Plenty of Room at the Bottom: Making Undersea Medicine a National Naval Responsibility

Photo by MC2 Sean Furey

By Dr. William R. D’Angelo

WORKING IN THE SEA CARRIES WITH IT EXTRAORDINARY CHALLENGES. THE NAVY HAS MADE IT A SPECIAL MISSION TO SUPPORT RESEARCH THAT HELPS SAILORS AND MARINES SURVIVE–AND EXCEL–IN THIS DIFFICULT ENVIRONMENT.

Humans are not made to live and work underwater. The Office of Naval Research (ONR) Undersea Medicine (UMed) National Naval Responsibility (NNR) comprises the science and technology efforts to overcome human shortfalls in operating in this extreme environment. The two main ways to do this are to enhance human physiology with pharmacological and other therapies, or to provide technology that protects from the environmental challenges. A less attractive option is to set limits on undersea operations. The goal of UMed is to understand and mitigate the basic physiology of exposure to extreme environments. This will allow for an expanded operational envelope (i.e., greater depth and time) for divers and combat swimmers, provide novel solutions for submarine escape, and enhance physical and cognitive undersea human performance.

The warfighting capabilities served by UMed can be thought of in three groups: vertical diving, horizontal diving, and submarine operations. Vertical diving entails both rapid operations involving rescue and recovery as well as a range of sustained operations that could include construction, salvage, husbandry, explosive ordnance disposal, and route clearance. Longer, deeper dives can use the technique of saturation diving, which allows the body to become saturated with breathing gas, thus expanding useful bottom time. Horizontal diving is the foray of naval special warfare and includes combat swimming and operating from SEAL delivery vehicles with a corresponding clandestine requirement. Submarine operations include long missions in confined spaces, crewing, and watchstanding issues as well as the building of the mental models required to make sense of the undersea environment. The capability to operate deeper, longer, safer, and cheaper depends on our ability to develop novel approaches to undersea biomedical issues.

As the physicist Richard Feynman said in his famous lecture on nanotechnology, “There’s plenty of room at the bottom.” Humans have not taken full advantage of the undersea terrain and will not be able to do so until major breakthroughs have been achieved. In addition, we have incomplete knowledge and understanding of the physiological consequences of exposure to extreme environments. Until we fully explore these reactions at the cellular, molecular, and biochemical level, and before we understand the response pathways involved to a higher degree of complexity, we cannot make these needed breakthroughs.

A global technical awareness study on undersea medicine was undertaken with ONR Global and the medical intelligence community. It demonstrated that ONR is by far the world leader in undersea medicine biomedical investments, yielding the highest productivity. Our nearest competitors are either frustrated at their lack of investment or hedging their bets on “shotgun” approaches that apply off-the-shelf pharmaceuticals to undersea medicine challenges. While it requires patience and long- term investment, the main tenets of the UMed NNR are to do the difficult work of exploring the basic physiology and, more important, to tie these findings together into coherent complex system descriptions that can be manipulated to enhance undersea performance.

The long-standing physical issue associated with diving has been decompression sickness (DCS), or the “bends,” as it was termed when discovered in 19th-century caisson workers. The body absorbs gas when the pressure is increased and releases it from the tissues when the pressure is relieved. In the most severe circumstances (termed a gas embolism), a gas bubble may become large enough to block a blood vessel and cause a stroke or even death. For the military, DCS came to the forefront in the 1900s when diving capabilities were being developed by the Royal Navy to work on, and rescue, the newly operational submarines. At this time, the first military dive tables were experimentally derived by physiologist John Scott Haldane in order to set strict limits on bottom times and to require careful decompression procedures to avoid DCS. Unfortunately, times have not changed dramatically in that the Navy still works under similar operational limitations. Diving efforts are hampered by limited bottom times, long decompression times, and the need to have prompt access to large and costly recompression chambers wherever diving will occur.

With the advent of more sophisticated breathing equipment and gas mixtures came the problem of hyperbaric oxygen toxicity. While oxygen generally is good, too much oxygen is actually bad. Hyperoxia can affect the central nervous system, lungs, eyes, and even the muscles. Named for the efforts of two 19th-century scientists, the central nervous system condition is called the Paul Bert effect, and the pulmonary condition the Lorrain Smith effect. In the worst case, hyperoxia can cause a seizure—leading to loss of the mask and drowning. Mitigating seizures, however, then increases the likelihood of pulmonary toxicity. Today, the Navy dives with very strict operational limits to avoid hyperbaric oxygen toxicity. If the solution for oxygen toxicity were found, this would also provide a new avenue to avoid DCS—with increasing portions of oxygen in the breathing mix, less diluent would be needed, thus reducing the decompression burden.

Contaminated water diving, cold water exposure, nutrition, and hydration are additional challenges common to the extreme underwater environment. These hazards are not limited to the diving community. Submariners escaping from a disabled submarine with a compromised pressure hull will be subject to potentially fatal DCS, embolism, or hyperbaric oxygen toxicity, and a submarine rescue scenario could result in mass DCS casualties that could overwhelm available recompressive treatment assets. Modern advances in biomedical science, including new tools from the fields of immunology, medical imaging, genetics, genomics, proteomics, and pharmacology provide fertile ground for addressing these issues.

Members of SEAL Delivery Vehicle Team Two prepare to launch one of the team’s SEAL Delivery Vehicles (SDV) from the back of a Los Angeles-class attack submarine. The SDVs carry Navy SEALs from a submerged submarine to enemy targets while staying underwater and undetected. Photo by PHC Andrew McKaskle

The genesis of the UMed NNR comes from a detailed review and assessment of the health of the existing undersea medicine research program and national capability performed in 2002 by the Undersea and Hyperbaric Medical Society and then-UMed program officer, Cmdr. Stephen C. Ahlers. The subsequent report found that “current funding is no longer sufficient to ensure a viable research program to adequately support the Department of the Navy in maintaining superiority in undersea operations and enhancing the performance and safety of the personnel engaged in these operations.” Other military services, national research agencies, and commercial interests provided only minimal funding for UMed-related research and the number of domestic institutions performing UMed research had declined four-fold. The cadre of scientists who provides national expertise had aged and was not being adequately replaced by younger investigators. The specialized facilities required were disappearing because of initial and life-cycle maintenance costs, the need for specialized support in hyperbaric engineering, and the requirements for safety inspections, space, and diving gases. Recommendations included the commitment by ONR of adequate, stable funding to assure scientific productivity, the training of new investigators, and the maintenance of a critical mass of UMed research facilities.

The case for a UMed NNR was then presented to Chief of Naval Research Rear Adm. William J. Landay by Capt. Charles R. Auker in August 2006. Approval for the NNR was granted three months later. Recommendations included establishing naval officer training for physiologists, psychologists, and medical officers. It was also recommended to revive the cosponsorship  of the triennial symposia in underwater and hyperbaric physiology, plan transition pathways from basic research to acquisition, and stabilize program management by hiring a Navy civilian program officer with an anticipated 8-10-year tenure. It was not recommended to increase annual funding levels at that time. Goals for the nascent NNR included enhancing undersea mission flexibility and efficiency, reducing risks to undersea operators, and decreasing the medical logistical burden.

Since that time, the UMed community remains healthy with the support of a stable NNR program. This community consists of M.D.s, Ph.D.s, engineers, and uniformed researchers. It also comprises the operators and program managers at the warfighting commands, the program offices, the Navy staff, and the Bureau of Medicine. Strong UMed research programs are under way at the Navy laboratories: the Naval Submarine Medical Research Laboratory, the Naval Medical Research Center, the Naval Health Research Center, and the neighboring Navy Experimental Diving Unit and Naval Surface Warfare Center in Panama City, Florida. The NNR supports academic research programs at Case Western Reserve University; Duke University; the State University of New York at Buffalo; the University of California, San Diego; the University of Connecticut; the University of Maryland; the University of Pennsylvania; the University of Southern California; and the University of South Florida, among others.

The NNR supports the Undersea and Hyperbaric Medicine Society meeting and, in collaboration with ONR Global, the European Undersea and Barometric Society and the South Pacific Undersea Medicine Society meetings. The physiology symposium series was not continued per se, but the annual program review, held in conjunction with the Deep Submergence Biomedical Development program review, has been a venue to gather the community and assess the overall health of the research. The program has been successful in supporting the graduate education of numerous young investigators who continue to remain in the field. Examples include Aaron Hall and Lt. Geoff Ciarlone at the Naval Medical Research Center, Greg Murphy at the Navy Experimental Diving Unit, and Dawn Kernagis, a recent inductee of the Women Diver’s Hall of Fame. Numerous equipment grants have helped maintain the facilities used to perform this research. Examples include the revitalization of the abandoned program at the State University of New York at Buffalo, the transfer of a Navy-engineered hyperbaric chamber for cellular experiments to the University of South Florida, and the recertification of the chamber at Simon Fraser University. Continued collaborations with ONR Global have supported the international community through the previously mentioned international conferences and funding international research in, for example, Australia, Canada, and New Zealand, and awarding travel to international experts for domestic meetings including the UMed program review.

HC2 Beau Chandler, left, prepares a patient for an intravenous line during a demonstration for patient care due to decompression illness in the hyperbaric chamber at U.S. Naval Base Guam. Photo by MC2 Chelsy Alamina

The UMed basic research investment from ONR remains the sole Department of Defense program dedicated to undersea human performance. The program is well integrated with biomedical efforts in the other services, the Special Operations Command, the Defense Advanced Research Projects Agency, and other institutions such as the National Aeronautics and Space Administration. Strong ties to warfighters and with advanced development partners are cultivated in order to understand the operational challenges and to transition products. The program is producing fundamental biomedical discoveries to both mitigate health risks and augment warfighter capabilities in this extreme environment. The recent global technical awareness study reinforced the findings from 2002 that the NNR was largely responsible for funding international peer-reviewed biomedical literature in UMed. The growing medical field of hyperbaric oxygen therapy is rooted in the Navy’s research using oxygen to treat DCS; the growth of this therapy has the added benefit that many hospitals are investing in new hyperbaric chambers. The community also will play a key role in the study and mitigation of aviation DCS that has recently arisen with our military aircraft.

The discovery of cellular gas channels under the UMed program is causing the biomedical textbooks to be rewritten. To survive, most cells must take in vital gas such as oxygen and expel waste gas such as carbon dioxide. We were all taught that this is simply done by diffusion of gases from higher concentration to lower through the cell membrane. Walter Boron from Case Western University made the ground-breaking discovery that certain channels can transport gas in a selective manner and he found that membranes can also be impermeable to gas depending on their composition. To bring this research to the next level, in 2016 Boron and his colleagues were awarded an Office of the Secretary of Defense interdisciplinary grant.

Going back to the cell membrane, the UMed NNR has supported another fundamental biomedical finding. It was determined by Stephen Thom of the University of Maryland that the increased pressure faced by tissues during diving causes small parts of the membrane to break off, form small spheres called microparticles (MPs) and enter the blood stream—taking with them whatever proteins were embedded. When these MPs were filtered from an animal showing symptoms of DCS after hyperbaric exposure and injected into an unexposed animal, it also showed DCS symptoms. While it is unknown if all MPs originating from hyperbaric exposure are the same, they have been found to be involved in an immune response and inflammation associated with DCS. Furthermore, it was thought that bubbles in the blood would correspond to DCS. It turns out there is very little correlation—a diver’s blood can bubble like champagne without any overt problem. A new theory is that bubbles form around MPs so that measuring MPs could be a better indication of DCS risk. Controlling MP production is therefore an avenue for treating DCS.

Fundamental findings also have been found with respect to hyperbaric oxygen toxicity treatment. Dominic D’Agostino at the University of South Florida evolved a remedy for central nervous system seizures known for several thousand years by the Greeks. It was found that epileptic seizures could be prevented by fasting the patient. In modern times, this finding was updated to prevent seizures using a high-fat, low-carbohydrate diet. Dr. D’Agostino has distilled the theory behind the high-fat diet approach and developed a dietary supplement called ketone esters that has demonstrated the seizure-delaying effect in an animal model. Since these seizures are a storm of activity that sweeps through the brain, it is thought that the ketones are metabolized by the brain through a different pathway thus preventing or delaying the seizures. While the supplement has shown to be non-toxic for short-time use, there is ongoing clinical research to address long-term effects as it transitions to the fleet. The ketone ester supplement also acts like a high-density fuel that may improve the performance of elite athletes; this is being investigated for use by special warfare operators. Ultimately, the mitigation of hyperbaric oxygen toxicity would open up the envelope for rebreather operations allowing longer and deeper dives.

CMCS Timothy Plummer, assigned to Underwater Construction Team 2, welds a top portion of cathodic protection to a pile in the port of Sattahip, Thailand. Photo by Builder 2nd Class Benjamin Reed

In the future, the UMed NNR has three high-priority goals for the transition of products to the fleet. The first area of focus is biomedical methods to reduce risks of DCS in a submarine escape scenario (which, by corollary, would apply to all Navy diving). This will entail the further study of the role of the immune and inflammatory responses in the mediation of DCS, biochemical methods of decompression, gas solubility manipulations, genetic studies of susceptibility and resilience to DCS, and the determination of biomarkers of decompression stress. The development of methods to eliminate decompression obligation would enable safer, more useful dive profiles, more efficient use of the limited number of divers, and less costly missions. The reduction in the need for recompression chambers and evacuation assets to treat DCS would decrease the logistic burden and cost of undersea operations. The second area of focus is the prediction and prevention of hyperbaric oxygen toxicity to the central nervous system, pulmonary system, and neuromuscular system. Testing is planned for two parallel approaches to delaying or preventing seizures. Combinations of two anticonvulsant drugs and in parallel combinations of several ketogenic supplements will be tested for efficacy and potential side-effects. While this phase of testing will occur in an animal model, because these substances are either Food and Drug Administration-approved or will be shortly, human testing is on the horizon. This is an important distinction since the path to new drug development is prohibitive for the Defense Department; it would likely take a decade and on the order of half a billion dollars to receive approval with only about a 2-percent chance of success. The products of the UMed NNR do not always translate into hardware; results are often guidance for exposure to hazards or changes to procedures.

The third area of focus is the collection of human performance baseline data for the typical special warfare combat swimming and SEAL delivery vehicle environments. In addition, methods and tools for human performance assessment in these environments will be developed. This is a vital first step in the development and assessment of mitigation strategies for challenges such as thermal stress.

Now 15 years after the original study by the Undersea and Hyperbaric Medical Society, the UMed program continues to meet the criteria of being an area of research that is uniquely important to the Navy, not otherwise adequately funded by non-naval sources, and at risk of loss of a national research capability. The NNR has allowed a stable funding profile, support for the training pipeline, and maintenance of essential infrastructure assets. A series of workshops with the UMed scientific and operational community in 2016 gave an opportunity to recount progress in the field and scope current challenges. UMed will continue to support overcoming human shortcomings from exposure to extreme environments and the expansion of the undersea operational envelope.

About the author:

Dr. D’Angelo is the undersea medicine program officer with the Office of Naval Research.