Dialysis disequilibrium syndrome

Dialysis disequilibrium syndrome is defined as a clinical syndrome of neurologic symptoms and signs that is seen in patients who undergo hemodialysis, especially when dialysis is first initiated ¹. The signs and symptoms vary widely from restlessness and headache to coma and death. Dialysis disequilibrium syndrome is a diagnosis of exclusion occurring in those that are uremic and hyperosmolar, in whom rapid correction with renal replacement therapy leads to cerebral edema and raised intracranial pressure with resultant clinical neurologic manifestations ². Dialysis disequilibrium syndrome is most commonly described in association with hemodialysis but can occur in patients with acute kidney injury requiring continuous renal replacement therapy ². To date, it has not been described in association with peritoneal dialysis. Dialysis disequilibrium syndrome is uncommon and becoming rarer, so performing randomized controlled trials to evaluate the effectiveness of potential therapies is almost impossible. This also makes studying the pathophysiology in humans challenging. Treatment of dialysis disequilibrium syndrome once it has developed is rarely successful. Dialysis disequilibrium syndrome is associated with mortality but is also preventable. Thus, measures to avoid its development are crucial, so identification of patients at risk, preventive measures, early recognition and prompt management of dialysis disequilibrium syndrome will minimize morbidity and mortality associated with this syndrome ³.

The exact incidence of dialysis disequilibrium syndrome is unknown, in part because only severe symptoms and signs, like seizures and mental status changes are recognized and reported as manifestations of dialysis disequilibrium syndrome ². Mild symptoms and signs like headache, nausea, and muscle cramps may represent the milder spectrum but not diagnosed as dialysis disequilibrium syndrome. These symptoms are common during the hemodialysis procedure and often attributed to volume depletion due to excessive ultrafiltration. Thus, dialysis disequilibrium syndrome may be more common than is reported. Suffice to say, changes in practice, in particular slowing down the rate of urea reduction in new dialysis patients, has resulted in dialysis disequilibrium syndrome becoming less common with time.

Dialysis disequilibrium syndrome key points

• Dialysis disequilibrium can occur in any patient undergoing hemodialysis, but it is more often seen when patients are undergoing their first treatment.
• Slow removal of urea during the first several treatments is critical for avoiding this syndrome.
• If a patient shows signs or symptoms of dialysis disequilibrium, steps to lower intracranial pressure can help reduce morbidity and mortality.

Dialysis disequilibrium syndrome causes

Dialysis disequilibrium syndrome is a diagnosis of exclusion occurring in those that are uremic and hyperosmolar, in whom rapid correction with renal replacement therapy leads to cerebral edema and raised intracranial pressure with resultant clinical neurologic manifestations ². Dialysis disequilibrium syndrome is most commonly described in association with hemodialysis but can occur in patients with acute kidney injury requiring continuous renal replacement therapy ². To date, it has not been described in association with peritoneal dialysis.

Development of cerebral edema

In recent years it has become clear that aquaporins (AQPs) regulate the movement of water in many tissues. The aquaporin present in the blood brain barrier, AQP4, resides in the cell membrane of the astrocytes ⁴. Mice that are null for AQP4 do not develop cerebral edema to the same degree that wild-type mice do ⁴. Thus, this aquaporin (AQP) plays a critical role in the development of cerebral edema.

Although AQP4 provides a route for the movement of water from the blood stream into the central nervous system (CNS), there must be an osmotic gradient driving the movement of water. In guinea pigs, the osmotic gradient that was needed to drive significant amounts of water into the CNS was found to be 45 mOsm/kg water ⁵. These studies were performed by acutely loading the guinea pigs with water and inhibiting water excretion by giving the animals vasopressin. This osmotic gradient is central to the understanding of the development of cerebral edema during the dialysis disequilibrium syndrome. The key question has been whether or not the gradient produced by the difference in urea concentration alone will account for the water movement into the brain ⁶. Current hypotheses to explain the osmotic gradient are the “Reverse Urea Effect” and the “Idiogenic Osmoles” hypothesis.

The “Reverse Urea Effect” is based on the fact that the urea concentration in the central nervous system (CNS) remains elevated because of its slower diffusion from the CNS to the blood than the diffusion of urea from the blood into the dialysate compartment. This is essentially the finding that the initial investigators found when they measured urea in the cerebrospinal fluid (CSF) of patients after the hemodialysis procedure and found it to be significantly higher than that of the blood stream. Careful measurements of blood and brain electrolyte, urea and water content in rats that were made uremic by ureteral ligation showed similar results ⁷. Rats that were dialyzed rapidly had a much higher urea concentration in the brain than in the blood. The increase in the urea concentration could account for the increased osmolality as there was no evidence of any new osmoles being produced.

The “Idiogenic Osmole” hypothesis is supported by experiments performed in dogs that were also made uremic by ureteral ligation ⁸. In these studies, animals were dialyzed rapidly (over 100 min) or slowly (over 200 min) to achieve the same decline in urea concentration in the blood. In the animals that were rapidly dialyzed, the brain tissue had a significantly higher osmolality (27 mOsm/kg water) than the blood at the end of the dialysis procedure. This difference in osmolality could not be explained totally by the changes in electrolytes and urea. Thus, the authors proposed that the increase of brain osmolality was secondary to the new formation of organic molecules called “idiogenic osmoles” ⁸.

While there are some disparities between the two hypotheses, there are a number of similarities. First, both investigators demonstrated that the urea concentration in the CNS was much higher than that in the blood at the end of dialysis and that there was an osmotic gradient for water movement into the brain. Secondly, there was ample evidence that there was an increased brain water content after the dialysis procedure, indicating that water had moved down the osmotic gradient into the brain. The differences revolve around the argument of the magnitude of the osmotic gradient and whether or not the high urea concentration could account for this.

The focus of attention on the magnitude of the gradient was the osmotic gradient found in a study of guinea pigs that showed a gradient of 45 mOsm/kg water would cause the development of cerebral edema ⁸. However, with recent data showing that the expression of both AQP4 and AQP9 is increased in the brains of uremic rats, it might be possible that a lower gradient would cause water movement, leading to the development of cerebral edema in uremic patients ⁹. It is also possible that the urea gradient might have a larger influence in uremic patients. The reflection coefficient of urea in the CNS has been measured in normal rabbits ¹⁰. With recent data showing that UT-B1 transporter expression in the brain decreases in uremic rats, the reflection coefficient could be higher so that a smaller gradient of urea would have a larger osmotic force ⁹. The increased expression of AQP4 and AQP9 and decreased expression of UT-B1 in uremic animals compared to non-uremic ones could result in a higher urea reflection coefficient for urea. This would allow for an increased water movement, with a smaller gradient of urea contributing to the disparity of these hypotheses.

The models used by the investigators were also slightly different. The model used by Arieff et al. was ureteral ligation in the dog ⁸, and the animals were then studied 3 days later. The model used by Silver et al. was the rat, and these animals were studied 42 hours after ureteral ligation ¹¹. The difference in the timing of uremia leaves open the possibility that uremic toxins that would lead to the production of “idiogenic osmoles” could occur after 48 hours of uremia. It is also possible that the uremic toxins themselves could be the “idiogenic osmoles.” These are questions that remain unanswered at the current time.

Evidence for cerebral edema in patients who had developed the dialysis disequilibrium syndrome comes from autopsy data and from radiologic imaging of the brain ¹². In careful studies of rats that had been nephrectomized, magnetic resonance imaging (MRI) confirmed the presence of cerebral edema after the rats received hemodialysis [23]. More interestingly, the authors concluded from the results of their diffusion-weighted MRI study that the edema was interstitial and not intracellular ¹³. Similar conclusions were drawn by Chen et al. ¹⁴ in their study of hemodialysis patients who underwent diffusion-weighted MRI after their dialysis treatment; these investigators found evidence of interstitial edema and not intracellular edema.

The effect of cerebral acidosis

The role of acidosis in the development of the disequilibrium syndrome is not entirely clear. It has been shown that despite the rapid elevation of blood pH with the bicarbonate infusion of the dialysate, the brain intracellular pH (pHi) and CSF pH are significantly lower in the rapidly dialyzed group ¹⁵. The arterial partial pressure of CO2 remained unchanged, suggesting that the production of the paradoxical CSF acidosis after rapid hemodialysis was not secondary to systemic hypoventilation.

The increased acidosis of the CNS can alter its ability to regulate solute and water transport through the blood brain barrier (BBB). In addition, the resulting changes in intracellular organic acids could impact the intracellular osmolality by displacing cations from their binding sites on intracellular proteins ¹⁵. Thus, the role of changes in CNS acid–base levels is very complex and will need further investigation.

The impact of the rate of removal of urea

Arieff et al. ⁸ examined directly the effect of the rate of urea removal by making the animals (dogs) uremic by ureteral ligation and studying them 3 days later. The initial urea concentration was about 70 mmol/l [approximately 200 mg/dl of blood urea nitrogen (BUN)]. One group of animals was dialyzed over 100 min with a blood flow rate of 12 ml/kg/min and another group was dialyzed over 200 min with a blood flow rate of 5 ml/kg/min. Both groups had identical urea concentrations at the end of dialysis of 25 mmol/l (approximately 70 mg/dl of BUN). These researchers showed that the fast dialysis group developed seizures and increased intracranial pressure, whereas the slow dialysis group did not develop seizures or cerebral edema. These results clearly demonstrate that the rate of urea removal is crucial to the development of the syndrome. Both groups of animals had the same decrease in urea (65 % reduction ratio of urea), but only the fast dialysis group had symptoms.

The difference in osmolality between the brain and blood was larger in the group that received the fast dialysis and led to the idea of “idiogenic osmoles” being created ⁸. What is not clear is whether or not the slow dialysis group had idiogenic osmoles present in their brain tissue before the dialysis procedure which were subsequently removed more efficiently because of the slower rate of dialysis.

Unfortunately, there are no human studies comparing various rates of removal of urea to determine the rate at which the disequilibrium syndrome will develop. One case report described a very high urea reduction ratio (70 %) for the initial dialysis that led to the syndrome and ultimately to death of the patient ¹⁶. However, another case report described symptoms occurring with a urea reduction ratio as low as 17 % over 2 hours ¹⁷. This patient had a very high urea concentration prior to dialysis (299 mg/dl or about 100 mmoles/l). Thus, not only is the rate of removal of urea critical to the development of the syndrome but also the initial urea concentration. This is most likely due to the fact that the blood–brain urea gradient at the end of dialysis will be higher in those patients with higher urea concentrations prior to dialysis ¹⁸.

In addition, other factors that predispose patients to the development of the syndrome will have an impact on which rate of removal will lead to disequilibrium. For example, patients with known seizure disorders or other neurologic conditions are more prone to develop symptoms during dialysis ¹⁹. Another concern for the pediatric nephrologist is the fact that younger patients are more prone to develop disequilibrium ²⁰. It is unknown why this is true, but it could be related to the smaller volume of distribution of urea in these patients. Thus, while it is not clear what the maximal rate of removal of urea is safe, it is critical to initiate hemodialysis with a low rate of urea removal.

Risk factors for developing dialysis disequilibrium syndrome

• First dialysis treatment
• Children
• Elderly
• High blood urea nitrogen (BUN)
• Hypernatremia
• Hyperglycemia
• Metabolic acidosis
• Preexisting neurologic abnormalities
• Preexisting cerebral edema
• Conditions associated with an increased permeability of the blood brain barrier, e.g., meningitis, vasculitis, central nervous system tumors, hemolytic uremic syndrome or thrombotic thrombocytopenic purpura

Dialysis disequilibrium syndrome prevention

Recognition of patients at highest risk for dialysis disequilibrium syndrome is important, providing an opportunity to implement even more cautious clearance in these populations as a preventive strategy. Vulnerable patients include the young and elderly as well as those that are hyperosmolar from severe uremia, hypernatremia and hyperglycemia. Additional risk factors include existing neurologic abnormalities and the presence of metabolic acidosis.

Since the dialysis disequilibrium syndrome is primarily the result of osmotic fluid shifts into the brain, avoidance of generation of a significant osmotic gradient between the blood and brain during hemodialysis should prevent the syndrome. This can be achieved using three strategies:

1. Reducing clearance so as to lessen the reduction of plasma osmolality, and thus osmotic gradient post dialysis,
2. Increasing the time over which clearance is performed and
3. Adding another osmotically active agent like sodium or mannitol as urea is removed by hemodialysis, so that plasma osmolality does not change significantly.

There are no controlled trials demonstrating ideal urea clearance and the time on dialysis over which to achieve the clearance in order to prevent dialysis disequilibrium syndrome. Compared with hemodialysis, a 5-hour hemofiltration treatment has a slower rate of urea reduction and lower post-dialysis cerebrospinal fluid (CSF) urea, that is, a smaller gradient between blood and CSF ²¹. In this study, hemofiltration reduced symptoms of dialysis disequilibrium syndrome.

In adults with end-stage renal disease (ESRD), reducing urea by 40% over 2 hrs is generally recommended when initiating dialysis. However, this recommendation is not evidence based and the prescription should be adjusted for less efficient and slower urea clearance in populations at high risk for dialysis disequilibrium syndrome.

Studies in guinea pigs revealed that a change in plasma osmolality of about 45 mmol/kg is required for cerebral edema to develop ²². Cerebral edema develops in children with hypernatremia when plasma osmolality is decreased by 48 mmol/kg per day, but not 24–28.8 mmol/kg per day; that is to say rapid correction of hypernatremia at a rate of 1 mmol/L per hour results in cerebral edema but not at a slower correction rate of 0.5–0.6 mmol/L per hour ²³. Hence the current recommendations for correcting chronic hypernatremia at a maximum rate of 0.5 mmol/L per hour or 12 mmol/L per day. This is equivalent to decreasing plasma osmolality by a maximum of 24 mmol/kg per day.

Since the reflection coefficient of sodium is 1 compared with 0.44 for urea, there may be room for allowance of a larger osmotic drop in renal failure as urea equilibrates between the brain and blood. However, as previously mentioned, this equilibration takes time, and hence for several hours during and following the hemodialysis procedure, urea serves as an effective osmole. Furthermore, the up-regulation of aquaporin and down-regulation of brain urea transporter B (UT-B) increases the likelihood of cerebral edema in uremic patients undergoing renal replacement therapy. Thus, targeting the urea reduction so as not to decrease the plasma osmolality by >20–24 mmol/kg per day makes sense. This amounts to urea reduction of not >56–67 mg/dL per day. If, in addition to urea, there are other substances like glucose or sodium contributing to hyperosmolality, then consideration should be given to slower correction of all the osmotically active substances, so as to limit the reduction of plasma osmolality. Supportive evidence of this approach is provided by a report of a patient with severe acute kidney injury who developed dialysis disequilibrium syndrome despite a modest 23% urea reduction over 10 hrs of continuous renal replacement therapy because a concomitant correction of hypernatremia led to plasma osmolality decreasing by 38 mmol/kg in 10 hours ²⁴.

It is not only the magnitude of urea reduction but the rate of reduction that is important. In animal studies, dogs dialyzed rapidly over 100 mins developed dialysis disequilibrium syndrome compared with those dialyzed slowly over 200 mins, despite similar degrees of urea reduction in the two groups ²⁵. It is important to note that in this study, animals dialyzed slowly had raised intracranial pressure, although they did not develop cerebral edema.

Thus, taking measures to limit clearance so as not to reduce plasma osmolality by >20–24 mmol/kg per day, while at the same time selecting for a longer duration of dialysis, should prevent dialysis disequilibrium syndrome. This can be achieved by choosing smaller dialyzers and reducing the blood flow rate, especially when dialysis is first initiated. Clearance can gradually be increased by approximately 20% daily over 3–4 days to achieve goal urea reduction of approximately 70% during the hemodialysis session. Of course, the more risk factors for dialysis disequilibrium syndrome present, the slower the rate and degree of urea reduction should be.

In uremic patients with severe fluid overload, consider performing ultrafiltration only followed by hemodialysis, or vice versa, in order to address the volume overload while limiting urea clearance. Plasma osmolality has been shown not to decrease during ultrafiltration alone, making this a safe option ²⁶.

Another strategy for reducing the osmotic gradient created by the rapid removal of urea during hemodialysis is to replace the urea with another osmotically active substance during the dialysis procedure, thus maintaining plasma osmolality. The most commonly used agents are sodium and mannitol, less commonly used agents include glucose and urea, while other agents like glycerol in dialysate have not been studied in humans.

Serum sodium can be raised during the dialysis procedure by using hypernatremic dialysate. In a small study, patients undergoing highly efficient hemodialysis, including some for the first time, were monitored clinically and by electroencephalography (EEG). Patients who underwent dialysis maintaining the plasma osmolality using higher dialysate sodium chloride concentrations of 144–154 mmol/L had a significantly lower incidence of EEG changes and none developed symptoms suggestive of dialysis disequilibrium syndrome compared with controls dialyzed against a standard 133 mmol/L sodium dialysate ²⁷.

Similarly, glucose and urea can be added to dialysate. Hyperglycemia induced by high glucose dialysate acts similarly to hypernatremia. Urea can be added to achieve the concentration to which one wants it to equilibrate, limiting the decline of urea concentration irrespective of the efficiency of hemodialysis. However, neither high glucose dialysate nor adding urea to dialysate is readily available for routine clinical use.

In a study evaluating high glucose dialysate (717 mg/dL) and intravenous mannitol (1 g/kg) on plasma osmolality in chronic dialysis patients, it was found that the usual 10 mmol/kg fall in plasma osmolality during hemodialysis was reduced by about 50% to 5.2 mmol/kg with the use of high glucose dialysate, to 4.3 mmol/kg with intravenous mannitol and 1.7 mmol/kg in patients treated with both ²⁸. The investigators found that mild symptoms of dialysis disequilibrium syndrome decreased from 67% to 10% in these patients, an effect independent of ultrafiltration rate. When used alone, intravenous mannitol is more effective than high glucose dialysate.

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 alkalization.

Dialysis disequilibrium syndrome symptoms

Signs and symptoms of dialysis disequilibrium syndrome:

Symptoms

• Nausea
• Emesis
• Headache
• Dizziness
• Muscle cramps
• Agitation
• Disorientation
• Confusion
• Tremors
• Visual disturbances

Signs

• Changes in mental status
• Asterixis
• Seizures
• Coma
• Death

The symptoms and signs of dialysis disequilibrium syndrome are secondary to the development of cerebral edema and have a temporal relationship to the dialysis procedure. Neurologic manifestations progress sequentially as cerebral edema worsens and intracranial pressure rises, and if not promptly recognized and managed, can lead to coma and even death ²⁹. The initial presentation of vomiting, headache, dizziness, agitation, disorientation, confusion, muscle cramps and tremors are common in chronic dialysis patients. They are usually ascribed to excessive or aggressive ultrafiltration, and hyper- or hypotension. However, dialysis disequilibrium syndrome can occur in patients on chronic dialysis and must remain in the differential diagnosis, especially when predialysis blood urea nitrogen (BUN) is high and/or there is another driver for hyperosmolality, for example, hyperglycemia or hypernatremia ²⁹. Studies measuring brain density in chronic dialysis patients using head computed tomography (CT) revealed decreased brain density or increased brain water during and after hemodialysis, but not in normal individuals or those on continuous peritoneal dialysis ³⁰. This suggests that cerebral edema may complicate the chronic hemodialysis treatment and lead to some of the commonly encountered neurologic symptoms like intra- and post-dialytic headache.

Dialysis disequilibrium syndrome diagnosis

When neurologic symptoms and signs develop in patients undergoing renal replacement therapy, especially hemodialysis but also continuous renal replacement therapy, the differential diagnosis includes uremic, toxic and infectious encephalopathy, electrolyte abnormalities like hyponatremia, hyper-or hypoglycemia, hemorrhagic and ischemic cerebrovascular accidents, subdural hematoma, malignant hypertension, and dialysis disequilibrium syndrome. There is no diagnostic test for dialysis disequilibrium syndrome; it is a diagnosis of exclusion.

Dialysis disequilibrium syndrome treatment

The most critical intervention is the prevention of dialysis disequilibrium syndrome. When dialysis disequilibrium syndrome is suspected, strong consideration should be given to discontinuing the dialysis treatment. If symptoms are very mild, blood flow rate should be reduced to decrease urea clearance. The patient should be closely monitored and the dialysis session discontinued immediately if symptoms worsen or if severe. Evaluation for other causes of neurologic deterioration should be undertaken and appropriately managed.

When it occurs, management of dialysis disequilibrium syndrome is supportive, as with any other patient with acute neurologic deterioration and suspected raised intracranial pressure and cerebral edema. Maintain the airway and consider hyperventilation. In addition, the cerebral edema can be treated by increasing plasma osmolality with mannitol or hypertonic saline to reduce the osmotic gradient between the blood and brain ³¹. Nevertheless, when advanced and severe, dialysis disequilibrium syndrome may progress rapidly and be fatal ³². Thus, early recognition of risk factors for dialysis disequilibrium syndrome in patients beginning renal replacement therapy for severe acute kidney injury and/or advanced chronic kidney disease, and execution of preventive measures is essential in managing these patients and improving outcomes.

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