Dialysis disequilibrium syndrome

This subject matter occasionally rises from the depths of the examiners' subconscious to menace the advanced trainees. Though it has never appeared in the Part II exam in any meaningful way, anecdotal recollections of survivors seem to suggest that it occasionally occurs in viva stations and confronting bedside tutorials.  Fortunately, the prevalence of this in the actual arena of clinical practice has decreased so much with modern methods of dialysis that authors have been referring to it as a "vanishing complication".

Pathophysiology of dialysis disequilibrium syndrome

At a basic level this is a condition which results from the cerebral oedema that occurs when an ineffective osmole is enthusiastically extracted from the extracellular fluid by dialysis. In this, it resembles the cerebral oedema that can develop with the rapid overcorrection of glucose in a patient with a hyperosmolar hyperglycaemic state.  Its one of those rare disease states that, when first recognised, was immediately and fully understood by the authors of the seminal article, with little else added in the subsequent years.

That seminal paper was Kennedy et al (1962), and is really just a letter to the editor of the Lancet. This group of clinicians noted that among renal failure patients with uraemia, a group failed to improve following dialysis - instead developing worsening confusion even while their biochemistry looked better. They made the connection between this phenomenon and the urea concentration, taking a hint from contemporary neurosurgical practices (where at the time it was routine to give doses of urea for cerebral oedema, in the same way as in the modern era one might give mannitol). Coming to the conclusion that some sort of a reverse version of this effect must have been operating in their patients, they followed this up with a series of experiments, demonstrating the lag between blood urea and CSF urea concentrations. In this manner, Kennedy et al were able to demonstrate that a concentration gradient is established during and after dialysis.

Effect of dialysis on CSF urea, from Kennedy et al (1962)

This was developed further by Pappius et al (1967) whose experimental animals ended up with a 12 mmol/L urea gradient across their blood-brain barrier while undergoing outpatient-style haemodialysis. This gradient develops because, though urea is an ineffective osmole, it's still effective enough over short timeframes. For the blood-brain barrier, the reflection coefficient (σ) of urea is about 0.44–0.59, where a σ value of 0.0 would be expected for a perfectly ineffective osmole and 1.0 for a perfectly effective one (for example, the σ for mannitol is 0.9). Without going into too much detail, this abstract ratio is a measure that describes the difference between the measured osmotic pressure across a membrane, and the pressure that would be expected from the van 't Hoff equation (which assumes the membrane is perfectly impermeable). The upshot of this measured value being not 1.0 is that urea can exert some osmotic pressure across the blood-brain barrier, which would give rise to a movement of water, and result in oedema. Moreover, during a long period of extracellular uraemia, idiogenic osmoles may also be generated by the cells of the central nervous system as a compensatory move.

So: from the above, two questions arise:

  • How much of a concentration gradient is required to produce a clinically significant movement of water, and
  • Does the intracranial pressure increase, and should we manage this in the same way as we manage all raised intracranial pressure?

Rate of urea change necessary to cause cerebral oedema

During a routine outpatient haemodialysis session, the dialytic and convective clearance of solutes results in an extracellular osmolality change of something like 20-30 mOsm/kg (Hagstam et al, 1969). Of these solutes, the vast majority must surely be urea. The other main solutes which contribute to osmolality are sodium (which remains stable because the dialysate contains a physiologically normal amount of sodium) and glucose (which would be expected to remain stable because the intensivist and the pancreas are both rather invested in maintaining a survivable blood glucose concentration in the patient). Ergo, a urea drop of 20-30 mmol/L over 3-4 hours is probably going to be well tolerated by otherwise well haemodialysis outpatients, which would correspond to a maximum drop of around 10 mmol/L/hr. 

Even with this clinically irrelevant and unnoticed osmolality change, the brain parenchyma does tend to take on a lot of water, as demonstrated through pre and post dialysis CTs by La Greca et al (1982) and through MRI by Chen et al (2007). Some of these patients were symptomatic (headaches and nausea) even with a modest fall in osmolality - around 23 mOsm/kg in the Chen paper, which reported on ESRD patients having their first dialysis session. Therefore, dialysis disequilibrium syndrome could still occur in vulnerable brains even with a supposedly "safe" rate of urea drop. Mistry (2019) quoted reports of proper coma-and-seizures DDS in patients with a urea drop ranging from 65% to a mere 28%.

Intracranial pressure in dialysis disequlibrium syndrome

All that nausea and vomiting reported in the studies mentioned above suggests that some kind of change in intracranial pressure might have occurred. As none of the dialysis disequilibrium syndrome patients ever get sick enough for long enough to warrant an intracranial pressure monitor, our evidence about this is collected opportunistically in studies of patients who have an ICP monitor for some serious intracranial reason and have some dialysis because they also incidentally have renal failure. Thus we have data on ICP changes with dialysis in patients with intracranial haemorrhage as in Krane, 1989, or traumatic brain injury as in Lund et al (2018). In the latter paper, the ICP increased by an average of about 5-10 mmHg, and was predictably highest in patients who were receiving rapid haemodialysis (occurring 75 minutes into the treatment). 

So, does that mean we can give them hypertonic saline and mannitol?

Management of dialysis disequilibrium syndrome

In short, yes. And there is probably more data and experience for mannitol here, probably because this condition has existed for a very long time, as has mannitol, whereas hypertonic saline is a relatively recent development. Giving mannitol to dialysis patients dates back to Hagstam et al (1969) and Rodrigo et al (1977). There was definitely an effect on the clinical features of disequilibrium syndrome, particularly in the latter study. Mannitol is still recommended for the management of acute severe dialysis disequilibrium syndrome by the sort of nepherologists who write narrative reviews for Seminars in Dialysis (Patel et al, 2008).

Clinical features of dialysis disequilibrium syndrome

Unsurprisingly, these are very similar to other clinical features of cerebral oedema and raised intracranial pressure:

  • Headache
  • Nausea
  • Vomiting
  • Dizzyness
  • Muscle cramps
  • Agitation
  • Tremors
  • Disturbed consciousness
  • Convulsions / seizures

Patel et al list these with references and percentage values, but most reasonable people would agree that knowing the exact percentages would not have any meaningful benefit. "Mild, transient, and self-limited" is how most authors describe the natural course of this disease in most patients. 

Prevention of dialysis disequilibrium syndrome

From everything above, the following preventative steps logically follow:

  • Cautious reduction in the blood urea concentration by 40% for the first dialysis session of a chronic renal failure patient previously not on haemodialysis
  • Slower dialysis sessions
  • Lower dose of dialysis
  • Addition of sodium to the dialysate or directly to the patient (as it has a higher reflection coefficient than urea, usually quoted as close to 1.0,  and so even a small amount of sodium should therefore offset the osmotic effects of urea removal)
  • Addition of urea to the dialysate could theoretically be the right solution here because it would prevent a large urea drop (and in any case urea is a fairly harmless molecule), but in practice this is never done, mainly because most hospitals do not stock sterile urea solution.


Kennedy, A. C. "Urea levels in cerebrospinal fluid after hemodialysis." Lancet 1 (1962): 410-411.

Pappius, Hanna M., J. H. Oh, and J. B. Dossetor. "The effects of rapid hemodialysis on brain tissues and cerebrospinal fluid of dogs." Canadian journal of physiology and pharmacology 45.1 (1967): 129-147.

Fenstermacher, J. D., and J. A. Johnson. "Filtration and reflection coefficients of the rabbit blood-brain barrier." American Journal of Physiology-Legacy Content 211.2 (1966): 341-346.

Ali, Muzzammil, and Umar Bakhsh. "A vanishing complication of haemodialysis: dialysis disequilibrium syndrome." Journal of the Intensive Care Society 21.1 (2020): 92-95.

Zepeda-Orozco, Diana, and Raymond Quigley. "Dialysis disequilibrium syndrome." Pediatric nephrology 27.12 (2012): 2205-2211.

Bhandari, Binita, and Saketram Komanduri. "Dialysis disequilibrium syndrome." (2020).

Patel, Nilang, Pranav Dalal, and Mandip Panesar. "Fellows’ forum fellows’ forum in dialysis edited by mark A. Perazella: dialysis disequilibrium syndrome: a narrative review." Seminars in dialysis. Vol. 21. No. 5. Oxford, UK: Blackwell Publishing Ltd, 2008.

Arieff, Allen I., et al. "Brain water and electrolyte metabolism in uremia: effects of slow and rapid hemodialysis." Kidney international 4.3 (1973): 177-187.

Lu, Renhua, Zhaohui Ni, and Claudio Ronco. "Effect of Extracorporeal Therapies on the Brain." Critical Care Nephrology. Elsevier, 2019. 811-815.

RODRIGO, FRANCISCO, et al. "Osmolality changes during hemodialysis: Natural history, clinical correlations, and influence of dialysate glucose and intravenous mannitol." Annals of Internal Medicine 86.5 (1977): 554-561.

Hagstam, K. E., B. Lindergård, and G. Tibbling. "Mannitol infusion in regular haemodialysis treatment for chronic renal insufficiency." Scandinavian Journal of Urology and Nephrology 3.3 (1969): 257-263.

Mistry, Kirtida. "Dialysis disequilibrium syndrome prevention and management." International Journal of Nephrology and Renovascular Disease 12 (2019): 69.

La Greca, G., et al. "Studies on brain density in hemodialysis and peritoneal dialysis." Nephron 31.2 (1982): 146-150.

Chen, C. L., et al. "A preliminary report of brain edema in patients with uremia at first hemodialysis: evaluation by diffusion-weighted MR imaging." American Journal of Neuroradiology 28.1 (2007): 68-71.

Krane, N. Kevin. "Intracranial pressure measurement in a patient undergoing hemodialysis and peritoneal dialysis." American Journal of Kidney Diseases 13.4 (1989): 336-339.

Lund, Anton, et al. "Intracranial pressure during hemodialysis in patients with acute brain injury." Acta Anaesthesiologica Scandinavica 63.4 (2019): 493-499.