Precious Bodily Fluids

The SPLIT trial was the long awaited randomized control trial that pitted normal saline against the balanced solution du jour, Plasma Lyte-148. I have never before dedicated to the statistical plan for a study before the wait up to SPLIT:

I wasn’t the only fluids nerd waiting for SPLIT. In the days and weeks after the study dropped at ESCIM in Berlin there was a lot of blog energy expended on the study:

• ESCIM.org
• R.E.B.E.L. EM
• St Emlyn’s
• PulmCrit (EMCrit)
• Emergency Medicine Literature of Note
• NephJC

And let’s face it the SPLIT trial did not go the way a lot of us wanted or expected. Everybody that was paying attention to the discussion had joined #TeamBalancedSolution. If you want to get a feel for the sense of inevitability of balanced solutions re-read the description from NephMadness 2014 or check out this editorial in KI.

SPLIT went the other way: it showed no adverse affects from saline and no advantage to balanced solutions. Much of the blogging about SPLT was fairly critical. Much of the criticism focused on the patient population (relatively low risk) and a lot of the criticism focused on the relatively low volume of fluid given to the participants. PulmCrit’s discussion on the volume of fluid is typical of much of the criticism:

How does this data apply to other situations?  A broader interpretation of the study is that administration of 1-2 liters of normal saline would not increase the risk of renal failure compared to plasmalyte.  This is not particularly controversial.  Even the most ardent supporters of balanced crystalloid would probably agree that fluid selection doesn’t make a big difference at a volume of 1-2 liters.  The proposed mechanism of nephrotoxicity due to saline is induction of a hyperchloremic metabolic acidosis, which tends to occur with larger volumes of fluid. 

Shaw, et al. did a beautiful retrospective analysis of 0.9% saline versus Plasma-Lyte with propensity scoring. They showed a litany of problems with 0.9% saline:

• In-hospital mortality was 5.6% in the saline group and 2.9% in the balanced group (P < 0.001)
• One or more major complications occurred in 33.7% of the saline group and 23% of the balanced group (P < 0.001)
• Balanced fluid was associated with fewer:
• complications (odds ratio 0.79; 95% confidence interval 0.66-0.97).
• Postoperative infections (P = 0.006)
• Renal failure requiring dialysis (P < 0.001)
• Blood transfusion (P < 0.001)
• Electrolyte disturbance (P = 0.046)
• Acidosis investigation (P < 0.001)
• Acidosis intervention (P = 0.02)

How much fluid was needed to provide all of this hazard? About 2 liters of saline and 1.6 liters of Plasma-Lyte:

One of the bedrock data points that showed harm from saline is Yunos’ prospective, but unblinded analysis. Covered here on PBFluids.

Yunos’s found the use of saline compared to Hartman’s (Australian for Ringer’s lactate):

• Mean increase in creatinine while in the ICU was 22.6 μmol/L vs 14.8 μmol/L (P = 0.03)
• The incidence of injury and failure class of RIFLE-defined AKI was 14% vs 8.4% (P <.001)
• The use of acute dialysis was 10% vs 6.3% (P = .005).

How much 0.9% saline had to be infused to get this disaster? 3.2 liters.

Another highly referenced article in the saline versus balanced solution cannon is Chowdhury’s randomized controled trial of healthy volunteers that used MRI imaging to measure renal blood flow following saline compared to plasmalyte 142 infusions. They found a significant reduction in mean renal artery flow velocity (P = 0.045) and renal cortical tissue perfusion (P = 0.008) from baseline with saline, but not Plasma-Lyte 148.

The volume of fluid needed to demonstrate decreased perfusion? Two liters.

After reading and digesting SPLIT, I’m still on #TeamBalancedSolution but my certainty has been shaken because to my mind SPLIT is the best done study with real patient oriented outcomes and it was convincingly negative.

I look forward to a spirited discussion in #NephJC on January 12th at 9pm EST and January 13th at 8 pm GMT.

I know this is vain, even for a personal blog, but I need a place to keep track of these.

Thank you very much Providence Internal Medicine Residents. It is precious to me. pic.twitter.com/RPWjLrhsIJ

— Joel Topf (@kidney_boy) June 21, 2014

Original (PDF)

Arrived by inter office mail today. pic.twitter.com/i968BmUIv5

— Joel Topf (@kidney_boy) December 23, 2015

Is this table helpful or too complex; didn't read #TCDR

— Joel Topf (@kidney_boy) December 21, 2015

Nephrology, more than other specialties is plagued by misplaced concreteness. We get false senses of precision because of the myriad of equations that spit out results to the milliliter. All of those equations from Kt/V, to water deficits, to IVF brain teasers depend on an estimate of total body water.

Everyone knows the rule of thumb that young males are 60% water, young females are 50% water and the percent body water falls as people age or get fatter.

Going beyond these rules of thumb, how is total body water measured empirically? The gold standard is heavy water dilution.

This works by giving a sample of heavy water and then waiting for it to equilibrate. Then the investigators measure the heavy water content of exhaled water vapor or a blood sample, the fraction of the water that is heavy water will be equivalent to the fraction of total water which is heavy water. Then since one knows the amount of heavy water given to the patient, one can calculate total body water.

When this is done, or when one reviews the primary literature, as was done in this study the numbers are a little different.

• Males: TBW (in liters) = 2.447 + (0.09156 × age) + (0.1074 × height) + (0.3362 × weight)
• Females: TBW (in liters) = –2.097 + (0.1069 × height) + (0.3362 × weight)

Everyone knows that if you give a liter of saline, all of it remains in the extracellular compartment.

But what if you give a patient just the salt from the saline and none of the water? How much does the solute contribute to the increase in the extracellular volume? How does 154 mmols of NaCl affect the size of the extracellular and intracellular compartments?

Assume the patient is a 70 kg lean young male with a serum osmolality of 280 mOsm/kgH2O. Ignore any renal losses during the process.

For full credit fill out the following:

Total body water:
Size of the extracellular compartment:
Size of the intracellular compartment:

Step one calculate the total number of osmoles the patient has:

70 kg lean young male means 60% total body water or 42 liters
42 liters times 280 mOsm/Kg = 11,760 osmoles in the body

Giving 308 mosm of solute will increase that to 12,068. There is no additional water so dividing that by 42 liters gives us a new osmolality of 287 mOsm/Kg water.

 
Remember that even though the solute is trapped in the extracellular compartment, the osmolality is the same across all body compartments since water can flow from compartment to compartment.

Now we need to find out how much the extracellular compartment expands in osmoles.

Before the addition of solute the extracellular compartment should be one third of total body water, so 14 liters times osmoality of 280 is 3920 mOsmoles. Add 308 and then divide that by the new osmolality to give you the new volume:

Total body water: 42 liters
Size of the extracellular compartment: 14.7 liters
Size of the intracellular compartment: 27.3 liters

So I checked in at DreamRCT and noticed that my DreamRCT is no longer in the top five.

I’m a big boy and can take this (very minor) form of rejection but I do want to plead my case for a moment. You can read the entire description of my DreamRCT here. One of the dirty little secrets of nephrology is the almost total lack of prospective data on hyponatremia. There are a number of RCTs with regards to tolvaptan, conivaptan and other approved, and soon to be approved, vaptans. But after those there is an evidence desert populated by only a few mirages made up of case reports and retrospective analysis. From this scant data we have built a comprehensive and detailed model of how sodium acts in the body and the importance of osmoregulation. But thats like theoretical physics without a supercollider. We need to test the model with real data.

Think about the fact that hyponatremia is the most common electrolyte disorder. We order metabolic profiles on every patient, every day, but when it comes to interpreting those results we might as well be reading hieroglyphics.

RCTs are difficult and expensive but there are particular areas where we should require them prior to treatment. One of these corners is when we treat people with no symptoms and we are effectively treating a number. High cholesterol, high blood pressure, and low sodiums are three such areas, however hypertension and hypercholesterolemia have both gone through the right of passage called a randomized controlled trial. I am confident that my patients with asymptomatic hypertension benefit from treatment. My patients with coronary disease and hypercholesterolemia will live longer and better with treatment with a high potency statin. On the other hand, patients with sodiums of 129 and no apparent symptoms are supposed to be at higher risk of falls, have a higher mortality from heart and liver failure. Does treating them reduce these risks?

¯_(ツ)_/¯

We can do better. Hyponatremia is the most common electrolyte disorder found in patients, we owe it to them to have real, prospective, data to answer these questions.

Go to UKidney to vote for my trial: No hyponatremia modification in asymptomatic hyponatremia. Thanks.

DreamRCT is a creative writing project for nephrologists. The assignment is to scour the landscape of nephrology knowledge for a corner that is dominated by dogma and retrospective evidence. Once the target is identified, the writer needs to summarize the gaps, and think up a creative way to shine science’s greatest flashlight on the subject, a randomized controlled trial.

We have recruited 16 people to submit DreamRCTs which were published today on MedPage Today. Thanks Ivan, Kristina and Elbert. It is a amazing collection of creativity; there are trials on kidney stones, electrolytes, dialysis, proteinuria and lupus. Please go check them out; read them and see which are great and which should be relegated to The Journal of Craptology.

After reading the DreamRCTs move on over to Jordan Weinstein’s excellent UKidney where it is time to channel your inner Mark Cuban and play Shark Tank with the DreamRCTs.

Which trial should be funded which shouldn’t. How much should each trial be awarded. You will get $100,000 to distribute among the trials. Think KickStarter meets NIH. You will not be alone in this endeavor. We have recruited an expert panel of clinical researchers to score the trials. At the conclusion of the contest we will look at how the experts spent their cash and how the crowd did. We will also award a small prize to the funder whose distribution best matches the expert panel.

DreamRCT only works if we get a critical mass of people to participate. Please check out the trials at MedPage Today and then go to UKidney to vote with your (completely virtual, don’t ask me for a refund) dollars. Announce the project at morning report, assign your fellows to vote and then submit discuss and submit your own DreamRCT, because in the end DreamRCT is not just a game but a shorthand expression for what we need to do to fix nephrology and heal our patients.

eJC, you know the other online nephrology journal club, invites people to write introduction to their monthly journal club.

Last August I worked with Bilal Saleem to review and summarize a neat study on anti-PLA2R in membranous.

This year I worked with Saiyed Muddasser on an article looking at cold dialysate for cardio protection. Take a look at the summary and then go to the eJC site and make a comment.