Coffey article

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Abrupt Withdrawal From Intrathecal Baclofen: Recognition and Management of a Potentially Life-Threatening Syndrome Robert J. Coffey, MD, Terence S. Edgar, MD, Gerard E. Francisco, MD, Virginia Graziani, MD, Jay M. Meythaler, MD, JD, Patrick M. Ridgely, MD, Saud A. Sadiq, MD, Michael S. Turner, MD ABSTRACT. Coffey RJ, Edgar TS, Francisco GE, Graziani V, Meythaler JM, Ridgely PM, Sadiq SA, Turner MS. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome. 2002;83: 735-41.

Objective: To suggest guidelines for the prevention, recognition, and management of a life-threatening syndrome (high fever, altered mental status, profound muscular rigidity that sometimes progressed to fatal rhabdomyolysis) in patients who experience the abrupt withdrawal of intrathecal baclofen (ITB) therapy.

Design: Retrospective literature and safety-file review.

Setting: Expert panel drawn from physiatry, neurology, and neurosurgery.

Participants: Experienced users of ITB therapy in the pediatric and adult populations in the United States.

Interventions: Not applicable.

Main Outcome Measures: We reviewed literature reports, MedWatch reports to the US Food and Drug Administration, and our own experiences. We critically analyzed patient management and drug therapy in the context of the pharmacology of baclofen and other antispastic agents.

Results: An abrupt reduction in ␥-aminobutyric acidB (GABA) agonist activity in the central nervous system can cause the ITB withdrawal syndrome, which is clinically and pathophysiologically distinct from autonomic dysreflexia, malignant hyperthermia, and neuroleptic-malignant syndrome.

ITB withdrawal evolves over 1 to 3 days, but may become fulminant if not recognized and treated early. The syndrome can be interrupted by the restoration of ITB therapy. However, supportive measures and high-dose benzodiazepine infusion may be life saving in the interval before ITB therapy is resumed. Dantrolene infusion may relieve muscle rigidity but does not reverse the other manifestations of GABAergic agonist withdrawal.

Conclusions: Most episodes of severe ITB withdrawal were preventable. Patients at risk can be identified and educated prospectively and given medication for emergency use. Treat-

From Medtronic Inc, Minneapolis, MN (Coffey, Ridgely); Departments of Neurology and Pediatrics, Arkansas Children’s Hospital, Little Rock, AR (Edgar); Department of Physical Medicine and Rehabilitation, University of Texas Health Sciences Center, Houston, TX (Francisco); Department of Rehabilitation Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (Graziani); Department of Physical Medicine and Rehabilitation, University of Alabama, Birmingham, AL (Meythaler); Department of Neurology, St. Luke’s–Roosevelt Hospital Center, New York, NY (Sadiq); and Pediatric Neurosurgery, Indianapolis Neurosurgical Group, Indianapolis, IN (Turner).

Accepted in revised form June 7, 2001.

Support for a panel meeting leading to this article provided by Medtronic Inc. A commercial party with a direct financial interest in the results of the research supporting this article has conferred or will confer a financial benefit upon the author or one or more of the authors.

Reprint requests to Patrick M. Ridgely, MD, Medtronic Inc, 710 Medtronic Pkwy NE, Minneapolis, MN 55432-5604, e-mail: pat.ridgely@medtronic.com.

0003-9993/02/8306-6808$35.00/0 doi:10.1053/apmr.2002.32820

ment with GABAergic agonist drugs may prevent potentially fatal sequelae.

Key Words: Baclofen; GABA; Infusion pumps, implantable; Rehabilitation; Spasticity; Spinal cord injuries. © 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation NTRATHECAL BACLOFEN (ITB) delivered by a proimplantable drug infusion system is commonly Iusedgrammable, to relieve medically intractable spasticity of spinal or cerebral origin.1-7 The effective dosage of ITB varies with the underlying condition, duration of therapy, and individual responses to the drug. Spasticity associated with spinal cord injury (SCI), multiple sclerosis, cerebral palsy, traumatic brain injury, stroke, dystonia, and stiff-man syndrome has been treated by using ITB.1-7 The drug and delivery system currently are approved in the United States for use in adults and children.

Mechanical drug delivery systems provide certain therapeutic advantages, but human errors or device malfunctions can occur. Either can cause drug over- or underdosage or the sudden cessation of drug administration. Overdosage of ITB can cause rostral progression of hypotonia; respiratory depression; coma; and, occasionally, seizures.8 Symptoms of ITB withdrawal most often are limited to return of the patient’s baseline spasticity and rigidity.5 However, abrupt withdrawal may cause generalized seizures, hallucinations, and symptoms that have been described as simulating autonomic dysreflexia, malignant hyperthermia (MH), or neuroleptic-malignant syndrome (NMS).9-20 In a minority of patients, the sudden withdrawal of ITB caused a life-threatening syndrome characterized by exaggerated rebound spasticity, muscle rigidity, fever, labile blood pressure or hypotension, and diminished level of consciousness. If not treated promptly and adequately, the syndrome progressed over 24 to 72 hours to include rhabdomyolysis with markedly elevated plasma creatine kinase (CK) levels, elevated transaminase levels, hepatic and renal failure, disseminated intravascular coagulation, and sometimes death.21,22 We reviewed previous publications, MedWatch reports to the US Food and Drug Administration (FDA), our own experiences (by retrospective chart review), and the results of the treatment strategies that were employed in all cases. We suggest an approach to the evaluation, recognition, and treatment of ITB withdrawal that is based on the pharmacology of baclofen and other antispastic agents. Because adverse event reporting to the FDA, to drug and device manufacturers, and in the medical literature is voluntary, the number of patients who have experienced ITB withdrawal of any severity is unknown.

Consequently, our methods most likely underestimated the total number of cases of severe ITB withdrawal that have occurred to date.

PHARMACOLOGY OF ITB Baclofen is an analog of the inhibitory amino-acid neurotransmitter, ␥-aminobutyric acid (GABA).23-26 GABA mediArch Phys Med Rehabil Vol 83, June 2002

736

INTRATHECAL BACLOFEN WITHDRAWAL, Coffey Table 1: Differential Diagnosis of ITB Withdrawal ITB Withdrawal

Mechanism

Abrupt decrease in CNS GABAB transmission

Clinical setting and timing

One to 3 day evolution of the life-threatening syndrome after abrupt cessation of ITB

Heart rate

Tachycardia

Blood pressure

Hypotension or labile blood pressure Body temperature Elevated

Mental status

Muscle activity

Other clinical features

Autonomic Dysreflexia

MH

Ryanodine receptor Disconnection of major mutation causing splanchnic sympathetic leakage of calcium outflow from supraspinal from sarcoplasmic control reticulum Acute onset during or Ongoing nociceptive after anesthesia, stimulus below the level especially halothane; of the spinal cord lesion patient may have prior (ie, urinary obstruction) or family history; in a T6 level or higher muscle biopsy SCI patient establishes diagnosis Bradycardia, sometimes Tachycardia followed by tachycardia Hypertension Hypertension Elevated

Normal, but skin temperature may be elevated Decreased level of consciousness

NMS

Acute loss of hypothalamic dopaminergic transmission

Hours after initiation of dopamine-blocking neuroleptic drugs, or abrupt cessation of dopamine agonist administration Tachycardia Hypertension Elevated, sometimes followed by hypothermia

Decreased level of Normal level of Dysphoria or malaise that consciousness consciousness with evolves to decreased level of dysphoria or consciousness apprehension Tremor, worsening to Generalized, sustained, Rebound spasticity and rigidity Spasticity and rigidity profound, generalized rigorous (tetanic) below the level of the greater than patient’s rigidity muscle contractions spinal cord lesion baseline Labile or hyperactive Piloerection and skin pallor CK elevation at onset; Prodromal itching or autonomic function, centrally acting muscle below level of injury; paresthesias, priapism in leukocytosis at onset relaxants are flushing, vasodilation, men; seizures may occur ineffective and profuse sweating during advanced syndrome above level of injury

ates feedback and feed-forward neuronal inhibition in widespread areas of the cerebral cortex, basal ganglia, thalamus, cerebellum, and spinal cord. GABAergic modulation of those circuits is essential for the maintenance of normal thalamocortical rhythms, discriminative sensory processing, fine motor control, and prevention of burst-mode (epileptogenic) neuronal discharges.23 Although overdosage or withdrawal of either intrathecal or oral baclofen can cause cerebral symptoms and signs, the mechanism by which ITB reaches and/or penetrates the brain remains unknown.27 Baclofen relieves spasticity and rigidity in people and experimental animals with cerebral injuries and complete or incomplete spinal cord transection by activating presynaptic GABAB receptors of Ia muscle spindle afferents.23-26 Activation of the G-protein–linked GABAB receptor causes slow synaptic inhibition by increasing the neuronal membrane’s potassium ion conductance and by diminishing calcium influx into the presynaptic terminal. This causes slow neuronal hyperpolarization and reduces the output of excitatory neurotransmitters, thereby reducing the number and amplitude of excitatory postsynaptic potentials along the dendrites of ␣motoneurons. Investigators hypothesize that the antispastic effects of baclofen may be potentiated by a separate mechanism that involves the inhibition of excitatory neurotransmitter release (possibly substance P) from nociceptive skin afferents— the activation of which elicits exaggerated flexor-withdrawal reflexes after SCI.23 Abrupt ITB withdrawal simulates other conditions associated with severe spasticity and central nervous system (CNS) hyperexcitability in part because chronic ITB Arch Phys Med Rehabil Vol 83, June 2002

infusion downregulates GABAB-receptor sensitivity.28 Thus, sudden withdrawal of baclofen may be associated with rebound excitation at all levels of the neuraxis that may not be overcome by the administration of small dosages of oral or ITB or other GABA agonists.29 DIFFERENTIAL DIAGNOSIS OF ITB WITHDRAWAL Because the underlying pathophysiology and treatments differ, ITB withdrawal should be differentiated from autonomic dysreflexia, MH, and NMS. Clinical features that distinguish these disorders are summarized in table 1. Autonomic dysreflexia is recognized by its occurrence in patients with SCI above the level of the major splanchnic outflow (T6 level or higher), the coexistence of paradoxical bradycardia with hypertension, the absence of fever, the lack of exaggerated rebound spasticity, and a normal level of consciousness.30 Signs of cutaneous vasoconstriction often are present below the level of injury, whereas vasodilation and perspiration appear above the level of injury. The patient population that is susceptible to autonomic dysreflexia overlaps with the population that may experience ITB withdrawal. The cessation of oral or ITB in such individuals causes a return of spasticity that can provoke an episode of autonomic dysreflexia.16 Loss of the hypothesized substance P–mediated antinociceptive effect of baclofen could exacerbate autonomic dysreflexia even further. However, the patient’s vital signs, mental status, and the degree of spasticity differentiate such an episode from severe ITB withdrawal.

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INTRATHECAL BACLOFEN WITHDRAWAL, Coffey Table 2: Previously Reported Cases of ITB Withdrawal

References

Diagnosis/Duration of ITB Therapy

Time From ITB Cessation to Onset of Withdrawal Symptoms

Cause for ITB Cessation/ITB Dose

Siegfried et al36

C4 SCI; 20mo

Empty pump reservoir; 840␮g/d

11⁄2d (36h)

Meinck et al22

Stiff-man syndrome; 2y

Two episodes: programming error (pump stopped) & refill with wrong drug concentration; 1440␮g/d

1d (both episodes)

Khorasani & Peruzzi33

C6 SCI; 17mo

2d

Grenier et al32 (case 1)

Brain injury; 1st refill

Postremoval of infected system; 100␮g/d Empty pump reservoir; 60␮g/d

Not reported

Grenier et al32 (case 2)

Brain injury; 1st refill

Empty pump reservoir; 50␮g/d

Not reported

Sampathkumar et al35; Reeves et al34

C5–6 SCI; 2.5y

Catheter break at proximal-distal connector; 300␮g/d

Al-Khodairy et al31

T8 SCI; episodic: 6mo–6.5y

Green & Nelson21 Samson-Fang & Gooch29

C1–2 SCI; 4y Cerebral palsy; 9mo

Four episodes: catheter leaks (2), catheter displacement, & end of battery life; 130–384␮g/d End of battery life; 390␮g/d Proximal-distal catheter disconnection; 350␮g/d

Ng et al17

C5 SCI; duration of therapy not reported

2d

Not reported

2d Not reported

Empty or low reservoir; ITB dosage not reported

1d

Medical and Surgical Treatment

Outcome

Oral baclofen 30mg, then 10mg qid. Empty pump refilled.

Stopped pump restarted (first episode). Pump refilled with correct concentration of baclofen, and 100␮g bolused through pump (second episode).

Neuromuscular block, dantrolene 10mg/kg IV repeated doses Dantrolene 2.5mg/kg IV, empty pump refilled with baclofen, and 30␮g bolused through pump.

Empty pump refilled with baclofen, and 30␮g bolused through pump Diazepam 5-mg IV repeated doses, then 15mg qid; enteral dantrolene 12.5mg bid, diprivan, midazolam, enteral baclofen, dosages not stated. Catheter repaired.

Oral baclofen, diazepam, tizanidine, dosages not stated. Catheter repaired (3x), pump replaced.

Baclofen by LP, 100␮g single dose.

Enteral baclofen 10mg tid, baclofen

by LP, 50-␮g single dose.

Seizures treated with enteral valproate, IV lorazepam, phosphenytoin, phenobarbitol, dosages not stated. Catheter repaired.

Oral antispasmodic agents and benzodiazepines, not otherwise specified. Pump refilled.

Recovery Death

Recovery Recovery

Recovery Recovery

Recovery

Death Recovery

Recovery

Abbreviations: IV, intravenous; LP, lumbar puncture; qid, 4 times daily; bid, twice daily; tid, 3 times daily.

MH is a familial disorder caused by a mutation in the gene for the ryanodine receptor, the calcium-release channel of the sarcoplasmic reticulum.23 Certain anesthetics, especially halothane, cause calcium leakage from the sarcoplasmic reticulum in affected individuals. This results in sustained, rigorous muscle contraction accompanied by high fever. If not treated promptly with dantrolene, MH can progress to rhabdomyolysis, multiple– organ system failure, and death. The intra- or immediate postoperative setting, laboratory evidence of disordered calcium metabolism, and the occurrence of previous episodes in the patient or family members strongly suggest MH. A muscle biopsy after recovery or in a previously affected family member can establish the diagnosis.

NMS consists of high fever, muscular rigidity, and potentially life-threatening autonomic hyperactivity caused by the administration of dopamine-receptor blocking neuroleptic drugs or by the sudden withdrawal of dopaminergic agonist drugs.23 The condition may occur after the administration of a single neuroleptic medication dose. NMS also has occurred after the ingestion of other medicinal or recreational drugs that influence monoaminergic or glutaminergic neurotransmission.

Treatment consists of administering a dopaminergic agonist (bromocriptine, amantadine, levodopa) in combination with intravenous dantrolene.

Although some features of the advanced ITB withdrawal syndrome resemble MH or NMS, several conditions associated with widespread rhabdomyolysis and multiple– organ system failure appear similar in their final stages. For example, sepsis, status epilepticus, exercise-induced hyperthermia, traumatic crush injury, and toxic, metabolic, or immune-mediated disor-

ders also can produce a clinical picture that includes coma, elevated CK and hepatic enzymes, hepatic and renal failure, disseminated intravascular coagulation, and death. Thus, accurate diagnosis is important before initiating treatment.

RESULTS Summary of Cases Ten previously reported cases17,21,22,29,31-36 are summarized in table 2, and 6 new cases are summarized in table 3. Among the 16 cases, underlying diagnoses included spasticity of spinal origin (n⫽11), spasticity of cerebral origin (n⫽4), and stiffman syndrome (n⫽1). Nine of the patients with spasticity of spinal origin had functional cervical cord injury levels and 2 had thoracic levels.

The duration of ITB exposure before reported episodes of withdrawal varied from 6 weeks to 6.5 years (mean, 27mo). All but 2 cases associated with initial pump refills occurred after 7 months of therapy.32 The mean baclofen dosage at the time of withdrawal was 529␮g/d (range, 50 –1140␮g/d in 13 cases in which dosages were known). Eight patients were receiving ITB at a dosage ⱖ300␮g/d; 3 patients were receiving ⱕ100␮g/d.

Severe withdrawal symptoms began within 1 or 2 days after cessation of ITB in the 12 cases in which data about symptom onset were reported.

Therapy was restored after reprogramming or refilling an empty, erroneously filled, or inactive pump during 7 withdrawal episodes in 6 patients, including case 1 of the present report.17,22,32,36 External manipulation of an inverted pump that kinked the proximal catheter segment restored drug delivery in Arch Phys Med Rehabil Vol 83, June 2002

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INTRATHECAL BACLOFEN WITHDRAWAL, Coffey Table 3: Previously Unreported Cases of Severe ITB Withdrawal

Case No.

Diagnosis Duration of ITB Therapy

Cause for ITB cessation; ITB dose

Time from ITB Cessation to Onset of Withdrawal Symptoms

Medical and Surgical Treatment

Outcome

Cerebral palsy, dystonia; 7mo Quadriparesis, multiple sclerosis; 10mo Idiopathic C5–T10 syrinx; 6y

Empty pump reservoir; 109␮g/d

1d

Oral baclofen 20mg every 8h⫻3d. Pump refilled.

Recovery

Pump inversion and catheter kink; 1092␮g/d

2d

Recovery

End of battery life; ITB dosage not reported Catheter disconnection; 1200␮g/d

1d

5

Thoracic SCI; 59mo Cervical SCI; 4y

6

C5 SCI; 7mo

Suspected refill-programming error; ITB dosage not reported

2d

Oral baclofen and valium, dosages unknown; IV midazolam, propofol; 50-␮g and 200-␮g ITB boluses via pump. Pump repositioned by external manipulation.

Enteral diazepam 10mg, bromocriptine 2.5mg every 6h, baclofen 20mg every 6h; ITB boluses 100␮g every 6h through pump; IV propofol, diazepam 2mg every 6h, lorazepam 2mg every 6h, midazolam 2mg every 6h, dantrolene 20mg every 6h⫻4 doses, then 200mg every 6h. Seizure prophylaxis: enteral gabapentin 400mg bid. Syringopleural shunt ligated.

None, except antibiotics (symptoms misdiagnosed as infectious).

Oral baclofen and valium, dosages unknown; 100-␮g ITB bolus via pump was not received by patient because catheter was disconnected.

None, except attempted cardioversion and emergency life-support measures; symptoms misdiagnosed as autonomic dysreflexia.

1 2

3

4

Withdrawal after syringopleural shunt surgery; 967␮g/d

Biphasic: 1d and 6d after spinal surgery

case 2 of the present report. Three patients required repairs of broken, dislodged, or disconnected catheters.29,31,34-36 One patient had his system removed because of infection.33 ITB withdrawal was fatal in 6 patients, including 4 new cases in the present report. One patient with stiff-man syndrome died during her second episode of withdrawal.22 The fatal event was caused by a drug concentration error. Two patients died before their pumps could be replaced. In both cases, the caregivers were told days or months in advance that the pumps and batteries needed replacing.21 In 1 case (case 4), withdrawal symptoms, misdiagnosed as an infection, led to a fatal delay in surgery. One patient died during emergency surgery to repair a catheter disconnection (case 5). Another fatality occurred after surgery to implant a syringoperitoneal shunt into a progressing, idiopathic cervicothoracic syrinx in a patient with a functioning drug delivery system (case 3). The last fatality (case 6) occurred 2 days after a pump refill, without having ITB withdrawal diagnosed or treated.

Previous Drug Therapy for ITB Withdrawal Thirteen patients received baclofen by 1 or more routes of administration as treatment for ITB withdrawal (enteral, n⫽8; via pump, n⫽8; lumbar puncture, n⫽2). An intended pump bolus was not actually administered in case 5 because the catheter disconnected. Benzodiazepines were administered to 7 patients (enteral, n⫽3; intravenous, n⫽2; enteral and intravenous, n⫽2), and dantrolene was administered to 4 patients (enteral, n⫽1; intravenous, n⫽3). Two patients, including case 3 of the present report, received enough dantrolene to produce an observable antispasmodic effect.33 Four patients received other medications that included neuromuscular blocking agents, dopamine agonists, and/or antiepileptic drugs. The patient who underwent removal of his system because of an infection did not receive oral baclofen or have his ITB dosage tapered preoperatively.33 DISCUSSION Restoration of ITB Therapy The definitive treatment for ITB withdrawal is the restoration of drug administration by the same route at or near the Arch Phys Med Rehabil Vol 83, June 2002

1d

Death

Death Death

Death

same dosage as before therapy was interrupted. Table 4 contains an algorithm for device troubleshooting and interim drug management in patients who experience severe or progressive symptoms of ITB withdrawal. Because of GABAB-receptor downregulation, oral or enteral baclofen, even in amounts at or near the maximum tolerated dosage (ⱖ120mg/d in 6 – 8 divided doses, in adults), may not halt progression of the developing withdrawal syndrome.29 When a patient in whom baclofen withdrawal is suspected presents to a facility that is not familiar with him/her, or ITB therapy, the physician responsible for the patient’s maintenance therapy or the drug distributor should be contacted immediately. If practical, transportation to the center that usually cares for the patient is advisable.

A physician experienced in the management of ITB therapy using a programmable infusion system should perform device troubleshooting or intrathecal drug administration maneuvers.

Interrogation of the pump status, refilling the pump with drug at the proper concentration, or taking biplane x-ray films of the pump and catheter would have identified or corrected the cause for 14 of the 16 reported cases of ITB withdrawal to date.

Troubleshooting potential device-related causes for the cessation of ITB therapy was discussed by Al-Khodairy et al.31 Depending on the findings, a surgeon should repair, revise, or replace any broken or malfunctioning system components promptly. Only an experienced physician should attempt to administer baclofen by a programmed pump bolus or by direct injection during a lumbar puncture. Nonapproved methods to administer ITB temporarily include using an external drug source and a needle into the catheter access port, or implanting an externalized intrathecal catheter.

Therapy With Other Drugs Restoration of ITB therapy sometimes was delayed after the diagnosis of withdrawal was established. The patients were so ill that high-dose oral or enteral baclofen was impractical to administer and unlikely to have been absorbed or to have been of benefit. In such cases, parenteral benzodiazepine infusion was the most rational treatment for the loss of central GABAergic neurotransmission.

Intravenous diazepam or midazolam should be administered by continuous or intermittent infusion in a setting in which

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INTRATHECAL BACLOFEN WITHDRAWAL, Coffey Table 4: Guidelines for the Management of ITB Withdrawal Emergency Treatment

Life-support measures: airway, ventilatory, and circulatory support, as needed.

Administer high-dose oral or enteral baclofen early in the clinical course, if the patient’s condition permits (ⱖ120mg/d in 6–8 divided doses for adults).*

A physician experienced with ITB therapy should restore drug infusion at or near the prewithdrawal dosage via the pump, if possible. Only an experienced physician should administer ITB via a programmed bolus, through the catheter access port, by lumbar puncture, or through an externalized intrathecal catheter.

Administer intravenous benzodiazepines by continuous or intermittent infusion until ITB therapy is restored.

Titrate dosage until the desired therapeutic effect is achieved.

Device Trouble-Shooting

Contact the physician who manages the patient’s ITB therapy, or the nearest available physician who is experienced in ITB management.

Interrogate the pump status using the manufacturer’s programming device, and perform biplane x-ray films of the pump and catheter system. Identify any mechanical disruption of the drug administration system (catheter leak, break, kink, dislodgement, other).

Depending on the results, an experienced physician should empty the pump reservoir, refill it with baclofen solution at the appropriate concentration, and perform system trouble-shooting procedures expeditiously to determine the cause of ITB therapy interruption.

Surgically repair, revise, or replace any broken or malfunctioning system components promptly.

* Oral baclofen should not be relied on as the sole treatment for ITB withdrawal, and safety in patients younger than 12 years of age has not been established. All patients should be monitored for such potential side effects as sedation, general central nervous system depression, and hypotension. The manufacturer’s recommended maximum daily oral dose for management of spasticity is 80mg.

airway, ventilatory, and cardiovascular support are available.

The dosage may be titrated upward rapidly, similar to the treatment of status epilepticus, until the desired therapeutic effects are achieved: muscle relaxation, normothermia, stabilization of blood pressure, and cessation of seizures (if present).

Benzodiazepines should be continued until ITB therapy is restored.

The rationale for benzodiazepine administration is to activate central receptors that relieve muscle spasms and rigidity and that also restore widespread neuronal inhibition when pharmacologic access to the baclofen-sensitive GABAB receptor is not possible. Benzodiazepine activation of GABAAreceptor chloride-channel complexes in the spinal cord relieves spasticity and rigidity by different pre- and postsynaptic mechanisms than baclofen.23-26 Thus, ITB-induced GABAB-receptor downregulation should have no adverse effect on the antispastic efficacy of benzodiazepines. Additional GABAA benzodiazepine effects on the brain include restriction of glutaminergic cortical excitation (sedative and antiepileptic effects), inhibition of N-methyl-D-asparate receptor–mediated burst neuronal discharges (antiepileptic effect), enhancement of striatal, pallidal, and cerebellar inhibitory motor circuits (motor control effect), and cyclic inhibitory influences on thalamocortical relay circuits (cortical-afferent modulation effect).23,24 Because of apparent similarities between the advanced ITB withdrawal syndrome and MH or NMS and because dantrolene directly reduces depolarization-induced calcium release from the sarcoplasmic reticulum (excitation-contraction uncoupling), dantrolene was administered to 4 patients, 3 who survived, and 1 who died (table 3, case 3).32-35 Khorasani and Peruzzi33 noted that even though divided doses of dantrolene (10mg/kg) apparently relieved spasticity in a patient with cervical SCI, MH was an unlikely diagnosis, and dantrolene was unlikely to have had any central GABAergic effects. They suggested that the patient’s fever resolved because repetitive and possibly thermogenic muscle contractions had ceased.

However, in table 3, case 3, administration of dantrolene reduced the patient’s temperature by only 0.7°C. Now that more cases have been reported and the mechanisms underlying the

manifestations of ITB withdrawal are better defined, treatment with benzodiazepines appears to be the most logical, effective, and safe method to restore central GABAergic inhibition.

Patient Population At Risk Prevention of fatal or life-threatening sequelae from abrupt ITB withdrawal requires attention to patients at risk; education of patients, caregivers, and physicians; prompt diagnosis of the syndrome as a distinct pathophysiologic entity; and urgent treatment to restore central GABAergic inhibition during the investigation and correction of the cause for interruption of therapy. Any patient with an ITB infusion system is theoretically at risk for drug withdrawal. However, most patients whose baclofen is stopped abruptly experience only a return of their baseline spastic condition until the cause for cessation of drug delivery is corrected.5 Such patients respond to oral baclofen in the interval before ITB therapy is restored. Despite limitations imposed by the voluntary nature of adverse event reporting, data reported to Medtronic and FDA suggest that only a small proportion of ITB patients who experience cessation of drug administration (from catheter, pump, or procedural causes) undergo the most severe form of ITB withdrawal. Nine of the 16 patients listed in tables 2 and 3 had functional cervical spinal cord levels. One patient (table 3, case 4) had an unspecified thoracic level injury. Thus, one might speculate that patients with a T6 or higher SCI, the same population that is at risk for episodic autonomic dysreflexia, may be vulnerable to the more severe manifestations of ITB withdrawal.16 Knowledge of the proportion of patients implanted for different indications and detailed information about a larger number of cases of ITB withdrawal would be required to confirm or refute that hypothesis. Ironically, withdrawal that causes only a return of pretreatment spasticity may be recognized and treated more expeditiously than the severe, life-threatening syndrome discussed here. Patients treated for dystonia or spasticity of cerebral origin may be at risk for experiencing withdrawal that goes unrecognized. Potential causes for diagnostic errors include the mistaken diagnosis of epileptic or posttraumatic seizures; compromised communication abilities in a subset of cerebral-origin Arch Phys Med Rehabil Vol 83, June 2002

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INTRATHECAL BACLOFEN WITHDRAWAL, Coffey

spasticity patients; or, in other cases, caregivers who are unfamiliar with the patient.29 ITB withdrawal was fatal in a patient with stiff-man syndrome after the second of 2 episodes.22 As suggested, the presence of antibodies to glutamic acid decarboxylase may place stiff-man patients at high risk for severe consequences of abrupt ITB cessation. Their GABAB receptors are downregulated because of chronic baclofen administration and antibodies to glutamic acid decarboxylase reduce the amount of endogenous GABA available for baseline functioning of central inhibitory pathways. The rapid and sustained administration of benzodiazepines, along with airway and ventilatory support, may be necessary to prevent a fatal outcome in stiff-man patients if ITB treatment cannot be restored promptly.

Removal of an ITB administration system for infection or other reasons usually involves hospitalization beforehand.

Even brief hospitalization would permit the rapid preoperative taper of ITB, whereas divided doses of oral baclofen are substituted incrementally in an inpatient setting. Our anecdotal experience suggests that patients tolerate ITB-dosage reductions as large as 20%/d during escalation of the oral or enteral baclofen dosage. Benzodiazepines may be held in reserve in case frank withdrawal symptoms appear. That regimen might have blunted ITB withdrawal symptoms if administered to the patient reported by Khorasani and Peruzzi.33 Intensive care facilities should be available for the institution of intravenous benzodiazepine infusion if the withdrawal syndrome progresses to a life-threatening level.

Patient, Caregiver, and Physician Education Prevention and early recognition of ITB withdrawal are shared responsibilities. Education of patients, family members, institutional caregivers, emergency and critical care physicians, and physicians who implant or maintain intrathecal drug delivery systems will increase awareness of ITB withdrawal within the community. Ideally, the syndrome can be recognized and treated before the life-threatening cascade of advanced manifestations appears. The highest risk patients and their caregivers should be the best educated ones. Fragile patients with spinal-origin spasticity and the subset of patients with cerebral-origin spasticity who also have compromised communication abilities may have 1 or more of the following issued to a caregiver for emergency use: a supply of oral baclofen, diazepam rectal gel (Diastat®), and/or a 2-mL vial of the 5-mg/mL intravenous formulation of diazepam with a disposable plastic syringe for rectal administration. Because an experienced physician familiar with the patient manages unanticipated adverse events best, bracelets or medallions that identify the individual as an ITB patient may be considered. The 24-hour telephone numbers of the drug distributor and (if available) a physician responsible for managing the patient’s ITB therapy can be engraved on the medallion.

Physicians should pay close attention to drug vial concentration and labeling, device labeling and therapy guidelines, pump alarms, and programmer messages. Pump refills should be scheduled at intervals that include an adequate time cushion to avoid reservoir depletion.17,21,22,32,36 Complications caused by such events should be preventable.

Restoration of Central GABAergic Modulation Published reports and reviews22,29,31-36 have emphasized the dramatic effects of restoring ITB therapy in patients who experience abrupt withdrawal. However, few have critically examined the rationale for the selection of drugs or dosages that were administered to patients during the interval between the diagnosis of baclofen withdrawal and the resumption of Arch Phys Med Rehabil Vol 83, June 2002

ITB treatment. When patients were treated early in the withdrawal cascade, oral baclofen at maximal tolerated dosages (ⱖ120mg/d in divided doses for adults) sometimes was sufficient to prevent progression to the more severe syndrome.

When the clinical situation made oral baclofen impractical or ineffective, high-dose intravenous benzodiazepine infusion, titrated to effect in an intensive care setting, was the most rational pharmacologic approach to restore GABAergic inhibitory tone in the brain and spinal cord.

Surgical repair or replacement of drug delivery system components sometimes may be necessary in patients with impending multiple– organ system failure. Because such surgery does not require deep levels of anesthesia, intraoperative management can include GABA agonist agents such as midazolam, similar to what was administered in the preoperative intensive care setting. In the unlikely event that a patient is too ill to leave the intensive care unit, an experienced physician may consider bedside placement of a temporary externalized intrathecal catheter (although use of such devices is not FDAapproved) for baclofen administration using an external infusion pump until the patient stabilizes sufficiently to be transported to the operating room for definitive surgical repair.

CONCLUSION ITB withdrawal is a potentially life-threatening syndrome that appears to be reversible if sufficient dosages of GABAmimetic drugs are administered in time. If ITB therapy cannot be restored promptly, and if enteral baclofen is not practical or effective, benzodiazepine infusion may be life-saving. Most reported episodes of ITB withdrawal were caused by preventable human errors or oversights. Close attention to pump refill and programming procedures may reduce the incidence of withdrawal. The identification of high-risk patients, the education of caregivers and emergency medical personnel, and the availability of physicians experienced in the management of ITB therapy should facilitate proper treatment, thereby increasing the likelihood of patient survival if severe ITB withdrawal occurs.

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Arch Phys Med Rehabil Vol 83, June 2002