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Original Article
Treatment of acute migraine by a partial
rebreathing device: A randomized
controlled pilot study
Cecilia H Fuglsang
1
, Troels Johansen
2,3
, Kai Kaila
4
,
Helge Kasch
5
and Flemming W Bach
1
Abstract
Background: Impaired brain oxygen delivery can trigger and exacerbate migraine attacks. Normoxic hypercapnia
increases brain oxygen delivery markedly by vasodilation of the cerebral vasculature, and hypercapnia has been
shown to abort migraine attacks. Stable normoxic hypercapnia can be induced by a compact partial rebreathing
device. This pilot study aimed to provide initial data on the device’s efficacy and safety.
Methods: Using a double-blinded, randomized, cross-over study design, adult migraine-with-aura patients self-adminis-
tered the partial rebreathing device or a sham device for 20 minutes at the onset of aura symptoms.
Results: Eleven participants (mean age 35.5, three men) self-treated 41 migraine attacks (20 with the partial
rebreathing device, 21 with sham). The partial rebreathing device increased mean End Tidal CO
2
by 24%, while retain-
ing mean oxygen saturation above 97%. The primary end point (headache intensity difference between first aura
symptoms and two hours after treatment (0–3 scale) – active/sham difference) did not reach statistical signifi-
cance (0.55 (95% CI: 1.13–0.04), p¼0.096), whereas the difference in percentage of attacks with pain relief
at two hours was significant (p¼0.043), as was user satisfaction (p¼0.022). A marked efficacy increase was seen
from first to second time use of the partial rebreathing device. No adverse events occurred, and side effects were
absent or mild.
Conclusion: Normoxic hypercapnia shows promise as an adjunctive/alternative migraine treatment, meriting further
investigation in a larger population.
Clinical study registered at ClinicalTrials.gov with identifier NCT03472417
Keywords
Migraine, headache, hypercapnia, CO
2
therapy, rebreathing
Date received: 4 April 2018; revised: 14 June 2018; 22 June 2018; accepted: 8 August 2018
Introduction
Studies measuring cerebral blood flow (CBF) have
shown that the early stages of migraine attacks are
characterized by cerebral vasoconstriction (1–6), impli-
cating hypoperfusion as a migraine trigger (7,8). Olesen
et al. (1) were the first to demonstrate that hypoperfu-
sion is often present more than an hour into or
throughout the pain phase of the migraine attack – a
finding which has been reported by several studies since
then (3,4,9), refuting the previous theory that migraine
pain is caused by cerebral vasodilation.
Rather than the hypoperfusion in itself, the actual
attack trigger may be the resulting decrease in oxygen
brain delivery (D
O2,brain
), since recent studies have
1
Department of Neurology, Aarhus University Hospital, Aarhus,
Denmark
2
Aarhus University School of Engineering, Aarhus University, Aarhus,
Denmark
3
BalancAir, Kongens Lyngby, Denmark
4
Molecular and Integrative Biosciences Research Program and HiLife,
University of Helsinki, Helsinki, Finland
5
Spinal Cord Injury Center of Western Denmark, Department of
Neurology, Regional Hospital of Viborg, Viborg, Denmark
Corresponding author:
Troels Johansen, Aarhus University School of Engineering, Finlandsgade
22, bldg. 5125, DK-8200 Aarhus N, Denmark.
Email: troels.johansen@ase.au.dk
Cephalalgia
2018, Vol. 38(10) 1632–1643
!International Headache Society 2018
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/0333102418797285
journals.sagepub.com/home/cep
demonstrated that hypoxia reliably triggers migraine
attacks in migraine patients (10,11) and headache in
healthy individuals (12), possibly because of hypoxia’s
propensity for inducing and perpetuating cortical
spreading depression (CSD) (13) – a migraine trigger
phenomenon implicated in migraine with aura (MA)
and possibly in migraine without aura (MO) as well
(4,14–17).
Past clinical studies have shown that hypercapnia is
efficacious in aborting migraine attacks (18–21) and
post-spinal headache (22). Two of the studies (18,22)
used CO
2
-rich gas mixtures administered from pressure
bottles. However, pressure bottles are impractical,
heavy and require refilling between treatments – a
likely reason that this treatment option never came
into clinical practice in spite of Marcussen and
Wolff’s early demonstration of its efficacy in
migraine (18).
Two other migraine studies used closed rebreathing
bags to induce hypercapnia (19,20). However, in such
devices, oxygen is quickly depleted, causing continually
worsening – and potentially life-threatening – hypoxia
if continued for too long.
Notably, stable normoxic hypercapnia can be
achieved by a partial rebreathing device (PRD) (23)
which works by capturing a controlled fraction of the
expired air, which is then rebreathed together with a
controlled amount of atmospheric air. The net effect
is a moderate reduction of alveolar ventilation, in
spite of the increase in minute ventilation elicited by
raising the arterial CO
2
tension (P
aCO2
). By nature of
its particular design, the PRD is able to induce a steady
state of moderate hypercapnia while retaining normal
arterial oxygen saturation (S
aO2
) (23).
In contrast to gas bottles, the PRD used in this study
is compact and very lightweight since no gas or power
supply is needed. Because it does not incur hypoxemia,
the PRD is inherently much safer than closed rebreath-
ing bags.
Using a double-blinded, randomized, controlled,
cross-over design, we performed a first clinical pilot
study on the efficacy and safety of the PRD in treat-
ment of migraine with aura (MA), with the additional
aim to obtain sample-size estimates for a future large-
scale clinical trial. MA was chosen as the patient group
because of the comparative ease of standardizing the
time point of treatment onset.
We aimed to control for any placebo effect and
regression towards the mean by using a sham device
as control and randomizing the device cross-over
sequence.
It was our hypothesis that by using the PRD to
increase P
aCO2
and D
O2,brain
early in MA attacks, the
attack severity could be reduced, without adverse
effects.
Methods
The clinical trial was approved by the Danish
Medicines Agency (ref. no. 2016092009) and the
Committee for Ethics in Science of Central Denmark
Region (ref. no. 1-10-72-245-16) and registered at
ClinicalTrials.gov (NCT03472417). The study protocol
is available from the authors by request.
All participant visits took place at the Headache
Clinic at Aarhus University Hospital.
Partial rebreathing device
Figure 1 shows the elements of the PRD:
.A flexible-volume rebreathing reservoir with laser
perforations in its walls. The diameter and spacing
of the perforations were carefully chosen to provide
a measured gas flow between the atmosphere and the
inside of the reservoir, so that even if the bypass
valve (see below) was completely closed, gas
exchange was still sufficient to prevent hypoxemia.
.A mouthpiece connecting the reservoir with the
mouth of the user.
.A bypass valve in the wall of the reservoir, with a
flow-through rate which can be adjusted by the use
of a slider. The inspired CO
2
concentration can
thereby be up- or down-regulated between set
limits, according to the baseline End-Tidal CO
2
(ETCO2) and ventilatory response of the individual.
Before use, the PRD is folded compactly and can be
carried in a pocket or purse.
The participants used the device by breathing
through the mouth piece, with the bypass valve
1
4
23
5
Figure 1. Schematic of the partial rebreathing device. 1:
Flexible-volume rebreathing reservoir, having in its walls laser
perforations; 2: Mouthpiece; 3: Mouthpiece opening, connecting
the inside of the reservoir with the mouth of the user; 4: Bypass
valve opening; 5: Adjustable slider, regulating the flow through
the bypass valve.
Fuglsang et al. 1633
previously fixed at the individual-specific setting deter-
mined in the Initial Device Test (see below). The par-
ticipants wore nose clips while using the device and
were instructed to breathe according to their spontan-
eous breathing drive.
The sham device only had a minimal effect on P
aCO2
because the air flow had been redirected by means of a
one-way check valve so that minimal rebreathing
occurred (Figure 2).
By necessity, the active and sham devices could not
be completely identical. In order to preserve the pla-
cebo effect of the sham device in spite of this difference,
the two devices were described to the test subjects as
providing two different levels of inspired CO
2
, and not
as a ‘‘real’’ versus a ‘‘fake’’ device.
Participants
Participants were recruited from a total group of 190
individuals who responded to an online post advertis-
ing the study. Individuals were enrolled and provided
written and verbal informed consent if they conformed
to the in/exclusion criteria (formulated according to the
guidelines of the International Headache Society (24)):
Inclusion criteria were: Between one and six monthly
attacks of migraine with typical aura, defined according to
theICHD-3betacriteria(25);age18to60years;migraine
onset before age 50; and, if in preventive migraine treat-
ment, dose had been stable for three months.
Exclusion criteria were: More than 14 days with
headache per month, or more than six days with non-
migraine headache per month; medication overuse; pul-
monary, cardiovascular, metabolic or psychiatric dis-
ease, cancer or anemia; and being pregnant or
breastfeeding.
Study procedures and outcome assessment
For the individuals enrolled in the study, general and
migraine-specific medical histories were recorded, and a
neurological examination was performed.
Subsequently, an initial device test was performed, in
which the participant used the active device for a min-
imum of 15 minutes while being guided by the study
personnel and monitored with a capnograph and pulse
oximeter (CapnoStream 20, Medtronic, Minneapolis,
MN, USA), in order to ensure that the PRD
elicited the target increase in ETCO2 and did not
incur either hypoxemia (defined as S
pO2
<90%) or
any side effects that were not pre-defined as acceptable
(see below). The target ETCO2 increase was set accord-
ing to a sliding scale so that participants with a
high baseline ETCO2 were increased less than individ-
uals with a low baseline ETCO2 (increases ranged
from 8 mmHg for the highest ETCO2 baselines and
10 mmHg for the lowest).
After being instructed in using the device and study
diary, each participant was randomized 1:1 to use either
active or sham in the first treatment period. The
informing/including study staff member performed the
randomization by randomly choosing a sealed envelope
containing an alpha-numeric code corresponding to a
specific device; these codes were randomly generated,
and the envelopes and devices packed by a different
study staff member. The study staff member (CH
Fuglsang) who enrolled and randomized the partici-
pants, provided device instructions and recorded all
data was, by this procedure, blinded to which device
(active or sham) the participant would use or had used
in a given period.
The participant then received the corresponding
home treatment kit containing the device, five dispos-
able rebreathing reservoirs, a pulse oximeter (with
an audio alarm preset at an S
pO2
of 90%), instructions
for use and the study diary for recording migraine
symptoms.
The participants were instructed to use the device for
20 minutes at the onset of first aura symptoms, fol-
lowed after 40 minutes by a further 20 minutes of
device use. The severities of four symptoms were to
be recorded at five time points: At first aura symptoms,
immediately after the first device use, and after one, two
and 24 hours. The four symptoms were headache,
nausea, light/sound sensitivity and functional disability,
all recorded on a scale from 0 to 3 (e.g. for headache:
0¼no headache, 1 ¼mild headache, 2 ¼moderate
headache, 3 ¼severe headache). The participants were
instructed not to use any other migraine treatment for
the first two hours.
Moderate hypercapnia can produce mild side effects,
including hyperpnea, feeling moderately colder or
warmer, mild restlessness or increased perspiration
Figure 2. Photo of the active device (left) and the sham device
(right), showing (a) the folded rebreathing reservoirs; (b) bypass
valves; (c) reservoir connectors, shown dismounted from
mouthpiece boxes (d); (e) sham device airflow redirection holes,
with protruding structure for preventing accidental blocking by
fingers, (f) sham device one-way check valve.
1634 Cephalalgia 38(10)
(26). For the purposes of the study, these side effects
had in advance been defined as acceptable and test sub-
jects were informed that these side effects could occur
but that they were natural and harmless. In some indi-
viduals, moderate hypercapnia can cause more unpleas-
ant, though not dangerous, side effects such as
dizziness, headache, and visual disturbances (26).
In case of such non-acceptable side effects or a drop
in S
pO2
to below 90%, test subjects were instructed to
pause the treatment for one minute, decrease the
inspired CO
2
fraction by means of the bypass valve
slider, and then continue the treatment. If the unaccept-
able side effects persisted, they were instructed to abort
the treatment completely.
After having treated two separate migraine attacks
with the device, the participants visited the Headache
Clinic and switched to the other device (active or
sham). At the end of each treatment period, the partici-
pants answered questions assessing their: a) overall sat-
isfaction with the device, b) subjectively experienced
treatment effect, c) preference for the device treatment
compared with their habitual migraine treatment, d)
likelihood of using the device for treating their migraine
attacks in the future if they had access to it, and e) side
effects using the device, if any.
Participant enrollment took place from November
2016 to January 2017 and the last participant com-
pleted the study in October 2017.
The study protocol specified that each treatment
period was limited to three months, and that subjects
that did not have at least one attack within a treatment
period would be excluded from the study. However, the
overall attack frequency turned out to be lower than
expected and initially reported by the test subjects, so to
preserve the power of the study it was decided to extend
the maximum duration of all test periods to five
months. No other study procedures or end points
were changed during the course or after completion
of the study.
Study end points
The pre-specified primary end point of the study was
Headache Intensity Difference between the moment of
the first aura symptoms and two hours later (HID2).
Secondary end points were:
A: Comparing time point 0, and two hours’ post-
treatment:
.Nausea Intensity Difference (NID2)
.Light/Sound Sensitivity Difference (LSSD2)
.Functional Disability Difference (FDD2)
.Pain relief (PR2); that is, the percentage of attacks in
which there was no or mild pain two hours after first
using the device
.Pain freedom (PF2); that is, the percentage of
attacks in which there was no pain two hours after
first using the device
B: Recorded at the end of each treatment period:
.Overall satisfaction with the device, 2toþ2 scale
(2¼wholly unsatisfied, þ2¼wholly satisfied)
.Subjective treatment effect, 0–4 scale (0 ¼no effect,
1¼small effect, 2 ¼moderate effect, 3 ¼good effect,
4¼very good effect)
.Treatment preference vs. participant’s normal treat-
ment, 2toþ2 scale (2¼much worse than normal
treatment,þ2¼much better)
.The likelihood that the participant would use this
device to treat their migraine attacks in the future
if it was available to them, 2toþ2 scale
(2¼would certainly not use the device,
þ2¼would certainly use the device)
.Occurrence, type and severity of side effects
.Adverse events
Statistical analysis
End point values for a device were averaged over the
two attacks with that device and analyzed in a pairwise
manner comparing the active and sham devices.
Wilcoxon signed rank tests were used for hypothesis
testing of the primary end point as well as for the sec-
ondary end points concerning headache, nausea, light/
sound sensitivity, functional disability, device satisfac-
tion, treatment effect, preference and likelihood of use.
None of the end point distributions showed marked
non-normality or outliers (see Figure 3, also confirmed
by Shapiro-Wilk tests of non-normality), leading to the
choice of means and standard deviations as the best
descriptive parameters of the data.
For the secondary end points concerning pain relief
and pain freedom, odds ratios and Pearson’s
2
tests
were used for comparing the proportions of attacks in
which there was respectively pain relief and pain free-
dom. No interim analyses were performed. The statis-
tical analyses did not adjust for multiple comparisons
or include multivariable analysis. The 5% significance
level was used, and all reported pvalues are two-tailed.
Stata version 11 was used for all analyses (the signrank
and cc commands respectively).
Results
In total, 18 MA patients were recruited and enrolled
from a total group of 190 individuals responding to an
online post advertising the study. The remaining 172
individuals did not conform to the in/exclusion criteria.
Fuglsang et al. 1635
Three of the enrolled participants were subsequently
excluded because they did not have at least one attack
within the first or second five-month treatment period.
One participant left the study due to illness unrelated to
the study, one participant was lost to follow-up and
two participants withdrew their consent before treating
an attack. Characteristics of the 11 participants who
completed the study are shown in Table 1 and 2.
Three of the test subjects had one treatment period
in which they only had one attack. For this reason, the
total number of attacks in the study was 41, of which 20
were with the PRD and 21 with the sham device.
Device effect on ETCO2 and S
pO2
Among the 18 enrolled participants that completed the
initial device test, mean baseline ETCO2 was
36.8 mmHg (range 26–41 mmHg). Using the active
device, ETCO2 increased to a mean of 45.8 mmHg
(range 39 to 51); that is, a mean increase of
9.0 mmHg (equal to a 24% increase compared to
baseline).
The average S
pO2
at baseline was 98.7% (range 95 to
100%), which decreased to 97.3% (likewise range 95 to
100%) during the active device use.
The baseline values and increases of ETCO2 and
S
pO2
among the 11 participants who completed the
study were very close to the values in the group of 18
(Table 1).
Migraine outcomes
Figure 3 and Table 3 show the results for the contin-
uous-variable end points.
For all end points, using the active device resulted in
lower average symptom scores (Table 3, Figure 3(a))
and higher average end-of-period test subject scores
(Table 3, Figure 3(b)) respectively, though variances
were large.
For HID2 (the pre-specified primary end point),
headache increased by 0.77 points (0–3 scale) from
first aura symptoms to two hours, as compared to an
increase of 1.32 with the sham device (mean difference
0.55 (95% CI: 1.13–0.04)), a result which was not
statistically significant (p¼0.096). Interestingly, a post
hoc analysis showed that the three participants with
greatest effect on HID2 were the three men.
The mean severity of all symptoms increased from
first aura symptoms to two hours, except for light/
sound sensitivity, which decreased slightly with the
active device (but increased with the sham device).
The higher satisfaction with the active over the sham
device was statistically significant (0.59 vs. 1.00 on the
2/þ2 scale (95% CI: 0.53–2.65), p¼0.022).
In 60% of attacks with the active device there was
pain relief at two hours, compared to 29% with the
sham device (Table 4), a difference which was statistic-
ally significant (odds ratio ¼3.75 (95% CI, exact: 0.86–
16.97), p¼0.043). Total pain freedom at two hours was
2
(a) (b)
4
3
2
1
0
–1
–2
–3
1.5
1
0.5
0
–0.5
–1
–1.5
–2
–2.5
–3
Active sham difference, 0 vs 2 hours
Active-sham difference
–3.5
Headache Nausea Treatment
effect
Treatment
preference
Satisfact.
w.device
Likelihood
to use
Disability
Light/sound
sens.
Figure 3. Box/scatter plots of the continuous-variable end points. (a) Active-sham differences of symptom scores of headache,
nausea, light/sound sensitivity and functional disability, comparing zero and two hours. (b) Active-sham differences of end-of-period
scores of subjective treatment effect, treatment preference, satisfaction with device and likelihood to use in future (for the subjective
treatment effect and treatment preference, some data points are missing). Circles are individual patient data points, horizontal black
bars indicate means, dark grey boxes indicate confidence intervals (mean 1.96 standard errors of the mean), light grey boxes indicate
the interval of the mean one standard deviation, and the red horizontal line indicates the zero-line (corresponding to no difference
between active and sham device). For the parameters in Figure 3(a), values below zero correspond to a better effect of the active over
the sham. For the parameters in Figure 3(b), values above zero correspond to a better effect of the active over the sham.
1636 Cephalalgia 38(10)
only achieved in 15% of attacks with the active device
and 14% with the sham device.
A post hoc comparison of the first and second attack
with a given device indicated a training benefit when
using the active device, PR2 being 45% in the first
attack with the active device and 78% in the second
attack (Figure 4, Table 4), PF2 also increasing (from
9% to 22%). This training effect was not seen with the
sham device (Figure 4, Table 4).
Figure 5 shows the changes in mean migraine symp-
toms over the first two hours, for the active and sham
devices respectively.
Values at 24 hours were not analyzed due to
a high incidence of missing study diary data at this
time point.
Side effects
During the initial device tests, two out of 18 partici-
pants experienced transient side effects (dizziness and
mild nausea respectively), which disappeared after a
break of two minutes and a one-step increase in the
bypass valve opening and did not reoccur after device
use was resumed.
Table 2. Participant migraine characteristics.
Gender Age
Age at migraine
onset Typical migraine symptoms
Aura symptoms, normal
onset time before pain
F 26 15 P, Pu, WPA, N, V, Pnp, Ptp, VD, CD VD, 20–25min.
F 26 10 P, WPA, N, V, Pnp, Ptp, VD, CD VD, 30–45min.
F 23 25 P, Pu, WPA, N, Pnp, Ptp, VD, CD VD, SpD, 15min.
F 29 27 P, Pu, N, Pnp, Ptp, CD VD, 30–60min.
F 35 13 P, Pu, N, Pnp, Ptp, VD, CD VD, SeD, 60–180min.
M 49 12 P, Pu, WPA, N, V, PtP, VD, CD VD, SpD, 30–60min.
F 20 8 P, Pu, WPA, N, V, PnP, PtP, VD, CD VD, 45min.
M 31 13 P, Pu, V, Ptp, VD VD, 60min.
M 47 35 P, N, Pnp, Ptp, VD, CD VD, SpD, 120–180min.
F 59 46 P, Pu, N, Pnp, Ptp, CD SeD, 60–120min.
F 45 27 P, Pu, WPA, N, V, Pnp, Ptp, VD, CD VD, SpD, 30–60min.
Abbreviations of migraine symptoms: P: Moderate/severe pain; Pu: Pain is pulsating/throbbing; WPA: Pain worsening with physical activity; N: nausea; V:
vomiting; Pnp: phonophobia; Ptp: photophobia; VD: visual disturbances; CD: cognitive disturbances.
Abbreviations of aura symptoms: VD: visual disturbances; SeD: sensory disturbances; SpD: speech disturbances.
Gender: F, Age: 45, Age at migraine onset: 27, Typical migraine symptoms: P, Pu,WPA, N, V, Pnp, Ptp, VD, CD. Aura symptoms, normal onset time: VD,
30-60 min.
Table 1. Participant characteristics.
Variable Value
n 11
Age (mean SD, median) 35.5 12.0, 31.0
Female/male 8/3
Caucasian (%) 100%
Height in cm (mean SD, median) 174.0 8.5, 170.0
Weight in kg (mean SD, median) 70.0 11.0, 67.0
Age at migraine onset (mean SD, median) 21.0 11.5, 15.0
Family history of migraine (%) 73%
Current migraine medications: Triptans: 55% (three additional participants
had used triptans earlier but no longer did)
NSAIDs or paracetamol: 73%
Prophylactic medications: 9%
Baseline ETCO2 in mmHg (mean SD, median) 37.1 4.5, 38.0
Baseline S
pO2
% (mean SD, median) 98.8 1.5, 99.0
Average no. of days between attacks in study (mean SD, median) 43.7 22.6, 35.0
Fuglsang et al. 1637
In the course of the treatments at home, the follow-
ing side effects were recorded:
.Sham device: Warm sensation (two participants,
one attack each), dry mouth (one participant, two
attacks), increased perspiration (one participant,
two attacks), irritated sensation (one participant, one
attack), unpleasant taste (one participant, one attack).
.Active device: Hyperpnea (three participants: One,
one and two attacks), dyspnea (two participants:
One and two attacks), warm sensation (two partici-
pants, one attack each), mild claustrophobia (one
participant, one attack), increased salivation (one par-
ticipant, one attack), anxiety (one participant, one
attack), restlessness (one participant, one attack).
In total, eight of the test subjects experienced a side
effect during one or both of the attacks with the active
device, while five experienced a side effect during one or
both of the attacks with the sham device. Side effects
occurred more frequently in the first than in the second
attack in a treatment period.
The participants had been instructed to stop using
the device in the event of excessive side effects, but at no
point during the study did a participant feel that the
side effects were strong enough for them to stop the
treatment.
No test subject reported any occurrence of arterial
desaturation to below the pulse oximeter alarm limit.
No adverse events occurred in the course of the
study.
Discussion
This small-scale randomized and controlled trial con-
stitutes the first clinical test of partial rebreathing for
migraine treatment. The primary end point, measuring
difference in headache at time of first aura symptoms
Table 3. Trial end points I, continuous-variable data.
Active Sham Active-sham difference
p-value
(Wilcoxon
signed
Mean 95% CI Mean 95% CI Mean 95% CI rank test)
Headache intensity difference, 0–2 hours 0.77 0.24–1.31 1.32 0.68–1.96 0.55 1.13–0.04 0.096
Headache intensity difference, 0–1 hours 0.80 0.19–1.40 1.11 0.46–1.77 0.32 0.96–0.32 0.26
Nausea intensity difference, 0–2 hours 0.09 0.34–0.53 0.55 0.08–1.17 0.45 1.08–0.17 0.28
Nausea intensity difference, 0–1 hours 0.00 0.40–0.40 0.48 0.05–1.01 0.48 0.97–0.02 0.072
Light/sound sensitivity difference, 0–2 hours 0.16 0.83–0.52 0.30 0.37–0.96 0.45 1.24–0.33 0.34
Light/sound sensitivity difference, 0–1 hours 0.20 0.75–0.34 0.59 0.05–1.24 0.80 1.43– 0.17 0.043
þ
Functional disability difference, 0–2 hours 0.14 0.34–0.61 0.43 0.24–1.10 0.30 0.98–0.39 0.50
Functional disability difference, 0–1 hours 0.14 0.26–0.53 0.43 0.15–1.01 0.30 -0.96–0.36 0.39
Satisfaction with device’s effect 0.59 0.09–1.28 1.00 1.92– 0.08 1.59 0.53–2.65 0.022
þ
Subjective treatment effect 1.40 0.56–2.24 0.50 0.17–1.17 1.00 0.08–2.08 0.099
Treatment preference vs. normal treatment 0.17 0.78–0.44 0.75 1.54–0.04 0.78 0.23–1.79 0.19
Likelihood to use device in future 0.09 1.06–0.88 1.18 1.92– 0.44 1.09 0.10–2.29 0.081
þStatistically significant at the 5% level.
Table 4. Trial end points II, binary data.
Active % Sham % Odds ratio 95% CI (exact) p-value (
2
test)
Pain relief % at two hours, average of both attacks 60 29 3.75 0.86–16.97 0.043
þ
Pain relief % at two hours, first attack 45 27 2.22 0.27–19.76 0.38
Pain relief % at two hours, second attack 78 30 8.17 0.75–113.44 0.037
þ
Pain freedom % at two hours, average of both attacks 15 14 1.06 0.12–9.03 0.95
Pain freedom % at two hours, first attack 9 18 0.45 0.01–10.42 0.53
Pain freedom % at two hours, second attack 22 10 2.57 0.11–168.26 0.47
þStatistically significant at the 5% level.
1638 Cephalalgia 38(10)
and after two hours, did not reach statistical signifi-
cance (p¼0.096). This could be because of the small
number of participants and large variance in this pilot
study, but it cannot of course be ruled out that the trial
would be negative even if sufficiently powered.
However, a full-scale trial of the device seems war-
ranted by the fact that the secondary end points mea-
suring device satisfaction and pain relief both reached
3
2.5
2
1.5
1
0.5
Headache intensity (0–3)Light/sound sensitivity (0–3)
Functional disability (0–3) Nausea intensity (0–3)
0
020
Headache
40 60 80 100 120 0 20 40 60 80 100 120
020
40 60 80 100 120
02040
Minutes
Minutes
Light/sound
sensitivity
Functional
disability
Active
Sham
Active
Sham
Active
Sham
Active
Sham
Minutes
Minutes
60 80 100 120
3
2.5
2
1.5
1
0.5
0
3
2.5
2
1.5
1
0.5
0
3
2.5
2
1.5
1
0.5
0
Nausea
Figure 5. Changes in symptom severity during the first two hours, for headache (top left), nausea (top right), light/sound sensitivity
(bottom left) and functional disability (bottom right). Mean values and corresponding 95% confidence intervals are shown.
Attacks with pain relief at
two hours (%)
Attacks with pain freedom at
two hours (%)
p < 0.05
p = n.s.
First use Second use
Active device Active device
Sham device Sham device
First use Second use First use Second use First use Second use
100
Pain relief % at two hours
Pain Freedom % at two hours
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Figure 4. Comparison of active vs. sham device effect on pain relief at two hours (left) and pain freedom at two hours (right),
showing differences between first use and second use of device.
Fuglsang et al. 1639
significance (p¼0.022 and p¼0.043 respectively). For
the remaining secondary end points, the mean active/
sham differences were likewise in favor of the active
device over the sham (i.e. symptom scores were on aver-
age lower and end-of-period test subject scores were
higher), though these differences were not statistically
significant.
The present findings are consistent with previous
studies having shown efficacy of systemic or local
hypercapnia in migraine treatment (18–21).
The difference between PR2 at first PRD treat-
ment (45%) and second PRD treatment (78%) indi-
cated an increased efficacy with training and/or
repeated use.
No adverse events occurred in the study, and side
effects were in general mild or absent. In the few
cases where non-acceptable side effects occurred (see
Study procedures and outcome assessment), the initial
device tests demonstrated that these could be effectively
and quickly addressed by briefly interrupting the treat-
ment, and their recurrence prevented by decreasing the
rebreathing level.
The small scale of this study naturally restricts the
strength of the conclusions that can be drawn, as does
the effect that cognitive impairment during MA attacks
could have on self-reported symptom scores.
Additionally, since attacks were treated at home, we
cannot confirm that treatment was performed correctly
or for the intended duration.
As is unavoidable in many device trials, subject
blinding was not perfect, specifically because of the
necessary physical differences between the two devices
and due to the higher incidence of CO
2
-induced
hyperpnea with the active device. We sought to miti-
gate this problem by describing the devices to the test
subjects as having different levels of CO
2
increase (as
opposed to one being ‘‘real’’ and the other ‘‘fake’’)
and stating that it was not known which CO
2
level
would have the best effect. Even so, there may still
have been some residual bias due to imperfect
blinding.
The migraine patients in the study were recruited
from the general population via a post on a social
media profile of Aarhus University Hospital. Our
aim with this approach was to recruit more typical
migraine patients than the patients normally referred
to the highly specialized Headache Clinic at the hos-
pital, of which many have chronic and/or very severe
or atypical migraine. It is possible that there may
have been a recruitment bias in the type of patients
that responded to this type of online post – a bias
which would reduce the generalizability of the
results.
Even in the light of the trial’s limitations and small
size, the data indicate that the PRD treatment may be
effective in a non-trivial percentage of MA patients. On
the other hand, it is also clear that some test subjects
only experienced a negligible treatment effect or none at
all. For these patients, it is promising that the study
indicated an increase in efficacy with each subsequent
treatment.
Several physiological mechanisms may underpin the
migraine treatment efficacy of normoxic hypercapnia,
indicated by this and earlier studies. A number of stu-
dies have indicated that transient increases of the extra-
cellular K
þ
concentration play an important role in the
triggering and propagation of CSD (17,28–32), which
may be an underlying attack trigger not only in MA but
MO as well (4,14–17). Clearance of K
þ
from the extra-
cellular space depends critically on proper functioning
of the Na
þ
/K
þ
-ATPase transporter, which in turn
requires an adequate supply of oxygen and glucose to
function (33,34). Indeed, inhibition of Na
þ
/K
þ
-ATPase
directly triggers spreading depression in hippocampal
slices (35).
Inadequate Na
þ
/K
þ
-ATPase function may thus be
the underlying mechanism behind the propensity of
ischemia for triggering spreading depolarizations in
animal models (36), and of hypoxia for triggering
migraine (10–12).
It is well established that hypercapnia has a
strong vasodilatory effect in the brain (37,38),
increasing total cerebral blood flow by as much as
7.4% for each mmHg increase in ETCO2 (27), in
turn increasing total D
O2,brain
by the same percentage
if normal S
aO2
is preserved. The efficacy of normoxic
hypercapnia in migraine may thus be a function of
bolstering Na
þ
/K
þ
-ATPase activity by reversing the
hypoperfusion (and any resulting tissue hypoxia)
responsible for triggering and propagating the
spread of CSD. Indeed, hypercapnic acidosis has in
animal models shown a marked inhibitory effect on
the triggering, propagation and duration of CSD
(39–41), as well as a general inhibition of neural
excitability (42,43).
For the purpose of increasing D
O2,brain
, an alter-
native to normoxic hypercapnia is to increase the
inspired oxygen fraction, and a recent study
showed some efficacy of high-flow oxygen for acute
migraine relief (44). However, due to the sigmoidal
shape of the oxygen dissociation curve, such
increases in P
aO2
only increase the arterial oxygen
concentration slightly compared to normoxia, and
very high inspired oxygen fractions may even incur
vasoconstriction and hypoperfusion (45). Being the
mathematical product of CBF and C
aO2
,D
O2,brain
can be increased significantly by the strong increase
in CBF achievable by normoxic hypercapnia, but
comparatively little by the small increase in C
aO2
elicited by hyperoxic normocapnia (though hyperoxia
1640 Cephalalgia 38(10)
could have other relevant effects apart from its
impact on D
O2,brain
).
Compared to pharmaceutical relief medications, the
PRD could potentially have a number of advantages,
among them:
.CO
2
-induced increases in CBF happen within
10 seconds of starting to breathe an increased
CO
2
fraction (46) and wash out of the body within
a few minutes of ending the treatment. This fast
onset of action enables early intervention, possibly
aborting or containing the progress of the CSD wave
– a hypothesis that could be tested in an imaging
study.
.As a drug-free treatment, PRDs could potentially be
combined with pharmaceuticals or replace them in
groups for whom standard medications are contra-
indicated, provided that sufficient PRD safety data
is obtained for the patient groups in question.
.PRDs avoid the common problem of oral medica-
tions being expelled by emesis before uptake through
the gastric tract is complete.
.The effects of moderate hypercapnia are well known
and generally mild, and any excessive CO
2
increases
can be directly sensed by the user, allowing him/her
to immediately decrease the device’s rebreathing
level and its bodily effects.
In light of such potential advantages and the promis-
ing results of this small-scale pilot study, we believe that
a large-scale clinical trial of the PRD treatment in
migraine is warranted.
In future studies, it will also be relevant to investigate
the background for (and correlates of) the PRD efficacy
variance, for at least two reasons. Firstly, it could help
identify predictors for a patient’s likely response to the
treatment, allowing more targeted studies into, and tar-
geted clinical use of, PRD treatment. Secondly, it could
make it possible to develop improvements to the device,
its timing/dosage or duration of use, in order to increase
the percentage of migraine patients deriving benefit from
the treatment. Some MA patients may be further in the
attack evolution than others before experiencing the
migraine aura, meaning that some of the participants
in this study had possibly passed a pathophysiological
‘‘point of no return’’ at the time of their cue to
start using the device (in this study the cue was the
aura symptoms). For this reason, it may be better to
start the treatment at the appearance of the very first
prodromes (which occur in the majority of both MA
and MO patients (6)), and not wait until the appearance
of aura.
This study specifically studied MA, so its results
may not be generalizable to other types of migraine
such as MO. However, several studies indicate that
CSD and/or cerebral hypoperfusion play important
roles in MO as well (4,14–17), and hypoxia has
been shown to trigger migraine attacks in both MO
and MA patients (10). This seems to indicate that a
clinical study of PRD treatment in MO would be
warranted.
In future clinical studies, the efficacy of PRD treat-
ment as an add-on to pharmaceuticals would be
another interesting focus.
Clinical implications
.Normoxic hypercapnia induced by a partial rebreathing device showed promise as an adjunctive or alter-
native, non-pharmacological treatment of episodic migraine with aura.
.The device efficacy increased with each subsequent use.
.Further studies should be undertaken to investigate the efficacy in a larger population and in migraine
without aura.
Declaration of conflicting interests
The authors declared the following potential conflicts of inter-
est with respect to the research, authorship, and/or publica-
tion of this article: T. Johansen is a co-founder, shareholder
and employee of BalancAir.
Funding
The authors disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: This study was sponsored by BalancAir.
ORCID iD
Troels Johansen http://orcid.org/0000-0001-5741-3461
Helge Kasch http://orcid.org/0000-0002-9302-4946
Flemming W Bach http://orcid.org/0000-0002-2518-9335
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