Continuing Education Activity

Dialysis disequilibrium syndrome (DDS) refers to an array of neurological manifestations that are seen during or following dialysis. The symptoms can range from mild symptoms such as headache, nausea, or blurred vision, as well as other CNS symptoms such as restlessness and confusion, to severe manifestations with coma and seizures in rare cases. This activity reviews the epidemiology, clinical presentation, management, and prevention of DDS in patients undergoing dialysis. It highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology of dialysis dysequilibrium syndrome.

• Identify patients who are at risk of developing dialysis dysequilibrium syndrome.

• Outline the severe manifestations of dialysis dysequilibrium syndrome and its prevention and management.

• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with dialysis dysequilibrium syndrome.

Introduction

Dialysis disequilibrium syndrome (DDS) refers to an array of neurological manifestations seen during or following dialysis, primarily after the new initiation of dialysis.[1][2] However, it can also be seen in chronic dialysis patients who miss their regular dialysis treatments. This syndrome is thought to arise from fluid shifts during hemodialysis, causing cerebral edema and a wide variety of neurological symptoms. In continuous renal replacement therapies (CRRT), where fluid shift is limited, dialysis disequilibrium syndrome is rarely reported.[3]

Etiology

The common risk factors that predispose a patient to dialysis dysequilibrium syndrome are listed as follows:[2][4][5][6][7][8] 

• First hemodialysis treatment
• High blood urea nitrogen (BUN) (above 175 mg/dL or 60 mmol/L) before initiation of dialysis
• Extremes of age – children and elderly
• Sudden change in dialysis regimen
• Pre-existing neurological diseases such as stroke, malignant hypertension, head trauma, or seizure disorder
• Presence of other conditions causing cerebral edema (hyponatremia, hepatic encephalopathy)
• Conditions causing increased permeability of the blood-brain barrier (sepsis, meningitis, encephalitis, hemolytic uremic syndrome, vasculitis)

Epidemiology

The first case of dialysis disequilibrium syndrome was reported in the literature in 1962.[1] The incidence of the syndrome is not clearly defined because of non-specific manifestations and difficulty in confirming the diagnosis, making it likely that DDS is underreported.[4] It is more likely to occur after rapid hemodialysis and in high-risk groups.[9] The overall incidence is believed to have decreased with time due to awareness of this condition and the implementation of preventive strategies.[2][5]

Pathophysiology

Dialysis disequilibrium has been recognized for more than a half-century, but the pathogenesis is not clearly understood. Below are the two commonly proposed theories:

• The reverse urea effect: Small solutes like urea are rapidly removed during hemodialysis, particularly in the setting of marked azotemia. Urea is usually considered an “ineffective” osmole because of its free diffusion across cell membranes. However, its natural diffusion lags behind the rapid removal of urea from the serum during hemodialysis, creating a transient osmotic gradient between plasma and brain cells. This leads to water shift into brain cells, producing cerebral edema. Cerebral edema is further enhanced by the adaptive increase of brain aquaporin channels and the decrease of urea channels in advanced chronic kidney disease.[10][11] Studies in rat models of DDS demonstrated that brain-to-plasma urea gradient is increased after hemodialysis and was associated with increased brain water content.[12][13] 

• Intracerebral acidosis: Studies have shown that there is a fall of intracellular pH in brain cells with concomitant carbon dioxide (PCO₂) retention among patients after initiation of dialysis. The fall in pH causes sodium and potassium that are bound to proteins to disassociate, making them osmotically active.[14][15] Additional contributing factors to intracerebral acidosis are the adaptive retention of brain organic osmolytes like glutamine, glutamate, taurine, and myoinositol. Retention of these osmolytes causes a paradoxical fall of intracellular pH leading to increased brain osmolality and cerebral edema.[10][12][14][16]

History and Physical

In patients with high blood urea nitrogen levels, symptoms are commonly seen in patients with chronic kidney disease (CKD) versus acute kidney injury, and with aggressive urea removal after initial dialysis treatment.[1] Most cases of DDS can be mild and self-limited, with patients reporting headache, nausea, or blurred vision as well as other CNS symptoms such as restlessness and confusion.[17] These symptoms usually begin soon after the initiation of dialysis and resolve within hours in most cases. Some symptoms, such as dizziness and muscle cramps that occur towards the latter part of dialysis, are also considered to be part of DDS.[18][19][20][21] Rarely, DDS can present as increased intraocular pressure.[22] In severe cases, symptoms can progress to seizure, somnolence, stupor, or coma leading to mortality.[17]

Evaluation

DDS is a clinical diagnosis. There is no specific laboratory testing or imaging. It remains a diagnosis of exclusion in suspected patients who develop symptoms after initial dialysis or resumption of dialysis after a period of non-compliance. Clinical conditions causing similar manifestations should be considered as a part of the differential diagnosis.

Treatment / Management

Management of DDS is primarily aimed at prevention rather than treatment after the onset of symptoms. However, once a patient develops symptoms, below are the measures that should be considered:

• Initiate sodium remodeling: Regardless of severity, DDS is initially treated by modifying the dialysis prescription. This is done by changing the sodium dialysate bath or engaging the changed prescription on the dialysis machine.[17] The symptoms should resolve as quickly as within 30 minutes. Therefore, dialysis need not be stopped. Residual symptoms (nausea, vomiting) after modification of prescription and sodium remodeling can be treated symptomatically. However, if symptoms do not resolve with treatment, it may be required to stop the dialysis occasionally to evaluate for other underlying causes of the symptoms. 

• Failure of sodium remodeling: In patients with severe symptoms of DDS despite sodium remodeling, a trial to decrease intracerebral pressure could be taken. Some experts suggest using 5 milliliters of 23% saline or 12.5 milligrams of intravenous mannitol to increase the plasma osmolarity and simultaneously decrease further osmotic shift, but these are based on anecdotal evidence and limited data. The addition of urea to the dialysate has also been reported to allow for repeated and intensive dialysis sessions, avoiding potential neurological problems.[23]

Modalities to prevent the development of DDS include implementing slow and gentle initial hemodialysis, limiting the clearance of urea to prevent the development of an osmotic gradient, increasing dialysate sodium level, and administration of osmotically active substances. Evidence-based guidelines are lacking, but most experts agree on the gradual clearance of urea.

For patients new to dialysis, short two-hour sessions at 150-200ml/min or sustained low-efficiency dialysis can be done, which can be followed by consecutive dialysis sessions in the following days.[24] The blood flow and dialysate flow can be simultaneously increased in small amounts if patients do not develop DDS during the first session. Blood flow can be further increased to match outpatient settings in successive treatments. Considerations should be given to inpatient initiation of dialysis in cases where BUN is > 100mg/dl or in patients with neurological symptoms such as altered mental status or myoclonus.

In patients who frequently miss dialysis, it is not always possible to repeatedly hospitalize them to initiate slow dialysis;  thus, the sodium modeling technique is used in such patients.[17] Some dialysis machines have sodium modeling capability, in which case linear or exponential features can be utilized to prevent hypertonicity at the end of the session.

Differential Diagnosis

The differential diagnosis of DDS includes uremia, stroke, subdural hematoma, metabolic disturbances (hyponatremia, hypoglycemia), drug-induced encephalopathy, or infection (meningitis, encephalitis). Tests like electroencephalography have been studied to improve the diagnosis but have limited potential.[25][26] MRI imaging, especially with diffusion-weighted images that help in evaluating brain water content, could be helpful to support the diagnosis.

Prognosis

Dialysis disequilibrium syndrome is usually self-limited, with symptoms resolving in a short interval. The prognosis is generally favorable, and dialysis does not need to be stopped in most cases. In severe cases, symptoms can progress to seizure, somnolence, stupor, or coma leading to death.[17]

Complications

The complications of dialysis disequilibrium syndrome include consequences from delay in recognition of the condition and delay in implementing prevention strategies. In rare cases, with the progression of cerebral edema, the symptoms can progress to severe neurological manifestations such as seizures, coma, or death in severe cases.[17]

Deterrence and Patient Education

Dialysis disequilibrium syndrome refers to a range of symptoms that may occur during dialysis, especially in patients in whom dialysis is initially started or who have missed frequent sessions of dialysis. It is believed to occur due to the rapid clearance of substances such as urea that accumulate in the blood. This can lead to an imbalance in the level of fluid inside the cells of the brain, causing swelling and symptoms such as headache, nausea, restlessness, confusion, or in severe cases, seizures, coma, and death. Although uncommon with increasing awareness, dialysis disequilibrium syndrome can be uncomfortable and distressful to patients. Patients should be advised to report any symptoms after dialysis is started to implement preventative measures. It is also important to educate patients and their families to maintain regular dialysis sessions to help minimize the risk of DDS.

Enhancing Healthcare Team Outcomes

An interprofessional team approach to caring for patients undergoing hemodialysis is vital to improve patient outcomes. The team should consist of a nephrologist, nephrology nurse practitioners and physician assistants, and dialysis nurses. All providers caring for patients with end-stage renal disease should be aware of dialysis disequilibrium syndrome as a cause of neurological symptoms during the initiation of dialysis. Although most presentations may be mild, it is important to prevent severe manifestations, which can be fatal. Preventive measures should be implemented, especially in patients who are at higher risk, to limit further morbidity and mortality in patients with end-stage renal disease.