Management of Post-Liver-Transplant Delirium with Melatonin: A Case Report

Melatonin is known to play a key role in managing multiple bodily functions such as controlling the chronobiologic cycle of the body and resetting the circadian rhythm. It also acts as an antioxidant at the intracellular level, has strong anti-apoptotic activity, has anti-inflammatory and analgesic properties, helps in adaptation to the environmental and neuroendocrine system, and delays the progression of various hormone-dependent malignancies. It also plays a role in immune regulation, neuroprotection, and sleep regulation. ¹

Given its role in the chronobiological cycle, melatonin has been evaluated for the prevention and management of delirium. ² The antioxidant properties of melatonin have been utilized for preventing and managing a range of liver injuries and diseases^{3, 4} and the prevention of medication-associated nephrotoxicity. ⁵ Given its potent antioxidant properties, it has also been used in organ transplant patients to prevent graft rejection. It has been evaluated in liver transplant patients as part of a multidrug pre-transplant pharmacological cocktail. ⁶

Delirium is one of the acute complications of a liver transplant, with a reported incidence of 21%, and is associated with prolonged hospital stay, longer intensive care unit stay, and higher six months mortality. ⁷ Accordingly, effective management of delirium in patients undergoing liver transplantation is of paramount importance. Considering the antioxidant, anti-inflammatory, and beneficial effects of melatonin, with no associated cardiac complications, it can be considered as a promising agent for the management of delirium in patients undergoing a liver transplant. However, no studies have evaluated the role of melatonin in the management of delirium in patients who have undergone liver transplantation. Here, we present a case who developed delirium during the immediate post-transplant period and was managed with melatonin.

Case Description

A 58-year-old female, diagnosed with type-2 diabetes mellitus, hypothyroidism, and non-alcoholic steatohepatitis, was considered for a liver transplant due to decompensated liver disease. Psychiatric evaluation before surgery did not reveal evidence of any psychiatric ailment.

On post-operative day 2, she was extubated and was maintaining saturation on oxygen supplementation with the mask. However, on the same day, she developed abnormal behavior in the form of agitation and persecutory delusion. On mental status examination, she was found to be conscious but uncooperative. She was easily distracted during conversation and did not cooperate with formal testing for attention. She was oriented to person but not to time or place. During the interview, she would drift off to sleep and had to be aroused by calling out her name repeatedly. These symptoms were seen to fluctuate during the day.

Given this, a diagnosis of delirium was made. Her Delirium Rating Scale Revised-98 (DRS-R-98) ⁸ total score was 29, and Mini-Mental State Examination (MMSE) score, 9. Review of all the investigations (including renal function test, fasting blood glucose levels, and serum electrolytes) did not reveal any abnormality except for hyponatremia (S. Na = 121 mEq/L), hypoalbuminemia (S. Albumin = 2.8 mg/dL) and deranged liver function tests (S. Bilirubin 3.9 mg/dL). Her liver function test showed an improvement trend, compared to her pre-transplant status. Ultrasound of the abdomen did not reveal any abnormality. A review of medications revealed that she was receiving intravenous methylprednisolone 300 mg/day and IV antibiotics in the form of imipenem and tazobactam for the prevention of post-transplant complications.

The delirium was considered to be of multifactorial etiology, with hyponatremia considered the primary cause, and post-operative pain, deranged liver functions, prolonged surgery, and use of methylprednisolone as other contributory factors.

Initially, the family members and other treating team members were educated about her condition and advised to provide re-orientation cues, avoid unnecessary stimulation, and avoid the frequent change of staff. Hyponatremia was corrected by an intravenous route along with the use of intravenous albumin for hypoalbuminemia.

At the initial evaluation, after discussing with the primary treating team, it was decided not to start any new medications. However, over the next day, she became more uncooperative and agitated, threatening to remove the tubing and not allowing anyone to go near her. Her DRS-R-98 score increased to 32, and the MMSE score reduced to 6. Given these symptoms, following a multidisciplinary team discussion and involvement of family members, she was started on tab. melatonin 1.5 mg at 9 pm. She slept well on the fourth post-operative night. The severity of her symptoms came down the next day, and she was slightly cooperative. Her DRS-R-98 score decreased to 26, and the MMSE score increased to 13. On the next night, she received melatonin 3 mg, with which her sleep remained better. From the fifth post-operative day, she was fully oriented and cooperative and did not have any persecutory delusions. Her DRS-R-98 score was 13, and the MMSE score was 19.

She was continued on melatonin 3 mg HS for the next week, and she maintained well. During this period, no side effects were noted that could be attributed to melatonin.

Discussion

We are not aware of any previous report of the use of melatonin in the management of delirium in a patient in the post-liver-transplant stage. The index case reveals that melatonin can be used safely in patients developing delirium in the context of a liver transplant. In the index case, melatonin led to an improvement in the symptoms within 24 hours, and the continued use of melatonin was not associated with any untoward side effects. Available data suggest that melatonin may have a beneficial effect in other organ transplantations, too, due to its antioxidative properties. Because the incidence of delirium is reported to be as high as 21% in patients undergoing liver transplant, ⁷ melatonin needs to be evaluated further for its efficacy in the prevention and management of delirium in this group of patients. Data also suggest the association of lower melatonin levels with the use of mechanical ventilation ⁹ and of abnormal melatonin release with sepsis, ⁹ which are established risk factors for delirium.

We did not consider an antipsychotic for the management of delirium because of the risk of cardiac side effects, which the hepatic team was not comfortable about. The second reason was that melatonin has been found to have antioxidant properties and has been used previously in people with liver injury.^{1, 3} Keeping these points in mind, melatonin was considered.

In the index case, the improvement in delirium could be due to the correction of underlying metabolic parameters (i.e., hyponatremia), the use of re-orientation cues, and the use of melatonin. Since, in general, the incidence of delirium is high in all the post-operative patients, melatonin may be an ideal agent that needs to be evaluated further for its efficacy in the management and prevention of delirium.