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Dantrolene Treatment for Abrupt Intrathecal Baclofen Withdrawal

1995; Lippincott Williams & Wilkins; Volume: 80; Issue: 5 Linguagem: Inglês

10.1097/00000539-199505000-00038

1526-7598

Arjang Khorasani, William T. Peruzzi,

Stroke Rehabilitation and Recovery

Intrathecal administration of baclofen produces cerebrospinal fluid (CSF) concentrations 100 times greater than those occurring with oral administration and has been used for treatment of spasticity in patients with spinal cord injury who are refractory to, or cannot tolerate, oral baclofen [1,2]. Since intrathecal administration of baclofen achieves high concentrations in the spinal cord with small doses, the incidence of central nervous system adverse effects such as sedation, drowsiness, vertigo, dizziness, weakness, fatigue, and confusion are significantly reduced [1]. Abrupt withdrawal of oral baclofen after long-term use may produce hallucinations, confusion, manicpsychotic episodes, seizures, autonomic dysreflexia, hyperthermia, and rebound severe spasticity [3,4]. Administration of oral baclofen may decrease the spasticity and the hyperthermia associated with abrupt oral baclofen withdrawal [4]. We present a case of severe hyperthermia and spasticity due to abrupt withdrawal of baclofen which was unresponsive to high-dose oral baclofen, but was responsive to dantrolene. Case Report A 36-yr-old tetraplegic male, who sustained a complete spinal cord injury at the sixth cervical level 17 mo prior to admission, was referred to our center for removal of the intrathecal catheter and baclofen infusion pump due to infection of the device. The infusion pump (Synchromed Registered Trademark; Medtronic, Inc., Minneapolis, MN) had been inserted 14 mo previously due to severe rigidity and spasticity of all extremities that was refractory to all traditional oral pharmacologic drugs. The intrathecal baclofen dose was titrated to deliver 100 micro gram/day. Vital signs on admission were: arterial blood pressure 122/78 mm Hg, heart rate 92 bpm, respiratory rate 20 breaths/min, and oral temperature 38 degrees C. The physical examination was significant for mild skin induration and erythema at the site of the baclofen pump. Empiric antibiotic therapy and oral baclofen (60 mg/day per os) were started. The infected pump was removed under local anesthesia (lidocaine 1.5%, 15 mL) and intravenous sedation (750 mg propofol and 5 mg midazolam). The postoperative course was significant for back pain and severe muscular spasm unresponsive to oral baclofen (100 mg/day). On the second postoperative day, the patient became incoherent, agitated, and combative with frequent muscular spasms (spontaneous muscular spasms > 10/min) which required supportive restraints on all extremities. He was transferred to the neurosurgical intensive care unit (NICU). Vital signs on admission (3:30 PM were: arterial blood pressure 124/80 mm Hg, heart rate 188 bpm, respiratory rate 34 breaths/min, and oral temperature 39.5 degrees C. His temperature rapidly increased to 42 degrees C, and he developed profound respiratory distress. Emergency endotracheal intubation was performed after intravenous administration of thiopental 500 mg and vecuronium 10 mg. The patient responded appropriately to neuromuscular block. Analysis of arterial blood gases revealed a mild metabolic acidosis. Laboratory values were normal except for the following: white blood cell count 9500 cells/mm3, lactic acid 2.9 mmol/L, and creatine phosphokinase 40,104 U/L (99% skeletal muscle fraction; drawn at 4:10 PM). Divided doses of dantrolene sodium 10 mg/kg were given for treatment of severe spasticity and the very remote possibility of malignant hyperthermia. The hyperthermia resolved gradually over the next few hours. A diagnostic lumbar puncture was not performed at this time because cultures were obtained at the time of surgery and the patient was being treated with appropriate antibiotics. Twenty hours after the initial presentation, he again became hyperthermic (41.4 degrees C) and the initial signs of agitation, incoherence, and combativeness returned. Similar divided doses of dantrolene were administered. Other laboratory values were unremarkable, except for positive cultures (Staphylococcus aureus) from the baclofen pump and a continued creatine phosphokinase increase (17,000 U/L; 99% skeletal muscle fraction). The trachea was extubated 3 days after NICU admission, and the dantrolene dose was tapered and discontinued 2 days later. The patient continues to receive baclofen (30 mg per os four times a day). Discussion The precise mechanism of action of baclofen as a muscle relaxant and antispasticity drug is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals or by stimulation of the gamma-aminobutyric acid-B (GABAB) receptor subtype [5,6]. Within the spinal cord, the receptors for baclofen have the greatest density in the substantia gelatinosa (lamina II) of the spinal cord of both rats and humans [7,8]. Kroin et al. [9] demonstrated that prolonged intrathecal administration of baclofen will result in a decrease in the GABAB binding density in the rat substantia gelatinosa in baclofen-treated rats as compared with saline-treated control rats. Supraspinal action of baclofen may also occur and contribute to its clinical effects or side effects [10,11] (sedation, drowsiness, respiratory depression). Although orally administered baclofen is an effective antispasmodic drug, intrathecal delivery of baclofen permits much higher CSF concentrations and limits the magnitude of the side effects [1]. GABA receptors are also present in the thalamus and hypothalamus region [12,13]. There are conflicting reports of the effect of intracerebroventricular and intraperitoneal baclofen on body thermoregulation. Although intracerebroventricular injection of baclofen 1 micro gram centered dot micro Liter-1 centered dot rat (-1) in rats produces hypothermia [14], the intraperitoneal administration of baclofen 30 mg/kg will produce hyperthermia [14,15]. Mandac et al. [4] reported hyperthermia and increased spasticity associated with abrupt oral baclofen tapering from 200 mg/day to 120 mg/day, which was treated with supportive therapy and increasing the baclofen dosage to 160 mg/day. After continuous infusion of baclofen in the lumbar region, the reported concentration of baclofen at the cervical level was 4.1 times less than that in the lumbar region [16]. This may enhance the safety of continuous intrathecal administration of baclofen and decrease the supraspinal central nervous system toxicity. The average reported CSF elimination half-life of baclofen has significant variability, ranging between 0.9 and 5 h [17] with a therapeutic effect lasting 9-16 h [17]. Abrupt cessation of baclofen therapy may produce a temporary rebound in spasticity, auditory or visual hallucinations, confusion, seizures [3], and even hyperthermia [4]. Although baclofen therapy was continued during perioperative management of our patient, the patient demonstrated signs of abrupt baclofen withdrawal. To our knowledge there are no case reports of successful dantrolene treatment of severe hyperthermia and rebound spasticity associated with abrupt intrathecal baclofen withdrawal. Although sepsis could also account for the presentation of our patient, the decision was made to treat the patient with dantrolene based upon severe spasticity, hyperthermia, increased creatine phosphokinase, mild metabolic acidosis, and the history of recent anesthesia and surgery. The reoccurrence of the initial presentation 22 h after NICU admission makes the diagnosis of sepsis very unlikely. Occurrence of hyperthermia 48 h after the anesthesia with no known triggering agents for malignant hyperthermia, and the frequent muscular spasms which required protective full restraints, made the consideration of malignant hyperthermia unlikely and favored baclofen withdrawal as the most likely diagnosis. Since dantrolene has no known GABAergic effect, the resolution of hyperthermia and the clinical picture likely are due to the disassociation of the excitation-contraction coupling effect of dantrolene and suppression of the thermogenesis effect of repeated muscle contraction and not as a result of the thermoregulatory effect of baclofen through activation or inhibition of GABA receptor [14,15].