Download Effect of Continuous Positive Airway Pressure on

Effect of Continuous Positive Airway Pressure
on Blood Pressure
A Placebo Trial
Joel E. Dimsdale, Jose S. Loredo, Judi Profant
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Abstract—This study examined the effect of continuous positive airway pressure (CPAP) treatment on blood pressure in
patients with obstructive sleep apnea. Thirty-nine patients with sleep apnea were studied. Ambulatory blood pressure
monitoring was obtained before and after patients were randomized to receive either 1 week of CPAP or placebo CPAP
(CPAP administered at ineffective pressure). Blood pressure was examined over daytime hours (6 AM to 10 PM) and
during nighttime hours (10 PM to 6 AM). Daytime mean arterial blood pressure decreased significantly but equally in both
the active treatment group and the placebo treatment group (P⫽0.001). Nighttime mean arterial pressure levels
decreased to a much greater extent over time in the patients who received active CPAP treatment (P⫽0.032). CPAP does
appear to decrease nighttime blood pressure. However, the decrease in daytime blood pressure may reflect a nonspecific
response (ie, placebo), since both the active treatment group and the placebo treatment group developed comparable
decreases in blood pressure. (Hypertension. 2000;35:144-147.)
Key Words: apnea 䡲 blood pressure 䡲 blood pressure monitoring, ambulatory 䡲 placebo effect
O
bstructive sleep apnea (OSA) is commonly associated
with increased blood pressure (BP).1– 4 Treatments for
OSA are multiple, but, after weight loss, the most commonly
used treatment is nocturnal continuous positive airway pressure (CPAP). The great majority of OSA patients can have
their apnea successfully treated with this methodology.5
Because of the comorbidity of hypertension and OSA,
many investigators have examined how CPAP affects BP
levels.6 –19 Table 1 summarizes these endeavors. As the table
suggests, many of the studies report a beneficial effect of
CPAP on BP. The studies suggest that CPAP acutely decreases nighttime BP in hypertensive OSA patients but not in
normotensive patients and that longer-term use of CPAP
decreases both nocturnal and diurnal BP. However, certain
design aspects are striking. The studies generally have a small
sample size (average of 14 patients per study), and most of
them use neither randomization nor a control group. Most
studies combined normotensives and hypertensives, and
many hypertensives were studied while they were receiving
antihypertensive treatment. Few studies examined patients in
the absence of antihypertensive medication. Most studies did
not describe how they dealt with data from patients who were
noncompliant with the CPAP treatment.
Only half of the studies used ambulatory blood pressure
monitoring (ABPM). ABPM techniques acquire a more
complete and representative sample of BP readings than
would be obtained by casual BP measurement in the physi-
cian’s office. In addition, ABPM allows examination of BP
patterns in awake and in sleeping patients.
Most notably, only 1 study used a placebo control (an oral
placebo) for CPAP, and that study found no effect of CPAP
on 24-hour ambulatory BP.8 BP is notoriously influenced by
nonspecific effects. The CPAP apparatus itself could be a
very powerful stimulus for placebo responses. For this
reason, we performed a double-blind placebo trial of CPAP
versus placebo CPAP on BP as gauged by ABPM.
Methods
Patients were located by public advertisements and word-of-mouth
referral. All patients signed written informed consent approved by
the University of California at San Diego Institutional Review
Board. Patients were eligible if they were between the ages of 30 and
65 years and were 100% to 170% of ideal body weight as determined
by Metropolitan norms.20 Patients were ineligible if they had any
major ongoing illness other than sleep apnea and hypertension.
Patients receiving antihypertensive medication had their medication slowly tapered and their BP status confirmed after a 3-week
washout. Patients’ BP was screened repeatedly (3 times on 2
occasions) after they had been seated resting for at least 5 minutes.
Individuals whose BP was ⬍140/90 mm Hg were considered normotensive. Patients whose BP was ⬎140/90 but ⬍180/110 mm Hg
were considered hypertensive and eligible to participate in this
protocol.
Sleep was screened at home with a Nightwatch system, and
individuals whose respiratory disturbance index (RDI) at home was
⬎20 were considered provisionally to have OSA.
Received April 7, 1999; first decision May 12, 1999; revision accepted September 8, 1999.
From the Departments of Psychiatry (J.E.D.) and Medicine (J.S.L.), University of California at San Diego, and San Diego State University/University
of California at San Diego Joint Doctoral Program in Clinical Psychology (J.P.).
Correspondence to Dr Joel E. Dimsdale, University of California at San Diego, La Jolla, CA 92093-0804. E-mail [email protected]
© 2000 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
144
Dimsdale et al
TABLE 1.
Studies of Effect of CPAP on BP
Author/Year
Sample Characteristics
BP Measurement
Effect of CPAP on Blood Pressure
Length of
Treatment
145
Findings
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Kellner C et al,6
1993
n⫽10 (6/10 with HTN);
RDI⫽28; age 54 y
BP measured every 30 min with
Finapres overnight before and after
CPAP
2–7 d
SBP decreased (P⬍0.05); DBP decreased (P⬍.05);
maximal BP decreased (P⬍0.01). Conclusion: CPAP
acutely lowers nocturnal BP
Naughton MT et
al,7 1995
n⫽9 healthy controls and
15 normotensive CHF
patients
BP measured every minute for 75
minutes while awake before and
during CPAP with automatic
sphygmomanometer
(Physio-Control Lifestat 200)
75 min at 0,
5, 7.5, 10 cm
H2O CPAP
pressure
No significant change in SBP or DBP in either group
(normals or CHF)
Engleman HM
et al,8 1996
n⫽13 OSA patients; age
51 y, RDI⫽49; 5 patients
with HTN; 4 of them on
medication
24-h ambulatory BP recording with
Spacelabs 90207 every half hour
for 24 h
Oral placebo
treatment vs
CPAP; CPAP
average use 4
h/night for 3 wk
Nondippers’ (5) daytime MAP decreased (p⫽0.01);
2/5 nondippers became dippers with CPAP
CPAP did not alter BP in HTN patients
Guilleminault C
et al,9 1996
n⫽6 UARS patients with
borderline HTN
(untreated); age 40 y;
RDI⫽2
BP measured every 30 min for 48
h with ABPM (model 630; Colin
Medical Instruments)
ⱖ30 d; 5/6
subjects
compliant with
CPAP
Daytime DBP decreased (P⫽0.05); SBP decreased
(P⫽0.05)
Night time BP: only DBP decreased (P⫽0.05)
Jennum P et
al,10 1989
n⫽13 OSA patients off
antihypertensive
medication; 6/13 with
HTN
BP measurement via A-line during
sleep baseline and after CPAP
1 night
BP decreased (P⬍0.05)
Ali NJ et al,11
1992
n⫽8 obese OSA patients;
normotensive
BP measured with Finapres while
on CPAP during the same night for
a 30-min period of non-REM sleep
⬍1 night
BP fell slightly but not significantly with CPAP
Suzuki M et
al,12 1993
n⫽9 obese OSA patients;
5/9 with HTN on
medication; RDI for
HTN⫽49; RDI for
normotensives⫽39
Up to 72-h ambulatory BP cuff
monitoring with ABPM-630 Colin
Medical Instruments
5 wk
HTN: BP fell (P⬍0.04); daytime BP fell (P⫽0.08);
nighttime BP fell (P⬍0.04)
Normotensives: no change in BP with CPAP
Mayer J et al,13
1991
n⫽12 HTN OSA patients;
off medication; RDI⫽58
Nighttime BP by arterial line;
daytime BP by BP cuff monitor
6 mo
Nighttime BP fell acutely (P⬍0.001); daytime BP
after 6 mo fell (P⬍0.01).
Conclusion: CPAP lowers nocturnal BP acutely and
chronically lowers diurnal BP
Wilcox I et al,14
1993
n⫽19 male OSA patients;
11/19 with HTN; off
medications; RDI⫽56 at
baseline
24-h ABPM with Oxford Medilog at
15-min intervals
Minimum of
8-wk
follow-up on
CPAP; 14/19
compliant with
CPAP
Compliant subjects (HTN and non-HTN): BP
decreased (P⬍0.05); noncompliant patients (4)
(CPAP⬍4 h/night): BP remained unchanged
Worsno CJ et
al,15 1993
n⫽18 OSA patients; 7/18
with HTN; on
medications; RDI⫽51
BP cuff readings with Dynamap
10 d
HTN patients: BP decreased (P⬍0.04); normotensive
OSA patients: no change in BP
Davies RJO et
al,16 1994
n⫽11 male OSA patients;
RDI⫽56; 6/11 with HTN;
3/6 HTN patients on
medication
Ambulatory BP cuff measurements
3 mo
Daytime BP: no change in BP; nighttime BP
decreased (P⬍0.02). Conclusion: only nocturnal SBP
showed a significant reduction with CPAP
Rauscher H et
al,17 1993
n⫽33 HTN OSA patients;
controls were 27 OSA
patients who refused
CPAP; RDI⫽49 for
treated and RDI⫽36 for
controls; mean CPAP use
6 h/night; on medication
BP cuff measurements made in
various places, eg, sleep lab,
doctor’s office
512 d
10/33 HTN patients stopped or reduced medication;
these patients also lost weight. 8/27 controls
stopped or decreased medication; these patients
also lost weight. Drop in BP was due to weight loss
and not to CPAP
Akashiba T et
al,18 1995
n⫽31 OSA patients;
12/31 with HTN
2 wk
Daytime SBP and DBP reduced
Akashiba T et
al,19 1993
n⫽5 HTN OSA patients;
RDI⫽76
10 d
BP during sleep was lowered; no clear lowering of
daytime BP on CPAP
Ambulatory BP cuff measurements
HTN indicates hypertension; CHF, congestive heart failure; UARS, upper airway resistance syndrome; REM, rapid eye movement; SBP, systolic blood pressure; and
DBP, diastolic blood pressure.
146
Hypertension
January 2000
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Patients wore a Spacelabs ambulatory blood pressure monitor
(model 90207) for a 24-hour period on 3 occasions: before CPAP/
placebo CPAP randomization, after 1 day of treatment, and after 7
days of treatment (indicated on graphs as day 0, day 1, and day 7).
The cuff was positioned carefully with a “Y” adaptor,
and placement was validated against a mercury sphygmomanometer.
The cuff position was outlined in ink on the patient’s arm so that the
cuff could be repositioned easily if it shifted over the course of the
day. BP was programmed to be taken every 15 minutes between 6
AM and 10 PM and every 30 minutes between 10 PM and 6 AM.
Standard criteria for artifact rejection were used in evaluating the BP
measures.
Patients were admitted to the University of California at San
Diego Clinical Research Center for a confirmatory overnight polysomnography (Nihon Koden, model 4412p). We recorded the following parameters: central and occipital electroencephalogram, bilateral electro-oculogram, submental and tibialis anterior
electromyogram, ECG, nasal/oral airflow using thermistor, and
respiratory effort using chest and abdominal inductance belts. Oxyhemoglobin saturation was recorded with a pulse oximeter (Biox
3740). Individuals whose RDI was ⬎15 were considered to have
OSA. On the next night, patients were randomized to receive either
CPAP or placebo CPAP. Patients receiving CPAP underwent standard CPAP titration with the use of a Devilbis CPAP machine and a
comfortably fitting mask. Pressure in the mask started at 2 cm H2O
and was increased over the night by 2-cm H2O increments until
apneic episodes were obliterated or until a pressure of 8 to 10 cm was
reached. Further pressure titration was then done in increments of 1
cm H2O on the basis of the presence of apnea, hypopnea, or snoring
associated with arousals. The titration was considered ended when
most respiratory events were controlled with CPAP while the patient
was in the supine position and in the second or third rapid eye
movement sleep period or until a pressure of 20 cm had been
reached. All patients had their apnea treated within this pressure
range.
Individuals randomized to receive placebo CPAP underwent a
mock titration night. They wore a special mask that had 5 onequarter-inch drill holes to create a large leak through the mask. Their
CPAP pressure was set at 2 cm H2O and was not advanced. All
CPAP units had a hidden compliance clock that allowed measurement of the amount of time the machine was switched on.
One day after CPAP or placebo CPAP treatment was initiated,
patients completed a second day of ABPM. They were then discharged from the hospital for 1 week of continuing CPAP or placebo
treatment at home. The research staff was in frequent contact with
patients to answer questions about mask placement and to encourage
compliance with the treatment. After 7 days of home treatment,
patients’ ambulatory BP was again studied with the use of the
Spacelabs ambulatory monitor.
Data were analyzed with repeated-measures ANOVA with the use
of SPSS software. If a significant effect was found for time alone, it
would imply that CPAP did not have a specific effect on BP. If there
was a significant interaction of time and treatment, it would imply
that the group receiving a particular treatment (presumably CPAP)
had a differential response to that treatment over time.
TABLE 2.
Patient Sample Characteristics
CPAP
n
Men/women
Age, y
Placebo CPAP
21
18
15/6
16/2
47.7⫾8.1
48.9⫾9.9
Body mass index
32.7⫾4.9*
28.5⫾5.0
RDI (baseline)
53.6⫾23.2
41.7⫾25.6
RDI (after 7 days of treatment)
3.2⫾3.9
28.1⫾22.9
Screening systolic BP
128⫾15
123⫾12
Screening diastolic BP
82⫾8
78⫾9
6/15
4/14
Hypertensives/normotensives
Values are mean⫾SD.
*Significantly greater than placebo CPAP (P⬍0.05).
group). Patients receiving CPAP demonstrated a significantly
greater drop in RDI than was observed in patients assigned to
the placebo CPAP group (time⫻CPAP interaction, P⫽0.001)
(Table 2).
ABPM revealed a main effect for time on daytime mean
arterial pressure (F⫽7.96, df⫽2, P⫽0.001) (Figure 1). The
daytime BP of both groups declined equivalently over the
1-week trial (ie, there was no effect specific to the CPAP
group per se). At nighttime, there was a time-by-group
interaction such that the BP of patients receiving CPAP fell
considerably more over time than the BP of patients assigned
to placebo CPAP (F⫽3.62, df⫽2, P⫽0.032) (Figure 2).
Discussion
The treatment of sleep apnea is rapidly evolving. Medications
have had limited value compared with weight loss, various
surgical procedures, and CPAP.21 For the vast majority of
patients, CPAP is an effective treatment of the apnea per se if the
patient complies with the treatment. Our results suggest, however, that the effects of CPAP on BP are not so straightforward.
Had we not administered a placebo version of CPAP, we
would have concluded that CPAP has a robust BP-lowering
effect. That conclusion is not strongly supported by our data.
Whereas CPAP lowered daytime mean arterial pressure, so
did placebo CPAP. There is very little acclimatization effect
to wearing an ABPM cuff22; that is, BP does not noticeably
Results
Table 2 summarizes the sample characteristics. Thirty-nine
individuals were studied. Individuals randomized to the 2
treatments were comparable in age, pretreatment RDI, and
screened BP; however, patients randomized to receive CPAP
were heavier (P⬍0.05). The mean mask pressure required
among the CPAP group was 10.1 cm H2O; placebo CPAP
patients all received CPAP at a pressure of 2 cm H2O
administered through a mask with numerous air holes to
produce a large air leak. Both patient groups complied
equivalently with the CPAP treatment over the 1-week
interval of home treatment (⬎5 hours per night for each
Figure 1. Effect of CPAP on daytime mean arterial pressure.
Mean arterial pressure was measured during daytime with
ABPM before treatment (day 0), after 1 day, and after 7 days of
treatment with either CPAP or placebo CPAP. There was a nonspecific time effect for lowering BP across both treatments
(P⫽0.001).
Dimsdale et al
Effect of CPAP on Blood Pressure
147
research. Even though CPAP is effective in treating apnea,
whether it benefits daytime BP is not clear.
Acknowledgment
This study was supported by grants HL-44915 and RR-00827 from
the National Institutes of Health.
References
Figure 2. Effect of CPAP on nocturnal mean arterial pressure.
Mean arterial pressure was measured during nighttime with
ABPM before treatment (day 0), after 1 day, and after 7 days of
treatment with either CPAP or placebo CPAP. CPAP leads to a
specific time-by-treatment effect on blood pressure (P⫽0.032).
Downloaded from http://hyper.ahajournals.org/ by guest on May 5, 2017
fall on a second 24-hour ABPM study. We interpret the
uniform decrease of BP in our study to a nonspecific effect of
treatment, ie, a placebo effect. Patients were observed closely
by our research staff, and all patients used impressive-looking
CPAP machinery while sleeping. The combination of professional attention and expectations from the machinery may
well have lowered daytime BP. In this sense, the placebo
effects of CPAP on BP join a long list of other treatments that
have beneficial although nonspecific effects.
However, it is not accurate to attribute all of the effects of
CPAP on BP to a placebo effect. We did observe a differential
effect of CPAP on nocturnal BP. In the absence of the waking
conscious awareness of the treatment (in which treatment had a
beneficial effect on both groups), only the patients receiving
effective CPAP lowered their nighttime BP.
We specifically examined weight and hypertension to
assess whether our findings would materially change after
controlling for these variables. Because of the difference in
weight between the treatment and placebo groups, we repeated the analyses using body mass index as a covariate. The
study still failed to reveal a specific time-by-treatment effect
on BP lowering after controlling for BMI. We also reanalyzed
the data using screening blood pressure (hypertension versus
normotension) as a grouping factor to determine whether
hypertension affected the response of BP to CPAP. We found
no evidence to suggest that CPAP had a greater BP-lowering
effect in hypertensive patients.
The study has a number of limitations. We examined
CPAP effects for only a 1-week interval because we were
uneasy about imposing a lengthy placebo CPAP treatment on
patients who had OSA. It is possible that the BP-lowering
effects of CPAP become even more apparent over a longer
time interval; indeed, Figure 1 suggests this, but we have no
data beyond a 1-week trial. Our patients all had substantial
levels of apnea (average RDI was 48.1), but in other ways
they were relatively healthy. We excluded patients with other
major illnesses requiring treatment, such as those with congestive heart failure, a history of myocardial infarction, or
morbid obesity. Perhaps such latter patients may obtain
substantially greater benefits with CPAP treatment.
Nonetheless, our study provides a cautionary note, demonstrating the value and importance of a placebo arm in medical
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Effect of Continuous Positive Airway Pressure on Blood Pressure: A Placebo Trial
Joel E. Dimsdale, Jose S. Loredo and Judi Profant
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Hypertension. 2000;35:144-147
doi: 10.1161/01.HYP.35.1.144
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