© 2015, Wiley Periodicals, Inc. DOI: 10.1111/echo.12815
Echocardiography
INTRAPULMONARY SHUNTS AND THEIR CLINICAL IMPLICATIONS FOR THE ECHOCARDIOGRAPHER
Intrapulmonary Shunt and SCUBA Diving: Another Risk Factor? Dennis Madden, M.Sc., Marko Ljubkovic, M.D., Ph.D., and Zeljko Dujic, M.D., Ph.D. Department of Integrative Physiology, University of Split School of Medicine, Split, Croatia
Laboratory and field investigations have demonstrated that intrapulmonary arteriovenous anastomoses (IPAVA) may provide an additional means for venous gas emboli (VGE) to cross over to the arterial circulation due to their larger diameter compared to pulmonary microcirculation. Once thought to be the primary cause of decompression sickness (DCS), it has been demonstrated that, even in large quantities, their presence does not always result in injury. Normally, VGE are trapped in the site of gas exchange in the lungs and eliminated via diffusion. When VGE crossover takes place in arterial circulation, they have the potential to cause more harm as they are redistributed to the brain, spinal column, and other sensitive tissues. The patent foramen ovale (PFO) was once thought to be the only risk factor for an increase in arterialization; however, IPAVAs represent another pathway for this crossover to occur. The opening of IPAVAs is associated with exercise and hypoxic gas mixtures, both of which divers may encounter. The goal of this review is to describe how IPAVAs may impact diving physiology, specifically during decompression, and what this means for the individual diver as well as the future of commercial and recreational diving. Future research must continue on the relationship between IPAVAs and the environmental and physiological circumstances that lead to their opening and closing, as well as how they may contribute to diving injuries such as DCS. (Echocardiography 2015; 32: S205–S210) Key words: SCUBA, IPAVA, arterialization, crossover, decompression sickness SCUBA Physiology: At first thought, diving and hyperbaric physiology may only seem relevant and interesting to a small group of people, particularly recreational SCUBA divers. However, professional divers are crucial in industries such as communications, construction, oil, and fish farming, along with first responders and the military. It is likely that divers or the study of hyperbaric physiology has had a positive impact on the things you depend on and may even take for granted nearly every day. A brief review of hyperbaric and diving physiology will provide the reader with a background necessary to see where intrapulmonary arteriovenous anastomoses (IPAVA) fit in, and why the div-
Funding Sources: The authors have received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FRP/2007-2013/ under REA grant agreement no. 264816. Address for correspondence and reprint requests: Zeljko Dujic, M.D., Ph.D., Department of Integrative Physiology, University of Split School of Medicine, Soltanska 2, 21 000 Split, Croatia. Fax: +385 21 557 951; E-mail: [email protected]
ing community is beginning to take an increased interest in them. Breathing under hyperbaric conditions, such as during SCUBA diving, results in an increased uptake of inert gas. Due to the increased pressure, the body is able to absorb more nitrogen in the tissues that would be possible at the surface. When breathing compressed atmospheric air, this inert gas is nitrogen. Advanced divers may use customized gas mixtures that replace some of the nitrogen with other inert gases to reduce the effect of nitrogen narcosis; a feeling of dizziness and mild euphoria resulting from breathing certain inert gases at great depth in the sea. As a diver ascends and the ambient pressure returns to normal levels, the tissues become supersaturated and, as they continue to off-gas nitrogen, as blood flows through various tissues, this nitrogen is absorbed until the blood is supersaturated and bubbles form. These bubbles are formed in the venous system and are termed venous gas emboli (VGE). VGE pass through the right chambers of the heart and on to the pulmonary circulation, where they are trapped and exhaled as nitrogen diffuses from the bubbles to air in the lungs. S205
Madden, et al.
Once thought to be the primary cause of decompression sickness (DCS or “the bends”) over the past few decades, with the help of increasingly sensitive equipment, it has been recognized that VGE are quite common, even following mild dive profiles.1,2 These bubbles are known as “silent” VGE and are clinically asymptomatic. Prior to these observations, VGE—especially in high loads—were considered to always lead to DCS. What is less common, and considered very dangerous, is when these bubbles cross over from the venous to arterial circulation.3,4 Similar to the VGE, although arterialization has the potential to cause more harm, this alone does not guarantee DCS. There are multiple techniques currently in use right now for both bubble detection and quantification. Bubbles, the Heart, and Echocardiography: There are two commonly used means of bubble detection; ultrasonic Doppler instruments and ultrasonic imaging. Although both are currently in use, two-dimensional imaging has become the standard for many groups; however, the cost associated is relatively high compared to Doppler technology, which remains in use. Doppler devices still have their advantages compared with ultrasound; they are relatively inexpensive, and data can be collected in the field with minimal training (although proper analysis requires a sensitive and trained ear). The advantages of imaging over Doppler include decreased time for bubble grading and a relative ease in assigning grades,5 a task which is often done subjectively. Additionally, the flexibility offered by multiple scanning modes and probes allows for specialized investigations, for example, specific areas and individual cardiac chambers can be targeted as needed to collect the most useful images. Furthermore, production of portable high-resolution scanners have allowed for easy bubble detection in almost any field condition associated with diving. Diving physiology data can be collected while in the hyperbaric chamber or during reallife conditions experienced in the open-sea or lake diving. Collecting data in the field are ideal since VGE loads are attenuated when a comparable dry dive is performed in a hyperbaric chamber.6 There are many ways to image the heart and one of the most commonly used is the apical view as it allows the operator the opportunity to observe bubbles in all four chambers. The apical four-chamber view is especially useful for diving and IPAVA research as it is easy to visualize arterializations. Figure 1 displays a four-chamber image collected following a SCUBA dive. When utilizing images such as these for bubble grading, a cardiac probe is used in the range of 1–10 MHz S206
Figure 1. Image displays (arrows) in the left ventricle (LV) and emboli in the right ventricle (RV). Image was obtained by a Vivid q (GE, Milwaukee, WI) with a cardiac probe on a subject after diving. RA = right atrium; LA = left atrium.
in B-mode. While the merits of individual grading systems are beyond the scope of this article, many systems rely on a semiquantitative grading scale that includes both subjective and quantitative elements, one of which is displayed in Table I as an example. Crossover and PFO: As mentioned previously, VGE crossover to the arterial circulation is considered very dangerous.4 The common path of VGE from the site where they are formed in the veins, through the right heart, and on to the pulmonary circuit for elimination. Bubbles that make it to the arterial side have opportunities to enter other tissues or block arterioles. If these bubbles interact with specific areas, such as brain and nervous tissues or joint capsules, they may directly lead to clinical signs and symptoms of DCS. The patent foramen ovale (PFO) is one of the more commonly known means for emboli to cross over to the arterial side.3,4,7–9 As a brief review, the PFO is a congenital defect where the opening between the two atria has failed to com-
TABLE I Grading of Ultrasonic Images Grade 1 2 3 4 5
Description No bubbles Occasional bubbles At least 1 bubble/4th cycle Continuous bubbling, at least 1 bubble/cm2 in all frames “White-out” individual bubbles cannot be seen
Bubble scoring system of Eftedal and Brubak.13
Relevance of Pulmonary Shunt in Diving
pletely seal. Rather than thinking of it as a hole in the wall, a more accurate visual would be a closed door that can open under specific circumstances. Although an arterialized gas bubble sounds extremely dangerous, recent studies following deep trimix dives (subjects were prescreened and PFO negative) revealed a higher incidence or arterialization that was expected, without any signs or symptoms of DCS.10,11 These aspects led to the investigation of the physiological determinants of arterialization in SCUBA divers. It has been theorized that arterialization occurs in PFO negative divers when the quantity of VGE becomes high enough that it overwhelms the pulmonary microcirculation’s ability to filter them out.12 This has been observed to occur at a grade of 4B on the modified Eftedal and Brubakk scale.13 Recently, an additional means for crossover was demonstrated in the field, that is, through opening of intrapulmonary arterialvenous anastomoses (IPAVA).14 Two prerequisites for crossover were reported: high VGE number post dive (“bubble producers”) and recruited/ open IPAVAs either at rest or more frequently during exercise.15 With same dive profile, diver’s VGE production varies greatly between individuals; what makes a person susceptible to an increased bubble production is still unknown. The acute and chronic consequences of arterialized emboli are still under investigation. While studies of long-term cognitive function show no impairment from injury-free SCUBA diving,16 other studies showing brain lesions in sport divers warrant further investigation into the subject.17 It seems clear that divers with a right-to-left shunt, whether PFO or IPAVA, are at a higher risk than those without.7,9,17 IPAVAs: Emboli found following a dive vary in size from 19 to 700 lm18 while the diameter of the capillaries at the site of gas exchange ranges from 6 to 15 lm. This essentially traps the bubbles and they diffuse into the lungs to be exhaled. Previously, agitated saline was used to create contrast bubbles to visualize crossover in the absence of a PFO. If injected bubbles could pass through IPAVAs under certain circumstances, then why not endogenous emboli resulting from decompression? Other characteristics of IPAVAs originally found in the laboratory are also interesting to divers in the field. Most notable are that IPAVAs open more readily when breathing hypoxic gas mixtures at rest and during exercise (FiO2 0.12, mean SaO2 86 7% and PaO2 47 5 Torr at rest and 73 5% and 37 5 Torr at 196 W), 19 and close when breathing (100% O2),20 as well as how they behave during exercise15,21,22 or
under combinations of these conditions.19 Extracardiac shunts and IPAVAs may be identified during a standard PFO test using agitated saline echocardiography. It is expected, in the presence of a PFO, that injected bubbles will immediately appear in the left cardiac cavities. However, if this crossover occurs after at least 4 cardiac cycles, the site of arterialization is outside the heart.23 Decompression injuries must be treated in a hyperbaric chamber as soon as possible and there is little to be done on the field or in transit; first aid consists of supplemental oxygen and restoring and maintaining proper hydration status. One of the proposed mechanisms of O2 administration is to increase the washout of nitrogen from then blood, and by extension to the tissues, by increasing the concentration gradient of the inert gas at the site of gas exchange. Recent studies potentially suggested another beneficial mechanism for the use of O2, closing the IPAVAs and preventing further arterialization, that is, if IPAVAs are the site of crossover in that particular instance.14 Indeed, the use of 100% O2 on divers was investigated in the field in divers with open shunts, resulting from exercise, who were arterializing.14 The arterialization stopped almost immediately, around 90 seconds after application, as observed previously in the laboratory.20 The exercise intensity in which IPAVAs open is individual and knowledge of the intensity at which this occurs may be useful. An individual who shunts at rest or at a very low percentage of their VO2max may have the same risk profile as a diver with a PFO and how that should affect the diver is discussed below. Although most divers may not be racing off to complete a track workout right after they surface, there are many activities associated with diving that could cross the threshold of a low intensity IPAVA shunting diver. Military combat divers may have to perform demanding activities on land after reaching their destination under water, and all divers may have to walk or climb while carrying heavy equipment. Finally, surface swimming in full kit can be physically demanding; any extended surface swimming during decompression could be another scenario for many to open shunts. These situations do not seem to be too imaginative, even for recreational divers, and this knowledge combined with the observation that divers produce VGE quite easily after even mild dives, one can see that many individuals may setup the conditions for arterialization quite frequently. Exercise and SCUBA Diving: Previous laboratory studies on IPAVAs provided enough information to hypothesize an additional means for VGE to arterialize in divers.15,20,21 It was proposed that these IPAVAs could open up S207
Madden, et al.
and provide a path that was less restrictive in diameter (compared to pulmonary microcirculation) to circulating VGE resulting from decompression, all that remained was to demonstrate these aspects in field conditions following open water SCUBA diving. We sought to test this idea in group of 23 divers who performed exercise on a cycle ergometer within 30 minutes of surfacing from a dive to 18 m of sea water for 47 minutes total dive time. Of these 23, we observed arterialization during exercise sessions in 12 subjects. Interestingly, 5 of those 12 subjects had an initial bubble grade
Echocardiography
INTRAPULMONARY SHUNTS AND THEIR CLINICAL IMPLICATIONS FOR THE ECHOCARDIOGRAPHER
Intrapulmonary Shunt and SCUBA Diving: Another Risk Factor? Dennis Madden, M.Sc., Marko Ljubkovic, M.D., Ph.D., and Zeljko Dujic, M.D., Ph.D. Department of Integrative Physiology, University of Split School of Medicine, Split, Croatia
Laboratory and field investigations have demonstrated that intrapulmonary arteriovenous anastomoses (IPAVA) may provide an additional means for venous gas emboli (VGE) to cross over to the arterial circulation due to their larger diameter compared to pulmonary microcirculation. Once thought to be the primary cause of decompression sickness (DCS), it has been demonstrated that, even in large quantities, their presence does not always result in injury. Normally, VGE are trapped in the site of gas exchange in the lungs and eliminated via diffusion. When VGE crossover takes place in arterial circulation, they have the potential to cause more harm as they are redistributed to the brain, spinal column, and other sensitive tissues. The patent foramen ovale (PFO) was once thought to be the only risk factor for an increase in arterialization; however, IPAVAs represent another pathway for this crossover to occur. The opening of IPAVAs is associated with exercise and hypoxic gas mixtures, both of which divers may encounter. The goal of this review is to describe how IPAVAs may impact diving physiology, specifically during decompression, and what this means for the individual diver as well as the future of commercial and recreational diving. Future research must continue on the relationship between IPAVAs and the environmental and physiological circumstances that lead to their opening and closing, as well as how they may contribute to diving injuries such as DCS. (Echocardiography 2015; 32: S205–S210) Key words: SCUBA, IPAVA, arterialization, crossover, decompression sickness SCUBA Physiology: At first thought, diving and hyperbaric physiology may only seem relevant and interesting to a small group of people, particularly recreational SCUBA divers. However, professional divers are crucial in industries such as communications, construction, oil, and fish farming, along with first responders and the military. It is likely that divers or the study of hyperbaric physiology has had a positive impact on the things you depend on and may even take for granted nearly every day. A brief review of hyperbaric and diving physiology will provide the reader with a background necessary to see where intrapulmonary arteriovenous anastomoses (IPAVA) fit in, and why the div-
Funding Sources: The authors have received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FRP/2007-2013/ under REA grant agreement no. 264816. Address for correspondence and reprint requests: Zeljko Dujic, M.D., Ph.D., Department of Integrative Physiology, University of Split School of Medicine, Soltanska 2, 21 000 Split, Croatia. Fax: +385 21 557 951; E-mail: [email protected]
ing community is beginning to take an increased interest in them. Breathing under hyperbaric conditions, such as during SCUBA diving, results in an increased uptake of inert gas. Due to the increased pressure, the body is able to absorb more nitrogen in the tissues that would be possible at the surface. When breathing compressed atmospheric air, this inert gas is nitrogen. Advanced divers may use customized gas mixtures that replace some of the nitrogen with other inert gases to reduce the effect of nitrogen narcosis; a feeling of dizziness and mild euphoria resulting from breathing certain inert gases at great depth in the sea. As a diver ascends and the ambient pressure returns to normal levels, the tissues become supersaturated and, as they continue to off-gas nitrogen, as blood flows through various tissues, this nitrogen is absorbed until the blood is supersaturated and bubbles form. These bubbles are formed in the venous system and are termed venous gas emboli (VGE). VGE pass through the right chambers of the heart and on to the pulmonary circulation, where they are trapped and exhaled as nitrogen diffuses from the bubbles to air in the lungs. S205
Madden, et al.
Once thought to be the primary cause of decompression sickness (DCS or “the bends”) over the past few decades, with the help of increasingly sensitive equipment, it has been recognized that VGE are quite common, even following mild dive profiles.1,2 These bubbles are known as “silent” VGE and are clinically asymptomatic. Prior to these observations, VGE—especially in high loads—were considered to always lead to DCS. What is less common, and considered very dangerous, is when these bubbles cross over from the venous to arterial circulation.3,4 Similar to the VGE, although arterialization has the potential to cause more harm, this alone does not guarantee DCS. There are multiple techniques currently in use right now for both bubble detection and quantification. Bubbles, the Heart, and Echocardiography: There are two commonly used means of bubble detection; ultrasonic Doppler instruments and ultrasonic imaging. Although both are currently in use, two-dimensional imaging has become the standard for many groups; however, the cost associated is relatively high compared to Doppler technology, which remains in use. Doppler devices still have their advantages compared with ultrasound; they are relatively inexpensive, and data can be collected in the field with minimal training (although proper analysis requires a sensitive and trained ear). The advantages of imaging over Doppler include decreased time for bubble grading and a relative ease in assigning grades,5 a task which is often done subjectively. Additionally, the flexibility offered by multiple scanning modes and probes allows for specialized investigations, for example, specific areas and individual cardiac chambers can be targeted as needed to collect the most useful images. Furthermore, production of portable high-resolution scanners have allowed for easy bubble detection in almost any field condition associated with diving. Diving physiology data can be collected while in the hyperbaric chamber or during reallife conditions experienced in the open-sea or lake diving. Collecting data in the field are ideal since VGE loads are attenuated when a comparable dry dive is performed in a hyperbaric chamber.6 There are many ways to image the heart and one of the most commonly used is the apical view as it allows the operator the opportunity to observe bubbles in all four chambers. The apical four-chamber view is especially useful for diving and IPAVA research as it is easy to visualize arterializations. Figure 1 displays a four-chamber image collected following a SCUBA dive. When utilizing images such as these for bubble grading, a cardiac probe is used in the range of 1–10 MHz S206
Figure 1. Image displays (arrows) in the left ventricle (LV) and emboli in the right ventricle (RV). Image was obtained by a Vivid q (GE, Milwaukee, WI) with a cardiac probe on a subject after diving. RA = right atrium; LA = left atrium.
in B-mode. While the merits of individual grading systems are beyond the scope of this article, many systems rely on a semiquantitative grading scale that includes both subjective and quantitative elements, one of which is displayed in Table I as an example. Crossover and PFO: As mentioned previously, VGE crossover to the arterial circulation is considered very dangerous.4 The common path of VGE from the site where they are formed in the veins, through the right heart, and on to the pulmonary circuit for elimination. Bubbles that make it to the arterial side have opportunities to enter other tissues or block arterioles. If these bubbles interact with specific areas, such as brain and nervous tissues or joint capsules, they may directly lead to clinical signs and symptoms of DCS. The patent foramen ovale (PFO) is one of the more commonly known means for emboli to cross over to the arterial side.3,4,7–9 As a brief review, the PFO is a congenital defect where the opening between the two atria has failed to com-
TABLE I Grading of Ultrasonic Images Grade 1 2 3 4 5
Description No bubbles Occasional bubbles At least 1 bubble/4th cycle Continuous bubbling, at least 1 bubble/cm2 in all frames “White-out” individual bubbles cannot be seen
Bubble scoring system of Eftedal and Brubak.13
Relevance of Pulmonary Shunt in Diving
pletely seal. Rather than thinking of it as a hole in the wall, a more accurate visual would be a closed door that can open under specific circumstances. Although an arterialized gas bubble sounds extremely dangerous, recent studies following deep trimix dives (subjects were prescreened and PFO negative) revealed a higher incidence or arterialization that was expected, without any signs or symptoms of DCS.10,11 These aspects led to the investigation of the physiological determinants of arterialization in SCUBA divers. It has been theorized that arterialization occurs in PFO negative divers when the quantity of VGE becomes high enough that it overwhelms the pulmonary microcirculation’s ability to filter them out.12 This has been observed to occur at a grade of 4B on the modified Eftedal and Brubakk scale.13 Recently, an additional means for crossover was demonstrated in the field, that is, through opening of intrapulmonary arterialvenous anastomoses (IPAVA).14 Two prerequisites for crossover were reported: high VGE number post dive (“bubble producers”) and recruited/ open IPAVAs either at rest or more frequently during exercise.15 With same dive profile, diver’s VGE production varies greatly between individuals; what makes a person susceptible to an increased bubble production is still unknown. The acute and chronic consequences of arterialized emboli are still under investigation. While studies of long-term cognitive function show no impairment from injury-free SCUBA diving,16 other studies showing brain lesions in sport divers warrant further investigation into the subject.17 It seems clear that divers with a right-to-left shunt, whether PFO or IPAVA, are at a higher risk than those without.7,9,17 IPAVAs: Emboli found following a dive vary in size from 19 to 700 lm18 while the diameter of the capillaries at the site of gas exchange ranges from 6 to 15 lm. This essentially traps the bubbles and they diffuse into the lungs to be exhaled. Previously, agitated saline was used to create contrast bubbles to visualize crossover in the absence of a PFO. If injected bubbles could pass through IPAVAs under certain circumstances, then why not endogenous emboli resulting from decompression? Other characteristics of IPAVAs originally found in the laboratory are also interesting to divers in the field. Most notable are that IPAVAs open more readily when breathing hypoxic gas mixtures at rest and during exercise (FiO2 0.12, mean SaO2 86 7% and PaO2 47 5 Torr at rest and 73 5% and 37 5 Torr at 196 W), 19 and close when breathing (100% O2),20 as well as how they behave during exercise15,21,22 or
under combinations of these conditions.19 Extracardiac shunts and IPAVAs may be identified during a standard PFO test using agitated saline echocardiography. It is expected, in the presence of a PFO, that injected bubbles will immediately appear in the left cardiac cavities. However, if this crossover occurs after at least 4 cardiac cycles, the site of arterialization is outside the heart.23 Decompression injuries must be treated in a hyperbaric chamber as soon as possible and there is little to be done on the field or in transit; first aid consists of supplemental oxygen and restoring and maintaining proper hydration status. One of the proposed mechanisms of O2 administration is to increase the washout of nitrogen from then blood, and by extension to the tissues, by increasing the concentration gradient of the inert gas at the site of gas exchange. Recent studies potentially suggested another beneficial mechanism for the use of O2, closing the IPAVAs and preventing further arterialization, that is, if IPAVAs are the site of crossover in that particular instance.14 Indeed, the use of 100% O2 on divers was investigated in the field in divers with open shunts, resulting from exercise, who were arterializing.14 The arterialization stopped almost immediately, around 90 seconds after application, as observed previously in the laboratory.20 The exercise intensity in which IPAVAs open is individual and knowledge of the intensity at which this occurs may be useful. An individual who shunts at rest or at a very low percentage of their VO2max may have the same risk profile as a diver with a PFO and how that should affect the diver is discussed below. Although most divers may not be racing off to complete a track workout right after they surface, there are many activities associated with diving that could cross the threshold of a low intensity IPAVA shunting diver. Military combat divers may have to perform demanding activities on land after reaching their destination under water, and all divers may have to walk or climb while carrying heavy equipment. Finally, surface swimming in full kit can be physically demanding; any extended surface swimming during decompression could be another scenario for many to open shunts. These situations do not seem to be too imaginative, even for recreational divers, and this knowledge combined with the observation that divers produce VGE quite easily after even mild dives, one can see that many individuals may setup the conditions for arterialization quite frequently. Exercise and SCUBA Diving: Previous laboratory studies on IPAVAs provided enough information to hypothesize an additional means for VGE to arterialize in divers.15,20,21 It was proposed that these IPAVAs could open up S207
Madden, et al.
and provide a path that was less restrictive in diameter (compared to pulmonary microcirculation) to circulating VGE resulting from decompression, all that remained was to demonstrate these aspects in field conditions following open water SCUBA diving. We sought to test this idea in group of 23 divers who performed exercise on a cycle ergometer within 30 minutes of surfacing from a dive to 18 m of sea water for 47 minutes total dive time. Of these 23, we observed arterialization during exercise sessions in 12 subjects. Interestingly, 5 of those 12 subjects had an initial bubble grade
