Decompression and Decompression Sickness Richard T. Mahon1 and David P. Regis*1 ABSTRACT: The ever-present desire of humankind to explore new limits introduced us to the syndrome of decompression sickness (DCS). This broad overview of DCS is aimed at its pathophysiology and basics of therapeutic strategies. After a brief explanation of decompression theory, historical vignettes will serve to inform the practical application of our increasing understanding of DCS risks. The pathophysiology, current practices, role of bubble monitoring, risk factors, and potential long-term effects of DCS are also discussed. The goal is to explain the current state of DCS understanding in the context of a robust observational and empirical history. However, DCS remains a syndrome consisting of a constellation of symptoms following a change in ambient pressure. Though great strides have been made, significant knowledge gaps remain. If the coming years advance the field even a fraction of what its predecessors accomplished, the health and safety of those who endeavor in the environment of changing pressures most certainly will be improved. Published 2014. Compr Physiol 4:1157-1175, 2014.

Introduction The ongoing pursuit of commerce, war, exploration, and recreation often puts one at odds with their surrounding environment. Such is the case with the field of decompression sickness (DCS). Historically, DCS has been a major source of morbidity (and mortality), with an incidence ranging from as high as 24% in Caisson workers in the 19th century; there are now less than 5 cases per 10,000 dives reported in modern day recreational diving. More than a century of empirical testing, astute observation, and serendipity has dramatically improved the safety of exposure to changes in ambient pressure. Though great strides have been made, DCS still occurs and large knowledge gaps surrounding its basic mechanisms remain. In this review of DCS, we set out to describe its pathophysiology (known and theoretical) as well as mitigation strategies. We intentionally excluded air gas embolism despite its potential catastrophic consequences since its pathophysiology is dramatically different than that of DCS. After introducing the syndrome of DCS, we will briefly review decompression theory, and then address unique environments associated with DCS. These examples will serve to demonstrate the historical struggle with this syndrome and how risk has been mitigated over time. Following that we will address pathophysiology, current practices, the role of bubble monitoring, risk factors, therapy, and potential long-term effects.

Manifestations of DCS DCS is part of the larger spectrum of hyperbaric related disease often referred to as Decompression Illness, which also includes arterial gas embolism (AGE). The two are delineated by their etiologies on the currently held premise that DCS is secondary to bubble formation of a supersaturated inert gas

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within the tissues and vasculature, while AGE is the direct introduction of bubbles into the arterial system secondary to pulmonary barotrauma and subsequent disruption of the alveolar/capillary interface (28, 144). DCS is generally divided in to two types. Type I consists of the classical ‘bends’ complaints of joint pain as well as cutaneous and lymphatic presentations. Type II DCS incorporates a myriad of cardiopulmonary and central nervous system (CNS) manifestations which are often described as mild (numbness, tingling, and paresthesias) or severe (overt cerebral, spinal, vestibular, auditory, and respiratory symptoms). While these classifications are part of a spectrum they can assist treating medical personnel with determining the type of treatment to be applied. Pain is the most frequently reported manifestation of DCS overall, with prevalence reported between 20% and 50% (28, 45). Symptom onsets can range from 10 min to 48 h after hyperbaric exposure with most presenting within 24 h (150). The most commonly affected anatomical locations include the limbs, particularly around the larger joints (knees, elbows, and shoulders), although a more recent Divers Alert Network report included the hands as well (29, 210). The usual presentation involves the insidious onset of dull aching pain that can only be localized to a general area, usually a peri-articular location. The individual may often ignore it initially (out of ignorance or denial) until the pain worsens to a point of intolerance despite attempts at conventional management. As seen from the caisson experience, many cases go unreported and * Correspondence

to [email protected] Medical Research Center, Undersea Medicine Department, Silver Spring, Maryland Published online, July 2014 (comprehensivephysiology.com) DOI: 10.1002/cphy.c130039 This article is a U.S. government work and is in the public domain in the U.S.A. 1 Naval

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will resolve on their own (104, 120). Type I DCS will normally respond rapidly to recompression and some have used this as a ‘test of cure’ to discern the pain of Type 1 DCS from musculoskeletal pain of other origins. Other less common Type I DCS disease includes cutaneous symptoms (∼ =3%) which can run the gamut from self-resolving pruritus with or without rash, to cutis marmorata which commonly presents as a progressive mottled erythematous pruritic/irritating rash that usually appears on the trunk and can be a harbinger of the more serious Type II DCS (56). Even rarer are lymphatic manifestations (50% at 21,200 ft and >70% at 22,500 ft and above. The lowest altitude report of DCS was a 5% incidence at 21,200 ft. However, DCS incidence abruptly climbed to 55% at 22,500 ft (227). Though the general role of oxygen to prevent DCS is detailed later, it is mentioned here because the use of oxygen prebreathing (OPB) to prevent DCS originated with altitude exposure and has been operationally employed since the 1940s. Oxygen changes the alveolar nitrogen partial pressure which in turn decreases arterial nitrogen tension (PaN2 ) and consequently nitrogen tissue levels. With 1 h of OPB before ascent to 25,000 ft DCS incidence decreases from approximately 90% to 40% during a 3-h observation period and time to DCS onset is delayed (225). Exercise during OPB enhances its benefit, presumably by accelerating nitrogen elimination.

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For an equivalent DCS risk, exercise allows for shorter OPB periods compared to the resting state (82, 221). However, the exact nature of the optimal exercise intensity and duration remains an area of controversy and study. In addition to the altitude achieved, the more rapid the ascent (such as with a sudden loss of cabin pressure) and the longer the duration at altitude clearly increase the risk of DCS. Furthermore, exercise at altitude increased DCS risk compared to seated rest (73,163). Though observational studies suggested increased risk in women, randomized controlled studies show that gender has no significant impact on altitude DCS risk (8, 222). Although some symptom patterns have changed over time, the most common patterns remained the same. Bends alone predominate at ∼60%; neurologic alone at ∼10%, followed by bends plus neurologic at ∼8%. Any combination of Type I and Type II symptom patterns constitute the remainder of case presentations (32). The majority of DCS at altitude involves joint pain and can be simply treated with descent and ground level oxygen (124). Immediate recompression therapy can be used for more severe symptoms (neurologic or cardiopulmonary DCS) or for symptoms not relieved by ground level oxygen (32, 124). An extreme form of hypobaric DCS is found in extravehicular activity (EVA). NASA defines EVA as beginning with depressurization of the airlock or space module, and ending with repressurization of the space module or airlock after crewmember ingress (149). As such, DCS risk is based on the internal pressure of the space vehicle and the pressure within the suit of the astronaut. The first space EVA was accomplished by the cosmonaut Alexei Leonov in 1965. This 24 min EVA was complicated by “ballooning” of his pressure suit preventing use of his chest mounted camera and potentially limited his ingress through the hatch of the Voshkod 2 spacecraft (166). Since then more than 700 EVAs have been performed, ranging from lunar walking, deep space EVAs, as well as space shuttle and space station excursions. In general, the EVA must have procedures in place to undergo exposure to reduced ambient pressure with minimal risk of DCS, all while working within a suit that allows enough mobility and dexterity to perform assigned tasks as well as provide cooling and environmental protection (189). Although no case of DCS has been directly reported after an American EVA mission to date, the risk of DCS in going from cabin pressure (generally 14.7 psi) to a common suit pressure (ranging from 4.3 to 5.6 psi; 22,000-30,000 ft) may be substantial (30). As in simple high altitude exposure, nitrogen elimination with OPB protocols have been aggressively studied and adopted to specific platforms. For example, space shuttle EVA procedures include a reduction in nitrogen pressure for 24 h, accomplished by breathing an oxygen enriched atmosphere (26.5% oxygen) and reducing cabin pressure, followed by an OPB period with continued oxygen breathing during an EVA. Whereas in the international space station (ISS), the OPB is begun while at the ISS internal pressure of

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14.7 psi and then continued after depressurization to 10.2 psi in an airlock and continued during the actual EVA. Despite the current success of these strategies in preventing DCS; as EVA missions advance to include ground exploration, construction and prolonged durations, DCS risk predictions as well as mitigation strategies will need to be modified. As with earthbound hypobaric DCS, it appears that the effects of OPB can be enhanced with exercise for EVA as well (221). However the specific timing, duration, and intensity of exercise may also influence DCS risk and is currently being studied (74). Additionally, the inability to fully simulate microgravity for earth-based studies limits direct applicability to the space environment. It is quite possible that exercise in microgravity would produce less micronuclei and thus be responsible for the lower incidence of DCS than would be predicted by earth-based studies. As space exploration increases, the nature of EVAs is likely to evolve and demand increased exertion (168), which may increase DCS risk (224). Further research into the effects of microgravity, workloads, and cardiovascular changes in space will be an ongoing need to maintain the aforementioned low DCS incidence in EVA (230).

VGE Detection and DCS Risk In the development of cures for any disease a reliable correlate of protection is preferred over testing against the disease itself so as to limit any risk to test subjects and the population for which the cure is to serve. This approach is even more crucial when the disease in question can be life-threatening. Such is the nature of bubble detection and monitoring for DCS. Doppler ultrasound has been used and refined by investigators for detecting VGE which are associated with, if not the direct cause of DCS (88, 178, 180-182). Furthermore, this technology along with newer visual ultrasound techniques has been shown to be useful in elucidating the role of microparticles (MPs) in DCS, as well as tracing the origins of bubbles (132, 152). The basic principle of any ultrasound monitoring is the generation of sound waves in the ultrasonic range (generally 2-10 MHz) by a transducer at a certain angle to the target of interest, and their reflection/scatter off the target back to a receiver (152). The difference in the frequencies generated and received is proportional to the velocity of the moving target. If a uniform medium, such as blood, is further perturbed by nonlaminar flow (particles of sizes other than red blood cells, etc.), then this scatter further changes the signal, with scattering intensity increasing as the sixth power of the radius of the scattering particle (152). Depth of penetration relies on transducer frequency, with lower frequencies in general penetrating more deeply (181). Similarly, the size of the target one wishes to detect relies on transducer frequency with higher frequencies providing finer resolution of smaller structures. Typical Doppler monitoring includes implantable perivascular cuff type transducer/receivers, catheter tip setups as well

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as noninvasive transcutaneous transducer/receivers for precordial and peripheral monitoring. Traditional Doppler scanning techniques use precordial screening of the right side of the heart for the collective return of bubbles from the periphery, then systematically follow the venous return from the heart to the periphery to locate the source (62, 181). Doppler ultrasound output would be in the form of audio or oscilloscope/“dopplergram” recordings with bubbles/VGEs manifesting as chirps or spikes, respectively (180-182). Two common methods for grading these outputs are the Spencer and Kisman-Masurel (K-M) codes (62, 182). Each is a 0 to 4 nonlinear grading system, meaning the grade number does not correspond linearly to the number of bubbles detected; a grade 3 could have 40 times the number of bubbles for a grade 2 (28). The system described by Spencer assesses the frequency of bubbles relative to the cardiac cycle with 0 being no bubbles and 4 being continuous bubbles throughout the cardiac cycle (182). Each grade for the K-M code consists of a three parameter code that is translated into the bubble grading score; the parameters include: bubble frequency similar to the Spencer system, percentage of cardiac cycles having a certain bubble frequency, and the third being the amplitude of the bubble signal (62). There is a body of data using this method to correlate general risk of DCS with bubble scores, especially at the extremes, but they are poor predictors of individual DCS risk. However, in most of the compiled data, the absence of VGE has a strong negative predictive value. Yet VGE detection, even the highest grades, only carries a DCS risk of approximately 10% for diving decompression (61, 64, 178, 182, 214). It is interesting to note that in contrast to diving, when a grade 4 was noted on decompression to altitude it had a 78% DCS incidence (208). This could indicate a difference in the populations sampled and/or a true difference in the bubble dynamics of altitude decompression versus diving decompression. Though purely speculative, going to altitude is essentially directly ascending from a saturation dive so one would surmise that the saturation state would produce more bubbles and DCS. Unfortunately, there are no good corroborating data of VGE scores and DCS after saturation diving which often uses helium instead of nitrogen as well. Although VGE have limited DCS diagnostic value following a single exposure, VGE scores from many exposures augment DCS incidence data by providing a quantitative measurement that appears to corroborate the often-subjective complaints seen in DCS (54). The more recent introduction of two-dimensional echocardiography to detect bubbles has further advanced the field of bubble detection. Eftdal and Brubakk have demonstrated the relative ease with which even untrained observers can use the technology with weighted kappa statistics of 0.85 and 0.77 for pig trans-esophageal echocardiogram images and diver transthoracic images, respectively (65). This is presumably due to the ability of the operator to use the cardiac images to more easily discern other heart sounds from bubbles which is not as easy with “blind” Doppler (28). While there

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is currently no gold standard for bubble grading, this offers a huge advantage over Doppler recordings that require up to a year of training and regular skill maintenance to be considered qualified; even just 6 months away from the lab has demonstrated diminished skill (172). Despite this, in qualified hands, the much less expensive Doppler is still comparable to the ultrasonic images for bubble grading with very good agreement when the subject is at rest (weighted kappa 0.86) but only moderate agreement (weighted kappa 0.45) after subject movement (28). While these ultrasonic techniques can detect intravascular bubbles they cannot detect static bubbles in tissue, which many hypothesize is the true origin of intravascular bubbles as even early experiments were unable to illicit bubbles in isolated animal blood (19, 100, 112, 113). Newer advances in ultrasound technology demonstrate the ability to detect static bubbles in tissue (21, 188, 229). Using dual-frequency ultrasound, Buckey et al. detected 1 to 10 μm bubbles (so-called microbubbles) in tissue whereby a pump frequency causes the bubble to resonate while the other is used as the imaging frequency and the subsequent detection is the sum and difference of these frequencies that the bubble emits (21,229). While still early in its development this technique has already demonstrated the ability to detect signals following both exerciseinduced tissue bubbles and bubbles from hyperbaric exposure (188, 229). In its current state, “VGE monitoring gives only a fraction of the total picture of what is happening in the body, but it is significant as it is the only objective and quantitative measure available to evaluate decompression stress” (140). While ultrasonic technology has advanced to the point that it has become a reasonable though conservative surrogate for determining overall risk, the days of using DCS as an endpoint for decompression table development have not quite drawn to a close because it does not convey a total or reliable picture. Though standardization of postdive assessment timing still needs consensus, its use for general DCS risk prediction, especially in field studies, is progressively broadening in acceptance (20).

Pathophysiology The disparity in VGE detection and DCS incidence illustrates gaps in our understanding of basic DCS mechanisms and that individual response to decompression “stress” is what actually determines DCS incidence. This is not to suggest that bubble formation be ignored. But sole reliance on the bubble leaves us only with a reasonable marker of disease risk that lacks the full explanation of DCS (66). Diving has been associated with a myriad of vascular and systemic reactions including endothelial dysfunction, platelet activation, complement changes and leukocyte activation (156). It is likely that differences in these parameters may explain the variability of DCS incidence and susceptibility.

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Vascular dysfunction

Microparticles

Vascular dysfunction from exposure to bubbles has been demonstrated in multiple studies with animals and humans. In the face of bubble contact, ex vivo endothelium demonstrates a calcium influx and a loss of mitochondrial function which appears mediated in part by stretch receptors (99,179). Ex vivo arterioles demonstrate less ability to vaso-relax after an injection of microbubbles, a finding that is abated with surfactant pretreatment (163,187). Similarly, pulmonary artery endothelial damage and loss of vaso-relaxation appear correlated with the presence of intravascular bubbles (155). Even, transient vascular dysfunction in the pulmonary artery was noted after bubble injection, despite lacking evidence of overt histologic endothelial damage (154). In intact animals, flourescein evaluation of retinal vasculature demonstrated vasoconstriction in arteries with and without observable intravascular bubbles (159). In humans, evidence of vascular dysfunction (decreased flow-mediated dilation) has been demonstrated after a single air dive that produced very few detectable bubbles, a finding that appears to be mitigating when breathing 100% oxygen during a dive (27, 131). In conjunction with endothelial dysfunction, white blood cell influx and other hematologic perturbations have also been demonstrated (154).

Recently, microparticles (MP) have lent the possibility of a unifying hypothesis to some of the mechanisms surrounding DCS. MP are 0.1 to 1 μm in diameter membrane vesicles shed from cells. In a murine model of DCS, MP increased with decompression stress and the mitigation of MP (particularly those arising from endothelial cells) appeared to decrease markers of tissue injury (196). Equally intriguing was the finding that MP isolated from decompressed rodents caused leukocyte activation and vascular leakage when they were injected into non-compressed-decompressed animals. Furthermore, MP that were stabilized or lysed prior to injection did not cause leukocyte activation or vascular leakage (240). How exactly white cell activation and MP relate to DCS in humans is just now being defined (157). Recent evaluation of MP in open water human dives showed an inverse correlation of MP with bubble scores, but a positive correlation with neutrophil and platelet activation (194, 198). Despite significant advances in basic physiologic understanding of DCS, “real world” mitigation strategies to manipulate these abnormalities and prevent DCS remain few. Though it is difficult not to implicate bubble formation in DCS, it is clear that a mechanistic explanation solely on bubble formation ignores a myriad of therapeutic targets. Further clarification of basic DCS mechanisms will improve safety and likely explain much surrounding DCS variability.

Coagulation and leukocyte function Bubbles are known to cause platelet activation in vitro and in animal models of DCS (200). Coagulation abnormalities in rodents correlated with DCS severity, and platelet activation with thrombi appears present in rabbits with DCS (164, 200). In humans, diving appears to be associated with platelet activation and activation of the fibrinolytic system with aspirin and dipyridamol mitigating some of these changes (4,157,161). However, there are no studies that directly relate this activation or mitigation to actual DCS (89). If one considers the presence of a bubble as foreign, then derangements in the immune system with decompression and DCS would not be surprising. Ward demonstrated susceptibility to DCS in rabbits based on complement activation (particularly in C5a) (216). When this concept was applied to humans undergoing arduous dives, individuals with evidence of complement activation in blood incubated with bubbles had a markedly higher incidence of DCS than in individuals with a lower level of complement activation (216). However, these results were not replicated by Hjelde who saw no evidence of C5a activity with decompression (106). Leukocyte activation also appears to have a role in DCS pathophysiology. Martin and Thom demonstrated evidence of leukocyte sequestration in rodents with DCS while Nossum et al. observed an influx of leukocytes in response to vascular damage (136, 154). Interestingly, Beta-integrin-mediated leukocyte adherence decreased with the use of 2.8 ATA of oxygen, which may further augment the benefit of oxygen breathing outside of its role in inert gas elimination (193).

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DCS Risk Factors The substantial variability in DCS susceptibility is evident in experimental trials, where only a fraction of subjects exposed to identical pressure/time/breathing gas history develop DCS. This variability appears to be both between and within individuals. A retrospective review of 240 subjects exposed to four or more altitude decompressions shows a substantial variation in relative DCS susceptibility, with some individuals experiencing more than twice the average incidence (225). Although not systematically reviewed, the same pattern has been demonstrated in diving studies. For instance “high bubbler” individuals who produce many VGE may be more susceptible to DCS than “low bubblers” (151). Thalmann noted, during validation of U.S. Navy decompression procedures, that some individuals are afflicted with DCS more often than others; these were considered to be at greater risk for permanent injury and discouraged from participation (191). In a review of altitude decompressions, a surprisingly large fraction (14%) was particularly resistant to DCS (225). However, as little detail is given on the number of exposures per subject, it is possible that those in the resistant group were exposed less often. There is clear evidence that individual susceptibility to DCS is not constant; in large decompression trials where the same subjects repeated identical exposures (separated by sufficient interval so as not to influence

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each other), it is typical for an individual to suffer DCS following one, but not other, exposures (53, 54). Individual risk factors based on anatomy, anthropomorphic traits, and gender to name a few, have been analyzed with variable results.

Body composition While not completely conclusive, of the variables mentioned, the one with the most available data is that of weight, and more specifically, body fat (BF). Based on the fact that nitrogen is up to five times more soluble than oxygen in fat, the main theory rests on fat acting as a nitrogen sink, which when decompressed, enhances bubble load via a steady, relatively slow release into the blood stream, enlarging the load/size of bubbles from other off-gassing tissues and thus increasing DCS risk; though others have suggested the role of actual fat emboli as well (11, 101, 127). Even in the early decades of hyperbaric research among caisson workers, it was anecdotally noted that larger workers seemed more predisposed to DCS (25,93). In one of the first controlled animal experiments Boycott and Damant demonstrated a positive association of percent BF content and DCS based on mouse and guinea pig work (25). Similarly, Antopol et al. were only able to induce DCS for the same profile in genetically obese mice versus normal mice in a number of different strains while Philp et al. showed a statistically significant (p < 0.05) higher risk for rats fed a prolonged (>6 weeks) high-fat diet versus normal controls (2,162). In human studies, Dembert et al. used a historical cohort to demonstrate that higher skin fold measurements in U.S. Navy divers, especially in truncal areas, put them at five to six times greater DCS risk than the general U.S. Navy diving population at the time (49). Webb et al. showed a similar correlation with altitude DCS but also included a cofactor of decreased VO2max (225). However, another retrospective cohort study using questionnaire reporting by Swedish male and female dive masters and instructors showed no correlation with any of the variables evaluated, including weight and BMI (96). This was despite showing a higher rate of DCS in their population versus other populations. Studies using VGE as a DCS surrogate are less compelling in terms of demonstrating increased bubble scores with increasing BF. Carturan et al. examined 40 male recreational SCUBA divers with Doppler ultrasound 60 min after a 30 min, 35 msw dive and found that age, weight, and VO2max had a far more significant effect on bubble scores than BF (37). A similar study 3 years later examined two different ascent rates followed by bubble monitoring at 10 min intervals post dive and showed that older, fatter and less physically fit divers produced more bubbles (38). More recently, Schellart et al. found no correlation of BF/BMI with increased bubble formation in two different studies, one of which included a theoretical model followed by a single dive profile in 53 male divers in support of their model outcomes (173, 174).

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Gender Along similar lines, females have been hypothesized to be at higher risk for DCS than males due to their relatively higher percentage of BF (36, 116, 167). Hart and Strauss also demonstrated via in vivo gas measurements on human volunteers that females release subcutaneous N2 more slowly than males, though values for muscle were similar (99). They theorized that this was due to differences in tissue perfusion, though no correction for BF was mentioned. Webb et al. used a prospective study of altitude DCS to show that it was BMI/VO2max and not gender that correlated with DCS risk; however, when evaluating bubble scores males had significantly higher rates of bubble formation versus females (226). Interestingly, their results indicated that females on hormonal contraceptives were at higher risk for DCS in the last 2 weeks of their menstrual cycle than those not on such therapy. Further corroborating these DCS findings is the retrospective cohort study of Swedish dive masters and instructors that showed no difference between males and females for DCS risk (96, 138). Therefore, while there are apparent physiologic gender differences, none currently have been shown to definitively contribute to DCS risk.

Age Similar to factors mentioned previously, many have found it difficult to separate the effects of age on DCS from other factors that are associated with aging, including increasing BMI/adiposity and the redistribution thereof, as well as diminishing VO2max . Dembert’s evaluation of U.S. Navy Divers did not show any increased risk for DCS based on age; similar conclusions were reached in a study of Swedish dive professionals, though the latter study did have a predominantly older age group (49, 53). In a retrospective database review, Sulaiman et al. showed a threefold increase for altitude DCS incidence for ages >42 years versus 18 to 21 years while other prospective and retrospective studies of altitude DCS showed no such trend (186, 222, 225). Among hyperbaric studies using VGE scores, a relationship of increased DCS risk with age and diminishing VO2max are collectively inconclusive as well (23, 34, 37, 38, 174).

PFO and DCS There has been much debate in the literature over the association of patent foramen ovale (PFO) and DCS, particularly Type II neurologic manifestations. A PFO is the remnant of an incomplete closure of the atrial septum after birth. Its patency is required and maintained in utero by a number of factors that permit the necessary physiologic right to left flow of blood that allows blood to bypass the fetal lungs thus shunting it to the placenta. Once ex utero the pulmonary vascular resistance decreases, resulting in raised left atrial pressure therefore closing the normal one-way valve system of the PFO. Based on

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autopsy findings and more recent echocardiography studies, it is estimated that between 20% to 33% of people asymptomatically maintain a PFO into adulthood with an average size of approximately 4.9 mm that increases with age (72,97). Most are asymptomatic because the average small size and normal physiologic left to right pressure gradient prevents any pathologic right to left shunting, though like DCS, there is an implication of PFO in cryptogenic stroke (98,190). The theory is that in the presence of a PFO, bubbles cause a reversal of the normal left to right pressure gradient allowing bubbles to bypass the lungs and directly access the arterial vasculature, causing paradoxical embolic events in the brain, spinal cord, and possibly skin (35, 80, 123, 143, 231, 234). As early as 1969 Fryer suggested that neurologic symptoms after diving could be caused by a PFO (170). However, it was not until the mid to late 1980s that real interest in the matter began; most likely coinciding with advances in echocardiographic techniques (19, 125, 143, 232, 233). Moon et al. demonstrated that despite a 37% incidence of PFO, the percentage of cases with severe neurological DCS and PFO was 61% versus only 5% in those without PFO (143). Wilmshurst further supported this finding by showing that despite a PFO prevalence of 24%, PFO was present in 66% of those presenting with neurologic DCS (232). A 1998 metaanalysis on divers with PFO and DCS by Bove noted that the odds ratio for having DCS with a PFO was 1.93 for all DCS, and 2.52 for type II DCS with 95% confidence intervals shown graphically to be >1; but they concluded that because the increase in overall cases is small (2.3-5.7 cases per 10,000 dives) routine echocardiographic screening was not justified (24, 47, 143, 232). Of note, Cross et al. did not show statistical significance, despite an arguably clinical significance, between the control (32%) and neurologic DCS groups (50%; p < 0.05). Cross’ group repeated their work with a larger sample size and found similar nonstatistically significant results (PFO with no DCS 32.7% vs. PFO with neurologic DCS 49.0%) (170). While there is much debate across papers over methodology, the preponderance of evidence suggests a valid association between PFO and neurologic DCS that is also corroborated by animal work (79, 170, 213, 214). Additionally, it appears that those with larger PFO’s (10 mm vs. 1-2 mm) as well as those performing more provocative dive profiles may also be at greater risk (129, 170, 231). Similarly a number of papers have shown an increased association with PFO and brain lesions on MRIs in divers (15, 35, 122, 123). Though the clinical significance for those who are asymptomatic is questionable, data on reduced events with PFO closure for those with symptomatic cerebral findings and findings of similar lesions in U2 pilots suffering from neurologic altitude DCS is compelling for clinical and subclinical consequences of these lesions (15, 117). Though findings in breath hold divers with PFO’s and neurologic DCS offer no additional insights (75, 238). Because dive table development to date is based on data from the general population with an average 25% to 30%

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incidence of PFO, and the apparently overall low impact on increased DCS risk in general, most experts do not recommend PFO screening prior to diving; it is assumed that their DCS risk is already incorporated into the dive tables by virtue of the fact that this population was used to develop them. However, those with known pre-existing PFO’s are counseled about the risks and successful closure is often a requirement for entry into military and commercial diving due to the higher likelihood of exposure to more risky, provocative dives (80, 170). Similarly, those who develop neurologic DCS or AGE should be referred for evaluation of a PFO because of the clearly demonstrated association between the two (80, 170, 203).

Dehydration and DCS Despite the perception and somewhat intuitive idea that dehydration is associated with DCS, very little in the literature consists of prospective controlled studies. It would make sense that dehydration would affect DCS risk due to a number of factors including reduced tissue perfusion and subsequent gas removal and/or through changes in bubble surface tension via hemoconcentration (72, 97, 98, 190). Furthermore, typical predive preparations are arduous and potentially challenge an individual’s fluid status, while water immersion is associated with increased intravascular volume and a subsequent naturesis. There are a few controlled trials that lend support to the dehydration/DCS theory, mostly in animals. In a rodent model, Philip describes a nonstatistically significant trend in DCS incidence between hydrated and dehydrated rats of 55% and 71%, respectively (126). However, a more recent study showed an opposite non-statistically significant trend for VGE detection in hydrated rats (mean bubble grade: 2.8 + 1.9) versus dehydrated rats (mean bubble grade: 1.6 + 2.2) (177). Though it should be noted that this latter study used a heliox saturation dive for its model which has been shown to affect bubble scores when compared to air and bounce dives (70). The use of a diuretic in swine significantly increased overall risk for severe cardiopulmonary DCS, and showed a trend toward increased CNS DCS while also demonstrating a quicker time to onset of cardiopulmonary symptoms and a trend toward more rapid death (70). The only available human data comes from a crossover trial of eight military divers that used oral prehydration with 1300 mL of a saline-glucose solution before a 30 msw for 30 min open water dive (77). The study demonstrated significantly reduced bubble activity via precordial Doppler monitoring with mean scores of 3.5 and 19.4 for prehydrated and nonprehydrated divers, respectively. Not surprisingly, there was a significant postdive plasma volume difference between the hydrated and nonhydrated groups. Based on the limited data available, there is only evidence to support the role of hydration in enhancing perfusion to diminish DCS risk. Furthermore, results have been mixed on the effects of hydration on inert gas washout in human

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subjects (6, 45). Though the trend is promising, the data are insufficient to elucidate the exact mechanisms involved. However, the predominance of evidence would suggest that proper hydration before a dive would reduce DCS risk.

Temperature It is reasonable to presume that environmental conditions influence DCS risk. A physiologically plausible mechanism by which temperature could impact DCS risk is by altering peripheral tissue perfusion and therefore gas uptake and washout. Indeed, whole body washout is increased in warmer water compared to cooler water (7). Only historic data are available for altitude DCS and suggests that cold exposure at altitude increases the risk (202). However, the importance of thermal status for diving was conclusively established by a trial that exposed divers to water temperatures of either 36 or 27◦ C. Compared to being cold throughout the dive, being warm on the bottom and cold during decompression increased DCS incidence to the same extent as doubling the bottom time while being warm during decompression decreased DCS incidence to the same extent as halving the bottom time (85).

DCS acclimatization There is evidence supporting acclimation to DCS via successive daily pressure exposures. A number of different tunnel projects examining hundreds of thousands of pressure exposures noted a drop in cases from the start of a project through the first few weeks (90, 120). Kindwall noted a drop from 8.6% the first week to just above 1% in the following week (120). Similarly, Golding et al. demonstrated a decrease over time with an incidence by week 2 to 3 that was 0.1% of that of the first day. This decreased incidence was associated with both the number of compressions experienced and the number of exposures at a given depth (90). Likewise, it was noted that de-acclimatization occurs when men were away from compressed work for a period of time, such as during strikes and holidays. Evidence from the literature also shows that shallower “work-up” hyperbaric exposures in the preceding days to a more DCS provoking no-decompression dive are protective (67, 169). Additionally, a retrospective database analysis of health outcomes in tuna farm divers showed evidence of acclimatization via Diver Health Scores (a scale of DCS symptoms and health status), but not to decompression stress itself (52). The search for definitive underlying mechanisms remains elusive, current theories fall into two general categories: (i) reduction of bubble formation and (ii) reduction of the host response to bubbles. These are not necessarily mutually exclusive and though there is no current evidence, the answer most likely falls along a spectrum of the two. It may even vary depending on a combination of variables including type and frequency of hyperbaric exposure along with other environmental factors in addition to individual physiologic variability. A recent example of exposure dependent response was

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demonstrated in rats where animals were exposed to different hyperbaric acclimatization regimens and evaluated by DCS incidence (142). Results demonstrated a trend for improved acclimatization to a provocative dive versus controls. Deeper “work-up” dives showed statistically significant improvement in DCS rate regardless of whether the rats did 4 or 9 work-up dives beforehand (169). A reduction of bubble formation has been demonstrated in inanimate systems as well as in animal and human studies. The theory being that by pretreating with higher pressures, pre-existing gas nuclei are forced into solution thus reducing bubble formation via gas nuclei reduction. Solutions and gels pre-treated with very high pressure exposures (from 20 to ≥1000 atmospheres) become resistant to further bubble formation; this was shown in shrimp and rodents as well (68, 100,121,184,207). Recreational divers showed a similar dose response. Monitoring VGE in 67 subjects and 281 dives during six different multiday (6-8 days) live-aboard trips demonstrated that while repetitive dives in a day increased high grade bubble scores by 53% (p < 0.001), multiday diving decreased scores by 25% (p < 0.001); scores were 20% higher for males than females. Older age groups for each sex had high-grade bubbles scores greater than their younger counterparts; 20% and 55% for males and females, respectively (61). Pontier et al. showed similar results for military divers pre and post a 90 day dive training period (165). It should be noted that neither of these studies had any DCS cases and that while a statistical correlation between high VGE scores and DCS has been described previously, a definitive association with VGE and acclimatization can only be inferred, even though bubble reduction is apparent. Likewise, evidence supports altered physiologic responses to repetitive daily hyperbaric exposures, most likely as a response to bubble formation. Hills demonstrated ex vivo passive relaxation in bovine and cadaveric cartilage and tendon exposed to hyperbaric pressure (105). A follow on evaluation of cytokines and gene expression in rat lungs exposed to repetitive diving showed significantly enhanced early growth response-1 (EGR-1) and TNF-α in control and acclimatized rats with DCS, versus acclimated animals without DCS (41). Elevated heat shock protein 70 (HSP70) levels showed a direct correlation with DCS incidence in rats and rabbits (107, 185). Furthermore, it was shown that prior heat shock treatment of rats attenuated bubble-induced lung injury and prior DCS exposure in rabbits reduced subsequent neurologic scores but neither reduced DCS incidence itself. This finding is intriguing in that HSP is increased by different stressors including endurance exercise (a mitigator of DCS) and has been associated with preventing tissue injury in other models as well as decreased bubble formation after diving when elicited by a pre-dive sauna (16, 71, 153). Complement activation has also been implicated in DCS acclimation, presumably through neutrophil activation and lung injury as demonstrated in rats (146). Studies in both humans and rabbits show variability to complement activation by bubbles that correspond to DCS susceptibility,

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and decomplementation of rabbits protects against DCS (146, 215-217). More recent work by Thom et al. further hints at this complex relationship between bubbles, DCS and MPs derived from leukocytes, erythrocytes, platelets, and endothelial cells in mice and humans exposed to decompressive stress (194197). It appears that it is only a matter of time before concrete mechanisms are established to explain DCS adaption and individual variability.

Exercise and physical conditioning Broome et al. demonstrated in swine that preconditioning prior to an arduous dive significantly reduced DCS in the experimental group (41.7%) compared to the sedentary control group (73.5%; p = < 0.015) independent of adipose content, age or weight (26). Physical conditioning as measured by VO2max was similarly shown to be protective against DCS in studies of altitude DCS, though this could not be completely separated from other variables including age/weight/BMI (222, 225). Likewise, VGE grading studies show similar correlations between VO2max in various hyperbaric scenarios further supporting the role of physical conditioning as a preventative measure for DCS (37, 38, 173). Fitness intimates some form of exercise on a regular basis. As such the influence of exercise before, during and after a change in ambient pressure would be expected to impact DCS risk. Exercise factors that would be expected to impact the risk of DCS would be the generation of micronuclei (229), nitric oxide (NO) generation, and obvious concerns with nitrogen uptake and elimination. As such, the effects of exercise would be anticipated to be different between altitude exposures and hyperbaric exposure. Though OPB certainly decreases DCS in altitude exposure; exercise while breathing air (deep knee bend) immediately prior to altitude exposure increases the amount of bubbles detected when subjects are decompressed to 22,000 feet. This finding was attributed to micronuclei generation and diminished the further the exercise was from decompression (50). During hypobaric exposure both mild and strenuous exercise increases the incidence of DCS and decreased the time to onset of DCS (223). However, it appears that moderate exercise after completing altitude exposure does not lead to DCS at ground level. After exposure to altitude that resulted in a 48% incidence of DCS (all resolving on descent) 31 subjects performed moderate exercise, with no cases of DCS occurring/recurring (226). The impact of exercise on diving, however, appears quite different. A single session of exercise training in rodents 20 to 48 h prior to a dive decreased DCS, where exercise just prior to a dive had no beneficial effects (235). Studies, of pre-dive exercise in humans from 2 to 24 h prior to a dive demonstrate decreased venous bubble formation (17, 59). A previous suggestion of no exercise immediately prior to diving has been met with a recent rebuttal, where 45 min of submaximal exercise immediately prior to an open

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water dive resulted in significant decrease in bubble detection (39). One postulate for the benefit of predive exercise centered on the generation of NO in decreasing micronuclei. Wisloff showed that NO inhibition (with L-NAME) significantly increased bubble formation and DCS in sedentary animals. More importantly, it was demonstrated that the increase in DCS was abated with a single exercise session 20 h prior to the dive (236). NO’s benefit was further supported when oral administration of a NO donor, both acutely and chronically, decreased DCS in rodents (237). It is not surprising then that a short acting NO donor in sedated swine immediately prior to decompression from 40 msw dramatically reduced bubble formation (139). This work was extended to humans demonstrating that a single spray of nitroglycerin prior to a 30 msw dive significantly reduced transthoracic bubbles (58, 60). During compression the increased metabolic rate of exercise consequently increases the amount of nitrogen absorbed (51). In various studies increased activity during “bottom time” have suggested an increased incidence of DCS. However, it appears that moderate exercise (50% maximum heart rate) during the decompression phase of a dive, or exercise during a decompression stop decreases bubble detection in the precordium and subclavian veins (59, 115). In opposition to altitude exposure, exercise after hyperbaric exposure seems to impart some degree of DCS risk. In 1949 Van der Aue reported a 34% increase in DCS in divers who lifted 25 lb weights immediately after no-decompression dives. This essentially lead to the recommendation of no exercise after diving (205). Recently exercise after diving increased the amount of bubbles detected in the arterial system (arterialization) by fourfold (133). Further work is needed to guide post dive exercise and DCS risk, as its pertinence to all diving communities is obvious.

Oxygen to Prevent DCS Oxygen use in decompression has been a consideration since the 1870s when Paul Bert first applied surface oxygen in some of his experimental models. While he considered the application of oxygen under increased pressure, he never pursued its study. Since that time oxygen use has advanced from a treatment modality for DCS to now demonstrating benefits in all phases of a dive. As a metabolically consumed gas, oxygen breathing allows for a difference between arterial and venous partial pressures. This difference in partial pressures then (in-part) is “filled” with inert gas, allowing its elimination from tissue (and bubbles) via exhalation. From this concept the term “oxygen window” was proposed by Behnke (12). Though present across all barometric pressures the “size” of the window affects the rate of diffusion of inert gas and is greatly influenced by the breathing mixture. While breathing air, the “size” of this window is greatest in hyperbaric environments; but the greatest percentage change in relative “size” while breathing 100% Oxygen is seen at altitude (206).

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The most common consideration for the use of oxygen under pressure, or hyperbaric oxygen (HBO), is in the treatment of DCS which will be addressed in a later section. However, recent developments have surrounded preventative strategies. One such modality is the concept of OPB. In the literature, OPB refers to breathing an enriched oxygen mixture prior to a decompression stress. This includes prior to hypobaric exposure, prior to initiating a dive, or prior to ascending from a hyperbaric exposure (22,134). Though often confused, OPB is not the use of oxygen after a decrease in ambient pressure such as in part of a decompression profile. Certainly, the ability of oxygen to eliminate dissolved nitrogen from tissue beds is significant to OPB use in preventing DCS. However, recent findings suggest a more nuanced effect of OPB with potential for novel approaches to DCS. Thom described the increase in perivascular NO levels in rodents exposed to 2.8 ATA oxygen (192). Given the benefits of pharmacologic NO donors in preventing DCS, it would be plausible that OPB at 2.8 ATA would provide benefits beyond inert gas elimination to include decreased NO generation, neutrophil adherence, and elimination of micronuclei (3, 139, 193). OPB prior to compression/decompression significantly decreased bubble formation in translucent prawns using an experimental design focused on the concept of decreasing micronuclei as a nidus for bubble formation (3). Butler reported that OPB 1 and 18 h prior to an arduous dive significantly decreased DCS incidence, inflammatory markers, and lung edema in rats. However, since his study design had tissues fully saturated, nitrogen elimination would not explain the findings (31). This micronuclei abatement concept was then successfully extended to OPB use during the compression phase of another dive in rats (118). Bosco has since applied a similar strategy to humans demonstrating that OPB at 1.6 or 2.2 ATA during the compression phase of an air dive at 4 ATA significantly reduced bubble formation and platelet activation. In that study even the use of normobaric oxygen appeared to have beneficial effects on platelet activation (22). Though this work did not induce DCS in subjects, its reduction of bubble formation suggests that OPB enhanced dive profile safety. Further support for the concept of micronuclei manipulation is the use of oxygen to accelerate decompression from an equivalent air depth of 2.8 ATA, where oxygen was most beneficial if used prior to the start of decompression (128). Operationally, OPB immediately prior to decompression originated during World War II to prevent high altitude DCS (200). Since then OPB for high altitude operations has been refined for particular exposures to include the combination of exercise with OPB. OPB immediately prior to decompression in hyperbaric environments outside of treatment protocols has been applied more recently in animal models. In 20 kg swine saturated at 5 ATA on air, as little as 10 min of OPB at 5 ATA significantly decreased DCS and prolonged latency to symptoms (48). This was then applied to 70 kg swine saturated at 2.8 ATA air and as little as 5 min of OPB significantly

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reduced severe DCS while 45 min of OPB eliminated all severe DCS compared to the control group (70% severe DCS) (134). While it is unlikely that human DCS studies will be applied to such an arduous exposure, human work in hyperbaric OPB has allowed for a safe accelerated decompression from saturation at 60 fsw where OPB offered a statistically significant decompression advantage over schedules of comparative length that did not include OPB (128).

DCS Therapy Hyperbaric oxygen Just as oxygen has been successfully shown to prevent DCS, it has equal efficacy in its management. While the management of DCS is currently limited to a few modalities that are predominated by HBO, an in depth discussion of its intricacies could constitute a book. Fortunately, as several excellent reviews have been published, only the physiologic principles behind DCS management will be discussed here (29, 145, 211). Though Bert first published the benefits of oxygen breathing to treat DCS in 1878, it was more than 50 years later when it was first used in conjunction with recompression to treat DCS and not until almost a century later was it adopted as a standard part of the treatment tables which are still in use today (10, 14, 91, 241). HBO hastens bubble dissolution, excess inert gas removal and delivery of oxygen to tissues potentially compromised in DCS. Recompression alone initially serves to stabilize or reduce bubble size. Following Boyle’s Law, recompression reduces symptomatic bubbles by redissolving the inert gas in the vasculature and tissue, alleviating obstructed blood flow and tissue stress. A pressure of 2 ATA (33 fsw) reduces bubble volume by 50% and bubble radius by 21.7%. However, at 6 ATA (165 fsw) only moderate further incremental changes result (29, 204). It is the use of HBO that allows bubble resolution. The bubbles formed during decompression contain a high concentration of inert gas. Breathing oxygen creates a concentration gradient in the lungs and vasculature that favors metabolically inert gas movement out tissues and bubbles leading to dissolution (12). Besides hastening inert gas removal from the body, breathing oxygen prevents further inert gas uptake, reducing overall treatment time (91). Even at surface pressure (1 ATA) breathing 100% oxygen can have beneficial effects and is the mainstay of initial first aid treatment for DCS prior to recompression (211). Furthermore, oxygen at 3 ATA produces an arterial oxygen tension of approximately 2000 mmHg and tissue tensions of 500 mmHg. With an arterial oxygen tension of 2000 mmHg, the dissolved component of oxygen alone is capable of sustaining life and allows for oxygen transport past areas of occlusion (87). Likewise, these high oxygen tensions allow for an increased diffusion distance from capillaries that can

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provide improved oxygen delivery despite reduced blood flow (171, 176). The main limitation of HBO is its risk of toxicity to the pulmonary and CNS at depths greater than 1.3 ATA. In particular, seizures are the most concerning manifestation of CNS toxicity and render HBO impractical beyond 3.0 ATA. Thus, current treatment tables limit the use of 100% oxygen to 3.0 ATA and incorporate intermittent air breathing periods to reduce risk (29, 91). Provisions are made in some tables for oxygen use deeper than 60 fsw at reduced concentrations, often in conjunction with helium, to avoid both nitrogen narcosis and exceeding 3.0 ATA oxygen. Despite some animal models that show more rapid bubble size reduction using helium versus air or oxygen alone, there is no human data with deeper tables that demonstrate an advantage to using helium (111-115). Furthermore, the cost and sophistication required for blending such gas mixtures would exceed the capabilities of most treatment facilities thus limiting its general use. In addition to bubble resolution and tissue perfusion HBO decreases vasogenic edema (particularly neurologic) and leukocyte adherence, and may inhibit apoptosis, all of which would plausibly improve DCS outcomes (108, 193, 242).

Adjunctive therapies for DCS Given the previous evidence that other physiologic and immunologic factors are at play in DCS beyond simple bubble effects; that severe forms of DCS can be indistinguishable from the protean manifestations of systemic shock; and the likely occurrence of DCS in remote locations, adjunctive therapies for DCS have been pursued (30,119,142,188,195,197). Oxygen itself has been shown to impact neutrophil activity by affecting integrin binding (40) and in animal models perfluorocarbons improve DCS survival without hyperbaric therapy, presumably via enhanced oxygen solubility and subsequent delivery to tissues (135). Unfortunately, immune, inflammatory, and coagulation modulation have been evaluated without any definitive proof of improved outcome to date other than a reduction in the number of treatments with the use of the nonsteroidal antiinflammatory drug tenoxicam (13). In fact, steroids were demonstrated to be detrimental when used prophylactically in a swine DCS model, thus negating any recommendations for its use (57). As mentioned previously, there is some evidence that hydration has been demonstrated to enhance inert gas elimination in humans and prevent DCS in swine supporting its judicious use intravenously (7, 70). Finally, because of some mixed evidence for its neuroprotective effects in cardiac bypass surgery, lidocaine has been considered for severe cases of neurological DCS (137, 211). Little has changed in DCS treatment since recompression with oxygen was introduced in the 1960s. This is primarily due to the very low incidence of DCS and the infeasibility of controlled human studies. While some adjunctive therapies have come and gone, current research and advancing techniques

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hold promise to further delineate the pathogenic mechanisms of DCS and provide modalities to further improve management regardless of its presentation.

Long-Term Effects While there are a number of reports linking various chronic medical findings to hyperbaric exposure, proving a direct relationship to DCS has been difficult. Furthermore, the clinical significance associated with various reports on imaging and neuropsychological testing remains controversial. A number of publications have reviewed the long-term effects of diving and hyperbaric exposure and the reader is referred to these for further detail (29, 44, 94, 130). Here, the focus will be on existing evidence for specific DCS related long-term effects. The most clinically significant effect related to DCS are the long-term sequelae from spinal cord DCS. Both Hill and Bert in their summary of various caisson and diving reports describe cases of limb and bladder paralysis due to the most severe effects with many deaths as a result of sepsis from chronic bed sores and urinary tract infections (14, 104). Fortunately, due to vast improvements in decompression practice such cases are rare, but recent studies and reviews still demonstrate that up to a third of divers presenting with spinal DCS will not have complete resolution of symptoms a month after injury with worse outcomes correlated to rapidity of onset and severity of symptoms (1,18,78). While other neurologic effects have been associated with hyperbaric exposures, correlations to overt DCS have been lacking and findings from imaging studies and neuropsychological testing often do not demonstrate any real clinically related manifestation; this includes mixed results for sequelae from inner ear DCS as well (9, 46, 63, 92, 94, 158, 175). Though clinically significant, the role of overt DCS and dysbaric osteonecrosis (DON) is unclear, though most investigators seem to agree that “silent” bubbles play some role in the initiation of DON and other diving associated pathologies (43, 109, 110). A remarkable case report of an MRI finding of what appear to be bubbles in two experienced divers presenting with first time Type I DCS that evolved into DON over 6 months does hint at a direct correlation (110, 183). However, even though Evans demonstrated a strong correlation between DON and DCS in his 1974 survey of compressed air workers, it is difficult to reconcile that with the fact that only 10% of compressed air workers presenting with DCS go on to have DON, and 25% of those with DON have no history of DCS (69, 110). Likewise, animal studies showed bone changes with and without DCS (2,110). Factors thought to play a role in this process include ischemic changes from bubble and nonbubble emboli, as well as nonembolic phenomenon such as vessel compression by extravascular bubbles dissolved in the fat of the rigid confines of bone, intimal thickening from chronic hyperbaric vascular changes, thrombosis, and possible action of vasoactive substances released by decompression stress (23, 43, 110). Nonischemic changes

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include immune responses, gas-induced osmotic shifts, and the effects of pressure on the specific anatomy of the locations predisposed to DON (43, 110). Risk factors associated with DON include increasing numbers of exposures, magnitude of exposure and obesity; these are not absolute, however, and there have been reports of DON after a single hyperbaric exposure (42, 43, 110, 162). Because of their chronic nature, it may be entirely impossible to separate the effects of some of the more subtle associations with hyperbaric exposure and the exposures of daily living. However, evidence presented above suggests that there is a chronic form of DCS due to a combination of “silent” bubbles and hyperbaria itself. As advances in hyperbaric research improve, adjustments to the current diving tables and decompression procedures may attempt to address and mitigate these problems. This would not be a completely novel concept; as far back as the early 1960s changes in decompression procedures for compressed air workers correlated with a significant reduction in DON (43). However, as more sophisticated diving technology makes its way into the realms of recreational diving there may very well be a surge in chronic manifestations, further highlighting the need to intensify research in these areas (76, 183).

Comprehensive Physiology

2. 3. 4. 5. 6.

7. 8. 9. 10.

11. 12.

13.

Conclusion Hopefully, our goal to explain the current state of DCS understanding in the context of a robust observational and empirical history was satisfied. However, DCS remains a syndrome of a constellation of symptoms following a change in ambient pressure. Though great strides have been made, significant knowledge gaps remain in the basic pathophysiology of the DCS. If the coming years advance the field a fraction of what its predecessors accomplished, the health, and safety of those who endeavor in the environment of changing pressures most certainly will be improved.

Acknowledgements The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. The authors are military members or employees of the U.S. Government and this work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that Copyright protection under this title is not available for any work of the United States Government. The authors wish to thank Ms. Diana Temple for her editorial contributions without which this publication would not be possible.

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237. Wisløff U, Richardson RS, Brubakk AO. Exercise and nitric oxide prevent bubble formation: A novel approach to the prevention of decompression sickness? J Physiol 555: 825-829, 2004. 238. Wong RM. Review articles: Decompression sickness in breath-hold diving. Diving Hyperb Med 36(3): 6, 2006. 239. Woodward CM. A history of the St. Louis bridge; containing a full account of every step in its construction and erection, and including the theory of the ribbed arch and the tests of materials. Illustrated by numerous wood-cuts and fifty full-page lithographs and artotypes. St. Louis: G. I. Jones and Company, 1881.

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Decompression and Decompression Sickness

240. Yang M, Milovanova TN, Bogush M, Uzun G, Bhopale VM, Thom SR. Microparticleenlargement and altered surface proteins after air decompression are associated with inflammatory vascular injuries. J Appl Physiol 112(1): 204-11, 2012. 241. Yarbrough OD, Behnke AR. The treatment of compressed air utilizing oxygen. J Ind Hyg Toxicol, 21(6): 213-8, 1939. 242. Yin D, Zhou C, Kusaka I, Calvert JW, Parent AD, Nanda A, Zhang JH. Inhibition of apoptosis by hyperbaric oxygen in a rat focal cerebral ischemic model. J Cereb Blood Flow Metab 23(7): 855-64, 2003. 243. Yount DE, Hoffman DC. On the use of a bubble formation model to calculate diving tables. Aviat Space Environ Med 57: 149-156, 1986.

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Decompression and decompression sickness.

The ever-present desire of humankind to explore new limits introduced us to the syndrome of decompression sickness (DCS). This broad overview of DCS i...
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