Baclofen Withdrawal Presenting as Multiorgan System Failure

Baclofen, the p-chlorophenol derivative of gamma-amino butyric acid (GABA) is a skeletal muscle relaxant widely used in the treatment of spasticity of spinal cord origin. The intrathecal administration of baclofen is an effective form of therapy in patients who do not respond to oral therapy or who cannot tolerate its side effects. The infusion system for intrathecal delivery has a significant failure rate, and severe withdrawal can result from such failure. We report a case of baclofen withdrawal in which the initial manifestations were those of multiorgan system failure resembling a severe infectious process. Case Report A 29-yr-old male patient with spastic quadriplegia secondary to a C5-6 cervical spinal cord injury was admitted to the intensive care unit with fever and hypotension. Two years earlier, he had undergone placement of a Medtronic Synchromed[trade mark sign] (Medtronics Inc., Minneapolis, MN) infusion system for continuous intrathecal delivery of baclofen to treat refractory muscle spasms. On admission, his temperature was 42[degree sign]C, blood pressure was 100/60 mm Hg, and heart rate was 100/bpm. Other than diffuse muscle spasms, his physical examination was unremarkable. Over the next 2 h, he became agitated, incoherent, and hypotensive requiring intubation, mechanical ventilation, and vasopressors. Muscle spasms increased necessitating IV diazepam. Empiric IV antibiotics for a presumed infectious etiology were initiated, but all cultures drawn before starting antibiotics were negative. Despite continued therapy, muscle spasms and fever persisted, and creatinine kinase levels increased rapidly to 11056 U/L (normal 52-336 U/L), consistent with rhabdomyolysis. Renal failure and disseminated intravascular coagulation developed. Baclofen withdrawal due to malfunction of the catheter system was suspected. Abdominal radiographs revealed discontinuity in the catheter system (Figure 1). Surgical exploration of the catheter system revealed a break in the spinal catheter. After reinsertion of the spinal catheter and reconstruction of the catheter-pump system, a bolus dose of baclofen (100 [micro sign]g) was administered intrathecally, and the continuous infusion was resumed. Over the next 2 days, the patient's muscle spasms improved dramatically, and the fever and hemodynamic instability resolved. The rapid recovery made an infectious etiology unlikely. Recovery was complete.Figure 1: Plain radiograph demonstrating discontinuity in the catheter system (arrow).Discussion Spasms and spasticity affect 15%-60% of patients with spinal cord injury [1]. Baclofen is the drug used most often in the treatment of spinal forms of spasticity [2]. Baclofen binds to GABA-B receptors and suppresses the release of excitatory neurotransmitters. Oral baclofen is ineffective in 25%-35% of patients and causes generalized central nervous system depression, because it distributes evenly between brain and spinal cord tissues. Intrathecal baclofen is used in patients unresponsive to oral therapy or in whom intolerable side effects occur [3]. Intrathecal administration results in sufficient concentration of the drug in the spinal cord with minimal plasma drug levels and negligible dose-related adverse effects. Doses of intrathecal baclofen are nearly 100 times smaller than the maximal oral doses. Patients with spinal cord injury are prone to autonomic hyperreflexia [4]. This can worsen with infections and result in hemodynamic instability, fever, and worsening muscle spasms [5]. However, if a patient with spinal cord injury receives baclofen, baclofen withdrawal should also be included in the differential diagnosis. Abrupt withdrawal of baclofen after long-term use can cause hallucinations, confusion, agitation, seizures, autonomic dysreflexia with resultant hypotension (or hypertension), hyperthermia, and severe rebound spasticity [6-8]. These symptoms usually develop within 12-72 h and can be lifethreatening [9]. They are probably related to the release of excitatory neurotransmitters that occurs when the inhibiting influence of baclofen is abruptly removed. When the drug is restarted, symptoms resolve within 24-72 h. The intrathecal baclofen administration system consists of an infusion pump placed subcutaneously in the abdominal wall, a pump catheter, and an indwelling spinal catheter (Figure 2). The pump can be programmed to deliver either a bolus or continuous infusion of the drug. The spinal catheter is susceptible to breaks, kinks, holes, occlusion by fibrosis at the catheter tip, dislodgment from the intrathecal space, and disconnection from the pump. The failure rate of the system at a median follow-up of 31 mo is 40% [10]. Newer programmable pumps, such as the one used in our patient, have a failure rate of approximately 7%.Figure 2: Schematic representation of the intrathecal drug delivery system illustrating common sites at which problems can occur.When disruption of intrathecal baclofen delivery is suspected, catheter integrity can be assessed by using plain radiographs. Pump function can be checked using its computer program, and fluid in the pump can be aspirated and measured. Surgical exploration may be necessary to identify and correct the problem. Assay of baclofen in the lumbar cerebrospinal fluid [10] and indium-111 diethylenetriamine pentaacetic acid flow studies (radionucleotide studies designed to detect defects in the pump delivery systems) [11] are less commonly used. Treatment of withdrawal consists of rapid reinstitution of intrathecal baclofen. Benzodiazepines and oral baclofen may help to control spasms until this is accomplished. Paralysis with a neuromuscular blocking drug may be needed in patients with intractable spasms. Dantrolene has been used in the treatment of severe hyperthermia and spasticity [12]. In summary, intrathecal baclofen infusion systems can malfunction and result in baclofen withdrawal. In the spinal cord-injured patient, the clinical manifestations of severe baclofen withdrawal may cause multiorgan system failure and mimic severe infection. Early recognition and appropriate management of baclofen withdrawal can significantly reduce associated morbidity and mortality.