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1 Swiss Paediatric Respiratory Physiology Research Group, University Children's Hospital Bern, CH-3010 Bern; and 2 Swiss Paediatric Respiratory Physiology Research Group, University Children's Hospital, 8032 Zürich, Switzerland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tidal fractional exhaled nitric oxide
(FENO) changes were investigated in healthy,
unsedated infants with or without prenatal tobacco exposure.
Tidal flow (
), FENO, and CO2
were measured in 20 healthy, unsedated infants [age: 25-58 days,
length: 56.5 ± 2.5 (SE) cm]. NO output (NO)
was calculated (NO =
FENO × ). Two approaches were used
to investigate within-breath changes of FENO
and NO. First, we identified phases II and III from the expiratory capnogram. Second, we divided expiration into time-based quartiles. Tidal FENO (range: 14.5 ± 1.6 to 17.6 ± 2.1 parts/billion: quartile 4 and phase II,
respectively) was not different between portions and exhibited
significant negative dependence. NO was
significantly dependent on the expiratory portion, with quartile 4 being significantly lower than the remaining expiratory
portions. Infants exposed to prenatal cigarette smoke
(n = 7) exhibited significantly lower
FENO and NO compared with
nonexposed (n = 13) infants. We conclude that tidal
FENO is dependent and that
NO may be a more suitable outcome parameter in
variable conditions. Prenatal tobacco exposure resulted in a
decreased FENO and NO in infants.
tidal breathing; lung function
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THERE IS EXTENSIVE
INTEREST in the measurement of exhaled nitric oxide (NO;
FENO) as a noninvasive marker of airway
inflammation. In adults and older children, measurement involves
exhaling at a constant flow () against a resistance and
obtaining a plateau in the FENO signal
(1, 14). Whereas this test is noninvasive, in
uncooperative patients, such as young children and infants, it is
unsuitable. In young children, tidal FENO has
been used to discriminate between healthy and asthmatic patients
(4). This technique involves the patient breathing through
a mouthpiece and the exhaled breath being sampled on-line to produce
tidal FENO. An expiratory resistance is added
to close the soft palate, hence removing contamination by nasal NO.
Guidelines state that techniques for sampling pulmonary
FENO should exclude contamination of
the sample with nasal NO (1). Infants are preferential
nasal breathers, and lung function measurements in this age necessitate the use of a face mask, increasing the difficulty of nasal NO exclusion. The addition of an expiratory resistance to ensure closure
of the soft palate during tidal breathing in quiet sleep may result in
failed or poor quality measurements in this age group. Wildhaber et al.
(24) have reported an adaptation of the single-breath
technique that excludes nasal NO and allows FENO to be obtained at a constant in
infants. The technique, however, requires the sedation of the infant,
and specialized equipment is needed to raise the infant's lung volume
and, therefore, has limited use, particularly in large epidemiological
studies. Baraldi et al. (5) have measured offline tidal
FENO in infants and small children using a
collection reservoir connected to a face mask, which is placed over the
mouth while the infant's nose is closed. The disadvantage of this
technique is that closure of the nostrils may disturb the infant,
inducing highly variable breathing patterns, and the subsequent
expiratory times (TE), tidal volumes (VT), and
may influence the resulting FENO
values. This appears critical, as the dependency of NO is well
established in both adults (20, 22) and children
(9). Furthermore, differences in TE and
due to disease may influence the subsequent tidal
FENO concentrations. These studies suggest that
FENO measurements in infants should fulfill the
following criteria: 1) be simple to apply, 2) be
noninvasive, 3) have negligible impact on the infant's
natural breathing patterns, and 4) account for the dependence of NO. It appears that, whereas the techniques described above have their advantages and disadvantages, they may not fulfill all
of these criteria.
The aim of this study was to initially develop a method for the on-line
collection of tidal FENO in infants that would
allow breath-to-breath monitoring of tidal FENO
and in natural sleep without disturbing the infant's normal
breathing pattern (criteria 1-3) and to determine
whether tidal FENO is dependent
(criterion 4). The washout characteristics of
CO2 were then used to identify separate regions of the NO
profile; these regions were subsequently utilized to test the ability
of the developed analysis methods to detect differences in
FENO and NO output (NO) in a
group of healthy infants with or without prenatal tobacco exposure
(PTE), as chronic cigarette exposure is known to reduce NO in adults (7, 15, 19).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients.
Twenty healthy infants, aged between 25 and 58 days, without a positive
maternal history of asthma or atopy, were studied unsedated, during
quiet sleep, in a supine position, with the head in the midline
position. Seven of the infants had PTE (PTE group) and received
variable exposure to passive, postnatal tobacco smoke, whereas the
remaining 13 infants had no tobacco exposure (control group). The two
groups of infants were matched for postnatal age, weight, and length.
Heart rate and arterial O2 saturation (Biox 3700;
Datex-Ohmeda, Helsinki, Finland) were monitored throughout the study.
Tidal measurements could be obtained in non-rapid eye movement sleep in
all infants. The ethics committee of the University Hospital of Berne
approved the study, and the parents were generally present during
testing. Anthropometric data are shown in Table 1.
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Study design.
Tidal FENO concentration may depend on which
part of expiration is examined. To determine which part of the
expiratory NO signal shows concentrations most similar to the NO
concentrations collected under constant conditions in infants
(24), we analyzed the on-line tidal
FENO profiles using two approaches to identify discrete portions of expiration (as described in detail below) and
compared the values with published data.
dependence of tidal FENO can easily
be determined by measuring synchronously, allowing the
breath-to-breath dependence to be assessed. The parallel
assessment of FENO and also allows the
determination of NO calculated as the tidal
FENO by the tidal
(NO = FENO × ).
We assessed the breath-by-breath dependence of
FENO in each expiratory portion.
The analysis of the tidal FENO signal was
performed by using two approaches. The first was based on the known
washout characteristics of CO2 from the lung, which
includes three distinct phases. Phase I equates to the gas expired from
the convective airways, phase II (PII) is due to progressive washout of
the airways with alveolar gas, whereas phase III (PIII) represents
emptying of CO2 from alveolar compartments. We identified
PII and PIII from the expiratory capnograph and used these to examine
discrete portions of the tidal FENO signal.
This method of identification will take into account differences in
expiratory washout characteristics (for example, those caused by
changes in tidal , volume, and TE) between
individuals and disease groups. The second approach used a time-based,
rather than volume-based, analysis by dividing each expiration into
four equal portions. The latter approach would allow examination of the
on-line tidal FENO signal without the need for
additional capnography and thus possibly allow a more simple clinical
application of the method.
The detection of alterations in tidal FENO due
to changes in respiratory physiology may differ, depending on the type
of disease. In disease, the alterations in tidal breathing patterns,
including TE, profiles, and VT, may
cause changes in the tidal FENO concentration unrelated to NO production. To ascertain if these factors played a
significant concomitant role between the control and PTE groups, we
tested for differences in TE, , VT, and
peak expiratory flow (PEF). The ability of a method to distinguish
between disease states can be quantified by defining the absolute
change between the groups, normalized for the variability of the
control group [i.e., the sensitivity index (SI)]. Furthermore, to
ensure that the additional dependence of
FENO was accounted for (as described above), we
included NO in the SI analysis.
Equipment.
Tidal , volume, FENO, and
CO2 were measured using commercially available infant lung
function equipment (Fig. 1) (Exhalyser; EcoMedics, Duernten, Switzerland). was determined using an ultrasonic flowmeter (Spiroson model M30.8001; EcoMedics), NO was
measured in exhaled air with a rapid response chemiluminescence analyzer (CLD 77 AM; EcoMedics) in the range of 0-100
parts/billion (ppb) with a sensitivity of 0.05 ppb. The response and
delay times of the analyzer were 100 ms (10 Hz) and 830 ms,
respectively. CO2 was monitored with the use of an infrared
analyzer with a resolution of 0.05% and a response time of 60 ms (16 Hz) (Pryon). Volume was calculated from the signal. The dead
space of the , NO, and CO2 measurement equipment was
3 ml, whereas the face mask had a volume of 15 ml. Current
recommendations for infant lung function testing advise that the
effective dead space of a face mask equate to 50% of the water
displacement volume of the mask (10); hence the effective
dead space of the measurement head was 10.5 ml (50% contribution of
face mask, i.e., 7.5 ml). The resistance of the measurement equipment
(Req) was 0.36 kPa · l
1 · s at an
of 100 ml/s and was within current recommendations of Req < 0.7 kPa · l1 · s at 100 ml/s in term neonates
(10). It is important to note that this resistance will
not cause the closure of the vellum and thus exclude nasal NO. A bias
of NO-free air was used to ensure that levels of
FENO were not contaminated by ambient NO. As
the NO was determined from a sidestream portal and CO2 and were determined in-line, the delay times were determined and adjusted so as to allow for real-time, breath-by-breath inspection of
the data. Data were sampled at a rate of 200 Hz with an accuracy of 12 bits.
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Measurement and analysis.
Infants were studied during quiet sleep, using a compliant silicon mask
(size 0 infant mask; Homedica) placed over the nose and mouth.
-volume loops were inspected for leak before measurement was
commenced. Tidal breathing was recorded for a period of 3-4 min
using Spiroware software (EcoMedics) and stored for later analysis.
Tidal , FENO, CO2, and
volume recordings were exported, and further analysis was carried out
using a custom-designed analysis software (MATLAB; Mathworks).
Individual breaths and, hence, expirations were identified, and all
further analysis was carried out on the individual expiratory portions
of the tidal breathing. To ensure consistency of analysis among
infants, only the first 100 breaths in the tidal breathing data were
analyzed. To investigate possible information contained within a single
expiration, we analyzed the data using two approaches, as follows.
, and NO within
the respective phases. Briefly, PII was defined as the interval bounded
by an expired CO2 concentration of 0.5% and end-tidal
CO2 of 60%, whereas the PIII interval was delimited by the
point at which 200% of the airway dead space was expired and 90% of
the VE. The mean airway dead space for the entire tidal
breathing trace was used and determined with the use of the Bohr
equation. A representative trace illustrating the phases is shown in
Fig. 2.
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, and NO.
Statistics.
Group data are presented as means ± SE if normally distributed or
as median and 25-75th percentiles if not normally distributed. The
breath-by-breath dependency of the tidal
FENO data was tested by fitting a linear
regression equations to the individual breath
FENO and for the two groups (PTE and
control) for each portion of expiration. A two-way ANOVA was used to
determine differences in the group FENO and
NO data between quartiles and phases and to test for
differences between infants exposed to prenatal cigarette smoke and
controls. The intra- and intersubject coefficients of variation (CV) of
the group data were calculated (CV = SD/mean). Differences in
intrasubject variability were tested by using one-way ANOVA. We
determined the SI of each portion of the PTE group, using SD units, as
the absolute change between the two groups in multiples of SD of the
control group. To ascertain if the PTE group differed significantly
from our control group, a t-test was used to test whether
the SD units were significantly shifted from zero. A one-way ANOVA of
the SD units was performed to determine whether any individual portion
was more sensitive to differences between the two groups. Significance
was accepted at the P < 0.05 level.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The group mean TE in the infants was 0.82 ± 0.05 (SE) s (range: 0.45-1.27 s), whereas the duration of PII and PIII
of the expiratory capnograph was 0.17 ± 0.09 s
(0.09-0.25 s) and 0.33 ± 0.027 s (0.15-0.58 s),
respectively. Infants receiving PTE had significantly reduced
TE (0.67 ± 0.07 s) compared with controls (0.90 ± 0.06 s; P < 0.03), which leads to a
tendency for an increased respiratory rate (46.2 ± 4.0 and
39.2 ± 1.9 breaths/min, respectively; P = 0.09).
Mean within each portion tended to be increased in the PTE
group; however, this tendency did not reach significance. No
significant differences in VT, PEF, or end-expiratory
CO2 were noted because of PTE.
Tidal FENO concentrations and output.
Individual and group tidal FENO (Fig.
3) and NO (Fig.
4) for PII and PIII and the four
expiratory quartiles are shown. Whereas the group mean
FENO tended to be highest in PII
(PII-FENO) and lowest in the final quartile of
expiration (Q4-FENO), these differences were
not significant. The group mean was significantly dependent on
the portion of expiration (P < 0.001), with Q4 being
significantly lower than all other portions of expiration (Q4-:
26.2 ± 2.0 ml/s; P < 0.05). The remaining
portions of expiration ranged between 34.7 ± 2.3 ml/s (Q1) and
50.3 ± 3.7 ml/s (Q2), with Q3, PII, and PIII being 41.4 ± 3.3, 46.0 ± 3.0, and 40.8 ± 2.9 ml/s, respectively. These
significant differences in lead to NO being
significantly influenced by the portion of expiration
(P < 0.001), with the final quartile
(Q4-NO) being significantly lower than the remaining portions. Infants with cigarette exposure in pregnancy exhibited significantly reduced FENO and
NO in all expiratory portions (Figs. 3 and 4,
respectively; P < 0.001). The breath-by-breath tidal
FENO exhibited significant negative
dependence in all portions in both groups of infants (Table
2).
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NO for each portion
of expiration in each infant over the 100 analyzed breaths (Fig.
5). There was a significant effect of
expiratory portion on the CV of both FENO
(P < 0.002) and NO (P < 0.001). Q4-FENO was
significantly more variable than the remaining phases and quartiles
(pairwise comparisons; P < 0.05), whereas both Q1- and
Q4-NO demonstrated increased intrasubject variability (P < 0.05). The intersubject variability
of FENO and NO was also
determined. The intersubject variability in tidal FENO was high, ranging between 34.6 and 48.8%.
Similarly, the intersubject variability of NO ranged
between 30.2 and 51.9%. No differences in intersubject variability
were noted, either in FENO or
NO for the differing portions of expirations. Those infants exposed to prenatal tobacco did not have significantly different CV values in any portion of expiration than those of controls
(P > 0.1). There were no significant differences in
levels of FENO, NO, or CV
for these parameters in either the volume-based (analysis A)
or time-based (analysis B) analysis methods, due to prenatal smoke exposure.
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NO because of PTE (Table
3). FENO in the
PTE group was lower than that in the control group in all portions.
Whereas no individual portion was significantly better able to
distinguish FENO in the PTE group from the
control group (one-way ANOVA; P = 0.98), all portions
were significantly shifted from zero (P < 0.005). A
similar outcome was noted for NO, with all portions
being significantly able to discriminate between the PTE and control
groups (P < 0.03) and no portion being able to
distinguish differences significantly better than any other
(P = 0.99).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we investigated the collection and analysis
of tidal FENO measurements in infants, such
that it was feasible to obtain FENO in
unsedated, sleeping infants (criteria 1 and 2)
without disturbing their breathing patterns (criterion 3).
Critical to this point is the preferential nasal breathing of infants,
requiring the measurement of nasal tidal breathing. We demonstrated
that tidal FENO was dependent
(criterion 4) and thus should be accounted for when tidal
FENO is monitored. We demonstrated that the
presented methods of analysis (volume and time based) could ascertain
differences between control infants with no maternal history of smoking
and those infants who had been exposed to prenatal cigarette smoke.
Tidal FENO.
In unsedated infants, we found FENO to range
between 13.1 ± 1.6 (SE) ppb for Q4-FENO
to 15.8 ± 1.6 ppb for PII-FENO. Sparse data on tidal FENO values in healthy children
are available. Baraldi et al. (5) measured mixed tidal
FENO in infants and young children using a
collection reservoir. The investigators reported values of 14.1 ± 1.8 ppb in acutely wheezy subjects and lower values of 5.6 ± 0.5 ppb in healthy controls. In a further study in older children, the same
authors reported reference values using an on-line tidal technique in
healthy children ranging between 6 and 15 yr and reported a mean
FENO level of 8.7 ppb (3). The tidal values in the present study are higher than those previously reported in healthy infants and children; these differences are most
likely explained by the significantly lower tidal values found
in young infants and highlight the importance of recording and
correcting for in tidal FENO
measurements (details below). The intrasubject variability differed
between expiratory phases and ranged between 9.3 and 15.1%. Similar to
previous studies in infants (24), the intersubject
variability of FENO was high, ranging from 34.6 to 44.6% in the Q3 and Q1 of expiration, respectively.
dependence of tidal FENO and
NO.
The present study demonstrated that breath-to-breath tidal
FENO exhibits significant negative
dependence in all portions of expiration. The negative
dependence of FENO is well recognized and has
been demonstrated in numerous studies (9, 16, 20). In the
present study, we used linear regression equations to test for
dependency, whereas studies in adults have shown that
FENO is exponentially related to expiratory
(20, 22). The use of exponential regression
analysis in this population did not improve the description of
alterations in FENO with . This most likely relates to the very small range found in infant tidal breathing (24.2 ± 0.3 to 59.5 ± 0.5 ml/s for Q4 and Q2,
respectively) compared with extended ranges used in adult
studies (5-1,500 ml/s). The dependence of tidal
FENO suggests that the measurement of
and the calculation of NO are essential in methods
not controlling the expiratory , such as the collection of
FENO using reservoir bags (5) or
the on-line tidal breathing method (3, 13).
NO was found to be significantly dependent on the
portion of expiration and ranged between 0.36 ± 0.04 and
0.79 ± 0.07 nl/s for Q4 and Q2, respectively. Wildhaber and
coworkers (24) measured forced
FENO in healthy infants [18.8 ± 12.4 (SD) ppb] at a of 50 ml/s, equating to a NO
of 0.94 nl/s. These authors demonstrated a significant effect of
parental atopy on FENO, irrespective of respiratory history. The population studied by these authors included three infants with no respiratory history and no parental atopy and had
a mean (range) FENO of 12.9 ppb (2.6-26.3
ppb), equating to a mean NO of 0.65 nl/s
(0.13-1.32 nl/s). Previous studies measuring tidal
FENO in infants have not reported the
corresponding values, and, hence, comparisons cannot be made.
Franklin et al. (9) reported FENO
values in 116 healthy, nonatopic children (aged 7-13 yr) of 7.2 ppb (6.4-8 ppb) at 75 ml/s, representing a NO
range of 0.48-0.6 nl/s. Artlich and coworkers (2)
reported similar values of NO (mean: 0.31 nl/s) in
11 healthy children. NO levels ranging between 0.2 and 0.65 nl/s have been reported in studies of healthy nonatopic adults
(7, 8, 17). The current data are in good agreement with
studies that use standardized measurement techniques and would suggest
that the presented analysis methods of tidal
FENO, when corrected for tidal values,
provide similar information as the forced techniques. The variability of NO was dependent on the phase of expiration. We
found that Q1 and Q4 were significantly more variable than the
remaining phases. This may be due to the more stable conditions
occurring during midexpiration.
PTE.
Our study population included seven infants who had been exposed to
tobacco smoke during pregnancy, and these infants exhibited significantly decreased FENO and
NO compared with nonexposed controls. Studies
conducted in adults have demonstrated that chronic cigarette exposure
decreases FENO, irrespective of the subject's health status (6, 15, 19). The role of passive smoke
exposure is less clear. Franklin et al. (9) found no
effect of passive cigarette smoke exposure in a community study of 7- to 13-yr-old children with no history of respiratory disease, possibly
indicating that the documented effects of cigarette smoke may only
apply to direct inhalation. We are not aware of any studies
investigating the role of PTE on neonatal FENO.
Hasan et al. (12) demonstrated that prenatal cigarette
smoke reduced neuronal NO synthase (nNOS), but not endothelial NO
synthase expression, in the caudal brain stem of neonatal rats. The
same group demonstrated that a downregulation of nNOS resulted in a
diminished ventilatory response to hypoxia in developing rats
(11). These results may provide indirect evidence of the
underlying mechanisms resulting in decreased respiratory drive and
hypoxic ventilatory response in infants of smoking mothers (23). Similarly, prenatal exposure to tobacco products may
downregulate nNOS expression in infants and hence potentially reduce
the contribution of nNOS to FENO. Whereas at
this time there is no known role of NO in smoke-exposed infants, who
are particularly prone to wheezing disorders, we conclude from the
present population that future studies of FENO
in infants need to take smoke exposure into account as a confounding variable.
Sensitivity of the presented methods.
We demonstrated that, whereas the differences in
FENO and NO between the
control and PTE groups were significant in all portions, no particular
portion was able to distinguish between the differences of the two
groups better. This result is not unexpected, if PTE does indeed
downregulate nNOS. The subsequent reduction in NO production would be
spread throughout the entire respiratory system and not be restricted
to a particular location. Whereas FENO appeared
to be more discriminatory than NO, these differences were not significant. This apparent increased sensitivity in
FENO probably relates to the increased
values found in the PTE group, causing reductions in
FENO unrelated to actual NO production. We
would stress the importance of measuring NO in
conditions associated with variable tidal values (such as
on-line tidal FENO measurements) or alterations
in tidal breathing patterns caused by respiratory disease.
Limits of the method.
A number of technical aspects may influence our results. The delay
times of the NO and CO2 sensors will influence the accuracy of the analysis. We determined the delay times before measurement and
corrected these signals, with respect to , before carrying out
any further analysis. The Req used (0.36 kPa · l1 · s at 100 ml/s) was
insufficient to close the vellum, and thus we were able to measure
FENO via the nose of the unsedated infants, allowing tidal breathing to be monitored without disturbing the infant's natural breathing patterns. However, should the expiratory be sufficiently high, it is conceivable that the subsequently increased resistance may close the vellum and hence alter the physiological system being measured, possibly explaining the differing FENO levels between the groups studied. An
airway pressure >4-5 cmH2O will cause the vellum to
close. The present equipment configuration would increase airway
pressure >4-5 cmH2O at values >120-140 ml/s. Whereas the PTE group had a tendency for increased PEF, the
highest PEF was 90.4 ml/s, and thus vellum closure will not have
occurred in any of the studied infants.
NO.
Alterations in control of breathing or tidal breathing patterns in
smoke-exposed infants may have potentially contributed to the noted
differences in FENO parameters. There was a
tendency for mean within each portion to be higher in infants
exposed to prenatal tobacco; these differences were, however, not
significant. It is conceivable that this nonsignificant increase in
may have contributed to the noted reduction in FENO levels but cannot explain the significant
differences in NO found between the control and PTE
groups. Indeed, the use of NO, rather than
FENO, as the parameter of choice would enable any differences in between groups to be accounted for and may enhance the ability of the presented methods to detect changes in NO
production beyond simple alterations in tidal breathing patterns.
Conclusions.
This study has demonstrated that on-line tidal
FENO and NO can be measured,
via a face mask, in unsedated newborn infants. This represents the
first on-line tidal FENO data in healthy
infants in this age group and in infants before an episode of
respiratory disease. The on-line measurement of tidal
FENO and NO proved to be a
simple (criterion 1) and noninvasive (criterion
2) technique that was able to be applied to the population studied
and allowed undisturbed FENO, , and
CO2 breathing patterns (criterion 3) to be
collected. The basis of the technique, therefore, satisfied the
requirements of the application of any infant lung function methodology.
dependent throughout expiration, indicating the importance of
measuring (criterion 4) in tidal
FENO conditions. Furthermore, this significant
dependence of FENO highlights the
importance that the technique of measuring the on-line tidal FENO does not alter the breathing pattern of
the subjects.
The simultaneous collection of FENO and
allowed tidal NO to be characterized in this group
of infants. NO values proved to be comparable to
previously reported values derived from standardized techniques. In
respiratory disease, differences in tidal breathing may alter the
pattern of FENO clearance from the air spaces
and, hence, cause changes in FENO and
NO levels and variability. No individual expiratory
portion discriminated the PTE group from controls better than any other
portion. This result was not unexpected and may relate to the effect of
PTE on nNOS throughout the airway tree. However, this may not be the
case in future studies of lower airway disease. Finally, we conclude
that both FENO and NO were reduced in those infants exposed to maternal smoking, compared with
healthy, nonatopic controls, suggesting that the presented analysis
methods are able to detect differences between normal and abnormal
physiological systems.
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ACKNOWLEDGEMENTS |
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The authors thank the staff of the Respiratory Medicine department for help in obtaining the data presented in this study, in particular Heidi Staub. The authors also extend thanks to Ruedi Isler of EcoMedics (Switzerland) for help and advice.
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FOOTNOTES |
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The work presented in this paper was supported by the Swiss National Science Foundation (Swiss Clinicians Opting for Research Grant 3200-052197.97/1), the National Health and Medical Research Council of Australia, AstraZeneca (Switzerland), and Swiss CF Foundation. G. L. Hall is a Neil Hamilton Fairley Fellow.
Address for reprint requests and other correspondence: U. Frey, Paediatric Respiratory Medicine, Dept. of Paediatrics, Univ. Hospital, Inselspital, Berne, CH-3010 Switzerland (E-mail: urs.frey{at}insel.ch).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 19 April 2001; accepted in final form 23 August 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
Anonymous
Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children.
Am J Respir Crit Care Med
160:
2104-2217,
1999
2.
Artlich, A,
Busch T,
Lewandowski K,
Jonas S,
Gortner L,
and
Falke KJ.
Childhood asthma: exhaled nitric oxide in relation to clinical symptoms.
Eur Respir J
13:
1396-1401,
1999[Abstract].
3.
Baraldi, E,
Azzolin NM,
Cracco A,
and
Zacchello F.
Reference values of exhaled nitric oxide for healthy children 6-15 years old.
Pediatr Pulmonol
27:
54-58,
1999[ISI][Medline].
4.
Baraldi, E,
Azzolin NM,
Zanconato S,
Dario C,
and
Zacchello F.
Corticosteroids decrease exhaled nitric oxide in children with acute asthma.
J Pediatr
131:
381-385,
1997[ISI][Medline].
5.
Baraldi, E,
Dario C,
Ongaro R,
Scollo M,
Azzolin NM,
Panza N,
Paganini N,
and
Zacchello F.
Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children.
Am J Respir Crit Care Med
159:
1284-1288,
1999
6.
Corradi, M,
Majori M,
Cacciani GC,
Consigli GF,
de'Munari E,
and
Pesci A.
Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease.
Thorax
54:
572-575,
1999
7.
Corradi, M,
Montuschi P,
Donnelly LE,
Pesci A,
Kharitonov SA,
and
Barnes PJ.
Increased nitrosothiols in exhaled breath condensate in inflammatory airway diseases.
Am J Respir Crit Care Med
163:
854-858,
2001
8.
Dupont, LJ,
Rochette F,
Demedts MG,
and
Verleden GM.
Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma.
Am J Respir Crit Care Med
157:
894-898,
1998
9.
Franklin, PJ,
Taplin R,
and
Stick SM.
A community study of exhaled nitric oxide in healthy children.
Am J Respir Crit Care Med
159:
69-73,
1999
10.
Frey, U,
Stocks J,
Coates A,
Sly P,
and
Bates J.
Specifications for equipment used for infant pulmonary function testing.
Eur Respir J
16:
731-740,
2000[Abstract].
11.
Gozal, D,
Gozal E,
Torres JE,
Gozal YM,
Nuckton TJ,
and
Hornby PJ.
Nitric oxide modulates ventilatory responses to hypoxia in the developing rat.
Am J Respir Crit Care Med
155:
1755-1762,
1997[Abstract].
12.
Hasan, SU,
Simakajornboon N,
MacKinnon Y,
and
Gozal D.
Prenatal cigarette smoke exposure selectively alters protein kinase C and nitric oxide synthase expression within the neonatal rat brainstem.
Neurosci Lett
301:
135-138,
2001[ISI][Medline].
13.
Jobsis, Q,
Schellekens SL,
Kroesbergen A,
Hop WC,
and
de Jongste JC.
Sampling of exhaled nitric oxide in children: end-expiratory plateau, balloon and tidal breathing methods compared.
Eur Respir J
13:
1406-1410,
1999[Abstract].
14.
Kharitonov, S,
Alving K,
and
Barnes PJ.
Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force.
Eur Respir J
10:
1683-1693,
1997[ISI][Medline].
15.
Kharitonov, SA,
Robbins RA,
Yates D,
Keatings V,
and
Barnes PJ.
Acute and chronic effects of cigarette smoking on exhaled nitric oxide.
Am J Respir Crit Care Med
152:
609-612,
1995[Abstract].
16.
Kroesbergen, A,
Jobsis Q,
Bel EH,
Hop WC,
and
de Jongste JC.
Flow-dependency of exhaled nitric oxide in children with asthma and cystic fibrosis.
Eur Respir J
14:
871-875,
1999
17.
Lehtimaki, L,
Turjanmaa V,
Kankaanranta H,
Saarelainen S,
Hahtola P,
and
Moilanen E.
Increased bronchial nitric oxide production in patients with asthma measured with a novel method of different exhalation flow rates.
Ann Med
32:
417-423,
2000[ISI][Medline].
18.
Rigatto, H.
Maturation of breathing.
Clin Perinatol
19:
739-756,
1992[ISI][Medline].
19.
Robbins, RA,
Floreani AA,
Von Essen SG,
Sisson JH,
Hill GE,
Rubinstein I,
and
Townley RG.
Measurement of exhaled nitric oxide by three different techniques.
Am J Respir Crit Care Med
153:
1631-1635,
1996[Abstract].
20.
Silkoff, PE,
McClean PA,
Slutsky AS,
Furlott HG,
Hoffstein E,
Wakita S,
Chapman KR,
Szalai JP,
and
Zamel N.
Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide.
Am J Respir Crit Care Med
155:
260-267,
1997[Abstract].
21.
Stromberg, NOT,
and
Gustafsson PM.
Ventilation inhomogeneity assessed by nitrogen washout and ventilation-perfusion mismatch by capnography in stable and induced airway obstruction.
Pediatr Pulmonol
29:
94-102,
2000[Medline].
22.
Tsoukias, NM,
and
George SC.
A two-compartment model of pulmonary nitric oxide exchange dynamics.
J Appl Physiol
85:
653-666,
1998
23.
Ueda, Y,
Stick SM,
Hall G,
and
Sly PD.
Control of breathing in infants born to smoking mothers.
J Pediatr
135:
226-232,
1999[ISI][Medline].
24.
Wildhaber, JH,
Hall GL,
and
Stick SM.
Measurements of exhaled nitric oxide with the single-breath technique and positive expiratory pressure in infants.
Am J Respir Crit Care Med
159:
74-78,
1999
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