Severe Bradyarrhythmia and Reduced Cardiac Output Due to Oral Baclofen Withdrawal in a 24-Year Old Man: A Case Report

Abstract

Patient: Male, 24-year-old

Final Diagnosis: Baclofen toxicity

Symptoms: Bradycardia • hypotension

Clinical Procedure: —

Specialty: Critical Care Medicine • Toxicology

Objective: Unusual clinical course

Background

Baclofen is a selective gamma-aminobutyric acid (GABA) receptor agonist and muscle relaxant prescribed to treat spasticity and muscle pain and is used off-label to treat alcohol use disorder and gastroesophageal reflux disease. Baclofen withdrawal syndrome is a rare condition that presents with abnormal cardiac rhythm and function. This report describes the case of a 24-year-old man who presented with polypharmacy overdose, including baclofen, who subsequently showed features of baclofen withdrawal, requiring baclofen reintroduction.

Case Report

A 24-year-old man was admitted to the Intensive Care Unit after suspected polypharmacy overdose of baclofen, escitalopram, and ethanol. Thirty-six hours later, the patient developed severe bradyarrhythmia and associated reduced cardiac output/arrest, requiring inotropic and vasopressor support. Extensive cardiac workup showed no abnormalities that could explain the symptoms; however, the patient had persistent episodes of severe bradyarrhythmia and loss of cardiac output. Given the lack of improvement, potential baclofen withdrawal was hypothesized for the episodes of bradycardia and low cardiac output. Low-dose baclofen was therefore reintroduced. After 36 h of reintroducing baclofen, all episodes of severe bradyarrhythmia and low cardiac output resolved. The patient went on to make a full recovery, with ongoing low-dose baclofen therapy. This case highlights that, even in the possible setting of baclofen toxicity, baclofen withdrawal must also be considered as a potential cause of bradycardia and low cardiac output leading to hypotension.

Conclusions

Baclofen withdrawal can lead to life-threatening cardiac depression. Re-introduction of baclofen might be therapeutic in the management of these cases.

Introduction

Baclofen is an agonist of the gamma-aminobutyric acid type B (GABA_B) receptor, acting on both pre- and postsynaptic neurons in the central and peripheral nervous systems [1]. It is used primarily to treat muscle spasticity, and is used off-label for alcohol use disorder and gastroesophageal reflux disease [1,2]. It can be administered orally or intrathecally for severe intractable muscle spasms of cerebral or spinal cord origin [1]. In patients with severe spasticity associated with spinal cord injury and multiple sclerosis, intrathecal administration is considered [1]. Baclofen overdose and its effects have been well documented and include central nervous system depression, respiratory depression, flaccid paralysis, hypotension, bradycardia, and seizures [1,3,4]. Baclofen withdrawal syndrome typically presents with symptoms such as altered mental status, worsening of spasticity, fever, nausea, weakness autonomic instability, and, in rare instances, cardiac arrest [1,4,5]. However, severe cardiac manifestations from withdrawal secondary to oral use have not been described. There is 1 case report of a patient experiencing cardiac arrest that was potentially secondary to intrathecal baclofen withdrawal; however, this patient’s case was complicated by a severe community acquired pneumonia [5]. Another case reported ventricular tachycardia secondary to baclofen withdrawal; however, this was once again after use of intrathecal baclofen [6]. Additionally, there is a case reported of a patient developing Takotsubo cardiomyopathy after intrathecal baclofen withdrawal, which was postulated to likely be secondary to increased sympathetic outflow from the spinal cord [7]. In this report, we describe the case of a 24-year-old man presenting with bradyarrhythmia and reduced cardiac output following oral baclofen withdrawal.

Case Report

The patient’s informed consent was obtained to publish his presentation as a case report.

A 24-year-old man was brought in by ambulance after suspected baclofen overdose and escitalopram and ethanol intake, as part of an intentional overdose. The patient had a past medical history of alcohol use disorder and seizures secondary to alcohol withdrawal. He had recently completed a home detoxication program for alcohol dependence. His regular dose of baclofen was 10 mg 3 times a day for alcohol use disorder and escitalopram 20 mg daily, both commenced 4 months ago. Upon the arrival of the paramedic staff, his Glasgow coma scale score was 8, and he was intubated at scene, due to concerns regarding airway protection, and brought to the Emergency Department. Upon calculation of the missing tablets in his blister packs, it was estimated that the patient had taken around 600 mg of baclofen and 160 mg of escitalopram. His blood ethanol level on arrival was 0.099%. His electrocardiogram (ECG) on presentation showed a heart rate of 68 beats per min and a normal corrected QT(QTc) interval of 431 ms. The patient did not have any episodes of ventricular tachycardia. He was then transferred to the Intensive Care Unit (ICU) for ongoing care. The patient was placed on an alcohol withdrawal scale, and supportive management was provided in the ICU, including sedation with propofol, fentanyl, and dexmedetomidine infusions, while awaiting washout of the ingested baclofen. The patient did not require any ionotropic or chronotropic supports upon admission to the ICU.

However, 36 h after admission to the ICU, the patient developed an episode of severe bradyarrhythmia, with the heart rate dropping to low 20s, with periods of asystole on monitoring (Figure 1). ECG showed bradyarrhythmia, with no signs of other conduction delay. His QTc always remained normal (Figure 2). This was associated with hypotension on invasive arterial blood pressure monitoring. The patient was administered 2 boluses of 600 mcg atropine, which were partially effective in raising the heart rate. The dexmedetomidine infusion was ceased because of the ongoing bradyarrhythmia. Nasogastric tube aspiration after this event was 400 mL, and the initial working hypothesis of a potential vagal response was made, as the patient was young and had no prior cardiac history.

Figure 1.

Telemetry of lead V2 and II showing severe bradyarrhythmia. Vertical lines denote 1-s intervals.

Figure 2.

Electrocardiogram showing bradycardia. Vertical lines denote 200-ms intervals. Heart rate: 45 beats per min; corrected QT interval: 430 ms.

The patient was extubated the next day, with lower doses of dexmedetomidine infusion; however, this resulted in another episode of severe bradyarrhythmia and hypotension, with systolic blood pressure of approximately 50 mm Hg. The patient was then commenced on an adrenaline infusion at 2 mcg/min to assist with maintaining of blood pressure and cardiac output. However, he then soon developed severe agitation and delirium that was not responding to dexmedetomidine infusion at 1.5 mcg/kg/h, intravascular haloperidol, or midazolam boluses; hence, the decision was made to reintubate the patient, and he was commenced on a midazolam infusion. The patient continued to experience episodic bradyarrhythmia on telemetry, despite stopping dexmedetomidine. A subsequent transthoracic echocardiography showed only mild impairment of left ventricular systolic function. Thyroid function test results were within normal limits. Serial ECGs showed normal QT intervals and no evidence of myocardial ischemia. Consultation with the toxicology service revealed that it was equally likely the patient had ongoing baclofen toxicity or baclofen withdrawal. While evidence for treatment of baclofen overdose was limited, the consensus between multidisciplinary teams was that the patient could potentially benefit from a low dose of baclofen administration, given that a small dose would likely mitigate withdrawal symptoms but not worsen ongoing toxicity. Hence, the patient was commenced on 5 mg of baclofen 3 times a day. The reintroduction of baclofen ceased all recurrent bradyarrhythmia episodes. The adrenaline infusion was ceased after 36 h, and the patient was able to be extubated 2 days later. He made a complete recovery and was subsequently discharged home.

Discussion

This case highlights that baclofen withdrawal syndrome can present with severe bradyarrhythmia with low cardiac output, even in patients presenting with baclofen overdose that may need reintroduction of low-dose baclofen. Baclofen withdrawal can be accompanied by cardiac arrest that is potentially fatal [6]. Furthermore, measurement of serum concentration of baclofen to aid in differentiating the symptoms associated with baclofen overdose or withdrawal syndrome is not recommended nor directly correlated to clinical status [1,8]. Hence, a high clinical index of suspicion is required to diagnose baclofen withdrawal. The diagnosis can also be clouded by the possibility of ongoing baclofen toxicity. This case highlights the importance of promptly recognizing baclofen withdrawal as a cause of severe bradyarrhythmia after overdose episodes, when there are no other clinical conditions contributing to bradyarrhythmia. Our patient was young with no identifiable cardiac pathology or drugs as a cause for ongoing bradyarrhythmia and hypotension other than baclofen withdrawal. Differential diagnoses included serotonin syndrome, ongoing baclofen toxicity, and propofol- or dexmedetomidine-related bradycardia.

The patient’s initial presentation of altered mental status requiring intubation suggests that baclofen was already absorbed and causing physiological effects. On day 3 after presentation, the patient was extubated, owing to improving mental status, which was suggestive of successful washout of the baclofen. Hence, the episodes of bradyarrhythmia afterward were unlikely to be due to prolonged baclofen toxicity. Furthermore, the resolution of symptoms after baclofen reintroduction is consistent with withdrawal [9]. This patient had a normal neurological examination, with no clonus nor hypertonia noted, and was on a single selective serotonin reuptake inhibitor, making the diagnosis of serotonin syndrome unlikely [10]. Moreover, the patient had bradyarrhythmia after extubation, with no propofol infusion running, making propofol-related bradycardia an unlikely culprit. As suggested in the timeline (Table 1), the bradyarrhythmia episodes continued 2 days after cessation of dexmedetomidine. Given that the terminal half-life of dexmedetomidine is 2 h, it is also unlikely that the bradyarrhythmia was related to dexmedetomidine [11].

Table 1.

Timeline of the patient’s clinical course during the hospitalization.

Day	Key events
1	Patient arrives in the ED Patient is transferred to the ICU
2	Dexmedetomidine infusion initiated in the morning with aim to extubate Episode of severe bradycardia with periods of asystole Dexmedetomidine infusion ceased
5	Dexmedetomidine infusion initiated in the morning at low dose Patient extubated Patient requires re-intubation due to ongoing refractory agitation Dexmedetomidine ceased after intubation
6	Ongoing episodes of bradycardia requiring adrenaline infusion
7	Ongoing episodes of severe bradycardia despite being on no dexmedetomidine Baclofen therapy is reintroduced Bradycardic episodes ceased; adrenaline infusion weaned
8	Successful extubation
9	Patient discharged from ICU to a general ward
12	Patient is discharged home

ED – Emergency Department; ICU – Intensive Care Unit.

This case shares some similarities and differences with previously described cases of baclofen withdrawal. Compared with the case described by Cardoso et al [5], this case did not involve overlapping septic shock, respiratory failure, and multiorgan failure preceding the bradyarrhythmia. The presentation in this case was an isolated baclofen toxicity, with the initial presentation causing altered mental status, which then resolved, followed by severe bradyarrhythmia, suggestive of withdrawal. Furthermore, this case involved oral baclofen withdrawal rather than intrathecally administered baclofen. However, in both cases, the symptoms of baclofen withdrawal commenced more than 24 h after the cessation of baclofen.

Green et al [6] describe a case of baclofen in a patient who was on both the oral and intrathecal administration. The withdrawal was characterized by tachyarrhythmia and hyperthermia, as opposed to the bradyarrhythmia noticed in this case.

Levy et al [7] describe a case of withdrawal from intrathecal baclofen that resulted in the development of Takotsubo cardiomyopathy, which resolved with restoration of baclofen therapy. This case highlights, as does our case, how reintroduction of baclofen can have therapeutic benefit. However, there were no bradyarrhythmia present in this case and it did not involve withdrawal from oral baclofen therapy.

Alvis et al [9] report an interesting case of baclofen withdrawal involving oral baclofen therapy. Similar to our case, this patient presented with altered mental status and required admission into the ICU for ventilatory support. Furthermore, this case also demonstrates the rapid improvement in patient’s symptoms when baclofen withdrawal is recognized, and the medication is reintroduced. However, this case did not involve any bradyarrhythmia episodes.

While many treatment options, including propofol infusions, benzodiazepines, dantrolene, and cyproheptadine, can be considered as adjunct therapies, the most definitive treatment is to re-initiate or supplement baclofen dosing [1]. It is worth noting that most of the evidence for the treatment described is based on limited sample sizes, and most are based on case reports. Nevertheless, the present case highlights that when there is a clinical suspicion of baclofen withdrawal accompanied by bradyarrhythmia, even in the setting of concern for potential ongoing toxicity, it can be useful to re-introduce baclofen at a low dose as a treatment for withdrawal syndrome, especially if it was associated with hypotension and low cardiac output, as noted in our case.

Conclusions

Baclofen withdrawal syndrome can present with life-threatening bradyarrhythmia and low cardiac output. Clinicians should have a high index of suspicion for withdrawal as a potential cause of bradyarrhythmia with reduced cardiac output in patients who may have been treated with baclofen. Reintroduction of low-dose baclofen to treat withdrawal is required in such patients.