Dialysis disequilibrium syndrome

Author 
Lionel U Mailloux, MD, FACP 

Section Editor 
Jeffrey S Berns, MD 

Deputy Editor 
Alice M Sheridan, MD 

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2013. | This topic last updated: Aug 9, 2012.

INTRODUCTION  — First described in 1962, the dialysis disequilibrium syndrome (DDS) is a central nervous system disorder described in dialysis patients [ 1,2 ]. It is characterized by neurologic symptoms of varying severity that are thought to be due primarily to cerebral edema.

New patients just being started on hemodialysis are at greatest risk, particularly if the BUN is markedly elevated (above 175 mg/dL or 60 mmol/L). Other predisposing factors include severe metabolic acidosis, older age, pediatric patients, and the presence of other central nervous system disease such as a preexisting seizure disorder [ 2 ].

This topic review will discuss dialysis disequilibrium syndrome. Issues related to mental status changes and acute problems during dialysis are presented separately. (See "Acute complications during hemodialysis" and "Psychiatric illness in dialysis patients" and "Seizures in patients undergoing hemodialysis" .)

PATHOGENESIS  — The symptoms of DDS are caused by water movement into the brain, leading to cerebral edema. Two theories have been proposed to explain why this occurs: a reverse osmotic shift induced by urea removal [ 1,3-5 ]; and a fall in cerebral intracellular pH [ 2 ].

Reverse osmotic shift  — Hemodialysis rapidly removes small solutes such as urea, particularly in patients who have marked azotemia. The reduction in BUN lowers the plasma osmolality, thereby creating a transient osmotic gradient that promotes water movement into the cells. In the brain, this water shift produces cerebral edema and a variable degree of acute neurologic dysfunction. The loss of extracellular water can also cause extracellular volume depletion which can contribute to the development of hypotension. (See "Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure): Metabolic and hemodynamic considerations" .)

The pathogenetic importance of urea in the DDS has been demonstrated by experiments in uremic rats [ 3-5 ]. In one report, for example, rapid dialysis lowered the BUN from 200 to 95 mg/dL (72 to 34 mmol/L) in 90 minutes [ 3 ]. This change was associated with a six percent increase in brain water. Neither undialyzed rats nor those rats dialyzed against a bath to which urea was added to prevent a fall in BUN developed cerebral edema. Furthermore, the retention of brain urea appears to be account for most of the increase in brain water [ 4 ].

Urea is generally considered an "ineffective" osmole, because of its ability to permeate cell membranes. However, this effect may take several hours to reach completion. Thus, there is insufficient time for urea equilibration when hemodialysis rapidly reduces the BUN; as a result, urea transiently acts as an effective osmole, promoting water movement into the brain. In the above experiments, for example, the 53 percent acute reduction in BUN was only associated with a 13 percent reduction in brain urea nitrogen [ 3 ].

Intracerebral acidosis and idiogenic osmoles  — Some investigators have suggested that the reverse urea effect cannot account for the development of cerebral edema in the DDS, since urea movement out of the brain is sufficiently rapid to prevent a large osmotic gradient between the brain and extracellular fluid [ 2 ]. They have proposed that a decrease in cerebral intracellular pH, occurring via an uncertain mechanism, is of primary importance [ 2,5 ]. Both displacement of bound sodium and potassium by the excess hydrogen ions and enhanced production of organic acids can increase intracellular osmolality and promote water movement into the brain [ 6 ].

However, an increase in brain organic osmolytes has not been confirmed in all studies [ 4,7 ]. In most reports, the reverse urea effect appears sufficient to explain most of dialysis disequilibrium [ 3,4 ].

CLINICAL MANIFESTATIONS  — The classic DDS refers to acute symptoms developing during or immediately after hemodialysis or the initiation of a continuous renal replacement therapy [ 8 ]. Early findings include headache, nausea, disorientation, restlessness, blurred vision, and asterixis. More severely affected patients progress to confusion, seizures, coma, and even death. It is now recognized, however, that many milder signs and symptoms associated with dialysis — such as muscle cramps, anorexia, and dizziness developing near the end of a dialysis treatment — are also part of this syndrome [ 2,6,9-12 ].

The incidence of DDS varies according to the patient population and the attention paid to the preventive measures described below. Severe DDS is now rare in adults because of the standard use of the preventive recommendations made below.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS  — The development of the above symptoms during dialysis is strongly suggestive of DDS. Nevertheless, there are a number of other disorders that must be excluded. These include uremia itself, subdural hematoma, cerebral infarction, intracerebral hemorrhage, meningitis, metabolic disturbances (hyponatremia, hypoglycemia), and drug-induced encephalopathy [ 6 ]. Drug accumulation is a particular problem in renal failure with drugs that are normally excreted by the kidney. Discussions related to the diagnosis of these disorders in the dialysis population are presented separately. (See "Acute complications during hemodialysis" and "Psychiatric illness in dialysis patients" and "Seizures in patients undergoing hemodialysis" .)

PREVENTION  — Prevention is the mainstay of therapy in the DDS, particularly in new dialysis patients who are at highest risk, or in patients who have extremely high BUN concentrations or neurologic symptoms. The initial dialyses should be gentle, but repeated frequently. The aim is a gradual reduction in BUN, which will be protective but may not prevent mild symptoms such as headache and malaise. Slow urea removal can be achieved by one of the following methods:

With hemodialysis, therapy can be initiated with two hours of dialysis at a relatively low blood flow rate of 150 to 250 mL/min with a small surface area dialyzer (0.9 to 1.2 m2), and concurrent rather than countercurrent blood and dialysate flow. This regimen, which is repeated daily for three or four days, is different from the standard every other day four-hour regimen at high flow rates. If the patient shows no signs of DDS, the blood flow rate can be increased by 50mL/min per treatment (up to 300 to 400 mL/min) and the duration of dialysis can be increased in 30 minute increments (up to four or more hours, as necessary for adequate solute removal).Patients who also have marked fluid overload can be treated with ultrafiltration (which removes less urea per unit time and does not change plasma osmolarity) followed by a short period of hemodialysis [ 7 ]. (See "Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure): Metabolic and hemodynamic considerations" .)The patient can be started on peritoneal dialysis in which the low rate of peritoneal blood flow results in a urea clearance per unit time that is much lower than that with hemodialysis. The DDS has not been reported with continuous peritoneal dialysis [ 2,13 ].Among patients with extremely elevated BUN or neurologic symptoms, dialysis should be initiated as an inpatient, although there are no data that have demonstrated better outcomes with this approach.

TREATMENT  — In general, symptoms of DDS are self-limited and usually dissipate within several hours. The management of mild nonspecific disequilibrium symptoms, such as nausea, vomiting, restlessness, and/or headache, is symptomatic [ 14 ]; however, in the acutely uremic patient with such symptoms who is undergoing dialysis, the blood flow rate should be slowed and consideration should be given to stopping the dialysis session [ 14 ].

Dialysis is stopped in the patient with seizures, coma, and/or obtundation. Patency of the airway should also be ensured [ 14 ]. In this setting, causes of these symptoms other than severe DSS should be considered. (See 'Diagnosis and differential diagnosis' above.)

Severe DDS with seizures can be reversed more rapidly by raising the plasma osmolality with either 5 mL of 23 percent saline or 12.5 g of hypertonic mannitol . However both maneuvers may be ineffective [ 15 ] and many dialysis units and hospitals have banned the use of 23 percent saline. Some physicians administer either 50 percent dextrose solution or 1.5 percent or 3.0 percent NaCl as alternatives to very hypertonic NaCl. Supportive care as described above is generally considered standard of care. A detailed discussion concerning the management of seizures in the patient undergoing hemodialysis is presented separately. (See "Seizures in patients undergoing hemodialysis" .)

Management is supportive in the patient with severe DSS and coma. In this setting, improvement should occur within 24 hours [ 14 ]. (See "Acute toxic-metabolic encephalopathy in children" and "Prevention and treatment of delirium and confusional states" .)

SUMMARY AND RECOMMENDATIONS

The dialysis disequilibrium syndrome (DDS) is characterized by neurologic symptoms that are thought to be due primarily to cerebral edema. New patients just being started on hemodialysis are at greatest risk, particularly if the blood urea nitrogen (BUN) is markedly elevated (above 175 mg/dL or 60 mmol/L). Other predisposing factors include severe metabolic acidosis, older age, pediatric patients, and the presence of other central nervous system disease such as a preexisting seizure disorder. (See 'Introduction' above.)The prevailing theory to explain the cerebral edema that underlies DDS is that a rapid reduction in urea by hemodialysis lowers the plasma osmolality creating a transient osmotic gradient that promotes water movement into the cells. An alternative hypothesis is that a decrease in cerebral intracellular pH causes increased intracellular osmolality and promotes water movement into the brain. (See 'Pathogenesis' above.)Classic DDS develops during or immediately after hemodialysis. Early findings include headache, nausea, disorientation, restlessness, blurred vision, and asterixis. More severely affected patients progress to confusion, seizures, coma, and even death. Milder signs and symptoms include muscle cramps, anorexia, and dizziness. The symptoms of DDS are self-limited and usually dissipate within several hours. (See 'Clinical manifestations' above and 'Treatment'above.)The differential diagnosis of DDS includes uremia itself, subdural hematoma, cerebral infarction, intracerebral hemorrhage, meningitis, metabolic disturbances (hyponatremia, hypoglycemia), and drug-induced encephalopathy. Drug accumulation is a particular problem in renal failure with drugs that are normally excreted by the kidney. (See 'Diagnosis and differential diagnosis' above.)Prevention is the mainstay of therapy in the DDS, particularly in new dialysis patients who are at highest risk, or in patients who have extremely high BUN concentrations or neurologic symptoms. The initial dialyses should achieve a gradual reduction in urea. Slow urea removal can be achieved by the following methods (see 'Prevention' above):

With hemodialysis, therapy can be initiated with two hours of dialysis at a relatively low blood flow rate of 150 to 250 mL/min with a small surface area dialyzer (0.9 to 1.2 m2), and concurrent rather than countercurrent blood and dialysate flow. This regimen is repeated daily for three or four days. If the patient shows no signs of DDS, the blood flow rate can be increased by 50 mL/min per treatment (up to 300 to 400 mL/min) and the duration of dialysis can be increased in 30 minute increments (up to four or more hours, as necessary for adequate solute removal). 

Patients who also have marked fluid overload can be treated with ultrafiltration (which removes less urea per unit time) followed by a short period of hemodialysis.The patient can be started on peritoneal dialysis in which the low rate of peritoneal blood flow results in a urea clearance per unit time that is much lower than that with hemodialysis. The DDS has not been reported with continuous peritoneal dialysis.Among patients with extremely elevated BUN concentration or neurologic symptoms, dialysis should be initiated as an inpatient.

The treatment of DDS depends upon the severity of symptoms (see 'Treatment' above):

Patients with mild nonspecific symptoms, such as nausea, vomiting, restlessness, and/or headache, are treated symptomatically; however, for the acutely uremic patient with such symptoms who is undergoing dialysis, the blood flow rate should be slowed and consideration should be given to stopping the dialysis session.Dialysis should be stopped in the patient with seizures, coma, and/or obtundation. Patency of the airway should also be ensured. In this setting, causes of these symptoms other than severe DSS should be considered.Severe DDS with seizures can be reversed more rapidly by raising the plasma osmolality with either 5 mL of 23 percent saline or 12.5 g of hypertonic mannitol . However both maneuvers may be ineffective and many dialysis units and hospitals have banned the use of 23 percent saline. Some physicians administer either 50 percent dextrose solution, or 1.5 percent or 3.0 percent NaCl as alternatives to very hypertonic NaCl. Supportive care as described above is generally considered standard of care.

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