Having reviewed the processes that give rise to bubble formation after decompression, the discussion now turns to consideration of the potential pathological effects of those bubbles. As discussed earlier, bubbles may form from dissolved gas in blood and/or tissue, and this section considers their potential pathological effects within those broad ‘anatomical’ categories. The discussion further subdivides the consequences of bubbles forming in blood into those effects arising primarily because of the presence of bubbles in blood and those arising from their distribution in blood via the circulatory system.
Presence of bubbles in blood
The presence of bubbles in blood appears capable of activating reactive formed elements such as platelets and white blood cells, as well as inflammatory cascades such as the kinin, complement and coagulation systems. The means by which this occurs are not clearly established, but there are several possibilities for interactive activations involving known mechanisms. For example, platelet and coagulation activation can occur through exposure to foreign surfaces such as glass or to collagen beneath damaged endothelium. Bubbles may act in a similar way by acting as a foreign surface or by damaging endothelium, the latter having been demonstrated experimentally. Similarly, white blood cells can be activated by damage to endothelium.
There is rarely any obvious evidence of a role for these inflammatory activations in the pathogenesis of milder forms of DCS, although it has been suggested that constitutional symptoms such as fatigue and malaise may occur as a result. These processes may be important in producing specific serious manifestations. For example, one hypothesis for spinal cord injury that has been substantially demonstrated in an animal model holds that bubbles initiate coagulation in the epidural veins, thereby leading to venous stasis and a venous infarction in the spinal cord. Inflammatory responses may also be important contributors in severe or fulminant DCS. For example, disseminated intravascular coagulation can lead to a coagulopathy, and such patients may also develop severe haemoconcentration and shock secondary to the endothelial ‘leakiness’ that can follow inflammatory activations.
Distribution of bubbles in blood
It has been previously noted that bubbles forming from supersaturated dissolved gas first appear in the veins. In addition to any inflammatory responses and resulting harm that this may elicit (described earlier), these bubbles can be transported in the circulatory system to sites distant from their point of origin.
The most obvious target organ in the distribution of VGE is the lungs. As previously discussed, it seems that for the most part the lungs can tolerate and efficiently remove even grade IV VGE without obvious harm. However, on relatively rare occasions divers may develop symptoms caused by the arrival of VGE in large numbers over a sufficiently short space of time to exceed a poorly understood clinical threshold. The trapping of copious bubbles in the pulmonary vasculature can cause a significant rise in pulmonary artery pressure, a ventilation-perfusion mismatch and the various inflammatory changes described earlier. These events manifest as dyspnea, retrosternal chest pain and cough, a constellation of symptoms sometimes referred to as the ‘chokes’, but more correctly called cardiopulmonary DCS. Symptoms typically occur within the first 30 minutes after surfacing, but the natural history is variable. There may be rapid progression to hypotension, collapse and occasionally death, probably as a result of acute right-sided heart failure. There are also many stories of these symptoms resolving spontaneously, especially if oxygen is breathed, because this would markedly enhance the rate at which bubbles are eliminated from the pulmonary circulation. Not surprisingly, because the substantial numbers of VGE required to produce cardiopulmonary symptoms are predictive of a potential for distribution of VGE in to the arterial system (see later) and also of a strong provocation for bubble formation in tissues, it is not surprising that cardiopulmonary DCS is often followed by symptoms of other organ involvement.
VGE may also distribute into the arterial circulation via pulmonary shunts or a PFO as previously described. Little is known about the factors that promote pulmonary shunting of VGE, although formation of large numbers of VGE appears important, and experiments in non-diving situations suggest that exercise is a likely risk factor. One small study in animals also suggested that use of theophylline (a bronchodilator) reduced the efficacy of the lungs as a filter for VGE; however, whether this effect was via recruitment of shunts or another mechanism is unknown. Because these shunts appear to be dynamic and cannot be investigated easily, our knowledge of their role in DCS is poor, although they are potentially very significant.
The behaviour of PFOs is better characterized. As described earlier, some PFOs shunt spontaneously, and there are data suggesting that such lesions are the most significant in causation of DCS. Other PFOs require provocation to raise right atrial pressure sufficiently to open the communication. This can be provided by something as simple as bending and straightening, straining to lift something or possibly even coughing. Along with the Valsalva manoeuvre, all these provocations have in common the tendency transiently to impede venous return to the right side of the heart, thereby causing a brief exaggerated ‘rush’ of blood into the right atrium on termination of the impediment. This transiently increases the right atrial pressure and may open a PFO that is normally kept closed by the prevalent positive left-to-right pressure gradient.
The previously mentioned association between the presence of a PFO and cerebral, spinal, inner ear, and cutaneous DCS implies that the passage of small VGE into the arteries can injure these organs. How these small bubbles cause injury is uncertain, although there are several possibilities.
It is known that a large bubble or bubbles embolizing the arterial supply to the brain can interrupt flow sufficiently to cause ischaemic injury. Patients embolized by large aliquots of gas in iatrogenic accidents and pulmonary barotrauma events can develop stroke-like syndromes that are often multifocal (see Chapter 6). However, it is uncertain that bubbles in the size range that typically arise in the veins after decompression would cause such injuries. Unlike solid emboli, bubbles are known to redistribute through the microcirculation, and small bubbles are likely to do so very quickly. Therefore, it seems implausible that small VGE passing to the arterial system would cause large cerebral infarctions. When such lesions are seen after diving, there should be a high index of suspicion for arterial gas embolism secondary to pulmonary barotrauma.
Nevertheless, it is plausible that sufficient numbers of these small bubbles entering the cerebral circulation may result in dysexecutive symptoms such as cognitive impairment, memory impairment and confusion, which are often labelled ‘cerebral DCS’. Exactly how small bubbles do this, however, is not certain. One possibility that has some experimental providence is that the passage of small bubbles through the microcirculation causes endothelial disruption with consequent inflammatory changes such as the activation and accumulation of white blood cells (see Chapter 6). This can cause a secondary decline in blood flow with a consequent degree of hypoxia, perivascular infiltration by the formed elements of blood, the release of inflammatory mediators and the development of tissue oedema; all of which may inhibit or injure nearby neurons. The widespread occurrence of this sort of event in the cerebral circulation could explain the ‘global’ cerebral impairment typically seen in cerebral DCS.
OTHER VULNERABLE NEUROLOGICAL ORGANS
Neurological organs other than the brain, such as the inner ear and spinal cord, are almost certainly exposed to fewer arterial bubbles than the brain because of their markedly poorer perfusion, meaning that fewer bubbles will be carried to these organs. Paradoxically, these organs may be more vulnerable to ischaemic injury caused by small bubbles for the same reason.
Modelling studies have demonstrated that after a dive the inner ear, for example, remains supersaturated with nitrogen for much longer than the brain, which washes out excess nitrogen within minutes. Thus, if VGE cross a PFO 15 minutes after a dive and enter the basilar artery, most of them will distribute to the brain, and perhaps a few will find their way into the tiny labyrinthine artery. However, whereas those VGE distributing to the brain will distribute through tissues that are not supersaturated, those entering the inner ear microcirculation will be exposed to supersaturated nitrogen and will likely grow as this gas diffuses into the bubble. Thus, despite being exposed to smaller numbers of bubbles, the inner ear may be selectively vulnerable to ischaemic injury because enlarging bubbles will be more likely to cause flow stasis. This mechanism may help explain the repeated reports of an association between PFO and inner ear DCS (implying that arterialized VGE play a role) and the finding that these patients often present with only inner ear symptoms even though a much larger number of VGE must have distributed to the brain. Although less well studied, it is likely that similar mechanisms can be responsible for spinal DCS, which probably has inert gas kinetics similar to those of the inner ear. Moreover, irrespective of whether the bubbles grow from inward diffusion of supersaturated nitrogen, the spinal cord and inner ear circulations are almost certainly vulnerable to the same pro-inflammatory effects of bubble passage as described earlier for the brain.
Other than the finding that arterialized VGE are implicated, exactly how the arrival of small bubbles in the arterial supply to the skin precipitates rash and itch is uncertain, although it could conceivably involve all the mechanisms (ischaemic and inflammatory) mentioned earlier in relation to the brain and other neurological organs. Indeed, one histopathological study of the cutis marmorata form of skin DCS reported endothelial disruption and perivascular inflammatory infiltrates entirely consistent with bubble-induced vasculitis. Questions remain, however, such as the reason for the typical finding of a localized lesion (often on the trunk) when arterialized VGE must distribute widely to cutaneous vascular territories. As with the selective vulnerability of the inner ear to vascular bubbles, the answer may lie in differing levels of post-dive inert gas supersaturation making some areas of skin more vulnerable than others.
As discussed earlier, bubbles may form in tissues where the supersaturation conditions are favourable. Once formed these bubbles could cause harm through the following mechanisms: direct damage to immediately adjacent tissue; indirect trauma within any tissue displaced by the bubble (e.g. stretching or compression of axons in the spinal cord or a peripheral nerve); ischaemia caused by pressing externally on blood vessels; haemorrhage through disruption of nearby blood vessels; stimulation of pain receptors; and incitement of inflammatory reactions initiated by tissue injury.
The pathophysiological paradigm for DCS described earlier is summarized in Figure 10.7.
Multiple disorders in single organ systems
It will not have escaped the astute reader’s attention that in the case of some organs this discussion has proposed more than one way in which they can be injured by bubbles in DCS.
The most conspicuous example is the spinal cord, in which injury may be caused by: bubbles forming in the spinal tissue itself, by bubbles inciting coagulation in the epidural vertebral venous plexus and by bubbles formed in the veins distributing to the cord via a right-to-left shunt and the arterial circulation. It is emphasized that this is not self-contradictory and that in fact the spinal cord may be injured by all these mechanisms under various circumstances. The existence of these various forms of bubble pathology may help explain inconsistent results when divers with spinal DCS are recompressed. For example, failure to elicit any improvement may be explained by coagulation in the epidural veins that would not be expected to resolve during recompression even if the inciting bubbles were removed. In contrast, a brisk improvement soon after recompression could suggest that tissue bubbles pressing on surrounding structures were the main culprit because in this case bubble resolution could be expected to elicit some benefit.
The other important example is the inner ear, which, as previously described, may be injured either by bubbles forming within the tissues or by bubbles that have shunted from the veins and arrive in the arterial system. As explained, if these arterial bubbles arrive while the inner ear remains supersaturated with nitrogen, then they may expand as tissue nitrogen diffuses into the bubble. It is generally presumed that cases of inner ear injury arising during decompression from deep dives are most likely to be caused by bubbles forming within the inner ear tissue itself, particularly if symptom onset is temporally related to a switch from a helium-based breathing mix to air or nitrox. It is impossible to distinguish among disorders in cases arising after surfacing, but the strong association between such cases and the presence of a large PFO suggests that a significant proportion of them are caused by arterial bubbles.