Baclofen-Related Neurotoxicity: Implication in a Fatality Associated With Hepatorenal Syndrome

To the Editor

The potential severity of toxicity associated with baclofen use in patients with renal impairment is underappreciated. Here, we report a fatality in which providers agreed that along with disseminated fungal infection and other serious complications in a patient with hepatorenal syndrome, baclofen-related toxicity was a factor that contributed to the patient’s demise. This opinion was corroborated by testing that revealed a relationship between baclofen administration and the character of symptoms present at the time of death in which causality was probable. ¹

A 56-year-old male transplant candidate with end-stage liver disease secondary to autoimmune hepatitis presented to the emergency department with malaise and severe pain emanating from a necrotic-appearing lesion on his right medial thigh. This nonhealing lesion had persisted through the preceding 6 weeks after he was kicked by a cow while farming. Despite hospital admission and empiric broad-spectrum antibiotic treatment, lesion worsening and onset of symptoms consistent with systemic inflammatory response prompted wide surgical excision. Tissue biopsy proved positive for Zygomyces sp. Antifungal treatment with liposomal amphotericin B and posaconazole was initiated. After 5 days’ treatment, renal function declined from a baseline serum creatinine (SCr) of 1.40 to 2.87 mg/dL. Posaconazole was continued but amphotericin was discontinued and because SCr continued to rise to 7.54 mg/dL, intermittent hemodialysis was initiated for acute oliguric renal failure. Eight days after admission, concern for a suspicious lung pathology prompted bronchoscopy with diagnostic bronchoalveolar lavage for possible infection. Procedural complications ensued with development of hydropneumothorax. Despite ongoing antimicrobial therapy, hemodialysis, and other supportive efforts, leukocytosis persisted and the patient’s organ function and overall condition failed to show substantial improvement. On hospital day 29, intractable hiccups prompted initiation of treatment with oral baclofen 5 mg 3 times daily. Due to an inadequate response, the baclofen dose was increased to 10 mg 3 times daily on treatment day 4. The following day, the patient displayed a significant decline in responsiveness with uncharacteristic lethargy and communication disability. Altered mental status was initially attributed to worsening hepatic encephalopathy and lactulose therapy was accordingly intensified with dose titration to 4 stools per day. Over the next 2 days, the patient’s mental ability continued to deteriorate and, shortly after a repeat large-volume paracentesis, respiratory function acutely declined. Severe hypoxemia secondary to low rate and depth of respiration, worsening bradycardia, and eventual unresponsiveness necessitated immediate endotracheal intubation and transfer to the intensive care unit. Soon after, cardiac arrest with pulseless electrical activity arose. Resuscitation efforts were unsuccessful. Autopsy was refused by the patient’s family.

Baclofen-related neurotoxicity in patients with compromised renal function has been well described.^2–4 Similar to our patient, the literature includes several case reports of toxicity involving hemodialysis-dependent patients receiving baclofen treatment for hiccups.^5,6 Although baclofen is relatively efficiently removed from blood by hemodialysis,^6,7 repeat or chronic interdialytic administration of usual doses is problematic. These toxic events are characterized by baclofen accumulation leading to a range of symptoms that may include encephalopathy, respiratory depression, decreased levels of consciousness and, as documented following acute baclofen overdose, coma to a depth such that it mimics severe brain stem injury and death. ⁸

Despite the fact that little or no relevant dosage information is provided in current compendial and proprietary resources, dose adjustment of baclofen is vitally important in patients with renal impairment. Based on pharmacokinetic characterizations in subjects with chronic kidney disease, recommended total baclofen doses are 10 mg/d for adults with an estimated creatinine clearance (CrCL) of 50 to 80 mL/min, 7.5 mg/d for patients with a CrCL of 30 to 50, and 5 mg/d for those not on dialysis with a CrCL <30. ⁹ In patients receiving chronic hemodialysis, baclofen should be avoided or, if no suitable alternative is available, limited to not more than 5 mg/d. ¹⁰