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Published ahead of print on March 12, 2004, doi:10.1164/rccm.200305-630OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 1224-1230, (2004)
© 2004 American Thoracic Society

Original Article

Hypoxia Suppresses Symptom Perception in Asthma

Danny J. Eckert, Peter G. Catcheside, Janet H. Smith, Peter A. Frith and R. Doug McEvoy

Adelaide Institute for Sleep Health and Department of Respiratory Medicine, Repatriation General Hospital, Daw Park; School of Molecular and Biomedical Science, Discipline of Physiology, University of Adelaide, Adelaide; and Department of Medicine, Flinders University, Bedford Park, South Australia, Australia

Correspondence and requests for reprints should be addressed to Danny Eckert, B.Sc. (Hons), Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, South Australia, Australia, 5041. E-mail: danny.eckert{at}rgh.sa.gov.au


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Any factor that inhibits the ability of an individual with asthma to recognize their symptoms appropriately may contribute to treatment delay, "near miss" events, and death during acute severe asthma. The purpose of this study was to investigate the effects of two common features of acute severe asthma—hypoxia and hypercapnia—on respiratory sensation. Sixteen individuals with stable asthma were exposed to three gas conditions (34 minutes each): isocapnic hypoxia (arterial blood O2 saturation of approximately 80%), hypercapnia (increase in end-tidal CO2 of approximately 5–10 Torr), or isocapnic normoxia on 3 separate days. The perceived magnitude of externally applied resistive loads, measured during each gas condition, was reduced throughout hypoxia compared with normoxia, and there was a trend for a progressive decline during hypercapnia. Within the 15-minutes postgas inhalation period, methacholine-induced symptoms of difficult breathing, chest tightness, and breathlessness, measured using modified Borg scales, were 25–30% lower after hypoxia compared with normoxia but were not reduced after hypercapnia. We conclude that 30 minutes of sustained hypoxia and possibly hypercapnia impair sensations of respiratory load and that the effects of hypoxia persist for at least 10 minutes after returning to normoxia.

Key Words: hypercapnia • bronchoconstriction • methacholine • dyspnea

Delay in seeking treatment during severe asthmatic episodes has been implicated as an important factor responsible for increased morbidity and mortality. Poor perception of the severity of an asthma attack has been proposed as a mechanism underlying treatment delay (1). Since the initial observations of Rubinfeld and Pain (2), several studies have demonstrated that individuals with asthma, particularly those prone to severe or near fatal asthma (1, 3–6), demonstrate blunted sensations to increased respiratory load. Therefore, any factor that suppresses respiratory sensation, be it an inherent persistent blunting of sensation or one that is acquired acutely, could expose patients with asthma to increased risk of morbidity or mortality (7).

Mild to moderate hypoxia, which occurs during most severe acute episodes of asthma (8, 9), has been demonstrated to have central nervous system depressant effects and can lead to impaired cognitive function (10). Central nervous system depressant effects of hypoxia may persist for up to an hour after removal of the stimulus (11). Recent research (12) in normal subjects demonstrated that 30 minutes of hypoxia (SaO2 of approximately 80%) depressed the perceived magnitude of externally applied resistive loads. These findings raise the possibility that individuals with asthma who may already have blunted respiratory sensations (1–6) could be further impaired in their ability to assess accurately the degree of airway obstruction during and after a period of hypoxia. This may in turn lead to treatment delays and an increased risk of asthma death.

Hypercapnia is a respiratory stimulant that enhances sensations of breathlessness and often accompanies life-threatening asthma (8, 9); however, there is some evidence to suggest that cognitive impairment occurs with moderate levels of hypercapnia (13, 14), although these findings are conflicting (15). The contribution of cognitive impairment to respiratory sensations during acute sustained mild to moderate hypercapnia in asthma remains unexplored.

We hypothesized that sustained moderate hypoxia would reduce respiratory sensations during bronchoconstriction in patients with asthma. We also hypothesized that sustained hypercapnia may lead to a relative depression of respiratory sensation. To test these hypotheses, the perception of dyspnea of subjects with asthma during methacholine-induced bronchoconstriction was measured immediately after 34 minutes of isocapnic hypoxia (SaO2 of approximately 80%) and 34 minutes of hypercapnia (change in end-tidal CO2 of approximately 5–10 Torr) and compared with an equivalent period of normoxia. The perceived magnitude of externally applied resistive loads was also compared during the three test gas conditions. Some of the results of this study have been previously reported in abstract form (16–19).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Nineteen stable individuals with asthma (5 males and 14 females) who satisfied the American Thoracic Society definition of asthma (20) gave informed written consent to participate in the study. Three women experienced nausea during hypoxia and were unable to complete the study. All patients were nonsmokers with a baseline FEV1 of more than 70% predicted. None of the patients used oral corticosteroids during or 3 months before the study, and none had required emergency treatment for asthma in the previous 2 years. The study was approved by the Daw Park Repatriation General Hospital and Adelaide University Human Research and Ethics Committees.

Study Design
A within-subjects study design was chosen. After a preliminary visit (see online supplement), test gases (isocapnic hypoxia, normoxic hypercapnia, and isocapnic normoxia) were administered for 34 minutes each on separate days approximately 1 week apart. Two methods were used to test for depressant effects of the test gases on respiratory sensations: First, during the gas exposures, patients rated the severity of a range of externally applied inspiratory resistive loads. Second, during room air breathing, immediately after each test gas exposure, respiratory sensations of difficult breathing, chest tightness, and breathlessness were quantified during methacholine-induced bronchoconstriction. Methacholine challenges were administered immediately after, rather than during, gas exposures to avoid potentially severe hypoxemia during bronchoconstriction coincident with hypoxic gas inhalation, combined with evidence that the central nervous system depressant effects of isocapnic hypoxia persist for at least 15 minutes after removal of the hypoxic stimulus (11).

Three Main Experimental Visits
Patients attended the laboratory in the morning after abstaining from caffeine, alcohol, stimulants, and all asthma medications for at least 24 hours. To characterize asthma stability during the preceding week, patients completed an asthma-control questionnaire (21). Pulmonary function testing, including spirometry and whole-body plethysmography, was performed at each visit. After 5–10 minutes of nasal room air breathing in single blind fashion and in random order, patients were presented with one of three experimental gases: either medical-grade air, hypoxic (fraction of inspired O2 of approximately 9%), or a hypercapnic gas mixture (medical air with a variable increases in CO2, approximately 150–600 ml · minute–1) for 34 minutes. A manual inspiratory bleed of CO2 was employed to maintain isocapnia during normoxia and hypoxia trials. During hypoxia trials, the inspired O2 fraction was adjusted as necessary to maintain SaO2 at approximately 80% (12). During the hypercapnia protocol, the inspired CO2 concentration was manipulated to mimic the biphasic ventilatory response observed during sustained hypoxia to allow comparisons between these test conditions controlled for drive (see the online supplement). SaO2, end-tidal CO2 (PETCO2), and minute ventilation were measured and carefully monitored throughout.

Externally Applied Inspiratory Resistive Loads
As described previously (12), five resistive loads (3.9 ± 0.1, 4.2 ± 0.1, 21.8 ± 0.3, 43.3 ± 0.9, and 74.4 ± 2.1 cm H2O · l–1 · second), were presented for a single breath, 12 times each in random order across the three 34-minute test gas conditions (see Figures E1 and E2 in the online supplement for circuit diagram and an example trace). The lower load was barely perceivable in most subjects, whereas the upper load would generally be rated as moderately severe to severe. The background resistance of the circuit was 2.42 ± 0.05 cm H2O · l–1 · second. Patients rated their perception of the severity of the loads using open magnitude scaling (12, 22). Perceptual sensitivity to loads during each gas condition was examined using both Steven's power function exponent (23) and the slope of linear regression analyses of perception scores versus inspiratory resistance and peak inspiratory pressure (PIP) (12). Because of a clearly superior fit to perceptual scores, PIP rather than external resistance was regarded as the primary measure of the respiratory stimulus during loading. Similarly, linear regression was superior to Steven's power function as a descriptive model of perception versus stimulus intensity. Consequently, the slope of the linear relationship between PIP and perception scores was regarded as the primary measure of perceptual sensitivity to external loads (see DISCUSSION in the online supplement for further detail). Recent data suggesting that linearity is the basic law of psychophysics (24) further support this approach.

Methacholine-induced Bronchoconstriction
Immediately after the 34-minute period of gas inhalation, patients underwent a modified Yan and colleagues (25) incremental methacholine bronchoprovocation test (see the online supplement for a detailed description). Briefly, saline, followed by methacholine doses associated with 5–10%, 15–20%, and 25–30% reductions in FEV1, was delivered using a handheld nebulizer. One minute after each inhalation, patients rated the severity of several components of dyspnea (difficult breathing, chest tightness, and breathlessness) using Borg category scales (26). Immediately after symptom perception assessment, two repeat measurements of FEV1 were performed. Three measurements of inspiratory capacity were completed before gas inhalation and after the maximal dose of methacholine to provide a measure of hyperinflation. Perceptual sensitivity under each gas condition was measured from the slope of the linear regression line that best fit the FEV1% decrement versus Borg category score relationship (27). For a detailed description see the online supplement.

Statistical Analysis
Analyses of covariance for repeated measures were used to compare decrements in inspiratory capacity and symptom perception scores between gas treatments, with the corresponding degree of airway obstruction as a varying covariate. All other variables comparing between-gas treatment effects were analyzed using analyses of variance for repeated measures. Significant analysis of variance effects and other multiple contrasts were examined using Student's paired t tests adjusted for multiple comparisons using the Dunn-Sidak procedure. Statistical significance was inferred when p < 0.05. All data are reported as means ± SEM.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Group baseline anthropometric, lung function, self-reported medication use, and methacholine cumulative provocation dose corresponding to a 20% fall in the postsaline FEV1 characteristics are displayed in Table 1 . Baseline FEV1 and asthma control were stable and did not differ between experimental visits (Table 2) .


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  		TABLE 1. Group anthropometric, lung function, medication, and pd20 characteristics

 

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  		TABLE 2. Main study baseline and bronchoprovocation characteristics||

 
During the hypoxic gas trials, SaO2 dropped rapidly within the first 5 minutes to 80.8 ± 0.6% and was maintained thereafter at 81.5 ± 0.6% (Figure 1A) . SaO2 was unchanged during normoxic and hypercapnic gas trials (98.5 ± 0.2% and 98.7 ± 0.2%, respectively). PETCO2 was slightly above baseline levels during normoxic and hypoxic gas trials (0.9 ± 0.3 and 1.5 ± 0.4 mm Hg, respectively). Mean PETCO2 did not differ between these two gas conditions (38.2 ± 0.7 and 38.0 ± 0.9 mm Hg, respectively, p = 0.769). During hypercapnic trials, PETCO2 was increased (Figure 1B) to stimulate minute ventilation and mimic the hypoxic ventilatory response (Figure 1C). Minute ventilation during these two gas conditions was higher than under normoxic control conditions (Figure 1C).



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  		Figure 1. Group SaO2 measured via pulse oximetry (A), end-tidal carbon dioxide pressure (PETCO2) measured at the mask (B), and minute ventilation (I) (C) during the three 34-minute gas trials. Values are means ± SEM (n = 16).

 
Perception of Externally Applied Resistive Loads ({psi}) during Gas Inhalation
{psi} Increased near linearly with PIP (Figure 2) . Although this relationship was well described by Stevens' power function {psi} = kPIPn (overall r2 = 0.930 ± 0.014, sum of squares = 21.8 ± 3.4) and was superior to that of Stevens' power function of resistance (SS p = 0.010), a linear model {psi} = aPIP + b provided a significantly better fit (overall r2 = 0.956 ± 0.006, sum of squares = 13.3 ± 1.9, vs. {psi} = kPIPn sum of squares p = 0.006). Consequently, we have based our primary between-gas and time comparisons on this model (see DISCUSSION in the online supplement for further justification). There was a significant effect of gas on the slope of the linear relationship (p = 0.019), with a lower overall slope during hypoxia compared with normoxia (see Table E1 in the online supplement) and a trend for a decline in slope over time during hypercapnia (p = 0.056; Table E1). Apart from a significant difference in the exponent for {psi} versus resistance between 1–5 minutes and 5–15 minutes during normoxia, there were no other differences in exponents or intercepts (k, b) between gas conditions or over time with perception expressed as a function of pressure or resistance (Table E1).



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  		Figure 2. Peak inspiratory pressure (PIP) versus the perceived magnitude of externally applied resistive loads ({psi}) during 34 minutes of isocapnic normoxia, isocapnic hypoxia, and hypercapnia. Values are means ± SEM (n = 16).

 
Inspiratory time during loaded breaths was prolonged with increasing load (1.81 ± 0.12 to 2.30 ± 0.02 seconds from smallest to largest load, p = 0.003). However, there were no significant differences in loaded breath inspiratory time between gases (p = 0.156) across time during gas inhalation (p = 0.788) and no interaction effects between load magnitude, time, or gas (p >= 0.103).

Bronchoconstriction: Perception of Symptom Intensity
Bronchoprovocation testing was completed within 15 minutes after gas inhalation. Time to complete testing did not differ significantly between gas conditions (Table 2). There was a significant decrease in SaO2 during bronchoprovocation, although the severity of desaturation was not statistically different between gas treatments (Table 2). Inspiratory capacity decreased after bronchoconstriction, but the decrease was not different between gas conditions, suggesting similar levels of gas trapping during methacholine challenges (Table 2).

With worsening levels of airway obstruction, patients reported more intense symptoms, and these relationships were significantly altered by gas treatment (analyses of covariance gas by FEV1 interaction; difficult breathing p < 0.001, Figure 3 ; chest tightness, p = 0.003; and breathlessness, p = 0.001).



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  		Figure 3. Perception of the intensity of "difficult breathing" versus the magnitude of methacholine-induced bronchoconstriction (FEV1, % of postsaline value) immediately after the 34 minutes of each gas treatment. Values are means ± SEM (n = 16).

 
For the symptoms of difficult breathing and chest tightness, the slope of the relationship between symptom score and FEV1 was significantly lower after hypoxia than after either hypercapnia or normoxia (Table 2). Symptoms after hypercapnia were not different compared with normoxia. For the symptom of breathlessness, the slope of the perception score–FEV1 relationship was significantly lower after hypoxia compared with that after hypercapnia, and approached statistical significance compared with the slope after normoxia (p = 0.076) (Table 2).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main finding of this study was that in a group of individuals with stable asthma, symptom perception during methacholine-induced bronchoconstriction was suppressed for at least 10 minutes after sustained isocapnic hypoxia when compared with equivalent periods of prior hypercapnic hyperventilation and normoxia. This finding was consistent for the specific dyspnea symptoms of "difficult breathing" and "chest tightness" and approached statistical significance for the symptom of "breathlessness." In the same subjects, perceptual sensitivity to externally applied inspiratory resistive loads, expressed as the slope of the linear relationship between perception scores and PIP, was decreased during hypoxia compared with normoxia. Although these effects were not apparent on the basis of Steven's power function analyses, Steven's function provided a significantly poorer fit. Furthermore, recent data favor linearity rather than Steven's power function as the basic psychophysical law (24).

Hypoxia is a clinical feature of moderate to severe acute episodes of asthma (8, 9). Initially, hypoxia stimulates ventilation via peripheral chemoreceptor activation. This is associated with sensations of dyspnea, either through increased intensity of respiratory motor command (28, 29) or heightened chemosensor activation per se (30). There is evidence to suggest that these responses may be impaired in asthma, particularly in patients with a history of near fatal episodes (1, 31). When hypoxia is sustained or repetitive in nature, there is a central accumulation of inhibitory neuroeffectors (32), which can result in depressive effects, such as centrally mediated depression of ventilation (32, 33) and cognitive function (10). These findings raise the possibility that hypoxia may cause a relative depression of respiratory sensation in disorders such as asthma. Research in healthy individuals provides additional support for this hypothesis. Lane and colleagues (28) reported that for equivalent levels of hyperventilation, lower scores of breathlessness were obtained during exercise with hypoxia than with exercise alone or exercise combined with hypercapnia. After 20 minutes of sustained isocapnic hypoxia (SaO2 of approximately 80%), Chonan and colleagues (34) demonstrated a reduced perception of dyspnea during a low-intensity exercise task compared with the early phase of hypoxia under resting conditions. This was despite ventilation during exercise being greater than during early hypoxia. The authors speculated that this sensory attenuation was due to central nervous system depression associated with sustained hypoxia. More recently and consistent with this hypothesis, Orr and colleagues (12) studying healthy subjects found that sustained isocapnic hypoxia (30 minutes, SaO2 approximately 80%) depressed the perception of externally applied resistive loads after several minutes of hypoxia compared with normoxic breathing. The slope of subject's respiratory sensation versus ventilation relationship has also recently been reported to be depressed with increasing hypoxia (35).

This study provides evidence that hypoxic depression of respiratory sensations also occurs in a population with asthma and that these depressant effects persist for at least 10 minutes after cessation of hypoxia. The persistence of central nervous system depression after hypoxia is consistent with earlier work in which depressed ventilatory responses to repeated hypoxic challenges were noted for up to an hour after a period of sustained hypoxia (11).

Perception of dyspnea and the underlying mechanisms responsible for respiratory resistive load detection is complex. Multiple sensory pathways (30) and several brain regions (36–38) are involved. Hypoxia increases central nervous system levels of specific neuroinhibitors such as endogenous opioids, adenosine, and gamma-aminobutyric acid (GABA) (32). Each has been implicated in blocking sensory pathways involved in the perception of pain (39–43). Although respiratory sensations are distressing rather than painful, similar hypoxia-sensitive pathways could potentially be involved. Hypoxia could disturb respiratory afferent pathways and neural processing at more than one level. Using an adult cat model, Zimmerman and Grossie (44) found that systemic arterial hypoxemia (less than approximately 80 mm Hg [SaO2 of approximately 92%]) had a depressive effect on afferent discharge of muscle spindles. However, the central nervous system has a rostral to caudal vulnerability to hypoxia (32) such that higher centers may be particularly sensitive to the inhibitory effects of hypoxia. Higgs and Laszlo (45) demonstrated an increase in perception of asthma after theophylline (a higher center and muscle function stimulant) administration in patients with asthma, providing some support for the importance of higher center pathways for sensations of dyspnea in asthma. In healthy individuals, acute hypoxia slows perceptual processing to auditory and visual stimuli (46–48). Patients with severe chronic obstructive pulmonary disease also appear to have abnormal auditory evoked responses, which is suggested to result from chronic hypercapnic–hypoxia exposure (49). Further studies are required to establish the sites of action and the neurochemical mechanisms responsible for hypoxia-induced blunting of dyspnea during bronchoconstriction.

Dynamic hyperinflation is a consequence of progressive flow limitation as bronchoconstriction develops and has been demonstrated to increase the perception of dyspnea (30). In this study, although inspiratory capacity significantly decreased (a marker of dynamic hyperinflation), there was no difference in the degree of hyperinflation after bronchoconstriction between the three gas trials. Thus, our results cannot be explained by differences in hyperinflation.

In support of our findings during bronchoconstriction, the subjects with asthma in this study showed a rapid and sustained decrement in {psi} for a given PIP during hypoxia. Using an identical protocol with similar resistances, the overall slope of the relationship between {psi} and PIP did not differ between normoxia and hypoxia when compared with the healthy individuals in our previous report (12) (see Figure E4 in the online supplement). However, in contrast to normal subjects who showed a delayed but progressive decline (12), individuals with asthma demonstrated rapid decrements in {psi} during sustained hypoxia. This may reflect an increase in susceptibility to the inhibitory effects of hypoxia. Webster and Colrain (50) recently demonstrated differences in respiratory and auditory cortical-evoked responses in adult patients with asthma compared with control subjects. Children with life-threatening asthma also appear to have altered neural processing of inspiratory load information (51). These findings suggest an underlying disturbance of cortical sensory processing.

An apparent trend for a gradual relative blunting of {psi} with hypercapnia may indicate different depressant effects on neural function compared with hypoxia. One possibility is that CO2 narcosis impaired cognitive function. Cognitive impairment has been shown in some previous studies (13, 14) but not others (15) at PETCO2 levels similar to the maximum PETCO2 values achieved in this study.

Methodologic Considerations and Implications
We measured asthma-induced symptom scores after test gas exposures and cannot therefore be certain whether our finding of reduced severity of "difficult breathing" and "chest tightness" after hypoxia would also apply during such a gas exchange disturbance if it accompanied, for example, an acute spontaneous asthma attack. Given our finding that sensation of externally applied loads, expressed in terms of PIP, were reduced during hypoxia, we think it likely that asthma symptom scores would be similarly affected. However, it must also be acknowledged that mechanical disturbances precede the onset of hypoxemia (52). Thus, any detrimental effects of hypoxia on respiratory sensation may be most evident relatively late in the evolution of an acute severe attack. If a patient with acute asthma is aware of breathing difficulties but with the advent of hypoxemia perceives improvement in symptoms, he or she may falsely conclude that the attack is abating. Approximately 15% of the population with asthma are known to be "poor perceivers" at detecting the mechanical changes associated with progressive airway obstruction (2). In the case of an acute severe episode of asthma, should the mechanical changes progress undetected and hypoxemia develops, such patients may be vulnerable to further hypoxic-induced suppression of respiratory sensation.

It must also be acknowledged that by controlling ventilation during hypercapnia to match that of hypoxia, hypercapnia decreased with time to relatively low levels, which limit the interpretation of this arm of the protocol. To assess definitively the effects of prolonged hypercapnia on respiratory sensation in asthma, a protocol consisting of sustained higher levels of PETCO2 may be more clinically relevant.

A further methodologic limitation of the study was that PETCO2 was not controlled precisely under the normoxia and hypoxia protocols. We think this is unlikely to have affected our conclusions. First, the rise in PETCO2 above eucapnic levels was small (1–1.5 mm Hg). Cognitive dysfunction does not appear to occur until a PETCO2 well above the levels encountered in the hypoxia and normoxia trials in this study (13, 14). Second, PETCO2 was not different during hypoxia and normoxia experiments. Another limitation of this study was that we did not measure minute ventilation or PETCO2 during bronchoconstriction and thus cannot determine whether the reduction in sensation of dyspnea resulted in a reduction in load compensation. There was slightly more desaturation (nonsignificant) during bronchoconstriction after hypoxia than after normoxia and hypercapnia; however, SaO2 is a relatively insensitive and imprecise measure of ventilatory adaptation to increased respiratory load. It would be interesting to know whether the reduced sensation of dyspnea resulting from prior hypoxia leads to a disproportionate fall in ventilation during bronchoconstriction.

The findings of this study suggest that individuals with asthma with apparently already blunted respiratory sensations may be further impaired by hypoxia to recognize increased respiratory load during times of airway obstruction. In this study, bronchoconstriction was limited to 65–70% of baseline. However, blunting of symptom perception could conceivably be much more pronounced at levels of obstruction typical of life-threatening episodes of asthma. Extrapolating the relationships established in this study to a postsaline FEV1 of 40% (i.e., corresponding to a moderately severe attack), patients would report "somewhat severe" to "severe" symptom intensities (approximately 4.6–5.0 Borg scale units) under normoxic conditions but only "moderate" symptom severity (approximately 3 Borg scale units) under hypoxic conditions. In acute asthma, CO2 retention could potentially play an independent role, further depressing symptom perception.

These findings reinforce the need for simple, accessible objective measures of lung function to assess asthma severity and to limit the reliance on symptom reporting. Preservation of oxygen saturation during acute severe asthma might be important in preserving symptom perception, preventing treatment delays, and reducing asthma morbidity and mortality.


   Acknowledgments
 
The authors are indebted to David Schembri and the Respiratory Function Laboratory staff at Repatriation General Hospital, Daw Park, South Australia, for their assistance with lung function measurements and to Thean Vlahakis and Paul Henshall of the Pharmacy Department for their assistance with preparation with the methacholine solutions. Dr. Lata Jayaram provided valuable advice on methods to assess asthma stability.


   FOOTNOTES
 
Supported by the Foundation Daw Park/Channel 9 Telethon and National Health and Medical Research Council of Australia.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: D.J.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; P.G.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; J.H.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; P.A.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; R.D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this article.

Received in original form May 9, 2003; accepted in final form March 11, 2004


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 DISCUSSION
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