The Thermal Hypothesis was a development of the earlier Airway Cooling Theory (Deal Jr, et al. 1979). The authors of the Airway Cooling Theory concluded that the magnitude of EIB was directly proportional to the thermal load placed on the airways, and it was the level of heat loss that determined the severity of bronchoconstriction. The Airway Cooling Theory was revised to the Thermal Hypothesis that developed over two main
studies (McFadden Jr 1990, Gilbert and McFadden Jr 1992). The revision of the cooling
18 theory to thermal hypothesis considers that airway cooling alone is insufficient to produce bronchial narrowing and that rapid rewarming is essential for obstruction to develop. It suggests that a thermal gradient must be present at the end of exercise. According to the thermal hypothesis, EIB is a vascular event involving vasoconstriction resulting from airway cooling during exercise, followed by a reactive hyperaemia when the airways re-warm on the cessation of exercise resulting in airway wall oedema (McFadden Jr 1990, McFadden Jr, Lenner and Strohl 1986). The subsequent narrowing of the airways is a direct response to these vascular events. The evidence came from a study that showed by preventing the airways from re-warming following exercise (breathing in cold air) the reduction in FEV1 was reduced from 25% to less than 10% in asthmatic participants (McFadden Jr, Lenner and Strohl 1986). McFadden and colleagues looked to strengthen the thermal theory in 1999 by comparing FEV1 before and after hyperventilation with either a warm or cold dry air to determine whether mucosal dehydration causes thermally induced asthma. Eight atopic-asthmatics performed isocapnic hyperventilation while breathing either dry cold (12.5 ± 2.7°C) or dry warm air (24.3 ± 0.7°C). FEV1 was measured pre and post each challenge, expired temperatures were continuously measured and water loss from the intrathoracic airways was calculated (Equation 1).
WL = ([Wci – Wce] . VE.
time) . 0.5
Equation 1. Water loss from the intrathoracic airways calculation Where WL is the volume of water lost to the environment in mg·L-1 air; Wci is the inspired water content in mg·L-1 air; Wce is the expired water content in mg·L-1; VE is minute ventilation in L·min-1; Time is the duration of the hyperventilation in minutes; and 0.5 is the percentage of water lost from the intrathoracic airways.
19 The researchers reported that the decrement in FEV1 was significantly greater when breathing cold air compared to warm air (%∆ FEV1 cold at 8 min post = 30.0 ± 4.7%, warm = 16.0 ± 4.7%; p = 0.01). Despite greater reductions in FEV1 during the cold condition, water loss was significantly less when compared to the warm condition (WL cold at 8 min = 4.8 ± 0.4 g, warm at 8 min = 7.1 ± g; p = 0.001), suggesting the decrement in FEV1 was temperature dependent. The authors stated that during the cold condition FEV1
decreased as water losses rose. However, the largest intrathoracic losses were associated with the smallest obstructive response (%∆ FEV1 cold at 8 min post = 30%, water loss = 4.7 mg; %∆ FEV1 warm at 8 min post = 16%, water loss = 7.1 mg; p = 0.002). The authors concluded that the water loss associated with hyperpnoea may promote EIB through an effect on the cooling-rewarming gradient rather than through airway dehydration. These conclusions supported previous work into the thermal hypothesis (McFadden Jr, Lenner and Strohl 1986, Gilbert, Fouke and McFadden Jr 1987). Early work by Gilbert and colleagues in 1987, found that after participants had cycled for 4 minutes breathing cold air (−16 ± 2°C), on cessation the airstream temperature increased rapidly, rising twice as fast in asthmatics when compared to non-asthmatic controls. They concluded that a reaction sequence consisting of vasoconstriction and airway cooling during exercise followed by a rapid re-supply of heat when exercise ceases was occurring, suggesting that a rebound hyperaemia may lead to airway oedema and EIB.
The thermal hypothesis assumes that an increase in the intra-airway temperature reflects an increase in the blood flow of the airways and that this provides a significant source of heat to the airways in rewarming them on cessation of exercise (Gilbert, Fouke
20 and McFadden Jr 1987). This theory has been challenged, with reports that changes in airway temperature are the result of a prolonged warming of the air in the alveoli as a consequence of flow limitations in asthmatics (Anderson and Daviskas 2000). Further, bronchial circulation is a very limited source of heat replenishment for the airways (Solway 1990), and represents only 1% of total cardiac output. Fundamental to the thermal hypothesis is the concept of vasoconstriction causing a reduction in bronchial blood flow.
Vasoconstriction is an unlikely response to inhaling hot dry air, and data from animal studies (Baile, et al. 1987) and humans (Agostoni, et al. 1990) demonstrate that there is an increase in blood flow, rather than a reduction when dry air is inspired. Those that developed the initial cooling and thermal theories (McFadden Jr, Lenner and Strohl 1986, McFadden Jr, et al. 1999, McFadden 1983) have acknowledged that bronchial blood flow increases with dry air hyperpnoea and have formally revised the thermal hypothesis. The theory now recognises that airway cooling associated with hyperpnoea will provoke an increase in bronchial blood flow in humans and is thought to regulate thermal losses and prevent tissue damage (McFadden Jr, et al. 1999, Kim, et al. 1996).
Bronchial circulation cannot be ruled out, and it has the potential to contribute to the pathogenesis of EIB. Bronchial circulation is an important source of water for the airways, and increases in osmolality of the airways causes an increase in circulation (Zimmerman and Pisarri 2000). The increase in bronchial circulation would not just increase the delivery of water to dehydrated airways in response to an osmotic stimulus, but would also aid in the clearance of bronchoconstrictive mediators (See section 2.2.1).
21 Previous research has produced findings that may not be explained by the Thermal Hypothesis. Severe EIB has still occurred whilst individuals have been inspiring hot dry air
(Aitken and Marini 1985, Anderson, et al. 1985) for example. Twenty out of twenty two asthmatic children recorded EIB after cycling for 8 minutes whilst inspiring hot (32-40°C) and dry (3-10 mg H20.L-1) air (Anderson, et al. 1985). Ten asthmatic adults exercised and recovered whilst breathing air at 36°C in an environmental chamber, yet they still had a mean fall in peak expiratory flow of 43% ± 18% (Hahn, et al. 1984). In another study, ten asthmatics and 10 control participants were exposed to 7 air conditions varying in temperature (−2 to 49°C) and relative humidity (10 to 100%). The authors concluded that dehydration and changing osmolality of the airways determined the level of bronchoconstriction as opposed to the thermal exchange (Aitken and Marini 1985).
Inhalation of hot dry gases has been shown to facilitate airway cooling too. It is thought that heat loss of the airways will always occur as a normal part of respiration and develops whenever the inhaled air requires transfer of heat and moisture to condition it (Zawadski, Lenner and McFadden Jr 1988). The Thermal Hypothesis cannot explain early findings that EIB severity was greatest when cold air (-10°C) was inspired both during and importantly for 4 minutes after exercise (Deal Jr, et al. 1979). In addition the Thermal Hypothesis does not implicate any involvement of the release of pro-inflammatory
mediators in EIB. If pro-inflammatory mediators were not involved then pharmacological treatments (see section 2.5) that reduce inflammation would be of no benefit. These findings are not compatible with the concept that the development of obstruction occurs due to cooling and rapid rewarming as proposed by the Thermal Hypothesis. In summary,
22 the weaknesses in the Thermal Hypothesis are that it does not include a role for bronchial smooth muscle, or inflammatory mediators in the mechanism of EIB.
In reviewing the Thermal Hypothesis literature there may be a number of errors in the research. The McFadden studies may have underestimated the level of water loss occurring within the airway so misjudged the importance of airway dehydration in EIB.
Moreover, the authors assumed that the expired air was fully saturated at its exiting temperature. Such assumptions have been questioned. Eschenbacher and Sheppard (1985) undertook studies of asthmatic subjects performing hyperpnoea of dry air at -20°C and +39°C. They found difficulties when measuring the expired air temperature when it was inspired at -20°C, as at -20°C, expirate would freeze and then condense on the thermocouple dampening the response time of the thermocouple. To overcome this, the authors completely separated the inspired and expired airstreams and measured both water and temperature during cold air hyperpnoea. The technical difficulties associated with measuring expired air temperature and water loss are likely to result in the very low expired air temperatures reported in the McFadden et al (1999) paper (Freed, et al. 2000).
The alternative hypothesis is the Osmotic Hypothesis. This was proposed as a result of the failures of the thermal hypothesis to fully elucidate the mechanisms behind EIB.