EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Here, we present 2 patients who developed central pontine myelinolysis after living-donor liver transplant. Both patients had abnormal sodium level before living-donor liver transplant. Patient 1 presented with severe hyponatremia on admission. After administration of 3% saline, her sodium level during the first 24 hours was kept at 100 mEq/L and then increased to 116 mEq/L during the next 24 hours. The level increased 5.8 mEq/L during the 4- to 5-hour transplant procedure. Patient 2 was admitted to the hospital with an unprovoked seizure. The serum sodium concentration was 111 mEq/L, which was treated with 3% saline infusion. Serum sodium concentration escalated to 118 mEq/L over an 8-hour period. Intraoperatively, both patients received large amounts of replacement fluids (0.9% normal saline and albumin), blood transfusion, and sodium bicarbonate during the anhepatic phase, all of which carry high sodium load. Variations in sodium levels changed rapidly in patient 1 during transplant surgery. After they underwent liver transplant, patient 1 had clear mental status and patient 2 demonstrated worsened mental status. On approximately day 14 and day 4 after liver transplant, magnetic resonance imaging showed diffuse abnormalities of the pons, resulting in diagnosis of central pontine myelinolysis. Although both patients survived, 1 remains in a vegetative state and the other continues to present with mild balance and swallowing abnormalities. To reduce the chance of inadvertent overcorrection in patients with hyponatremia, it is therefore important that sodium concentrations should be monitored frequently and fluids and electrolytes titrated carefully.

Key words : Fluid replacement, Hyponatremia, Sodium level

Central pontine myelinolysis (CPM) is an uncommon neurologic complication caused by damage to the myelin sheath. The incidence of CPM after liver transplant ranges from 0.8% to 1.4%,^1,2 and the condition carries a 30-day posttransplant mortality rate of 6.1% and a 1-year posttransplant mortality rate of 16.5%.³ A rapid rise in serum sodium concentration due to overcorrection of hyponatremia during surgery is one of the causes of postoperative CPM.1-3 Here, we describe the diagnosis, manage-ment, and outcome of CPM in 2 patients who developed neurologic conditions during living-donor liver transplant (LDLT).

Case 1
A 61-year-old female underwent LDLT for primary biliary cirrhosis. Six days before admission, she presented with a 1-month history of dizziness, muscle cramps in the arms and legs, and poor intake. Neurologic examination revealed that the patient was slightly confused and had a short attention span, although she was able to spontaneously open her eyes. Model for End-Stage Liver Disease (MELD) assessment revealed a score of 24. Her serum sodium concentration was < 100 mEq/L on admission. Administration of 3% saline over the next 48 hours increased the serum sodium level to 116 mEq/L, at which point LDLT was performed. The surgical time was 255 minutes, and there was an estimated blood loss of 2000 mL.

During surgery, 4 units of packed red blood cells (PRBCs) and 8 units of fresh frozen plasma (FFP) were infused. During the anhepatic phase, a buffering solution (80 mL of 7% 16.67 mEq sodium bicarbonate) was administered as a preventative measure against the development of metabolic acidosis. The sodium level changed throughout the patient’s care, ranging from 116 mEq/L at the beginning of surgery, to 114.6 mEq/L before reperfusion, to 117.7 mEq/L after reperfusion, and to 121.8 mEq/L at the end of the surgery.

During the first postoperative week, she developed pneumonia with respiratory failure and was maintained at deep sedation with midazolam. Twelve days after LDLT, sedation medications were discontinued when liver function and pneumonia status were improved. At 48-hour observation, the patient was still in a deep coma and developed complete paralysis. Magnetic resonance imaging (MRI) revealed marked pontine lesions (Figure 1). Because of severe brain damage, the patient entered a vegetative state, and she was transferred to a long-term care facility on day 52 of hospitalization. At follow-up 1.5 years after surgery, she was still in a vegetative state.

Case 2
A 69-year-old woman with end-stage liver disease, hepatitis C, esophageal varices, and hepatic encephalopathy and who was not scheduled to undergo LDLT presented to the emergency department 2 hours after having had an unprovoked seizure. On presentation, she was lethargic and stuporous. During physical examination, she had upper and lower limb weakness and responded only to painful stimuli. Laboratory test results revealed a serum sodium concentration of 111 mEq/L and an ammonia level of 118 μg/dL. Administration of intravenous 3% saline over an 8-hour period resulted in a serum sodium concentration of 119.9 mEq/L, at which time infusion was stopped.

The patient’s mental status was improved on day 3 of hospitalization but then worsened. On approximately day 8, she developed encephalopathy and frequent seizures. Eleven days after admission, she underwent LDLT. The patient’s MELD score at this time was 26, and her serum sodium level was 132 mmol/L on the day of surgery. The surgical time was 420 minutes, and there was an estimated blood loss of 3500 mL. During surgery, 10 units of PRBCs and 8 units of FFP were infused. The patient received 60 mL of sodium bicarbonate in the anhepatic phase. At the end of surgery, her serum sodium level was 138 mEq/L. On postoperative day 4, she developed general paroxysmal tremor with moderate coma. Figure 2 shows the patient’s brain MRI, with results leading to a diagnosis of CPM. After 9 weeks, she required partial assistance for mild abnormalities of balance and nasogastric tube feeding for swallowing dysfunction. The patient was discharged on day 66 of hospitalization. At 4-month follow-up, she had regained the ability to perform essential self-care activities.

Central pontine myelinolysis after liver transplant was first described by Starzl and associates in 1978.⁴ The condition is characterized by a lesion involving the central pons in patients with brain stem dysfunction ranging from dysphagia, dysarthria, flaccid tetraparesis, and quadriparesis to locked-in syndrome in severe cases.1 Patients with hepatic insufficiency typically have a number of factors that predispose them to developing CPM, such as electrolyte imbalances, diabetes mellitus, malnutrition, and hyponatremia. Although the cause of this potentially harmful lesion is not completely understood, the development of CPM is commonly associated with rapid correction of hyponatremia.

Hyponatremia and high MELD score are associated with increased morbidity and mortality in patients with acute or chronic liver failure and in patients on liver transplant wait lists.^5-7 Many studies have shown that hyponatremia is a risk factor for CPM and that rapid sodium replacement is one of the principal stimuli.^1,2,8Possible mechanisms of CPM include (1) glial dehydration and shrinkage due to a hyperosmotic state, resulting in separation of the axon from its myelin sheath with myelin injury and necrosis, and (2) fast recovery and maintenance of an intracellular osmolar state causing high-energy demand in the face of inadequate energy supply, resulting in oligodendroglial cell apoptosis.9 Intraoperatively, these patients receive large amounts of replacement fluids (0.9% saline and albumin), PRBCs, and FFP, all of which carry high sodium load, resulting in a rapid serum sodium shift.^2,3 It is recommended that correction of hyponatremia not exceed 5 mEq/L within the first hour and that the first 24 hours should be limited to no more than 10 mEq/L. It is also suggested that the increase in sodium concentration thereafter should be restricted to no more than 8 mEq/L per 24 hours and should be stopped when the sodium level reaches 130 mEq/L or when neurologic symptoms and signs have dissipated.¹⁰

Patient 1 presented with severe hyponatremia (< 100 mEq/L) on admission. After administration of 3% saline, sodium levels ranged from 100 to 116 mEq/L over 24 hours and then increased approximately 5.8 mEq/L during the 4- to 5- hour transplant procedure, thus surpassing the recom-mended limit of 0.5 to 1.0 mEql/L per hour and not more than 8 mEq/L per 24 hours that is considered safe.^10,11 Compared with patient 1, the severity of preoperative hyponatremia in patient 2 was slight. During an 8-hour period, her serum sodium concentration elevated about 1.11 mEq/L over every hour. Previous studies have suggested that serum sodium levels should be monitored a minimum of every 4 to 6 hours when patients receive continuous infusion with intravenous 3% sodium chloride over 20 minutes.^12,13

Neurologic symptoms can appear up to 15 days after brain injury, depending on the region of the brain that is affected.^1,12 We concur that MRI is presently the best modality available to confirm the diagnosis of CPM because of its superior capacity to demonstrate the lesions characteristic of the disease.¹² Characteristic features seen on MRI include a trident-shaped area of increased signal intensity in the central portion of the pons on T2-weighted and fluid-attenuated inversion recovery images and hypointensity on T1-weighted images. T2-weighted imaging is more sensitive for showing early or mild CPM lesions, and diffusion-weighted imaging may be a better method for identifying early patho-physiologic changes.^14,15 Magnetic resonance images in our patients demonstrated different extents of abnormal signal intensity within the central pons.

In conclusion, the best treatment for CPM is prevention or early diagnosis. It is important to emphasize that sodium concentration should be monitored frequently and fluids and electrolytes titrated carefully to reduce the chance of inadvertent overcorrection in patients with hyponatremia. There is no cure or specific therapy for CPM. Care is purely supportive with the goal of preventing complications ranging from dysphagia and quadriparesis to locked-in syndrome.

Volume: 17 Issue: 4 August 2019

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