Precious Bodily Fluids

From Sterns’ article on sodium polysterene sulfonate (Kayexalate) and its ineffectiveness for treating hyperkalemia:

Sodium polystyrene sulfonate (SPS), an ion-exchange resin designed to bind potassium in the colon, was approved in 1958 as a treatment for hyperkalemia by the US Food and Drug Administration, 4 years before drug manufacturers were required to prove the effectiveness and safety of their drugs.

From Watson’s counter editorial on sodium polysterene sulfonate and that its reasonable safety and effectiveness:

When SPS resins were first introduced, dialysis was an in- frequent procedure, and loop diuretics were in development.

You mean loop diuretics had to be developed? There was a time before lasix? Mind blown.

More random potassium trivia. The risk of hyperkalemia in anuric dialysis patients rises twice as high if they are on ACEi or ARB. Colonic and skin potassium excretion?

There were 70 individuals (0.21%) who had more than 20 events [in one year of reporting!, Only one episode per day allowed], and a greater proportion of these patients had CKD, ACE-I and/or ARB use, and diabetes than the general population with hyperkalemia.

Imagine for a moment, a patient with hypertension and galactorrhea. The patient is on risperidone, a notorious cause of galactorrhea. So the patient has hypertension and drug induced galactorrhea. But Occam’s Razor is irritating my brain. There must be a single diagnosis that ties these two symptoms together. Could she have a pituitary tumor causing Cushing’s disease and a prolactinoma? So I turn to my global and highly educated consulting crew, Twitter:

anyone aware of connection between galactorrhea and hypertension?
— Joel Topf (@kidney_boy) March 7, 2013

I received a few great responses:

@kidney_boy Did you know that William of Occam died of multiple causes?
— David Juurlink (@DavidJuurlink) March 7, 2013

and

@kidney_boy @davidjuurlink do you guys know Hickam’s dictum? A patient can have as many diseases as he damn well pleases.
— Irfan Dhalla (@IrfanDhalla) March 7, 2013

Hickam’s Dictum. I’d never heard of it even though Hickam ultimately became Dean of Indiana University, where I did residency.

For a long time I’ve wanted a counter argument to Occam’s Razor and now I have one. Thanks Jimmy Wales!

I am on the National Kidney Foundation of Michigan’s Scientific Advisory Board. Today, at the board meeting, Celeste Castillo gave a presentation on patient and family centered care. She is a dialysis patient and told a personal story of patient centered communication. She developed end-stage renal failure when she was in college. Every week-end she wanted to do what other college students did and that was drink, so every Tuesday she would show up at dialysis with too much fluid.

Her nephrologist kept wagging his finger at her until one day he sat with her on a Tuesday and started working through the problem with her. The solution: skip the beer and learn to love…tequila. Twelve ounces of beer is roughly equivalent to 1 ounce of tequila, presto, 91% reduction in volume.

Tequila for the win.

In 1971, Congress was debating adding a dialysis benefit to Medicare, and extending that benefit to all Americans. As part of his testimony to the House Ways and Means Committee, Shep Glazer was dialyzed in front of the committee. The process only lasted a few minutes but the event is considered to be the moment where Congress became committed to providing the benefit.

Glazer’s testified the following:

I am 43 years old, married for 20 years, with two children ages 14 and 10. I was a salesman until a couple of months ago until it became necessary for me to supplement my income to pay for the dialysis supplies. I tried to sell a noncompetitive line, was found out, and was fired. Gentlemen, what should I do? End it all and die? Sell my house for which I worked so hard, and go on welfare? Should I go into the hospital under my hospitalization policy, then I cannot work? Please tell me. If your kidneys failed tomorrow, wouldn’t you want the opportunity to live? Wouldn’t you want to see your children grow up?

The part of the story I never knew was that George Schreiner, the Chief of Nephrology and head of the National Kidney Foundation was the primary architect involved in lobbying congress for the dialysis benefit. He provided the dialysis machine but the National Kidney Foundation did not want to lend dignity to what they considered a risky stunt and barred Schreiner from attending.

So Schreiner sent his fellow to attend the procedure.

Can you imagine getting that page from your attending. “Hey, listen Topf, I’ve been barred from the hearing, but here’s what we’re going to do: You are going to take that dialysis machine, in that truck, to Capital Hill and then set it up. Just like I taught you. Yeah, in the hearing room for the House Ways and Means Committee. Yeah, they’ll all be there. Just ignore the national press. And the TV cameras. Then I need you to give dialysis to this guy who’s flying in to testify. After that, come on back and we’ll finish rounds. Okay?”

The fellow was James Carey who had this to say about the event:

Several years later, Carey disclosed to Schreiner that Glazer had gone into ventricular tachycardia during the dialysis session before the committee. Carey had immediately clamped the lines. The “treatment” was very short, perhaps five minutes in all, long enough to open the blood lines but hardly a dialysis session. Nevertheless, the few members of the committee who were present characterized the episode as “excellent testimony.”

That was when being a nephrology fellow was really cool.

As recounted in Biomedical Politics and Christopher Blagg in AJKD.

One of the causes of hypernatremia is water loss from the skin. This is increased in hot weather or if the skin damaged due to a lesion, burn or other wound. But I did not know hypernatremia cold result from cutaneous salt absorption.

Cutaneous Salt Toxicity

Fatal hypernatremia Na = 196

So in parts of the Middle East, Turkey, India, and China it is traditional to salt a newborn. Salt is dissolved in water, and olive oil and rubbed on the skin. There have been multiple reports (PubMed search | case report PDF | Google Search) of systemic cutaneous absorption of salt that causes hypernatremia.

Report from Neonatal Intensive Care Unit in Amman Jordan

1. Three days old boy admitted with severe hypernatremia, serum sodium 194 mmol/L and intracranial hemorrhage who died.
2. Eight days old girl with hypernatremia, serum sodium 164 mmol/L, severe hyperbilirubinemia, serum bilirubin 30 mg/dl, and intracranial bleeding.
3. Fourteen days old boy with generalized healing skin lesions, had normal head circumference at birth but developed severe microcephaly subsequently.
4. Six days old girl admitted with fever, meningitis and UTI, serum sodium 142 mmol/L.
5. Seven days old boy with hyperbilirubinemia, serum bilirubin 21.5 mg/dl, and serum sodium 155 mmol/L.

 A turkish report (unsourced from a website on Turkish Living):

…from a study conducted in Turkey in 2008 about practices in pregnancy and post partum… Eighty percent of the respondents were literate/primary school graduates, 45% had given birth at home. The most potentially harmful practices among women were swaddling (81%), dressing the baby with a sand-filled nappy (‘holluk’) (35%), and bathing the baby in salt water (40%). A relationship between traditional postpartum practices and demographic characteristics of women such as age, educational status, age at marriage and birth place was observed P<0 .05.="">

Sounds like this practice is still common in Turkey. A neonatal team from Jordan did a presentation on this practice at a conference and their slides are online. As part of the research they interviewed 112 women who gave birth at their hospital.

According to Wikipedia this is also a biblical practice. Ezekial 16:4

Newborn babies were rubbed with salt. A reference to this practice is in Ezekiel 16:4: “As for your nativity, on the day you were born your navel cord was not cut, nor were you washed in water to cleanse you; you were not rubbed with salt nor wrapped in swaddling cloths.”The significance of rubbing a newborn with salt is to indicate that the child would be raised to have integrity, to always be truthful.

What do CAM advocates say about this natural and traditional folk practice?

Just bought this last night from Fotolia

Came across this page while researching up the tradition of salting a newborn. We live in a golden era.

Any one ever see this?

Full text available here.

I hope to get back to this at some time but for now here are some comments from twitter:

@kidney_boy Interesting paper. Should we routinely check FeUrea & serum urate in nonedematous hypoNa pts?
— jbdoc (@jbdoc) March 3, 2013

and

@kidney_boy also, bedside u/s has improved vol status determination in my practice
— jbdoc (@jbdoc) March 3, 2013

Precious Bodily Fluids is part of the old guard among nephrology blogs. My first post was May 30th, 2008. Nate Hellman, creator of the Renal Fellow Network was a month earlier on April 23rd, 2008. But we were by no means the first.

The first nephblogger was Joshua Schwimmer. March 7, 2005! I remember reading Josh intermittantly right from the beginning. I even met him for coffee during an ASH meeting in 2006 or so. He was a fan of the Fluids book and encouraged me to blog. When I finally got my ass in gear and started blogging it was his endorsement which turned the microphone on. When he announced PBFluids I had already been working on it for months and suddenly I went from no traffic to a little traffic.

With the caption, K=9. Josh has evloved into the professor emeritus who has establish his role in academics and is now free to investigate what ever touches his fancy.

The current cohort of talented neph bloggers all owe Joshua a debt of gratitude. Next time you see him, kiss the ring.

Spring training is in full swing and my invitation to rejoin my fantasy baseball league has arrived. I was excited to be invited back after my poor showing last year. Yes, I’m looking at you Cliff Lee.

It got me thinking that the game I would really like would be fantasy medical scientist. You would draft a cohort of medical researchers. You would need a complete roster with a cardiologist, oncologist, ID/microbiologist, surgeon (or surgical sub-specialist) a nephrologist, endocrinologist and two other medical scientists to play utility positions.

For the next year you would score points for every paper published by the scientist. The points awarded would be the impact factor of the journal. You would lose triple impact factor for retractions.

Who’s in?

Updates from Twitter:

@kidney_boy Triple Crown for a scientist who publishes as 1st author/ journal with high impt factor/ 3 citations in 3 months
— Edgar V. Lerma (@edgarvlermamd) March 3, 2013

Nephrology Merit Badge for digging deep into CPG

A few weeks ago I posted about using ceftriaxone and ampicillin for enterococcal infective endocarditis. There are a few studies which support this aminoglycoside avoidance and to my eyes it seemed like a reasonable therapeutic option, especially in my patients who are often at high risk of aminoglycoside toxicity. I pinged twitter to see if I was fooling myself into believing what I wanted to believe or if this was a viable therapeutic option.

Hey ID docs, what do you think about treating enterococcus endocarditis without gent?Check out this article:ncbi.nlm.nih.gov/pubmed/23392394
— Joel Topf (@kidney_boy) February 14, 2013

The first responders (of the twitter variety) were the pharmacologists:

@kidney_boy @pharmertoxguy I believe you have all the key trials on this subject including the most recent. Enjoyed the post.
— Timothy Aungst (@TDAungst) February 14, 2013

@kidney_boy Not a lot of data for our old gent stronghold on synergy. Good post. @tdaungst
— Bryan D. Hayes (@PharmERToxGuy) February 14, 2013

Thanks @pharmertoxguy @tdaungstI was looking for RCT of Amp+placebo v Amp+Gent could not find one but Amp+Gent is 1A rec. How?
— Joel Topf (@kidney_boy) February 14, 2013

Then Med student, Alex Michaels, called me out on how my post relied on observational data:

@kidney_boy this seems to go against you’re preaching of EBM. all cited articles in your post are observational non rct vs 1A guidelines?!
— Alex Michaels (@amichaels04) February 14, 2013

I replied with increasing desperation:

@amichaels04 in the absence of RCT this is all we have. It would be great if you can come up with any 1A worthy studies. Couldn’t find any.
— Joel Topf (@kidney_boy) February 14, 2013

Then the always insightful but confrontational Jim Smith weighed in with the conservative point of view:

@kidney_boy do you think evidence is strong enough to defend going against IDSA recs in the event of a poor outcome?
— Jim Smith (@jklm) February 15, 2013

@kidney_boy Yeah, but hindsight is always 20/20. I’m wondering if evid is strong enough to go against what seems to be SOC from outset.
— Jim Smith (@jklm) February 15, 2013

(SOC is standard of care)

@kidney_boy I’m not saying it’s wrong to do/try. But I’d be very interested in opinion of ID experts. Have you heard from any?
— Jim Smith (@jklm) February 15, 2013

This back-and-forth began to crystalize what bothered me most about the ISDA/AHA guidelines, they graded the evidence as 1A but the supporting text did not link to one randomized controlled trial. Up to now I had not received any input from infectious disease experts so I started to fish for them.

@jklm just some pharmDs (the real brains in therapeutics)
— Joel Topf (@kidney_boy) February 15, 2013

@janinemccready @abx_id_doc @drjudystone Could you look at this post and tell me what I got wrong.pbfluids.com/2013/02/aminog…Thanks
— Joel Topf (@kidney_boy) February 15, 2013

Dan Riciuto was the first to get back to me. Here is summary of his 5 tweets (1, 2, 3, 4, 5)

Nice post. Always good to question dogma. I’ll try an get back to you later with a bit more detail. I think enterococcus is actually more difficult to treat than say Staph, though two weeks of gentamicin may be fine. I’ve used ampicillin and ceftriaxone but there is a lot of side effects, fluid and sodium load with the high dose ceftriaxone.

I replied:

The guidelines say amp gent is 1A rec but then they don’t give any refs to support “multiple RCT” to satisfy 1A strength. I also searched UpToDate and they also don’t cite any RCTs, just observational data. Does the emperor have no clothes? (Tweet 1 and 2)

He continued

There are very few RCTs in ID unless it is with a new antibiotic and hardly any in relatively rare conditions like infective endocarditis. Which is why if your read the definition from the guidelines a “Class I: Conditions for which there is evidence, general agreement, or both that a given procedure or treatment is useful and effective.

I replied, that I am not as concerned about the classification (1, 2, 3) but rather the strength of evidence. Why is this recommendation 1A not 1B
He Concluded

@kidney_boy You are right. I will look further, but pretty surenot based on RCT.I’ll email the author.
— Dan Ricciuto (@Abx_ID_Doc) February 16, 2013

Janine McCready also helped out:

@kidney_boy1/6 Thanks for q & nice post. Enterococcal IE harder to treat than other bugs as demo’d by high mortality even with ‘cidal tx.
— Janine McCready (@janinemccready) February 16, 2013

Here is Janine McGready’s full 6 tweet reply reassembled and de-abbreviated. (here are the original tweets for verification of my twitter translation 1, 2, 3, 4, 5, 6):

Thanks for question and nice post. Enterococcal IE is harder to treat than other bugs as demonstrated by the high mortality even with bactericidal treatment. Old studies show 60% failure with penicillin alone, prompting the addition of aminoglycosides. If you have an ampicillin sensitive strain with a low MIC it may be ok to use a shorter course of gentamicin or ampicillin with ceftriaxone. I’ll take a better look at the new study but I have used high dose ampicillin or ampicillin + ceftriaxone with success. The key is getting a bactericidal combination. The rationale for the addition of ceftriaxone (if I understand it correctly) is that it saturates the penicillin binding proteins (pbps) making the combination bactericidal. In my practice it’s always a balancing act and I usually pull the plug on the aminoglycoside after 2 wks and consider substituting ceftriaxone if there is any concern regarding nephrotoxicity or worrisome and irreversible vestibulo/ototoxicity. Sorry the response so is long, hope that helps…

At this point I came to the conclusion that Amp + ceftriaxone is a viable second tier option in patients with aminoglycoside toxicity or high risk for aminoglycoside toxicity. However I felt betrayed by the authors of the AHA/ISDA guidelines. The recommendation for ampicillin and gentamicin appears to be a 1A recommendation.

Here are all of the articles which are referenced in the section on enterococci:

126. streptomycin = gentamicin observation
127. gentamicin dosing observation
128, 129. using duration of symptoms to determine duration of therapy (PubMed 1, PubMed 2) observation
130. Aminoglycoside for only 15 days? observation
131. 5 phenotypes of VRE in vitro
132. linezolid for VRE observation
133. Treating multidrug resistant enerococci, disease model
134. Amp and ceftriaxone, disease model, not human data
135. Amoxicillin and cefotaxime rabbit endocarditis
136. Amp and ceftriaxone observation

That’s it. All observational data or experimental data in animals or disease models. Not a single reference to back up the slew A1 grades found in Tables 9 and 10.

Evidence-Based Scoring System from AHA and ISDA Infective Endocarditis Guidelines

When I first started investigating this I kept expecting to find an RCT buried in some old journal but now I just think the authors broke the rules. I don’t know if I should feel foolish for trusting the authors of clinical practice guidelines or self-rightous for smoking these jokers out. Is this kind of deception common in CPGs or is this a particularly sloppy guideline. The nephrology guidelines produced by K/DOQI and KDIGO have all been top notch and transparent with the unfortunate lack of data and reliance on expert opinion. I hope the ISDA/AHA is an exception rather than the rule.