The effect of changing ventilator settings on indices of ventilation inhomogeneity in small ventilated lungs
 G Schmalisch^{1}Email author,
 H Proquitté^{1},
 CC Roehr^{1} and
 RR Wauer^{1}
DOI: 10.1186/14712466620
© Schmalisch et al; licensee BioMed Central Ltd. 2006
Received: 21 March 2006
Accepted: 18 August 2006
Published: 18 August 2006
Abstract
Background
In ventilated newborns the use of multiple breath washout (MBW) techniques for measuring both lung volume and ventilation inhomogeneity (VI) is hampered by the comparatively high dead space fraction. We studied how changes in ventilator settings affected VI indices in this particular population.
Methods
Using a computer simulation of a uniformly ventilated volume the interaction between VI indices (lung clearance index (LCI), moment ratios (M_{1}/M_{0}, M_{2}/M_{0}, AMDN_{1}, AMDN_{2}) of the washout curve) and tidal volume (V_{T}), dead space (V_{D}) and functional residual capacity (FRC) were calculated. The theoretical results were compared with measurements in 15 ventilated piglets (age <12 h, median weight 1135 g) by increasing the peak inspiratory pressure (PIP). FRC and VI indices were measured by MBW using 0.8% heptafluoropropane as tracer gas.
Results
The computer simulation showed that the sensitivity of most VI indices to changes in V_{D}/V_{T} and V_{T}/FRC increase, in particular for V_{D}/V_{T} > 0.5. In piglets, the raised PIP caused a significant increase of V_{T} from 15.4 ± 9.5 to 21.9 ± 14.7 (p = 0.003) and of the FRC from 31.6 ± 14.7 mL to 35.0 ± 15.9 mL (p = 0.006), whereas LCI (9.15 ± 0.75 to 8.55 ± 0.74, p = 0.019) and the moment ratios M_{1}/M_{0}, M_{2}/M_{0} (p < 0.02) decreased significantly. No significant changes were seen in AMDN_{1} and AMDN_{2}. The withinsubject variability of the VI indices (coefficient of variation in brackets) was distinctly higher (LCI (9.8%), M_{1}/M_{0} (6.6%), M_{2}/M_{0} (14.6%), AMDN_{1} (9.1%), AMDN_{2} (16.3%)) compared to FRC measurements (5.6%). Computer simulations showed that significant changes in VI indices were exclusively caused by changes in V_{T} and FRC and not by an improvement of the homogeneity of alveolar ventilation.
Conclusion
In small ventilated lungs with a high dead space fraction, indices of VI may be misinterpreted if the changes in ventilator settings are not considered. Computer simulations can help to prevent this misinterpretation.
Background
In ventilated newborns respiratory problems are often caused by impaired lung development and uneven alveolar ventilation. Surfactant deficiency or dysfunction may increase the ventilatory inhomogeneity by collapse or over distention of the alveoli. Thus, there is an increasing clinical interest in multiple breath washout techniques (MBW) to measure both the functional residual capacity (FRC) and ventilatory inhomogeneity (VI) indices [1–4]. Lung clearance index (LCI) and moment ratios of the wash out curve are the most frequently used indices in infancy [5]. Commonly, the first and the second moment related to the zeroth moment (M_{1}/M_{0}, M_{2}/M_{0}) are calculated.
Most VI indices are easily calculated, however, a key disadvantage is their dependency on the breathing pattern [6]. In 1975, Saidel et al. [7] suggested that this dependency can be reduced by performing a moment analysis of the washout curve plotted as a function of the cumulative exhaled volume related to the FRC. However, the dependency of the moment ratios on the ventilatory dead space (V_{D}) remained. Therefore, Habib and Lutchen [8] replaced the cumulative exhaled volume by the cumulative alveolar volume to reduce the influence of V_{D}. They referred to the first two moment ratios of the wash out curve as alveolarbased mean dilution numbers AMDN_{1} and AMDN_{2}.
Dead space fractions (V_{D} related to the tidal volume V_{T}) in adults commonly lie between 0.05 to 0.2 [8]. In ventilated newborns the dead space fraction V_{D}/V_{T} is often markedly higher [9] depending on the ventilator settings. Typical values lie between 0.4 and 0.6 [10] and in preterm or surfactantdepleted lungs V_{D}/V_{T} can rise up to 0.7 [11]. Such small lungs are ventilated with a relative low tidal volume to prevent volutrauma. Mainstream flow sensors and gas analyzers considerably increase the apparatus dead space so that high dead space fractions are not uncommon. The effect of an increased V_{D}/V_{T} on the sensitivity of VI indices to parameter changes is not well known. Therefore, the aim of this study was to investigate how changing ventilator settings affect the different VI indices in this particular population by mathematical modelling and by measurements in newborn piglets using the MBW technique with heptafluoropropane (HFP) as tracer gas.
Methods
Modelling
In patients ventilated with a constant V_{T} the LCI is given by
where N_{LCI} is the number of breaths required to lower the end tidal tracer gas concentration to 1/40^{th} of the starting concentration [12]. The ideal washout curve of an inert gas from a uniformly ventilated volume can be expressed as
where c^{n} is the endexpiratory gas concentration of the n^{th} breathing cycle and c_{0} is the initial gas concentration. Using computer simulations of the washout curve LCI can be calculated as a function of V_{T}/FRC and V_{D}/V_{T}.
The moments M_{0}, M_{1}, M_{2} of the washout curve were calculated up to N_{LCI}. For a constant V_{T} the moment ratios are given by
where "i" is the number of the breathing cycle. For an infinite number of cycles M_{1}/M_{0} has a fixed limit given by
Following Habib and Lutchen [8], the replacement of V_{T} by the alveolar ventilation V_{T}V_{D} yield the alveolarbased mean dilution numbers
For a wellmixed volume and an infinite number of breathing cycles, AMDN_{1} is equal one regardless of V_{D}/V_{T} or V_{T}/FRC
and an AMDN_{1} > 1 implies inhomogeneity purely at alveolar level [8]. For very low dead spaces (V_{D}/V_{T}≈0) the alveolarbased mean dilution numbers are equal the moment ratios (AMDN_{1} = M_{1}/M_{0}, AMDN_{2} = M_{2}/M_{0}). An important feature of all VI indices is that they rise with increasing inhomogeneity of the alveolar ventilation which can be shown easily by computer simulations of multicompartment models.
Animal experiments
Fifteen newborn piglets (age <12 h, median weight 1135 g) placed in supine position within a heated incubator were anesthetized (azaperon 8 mg·kg^{1} and ketamin 10 mg·kg^{1}), intubated (shortened neonatal endotracheal tube (ETT) with 3.5 mm outer diameter, Vygon, Ecouen, France), paralyzed (pancuroniumbromide 0.2 mg·kg^{1}·hour^{1}) and mechanically ventilated with a neonatal ventilator (Babylog 8000, Draeger, Lübeck, Germany). During the study period, air flow (6 L/min), respiratory rate of 40/min and fraction of inspired oxygen (FiO_{2}) of 1.0 were kept constant. Positive endexpiratory pressure (PEEP) was set to zero, peak inflation pressure (PIP) was set initially to 8.3 ± 3.1 cmH_{2}O and elevated to 12.1 ± 5.0 cmH_{2}O. Ventilatory parameters were taken from the Babylog 8000 and recorded continuously. Lung volume and VI indices were measured by heptafluoropropane (HFP) wash in and wash out as previously described [13]. Briefly, a new infrared HFP sensor was sited between the flow sensor of the Babylog 8000 and the ETT. The total apparatus dead space of HFP sensor, flow sensor and ETT was 4.5 mL determined by water displacement. The constant flow of the ventilator was 8 L/min in all measurements. Using a mechanical valve to start wash in or wash out, a HFP flow from a gas cylinder (medical grade HFP, Solvay, Hannover, Germany) was fed into the inspiratory limb of the ventilatory circuit to achieve a constant HFP concentration of 0.8%. The flow signal of the Babylog 8000 and the concentration signal from the HFP sensor were used to calculate FRC and the VI indices from the washin or washout curve up to 1/40^{th} of the starting concentration by an external computer. The Fowler dead space V_{D} was determined from the first 5 cycles. The calculation was stopped automatically after N cycles when the total amount of alveolar turnovers exceed the tenfold of the calculated FRC (minimum number 40 cycles).
After instrumentation and onset of mechanical ventilation a stabilisation period of 15 minutes was allowed before the measurements were started with a HFP washin procedure (FRC_{washin}) and a consecutive washout procedure (FRC_{washout}). Such a cycle was accepted for evaluation if the deviation between FRC_{washin} and FRC_{washout} was lower than 20% and the V_{T} was higher than 4.5 mL (V_{Dapp}). In order to investigate the effect of ventilator settings on VI indices PIP was increased by 4 cm H_{2}O. After a stabilisation period of 15 minutes the MBW was repeated in the same manner.
Computer program
A computer program written in Visual Basic (Microsoft Corpor., USA) as a macro of a EXCEL worksheet (Microsoft Office 2000, Microsoft Corpor., USA) was developed to compare the VI indices measured in the piglets with the VI indices of a uniformly ventilated volume using the same ventilator settings [see Additional file 1]. The program calculates the washout curve according equation 2 and the corresponding VI indices according equations 1, 3 and 5.
Statistics
For each measurement in the piglets at least 5 washin and washout cycles were performed and averaged. Data are presented as mean ± SD and mean individual differences with 95% CI as appropriate. Differences in the animals were compared by the paired ttest. To assess the withinsubject variability of repeated measurements the coefficient of variation (CV) was calculated for all parameters and compared by a rank test. A level of statistical significance of p < 0.05 was accepted.
Results
Computer simulation
Animal study
Effect of increased peak inspiratory pressure on ventilation, FRC and ventilatory inhomogeneity indices in 15 ventilated piglets (Presented are groups means ± SD and the mean individual changes with 95%CI compared to the baseline)
Baseline  Increased peak inspiratory pressure  Mean individual difference in % with 95%CI  P value  

V _{ T } (mL)  15.4 ± 9.5  21.9 ± 14.7  38.9 (20.4 to 57.45)  p = 0.003 
FRC (mL)  31.6 ± 14.7  35.0 ± 15.9  11.1 (4.5 to 17.8)  p = 0.006 
V _{ T } /FRC  0.48 ± 0.17  0.59 ± 0.20  25.0 (10.7 to 39.4)  p = 0.003 
V _{ D } /V _{ T }  0.49 ± 0.15  0.43 ± 0.13  10.2 (21.0 to 0.5)  p = 0.006 
LCI  9.17 ± 0.75  8.55 ± 0.74  6.4 (11.8 to 1.0)  p = 0.019 
M _{ 1 } /M _{ 0 }  2.03 ± 0.16  1.84 ± 0.16  9.4 (14.0 to 4.9)  p = 0.006 
M _{ 2 } M _{ 0 }  8.41 ± 1.60  7.22 ± 4.80  12.1 (23.1 to 1.4)  p = 0.017 
AMDN _{ 1 }  1.034 ± 0.30  1.028 ± 0.19  0.6 (9.1 to 7.9)  p = 0.886 
AMDN _{ 2 }  2.88 ± 1.56  3.01 ± 1.06  4.5 (9.9 to 18.1)  p = 0.515 
A significant decrease was also seen in the LCI (p = 0.019) and the moment ratios M_{1}/M_{0} (p = 0.006) and M_{2}/M_{0} (p = 0.017). No significant changes were seen in AMDN_{1} and AMDN_{2}.
There was a strong correlation between LCI and the moment ratios (M_{1}/M_{0}, M_{2}/M_{0}) with r = 0.885 and r = 0.907, respectively, and independent of which PIP was used. Thus, it was not surprising that there was a similar effect of the increased PIP on LCI and the moment ratios (M_{1}/M_{0}, M_{2}/M_{0}). No statistically significant correlations were found between the alveolarbased mean dilution numbers (AMDN_{1}, AMDN_{2}) and LCI, M_{1}/M_{0} and M_{2}/M_{0}.
The withinsubject variability of the measured parameters showed considerable variations but it was not affected by the increase of the PIP. The median CV of all FRC measurements was 5.6%. The median CV of the LCI was significantly greater (9.8%, p = 0.0004). Compared with the LCI the CV of M_{1}/M_{0} was significantly smaller (6.6%, p = 0.003), whereas the CV of M_{2}/M_{0} was distinctly greater (14.6%, p = 0.004). The CVs of AMDN_{1} (9.1%) and AMDN_{2} (16.3%) were always greater than the CVs of the other moment ratios.
Modelling of ventilatory inhomogeneity indices of a uniformly ventilated volume using the measured V_{D}/V_{T} and V_{T}/FRC of table 4
Modelling 1  Modelling 2  Difference in %  

Model parameters  
V _{ D } /V _{ T }  0.49  0.43  
V _{ T } /FRC  0.48  0.59  
Inhomogeneity indices  
LCI  8.16  7.67  6.00% 
M _{ 1 } /M _{ 0 }  1.79  1.61  10.08% 
M _{ 2 } /M _{ 0 }  6.48  5.48  15.41% 
AMDN _{ 1 }  0.91  0.92  0.49% 
AMDN _{ 2 }  1.69  1.78  5.66% 
Discussion
The measurement of lung volume and ventilation inhomogeneity by MBW is a fascinating, noninvasive technique. It is relatively easily performed, even in ventilated patients. In a previous study [13], we have shown that by this technique the effect of surfactantdepletion by lung lavage on the FRC and the VI indices is reliably measured: before and after lavage V_{D}/V_{T} was not significant different, therefore, the significant increase of the VI indices has to be predominantly attributed to the effect of lung lavage. In the present study the measurements were performed in healthy lungs and V_{D}/V_{T} was distinctly changed by an increase of the PIP. As shown in Fig. 5 the changes of the VI indices are mainly caused by physical laws of gas mixing.
The interpretation of significant changes in VI indices may be misleading if their dependency on the ventilator settings is not considered. This is a particular problem in small lungs where the relatively high dead space fraction increases the sensitivity of VI indices to parameter changes. Any changes in V_{D} (e.g. by applying of a new mainstream sensor) or changes in V_{T} and FRC (e.g. by changing of ventilator settings or by surfactant substitution) will affect the VI indices and therefore hamper their comparability.
As shown by the computer simulation, most VI indices increase with increasing V_{D}/V_{T}. This may explain why in newborns much higher VI indices values were measured [4, 13, 14] than in spontaneously breathing children [15, 16]. These higher values in newborns are more likely an expression of functional dependencies than the result of impaired alveolar ventilation. The relatively good agreement between the VI indices measured in healthy piglets (Table 1) and the calculated VI indices of a uniformly ventilated volume (Table 2) was surprising. There was only a small difference in the VI indices between the animal measurements and the modelling which can be attributed to the more complex ventilation distribution in the lungs of the piglets.
In infancy the LCI is one of most frequently used VI index [16–19] and easy to comprehend. It describes the number of turnovers to lower the end tidal tracer gas concentration to 1/40^{th} of the starting concentration. Theoretically, the LCI is a static value of the flat tail of the washout curve and may vary if the signal is noisy. This explains its relatively high withinsubject variability. The limitation on N_{LCI} breathing cycle seems to be useful to reduce the influence of the signal noise on the measured LCI. Its main disadvantage is its high dependency on V_{T}/V_{D} as shown in Fig. 1.
Moment ratios are more abstract mathematical measures considering the whole washout curve. Only for M_{1}/M_{0} a theoretical value for a well ventilated volume exists (equation 4). M_{1}/M_{0} reflect more the first part of the washout curve, whereas M_{2}/M_{0} better describe the tail of the curve. Therefore the withinsubject variability of M_{2}/M_{0} is distinctly higher compared to M_{1}/M_{0} and similar to the withinsubject variability of the LCI. A moment analysis makes higher demands on the wash out curve compared to LCI measurements. It requires a rapid rise of the tracer gas after the switchon so that the full tracers gas concentration is reached during the first inspiratory cycle. This is sometimes difficult to achieve, in particular if the tracer gas is fed into the inspiratory limb of the ventilator circuit, far from the ETT, which may delay such a swift rise. Such a delay is tolerable for FRC measurements but will affect the calculation of the moment ratios.
In contrast to LCI and the ratios M_{1}/M_{0} and M_{2}/M_{0}, no significant effect of the increased PIP on AMDN_{1} and AMDN_{2} was seen, as predicted by the computer simulation. These parameters suggested by Habbib and Lutchen [8] seem indeed to be less sensitive to the changes in the breathing pattern than the other ones. This dos not necessarily mean that they have a higher predictive value: with the exception of the above authors [8], a higher diagnostic value of these corrected moments could not be demonstrated until now [20]. The main problem with these parameters is that they need an exact determination of the Fowler dead space. This is often difficult to evaluate in small lungs because the three phases of the gas concentrationvolume diagram of the exhaled air are often not well defined [11]. This may explain why in animals AMDN_{1} and AMDN_{2} often showed a very high withinsubject variability (>20%). This high variability may limit their diagnostic value.
A central problem of all moment ratios is their dependency on the number of evaluated breathing cycles [14]. The computer simulation has already shown that the theoretical values for M_{1}/M_{0} and AMDN_{1} were not reached due to the finite number of evaluated cycles (Fig. 2). This hampers the comparability of the data between different laboratories if the start and the end of the evaluated breathing cycles are not specified.
The withinsubject variability of LCI, M_{1}/M_{0} and M_{2}/M_{0} in our study was similar to those measured by Shao et al. [14] in preterm infants. In both studies the variability of the VI indices was distinctly higher compared with the CV of the FRC. Thus, in small ventilated lungs the determination of VI indices needs a higher number of washin and washout cycles than for FRC measurements to obtain reproducible results.
Conclusion
With the availability of dead spaceminimized mainstream gas analyzers there is an increasing interest to measure ventilation inhomogeneity by MBW techniques. However, the use of VI indices in small lungs needs particular attention. Especially in small ventilated lungs with a relatively high dead space fraction most indices are significantly affected by ventilator settings. Changes in tidal volume and lung volume, or changes in the apparatus dead space hamper their comparison. Model simulations of a uniformly ventilated volume can help to decide if the changes in the VI indices are caused by changing ventilator settings or whether they indicate any changes in the homogeneity of alveolar ventilation.
Abbreviations
 c^{n} :

Endexpiratory tracer gas concentration of the n^{th} breathing cycle
 CV:

Coefficient of variation
 ETT:

Endotracheal tube
 F_{I}O_{2} :

Fraction of inspired oxygen
 FRC:

Functional residual capacity
 FRC_{washin} :

Functional residual capacity measured by washin of the tracer gas
 FRC_{washout} :

Functional residual capacity measured by washout of the tracer gas
 HFP:

Heptafluoropropane
 ICU:

Intensive care unit (for newborn infants)
 LCI:

Lung clearance index
 M_{1}/M_{0} :

Firsttozeroth moment ratio
 M_{2}/M_{0} :

Secondtozeroth moment ratio
 MBW:

Multiple breath washout
 N:

Number of breathing cycles
 N_{LCI} :

Number of breaths required to lower the tidal tracer gas concentration to 1/40^{th} of the starting concentration
 PEEP:

Positive endexpiratory pressure
 PIP:

Peak inflation pressure
 V_{D} :

Deadspace volume
 V_{Dapp} :

Apparatus deadspace volume
 V_{T} :

Tidal volume
 VI:

Ventilation inhomogeneity
Declarations
Acknowledgements
The authors thank Ariane Kusztrich for her assistance in the animal experiments and Jessica Blank for her support in data analysis.
Authors’ Affiliations
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