Effects of Twenty Days of the Ketogenic Diet on Metabolic and Respiratory Parameters in Healthy Subjects

Abstract

Purpose:
The effects of the ketogenic diet (KD) on weight loss, metabolic, and respiratory parameters were investigated in healthy subjects.

Methods:
Thirty-two healthy subjects were randomized into two groups. The KD group followed a ketogenic diet for 20 days (KD t 0-t 20), then switched to a low-carbohydrate, no-ketogenic diet for 20 days (KD t 20-t 40), and finally was on a Mediterranean diet (MD) for 2 more months (KD t 40-t 2m). The MD group followed a MD for 20 days (MD t 0-t 20), then followed a MD of 1400 kcal over the next 20 days (MD t 20-t 40), and completed the study with the MD for 2 months (MD t 40-t 2m). Body weight, body fat, respiratory rate, and respiratory gas parameters (including respiratory exchange ratio (RER) and carbon dioxide end-tidal partial pressure (PETCO2), oxygen uptake (VO2), carbon dioxide production (VCO2), and resting energy expenditure (REE)) were measured at each point.

Results:
A significant decrease (p < 0.05) in RER was observed after 20 and 40 days in the KD group, but not in the MD group. In the KD group, significant reductions were observed for both carbon dioxide output and PETCO2, however, there was no significant change in VO2, VCO2, and REE. While both diets significantly decreased body fat mass, the KD diet overall proved to have a higher percentage of fat loss versus the MD diet.

Conclusion:
The KD may significantly decrease carbon dioxide body stores, which may theoretically be beneficial for patients with increased carbon dioxide arterial partial pressure due to respiratory insufficiency or failure.

Full text

Effects of Twenty Days of the Ketogenic Diet on Metabolic
and Respiratory Parameters in Healthy Subjects
Rubini Alessandro
1
•Bosco Gerardo
1
•Lodi Alessandra
1
•Cenci Lorenzo
1
•
Parmagnani Andrea
1
•Grimaldi Keith
2
•Zhongjin Yang
3
•Paoli Antonio
1
Received: 30 June 2015 / Accepted: 21 September 2015
Springer Science+Business Media New York 2015
Abstract
Purpose The effects of the ketogenic diet (KD) on weight
loss, metabolic, and respiratory parameters were investi-
gated in healthy subjects.
Methods Thirty-two healthy subjects were randomized
into two groups. The KD group followed a ketogenic diet
for 20 days (KD t
0
–t
20
), then switched to a low-carbohy-
drate, no-ketogenic diet for 20 days (KD t
20
–t
40
), and
finally was on a Mediterranean diet (MD) for 2 more
months (KD t
40
–t
2m
). The MD group followed a MD for
20 days (MD t
0
–t
20
), then followed a MD of 1400 kcal
over the next 20 days (MD t
20
–t
40
), and completed the
study with the MD for 2 months (MD t
40
–t
2m
). Body
weight, body fat, respiratory rate, and respiratory gas
parameters (including respiratory exchange ratio (RER)
and carbon dioxide end-tidal partial pressure (PETCO
2
),
oxygen uptake (VO
2
), carbon dioxide production (VCO
2
),
and resting energy expenditure (REE)) were measured at
each point.
Results A significant decrease (p\0.05) in RER was
observed after 20 and 40 days in the KD group, but not in
the MD group. In the KD group, significant reductions
were observed for both carbon dioxide output and
PETCO
2
, however, there was no significant change in VO
2
,
VCO
2
, and REE. While both diets significantly decreased
body fat mass, the KD diet overall proved to have a higher
percentage of fat loss versus the MD diet.
Conclusion The KD may significantly decrease carbon
dioxide body stores, which may theoretically be beneficial
for patients with increased carbon dioxide arterial partial
pressure due to respiratory insufficiency or failure.
Keywords Ketogenic diet Respiration parameters 
Metabolism Resting energy expenditure
Introduction
The ketogenic diet, which is of a high-fat, adequate-pro-
tein, low-carbohydrate content, is originally designed to
treat refractory epilepsy in children. Though underlying
mechanisms are not fully understood, systemic acidosis,
electrolyte changes, and hypoglycemia induced by the
ketogenic diet have all been suggested to be responsible for
its therapeutic effects [1]. Recent studies have suggested
that the ketogenic diet may be used as an adjunc-
tive therapy in many other pathological conditions such as
diabetes mellitus, polycystic ovary syndrome, acne, neu-
rological diseases, cancer, and the amelioration of respi-
ratory and cardiovascular disease risk factors [2,3].
Moreover, very low-carbohydrate ketogenic diets are more
effective for body weight reduction and fat loss compared
to balanced or low-calorie Mediterranean diets, at least in
the short-medium term [4,5]. Despite the widespread use
of the ketogenic diet, its effect on respiratory parameters is
still not well investigated. One of the metabolic effects of
the ketogenic diet is the higher than usual oxidation of fats,
which reduces the respiratory exchange ratio (RER) values
[6,7]. Measured RER can be used to estimate the respi-
ratory quotient (RQ), an indicator of which fuel
&Zhongjin Yang
Yangz@upstate.edu
1
Department of Biomedical Sciences, University of Padova,
35131 Padua, Italy
2
Biomedical Engineering Laboratory, University of Athene,
15773 Athens, Greece
3
The Institute for Human Performance, SUNY Upstate
Medical University, Syracuse, NY 13210, USA
123
Lung
DOI 10.1007/s00408-015-9806-7

(carbohydrate or fat) is being metabolized to supply the
body with energy. Metabolic carbon dioxide output
(VCO
2
) can be calculated as the product of alveolar ven-
tilation times alveolar fractionalcarbon dioxide content. A
recent study suggests that administering the ketogenic diet
for 6 months in patients with medically refractory epilepsy
increased fat oxidation, and decreased RER and the RQ,
without appreciable changes in resting energy expenditure
(REE) [7]. Theoretically, the ketogenic diet decreases RER
and metabolic carbon dioxide production, therefore, may
lead to a decreased arterial carbon dioxide partial pressure
(PETCO
2
) and decreased pulmonary ventilation. These
effects may be useful as an adjunctive therapy in managing
patients with respiratory failure. However, this respiratory
aspect of the ketogenic diet has not been previously
investigated. In the present report, we studied the effect of
the ketogenic diet on metabolic and respiratory parameters,
including RER, PETCO
2
, and pulmonary ventilation in
healthy subjects, during and after the ketogenic diet period,
and we compared these effects with the results obtained
during and after a Mediterranean diet protocol. The effects
of the ketogenic diet and Mediterranean diet protocol on
body weight and fat mass (FM) have also been
investigated.
Materials and Methods
Subjects
Participants were recruited via advertisement placed in two
pharmacies located in the province of Vicenza (Veneto,
Italy). Primary eligibility criteria included being
18–65 years old, BMI 25 to 30 kg/m
2
, currently on a diet
with normal to high amount of carbohydrate
([55 %)/compatible to a modified ketogenic diet i.e., a
Mediterranean ketogenic diet with phytoextracts (KD) [8–
10]. The subjects had normal renal function and no dia-
betes, nor were they pregnant or lactating. Changes of
habits, like starting a new exercise program or taking new
drugs during experimental period, would be excluded from
final analysis. Forty female subjects were initially recruited
in this study; six were excluded for medical reasons, one
was following a low-carbohydrate diet already and 1
refused to participate after the first interview, thus 32
subjects participated in the study and were randomized into
two groups (n=16 for each group): MD (age 44.7 ±13.9,
BMI 27.5 ±2.8, weight 77.2 ±9.8 kg) and KD (age
51.4 ±12.4, BMI 29.3 ±2.8, weight 82 ±12.4 kg). The
study was approved by the Ethical Board of the University
of Padova, Department of Biomedical Sciences, and con-
formed to standards for the use of human subjects in
research as outlined in the current Declaration of Helsinki.
Investigators explained the purpose of the study, the pro-
tocol to be followed, and the experimental procedures to be
used prior to allowing participants to enter the study.
Subjects received no monetary compensation for their
participation and signed a voluntary consent before initi-
ating the diet.
Diet
During a preliminary meeting, diets were explained and
each participant received a detailed menu containing per-
mitted and non-permitted food. The KD subjects were
followed for 20 days on a ketogenic diet (KD t
0
–t
20
) with
extremely low carbohydrate (\30 g/day). The diet used
meals that mimic the aspect and the taste of carbohydrate,
but with virtually zero carbohydrate, and added with phy-
toextracts (Tisanoreica

by Gianluca Mech SpA, Asigliano
Veneto, Vicenza, Italy). The permitted food during the
ketogenic diet phase was cooked or raw green vegeta-
bles (200 g/meal); meat, fish, or eggs (1 time/day); and
olive oil 30 g/day. Allowed drinks were water, infusion tea,
Mocha coffee, and specific herbal extracts (Estratti
Decottopia Tisanoreica

by Gianluca Mech SpA, Asi-
gliano Veneto, Vicenza, Italy). The diet was also integrated
with four PATs

per day (PAT is the acronym for Porzione
Alimentare Tisanoreica =Tisanoreica Nutritional Por-
tion), which is composed of high-quality proteins (each
PAT is equivalent to 18 g of protein) and virtually zero
carbohydrates. After the ketogenic diet phase, the subjects
were followed on a low-carbohydrate no-ketogenic diet
over the next 20 days (KD t
20
–t
40
). During this period,
complex carbohydrates (50–80 g/day) and cheese
(60 g/day) were introduced and the number of permitted
PATs was reduced to two, while the other indications
remained unchanged. The distribution of nutrients (pro-
teins, carbohydrates, and fats) in terms of percentage of
total caloric intake was 43, 14, and 43 % during the
ketogenic phase, and 27, 34, and 39 % during the next
stage, respectively. Throughout the ketogenic period, all
subjects consumed 30 ml of extract A and 30 ml of extract
B diluted in 1.5 l water, daily. They also consumed 15 ml
of extract C before breakfast and lunch, diluted in one glass
of water. Following 20 days, after dinner, 20 ml of extract
D diluted in one glass of warm water was added. The diet
protocols have been tested in our previous researches [5,9,
10].
The MD group followed a Mediterranean diet, con-
suming 1200 kcal/day for 20 days (MD t
0
–t
20
), and it was
then followed with another set of Mediterranean diet con-
sisting of 1400 kcal/day over the next 20 days (MD
t
20
–t
40
). The macronutrient percentage during the
Mediterranean diet consisted of 15 % protein, 60 % car-
bohydrate, and 25 % fat for the total daily caloric uptake.
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123

After the initial 40 days, both the KD and MD groups were
followed on a Mediterranean diet with a total daily caloric
uptake of 1400 kcal. The Mediterranean regime consisted
of a balanced diet, in which the use of whole grain pasta,
bread, and rice was permitted, mainly at breakfast and
lunch, but in a smaller quantity at dinner. Raw and cooked
vegetables were prescribed at lunch and dinner; fruits were
permitted as snacks in the morning or in the afternoon; and
proteins (meat/fish/cheese/eggs/bean curd, etc.) were pro-
vided only at dinner. Sweets, pizza, and alcoholic drinks
were allowed once a week and the accepted dressings were
olive oil, salt, spices, and vinegar. Moderate physical
activity and the use of infusions during the daytime were
also suggested.
Detailed composition of the diet is listed in Tables 1,2,
and 3.
Measurements
Subjects were invited to the Laboratory of Physiology,
Department of Biomedical Sciences, University of Padua,
where measurements were performed. REE and RR and
body weight were measured in the morning after overnight
fasting at the start of the study (t
0
), after 20 days (t
20
), at
the end of the diet-period (t
40
), and 2 months after the end
of the study (t
2m
). Subjects were weighed at the same time
of the day at the start (t
0
), at t
20
,t
40
, and t
2m
using the same
weighing scales (Digital Scale Joycare

Jc431). Body
composition analysis was performed using the Akern STA-
BIA instrument, which provided us with the following
information: fat free mass (FFM), FM, total body water
(TBW), and muscular mass. REE was analyzed using
oxygen uptake (VO
2
), carbon dioxide production (VCO
2
),
and RER measurements with a Vmax

Encore 29 System
(Vmax) (Viasys Healthcare, Inc., Yorba Linda, CA). Vmax
used a mixing chamber and generated VO
2
and VCO
2
;
those data were converted to REE expressed in Kcal/d
using appropriate RR values and established tables based
on the Weir equation [10]. The device was calibrated with
reference gases prior to each participant. Oxygen uptake
was measured (ml/min) and also normalized to body
weight (ml/kg/min), and the respiratory RR was deter-
mined. After resting for 15 min, the data were collected for
30 min, and only the last 20 min were used to calculate the
respiratory gas parameters [9].
All tests were performed in the morning before breakfast
(7–8 am), while the subjects were seated. The room was
dimly lit, quiet, and approximately 24 C. Subjects were
requested to abstain from caffeine or alcohol consumption
for 24 h prior to the measurement.
Statistical Analysis
The data were expressed as mean and standard deviation.
Bland–Altman plots and comparison of the test–retest
measurements performed in our laboratory confirmed good
reproducibility of the measurements for RR and VO
2
(ICC
[0.85 and [0.9, respectively, with p\0.05). A one-way
ANOVA for repeated measurements was used (GraphPad
Prism version 4.00 for Windows, GraphPad Software, San
Diego, California USA). Tukey’s post hoc test was used.
p\0.05 was considered significant. Normality of the data
was checked and subsequently confirmed using the Sha-
piro–Wilk test. The present sample size was selected based
on a power analysis. Body weight and body FM data were
analyzed using two-way ANOVA test for repeated mea-
sures, and unpaired t-tests with Welch’s correction were
performed when appropriate.
Results
Respiratory Gas Analysis
As shown in Fig. 1, the KD group showed a significant
decrease (p\0.05) in the mean value of RER after
20 days of ketogenic diet. The RER was maintained at
lower levels even after 40 days (t
40
), when subjects were
no more in ketosis. The reduction in PETCO
2
(Fig. 2) was
observed after both the ketogenic diet and Mediterranean
diet. There were no significant changes in VO
2
(Fig. 3),
VCO
2
(Fig. 4), and VE (Fig. 5).
The MD group did not show any significant difference
(data not shown).
As shown in Fig. 6, a significant body weight loss was
noticed in both groups between t
0
and t
20
(p\0.01), the
body weight loss was more significant in the KD group
than in the MD group. The mean values of body weight in
both groups are as follows:
Table 1 Diet composition in
KD diets (values are expressed
in mean per day)
KD t
0
–t
20
KD t
20
–t
40
KD t
40
–t
2m
Daily energy, Kcal/day 848 938 1400
Protein, g/day (% daily energy) 92 (43.4) 64.4 (27.5) 52.5 (15)
Carbohydrate, g/day (% daily energy) 30 (14.1) 80 (34.1) 210 (60)
Fat, g/day (% daily energy) 42 (42.4) 42 (38.4) 54.4 (35)
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123

Table 2 Plant extracts during the KD group’s diet (from)
Plant extracts ml/day Composition
Extract A 30 Durvillaea Antarctica, Black Radish, Mint, Liquorice, Artichoke, Horsetail, Burdock,
Dandelion, Rhubarb, Gentian, Lemon Balm, Chinaroot, Juniper, Spear Grass, Elder, Focus,
Anise, Parsley, Bearberry, Horehound
Extract B 30 Serenoa, Red Clover, Chervil, Bean, Elder, Dandelion, Uncaria, Equisetum, Horehound,
Rosemary
Extract C (only during the first
ketogenic phase)
30 Eleuthero, Eurycoma Longifolia, Ginseng, Corn, Muira Puama, Grape, Guarana
`, Arabic
Coffee, Ginger
Extract D (only during the second
non-ketogenic phase)
20 Horsetail, Asparagus, Birch, Cypress, Couch Grass, Corn, Dandelion, Grape, Fennel, Elder,
Rosehip, Anise
Table 3 Main active ingredients of phytoextracts and their reported beneficial effects (from)
Extract Main active ingredients Reported beneficial effects
A Mint Indigestion
Black radish Antioxidant
Burdock Choleretic, increases bile secretion helping digestion
B Serenoa Repens (Saw Palmetto) Hormonal regulating effect
White bean Alpha-amylase inhibitory properties have been reported to aid
weight loss and glycemic control
C Ginseng Ameliorate the commonly reported symptoms of weakness and tiredness
during 1st phase of ketosis (1/2 weeks)
Muira puama
Guarana
`
D Equisetum
Dandelion (Taraxacum officinale)
Fig. 1 The effect of ketogenic diet on respiratory exchange ratio
(RER) measured at different time points during the diet period.
Ketogenic diet significantly decreased the respiratory exchange ratio
as measured on day 20. RER continues to decrease as measured on
day 40, and returned to the baseline as measured in 2 months. t
0
day
0, the value as baseline; t
20
as measured on day 20; t
40
as measured on
day 40; t
2m
as measured in 2 months. **p\0.01. Values are shown
as mean and SD
Fig. 2 The changes of carbon dioxide end-tidal partial pressure
(PETCO
2
) measured at different time points during the diet period.
Comparing with the baseline of PETCO
2
at the start of the study (t
0
),
significant decrease (p\0.05) was observed after 20 days (t
20
)of
ketogenic diet, at the end of the diet-period (t
40
), and 2 months after
the end of the weight reduction program (t
2m
). t
0
day 0, the value as
baseline; t
20
as measured on day 20; t
40
as measured on day 40; t
2m
as
measured in 2 months. **p\0.01. Values are shown as mean and
SD
Lung
123

•KD: t
0
82.0 ±12.4; t
20
77.8 ±12.0; t
40
74.8 ±11.7;
t
2m
73.5 ±12.6
•MD: t
0
77.2 ±9.8; t
20
74.4 ±10.0 t
40
72.5 ±9.6; t
2m
72.1 ±10.7
The average weight loss was 8.4 kg for the KD group
and 5.1 kg for the MD group at t
2m
.
As shown in Fig. 7, both groups showed a good drop in
FM between t
0
and t
20
, although it was more significant for
the KD group (pvalue MD t
20
\0.01; pvalue KD
t
20
\0.001). The average of the FM lost in this group
between t
40
and t
2m
is 1 kg in KD and 0.2 kg in MD group.
All subjects completed the experimental trial.
Discussion
The main findings in the present study are that (1) the
ketogenic diet significantly decreased the value of RER; (2)
the ketogenic diet significantly decreased carbon dioxide
end-tidal partial pressure (PETCO
2
); (3) the ketogenic diet
Fig. 3 The changes in oxygen uptake (VO2) measured at different
time points during the diet period. There was no significant change in
VO2 during the entire diet period. t
0
day 0, the value as baseline; t
20
as measured on day 20; t
40
as measured on day 40; t
2m
as measured in
2 months. Values are shown as mean and SD
Fig. 4 The changes in carbon dioxide production (VCO2) measured
at different time points during the diet period. There were no
significant changes observed during the diet period. t
0
day 0, the value
as baseline; t
20
as measured on day 20; t
40
as measured on day 40; t
2m
as measured in 2 months. Carbon dioxide output relies largely on the
amount of energy your body is using. Values are shown as mean and
SD
Fig. 5 The changes in expired total ventilation (VE) measured at
different time points during the diet period. There were no significant
changes observed during the diet period. t
0
day 0, the value as
baseline; t
20
as measured on day 20; t
40
as measured on day 40; t
2m
as
measured in 2 months. Values are shown as mean and SD
Fig. 6 The effect of ketogenic diet on body weight measured at
different time points during the diet period. Significant body weight
loss was observed in both diet groups. t
0
day 0, the value as baseline;
t
20
as measured on day 20; t
40
as measured on day 40; t
2m
as measured
in 2 months. No significant differences were detected between
treatments. Values are shown as mean and SD
Fig. 7 The effect of ketogenic diet on body fat mass measured at
different time points during the diet period. Significant body fat mass
loss was observed in both diet groups. t
0
day 0, the value as baseline;
t
20
as measured on day 20; t
40
as measured on day 40; t
2m
as measured
in 2 months. At t
2m
, KD group showed significant decrease
(*p\0.05) compared to MD group. Values are shown as mean and
SD
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123

had no significant effect on REE, oxygen consumption
(VO
2
), carbon dioxide production (VCO
2
), or expired total
ventilation (VE); (4) the ketogenic diet significantly
decreased body mass and body FM.
The RER is the ratio between the amount of CO
2
pro-
duced and molecules of O
2
consumed in one breath. A RER
of 0.70 indicates that fat is the predominant fuel source, a
RER of 0.85 suggests a mix of fat and carbohydrates, and a
value of 1.00 or above is indicative of carbohydrates being
the predominant fuel source. Deceased RER seen in the
present study reflects fat as the predominant fuel source
during consumption of the ketogenic diet. This is in agree-
ment with our previous study [6] and others [7].
Oxygen consumption is linearly related to the workload;
consumption of different diets should not significantly
change REE. A recent study showed that administering the
ketogenic diet for 6 months in patients with medically
refractory epilepsy increased fat oxidation without chang-
ing REE [7]. Our data are in agreement with their findings
that KD did not change REE. As pointed out by Tagliabue
et al. the body has a great capacity to adjust substrate
oxidation to substrate intake after approximately 1 week of
carbohydrates and fats. Fat oxidation increased in our study
as an adaptation to the high-fat intake, typical of the KD.
The consequence of an isoenergetic exchange of fat for
carbohydrate is that the results can also be interpreted as
being an adaptation to a low-carbohydrate intake [11,12].
We have previously demonstrated that using KD for
30 days can decrease body weight and body FM without
negative effects on strength performance in high level
athletes [9]. The data from the present study validate the
weight reduction effect of KD. We previously suggested
that KD reduced body weight and FM loss and it may be due
to reduced REE in elite artistic gymnasts caused by glu-
coneogenesis and the thermic effect of proteins [9]. In the
present study, in healthy subjects the reduced body weight
and FM were not associated with reduced REE. The pos-
sible mechanisms may be due to reduction in lipid synthesis
and increased lipolysis mechanisms, reduction in at rest RQ
and, therefore, an increase in fat metabolism for energy use.
High-fat content in the ketogenic diet causes ketosis and
metabolic acidosis, which leads to a reduction in carbon
dioxide metabolic production for a given oxygen con-
sumption. As shown in the present study, REE was not
changed; therefore, the total oxygen consumption was not
altered by the ketogenic diet. The carbon dioxide metabolic
production should decrease as the present study demon-
strated. As a consequence, decreased pulmonary ventila-
tion parameters values should be expected. Expired minute
volume is an important parameter in respiratory medicine
due to its relationship with blood carbon dioxide levels.
Blood carbon dioxide levels generally vary inversely with
minute volume. For example, a person with increased
minute volume should demonstrate a lower blood carbon
dioxide level. The healthy human body will alter minute
volume in an attempt to maintain physiologic homeostasis.
However, our data do not follow this principle; reduced
carbon dioxide metabolic production is not associated with
increased expired total ventilation. This phenomenon sug-
gests that reduced carbon dioxide output may be due to a
decreased carbon dioxide body store. This may be partially
caused by reductions in body mass and FM, and/or, greater
oxygen uptake necessary to obtain the same energy yield as
on a mixed diet due to increased fat oxidation after the
ketogenic diet. According to the definition of carbon
dioxide store, the amount of CO
2
contained in the body as a
gas and in the form of carbonic acid, carbonate, bicar-
bonate, and carbaminohemoglobin, during a steady state of
ventilation and aerobic respiration, the rate at which CO
2
leaves the body equals the rate at which it is produced, and
CO
2
store remains constant. The ketogenic diet decreases
the production of CO
2
, and since the rate of CO
2
leaving
the body does not change (no change in expired volume),
the CO
2
store consequently decreases.
Few studies have described the consequent changes in
pulmonary ventilation and/or arterial carbon dioxide partial
pressure during high fat metabolism. For example, Saba-
pathy et al. examined the relationship between minute
ventilation, CO
2
production, and blood lactate concentra-
tions during incremental exercise performed with reduced
muscle glycogen stores [13]. Peak oxygen uptake was
unchanged with glycogen reduction. Peak blood lactate
decreased significantly. At any percentage of peak oxygen
uptakes, O
2
uptake and minute ventilation were similar for
both treatment conditions, whereas VCO
2
and RER values
were lower during the reduced glycogen trial than under
normal glycogen conditions. Therefore, VE/VCO
2
tends to
be higher and end-tidal CO
2
partial pressure tends to be
lower during exercise performed in the reduced glycogen
state. Minute ventilation was significantly correlated
with CO
2
production under both treatment conditions.
Minute ventilation during exercise was similar under both
treatment conditions. This suggests that factors other than
CO
2
delivery to the lung and metabolic acidosis play an
important role in regulating minute ventilation during
exercise. Similar results were also reported [14]. Cai et al.
evaluated the efficacy of feeding a high-fat, low-carbohy-
drate (CHO) nutritional supplement as opposed to a high-
carbohydrate diet in COPD patients on parameters of pul-
monary function. They found that lung function measure-
ments decreased significantly and forced expiratory
volume increased significantly in the high-fat, low-carbo-
hydrate diet group. Their study demonstrates that pul-
monary function in COPD patients can be significantly
improved with a high-fat, low-CHO oral supplement as
compared with the traditional high-CHO diet. These
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123

findings suggest that factors other than CO
2
delivery to the
lung and metabolic acidosis play an important role in
regulating ventilation during ketogenic diet. The present
study supports their findings that the high-fat diet may
decrease the carbon dioxide store, and therefore, improve
pulmonary ventilation. In this preliminary study we tested
healthy subjects; it is reasonable to suppose that the vari-
ations of blood gases during a ketogenic diet follow the
same trend in normal subjects and in respiratory compro-
mised patients. The ketogenic diet has been described to be
associated with an increased leptin blood concentration
[15], and leptin has been recognized as an effective ven-
tilation stimulant [16,17]. Thus, the ketogenic diet-induced
reduction in carbon dioxide metabolic load is coupled with
a reduced carbon dioxide partial pressure value, with
maintained pulmonary ventilation.
Hypercapnic respiratory failure (type II) is characterized
by an increased carbon dioxide arterial partial pressure
values higher than 50 mm Hg. Through the specific treat-
ment on the etiology of respiratory failure, the ketogenic
diet may provide the potential useful effects because it
lowers carbon dioxide arterial partial pressure values. In
our opinion, it is not possible to definitely state that the
observed changes in PETCO
2
may be clinically relevant in
all conditions. Such a little change may reveal not to be
decisive in some clinical settings, but even such minor
changes may have clinically relevant consequences in
border-line patients with risk of respiratory failure.
One limitation of our study was the relative low number
of subjects and the heterogeneity of sample (even though
the differences of investigated variables at the start of the
study was not statistically significant). Further studies are
needed to verify this working hypothesis. In particular, it
would be of interest to verify that the constancy of pul-
monary ventilation is associated with a lack of any sig-
nificant changes in the mechanical work of breathing. This
would suggest that respiratory failure patients undergo
reduced arterial carbon dioxide partial pressure values
without an incremented risk of respiratory failure on a
mechanical basis because of respiratory muscle fatigue.
Acknowledgments We wish to thank Kim Hare and Marcelyn
Cook for their English editorial assistance.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict
of interest.
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