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:

Journal Club: Aspirin and FGF-23

The first article was an intriguing look at various renal function parameters and how they respond to various doses of aspirin. All the patients were pre-treated with enalepril and a thiazide diuretic for 6 days. Then they were given one of four doses of aspirin:

  1. placebo
  2. 80 mg
  3. 160 mg
  4. 320 mg

They found decreased GFR, decreased sodium clearance, decreased solute clearance and decreased free water clearance with 160 mg and 320 mg but the effect was transient with all factors returning to baseline 4 hours after the aspirin was administered.

The article has a long introduction and discussion outlining all of the heart failure studies which have shown that aspirin can be harmful or can decrease the effectiveness of ACEi in heart failure.

The study is small (n=16, with each participant randomized to two doses of aspirin with a 2 week washout between doses) and the authors fail to fully describe the cohort. The primary weakness is the authors want to extrapolate there findings over 6 hours to the effect of aspirin taken chronically for years. Additionally they make the leap of using aspirin-induced changes in renal function to be a proxy for interference with ACEi effect on heart failure survival.

Nonetheless it will change the way I practice. I had previously given my patients (who essentially all are on diuretics and ACEi) the green light to take aspirin any way they want. I will now suggest they limit themselves to 81 mg for CAD protection.

The second article was the NEJM article on FGF-23 and the risk of mortality in hemodialysis patients. FGF-23, or fibroblast growth factor-23, is a newly discovered molecule which regulates the phosphorous in the body. It is one of the primary phosphatonins, signals which increase the renal excretion of phosphorous. Additionally they suppress 1-alpha hydroxylase lowering the amount of 1,25 dihydroxy-vitamin D.

This is prospective cohort with nested case-control of incident dialysis patients in the U.S. The investigators looked at 200 patients who died (cases) in the first year and compared them to 200 patients who survived one year (control). FGF-23 was measured on the first day of dialysis. They divided the cohort into quartiles based on phosphorous and found that patients who subsequently died had increased FGF-23. They found a graded increase in the risk of death with increased FGF-23 level that was signifigant in the whole cohort and inevery quartile of phosphorous except the highest.They also showed a dose responce of mortality to FGF-23 levels in the whole cohort in the crude data, case-mix adjusted and multivariate adjusted.

The authors in the discussion point out that the association of FGF-23 with mortality is stronger than that found with phosphorous and mortality. They found FGF-23 levels were 22% lower in African-Americans than in Caucasians. The authors leave a tease that this lower level of FGF-23 level may explain the improved survival found in African Americans on dialysis.

Melamine Milk Poisoning and Kidney Stones

Nephrology rears its ugly head in the news cycle.

The NYT weighs in. China Says Complaints About Milk Began in 2007

The top food official resigns. I bet he is happy to get away with a forced resignation compared to Zheng Xiaoyu, former head of the chinese FDA who was executed for corruption following the tainted phamaceutical debacle last year.

The interesting is that the same toxin, melamine, was implicated in the pet food renal failure problem in 2007. At that time, the US FDA provided lots of assurances that malamar is not that toxic. Is this a pediatric issue? In some of the articles following the pet food issue a second compound, cyanuric acid, was implicated in the pathophysiology. I have not read anything about cyanuric acid.

More on this as it develops.

The only data I could find on the concentration of melamine in the milk products comes from this ChinaDaily article.

The highest concentration of melamine was found in Sanlu products. Tests show every kg of Sanlu milk food contains 2.56 g of melamine, which can make milk appear rich in protein in quality tests. The chemical is usually used to make plates, bowls, mugs and sundry other products, but is banned from being used in the food industry.

The other tainted products contain between 0.09 mg to 619 mg of melamine per kg.

During the pet food scare of 2007, there was concern that some of the melamine contaminated pet-food reached live-stock and ended up contaminating the food supply. The FDA estimated the tolerable daily intake of melamine at 0.63 mg/kg.

The point of departure (POD) is the NOAEL of 63 mg/kg/day from the rodent subchronic bioassay. This POD was then divided by two 10-fold safety/uncertainty factors (SF/UF) to account for inter- and intra-species sensitivity, for a total SF/UF of 100. The resulting Tolerable Daily Intake (TDI) is 0.63 mg/kg bw/day. The TDI is defined as the estimated maximum amount of an agent to which individuals in a population may be exposed daily over their lifetimes without an appreciable health risk with respect to the endpoint from which the NOAEL is calculated.

Using the concentrations from the China Daily article and the FDA limits on tolerability a 7 kg baby would need to ingest 1.7 liters of Sanlu milk to exceed this safe limit (of note, at the highest concentration only 7 mL would exceed the safe limit). Either the safety estimate was off or there is an additional compound causing the toxicity.

Google search for melamine

Teaching Medical Students

Last Friday I started teaching third year medical students. This is the first time I have taught medical students (in isolation, there are always medical students at my lectures for the residents) since 2003, when I ran a teaching section for renal physiology for first year medical students at Pritzker School of Medicine, University of Chicago with John Asplin.

I am now teaching the medical students two lectures every rotation, the first on sodium and the second on potassium and calcium. I hope to expand this to ABGs and another electrolyte lecture so I can isolate potassium and spend an entire hour on it.

I modified my Don’t Panic handout for the students. During the lecture I realized that the SIADH section was weak and too complex for the students. I will probably change it to focus on the fact that ADH reduces water excretion and that this can be adaptive (early CHF, volume depletion, hyperosmolar) or maladaptive (SIADH). I will change the section on the dilution of urine to a background box as I think it is important but only interesting to nephrologists and similar wierdos.

I will add a focus on a few clinical scenarios with increased ADH.

I still need to expand the hypernatremia section.

iPhone version

Journal Club: Bicarb for contrast nephropathy and calcitriol for CKD 3 and 4

The first article was a retrospective study on the use of calcitriol in patients with CKD stage 3 and 4. The outcome was mortality and mortality plus dialysis. The authors were able to demonstrate a significant reduction in both outcomes with the use of calcitriol. Some interesting points were the lack of a dose effect and the effect was independent of PTH. The authors suggest that the benefit of activated vitamin D therapy is not due to its affect on PTH.

Association of oral calcitriol with improved survival.

The second article was the latest study on contrast nephropathy.

Sodium bicarbonate vs sodium chloride.

This well done randomized, single-blinded, controlled trial showed no difference between isotonic NaCl and nearly isotonic bicarbonate.

Hepatorenal syndrome Journal Club

Journal club today reviewed this article on the treatment of hepatorenal syndrome (HRS) with terlipressin. What a breath of fresh air in the field of HRS, a real randomized double blind placebo controlled trial!

Terlipressin is part of the new wave of HRS that focus on splanchnic vasoconstriction to reverse one of the initiating events in the pathologic cascade that results in HRS. I have been using the combination of octreotide and midodrine to exploit the same therapeutic target. I have had mixed results. I am not aware of any prior controlled trials of this therapeutic target.

Enrollment criteria:

  • Age ≥18
  • Liver disease
  • Doubling of serum cr to ≥2.5 mg/dL in less than 2 weeks with no responce to stopping diuretics and giving plasma expansion

Exclusion criteria

  • Obstructive nephropathy
  • Parenchymal renal disease (ATN, glomerular disease, interstitial nephritis)
  • Use of renal toxic medications
  • Shock
  • Uncontrolled bacterial infection
  • Uncorrected fluid losses
  • Liver disease due to factors which are also nephrotoxic (e.g. acetominophen)
  • Severe cardiovascular disease (investigators discretion)

Intervention: Patients were randomized to either 1 mg terlipressin q6h or matching placebo. If after 3 days the patients had not had a decrease in Cr of 30% the study drug was doubled to 2 mg q6h. The protocol recommended daily albumin infusions (100 g on day one and 25 g daily after that). The protocol prohibited concomitant use of vasocontrictors (dopamine, norepinephrine) prostaglandin, NSAIDs.

Primary end-point: percent of patiens with a serum Cr ≤1.5 on two measurements 48 hours apart without dialysis, death or recurrence of HRS.

Secondary end-points:

  1. Change in serum Cr from baseline to day 14
  2. incidence of treatment failure (Cr ≥ baseline after day 7, dialysis, death)
  3. Combined incidence of treatment success and partial response (Cr decreased by >50% but not ≤ 1.5) without diqalysis or recurrence of HRS
  4. Survival [Yay!] at 60 days (though they did not show the results)
  5. Transplant-free survival at 60 days (though they did not show the results)
  6. Survival at 180 days
  7. Transplant-free survival at 180 days


They randomized 112 patients from 35 centers.
More patients in the terlipressin group had a Cr > 7, though the average creatinine was 3.96 in the experimental group and 3.85 in the control group.

The Table 1 did not have p values to allow you to compare differences between the two groups.

The primary outcomes were summarized in Table 2:
The primary outcome is the first line “Treatment success at day 14” and unfortunately they “Missed it by that much” with a p value of 0.093. The next line is HRS reversal which according to the article is the traditional definition of response to therapy in prior investigations of HRS. It is interesting that if the authors had used this “traditional” end-point we would be dancing in the streets about a positive therapy but since they selected a more stringent criteria of response (under pressure from the FDA?) they have a negative trial. The power analysis they provided states they predicted a 50% response rate for terlipressin and a 5% response for the placebo. They actually found a 25% response for terlipressin and 12.5% for placebo. So one cold look at this as an underpowered study because they did not meet the effectiveness they estimated in the power analysis.

The authors then provide an intriguing figure which shows that the patients who recovered in the placebo group, all recovered very early while the recoveries in the terlipressin group occurred through the period the drug was administered.
I believe the point was to show proof of efficacy, implying that the early spontaneous recoveries in the placebo group were due to misdiagnosis or lack of serious disease while the recovery of patients in the terlipressin’s group increased with increasing duration of therapy. I find this fairly compelling.

One of the secondary outcomes was survival (Yay!). There was no difference in survival between the two groups.

Though I love investigators that have the cojones to look at survival, it is a little strange in HRS because the renal failure is secondary to another life threatening primary illness, liver failure. Even if the therapy is perfectly effective at reversing the renal failure, the long-term survival is dependent on getting a liver transplant or spontaneous recovery of the liver disease. One might argue that curing the renal failure would extend the life of the patient making a transplant more likely but since renal failure is a large component of the MELD score, curing the renal failure actually pushes patients down the list for a liver transplant. So in my mind, the lack of a survival benefit in the treatment of HRS is not nearly as damaging as it normally is.

My final conclusion is that though the study did nt reach scientific signifigance for its primary outcome it did demonstrate compelling evidence for positive biologic activity and since all of the alternative therapies have worse data I would use terlipressin if it was available. My guess though is this negative trial will mean that it will not be licensed and distributed in the U.S.

Sodium and Potassium for ER residents

Yesterday I lectured the St John ER residency program. The ER residency has an impressive commitment to education. They set aside a half day every wednesday for their resident to get dedicated didactic time. They have great attendance with a good number of attendings showing up.

I have been asked to give three lectures and yesterday was the first. I gave a double lecture (running time about 90 minutes) on sodium and potassium. The fact that I could run over the standard 50 minute alotment normally given for medicial education is due to the fact that they have blocked an entire afternoon rather than try to shoehorn a lecture into lunch or before rounds.

The sodium lecture was the first time I used the Sodium handout I created for the St John IM residents. I gave the lectuer Seder-Style with the residents reading different sections, answering questions and me adding commentary. The ER residents are smart and empowered to ask questions. I felt that there was great two-way interactivity.

Dont Panic Sodium

Sodium iPhone format
Sodium booklet format

The potassium lectuer is an abrdged potassium lecture which is stripped to the bare bones of differential and treatment. It is a traditional powerpoint lecture. Immediately when I started this lectuer I saw about half a dozen exhausted interns fall asleep. My next project is to create a potassium haggadah.

Potassium powerpoint