What 2012 lung function ultrasound physiology

WHAT 2012

LUNG
FUNCTION
Attilio Boner

University of
Verona, Italy

Breastfeeding is associated with increased lung
function at 18 years of age: a cohort Study
Soto-Ramı´rez, Eur Respir J 2012;39:985

Effect of breastfeeding (FVC) (Litres)
at 18 yrs of age by height
 A birth cohort.
 Breastfeeding
duration.

 Spirometric tests
at 10 and 18 yrs.

Breastfeeding is associated with increased lung
function at 18 years of age: a cohort Study
Soto-Ramı´rez, Eur Respir J 2012;39:985

A longer Effect of breastfeeding (FVC) (Litres)
at 18 yrs of age by height
 Aduration of
birth cohort.
breastfeeding
Breastfeeding
 contributes to
duration.
lung health in
 Spirometric and
childhood tests
adolescence.
at 10 and 18 yrs.

Redefining Spirometry Hesitating Start Criteria Based
on the Ratio of Extrapolated Volume to Timed FEVs.
McKibben CHEST 2011;140:164
Volume-time tracing showing cut-off values
 To investigate defining a hesitating start at 1, 3, and 6 s of
exhalation for 1501 workers (n=13025 trials).
hesitating start criteria
for spirometry maneuvers.
 24945 trials.
 Back extrapolation method:
1) extrapolated
volume[EV]/FEV1
2) EV/FEV3
3) EV/FEV6
on EV/FVC
were determined.

Redefining Spirometry Hesitating Start Criteria Based
on the Ratio of Extrapolated Volume to Timed FEVs.
McKibben CHEST 2011;140:164
The values for
EV/FEV1, EV/FEV3 , and EV/FEV6
 To investigate corresponding to the 5% EV/FVC value
were determined to be
hesitating start criteria 6.62%, 5.59%, and
for spirometry maneuvers. 5.25%, respectively.

 24945 trials. A new hesitating start criterion
using EV/FEV6 of 5.25%
 Back extrapolation method: is recommended for tracings that
do not achieve a plateau or
1) extrapolated when an FEV6 is performed.
volume[EV]/FEV1
An EV/FEV3 of 5.59%
2) EV/FEV3 could be incorporated into spirometry
3) EV/FEV6 software as an early warning signal
on EV/FVC that could help operators
identify trials with
were determined. potential hesitating starts.

Effect of Late Preterm Birth on Longitudinal Lung
Spirometry in School Age Children and Adolescents.
Kotecha, Thorax 2012;67:54

What is the key question
• We sought to compare lung function at 8-9 and 14-17 yrs
in children born late preterm (33-34 and 35-36 weeks gestation)
with children of similar age born at term (≥37 weeks gestation).
• We also compared children born at 25-32 weeks gestation with
children born at term.

At 8-9
yrs, all
spirometry measures were
 All births from the lower in the 33-34
Avon Longitudinal Study
wk gestation group than in
of Parents and Children
controls born at
(n=14049).
term but were
 Spirometry at 8-9 yrs (n=6705) similar to the spirometry
and/or 14-17 yrs (n=4508). decrements observed in the
25-32 wk gestation group.
 4 gestation groups.
35-36 wk gestation group
and term group
had similar values.


At 14-17
 All births from the yrs, in the late
Avon Longitudinal Study preterm
of Parents and Children group, FEV1 and
(n=14049). FVC were similar
to the term group
 Spirometry at 8-9 yrs (n=6705)
but
and/or 14-17 yrs (n=4508).
FEV1/FVC and FEF25-75%
 4 gestation groups. remained significantly lower
than term controls.


At 14-17
 All births from the yrs, in the late
Avon Longitudinal Study
Some improvements preterm
ofin lung function values
Parents and Children group, FEV1 and
(n=14049).
were noted FVC were similar
in children born at to the term group
 Spirometry at 8-9 yrs (n=6705)
but
33-34 we gestation
and/or 14-17 yrs (n=4508).
FEV1/FVC and FEF25-75%
by the age
 4 gestation groups. remained significantly lower
of 14-17 yrs. than term controls.


 All births from the Children requiring
Avon Longitudinal Study mechanical ventilation
of Parents and Children in infancy at 25-32
(n=14049). and 33-34 wk gestation
 Spirometry at 8-9 yrs (n=6705) had lower airway function
and/or 14-17 yrs (n=4508). (FEV1 and FEF25-75)
at both ages
 4 gestation groups. than those not ventilated
in infancy.


What is the bottom line
• Children born at 33-34 weeks gestation have significantly
lower lung function values at 8-9 yrs, similar to decrements
observed in the 25-32 weeks group, although these differences
were reduced by 14-17 yrs of age.

Why read on
• The findings from this study suggest that children born
at 33-34 weeks gestation may be at risk of decreased
lung function at 8-9 yrs of age.
By 14-17 yrs there were improvements in FEV1.

Low cognitive ability in early adulthood is associated
with reduced lung function in middle age: the Vietnam
Experience Study Carroll Thorax 2011;66:884

Objective
Reduced lung function has been linked to poorer cognitive ability
later in life.
In the present study, the authors examined the converse:
whether there was a prospective association between
cognitive ability in early adulthood and lung function in middle age.


Mean FEV1 by quartile of IQ

 4256 male Vietnam-era
US veterans.
 Cognitive ability when
partecipants were 20
years old (range 17-34).
 FEV1 at 3-day medical
examination in 1986.


Not only is Mean FEV1 by quartile of IQ
lung function related
to subsequent
US veterans. ability,
cognitive
but poor cognitive
ability earlier in life
is also associated with
reduced lung function
in middle age.


1.The association between Mean FEV1 by quartile of IQ
FEV1 and subsequent
cognitive ability is generally
4256 male Vietnam-era
explained in terms of processes
US veterans.
such as inflammation, impaired
fibrinolytic activity, oxidative
stress and hypoxia 20
partecipants were associated
yearswith (range 17-34).
old compromised
respiratory function.


2.Various pathways that Mean FEV1 by quartile of IQ
might link low cognitive
ability with subsequent
impaired lung function:
US veterans.
a greater propensity for
unhealthy
behaviour, including
years old (range alcohol
smoking, 17-34).
consumption and poorer
medical adherence
and surveillance.


3.Another possibility is Mean FEV1 by quartile of IQ
that low cognitive ability
might be a marker of
poorer „system integrity‟,
US veterans.
such that various physiological
systems mount less
partecipants were injurious
resistance to 20
environmental
exposures across the
 FEV1 atlife course.
3-day medical


4.Finally, both poor lung Mean FEV1 by quartile of IQ
function and low cognitive
ability have also been
regarded as markers of early
US veterans.
life adversity including
exposure to suboptimal
nutrition, poverty,20
partecipants were chronic
yearschildhood illness
old (range 17-34).
 FEV1 psychosocial stress.
and at 3-day medical

Risk associated
with poor lung
function

Nature and severity of lung function abnormalities in
extremely pre-term children at 11 years of age
Lum ERJ 2011;37:1199
 Extremely pre-term (EP) % EP children with lung function
followed at 11 yrs of age. abnormalities of age 11 yrs
 Alterations 80 -

78%
in the lung periphery
70 -
or more centralised airway.
60 -
 Spirometry, plethysmography, 50 –
diffusing
40 –
capacity, exhaled nitric
oxide, multiple-breath 30 –
washout, skin tests and 20 –
methacoline challenge.
10 –
 49 EP and 52 control children. 0

Lum ERJ 2011;37:1199
Evidence of
airway
78%
70 -
obstruction, ventilat
60 -
ion inhomogeneity,
gas trapping
diffusing
40 –
oxide,
and
multiple-breath 30 –
washout, airway
skin tests and 20 –
hyperresponsiveness.
10 –

Lum ERJ 2011;37:1199
The prevalence
of lung function

78%
abnormalities, 70 -
which is largely obstructive 60 -
in nature and likely
to have long-term
diffusing
40 –
implications, remains high
oxide, multiple-breath 30 –
among 11-yr-old
methacoline challenge. EP.
children born
10 –

Lum ERJ 2011;37:1199
Spirometry
in the lung periphery proved

78%
70 -
or an effective means
more centralised airway.
60 -
 Spirometry, detecting
of plethysmography, 50 –
these persistent
diffusing
40 –
oxide,
abnormalities.
multiple-breath 30 –
10 –

Relationship between parental lung function and their
children‟s lung function early in life
van Putte-Katier ERJ 2011;38:664

A significant positive
 Lung function was
relationship between
measured before
the infant‟s
the age of 2 months
respiratory compliance
using the single
and parental
occlusion technique
forced expiratory flow
in 546 infants.
at 25–75% of forced vital
 Parental data on lung capacity (FEF25–75%),
function (spirometry). FEV1, and forced vital
capacity.


measured before A significant
the age of 2 months negative relationship
using the single was found between the
occlusion technique infant‟s respiratory
in 546 infants. resistance
and parental FEF25–75%
 Parental data on lung and FEV1
function (spirometry).


measured before for
Adjusting A significant
shared environmental
the age of 2 months negative relationship
using the single was found between the
factors infant‟s respiratory
occlusion technique
did not change
in 546 infants. resistance
the observed results. and parental FEF25–75%
 Parental data on lung and FEV1
function (spirometry).


Parental lung function levels
 Lung are predictors of the
function was
measured before
respiratory mechanics of A significant
their age of 2 infants, which can
the newborn months negative relationship
only partially be explained by
using the body size.
single was found between the
occlusion suggests genetic infant‟s respiratory
This technique
in 546 infants. in familial
mechanisms resistance
aggregation of lung function, and parental FEF25–75%
 Parental data on lung
which are already detectable and FEV1
function early in life.
(spirometry).

Increasing Severity of Pectus Excavatum is Associated
with Reduced Pulmonary Function
Lawson, J Ped 2011;159:256

 Spirometry data in 310
patients and lung volumes
in 218 patients aged
6 to 21 years.

 Severity of deformity
(based on the Haller index).

 The Haller index was calculated
as the inner transverse
thoracic diameter divided by
the anteroposterior distance
between the anterior thoracic
wall and the spine at the
narrowest point at CT scan.

Lawson, J Ped 2011;159:256

% of patients with
patients and lung volumes
in 218 patients aged 15 -
6 to 21 years.
14.5%
 Severity of deformity 10 –

 The Haller index was calculated 05 -
1.9%
the anteroposterior distance 00
obstructive restrictive
between the anterior thoracic pattern pattern
wall and the spine at the (FEV1/FVC <67%) (FVC and FEV1<80%;
narrowest point at CT scan. FEV1/FVC>80%)

Lawson, J Ped 2011;159:256

patients and lung volumes Relative frequency of reduced FVC
in 218 patients aged by Haller index
6 to 21 years.

 Severity of deformity


Lawson, J Ped 2011;159:256

patients and lung volumes Relative frequency of reduced FVC
Patients with a Haller by Haller index
in 218 patients aged
index of 7 are >4
6 to 21 years.
times more likely to
 Severity an deformity
have of FVC of ≤80%
than those with a
Haller index of
4, and are also 4
as the inner transverse to
times more likely
exhibit a restrictive
pulmonary pattern.

Will the Small Airways Rise Again?
Irvin AJRCCM 2012;184:499
The theoretical relationship between
airway resistances and airway generation.

The x plot tokens
indicate the calculation
of resistance using the
laminar flow
equation, length, and
total cross-sectional
area of all the airways
within that generation.


If the patency of the
peripheral airways is
compromised or
aiways narrowed, then
resistance of these small
airways might rise
(dotted line).
However, total resistance
would not raise enough
to be detected given the
normal variation (~10%).


The finding that
respiratory symptom
resistance is elevated
and resistance is
frequency dependent
suggests that the site
of dysfunction might
reside in airways of
intermediate
size, (double-headed
arrow).


• The significance of this diagram is that small (< 2mm) airways
from generation 11 and downward contribute almost nothing
(< 10%) to total airway flow resistance.

• The human lung has so many small airways that total
cross-sectional area in the distal generations of the tracheal
bronchial have collectively a very low resistance due to the
large cross-sectional area.


• The significance of this diagram is that small (< 2mm) airways
from generation 11 and downward contribute almost nothing
(< 10%) to total airway flow resistance.

• The human lung has so many small airways that total
cross-sectional area in the distal generations of the tracheal
bronchial have collectively a very low resistance due to the
large cross-sectional area.

“The silent zone”


• Resistance is measured, such as Raw and Sgaw with the
body plethysmograph or respiratory symptom resistance with
forced oscillations.
• Many common lung diseases start or manifest in this “silent zone”
of the lung, but the tests developed were either too technically
challenging or irreproducible to gain wide acceptance.
• The key issue then (and still remaining today) is how best to
measure disease in these pesky small airways.
• FEV1 is a polyvalent outcome variable affected by many other
factors besides airway caliber. In asthma, the fall in FEV1 can be
explained by a fall in FVC due to a rise in residual volume (RV
), where RV measures airway closure and hence small airway
function and is correlated to symptoms.


• Respiratory symptom resistance (Rrs) is simply not the same
thing as FEV1. Yes, there are studies that show the two can be
correlated, but nevertheless these two endpoints are in fact very
different.

• To perform the FEV1 maneuver one must inhale to TLC, which in
the normal person abolishes tone of the airway or bronchodilation.

• Second, Rrs is measured during quiet breathing and would measure
both the structural and tonic components of airway diameter.

• Finally, the measurement of Rrs also includes tissue resistance.

Relating small airways to asthma control by using
impulse oscillometry in children Douros, JACI 2012;129:671

Background
Previous reports suggest that the peripheral
airways are associated with asthma control.
Patient history, although subjective, is used
largely to assess asthma control in children
because spirometric results are many times
normal values.
Impulse oscillometry (IOS) is an objective
and noninvasive measurement of lung function
that has the potential to examine
independently both small- and large-airway
obstruction.


Background
Because low oscillation frequencies (<15 Hz)
can be transmitted more distally in the lungs R5 R5
compared with higher
frequencies, R5 reflects
obstruction in both the small R20 R20
and large
airways, R20
reflects the large airways only, and the R5-R20
difference of R5 and R20 (R5-20) is an index R5 – R20
of the small airways only.
The resistance will become more frequency
dependent if peripheral resistance increases.


Small-airway IOS
measurements, including the
difference of R5 and R20 [R5-
20], X5, Fres, and AX, of children
 Asthmatic and with uncontrolled asthma (n=44)
healthy children were significantly different from
(6-17 years) those of children with controlled
asthma (n=57) and healthy children
 Spirometric and
(n=14), especially before the
impulse oscillometry
administration of a bronchodilator.
(IOS) evaluation
However, there was no difference in
before and after
large-airway IOS values (R20).
bronchodilator X5 = Reactance of the respiratory system at 5 Hz
Fres = Resonant frequency of reactance
AX = Reactance area


Receiver operating characteristic
analysis showed cut points for
 Asthmatic and baseline R5-20 (1.5 cm H2O x L-1 x s)
healthy children and AX (9.5 cm H2O x L-1) that
(6-17 years) effectively discriminated controlled
versus uncontrolled asthma and
 Spirometric and correctly classified more than 80%
impulse oscillometry of the population.
(IOS) evaluation
before and after
bronchodilator
AX = Reactance area


Uncontrolled
asthma is Receiver operating characteristic
associated with analysis showed cut points for
small airways
 Asthmatic and baseline R5-20 (1.5 cm H2O x L-1 x s)
dysfunction, and
healthy children and AX (9.5 cm H2O x L-1) that
(6-17 years) be a
IOS might effectively discriminated controlled
reliable and versus uncontrolled asthma and
 Spirometric and correctly classified more than 80%
noninvasive method
impulse oscillometry of the population.
to assess asthma
(IOS) evaluation
control in
before and after
children
bronchodilator
AX = Reactance area

lung function
non-collaborante

The Relationship of the Bronchodilator Response
Phenotype to Poor Asthma Control in Children
with Normal Spirometry Galant, J Ped 2011;158:953

OR in BDR ≥10% and ≥12% versus
 Clinical indexes of negative responses for
poorly controlled 4 –
asthma.

 Pre- and post-
3 –
3.4
bronchodilator
spirometry.
2 –
2.2
1 –
1.9 1.7
 Bronchodilator p<0.05 p<0.01 p<0.01 p<0.001
response (BDR) at
0
≥8%, ≥10%, and ≥12%. atopy nocturnal β2agonist exercise
symptoms use limitation
in females

The Relationship of the Bronchodilator Response
Phenotype to Poor Asthma Control in Children
with Normal Spirometry Galant, J Ped 2011;158:953

OR in BDR ≥10% and ≥12% versus
The BDR phenotype
 Clinical indexes of negative responses for
≥10% is significantly
poorly controlled 4 –
related to poor
asthma.
asthma
control, providing a
 Pre- and post-
3 –
3.4
potentially useful
bronchodilator
objective tool in
spirometry. naïve
2 –
2.2
controller
children even when the 1 –
1.9 1.7
 Bronchodilator
pre-bronchodilator p<0.05 p<0.01 p<0.01 p<0.001
response (BDR) at
spirometry result 0
≥8%, ≥10%, and ≥12%.
is normal. atopy nocturnal β2agonist exercise
symptoms use limitation
in females

Sex dependence of airflow limitation and air trapping
in children with severe asthma Sorkness JACI 2011;127:1073
Airflow limitation measured
as FEV1/FVC% predicted.

 77 children with
severe asthma.
nonsevere asthma ages
6 to 17 yrs.
 Baseline spirometry
and plethysmographic
lung volumes after a
bronchodilation with up
to 8 puff of albuterol.

BSLN; baseline * vs respective female, severe asthma subgroup;
** vs respective nonsevere subgroup;
PstBD; post bronchodilation
*** vs baseline.


Subjects in the
nonsevere asthma group
severe asthma.
had modest
 71 children with at baseline,
airflow limitation
with only 19% having
6 to FEV1/FVC ratio below
17 yrs.
 Baseline spirometry normal
the ower limit of
(<89% predicted for boys and
lung volumes afterfor girls)
<90% predicted a
and no differences
to 8 between albuterol.4).
puff of sexs (p>
*** vs baseline.


The severe asthma group
 77 exhibited with
children
greater airflow
severe asthma. the nonsevere
limitation than
 71 children0.0001) with 54%
group (p< with
nonsevere asthma ages the
of the girls and 73% of
6boys having the FEV1/FVC%
to 17 yrs.
 Baseline spirometrynormal,
predicted below
and the boys significantly
lung volumes obstructed
more after a
bronchodilation with up .
than the girls (p=0.017)
*** vs baseline.


 77 children with with
The subjects
severe asthma. asthma
nonsevere
and the girls with
nonsevereasthma exhibited
severe asthma ages
reversal of airflow
6 to 17 yrs.
limitation into
 Baseline spirometry the
normal range.
lung volumes after a with
However, the boys
severe asthma reversed
incompletely.
*** vs baseline.

Airtrapping measured
as plethysmographic RV/TLC% predicted.

The severe asthma group
exhibited air-trapping
severe asthma.
compared with the
nonsevere group
(p <0.0001), and
6 to 17 yrs.
the boys had significantly
more air-trapping
lungthan the after in the
volumes girls a
bronchodilationgroupup
severe with
(p =0.023).
*** vs baseline.


 77After bronchodilation,
children with
severe asthma. severe
the girls with
 71 children with residual
asthma had no
air trapping.
6 to 17 yrs.contrast,
In
the boys with severe
asthma had incomplete
lung volumes after a
reversal of air-trapping.
*** vs baseline.

Thus,
boys with severe
 77 children with asthma
had greater baseline airflow
severe asthma.
limitation and
 71 children with girls with
air-trapping than
severe asthma and, unlike
6 to 17 yrs. had incomplete
the girls,
reversal PstBD, indicating
and plethysmographic of
that the adult patterns
lung volumes after apresent
severe asthma are
in boys but only partially
developed in girls.
*** vs baseline.

Pattern of airway physiology in children with severe
asthma De Benedictis JACI 2011;128:904

• The early pattern of disturbed airway physiology identified
in boys with severe asthma in the SARP study may actually
be a clue to different lung growth between sexes.
The structure of the lung is a crucial determinant of ventilatory
function and contributes to the sex differences in airway
behavior across the human life span.
• Such sex differences are mainly attributable to the different
growth patterns of airways in relation to air spaces
(dysanapsis).
Mead J Dysanapsis in normal lung assessed by the relationship between maximal
flow, static recoil, and vital capacity. Am Rev Respir Dis 1980;121:339.

Riduzione di
funzionalità nel
tempo

Lung function decline in relation to mould and
dampness in the home: the longitudinal European
Community Respiratory Health Survey ECRHS II
Norbäck Thorax 2011;66:396
% of houses with

 Participants in the 50 –
European Respiratory 50.1%
Health Survey initially
examined aged 20-45 yrs
40 –
41.3%
and 9 yrs later (n=6443). 30 –

 Dampness (water damage 20 –
or damp spots) and
indoor mould, ever and in 10 –
the last 12 months.
0
Any dampness Indoor mould

Additional decline in FEV1 ml/year
0
 Participants in the
European Respiratory -2.25
and 9 yrs later (n=6443). -5

 Dampness (water damage -7.43
or damp spots) and
indoor mould, ever and in
the last 12 months. -10
Women with In women with
dampness observed damp spots
at home in the bedroom

Additional decline in FEV1 ml/year
0
 Participants in the
Dampness and
Europeanmould growth
indoor Respiratory -2.25
is common in
dwellings, and the
andpresence of(n=6443).
9 yrs later damp -5
is a risk factor for
 Dampness (water damage
lung function decline,
-7.43
orespecially in women.
damp spots) and
indoor mould, ever and in
the last 12 months. -10
Women with In women with
dampness observed damp spots
at home in the bedroom


1) The additional mean lung function
decline, -2.25 ml/year for self-
reported dampness and -7.43 ml/year for
observed dampness in the bedroom, is of the same
order of magnitude as estimated for moderate
tobacco smoking in the same ECRHS cohort.

2) The reason for the sex difference in effect remains
unclear, but could be due to either higher susceptibility
or a longer exposure time in the dwelling for women.

Longitudinal associations of socioeconomic position in
childhood and adulthood with decline in lung function
over 20 years: results from a population-based cohort
of British men. Ramsay Thorax 2011;66:1058
FEV1 and FVC
declined over time;
the decline increased
 7735 British men progressively from social
aged 40-59 yrs. class I (highest) to V (lowest);
p ≤0.0001 for trend
 Followed-up These differences remained after:
from 1978-1980
to 1998-2000. 1) adjustment for age;
2) cigarette smoking;
 FEV1 and FVC. 3) BMI;
 Socioeconomic position. 4) physical activity;
5) history of bronchitis.

Mean lung function decline adjusted for age
and baseline values according to combined
childhood and adult social class


Given that lung function is a strong predictor
of mortality and morbidity in later life, the role of
socioeconomic position on health in later life
is likely to be important.
The exact mechanisms underlying the associations between
socioeconomic position and decline in lung function merits
further research.


Likely contributors to this association are:
1) poor diet;
2) environmental factors (air pollution,housing
environment,occupational exposures).

Some of these factors could be operating from early in life in
addition to maternal undernutrition and low birth weight.

Fetal hyperglycemia alters lung structural development
in neonatal rat. Koskinen Pediatr Pulmonol 2012;47:275

Maternal hyperglycemia

Decreased lung weight, thinner
alveolar septa and increased
cellular apoptosis

Fetal hyperglycemia alters lung structural development
in neonatal rat. Koskinen Pediatr Pulmonol 2012;47:275
Barium-filled pulmonary arteriogram.
(A) Control lung; (B) lung exposed to maternal hyperglycemia

A B

Hyperoxia arrests alveolar development through
suppression of histone deacetylases in neonatal rats
Zhu Pediatr Pulmonol 2012;47:264

1) Bronchopulmonary dysplasia
(BPD) mainly occurs in
preterm infants. It is
histopathologically
characterized by fewer and
larger alveoli and less
secondary septa, suggesting
an arrested or disordered
lung development.

2) Histone deacetylase (HDAC)
plays an important role by
regulating gene transcription.


Rats subjected to hyperoxia (85% O2)

Arrest of
alveolarization, and an
Suppression of the HDAC1/HDAC2 elevated expression of the
expression and activity, and the cytokine-induced neutrophil
overall HDAC activity chemoattractant-1 (CINC-1)
in the lungs of newborn rats.


Rats subjected to hyperoxia (85% O2)

Preservation of
HDAC activity by
theophylline
significantly improved
alveolar development Arrest of
and attenuated alveolarization, and an
CINC-1 release.
Suppression of the HDAC1/HDAC2 elevated expression of the
expression and activity, and the cytokine-induced neutrophil
overall HDAC activity chemoattractant-1 (CINC-1)
in the lungs of newborn rats.

Hyperoxia arrested alveolar development

Control Hyperoxia

Alveolarization Continues during Childhood
and Adolescence. New Evidence from Helium-3 Magnetic
Resonance Narayanan AJRCCM 2012;185:186

The current hypothesis is that
human pulmonary alveolarization The
is complete by 3 yrs. number of alveoli
Using helium-3 (3He) magnetic is estimated to
resonance (MR) to assess
alveolar size noninvasively increase across
between 7 and 21 yrs, during the age range
which lung volume nearly
quadruples. studied (7-21 yrs).
If new alveolarization does not
occur, alveolar size should
increase to the same extent.
109 healthy subjects
aged 7–21 yrs.

Scatterplot of mean peripheral airspace dimension Xrms
against (left panel) age and (right panel) FRC.

Scatterplot of mean peripheral airspace dimension Xrms
against (left panel) age and (right panel) FRC.

Green lines indicate the following in a
child with an initial FRC of 1 L: top
line, predicted change in Xrms with
FRC if lung growth was accomplished only
by expansion of preexisting alveoli
(scenario of no alveolarization);
middle line, predicted change if rate of
neoalveolarization was 0.54 (predicted
from apparent diffusion coefficient vs.
FRC multilevel model);
lower line, predicted change if all growth
of lung was by neoalveolarization.

Number of alveoli in the developing human
The current hypothesis is that lung estimated by morphometry from
human pulmonary alveolarization previously published studies.
is complete by 3 yrs.
Using helium-3 (3He) magnetic
resonance (MR) to assess
alveolar size noninvasively
between 7 and 21 yrs, during
which lung volume nearly
quadruples.
If new alveolarization does not
occur, alveolar size should
increase to the same extent.
109 healthy subjects 7 21

aged 7–21 yrs.


Conclusions
Our observations are best explained by postulating that the
lungs grow partly by neo-alveolarization throughout childhood
and adolescence.
This has important implications: developing lungs have the
potential to recover from early life insults and respond to
emerging alveolar therapies.
Conversely, drugs, diseases, or environmental exposures could
adversely affect alveolarization throughout childhood.

An audit of hypoxaemia, hyperoxaemia, hypercapnia
and acidosis in blood gas specimens
O‟Driscoll B.R, Eur Respir J 2012;39:219
• The emergency management of hypoxaemic patients requires clinicians to avoid
the hazard of dangerous hypoxaemia due to under-treatment with
oxygen, whilst also avoiding the hazards of hypercapnic respiratory failure
(iatrogenic hypercapnia) and oxygen toxicity, which may be caused by
over-treatment with oxygen.
• Some patient groups, particularly those with chronic obstructive pulmonary
disease (COPD), are especially vulnerable to uncontrolled oxygen therapy and
mortality in this patient group was doubled when high-concentration oxygen was
used compared with controlled oxygen therapy.
• Hyperoxaemia is associated with increased mortality in patients with
stroke, and in survivors of cardiac resuscitation and critically ill patients in the
intensive care unit (ICU).
• The British Thoracic Society (BTS) guidelines for emergency oxygen use
recommend a target oxygen saturation range of 94–98% for most emergency
medical patients and a lower target range of 88–92% for those at
risk of hypercapnic respiratory failure.

% samples with
30 –

 Database of blood gas 26.9%
analysis results from 20 –
3,524 specimens.

 19% were said to be 10 –
breathing air at the
time of sampling and
81% were on 0
5.6%
oxygen therapy Hypercapnia with PCO2>6.0 kPa PO2 < 8.0 kPa or
ranging 24–100%. or 45 mmHg consistent with 60 mmHg with normal PCO2
type 2 respiratory failure (type 1 respiratory failure)


% samples with

40 –
 Database of blood gas 41.3%
analysis results from
30 –
3,524 specimens.
30%
20 –
 19% were said to be
breathing air at the 10 –
time of sampling and 10%
81% were on 0
oxygen therapy hyperoxaemic grossly hyperoxaemic
oxygen
ranging 24–100%. saturation >98% with PO2 >15.0 kPa with PO2 ≥20 kPa
(112 mmHg) (≥150 mmHg)


% samples with
10.2% samples
40 –
had oxygen
 Database of blood gas
saturation <90%
41.3%
but only 2.7% 30 –
3,524 specimens.
were severely 30%
20 –
hypoxaemic withbe
 19% were said to
oxygen
saturation <80%
81% were on 0
oxygen
(112 mmHg) (≥150 mmHg)


% samples with
Hypercapnic
(type blood gas 40
 Database of2)
–
41.3%
respiratory failure
30 –
was 5X more
3,524 specimens.
common than pure
30%
20 –
 19%hypoxaemia be
were said to
(type 1
time of sampling and
respiratory 10%
81% were on
failure) 0
oxygen
(112 mmHg) (≥150 mmHg)


% samples with

These 40 –
 Database of blood gas
findings 41.3%
suggest 30 –
3,524 specimens.
that oxygen 30%
needs saidbe be 20 –
 19% were to to
used with
more caution
81% were on
in hospitals 0
oxygen
(112 mmHg) (≥150 mmHg)

Randomised controlled trial of high concentration
versus titrated oxygen therapy in severe exacerbations
of asthma Perrin Thorax 2011;66:937
Proportion of patients with a rise
 106 patients with severe in PtCO2 ≥ 4 mm Hg at 60 min
exacerbations of asthma 50 -
FEV1 ≤ 50% pred.

 High concentration oxygen
40 – 44%
(8 l/min via medium
concentration mask) or 30 – RR=2.3
p < 0.006
titrated oxygen (to achieve
oxygen saturations between 20 –
93% and 95%) for 60 min. 19%
10 –
 Transcutaneous partial
pressure of carbon dioxide 000
(PtCO2) was measured at High Titrated oxygen
0, 20, 40 and 60 min. concentration
O2 group

Proportion of patients with a rise
in PtCO2 ≥ 4 mm Hg at 60 min
 106 patients with severe
50 -
exacerbations of asthma.

 High concentration oxygen 40 – 44%
(8 l/min via medium
concentration mask) or 30 – RR=2.3
titrated oxygen (to achieve p < 0.006
oxygen saturations between 20 –
93% and 95%) for 60 min.
19%
10 –
pressure of carbon dioxide
(PtCO2) was measured at 000
High Titrated oxygen
0,20,40 and 60 min. concentration
O2 group


 106 patients with severe Proportion of patients with a rise in
exacerbations of asthma PtCO2 ≥ 8 mm Hg
FEV1 ≤ 50% pred.
40 –
(8 l/min via medium 30 –
concentration mask) or
oxygen saturations between
20 – 22%
93% and 95%) for 60 min.
10 –
RR=3.9
6%
High
(PtCO2) was measured at concentration Titrated oxygen
0, 20, 40 and 60 min. oxygen group


Proportion of patients with a rise in
 106 A titrated oxygen
patients with severe
PtCO2 ≥ 8 mm Hg
regime is recommended
exacerbations of asthma.
in the treatment of 40 –
severe asthma, in
(8 l/minwhich oxygen is
via medium 30 –
administered only to
patients with
oxygen saturations between 20 – 22%
93%hypoxaemia, 60 a dose
and 95%) for in min.
that relieves 10 –
hypoxaemia without RR=3.9
causing hyperoxaemia
6%
(PtCO2) was measured at High
0, 20, 40 and 60 min. concentration Titrated oxygen
oxygen group


 106 patients with severe
exacerbations of asthma
100 – % patients admitted to
FEV1 ≤ 50% pred. 90 – the hospital
80 –
 High concentration oxygen 70 –
(8 l/min via medium 60 – p<0.042
50 –
oxygen saturations between 40 – 52%
93% and 95%) for 60 min. 30 –
20 – 32%
10 –
pressure of carbon dioxide
(PtCO2) was measured at 0
0, 20, 40 and 60 min. High O2 Titrated
group O2 group

It is well recognised that:

1. high concentration oxygen therapy may lead to carbon dioxide
(CO2) retention when administered to patients with acute
exacerbations of chronic obstructive pulmonary disease
(AECOPD) Westlake EK, Q J Med 1955;94:155e73.
Murphy R, Emerg Med J 2001;18:332e9.

2. that worsening ventilation-perfusion mismatch due to release
of hypoxic pulmonary vasoconstriction with a resulting
increase in physiological dead space is one of the major
mechanisms causing this effect. Aubier M, Am Rev Respir Dis 1980;122:747e54.
Dick C, Am J Respir Crit Care Med 1997;155:609e14.
Robinson TD, Am J Respir Crit Care Med 2000;161:1524e9.
Sassoon CS, Am Rev Respir Dis 1987;135:907e11.

End-tidal carbon dioxide monitoring in very low birth
weight infants: Correlation and agreement with arterial
carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367

1) Hypocarbia and/or hypercarbia are implicated as a causative
factor in periventricular leukomalacia, intra-ventricular
hemorrhage, and chronic lung disease.

2) Extreme fluctuations in partial pressure of arterial carbon
dioxide (PaCO2) and higher max PaCO2 are associated with
worse neurodevelopmental outcomes.

Prevention of extreme hypocarbia and/or hypercarbia in
preterm infants is essential.


3) Though arterial blood gas analysis is the gold standard of
monitoring partial pressure of arterial oxygen (PaO2) and
PaCO2, it leads to blood loss and iatrogenic anaemia, may
cause procedural pain, and each sample is only a snapshot
view of the sampling moment.
4) End-tidal carbon dioxide (ETCO2) measurement is a
continuous and non-invasive indirect measurement of blood
carbon dioxide tensions with fast response time to changes
in blood CO2.
5) The principal determinants of ETCO2 are alveolar
ventilation, pulmonary perfusion (cardiac output), and CO2
production.

Scatterplot (with identity line) of
end-tidal CO2 and PaCO2 relationship

r=0.69 p<0.0001

 Simultaneous end-tidal
and arterial CO2 pairs.

 143 ventilated low birth
weight infants (VLBWI).

Scatterplot (with identity line) of
end-tidal CO2 and PaCO2 relationship

r=0.69 p<0.0001

There was a significant
correlation
 143(r = 0.69; P < 0.0001)
ventilated low birth
between ETCO2 and
PaCO2 values.


Bland-Altman plot of the difference between
the end-tidal and arterial CO2 versus the
average of the two simultaneous readings

r=0.16 p=0.06




r=0.16 p=0.06
But the ETCO2 value
andwas lower than the
arterial CO2 pairs.
corresponding PaCO2
value in 94%
pairs, with a mean
bias of
13.5 ± 8.4 mmHg



ETCO2 should not
r=0.16 p=0.06

replace PaCO2
measurements in
 143ventilated VLBWI,
ventilated low birth
weight may have a role
but infants (VLBWI).
to detect trends of
PaCO2.

Effects of maternal food restriction on offspring lung
extracellular matrix deposition and long term pulmonary
function in an experimental rat model
Rehan Pediatr Pulmonol 2012; 47:167

 Intrauterine growth restriction (IUGR) increases the risk of
respiratory compromise throughout postnatal life.
 However, the molecular mechanism(s) underlying the
respiratory compromise in offspring following IUGR is not
known.
 We hypothesized that IUGR following maternal food
restriction (MFR) would affect extracellular matrix deposition
in the lung, explaining the long-term impairment in pulmonary
function in the IUGR offspring.


IUGR pups

Rat model with At postnatal day 21, and at 9 months (9M)
maternal food of age the expression and abundance of
restriction elastin and alpha smooth muscle actin
(αSMA), two key extracellular matrix
proteins, were increased in IUGR lungs
when compared to controls (P < 0.05)


Compared to
controls, the MFR
group did have
significantly decreased IUGR pups
pulmonary compliance
Rat 9M (P < 0.05) vs andpostnatal day 21, and at 9 months (9M)
at model with At
increased food
maternal responsiveness age the expression and abundance of
of
restriction
to methacholine challenge.elastin and alpha smooth muscle actin
(αSMA), two key extracellular matrix
proteins, were increased in IUGR lungs
when compared to controls (P < 0.05)

Tomato juice protects the lungs of the offspring of
female rats exposed to nicotine during gestation and
lactation. Maritz Pediatr Pulmonol 2011;46:976

Maternal nicotine exposure
during pregnancy and lactation

Structural changes
started to appear around
postnatal day 42, that
is, 3 weeks after weaning
and thus the onset of
nicotine withdrawal.
Structural integrity of
the lungs of the offspring



Rich source of
antioxidants such as
lycopene, will prevent Structural changes
the effects of started to appear around
nicotine on the lungs postnatal day 42, that
of the offspring. is, 3 weeks after weaning
and thus the onset of



All these nicotine-
induced structural
changes were Structural changes
prevented by started to appear around
supplementing the postnatal day 42, that
mother's diet with is, 3 weeks after weaning
tomato juice and thus the onset of


Nicotine + tomato juice Nicotine. Arrows = emphysema

Dietary antioxidants and forced expiratory volume
in 1 s decline: the Health, Aging and Body Composition
study Bentley, Eur Respir J 2012;39:979

1) Ageing has been described as the accumulation of oxidative
damage that is incompletely repaired by the body‟s antioxidant
defences.

2) This damage is caused by free radicals
produced in the body via normal metabolic
processes and inflammation, and by
exogenous free radicals, such as from
smoking and noxious gases.

3) In the lungs, ageing is associated with declining lung
function, and rate of decline increases with advancing age.


In continuing smokers higher intake of fruit and
vegetables were associated with a slower rate
of FEV1decline compared with a lower intake
 1,443 participants 0 –
completed a food
frequency questionnaire.
p=0.003
-10 –
 Self-reported
smoking history. +
 FEV1 at both baseline -20 –
and after 4 yrs of
-24mL/yr
followup.
-30 -


In quitters vegetables were associated with a slower rate
(a current smoker at of FEV1decline compared with a lower intake
 study participants had
1,443
baseline who 0 –
completed a food
quit during follow-up),
higher intake was
p=0.003
associated with an -10 –
 Self-reportedrate of
attenuated
smoking history.
decline for each +
nutrient studied -20 –
 FEV(1p≤0.003 for all
at both baseline
and after 4 yrs of
-24mL/yr
models).
followup.
-30 -


vegetables were associated with a slower rate
 1,443 participants
In nonsmoking 0 –
completed a food
participants,
there was little or p=0.003
no association
 Self-reported -10 –

smoking history.rate
of diet and +
of decline
 FEV1 at both baseline -20 –
in FEV1. -24mL/yr
and after 4 yrs of
followup.
-30 -


The intake of vegetables were associated with a slower rate
nutrients with
 1,443 participants 0 –
completed a food
antioxidant
properties may
p=0.003
modulate lung function
 Self-reported -10 –
decline in older
smoking history.
adults exposed to
+
 FEV1 at bothsmoke. -20 –
cigarette baseline -24mL/yr
and after 4 yrs of
followup.
-30 -

Dietary factors and lung function in
the general population: wine and resveratrol intake
Siedlinski M , Eur Respir J 2012;39:385

ABSTRACT: Wine intake is associated with a better lung function
in the general population, yet the source of this effect is unknown.
Resveratrol, a polyphenol in wine, has anti-inflammatory properties
in the lung, its effects being partially mediated via induction of
Sirtuin (SIRT)1 activity.
We assessed the impact of wine and resveratrol intake, and
SIRT1 single-nucleotide polymorphisms (SNPs) on lung
function in the general population.


• Resveratrol intake was
 Effects of red and associated with
white wine and higher FVC levels.
resveratrol intake.

 FEV1, FVC and FEV1/FVC.
• White wine intake with
 Population-based cohort higher FEV1 levels and
(n=3,224). lower risk of
airway obstruction.

Mean adjusted FEV1 and FVC for the subjects according to
the average intake of white wine and total
resveratrol
FEV1 white FEV1 total resveratrol
wine

FVC white wine FVC total resveratrol

Polyphenolic
the average intake of white wine and total
compounds present in white
resveratrol
wine may exert beneficial
FEV1 total resveratrol
FEV1 white
effects on lung function.
wine
Plausible candidates in this
respect are tyrosol and
hydroxytyrosol, polyphenolic
white wine molecules
FVC total resveratrol
FVC white wine that, similar to
resveratrol, exhibit
antioxidant and
cardioprotective
effects

the average intake The white wine and total
of positive
resveratrol we observed between
association
FEV1 white white FEV1 total resveratrol
wine intake and higher
wine FEV1 reflects a very modest
average consumption of 1.0–1.5
glasses of white wine per week
(i.e. 7.4 g·day-1) and, thus, we
FVC white wine by no meanstotal to suggest that
FVC aim resveratrol
more than moderate white wine
drinking could be considered
as beneficial health
behaviour.


Beneficial effects of wine consumption are postulated to account for the
„„French paradox‟‟, the observation of lower mortality due to coronary
heart disease in the French population despite this
population‟s relatively high consumption of a cholesterol- and
saturated fat-rich diet.
The proposed mechanism includes the inhibition of platelet reactivity by
wine and resveratrol is a prominent candidate responsible for the vascular
protection provided by wine.
However, our study shows that white wine intake and not redwine
intake, the major dietary resveratrol source, is associated with a lower
risk of airway obstruction and with higher FEV1, both of which are indices
of COPD.
This is of great importance given the fact that reduced lung function is a
marker for cardiovascular-related mortality.

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