Acupuncture Efficacy in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease During Hospitalization: a Randomized Controlled Trial
Phase: NA
Conditions: COPD Exacerbation
Sponsor: Bnai Zion Medical Center

Official title: Treatment of acute exacerbations of chronic obstructive pulmonary disease with 
acupuncture during hospitalization: a three-arm double-blinded randomized sham-controlled 
trial 
NCT number: NCT03398213 
Date of the document: June 3, 2020 
 
Methods: 
Study design: This is a three-arm 1:1:1 randomized-controlled trial evaluating the efficacy and 
safety of the addition of acupuncture to SOC as compared to sham-procedure added to SOC 
(sham-control) and to SOC only (SOC-control) for treatment of AECOPD in patients 
hospitalized in internal medicine departments. The study protocol was reviewed and approved 
by the Institutional Review Board (IRB) in accordance with the Helsinki Declaration (0108-17-
BNZ) and registered at www.clinicaltrials.gov (NCT03398213). Trial methods and results were 
reported according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 
guidelines.19 
Participants: Patients hospitalized in internal medicine departments with a previous diagnosis 
of COPD3 were evaluated by department physicians. Inclusion criteria included a previous 
diagnosis of COPD and a clinical diagnosis of AECOPD as defined by the GOLD criteria.3 
Exclusion criteria included hemodynamic instability, a platelet count below 20x109/L, expected 
respiratory deterioration requiring mechanical ventilation in the next 24 hours, or an inability 
to provide informed consent. Primary socio-demographic and medical data were recorded and 
compared between the three study groups. 
Setting: The study was set in internal medicine departments of Bnai Zion medical center, a 
tertiary hospital in Haifa, Israel. 
Interventions: The intervention protocol was based on a literature review and the Delphi 
process. A panel of eight acupuncturists of at least 5 years of experience in treating hospitalized 
patients were consulted. The experts were asked to review and analyze the literature regarding 
Traditional Chinese Medicine (TCM) and COPD, delineate relevant TCM syndromes and 
associated "critical" acupoints and treatment frequency. Their suggestions were based on 
literature data and their professional experience. Finally, three cycles of stepwise anonymous 
discussions were taken to obtain a consensus on the treatment approach. The conclusion was to 

assign the patients into three groups for four daily consecutive treatment sessions and a 4-day 
follow-up. 
Standard-of-care (SOC) only: Patients received SOC for AECOPD according to a standard 
protocol based on the GOLD guidelines.3 Such therapy included oxygen to maintain saturation 
around 90%, inhalations, antibiotics and systemic corticosteroids for five days. Noninvasive or 
mechanical ventilation were added depending on the severity of the AECOPD, as determined 
by clinical evaluation and blood gases. 
True acupuncture + SOC group: Acupuncture treatment was documented according to 
STRICTA guidelines.20  
- 
Acupuncture rationale: The acupuncture was performed in a TCM style. During the 
Delphi process, a list of acupoints relevant to acute lung conditions were determined 
and associated with different TCM syndromes. Practitioners systematically documented 
syndrome diagnosis according to TCM reasoning and used only acupoints appearing in 
the list and corresponding to the TCM diagnosis. 
- Details of needling: During the treatment, the acupuncturists used 75% alcohol pads to 
sterilize the skin around the acupoints. Subsequently, sterile disposable needles were 
inserted in the acupoints. An average of five Eco FDA-approved needles of 3-cm length 
and 0.22-mm diameter were inserted. The puncture depth varied with anatomical 
location from 0.5 to1 cm. Manual needle stimulation was performed, but de qi sensation 
(e. g. dullness, sourness, heaviness, tingling sensation around the needle) was not 
sought. 
- 
Treatment regimen: Four daily consecutive 15-20-minute sessions were administered. 
- 
Other components of treatment: Patients in this group also received SOC as described 
earlier. No other complementary medicine therapies were added. Explanations were 
given to patients on potential benefits and side effects of acupuncture and treatment was 
administered only after they signed informed consent. 
- 
Practitioner background: The treatment was administered by eight acupuncturists with 
at least 5 years of clinical experience in a hospital setting. 
- 
Control intervention: The two control groups were SOC only (SOC-control) and SOC 
with sham-procedure (sham-control). 
Sham-procedure + SOC group: Department physicians underwent a one-hour training on 
placing plasters on ear-points that have no relevance to lung conditions. During this training, 

they were taught they are actually treating patients by stimulating ear acupoints and that the aim 
of the study was to compare the efficacy and safety of acupuncture administered by an 
experienced acupuncturist as compared to acupressure administered by unexperienced medical 
staff after a short training. Patients were told they are receiving ear-point stimulation. Therefore, 
this study arm was double blinded. SOC was administered as well as described earlier. 
Outcomes: 
The primary outcome was dyspnea intensity pre- and post-treatment in the 4 days of follow-up. 
It was measured daily, before and one hour after treatment (for acupuncture and sham-control 
groups) or after first evaluation (for SOC-control group), via the modified Borg (mBorg) scale, 
which is a validated scale that has been used to evaluate the degree of dyspnea (0- no dyspnea, 
to 10- worse dyspnea) in both stable COPD and AECOPD.21,22 Dyspnea intensity was chosen 
as primary outcome since it has been shown to predict clinical outcomes in AECOPD.23 
Secondary outcomes included: 
Variation of clinical symptoms: Including cough intensity and sputum production associated 
with the AECOPD, as evaluated on a Visual Assessment Scale from 0 (no symptom) to 10 
(maximally symptomatic), throughout the 4 days of evaluation. 
Variation of physiologic features: Venous blood gases (pH and pCO2) and oxygen saturation 
were measured before intervention and daily in the four evaluation days. Respiratory rate (RR) 
was measured daily, before and one hour after treatment (for true acupuncture and sham-control 
groups) or after first evaluation (for SOC-control group). 
Treatment failure: Defined as death during hospitalization or need for noninvasive or 
mechanical ventilation. Treatment failure incidence was evaluated and compared between the 
three groups. 
Duration of hospitalization: Evaluated and compared between the three study arms. 
Safety: Acupuncture-related side effects were systematically evaluated after treatment in the 
true acupuncture group via the validated Acup-AE questionnaire administered to the patient by 
the acupuncturist immediately after therapy.24 
Minimal sample size: In a previous study evaluating the efficacy of acupuncture vs sham-
acupuncture in 68 patients with chronic COPD (34 patients in each group), a 3.6±1.9 units 
improvement in dyspnea (according to mBorg scale) was found in the acupuncture arm, as 

compared with a 0.4±1.2 units improvement in the sham-acupuncture arm.8 According to these 
data and ANOVA test with alpha of 0.05 and an 80% power, we calculated a minimal sample 
size of 66 patients (22 in each group) for the current study. 
Randomization: Patients meeting inclusion/exclusion criteria were randomized to either SOC 
with acupuncture (true acupuncture), SOC with sham-procedure (sham-control) or SOC only 
(SOC-control) using 1:1:1 permuted block randomization. The permuted block randomization 
list was generated by Excel software. To guarantee allocation concealment, randomization was 
done by an independent research assistant who did not participate in any other parts of the 
research and assigned the group code to each participant according to the randomization list. 
The independent research assistant was blinded to the meaning of the group code. 
Blinding: Data collectors, department physicians, physicians administering the sham-procedure 
and the statistician were blinded to the group allocation status; acupuncturist blinding is clearly 
not possible, however, contact time with patients was the same in both true acupuncture and 
sham-control arms (15-20 min). Patients receiving both true acupuncture and sham-procedure 
were told they are treated for their respiratory condition by acupuncture/acupressure. The group 
allocation status was revealed after completion of the study. 
Statistical analysis: Demographic and clinical data was analyzed at baseline to measure the 
balance among the study groups. Quantitative variables were described using mean ± standard 
deviation or median and 25th-75th percentiles (Q1, Q3) depending on their distribution. 
Qualitative variables were described using frequency and percentage distributions. Next, we 
showed that our variables distribute equally between the study groups. For comparing normally 
distributed variables between our study groups, we used the ANOVA test. For comparing 
variables that do not distribute normally between our study groups, we used the Kruskal-Wallis 
test with adaptation to pairwise comparison. For comparing qualitative variables between our 
study groups, we used the independent Chi-square test and Fisher exact test. Bonferroni 
adjustment was used for multiple comparisons for each independent comparison of true 
acupuncture vs sham-control, true acupuncture vs SOC-control and sham-control vs SOC-
control. Since the variation of dyspnea intensity between day 1 and day 2 had a normal 
distribution, a multivariate linear regression analysis was performed after collinearity, 
interaction and confounding analysis, in order to neutralize the effect of the different 
sociodemographic and medical covariates on the primary outcome in the 3 study arms. The 
adjusted unstandardized regression coefficients were given with confidence interval (CI), while 

a p<0.05 was considered as statistically significant. Data analysis was performed using IBM 
SPSS version 22 statistics software. 
 

Results: 
Baseline patient data: 104 patients were screened for eligibility from November 2017 to 
February 2020. Among them, 72 met inclusion criteria and were recruited. Twenty-six of them 
were assigned to the true acupuncture arm, 24 to the sham-control arm, and 22 to the SOC-
control arm. Baseline demographic and clinical characteristics were similar in patients from the 
3 study arms as shown in Table 1. To note, all the patients randomized to any of the three groups 
completed treatments per-protocol (Fig. 1). 
Primary outcome: Baseline dyspnea was similar in the three groups. A statistically significant 
difference between the three groups in dyspnea intensity was found from the first day of 
evaluation after treatment (median [Q1, Q3] mBorg score 5.0 [4.0, 5.0] in true acupuncture, 6.0 
[4.25, 7.875] in sham-control and 7.5 [5.5, 8.0] in SOC-control, p=0.014 – significant difference 
of both true acupuncture vs sham-control: p=0.031, and true acupuncture vs SOC-control: 
p=0.014, but non-significant between sham-control and SOC-control: p=0.34), and until day 3 
after treatment (Fig. 2A). After adjustment for such covariates in a multivariate linear regression 
analysis, the association of study arm with improvement of dyspnea from day 1 to day 2 
remained statistically significant (Table 2). 
Secondary outcomes: 
- 
Patient-reported outcomes: 
Baseline VAS scores for cough and sputum intensity were similar in the three study arms (Table 
1). No statistically significant difference in the cough intensity was observed between the three 
study arms throughout the 4 days of follow-up (Fig. 2). However, a statistically lower level of 
sputum production was observed in the true acupuncture arm as compared with sham-control 
and SOC-control from day 2 (p=0.04) (Fig. 2). Post-hoc analysis showed a statistically 
significant difference between true acupuncture and sham-control in day 2 (p=0.024), day 3 
(p=0.010) and day 4 (p=0.018), while only on day 2 between true acupuncture and SOC-control 
(p=0.044), and no statistically significance between sham-control and SOC-control. 
- 
Physiologic assessment: 
Baseline physiologic data were similar in the three groups (Table 1). A statistically significant 
difference was observed in respiratory rate (RR) at day 2 after treatment (p=0.002), with 
significant difference both between true acupuncture and sham-control (p=0.005) and between 
true acupuncture and SOC-control (p=0.003), but not between sham-control and SOC-control 

(p=0.050), while all other RR measurements were statistically similar between the 3 arms 
throughout the 4-day follow-up (Fig. 3A). 
Concerning pH, a statistically significant difference was observed at day 4 between the 3 groups 
(p=0.048), although post-hoc analysis did not show any statistical significance when comparing 
groups head-to-head (Fig. 3C). 
No statistically significant difference was observed when comparing other physiologic 
measures between the 3 study groups (Fig. 3). 
- 
Treatment failure: 
No death or mechanical ventilation occurred in the study participants during follow-up. 
However there had a total of 4 treatment failures, all of them were non-invasive ventilations, 
which occurred in 2 (8%) patients in the true acupuncture arm, 1 (4.3%) in the sham-control 
arm and 1 (5%) in the SOC-control arm (p=0.83). 
- 
Duration of hospitalization: 
No difference was noted in terms of duration of hospitalization between the three study arms 
(5.5±2.3 days for true acupuncture vs. 6.0±2.9 days for sham-control and 6.3±2.9 days for SOC-
control, p=0.050). 
- 
Safety: 
No side effect of acupuncture treatment was reported during the study period as assessed by the 
Acup-AE questionnaire. 
 

Tables and Figures: 
Table 1: Baseline characteristics 
Characteristics 
True acupuncture 
(N=26) 
Sham-control 
(N=24) 
SOC-control 
(N=22) 
p 
Age (mean ± SD) 
69.2±10.1 
70.7±8.1 
67.4±9.3 
0.47 
Gender (Men) 
20 (77%) 
15 (62%) 
17 (77%) 
0.43 
Comorbidities 
Cardiovascular 
Respiratory (other than COPD) 
Gastroenterological 
Renal / Urologic 
Metabolic / Endocrinological 
Hematological / Oncological 
Neurological 
 
18 (69%) 
7 (27%) 
2 (8%) 
7 (27%) 
15 (58%) 
3 (12%) 
4 (15%) 
 
20 (83%) 
2 (8%) 
4 (17%) 
3 (12%) 
13 (54%) 
6 (25%) 
0 (0%) 
 
15 (68%) 
5 (23%) 
5 (23%) 
5 (23%) 
13 (59%) 
3 (14%) 
1 (5%) 
 
0.42 
0.23 
0.34 
0.44 
0.94 
0.40 
0.09 
Smoking status 
Smoker 
Former smoker 
Never smoked 
 
13 (50%) 
13 (50%) 
0 
 
16 (67%) 
8 (33%) 
0 
 
14 (64%) 
8 (36%) 
0 
 
0.44 
CCI (median [Q1, Q3]) 
6.0 [3.5, 6.0] 
5.0 [4.0, 6.75] 
4.5 [3.0, 7.25] 
0.87 
COPD severity 
Mild: FEV1 ≥ 80% 
Moderate: 50% ≤ FEV1 < 80% 
Severe: 30% ≤ FEV1 < 50% 
Very severe: FEV1 < 30% 
Unknown 
 
1 (4%) 
 4 (15%) 
 7 (27%) 
5 (19%) 
9 (35%) 
 
0 (0%) 
 5 (21%) 
 11 (46%) 
4 (17%) 
4 (17%) 
 
1 (5%) 
5 (23%) 
9 (41%) 
4 (18%) 
3 (14%) 
 
 
0.69 
Pulmonary hypertension 
None 
Mild: mPAP = 25-40 mmHg 
Moderate: mPAP = 41-55 mmHg 
Severe: mPAP > 55 mmHg 
Unknown 
 
10 (38%) 
4 (15%) 
3 (12%) 
0 
9 (35%) 
 
15 (62%) 
3 (12%) 
0 
0 
6 (25%) 
 
16 (73%) 
3 (14%) 
2 (9%) 
0 
1 (5%) 
 
 
 
0.11 
COPD exacerbation hospitalizations 
0 
1-4 
≥5 
 
19 (73%) 
6 (23%) 
1 (4%) 
 
12 (50%) 
11 (46%) 
1 (4%) 
 
9 (41%) 
9 (41%) 
4 (18%) 
 
 
0.09 
Treatment 
Inhalations 
Systemic corticosteroids 
Theophylline 
Oxygen home therapy 
BiPAP 
 
24 (92%) 
3 (12%) 
0 
8 (31%) 
4 (15%) 
 
23 (96%) 
3 (13%) 
0 
12 (52%) 
2 (8%) 
 
22 (100%) 
1 (5%) 
1 (5%) 
8 (36%) 
4 (18%) 
 
0.41 
0.61 
0.32 
0.29 
0.60 
APACHE-II at admission (mean ± SD) 
13.3±3.6 
12.0±4.4 
11.0±3.8 
0.14 
Baseline data (median [Q1, Q3]) 
Dyspnea (mBorg) 
Cough (VAS) 
Sputum (VAS) 
 
8.0 [5.5, 8.75] 
7.5 [5.0, 8.0] 
6.0 [1.5, 7.5] 
 
6.5 [5.0, 8.5] 
5.0 [5.0, 7.4] 
6.0 [4.25, 6.0] 
 
7.75 [6.0, 8.5] 
5.0 [3.6, 7.5] 
5.0 [1.9, 6.0] 
 
0.82 
0.35 
0.22 
O2 saturation 
≤ 80% 
81-89% 
≥ 90% 
 
4 (15%) 
9 (35%) 
13 (50%) 
 
1 (4%) 
10 (42%) 
13 (54%) 
 
0 
10 (45%) 
12 (55%) 
 
0.30 
PCO2 (mmHg) 
< 45 
45-60 
60-80 
> 80 
 
6 (23%) 
12 (46%) 
5 (19%) 
3 (12%) 
 
3 (12%) 
17 (71%) 
4 (17%) 
0 
 
8 (36%) 
9 (41%) 
5 (23%) 
0 
 
 
0.10 
pH 
< 7.2 
7.2-7.3 
> 7.3 
 
0 
5 (19%) 
21 (81%) 
 
0 
4 (17%) 
20 (83%) 
 
0 
1 (5%) 
21 (95%) 
 
 
0.30 
Respiratory rate (/min) (median [Q1, Q3]) 
21 [16, 23.75] 
22 [16.5, 26] 
20 [16, 22] 
0.26 
Legend: CCI: Charlson Comorbidity Index; mPAP: Mean Pulmonary Arterial Pressure; SOC: Standard-Of-Care. 

Table 2: Multivariate linear regression analysis on variation of dyspnea from day 1 to day 2 
Factors and covariates 
Adjusted unstandardized 
coefficient (B) 
95% Confidence interval 
p value 
Inferior 
Superior 
Constant (Intercept) 
2.088 
-3.409 
7.584 
0.457 
Study Arm 
True acupuncture 
Sham-control 
SOC-control 
 
2.172 
0.390 
0 
 
0.421 
-1.319 
- 
 
3.923 
2.099 
- 
 
0.015 
0.655 
- 
Cardiovascular comorbidities (0=No, 1=Yes) 
-0.322 
-2.935 
1.391 
0.713 
Gastroenterological comorbidities (0=No, 1=Yes) 
4.703 
2.527 
6.879 
<0.001 
Hospitalizations for COPD in the last year 
-0.379 
-0.756 
-0.003 
0.048 
Age 
-0.040 
-0.133 
0.053 
0.400 
APACHE-II 
0.118 
-0.099 
0.336 
0.287 
Charlson Comorbidity Index 
-0.026 
-0.406 
0.354 
0.894 
 
 

Figure 1: Flow-chart 
 
Legend: SOC: Standard-of-care. 
 
Screened for eligibility 
(n=104)
Randomization (n=72)
Allocated to SOC only 
(n=22):
Received allocated 
intervention (n=22)
Did not receive allocated 
intervention (n=0)
Follow-up: up to one week 
or until discharge (n=22):
Lost to follow-up in hospital 
(n=0)
Discontinued intervention 
(n=0)
Analyzed (n=22)
Allocated to true 
acupuncture + SOC 
(n=26):
Received allocated 
intervention (n=26)
Did not receive allocated 
intervention (n=0)
Follow-up: up to one week 
or until discharge (n=26):
Lost to follow-up in hospital 
(n=0)
Discontinued intervention 
(n=0)
Analyzed (n=26)
Allocated to sham 
procedure + SOC (n=24):
Received allocated 
intervention (n=24)
Did not receive allocated 
intervention (n=0)
Follow-up: up to one week 
or until discharge (n=24):
Lost to follow-up in hospital 
(n=0)
Discontinued intervention 
(n=0)
Analyzed (n=24)

Figure 2: Between-group comparison of patient-reported outcomes 
 
 
 
 
p value 
0.82 
0.014 
0.019 
0.002 
0.003 
0.009 
0.053 
0.067 
 
p value 
0.35 
0.13 
0.10 
0.19 
 
 
p value 
0.22 
0.04 
0.022 
0.04 
 
 
0
1
2
3
4
5
6
7
8
9
10
Day 1
before
Day 1
after
Day 2
before
Day 2
after
Day 3
before
Day 3
after
Day 4
before
Day 4
after
Median mBjorg (0-10)
2A. Dyspnea
True acupuncture
Sham procedure
SOC
7.5
4.5
3
2.5
5
5
5
4.5
5
5
5
5
0
2
4
6
8
10
Day 1
Day 2
Day 3
Day 4
Median VAS (0-10)
2B. Cough intensity
True acupuncture
Sham procedure
SOC
6
2.75
2
2
6
5.5
5
5
5
4.5
4.5
5
0
2
4
6
8
10
Day 1
Day 2
Day 3
Day 4
Median VAS (0-10)
2C. Sputum intensity
True acupuncture
Sham procedure
SOC

Figure 3: Between-group comparison of physiologic features 
 
 
p value 
0.26 
0.19 
0.19 
0.002 
0.53 
0.18 
0.93 
0.17 
 
 
 
p value 
0.30 
0.63 
0.16 
0.25 
 
 
p value 
0.30 
0.17 
0.33 
0.045 
 
p value 
0.10 
0.61 
0.38 
0.29 
 
0
5
10
15
20
25
30
Day 1
before
Day 1
after
Day 2
before
Day 2
after
Day 3
before
Day 3
after
Day 4
before
Day 4
after
MEDIAN RR (/MIN)
3A. Respiratory rate
True acupuncture
Sham procedure
SOC
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Day 1
Day 2
Day 3
Day 4
Patients' percentage
3B. SaO2 evolution
SaO2<81
SaO2 81-89
SaO2>89
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Day 1
Day 2
Day 3
Day 4
PATIENTS' PROPORTION
3C. pH evolution
pH<7.2
pH 7.2-7.3
pH>7.3
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Acupuncture
Sham
SOC
Day 1
Day 2
Day 3
Day 4
Patients' percentage
3D. pCO2 evolution
PCO2<45
PCO2 45-60
PCO2 60-80
PCO2>80