Dantrolene-Induced Hepatitis: A Rare Culprit in the PICU

Abstract

Dantrolene is used for reversal of malignant hyperthermia and for improvement in spasticity following stroke which are Food and Drug Administration-approved indications. It is an infrequently used medication in the pediatric intensive care unit and is usually continued from the operating room or sedation suite after suspicion for malignant hyperthermia, secondary to other medications and anesthetic agents. Hepatitis has been described as a side effect of the medication after prolonged use and at doses of more than 100 mg/d mainly in adults. We described in this case report a patient in which the drug was used for sympathetic overactivity in the PICU and development of asymptomatic hepatitis on day 3 after starting the medication at a dose much lower than previously described.

Introduction

Dantrolene is commonly used for reversal of malignant hyperthermia which can be a catastrophic complication secondary to many anesthetic and sedative agents. ¹ Human and animal studies revealed that administration of dantrolene and supportive measures have been effective in reversing the hypermetabolic process of malignant hyperthermia. Dantrolene is a long-acting muscle relaxant and its mechanism of action is to prevent the release of calcium from the sarcoplasmic reticulum which dissociates the excitation–contraction coupling in skeletal muscles. ¹ The same mechanism of the drug provides its use against spasticity in patients with upper motor neuron lesions, such as stroke, by preventing sustained muscle spasms. ² Multiple studies involving patients with stroke and pediatric patients with cerebral palsy have described the efficacy of dantrolene in these cohorts. ³ Central nervous system effects of the drug include drowsiness which can be helpful in patients with excessive spasticity secondary to stimulation. ¹ There were previous reports of dantrolene-induced hepatic injury in adults and the spectrum of the disease varies from asymptomatic elevation of liver enzymes to fulminant hepatic failure. The prevalence of hepatic injury in postmarket release surveillance studies was 1.8%. ⁴

Case Description

A 5-year-old male patient with cerebellar-pontine hypoplasia, seizure disorder, tracheostomy dependence, severe gastroesophageal reflux, and paraesophageal hernia was admitted to our hospital for Nissen fundoplication, gastrojejunostomy tube placement, and optimization of his pulmonary regimen. At the start of hospitalization, the patient was placed on continuous mechanical ventilation at baseline settings which were gradually weaned off and transitioned to tracheostomy collar with no supplemental oxygen. Medications administered during hospitalization include methadone for opioid withdrawal, levetiracetam for seizure control, scheduled lorazepam for seizure control and agitation, as well as lansoprazole and ranitidine for severe gastroesophageal reflux. Three days after his Nissen procedure, the patient began to develop high-grade fever, tachycardia out of proportion and not related to the fever along with increased spasticity. Systemic and localized infection was ruled out with imaging and cultures. The patient did not have clinical or electrographic seizures as a potential cause of these clinical findings.

In view of significant hypertonicity, agitation, and other signs of sympathetic overactivity ( Table 1 ), dantrolene was started at a dose of 10 mg/d. Three days after starting dantrolene, the patient was noted to have a significant elevation of hepatic enzymes on surveillance laboratory tests. Peak liver enzyme levels were serum glutamic oxaloacetic transaminase 1,887 U/L and serum glutamic pyruvic transaminase 859 U/L with no abnormalities in other liver function tests including serum bilirubin 0.4 mg/dL and prothrombin time. Creatine kinase was mildly elevated (250 U/L). In view of the elevation of liver enzyme levels, dantrolene was discontinued and liver enzyme levels trended down over the next 7 days. The patient's vital signs, and laboratory test results and their trends are shown in Tables 1 and 2 , respectively. The patient was started on baclofen 10 days after discontinuation of dantrolene, and subsequent improvements in spasticity and autonomic hyperactivity were observed ( Table 1 ).

Table 1. Vitals before and after starting dantrolene.

Vitals	Before starting dantrolene	D1 (first dose given)	D2 (second dose given)	D3 (medication stopped)	D4	D5
Temperature	39.8°C	38.8°C	38.2°C	37.8°C	38.2°C	38.4°C
Respirations	28/min	24/min	28/min	22/min	24/min	22/min
SpO 2	97%	97%	96%	98%	98%	98%
Heart rate	180–190/min	160–180/min	140–160/min	140–160/min	140–150/min	130–160/min
Blood pressure	138/93 mm Hg	130/82 mm Hg	104/80 mm Hg	104/58 mm Hg	110/76 mm Hg	122/78 mm Hg
Vitals	D7	D10	D12 (baclofen started)	D13	D14	D15
Temperature	38.8°C	39.2°C	39.1°C	38.2°C	37.9°C	37.7°C
Respirations	26/min	24/min	22/min	26/min	24/min	24/min
SpO 2	97%	98%	97%	98%	97%	98%
Heart rate	150–180/min	160–190/min	150–190/min	140–170/min	110–130/min	100–130/min
Blood pressure	128/82 mm Hg	134/90 mm Hg	130/82 mm Hg	120/68 mm Hg	118/72 mm Hg	110/64 mm Hg

Abbreviation: SpO ₂ , oxygen saturation.

Table 2. Table describing the elevation of liver enzymes and their improvement following use of dantrolene.

	D1 (dantrolene started, 10 mg/d)	D2 (same dose given, 10 mg/d)	D3 (medication stopped after third dose)	D4	D5	D7	D9	D11	D15
T. Bil			0.6	0.5	0.4	0.3	0.3	0.2	0.3
ALP			158	176	189	159	154	143	155
AST			1,887	1,982	1,803	846	594	463	221
ALT			859	958	1,016	682	521	394	278
T. protein			6.1	6.0	6.6	6.7	6.2	5.9	6.9
S. alb			3.5	3.7	4.1	3.9	3.9	3.7	4.3
PT/INR			1.2		1.1		1.1
CK levels			252	210	214		190

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase (IU/L); AST, aspartate aminotransferase; CK, creatine kinase; D#, describe chronological days after starting dantrolene; INR, international normalized ratio; PT, prothrombin time; S. alb, serum albumin (g/dL); T. Bil, total bilirubin (mg/dL); T. protein, total protein (g/dL).

Note: Reference laboratory values: Bilirubin—0 to 0.4 mg/dL, AST—5 to 50 U/L, ALT—5 to 50 U/L, ALP—80 to 345 U/L, total protein—6 to 8 g/dL, albumin—3.5 to 5 g/dL, creatine kinase—0 to 170 U/L.

Discussion

The spectrum of hepatic injury with dantrolene can be variable and has mostly been reported at doses higher than 200 mg/d and when used for more than 30 days. ^{5 6} There is greater likelihood of potentially fatal, dantrolene-induced hepatitis following use in females over the age of 35 years and elderly patients. ¹ Hepatic injury with use of this medication has been rarely described in the pediatric age group and no case reports have been published in the last decade in pediatric patients to our knowledge. The key difference in this case from previously published literature described in adults was that the elevation in liver enzyme levels was quite early in the course of treatment on day 3 after starting the medication. The observed transaminitis was also secondary to a dose, 10 mg/d, which had not been previously reported to cause liver injury. ⁷

The mechanism by which dantrolene causes liver toxicity is not well understood, and could be due to the accumulation of reactive metabolites formed via secondary drug metabolism in the liver because most cases of toxicity have occurred after a prolonged exposure to the medication. ⁸ It is unlikely to be a hypersensitivity reaction because of the latency period after exposure to the drug, and also because most cases show no evidence of fever, rash, or eosinophilia as seen with allergic drug reactions. ⁵ Liver enzymes can show improvement and completely resolution to normal levels after discontinuation of dantrolene if there has not been irreversible damage.

Conclusion

Our case emphasizes that although dantrolene is uncommonly used in the pediatric critical care environment, it can be associated with liver injury. The spectrum of liver damage can range from asymptomatic elevation of liver enzymes to fulminant liver failure. It can start early in the treatment course and at doses much lower than in previously published literature. Liver function tests should therefore be closely monitored after starting dantrolene, and the medication should be stopped at the earliest evidence of liver toxicity. The timeline for resolution of dantrolene-induced liver enzyme elevation can be variable, and the use of alternative medications for spasticity should be strongly considered following any observed evidence of liver dysfunction following the administration of dantrolene.

Funding Statement

Funding None.