Disequilibrium Syndrome

What Is Disequilibrium Syndrome?

Disequilibrium syndrome is a clinical symptom develops due to deterioration of the central nervous system noticeable in hemodialysis. The symptoms of disequilibrium syndrome may occur in patients immediately after the first hemodialysis initiated or in any phase after continuing to take subsequent therapy. The attribution of disequilibrium syndrome symptoms is for central edema formation.

Dialysis Disequilibrium Syndrome

The first reported clinical description about disequilibrium syndrome found in 1962. According to this report, mental status improvement found in some patients, while most of the patients suffered mental conditions, even after improvement of chemical parameters of the blood1-5.


The formation central edema causes increase intracranial pressure, therefore, symptoms are quite similar as acute hyponatremia, The included symptoms are 5

  • Restlessness,
  • Headache,
  • Mental confusion
  • Occasional muscle twitching
  • Coma

Apart from this above mentioned symptoms, following physical sign may also observe

  • Tachypnea
  • Tachycardia
  • Accessory muscle use
  • Left lung base crackles

Other diagnostic finding of disequilibrium syndrome are as follows4

  • Uremia
  • Dialysis dementia
  • Hypoglycemia
  • Acute cerebrovascular event
  • Nonketotic hyperosmolar coma
  • Excessive ultrafiltration and seizure
  • Hyponatremia
  • Malignant hypertension
  •  Subdural hematoma

Disequilibrium Syndrome In Dialysis

The exact etiology of the Disequilibrium Syndrome is yet to discover. According to the laboratory findings, the level of urea in blood is lesser in blood than cerebrospinal fluid (CSF) in Disequilibrium Syndrome.

The microenvironment of the nervous system depends upon solute and water exchange through Blood Brian Barrier (BBB). The lateral and fourth ventricles of the choroid plexus, which composes microenvironment of the brain make BBB and blood–CSF barriers. All these internal structures are responsible for regulating the composition of ECF (extracellular fluid) and CSF.

The microvasculature of the BBB is made with endothelial cells, which provides a complex tight junction between the cells. This regulates movements of ions and small organic solutes between the blood and the extracellular space. Apart from this tight junction, osmotic pressure across the BBB also helps to maintain the balance of water and solutes in the CSF compartment.

The level of urea in CSF is very low in normal individual and patient in pre-dialysis condition also showed a lower level of urea in comparison with blood. But after hemodialysis, the concentration of urea is more in CSF and the osmotic gradient in BBB altered. The higher concentration of urea in CSF leads to increase water content in the central nervous system, which enhances intracranial pressure.

The symptoms of Disequilibrium Syndrome arises due to formation central edema. The reason of central edema formation is due to “Reverse Urea Effect”. The “Reverse Urea Effect” occurs due to higher urea content in CSF is remains for a prolonged period, as it cannot quickly diffuse. Therefore, a large quantity of water move towards CSF and accumulate in the CSF compartment, which causes the formation of central edema. Furthermore, investigation study report stated that formation of edema is in interstitial and not intracellular6,7,8.


The aim of the treatment in disequilibrium syndrome is to reduce the intracranial pressure of the affected patient. The general management includes8,9

  • Administration of hypertonic saline including mannitol to raise blood osmolality
  • Application of ventilation to hyperventilate the patients

The incidence of disequilibrium syndrome is associated with hemodialysis. To avoid this serious outcome, the preventive measures must be followed. The principle factor for causing of disequilibrium syndrome is a progression of osmotic gradient due to water accumulation into the brain. The prevention can be achieved by preventing the raising of an osmotic gradient. Hemofiltration is one of the simple ways to achieve this.


The mechanism of hemofiltration follows the convective removal of solute instead of diffusive removal from patients during hemodialysis. Fast osmolalities of the body fluid compartment do not alter by following this mechanism, as happen with standard hemodialysis. Thus symptomatic relieve can obtain by hemofiltration 8,10.

Slow Removal Of Urea

The rate of removal of urea depends upon the process of dialysis. Fast dialysis removes urea very fast and that causes seizure attacks. But slow hemodialysis causes the slow removal of urea and does not cause any symptoms of seizures. Therefore, slow hemodialysis can be also a preventive measure to avoid disequilibrium syndrome symptoms 8, 11.

Combination of Mannitol and Glucose Infusion

The common infusion given in hemodialysis procedure is either high glucose solution or mannitol to reduce the osmolality alteration. In comparing single infusion, mannitol administration provides the better result to avoid disequilibrium syndrome than high glucose solution. But, researchers also expect the combination of these two maneuvers can reduce the associated osmolality alteration along with the incidence of symptoms of disequilibrium syndrome.8,12

 Glycerol Infusion

Animal studies showed that instead of mannitol, glycerol infusion can provide a much more favorable outcome to prevent disequilibrium syndrome. Preclinical data also showed that addition of glycerol in dialysate provides normal EEG report. This type of study yet not perform on a human8,13.

Addition of Urea in Dialysate

Development of blood-brain-urea gradient can be prevented by using urea in the dialysate. Animal model based research showed the addition of urea itself in dialysate causes prevention of osmotic gradient development and also associated sign and symptoms of disequilibrium syndrome8.


  1. Harris CP, Townsend JJ. Dialysis disequilibrium syndrome. West J Med. 1989;151:52–55.
  2. Arieff AI. More on the dialysis disequilibrium syndrome. West J Med. 1989;151:74–76.
  3. Arieff AI. Dialysis disequilibrium syndrome: current concepts on pathogenesis and prevention. Kidney Int. 1994;45:629–635. doi: 10.1038/ki.1994.84.
  4. Mahoney CA, Arieff AI. Uremic encephalopathies: clinical, biochemical, and experimental features. Am J Kidney Dis. 1982;2:324–336.
  5. Kennedy AC, Linton AL, Eaton JC. Urea levels in cerebrospinal fluid after haemodialysis. Lancet. 1962;1:410–411. doi: 10.1016/S0140-6736(62)91365-X.
  6. Liebner S, Czupalla CJ, Wolburg H. Current concepts of blood–brain barrier development. Int J Dev Biol. 2011;55:467–476. doi: 10.1387/ijdb.103224sl.
  7. Paolinelli R, Corada M, Orsenigo F, Dejana E. The molecular basis of the blood brain barrier differentiation and maintenance. Is it still a mystery? Pharmacol Res. 2011;63:165–171. doi: 10.1016/j.phrs.2010.11.012.
  8. Diana Zepeda-Orozco, Raymond Quigley; Dialysis disequilibrium syndrome; Pediatr Nephrol. 2012 Dec; 27(12): 2205–2211. Published online 2012 Jun 19. doi: 10.1007/s00467-012-2199-4; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491204/
  9. Bagshaw SM, Peets AD, Hameed M, Boiteau PJ, Laupland KB, Doig CJ. Dialysis Disequilibrium Syndrome: brain death following hemodialysis for metabolic acidosis and acute renal failure—a case report. BMC Nephrol. 2004;5:9. doi: 10.1186/1471-2369-5-9.
  10. Kishimoto T, Yamagami S, Tanaka H, Ohyama T, Yamamoto T, Yamakawa M, Nishino M, Yoshimoto S, Maekawa M. Superiority of hemofiltration to hemodialysis for treatment of chronic renal failure: comparative studies between hemofiltration and hemodialysis on dialysis disequilibrium syndrome. Artif Organs. 1980;4:86–93. doi: 10.1111/j.1525-1594.1980.tb03911.x.
  11. Port FK, Johnson WJ, Klass DW. Prevention of dialysis disequilibrium syndrome by use of high sodium concentration in the dialysate. Kidney Int. 1973;3:327–333. doi: 10.1038/ki.1973.51.
  12. Rodrigo F, Shideman J, McHugh R, Buselmeier T, Kjellstrand C. Osmolality changes during hemodialysis. Natural history, clinical correlations, and influence of dialysate glucose and intravenous mannitol. Ann Intern Med. 1977;86:554–561.
  13. Arieff AI, Lazarowitz VC, Guisado R. Experimental dialysis disequilibrium syndrome: prevention with glycerol. Kidney Int. 1978;14:270–278. doi: 10.1038/ki.1978.119.

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