History of Present illness
A female in her 60s with a history of spastic quadraparesis secondary to paraneoplastic syndrome following breast cancer, currently managed by an intrathecal baclofen (ITB) pump, presents to the emergency department (ED) for concerns of baclofen pump malfunction. The patient has had changes in her speech, increased rigidity, tremors, and diaphoresis. The patient’s baclofen pump began to alarm at her skilled nursing facility early that day. The patient had a previous baclofen pump malfunction in 2013 that resulted in intubation and admission to an intensive care unit. The patient’s intrathecal baclofen pump was placed in September 2005 by a neurosurgery group at an outside hospital and is currently managed by Physical Medicine and Rehabilitation (PMR).
Past Medical History: Ductal carcinoma in situ, paraneoplastic syndrome, pulmonary embolism
Past Surgical History: Anterior cervical decompression with fusion, right breast needle core biopsy, intrathecal baclofen pump insertion
Medications: Intrathecal baclofen, fluoxetine
Allergies: No known drug allergies
Vital Signs: T 98.1°F HR 131 BP 194/114 RR 26 SpO2 98%
Physical Exam: The patient appears her stated age and is slow to respond, but oriented to person, place, and time. There are bilateral lower and right upper extremity contractures. The patient appears diaphoretic. She is tachycardic and tachypneic, but protecting her airway. Abdominal, cardiovascular, and pulmonary exams are otherwise benign. Neurologic exam is difficult to assess given the patients baseline contractures, but she is able to follow simple and two step commands, and no cranial nerve deficits are noted. There is no skin erythema overlying her baclofen pump and no alarms heard.
PMR was consulted and confirmed pump malfunction and the patient was quickly diagnosed with early baclofen withdrawal. She was given a total of 8 mg of lorazepam over 2 hours with little response. Pump replacement was recommended in addition to high dose oral baclofen in the interim for withdrawal symptoms. Neurosurgery was also consulted for operative repair or replacement of her baclofen pump. While in the ED, the patient became febrile with continued altered mental status, hypertension, tachycardia, and tachypnea. A dexmedetomidine drip was started in the ED and she was admitted to the Neuroscience Intensive Care Unit (NSICU) for further management of baclofen pump failure and baclofen withdrawal.
Throughout her hospitalization, the patient required several different medications for the management of baclofen withdrawal including dexmedetomidine, lorazepam, cyproheptadine, oral baclofen, fentanyl, and diazepam. Neurosurgery successfully replaced the patient’s intrathecal baclofen pump on hospital day two. PMR slowly up-titrated her intrathecal baclofen while weaning the multiple additional medications used to control her baclofen withdrawal. Her hospital course was complicated by sepsis secondary to a urinary tract infection which improved with antibiotics.
The patient was transferred from the NSICU to the neurology floor team on hospital day six. On hospital day nine, the patient’s vital signs had normalized, she was at her baseline mental status, and her spasticity was improving. The patient was discharged from the hospital to a skilled nursing facility with PMR follow-up. At discharge, the patient’s oral baclofen and cyproheptadine were still being down titrated.
Ten days following discharge the patient was seen by PMR at an outpatient visit and no adjustments to the baclofen pump were made at that time. The patient again presented to the ED 12 days after hospital discharge for lethargy concerning for baclofen toxicity. PMR was again consulted and her baclofen pump infusion rate was decreased. The patient was admitted to the medicine service and an extensive altered mental status work-up was completed and unremarkable. Her mental status returned to baseline following baclofen pump adjustment and she was discharged back to her nursing facility.
Baclofen is a gamma-amino butyric acid (GABA) agonist that acts at both pre-synaptic and post-synaptic GABA receptors. Pre-synaptically, baclofen prevents calcium influx. Calcium is required for neurotransmitter release on the presynaptic terminal, therefore baclofen decreases the amount of presynaptic neurotransmitter release. Post-synaptically, baclofen increases potassium efflux. A potassium ion gradient is present with high potassium levels within the neuronal stroma and low potassium levels in the extracellular fluid. This potassium gradient creates an overall negative resting membrane potential.
Baclofen opens potassium channels, resulting in increased efflux of potassium and neuronal hyperpolarization. This decreases the ability of the neuron to depolarize. Clinically, this results in inhibition of neurons. Therefore, baclofen is used in spastic conditions where imbalance of neuronal activity leads to increased excitation at the neuromuscular junction.
Baclofen has been found to be very effective in reducing spasticity when compared to other drugs. It exerts its effect by decreasing the hyperactivity of stretch reflexes, cutaneous reflexes, muscle spasms and clonus.2 Baclofen does not readily cross the blood brain barrier, so high doses of oral baclofen are often required to achieve effect. These high oral doses result in many undesired side effects including muscle weakness, nausea, somnolence, and paresthesia. These side effects are experienced in approximately 25% - 75% of patients treated with oral baclofen. The dose of baclofen can be decreased by greater than 100-fold by delivering ITB via a pump. The pump has an attached reservoir and is implanted in the abdominal wall, which is connected to a catheter extending into the anterior spinal canal and enters the intrathecal compartment. The rate and schedule of baclofen delivery is then titrated to effect.
Baclofen pumps are also associated with side effects. These are often related to a failure of delivery of baclofen to the intrathecal space, resulting in baclofen withdrawal. The rate of complications associated with ITB delivery is reported to be between 24-40%.[5,6] Complications more commonly involve catheter malfunction (catheter kink, migration, and disconnection) as opposed to an empty reservoir or failure of the pump itself. Symptoms of baclofen withdrawal will occur 24-48 hours after decreased delivery of baclofen to the intrathecal space. The presentation is often consistent with withdrawal from other central nervous system depressants such as benzodiazepines and alcohol. The patient will often present with neuropsychiatric symptoms (altered mental status, hallucinations, and confusion), increased spasticity, hypertension, tachycardia, hyperthermia, and seizures. It is important to differentiate the patient’s current spasticity from the patient’s baseline, as this patient population will have spasticity at baseline.
While baclofen withdrawal must be kept at the top of the differential for any patient with an ITB pump presenting with altered mental status and the previously described vital sign abnormalities, there are many other conditions which should be considered by emergency physicians. The differential diagnosis of baclofen withdrawal includes autonomic dysreflexia, sepsis, serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, benzodiazepine withdrawal, and alcohol withdrawal. These should be considered in every patient that presents with symptoms resembling baclofen withdrawal as this patient population is often at high risk for infection and polypharmacy. It is not unreasonable to undergo an infectious workup including blood and urine cultures while empirically treating for a presumed infection.
While the diagnosis of baclofen withdrawal is made on purely clinical grounds, the determination of a cause will further solidify the diagnosis. Imaging modalities such as an upright abdominal X-ray or CT scan are able to characterize the catheter and evaluate for discontinuity, kink, dislodgement, or other mechanical causes inhibiting the delivery of baclofen. The baclofen pump should also be interrogated to evaluate for pump malfunction and reservoir status as the patient may need a new pump or simply a baclofen refill. Baclofen pump refill varies based on institution, but can typically be completed by a PMR physician or the provider who manages the patient’s baclofen pump. Baclofen pump refill should not be attempted in the ED prior to consultation with the physician who manages the patient’s baclofen pump.
The treatment of baclofen withdrawal begins with early and aggressive resuscitative measures. Intravenous access should be obtained, the patient should be on cardiac monitoring, and airway, breathing, and circulation must be assessed and intervened on as necessary. The direct medical management of baclofen withdrawal centers on increasing GABA activity. Because these patients receive baclofen chronically, GABA receptors are down regulated resulting in hyperactive afferent nerve impulses. The goals of treatment in baclofen withdrawal are focused on prevention of central nervous system complications (seizures, altered mental status, and delirium), hyperthermia, extreme derangements in blood pressure, and spasticity. Oral baclofen alone is not adequate for baclofen withdrawal. The slow onset of oral baclofen (3-4 days) makes it ineffective in the acute care environment. However, these patients often have prolonged hospital stays and may benefit from oral baclofen later in their hospitalization, so its administration in the ED should be considered.
ITB is ultimately what these patient’s need, but is often not feasible in the ED. Previous case reports discuss ITB delivered via lumbar puncture for the management of patients experiencing baclofen withdrawal.[3,8,7] While there is minimal data, this is reportedly an effective treatment of ITB withdrawal. This procedure is technically challenging and can result in worsening complications if damage is caused to the catheter system. Therefore, only experienced physicians should deliver ITB via lumbar puncture, and this procedure should not be performed in the ED without neurosurgical consultation.
There are many alternative agents that can be utilized in the acute management of baclofen withdrawal. Benzodiazepines are the most common adjuvant therapy for baclofen withdrawal and should be administered based on withdrawal symptoms. Lorazepam, diazepam, and midazolam can be used and should be titrated until vital signs are normal, spasms have decreased, and seizures have been controlled. Propofol is another medication that has been found to be useful in baclofen withdrawal. Propofol has presynaptic activity at GABA receptors, which will improve many of the symptoms of baclofen withdrawal caused by GABA down regulation. Similar to benzodiazepines, propofol should be titrated based on the patient’s clinical symptoms. Propofol’s short half-life is advantageous for titration, but has significant respiratory and hemodynamic side effects. If using propofol of ITB withdrawal, the patient will almost always require endotracheal intubation and admission to an intensive care unit.
When considering the plan for airway management in the ED, it is important to avoid succinylcholine given the potential for rhabdomyolysis and hyperkalemia from baclofen withdrawal. The neurocritical care unit is likely the most appropriate disposition for these patients given the extensive neurological monitoring required and the possiblity of neurosurgical intervention. Continuous EEG should be strongly considered, as the neurologic exam can be unreliable in the setting of deep sedation. This can be initiated in the ED, and if there is any evidence of seizure activity aggressive treatment should be initiated. Furthermore, vital signs and reassessments should take place frequently both in the ED and the intensive care unit until the patient’s symptoms have resolved.
Additional novel treatments have been described for baclofen withdrawal that does not respond to high dose benzodiazepine therapy. There is significant symptom overlap between ITB withdrawal and serotonin syndrome and cyproheptadine can be an effective adjuvant treatment of baclofen withdrawal. Baclofen withdrawal has spasticity reminiscent of neuroleptic malignant syndrome, and the use of dantrolene has additionally been reported by a few authors as further adjuvant treatment.4 Although cyproheptadine and dantrolene should not be the initial treatment, they should be considered in baclfoen withdrawal refractory to benzodiazepines and propofol.
The patient described above was successfully managed with dexmedetomidine for severe baclofen withdrawal. While there is a wide consensus that dexmedetomidine is an effective treatment for alcohol withdrawal, there is only a single case report of successful management for baclofen withdrawal. Dexmedetomidine is a highly selective alpha-2 adrenergic agonist with a superior safety profile in comparison to benzodiazepines or propofol. Dexmedetomidine was found to be non-inferior in terms of time spent at the target sedation range with shorter times to extubation and decreased respiratory depression. This likely played a significant role in the avoidance of intubation in the patient described previously, making dexmedetomidine a promising option for the future treatment of ITB withdrawal.
While medical management of baclofen withdrawal is primarily focused on replacing intrasynaptic GABA, the hyperthermia and rhabdomyolysis often associated with ITB withdrawal must also be managed. Hyperthermia should be treated with aggressive cooling measures. The relief of spasticity and hyperthermia will stop ongoing muscle destruction and aid in the treatment of rhabdomyolysis. Intravenous fluids should be administered to maintain kidney perfusion and urine output to decrease kidney injury from rhabdomyolysis. These patients must additionally be monitored for electrolyte abnormalities associated with rhabdomyolysis, specifically hyperkalemia.
While ITB is central in the treatment of many spastic conditions, baclofen withdrawal is a dangerous complication of ITB cessation. While the differential must be broad, baclofen withdrawal must be considered in all patients with an ITB pump presenting with seizures, altered mental status, or abnormal vital signs. ITB is the ultimate treatment for baclofen withdrawal, however benzodiazepines or propofol are often effective temporizing measures. Although little evidence is currently present, dexmedetomidine was successfully used in the case presented and should be considered as a potential temporizing treatment in refractory ITB withdrawal. These medications should be aggressively titrated to effect based on improvement of the patient’s symptoms. If necessary, the patient should undergo endotracheal intubation. Lastly, hyperthermia and rhabdomyolysis are often associated with ITB withdrawal and must be simultaneously managed. Recognition and initiation of the treatment of baclofen withdrawal in the ED is critical, and these patients should be admitted to the NSICU for further management.
These medications should be aggressively titrated to effect based on improvement of the patient’s symptoms. If necessary, the patient should undergo endotracheal intubation. Lastly, hyperthermia and rhabdomyolysis are often associated with ITB withdrawal and must be simultaneously managed. Recognition and initiation of the treatment of baclofen withdrawal in the ED is critical, and these patients should be admitted to the NSICU for further management.
Authored by Adam Gottula, m.D.
Posted by Matthew Scanlon, m.D.
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