02 December 2014

Exercise associated hyponatremia and ultramarathon running

November has come to an end. It was an unusually dark and cloudy month and I had actually not a single sun hour during the whole month. Something of a personal record, even worse than when I lived in Seattle one cloudy and foggy winter (and there you can always go up in the mountains). Indeed rather depressing, but from a running perspective it was a good month with warm temperatures and not too much rain. The training has been rather repetitious and I have been logging rather solid volume weeks, but without anything extraordinary. I am now looking forward to finalize my race plans for next year now so that I will get clear goals to train for and adapt my training to, but I am still waiting for the outcome of some lotteries. As the races I am considering are very different my upcoming training will to a great extent be dictated by this.
 

Fog during November morning commute run
 
I also hope I will be more inspired to write on the blog once I have clear goals. Now I have been rather content with reading others and there have neither been any new scientific articles or discussions regarding mountain ultramarathons prompting me to do research in a particular area. Nevertheless, the other day I came into a discussion again whether ultramarathon running is dangerous or not. It is a rather sensitive topic and some runners become quite agitated when someone says it indeed is dangerous. Even though it has not been shown in any good large prospective studies yet, I am personally completely convinced that ultramarathon runners, with an active lifestyle, in general are much healthier with less disease and lower mortality than people with an increasingly sedentary lifestyle. Future studies will tell me whether I am right, but early data from the ULTRA study of over 1000 ultrarunners indicated that it is correct (Hoffman & Krishnan “Health and exercise-related medical issues among 1,212 ultramarathon runners: baseline findings from the Ultrarunners Longitudinal TRAcking (ULTRA) Study” PLoS One 2014; 9:e83867).

However, I am also completely convinced that ultramarathon running, and in particular mountain ultra trail running, is quite dangerous. Just being in the mountain environment is dangerous and there is no way to avoid the sometimes lethal objective dangers on the mountain, as I have discussed before in my blog. I am also certain that running ultramarathons is quite stressful for the body and that it in some individuals can induce injuries and illness both long-term, like stress-fractures, and short-term, like exercise-associated hyponatremia (EAH), the subject of this blog post, that the affected person would not have experienced if he or she had not been putting the body to the stress of running for such long distances. The line between a healthy physiological reaction and a damaging pathological reaction to an endurance exercise is sometimes quite thin and to refuse to accept this is poor management of the subjective risks associated with ultramarathon running.

What provoked the discussion about whether it is dangerous to run an ultramarathon or not was a discussion about a post at one of the most popular Swedish trailrunning blogs where the blogger according to her self-described symptoms probably developed a very severe exercise-associated hyponatremia (EAH) during one of the UTMB races this year. It is clear from the post itself and the comments on it that the knowledge about EAH; its causes and its dangers in many ultramarathon runners appears clearly very limited. That is really sad as some knowledge about EAH literally can save lives. On the other hand, I barely had heard about EAH before I started running longer distances and there are indeed many erroneous conceptions about EAE. Some of the statements in the blog post we discussed clearly confirm this and I become quite agitated when erroneous and misleading information is given that can lead to more runners risking their health unnecessary. In the following I will at least try to give solid facts, at least as far as we know today in 2014, about EAH, ultramarathon running and hydration and to answer some of the common questions. My apologies again if the blog post is too technical.

 
What is Exercise-associated hyponatremia (EAH)?
EAH is defined as low serum or plasma sodium concentration below the normal reference range of 135 mEq/L (or  < 135 mmol/L) during or after exercise.

Good review articles about EAH is the WMS Practice Guideline about EAH published in 2013 (Bennett et al 2013 “Wilderness Medical Society practice guidelines for treatment of exercise-associated hyponatremia” Wild Environ Med 2013; 24: 228-240) and Rosner & Kirven’s review article from 2007 (Rosner & Kirven “Exercise-Associated Hyponatremia” Clin J Am Soc Nephrol 2007; 2: 151-161).

What is Exercise-Associated Hyponatremic Encephalopathy (EAHE)?
EAHE is EAH with symptoms of cerebral edema such as for instance altered mental status, altered level of consciousness, headache, convulsion/seizures or coma.

What are the mechanisms behind EAH?
There are three major pathological mechanisms behind EAH:

1) Excessive fluid intake (overhydration; water intoxication)
2) Impaired urinary water secretion largely due to persistent inappropriate secretion of arginine vasopressin (AVP) (also called antidiuretic hormone [ADH])
3) Failure to mobilize sodium (Na+) from osmotically inactive sodium stores in the body or alternatively inappropriate osmotic inactivation of circulating Na+

It appears that these mechanisms are needed together for development of EAH in most cases, except in those circumstances where the water intake is extremely excessive (>1500 mL/h). The causes of the inappropriate AVP secretion in EAH and its role in the disease is the focus of ongoing research (see for instance Cairns & Hew-Butler “Incidence of Exercise-Associated Hyponatremia and its association with nonosmotic stimuli of Arginine Vasopressin in the GNW100s ultra-endurance marathon” Clin J Sport Med 2014; Epub ahead of print; Hew-Butler “Arginine vasopressin, fluid balance and exercise: is exercise-associated hyponatraemia a disorder of arginine vasopressin secretion?” Sports Med 2010; 40: 459-79). However, it appears likely that in some individuals the stress of long endurance activities such as ultramarathon running might cause the high AVP secretion.


Main mechanisms behind EAH. From Bennett et al 2013
 
When was EAH first described?
The first case of symptomatic EAH was described in 1981 in a runner admitted to hospital after she became unconscious and had a grand mal epileptic seizure during the 56 mile (90 km) Comrades Marathon in Durban, South Africa. Her sodium concentration upon admittance to hospital was 115 mmol/L confirming EAHE. She recovered and regained consciousness after 2 days and was released from hospital after 4 days. This case and three other of ultra-endurance athletes were described by Noakes and colleagues in a seminal publication in 1985 (Noakes et al “Water intoxication: a possible complication during endurance exercise” Med Sci Sports Exerc 1985; 17: 370-5). Regretfully, it then took many years before the link between overhydration and EAH was widely accepted and hydration recommendations were changed (Noakes et al “Case proven: Exercise associated hyponatremia is due to overdrinking. So why did it take 20 years before the original evidence was accepted? Br J Sports Med 2006; 40: 567-72). It has regretfully also taken many years before a standard first-line treatment for EAH has been accepted (Moritz & Ayus “Exercise-associated hyponatremia: Why are athletes still dying?” Clin J Sport Med 2008; 18: 379-381).

What are the risk factors for EAH?
The risk factors for EAH has been studied in a number of large studies, for instance in 488 Boston Marathon runners (Almond et al “Hyponatremia among runners in the Boston Marathon” N Engl J Med 2005; 352: 1550-6) and following 2135 weighed competitive athletic endurance performances (Noakes et al “Three independent biological mechanisms cause exercise-associated hyponatremia: Evidence from 2,135 weighed competitive athletic performances” Proc Natl Acad Sci USA 2005; 102: 18550-55). The main confirmed risk factors for EAE are:

1) Excessive water intake (in particular > 1.5 L/h) during exercise
2) Pre-exercise overhydration
3) Long race time (> 4 hour)
4) Low Body Mass Index (BMI) (i.e. small athletes following fluid intake guidelines for larger individuals)
5) High Body Mass Index (BMI) (i.e. slower unfit athletes drinking generous amounts of fluid as they are exercising at a lower intensity)

In some studies female sex have been associated with a higher incidence of EAH, but when adjusted for body weight/BMI and race time this appears not to be an independent risk factor. The use of drugs such as non-steroid anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs) and thiazide diuretics has also been associated with a higher risk for EAH, but further studies are needed to confirm this. No good study has compared the risk of EAH in various temperatures, but it appears that endurance exercise at either very high or very low temperatures might be a risk factor and more research is needed here as well.

Can you develop EAH in cold weather?
Yes, there are several case reports of EAH in cold weather conditions. Indeed, one of the highest frequencies of EAH in an ultraendurance event was recorded in the 100-mile Iditasport ultramarathon were 7/16 (44%) investigated participants were found to be hyponatremic (Stuempfle et al “Hyponatremia in a cold weather ultraendurance race” Alaska Med 2002; 44: 51-5).

Is EAH related to the sweat rate and/or content of the runner?
This is controversial and unclear. There is a highly variable degree of sweat rate and sodium loss from sweat (ranging from 15 to 65 mEq/L) and compared with the general population endurance athletes appear to have lower sweat sodium levels and loss of hypotonic sweat might raise serum sodium levels (Buono et al “ Sodium ion concentration vs sweat rate relationship in humans” J Appl Physiol 2007; 103: 990-994). However, on the contrary, sweat loss might also provide a stimulus to AVP release and impair urine excretion of water and in association with consumption of hypotonic fluids might lead to development of EAE. This might be one scenario for development of EAH in athletes with net weight loss. Furthermore, it has recently been investigated whether there could be any genetic association between impaired sweat function as in cystic fibrosis and EAH without finding any correlation (Lewis et al “The need for salt: does a relationship exist between cystic fibrosis and exercise-associated hyponatremia?” J Strength Cond Res 2014; 28: 807-13).

How common is EAH in ultramarathon running?
The incidence of EAH without symptoms (asymptomatic EAH) has in 100-mile ultramarathon races in North America been found to be between 30 and 51% (Stuempfle et al “Hyponatremia in a cold weather ultraendurance race” Alaska Med 2002; 44: 51-5; Lebus et al “Can changes in body mass and total body water accurately predict hyponatremia after a 161-km running race?” Clin J Sport Med. 2010; 20: 193-9; Hoffman et al “Hyponatremia in the 2009 161-km Western States Endurance Run” Int J Sports Physiol Perform 2012; 7: 6-10; Hoffman et al “Exercise-associated hyponatremia and hydration status in 161-km ultramarathoners” Med Sci Sports Exerc 2013; 45: 784-91). Interestingly, a recent small study of 15 runners of the Great North Walk (GNW) 100 ultramarathon showed that the incidence of EAH during any point during the race was 10/15 (67%) , while the post-race incidence was 4/15 (27%), indicating firstly that asymptomatic EAH might be even more common than this during ultramarathons, but also secondly that most runners are able to self-correct low sodium status.

The incidence of symptomatic EAH and EAHE in ultramarathon running is not known, but most likely below 5%. In collapsed runners of Boston marathon, 63/1319 (4.8%) runners were found to have hyponatremia (Siegel et al “Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy” Am J Clin Pathol 2009; 132: 336-340). Among the medical emergencies during an ultramarathon EAE is certainly something to be prepared for as a race organization (McGowan & Hoffman “Characterization of medical care at the 161-km Western States Endurance Run” Wilderness Environment Med 2014; Epub ahead of print). 

Is it only in ultramarathon running EAH is present?
No, even though the highest incidence rates of asymptomatic EAH has been reported in 100-mile ultramarathons, it has been found to be present in over 10% of athletes in other ultraendurance activities such as Ironman triathlon and open-water ultra-swimming (Knechtle “Nutrition in ultra-endurance racing – aspects of energy balance, fluid balance and exercise-associated hyponatremia” Medicina Sportiva 2013; 17: 200-10; Knechtle et al “Prevalence of exercise-associated hyponatremia in male ultraendurance athletes” Clin J Sport Med 2011; 21: 226-232). In shorter running races such as marathon the incidence of asymptomatic EAH can also be over 10%, (for instance in a study of Boston marathon runners 62/488 [13%] developed asymptomatic EAH [Almond et al “Hyponatremia among runners in the Boston Marathon” N Engl J Med 2005; 352: 1550-6]). Symptomatic EAH is rare and below 1% in marathon runners (Hew et al “The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners” Clin J Sport Med 2003; 13: 41-47), but it indeed occurs and even in shorter races such as half-marathon severe cases of EAH have been reported (Glace & Murphy “Severe hyponatremia develops in a runner following a half-marathon” JAAPA 2008; 21: 27-29). Symptomatic EAH has also been reported in hikers and military personnel with increased frequency. For instance in Grand Canyon hikers seeking medical care from exercise-associated collapse or exhaustion the incidence of EAH was 16% with an estimated rate of between 2-4 per 100,000 persons (Baker et al “Hyponatremia in recreational hikers in Grand Canyon National Park” J Wilderness Med 1993; 4: 391-306 and Baker et al “Exertional heat illness and hyponatremia in hikers” Am J Emerg Med 1999; 17; 532-39). In the US military services, there were 1329 reported cases of EAH between 1999 and 2011, giving an incidence of 12.6 per 100,000 person-years, among active duty members (O’Donnell et al “Army Medical Surveillance Activity Update:  exertional hyponatremia, active component, U.S. Armed Forces, 1999-2011” Medical Surveillance Monthly Report 2012; 19: 20-23).

What are the signs and symptoms of EAH?
In most cases there are no signs or symptoms of EAE. If there are symptoms of EAH these could be very diverse both in nature and in intensity. Common symptoms are for instance often fatigue/weakness, increased thirst, elevated temperature, tachycardia, orthostasis, nausea/vomiting, headache/dizziness, blurred vision, confusion/disorientation, obtundation, seizure, coma, respiratory distress, oliguria and diuresis.

Can EAH present with difficulties breathing?
Yes. In severe cases of EAH there might be fluid accumulation in the lungs, so called pulmonary edema. This is also called the Ayus-Arieff syndrome  (Ayus & Arieff “Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure” Chest 1995; 107: 517-521).

Are you always having symptoms when you have EAH?
No, on the contrary there are no symptoms in most cases. See answers to questions above.

Are there other diseases affecting ultramarathon runners with similar symptoms?
Yes, for instance heat illness, dehydration or acute mountain sickness (AMS) often present with similar symptoms (Bennett et al 2013 “Wilderness Medical Society practice guidelines for treatment of exercise-associated hyponatremia” Wild Environ Med 2013; 24: 228-240).

How to diagnose EAH in the field and at the hospital?
Proper diagnosis of EAH requires measurement of blood sodium concentration. More and more races understand the importance of this and have point-of-care sodium measurement in the field available during the race. However, if no sodium measurement is possible in the field, as is often the case, a preliminary diagnosis of EAH can be made based on a history of overhydration and/or symptoms in severe cases and treatment initiated during transport to a medical center for proper diagnosis and further treatment. In all cases, hypotonic or isotonic fluid intake or administration should be restricted unless clear indications for fluid replacement, such as unstable blood pressure or severe acute kidney injury, are present until EAH has been ruled out with a sodium measurement as inappropriate hydration might worsen the hyponatremia with potential devastating consequences (Siegel et al “Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy” Am J Clin Pathol 2009; 132: 336-340). It should also be noted that a single venous post-race measurement of sodium might underestimate the severity of arterial hyponatremia and the patient needs to be observed and followed with repeated measurements in unclear cases, also as water remaining in the gastrointestinal tract might be quickly absorbed following cessation of exercise and result in rapid worsening of EAH (Halperin et al “Letter to the editor: Hyponatremia in marathon runners” N Engl J Med 2005; 353: 428; Ayus et al “Hyponatremia, cerebral edema and noncardiogenic pulmonary edema in marathon runners” Ann Intern Med 2000; 45: 14-19).

Can body weight change during exercise indicate EAH?
Yes, partly. Importantly, EAH can in some cases occur in individuals with weight loss so lack of weight gain can never rule out EAH. However, most individuals with EAH are gaining weight and EAH should therefore be suspected in ultramarathon runners who have gained weight during the race (Noakes et al “Three independent biological mechanisms cause exercise-associated hyponatremia: Evidence from 2,135 weighed competitive athletic performances” Proc Natl Acad Sci USA 2005; 102: 18550-55; Speedy et al “Hyponatremia in ultradistance triathletes” Med Sci Sports Exerc 1999; 31: 809-15). Many ultramarathon races and organized ultraendurance events are monitoring body weight and in the presence of weight gain fluid and sodium intake should be reduced until weight returns to 2% to 4% body weight loss from baseline level (Bennett et al 2013 “Wilderness Medical Society practice guidelines for treatment of exercise-associated hyponatremia” Wild Environ Med 2013; 24: 228-240)

Can EAH be prevented?
Yes, by avoiding overhydration. Athletes should focus on decreasing overdrinking during exercise by drinking according to thirst. Race organizers might consider reducing the overavailability of fluids (Bennett et al 2013 “Wilderness Medical Society practice guidelines for treatment of exercise-associated hyponatremia” Wild Environ Med 2013; 24: 228-240).

Is it possible to avoid EAH by taking salt tablets or drinking electrolyte solutions during a run?
No. Sodium supplementation during exercise has in several studies been shown to not prevent development of EAH in activities lasting less than 18 hours (Speedy et al “Oral salt supplementation during ultradistance exercise Clin J Sport Med. 2002; 12: 279-84; Hew-Butler et al “Sodium supplementation is not required to maintain serum sodium concentrations during an Ironman triathlon” Br J Sports Med 2006; 40: 255-59; Twerenbold et al “Effects of different sodium concentrations in replacement fluids during prolonged exercise in women Br J Sports Med 2003; 37: 300-03; Barr et al “Fluid replacement during prolonged exercise: effects of water, saline, or no fluid”
Med Sci Sports Exerc 1991; 23: 811- 17). It is a common misunderstanding that it is possible to avoid hyponatremia by ingestion of sodium, but it has in these studies convincingly been shown that it is the amount of fluid, and not sodium, ingested which is important for blood sodium concentrations during exercise.

How should EAH be treated?
Treatment of EAH should be handled by educated medical personnel. Firstly, treatment consists of avoiding further overhydration by avoiding isotonic or hypotonic fluid replacement (intravenous or oral) when the diagnosis of EAH is under consideration until urination commences. In cases of dehydration and rhabdomyolysis with impending acute kidney injury, a possible alternative diagnosis in some cases, hydration is on the contrary of importance and it is therefore important to rapidly measure sodium for a definite diagnosis. However, in the risk-balance between diagnosis with different treatments it needs to be noted that there is no documentation in the scientific literature linking exercise-related dehydration to life-threatening conditions, while EAH certainly can be lethal (Noakes “Hyponatremia in distance athletes: pulling the iv on the “dehydration myth” Phys Sportsmed 2000; 28: 71-76).  Secondly, if there is definite severe EAH or if there is suspicion of symptomatic EAH/EAHE with neurological deterioration even if no sodium measurement is available treatment with hypertonic saline should be considered. In milder cases oral hypertonic saline solution (for instance 3-4 bouillon cubes in 125 mL [½ cup] of water [~9% saline]) can be given. In more serious cases intravenous hypertonic saline should be considered (100 mL bolus of 3% hypertonic saline, which can be repeated twice at 10-minute intervals) (Bennett et al 2013 “Wilderness Medical Society practice guidelines for treatment of exercise-associated hyponatremia” Wild Environ Med 2013; 24: 228-240).


Treatment algorithm for EAH treament in the field. From Bennett et al 2013.

Can you die from EAH?
Yes. There are regretfully over 10 confirmed deaths due to EAH found in the scientific literature and most likely many more not published cases.

3 comments:

  1. Hi Peter,

    Thanks for reiterating that salt consumption during an event will not preclude development of EAH. Consumption of salt as a remedy for EAH is a widely-held misconception in the ultrarunning community. Noakes takes about 150 pages of his book "Waterlogged" to dispell this mis-information and you have done a great job summarizing it here as well.

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    1. Thanks Robert! Embarrasing that I forgot to mention Noakes book "Waterlogged: The Serious Problem of Overhydration in Endurance Sports" from 2012 in the post as it with its 448 pages must be something of the reference book in the area. I have not read it, however, but refer to some of his original studies and review articles instead. Is the book worth reading? I see that it is quite expensive on Kindle store, and time is short now before Christmas anyway in particular as the ski season for my family starts this weekend, so it will probably be a future project.

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  2. Hi Peter,

    Yes, I think the book is a worthwhile read although, for your post, referring to the pertinent original refereed articles is, in my opinion, preferred. The book gives a good historical perspective and goes into great depth about the unscrupulous "Sports Drink" industry and the apparent collusion with the American College of Sports Medicine- something you may have additional interest in. I have read the book twice and continue to refer to it from time to time, so it has been a good reference tool.

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