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Fatal consequences of a simple mistake: How can a patient be saved from inadvertent intrathecal vincristine?

Clinical Neurology and Neurosurgery, 1, 113, pages 68 - 71

1. Introduction

Since its introduction in 1963, vincristine sulfate, commonly known as vincristine, has been widely used as a chemotherapeutic agent for a variety of malignancies including lymphoma, leukemia, rhabdomyosarcoma, neuroblastoma, and Wilms tumor. Vincristine is administered intravenously as bolus often in combination with other multidrug chemotherapy regimen.

Despite its long-term extensive use and the Food and Drug Administration recommended box label warning, there have been a number of cases in which vincristine was inadvertently administered intrathecally. If administered intrathecally, vincristine causes severe and irreversible central nervous system toxicity and motor dysfunction followed by progressive ascending radiculomyeloencephalopathy, coma and death [1] . The error generally occurs when vincristine is confused with therapeutic agents normally administered intrathecally, such as methotrexate or cytarbine. Intrathecal administration of vincristine was first described to cause a fatal ascending myeloencephalopathy in humans in 1968 in the United States [2] . Since then, over 16 cases in the United States and over 60 cases worldwide have been reported in the literature [3] . However, the true incidence of inadvertent intrathecal vincristine administration is not known. Some of these incidents, particularly lethal events, prompt publication and others reported to organizations such as the Institute for Safe Medication Practices. Inadvertent intrathecal vincristine administration also occasionally has received media attention.

Direct aspiration of the fluid in the spinal intrathecal space is commonly performed to reduce the binding of vincristine to the neurotubules and thereby to preventing progressive neuronal destruction within the spinal cord and brain. In most instances ( Table 1 ) patients have died despite therapy with the time to death ranging from 3 to 75 days with an exception of one patient who was in coma for 1 year [2], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], and [15]. In other instances ( Table 2 ), patients survived with paraparesis or tetraparesis following supportive care therapy [16], [17], [18], [19], [20], [21], and [22]. In this communication, we report a case of accidental intrathecal vincristine administration in which a lethal outcome could not be prevented.

Table 1 Management of inadvertent intrathecal administration of vincristine without fresh-frozen plasma.

Patient Time after Incident Treatment Survival Reference
Sex Age        
Female 2 years Shortly after LD: CSF exchange by 0.9% saline in 24 h 3 days Schochet et al. [2]
NS 5 years After 30 min CSF aspiration; hydrocortisone 12 days Shepherd et al. [4]
Female 29 years Immediately CSF aspiration; CSF exchange in 12 h; dexamethasone 14 days Slyter et al. [5]
Female 5 years After 30 min None 17 days Manelis et al. [6]
Female 2 years Immediately EVD (Ommaya) and LD: CSF exchange by 0.9% saline in 90 min; folinic acid 6 days Gaidys et al. [7]
Male 16 years After 48 h Folinic acid; dexamethasone after 48 h of incident 36 days Williams et al. [8]
Male 56 years Immediately CSF aspiration 30 days Bain et al. [9]
Male 23 years After 10 min CSF aspiration; dexamethasone folinic acid, vitamin B12, thiamine pyridoxine 365 days (in Coma) Bleck and Jacobsen [10]
Male 15 months After 3 h Folinic acid; hydrocortisone 75 days al Fawaz [11]
Female 27 years After 24 h NS 10 days Lau [12]
Female 59 years After 10 min NS 40 days Meggs and Hoffman [13]
Male 3 years NS NS 6 days Kwack et al. [14]
Female 5 years Immediately NS 7 days Dettmeyer et al. [15]
Male 57 years Immediately NS 28 days Dettmeyer et al. [15]
Female 38 years After 40 min CSF aspiration; EVD and LD: CSF exchange by Ringers lactate solution 10 days Reddy et al. (this report)

NS: not specified; CSF: cerebrospinal fluid; EVD: external ventricular drain; LD: lumbar drain.

Table 2 Management of inadvertent intrathecal administration of vincristine with fresh-frozen plasma.

Patient Time after incident Treatment Survival Reference
Sex Age        
NS Adult Immediately EVD (Ommaya) and LD: CSF exchange by Ringers lactate and FFP in 24 h; glutamic acid Survived with paraparesis Dyke [16]
Male 6 years Immediately CSF aspiration; EVD and LD: CSF exchange by Ringers lactate and FFP; glutamic acid, folinic acid, pyridoxine Survived with tetraparesis Zaragoza et al. [17]
Female 10 years Immediately CSF aspiration; LD and EVD: CSF exchange by Ringers lactate and FFP in 24 h; methylprednisolone Survived with tetraparesis Michelagnoli et al. [18]
Female 4 years Immediately CSF exchange by saline; LD and EVD: CSF exchange by plasmalyte and FFP for 12 h; folinic acid, glutamic acid, dexamethasone 13 days Fernandez et al. [19]
Male 7 years Immediately CSF exchange by Ringers lactate; LD and EVD: CSF exchange paraby Ringers lactate and FFP for 24 h; glutamic acid Survived with paraparesis Al Ferayan et al. [20]
Female 7 years Immediately CSF aspiration; EVD and LD: CSF exchange by Ringers lactate and FFP for 24 h; glutamic acid, Survived with paraparesis Iqbal et al. [21]
Male 32 years Immediately CSF aspiration; EVD and LD: CSF exchange by Ringers lactate and FFP for 144 h; glutamic acid, folic acid, pyridoxine Survived with paraparesis Qweider et al. [22]

NS: not specified; CSF: cerebrospinal fluid; EVD: external ventricular drain; LD: lumbar drain; FFP: fresh-frozen plasma.

2. Case report

A 38-year-old female was newly diagnosed with Burkitt's lymphoma approximately 45 days prior to the incident. The performance status of the patient was poor. She received chemotherapy containing cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) on an outpatient basis. Initially the treatment with chemotherapy seemed to be well tolerated. However, 2 weeks later the patient developed right sided facial paralysis warranting the examination of central nervous system with MRI and lumbar puncture. Intracranial imaging by MRI was negative at this time, however, the CSF analysis showed the presence of lymphoma cells. After discussing these results, the patient opted to undergo intrathecal chemotherapy. An Ommaya reservoir was placed 23 days after the CHOP-R chemotherapy initiation and 2 days later, weekly doses of intrathecal methotrexate and cytarabine were administered. Simultaneously, a standard intravenous regimen of cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD) was also started. The patient had an uneventful course until the 52nd day from the initial diagnosis, during routine administration of chemotherapy; vincristine was accidentally given intrathecally. The label on the drug vial was mistaken for methotrexate when in actuality it was vincristine. The mistake was identified approximately 40 min after the administration, and immediately CSF was removed via the Ommaya and replaced with warm lactated ringer's (LR) solution. Neurosurgery was consulted and the patient was taken immediately to the operating room for removal of Ommaya reservoir and placement of an external ventricular drain and a lumbar drain. The patient's ventricular system was then irrigated every 6 h with 60 ml of LR which was simultaneously drained from the lumbar spine. She was started on intravenous vitamin B12, pyridoxine, folinic acid, and decadron. The patient and her family were immediately notified of the error and of the possible dire consequences.

Clinical course: The patient was monitored every 1 h with neurologic checks and irrigation of CSF as outlined above. The clinical course of the patient is depicted in the flow chart ( Fig. 1 ). On day 3 post-injection, the patient complained of decrease in hearing, double vision, and tingling in both of her legs. On day 4, external ventricular drain and lumbar drains were removed. After lengthy discussions with the patient and family, she elected to make herself “Do Not Resuscitate” (DNR) status and to be moved to the floor to be with her family. On day 5, the patient developed nausea, vomiting, loss of hearing, and tingling in her tongue as well as difficulty in identifying her relatives and reading. On day 6, the patient was lethargic and her respirations became uneven. On day 7, the patient stopped eating and became unresponsive on day 8. She died from respiratory failure on the 10th day after the incident, despite the use of thorough flushing of the subarachnoid space along with other intensive supportive therapy. The family denied autopsy for pathological evaluation.

gr1

Fig. 1 Flowchart of clinical course of the patient.

3. Discussion

There are number of case reports about accidental intrathecal administration of vincristine [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], and [22]. This case once again illustrates the critical need not only to prevent the devastating error of intrathecal administration of vincristine but also to develop successful therapies against vincristine induced central nervous system toxicity. Despite immediate identification of the error and prompt administration of a protocol, the patient in this report died.

Nearly all instances show that inadvertent intrathecal administration of vincristine has resulted in ascending radiculomyeloencephalopathy and death within days/weeks ( Table 1 ). The mechanism by which this is brought about is through vincristine binding to tubulin and forming neurofilament aggregates and destroying the dynamic neuronal cytoskeleton of the neurons. Clinically, the first sign is evident in the neurons that innervate the distal lower extremity. Subsequently, autonomic dysfunction such as difficulty in micturition, severe constipation, abdominal pain and ileus may occur. Generalized inflammation and dysfunction of the CNS lead to respiratory failure and death.

Histological findings of earlier cases have revealed the degeneration of myelin and axons and pseudocystic formation [19] . Furthermore, histopathological signs of tissue damage were shown to be greatest in the area of injection site implicating drug concentration as a key predictor of damage [19] and [22]. Therefore, various attempts have been made by diluting CSF concentration to limit the damage caused by an inadvertent intrathecal administration of vincristine.

In only 6 cases where the treatment was administered immediately after the intrathecal injection of vincristine, a fatal outcome was prevented ( Table 2 ). However, the patients who survived in these instances experienced significant neurological deficit including paraparesis and tetraparesis. It should be noted that the treatment after the intrathecal injection of vincristine had subtle differences in cases where it was possible to avoid fatal outcome compared to those cases where a fatal outcome could not be prevented. In the 6 cases where the fatal outcome was prevented, the treatment consisted of CSF irrigation fluid plus fresh-frozen plasma following CSF aspiration. It is believed that adding fresh-frozen plasma to CSF irrigation fluid causes a rapid binding of vincristine to blood components and minimizes the neurotoxicity of vincristine. In proposed bioavailability studies, it has been shown that greater than 50% of vincristine is bound to blood components within 20 min when given intravenously [23] . Based on these bioavailability studies, Qweider et al. recently published their case report advocating adding fresh-frozen plasma to CSF irrigation fluid [22] .

In addition to aggressive CSF dilution, the administration of neuroprotective agents such as pyridoxine, folic acid, glutamic acid, and corticosteroids has been widely used. There is little empirical evidence to support these agents, but nonetheless they are “standard” treatments currently being employed to avert neurotoxic effects of intrathecally administered vincristine.

While the above therapies have made headway in treating patients after the intrathecal injection of vincristine, the outcome remains largely a fatal event. In addition to the harm done to the patient, it is impossible to assess the emotional and psychological toll on families of the patient and the healthcare team.

The best treatment for this remains avoidance of the situation from the beginning. Many guidelines have been proposed to ensure this drug is administered safely. Perhaps the strongest and best tool is for intrathecal drugs to be sequestered from intravenous drugs. Other recommendations in the United States include clear labeling of vincristine as “Fatal if given intrathecally, for intravenous use only, do not remove covering until moment of injection.” In addition, a protocol based specific training of healthcare providers to prepare, deliver, and administer vincristine and chemotherapy drugs, has been included in the recommendations. Moreover, implementing a formal checking procedure or “time out” prior to vincristine administration have been included [3] . In our practice, the above recommendations were implemented but it is unclear whether a formal “time out” was taken prior to inadvertent administration of vincristine.

4. Conclusion

Inadvertent intrathecal administration of vincristine remains a rare incident, but devastating cause of patient morbidity and mortality. Treatment modalities are still largely ineffective. Local dilution of vincristine is ineffective in averting vincristine induced neuronal damage. Early placement of external ventricular drain and lumbar drain with copious irrigation of the CSF remain a standard option, however severe disability or fatal outcome are commonly seen. The only treatment measure that has shown some success in few instances like this is immediate aggressive central nervous irrigation before vincristine binds to brain tissue. The addition of fresh-frozen plasma to CSF irrigation fluid seems to be beneficial in reducing the neurotoxic effects of vincristine but require further evaluation.

References

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Footnotes

Department of Neurosurgery, Louisiana State University Health Sciences Center – Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA

lowast Corresponding author. Tel.: +1 318 675 6404; fax: +1 318 675 7111.