Delirium Treatment With Acupuncture in Internal Medicine Departments: a Randomized Sham-controlled Clinical Trial
Phase: NA
Conditions: Delirium in Old Age
Sponsor: Bnai Zion Medical Center

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Official Title: The treatment of delirium in older adults hospitalized in internal medicine 
departments: an open-label pragmatic randomized-controlled trial 
NCT number: NCT03398928 
Date of the document: June 1, 2020 
 
METHODS: 
Trial Design: This is a pragmatic open-label randomized-controlled trial. The patients were 
allocated to one of two arms: acupuncture with standard-of-care (SOC) and SOC only (Fig. 1). 
The study protocol was reviewed and approved by the Institutional Review Board in accordance 
with the Helsinki Declaration (0102-14-BNZ) and registered at www.clinicaltrials.gov 
(NCT03398928). Trial methods and results were reported according to the Consolidated 
Standards of Reporting Trials (CONSORT) for non-pharmacologic interventions 2010 
guidelines.24 
Setting and participants: Trial site investigators identified consecutive eligible patients 
admitted to internal medicine departments at Bnai-Zion Medical Center, a 450-bed, academic 
hospital located in Haifa, Israel. Physicians and nurses screened daily all hospitalized patients 
aged 65 years and more for delirium, regardless of baseline cognitive function, using the 
validated 4AT delirium screening tool.25 For patients found to have a positive 4AT screening 
result, investigators used the validated, four-feature-Confusion Assessment Method (CAM) 
tool26 to confirm the presence of subsyndromal delirium or delirium according to DSM-5 
definition. Delirium was deemed to be present when both an acute and fluctuating course and 
inattention and either disorganized thinking or an impaired level of consciousness was 
identified,26 while subsyndromal delirium was defined as acute and fluctuating course criteria 
and any one of the three other criteria.27 Participants were considered eligible for the study if 
they met all study criteria. Informed consent was obtained from patients or their next-of-kin as 
detailed in a preceding manuscript.28 Patients were enrolled either at hospital admission 
(prevalent delirium) or during hospitalization (incident delirium). Patients with prevalent 
delirium were randomized within 48 hours of admission; patients with incident delirium were 
randomized within 48 hours of delirium occurrence. All patients were classified as having 
subsyndromal, hyperactive, hypoactive or mixed type delirium. Information was extracted from 

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patients, family and medical records to ensure that all study criteria are met before the patient 
or his/her next-of-kin was approached for consent. 
Inclusion criteria: 
(1) Hospitalized to an inpatient internal medicine unit. 
(2) Age ≥ 65 years. 
(3) Diagnosed with delirium or subsyndromal delirium within the past 48 hours. 
Exclusion criteria:  
(1) Having a contraindication to acupuncture (e.g., platelets ≤  20 x 109/L).29 
(2) History of severe dementia (documented history and/or IQCODE score ≥ 4). 
(3) Acute neurological injury (stroke). 
(4) History of schizophrenia or a formal thought disorder. 
(5) Active acute alcohol or drug withdrawal. 
(6) History of end stage liver failure. 
(7) Communication barriers preventing delirium assessment. 
Interventions: Enrolled patients were allocated to one of the following treatment groups:  
1. Acupuncture with SOC (acupuncture group): up to 5 sessions of acupuncture in a 1-week 
period or until discharge, and SOC treatment for up to 1 week or until discharge. 
2. SOC only (SOC or control group): up to 1 week or until discharge . 
The development of the intervention protocol was inspired from the 2008 Medical Research 
Council guideline for developing complex interventions, as described in a previous 
manuscript.28 Acupuncture treatment was reported according to STRICTA guidelines30 in 
http://www.stricta.info. 
Acupuncture rationale: The acupuncture was performed in a Traditional Chinese Medicine 
(TCM) style. Patients were categorized according to TCM syndromes of  hyperactive delirium 
(Fire blazing and Phlegm fire); hypoactive delirium (Qi deficiency, Yang deficiency, Yang 
deficiency with Phlegm, and Qi obstructed), or mixed delirium (Blood and Qi deficiency, and 

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Yin deficiency). The TCM categorization was based on pulse diagnosis and clinical 
observation. Due to the difficulty of tongue examination and anamnesis in delirious patients, 
these elements were rarely used in the diagnostic process.31 Then, TCM-based acupuncture 
treatment was performed according to the delirium TCM syndrome category.31 
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 Seirin FDA-approved needles of 5-cm length and 0.2-mm 
diameter were inserted. The puncture depth varied with anatomical location from 0.5 to 1 cm. 
Manual needle stimulation was performed and de qi sensation (e.g. dullness, sourness, 
heaviness, tingling sensation around the needle) was not sought. 
Treatment regimen: The number of acupuncture treatments was set at up to five treatments in 
the one-week study period (treatments was not provided on weekends) or until the patient is 
delirium-free for 48 hours. Each session lasted 15-20 minutes. 
Other components of treatment: Patients of acupuncture group also received SOC. Prior to the 
start of the study, a multicomponent protocol for delirium management was developed and 
implemented in internal medicine departments. This protocol was based on best literature 
evidence, current practice guidelines32,33 and the opinions of geriatric and psychiatric 
consultants, and  included both pharmacological and non-pharmacologic interventions as 
published in a preceding manuscript.28 All clinicians working in the internal medicine 
departments were educated regarding the protocol and its use. This protocol was defined “SOC” 
for the study. Since the actual care of patients may differ according to clinical data and physician 
consideration, the use of psychotropic drugs (including antipsychotics) during hospitalization 
were documented and compared between the study arms. No other complementary medicine 
therapies other than acupuncture were added. Explanations were given to patients and their 
next-of-kin 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 seven acupuncturists with at least 
5 years of clinical experience in a hospital setting. 
Control intervention: In the control group, patients received SOC only. 
Outcomes: All daily outcomes were collected daily for one week after randomization or until 
the patient was discharged from the hospital. 

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Primary outcome: Our primary endpoint was resolution of delirium during the 7 days of 
evaluation and was measured as time-to-first remission of delirium and number of delirium-
free days, based on daily assessment of CAM scale. 
Secondary outcomes: 
1. Delirium severity: Comparison of the sum of long CAM-severity (CAM-S) score34 from day 
2 (before treatment in the second day of the study) until day 7 (last day of evaluation). The 
CAM-S tool includes 10 delirium-related items, the first one being rated on a 0-1 scale and the 
nine followings in a 0-2 scale for a total score ranging from 0-19. The items include the four 
CAM items described earlier in addition to disorientation, memory impairment, perceptual 
disturbances, psychomotor agitation, psychomotor retardation and altered sleep-wake cycle. 
The sum of long CAM-S score has been shown to best reflect both 30-day and 90-day post-
hospital outcomes in patients with delirium.34 
2. Number of days an antipsychotic drug was administered: as mentioned in the daily study 
investigator chart review. 
3. Pain: based on twice daily Visual Analogue Scale (VAS) scores for communicating patients 
and FRAAC (Facial expression, Respiration, Activity, Audibility, Cry and consolability) scores 
for non-communicating patients. Both scales are rated on a 0-10 score and are comparable in 
terms of pain severity. They were routinely recorded twice daily by registered nurses. 
4. Sleep quality: as assessed by the tenth CAM-S item. 
5. Delirium complications: daily evaluation of falls, pulling-out intravenous or urinary 
catheters, new or increase in pressure ulcers grade. 
6. Length of hospital stay 
7. Functional status at discharge: based on Katz ADL at discharge as evaluated by study 
investigators.  
8. Safety and adverse events: A checklist with acupuncture adverse events based on the AcupAE 
questionnaire35 was adapted to our study. All adverse events were recorded and monitored 
daily. Acupuncture-associated adverse events were discussed by the research team and the 
family of patients and addressed accordingly. Severe adverse events requiring patient exclusion 

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from the clinical trial included pneumothorax, massive bleeding, or infection in the acupoint 
area requiring systemic antibiotic treatment. 
Sample size calculation: Since no previous study has evaluated an acupuncture-based 
intervention in older adults with delirium, a pilot study of 32 patients [acupuncture group 
(n=24); control group (n=8)] was designed to estimate accurately the sample size for our current 
study. In the pilot study, delirium-free days were 3.2±1.6 in the acupuncture group as compared 
with 1.7±2.4 in the control group. Taking into account a Type I error (alpha) of 0.05, a power 
of 0.80, pairwise comparison between our two study arms, and using G*Power 3.1.9.4 software, 
we calculated a minimal sample size of 28 patients in each of the 2 study arms. 
Randomization: Patients were randomized in two groups by convenience allocation according 
to acupuncturists' working days: patients with delirium diagnosed on Sunday, Monday, 
Wednesday or Thursday were assigned to the acupuncture arm, while patients with delirium 
diagnosed on Tuesday, Friday or Saturday were assigned to SOC arm. Blinding was clearly not 
feasible. 
Statistical methods: Demographic and clinical data was analyzed at baseline to measure the 
balance among the study groups. Quantitative variables were described using mean and 
standard deviation or median with range (minimum and maximum) depending on their 
distribution. Qualitative variables were described using frequency and percentage distributions. 
Next, we showed that our variables distribute equally between the two groups. For comparing 
normally distributed variables between our study groups, we used the t-test for independent 
samples. For comparing variables that do not distribute normally between our study groups, we 
used the Mann-Whitney test. For comparing qualitative variables between our study groups, we 
used the independent Chi-square test and Fisher exact test. Time-to-first delirium remission was 
evaluated using the Kaplan-Meier product limit survival estimator with log-rank between-group 
comparison and Cox regression was performed for multivariate adjustment of potential 
confounders. Hazard ratio (HR) with confidence intervals (CI) was calculated for each 
independent variable and controlled for all other independent variables in the regression. 
Patients who died or were discharged before day 7 had all subsequent days counted as the last 
day of evaluation in terms of both CAM and CAM-S. Intention-to-treat (ITT) analysis was 
planned to provide more information on the effect of the intervention. We explored the variables 
for possible collinearities, interaction, and confounders. All comparisons were two-sided with 

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significance level set at p<0.05. Data analysis was performed using IBM SPSS version 22 
statistics software. 
 

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RESULTS: 
Baseline patient data: Overall, 132 patients were screened for eligibility. Among them, 81 were 
recruited – 50 to the acupuncture arm and 31 to the SOC arm. Baseline sociodemographic and 
medical characteristics were similar in the two study arms as shown in Table 1. To note, all the 
patients randomized to the acupuncture arm were treated with acupuncture, while no patient 
assigned to the SOC arm received acupuncture (Fig. 1), so the planned ITT analysis was not 
required. In the acupuncture arm, 14 (28%) were censored (dead/discharged in the 7 days of 
follow-up), as compared with 8 (26%) in the SOC arm (p=0.87). No difference in the baseline 
characteristics was noted between censored patients and patients completing the 7 days of 
follow-up. 
Primary endpoint: Time-to-first delirium remission was shorter in the acupuncture arm as 
compared to the SOC arm (p<0.001 for log-rank comparison, Fig. 2A). In the 7 days of 
evaluation, we calculated a number needed to treat (NNT) of 3 for first delirium remission. A 
multivariate Cox regression analysis was also conducted to evaluate the association of study 
arm allocation with the primary outcome (time-to-first delirium remission), adjusted for 
potential sociodemographic and medical confounders (age, gender, APACHE-II score, 
Charlson comorbidity index, number of psychotropic drugs, mobilization, cognitive 
impairment, reason for admission and type of delirium). The analysis showed that after 
adjusting for potential confounders, the time-to-first remission of delirium in the acupuncture 
arm was significantly shorter than in the SOC arm [HR 0.267 (95% CI 0.098-0.726, p=0.010), 
Fig. 2B], while HR of potential confounders were not statistically significant. This means that 
acupuncture associated with SOC significantly increased the incidence of delirium remission 
by about 4-times, as compared to SOC only, after adjusting for sociodemographic and medical 
characteristics (model significance: p=0.042). Furthermore, in the 7 days of evaluation, a 
significantly higher number of delirium-free days was found in the acupuncture arm [median 
5.5 (0-6)] as compared with the SOC arm [median 0 (0-6)], p<0.001. Based on these results, 
the power of the study was calculated as 100%. 
Secondary endpoints: 
Delirium severity: The long CAM-S sum from day 2 to day 7 of evaluation was significantly 
lower in the acupuncture group [11 (24%) with no delirium, 6 (13%) with low severity, 9 (20%) 
with moderate severity and 19 (42%) with high severity] as compared with the control group 

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[3 (11%) with no delirium, 0 with low severity, 1 (4%) with moderate severity and 24 (86%) 
with high severity], p=0.002, Fig. 3. 
Number of psychotropic drugs-free days: The number of psychotropic drugs-free days in the 7 
days of evaluation was similar in the two study groups [median: 7 (0-7) in acupuncture arm vs 
7 (0-7) in SOC arm, p=0.253]. 
Pain: No difference in daily evaluation of pain intensity was found between the two study arms 
in the 7 days of evaluation. 
Sleep: According to the tenth CAM-S item daily evaluation, no difference was found in terms 
of quality of sleep between the study arms during the 7 days of evaluation. 
Delirium complications: No difference was found in terms of delirium-related complications 
between the study arms [median: 0 (0-6) complications in acupuncture arm vs 0 (0-1) 
complications in SOC arm, p=0.665]. 
Length of hospitalization: The duration of hospitalization was similar in the 2 study arms 
[median: 13 (2-67) days in the acupuncture arm vs 12 (2-54) in the SOC arm, p=0.945]. 
Functional status at discharge: Katz ADL at discharge was similar in the two study arms 
[median: 2 (0-6) in the acupuncture arm vs 3.5 (0-6) in the SOC arm, p=0.945]. 
Safety: No safety event was reported according to daily AcupAE evaluation. 
 
 
 

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Tables and figures: 
Table 1: Baseline characteristics 
Baseline characteristics 
Acupuncture + SOC (n=50) 
SOC only (n=31) 
p 
Male gender – N (%) 
25 (50%) 
19 (61%) 
0.36 
Age (years) – Mean (SD) 
84.0 (7.8) 
85.3 (6.7) 
0.45 
Prevalent delirium – N (%) 
26 (52%) 
16 (52%) 
1.00 
APACHE-II – Median (min-max) 
9 (5-22) 
11 (6-19) 
0.31 
Number of medications – Median (min-max) 
8 (0-16) 
9 (1-15) 
0.38 
Number of psychotropic drugs – Median (min-max) 
1 (0-5) 
1 (0-3) 
0.66 
Mobilization – N (%) 
Normal 
24 (48%) 
9 (19%) 
0.19 
Walking aid 
15 (30%) 
15 (48%) 
Wheelchair 
2 (4%) 
3 (10%) 
Bedridden 
9 (18%) 
4 (13%) 
IQCODE – N (%) 
Normal cognitive status 
28 (56%) 
12 (39%) 
0.35 
Mild dementia 
17 (34%) 
16 (52%) 
Moderate dementia 
4 (8%) 
3 (10%) 
Severe dementia 
1 (2%) 
0 
ADL – Median (min-max) 
4.5 (0-6) 
4 (0-6) 
0.36 
Reason for admission – N (%) 
Infection 
19 (38%) 
12 (39%) 
0.94 
Dyspnea 
9 (18%) 
9 (29%) 
General Deterioration 
8 (16%) 
4 (13%) 
Falls 
3 (6%) 
3 (10%) 
Anemia 
2 (4%) 
1 (3%) 
Other 
9 (18%) 
2 (6%) 
Delirium category – N (%) 
Hyperactive 
23 (46%) 
12 (39%) 
0.45 
Hypoactive 
15 (30%) 
12 (39%) 
Mixed 
9 (18%) 
3 (10%) 
Subsyndromal 
3 (6%) 
4 (13%) 
Hearing and/or visual impairment – N (%) 
26 (52%) 
22 (71%) 
0.11 
Charlson Comorbidity Index – Median (min-max) 
7 (4-13) 
7 (4-11) 
0.97 
Baseline delirium severity (Long CAM-S) – Median (min-max) 
8 (3-15) 
9 (4-14) 
0.63 
Legend: ADL: Activities of Daily Living; APACHE: Acute Physiology And Chronic Health 
Evaluation; CAM-S: Confusion Assessment Method Severity; SOC: Standard-of-care. 
 
 

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Figure 1: CONSORT Flow Diagram for non-pharmacologic interventions 
Legend: SOC: Standard-of-care 
 
 
 
 Assessed for eligibility 
(n= 132)
 
Randomized (n = 81) 
Allocated to acupuncture + SOC (n = 50) 
Received allocated intervention (n = 50) 
Did not receive allocated intervention 
(give reasons) (n = 0) 
Excluded (n= 51) 
   Not meeting inclusion criteria (n= 48) 
   Declined to participate (n= 3) 
   Other reasons (n= 0) 
Lost to follow-up (give reason) (n = 0) 
Discontinued intervention (give reasons) 
(n = 0) 
 
Analysed (n = 50) 
Excluded from analysis (give reasons) (n = 50) 
Enrollment
 
Patients
 
Allocation: 
patients
 
Follow-up 
patients
 
Analysis 
patients
 
Care providers (n = 7), teams (n = 1), 
centers (n= 1) performing the intervention 
Number of patients treated by each care 
provider (median = 6 [min=1, max=18])  
Lost to follow-up (give reason) (n = 0) 
Discontinued intervention (give reasons) 
(n = 0) 
 
Analysed (n = 31) 
Excluded from analysis (give reasons) (n = 31) 
Allocation: Care 
Providers
 
Allocated to SOC only (n = 31) 
Received allocated intervention (n = 31) 
Did not receive allocated intervention (n = 0) 
 

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Figure 2: Time to first delirium remission 
 
A. p<0.001 
 
B. HR 0.267 (95% CI: 0.098-0.726, p=0.010) 
A. Kaplan-Meier graph with Log-rank comparison of time to first delirium remission between 
study groups. B. Cox regression analysis of time to first delirium remission considering 
sociodemographic and medical covariates. 
Legend: SOC: Standard-of-care. 
 
 

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Figure 3: Delirium severity 
 
Legend: CAM-S: Confusion Assessment Method Severity; SOC: Standard-of-care. 
24.40%
10.70%
13.30%
20.00%
3.60%
42.20%
85.70%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Acupuncture + SOC (n=45)
SOC only (n=28)
DELIRIUM SEVERITY (CAM-S SUM DAY 2-7)
None (CAM-S sum = 0-3)
Low (CAM-S sum = 4-6)
Moderate (CAM-S sum = 7-13)
High (CAM-S sum ≥ 14)