Research

Original Investigation

Device-Guided Breathing as Treatment for Hypertension

in Type 2 Diabetes Mellitus
A Randomized, Double-blind, Sham-Controlled Trial
Gijs W. D. Landman, MD, PhD; Iefke Drion, MD; Kornelis J. J. van Hateren, MD, PhD; Peter R. van Dijk, MD;
Susan J. J. Logtenberg, MD, PhD; Jan Lambert, MD, PhD; Klaas H. Groenier, PhD; Henk J. G. Bilo, MD, PhD, FRCP;
Nanne Kleefstra, MD, PhD

IMPORTANCE Biofeedback with device-guided lowering of breathing frequency could be an

alternate nonpharmacologic treatment option for hypertension. Evidence from trials with
high methodologic quality is lacking.
OBJECTIVE To evaluate the effects of device-guided lowering of breathing frequency on
blood pressure in patients with type 2 diabetes mellitus and hypertension.
DESIGN Single-center, double-blind, sham-controlled trial.
SETTING A large nonacademic teaching hospital in the Netherlands.
PARTICIPANTS Patients with type 2 diabetes mellitus and hypertension.
INTERVENTION Fifteen-minute sessions with either the device that guides breathing through

musical tones to a lower breathing frequency (aiming at <10 breaths/min) or a sham device
(music without aiming at lowering of breathing frequency) for an 8-week study period.
MAIN OUTCOMES AND MEASURES Systolic and diastolic blood pressure measured in the

physicians office.
RESULTS Forty-eight patients were randomized; 21 patients (88%) in the intervention group
and 24 patients (100%) in the control group completed the study. There were no significant
changes in systolic and diastolic blood pressure, with a difference in systolic blood pressure of
2.35 mm Hg (95% CI, 6.50 to 11.20) in favor of the control group and a difference in diastolic
blood pressure of 2.25 mm Hg (95% CI, 2.16 to 6.67) in favor of the intervention group.
Three patients in the intervention group experienced adverse events.
CONCLUSIONS AND RELEVANCE This high methodologic quality study shows no significant
effect of device-guided lowering of breathing frequency on office-measured blood pressure
in patients with type 2 diabetes. On the basis of this study, together with results from all but
one previous trial, device-guided lowering of breathing frequency does not appear to be a
viable nonpharmacologic option for hypertension treatment.

JAMA Intern Med. 2013;173(14):1346-1350. doi:10.1001/jamainternmed.2013.6883

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Author Affiliations: Diabetes Centre,

Isala Clinics, the Netherlands
University Medical Center, Zwolle
(Landman, Drion, van Hateren, van
Dijk, Groenier, Bilo, Kleefstra);
Department of Internal Medicine,
Isala Clinics, the Netherlands
University Medical Center, Zwolle
(Lambert, Bilo); Department of
Internal Medicine, University Medical
Center Groningen, Groningen, the
Netherlands (Landman, Logtenberg,
Bilo, Kleefstra); Department of
General Practice, University Medical
Center Groningen, Groningen, the
Netherlands (Groenier); Langerhans
Medical Research Group, Zwolle, the
Netherlands (Kleefstra).
Corresponding Author: Gijs W. D.
Landman, MD, PhD, Diabetes Centre,
Isala Clinics, PO Box 10400, 8000 G.
K. Zwolle, the Netherlands (g.w.d
.landman@isala.nl).
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Device-Guided Breathing for Hypertension

ype 2 diabetes mellitus (T2DM) and hypertension

commonly occur together.1 Management of hypertension through pharmacologic as well as nonpharmacologic interventions is effective in preventing cardiovascular
events.2
An example of a nonpharmacologic intervention is a
breathing-focused biofeedback device approved by the Food
and Drug Administration and available without prescription
(RESPeRATE; InterCure Ltd).3-5 Through use of biofeedback 15
minutes each day, the objective for the device is to lower blood
pressure (BP) by guiding breathing frequency with musical
tones to less than 10 breaths/min.4,6 The mechanisms proposed are an adaptation of the pulmonary stretch receptors and
baroreceptor reflex, which lead to vascular and cardiac
relaxation.4,7 Slow breathing also could lead to stimulation of
the parasympathetic system or reduced sympathetic
activation.7-9
A recent systematic review and meta-analysis3 of 8 randomized clinical trials showed a potential small benefit of
device-guided breathing on systolic BP after short-term
follow-up. However, the methodologic quality of the
included studies was variable. An editorial10 and systematic
review 3 emphasized that an independent double-blind
study design with a proper control group would be necessary to determine whether device-guided breathing has any
effect on BP. Therefore, we reevaluated the effects of the
RESPeRATE device on office-measured BP in patients with
T2DM and hypertension in an investigator-initiated, doubleblind, sham-controlled trial.

Methods
Study Design
The present study was a single-center, randomized (1:1),
double-blind, sham-controlled trial conducted in patients with
T2DM and hypertension (Figure) and aimed to investigate the
effects on hypertension of biofeedback by lowering breathing frequency with musical tones (with the RESPeRATE device). The device was to be used 15 min/d during an 8-week
intervention period.

Study Sample
Patients were recruited from the internal medicine outpatient clinic of the Isala Clinics in Zwolle, the Netherlands. Eligibility criteria were age 18 years or older, a diagnosis of T2DM,
hypertension treated with 1 or more antihypertensive drugs,
systolic BP between 130 and 170 mm Hg at the previous and
last visits (the same day as baseline measurement) to the internist, and unchanged hypertension treatment during the preceding 3 months. The systolic BP before randomization had to
be between 140 and 160 mm Hg. Exclusion criteria were orthostatic hypotension (because it theoretically could mitigate the effects of the device10), heart failure (New York Heart
Association class III or IV), severe lung disease, hospitalization in the past 3 months, deafness, blindness, and insufficient cognitive abilities or knowledge of the Dutch language.
Orthostatic hypotension was defined as a fall in BP of at least
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Original Investigation Research

Figure. Participant Flow Diagram

292 Assessed for eligibility
244 Excluded
91 Did not meet inclusion
criteria
153 Declined to participate
48 Randomized
24 Allocated to sham group
24 Received allocated intervention

24 Allocated to intervention group

24 Received allocated intervention

0 Lost to follow-up

3 Lost to follow-up
2 Dyspnea, refused second
study visit
1 Died

24 Analyzed

21 Analyzed

20 mm Hg systolic or 10 mm Hg diastolic pressure either 1 or 3

minutes after changing from a supine to upright position.11,12

Study Groups and Procedures

The RESPeRATE device consists of a control box, a sensor that
attaches around the users chest, and a set of headphones. Users listened to a melody through the headphones, which guides
them to slow their breathing rate, preferably to less than 10
breaths/min. The control group used a visually identical device guiding users to a breathing frequency of approximately
14 breaths/min.
Patients visited the clinic twice. The first investigator
(G.W.D.L.) performed baseline measurements and determined eligibility for inclusion (not randomization). The use of
the device and home BP monitor was explained by a second
investigator (I.D.). All patients were informed that the objective was to study the effects of music therapy. All instructions were given both verbally and in writing and were repeated after 1 week by telephone. Patients were asked to
perform the exercise 15 minutes each day at approximately the
same time of day for 8 weeks. During the second visit, patients were seen by a third investigator (K.J.J.v.H. and P.R.v.D.)
blinded to treatment allocation. Data on home BP measurements from the study diary were collected, and questions about
knowledge of the working mechanism and the brand name
RESPeRATE were asked to test the success of blinding.

Outcome Measures
The primary and secondary outcome measures were change
in office-measured systolic and diastolic BP, respectively. Additional outcome measures were changes in home-measured
systolic and diastolic BP. Health-related quality of life was originally planned as a secondary outcome, but prior to inclusion
the protocol was amended because of logistic reasons.

Measurements
Baseline data consisted of medical history, smoking status,
laboratory data, medication use, height, BP, and body
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Device-Guided Breathing for Hypertension

Table 1. Characteristics at Baseline by Treatment Group

Characteristic

Intervention
(n = 24)

Control
(n = 24)

Age, mean (SD), y

63.8 (7.9)

65.1 (8.4)

.59

Male sex, No. (%)

13 (54)

17 (71)

.23

HbA1c level, mean (SD), %

P Value

8.0 (1.1)

7.4 (1.1)

.04

BMI, mean (SD)

31.8 (6.2)

34.3 (7.8)

.22

Heart rate, mean (SD), beats/min

75.1 (13.4)

74.8 (12.4)

.79

Office-measured BP, mean (SD), mm Hg

Systolic
Diastolic

151.6 (8.3)
82.1 (14.7)

No. of antihypertensive drugs, median (IQR)

2 (1-3)

.57

80.7 (8.9)

.18

3 (1-4)

.32

Oral glucose-lowering agents, No. (%)

12 (50)

14 (58)

.56

Insulin user, No. (%)

18 (75)

18 (75)

>.99

Macrovascular disease, No. (%)

10 (42)

16 (67)

.08

5 (21)

4 (17)

.71

Smoker, No. (%)

weight. Blood pressure was measured following a standardized protocol, using a validated digital BP monitor (UA-767
Plus 30; A&D Medical).13,14 Home BP was measured on the
first and last day of the study, after patients remained
seated for a minimum of 5 minutes before performing the
exercise. Data on the number and duration of treatment sessions were uploaded from the intervention and sham
devices to determine adherence.

Abbreviations: HbA1c, hemoglobin

A1c; BMI, body mass index (calculated
as weight in kilograms divided by
height in meters squared); BP, blood
pressure; IQR, interquartile range.
SI conversion factor: To convert
HbA1c to a proportion of total
hemoglobin, multiply by 0.01.

20; SPSS Inc). The study was approved by the medical ethics
committee of the Isala Clinics. All patients gave written
informed consent.

Results
Patients

Block randomization (blocks of 8) was done by a third party

using sealed, nontransparent envelopes. Sample size was
calculated with G*Power 3.0 software (http://www.psycho
.uni-duesseldorf.de/abteilungen/aap/gpower3/download-and
-register). The SDs of the change in systolic BP in previous studies were 9.4 mm Hg15 and 10.9 mm Hg.14 To detect a 10mm
Hg absolute reduction in systolic BP, with a power of 0.85, a
2-tailed value of .05, and an SD of 11 mm Hg (assuming a
correlation of 0.5 between baseline and end-of-treatment
measures), the total sample size would be 44. For possible
loss to follow-up, we increased the sample size to 48. A
10mm Hg margin in systolic BP was predefined as clinically
significant.

From September 8, 2009, through June 15, 2012, a total of

292 white individuals were invited to participate (Figure).
From the 48 patients randomized, 3 in the intervention
group stopped their participation prematurely: 1 died and 2
withdrew consent, leaving 21 intervention patients (88%)
available for analysis of office- and home-measured BP. All
24 patients in the control group were available for analysis
of office-measured BP; home-measured BP was analyzed for
14 individuals (58%). No protocol violations were made with
regard to adjustment of antihypertensive medication. Baseline characteristics are reported in Table 1. The blinding procedure was successful. No participants reported knowing
about the therapy in the other treatment group. One patient
reported an unsuccessful attempt at unblinding the study
through an Internet search.

Statistical Analysis

Intervention

Data entry was performed in duplicate. Analyses were carried out by a statistician (K.H.G.) blinded to treatment allocation. Mixed-effect models were used to estimate the effect of
the intervention on BP after 8 weeks with and without adjustment for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared) and hemoglobin A 1c level. Analyses were performed according to the
intention-to-treat principle.
Two per-protocol analyses were carried out. The first excluded patients who did not reach the target breathing rate and
the second excluded nonadherent (performing <90% of all sessions) patients in the intervention group.
A 2-sided significance level of 5% was used. Analyses
were performed using commercial software (SPSS, version

Mean (SD) breathing frequency during the exercise was 5.7 (2.0)
breaths/min in the intervention group and 14.3 (0.6) breaths/
min in the control group (P < .001). Treatment with the intervention device did not lead to a significant difference in officemeasured systolic BP (2.35 mm Hg; 95% CI, 6.50 to 11.20, in
favor of the control group). Furthermore, there was no significant difference in office-measured diastolic BP (2.25 mm Hg;
95% CI, 6.67 to 2.16, in favor of the intervention group)
(Table 2). After adjusting for age, sex, body mass index, and
hemoglobin A1c level, the difference in office-measured systolic BP was 1.11 mm Hg (95% CI, 7.59 to 9.82, in favor of the
control group); the difference in office-measured diastolic BP
was 3.48 mm Hg (95% CI, 0.42 to 7.38, in favor of the intervention group). Treatment with the intervention device did not

Randomization and Sample Size Calculation

1348

151.2 (10.6)

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Device-Guided Breathing for Hypertension

Original Investigation Research

Table 2. Estimated Changes in Measurements of BP

Mean Change in BP
Intervention
(n = 21)

Control
(n = 24)a

Systolic

6.03

8.38

Diastolic

5.92

3.67

Characteristic

Difference in BP, Mean (95% CI)b

Office-measured BP, mm Hg
2.35 (6.50 to 11.20)
2.25 (6.67 to 2.16)

Home-measured BP, mm Hg
Systolic

3.66

0.64

3.02 (13.22 to 7.17)

Diastolic

1.38

1.48

0.10 (6.88 to 7.08)

lead to significant differences in home-measured BP compared with the control group (Table 2).
Per-protocol analysis in adherent patients (14 in the intervention group [67%] and 18 in the control group [75%]) showed
a nonsignificant difference in systolic BP of 2.67 mm Hg (95%
CI, 6.97 to 12.32, in favor of the control group), and the difference in diastolic BP was 1.14 mm Hg (95% CI, 6.27 to 4.00,
in favor of the intervention group). Two patients (10%) in the
intervention group had an average breathing frequency greater
than 10 breaths/min. When excluding these patients, the nonsignificant difference in office-measured systolic BP was 2.19
mm Hg (95% CI, 6.49 to 10.87; P = .61, in favor of the control
group).

Safety
There were 3 adverse events, all in the intervention group. One
patient died of respiratory failure due to underlying heart failure. Another patient reported shortness of breath. The third
patient had atypical chest pain with shortness of breath and
sought care at the emergency department. Both individuals
refused to continue using the device and were unavailable for
further BP measurements.

Discussion
To our knowledge, this is the first randomized, doubleblind, sham-controlled trial investigating short-term effects
of device-guided slowing of breathing in patients with
T2DM and hypertension. Our study did not show beneficial
effects of device-guided slowing of breathing on office- and
home-measured BP. Per-protocol analyses excluding
patients not reaching the target breathing frequency and
analyses excluding nonadherent patients showed similar
results. We observed 3 adverse events in the intervention
group; 2 of these could have been related to the use of the
RESPeRATE device.
A recent systematic review and meta-analysis3 including
8 trials investigating the RESPeRATE device showed that all
previous studies were subject to methodologic flaws. None of
these studies had a sham-controlled, double-blind design. Only
4 studies had a design with a control group qualifying as a reasonable control group.4,14-16 Three studies claimed to have a
double-blind design but used either a Walkman4,16 or no control device.17 Only 1 of the 8 studies included in the systematic review and meta-analysis reported a significantly lower
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Abbreviation: BP, blood pressure.

a

Ten patients did not perform home

BP measurements.

Difference is control intervention,

unadjusted for baseline values.

office-measured systolic BP,18 and 2 studies reported a significantly lower office-measured diastolic BP.16,19 The metaanalysis indicated that there could be a modest beneficial
effect of short-term use of the RESPeRATE device, with a
decrease in systolic BP of 3.1 mm Hg (95% CI, 1.4-4.7).3 The
study18 with the largest effect on the results of the metaanalysis also had the highest risk of bias; that study had no
adequate control group, was not blinded, and was carried
out by the manufacturer. The manufacturer was involved in
all but 3 studies.14,15,20 All studies that reported a beneficial
effect of the RESPeRATE device were initiated or sponsored
by the manufacturer.3,16,18,19 A sensitivity analysis excluding
sponsored studies showed no effect of device-guided
breathing on BP. The authors of the aforementioned
meta-analysis3 postulated a possible conflict of interest in
their results.
Our study was investigator-initiated and its strength lies
in the use of a sham device by the control group and the
successful double-blinding procedure. Our trial was limited
by a short duration of 8 weeks and was relatively small.18
We predefined a 10mm Hg margin as clinically significant,
arguing that this margin was acceptable for a device requiring a tremendous amount of effort and persistence.
Although we were able to exclude an advantage of 10 mm
Hg with 85% power, this 10mm Hg margin used for the
sample-size calculation is subject to debate. Given the relatively wide 95% CI of the difference in systolic BP, we also
could not exclude a relevant harmful effec t of the
RESPeRATE device. Furthermore, only 16% of eligible
patients were included. We had to extend the inclusion
period by 2 years because of this low participation rate.
Most patients refused participation because of the timeconsuming nature of the device, indicating that the target
population of RESPeRATE will likely be small. Several other
recruited patients did not meet our inclusion criteria, which
indicates that our study population is representative for a
few of the Dutch population of patients with T2DM and
hypertension. The generalizability was further limited to a
white population.
In conclusion, this study showed no beneficial effects of
the RESPeRATE device on BP in patients with T2DM and
hypertension. Furthermore, possible harmful effects were
seen. By confirming the results of 7 of the 8 previous trials,
the promotion of the RESPeRATE device as an effective biofeedback modality for hypertension treatment should be
reevaluated, at least for white patients with T2DM.
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Research Original Investigation

ARTICLE INFORMATION
Accepted for Publication: February 28, 2013.
Published Online: June 10, 2013.
doi:10.1001/jamainternmed.2013.6883.
Author Contributions: Dr Landman had full access
to all the data in the study and takes full
responsibility for the integrity of the data and
accuracy of the data analysis.
Study concept and design: Landman, van Hateren,
Logtenberg, Bilo, and Kleefstra.
Acquisition of data: Landman, Drion, van Hateren,
van Dijk, and Lambert.
Analysis and interpretation of data: Landman,
Lambert, Groenier, and Bilo.
Drafting of the manuscript: Landman and Drion.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: van Hateren and Groenier.
Obtained funding: Bilo.
Administrative, technical, and material support:
Landman, Drion, van Dijk, and Lambert.
Study supervision: Bilo and Kleefstra.
Conflict of Interest Disclosures: None reported.
Funding/Support: InterCure Ltd provided the
RESPeRATE and sham devices.
Role of the Sponsors: The trial was sponsored by
the Medical Research Foundation Zwolle.
Additional Contributions: We thank all the
patients who participated in this trial. Ineke
Kloppenberg, as well as Sabine Diepeveen, MD,
PhD, Ad Kamper, MD, PhD, and Jan-Evert Heeg,
MD, PhD, assisted with the inclusion.
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