Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

INTRATHECAL OVERDOSE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This document discusses adverse events and therapy for inadvertent intrathecal administration of drugs not intended for this use, and inadvertent intrathecal overdose of drugs intended to be administered intrathecally.

Specific Substances

    1) Intrathecal overdose
    2) Intraventricular overdose
    3) Accidental intrathecal administration
    4) Accidental intrathecal injection
    5) Accidental intraventricular administration
    6) Accidental intraventricular injection
    7) Unintentional intrathecal administration
    8) Unintentional intrathecal injection
    9) Unintentional intraventricular injection
    10) Unintentional intraventricular administration

Available Forms Sources

    A) USES
    1) Medications may be administered intrathecally to treat pain (eg, opioids), muscle spasm (eg, baclofen), provide neuromuscular blockade for surgical procedures (eg, local anesthetics), treat malignancy (eg, methotrexate), provide contrast for radiologic studies (eg, ionexol), and less often to treat CNS infection (eg, tetanus immune globulin, amphotericin). Intraventricular administration is occasionally used to treat meningeal malignancy.
    2) Unintentional intrathecal administration of medications or overdose has resulted from confusion between similar looking preparations, inappropriate labeling, inappropriate dilution of a drug intended for intrathecal administration, and failing to adequately check orders, and instillation into the wrong catheter (Meel, 1998; Fernandez et al, 1998).
    3) Overdose has also arisen from malfunctions of intrathecal pumps, malposition of intrathecal catheters, or inadvertent intrathecal administration during an attempt to refill an intrathecal pump reservoir (Kofler et al, 1992; Saltuari et al, 1992; Yeh et al, 2004).
    a) MALFUNCTION OF INTRATHECAL PUMP: In one case report, intrathecal pump malfunction resulted in an overinfusion of fentanyl intrathecally (Maino et al, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) SUMMARY - Xenobiotics can cause severe toxicity when administered intrathecally. In general, substances that are known to be neurotoxic when administered by other routes (intravenous or oral), and substances that are known to be caustic or tissue irritants (eg, when extravasated) should be assumed to be severely neurotoxic if unintentionally administered intrathecally. In addition, consideration should be given to excipients, such as propylene glycol, that may cause or contribute to toxicity. The following describes known effects for specific drugs and chemicals that have been unintentionally administered intrathecally or administered in overdose.
    2) ANTHRACYCLINES
    a) DAUNORUBICIN - Unintentional intrathecal injection caused severe neurotoxicity and death in a child.
    b) DOXORUBICIN - Intrathecal administration caused paraplegia, arachnoiditis and hydrocephalus in an adult. She had partial recovery with rehabilitation and supportive care.
    3) BLEOMYCIN - Intrathecal administration, treated immediately with CSF drainage followed by CSF exchange with normal saline, caused only headache and nausea.
    4) BORTEZOMIB: Fatalities have been reported with intrathecal administration of bortezomib.
    5) CEPHALOSPORINS - Intrathecal administration of cefazolin caused back pain and seizures. Intrathecal administration of cefotiam caused pain, myoclonus, rhabdomyolysis, dyspnea, and respiratory depression with eventual recovery.
    6) CHYMOPAPAIN - Subarachnoid and intracerebral hemorrhages have been reported after unintentional intrathecal injection of chymopapain.
    7) CYTARABINE - A 2.5-year-old child with relapsed leukemia did not develop acute toxicity after he unintentionally received 200 mg cytarabine intrathecally instead of the intended 12 mg dose.
    8) DIGOXIN - Intrathecal administration caused transient paralysis, paresthesia, areflexia, agitation, tachycardia, hypertension, and urinary retention. Of note, intravenous digoxin is dissolved in 40% propylene glycol and 10% ethanol. It is possible that the reported toxicity in this case is related to the excipients.
    9) FENTANYL - In one case report, intrathecal pump malfunction resulted in an overinfusion of fentanyl intrathecally.
    10) GADOPENTETATE DIMEGLUMINE - An adult developed acute encephalopathy after 20 mL of intrathecal gadopentetate dimeglumine, but recovered.
    11) IONIC CONTRAST MEDIA - Intrathecal administration of ionic contrast media causes a characteristic "ascending tonic clonic seizure syndrome". Patients may develop paresthesias in the lower extremities within a few hours of the event. This is soon followed by myoclonic jerking of the lower extremities which may occur spontaneously or be precipitated by minimal tactile stimulation. Myoclonic jerking progresses to the upper extremities and tonic clonic seizures may develop. If not aggressively controlled, the myoclonus/seizures cause hyperthermia, rhabdomyolysis, and metabolic acidosis, which may precipitate renal failure and death.
    12) LABETALOL - No adverse effects were noted after 15 mg intrathecal labetalol in an adult.
    13) LOCAL ANESTHETICS - Total spinal anesthesia (coma, respiratory failure, flaccid paralysis, mydriasis) can develop after intrathecal overdose of local anesthetics.
    14) MERCURY - Intrathecal administration of mercurochrome caused impaired consciousness, nuchal rigidity, aphasia and left sided facial weakness, followed by fever, restlessness, and confusion. The patient was treated with lumbar drainage and systemic chelation, and had sensory-motor polyneuropathy, ataxia and impaired memory on long term follow up.
    15) METHADONE - Complications from intrathecal infusion of methadone-contaminated morphine included epidural abscess, intradural/extradural abscess, sterile meningitis, intramedullary mass in the conus, intrathecal mass and inflammation, mental status change and drowsiness.
    16) METHOTREXATE - Intrathecal or intraventricular methotrexate overdose can cause headache, back pain, seizures, coma, confusion, respiratory failure, hypotension, and death.
    17) METHYLENE BLUE - Initial vomiting, shock and collapse followed by paraplegia, radiculopathy, cauda equine syndrome, cranial nerve dysfunction, encephalopathy, optic neuritis and meningeal irritation have been reported after intrathecal injection of methylene blue.
    18) MEZLOCILLIN - Intraventricular administration of 4 g mezlocillin caused protracted seizures in a woman with traumatic brain injury. The patient recovered and returned to baseline.
    19) MORPHINE - Hypotension, respiratory depression, hypertension, CNS depression, agitation, and protracted seizures have been reported after intrathecal morphine overdose.
    20) POTASSIUM CHLORIDE - Intrathecal administration of potassium chloride caused pulmonary and cerebral edema and was rapidly fatal.
    21) RIFAMPICIN - Intravenous infusion of rifampicin 600 mg/hr for 4 hours caused no observable adverse effects.
    22) SUFENTANIL - Severe pruritus and some difficulty swallowing were reported in a woman in active labor after an inadvertent intrathecal sufentanil overdose. No other adverse events were reported. The infant's heart rate dropped prior to delivery, but apgar scores were normal at 1 and 5 minutes.
    23) TRAMADOL - Intrathecal administration caused diaphoresis, hypotension, back pain, arching spasms, and myoclonus.
    24) TRANEXAMIC ACID - Unintentional intrathecal administration of tranexamic acid has caused acute back and lower extremity pain, hypertension followed by hypotension, seizures, coma, respiratory arrest, ventricular fibrillation, and death.
    25) VINCRISTINE - is extremely neurotoxic. Intrathecal injection is commonly fatal. Manifestations include ascending sensorimotor impairment, paralysis, opisthotonus, encephalopathy, coma and respiratory failure. A few patients have survived with immediate, aggressive therapy, but have had permanent neurologic impairment.
    26) VINDESINE - Intrathecal vindesine caused ascending neuropathy and encephalopathy in an adult; she died 6 weeks after exposure.

Laboratory Monitoring

    A) Intensive care monitoring is generally required after intrathecal overdose or unintentional intrathecal administration of a substance not intended for that purpose. Monitor vital signs frequently. Institute continuous cardiac and pulse oximetry monitoring. Monitor serial neurologic exams.
    B) Other laboratory monitoring (eg, serial CBC with differential, serum electrolytes, renal function) may be necessary depending on the specific substance involved.
    C) Cranial or spinal CT or MRI may be useful in patients who developed neurologic abnormalities.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) Specific recommendations for specific substances follow. If a substance is administered intrathecally and there is no published literature with which to guide therapy, it is best to assume it is potentially neurotoxic and begin aggressive treatment. Any substance that is an irritant or caustic if it extravasates, and any substance that causes neurotoxicity when administered by another route (ie parenterally or orally) should be assumed to have the ability to cause severe neurotoxicity if administered intrathecally. Rapid, aggressive attempts to remove the substance (cerebrospinal fluid (CSF) drainage, CSF exchange, and ventriculolumbar perfusion) are advised in these cases.
    B) CEREBROSPINAL FLUID REMOVAL - Keep the patient upright if possible. Immediately drain AT LEAST 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon immediately for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline (NS) or lactated ringers (LR) through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for at least 24 hours). Fresh frozen plasma (FFP) (25 mL FFP/liter NS or LR) or albumin 5% should be added to the fluid used for perfusion to increase protein binding and replace CSF protein. Administer dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    C) ANTHRACYCLINES - Published experience is with doxorubicin and daunorubicin, which were extremely neurotoxic; it is safest to assume that other agents (epirubicin, idarubicin, mitoxantrone, valrubicin) may also be neurotoxic. Keep the patient upright. Aggressive attempts to remove as much drug as possible should begin immediately, including immediate drainage of as much cerebrospinal fluid (CSF) as possible, followed by CSF exchange and ventriculolumbar perfusion. Administer corticosteroids to prevent arachnoiditis.
    D) BACLOFEN - Supportive care including endotracheal intubation and mechanical ventilation if necessary is the mainstay of treatment. Seizures may develop and require anticonvulsant therapy (benzodiazepines, barbiturates, propofol). Drainage of cerebrospinal fluid may accelerate recovery after large overdoses.
    E) BLEOMYCIN - Limited data. The only case reported to date was treated with cerebrospinal fluid (CSF) drainage and CSF exchange with good outcome.
    F) CEPHALOSPORINS - Limited experience. Treat seizures with anticonvulsants, ventilatory support as necessary. Cerebrospinal fluid (CSF) drainage and CSF exchange should be considered.
    G) CHYMOPAPAIN - Is a severe tissue irritant and has caused subarachnoid and intraventricular hemorrhage. Aggressive attempts at removal (cerebrospinal fluid (CSF) drainage, CSF exchange and ventriculolumbar perfusion) should be initiated. Monitor neurologic exam. Cranial CT, intracranial pressure monitoring and neurosurgical intervention may be necessary.
    H) CYTARABINE - Limited data. Perform cerebrospinal fluid (CSF) drainage and CSF exchange after significant overdose.
    I) DIGOXIN - Limited data. Provide supportive care. Consider cerebrospinal fluid drainage
    J) GADOPENTETATE DIMEGLUMINE - Limited data. Provide supportive care, cerebrospinal fluid drainage.
    K) IONIC CONTRAST MEDIA - Aggressive seizure control (benzodiazepines, barbiturates, propofol) is mandatory to prevent secondary complications of hyperthemia, acidosis, rhabdomyolysis, renal failure and disseminated intravascular coagulation. Neuromuscular paralysis with continuous propofol or barbiturate infusion titrated to burst suppression by continuous EEG monitoring is likely to be necessary. Cerebrospinal fluid (CSF) drainage and CSF exchange should be initiated as soon as possible. Treat hyperthemia by controlling seizures and aggressive cooling. Fluids and pressors may be necessary to treat hypertension. Aggressive hydration in patients who develop rhabdomyolysis.
    L) LOCAL ANESTHETICS - Endotracheal intubation and mechanical ventilation are likely to be necessary. Drainage of cerebrospinal fluid may accelerate recovery.
    M) MERCURY is neurotoxic. Keep the patient upright and begin aggressive attempts to remove as much mercury as possible, including immediate cerebrospinal fluid (CSF) drainage, followed by CSF exchange and ventriculolumbar perfusion. Systemic chelation (unithiol, succimer, dimercaprol) should be administered as well.
    N) METHOTREXATE: Inadvertent intrathecal overdose of methotrexate can cause severe toxicity. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. This is probably sufficient therapy in patients with less than 7-fold overdose or less than 100 mg of methotrexate. CSF exchange, ventriculolumbar perfusion, and intrathecal administration of glucarpidase should be performed after large overdoses (in children intrathecal overdoses greater than 120 mg or more than 15 times the intended dose). Glucarpidase rapidly catabolizes methotrexate to an inactive metabolite. It is available in the United States under an expanded access and cost recovery program and in Europe and elsewhere outside the United States on a named patient basis. To obtain glucarpidase in the United States, contact 1-888-327-1027 for intrathecal use. Dosage is intrathecal administration of 2000 Units over 5 minutes. Administration of corticosteroids (dexamethasone 4 mg IV every 6 hours for 4 doses) and leucovorin (100 mg IV every 6 hours for 4 doses) also may help. DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.
    O) METHYLENE BLUE - Monitor neurologic exam. Keep the patient upright and begin aggressive attempts to remove as much drug as possible, including immediate cerebrospinal fluid (CSF) drainage, followed by CSF exchange. Consider ventriculolumbar perfusion.
    P) MORPHINE - Treat seizures (benzodiazepines, barbiturates, propofol) and support blood pressure with fluid and pressors as needed. Naloxone infusion may be useful. Intubate and ventilate as needed. Cerebrospinal fluid drainage may accelerate recovery.
    Q) PENICILLINS - Treat seizures aggressively (benzodiazepines, barbiturates, propofol). Cerebrospinal (CSF) drainage and CSF exchange may be useful after a large overdose.
    R) POTASSIUM CHLORIDE has been rapidly fatal. Keep the patient upright and begin aggressive attempts to remove as much drug as possible, including immediate cerebrospinal fluid (CSF) drainage, followed by CSF exchange and ventriculolumbar perfusion. Monitor for hyperkalemia and treat as necessary.
    S) TRAMADOL - Limited experience. Treat seizures/myoclonus (benzodiazepines, barbiturates, propofol), support blood pressure with fluids and pressors. Intubate and ventilate as needed. Cerebrospinal fluid (CSF) drainage should be performed immediately followed by CSF exchange. Consider ventriculolumbar perfusion.
    T) TRANEXAMIC ACID - Highly neurotoxic. Keep the patient upright and begin aggressive attempts to remove as much drug as possible, including immediate cerebrospinal fluid (CSF) drainage, followed by CSF exchange and ventriculolumbar perfusion. Aggressive seizure control (benzodiazepines, barbiturates, propofol) may be necessary. Support blood pressure with fluids and pressors as needed. Endotracheal intubation and mechanical ventilation are likely to be needed. Monitor for ventricular dysrhythmias and treat per ACLS guidelines.
    U) VINCA ALKALOIDS - Experience is mostly with vincristine. All (vinblastine, vindesine, vinorelbine) should be assumed to be extremely neurotoxic. Keep the patient upright and begin aggressive attempts to remove as much drug as possible, including immediate cerebrospinal fluid (CSF) drainage, followed by CSF exchange and ventriculolumbar perfusion with normal saline (NS) or lactated ringers (LR) to which has been added 25 mL of fresh frozen plasma per liter NS or LR for AT LEAST 24 hours (rate of perfusion should be in the range of 50 to 150 mL/hr). Administer corticosteroids to prevent arachnoiditis. Administer intravenous or oral folinic acid, glutamic acid, and pyridoxine.
    V) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    W) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.

Range Of Toxicity

    A) SUMMARY - In general, even small amounts of substances that are known to be neurotoxic when administered by other routes (intravenous or oral), and substances that are known to be caustic or tissue irritants (eg, when extravasated) should be assumed to be severely neurotoxic if unintentionally administered intrathecally. Consideration should be given to excipients, such as propylene glycol, that may cause or contribute to toxicity.
    B) BACLOFEN - Doses up to 10 mg intrathecally have caused severe toxicity, but patients have recovered with supportive care.
    C) BLEOMYCIN - An adult had minimal toxicity after 30 mg intrathecal bleomycin; he was treated with aggressive immediate CSF drainage and exchange.
    D) CEFAZOLIN - An adult developed severe toxicity, but survived after 1.5 g intrathecally. Another adult died after 24 to 37 mg intrathecally.
    E) CEFOTIAM - An adult developed severe toxicity, but recovered after 1.5 g cefotiam intrathecally.
    F) CYTARABINE - A 2.5-year-old child with leukemia did not develop acute toxicity after he unintentionally received 200 mg cytarabine intrathecally instead of the intended 12 mg dose.
    G) DAUNORUBICIN - Unintentional intrathecal injection of 17 mg was lethal in a child despite cerebrospinal fluid exchange and drainage.
    H) DIGOXIN - An adult developed moderate toxicity, but recovered after 0.5 mg digoxin intrathecally.
    I) DOXORUBICIN - An adult developed severe neurotoxicity after 14.5 mg intrathecal doxorubicin. She survived with lower extremity weakness.
    J) GADOPENTETATE DIMEGLUMINE - An adult developed acute encephalopathy after 20 mL intrathecal gadopentetate dimeglumine, but recovered.
    K) IONIC CONTRAST MEDIA - As little as 10 mL of intrathecally administered ionic contrast media has been fatal in adults.
    L) LABETALOL - Intrathecal administration of 15 mg labetalol resulted in no observable effects.
    M) LOCAL ANESTHETICS - A 14-year-old girl unintentionally received 5 mL 2% lidocaine and 10 mL 0.5% bupivacaine followed by an infusion of bupivacaine intrathecally instead of epidurally. She was apneic and flaccid, but recovered with supportive care.
    N) MERCUROCHROME - An adult developed severe neurotoxicity after 5 mL mercurochrome (26 mg mercury) was instilled into the cavity of a cerebrospinal fluid fistula. She was treated aggressively (CSF drainage and chelation), and survived with residual neuropathy and memory impairment.
    O) METHYLENE BLUE - Intrathecal injection of as little as 1 mL of 1% methylene blue has caused acute collapse followed by spinal cord injury with permanent neurologic deficits.
    P) MORPHINE - Severe toxicity (status epilepticus, hypertension) has developed in adults after 250 mg to 510 mg intrathecally. Sedation and respiratory depression were reported after 15 mg intrathecally.
    Q) METHOTREXATE - In a meta-analysis of pediatric overdoses of intrathecal methotrexate, nonfatal cases were reported with doses ranging from 50 to 120 mg (less than a 15-fold overdose) of methotrexate. Intrathecal overdoses of greater than 500 milligrams are generally associated with severe morbidity or death.
    R) MEZLOCILLIN - Intraventricular administration of 4 g mezlocillin caused protracted seizures in a woman with traumatic brain injury.
    S) POTASSIUM CHLORIDE - 3 mL of 15% potassium chloride intrathecally was fatal in an adult.
    T) RIFAMPICIN - No effects were reported in an adult who received 2400 mg rifampicin intrathecally over 4 hours.
    U) TRAMADOL - Severe back pain, spasms, and myoclonus developed after 25 mg intrathecal tramadol was administered to a woman with end stage cancer. She died 2 days later, likely from underlying disease.
    V) TRANEXAMIC ACID - Adult fatalities have been reported after 300 and 500 mg intrathecally. An adult survived an intrathecal injection of 50 mg, but developed status epilepticus and was left with permanent cognitive deficits and peroneal nerve palsies.
    W) VINCRISTINE - Doses of 0.3 mg to 2 mg intrathecally have been fatal. Patients have survived intrathecal injection of 0.5 to 2 mg with immediate, aggressive care, but had residual neurologic impairment.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) SUMMARY - Xenobiotics can cause severe toxicity when administered intrathecally. In general, substances that are known to be neurotoxic when administered by other routes (intravenous or oral), and substances that are known to be caustic or tissue irritants (eg, when extravasated) should be assumed to be severely neurotoxic if unintentionally administered intrathecally. In addition, consideration should be given to excipients, such as propylene glycol, that may cause or contribute to toxicity. The following describes known effects for specific drugs and chemicals that have been unintentionally administered intrathecally or administered in overdose.
    2) ANTHRACYCLINES
    a) DAUNORUBICIN - Unintentional intrathecal injection caused severe neurotoxicity and death in a child.
    b) DOXORUBICIN - Intrathecal administration caused paraplegia, arachnoiditis and hydrocephalus in an adult. She had partial recovery with rehabilitation and supportive care.
    3) BLEOMYCIN - Intrathecal administration, treated immediately with CSF drainage followed by CSF exchange with normal saline, caused only headache and nausea.
    4) BORTEZOMIB: Fatalities have been reported with intrathecal administration of bortezomib.
    5) CEPHALOSPORINS - Intrathecal administration of cefazolin caused back pain and seizures. Intrathecal administration of cefotiam caused pain, myoclonus, rhabdomyolysis, dyspnea, and respiratory depression with eventual recovery.
    6) CHYMOPAPAIN - Subarachnoid and intracerebral hemorrhages have been reported after unintentional intrathecal injection of chymopapain.
    7) CYTARABINE - A 2.5-year-old child with relapsed leukemia did not develop acute toxicity after he unintentionally received 200 mg cytarabine intrathecally instead of the intended 12 mg dose.
    8) DIGOXIN - Intrathecal administration caused transient paralysis, paresthesia, areflexia, agitation, tachycardia, hypertension, and urinary retention. Of note, intravenous digoxin is dissolved in 40% propylene glycol and 10% ethanol. It is possible that the reported toxicity in this case is related to the excipients.
    9) FENTANYL - In one case report, intrathecal pump malfunction resulted in an overinfusion of fentanyl intrathecally.
    10) GADOPENTETATE DIMEGLUMINE - An adult developed acute encephalopathy after 20 mL of intrathecal gadopentetate dimeglumine, but recovered.
    11) IONIC CONTRAST MEDIA - Intrathecal administration of ionic contrast media causes a characteristic "ascending tonic clonic seizure syndrome". Patients may develop paresthesias in the lower extremities within a few hours of the event. This is soon followed by myoclonic jerking of the lower extremities which may occur spontaneously or be precipitated by minimal tactile stimulation. Myoclonic jerking progresses to the upper extremities and tonic clonic seizures may develop. If not aggressively controlled, the myoclonus/seizures cause hyperthermia, rhabdomyolysis, and metabolic acidosis, which may precipitate renal failure and death.
    12) LABETALOL - No adverse effects were noted after 15 mg intrathecal labetalol in an adult.
    13) LOCAL ANESTHETICS - Total spinal anesthesia (coma, respiratory failure, flaccid paralysis, mydriasis) can develop after intrathecal overdose of local anesthetics.
    14) MERCURY - Intrathecal administration of mercurochrome caused impaired consciousness, nuchal rigidity, aphasia and left sided facial weakness, followed by fever, restlessness, and confusion. The patient was treated with lumbar drainage and systemic chelation, and had sensory-motor polyneuropathy, ataxia and impaired memory on long term follow up.
    15) METHADONE - Complications from intrathecal infusion of methadone-contaminated morphine included epidural abscess, intradural/extradural abscess, sterile meningitis, intramedullary mass in the conus, intrathecal mass and inflammation, mental status change and drowsiness.
    16) METHOTREXATE - Intrathecal or intraventricular methotrexate overdose can cause headache, back pain, seizures, coma, confusion, respiratory failure, hypotension, and death.
    17) METHYLENE BLUE - Initial vomiting, shock and collapse followed by paraplegia, radiculopathy, cauda equine syndrome, cranial nerve dysfunction, encephalopathy, optic neuritis and meningeal irritation have been reported after intrathecal injection of methylene blue.
    18) MEZLOCILLIN - Intraventricular administration of 4 g mezlocillin caused protracted seizures in a woman with traumatic brain injury. The patient recovered and returned to baseline.
    19) MORPHINE - Hypotension, respiratory depression, hypertension, CNS depression, agitation, and protracted seizures have been reported after intrathecal morphine overdose.
    20) POTASSIUM CHLORIDE - Intrathecal administration of potassium chloride caused pulmonary and cerebral edema and was rapidly fatal.
    21) RIFAMPICIN - Intravenous infusion of rifampicin 600 mg/hr for 4 hours caused no observable adverse effects.
    22) SUFENTANIL - Severe pruritus and some difficulty swallowing were reported in a woman in active labor after an inadvertent intrathecal sufentanil overdose. No other adverse events were reported. The infant's heart rate dropped prior to delivery, but apgar scores were normal at 1 and 5 minutes.
    23) TRAMADOL - Intrathecal administration caused diaphoresis, hypotension, back pain, arching spasms, and myoclonus.
    24) TRANEXAMIC ACID - Unintentional intrathecal administration of tranexamic acid has caused acute back and lower extremity pain, hypertension followed by hypotension, seizures, coma, respiratory arrest, ventricular fibrillation, and death.
    25) VINCRISTINE - is extremely neurotoxic. Intrathecal injection is commonly fatal. Manifestations include ascending sensorimotor impairment, paralysis, opisthotonus, encephalopathy, coma and respiratory failure. A few patients have survived with immediate, aggressive therapy, but have had permanent neurologic impairment.
    26) VINDESINE - Intrathecal vindesine caused ascending neuropathy and encephalopathy in an adult; she died 6 weeks after exposure.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Intensive care monitoring is generally required after intrathecal overdose or unintentional intrathecal administration of a substance not intended for that purpose. Monitor vital signs frequently. Institute continuous cardiac and pulse oximetry monitoring. Monitor serial neurologic exams.
    B) Other laboratory monitoring (eg, serial CBC with differential, serum electrolytes, renal function) may be necessary depending on the specific substance involved.
    C) Cranial or spinal CT or MRI may be useful in patients who developed neurologic abnormalities.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Intensive care monitoring is generally required after intrathecal overdose or unintentional intrathecal administration of a substance not intended for that purpose. Monitor vital signs frequently. Institute continuous cardiac and pulse oximetry monitoring. Monitor serial neurologic exams.
    B) Other laboratory monitoring (eg, serial CBC with differential, serum electrolytes, renal function) may be necessary depending on the specific substance involved.
    C) Cranial or spinal CT or MRI may be useful in patients who developed neurologic abnormalities.

Range Of Toxicity

Summary

    A) SUMMARY - In general, even small amounts of substances that are known to be neurotoxic when administered by other routes (intravenous or oral), and substances that are known to be caustic or tissue irritants (eg, when extravasated) should be assumed to be severely neurotoxic if unintentionally administered intrathecally. Consideration should be given to excipients, such as propylene glycol, that may cause or contribute to toxicity.
    B) BACLOFEN - Doses up to 10 mg intrathecally have caused severe toxicity, but patients have recovered with supportive care.
    C) BLEOMYCIN - An adult had minimal toxicity after 30 mg intrathecal bleomycin; he was treated with aggressive immediate CSF drainage and exchange.
    D) CEFAZOLIN - An adult developed severe toxicity, but survived after 1.5 g intrathecally. Another adult died after 24 to 37 mg intrathecally.
    E) CEFOTIAM - An adult developed severe toxicity, but recovered after 1.5 g cefotiam intrathecally.
    F) CYTARABINE - A 2.5-year-old child with leukemia did not develop acute toxicity after he unintentionally received 200 mg cytarabine intrathecally instead of the intended 12 mg dose.
    G) DAUNORUBICIN - Unintentional intrathecal injection of 17 mg was lethal in a child despite cerebrospinal fluid exchange and drainage.
    H) DIGOXIN - An adult developed moderate toxicity, but recovered after 0.5 mg digoxin intrathecally.
    I) DOXORUBICIN - An adult developed severe neurotoxicity after 14.5 mg intrathecal doxorubicin. She survived with lower extremity weakness.
    J) GADOPENTETATE DIMEGLUMINE - An adult developed acute encephalopathy after 20 mL intrathecal gadopentetate dimeglumine, but recovered.
    K) IONIC CONTRAST MEDIA - As little as 10 mL of intrathecally administered ionic contrast media has been fatal in adults.
    L) LABETALOL - Intrathecal administration of 15 mg labetalol resulted in no observable effects.
    M) LOCAL ANESTHETICS - A 14-year-old girl unintentionally received 5 mL 2% lidocaine and 10 mL 0.5% bupivacaine followed by an infusion of bupivacaine intrathecally instead of epidurally. She was apneic and flaccid, but recovered with supportive care.
    N) MERCUROCHROME - An adult developed severe neurotoxicity after 5 mL mercurochrome (26 mg mercury) was instilled into the cavity of a cerebrospinal fluid fistula. She was treated aggressively (CSF drainage and chelation), and survived with residual neuropathy and memory impairment.
    O) METHYLENE BLUE - Intrathecal injection of as little as 1 mL of 1% methylene blue has caused acute collapse followed by spinal cord injury with permanent neurologic deficits.
    P) MORPHINE - Severe toxicity (status epilepticus, hypertension) has developed in adults after 250 mg to 510 mg intrathecally. Sedation and respiratory depression were reported after 15 mg intrathecally.
    Q) METHOTREXATE - In a meta-analysis of pediatric overdoses of intrathecal methotrexate, nonfatal cases were reported with doses ranging from 50 to 120 mg (less than a 15-fold overdose) of methotrexate. Intrathecal overdoses of greater than 500 milligrams are generally associated with severe morbidity or death.
    R) MEZLOCILLIN - Intraventricular administration of 4 g mezlocillin caused protracted seizures in a woman with traumatic brain injury.
    S) POTASSIUM CHLORIDE - 3 mL of 15% potassium chloride intrathecally was fatal in an adult.
    T) RIFAMPICIN - No effects were reported in an adult who received 2400 mg rifampicin intrathecally over 4 hours.
    U) TRAMADOL - Severe back pain, spasms, and myoclonus developed after 25 mg intrathecal tramadol was administered to a woman with end stage cancer. She died 2 days later, likely from underlying disease.
    V) TRANEXAMIC ACID - Adult fatalities have been reported after 300 and 500 mg intrathecally. An adult survived an intrathecal injection of 50 mg, but developed status epilepticus and was left with permanent cognitive deficits and peroneal nerve palsies.
    W) VINCRISTINE - Doses of 0.3 mg to 2 mg intrathecally have been fatal. Patients have survived intrathecal injection of 0.5 to 2 mg with immediate, aggressive care, but had residual neurologic impairment.

Minimum Lethal Exposure

    A) CEFAZOLIN
    1) CASE REPORTS - An adult received 2 to 3 mL of a solution containing Omnipaque and 12.5 mg/mL cefazolin during attempted discography; there were at least 2 confirmed dural punctures during the procedure. She developed back pain, vomiting, disorientation, seizure activity, dilated pupils and dystonic movements. Recurrent seizures and worsening acidosis complicated her course. The patient developed ventricular tachycardia, and resuscitation was unsuccessful (Boswell & Wolfe, 2004).
    B) DAUNORUBICIN
    1) Inadvertent intrathecal injection of 17 mg was lethal in a child despite cerebrospinal fluid exchange (160 mL) and drainage (450 mL over 3 days) (Mortensen et al, 1992).
    C) IONIC CONTRAST MEDIA
    1) CASE SERIES - Five adults developed ascending myoclonus and intractable seizures and died after inadvertently receiving 10 to 15 mL of ionic contrast media intrathecally (Bohn et al, 1992).
    D) METHOTREXATE
    1) PEDIATRIC
    a) A 9-year-old died after receiving 650 milligrams of methotrexate intrathecally (54-fold overdose). She developed seizures within one hour of exposure and became comatose; the child never regained consciousness. Death, due to sepsis, occurred one month later. However, another 9-year-old child had "massive" neurological damage following a 650 milligram overdose, but survived (Trinkle & Wu, 1996).
    b) Another fatal case was reported in a 7-year-old after receiving 1000 milligrams of methotrexate with "widespread" brain damage reported. Death followed several days after the exposure (Trinkle & Wu, 1996).
    c) A 7-year-old boy died after 650 mg intrathecal methotrexate (Ettinger, 1982).
    d) Intrathecal overdoses of more than 500 milligrams are generally associated with severe morbidity or death (Jardine et al, 1996).
    E) POTASSIUM CHLORIDE
    1) CASE REPORT - An adult who inadvertently received 3 mL of 15% potassium chloride intrathecally developed severe pulmonary and cerebral edema and died within 2.5 hours of the event (Meel, 1998).
    F) TRAMADOL
    1) CASE REPORT - Approximately 25 mg of tramadol was unintentionally administered intrathecally to a woman with end stage, metastatic squamous cell carcinoma. Within 10 minutes, she became hypotensive and diaphoretic, then developed severe back pain, with arching spasms and myoclonic jerks of her lower extremities. She had no change in her sensorium. The myoclonus and hypotension persisted until her death 48 hours later. Death was likely related to her underlying disease (Barrett & Sundaraj, 2003).
    G) TRANEXAMIC ACID
    1) CASE REPORT - An adult unintentionally received 3 mL of 10% tranexamic acid intrathecally. She immediately complained of burning pain in her legs, within 10 minutes myoclonic twitching of her facial muscles. Twenty-five minutes after exposure, hypotension and coma developed. She died 10 hours after the event due to intractable ventricular fibrillation (Garcha et al, 2007).
    2) CASE REPORT - A 49-year-old woman unintentionally received 500 mg of tranexamic acid intrathecally. She immediately developed severe back and gluteal pain and hypertension. This was followed 2 minutes later by generalized seizures. Ventricular fibrillation developed and was unresponsive to resuscitation attempts (Yeh et al, 2003).
    H) VINCRISTINE
    1) Intrathecal doses of 0.3 to 2 mg have been fatal (Qweider et al, 2007).

Maximum Tolerated Exposure

    A) BACLOFEN
    1) CASE REPORT - A 66-year-old man with multiple sclerosis received 30,000 mcg of baclofen intrathecally. Shortly thereafter, he developed blurred vision, labored breathing, and lower extremity weakness. Over the next several hours he became comatose, with flaccid quadriplegia and hypotension. The patient gradually recovered over the next 2 days with supportive care (Fakhoury et al, 1998).
    2) CASE REPORT - A 44-year-old woman with multiple sclerosis became somnolent and disoriented, with weakness of the extremities, flaccid muscle tone, respiratory depression and bradycardia after receiving 8700 mcg of baclofen intrathecally. She recovered with supportive care (Dressnandt et al, 1996).
    3) CASE REPORT- A 16-year-old boy with spasticity secondary to traumatic brain injury was treated with intrathecal baclofen at 200 to 400 mcg/day. He unintentionally received an overdose of 10 mg and developed somnolence, flaccidity, areflexia, nystagmus, and respiratory depression requiring mechanical ventilation. Focal seizures with secondary generalization occurred 6 hours after the overdose, with status epilepticus lasting 90 minutes. Gradual recovery occurred over the next 6 days. He was treated with anticonvulsants, physostigmine and drainage of 30 mL cerebrospinal fluid (Kofler et al, 1992; Saltuari et al, 1992).
    B) BLEOMYCIN
    1) An adult inadvertently received 30 mg of bleomycin intrathecally. He was immediately treated with drainage of 93 mL CSF, followed by CSF exchange with normal saline. Another 196 mL of saline diluted CSF was removed. He developed moderate headache and nausea. He had a full recovery (Loebermann et al, 2005).
    C) CEFAZOLIN
    1) CASE REPORT - An adult received 1.5 g cefazolin intrathecally. Within 10 minutes, she developed sciatic pain, diaphoresis and nausea. This was followed by increasing pain, paraplegia, dilated pupils, protracted seizures and hypotension. She received aggressive seizure control and vasopressor support, and recovered over the next 15 days. She had residual weakness in her right lower extremity which resolved over the next 15 minutes (Lang et al, 1999).
    D) CEFOTIAM
    1) CASE REPORT - An adult unintentionally received 1.5 g of cefotiam intrathecally. Shortly thereafter, he developed lower extremity cramps, and abdominal pain. About 2 hours after the event, he developed myoclonic jerking, agitation, severe pain, dyspnea, and hypercapnia. He was intubated and sedated, but required high doses of clonazepam to control the myoclonus. He developed hypotension, mild rhabdomyolysis, and myoclonic jerking, which persisted for at least 60 hours. He eventually recovered (Brossner et al, 2004).
    E) CYTARABINE
    1) A 2.5-year-old child with relapsed leukemia did not develop acute toxicity after he unintentionally received 200 mg of cytarabine intrathecally instead of the intended 13 mg dose. He was treated with exchange of 50 mL cerebrospinal fluid (CSF) with isotonic saline (Lafolie et al, 1988).
    F) DIGOXIN
    1) CASE REPORT - Two hours after suspected intrathecal administration of 0.5 mg digoxin, an adult developed paresthesias and paralysis of his lower extremities, umbilicus, agitation, tachycardia, and hypertension. Limb reflexes were absent, and abdominal distension and urinary retention also developed. By 24 hours, strength, sensory function and reflexes were normal and there was no long term sequelae (Bagherpour et al, 2006).
    G) DOXORUBICIN
    1) CASE REPORT - An adult inadvertently received 14.5 mg of doxorubicin intrathecally and was treated with immediate CSF exchange (500 mL total) immediately. She developed severe ascending sensory and motor neuropathy, hydrocephalus and adhesive arachnoiditis. The patient survived with residual leg weakness (Jordan et al, 2004).
    H) GADOPENTETATE DIMEGLUMINE
    1) CASE REPORT - A 64-year-old man unintentionally received 20 mL (10 mmol) of gadolinium dimeglumine intrathecally. He developed acute encephalopathy, but recovered over the next 10 days (Arlt et al, 2007).
    I) IONIC CONTRAST MEDIA
    1) Adults have survived injections of 10 to 14 mL of ionic contrast media intrathecally. Most of the survivors have received aggressive care (Bohn et al, 1992; Rosati et al, 1992).
    J) LOCAL ANESTHETICS
    1) A 14-year-old girl inadvertently received 5 mL of 2% lidocaine and 10 mL of 0.5% bupivacaine followed by an infusion of bupivacaine intrathecally instead of epidurally. She was apneic and flaccid, but recovered (Tsui et al, 2004).
    K) LABETALOL
    1) An adult unintentionally received 15 mg labetalol intrathecally; no adverse effects developed (Balestrieri et al, 2005).
    L) METHOTREXATE
    1) GENERAL
    a) Intrathecal overdoses of more than 500 milligrams are generally associated with severe morbidity or death (Jardine et al, 1996).
    b) Patients treated with glucarpidase (Voroxaze(TM), carboxypeptidase G) have survived intrathecal methotrexate overdoses of 196 to 600 mg with minimal (memory impairment), or no neurologic deficits (Widemann et al, 2004).
    2) ADULT
    a) CASE REPORT - A 34-year-old male with a history of aggressive lymphoma developed confusion and generalized seizures within 2 hours of an inadvertent dose of 1200 mg methotrexate intrathecally instead of the prescribed 15 mg (an 80-fold overdose). The patient was immediately treated with intravenous leucovorin, and CSF exchange was started within 6 hours of the exposure. The patient's course was complicated by ARDS and sepsis, along with residual cognitive and motor dysfunction (Finkelstein et al, 2004).
    M) PEDIATRIC
    1) CASE SERIES - In a meta-analysis of methotrexate intrathecal overdoses in children, 6 of the nonfatal cases (age 2 to 12 years) received between 50 and 120 milligrams (less than a 15-fold overdose) (Trinkle & Wu, 1996).
    a) Of the children who received overdoses under 15-fold, none had any symptoms of central nervous system toxicity, including 2 cases who did not receive corticosteroids. Most of these patients were treated with drug removal by CSF aspiration and/or CSF exchange. A 9-year-old child had "massive" neurological damage following a 650 milligram overdose, but survived. All patients had received folinic acid either IV or IM as rescue therapy (Trinkle & Wu, 1996).
    2) A 15-month-old girl received 85 mg of intrathecal methotrexate (intended dose 6 mg). She was treated with intravenous leucovorin and dexamethasone and developed only mild headaches (Ettinger et al, 1978).
    3) An 11-year-old boy received 120 mg of intrathecal methotrexate and a 4-year-old boy received 100 mg of intrathecal methotrexate. Both were treated with cerebrospinal fluid exchange and intravenous folinic acid and neither developed neurotoxicity (Jakobson et al, 1992).
    N) MERCUROCHROME
    1) CASE REPORT - An adult developed a cerebrospinal fluid fistula with a subcutaneous cavity after surgery for spinal stenosis. A mercurochrome disinfectant (5 mL, 26 mg mercury) was instilled into the subcutaneous cavity as it was believed to be an infected wound. The patient developed impaired consciousness, nuchal rigidity, aphasia and left sided facial weakness, fever, restlessness, and confusion. She was treated with lumbar drainage, systemic chelation and physical therapy. Eighteen months after the event, she had sensory motor polyneuropathy, ataxia and impaired memory (Stark et al, 2004).
    O) METHYLENE BLUE
    1) CASE REPORT - A 32-year-old man became weak, nauseated, diaphoretic and collapsed shortly after administration of 1 mL of 1% methylene blue intrathecally to evaluate cerebrospinal fluid rhinorrhea. The next day he had lower extremity weakness, bowel and bladder incontinence, and sensory loss below the manubrium. He developed weakness in all extremities, with sensory loss in the S5, S4, and S3 dermatomes. Partial recovery occurred over the next two years (Schultz & Schwarz, 1970).
    2) CASE SERIES - Injection of 1 to 2 mL of 1% methylene blue has caused acute pain, cauda equina, and paraplegia in several patients; many had permanent neurologic deficits (Evans & Keegan, 1960).
    P) MEZLOCILLIN
    1) CASE REPORT - An adult with severe traumatic brain injury unintentionally received 4 g of mezlocillin intrathecally. She developed recurrent generalized seizures 6 hours after the mezlocillin administration, but gradually recovered. Treatment included cerebrospinal fluid (CSF) drainage, followed by CSF exchange (Kristof et al, 1998).
    Q) MORPHINE
    1) CASE REPORT - An adult who received 250 mg of morphine intrathecally initially developed hypotension, followed by hypertension, myoclonus, and recurrent seizures. She was treated with CSF irrigation (900 mL over 1 hour), aggressive seizure control, and recovered completely (Groudine et al, 1995).
    2) CASE REPORT- An adult received 450 mg morphine intrathecally. She developed hypertension and recurrent seizures. She was treated with benzodiazepines, phenytoin and barbiturates, naloxone, and nitroprusside. Intracranial pressure monitoring was instituted, and a lumbar drain was placed to remove 10 mL CSF/hour. Recovery was complete with no residual neurologic deficits (Sauter et al, 1994).
    3) CASE REPORT - An adult who received 25 mg of intrathecal morphine developed transient hypotension and mild sedation. She was treated with intravenous ephedrine and a naloxone infusion. She recovered (Cannesson et al, 2002).
    4) CASE REPORT - An adult developed status epilepticus, hypertension followed by hypotension, after receiving 510 mg morphine intrathecally. She recovered with supportive care (Yilmaz et al, 2003).
    5) CASE SERIES - Four adults developed drowsiness, apnea, and central cyanosis without hemodynamic compromise about 90 minutes after surgery in which 15 mg morphine was administered intrathecally instead of 1.5 mg. All were intubated and mechanically ventilated and recovered within 24 hours (Pomonis et al, 1986).
    R) TRANEXAMIC ACID
    1) CASE REPORT - A 68-year-old man developed status epilepticus, multiorgan dysfunction, and polyneuropathy after inadvertent intrathecal injection of 50 mg tranexamic acid. He was treated with anticonvulsants. He improved over one month, but had residual bilateral peroneal palsy and cognitive deficits (de Leede-van der Maarl et al, 1999).
    S) RIFAMPICIN
    1) CASE REPORT - An adult with postoperative infection after a spinal decompression inadvertently received intrathecal rifampicin 600 mg/hr for 4 hours instead of vancomycin. He was closely monitored, but no adverse effects developed (Senbaga & Davies, 2005).
    T) VINCRISTINE
    1) Patients have survived intrathecal injection of 0.5 to 2 mg vincristine with immediate, aggressive care. These patients have had permanent residual neurologic dysfunction (Qweider et al, 2007).
    2) CASE REPORT - A 32-year-old man with Burkitt lymphoma received 1 mg of vincristine intrathecally. Immediately afterward 6 mL of cerebrospinal fluid was aspirated and the patient was placed in a sitting position. External ventricular and lumbar drains were placed and the CSF was irrigated with lactated ringer's solution plus fresh frozen plasma at 50 to 80 mL/hr for 6 days. Intrathecal irrigation was stopped on day 6 due to severe respiratory alkalosis, and resumed from day 7 to day 10. He was also treated with intravenous folic acid, glutamic acid and pyridoxine. Urinary retention and fecal incontinence occurred on the 2nd day. On the 8th day, he developed lower extremity paraparesis, which became more severe and ascending. By day 14, dysesthesia of the feet and perianal hypesthesia had developed. By day 60, he had incomplete sensorimotor deficit below T-9 (Qweider et al, 2007).
    3) CASE REPORT - A 7-year-old girl received 0.5 mg vincristine intrathecally. Immediately afterwards 75 mL of cerebrospinal fluid (CSF) was withdrawn and replaced with ringers lactate. A catheter was placed in the right lateral ventricle as well as a lumbar subarachnoid drain. CSF lavage was started at 100 mL/hr. After the first liter, 15 mL of fresh frozen plasma was added to subsequent liters and the lavage rate reduced to 55 mL/hr; CSF lavage was continued for 24 hours. She also received oral glutamic acid. On day 7, she developed urinary retention and loss of strength and sensation in her legs, which progressed to complete sensorimotor paraplegia. After several weeks, some recovery was noted, but the patient had residual motor paraparesis (AlFerayan et al, 1999).

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Adamson PC, Balis FM, McCully CL, et al: Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2. J Clin Oncol 1991; 9(4):670-674.
    3) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    4) Ajmal M: Accidental intrathecal injection of aminophylline in spinal anesthesia. Anesthesiology 2011; 114(4):998-1000.
    5) AlFerayan A, Russell NA, AlWohaibi M, et al: Cerebrospinal fluid lavage in the treatment of inadvertent intrathecal vincristine injection. Childs Nerv Syst 1999; 15(2-3):87-89.
    6) Alcaraz A, Rey C, Concha A, et al: Intrathecal vincristine: fatal myeloencephalopathy despite cerebrospinal fluid perfusion. J Toxicol Clin Toxicol 2002; 40(5):557-561.
    7) Arlt S, Cepek L, Rustenbeck HH, et al: Gadolinium encephalopathy due to accidental intrathecal administration of gadopentetate dimeglumine. J Neurol 2007; 254(6):810-812.
    8) BTG International Ltd: BTG Development Pipeline: Voraxaze(R) (glucarpidase). BTG International Ltd. London, United Kingdom. 2011. Available from URL: http://www.btgplc.com/development/our-pipeline. As accessed 2011-03-20.
    9) Bagherpour A, AmriMaleh P, & Saghebi R: Accidental intrathecal administration of digoxin. Anesth Analg 2006; 103(2):502-503.
    10) Balestrieri PJ, Hamza MS, Ting PH, et al: Inadvertent intrathecal injection of labetalol in a patient undergoing post-partum tubal ligation. Int J Obstet Anesth 2005; 14(4):340-342.
    11) Barrett NA & Sundaraj SR: Inadvertent intrathecal injection of tramadol. Br J Anaesth 2003; 91(6):918-920.
    12) Blaney SM, Poplack DG, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995; 13(1):177-179.
    13) Bleck TP & Jacobsen J: Prolonged survival following the inadvertent intrathecal administration of vincristine: clinical and electrophysiologic analyses. Clin Neuropharmacol 1991; 14(5):457-462.
    14) Bohn HP, Reich L, & Suljaga-Petchel K: Inadvertent intrathecal use of ionic contrast media for myelography. AJNR Am J Neuroradiol 1992; 13(6):1515-1519.
    15) Boswell MV & Wolfe JR: Intrathecal cefazolin-induced seizures following attempted discography. Pain Physician 2004; 7(1):103-106.
    16) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    17) Brossner G, Engelhardt K, Beer R, et al: Accidental intrathecal infusion of cefotiam: clinical presentation and management. Eur J Clin Pharmacol 2004; 60(5):373-375.
    18) Cannesson M, Nargues N, Bryssine B, et al: Intrathecal morphine overdose during combined spinal-epidural block for Caesarean delivery. Br J Anaesth 2002; 89(6):925-927.
    19) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    20) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    21) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    22) Coleman L, Carvalho B, Lipman S, et al: Accidental intrathecal sufentanil overdose during combined spinal-epidural analgesia for labor. Int J Obstet Anesth 2009; 18(1):78-80.
    23) Cusick JF, Ho KC, & Schamberg JF: Subarachnoid hemorrhage following chymopapain chemonucleolysis. Case report. J Neurosurg 1987; 66:775-778.
    24) Dalton C, Keenan E, & Stevenson V: A novel cause of intrathecal baclofen overdosage: lessons to be learnt. Clin Rehabil 2008; 22(2):188-190.
    25) Darbari FP, Melvin JJ, Piatt JH, et al: Intrathecal baclofen overdose followed by withdrawal: clinical and EEG features. Pediatr Neurol 2005; 33(5):373-377.
    26) Davis RJ, North RB, Campbell JN, et al: Multiple cerebral hemorrhages following chymopapain chemonucleolysis. Case report. J Neurosurg 1984; 61(1):169-171.
    27) DeAngelis LM, Tong WP, & Lin S: Carboxypeptidase G2 rescue after high-dose methotrexate. J Clin Oncology 1996; 14:2145-2149.
    28) Delhaas EM & Brouwers JRBJ: Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Int J Clin Pharmacol Ther Toxicol 1991; 29:274-280.
    29) Dettmeyer R, Driever F, Becker A, et al: Fatal myeloencephalopathy due to accidental intrathecal vincristin administration: a report of two cases. Forensic Sci Int 2001; 122(1):60-64.
    30) Dressnandt J, Weinzierl FX, Tolle TR, et al: Acute overdose of intrathecal baclofen. J Neurol 1996; 243(6):482-483.
    31) Dyke RW: Treatment of inadvertent intrathecal injection of vincristine (letter). N Engl J Med 1989; 321:1270-1271.
    32) Ettinger LJ, Freeman AI, & Creaven PJ: Intrathecal methotrexate overdose without neurotoxicity: case report and literature review. Cancer 1978; 41(4):1270-1273.
    33) Ettinger LJ: Pharmacokinetics and biochemical effects of a fatal intrathecal methotrexate overdose. Cancer 1982; 50(3):444-450.
    34) Evans JP & Keegan HR: Danger in the use of intrathecal methylene blue. JAMA 1960; 174:856-859.
    35) Fakhoury T, Abou-Khali B, & Blumenkopf B: EEG changes in intrathecal baclofen overdose: a case report and review of the literature. Electoencephalograph & Clin Neurophys 1998; 107:339-342.
    36) Fernandez CV, Esau R, Hamilton D, et al: Intrathecal vincristine: an analysis of reasons for recurrent fatal chemotherapeutic error with recommendations for prevention. J Pediatr Hematol Oncol 1998; 20(6):587-590.
    37) Finkelstein Y, Zevin S, & Heyd J: Emergency treatment of life-threatening intrathecal methotrexate overdose. Neurotoxicol 2004; 25:407-410.
    38) Garcha PS, Mohan CV, & Sharma RM: Death after an inadvertent intrathecal injection of tranexamic acid. Anesth Analg 2007; 104(1):241-242.
    39) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    40) Groudine SB, Cresanti-Daknis C, & Lumb PD: Successful treatment of a massive intrathecal morphine overdose. Anesthesiology 1995; 82(1):292-295.
    41) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    42) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    43) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    44) Jakobson AM, Kreuger A, & Mortimer A: Cerebrospinal fluid exchange after intrathecal methotrexate overdose. A report of two cases. ACTA Paediatr 1992; 81:359-361.
    45) Jardine LF, Ingram LC, & Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematolog Oncol 1996; 18:302-304.
    46) Jones TF, Feler CA, Simmons BP, et al: Neurologic complications including paralysis after a medication error involving implanted intrathecal catheters. Am J Med 2002; 112(1):31-36.
    47) Jordan B, Pasquier Y, & Schnider A: Neurological improvement and rehabilitation potential following toxic myelopathy due to intrathecal injection of doxorubicin. Spinal Cord 2004; 42:371-373.
    48) Kaiser KG & Bainton CR: Treatment of intrathecal morphine overdose by aspiration of cerebrospinal fluid. Anesth Analg 1987; 66:475-477.
    49) Killeffer JA & Kaufman HH: Inadvertent intraoperative myelography with Hypaque: case report and discussion. Surg Neurol 1997; 48(1):70-73.
    50) Kofler M, Saltuari L, & Schmutzhard E: Electrophysiological findings in a case of severe intrathecal baclofen overdose. Electroencephalograph Clin Neurophysiol 1992; 83:83-86.
    51) Kristof RA, Clusmann H, Koehler W, et al: Treatment of accidental high dose intraventricular mezlocillin application by cerebrospinal fluid exchange. J Neurol Neurosurg Psychiatry 1998; 64(3):379-381.
    52) Kwack EK, Kim DJ, & Park TL: Neural toxicity induced by accidental intrathecal vincristine administration. J Korean Med Sci 1999; 15:688-692.
    53) Lafolie P, Liliemark J, Bjork O, et al: Exchange of cerebrospinal fluid in accidental intrathecal overdose of cytarabine. Med Toxicol Adverse Drug Exp 1988; 3(3):248-252.
    54) Lang EW, Weinert D, & Behnke A: A massive intrathecal cefazoline overdose. Europ J Anaesthesiol 1999; 16:204-205.
    55) Lau G: Accidental intraventricular vincristine administration: an avoidable iatrogenic death. Med Sci Law 1996; 36(3):263-265.
    56) Lee AC, Wong KW, Fong KW, et al: Intrathecal methotrexate overdose. Acta Paediatr 1997; 86(4):434-437.
    57) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    58) Loebermann M, Kahl C, Steiner B, et al: Accidental intrathecal administration of bleomycin: favorable outcome after pneumo-encephalus and cerebrospinal fluid exchange: a case report. Leuk Lymphoma 2005; 46(6):941-943.
    59) Lyew MA, Mondy C, Eagle S, et al: Hemodynamic instability and delayed emergence from general anesthesia associated with inadvertent intrathecal baclofen overdose. Anesthesiology 2003; 98(1):265-268.
    60) Maino P, Koetsier E, & Perez RS: Fentanyl overdose caused by malfunction of SynchroMed II intrathecal pump: two case reports. Reg Anesth Pain Med 2014; 39(5):434-437.
    61) Manelis J, Freudlich E, Ezekiel E, et al: Accidental intrathecal vincristine administration. Report of a case. J Neurol 1982; 228(3):209-213.
    62) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    63) Maruyama K, Setoguchi Y, Maruyama J, et al: Intrathecal injection of high-dose meglumine amidotrizoate with complete recovery. Intensive Care Med 1993; 19(4):232-234.
    64) Meel B: Inadvertent intrathecal administration of potassium chloride during routine spinal anesthesia: case report. Am J Forensic Med Pathol 1998; 19(3):255-257.
    65) Meggs WJ & Hoffman RS: Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3):243-246.
    66) Michelagnoli MP, Bailey CC, Wilson I, et al: Potential salvage therapy for inadvertent intrathecal administration of vincristine. Br J Haematol 1997; 99:364-367.
    67) Mortensen ME, Cecalupo AJ, Lo WD, et al: Inadvertent intrathecal injection of daunorubicin with fatal outcome. Med Pediatr Oncol 1992; 20(3):249-253.
    68) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    69) Park KW , Im SB , Kim BT , et al: Neurotoxic manifestations of an overdose intrathecal injection of gadopentetate dimeglumine. J Korean Med Sci 2010; 25(3):505-508.
    70) Penn RD & Kroin JS: Treatment of intrathecal morphine overdose. J Neurosurg 1995; 82(1):147-148.
    71) Pomonis SP, Economacos G, & Costopanajiocoy SP: Overdose of intrathecal morphine. Anaesthesia 1986; 41(6):670-.
    72) Poplack DG: Massive intrathecal overdose: check the label twice. N Engl J Med 1984; 311:400-402.
    73) Product Information: VELCADE(R) intravenous, subcutaneous injection, bortezomib intravenous, subcutaneous injection. Millennium Pharmaceuticals (per manufacturer), Cambridge, MA, 2012.
    74) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    75) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    76) Protherics PLC: Voraxaze(TM) - an enzyme that breaks down methotrexate (MTX). Protherics PLC. United Kingdom. 2008. Available from URL: http://www.protherics.com/Products/Voraxaze.aspx.
    77) Qweider M, Gilsbach JM, & Rohde V: Inadvertent intrathecal vincristine administration: a neurosurgical emergency. Case report. J Neurosurg Spine 2007; 6(3):280-283.
    78) Riva L, Conter V, Rizzari C, et al: Successful treatment of intrathecal methotrexate overdose with folinic acid rescue: a case report. Acta Paediatr 1999; 88(7):780-782.
    79) Rosati G, LetodiPriolo S, & Tirone P: Serious or fatal complications after inadvertent administration of ionic water-soluble contrast media in myelography. Eur J Radiol 1992; 15(2):95-100.
    80) Rutili A, Maggiani M, Bertelloni C, et al: Persistent overdose caused by a very small dose of intrathecal morphine in an elderly patient undergoing vaginal hysterectomy: a case report. Minerva Anestesiol 2007; 73(7-8):433-436.
    81) Saltuari L, Marosi MJ, & Kofler M: Status epilepticus complicating intrathecal baclofen overdose (letter). Lancet 1992; 339:373-374.
    82) Salvolini U, Bonetti MG, & Ciritella P: Accidental intrathecal injection of ionic water-soluble contrast medium: report of a case, including treatment. Neuroradiology 1996; 38(4):349-351.
    83) Sauter K, Kaufman HH, Bloomfield SM, et al: Treatment of high-dose intrathecal morphine overdose. case report. J Neurosurg 1994; 81(1):143-146.
    84) Schultz P & Schwarz GA: Radiculomyelopathy following intrathecal instillation of methylene blue. A hazard reaffirmed. Arch Neurol 1970; 22:240-244.
    85) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    86) Senbaga N & Davies EM: Inadvertent intrathecal administration of rifampicin. Br J Clin Pharmacol 2005; 60(1):116-.
    87) Sharr MM, Weller RO, & Brice JG: Spinal cord necrosis after intrathecal injection of methylene blue. J Neurol Neurosurg Psychiatry 1978; 41(4):384-386.
    88) Shepherd DA, Steuber CP, Starling KA, et al: Accidental intrathecal administration of vincristine. Med Pediatr Oncol 1978; 5(1):85-88.
    89) Shirley KW, Kothare S, Piatt JH, et al: Intrathecal baclofen overdose and withdrawal. Pediatr Emerg Care 2006; 22(4):258-261.
    90) Smith SW & Nelson LS: Case files of the New York City Poison Control Center: antidotal strategies for the management of methotrexate toxicity. J Med Toxicol 2008; 4(2):132-140.
    91) Spiegel RJ, Cooper PR, & Blum RH: Treatment of massive intrathecal methotrexate overdose by ventriculolumbar perfusion. N Engl J Med 1984; 311:386-388.
    92) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    93) Stark AM, Barth H, Grabner JP, et al: Accidental intrathecal mercury application. Eur Spine J 2004; 13:241-243.
    94) Tartiere J, Gerard JL, Peny J, et al: Acute treatment after accidental intrathecal injection of hypertonic contrast media. Anesthesiology 1989; 71(1):169-169.
    95) Teddy P, Jamous A, Gardner B, et al: Complications of intrathecal baclofen delivery. Br J Neurosurg 1992; 6(2):115-118.
    96) Tournel G, Becart-Robert A, Courtin P, et al: Fatal accidental intrathecal injection of vindesine. J Forensic Sci 2006; 51(5):1166-1168.
    97) Trinkle R & Wu JK: Errors involving pediatric patients receiving chemotherapy: A literature review. Med & Pediat Oncol 1996; 26:344-351.
    98) Tsui BC, Malherbe S, Koller J, et al: Reversal of an unintentional spinal anesthetic by cerebrospinal lavage. Anesth Analg 2004; 98(2):434-6, table.
    99) Wang RY : Antineoplastics. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed, 8th. McGraw Hill, New York, NY, 2006.
    100) Widemann BC & Adamson PC: Understanding and managing methotrexate nephrotoxicity. Oncologist 2006; 11(6):694-703.
    101) Widemann BC, Balis FM, & Murphy RF: Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J Clin Oncol 1997; 15:2125-2134.
    102) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.
    103) Williams ME, Walker AN, Bracikowski JP, et al: Ascending myeloencephalopathy due to intrathecal vincristine sulfate. a fatal chemotherapeutic error. Cancer 1983; 51(11):2041-2047.
    104) Yeh RN, Nypaver MM, Deegan TJ, et al: Baclofen toxicity in an 8-year-old with an intrathecal baclofen pump. J Emerg Med 2004; 26(2):163-167.
    105) Yeh HM, Lau HP, Lin PL, et al: Convulsions and refractory ventricular fibrillation after intrathecal injection of a massive dose of tranexamic acid. Anesthesiology 2003; 98(1):270-272.
    106) Yilmaz A, Sogut A, Kilinc M, et al: Successful treatment of intrathecal morphine overdose. Neurol India 2003; 51:410-412.
    107) Zaragoza MR, Ritchey ML, & Walter A: Neurourologic consequences of accidental intrathecal vincristine: a case report. Med Pediatr Oncol 1995; 24(1):61-62.
    108) de Leede-van der Maarl MG, Hilkens P, & Bosch F: The epileptogenic effect of tranexamic acid. J Neurol 1999; 246(9):843-.
    109) vanderLeede H, Jorens PG, Parizel P, et al: Inadvertent intrathecal use of ionic contrast agent. Eur Radiol 2002; 12(Suppl 3):S86-S93.