic bronchiectasia, may mitigate disease exacerbations and enhance a patient's activity level when applied alone, but it does not improve PF (Panahi et al. 2016; Ohbayashi 2017).

Given the complicated onset mechanisms of AECOPD, single-drug therapies in the past have often failed to achieve marked effects when recovering patients’ PF indices, whereas some drug combinations used together achieve synergistic effectiveness for enhanced efficacy, PF, and ventilatory capacity (VC) (Bourbeau et al. 2016; Kaufman 2017; Rajala et al. 2017). Therefore, in order to provide more strategies for treating AECOPD patients, this study compared the clinical efficacies of combination therapy with albuterol and tiotropium bromide with routine treatment by observing and comparing PF changes.

Materials and methods

General materials

A total of 72 patients with AECOPD were admitted to our hospital from September 2016 to June 2018 and were divided into the observational group (OG; n = 38; albuterol + tiotropium bromide) and the control group (CG; n = 34; routine treatment). There were 20 males and 18 females in the OG, with an average age of 56.67 (±7.58) years, while the CG consisted of 19 males and 15 females aged 55.52 (±5.49) years. Inclusion criteria consisted of the following: compliance with the diagnosis criteria for AECOPD and requirements of this study; age < 80; worsening syndromes such as dyspnea, fever, cough, and expectoration; onset in the past two weeks; and demanding hospital treatment. Exclusion criteria were: severe heart, liver, or kidney dysfunctions; mental disorder; psychological block; diseases of the heart, liver, kidney, hematopoietic, or immune systems; hyperthyrea; acute heart failure; pulmonary interstitial fibrosis; lung cancer; tuberculosis; pulmonary embolism; bronchiectasia and rhinallergosis; incomplete medical records; allergy to the drugs studied; taking medicines affecting the study results; poor drug tolerance; drug contraindications; and non-compliance with the doctor's advice on medication. This study was approved by the Ethics Committee of Linyi People's Hospital. The research objects and their families were informed and they signed a fully-informed consent form.

Methods

After basic treatments including apophlegmatisant (a medicine for treating cough and asthma), low-flow oxygen uptake, and anti-infection medication in the hospital, patients in the CG were given tiotropium bromide (Nanchang Hongyi Pharmaceuticals Co., Ltd., H20130110) at a dose of 18 μg per day; in addition to receiving all treatments of the CG, patients in the OG additionally inhaled 2 mL of albuterol sulfate (Qilu Pharmaceuticals Co., Ltd., H37021518) in the morning and at night. This treatment lasted for three months.

Observation indices

Before and after four courses of treatment, blood gas and PF indexes were measured with a blood gas analyzer (Shanghai Radiometer Medical Appliance Co., Ltd., ABL90), and a photoelectric PF detector (Anhui Hongzhong Medical Devices Co., Ltd., Microspiro Hl-205), respectively. PF indices included forced vital capacity (FVC), forced expiratory volume in one second (FFV1%), (FEVI/FVC), and peak expiratory flow (PEF); the degree of dyspnea was measured with the modified British Medical Research Council (MMRC) scale before and after treatment (Make et al. 2015). On this scale, a higher score indicates more severe dyspnea. Quality of life was evaluated by the St. George's respiratory questionnaire (SGRQ) (Tee 2017) and indicated with a mark between 0 (minimum damage) and 100. 0 (severe damage).

Efficacy criteria

‘Markedly effective’ was defined as symptoms such as cough, expectoration, gasping, palpitations, cyanosis, edema, and lung rales were basically mitigated in tranquility. An ‘effective’ status demonstrated that symptoms such as cough, expectoration, gasping, and palpitations were obviously mitigated, and lung rales were reduced. Ineffective was defined as these symptoms and vital signs were neither improved nor deteriorated. OR = Markedly Effective Rate + Effective Rate.

Statistical analysis

Statistical analysis was performed with SPSS22.0 (IBMCorp, Armonk, NY, USA). In cases of numerical data expressed as means ± standard deviation, comparison studies were carried out through t test; in the case of nominal data expressed as (%), comparison studies were carried out through the χ² test. For all statistical comparisons, significance was defined as p < 0.05.

Results

Patients

No significant difference was found between the two groups in terms of age, BMI, course of disease, gender, history of smoking and drinking alcohol, domicile, and grading (p > 0.05, Table 1).

Table 1. Intergroup comparison of basic materials.

Type	OG(n = 38)	CG(n = 34)	t/χ^2	P
Gender			0.076	0.782
Male	20(52.63)	19(55.88)
Female	18(47.37)	15(44.12)
Age (y)	56.67 ± 7.58	55.52 ± 5.49	0.730	0.468
BMI(kg/m^2)	24.42 ± 1.34	23.85 ± 1.49	1.709	0.092
Domicile			0.422	0.673
Urban	22(57.89)	18(52.94)
Rural	16(42.11)	16(47.06)
History of Smoking			0.888	0.346
Yes	24(63.16)	25(73.53)
No	14(36.84)	9(26.47)
Exercise Habit			1.158	0.282
Yes	17(44.74)	11(32.35)
No	21(55.26)	23(67.65)
History of Drinking Alcohol			0.134	0.715
Yes	15(39.47)	12(35.29)
No	23(60.53)	22(64.71)
Course of Disease (y)	8.72 ± 1.32	8.69 ± 1.16	0.102	0.919
Grading			0.518	0.772
I	5(13.16)	3(8.82)
II	21(55.26)	19(55.88)
III	11(28.95)	12(35.29)

Intergroup comparison of blood gas analysis

Before treatment, the two groups demonstrated no significant difference in PaO₂ and PaCO₂; after treatment, PaO₂ rose and PaCO₂ dropped in both groups: more significantly in the OG (p < 0.05, Figure 1).

Figure 1. Intergroup comparison of results of blood gas analysis.

Note: *p < 0.05 vs conditions before treatment; #p < 0.05 vs OG after treatment.

Intergroup comparison of PF indices

Before treatment, the FEV1, FEV1/FVC, and PEF were not statistically different between the two groups; after treatment, these three indices rose sharply in both groups, and more significantly in the OG (p < 0.05, Figure 2).

Figure 2. Intergroup comparison of PF indexes.

Note: *p < 0.05 vs conditions before treatment; #p < 0.05 vs OG after treatment.

Intergroup comparison of efficacy

The OG contained a greater percentage of marked effective cases and effective cases than did the CG, whereas the CG had a greater number of ineffective cases (p < 0.05, Table 2).

Table 2. Intergroup comparison of efficacy.

Type	OG (n = 38)	CG (n = 34)	χ^2	P
Markedly effective	9(23.68)	4(11.76)	4.086	0.043
Effective	25(65.79)	20(58.82)
Ineffective	4(10.53)	10(29.41)
OR	34(89.47)	24(70.59)

Intergroup comparison of incidence of adverse reactions

Adverse reactions before and after treatment were compared between the two groups. The OG reported one case of dry mouth (2.63%), one of palpitation (2.63%), two of nausea (5.26%), and one of constipation (2.63%) with a total incidence of 10.53%. In the CG, adverse reactions found were dry mouth (two cases; 5.88%) and constipation (one case; 2.94%), leading to a total incidence of 8.82% (not significant; Table 3).

Table 3. Intergroup comparison of incidences of adverse reactions.

Type	OG (n = 38)	CG(n = 34)	χ^2 value	P
Dry mouth	1(2.63)	2(5.88)
Palpitation	1(2.63)	(0)
Nausea	2(5.26)	(0)
Constipation	1(2.63)	1(2.94)
Total incidence	4(10.53)	3(8.82)	0.059	0.808

Intergroup comparison of SGRQ scores before and after treatment

Before treatment, the two groups did not have statistically different SGRQ scores; after treatment, however, both groups experienced a sharp score reduction (p < 0.05), which has greater significant in the OG (p < 0.05, Table 4).

Table 4. Intergroup comparison of SGRQ scores before and after treatment.

Group	Before treatment	After treatment
OG (n = 38)	58.89 ± 47	42.14 ± 4.32*
CG(n = 34)	58.16 ± 5.31	49.55 ± 3.97*
T	0.095	4.086
P	0.925	0.043

Note: *p < 0.05 vs conditions before treatment; 6.23 ± 0.41 4.95 ± 0.23 6.79 ± 0.45

Intergroup comparison of time to improve clinical symptoms

The time to improve clinical symptoms including cough, gasping, and lung rales, was significantly shorter in the OG than in the CG (p < 0.05, Table 5).

Table 5. Intergroup comparison of time to improve clinical symptoms (d).

Group	Time to eliminate cough	Time to eliminate gasping	Time to eliminate lung rales
OG (n = 38)	5.17 ± 0.38	3.37 ± 0.18	4.82 ± 0.27
CG(n = 34)	6.23 ± 0.41	4.95 ± 0.23	6.79 ± 0.45
t	11.34	32.19	22.19
P	<0.01	<0.01	<0.01

Intergroup comparison of MMRC scores before and after treatment

Before treatment, the two groups were not statistically different in MMRC scores, but after treatment, the index reduced sharply in both groups (p < 0.05), and more significantly in the OG (p < 0.05, Figure 3).

Figure 3. Intergroup comparison of MMRC before and after treatment.

Note: *p < 0.05 vs conditions before treatment; #p < 0.05 vs OG after treatment.

Discussion

COPD is a disease characterized by airflow limitation, long course, and easy onset, and it is accompanied by high airway reactivity, causing irreversible damage to PF. AECOPD is a phenomenon of serious deterioration as a result of acute onset of COPD in the consequence of severe lung infection. If AECOPD is not carefully and timely treated, it can further develop into pulmonary heart disease and respiratory failure, which seriously affect the quality of life and safety of patients (Adeloye et al. 2015; Lipson et al. 2018; Wei et al. 2018).

The key to clinical COPD treatment lies in effectively relieving patients from airway resistance and respiratory muscle fatigue, maintaining clear respiratory tract, and actively improving dyspnea-related syndromes to enhance patient PF. Throughout long-term clinical practice, single-drug therapies may have limited effects on COPD patients in terms of mitigating respiratory tract obstruction and respiratory muscle fatigue, but some drugs are capable of mitigating syndromes, improving PF, and slowing the progress of COPD (Rabe 2007). Therefore, medication still plays a vital role in the clinical treatment of COPD, and aerosol rebreathing method (ARM) is widely recognized for its effectiveness with AECOPD (Xiong et al. 2008). Ordinary drugs for ARM include receptor agonists and glucocorticoids (Hartman et al. 2015). As a selective β2 adrenergic receptor agonist, the aerosol particles of albuterol are driven by high-flow oxygen to reach the bronchioli terminals rapidly, where they inhibit the cholinergic nerve form releasing acetylcholine in large amounts and block the M receptors in the air tract, thus relaxing and humidifying bronchial smooth muscle, reducing mucus secretion and airway resistance, and increasing airway diameter. This results in better PF and respiratory mechanics and higher blood oxygen level in patients (Lötvall et al. 1998; Cazzola et al. 2015). Tiotropium bromide is a specific long-lasting antimuscarinic drug that can competitively inhibit M1 and M3 cholinergic receptors and reduce the tension of the cholinergic nerve, relax smooth muscle, and dilate the bronchus (Cazzola et al. 2015; Trudo et al. 2015). Relevant studies have revealed that the efficacy of tiotropium bromide is dose-dependent and may last 24 h to effectively mitigate bronchial spasms during sleep (Alvarado-Gonzalez and Arce 2015). Therefore, tiotropium bromide can maintain long-term PF improvement, bronchiectasia, and dyspnea mitigation. Panahi et al. (Panahi et al. 2016) found in their study that tiotropium bromide effectively mitigated major syndromes found in COPD patients and their overall SGRQ score, while Santus et al. (Santus et al. 2012) demonstrated the more ideal anti-inflammatory activity of tiotropium bromide when compared with formoterol by reducing the hyperoxides and LTB4 in the peripheral neutrophils of COPD patients. In a study designed by Vogelmeier et al. (Vogelmeier et al. 2013), a combined therapy significantly and consistently improved the PF of COPD patients, while in the present study, the combination of albuterol and tiotropium bromide, when compared with routine therapy, yielded a high OR and consumed less time to improve clinical symptoms, although no statistical difference arose in the total incidence of adverse reactions. These data suggest that the combination is an effective and feasible therapy for COPDs.

The alveolar wall and airway of COPD patients has different degrees of damage cumulatively resulting in a decrease in the lung's elastic resilience, FEV1, FEV1/FVC, and PEF and resulting in a significant increase in residual gas volume. A test of PF indexes before and after treatment showed that after treatment, both groups experienced a marked increase in FEV1, FEV1/FVC, and PEF (p < 0.05), which was more significant in the OG. Moreover, the results of blood gas analysis showed that the reductions in PaO₂ and PaCO₂ were more obvious in the OG after treatment, indicating the combination of albuterol and tropium bromide improves the PF and quality of life of these patients.

Although the study subjects were selected in strict accordance with the inclusion and exclusion criteria, the study failed to compare the long-term efficacy and the hazards related to AECOPD patients, which shall be ameliorated in future studies.

In conclusion, the combination of albuterol and tiotropium bromide is an effective treatment for patients with AECOPD as it can improve their conditions and PF without raising the incidence of adverse reactions.

Disclosure statement

No potential conflict of interest was reported by the authors.