Recognition of adverse effects-no quick and dirty way

The recent flurry of scientific comment, speculation, 6 o'clock news type hype, accusations about everyone concerned-except perhaps patients- and thoughtful commentary about the possibility that Avandia increases the risk of ischemic events makes me sit back and think about how did we get to where we are.

The randomized clinical trial is unrivaled in its ability-when properly done-to defy the confounders and the biases and point to a treatment that is efficacious and provides some information about adverse effects and can compare fairly the treated and untreated groups. It deserves its place as king of the hill in the realm of evidence and evidence based medicine because of its ability to eliminate selection bias and ideally chase away the known and unknown confounders that seem to lurk everywhere.

However, in regard to adverse effects (AE) detection RCTS are imperfect and not the most powerful tool in the shed. RCTs are typically short lived and even the larger ones often are too small to have adequate power to detect low frequency AEs. Further,RCTs are designed to demonstrate efficacy-or in some cases the much weaker standard of proof- non-inferiority. The patients in the trial often are less diverse and complicated that a typical subset of patients from real clinical life that will likely be taking the medication.This commentary by Ioannidis,Goodman and Mulrow in the Annals of Internal Medicine speaks more authoritatively that I can in regard to this point emphasizing the limitations of randomized trials in this regard. Further, they make suggestion to make postmarketing surveillance more "routine and efficient".

"Routine and efficient" certainly seems lacking as lately alarm about AEs associated with two blockbuster drugs was sounded by cardiologists and statisticians at Cleveland Clinic rather than the drug manufacturers or the FDA. Regardless of how correct or misleading their analysis may ultimately turn out to be (if there is ever an "ultimately"), I doubt we can always rely or a Dr. Nissen or whoever to oversee the vast drug related adverse effect data set.

It falls on the shoulders of case reports and observational data and meta-analyses to fill in the gaps regarding those less common AEs and those that only develop after the patient has been on the medication for a longer period of time.Sometimes these AEs burst on the headline news with alarming findings as with drug eluting stents,Vioxx, Ketek, and now,it seems, Avandia. They certainly can be alarming but they should not be surprising.

With more patients, and more time, more AEs will become apparent but the AEs have to be plucked out of a data which is plagued by potential confounders, the management of which has generated various statistical techniques which ,in my opinion,exceeds the level of statistical expertise possessed by most physicians and medical journal editors. I have written before about the difficulty in choosing between competing techniques proposed to tame the observational data.

So the RCT may just be the beginning of the data accumulation. The RCT is also the beginning of the onslaught of information,dis-information, useful educational material, misleading spin and well thought out marketing efforts of the drug manufacturer,educational efforts by patient organizations, guidelines from various groups and delicious "educational company"sponsored dinners punctuated by "thought leader" physicians showing slides typically prepared by the company.

Hopefully, postmarketing trials will come more efficient and routine and timely (Nissen's Avandia meta-analysis appeared about 8 years after FDA approval), but this will require a greater or more forceful role for the FDA-an agency which currently enjoys a reputation only slightly less tarnished than big Pharma. Something positive may come out of congressional hearings into various activities of the FDA and then perhaps remedial legislation but is not the current FDA the product of earlier congressional efforts to mitigate what was considered at the time by some a dangerously slow medication approval process?

Meanwhile, until a new day appears, we need to not be overly reassured by "negative findings" regarding side effects derived from RCTs. Ioannidis and co-authors included this quote in the above referenced commentary:

"It is almost always inappropriate to make statements about "no difference"in adverse event rates between groups on the basis of nonsignificant P values. Rates of adverse events that are derived from single,modest sized trials that are not statistically different typically do not exclude with certainty the possibility of major, clinically important differences in harms between groups."

Avandia manufacturer issues reply to NEJM article

On their website GSK presents some arguments and evidence to counter the headline-producing NEJM article by Dr. Nissen,who is getting the reputation of the Drugslayer. The NEJM meta-analysis implicated rosiglitazone with causing an increase in cardiovascular events. Denials of heart attack risk by GSK and the complexity and obscure fine points of analysing meta-analysis and ongoing monitoring projects notwithstanding,the drug is in trouble and it is more bad news for the rapidly diminishing reputation of the FDA.

A recent (May 22,2007) entry by Dr. Roy Poses gives us some useful context for the Nissen article and related events and is well worth reading.

Patients who are currently taking Avandia are referred to their physician for advice and counseling. What the doctor ought to say to his patient is not all that clear. This post by Dr. Charles links to an article that tells us what Dr. Psaty says he would tell patients. Psaty was a co-author of the editorial discussing the meta-analysis.

After you read the NEJM article and the related editorial and the reply by GSK you may well reach the conclusion that there seems to be an increased risk of ischemic events with rosiglitazone) and so far probably not with Actos ( pioglitazone) as some data suggest risk may be a little lower with Actos.Or you may conclude the data are not sufficient to change anything. Does an action item flow from that tentative conclusion that there is an increased risk? Should you stop Avandia?

GSK tells us that they have data which does not support Dr. Niessen's findings. I would like someone with more meta-analytical skills than I have to explain why it is fair to exclude those trials in which there were no deaths, which is what Nessin did.I expect we will hear a lot more statistical jabs back and forth before we hear the end of this issue.

Should you switch to Actos? Maybe your patient is taking Avandia becuase that is the only glitizone that his insurance plan will allow.Should you tell the patient lets just wait and see ? Will the FDA act and do something to take the physician off the hook? Will a meta-analysis be forthcoming that suggests metformin increases cardiovascular events?

SIADH or SIAD-where did the "h" go and does it matter?

Fifty years ago the syndrome of inappropriate secretion of anti-diuretic hormone was described in a lung cancer patient and the term SIADH (Syndrome of inappropriate anti-diuretic hormone secretion) entered the medical vocabulary. The anti-diuretic hormone was later identified as arginine vasopressin (AVP). I have thought for some time that things would have been simpler and easier to think about if instead of anti-diuretic hormone this water retaining hormone would have actually been called "water retaining hormone" but its too late now.

A recent article in NEJM informs the readers that only about one-third of cases of SIADH have non-suppressed levels of arginine vasopressin so that the term "Syndrome of Inappropriate Antidiuresis " is more correct or appropriate.

I thought this was something new rather than some subtlety I have just missed but a perfunctory Google search leads to more than one not- very- recent article than used that term in the sense of SIADH being a subset of SIAD. So the term has been around for more than a year or two.

So what is the pathophysiology in those cases without levels of ADH that are too high for the situation? In some the "osmostat" is reset.This means that ADH release is suppressed only at a lower level of serum osmolality than normal. In other cases, the vasopressin renal receptor is somehow able to concentrate urine even in the absence of arginine vasopressin.These variation in the aquaporin receptor-recently reported in the NEJM bring about a Nephrogenic syndrome of inappropriate antidiuresis.

The authors of the Clinical Practice Review in the May 17.2007 NEJM (Ellison DH and Berl T, MEJM 356;20 p 2064) state that:

"Measurement of the serum level of arginine vasopressin is not recommended routinely, because urinary osmolality above 100 mOsm per kilogram of water is usually sufficient to indicate excess circulating arginine vasopressin."

I am confused by this. I had considered an osmolality above 100 an important criterion for the diagnosis. Yet we are told that only about 1/3 of cases ( that meet the criteria that include the urine osmolality criterion) a have elevated arginine vasopressin.So the urine osmolality criterion does not mean elevated AVP is about 2/3 of cases. In fact, had the authors of the article that described the aquaporin mutations made that assumption the syndrome might still await description and a entire new avenue of water balance physiology would not have been opened.

In any event, apparently the presence or absence of the "h" seems to make no difference in the recommended therapy which as the authors clearly indicate is fraught with disagreement about the specifics.

Treatment has always seemed to involve avoiding hard places and rocks. One risk is that the cerebral edema induced by the hypo-osmolality is clearly a bad thing and should not be allowed to persist and worsen and on the other hand there is the somewhat mysterious spectre of osmotic demyelination which is typically referred to by one of it forms namely central pontine myelinolysis. Here is an excellent 1997 reference which includes a description of the impressive deductive abilities of the ancient ( circa 1940s and 1950s) neurologists who seemed to be able to see into the brain without benefit of MRIs and described the pontine loss of myelin.


The myelinolysis seems to be caused by too rapid correction of the hyponatremia, at least that is the consensus theory while some authors still blame the severe hyponatremia per se.But how rapid is too rapid?It is thought to be more likely to occur with correction in chronic cases ( the brain cells seems to adapt to hyponatremia by loosing osmotically active molecules and thereby limiting the degree of cerebral edema.)

If most-according to the recent NEJM review) cases do not actually have elevated ADH levels ,what does that mean for the efficacy or safety of the "vaptan" group of drugs. There are at least four vasopressin-receptor antagonists with one intravenous drug (conivaptan-trade name Vaprisol) approved already and oral prparations in the drug pipeline. I wonder if the ADH level is not high what good (harm?) would happen if they are used and the ADH level is not the culprit?

Screening for abdominal aortic aneurysm-looks like a good idea

The May 15,2007 issue of the Annals of Internal Medicine features several articles and an editorial strongly supporting screening for AAAs -at least in men 64 to 74 years of age ,if they ever smoked ( I guess when you get to 75 you are too old to worry about).The USPSTF recommends one time screening for men aged 64 to 75 who have ever smoked but not for the never-smokers. The Annals editorial makes a reasonable argument that non-smokers should be included as well.

One of the articles, done in Great Britain, indicated than the screening is even cost effective.

There is a systematic review (Lederle et al)of treatment of unruptured abdominal aortic aneurysms which found for those aneurysms less than 5.5. cm in diameter no benefit was demonstrated either in all cause or in AAA related mortality.

However,for larger aneurysms and rapidly enlarging aneurysms repair is indicated. I say "repair" because now there is an alternative to the major AAA surgery in the form of a endovascular repair, about which the jury is out regarding the long term results. Certaintly the post procedure recovery time is much more pleasant with the endo aproach.

According to the MKSAP 14,( pg. 72 of the Cardiovascular Medicine booklet) surgery is indicated for AAA greater then 5.5cm in men and for those greater than 4.5. to 5.0 in women. A ruptured AAA is said to have an approximately 80% mortality. One of my former partners collapsed in the hospital while rounding and was very quickly attended by an excellent vascular surgeon who quickly diagnosed the problem and in spite of a rush to the O.R. and a very expeditious effort at surgery, he died on the table.

Ever alert as I am to gratuitous comments promoting P4P particularly from the American College of Physicians, I could not help but chaff a bit at one comment slipped into the editorial.

"AAA screening should be considered ...in pay-for-performance and other large- scale quality initiatives"

I can remember a time-not that long ago really-when a recommendation was made because it was the right thing to do for the patient not because of P4P (aka being bribed to do the right thing) and not because some insurance entity was going to check to see if we had done it according to their version of what should be done.

Patient-Centered Care-what does it mean?

If you ask patients or other physicians what " patient centered care" (PCC) means I believe you would hear comments like these:

"care in which the doctor places the patient and his/her interests first",
"the physician treats the patients with respect and dignity"
"it's putting the patient first,caring about the patient,treating the patient like you would like to be treated, respecting the patient's values"

These are actual quotes or paraphrases of answers I have heard for doctors and patients and friends.

The Institute of Medicine's definition captures some of this in the following;

"Providing care that is respectful of and responsive to individual patient preferences,needs and values and ensuring that patient values guide all clinical decisions."

Who could argue with that and would not that be a sufficient imperative and worthy objective?

Apparently that is not enough in the eyes of some medical policy wonks.

Authors from the "Quality Improvement Program of the Commonwealth Fund" have declared their " 7 attributes for primary care practices " are something that patients " will value highly".

Their article in the Archives of Internal Medicine describes the results of a survey which inquired about the degree to which their stipulated definition of PCC was incorporated into a set of primary practices that they sent survey questions..

Their comments section emphasize the poor showing in regard to two areas in particular which apparently have risen to issues of major importance: the development of patient registries and patient feedback surveys. We learn that, for example that the American Board of Internal Medicine now requires in their competency maintenance scheme that physicians show competence in patient registries development and survey feedback.

They conclude stating "physicians should be well positioned (once they get the right tools) to provide the services and care that patients want and have the right to expect"

"The right to expect patient surveys" ??
We have come quite a ways from the simple admonition in 1927 by Francis W. Peabody that; "the secret of the care of the patient is caring for the patient." No easy survey audit of that is available.

I think that is what this is all about.People who are making a career at least in part by being quality gurus and who strive to be the judges of quality care need to have "quality indicators" that are easily measurable.They thrive on the search for rules in a world of exceptions and quick and dirty ways to determine if someone else is practicing their version of quality care.

Patient surveys have suggested patients want their doctors to be through,caring, respectful,and I suggest patients could not care less if they are given a survey or are aware that there is a patient registry or if their physician uses a computer based decision making program.

Using electronic means to have real time updated information about your patient and about current medical knowledge and consensus recommendations is important and offers great promise as are workable, efficient office management techniques (appointment access , facilitating consultations and referrals and lab test followup etc.) but..

Measuring how good you are as a physician by asking if you do surveys and have a patient registry is specious. It is form over substance. It is also using words that have a general common sense meaning -patient centered- to mean a list of requirements made up by one or more groups of self appointed experts in quality that may or may not have any direct relationship to level of care or the level of patient satisfaction.

The ACGME and ABIM have "determined" that a key competency of internists involves during patient surveys. Where is the evidence that surveys about services received a)reflects what the recipient really wants or values b)has been linked to any meaningful changes in medical practice with associated outcome changes?

Some data may exist but it seems to be that ABIM and ACGME have adopted this feel-good position even without the solid evidence base of the evidence based medicine to which everyone is obligated to pledge allegiance in every medical publication. Interestingly, in this Archives article, the authors offer no evidence to the efficacy or safety of their proposal and simply quote "authorities" including themselves.

Physicians practiced patient centered medicine-in the sense of what people generally think such a term would mean-before there were computers, patient surveys and patient data bases and will continue to be practiced as long as the physician does in fact place the patient first and takes seriously his fiduciary duty to the individual patient. That duty will be harder and harder to fulfill the more guidelines,rules,P4P imperatives,quality newspeak and CMS directives impinge upon and exert a demoralizing control over medical practice.

A flurry of new guidelines and rules regarding erythropoiesis stimulating agents

CMS has issued draft guidelines regarding the use of erythropoiesis stimulating agents (ESAs) that are certain to cause worry among patients, oncologists and kidney doctors.The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative has revised its guidelines saying in part that ESA therapy should not go above 13 grams/dl. The Foundation may still be wondering what hit it after a recent article and very critical editorial in JAMA.

CMS has very detailed rules about who can and who cannot received ESA, for how long and how much can be given. The oncologists and hematologists will not be able to use ESA for myelodysplasia or myeloid cancers.

ASCO reacted quickly sending email to its members. ASCO stated that some of the CMS proposals lacked scientific basis and at times contradicted scientific evidence and were in conflict with expert opinion as well as current practice. They expressed concern that this would set a dangerous precedent. Well, the dangerous precedent ship left the dock a long time ago. I remember in the 1970s my concern and disbelief that Medicare disallowed payment for oxygen therapy for COPD patients unless their O2 saturation was less than 88%.

It is no great feat of imagination to envision cancer and kidney docs doing what they thought was the right thing-i.e. going by national guidelines- now facing patients who are reading that their physicians were not doing the right things even perhaps harming them and now Medicare will no longer pay for certain treatments . Talk about a trust issue. Talk about how a single payer will solve American medicine's problems.

When medical decisions are taken out of the hands of the individual physician and the individual patients-and they are now with Medicare-this is exactly what you get. Doctors await the latest pronouncement about what they can and cannot do. What the government told you yesterday to do may not be what they tell you to do today and you may well get blamed for what you did yesterday. It is no longer "what should I do for my patient", it is what will the government let me do or make me do for my patient. Remember when Medicare was passed, the statute itself said that the government would not interfere with the practice of medicine. Talk about a trust issue.

Coenzyme Q Parkinsons trial -negative results-what about statin myopathy?

A recent randomized clinical trial with 300 mg.0f CoQ 10 per day for three months failed to show any benefit.

Hope for a neuroprotective effect of CoQ 10 was based in part on animal experiments in which mice with MPTP induced Parkinsonian symptoms were shown to have reduced loss of dopaminergic axons when treated with Coenzyme Q.

CoQ 10 has mainly been a star in the world of alternative medicine but also appears from time in efforts to gain acceptance in the more respected world of conventional medicine. In Europe, it seems to have claimed some role in treatment of heart failure and for time to time I have seen cardiologists adding it on to patients with severe HF. At least one Meta-analysis of clinical trials from Europe concluded it had some role in HF treatment.

Some Co Q 10 believers have latched onto the notion that CoQ10 is essential to prevent a putative loss of that enzyme brought about by statin therapy. In their view statin therapy has largely been responsible for what they characterize as a pan-epidemic of heart failure. In their argument they point triumphantly to the fact that Merck did patent a combination of a statin and CoQ 10. I had written about CoQ10 two years ago and mentioned that some physicians were tentatively using it in patients taking a statin who complained of muscle pain but had normal CK levels. That approach may have some validity.

Dr. Robert L. Wortmann, from the University of Oklahoma Medical School, provides some anecdotal evidence for its value in statin associated myalgia/myopathy syndrome. Anecdotal evidence , of course, does not enjoy the top dog role in the evidence hierarchy but in some cases the greater experience of a subject matter expert might have to suffice until the randomized trial data comes along if it ever does. Dr. Worthman and his group were able to accumulate a number of cases and in their opinion a trial of Co Q 10 sometimes seemed to work. They found that a number of patients were heterozygotes for one of several inborn errors of muscle metabolism such as McArdle disease but were asymptomatic before taking one of the statins.
CoQ10 seems fairly side effect free ( it might interfere with coumadin) but it is not cheap and drug insurance plans won't cover it so most docs may well try a different statin and then punt over to Zetia.

Sarcoid like clinical picture reported in 911 rescue workers

A recent publication, referenced here, reports twenty eight 911 rescue workers with a sarcoid type clinical picture. The article, Published in the May 2007 issue of Chest is available in abstract form here.

Patient were described with hilar nodes and parenchymal changes as well as extra-pulmonary findings.

There is some precedent for the relationship between occupational/environmental exposures and granulomatous type pulmonary reaction. For example,exposure to zirconium has been reported to cause pulmonary granulomatous reactions. Much less obscure has been the well established relationship between exposure to beryllium oxide-used in the manufacture of fluorescent light bulbs-and a clinical picture at times indistinguishable from sarcoid. Unique among pneumoconioses a blood test (beryllium specific lymphocyte proliferation test) is available for specific diagnosis.

Sarcoid is generally considered a hypersensitivity reaction to something (or somethings) but a common etiology for all cases has eluded detection.

It is not surprising that the mixture of respirable particles to which 911 rescuers were exposed would cause lung disease of some sort. Harder to understand is the authors of the Chest article observation that NYFD members demonstrated a higher than expected rate of sarcoid preceding the 911 catastrophe. On the other hand, clusters of cases have appeared from time to time in various places and among various occupational groups (e.g nurses) but over time no confirming data developed that indicated a real pattern.

Medical news- the trivial and the amazing

First the trivial:

A recently reported research paper should be reassuring to those folks who have been concerned about the resilency and general toughness of humans. Researchers have determined that all children exposed to some "trauma" do not develop Post Traumatic Stress Syndrome (PTSS).

Another surprising finding-at least to someone who has never watched the six o'clock news or read the newspaper- was that exposure to traumatic events was common. So it seems that traumatic events are widespread and most people get over them.

And the Amazing.

You may remember the physician who incurred the wrath of the politically correct by calling an obese patient "fat". Here is a link to a site that quotes the letter from him nominating himself to be Dean of Harvard Medical School.If I were on the selection committee I would want to interview him; I 'll bet he won't get the call.

More bad news for the physician trust issue-Rebates for EPO ?

A recent issue of the the New York Times reveals that some physician groups have been receiving rebates from drug manufacturers for parenteral recombinant erythropoetin. While volume related rebates to purchasers of various products has been routine and legal the implication is that some physician groups ( nephrologists and oncologists) who may profit from these arrangements are overusing the medications such overuse possibly risking harm to their patients.

Profit to dialysis centers from EPO use as well the possibility of profit enhancement by rebates was mentioned in a recent JAMA editorial which was critical of current guidelines which I discussed recently.

It is hard-if not impossible-to find news of any current trend that would improve what may well be a declining trust in physicians on the part of patients. A recent commentary by the president of the AMA maintains that trust in doctors is quite high ( better that say what politicians enjoy) but everything I read points in the direction of falling trust.

The time and money crunch basically brought about by managed care is a major driver in dwindling trust. Less time with the patient can only be bad. Missed or incorrect diagnoses for the individual patient impacted by it has to be one of the biggest trust busters possible. A hurried encounter with your doc leads only to the impression that he does not really care. A letter from your insurance company telling you your physician is delisted because he doesn't meet the quality requirements may completely destroy trust even though the criteria used may be entirely bogus and born of cost control and not a tool to make your care better.

The renal doctors I have known professionally are not the sort of people who would knowingly overuse a medication ( i.e give too much EPO) to make a profit.I have no personal knowledge of large dialysis companies that would enable me to have the same sense of reassurance. The JAMA editorial lays some possible blame at the feet of the writers of the guidelines which may have recommended doses of EPO or targets for hemoglobin that lead to more harm than good and predictably there was at least the implication of increasingly talked-about conflict of interest on the part of the members of the guideline writing panel.

I don't know if trust in physicians is lower now than before but I do know that my trust titer has tanked and I am many times more skeptical and critical in regard to medical articles that in the not too distant past I would have read without a nagging doubt about the motives of the authors.

Still more good things from statins?

I had wondered before about whether there was anything that statins did not help.The latest breaking observational study suggest that the risk of sepsis in dialysis patients is markedly lowered by statins.

It obligatory to mention whenever an observational study is cited or discussed to say since this was not a randomized trial we cannot infer causality and this should be considered an"hypothesis generating study".

Even so,it is another block in the argument building to emphasize the non-LDL lowering effect of statins,aka "pleotrophic effect".

The makers of the several statin drugs hope to build on the pleotrophic effect foundation to counter the appeal of Zetia which when teamed with a statin ( Vytorin is Zetia plus Zocor) brings about an impressive decrease in LDL cholesterol. The lower-is -better mantra on the part of the National Cholesterol Panel and its ever decreasing LDL target is just what one would want to encourage sales of Zetia and Vytorin. One counterargument from the statin camp is that " yes Zetia plus statin really lowers the LDL but the statin does more than lower the LDL.It has pleotrophic effects" i.e it decreases inflammation or tendency to clot,pacifies platelets or something beside lowering the LDL to decrease the likelihood of an acute coronary syndrome.

Of course, statins have effects other than LDL lowering. How many drugs do just one thing? Even though we emphasize one aspect and even classify a drug on the basis of that one action, e.g. beta-blockers,calcium channel blockers etc,these drugs all have effects other that the one for which they were named.

Crestor ran into a bit of bad sailing what with Vytorin blazing onto the scene and then Sidney Wolfe ( of Public Citizen ) requesting that the FDA remove Crestor from the market arguing that Crestor had a greater risk of myopathy and possibly renal disease. Here is the FDA letter replying to his request and denying it.

If recent thought- leader dinner talks are any indication Crestor is fighting back arguing the shrinkage of plaque that occured with the ASTEROID trial with Crestor -an effect I believe that has not been seen with the rival statins and promoting the idea that the best indicator of risk and of decreasing risk is the level and then the improvement in the LDL/HDL level, a parameter in which Crestor seems to do rather well.

It may well be that the "best" number to treat to is one that uses the LDL/HDL ratio but so far ( at least with ATP 111) the cholesterol mavens encourage docs to use LDL targets and their desire to go with the ATP playbook is one of the reasons that Vytorin is doing so well and Crestor is on the evening dinner circuit to persuade/convince docs that we need to dance with those that brought us, ie the statins which have shown mortality benefit and that as yet has not been demonstrated with Zetia. Stay tuned, I believe a long term study of the effect of Zetia on coronary event rate is being done.

More on marathoner's hyponatremia

A recent article in the American Journal of Medicine (AJM) provides some new data on the mechanisms(s) at work in the condition of marathoner's hyponatremia. I become more interested in this condition particularly as I fall deeper and deeper in the back of pack running group of aging marathoners. It seems that the really slow folks are more likely to end up in the medical tent with low serum sodium values-and with other problems as well- although it has also been reported in elite runners. ADH was singled out as the one of the likely suspects by Dr. Noakes, a long time guru of long distance running physiology, and I referenced some of his research and thoughts here.

Just as I was reviewing the subject the ever alert DB posted this entry.


Over the years as more folks ran marathons, adequate hydration was first emphasized and then perhaps overemphasized and now overhydration seems to be a major factor in causing runner's hyponatremia. (endurance event participants is a more accurate term as it is not running per se that is necessary to bring this on.) The early zeal for encouraging fluid intake was the notion that dehydration was the principal driving determinative factor in heat stroke in endurance runners. More recently and on the heels of case reports of severe hyponatremia in a few marathoners including at least seven reported fatalities and less severe decrements in serum sodium values in others, less enthusiastic fluid replacement has been emphasized for the runners and apparently fewer cases of runner's hyponatremia are being seen. For example, a recent version of the New York Marathon Handbook recommends 8 oz every twenty minutes . An intake of 400 to 800 ml/hour has been recommended by the International Marathon Medical Directors Association (IMMDA) as opposed to the older mantra of drink "as much as possible".

It is suggested by the authors of the AJM article than this may be a form of SIADH or the syndrome of inappropriate secretion of ADH and while excessive ingestion of water may be necessary it is not sufficient to cause the condition. The back of the pack runners and those who drink too much are most likely to lower their serum sodium values to dangerous levels.The current AJM article reported inappropriate levels of ADH placing the blame on ADH while an earlier report by Noakes did not find elevated ADH levels in endurance athletes who were hospitalized with severe hyponatremia. Perhaps differences in the sensitivity of the various assays used or some aspect of timing or some other procedural matters may be found to explain this apparent discrepancy. Regardless, there seems to be some combination of excessive fluid intake and fluid retention by whatever mechanism(s)-and I think a SIADH type picture is an appealing possible mechanism-resulting in a clinical situation where what you do not need is normal saline.

Since starting normal saline might well seem like the proper thing to do in collapsed runners,the suggestion has been made to have equipment on hand in the emergency treatment facilities set up to service marathons to quickly check the serum sodium level. This advice makes sense and the availability of bedside sodium testing makes it workable. Interestedly, Noakes who has finished more than 70 marathons himself and probably has more hands-on experience than anyone reports than most collapsed runners need only to be placed supine with their feet elevated and things get OK very quickly. This is not intended to diminish the importance of the recognition (by blood sodium measurements) and appropriate treatment of hyponatremia.

Interesting data from the 2003 Boston Marathon is available.Of the 17,548 runners who began the race 17,030 finished and 140 collapsed runners were evaluated and treated .Sodium measurements were done and 30 were hypernatremia (GL 146) while 9 were hyponatremic ( LT 135). The pre race fluid replacement advice was the 400-800 ml /hr so it appears that folks were cutting back on the fluid intake during the race. You cannot know what the serum sodium is in a collapsed runner without measuring it.

A different picture emerged from a study done at the Hawaii Ironman Triathlon, where hyponatremia was seen in 30% of those requiring treatment. The temperature for that race was in the high 80s for much of the race while at the 2003 Boston race the end of race high temp was only 71.The Hawaii race was done at a time before the new hydration advice was published and and is a much longer event than a 26.2 mile run.

Point-of-care sodium measurements really have to part of the medical facilities available in endurance events and the large number of hypernatremic runners noted at Boston might mean that further fine tuning of the hydration advice may still be needed.