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1Fisiopatologia Respiratoria and 8Terapia Intensiva Cardiochirurgica, Azienda Ospedaliera S. Croce e Carle, 12100 Cuneo; 2Dipartimento di Bioingegneria, Politecnico, 20133 Milano; 3Centro di Bioingegneria, Fondazione Don Gnocchi Instituto di Ricovero e Cura a Carattere Scientifico, 20148 Milano; 5UOF di Riabilitazione Respiratoria, Fondazione Don C. Gnocchi "ONLUS," 50020 Pozzolatico; 6Dipartimento di Medicina Interna, Università di Firenze, 50134 Florence; 7Centro Cardiologico Monzino Istituto di Ricovero e Cura a Carattere Scientifico, Istituto di Cardiologia, Università di Milano, 20122 Milano; and 9Dipartimento di Medicina Interna, Università di Genova, 16132 Genoa, Italy; and 4Meakins Christie Laboratories and McGill University, Montreal, Canada H3A 2T5
Submitted 26 March 2003 ; accepted in final form 30 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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m40) and partial
(p40) forced expiratory maneuvers,
lung volumes, lung elastic recoil, lung resistance (RL), dynamic
elastance (Edyn), and within-breath resistance of respiratory system (Rrs).
RL and Edyn were measured during tidal breathing before and for 2
min after a deep inhalation and also at different lung volumes above and below
functional residual capacity. Rrs was measured at functional residual capacity
and at total lung capacity. Before MCh, saline infusion caused significant
decrements of forced expiratory volume in 1 s,
m40, and
p40, but insignificantly affected
lung volumes, elastic recoil, RL, Edyn, and Rrs at any lung volume.
Furthermore, saline infusion was associated with an increased response to MCh,
which was not associated with significant changes in the ratio of
m40 to
p40. In conclusion, mild airflow
obstruction and enhanced airway responsiveness were observed after saline, but
this was not apparently due to altered elastic properties of the lung or
inability of the airways to dilate with deep inhalation. It is speculated that
it was likely the result of airway wall edema encroaching on the bronchial
lumen. lung elastic recoil; pulmonary resistance; dynamic elastance; methacholine challenge; deep inhalation
We reasoned that fluid accumulation in the airway wall could lead to airway narrowing, either because the airways become stiffer, and thus less distensible with the increase in lung volume, or the increased wall thickness encroaches on the bronchial lumen. To test this hypothesis, we studied the effects of rapid intravenous saline infusion on volume history on lung and airway mechanics in response to inhaled methacholine (MCh) in seven volunteers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Seven volunteers participated in the study after giving an informed consent, as approved by the local Ethics Committee. Average anthropometric and functional data are presented in Table 1. Five subjects considered themselves healthy. One subject had mild intermittent asthma treated with short-acting bronchodilators on demand, and another had a history of past asthma, with no symptoms in the last 6 yr.
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Study Design
Spirometry and MCh bronchial challenge were measured on a prestudy day, when all subjects underwent a clinical examination of the cardiovascular system and an echocardiogram to exclude the risk of rapid saline infusion in a subject with subclinical cardiovascular disease. Thereafter, the subjects attended the laboratory on 2 random study days. On one occasion (saline-infusion day), lung mechanics were measured at baseline, 2 min after saline infusion, and again 2 min after inhalation of a MCh dose equal to the dose causing a 20% decrease in 1-s forced expiratory volume (PD20). On the other occasion (control day), the same protocol was followed, with the exception that the saline infusion was replaced by a 20-min rest.
Lung Function Measurements
Mouth flow was measured by a mass flowmeter (Sensor-Medics, Yorba Linda,
CA), and volume was obtained by numerical integration of the flow signal.
Spirometry and flow-volume curves were obtained by maneuvers consisting of six
to eight regular tidal breaths, a forced expiration initiated from end-tidal
inspiration to residual volume (RV) [partial expiratory flow-volume curve
(PEFV)], followed by a fast inspiration to total lung capacity (TLC) and a
forced expiration to RV [maximal expiratory flow-volume curve (MEFV)].
Breath-holding time before PEFV and MEFV was always <1 s. Flow was taken at
40% of control forced vital capacity (FVC) on both MEFV
(m40) and PEFV
(p40), and their ratio (M/P) was
calculated. Thoracic gas volume (TGV) was measured with the subjects sitting
in a body plethysmograph (Autobox, SensorMedics, Yorba Linda, CA) and panting
against a closed shutter at a frequency slightly <1 Hz with their cheeks
supported by their hands. TLC was obtained as the sum of TGV and inspiratory
capacity measured immediately after reopening of the shutter; RV was
calculated as the difference between TLC and a slow expiratory vital capacity.
Functional residual capacity (FRC) was obtained from TGV and corrected for any
difference between the volume at which the shutter was closed and the average
end-expiratory volume of the four preceding regular tidal breaths. Predicted
values for spirometry and lung volumes are from Quanjer et al.
(26).
Quasi-static pressure-volume (P-V) curves were measured during intermittent and brief interruptions of flow during a relaxed expiration from TLC. Esophageal pressure (Pes) was measured by a 10-cm-long balloon placed in the lower onethird of the esophagus after topical anesthesia of the nose and throat. The balloon was filled with 1 ml of air and connected to a piezoelectric pressure transducer (Microswich; ±200 cmH2O). Mouth pressure (Pm) was measured by a catheter connecting the mouthpiece to a piezoelectric pressure transducer (Microswich; ±200 cmH2O). Transpulmonary pressure (Ptp) was the difference between Pm and Pes. Placement of the balloon was considered correct if Ptp remained stable during gentle inspiratory and expiratory efforts against a partially occluded airway. Volume and Ptp values were measured at zero flow and subsequently fitted by the Salazar and Knowles's equation (28): V = A - B e-KP, where V is lung volume at TLC, A is the volume asymptote above TLC, P is Ptp, B is volume at a pressure of zero, and K reflects the curvilinear shape of the P-V relationship.
Lung resistance (RL) and dynamic elastance (Edyn) were measured during tidal breathing by a DIREC System 200/201 (Raytech Instruments, Vancouver, BC). Flow was measured by a Hans Rudolph pneumotachograph connected to a full-scale differential pressure transducer (±5 cmH2O, flow range: 0–400 l/min; Validyne). Pes and Pm were sensed by two DP15 Validyne differential pressure transducers (±150 cmH2O). Flow, volume, and pressure signals were fed into dedicated software (DR9, Raytech Instruments) and then processed with the aid of a program written in MATLAB (19). Irregular breaths, sights, and breaths with negative Ptp were discarded. For each breath, the pressure difference in phase with volume was subtracted, so that the slope of Ptp vs. flow was RL (20). Edyn was the difference in Ptp at zero flow between end inspiration and end expiration divided by tidal volume (VT).
The within-breath resistance of the respiratory system (Rrs) was measured
during 
1 min of quiet breathing and at TLC by applying a sinusoidal
pressure oscillation at the mouth, while the cheeks were firmly supported by
the operator. The forcing signal was generated by a personal computer
connected to an analog-to-digital (A/D)-D/A board (DAQ-CARD 1200, National
Instruments, Austin, TX) and sent to a power amplifier (model Proline EQ552,
Eurosound, Milan, Italy) connected to a 25-cm-diameter loudspeaker (model
HS250, Ciare, Ancona, Italy) mounted on a rigid box of 3.0-liter internal
volume. The loudspeaker connected to the mouthpiece through a short connecting
tube (22-cm long, 19-mm ID). A low-resistance, high-inertance tube (35-mm ID
and 1.5-m length) was used to connect the pressure generator to the atmosphere
and allow the subjects to breathe
(12). The additional dead
space of the tube was reduced by a 15 l/min bias flow applied between the
pressure generator and the pneumotachograph. Airway opening pressure was
measured by a piezoresistive pressure transducer (model SCX01, Sen-Sym,
Milpitas, CA) connected to the mouthpiece. Airway opening flow was measured
with a screen-type pneumotachograph (model 4700A; Hans Rudolph, Kansas City,
MO) connected to a Celesco pressure transducer (model LCVR, 0–2
cmH2O; Celesco Instruments, Canoga Park, CA). All signals were
sampled at 200 Hz by the same A/D-D/A board used to generate the forcing
signal. The frequency response of both systems was assessed by the method
proposed by Brusasco et al. (5)
and was flat up to 30 Hz. The within-breath respiratory impedance was
estimated from the pressure and flow signals by using an algorithm based on
cross correlation (15,
25).
Protocol
Mechanics of breathing. RL and Edyn were first measured on at least 10 or more spontaneous tidal breaths and then for at least 90 s after a deep inhalation (DI) to TLC. This first set of maneuvers was used to calculate baseline RL and Edyn and to assess their recovery after DI by linearly regressing all values recorded from the point at which spontaneous tidal breathing was resumed to the point at which a clear plateau was observed (24). Thus, for each experimental condition, there were 1) baseline values of RL and Edyn, referred as to pre-DI; 2) intercept values indicating the magnitude of the effects of DI; and 3) slope values indicating recovery times after DI. A second set of measurements of RL and Edyn was obtained while the subjects maintained their breathing pattern as regularly as possible for at least 10 breaths at four specific lung volumes (i.e., FRC, FRC + 1 VT, FRC + 2 VT, and FRC - 1 VT), with the aid of a visual feedback from a computer screen. The dependence of Edyn and the inverse of RL [lung conductance (GL)] on lung volume were estimated by linearly regressing their values against the lung volumes at which they were collected.
PEFV, MEFV, lung volumes, and quasi-static P-V curves were measured at least in triplicate at baseline and after saline infusion and once after MCh. RL and Edyn were measured once before and once after DI under all experimental conditions. Rrs was measured once at all times.
Saline infusion. Saline solution was infused at a dose of 30 ml/kg over 20 min. Arterial blood pressure was continuously monitored through a Finapres device (Finapres 2300, Ohmeda, Englewood, CO), with the cuff positioned on the middle or ring finger of the nondominant hand (23).
Bronchial challenge. Solutions of MCh were prepared by adding distilled water to dry powder MCh-chloride (Laboratorio Farmaceutico Lofarma, Milan, Italy). Aerosols were delivered by an ampoule dosimeter device (MB3 MEFAR, Brescia, Italy), which delivers particles with a median mass diameter ranging between 1.53 and 1.61 µm. Aerosols were inhaled during quiet tidal breathing in a sitting position. On the prestudy day, the test ended when the forced expiratory volume in 1 s (FEV1) decreased by at least 20% of control or after a dose of 10,000 µg was administered. The MCh PD20 was calculated by linear interpolation between two adjacent points of the dose-response curve. Either the PD20 or the maximal dose achieved was used to induce bronchoconstriction on study days.
Statistical Analysis
A mixed between- and within-groups ANOVA with Duncan post hoc comparisons was used. Values of P < 0.05 were considered statistically significant. Data are presented as means ± SD.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Lung function was normal at baseline in all subjects, except in the volunteer with past asthma in whom FEV1-to-FVC ratio was 0.67, suggesting mild airflow obstruction. Average lung function data were not significantly different between saline and control days (Table 2).
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Taking a DI resulted in a significant and systematic increase in forced expiratory flow on both days (Table 2), as documented by M/P always being >1 (P < 0.05), no changes in RL, and a significant (P < 0.05) decrease in Edyn (Table 3 and Fig. 1). Rrs significantly decreased (P < 0.001) when lung volume was increased from FRC to TLC (Table 3 and Fig. 2).
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Edyn, but not GL, significantly increased with lung volume (P < 0.05) (Table 4 and Figs. 3 and 4).
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Effects of Saline Infusion on Lung Function Before MCh
On the saline-infusion day, there were significant reductions in
FEV1 (P < 0.01), FVC (P < 0.01),
m40 (P < 0.01), and
p40 (P < 0.02) compared
with baseline (Table 5). The
decrease in FVC was accompanied by a trend to decrease TLC and increase RV.
However, there were no significant changes in lung elastic recoil,
RL, Edyn, and Rrs (Tables
3 and
5). Also, the effects of DI on
RL and Edyn (Table 3
and Fig. 1) and on Rrs
(Table 3 and
Fig. 2) and the slopes of the
linear regression of GL and Edyn vs. volume
(Table 4 and Figs.
3 and
4) after saline infusion were
substantially unchanged compared with baseline. No significant differences in
arterial diastolic and systolic blood pressure were observed between control
(76 ± 6 and 136 ± 11 mmHg, respectively) and saline infusion (80
± 11 and 148 ± 30 mmHg, respectively). On the control day, no
significant differences from baseline were observed at the matched time points
(Tables 3 and
5, and Figs.
1,
2,
3,
4).
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Effects of Saline Infusion on Lung Function After MCh
On the saline-infusion day, the fractional decrements in FEV1,
m40, and
p40 with MCh were significantly
greater than on the control day (P < 0.01, P < 0.001,
and P < 0.001, respectively), thus suggesting enhancement of
MCh-induced bronchoconstriction by prior saline infusion
(Table 5). In contrast, the
increments in FRC, RV, RL, and Edyn with MCh (Tables
3 and
5) and the remarkable
decrements of RL, Edyn, and Rrs with DI and of FVC (Tables
3 and
5, and Figs.
1 and
2) that occurred with airway
narrowing were similar between days. With the DI, there was a significant
bronchodilatation, as suggested by increase in maximum flow (P <
0.001, Table 5) and decrements
in RL, Edyn, and Rrs (P < 0.001 for all,
Table 3) to values still
significantly different than the relevant values after the DI at baseline and
before MCh (P < 0.05 for all). Finally, lung elastic recoil
remained similar to baseline values (Table
5), and the slopes of the linear regressions of GL and
Edyn against lung volume (Table
4 and Fig. 3 and
4) were significantly
different, but not significantly different between days.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Rapid intravenous infusion of an isosmotic solution, such as saline 0.9%, is expected to be followed by fluid leakage from both pulmonary and bronchial vessels (7, 10, 13, 16, 22, 30–33). The ensuing events include filling of the spaces around the alveoli and the complex vascular network accompanying the airways (29), likely promoted by negative interstitial pressure. The latter could tend to drive liquid from the submucosa to the adventitia. In line with previous reports (7, 22), we did not observe occurrence of pulmonary edema after saline infusion, as documented by the absence of changes in the quasi-static Ptp-volume curves, Edyn at FRC, and the change in Edyn with lung volume. The amount of fluid infused was insufficient to cause gross pulmonary edema, although the decrease in FVC caused by saline infusion is consistent with pulmonary vascular congestion (8).
In animals, saline infusion has been shown to cause airway wall edema, as documented by morphometry (13, 30) and high-resolution computed tomography (3, 4, 32). Left atrial pressure elevation and bradykin infusion have similar effects on the airway wall (1, 2, 31, 32). Although we do not have the same compelling demonstration in our subjects, we postulate that the decrease in flow and the leftward shift of the dose-response curve to MCh in our volunteers was caused by hyperemia, vascular congestion, and mild edema after saline. With the reasonable assumption that the extent of edema remained in the airway wall for a sufficient time after the infusion to allow measurements to be completed after induced constriction, our data let us speculate on how airway vascular congestion can alter lung function. Bronchial arteries supply the airways with an external adventitial plexus tightly connected through anastomoses to a submucosal plexus (9). In theory, fluid might have been distributed homogeneously across the airway wall or mostly in its submucosal or adventitial layer. Deposition of the fluid in the adventitial layer wall infiltrating the connections between airways and surrounding parenchyma would render the forces of interdependence less effective to distend the bronchi. Similarly, fluid accumulation in the mucosa and submucosa should encroach on the lumen (21) and could render the airway wall stiffer and less distensible to the mechanical stress applied by a DI. Finally, lack of radial tension caused by uncoupling of airways from the surrounding parenchyma could interfere with tidal stresses applied to the airway during breathing, which are thought to break cross bridges and maintain the airways dilated. This would facilitate the latch state of the airway smooth muscle (11) and make the airways stiffer.
Our findings seem to rule out these mechanisms as potential causes of bronchoconstriction and hyperresponsiveness. First, neither the relationship of GL with lung volume nor the response of RL to the DI were modified by saline. This was especially evident after MCh, when the decrease in RL with the DI and its recovery over time after saline were not different from those at matched time points without saline. Thus it appears that the effect of the DI on lung mechanics was not at all hampered by saline. Second, the response of Edyn to the DI was similar both before and after MCh on both days. Assuming that Edyn reflects airway and parenchymal tone, especially with bronchoconstriction, as well as inhomogeneous distribution of narrowing across parallel airways (18), then the similar decrease in Edyn after DI and recovery to baseline values both before and after MCh on both days would suggest, once again, that saline infusion did not alter the reestablishment of tone and airway caliber after the DI. A third line of evidence comes from the analysis of Rrs within tidal breaths and at TLC. At baseline, the decrease in Rrs after DI was similar on saline-infusion and control days. Thus saline infusion was unable to alter the bronchodilator response to DI. After MCh, there was a remarkable decrease in Rrs with DI, which was, once again, similar on both study days. Interestingly, the minimum values achieved at TLC were slightly, although significantly, higher than before MCh. All of these data are in line with two studies conducted in sheep, in which bronchial edema caused by bradykinin, an inflammatory mediator, did not prevent a full lung inflation from reversing MCh-induced airway narrowing (1, 2). Thus it emerges that airway edema itself appears not to affect the ability of DI to reverse airflow obstruction.
The airway narrowing and the increased response to MCh observed after saline infusion could be attributed to a reflex bronchoconstriction and/or encroachment on bronchial lumen. The first mechanism is deemed to occur mostly in the peripheral airways 10–15 min after saline infusion and to be triggered by stimulation of neuroreceptors by both bronchial and pulmonary edema (14, 16). Because this was roughly the time when we made our measurements before MCh was inhaled after the end of saline infusion, it could be possible that some reflex caused a decrease in flow, at least before inducing constriction with MCh. However, the unchanged M/P after saline speaks against this hypothesis. Indeed, if we assume that neural reflex bronchoconstriction and the ensuing increase in bronchial tone blunt the bronchodilator response to DI, as we postulate above, then it is hard to reconcile airway smooth muscle shortening triggered by a neural reflex without an altered response to DI. More likely, the effects of saline infusion were due to a greater encroachment of the submucosal layer on the bronchial lumen. Although we cannot prove it, we speculate that vascular engorgement, fluid extravasation in the submucosal area, and edema could decrease the bronchial lumen, either by precipitating buckling (4, 30) or by a space competition mechanism (13).
So far, we have only considered the functional effects of saline infusion on edema formation across and not axially along the airways. Saline infusion decreased partial and maximum flows, but did not increase RL and/or Rrs. This suggests that most of the edema formed in the intraparenchymal airways upstream from flow-limiting segments.
In conclusion, our results suggest that airway narrowing and hyperresponsiveness occurring after rapid intravenous infusion of saline solution were not due to the inability of the edematous airways to distend with the deep breaths. More likely, it was the increased thickness of the submucosa that encroached on the lumen of the intraparenchymal airways, thus leading to a decrease in maximum flow with the smooth muscle either relaxed or contracted.
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FOOTNOTES |
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Original submission in response to a special call for papers on "Airway Hyperresponsiveness: From Molecules to Bedside."
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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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) days.
The average linear regression lines of all individual subjects on
saline-infusion (thick line) and control (dashed line) days are shown.
A: baseline. B: before methacholine. C: after
methacholine.