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J Appl Physiol 98: 2064-2071, 2005. First published February 3, 2005; doi:10.1152/japplphysiol.01151.2003
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Temporal nitric oxide dynamics in the paranasal sinuses during humming

Lars Menzel,1 Alexander Hess,2 Wilhelm Bloch,3 Olaf Michel,2 Klaus-Dieter Schuster,4 Ralph Gäbler,1,5 and Wolfgang Urban1

1Department of Applied Physics, University of Bonn, Bonn; 2Department of Oto-RhinoLaryngology, University of Cologne, Cologne; 3Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne; 4Institute of Physiology I, University of Bonn, Bonn; and 5INVIVO GmbH, Adelzhausen, Germany

Submitted 27 October 2003 ; accepted in final form 13 January 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
In this study, the temporal shape of voice-induced nitric oxide (NO) signals in exhaled air has been investigated in eight healthy individuals by means of laser magnetic resonance spectroscopy. The results of the experimental part have been compared with calculated signals obtained by using a simple one-compartment model of the paranasal sinuses. In the experimental part, a rapidly increasing NO concentration has been found when the subjects started humming. After reaching a maximum, the emission starts to decrease with the shape of an exponential decay and finally reaches a constant level. The time constant of this decay (NO washout) is 3.0 ± 1.2 s. The peak height of the NO emission during humming increases when the time between two humming processes increases. When no voice-induced NO emission takes place, the NO concentration in the paranasal sinuses rebuilds again to a maximum concentration. The typical time constant for the NO recovery is 4.5 ± 3.2 min. A three-compartment model defining exactly the geometry and anatomy of the paranasal sinuses has been developed that is based on three main assumptions of the NO dynamics: 1) constant NO production of the epithelium in the sinuses; 2) the rate of the chemical reaction of NO with the epithelium of the paranasal sinuses is proportional to the NO concentration; and 3) the emission of NO from the sinuses (volume/s) is proportional to the NO concentration. It is shown that the three-compartment model under the experimental conditions can be reduced to a one-compartment model, which describes the complete temporal behavior of the NO exchange.

laser magnetic resonance spectroscopy; nitric oxide emission; noninvasive measurement

IN PREVIOUS STUDIES (7, 8, 10, 12, 19), the paranasal cavities have been determined to contain higher amounts of the short-living radical nitric oxide (NO) than the nasal cavity and other compartments of the upper respiratory tract.

Because of the antiviral and bacteriotoxic properties of NO, it is postulated that the molecule NO may maintain the sterility of the paranasal cavities (3). Individuals with a constitutional lower NO concentration in the sinuses suffer more frequently from infections of paranasal sinuses and airways (e.g., in Kartagener's syndrome). They might owe their situation to a reduced capability of producing NO (9).

However, up to now, knowledge about dramatically increased NO concentration in sinuses could be obtained only by invasive methods. Recently, the group around Weitzberg and Lundberg (12, 19) described the phenomenon of high, exhaled NO concentration during humming. Obviously humming leads to an increased volume exchange between the sinuses and the nasal cavity. Maniscalco et al. (12) suggested that measurement with and without humming could be of use to estimate sinus ventilation.

In the present study, the authors demonstrate that the detailed investigation of this phenomenon can be used to develop a model for the NO concentration in the paranasal cavities and exchange into the nasal cavity by means of a noninvasive tool. Nasal diseases, e.g., different types of rhinosinusitis, allergic rhinitis, etc., are thought to lead to alteration of NO regeneration and exchange. Only a simple, noninvasive method is suited to investigate the NO kinetics in individuals to correlate with clinical appearance of the disease.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The study of the temporal shape of the NO emission from the paranasal sinuses has been performed in two parts. In the first part, the washout phenomena of NO induced by sound waves have been investigated. The second part focuses on the process of the NO rebuilding in a period when no voice-induced emission takes place.

In the first set of measurements, eight subjects (age between 25 and 28 yr, 6 men and 2 women) and, in the second, five subjects (age between 23 and 29 yr, 4 men and 1 woman) took part. All of them were nonsmokers without any acute or chronic diseases of the respiratory tract. This study was performed on volunteers after receiving approval from the University of Cologne Human Ethics Committee.

Experimental setup.   In this study, both the NO concentration and the flow rate of the exhaled air were monitored online with a resolution in time of <300 ms. The subjects were inhaling ambient air with a NO concentration of <2 parts/billion (ppb). The air was exhaled through the nose and directed to a flow sensor by a Y-shaped glass adapter, which was tightly fitted to the anterior entrance of the nose (see Fig. 1). The flow rate was measured by using a calibrated sensor of a commercially available pneumotachograph (modified rhinomanometer, model A440, Allergopharma, Hamburg, Germany), which measures the differential pressure of the airstream in front of and behind an iris. A small fraction of the exhaled air (0.8 l/min) was directed to a laser magnetic resonance spectrometer (LMRS). This spectrometer enables the NO detection of concentrations from 1 ppb up to several parts/million (ppm) (13). All data have been recorded by using a two-channel analog-to-digital converter and a computer.



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  		Fig. 1. Experimental setup. LMR, laser magnetic resonance; PC, personal computer; {Delta}P, change in pressure; U, output voltage of pneumotechograph.

 
Breathing pattern.   The breathing cycles were set to the following breathing pattern. In the first part of the study, the subjects initially had to inhale and exhale through the nose over a period of at least 1 min. Afterward, they inhaled and started humming for 10–20 s. The cycle of inhaling and humming was repeated three times. The duration of the last humming period was at least 15 s.

In the second part of the study, the subjects began with normal breathing (inhaling and exhaling through the nose) for 1 min, followed by humming for 15 s. Afterwards, they continued with normal breathing, "regeneration time" (Tr), which was set to 30 s and 1, 2, 5, and 10 min. During this time, Tr, the subject was not allowed to speak, laugh, or make any other kind of noise in the respiratory tract. After this time, the subjects started humming for a period of 10 s. The process of initial humming, normal breathing (Tr), and humming was repeated by each subject four times for Tr = 30 s to 2 min, three times for Tr = 5 min, and twice for Tr = 10 min.

Data analysis.   After the data were recorded, the rate of NO emission, E(t), from the subjects was calculated by multiplying the measured NO concentration, C(t), and the flow rate, F(t). The function E(t) represents the volume of NO that is exhaled per time interval (NO volume per second). The resulting physical unit of the NO emission E(t) is nanoliters per second.

(1)
where C(t) is in nl/l and F(t) is in l/s.

This number is important because the flow rate of exhalation has not been set to a constant value. The E(t) yields the amount of NO released by the human body (especially the upper airways) and is less influenced by the individual speed of breathing compared with the concentration C(t).

LMRS for NO detection.   The technique of the LMRS (described in detail in Ref. 13) is based on the interaction of NO with the polarized radiation of a CO laser at 5.2-µm wavelength. This interaction leads to a rotation of the plane of polarization, which depends on the NO concentration. This so-called Faraday effect can be measured to a very sensitive degree, and it is linear over several orders of magnitude. To avoid the adsorption of the NO molecules to the walls of the setup, only glass, stainless steel, and Teflon were used.

The whole setup was calibrated each day by using NO-free synthetic air and a mixture of 1 ppm NO in nitrogen.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
First part: "washout time" of the NO emission.   In the first part of the study, the temporal shape of the NO concentration was found to be similar to the example shown in Fig. 2. When the subject starts humming, the NO concentration rapidly increases to a value of several tens up to several hundred ppb, and also the E(t) increases up to several 10 nl/s. After an initial maximum, the concentration and the emission, respectively, started to decrease and finally reached a constant level, which is approximately one-fourth of the maximum peak. After the initial peak, the shape of the E(t) was found to be quite similar to an exponential decay of the following type.

(2a)
where t is time (s), E(t) is in nl/s, E{infty} is E(t) at the end of the humming period (nl/s), A is a constant (height of NO peak minus plateau E{infty}) (nl/s), and {tau}W is the time constant of the NO wash out (s).



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  		Fig. 2. Nitric oxide (NO) concentration, flow rate, and NO emission. ppb, Parts/billion.

 
The reason for this shape is explained later on in DISCUSSION. To determine the time constant {tau}W for the eight different subjects, a computer program for nonlinear curve fits was used to fit an exponential decay (first order) to the E(t). It was possible to determine the decay constant for six of the eight subjects. The E(t) of two subjects could be distorted by a small and fast oscillating flow rate during humming. It was not possible to fit an exponential decay to those curves (subjects 1 and 3 in Fig. 3).



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  		Fig. 3. Time constant of NO washout ({tau}W). Values are means ± SD.

 
The decay constant of the subjects is depicted in Fig. 3. The mean value of the "washout time" {tau}W is 3.0 ± 1.2 s. We have checked the reproducibility of this constant for one subject. The time constant of subject 6 has been measured once on 2 different days. Both values are the same within the error bars of the measurement.

The voice frequency of the subjects has almost been constant during humming. An influence of different frequencies to the NO output has not been investigated. When altering the frequency, phenomena-like resonances might have an influence on the volume of NO that is released by the sinuses.

Second part: time constant of NO recovery.   In the second part of the study, the peak height maximum of the E(t) (Emax) during humming after the Tr was determined [Emax(Tr)]. The correlation between this peak height and the Tr of NO recovery is given as an example for one subject in Fig. 4. For all five subjects, an increasing maximum NO concentration and emission was found when the time Tr between the initial and the subsequent humming process was increased. The data points can also be interpolated by an exponential function similar to Eq. 2a.

(2b)
where Tr is in seconds, Emax(Tr) is in nl/s, Emax{infty} is equilibrium concentration (nl/s), A is maximum deviation from the equilibrium (A < 0) (nl/s), and {tau}R is time constant of the NO recovery (s).



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  		Fig. 4. Regeneration of the NO emission, E(t). Values are means ± SD.

 
In this case, the function Emax(Tr) continuously increases, and, as a result, A < 0 in Eq. 2b. The constant A indicates the maximum distance (at Tr = 0) from the equilibrium concentration Emax{infty}. The Tr constant {tau}R is much higher compared with the time constant {tau}W, which characterizes the washout. The data points and the error bars for each subject, as shown in Fig. 4, are given by the mean value and standard deviation of the repetitions of measurements for each breathing cycle (2, 3, or 4 times). The Emax(Tr) at the recovery time Tr = 0 is defined as the constant rate of emission at the end of a long humming period (t ≥ 15 s).

The mean value of the time constant {tau}R is 4.5 ± 3.4 min. This value is much higher compared with the decay time {tau}W observed in the first part of this study (~90 times higher).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The temporal shape of the NO concentration and the emission during humming show characteristic patterns, which contain information about the NO production and reaction in the paranasal sinuses and also the mechanism of NO emission. In the following section, four characteristic properties of the measured signals will be discussed. 1) A rapidly increasing NO concentration and NO emission occurs when the subjects start humming. 2) After the initial maximum, the E(t) starts to decrease with a shape of an exponential decay. 3) At the end of a humming period, the E(t) is almost constant and does not go down to 0 nl/s. 4) The height of the initial peak depends on the previous time period Tr when no voice-induced emission takes place.

The increasing NO concentration (characteristic 1) is induced by the sound waves, which lead to the ventilation of the NO-filled paranasal sinuses through the ostia (11, 12, 19).1 In previous studies, the normal NO concentrations in the paranasal sinuses have been determined to be 9.1 ± 3.8 ppm (10), which is much higher than typical concentrations in nasal breathing (13).

In the same way as air with a high NO concentration is expelled from the sinuses, air with a low concentration streams through the ostia into the closed volume. This effect causes a dilution of the high NO concentration in the sinuses, and thus the measured NO emission decreases (characteristic 2). The exponential shape will be explained in the next section.

The NO production in the paranasal sinuses (and the upper airways in general) persists also during voice-induced gas exchange. NO, which is produced by the epithelium in the sinuses, is washed out into the nasal cavity in a very short time by the voice-induced air flow. This might explain the finite E(t) at the end of the humming period (characteristic 3).

After the stored NO is removed from the paranasal sinuses, the concentration is rebuilt again. The longer the time without a fast ventilation of the paranasal sinuses, the higher the NO concentration in the sinuses (characteristic 4). The concentration will finally reach a maximum. NO is a very reactive gas. If the rate of NO production and reaction at the epithelium are the same, the concentration does not increase.

Model of the paranasal sinuses.

All of these findings have been combined into a very simple one-compartment model of the paranasal sinuses. This model should help to explain the reasons for the typical dynamics of the NO concentration and emission. The prediction of the shape of the NO emission derived from this model is a good fit of the measured results of the two studies. It can also be shown that a three-compartment model that describes exactly the geometry and anatomy of the NO gas exchange dynamics in the paranasal sinuses does not improve the results of the studies.

In the model, the paranasal sinuses have been considered to be only one volume with a small opening (Fig. 5). In this cavity, a constant NO production by the walls (epithelium) takes place, which leads to the following change of the NO concentration in the paranasal sinuses [Ci(t)].

(3)
where Ci(t) is in nl/l, and rP is rate of NO production of the epithelium (nl·l–1·s–1).



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  		Fig. 5. One-compartment-model of the paranasal sinus. F(t), flow rate; Ca(t), NO concentration outside the sinuses; Ci(t), NO concentration in paranasal sinuses.

 
In addition to the NO production of the walls, NO reaction also takes place. Chemical reactions remove the NO in the cavity. If we consider only chemical reactions of first order, the NO concentration is influenced in the following way (17).

(4)
where rR is rate of NO reaction (s–1).

If a sound wave is directed to the opening of the cavity, the volume is ventilated and air streams into and out of the volume. The change of the NO concentration is given by the following equation.

(5)
where rH is E(t) induced by humming (s–1), and H(t) is 1 or 0 (voice induced emission on/off).

H(t) is a function that equals 1 or 0 and indicates whether the subject is humming or not. If we combine all of the parts (e.g., sum of NO production, reaction, and expression), the following differential equation is derived.

(6)
with {beta}S = dCi/dt, rP = RP/VS, rR = RR/VS, and rH = TS/VS, where {beta} is capacitance coefficient of the gas phase, S is the NO partial pressure (Torr) of the PO sinus, RP is NO production (nl/s), VS is volume of the sinus cavity, RR is NO reaction (nl·s–1·mmHg–1), and TS is transfer factor of the paranasal sinus (nl·s–1·mmHg–1). Equation 6 is identical to the differential equations obtained by a one-compartment model (2, 5, 16) specific to the airways and alveolar regions.

A solution of the differential equation can be derived in every continual time interval {Delta}tn of the function H(t) [e.g., in all time intervals {Delta}tn when H(t) = 0 or H(t) = 1]. The solutions for Ci(t) and the NO emission are given by the following equations.

(7)

(8a)
where Ci,n(t) is NO concentration in the sinuses during {Delta}tn, An and Bn are constants in {Delta}tn (nl/l), E(t) is in nl/s, and VS is in ml.

If humming takes place [H(t) = 1], the solution of Eq. 6 equals the exponential decay in Eq. 2a. The differential equation (Eq. 6) also contains the rebuild of NO in a period when no ventilation of the paranasal sinuses takes place [H(t) = 0]. The maximum concentration of NO in the paranasal sinuses is determined by the equilibrium of NO production and NO reaction; the E(t) at the end of a humming period; and by the equilibrium of the NO production, reaction, and ventilation.

Theoretical deduction of physiological parameters from the measured signals of E(t).

Figure 6 shows a measured signal of the exhaled NO concentration and also a signal that has been calculated by using the differential equation Eq. 6, a numerical method, and a smoothing algorithm to simulate the resolution in time of the LMRS. The comparison of the measured signal and the calculated NO concentration indicates that the simple model yields the characteristic features of NO dynamics, which have been found in the experimental part.2



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  		Fig. 6. NO signals. Measured and calculated signals are shown.

 
Even if the model is based on some significant simplifications of the NO production and transport mechanisms and also does not take into account the detailed physiological properties of the sinuses, the result of the theoretical model is very close to that of the measured signals.

Now the most important question is how we can derive the physiological parameters rP, rR, and rH (rate constants for NO production, NO reaction, and NO washout, respectively) from the measured signals of E(t). The model gives us some ideas how to answer this question.

The following section describes a theoretical way how we can deduce these parameters. The validity and reliability of these results remain to be proved through further clinical research.

First we shall prove that Eq. 7 fulfills the requirements of the differential equation Eq. 6. The derivative of Eq. 7 is:

(9)

(10)

Equation 10 fulfills the differential equation Eq. 6 with the following analogy

(11)

(12a)

(12b)
In a period when humming takes place [H(t) = 1], the time constant {tau} of the exponential decay of Ci(t) is determined by the parameters rR and rH. The faster NO is released from the paranasal sinuses, the faster is the decay of the concentration Ci(t) and also the faster the decay of the E(t), which is proportional to Ci(t).

In a period when no humming takes place [H(t) = 0], the time constant of the NO recovery is determined only by rR. The lower the NO reaction, the slower the NO recovery takes place.

At the end of a long humming period or after a long Tr, Ci(t) is constant, and the derivative equals zero.

(13)
Equations 10 and 13 indicate that the constant Bn equals the NO concentration at the end of a humming period [H(t) = 1] or the concentration after a long time of regeneration [H(t) = 0].

From Eqs. 11, 12a, and 12b, we get the following result

(14a)

(14b)
This result shows that the NO concentration, and also the NO emission, after a long humming period or a long Tr is proportional to the rate of NO production.

The model states that, if we measure E(t) in a period when the subject is humming and also after different Tr values, it is possible to calculate the rR and rH. This can be done in the following way. The time constants {tau}W and {tau}R (washout and regeneration, respectively) can be explored from the measured data by applying a program for nonlinear curve fits to E(t). Alternatively, the classical method of a linear interpolation of the logarithm of the function E(t) can be used.3

The first step is evaluation of {tau}W and {tau}R. The second step is

(15)

(16)

The model states that we can determine the individual constants rR and rH just by measuring the washout time and Tr. We do not need any information about the size of the ostia to get these constants. If we also have the information about the VS and the E(Tr -> {infty}) after a long Tr, we can also determine the rP (Eqs. 8, 14a, and 14b). The fourth step

(17)
Alternatively

(18)

The model predicts that the time-resolved NO measurements yield the information about parameters, which precisely describe the NO production, NO reaction, and the NO washout in the paranasal sinus. This method requires a minimum of input data and measurements to deliver these values. Calculated values for the parameters rW, rR, rH, rP, and RP are presented in Table 1 using a constant sinus volume (VS = 0.0293 liter, sum of sinus frontalis and sinus maxillaries, Table 2) for all test persons. A comparison of the calculated values for the rate constant rP with the invasively measured NO liberation rate RP shows good agreement (6), considering that the liberation rates correspond: rP = RP/VS.


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  		Table 1. Calculated values of the NO rate constants (Eqs. 15–18)

 

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  		Table 2. Physiological values for paranasal sinuses (18)

 
This is a practical example for noninvasive determination of physiological parameters in paranasal sinus that up to now could only be determined invasively. Individual variations of the sinus volume can influence the values of the parameters; therefore, additional determination of sinus size by noninvasive radiological techniques should improve the accuracy of the calculated values.

It is shown that the simple physical one-compartment model can be used instead of the commonly used physiological three-compartment model (2, 5, 16) specific to the airways and alveolar regions that have been developed to understand the physiology and the gas exchange mechanisms, leaving out the compartments that do not contribute to the temporal gas exchange.

The NO gas exchange in the paranasal sinuses can be modeled straightforward by a three-compartment model (Fig. 7), representing the tissue, the paranasal sinus, and the nasal cavity. Based on a mass balance for each compartment, the changes of the gas amount correspond to the sum of the in- and outgoing gas flows. Including a phase transition within the three-compartment model, the partial pressure has to be taken into account for the gas transport rather than the concentration gradient. Gas concentrations within the tissue are given by Henry's law, F = {alpha} x P (solubility coefficient x partial pressure). In analogy, a solubility coefficient {beta} for the gas phase is introduced. This leads to a set of three differential equations (Eqs. 20a, 20b, and 20c).



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  		Fig. 7. Three-compartment model of the paranasal sinuses. RP, NO production; PT, partial pressure of tissue compartment; RR, NO reaction; {alpha}, solubility coefficient for NO in water; VT, volume of tissue compartment; DT, diffusing capacity; PS, partial pressure of paranasal sinus cavity; {beta}, capacitance coefficient of the gas phase; VS, volume of the sinus cavity; TS, transfer factor of the paranasal sinus; PN, partial pressure of the nasal cavity; E, expiratory gas flow; VN, volume of the nasal cavity; PA, partial pressure of the airways.

 
For each compartment, the change of NO amount corresponds to the sum of production and consumption processes (Fig. 7). For the tissue compartment, this leads to the equation (Eq. 19):

(19)
where PT is partial pressure of tissue compartment (mmHg), {alpha} is the solubility coefficient for NO in water, which is 4.8 x 10–5 (nl·nl–1·mmHg–1), VT is volume of tissue compartment, T is temporal change of PT, T is gas flow of the tissue compartment, DT is diffusing capacity (nl·s–1·mmHg–1), and PS is partial pressure of the paranasal sinus cavity. With the condition T = 0, which means no gas flow within the tissue compartment, this results in Eq. 20a. With an identical boundary condition, gas flow of the paranasal sinus (S) = 0 and gas flow of the nasal cavity (N) = 0 for the other compartments, we obtain Eqs. 20b and 20c.

(20a)

(20b)

(20c)
where {beta} is capacitance coefficient of the gas phase, which is 0.00116 (nl·nl–1·mmHg–1), VS is volume of the paranasal sinus, PN is partial pressure of the nasal cavity, E is expiratory gas flow, PA is partial pressure of the airways, VN is volume of the nasal cavity, and N is the temperal change of PN. The general solution of the differential Eqs. 20a–20c is a sum of three exponential functions. Before solving the differential equations, we try to simplify the three-compartment model using physiological values (Table 2) for the volume and the dimensions of paranasal sinuses and nasal cavity. The surface of the sinuses is estimated by the surface of a cuboid with the given lengths of the sinuses.

With the thickness of the mucosa (0.02 mm), the volume of the tissue compartment of the sinus frontalis is about VT = 0.09 cm3, whereas the volume of the tissue compartment of the sinus maxilaris is about VT = 0.131 cm3.

A comparison of the time constants of the tissue and the paranasal sinus compartment yields

(21)

(22)

For the sinus frontalis, this results in VS/VT > 55.5 and {tau}S/{tau}T > 1,332, where {tau}S is the time constant of paranasal sinus and {tau}T is time constant of tissue compartment. For the bigger volume of the sinus maxillaries, the ratio becomes even VS/VT > 185 and {tau}S/{tau}T > 4,440.

Therefore, the tissue compartment either for sinus frontalis or sinus maxilaris can be neglected for the temporal behavior of the NO exchange, resulting in the following two-compartment model (Fig. 8).



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  		Fig. 8. Two-compartment model.

 
The measured expiratory flow rate during humming (Fig. 2) was about E = 250 ml/s. With this, the time constant for the NO changes of the nasal cavity is {tau}N = VN/E = 0.136 s. Compared with the measured and fitted NO washout time {tau}W, this results in a ratio for the time constants of

(23)
Under our experimental conditions, the nasal cavity is flushed so fast that the nasal cavity compartment can be neglected for the temporal dynamics of the exhaled NO.

This further simplification of the two-compartment model leads to a one-compartment model (Fig. 9), resulting in the differential equation (Eq. 24).

(24)
The ratio of the time constants (Eq. 23) is so big that the gas exchange TSPN is extremely small and, therefore, can be neglected (TSPN = 0). Together with PT = PS, we obtain Eq. 25.

(25)
Equation 25 describes the differential equation with humming (TS > 0), whereas the experimental situation for no humming is simply described with TS = 0. With {beta}S = dCi/dt, RP/VS = rP, RR/VS = rR, and TS/VS = rH, Eq. 25 becomes identical to Eq. 6.



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  		Fig. 9. One-compartment model.

 
Starting from a three-compartment model to describe the temporal behavior of the NO exchange of the paranasal sinuses during humming, we have shown that the experimental and physiological boundary conditions simplify the initial model dramatically to a one-compartment model.

Maniscalco and coworkers (12) suggested that the combination of nasal NO measurement with and without humming could be used to estimate the sinus ventilation and to separate nasal mucosal NO output from sinus NO in healthy individuals and those who are suffering from nasal diseases.

Our model includes the NO production, absorption, and washout in paranasal sinus and is less affected by the various factors that determine gas exchange between the sinuses and the nasal cavity. In addition to the recent analysis of the influence of these factors for NO exchange between sinus and nasal cavity (11, 19), this noninvasive method allows one to get information about the NO turnover in paranasal sinus and the dynamic of NO exchange. Up to now, models for production and absorption of NO were only described for the nasal cavity (1, 4).

For clinical purposes, however, the typical morphological deviations of some nasal diseases must be taken into account when observing the NO concentration inside and outside the sinuses. Many nasal diseases are accompanied by severe dysfunction of the paranasal ostia. So we may expect in nasal diseases with closure of the ostia (e.g., paranasal empyema) a lower or a zero NO washout (depending on the number of "switched off" sinuses) compared with healthy individuals (14).

Also paranasal polyps can lower the ventilated volume of the sinuses and may disturb exchange of gases. Besides this, we have to consider alterations of the pattern of expression of the different NO synthase isoforms and their activity during acute and chronic inflammations in the nasal cavity (7, 8, 14, 15).

On the other hand, after paranasal surgery, depending on the type of operation, the sinuses get a better connection to the nasal cavity. After radical paranasal surgery, we may expect a near-zero washout of NO during humming. Therefore, for clinical purposes, the value of this method depends considerably on endoscopic and radiological findings, e.g., computed tomography scan, as well as on the anamnesis.

In addition to patients with chronic nasal diseases, as mentioned above, many individuals can be observed who are suffering from recurrent and frequent acute sinusitis and other inflammations of the airways without showing typical anatomical explanations for insufficient ventilation of the nose, e.g., hyperplasia of the turbinates or deviation of the nasal septum. In these cases, a dysfunction of the mucosa (e.g., immotile cilia) and immunological variations (e.g., deficiency of immunglobulin A) may be assumed to be the pathogenic reason. Furthermore, constitutional low concentration of NO in the paranasal cavities, as found in patients with Kartagener syndrome, is thought to increase proneness to acute sinusitis (9). Because NO promotes the sterility of the paranasal sinuses, a simple, noninvasive diagnostic tool is required to determine the NO concentration in these patients in noninfectious intervals. The understanding of the washout kinetic of NO during humming and the LMRS method may represent a new, noninvasive possibility to determine and correlate individual differences in NO production with the propensity toward and frequency of paranasal inflammations.


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This study was supported by Grant Sonderforschungsbereich 334 of the Deutsche Forschungsgemeinschaft.


   ACKNOWLEDGMENTS
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The authors thank Paul L. Skidmore and Stefan Sonneberger for carefully reading this manuscript.

The E-mail address of L. Menzel is mail@lars-menzel.net.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. Bloch, Dept. of Molecular and Cellular Sport Medicine, German Sport Univ. Cologne, Carl-Diem-Weg 6, D-50927 Cologne, Germany (E-mail: w.bloch{at}dshs-koeln.de)

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.

1 A very simple experiment, which visualizes the effect of the sound-induced ventilation of a volume through a small hole, can be performed by using a simple glass bottle. The bottle must be filled with smoke and closed by a seal with a small hole. A stream of smoke comes out when the bottle is posed in front of a speaker, and the sound is switched on. When we analyzed the influence of acoustic resonances by tuning the frequency from lower to higher frequencies, we made the following observation. The effect of smoke emission does not appear at very low frequencies, and then starts and continues up to higher frequencies. No resonance frequencies could be observed. Back

2 An easy method to simulate the concentration Ci(t) can be performed by using a computer program like "Excel" and a numerical approach to find the right solution to the differential equation. We need three columns [time, H(t), Ci(t)]. First the time column is filled with values such as 0.00, 0.01, 0.02, 0.03 s,... ({Delta}t = 0.01 s). Afterward, the values of the H(t) column are defined [H(t) = 1 or 0], depending on the time when humming takes place or not. Then we assume an initial NO concentration (e.g., 10 ppm). The concentration Ci (t = 0.01 s) equals Ci (t = 0.00 s) + 0.01 s·{rP – Ci (t = 0.00 s) [rR + H (t = 0.00 s) rH]}, Ci (t = 0.02 s) = Ci (t = 0.01 s) + 0.01 s·{rP – Ci (t = 0.01 s) [rR + H (t = 0.01 s) rH]}, and so on. The shape of Ci(t) and E(t) can easily be calculated for the whole period of time. If we consider the NO from the sinuses to be the main source of NO during humming, the NO concentration outside the sinuses Ca(t) can be calculated in the following way: Ca(t) = E(t)/F(t). F(t) is the exhalation flow rate. Back

3 The time constant {tau} is the same in the function Ci(t) and E(t) because both functions are proportional to each other. Back


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