Wednesday, February 27, 2013

When 1A evidence is not 1A evidence.

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


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

I replied with increasing desperation:

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


(SOC is standard of care)

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.

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
Janine McCready also helped out:

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.








Updates from Twitter (where else?):


Link to a nice post, on a JAMA article looking at the reliability of clinical practice guidelines.

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Monday, February 25, 2013

Nephrology Merit Badges, an update

Six months ago I proposed nephrology merit badges:
One of the common resident complaints regarding nephrology is that it's too hard. The nephrologist response to this complaint  is usually to deny the difficulty, because its not hard for the nephrologist. Perhaps that denial is counterproductive, first it's hard to disrupt a widely held belief that is continually reinforced by the community of medicine, secondly when you deny the difficulty you insult the intelligence of the student struggling with new concepts. Its essentially saying, "Hard? differentiating among the pulmonary renal syndromes is easy, what are you stupid?"

Instead of denying the difficulty we should re-frame the meme. Yes, nephrology is hard and look how cool it is that you mastered these concepts.

Merit badges, or pieces of flare as my fellow interjected, would add levity and encourage residents to tackle deeper concepts.
Since that time a number of residents, fellows and students have earned nephrology merit badges. The concept has evolved a bit as the badges are being awarded to comemorate specific patient encounters rather than general concepts. So it's still a work in progress. Here is a summary of the badges:

Sodium Ninja. See this post.

 Master of Electricity. This badge was awarded to the residents who were able to quickly and professionally handle a shocking situation. A patient in the acute dialysis unit was repeatedly being shocked by her malfunctioning ICD. Every five to ten seconds, BAM another electric boot to the chest. This went on for what seemed like hours, bit was only a few minutes until the residents were able to procure a magnet to place on the chest and reset the ICD.

Sweet as Black Coffee. This badge was awarded to the residents who were able to accuratly diagnose the etiology behind a case of hypoglycemia. The hypoglycemia was due to adrenal insufficiency and once this hormone was properly replaced the patient's mood improved as much as his glucose did. Seeing him come alive was almost like Gandolph releasing Theoden from Saruman's control. The name of the badge comes from one of my favorite brain teasers: what has more sugar, lightly sweetened coffee (one teaspoon of sugar) or all the blood in the body? The answer is the coffee:


↵ Use original player
The Lord of the Rings: The Two Towers (2002) - Gandalf Releases Theoden
By 94981745
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Hepatorenal Syndrome. This badge was awarded to the residents who successfully guided their patient through the trecherous waters of hepatorenal syndrome. The symbol behind the organs is supposed to be specter of death but may actually be a heavy metal band symbol. I have not been overly impressed with the quality of research which supports the use of midodrine and octreotide in HRS(PubMed1 PubMed2), but there is no doubt in my mind that HRS was nearly universally fatal when I was a resident in the late 90's and now I have a hard time remembering the last time I saw a patient die of the condition.

Orthostatic Hypotension. This badge is awarded to the residents who successfully managed resistant orthostatic hypotension. Once the patient has failed midodrine, sodium supplements, elevating the head of the bed, florinef, and waist high compression stockings, you are left with pyridostigmine (Mestinon). This cholinesterase inhibitor, used most often in the treatment of myesthenia gravis, can be used in orthostatic hypotension. The other use of pyridostigmine is an organophosphate antidote, hence the joke.

Koch meets Cochrane. This merit badge was created for the team that did the core research on the data backing up the AHA and ISDA recommendations to use ampicillin and gentamicin for enterococcal infective endocarditis. I plan on posting a follow-up on that situation shortly. I love the illiteration of this badge.







Scout Master's iPad with a full complement of merit badges
All the badges can be downloaded here as a PDF.
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Saturday, February 23, 2013

Tolvaptan, a cost benefit analysis

I have a patient who is enrolled in the ongoing TEMPO 4:4 trial. This is another randomized placebo controlled trial of tolvaptan similar to the ground breaking Tempo 3:4 released at Kidney Week 2012. The principle differences seem to be, enrolling people with lower kidney function (GFR >30 versus > 60 ml/min in 3:4).

Recently, he told me about one of his 24-hour urine collections that he has to do as part of the study. He made 7.7 liters of urine in twenty-four hours. As I was pulling my chin off the floor, he asked me if I thought he was on placebo. No, probably not. He agreed.

He has been on "study-drug" for over a year and the polyuria is really disruptive. He is getting up 3-4 times a night and now he needs to take naps during the day because he isn't getting enough sleep at night.
The guy is on 120 mg of study drug/tolvaptan a day, polyuria is going to be inevitable. The conversation then progressed to how much time the drug may give him off dialysis compared to placebo. Here is the back-of-the-envelope calculation we did to determine if the drug was worth the inconvenience.

His mother reached ESRD at age 55, he seems to be doing a bit better than her, possibly due to the ARB, or just due to phenotypic variance, but we used 55 as the target, that gave him roughly a dozen years or tolvaptan. Using the change in GFR from the sensitivity analysis for males you get the following:


He felt that for him the over-under was about 5 years, and since this beat that handily he was satisfied.

The patient saw a draft of this post and consented to the release of this personal health information.



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Sunday, February 17, 2013

200 calories on a plate

Each one of these pictures is a plate with 200 calories. Interesting to see the amazing diversity in caloric density.

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