Pneumomediastinum: A case report of baclofen toxicity

Abstract

Introduction

Baclofen is a γ -aminobutyric acid (GABA) agonist used to treat spasticity; however, it may be toxic at dosages above 200 mg. The psychological, nervous, cardiovascular, gastrointestinal, musculoskeletal, and respiratory systems are all affected. This report represents a case with the rare respiratory complications brought on by baclofen toxicity: atelectasis and pneumomediastinum.

Presentation of case

A 19-year-old female was admitted to the emergency department after attempting suicide by taking 20 baclofen tablets (500 mg). Imaging revealed pneumomediastinum, atelectasis, and a leftward displacement of mediastinal structures. Her therapy included a chest tube to relieve the pneumomediastinum and sodium valproate, promethazine, biperiden, and quetiapine for neurological symptoms. Four days after being admitted, she was successfully extubated without any complications.

Discussion

Baclofen activates GABA-A and GABA-B receptors. High doses of baclofen may induce central nervous system and respiratory depression, requiring intensive care. GABA receptors may cause hallucinations, delusions, and agitation in baclofen overdose. High dosages of baclofen may cause bronchial and bronchiolar muscular spasms, leading to breathing problems and atelectasis. Recent animal studies on baclofen toxicity showed that increased alveolar pressure, circulatory abnormalities, edema, alveolar hemorrhages, and infiltration cause rupture and pneumomediastinum. Pneumomediastinum may need bed rest, oxygen, antitussives, and analgesics, but severe cases may necessitate a chest tube.

Conclusion

A high index of suspicion is required for early diagnosis of acute baclofen poisoning, which could manifest as respiratory complications, including pneumomediastinum and atelectasis. Since most cases are benign, it is still crucial for clinicians to detect complications early for further management.

Highlights

• •The dosage of baclofen toxicity is not well established, though life-threatening complications are more seen above 200 mg.
• •Baclofen toxicity may result in psychiatric symptoms, including hallucinations, agitation, mania, and catatonia.
• •Clinicians should consider the possibility of atelectasis and pneumomediastinum in baclofen toxicity for proper management.

1. Introduction

Baclofen is an agonist for the inhibitory neurotransmitter γ -aminobutyric acid (GABA), used widely for relaxing spasticity. A predictable dosage of toxicity is not yet established, though over 200 mg of baclofen may cause life-threatening complications [1]. It affects many systems involving psychiatric (hallucinations, agitation, mania, catatonia), neurological (hyporeflexia, tremor, confusion, impaired memory, lethargy, somnolence, seizures, encephalopathy, coma), cardiovascular (conduction abnormalities, prolonged QTc interval, autonomic dysfunction: bradycardia, tachycardia, hypotension, hypertension), gastrointestinal (nausea, vomiting), musculoskeletal (hypotonia), and respiratory system (respiratory failure) [2]. Though research on the respiratory adverse effects of baclofen overdose is few, some animal studies have shown both acute and chronic histopathological changes in pulmonary tissues, including atelectasis, emphysema, and degenerative changes of alveoli in the context of inflammation and hypoxia [3,4]. Therefore, we report a young female with baclofen toxicity admitted to the emergency department (ED) with unique presentations of atelectasis and pneumomediastinum (PM) and further presentations of hallucination, agitation, catatonia, and mania. This case report is based on the SCARE 2020 Guidelines [5].

2. Presentation of case

A 19-year-old female was admitted to the ED with a loss of consciousness. Her parents found her unconscious in the morning, with no sign of vomiting. They claimed she had overused 20 tablets of baclofen 25 mg as a suicide attempt following the previous night's emotional stress of familial argument. They also reported that following her mother's spinal cord injury the past year, she revealed symptoms of PTSD and depression. Since then, although she has used venlafaxine 75 mg daily and clomipramine 25 mg daily, she still has symptoms. She is no smoker or tobacco user and has no further specific past medical or family history.

The patient was afebrile on arrival, with an O₂ saturation of 70 %. Her GCS was 4/15, and she had no response to the painful trigger. She was immediately intubated according to the RSI approach and transferred to ICU. On physical examination, prominent JVP, bilateral crackle, and decreased sound on the left lung were detected. Pupils were reactive and had a normal size. There was no sign of subcutaneous emphysema on the neck and anterior chest wall, trauma, or deformity.

Applying chest X-ray and CT scan, pneumomediastinum, atelectasis of left inferior lobe, and left shift of mediastinum components, including trachea, were seen (Fig. 1). ECG was normal, but the heart was invisible on echocardiography because of the wide pneumomediastinum. Because of suspicion, a brain CT scan and consequent MRI also did not disclose any abnormalities. Concerning pneumomediastinum, the surgeon inserted a chest tube through the left intercostal space in the midaxillary line, and the air was immediately released. The tube was successfully removed after the fourth day.

Fig. 1.

A: CT scan of the patient's chest showing pneumomediastinum, atelectasis of left inferior lobe, and left shift of mediastinum components. B: CT scan taken after chest tube insertion and lung re-expansion.

Regarding the infeasible cause of pneumomediastinum, counseling with respiratory and infectious services was ordered. Though the patient had no fever or typic consolidation of aspiration, she was managed conservatively with intravenous administration of prophylactic antibiotics (clindamycin and ceftriaxone). Although bronchoscopy and CT assessments excluded life-threatening causes of pneumomediastinum, multiple white-yellow plaque lesions and ulcers were found. Therefore, she has additionally been treated with fluconazole 100 mg daily.

After the patient regained consciousness on the third day, she suffered from mania, catatonia, logorrhea, visual hallucination, and agitation. Consequently, sodium valproate (220 mg TDS), promethazine (8 mg BD), biperiden (2 mg BD), and quetiapine (100 mg 1/2 at night) were administered by the psychiatrist.

Her urine toxicology result was negative for amphetamine, benzodiazepine, buprenorphine, cocaine, marijuana, methadone, methamphetamine, morphine, tramadol, and tricyclic antidepressants. Since the patient's infectious, autoimmune, and metabolic workup also showed negative CRP, ESR, and ANA, baclofen toxicity was diagnosed. Regarding her history, no further urine toxicology was requested. Finally, four days after admission, the patient was successfully extubated without complication or recurrence of pneumomediastinum in the imaging. Monthly clinical follow-up was recommended to care for her. No complications were reported after three months.

3. Discussion

There has been a rise in baclofen poisoning due to its remarkable use. The dosage at which toxicity becomes predictable is not well established. However, earlier studies reported more complications in cases of higher than 200 mg per day [2]. Baclofen is a selective agonist of GABA-B receptors, while it also might activate GABA-A receptors at high dosages [3]. Nonetheless, GABA-B receptors are likely active both pre- and post-synapse, which may account for nonspecific signs of CNS depression and even stimulation of baclofen poisoning [2,6].

Similar to the present case, the Naranjo Probability Scale found a potential association between baclofen overdose and psychiatric symptoms, including hallucinations, delusions, catatonia, agitation, and mania [2,7,8]. It is conceivable that baclofen affected the pathophysiology of psychosis by inducing the imbalance between GABA-A and GABA-B receptors and GABA interneurons and their effects, including negative inhibition of dopaminergic projections in the mesolimbic pathway [[7], [8], [9]].

High dosages of baclofen are also known to induce spasms of bronchial and bronchiolar smooth muscles by the GABA-A pathway, along with intercostal tone decrease and severe relaxation through GABA-B signaling [3]. Baclofen also blocks the inspiratory neurons of the pneumotaxic center's solitary tract nucleus, responsible for the automatic control of respiratory volume. It prevents phrenic nerve impulses from activating the diaphragm [10]. Overall, these findings support breathing difficulties and an increased risk of atelectasis in hypoxia [3].

Regarding the patient's PM, the pathophysiology entailed an increased pressure gradient between the intra- and extra-alveolar, allowing air leakage from small alveolar openings and ruptured alveoli into the perivascular adventitia, resulting in interstitial emphysema. This pressure differential causes air to split parallel vascular sheaths in the direction of the hilum. Notwithstanding, due to the continuity of the visceral layers of the deep cervical fascia with the mediastinum, air typically unpacks into the neck, thus limiting physiologic tamponade and pneumothorax [11]. However, there was no evidence of subcutaneous emphysema in the patient.

Furthermore, inhalation of cocaine, methamphetamine, marijuana, and ecstasy had all been linked to PM in previous studies [12]. However, to the best of our knowledge, this is the first case of pneumomediastinum following oral administration of baclofen. In this regard, belching or vomiting, boerhaave syndrome, tracheal, esophageal, baro-, or iatrogenic trauma with rupture could cause PM [12,13]. A positive history of respiratory problems, such as bronchial asthma or COPD, and a smoking or drinking habit are also associated with PM [12,13]. In contrast, it might be no obvious association between interalveolar pressure and intrathoracic visceral perforation, known as spontaneous pneumomediastinum (SPM) [12,13]. In the present case, no evidence was supportive of these mechanisms. Though we cannot rule out SPM, recent animal studies' findings support the hypothesis that baclofen toxicity can contribute to PM [3,4].

Toxic pulmonary alterations are previously confirmed due to both the direct idiosyncratic or toxic effects of drugs and indirect inflammatory damage induced [4]. Thus, although there is a lack of research on the impact of baclofen on the lungs, a possible hypothesis is available based on studies conducted on rats. In this regard, 3 h after administering 85 mg/kg of baclofen, circulatory disturbances were seen with venous and capillary plethora and sludge, emphysematous regions, and complete and partial atelectasis. In addition, considerable WBC infiltration of interalveolar septa and regions of interalveolar septa thickening related to edema were identified. Twenty-four hours later, the signs persist, and further alveolar hemorrhages exist [3]. In another study, rats exposed to acute toxicity levels of baclofen also had edematous lung tissue. There was a small amount of eosinophilic material in the alveoli. The capillaries in the alveolar wall seemed dilated, with a mild inflammatory response but little visible degenerative change [4].

Increased intra-alveolar pressure may cause alveoli to rupture in pulmonary edema, alveolar hemorrhage, septal thickness, and infiltration. When there is an excess of fluid or blood in the alveoli, the pressure within the alveoli rises since oxygen cannot efficiently enter the circulation through the thickened alveolar walls. When the alveolar walls rupture due to excessive pressure, the result is PM [14]. Alveolar injury and rupture may also result from infiltrating inflammatory cells, such as macrophages and neutrophils, which may release toxic substances. In summary, the increased pressure within alveoli and consequent rupture could contribute to respiratory complications of baclofen toxicity.

Managing baclofen toxicity is primarily symptomatic, supportive, considering airway, breathing, and circulation stabilization, and preventive endotracheal intubation and ventilation due to the CNS and respiratory depression [1]. Patients with PM often present with a normal appearance and hemodynamic stability and hence only need bed rest, maybe oxygen, antitussives, and analgesics. Concurrent pneumothorax and subcutaneous emphysema may necessitate the placement of a chest tube [12]. Although putting a chest tube for PM alone is uncommon, invasive therapy is unavoidable in life-threatening conditions [15]. After chest tube placement, our patient's condition improved promptly, and within a few days, she could be weaned off ventilation. All in all, emergency patients with concerns about secondary PM should be admitted for further diagnostic tests or surgery [12].

4. Conclusion

Given that alveolar rupture is the leading cause of more than 95 % of cases with PM [16] and the possible role of baclofen toxicity contributing to respiratory complications, the condition of our patient supports the hypothesized link between baclofen toxicity and alveolar rupture leading to PM. Together with more in situ and clinical trials, these results might aid in comprehending pathogenesis. Finding the missing parts of this puzzle might assist clinicians in preventing or detecting PM in baclofen poisoning more promptly.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethics approval

This case was exempt from ethical approval as informed consent was obtained directly from the patient report in accordance with the declaration of Helsinki.

Funding

None.

Author contribution

Conceptualization: BAF.

Investigation and Supervision: VRV.

Writing – original draft, and Writing – review & editing: FZM and RR.

Writing – review & editing, and Visualization: MG.

Guarantor

Dr. Babak Alavi Farzaneh.

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Conflict of interest statement

The authors declare that they have no conflict of interest.