Wednesday, March 26, 2014

Transparency in Medical Care

There is a concern that one of the principle reasons for why healthcare costs are so expensive and why the Affordable Care Act (ACA) will have a limited influence on healthcare costs is that there is little direct information pertaining to prices for given services. This “blind” pricing creates an environment of uninformed consumption where individuals hope that they receive a competitive/fair price rather than know they got a competitive price. Therefore, some individuals believe that if hospitals and other medical institutions list their prices for given services consumers will be able to comparison shop using market forces and competition to lower prices. To this end a number of proponents for this form of transparency hope for the establishment of a procedure marketplace similar in design to existing online booking agents like Expedia, Travelocity, etc.

Note that a number of transparency sites already exist operated by various insurance companies. Some of these insurance companies, like Cigna and United Healthcare, have sites that are fairly effective at demonstrating to consumers differences in price between various hospitals for various procedures whereas others like Healthnet and Kaiser Permenente have sites that fair badly at accomplishing this goal.1 Unfortunately most people do not realize that these sites exist because few people actually use them. It stands to reason that the existence of these individual sites provides support for the creation of a centralized procedure marketplace. However, there are some important issues that must be addressed before this new procedure marketplace (PrMa) could be developed.

First, it is not accurate to compare medical services to consumer goods like pears or toilet paper. The principle distinction between these two categories is that there is a limited supply market for medical services, which involve inherent price modifiers. Basically there are only a limited number of physicians and surgeons that can perform a given examination or procedure. Therefore, even if hospital A offers a lower price on an angioplasty versus hospital B there are only so many angioplasties hospital A can perform, thus the influence of the lower price on business gained for hospital A and business lost for hospital B is conditional and limited; depending on the market size this limit may allow hospital B to avoid lowering their prices even in a transparent and competitive environment and yet retain the same number of patients/customers.

Another problem is that supporters of a PrMa appear to view it in the most simplistic manner possible where all parties pay for medical services out of their own pocket rather than utilize health insurance as a cost modifier. Clearly this presumption is inaccurate, especially after the passage of the ACA placing a mandate on health insurance coverage for all citizens of the United States. Therefore, any transparency in prices will need to include the reduced negotiated rates by given insurance providers as well as co-payments and deductibles for given plans in addition to clear information regarding hospitals that are in a given network. Even if transparency is created for these elements there still exists significant price inelasticity based on the factors tied to the insurance companies.

Extending on this above point is a major reason Expedia and similar sites work is because consumers can select any flight from any participating airline and the price shown is the price paid, there are no second party negotiations creating changes in that price. Airlines participate because there is typically a glut of supply (available seats) and selling a seat at a 20% discount is superior to not selling a seat at all and this sale is more efficient on Expedia and other similar sites. A PrMa site could not produce similar results because there is more complexity. Due to a limited number of surgeons and operating venues there is a supply-based limiting factor that heavily influences the ability to profit due to volume for healthcare providers. Therefore, hospitals are going to charge as much as they can in order to maximize profits. This limiting factor makes it difficult for insurance companies to undercut a competitor to increase customer number; this fact also ignores the ease of switching insurance companies.

This limiting factor creates an environment where health insurance companies do not have ultimate bargaining power with healthcare providers. There is a limit to how much of a “discount” health insurance companies can negotiate based on competing profit potential for both insurance companies and hospitals. Finally based on market segregation of health insurance there is little reason for health insurance companies to participate in such a website. Due to the limiting supply factor it stands to reason that they would be as likely to lose money as make money, thus there is no real reason for any to actually participate in such service unless required by law.

The problem is further complicated in that customers purchasing plane tickets have a greater level of flexibility increasing the value of the transparency. For example suppose a person wants to travel to Miami and one week later wants to travel to Stockholm. The lack of contract between different airlines allows this individual to purchase a ticket from carrier A for price x to travel to Miami and then purchase a ticket from carrier B for price y to travel to Stockholm. In a PrMa the consumer is tied to their insurance company. Person A cannot easily switch insurance companies even if another insurance company has negotiated a lower price on a particular surgery at hospital A. Basically this restriction limits most consumers to only comparing prices between different hospitals not different insurance companies. Even for those shopping for new health insurance policies have difficulties because of a lack of knowledge regarding what procedures they would need in the future.

Worse still there are significant legal questions associated with transparency laws that conflict with gag clauses, most favored nation/provider arguments and possible trade secrets. Gag clauses are the most concerning challenge disallowing the publication of provider-insurer contracts. Arguments on the grounds of trade secrets and most favored providers are usually fairly soft and are cited more for their ability to act as a litigation threat versus their legal viability; however, courts have become more corporation friendly in the past decade and could buy an argument regarding the way a price is negotiated between insurance company and healthcare provider as a form of trade secret as strange as it sound intuitively for revealing a final price would not reveal any negotiation strategy.

Other concerns are that such a pricing tool would only be applicable for preventative or chronic care versus acute/emergency conditions for individuals suffering from a stroke could hardly compare prices on the Internet or telephone on which hospital to be rushed to for lifesaving surgery. Also unlike airlines, prices for medical services are influenced by geographical cost of living because they are not as volume flexible. Therefore, it must be guaranteed that new competitive transparency does not lead to such a great price reduction that it hurts healthcare workers. Clearly due to their earned skill set physicians will have salary security, but nurses, medical technicians and other “more disposable” hospital personnel could be fired or receive a cut in salary in order to maintain hospital profits if prices drop significantly due to increased competition. This salary cut could damage the overall care in the hospital because cost of living for a given region would create an inherent price and salary floor creating staffing shortages.

One concern that may not be imperative to address is the alteration of hospital and insurance billing practices. Some individuals believe that hospital and insurance billing need to be changed to more specific invoice-like documents with less medical and/or technical jargon so consumers can easily identify what goods and services are charged at what prices. However, an itemized breakdown of price may not be necessary because consumers don’t care about what each individual item involved in a medical procedure costs, they only care about the total cost of the procedure. For example patients staying overnight for observation do not need to know how much hospital food, catheters and pain medication cost individually, just the total cost of spending the night.

However, there is an important consideration for multiple pricing in a transparent real-time marketplace. By necessity hospitals outsource certain responsibilities to other medical service providers (radiologists, anesthesiologists, etc.) where some of the large price tag procedures require multiple bills from these multiple service providers. Therefore, diligent maintenance of transparency will be required to track each time a specific provider changes the price for his/her/its services to ensure accuracy in the overall price.

Fortunately one of more easily solvable concerns is that prices need to be intertwined with quality of the service. There is a natural psychology for consumers to equate a lower price with lower quality, especially if the difference in price is hundreds to thousands of dollars. Therefore, safety records for hospitals will need to be referenced in addition to the price for their services otherwise individuals may be reluctant to select lower priced service options defeating the entire point of price transparency.

Another significant concern that is seemingly never considered by PrMa proponents is that these direct price comparison tools may actually increase costs instead of reducing them. The idea of transparency functions on a general principle of capitalism that businesses with a common product will compete against each other because it is generally thought that consumers should migrate to the lower priced good, quality being similar; however, what individuals typically forget about this principle is that a goal of modern capitalism is to maximize profits.

Current gag clauses between hospitals and insurance providers limit the information that insurance providers and hospitals have to maximize profits. For example suppose hospital A charges $1,000 for a service and hospital B charges $2,500 for a service. In the current environment this difference is not readily known even between hospitals. In most versions of the transparent environment desired by proponents this information would be available to all parties. What stops hospital A from raising their price on the particular service from $1,000 to $2,000 instead of hospital B lowering their price from $2,500 to $1,250? This possibility should be a serious concern for transparency proponents.

Currently it appears that a dream of creating an Expedia-like website for comparison of prices and quality of care for various medical procedures will be very difficult, if not impossible to achieve. A better option would be focusing on expanding the transparency procedure comparison websites that some health insurance companies have already set up. Creating state and federal statutes to expand the details, features and accuracy of these websites on an individual basis should effectively deal with large disparities in price between hospitals and other medical providers. The reason this strategy will work is that individuals cannot jump between insurance companies and their respective coverage easily and the ACA demands all individuals have health insurance or face a fine; after a few years this fine will be of sufficient size that almost all individuals will have health insurance. Therefore, if all insurance companies have effective price transparency websites, those run by Cigna and United Healthcare are a suitable start, then consumers who are already “locked-in” to company will have a website that will help them plan for more cost effective medical treatment. Overall transparency procedure proponents should focus on the creation and optimization of these individual websites and phone information tied to specific insurance companies due to their ease of establishment and greater effectiveness versus a broad all-encompassing system.

Citations –


Wednesday, March 19, 2014

Early Departing Athletes and Education

There is widespread belief that the NBA and NCAA will work together in the near future to establish an age/experience floor for potential prospects where individuals who want to play in the NBA will need to attend at least two years of college or have some form of equivalent experience. This change would be an important element in establishing a meaningful methodology to attack the general perception of a lack of education among student athletes who leave college early to play professionally. In the current system a number of individuals focus on their NBA prospects through their adherence to the one-year minimum rule, but that “year” in college is really only about four-five months with only the first semester or first two quarters actually mattering because these individuals are only focused on maintaining their basketball eligibility. For these “one-and-done” players after eligibility is assured there is no further incentive to attend class and utilize the value of the scholarship.

A change in the minimum requirement from one year to two years forces these players to take classes seriously for at least one and half genuine years. This extra effort is especially important because for a vast majority of freshman, regardless of their athletic affiliations, the first year of college is much more general in the educational focus which limits the usefulness of that education without follow-up from the specificity of major study in sophomore, junior and senior years. Therefore, it could be argued that spending only a “year” in college is a generally meaningless 4-5 months that has little value to a “one-and-done”.

If the two-year minimum is established there still needs to be a focus applied to athletes to ensure that the educational opportunities they receive are suitable and targeted. Note that while the topic focuses on educational opportunities for student athletes in general, there will be additional attention paid to student athletes who leave college early before completing their degrees in an attempt to acquire employment as a professional athlete; therefore, this discussion primarily involves football and male basketball players. Finally it is important to acknowledge the fact that most student athletes, despite the stereotypes, actually complete school with a degree in a field that allows them to have a promising future career outside of playing sports.

One of the problems with a career as a professional athlete is that it has an inherently short lifespan. Very few athletes play beyond the age of 35 and those who do either play at a league minimum or on the waning years of a long-term contract that will be their last contract. Understand that there should be little sympathy for these individuals because league salary minimums in all four major sports (football, baseball, basketball and hockey) are considerably higher than a vast majority of jobs. However, with a career lasting only 5-15 years and 25-35+ years remaining before eligibility for Social Security, a majority of players will need to find secondary careers to fill this gap.

Facilitating the development of this second career can be difficult because these individuals have been competing in athletics for their prime adult professional development years and entry into a secondary career marketplace will typically result in competition with younger more experienced and prepared candidates. Due to the connections-based elements in the job market some of these athletes can parlay their fame into opportunity, but for most this strategy will not work. Therefore, colleges must create a new strategy for education that can help athletes manage these weaknesses when attempting to acquire a second career after their playing days are over.

With regards to this second career some individuals have argued that student-athletes should be allowed to major in their participating sport, i.e. football players should be allowed to major in “football”, basketball players in “basketball”, etc. Clearly this idea is not so ridiculous that it should be immediately dismissed out of hand with a sarcastic attitude that such a “degree” would be cookie-cutter and worthless. However, the problem with the various proposals that embody this idea is that the degree is not targeted. Society is continuously becoming more and more specialized and the idea behind this new type of “sports” major is too broad. Think about the nature of the job application process, when application-sorting software is “thinning the herd” is it going to select an application for the interview process if that individual majored in “basketball”?

Some could argue that the general failure of the “sports” major to attract the attention of employers and their resume software would be more indicative of negative stereotyping than lack of skill. While there would be some truth to this belief, the generality of the major itself would lead software and humans to draw their own negative conclusions regarding the efficacy of the major. Simply seeing a particular sport implies a focus on playing that sport not on other associated analytical intricacies. Proponents would argue that this is not correct, but even if the studied curriculum supports that position, there is still limited information regarding exactly what elements were studied. It is akin to comparing a major in medicine versus a major in radiology; one clearly defines the section of expertise where the other defines generality.

Unfortunately the weakest aspect of these proposals is that some of the proposed curriculum for a degree in “football” includes “labs” that are worth credit, but appear to be nothing more than simple practice sessions. Proponents would counter that performing arts majors typically receive credit for conducting practice sessions to hone their skills, so there should be little difference between those majors and this new “sport” major. While on its face this comparison may seem apt it runs into a philosophical problem regarding longevity. Most careers as a musician, actor, or even dancer can last decades while a career as a professional athlete typically lasts only five-ten years. This timeframe difference places a greater weight for value on practice for performance arts versus athletes.

Another concern regarding these “lab” sessions is that the failure rate for becoming a professional athlete is incredibly high even for those individuals who believe and have others who believe that they will be successful. Failure as a professional athlete would result in a career change, but the “lab” sessions acting as valid credits towards a major would be basically worthless to the individual due to their general player-only specificity. Therefore, it would be better if a more flexible study system were developed in place of these labs.

Also having such a specific major would compartmentalize athletes both among each other and among other non-student athletes, which could lead to problems. For example while everyone likes to believe in honest evaluation, among student athletes there have been numerous examples of favoritism within numerous universities, especially for football and male basketball players due to the money involved in those particular sports and general passion. Isolating numerous athletes in the same general academic regiment could increase the probability that standards become lax further reducing the usefulness of the degree. Additionally how many different specific sport majors are going to exist? Will female field hockey players have a “field hockey” major or will wrestlers have a “wrestling” major? What influence would this expansion have on resource utilization at a given university?

A final immediate concern with the idea of a “sport” major is that it seems unnecessary. In some context to a cynic it feels like a strategy to simply increase the probability of retaining eligibility for the student-athlete. Again the short length of career associated with a professional athlete limits the usefulness of such a major due to its generality; basically it is a major for the first five to ten years of an individual’s career with little value in the last twenty to thirty. Going forward with such a mindset is institutionally irresponsible. Instead creating a targeted program for athletes among already existing majors with an increased level of flexibility for appropriate specificity seems more appropriate to support the multiple phases of an athlete’s career as well as their mental growth.

It is important to note that these targeted programs will not be mandatory in any way; clearly it is the prerogative of any individual to study whatever he/she desires in college. However, for those individuals who do not have a strong opinion about what they want to do after their playing days are over a brief interview should be conducted with career counselors before enrollment to identify interests. The key issue in these targeted programs is to apply the experience and skills that athletes acquire during their playing days to ease the transition from primary career as a player to the secondary career as something else.

The first step to identifying these educational programs is to identify the most likely secondary career possibilities. While some caution may be prudent to avoid stereotyping regarding the intelligence of most athletes, the real nature of this identification is to focus on the interests of the athletes. Obviously one of the most popular secondary careers is broadcasting either on a national stage for an organization like NBC, ESPN or FOX or on a local level typically on radio broadcasts for the alma mater. Another common option is to move from player to coach or front office position for a particular sports organization. The third and last “common” secondary career is moving from player to agent using experience in the industry as a player and interactions with existing agents to create a credential basis.

In addition to these “common” secondary careers other possibilities for athletes include becoming a financial advisor or accountant to help other players manage their money successfully; also modern sports have embraced the inclusion of advanced statistical analysis to help make personnel decisions opening up numerous additional job opportunities in these analytical fields for sports organizations. Quality medical personnel are almost always in demand allowing former athletes to become medical trainers for various institutions, either high schools and colleges or a sports team, without the need to acquire medical degrees. Finally for a number of former athletes maintaining quality physical performance demands understanding nutrition and proper off-the-field exercise regimens, elements that can be used to transition into a secondary career as a personal trainer. Fortunately most colleges already offer coursework that grant the necessary skills to succeed in these fields. With this in mind it is appropriate for schools to properly guide student-athletes who are interested in them to the necessary course work to maximize success.

These secondary career strategies are easily established for those who stay in college and receive a degree; however, what does a university do about individuals who leave college early for the professional ranks before acquiring a degree? Clearly if these individuals want to maximize their success at the professional ranks they cannot continue to attend classes due to only a limited amount of time available to spend in class versus studying and practicing at the professional level. Therefore, if pursuit of a degree is postponed for typically at least five years, what is the strategy to initiate a return to this pursuit? One of the obvious problems with restarting study after a long layoff is the diminishment of knowledge over that layoff. Some educational critics cite this “loss of knowledge” as a reason for administering year-round school because of time off for just the three months of summer. Imagine what type of loss will occur over five or more years, one might think that an individual would have to start all over from the beginning. So what should be done?

There are two important elements to this “return to education” issue. The first element is what financial responsibilities do colleges have to former student-athletes who leave for the professional leagues early and then later want to return to continue their education? When a player leaves for the pros that individual foregoes any remaining eligibility to compete at the college/amateur level; therefore, any continuation of an athletic scholarship would be unlikely because there is no quid-pro-quo involved. However, a special academic scholarship could be created for returning former players if those players had certain grade point averages upon leaving the college treating this returning player similar to an academic scholarship received by an incoming high school student. Note that a grade point average floor is required for this new scholarship category because such a floor demonstrates that these former players were taking their studies seriously and actually acquiring knowledge for a secondary career instead of simply trying to maintain their eligibility.

Another possible strategy is to simply extend the athletic scholarship as a single sided element. Some would support this strategy because overall due to economy of scale universities have to invest only a very small amount of money per student and it could be argued that the player in question produced more than fair value during his/her playing days and this scholarship is simply balancing that budget.

The second element is how to prime the returning player for reentry into the educational environment. Unfortunately there is no easy means to accomplish this priming because these “new” incoming students have been away from a study heavy environment for years. It would be difficult to simply go back to square one and start over. One strategy would involve incorporating a pass-fail system for certain classes during the first semester back and then use a grading system for the second semester and beyond; this would create a gauged “stress” environment for the returning players ramping up the difficulty with time allowing for acclimatization to the study environment. However, one concern with this method is that students will not take the first semester seriously because it is pass-fail and thus will not develop the proper mindset for future classes when the grading system changes. The best option may be simply to develop course work so there are interactive elements that catalyze interest in the study portions of the work because of their necessity to succeed in the interactive portions. This design would also help students who are entering these particular fields from high school as well.

Another important element for this priming is to eliminate any stigma associated with age. Some individuals have trepidation about returning to college because at the age of 28+ they think that society feels it is strange that a person so “old” is still attempting to acquire a degree. Another negative rationality may be that returning to college because their playing career is over brands the individual as a failure. Neutralizing these negative elements chiefly involves creating a mindset where returning to college does not represent failure, but instead the pathway to secondary success because the time allotted for their first career has now ended and it is time to find success in another career.

The most important elements to addressing the concern with athletes and their education are course design and associated interest. The first important step is when an athlete enters the college environment to inform the individual of the probability that he will be able to retire after their playing career is over (very low) and identify their interests to gauge what field will produce a desired secondary career. Linking interest instead of simply focusing on keeping the athlete eligible will actually increase eligibility probability through increased engagement and work interest as well as increase skill acquisition. Clearly one of the critical duties of college is to further the development of quality individuals who will produce positive effects in society, thus course work to this end must be taught early; however, there must also be introductory courses for skills required to pursue the secondary career as well.

Overall the creation of a “sport” major for certain sports appears to be a needless strategy that has few benefits. The general gamble of such a degree is that an individual majoring in Basketball will be able to somehow use the major to significantly enhance his ability to make more money as a professional basketball player to the point where once the playing career ends that individual will have enough money to effectively retire from the workforce. This strategy is a gamble because if that does not happen due to bad luck, injury or just lack of ability then this individual will have acquired a major that is effectively worthless even more so than the stereotypical “sociology” or “general studies” degrees that are ridiculed by other parties. Some may counter that a “sports” major would allow secondary careers like the ones mentioned above, but the flaw with that argument is that there is no reason to establish a “sports” major because specialization majors for those types of careers already exist. Basically a “sports” major would be perceived, and due to the typically proposed “labs” taking credits and time, effectively be a dumb down version of those already existing majors. Therefore, instead of establishing a “sports” major, the goal of improving education among athletes should focus on better applying what colleges already offer to what interests student-athletes.

A Possible Strategy for Dealing with Stroke Damage

Interestingly despite the hype and fear attributed to cancer, stroke is the second leading cause of death in the developed world behind only heart disease and responsible for approximately 10% of deaths worldwide.1,2 There are two major types of stroke: ischemic and hemorrhagic. An ischemic stroke is due to a lack of blood flow largely born from a blockage (arterial embolism, thrombosis, etc.). A hemorrhagic stroke is due to a hemorrhage in the brain resulting in abnormal blood flow creating significant losses in most areas of the brain and overflows in others. Not surprisingly limiting blood flow to the brain can rapidly facilitate the loss of brain function due to cellular malfunction and death resulting in difficulty moving one or more parts of the body, trouble talking and hearing, visual difficulty, as well as other motor and cognitive breakdowns eventually leading to death.

Ischemic strokes are more common than hemorrhagic (approximately 80% to 20%) and have four major causes: 1) Thrombosis; 2) Venous thrombosis; 3) Embolism; 4) Systemic hypoperfusion.1,3 Thrombosis involves the obstruction of a blood vessel due to clot formation in the local region. Embolisms are obstructions, typically clots, fat globules or gas bubbles, that form elsewhere in the body that result in blocked blood flow in some other region away from the location of the obstruction. Systemic hypoperfusion is a general decrease in blood supply born from a psychological condition like shock. Due to the fatal outcomes associated with a stroke numerous methods have been developed to recognize its onset, occurrence and aftermath. The onset of most strokes involve face weakness, arm drift and abnormal speech as early symptoms.4

These symptoms only describe overt strokes; another type of stroke is covert where symptoms are relatively absent. Fortunately covert strokes typically result in less brain damage than overt strokes. However, despite the reduced permanent damage, covert strokes are much more common (5x more probable) and can result in significant mental problems like dementia and depression.5 Unfortunately the ongoing problem with strokes is that despite continuing advances in treatment and rehabilitation a vast majority of people who suffer from a stroke will have a permanent cognitive and/or motor impairment.

Some prevention methodologies have been proposed to reduce the probability of a stroke or reduce the damage that occurs during a stroke. Not surprisingly there is significant support for routine physical activity as a means to reduce the probability of an ischemic stroke.6-8 In fact meta-analysis suggests that the benefits of exercise are indiscriminate with regards to sex and that the most active individuals have a 25% reduced rate of stroke versus those who are least active.7

One rationality for why consistent exercise is able to achieve this result is the improvement of vascular function, which increases blood flow efficiency, reduces hypertension and limits infarct size.9,10 Another possibility may simply be that those who exercise the most have healthier lifestyles on a whole then those who do not exercise a lot; however, this rationality foregoes the general health benefits exercise brings. Unfortunately due to the nature of a stroke there is little one can do from a preventative standpoint beyond live a reasonably healthy life of no smoking, no to very moderate drinking, exercise and proper diet.

Some could argue that one should take anti-coagulants like warfarin or blood thinners like aspirin, but these pharmaceutical agents are more reactionary treatments intended to prevent repeat strokes or secondary short-term strokes (similar to aftershocks) versus reducing damage derived from principle strokes. Aspirin is especially used by individuals who have previously suffered myocardial infarctions or with high cardiovascular risk factors like atherosclerosis.5 Some also support the use of clopidogrel and dipyridamole to increase the probability of platelet flow to avoid platelet aggregation, which can lead to clot formation.5 However, there are some concerns that improper timing in treatment with anti-coagulation agents could create a net physiological detriment.11 After the event ischemic strokes are commonly treated with thrombolysis (i.e. clot busting drugs) or intra-arterial fibrinolysis (site injection through a catheter) whereas hemorrhagic strokes typically require neurosurgery due to the excessive bleeding.5

However, these reactionary methods are active methods for reducing damage born from a stroke, which are largely dependent on the existence of secondary available parties because the suffering individual is frequently rendered incapable of assisting him/herself. The development of a passive method to reduce damage without the need to take drugs would go a long way to increasing the probability for reducing damage from strokes, reducing long-term healthcare costs and increasing qualify of life. One possibility for a more passive “damage prevention” therapy revolves around neutralization of reactive oxygen species (ROS).

In the 80s it was theorized that oxidative stress induced damage from ROS was prevalent in the reperfusion stage of post-ischemic strokes and accounted for a significant amount of damage, especially because cells have a reduced capacity to neutralize ROS in ischemic stroke conditions.12-16 The origin of ROS in cerebral ischemia is derived from the events that occur during reoxygenation after spontaneous or thrombolytic reperfusion. The abnormally large and rapid influx of oxygen after the depravation of oxygen leads to accelerated enzymatic reactions, especially in the electron transport chain facilitating the creation of larger than normal concentrations of ROS.

In addition there is a slower build-up of natural antioxidants due to transcription and translation delays due to the lack of oxygen and other signaling molecules. Unfortunately there are still questions regarding the exact mechanisms of this injury, i.e. if it differs from oxidative damage born from ROS in other parts of the body, but the presence of peroxynitrite (ONOO-) and hydroxyl radicals (OH-) are considered important for significant ischemic damage due to their aggressive and indiscriminate damage potentials.17,18

If the ROS damage theory is correct then an obvious prevention strategy would be to increase antioxidant concentrations. However, increasing these concentrations on a dietary or pharmaceutical level has an immediate problem in that both types of antioxidants have difficulties passing the blood brain barrier, if they can at all. Another problem is that there are questions to the general effectiveness of significant antioxidant concentrations derived from pharmaceutical origins where consumption may actually endanger health rather than improve it due to restraints on the ability of cells to absorb these antioxidants.

Another concern with an antioxidant strategy is that while ROS are cytotoxic at large concentrations most also have important roles as signaling molecules that regulate various processes like cellular differentiation, proliferation and apoptosis or even protect against bacterial infections.19-21 Thus there is the possibility that increasing antioxidant concentration too much can neutralize these signaling operations and create negative biological outcomes. Therefore, an alternative strategy is required if antioxidants are going to be utilized to reduce ROS damage in strokes.

The best strategy seems to be providing a natural reactant molecule that will allow the body to facilitate increased natural antioxidant protection. One option for achieving this “on-site limited neutralization” strategy may be increasing gaseous biological hydrogen. Previous research has demonstrated that hydrogen can selectively reduce ONOO- and OH- and have a protective effect on cerebral, hepatic, intestinal, lung and myocardium I/R injury along with neonatal hypoxia ischemia and cerebral ischemia.22-27 This protective effect seems to depend on hydrogen concentrations of approximately 25 umol/L.22

The antioxidant effect of hydrogen also has various secondary advantages: 1) its high natural permeability allows it to penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus; 2) it appears to have a specific selectivity which targets highly reactive ROS leaving less active ROS to perform their necessary secondary messenger signaling functions; 3) a toxicity threshold that is so high that hydrogen is basically non-toxic at any realistic concentration.22

There are two major methods for increasing gaseous hydrogen concentration in the body. First, direct consumption typically achieved by consuming hydrogen-doped water or inhaling hydrogen gas. Hydrogen water is commonly created through electrolysis increasing free hydrogen concentration to anywhere from 0.6 mM to 0.8 mM whereas inhalation of hydrogen gas typically occurs in a 2% by volume hydrogen mixture.28 Basically the feed is designed to replace nitrogen with hydrogen maintaining oxygen concentration.

The second method for increasing biological hydrogen concentration utilizes bacteria in the intestinal system. Bacteria are able to produce excess amounts of hydrogen as a byproduct of fermentation. In most situations there is little to no biological influence from this hydrogen production due to the typical level of normal hydrogen concentrations.29 However, if an individual consumes certain foods fermentation levels can be increased dramatically producing a biologically relevant effect.

One of these key “hydrogen producing” foods is lactulose. Lactulose is a synthetic sugar comprised of one fructose and one galactose molecule and is commonly used in the treatment of constipation.30 The principle reasons for the hydrogen capacity of lactulose is its complex nature and it cannot be digested by the human digestive infrastructure. 20 grams of lactulose can increase exhaled hydrogen to a similar level as 300 ml hydrogen saline with a longer resident time in the body.2,30 While lactulose is relatively non-toxic from a direct consumption perspective there are some concerns that excessive and routine consumption can result in an increased probability for small intestinal bacterial overgrowth.

What is the methodology behind how hydrogen is able to neutralize ROS? Past research supports increasing hydrogen concentrations leading to increases in HO-1, CAT and SOD all agents that are able to neutralize various ROS.31,32 However, after more detailed analysis hydrogen also seems to increase the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).16 Nrf2 is viewed as one of the principle pathways that governs the expression of molecules which act to neutralize oxidative stressors. Some believe that this activation is based on a form of hormesis where H2 is able to mitigate the effects of more toxic ROS species allowing overexpression of less toxic ROS, which leads to the activation of Nrf2 eventually neutralizing the lesser ROS species.22 In scenarios that lack sufficient H2 concentrations there is a higher probability of the more toxic ROS trigger cell damage and apoptosis limiting the future activation of the Nrf2 pathway leading to a cascade damage effect.

This hormesis process is thought to occur as followed. Under normal conditions Nrf2 is stored in the cytoplasm by Kelch like-ECH-associated protein (Keap1) and is tagged by Cullin 3 for ubiquitination resulting in a typical half-life of only 20 minutes. Under oxidative stress conditions it is thought that cysteine residues in Keap1 are disrupted dramatically reducing the probability of Cullin 3 tagging both through reducing binding efficiency and increasing Nrf2 mobility as disruption of Keap1 allows Nrf2 to translocate into the nucleus. Presence in the nucleus allows Nrf2 to form a heterodimer with small Maf protein and bind antioxidant response element (ARE) that activates numerous anti-oxidative genes initiating their transcription and translation.

However, hormesis is a somewhat controversial idea biologically. So others believe that hydrogen directly activates Nrf2-dependent genes like HO-1 and it is Nrf2 activation that results in the neutralization of ROS. This belief is supported by research where the protective effects of hydrogen were lost in Nrf2-deficient mice.31 While there exists the possibility that hydrogen can directly scavenge ROS the activation of Nrf2 appears to be the dominant method behind the correlation between increased hydrogen concentration and reduced ROS damage. However, the exact relationship between hydrogen, ROS neutralization and Nrf2 activation remains unclear. Despite the lack of specific details in this relationship, both the consumption of hydrogen doped saline/water and the consumption of lactulose increase hydrogen concentrations in vivo and also has neuroprotective effects with regards to strokes.27

Another possible mechanism for hydrogen-induced protection could involve not hydrogen directly, but the conversion of hydrogen to hydrogen sulfide (H2S). There is some evidence to suggest that H2S is a cytoprotective against oxidative stress in similar context to Nrf2,33-36 especially with regards to peroxynitrite (ONOOH/ONOO-) or hypochlorite (HOCL).37,38 While some believe that this antioxidant ability is derived from direct scavenging of oxidants due to its comparable reactivity to cysteine and glutathione,33,38,39 this belief does not seem accurate because the reaction between H2S and ROS is too slow41 and the H2S concentration is too low in vivo40,42 even despite the possibility of metallic catalyst availability.43 Therefore, H2S may interact with Nrf2 increasing expression rates and thereby increasing its protective effects against ROS. Of course one of the problems with theorizing about the role of H2S as an antioxidant is the lack of reliable methods to specifically measure H2S in vivo to tie H2S concentration increases to Nrf2 concentration increases.44,45

There is remaining uncertainty corresponding to increasing gaseous hydrogen concentration in the blood and its role in managing stroke damage, but studies in mice have demonstrated encouraging results regarding stroke induced damage reduction that should drive further study in humans.2,27 In fact some preliminary studies with lactulose has demonstrated reduced symptoms in Parkinson disease patients.27 With the general cost of lactulose or hydrogen doped water being very cheap if this method is applicable to reducing damage from strokes in a passive manner (just drink x amount of hydrogen doped water a day) millions of dollars can be saved in healthcare expenses as well as increasing the quality of life for numerous people. Overall while this hydrogen preventative theory is in its early stages of development, it would be in the best interest of official organizations like the American Stroke Association to investigate human applications of increasing hydrogen concentrations to reduce stroke damage.

Citations –

1. Donnan, G, et Al. “Stroke.” Lancet. 2008. 371:1612-1623.

2. Chen, X, et Al. “Lactulose: an effective preventive and therapeutic option for ischemic stroke by production of hydrogen.” Medical Gas Research. 2012. 2:3-7.

3. Sims, N, and Muyderman, H. “Mitochondria oxidative metabolism and cell death in stroke.” Biochim. Biophys. Acta. 2010. 1802:80-91.

4. Wikipedia Entry – Stroke.

5. Vermeer, S, Longstreth Jr., W, and Koudstall, P. “Silent brain infarcts: a systematic review.” Lancet Neurology. 2007. 6:611-619.

5. Goldstein, L, et Al. “Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006. 113:e873–e923.

6. Reimers, C, Knapp, G, and Reimers, A. “Exercise as stroke prophylaxis.” Deutsches Arzteblatt International. 2009. 106:715-721.

7. Middleton, L, et Al. “Physical activity in the prevention of ischemic stroke and improvement of outcome: a narrative review.” Neuroscience and Biobehavioral Reviews. 2013. 37:133-137.

8. Leung, F, et Al. “Exercise, vascular wall and cardiovascular diseases: an update (part 1). Sports Medicine. 2012. 38:1009-1024.

9. Yung, L, et Al. “Exercise, vascular wall and cardiovascular diseases: an update (part 2). Sports Medicine. 2009. 39:45-63.

10. Paciaroni, M, et Al. “Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials.” Stroke. 2007. 38:423-30.

11. Flamm, E, et Al. “Free radicals in cerebral ischemia.” Stroke. 1978. 9:445-447.

12. Chan, P. “Oxygen radicals in focal cerebral ischemia.” Brain Pathol. 1994. 4:59-65.

13. Ozkul, A, et Al. “Oxidative stress in acute ischemic stroke.” J. Clin. Neurosci. 2007. 14:1062-1066.

14. Nanetti, L, et Al. “Oxidative stress in ischaemic stroke. Eur. J. Clin. Invest. 2011. 41:1318-1322.

15. Shi, D, et Al. “Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression.” Free Radical Biology and Medicine. 2013. 65:731-741.

16. Chen, H, et Al. “Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection.” Antioxid. Redox Signaling. 2011. 14:1505–1517.

17. Chan, P.H. “Oxygen radicals in focal cerebral ischemia.” BrainPathol. 1994. 4:59–65.

18. Sauer, H, Wartenberg, M, and Hescheler, J. “Reactive oxygen species as intracellular
messengers during cell growth and differentiation.” Cell. Physiol. Biochem. 2001. 11:173–186.

19. Liu, H, et Al. “Redox-dependent transcriptional regulation.” Circ. Res. 2005. 97:967–974.

20. Winterbourn, C. “Biological reactivity and biomarkers of the neutrophil oxidant,
hypochlorous acid.” Toxicology. 2007. 181:223–227.

21. Ohsawa, I, et Al. “Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.” Nature Medicine. 2007. 13(6):688-707.

22. Fukuda, K, et Al. “Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress.” Biochem. Biophys. Res. Commun. 2007. 361:670–674.

23. Zheng, X, et Al. “Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats.” Free Radic.Res. 2009. 43:478–484.

24. Zheng, J, et Al. “Saturated hydrogen saline protects the lung against oxygen toxicity.” Undersea Hyperbaric Med. 2010. 37:185–192.

25. Sun, Q, et Al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp. Biol.Med. 2009. 234:1212–1219.

26. Cai, J, et Al. “Neuroprotective effects of hydrogen saline in neo-natal hypoxia–ischemia rat model.” Brain Res. 2009. 1256:129–137.

27. Ito, M, et Al. “Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats.” Medical Gas Research. 2012. 2:15-22.

27. Levitt, M. “Production and excretion of hydrogen gas in man.” New England Journal of Medicine. 1969. 281:122-127.

28. Voskuijl, W, et Al. “PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial.” Gut. 2004. 53:1590-1594.

29. Kawamura, T, et Al. “Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo.” Am. J. Physiol. Lung Cell Mol. Physiol.” 2013. 304:L646–L656.

30. Li, J, et Al. “Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines.” Brain Res. 2012. 1486:103–111.

31. Li, Qian, and Lancaster Jr, J. “Chemical foundations of hydrogen sulfide biology.” Nitric Oxide. 2013. 35:21-34.

32. Fu, Z, et Al. “Hydrogen sulfide protects rat lung from ischemia-reperfusion injury.” Life Sci. 2008. 82:1196-1202.

33. Jha, S, et Al. “Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and anti-apoptotic signaling.” Am. J. Physiol. Heart Circ. Physiol. 2008. 295:H801-H806.

34. Kimura, Y, Goto, Y, and Kimura, H. “Hydrogen sulfide increase glutathione production and suppresses oxidative stress in mitochondria.” Antioxid. Redox. Signal. 2010. 12:1-13.

35. Whiteman, M, et Al. “The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite scavenger?” J. Neurochem. 2004. 90:765-768.

36. Whiteman, M, et Al. “Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain?” Biochem. Biophys. Res. Commun. 2005. 326:794-798.

37. Tapley, D, Buettner, G, and Shick, J. “Free radicals and chemiluminescence as products of the spontaneous oxidation of sulfide in seawater, and their biological implications.” Biol. Bull. 1999. 196:52-56.

38. Carballal, S, et Al. “Reactivity of hydrogen sulfide with peroxxynitrite and other oxidants of biological interest.” Free Radic. Biol. Med. 2011. 50:196-205.

39. Chen, K, and Morris, J. “Kinetics of oxidation of aqueous sulfide by O2.” Environ. Sci. Technol. 1972. 6:529-537.

40. Nagy, P, and Winterbourn, C. “Rapid reaction of hydrogen sulfide with the neutrophil oxidant hypochlorous acid to generate polysulfides.” Chem. Res. Toxicol. 2010. 23:1541-1543.

41. Baxter, C, and Van, R. “The oxidation of sulfide to thiosulfate by metalloprotein complexes and by ferritin.” Biochim. Biophys. Acta. 1958. 28:573-578.

42. Olson, K. “A practical look at the chemistry and biology of hydrogen sulfide.” Antioxid. Redox. Signal. 2012. 17:32-44.

43. Whiteman, M, et Al. “Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools.” Clin. Sci. (Lond). 2011. 121:459-488.