Tag: Diuretics

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But for the grace of God…

I often get a call from a nurse saying something to the effect of, “Dr. Smith is ready to discharge this patient home as long as he is cleared by nephrology.”

I will tell you, that the pre-test probability that I will “clear” the patient for discharge is high. I want patients to go home and I feel that a lot of what we do in the hospital can be achieved as an outpatient. Send the patient home and I’ll see them in clinic. But one needs to be careful.

I didn’t discharge the patient, but received him when he was readmitted. The patient was admitted with bilateral pleural effusions and respiratory distress. Patient was diagnosed with COPD exacerbation and heart failure.

The patient was on furosemide 40 mg daily at home and this bumped to 80 mg IV twice a day on admission.

Nephrology was consulted to assist with diuretics and added some metolazone on day 2. That was a one time order and not repeated. Adding a thiazide, metolazone, to a loop diuretic part to increase diuresis is called sequential nephron blockade. One cause of diuretic resistance, is with chronic loop diuretic use, sodium resorption that occurs after the thick ascending limb can short circuit effective loop blockade. So by stacking diuretics that act distal to the loop increases the effectiveness of the loop diuretic.

The addition of a thiazide or K sparing diuretic to a loop diuretic is an example of sequential nephron blockade.

Robert Centor and I did a podcast about the concept a few years ago. We talked about this seminal article by Dave Ellison.

I would have been a bit nervous adding a thiazide in a patient who already had hyponatremia, but the following day the labs look okay.

The following day is the day of discharge. The morning potassium is replaced with a combination of oral and IV potassium as well as 2 grams of magnesium sulfate.

The nephrologist clears the patient for discharge as long as the potassium is normal. The potassium is almost normal and the patient is sent home. On a combination of furosemide and metolazone!

Three days later the patient collapsed at home and during resuscitation is found to have a cardiac arrhythmia and potassium of 1.6.

Know your diuretics. Respect the diuretics

Also keep in mind this propensity matched trial of metolazone in acute decompensated heart failure. They found a large fraction of the excess mortality found with metolazone could be explained by hypokalemia.

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Annals of Internal Medicine Podcast

One of the best medical bloggers is Robert Centor. He has been blogging since the flood (Don’t believe me? Here is his first blog post from May 19th, 2002) and beyond longevity he has been able to develop an enthusiastic engaged audience. He is both prolific and brilliant. I have had a few interactions with him virtually. And we are RunKeeper friends so I keep an eye on his fitness. (He repeatedly trounces me in workouts-per-month).

Dr. Centor introduced me to The Curbsiders. When I saw that he was a guest on The Curbsiders, it was an instant badge of approval and I started listening. He also is, famously, the Chair of Medicine at Kashlak Memorial Hospital.

Last year he heard my diuretics discussion on The Curbsiders and invited me to participate in a podcast for the American College of Physicians. I said yes and then didn’t hear from him for almost year. Then he resurfaced and we recorded the podcast. Then another 6 months went by. I had forgotten about the thing and then last week the podcast dropped. 

I think it turned out good (except for me saying medullary collecting duct when I meant cortical collecting duct. How embarrassing.)

The Annals On Call catalog of podcasts looks amazing. It is apparent that the slow pace I experienced was due to Dr. Centor building a deep catalog for his first season. Impressive work, but not unexpected from the guy who has been furiously blogging for 16 years.

https://twitter.com/KashlakHospital/status/1052197504186544128
I can assure you my recording set-up is quite a bit more modest.

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Articles that changed the way I practice: ACCOMPLISH

I was searching PBFluids and could not find any posts about ACCOMPLISH which surprised me. I then went to the Renal Fellow Network and found a similar lack of commentary. Dito for Nephron Power, and Nephrology on Demand. Even The Kidney Doctor with 100+ posts (and in the process putting the rest of the nephrology blogosphere to shame) in the last 2 months comes up empty handed.

Now some of this may be due to faulty blog search and some of this may be due to the fact that the study is approaching 3 years of age, but regardless ACCOMPLISH is important enough that it should get higher profile coverage.

The study was published in the NEJM in 2008

The acronym is an obviously:

  • Avoiding 
  • Cardiovascular events through 
  • COmbination therapy in 
  • Patient 
  • LIving with 
  • Systolic 
  • Hypertension

From the title, if not the acronym, the point of the study should be clear: The study pits benazepril and amlodipine (Lotrel) against benazepril and hydrochlorothiazide (Lotensin).

The politics of this fight are interesting as this study tries to right one of the possible mis-steps in the wake of ALLHAT. ACCOMPLISH used the thiazide diuretic that is actually most often used in the U.S. and the only thiazide that is used in combination pills, hydrochlorothiazide (yes I know I’m ignoring Tenoretic, atenolol and chlorthalidone, but every other combination pill uses hydrochlorothiazide). ALLHAT used chlorthalidone as its diuretic and when this largest-ever hypertension study concluded that there was no difference among chlorthalidone, amlodipine and lisinopril on fatal coronary heart disease and non-fatal heart attacks, thiazides became institutionalized as the primary agent to treat hypertension.

Figure depicting the primary outcome from ALLHAT
The money shot from JNC7 (pdf) institutionalizing thiazide-type diuretics

The problem stems from the fact that hydrochlorothiazide and chlorthalidone are unique molecules with significant biologic and pharmacokinetic differences.

This year Dorsch et al re-analyzed data from the MRFIT trial. This was a long-term primary prevention trial from the 70’s that changed protocols mid-stream and converted patients from HCTZ to chlorthalidone. This allowed Dorsch’s team to look for differential effects of the two diuretics. They found a 21% reduction in cardiovascular events with chlorthalidone:

If you are interested in the reasons behind the differences read John Flack’s editorial associated with Dorsch’s analysis and look at a 2004 review by Carter et al.

So ACCOMPLISH set out to show that the ACEi CCB combination is superior to the ACEi HCT combination. They randomized 11,506 patients to one of these two arms. The dosing titration seems fair:

  1. 20 benazepril and either 5 of amlodipine or 12.5 of dydrochlorothiazide
  2. if BP is not < 140/90 (130/80 in CKD and DM) increase to 40 mg of benazepril
  3. if BP is not < 140/90 (130/80 in CKD and DM)  increase to 10 of amlodipine or 25 of hydrochlorothiazide
  4. if BP is not < 140/90 (130/80 in CKD and DM)  add additional agents as needed
The cohort was rather sick with previously diagnosed hypertension and an additional history of at least one of the following:
  • Coronary events
  • Impaired renal function
  • Peripheral artery disease
  • LVH
  • Diabetes.
The end point was time to first cardiovascular event, or death from cardiovascular disease.
The study was well run but the blood pressures were not perfectly equal between groups with a small but statistically signifigant difference in the blood pressures between the two groups:
  • 131.6/73.3 in the Benazepril-Amlodipine group
  • 132.5/74.4 in the Benazepril-Hydrochlorothiazide group
  • A difference of 0.9/1.1 in favor of the Benazepril-Amlodipine group
The study was terminated early because the data and safety monitoring committee observed a difference between the two groups that exceeded the pre-specified stopping rule. They found a 20% risk reduction in only 30 months. This represented an absolute risk reduction of 2.2% which translates into a Number Needed to Treat of only 45.
Entering EBM free zone:

To my eyes, ACCOMPLISH better represents the patients I see than ALLHAT. All of the patients that come to my CKD clinic have high blood pressure and almost all also have the additional co-morbidities needed for enrollment. After fully digesting ACCOMPLISH I have made two changes in my practice pattern:

  1. I am starting patients with ACEi + CCB or ARB + CCB. I have been impressed by the effectiveness of Lotrel and Exforge as single pill solutions to a lot of hypertension.
  2. I avoiding hydrochlorothiazide where ever possible. This usually requires re-jiggering a number of medications but a common switch will be to move patients from a list that looks like this:
    1. Lisinopril HCT
    2. Amlodipine

          To a list that looks like this:

    1. ACEi CCB combination pill
    2. Chlorthalidone

This results in significant improvement in blood pressure control.
I have to thank ACCOMPLISH to opening my eyes to this change.

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I love the smell of July 1st in the morning

As has been the tradition since 2008, I had the honor of giving the morning report on July 1st for the St John Hospital and Medical Center Internal Medicine Residency Program. July one, openning day of the academic year. The conference room was crackling with the energy of fresh interns and the equally excited second years ready to run their own teams.

Giving the lecture was a lot of fun. There were a lot of insightful questions, some because the questioner is terrified and others to show how smart she is. Nobody looked sleep deprived, so the ratio of deer-in-the-headlights to asleep-at-their-desk was unnaturally high.

The lecture covered three topics:

  1. total body water and how to choose an IV fluid
  2. diuretics
  3. dysnatremia
There is no way I could get through the deck in the 50 minutes of time we had. It probably would take 90 minutes to cover it all. In delivering the talk I focused on the mood of starting this great adventure.
Here are some tips to using this presentation:
The first slide has Munch’s Skrik, which I explain translates as July 1st

Slide 4 has my favorite quote about kidney function. Homer Smith essentially uses 150 words to explain the point that the job of the kidneys is not to make urine anymore than the job of a factory is to make smoke.

The lungs serve to maintain the composition of the extra-cellular fluid with respect to oxygen and carbon dioxide, and with this their duty ends. The responsibility for maintaining the composition of this fluid in respect to other constituents devolves on the kidneys. It is no exaggeration to say that the composition of the body fluids is determined not by what the mouth takes in but what the kidneys keep: they are the master chemists of our internal environment. Which, so to speak, they manufacture in reverse by working it over some fifteen times a day. When among other duties, they excrete the ashes of our body fires, or remove from the blood the infinite variety of foreign substances that are constantly being absorbed from our indiscriminate gastrointestinal tracts, these excretory operations are incidental to the major task of keeping our internal environments in the ideal, balanced state.  

Slides 5-9 emphasize that this topic is not a niche topic, the issues of fluids and electrolytes comes up everyday, on every patient.

Slide 11, warn everyone that the unfortunate person who gains 30 kg in this slide is a medicine resident gorging on donuts at morning report.

Slide 18, remind everyone that LR is for surgeons. Deny any knowledge of the reason for this peculiarity. Explain that this is further evidence that they are an alien species unrelated to hard working, honest IM docs.

Slide 27 Explain that the question, “Would you give a drowning man a glass of water?” was taught to me by one of the most foul-mouthed senior residents when I was an intern. I want to show that the lessons learned this year will be the stories you tell interns decades later. Interns will learn more this year than any other year of their life, except their first year of life.

Slide 29 recommend everyone read House of God. 

Here is the lecture in PDF and Powerpoint

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Gitelman syndrome and Pregnancy

One of my Gitelman patients (whom I kidding, “one of my Gitelman patients”, how about “my only Gitelman patient”) finally got pregnant. We had been managing her with amiloride and a truck load of oral potassium and magnesium supplements. I was shocked to find that amiloride is acceptable in pregnancy with a track record of successful births. Prior to starting amiloride the patient was taking twenty-eight 20 mEq pills of KCl a day. She abandoned her prior nephrologists when she was told to further increase her potassium pills.

from UpToDate

We are now using magnesium sulfate infusions 4 grams twice a week to keep her magnesium north of zero. She was able to keep her magnesium around 1.4 with oral supplements and amiloride prior to being pregnant but now, despite 8 grams of weekly IV magnesium her magnesium is sitting around 1.1. This probably represents one of downsides of the up-regulated GFR of pregnancy.

Interestingly, she saw her labs and saw that her sodium was 132. Modest hyponatremia is a normal finding in pregnancy, so she decided to increase her dietary sodium intake. Bad move, increased renal sodium loads increases renal magnesium losses. Her serum mag fell 30% to 0.8.

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Renal Week 2008: CKD and CVD: Antihypertensive therapy

Case report of a patient with HTN
Ray Townsend is the MC (sweet). He presnts a patient with HTN and modest CKD. Cr 1.4 up from 0.9 in 2001.

Ray passes off to Domenic Sica.

Antihypertensive Drug Therapy in patients with HTN and CKD.

Volume expansion

  • Patient was on 25 mg of HCTZ. No need to change to loop if the patient is euvolemic. Chlorathalidone vs hctz
  • Ernst HTN 2006. chlorathalidone reduced 24hr mean bp more (7 vs 12) non-ckd patients. night time bp drop was even more pronounced 6 vs 13 mmHg.
  • Recommends switch within class from hctz to chlorthalidone
  • the increase in calcium may help with PTH. interesting.
  • elison JCI 83: 113; 1989 images of hypertrophy of DCT with loop diuretics
  • He’s pushing torsemide
  • Using FeNa to determine if patient is responding to loops (look for fena>3%)
  • Why is there variability in bioavailability of furosemide: floculation of pills stops some absorption. Use of liquid furosemide doesn’t help because of only a limited area of absorbtion: early duodenum only.
  • He likes the torsemide

Drug accumulation

At gfr 30-50 need to think about dose adjustment.
Renally cleared: atenolol, nadolol, betaxolol

Hepatically cleared
propanolol, metoprolol, carvedilol

Dose response to beta-blockers is flat in CKD.

Don’t titrate atenolol. It is renally cleared and patients are already retaining the drug before you increase the dose. Though the BP effect is not dose dependent, the adverse effects are.

Aldosteronism

  • 20% of patients with CKD.
  • Likely this patient will have aldo level of 14-20 and renin less than 1
  • Aldosterone antagonists (AA) reduce proteinuria
  • Need diuretic on board to get much BP effect
  • Half-life of spironolactone is 24 hours, in liver disease 120 hours, and in CKD multiple days. These figures include active metabolites. He feels eplerenone is safer because you won’t get accumulation.
  • Consider qod dosing of spironolactone. Consider 12.5 mg qd
  • beware of heparin causing hyperkalemia with AA
  • Similar warning for ACEi, ARB, TMP/SMX

Clonidine

  • in CKD clonidine is renally cleared. This decreases rebound htn by extending the half life
  • initially clonidine has a steep dose responce at low doses but then flattens
  • causes dose dependent volume retension. this is worse with TTS
  • at higher doses the peripheral alpha stimulation will overcome the central reduction in alpha activity so patients get increase in BP. This is seen in clonidine OD or with autonomic dysfunction.

CCB

  • Amlodipine has half-life of 40 hours
  • nifedipine’s half-life goes from 2 to 4 hours in renal failure
  • Edema with CCB is worse in patients with CKD because they already have increased volume

ACEi

  • 10 in the US
  • fosinopril and trandolopril have significant hepatic clearance
  • ARB are not renally excreted
  • dialyzable: captopril, enalepril, lisinopril. Use in overdose.

Statin

  • AUC of simva increases 4 fold with diltiazem
  • Cool case report of a patient on 80 of simva who was admitted for A-fib with RVR and gets started on a diltiazem gtt. He developed rhabdo a few days later.

That’s it. Question time.

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Bumex, same short pharmacokinetics of lasix with better bioavailability

I’m working more at Providence Hospital and I find that the intensivists and cardiologists love the Bumex. This opinion is shared by some prominant nephrologists. Unfortunately bumetanide suffers from the same short pharmacokinetics as furosemide: half life of about 90 minutes after oral or IV dosing. The big advantage bumetanide has over furosemide is more predictable bioavailability after oral dosing. Torsemide trumps both of them with excellent bioavailablity and a half-life of 210 minutes.

The reason that bumex is preferred is the beleif that it is a more potent diuretic than furosemide. According to Brater, all of the loop diuretics have similar potency and decisions among the loops should be based on pharmaokinetics (as opposed to pharmacodynamics). Here is the statement in his NEJM review of diuretic therapy.


Phamacokinetics of torsemide, bumetanide and furosemide from the package inserts. And here is the table from Brater’s reveiw: