The folly of chasing urine output with fluid in sepsis

Through medical school and house office years it is easy to develop many ‘reflex’ responses to certain conditions. Treating low urine output with fluid is one of these.

This makes sense in certain conditions. Hypovolemia leads to reduced renal perfusion. Correcting hypovolemia is therefore a good thing. Aggressive fluid resuscitation to restore renal perfusion makes sense in conditions where the patient is significantly fluid deplete, like enteritis or DKA, or where diuresis is helpful to prevent nephrotoxicity such as rhabdomyolysis or tumour lysis syndrome.

Unfortunately this has been extrapolated to every condition associated with AKI, resulting in massive fluid volumes being given to patients in the hope that the fluid will somehow drive the kidneys to work better. This is entirely devoid of physiological sense. This is most apparent in septic conditions. I particularly recall patients on the surgical ward with pancreatitis, who were given fluids for their oliguria and renal failure until they were swollen like the Michelin Man.

Chest Journal has published an article this month (1) addressing fluid management in acute kidney injury. This narrative is supported by a 2017 article of the same name. There are a few things to note.

Firstly, there is really no scientific evidence that macrovascular renal blood flow is routinely compromised in sepsis. Septic patients may be hypovolemic due to fluid shifts into the extracellular space but generally the problem is one of vasodilatation. The pathophysiology of acute kidney injury in sepsis is complex and involves tubular apoptosis and dysfunction at the cellular level.

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Jugular Venous PRESSURE- so why do we use it to assess volume?

There is perhaps no physical exam sign more enthused about by consultants and more bluffed by students than the jugular venous pressure (JVP). While initially I was not a believer, I have come recently to appreciate its usefulness. This epiphany did not occur without significant time spent perusing the literature and finally coming to understand what the JVP does and does not tell you.

The first point to make abundantly clear is that JVP is simply a surrogate for central venous pressure (CVP). This roughly estimates the right atrial pressure. The obvious first question a sceptic would ask is how good a job it does at this?

Well, if we refer to the JAMA rational clinical exam series from 2009 (1), a systematic review of sorts on different examination findings, we see that the JVP, and hepatojugular reflux, correlates reasonably well with invasively measured CVP. The table of likelihood ratios below combines findings from the three studies addressing this question, including one where hilariously medical students were better at estimating CVP than staff physicians.

JVP
Credit: Reference (1)

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Plasmalyte is safe (and actually better) in hyperkalemia

In some indistinct corner of a ward somewhere where I spent the majority of my first house officer year, a laminated sign is blu-tacked to the wall which reads as follows:

“Normal Saline is the only fluid that should be used for patients with end stage renal failure”.

While on the face of it this serves to prevent some poor house officer charting fluid with 20mmol KCL in it to a patient on dialysis, normal saline is actually a poor choice for someone with renal failure or hyperkalemia.

While surgeons are known to sometimes insist on some bizarre things, their insistence on using plasmalyte as a resus fluid is well founded. This elegantly balanced crystalloid contains not only physiological amounts of Na and Cl (unlike NaCl which delivers an unphysiologic 150mmol/L of Cl) but also magnesium, acetate and gluconate. The latter two are converted into bicarbonate, and their metabolism provides 66kJ of energy per litre of fluid (1).

Plasmalyte also contains 5mmol per litre of potassium, hence the twitchiness of people to use it in hyperkalemia or renal failure. This worry, however, appears to be a misapplication of physiology.

If you take a second to think about it, there is no reason why addition of normokalemic fluid to plasma should make someone hyperkalemic (for a potassium of 5 is still a normal potassium). In fact, if you replaced all of someone’s plasma with plasmalyte, you could not get a potassium above 5. This is explained much more elegantly in this post on the veritable emcrit blog (2).

The second important point also explained in this post is that most potassium is intracellular and potassium levels are really largely dependent on cellular shifts more than anything else. Normal saline tends to cause a hyperchloremic metabolic acidosis because of the unphysiological quantities of chloride, which impair H+ excretion. Potassium will shift out of cells in response to buffer this. The end result is that potassium levels rise more with the administration of normal saline, even though  it contains no potassium in the bag, than with plasmalyte, which has a significant alkalinising effect (2).

Of course theory is no good without the studies to back it up, and the studies all strongly point in one direction. Three studies (3-5) looked at the perioperative administration of Ringers Lactate (LR) (a fluid similar to plasmalyte which contains 4 mmol/L of potassium) compared to Normal Saline in patients with end stage renal disease undergoing transplantation. Average potassium levels rose in the Normal Saline group in all three studies and fell or stayed the same in the LR groups. In fact, the first study had to be terminated early because 19% of the NS group developed hyperkalemia while none in the LR group did.

To satisfy you fully, let us turn to the evidence for plasmalyte directly. Adwaney and colleagues (6) demonstrated that, in the same setting of renal transplantation, recipients of plasmalyte had a significantly lower need for renal replacement therapy in days 1-3 post-op (OR of 0.15) and had a 2% incidence of hyperkalemia versus 17% in the NS group (despite pre-op potassium being the same).

Also recently Weinberg et al. (7) confirmed that NS caused significantly more hyperkalemia and acidosis in renal transplant recipients than plasmalyte.

Conclusion

The evidence is quite uniform and strong in a way that is uncommon for this type of topic. Not only does plasmalyte appear to be safe in renal failure/hyperkalemia, it is actually safer than normal saline. Understanding why this is the case delivers an important lesson in fluid physiology.

 

References

  1. http://www.medsafe.govt.nz/profs/Datasheet/p/plasmalytesol.pdf
  2. https://emcrit.org/pulmcrit/myth-busting-lactated-ringers-is-safe-in-hyperkalemia-and-is-superior-to-ns/
  3. Anesth Analg. 2005 May;100(5):1518-24, table of contents. A randomized, double-blind comparison of lactated Ringer’s solution and 0.9% NaCl during renal transplantation. O’Malley CM1, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, Bennett-Guerrero E.
  4. Ren Fail. 2008;30(5):535-9. doi: 10.1080/08860220802064770. Effects of normal saline vs. lactated ringer’s during renal transplantation. Khajavi MR1, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, Najafi A.
  5. Saudi J Kidney Dis Transpl. 2012 Jan;23(1):135-7. A comparative study of impact of infusion of Ringer’s Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation. Modi MP, Vora KS, Parikh GP, Shah VR.
  6. Perioperative Plasma-Lyte use reduces the incidence of renal replacement therapy and hyperkalaemia following renal transplantation when compared with 0.9% saline: a retrospective cohort study . Anamika Adwaney David W Randall  Mark J Blunden  John R Prowle Christopher J Kirwan. Clinical Kidney Journal, Volume 10, Issue 6, 1 December 2017, Pages 838–844, https://doi.org/10.1093/ckj/sfx040
  7. Effects of intraoperative and early postoperative normal saline or Plasma-Lyte 148® on hyperkalaemia in deceased donor renal transplantation: a double-blind randomized trial. BJA October 2017Volume 119, Issue 4, Pages 606–615. L. Weinberg, L. Harris, R. Bellomo, F.L. Ierino, D. Story, G. Eastwood, M. Collins, L. Churilov, P.F. Mount