Renal replacement therapy, Dialysis Disequilibrium Syndrome and Myelinolysis
Introduction
The case was chosen to illustrate the potential complications of renal replacement therapy and correcting hyper or hypo-osmotic fluid states too quickly.
Clinical problem
A 49 year old man presented to hospital with dehydration and confusion following a seven day history of vomiting. His urine output was minimal in the last four days before admission. He had been taking Diclofenac for back pain. There was no significant past medical history.
On admission he was clinically stable and was found to have severely deranged biochemistry. His creatinine was so high that the laboratory had difficulty measuring the first two samples. The third sample was measured at >8800µ/ml. His urea was 85mmol/L, phosphate 6.8mmol/L, sodium 136mmol/L, potassium 6.7mmol/L, base excess -17 and pH 7.1. Urine dipstick was strongly positive for blood and protein. He became increasingly confused and was transferred to the ICU.
Management
On the ICU he was intubated, fluid optimised and commenced on haemodiafiltration. After the first session of dialysis his urea fell to 58mmol/L and he was noted to have fixed dilated pupils. Standard neuroprotective measures to limit raised intracranial pressure were instituted.
The pupil changes resolved a few hours later before a CT scan could be arranged. At this time the patient was rousable from sedation and breathing spontaneously. A renal ultrasound was normal and later that day he was extubated with normal neurology apart from mild confusion attributed to his still high urea. Eight hours later the patient required re-intubation due to increasing confusion and respiratory failure. A brain CT scan was performed and reported as normal and supportive care continued. He developed a respiratory infection with sputum cultures showing haemophyllus influenza and staphylococcus aureus and was treated with appropriate antibiotics. Toxicology and immunology screen were negative. He had a renal biopsy which showed acute tubular necrosis. Sedation was stopped when he was judged ready for respiratory weaning. His Glasgow Coma Score (GCS) remained 3 and his pupils were again noted to be fixed and dilated. A second CT brain was performed 13 days after admission showed lesions in the mid brain and pons consistent with brain stem myelinolysis. Myelinolysis is best imaged on MRI but this facility was unavailable in our hospital for ventilated patients. Whilst not fulfilling all the criteria for brainstem death, his GCS remained 3 with fixed dilated pupils, absent tendon reflexes and no nystagmus to cold water. An EEG showed preservation of cortical activity but no brain stem activity. The patient did not show any meaningful spontaneous activity for 18 days without sedation and his life support was withdrawn after discussion with the family. Autopsy was not deemed necessary as the coroner was satisfied with the provisional diagnosis.
Discussion
Renal replacement therapy (RRT) is a common treatment in critically ill patients. While often lifesaving, it can be associated with many potentially devastating neurological sequelae. Dialysis disequilibrium syndrome (DDS) is a well recognized result of RRT but has rarely been reported in critically ill patients. Myelinolysis as a result of DDS is extremely rare with few previous case reports in the literature.
Neurological sequelae of RRT include cerebrovascular accidents, subdural haematomas, raised intracranial pressure with papilloedema, Wernicke’s encephalopathy, hypertensive encephalopathy and the dialysis disequilibrium syndrome [1].
The dialysis disequilibrium syndrome was first reported in 1962 by Kennedy and co-workers. It is caused by cerebral oedema and whilst there is some disagreement about the pathogenesis of DDS, it is generally attributed to the osmotic gradient created by the faster removal of urea from the plasma than from the brain due to the blood brain barrier. This creates movement of water into the brain and cerebral oedema. [2]
The literature shows consensus that DDS occurs most commonly during or immediately after a patient’s first dialysis but there is disagreement whether this is more common in patients with end-stage renal disease or acute renal failure. DDS has been widely reported to cause symptoms including confusion, agitation, restlessness, lethargy, headache, nausea, vomiting, muscle cramping and psychosis. Symptoms usually begin during or immediately after dialysis and resolve within 24h. However DDS can also result in seizures, coma, myelinolysis and rapid death.
Myelinolysis is a well recognized demyelinating condition. First described by Adams et al. in 1959 in their chronic alcoholic patients, it has now been described in the malnourished, the chronically debilitated, the renal, the hepatic and the transplant patients among others. Pathologically, it is defined as a symmetric area of myelin disruption in the center of the base of pons. In at least 10% of patients with CPM, demyelination also occurs in extrapontine regions, including the mid brain, thalamus, basal nuclei, and cerebellum. The exact mechanism that strips the myelin sheath is unknown. Possible mechanisms include hyperosmotically induced rapid water shifts from intracellular to extracellular spaces producing relative glial dehydration and myelin degradation and/or oligodendroglial apoptosis [3]. It has a wide range of consequences, ranging from mild neurological symptoms to death. Myelinolysis has been reported after the rapid sodium correction that can result from dialysis [4]. However, the pontine and extrapontine lesions of myelinolysis have been shown to occur very rarely secondary to DDS in end stage renal failure patients. Mostly the lesions resolve rapidly, suggesting transient oedema rather than permanent damage to myelin sheaths. These reports agree with previous observations that myelinolysis from other causes is often clinically insignificant [3]. It has been postulated that uraemia may be protective against myelinolysis in rapid sodium correction as the osmotic effects of the plasma sodium rise counteract the osmotic effects of brain urea. This case was different however in that the precipitating cause was severe acute pre-renal failure in a previously fit and well individual undergoing first dialysis and that the demyelination was clearly irrecoverable.
The immediate indication for renal replacement therapy in our patient was correction of metabolic acidosis and hyperkalaemia. To prevent DDS the patient was dialysed with the lowest flow rate possible (100mls/min) and for only half the usual time (2 hours instead of 4). The patient’s urea after this cycle fell to 58 (a 32% fall). The rate of acceptable urea removal has not been defined – only that it should be slow. Unfortunately the decrease in urea in our patient was enough to create signs of DDS with a clinical picture suggesting cerebral oedema and raised intracranial pressure. In a similar case of dialysis for ARF, severe DDS was reversed with neuroprotective measures [5] and this proved to be true in our case also with the patient waking up and being extubated a few hours later with no initially apparent neurological sequelae.
Sodium profiling, high sodium or hyperglycaemic dialysate have been attempted with variable results in preventing DDS in patients undergoing initial haemodialysis for acute renal failure. Patients who develop myelinolysis usually do so hours to days after the precipitating cause with the onset of encephalopathy [6]. Myelinolysis was not initially considered in this patient and the confusion necessitating re-intubation was attributed to uraemia. The progressive nature of the condition and the fact that demyelination is easier to see on MRI explains why the first CT scan did not reveal any obvious abnormality. Myelinolysis is widely regarded as having a dismal prognosis, particularly if severe, but a number of case reports demonstrate varying degrees of recovery. A recent case series has suggested that outcome does not depend upon the severity of neurological deficit at presentation [7]. ‘Locked in’ syndrome has also been reported. For this reason our patient was given several weeks to show signs of neurological improvement.
Lessons learnt
Renal replacement therapy has serious complications.
Osmotic fluid shifts can induce cerebral oedema which in turn can lead to death.
Osmotic fluid shifts can be avoided or limited by careful and slow correction of the underlying abnormality if it is extreme.
References
Walters RJ, Fox NC, Crum WR, Taube D, Thomas DJ. Haemodialysis and cerebral oedema. Nephron, Feb 2001, vol. 87, no. 2, p. 143−7.
Arieff A. Dialysis disequilibrium syndrome: Current concepts on pathogenesis and prevention. Kidney Internat 1994, 45:629-635.
Kleinschmidt-DeMasters BK, Rojiani AM, Filley CM. Central and Extrapontine Myelinolysis: Then...and Now. Journal of Neuropathology and Experimental Neurology. Jan 2006. Vol. 65, Iss. 1; pg. 1, 11 pgs
Huang-Wen−Yi, Weng−Wei−Chieh, Peng−Tsung−I. Central pontine and extrapontine myelinolysis after rapid correction of hyponatremia by hemodialysis in a uremic patient. Renal failure, 2007, vol. 29, no. 5, p. 635−8.
DiFresco V, Landman M, Jaber B, White A. Dialysis disequilibrium syndrome: an unusual cause of respiratory failure in the medical intensive care unit. Intensive Care Medicine 2000, 26:628-630
Martin RJ. Central pontine and extrapontine myelinolysis: The osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 2004;75(suppl 3):iii22-iii28
Santinelli R, Tolone C. Pontine myelinolysis in a child with carbamate poisoning. Clinical toxicology, 2006, vol. 44, no. 3, p. 327−8.
