Dialysis Disequilibrium Syndrome (DDS)

Disequilibrium syndrome (DDS) is a rare but serious complication of hemodialysis. It is characterized mainly by neurological symptoms such as fatigue, mild headaches, nausea, vomiting, disturbed consciousness, convulsions and coma. The symptoms are usually mild, transient and self-limiting and rarely, it can be fatal. Symptoms are often seen in patients with very high plasma urea concentrations, patients with chronic kidney disease (CKD) and with aggressive urea removal with the initiation of hemodialysis treatment1. The exact incidence of dialysis equilibrium Is not known, but seems to be decreasing since the early days of hemodialysis, most likely due to the fact that current patients are initiated on dialysis at much lower urea concentrations than previously2.

Etiology:

Disequilibrium syndrome commonly occurs in:2,3

  • Elderly and pediatric patients
  • Patients with pre-existing central nervous system (CNS) lesions (recent stroke, head trauma) or conditions characterized by cerebral edema (malignant hypertension, hyponatremia, hepatic encephalopathy)
  • High pre-dialysis BUN
  • Severe metabolic acidosis
  • High risk patients: traumatic brain injury, intracerebral hemorrhage and intracranial mass

Pathophysiology

The exact pathophysiology is not very well known. However, the development of the DDS may be attributed to cerebral edema secondary to water movement into the brain. There are two main theories:

First, the DDS is attributed to the faster decline of urea concentration in the blood than in the brain during dialysis session. This lag creates and osmotic gradient that promotes net water shift from the blood into the brain, leading to cerebral edema and increased intracranial pressure (ICP). Second, dialysis may generate a CO2 gradient between plasma and cerebrospinal fluid (CSF) lowering the pH in the CSF and brain tissue. This change may promote an increase in brain cell osmolality due to the rise in H+ concentration and the in-situ generation of osmols (acid radicals from protein metabolism) resulting in brain edema. Cerebral edema and increased ICP are the primary contributing factors of disequilibrium syndrome and are the target of therapy4.5.

Diagnosis:

The diagnosis is made based on the signs and symptoms:2

Mild Moderate Severe
Headache Nausea Seizures
Restlessness Vomiting Coma
Hypertension Death

The symptoms above are not specific for disequilibrium syndrome, other diagnosis
must be considered and ruled out. Below are the differential diagnoses for signs and symptoms of dialysis equilibrium.

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

Management3

Since the principle factor leading to the disequilibrium syndrome is the development of an osmotic gradient causing water to move into the brain, preventing the development of this gradient would help prevent the syndrome. Thus, the management should be based primarily on preventative measures to reduce the development of cerebral edema especially during initiation of hemodialysis in new patients. Strategies to prevent dialysis equilibrium syndrome in high-risk patients include:2

Slow, gentle initial hemodialysis:

For CKD patients, with a high urea concentration starting on hemodialysis, a low clearance treatment may be performed by decreasing the dialysis time, decreasing the blood flow rate, and by using a less efficient (small) dialyzer or a combination of these techniques.

  • Arieff et. al. found that rapid HD (100 minutes with a blood flow of 12ml/kg per minute and a dialysate flow rate of 500 ml/min) produced an elevated CSF pressure and seizures. In contrast, slower HD (200 minutes at 5ml/kg per minute blood flow rate and a dialysate flow rate of 500ml/min) elevated CSF pressure without causing seizures6.
  • Zepeda-Orozco et al. recommended a short HD session of 2 hours with a low blood flow rate and a dialysate flow rate of 200 ml/min and a urea reduction ratio goal of 0.4 as initial prescription for patients at risk for DDS4.

High Sodium Dialysate/Sodium Profiling:

Another intervention to minimize osmotic disequilibrium may involve utilization of a high dialysate sodium concentration (fixed or profiled). An increase in serum sodium of 2 mEq/l yields an osmotic force equivalent to about that of 11 mg/dl of BUN. The use of a fixed high dialysate sodium of 143–146 mEq/l for the initial treatment may be used in high risk patients7. Additionally, sodium profiling that employs the same concept, the high sodium dialysate initially during the treatment targets the osmotic effects of early urea removal and lowering of the sodium dialysate later in the treatment, thus keeping the plasma osmolality in physiological range8.

Administration of osmotically active substances

Addition of an osmotic agent (sodium, mannitol and glucose) to the blood stream may help prevent the development of a blood-brain osmotic gradient and consequently help prevent cerebral edema Mannitol or hypertonic saline may be used to raise the blood osmolality.

In addition to the hyperosmolality, addressing other factors that could contribute to cerebral edema and hypoxia may be important. Using a lower bicarbonate dialysate concentration and improving metabolic acidosis more gradually may ameliorate the adverse effects of rapid alkalization9.

If the patients develop seizures it is suggested to:

  • Discontinue dialysis until seizure and vital signs has been stabilized.
  • Use of antiepileptic drugs (AEDs) not cleared by dialysis may be used to control seizures.

 References:

  1. KENNEDY, A. C., LINTON, A. L., EATON, J. C. Urea levels in cerebrospinal fluid after haemodialysis. Lancet (London, England) 1, 410–1 (1962). www.ncbi.nlm.gov/pubmed/14455152
  2. Saha, M., Allon, M. Diagnosis, Treatment, and Prevention of Hemodialysis Emergencies. Clin. J. Am. Soc. Nephrol. 12, 357–369 (2017). www.ncbi.nlm.gov/pubmed/27831511
  3. Patel, N., Dalal, P., Panesar, M. Dialysis disequilibrium syndrome: a narrative review. Semin. Dial. 21, 493–498 (2008). www.ncbi.nlm.gov/pubmed/18764799
  4. Zepeda-Orozco, D., Quigley, R. Dialysis disequilibrium syndrome. Pediatr. Nephrol. 27, (2012). www.ncbi.nlm.gov/pubmed/22710692
  5. Arieff, A. I. Dialysis disequilibrium syndrome: current concepts on pathogenesis and prevention. Kidney Int. 45, 629–35 (1994). www.ncbi.nlm.gov/pubmed/8196263
  6. Arieff, A. I., Massry, S. G., Barrientos, A., Kleeman, C. R. Brain water and electrolyte metabolism in uremia: effects of slow and rapid hemodialysis. Kidney Int. 4, 177–87 (1973). www.ncbi.nlm.gov/pubmed/4750910
  7. Port, F. K., Johnson, W. J., Klass, D. W. Prevention of dialysis disequilibrium syndrome by use of high sodium concentration in the dialysate. Kidney Int. 3, 327–33 (1973). www.ncbi.nlm.gov/pubmed/4792047
  8. Stiller, S., Bonnie-Schorn, E., Grassmann, A., Uhlenbusch-Körwer, I., Mann, H. A critical review of sodium profiling for hemodialysis. Semin. Dial. 14, 337–47 (2001). www.ncbi.nlm.gov/pubmed/11679103
  9. Mistry, K. Dialysis disequilibrium syndrome prevention and management. Int. J. Nephrol. Renovasc. Dis. 12, 69–77 (2019).

P/N 102564-01 Rev B 3/2020