EXERCISE-ASSOCIATED HYPONATREMIA

Abstract

Exercise-associated hyponatremia (EAH) is defined by an acute fall in the serum or plasma sodium concentration to below 135 mmol/L that occurs during or up to 24 hours after prolonged physical activity. EAH has been reported in nearly every form of endurance activity and has a common pathogenic feature of excessive water intake which is usually coupled with elevated vasopressin levels. Symptomatic EAH is uncommon but can be a cause of mortality in otherwise healthy adults and children. Rapid recognition and appropriate treatment with hypertonic saline are essential to maximizing outcomes and preventing death.

INTRODUCTION

Exercise associated hyponatremia (EAH) was described more than 3 decades ago and through the efforts of numerous investigators the pathogenesis, prevention, and therapy of this condition are now well understood with the significant role of overhydration being the primary etiologic factor (1). It is clear that EAH represents a preventable condition associated with significant morbidity and mortality in otherwise healthy individuals engaged in endurance activities (2-8). In recent years, EAH has been documented in a broader range of activities including in hikers, kayakers, climbers, and other endurance athletes (9-14). Given the common pathogenic features, it is likely that anyone engaged in prolonged physical activity who is drinking copious amounts of fluids is at high risk for EAH (15,16).

EPIDEMIOLOGY

EAH is defined by a serum or plasma sodium concentration below the normal reference range of 135 mmol/L that occurs during or up to 24 hours after prolonged physical activity (7). The reported incidence of EAH varies widely, in part because the diagnosis is based solely on an abnormal biochemical result in an appropriate clinical setting. Thus, reporting bias exists as the majority of asymptomatic individuals will not have laboratory testing or an indication for testing. Most cases of EAH may be asymptomatic and these are usually detected from blood samples taken from consenting athletes participating in research screening protocols or for other reasons, with a reported incidence ranging from 0% to 51% (13,17-19). Typically, higher incidence rates for EAH are seen in longer endurance activities such as Ironman Triathlons.

The incidence of asymptomatic EAH is greater than the incidence of “symptomatic” EAH, which refers to a biochemical diagnosis of EAH combined with clinical symptoms and signs consistent with hyponatremia that can range from headache, nausea, and vomiting to confusion and seizures. All of the symptoms of EAH are related to the central nervous system and reflects acute rises in intracranial pressure due to cellular edema. The most severe level of EAH manifests as significant mental status changes resulting from cerebral edema (termed exercise-associated hyponatremic encephalopathy [EAHE]), and may at be times associated with noncardiogenic (neurogenic) pulmonary edema (5,6). At least, 12 confirmed deaths of public record have been directly attributed to complications associated with EAHE; however, this number is likely an underrepresentation of the true mortality associated with EAH (20-24). The overall incidence of symptomatic EAH in marathon runners is typically less than 1%, but the percentage of EAH seen in all symptomatic athletes seeking medical care has been reported to be as high as 23% in an Ironman Triathlon and 38% in runners participating in a marathon and ultramarathon in Asia (24-27). An increasing trend is that symptomatic EAH is now being reported in much shorter distance events (28, 29).

Symptomatic cases of EAH have also been reported with increased frequency in hikers. The reported incidence of hyponatremia in Grand Canyon hikers seeking medical care from exercise-associated collapse or exhaustion from May 31, 1993, through September 31, 1993, was 16% with an estimated incidence rate between 2.0 and 4.0 per 100,000 persons (9,30,31). US military services have reported an increased incidence of EAH cases primarily in Marine Corps and Army infantry personnel over the past decade (32,33). However, newer data (1999 to 2012) released in March 2013 show an EAH incidence rate of 6.7 cases/100,000 person-years in US military services. These new data suggest that the annual incidence of EAH may have decreased by almost 50% from 2010 to 2012 and may reflect changes in recommendations regarding safe hydration levels (34,35).

PATHOGENESIS OF EAH

Two major pathologic mechanisms largely account for the development of EAH: 1) excessive fluid intake; and 2) impaired urinary water excretion, largely as a result of persistent secretion of arginine vasopressin (AVP), also referred to as antidiuretic hormone or ADH (4,5).

Excessive Fluid Intake

Overhydration appears to be the primary risk factor for the development of EAH. This is reflected in the weight gains seen in the majority of, but not all, athletes who become symptomatic with EAH. Individuals with normal renal function, ingesting a regular diet, can excrete between 500 and 1000 mL/h of water (36). With the additional nonrenal losses of water as a result of sweat and insensible fluid losses, athletes should be able to consume as much as 1000 to 1500 mL/h before developing water retention and dilutional hyponatremia. Thus, although fluid ingestion is necessary to develop EAH, it is likely not sufficient in itself except in those circumstances in which water intake is very excessive (>1500 mL/h). Thus, other factors must play a role in leading to EAH.

Inappropriate Vasopressin Secretion

Failure to suppress AVP can markedly reduce the ability of the kidneys to excrete a water load. Under normal circumstances, ingestion of excessive water should suppress AVP secretion, leading to production of dilute, high-volume urine (urine osmolality as low as 50 mOsm/kg and a volume of 500 to 1000 mL/h). If AVP is not suppressed appropriately with water loading, then the ability to produce dilute urine is markedly impaired (for instance, a low-level persistence of AVP can result in a fixed urine osmolality of 150 mOsm/kg and a decrease in the rate of water excretion by two-thirds as compared with a urine osmolality of 50 mOsm/kg). In fact, the available data support the concept that many athletes who experience EAH have submaximal suppression of AVP and an inappropriately high urine sodium and osmolality (23,35,37). There are a number of nonosmotic stimuli that lead to secretion of AVP that may be operable in endurance athletes: intense exercise itself, nausea or vomiting, hypoglycemia, and nonspecific stresses such as pain and emotion (38-41). These stimuli through their effects on the hypothalamus can lead to AVP secretion despite the serum osmolality being lower than normal. Not all AVP release in athletes may be inappropriate, as excessive sweat losses may induce volume depletion and appropriate secretion of AVP in an effort to conserve intravascular volume. This appropriate AVP secretion may be important in the subset of athletes who develop hypovolemic hyponatremia. In this case, the volume losses are replaced by hypotonic fluids while renal water retention inhibits the ability to excrete this water load.

Other Factors

An interesting and perplexing finding has been that only a minority of athletes with weight gain (from ingestion of hypotonic fluids) will develop hyponatremia. In these athletes, some mechanism protects the serum sodium from falling below normal despite excess fluid gain. A possible mechanism for maintenance of a normal serum sodium level despite weight gain is the release of sodium from internal stores (42). Up to 25% of body sodium is bound in bone (to negatively charged proteoglycan matrix) and, although not osmotically active, is potentially recruitable into an osmotically active form (43-46). Thus, this pool could minimize the fall in serum sodium induced by overhydration or exacerbate hyponatremia if not mobilized. Whether impairment of this system might play a role in the development of EAH in some individuals is not clear (19).

The absorption of water retained in the gastrointestinal tract at the end of a race has been suggested as a cause for an acute drop in serum sodium concentration (22,25). This may account for a transient lucid period after finishing a race followed by the acute development of clinical signs of EAHE within approximately 30 minutes after a competition as the retained water in the gastrointestinal tract is absorbed into the circulation.

The issue of whether sweat sodium loss contributes to the development of EAH remains controversial. There is a highly variable degree of sodium loss from sweat (ranging from 15 to 65 mmol/L), and compared with the general population, endurance athletes generally have lower sweat sodium levels (47,48). The direct effect of losing hypotonic sweat would be to raise the serum sodium. However, sweat loss could contribute to the development of hyponatremia if the degree of fluid loss were sufficient to produce significant volume depletion and provide a stimulus to AVP release, thereby impairing excretion of water. In this case, there would also have to be ingestion of hypotonic fluids (i.e., replacing hypotonic sweat fluid loss with an even more hypotonic fluid).

RISK FACTORS

As stated above, the major risk factor for developing EAH is excessive water intake beyond the capacity for renal water excretion (49,50). Other independent risk factors include longer race times and a low or high body mass index (7, 23, 25, 49, 51). Although the incidence of women experiencing symptomatic hyponatremia appears to be greater than that of men in some environments, when adjusted for body mass index and racing time, the apparent sex difference has not been shown to be statistically significant (51).

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been implicated as a risk factor in the development of EAH by potentiating the water retention effects of AVP in the kidney (52-60). However, data are still conflicting and further investigation is necessary to determine whether NSAID usage is a clear risk factor for the development of EAH. Other medications associated with the syndrome of inappropriate antidiuretic hormone, such as selective serotonin reuptake inhibitors, may also increase the risk for EAH, but data are not conclusive.

PREVENTION

The primary strategy to prevent EAH is to avoid overdrinking during exercise. Because fluid losses through sweat and urine are highly dynamic and variable across individuals participating in a variety of outdoor activities, recommending fixed ranges of fluid intake are not appropriate and even potentially dangerous. Using the sensation of thirst as a real-time guide to fluid ingestion during exercise appears safe and effective and eliminates both of the detrimental extremes of fluid balance (dehydration and overhydration) (7,61-64). Therefore, participant education on this approach to hydration during exercise is an important prevention strategy. Another strategy that has been shown to reduce the incidence of hyponatremia during endurance events is to reduce the availability of fluids along the routes of exercise (65). There is no evidence that sports beverages can lower the incidence of EAH (5). This is likely due to the fact that the sodium content of these drinks is in the range of 20 to 30 meq/L.

Monitoring Body Weight

Because overconsumption of hypotonic fluids beyond the capacity to excrete any fluid excess is often key in the pathophysiology of EAH, the monitoring of body weight change is one strategy commonly used in 161-km ultramarathons to help prevent overhydration. As a result of the combination of substrate losses and the liberation of glycogen-bound water during exertion, some weight loss is appropriate during exercise. Therefore, in the presence of weight gain during exercise, fluid intake should be reduced. If feasible, weight scales can be made available at organized athletic events for this purpose, but care should be taken to assure proper scale calibration and placement on solid level surfaces, and participants should be educated in proper use of body weight information.

Educate Event Support and Medical Personnel

Event support staff should have a basic understanding of EAH to avoid the provision of improper hydration advice to participants because it has been previously shown that participants in endurance events have a poor understanding of the relationship between drinking habits and hyponatremia (66,67). On-site medical personnel should be aware of proper treatment of EAH. This should include the recognition that hypotonic fluid replacement (intravenous or oral) should be avoided when the diagnosis of EAH is under consideration to prevent further declines in blood sodium concentration. Such education can be provided by event medical directors via pre-race briefings and the use of suggested reading material or educational videotapes.

FIELD TREATMENT

Appropriate management of EAH depends first on correctly diagnosing the condition. EAH must be routinely considered in the differential diagnosis of an individual presenting for medical attention during or shortly after exercise or strenuous activity. EAH can easily be mistaken for dehydration, heat illness, or acute altitude illnesses because of overlapping signs and symptoms if the diagnosis is not considered (68,69).

Differentiation between dehydration and EAH is critical as provision of isotonic or hypotonic fluids is appropriate for the dehydrated athlete, whereas such treatment could be detrimental for an athlete with EAH in whom the administration of these hypotonic or isotonic fluids may worsen symptoms or delay recovery (70,71). A conclusion of the Second International Exercise Associated Hyponatremia Consensus Development Conference was that “medical directors should ensure the availability of onsite serum sodium concentration analysis (7).” When EAH is routinely considered in the differential diagnosis of a collapsed participant and point-of-care serum sodium concentration analysis is available, the field diagnosis of EAH becomes straightforward. The reality is that on-site analysis of serum sodium concentration is not widely available at organized endurance competitions, nor is it currently feasible to widely implement. This is also the case with most wilderness activities.

HYPERTONIC SALINE

It is possible to commence and even complete treatment for EAH in the field (72-75). Individuals with EAH who are neurologically stable can be advised to limit fluid intake and consume salty snacks, soups or bouillon, or a small volume of hypertonic fluid until the onset of urination. They should be observed for at least 60 minutes during the initial post-exercise period because water remaining in the gastrointestinal tract can be quickly absorbed at the cessation of exercise and result in rapid development of symptoms from EAH (22,25). More urgent medical attention, including planning for transfer to definitive care, is required if signs or symptoms of EAHE develop. Once any neurological symptoms more serious than headache develop, regardless of the degree of hyponatremia, treatment with hypertonic 3% saline is indicated. When able to tolerate oral intake, a hypertonic (approximately 9% saline) solution of concentrated broth (3 to 4 bouillon cubes in 125 mL [1/2 cup] of water) would be an appropriate initial treatment (73-75).

If the individual is unable to tolerate oral intake, or when there is no improvement or symptoms worsen with oral hypertonic saline, the recommended treatment is a 100-mL bolus of 3% hypertonic saline infused through a peripheral vein in less than 60 seconds. This can be repeated two additional times at 10-minute intervals if there is no clinical improvement (7). Experience has proven this treatment to be without untoward symptoms at the infusion site (no burning, phlebitis, or residual discomfort) and no risk of osmotic demyelination or central pontine myelinolysis (7,22,23,25,35). This amount of hypertonic 3% saline is generally effective at raising the serum sodium by 3 to 5 meq/L and significantly decreasing intracranial pressure. Follow-up monitoring and, if needed, additional therapy should follow in an acute care environment.

CONCLUSIONS

EAH has a complex pathogenesis and multifactorial etiology; but ultimately, overhydration is critical in its development. It can result in devastating outcomes to participants in both organized or individual endurance activities in urban or in remote backcountry environments.

Preventing EAH is the key factor in protecting participants in endurance events and other wilderness activities. Currently, there is no one recommendation that fits all individuals for fluid and salt consumption during endurance events, although prudent general guidelines include drinking to thirst and specifically avoiding excessive fluid intake. There is an ongoing need for education to ensure that participants understand the risk of overhydration.

DISCUSSION

Zeidel, Boston: Wonderful talk. There's a lot of new research coming out on the hypothalamic control of ADH release in thirst and salt intake. I have to believe that all these individuals have messed up hypothalami and you've got Patrice Guyenet at your institution. It might be very interesting to see if this could be looked at in some fashion to understand what goes wrong in these people so that their thirst mechanism isn't right, and the water handling is probably affected by the exercise.

Rosner, Charlottesville: It does seem to be that this is really a conditioned behavior more than anything. You ask these people, and it's not thirst that's really guiding their activity. It's really the sense that they feel like they've been told that they have to drink constantly.

Barish, Baltimore: There's an issue here, because the leading cause of death among athletes is still heat stroke. I think the high school coaches are very concerned that they're under-hydrating their athletes and that they will be held responsible for the issue of heat stroke. So it's kind of a balancing act. When you talked about those two high school athletes, I wonder if their coaches were going in the wrong direction in over-hydrating them, being concerned about heat stroke.

Rosner, Charlottesville: I think one of the most dangerous activities in the United States is summer football practice; it's just a bad thing. The answer is quite simple. What we've advocated is just put a scale on the sidelines. If you have an athlete who is clearly losing a lot of weight and sweating profusely, they need hydration and electrolyte supplementation. If the athlete is drinking so much that after an hour they've actually gained weight, that's a problem and they need to stop. So it could be that simple. The other thing to remember is that our own thirst mechanism is incredibly powerful. We're not telling people not to drink. We're telling people to drink sensibly and not to over drink.

Barish, Baltimore: The new guideline in the NFL is no pads and no heavy contact for the first 10 to 14 days, with fans on the side. So they completely changed their protocol for this. That was excellent, and it's just the issue of over-hydration and under-hydration and it's a problem both ways.

Rosner, Charlottesville: NFL teams have closely monitored players hydration and take this issue very seriously.

Oates, Nashville: The urine that you showed looked like rhabdomyolysis.

Rosner, Charlottesville: It was.

Oates, Nashville: I wonder if you have correlated your results with myoglobin and blood in urine?

Rosner, Charlottesville: There's a curious phenomenon in that the athletes who get the most severe hyponatremia also get rhabdomyolysis and really bad rhabdomyolysis. We're not sure exactly about the mechanism, but that correlation is very strong. There's some reasons hypothetically why they may be linked, but there seems to be a link between getting severe rhabdomyolysis and severe hyponatremia. What I can't tell you is what the prevalence is of rhabdomyolysis among all marathon runners, because we just don't check. But I can tell you that in the people that we do check it's very, very common.

Oates, Nashville: Serotonin reuptake inhibitors promote hyponatremia. I wonder if you've examined that in your studies.

Rosner, Charlottesville: So, both NSAIDS and SSRIs are certainly associated epidemiologically with a higher risk of developing this.

Sacher, Cincinnati: Actually many of these patients have hemoglobinuria because of march hemoglobinuria and actually hemolysis.

Weir, Baltimore: As an aging marathoner myself, if you want to be competitive you try not to drink unless you have to because it's time consuming, both in terms of what goes in and what must come out, obviously. Is there any correlation in your efforts of looking at the time of the race versus the risk for hyponatremia? I would submit to you that the people who are really competitive and trying to get keep their times low are going to be probably be drinking less and be less susceptible to this.

Rosner, Charlottesville: You're exactly right. So, longer marathon times are associated with a higher risk. Not surprising they're drinking more. There's a clear myth that drinking improves performance. It's actually the opposite. People who actually lose a certain amount of weight actually do better. You can probably look at that from your own experience. The winning marathon runners seldom if ever drink anything. In fact, if you look at data collected prior to 1981, there's no evidence that holding back — or not over hydrating — decreases your performance. So, I think you're exactly right.

Weir, Baltimore: Any research on angiotensin-2 levels along with your arginine vasopressin?

Rosner, Charlottesville: No, we don't have any data on that, sorry.

Weir, Baltimore: It would be worth looking into that.

Wilson, Durham: Has your group or any other group reached out to the most vulnerable group, our high school students? I think they probably have the highest death rate. I know the NFL has a lot of money and publicity, but what are we doing to save the children?

Rosner, Charlottesville: The last consensus conference that we had, which was about 2 years ago, we actually partnered with some exercise groups. We've tried hard. I will say, the receptivity to our efforts has been less than optimal. There are people who have very strong beliefs. The biggest group that we fight is the athletic trainers who really just frankly are wedded to the idea that more hydration is good.

Wilson, Durham: Having had student athletes as my children, the trainers are usually very poorly trained.