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As mentioned in Section 2.2, carbon dioxide level plays a key role in the control of ventilation. Normal carbon dioxide levels are reported in various textbooks to be between 4.66 and 5.99 kPa (Esquinas, 2010; Murphy et al., 2009), with the lower threshold limit necessary to produce hypocapnia symptoms reported to be at 3.99kPa (Gardner, 1990; Rafferty et al., 1992). It has been suggested that ‘hidden’ hyperventilation is associated with asthma (Bruton & Holgate, 2005; Stalmatski, 1997). This theory has been given some support in studies that demonstrated hyperventilation symptoms in asthma patients. In a study by Thomas et al. (2001), 30% of the 219 patients with mild and moderate asthma were reported to have experienced symptoms of hyperventilation when

surveyed with the Nijmegen questionnaire.

The primary cause of a reduction in carbon dioxide is over-breathing or hyperventilation, defined as alveolar ventilation that is inappropriately high for the metabolic production of carbon dioxide (Gardner & Lewis, 2005a). This leads to a reduction in arterial carbon dioxide levels, which in turn leads to respiratory alkalosis and the paraesthesia sensation. High arterial carbon dioxide level is reported to have a bronchodilatory effect in healthy individuals (Scichilone et al., 2001), and a reduction in arterial carbon dioxide level can lead to bronchoconstriction. It has also been reported that asthmatic individuals are more sensitive to carbon dioxide level, so that a small change in carbon dioxide level is likely to lead to bronchoconstriction. Van den Elshout et al. (1991) studied the effects of hypercapnia and hypocapnia on respiratory resistance in both normal and asthmatic subjects. It was found that in

asthmatics, a reduction in end tidal carbon dioxide level of only 1kPa caused a 13% increase in airway resistance, while the same reduction in carbon dioxide level had no effect on healthy subjects. Conversely, an increase in end tidal carbon dioxide level of only 1kPa resulted in a significant fall in airway

resistance in both asthmatic and normal subjects. It currently remains unclear as to why airway smooth muscles in asthma patients are more sensitive to changes in carbon dioxide than in healthy individuals.

There is currently a lack of strong empirical evidence that demonstrates the association between clinical signs of hyperventilation and carbon dioxide levels. A recent review by Meuret and Ritz (2010) reviewed several earlier studies that documented a reduction of carbon dioxide levels in asthma patients (Hormbrey et al., 1988; McFadden & Lyons, 1968) and concluded that some asthma patients have reduced carbon dioxide levels. However, most of the reviewed studies were based on acute asthma or ‘symptomatic’ asthma populations. Hyperventilation and hypocapnia are well-recognised features of acute asthma (Bruton & Holgate, 2005; Osborne et al., 2000). It is not certain why carbon dioxide level has any clinically relevant pathogenic role during the stable period of the asthma.

The study by Osborne et al. (2000), described in Section 2.3.2, had also investigated whether carbon dioxide level can be correlated with

hyperventilation symptoms and respiratory parameters. The association between end tidal carbon dioxide and breathing rate was assessed using a Spearman rank correlation. A small but statistically significant difference in end tidal carbon dioxide was observed between healthy individuals and mild to moderate asthma patients (a difference of 0.39 kPa). No statistically significant correlations were found between end tidal carbon dioxide and other respiratory parameters, and the correlation coefficients were not presented. This study showed a small but statistically significant difference in end tidal carbon dioxide levels between healthy volunteers and mild to moderate asthma patients. It is currently unclear whether the observed small non-significant differences in respiratory parameters between the two groups were the reason for the reduced end tidal carbon dioxide level.

A small but statistically significant difference in end tidal carbon dioxide levels between healthy individuals and mild to moderate asthma sufferers (a

difference of 0.29 kPa) was also reported in a study by Delvaux (2002). A weak but statistically significant negative correlation (p<0.05) was found between end tidal carbon dioxide levels and ventilation (Pearson r = -0.37). The author

concluded that increased tidal volume was responsible for the reduced end tidal carbon dioxide levels. However, this result should be interpreted with caution due to the large number of correlation comparisons (over ninety), which

increases the chances of getting significant results by chance (a false positive, or Type I error). The correlation coefficient also demonstrated a weak

correlation between the two parameters. It therefore remains unclear whether increased tidal volume is associated with reduced end tidal carbon dioxide levels.

To date, a limited number of studies have been found that investigate the relationship between breathing pattern and end tidal carbon dioxide in severe asthma patients. If carbon dioxide level indeed plays a pathogenic role, it would be logical to hypothesise that altered carbon dioxide levels can also be

Sigh appears to be a vague notion; no universal definition of a sigh and of the ‘normal’ sigh rate could be found during the literature search. A wide variety of definitions for sigh in adults have been used in the literature. These include: twice the mean tidal volume (Wilhelm et al., 2001b); 2.5 times the mean tidal volume (Vlemincx et al., 2009b); three times the mean tidal volume (Bendixen et al., 1964); four times the mean tidal volume (Prys-Picard et al., 2006); and twice the mean inspiratory tidal volume (Wuyts et al., 2011). The reasons for these different definitions are unclear, since authors rarely report the rationale behind their choice of sigh definition in studies. In the author’s opinion, the variation is possibly due to the wide range of tidal volume recorded in different sample populations, so that a particular definition from one population might not be an optimal definition for another population. However, the lack of a working definition means that comparison between studies is difficult, as it cannot be certain whether the same results would be obtained if different criteria were applied.

As a result of the different sigh definitions, there is no universal agreement for the normal sigh rate within the literature. It has been suggested that normal healthy adults have a sigh rate of approximately ten sighs per hour (Fredberg, 2001). However, a different sigh definition is likely to result in a different sigh rate. When sigh was defined as twice the mean inspiratory tidal volume, sigh rates of ten sighs per hour (Wuyts et al., 2011) and eight sighs per hour (Vlemincx et al., 2010) were reported in healthy individuals. When sigh was defined as breaths greater than twice the expiratory tidal volume, a sigh rate of twenty-two sighs per hour was reported (Wilhelm et al., 2001b). The lack of an agreed definition within the literature makes it difficult to compare the sigh rates between different studies.

An increased number of sighs is commonly believed to be a contributing factor to altered carbon dioxide levels in some asthma patients (Gardner & Lewis, 2005b). The relationship between sigh breaths and asthma patients has not

been previously investigated. There are some studies that investigated sigh and carbon dioxide levels in patients diagnosed with panic attack disorder. For example, Wilhelm et al. (2001b) investigated sigh in a group of patients

diagnosed with panic disorder. The study recruited sixteen patients diagnosed with panic disorder, fifteen patients with generalised anxiety disorder and a further seventeen healthy controls. Tidal volume in a seated position was measured by respiratory inductive plethysmography, calibrated with the least squares method during a thirty-minute recording period. During the recording

period, participants were instructed to keep still with their eyes open. ETCO2

was measured via nasal prongs connected to a standard capnograph. The

mean levels of ETCO2, tidal volume and sigh frequency were calculated over all

breaths for each individual.

The results showed that the panic disordered group had a higher sigh frequency (0.7 sighs per minute) than both the generalised anxiety disorder group (0.47 sighs per minute) and the control group (0.36 sighs per minute). There was a

statistically significant correlation between ETCO2 level and sigh frequency in

the pooled results from all participants (r = -0.47, p<0.02). However, while the authors suggest that sigh is a contributor to altered end tidal carbon dioxide level, the correlation coefficient index suggests only a moderate correlation

between ETCO2 levels and sigh frequency despite reaching a statistically

significant level. This casts some doubt over the significance of the association

between sigh and ETCO2 level.

To date, there is only a limited number of studies that investigate the relationship between sigh and carbon dioxide level in the severe asthma population. A case study reported a difference in sigh rate in a patient with difficult-to-treat asthma after breathing retraining exercise (Prys-Picard et al., 2006). In the same study by Prys-Picard et al. (2006), breathing pattern at rest was monitored by respiratory inductive plethysmography over a five-minute period. The recording conditions and the position of recording were not

documented. The study reported that on average the patient had 1.2 sighs per minute over the five-minute recording period at baseline, and this was reduced

Picard et al. (2006) was higher than the number of sighs previously reported in healthy individuals. Tobin et al. (1983a) reported that healthy individuals aged between18 and 60 had one or no sighs during a fifteen-minute recording period. Therefore, the results of Prys-Picard et al. (2006) appear to suggest that some asthma patients may have a higher sigh rate than healthy individuals. However, the results from the study cannot be applied to a wider population due to the fact that that data was from a single subject case study, as well as the lack of reported inclusion and exclusion criteria. In addition, a direct comparison between these two studies may not be fair due to the differences in the definition of sigh. Prys-Picard et al. (2006) defined a sigh as four times larger than the mean tidal volume, whereas Tobin et al. (1983a) defined a sigh as three times the mean tidal volume.

2.3.5 Summary

The evidence to date suggests that carbon dioxide levels may play a role in the pathophysiology of asthma, since a lower carbon dioxide level has been

repeatedly observed in studies. While a low carbon dioxide level is likely to occur as a result of hyperventilation, existing studies have not reported an association between carbon dioxide levels and clinical signs of hyperventilation in terms of marked differences in tidal volume and respiratory rate between mild to moderate asthma patients and healthy controls during the stable period.

Sigh frequency has been proposed as a contributing factor to altered levels of carbon dioxide. To date, there are limited published studies investigating whether there is altered carbon dioxide levels or sigh frequency in severe asthma patients. If altered carbon dioxide levels and sigh frequency can be observed in severe asthma patients and sigh is found to be associated with altered carbon dioxide levels, it might then be possible to use these parameters as potential outcomes measures for intervention.

Variability is the term used to describe states of dynamic behaviour of a system, and can be defined as the amount of fluctuation within the system (Khoo, 2000). This study defines the term ‘breathing pattern variability’ as the level of

fluctuation of individual parameters within the overall breathing pattern. The existence of variability is assumed to provide the respiratory system with flexibility to induce changes to response to changing environmental demands. There is a growing body of literature to suggest that normal healthy respiratory patterns are characterised by breath-by-breath variability.