Dialysis Disequilibrium Syndrome: A Severe Case with Neurologic Recovery – A Case Report

Abstract

Introduction

Dialysis disequilibrium syndrome is a serious complication occurring during hemodialysis initiation and after a break from hemodialysis, with a myriad of neurological symptoms.

Case Presentation

We report a case of a 68-year-old woman with a history of hypertension, type 2 diabetes mellitus, and recently diagnosed end-stage kidney disease. She presented to the emergency room with disorientation and hypertensive urgency and had started hemodialysis 3 months prior but declined further treatment. Laboratory data revealed blood urea nitrogen of 151 mg/dL, creatinine of 18 mg/dL, bicarbonate level of 5 mEq/L, and potassium of 6.6 mEq/L. A temporary hemodialysis catheter was inserted, and dialysis was initiated with a blood flow rate of 300 mL/min and a dialysate flow rate of 600 mL/min, using an Optiflux 180NRe dialyzer (surface area 1.7 m²) for a duration of 3 h. The patient developed seizure activity after 2 h and 55 min, described as tonic-clonic seizure lasting 5 min. The urea reduction ratio was 57.6%, and the bicarbonate level increased from 5 to 16 mEq/L. She remained in a stuporous state, with no response to stimuli. She was transferred to the intensive care unit and received 20% mannitol 0.5 g/kg (40 g), followed by 3% hypertonic saline (30 mL bolus, then 50 mL/h infusion), with the aim of maintaining a serum sodium concentration between 145 and 155 mEq/L. Forty-eight hours later, she began to open her eyes to voice and consistently followed commands.

Conclusion

Our patient’s dialysis disequilibrium syndrome severity correlated with the urea reduction ratio and severe metabolic acidosis, highlighting the importance of achieving a low urea reduction ratio (<40%) and a targeted rise in bicarbonate levels, both of which are risk factors for dialysis disequilibrium syndrome. In addition, the use of 3% saline and mannitol is an important preventive and rescue strategy.

Introduction

Dialysis disequilibrium syndrome is characterized by neurological symptoms that occur after hemodialysis, especially in new dialysis patients [1]. The symptoms range from mild, subtle features such as headache and restlessness to more severe symptoms, such as nausea, vomiting, confusion, seizures, coma, and death. The rapid removal of urea from plasma during hemodialysis, with delayed urea clearance in the brain, leads to water movement into the brain cells along an osmotic gradient, increasing intracranial pressure [2, 3]. The incidence of dialysis disequilibrium syndrome has significantly decreased as patients undergoing initial treatment are often treated with slow blood and dialysate flows. However, physicians should also remain vigilant when dialyzing patients after a long break from hemodialysis treatments as it can also precipitate dialysis disequilibrium syndrome, leading to severe morbidity and mortality, especially in underserved communities. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553357).

Case

We present the case of a 68-year-old woman with a history of hypertension, type 2 diabetes mellitus, and a recent diagnosis of end-stage kidney disease, who arrived at the emergency room with disorientation. The patient had started hemodialysis 3 months earlier via a temporary hemodialysis catheter but left the hospital against medical advice and refused further hemodialysis treatments. On arrival, she was disoriented and intubated in the emergency department because of dyspnea and altered mental status. Chest radiography revealed pulmonary edema, and vital signs revealed a blood pressure of 236/100 mm Hg. Laboratory results indicated a blood urea nitrogen (BUN) of 151 mg/dL, creatinine level of 18 mg/dL, bicarbonate level of 5 mEq/L, and potassium of 6.6 mEq/L (Table 1). A temporary hemodialysis catheter was inserted, and dialysis was initiated at a blood flow rate of 300 mL/min and a dialysate flow rate of 600 mL/min using an Optiflux 180NRe dialyzer (surface area, 1.7 m²), bicarbonate dialysate concentration of 38 mEq/L for a treatment duration of 3 h. Approximately 2 h and 55 min into the session, she developed seizure activity characterized by a tonic-clonic seizure lasting about 5 min, accompanied by bowel incontinence and melanotic stool. Hemodialysis was immediately halted, blood returned, and she received lorazepam 2 mg intravenously twice, which stopped the seizure. Computed tomography of the head showed no acute abnormalities. Post-dialysis laboratories were performed, and the urea reduction ratio (URR) was 57.6%.

Table 1.

Laboratory data for the patient before and after the first dialysis session

​	Reference ranges	Pre-HD	Post-HD
Sodium serum	132–144 mEq/L	137	136
Potassium serum	3.4–5.1 mEq/L	6.6 (HH)	3.3 (L)
Chloride serum	101–111 mEq/L	109	97 (L)
CO2 content serum	22–32 mEq/L	5 (LL)	16 (L)
Anion gap	1–13	23 (H)	23 (H)
Glucose	70–125 mg/dL	132 (H)	74
Urea nitrogen serum	8–22 mg/dL	151 (HH)	64 (H)
Creatinine	0.4–1.0 mg/dL	18.0 (H)	9.2 (H)
Glomerular filtration rate calc	>90 mL/min/1.73 m2	2 (L)	4 (L)
Osmo, calculated	275–300 mOsm/kg	325 (H)	289
Protein, total serum	6.0–8.3 g/dL	7.0	5.9 (L)
Albumin, serum	3.5–5.0 g/dL	4.1	3.4 (L)
Calcium, total serum	8.9–10.3 mg/dL	8.8 (L)	8.5 (L)

Bold values denote values out of range with H representing above normal range while L represents below normal range, HH and LL indicate significantly high above range or significantly Low below range, respectively.

She was transferred to the intensive care unit and treated with 20% mannitol 0.5 g/kg (40 g), followed by 3% hypertonic saline (30 mL bolus, then 50 mL/h infusion), targeting a serum sodium concentration of 145–155 mEq/L over 48–72 h, titrated with serial sodium monitoring, not to exceed 10 mEq/L rise in 24 h. She remained in a stuporous state, unresponsive, with no spontaneous eye movements, visual tracking, or responses to stimuli. An electroencephalogram showed moderate diffuse background slowing and poor organization, and findings were consistent with moderate-to-severe diffuse cerebral dysfunction of nonspecific etiology. A magnetic resonance imaging scan performed 48 h later revealed a small, punctate, subacute ischemic infarct in the left parietal lobe and mildly increased FLAIR signal hyperintensity in the cerebral white matter. These findings were more consistent with cerebral infarct in the setting of a hypertensive crisis, though increased FLAIR intensity can occur with dialysis disequilibrium, usually of a more diffuse and nonspecific nature. She was evaluated by neurology, and a diagnosis of dialysis disequilibrium syndrome and subacute cerebrovascular accident was made. The patient’s mental status gradually improved over the following 48 h, and she began following simple commands. Approximately 72 h later, she began opening her eyes to voice and consistently followed commands. Repeat dialysis was performed 72 h after the initial session, with blood flow of 200 mL/min and dialysate flow of 400 mL/min, for 2 h. Optiflux 160NRe (surface area 1.5 m2) was used, with linear sodium modeling from 149 to 145 mEq/L. The patient tolerated the procedure well and was extubated. The patient was subsequently discharged following a tunneled catheter placement and outpatient hemodialysis was scheduled.

We followed up with our patient; she experienced good neurological recovery and continued to adhere to hemodialysis treatments. The patient provided informed consent for the case report.

Discussion

Early identification of the risk factors for dialysis disequilibrium syndrome is essential for implementing strategies to reduce its incidence. The risk factors reported for this condition are elevated blood urea nitrogen levels greater than 100 mg/dL, severe metabolic acidosis, advanced age, and preexisting or coexisting conditions [4]. Neurological issues such as cerebrovascular disease and hypertensive crises increase the risk for dialysis disequilibrium syndrome. On the other hand, lower blood flow and dialysate rates may be more effective in reducing the risk of dialysis disequilibrium syndrome, and maintaining a controlled urea reduction rate below 40% is recommended. Higher blood and dialysate flow rates, along with a longer dialysis treatment, resulted in a urea reduction ratio of 57%. This was the probable cause of the severe symptoms experienced by our patient and required the use of hypertonic solutions to improve her symptoms. Therefore, lower blood flow rates, closer to 150–200 mL/min, with dialysate rates of 300–400 mL/min, may be more suitable for these patients, with a short duration of therapy not exceeding 2 h in vulnerable individuals [4].

The pathophysiology of dialysis disequilibrium syndrome is not completely understood but is multifactorial. A commonly proposed mechanism is the rapid reduction in plasma urea during hemodialysis relative to the brain, creating an osmotic gradient that promotes water movement into the brain cells and cerebral edema [1]. While some experimental studies have questioned this mechanism, others have demonstrated increased brain water content and elevated brain-to-plasma urea ratios in dialyzed uremic animals compared to non-dialyzed controls, supporting an osmotic basis [2, 3]. Additional contributors may include altered urea and water transport across the blood-brain barrier, with reduced urea transporter expression and compensatory upregulation of aquaporin channels in uremic states [5].

Dialysis disequilibrium syndrome is also thought to be partly due to the regulation of cell volume in response to extracellular tonicity, which depends on effective osmoles (sodium and glucose) that do not cross the cell membranes, unlike urea, which is usually believed to equilibrate well. Cells produce osmolytes, also called idiogenic osmoles (glycine, taurine, and inositol), in response to hypertonic conditions, aiming to prevent fluid shifts out of the cells into areas of higher solute concentration [6]. In rapid hemodialysis, the sudden decrease in plasma solute concentration and relative delay in the loss of organic osmoles from brain cells facilitate water movement into the cells, resulting in cerebral edema. It is important to note that measurements of tissue osmolality can have uncertain validity, and experimental studies to prove this theory may be lacking [6].

In addition, a key pathophysiological mechanism leading to dialysis disequilibrium syndrome involves the rapid correction of serum bicarbonate in patients with severe metabolic acidosis – exemplified in this specific patient, whose initial bicarbonate level was 5 mEq/L but increased to 16 mEq/L during treatment – a change of 11 mEq/L that exceeds 10 mEq/L – and is associated with a reduction in ventilatory drive [7]. This drive was previously active when the patient was severely acidotic, but when diminished, it leads to an increase in cerebrospinal fluid PCO₂. This paradoxical intracerebral acidosis displaces intracellular Na+ and K+ ions, which are bound to proteins by H+ ions, thereby making them osmotically active, increasing brain osmolality, and exacerbating cerebral edema, contributing to her severe symptoms [2, 5]. In fact, some experts argue that acidosis may be more important than urea as a major risk factor for dialysis disequilibrium, and worse neurologic symptoms are often associated with severe metabolic acidosis, with rapid correction of metabolic acidosis rather than urea reduction as the important contributor to the development of dialysis disequilibrium [8]. Dialysis disequilibrium syndrome is rare; however, we found that in severe cases or fatal cases, the initial bicarbonate was often quite low (2–6 mEq/L) with a rapid rise during the treatment, and some of these cases were associated with severe cerebral edema, herniation, and brain death, emphasizing the importance of this association [7–9]. A lower dialysate bicarbonate concentration, despite profound acidosis, to minimize the rise in bicarbonate levels, rather than a standard protocol, may be optimal for patients at risk for dialysis disequilibrium syndrome.

Finally, the treatment and prevention of dialysis disequilibrium syndrome rely on our understanding of the pathophysiology of the disorder; therefore, increasing plasma osmolality with 3% saline and mannitol, which can be administered during dialysis, as well as sodium modeling, either linear or exponential modeling, with a high initial sodium that is reduced to a lower level during the treatment is helpful in preventing or reducing fluid shifts during dialysis. Furthermore, hyperventilation is another treatment strategy that reduces arterial PCO₂ and, consequently, cerebrospinal fluid PCO₂, preventing intracerebral paradoxical acidosis, which can worsen fluid shifts and result in cerebral edema.

Conclusion

Dialysis disequilibrium syndrome remains a rare but significant complication of hemodialysis, particularly in patients who start dialysis or resume after a prolonged break. Our patient’s dialysis disequilibrium syndrome severity correlated with urea reduction ratio and her severe metabolic acidosis, highlighting the importance of achieving a low urea reduction ratio (<40%) and a targeted, limited rise in bicarbonate levels. Careful risk assessment and conservative dialysis protocols with slow urea clearance – using low blood and dialysate flows, a short duration, ideally not exceeding 2 h, and a reduced bicarbonate dialysate concentration in the most vulnerable patients – are crucial; mannitol and 3% saline serve as important preventive and rescue measures, along with close neurological monitoring to avoid morbidity and mortality. Increased awareness of dialysis disequilibrium syndrome is vital in underserved populations and in patients with lapses in dialysis care.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. Ethical approval was not obtained for this study because it was a single-case retrospective report, and Institutional Review Board approval is not required under our institutional and local guidelines. Written informed consent was obtained from the individual(s) for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts to declare.

Funding Sources

The authors declare that they have no relevant monetary interests.

Author Contributions

Ewalola Ijaduola, MD: E.I.: conceptualization; data curation; writing – original draft; and writing – review and editing. Sana Waheed, MD: S.W.: conceptualization; data curation; writing – original draft; and writing – review and editing. Khalid Bashir, MD: K.B.: writing – review and editing. E.I., S.W., and K.B. take responsibility for reporting this study honestly, accurately, and transparently and accept accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Funding Statement

The authors declare that they have no relevant monetary interests.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.