Pro: Most Climbers Develop Subclinical Pulmonary Interstitial Edema

Abstract

Introduction

Interstitial edema is the first appearance of water accumulation in the lung and has been reported to affect a large majority of otherwise healthy climbers during acute exposure to high altitude. In the following, we will review the hypoxia-induced changes of the main mechanisms implicated in the regulation of lung fluid homeostasis, the changes induced in lung physiology by interstitial fluid accumulation, and the diagnostic tools available to demonstrate the presence of interstitial edema at high altitude

Control of Lung Interstitial Water Volume

The air–blood barrier (ABB) hosts the capillary network whose surface area is ∼2000 cm²/g lung tissue. This incredibly high capillary surface area coupled to the extreme thinness of the ABB (0.2 to 0.3 μm) optimizes gas diffusion thanks to a functional setting that reduces to a minimum fluid filtration from capillaries to the interstitial space, as well as the volume of the extravascular water. The relative “dryness” of the lung interstitium is maintained by a subatmospheric interstitial pressure of ∼−10 cm H₂O (Miserocchi et al., 1990) that results from the balance between a relatively low water and solute permeability in the microvascular district and a powerful draining action of lymphatics When conditions of increased microvascular filtration are established, the lung, at variance with other organs, strongly resists the development of edema, thanks to several mechanisms that cooperate to keep at a minimum the volume of the extravascular fluid, and only allows its minimal increase (Miserocchi, 2009). A key role in buffering the increase in extravascular water is played by proteoglycans (PG) in two ways (Miserocchi et al., 2001a). These molecules are highly hydrophilic and therefore can bind excess interstitial water through their glycosaminoglycan chains, forming gellike structures whose steric hindrance allows the control of the permeability of the pores of the basement membrane and of the channels within the interstitial matrix where water circulates. The other important role played by proteoglycans reflects their macromolecular assembly as link proteins, assuring low tissue compliance. This mechanical feature represents the main line of defense against the development of edema. In fact, a minor increase in extravascular water volume (in the range of 10% of resting value) results in a remarkable increase in interstitial pressure (from ∼−10 up to ∼5 cm H₂O), which, in turn, counteracts further microvascular fluid filtration (the“tissue safety factor” against edema development) (Miserocchi et al., 2001a) This condition has been identified as interstitial lung edema and ought to be regarded as the main mechanism protecting the lung against the development of severe edema. The volume of the lung interstitial compartment is so strictly controlled that it is difficult to detect initial deviations from the physiological state; in practice, a great advantage in the physiological setting turns to be a disadvantage on a clinical basis because it prevents an early diagnosis of developing disease (Miserocchi, 2009).

In this regard, it is noteworthy to recall that in an experimental model of lung edema in rats, it was shown that reactance measured at low frequency (4 to 5 Hz) (an index reflecting the elastic properties of the tissues or the resistance of distal airways) decreased progressively and significantly with time when interstitial edema was developing, while water accumulation in the interstitial compartment was maintained steady within 10% of control value (Dellacà et al., 2008). Therefore, it was concluded that monitoring of reactance could have a potential use in clinical practice as an early marker of developing edema, before any change in lung compliance or alveolar fluid accumulation occurs.

Hypoxia Exposure in Experimental Animals

In an animal model, 12% oxygen exposure, roughly corresponding to 4300 m, lowered arterial Po₂ and Pco₂ down to ∼38 and ∼26 mmHg, respectively. Further, an increase in interstitial fluid content was witnessed by the progressive increase in interstitial pressure, indicating, in turn, a parallel increase in microvascular filtration. Biochemical determinations also demonstrated some degree of disorganization of the extracellular matrix, particularly at the expense of the PGs of the basement membrane (Miserocchi et al., 2001b; Miserocchi, 2007), a finding justifying the increase in microvascular permeability. The latter, together with the increase in cardiac output and capillary recruitment, represents factors increasing microvascular filtration. In vitro studies on endothelial cell grown in culture confirmed the increase in permeability of the monolayer on exposure to low oxygen concentrations owing to the opening of small intercellular gaps between contiguous cells. These phenomena are reversible (Parker et al., 1981; Ogawa et al., 1990; Yan et al., 1997).

Hypoxia Exposure in Humans

The point is this: how can we detect interstitial edema and which results are available from high altitude studies? The gold standard to assess extravascular lung water is the imaging technique. Chest roentgenography is sensitive for the detection of pulmonary edema, even if confined in the interstitial space (Anholm et al., 1999), but high-resolution computed tomography (HRCT) is more sensitive and specific. (Kazerooni, 2001). In fact, this technique can identify abnormal water content not recognizable by routine chest radiography in the lungs (Kato et al.,1996), thus allowing detection of early stages of pulmonary edema (Brasileiro et al., 1997). The results of chest X rays at high altitude show a variable percentage of interstitial fluid accumulation in the lungs, while, to the best of our knowledge, no HRCT studies at high altitude are available in the literature.

Recently, a new method to assess extravascular lung water has been developed using lung echocardiography. This method, based on the appearance of B-lines (also termed ultrasound lung comets), has shown good correlation with the findings of the chest X ray, HRCT, and the thermodilution technique. The results have also been reported to be significantly related to the wet:dry ratio of the lung tissue (Picano et al., 2006; Jambrik et al., 2010).

This method has been recently applied to monitor 18 subjects at different altitudes during the trek to the South Everest Base camp and has shown an increase in extravascular lung water in 83% of otherwise healthy climbers at 3440 m and in 100% at 4790 m. Data displayed a significant negative correlation with oxygen saturation, but no correlation with the contextually indirectly measured pulmonary artery systolic pressure (Pratali et al., 2010).

Therefore, the most recent imaging techniques allow detecting subclinical lung edema during high altitude exposure, which seems independent from an exaggerated increase in pulmonary artery pressure and the development of severe AMS.

An indirect method to assess interstitial edema is through changes in some lung function parameters. Lung function tests are the most available tool during high altitude research. The question is: which are the more sensitive tests to detect the consequences of interstitial edema in the lung and airways structure? Elastic properties of the lung reflect the mechanical features of the fibrillar component (collagen I and elastic fibers), as well as the viscous behavior mostly attributable to the nonfibrillar component (macromolecular assembly of the link proteins of the extracellular space, including the proteoglycan family). A minor component can also be attributed to the smooth muscles of the vessels and bronchi. Data concerning lung compliance are contradictory: some studies showed a decrease during high altitude exposure (Jaeger et al., 1979; Pellegrino et al., 2010), others did not find significant changes (Dehnert et al., 2010), and others showed an increase (Gautier et al., 1982). All these studies were performed in a limited number of subjects. It is important to know that, even in studies in which a significant decrease in compliance has been reported, no clinical sign of lung involvement has been found.

Another option is to consider the potential decrease in patency of the small airways owing to the development of interstitial edema. As is well known, small airways are more difficult to assess than central airways, so functional diagnosis of peripheral airways involvement continues to be a challenge. The spirometric index that has been classically proposed to indicate the involvement of the distal lung is vital capacity (VC). Indeed, many papers have reported a decrease in slow and forced vital capacity (FVC) both in the hypobaric chamber (Welsh et al., 1993) and in the field, at least in part attributed to the presence of interstitial edema (Mansell et al., 1980; Cogo et al., 1997; Mason et al., 2002; Compte-Torreo et al., 2005; Fischer et al., 2005). In one paper, a simultaneous decrease of FVC and electrical impedance tomography (EIT) was found at 3800 m. Because EIT is known to be inversely related to intrathoracic extravascular lung fluid, the data are consistent with the development of interstitial edema (Mason et al., 2003). However, the measurement of VC can also be affected by other changes owing to high altitude exposure, such as the transiently decreased respiratory muscle force (Deboeck et al., 2005; Fasano et al., 2007b). Further, if FVC instead of slow VC is measured, the effect of the reduced density of the air should also be taken into account. So it is clear that many potentially confounding conditions can make forced and slow vital capacity a less reliable tool at high altitude. The use of FEF25-75 raises the same problems, besides the fact that it has a high variability (Pellegrino et al., 2005). Therefore, it is clear that common spirometric parameters offer limited information with regard to the peripheral airways, and it thus seems necessary to move beyond them.

Among the available functional measures that can be employed to evaluate distal lung function, the two recommended tests are the nitrogen single breath (sbN2) and measurement of respiratory impedance by the high-frequency oscillation technique. With the first technique, it is possible to show, after analysis of the sbN2 wash-out curve, an increased closing volume or closing capacity, reflecting early closure of small airways (Macklem, 1988).

Closing volume has been reported significantly increased in 75% of almost 250 healthy climbers after arrival at 4559 m; the increase was higher in subjects with radiological evidence of interstitial edema (15% of the total). This fact has been interpreted to be owing to small airway compression on expiration by edematous tissue (Cremona et al., 2002). Similar results were reported by Senn and colleagues (2006) in the same setting and as being consistent with interstitial fluid accumulation, but not indicating a subsequent progression to clinical HAPE. The authors of this paper underline a very important point: the large interindividual variability, as demonstrated by the different extent and time course of the lung function changes.

More recently, Denhert and colleagues (2010) performed extended lung function evaluation in subjects at the same altitude and did not demonstrate any changes in any of the parameters measured. The conclusion was that there was no interstitial edema. It is not easy to explain why they were unable to reproduce the previous results. We do not think it could be owing to poor performance of the lung function tests in the previous studies. Probably, the proposed tests are not sensitive enough or too dependent on other high altitude or methodological factors.

The high-frequency oscillation technique measures changes in lung impedance during tidal breathing: at low oscillation frequencies (<5 Hz), lung impedance mostly reflects the resistance and viscoelastic properties of the small airways and of the lung tissue (Johnson et al., 2005; Contoli et al., 2010). A recent study (Pellegrino et al., 2010) reported a decrease in reactance in healthy subjects during exposure to 4559 m, confirming data previously obtained in experimental animals developing interstitial edema (Dellacà et al., 2008). Also in this study, a high standard deviation suggests a high interindividual variability. These results indicating the presence of interstitial edema are in line with other data (published only as an abstract) showing a significant decrease in reactance in healthy climbers during high altitude, but not in hypobaric chamber exposure to similar altitudes (Fasano et al., 2007a). It is noteworthy that in all studies the functional changes of respiratory parameters were only slightly related to the presence of AMS, both on the clinical level and from the Lake Louise questionnaire score, which, however, largely neglects respiratory symptoms to favor neural symptoms.

Taken together, all the reported data at both the experimental and clinical levels strongly suggest that exposure to high altitude induces an extravascular lung fluid accumulation that can probably be considered a “paraphysiological” condition that does not necessarily proceed to severe edema with alveolar flooding. In fact, interstitial edema is present anytime microvascular filtration is increased, because it represents the mechanism that protects against the development of severe edema; this is likely to be the case at high altitude. In general, interstitial lung edema ought to be considered as a sharp edge between tissue repair and manifestation of a severe disease. What characterizes HAPE-prone subjects is still under debate and is a topic for further research. Recent data have provided the evidence that, in chronic hypoxia, regional differences in the proneness to develop severe edema within the same animal can be justified by focal alterations in microvascular permeability, leading to a perturbation in interstitial fluid balance (Rivolta et al., 2010).

It is at present still difficult to compare the condition of interstitial lung edema, as defined from the experimental animal model, to humans. It is likely that a combination of techniques, such as more sensitive lung function tests and imaging, will be the most suitable approach to definitively demonstrate the presence of even a mild perturbation in extravascular water balance in the majority of subjects exposed to high altitude.

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