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Death and neurological devastation from intrathecal vinca alkaloids:
Prepared in syringes = 120; Prepared in minibags = 0
September 5, 2013
In July, ISMP Canada published selected findings from the 2012 ISMP International Medication Safety Self Assessment for Oncology.(1) The assessment, which was funded by the International Society of Oncology Pharmacy Practitioners (ISOPP), was developed by ISMP and ISMP Canada with help from an international panel of oncology and safety experts.(2) From April to October 2012, more than 350 oncology practice sites from 13 countries submitted results for analysis. This analysis uncovered a particularly troubling risk that appears to be weakly addressed, especially in the US: the risk of administering vinCRIStine or another vinca alkaloid intrathecally instead of intravenously.

While overall compliance among respondents was high for a risk-reduction strategy associated with labeling containers of vinCRIStine with a prominent warning, implementation was disturbingly low for three key recommendations (see Table 1 in the PDF version of the newsletter) that ISMP has promoted(3) since 2001, The Joint Commission has endorsed(4) since 2005, and the World Health Organization has recommended(5) since 2007:

---Dispense intravenous (IV) vinCRIStine in a minibag of a compatible solution (e.g., 25 mL for pediatric patients and 50 mL for adults) and never dispense and/or administer the drug using a syringe.
---Prohibit IV vinCRIStine in areas where intrathecal medications are administered and/or stored.
---Confirm that any prescribed intrathecal medications have been administered before dispensing IV vinCRIStine.

An ISMP survey conducted in 2005(6) uncovered minimal adoption of these three recommendations among responding hospitals. A follow-up survey in 2008(7) showed small, incremental improvement, but the risk of making an error remained substantial. Now, more than a decade since the first time ISMP published these recommendations, the 2012 oncology self-assessment results suggest that only about half of US oncology practice sites dilute IV vinCRIStine for administration in a small volume bag or receive confirmation that intrathecal drug administration has been completed before dispensing IV vinCRIStine. Only about two-thirds prohibit IV vinCRIStine in areas where intrathecal medications are stored or administered (see Table 1, page 1).(1)

Incidence
The first reported case of fatal ascending myeloencephalopathy caused by the intrathecal administration of IV vinCRIStine occurred in the US in 1968.(8) Between 1968 and 2007, 17 cases in the US plus 49 cases worldwide were reported in the literature.(9) Practically all of these events resulted in death; the few patients who survived experienced devastating neurological effects including persistent vegetative state and quadriplegia.

In 2008, ISMP reported a fatality in which a 25-year-old woman with non-Hodgkin’s lymphoma received another vinca alkaloid, vindesine, intrathecally.(10) In 2010, we wrote about another fatal event in which a young woman was supposed to receive a dose of intracerebroventricular methotrexate but instead received intracerebroventricular vinCRIStine through an Ommaya reservoir.(11) Another case was reported in 2010 in which a 33-year-old man with acute lymphocytic leukemia in complete remission accidentally received an intended maintenance dose of IV vinCRIStine via a lumbar puncture and died.(12) In 2011, two additional fatalities were reported in the literature. In one, a 38-year-old woman newly diagnosed with Burkitt’s lymphoma died in a US hospital after accidental administration of IV vinCRIStine by the intrathecal route.(13) The other case report involved a 63-year-old man with lymphoma from Thailand who received vinCRIStine intrathecally.(15)

There have also been cases not reported in the literature but gathered from other sources such as FDA MedWatch reports, legal claims, non-US regulatory agencies, media sources, and personal communications; the sum total of cases worldwide is 120, with 44 occurring in the US and Canada.(14) However, the true incidence of intrathecal administration of IV vinCRIStine or other vinca alkaloids is not known. What we do know is that wrong route vinCRIStine errors continue to occur, and although they may happen infrequently, they are always excruciatingly painful over days or weeks until almost certain death, and they are always preventable.

Causes
In most cases of published events, the causes of inadvertent intrathecal vinCRIStine administration have not been fully described. However, many events appear to be related to mistaking IV vinCRIStine for an intrathecal medication, such as methotrexate, cytarabine, or hydrocortisone.(6,7,9,11-16) Other causes include: the mislabeling of syringes; bringing IV and intrathecal medications into a treatment area together; failing to administer vinca alkaloids in a specialty oncology unit or with only experienced, oriented staff familiar with current operational and clinical standards, procedures, or protocols; administering chemotherapy outside of normal hours; not conducting an independent double check or “time out” before intrathecal medication administration; and incomplete or missing warning labels.(6,7,9,11,16,17)

Most effective strategy
While further details might be absent about additional underlying causes of these errors, one thing is clear. To the best of our knowledge, every error involving inadvertent intrathecal administration of vinCRIStine or another vinca alkaloid during the past 45 years has involved preparation and administration of the vinca alkaloid in a syringe. We are not aware of a single incident in which IV vinCRIStine or another vinca alkaloid had been prepared in a minibag and then administered intrathecally. Thus, a consensus exists that the most effective strategy currently available to prevent this tragic and frequently fatal event from occurring is to stop dispensing and administering IV vinCRIStine or other vinca alkaloids in syringes.(6,7,9,16-18) Even dilution and preparation of IV vinCRIStine or vinca alkaloids in large syringes of 10-20 mL has resulted in fatal misadministration via the intrathecal route.(16,18)

This strategy—dispensing and administering IV vinCRIStine and vinca alkaloids in a small-volume minibag—ensures that the drug will look distinctly different than a syringe containing a medication that may be administered via the intrathecal route. It places the drug in a larger volume of fluid and in a different container for drug administration (infusion from a minibag via IV tubing), neither of which lends itself well to intrathecal administration. It would be nearly impossible to administer a vinca alkaloid prepared in a minibag to a patient through a spinal needle.(18)

Trissel et al. reported that diluted vinCRIStine is stable in larger volumes,(19) so there is no question regarding stability. Earlier this year, the US Food and Drug Administration (FDA) approved an addition to vinCRIStine labeling that states: To reduce the potential for fatal medication errors due to incorrect route of administration, vinCRIStine sulfate injection should be diluted in a flexible plastic container and prominently labeled as indicated for intravenous use only. ISMP believes this strategy should be implemented in all hospitals that administer IV vinCRIStine, even if intrathecal medications are not currently prescribed, as practices can change. A unique connector for intrathecal/epidural syringes, a strategy currently under evaluation and development, will help reduce the risk of wrong route errors. But even with this strategy, there is still a small risk that IV vinCRIStine or another vinca alkaloid could be prepared in the wrong type (intrathecal/epidural) of syringe. Thus, ISMP strongly recommends dispensing and administering IV vinCRIStine and other vinca alkaloids in minibags, not syringes.

Very low extravasation risk
Some practitioners have expressed concern that administering diluted IV vinCRIStine via a minibag might increase the risk of extravasation and subsequent injury. However, data suggests that the risk of extravasation is very low, regardless of the method used to administer the drug. A study in Australia involving 68 cancer centers evaluated more than 44,000 doses of vinca alkaloids administered via syringe or minibag to adult and pediatric patients and found that the extravasation rates were similar and low—0.03% with syringes and 0.04% with minibags.(20) Preliminary data from another study conducted in children and adults found no cases of extravasation during administration in minibags.(21) These data strongly support the safe use of minibags in adults and children.(22) The risk of extravasation injury is miniscule when compared to the risk of near certain death or severe neurological injury from administering vinca alkaloids intrathecally. Dilution of the vinca alkaloid also reduces the impact of any extravasation that might occur.

Conclusion
Patient safety has been at the forefront of many international, national, state, and local healthcare agendas during the past decade. However, the importance of proactively reducing the risk of tragic medication errors has been minimized too often because the events have occurred infrequently. “Rare” but harmful events should not be discounted simply because of low frequency. Yes, cost and labor may be a little higher to dilute a vinca alkaloid and prepare it in a minibag, and although vinCRIStine in a minibag can be administered at a similar rate as in a syringe, a little more time may be needed to monitor the patient. But we should all commit to making sure that this tragic event never happens again. After all, patients rarely survive after IV vinCRIStine or another vinca alkaloid has been administered intrathecally, and the subsequent decline until death is slow and painful, both emotionally and physically for the patient and their loved ones. No more evidence than this should be needed to raise the urgency with which organizations pursue eradication of this rare but fatal and preventable error.

References
1) ISMP Canada. Preliminary results from the International Medication Safety Self Assessment for Oncology. ISMP Canada Safety Bulletin. 2013;13(6):1-5.
2) ISMP and ISMP Canada. 2012 ISMP International Medication Safety Self Assessment for Oncology.
3) ISMP. This month’s Hospital Pharmacy includes an article that demonstrates vinCRIStine stability. ISMP Medication Safety Alert! 2001;6(14):2.
4) The Joint Commission. Preventing vincristine administration errors. Sentinel Event Alert. 2005;34.
5) World Health Organization. Vincristine (and other vinca alkaloids) should only be given intravenously via a minibag. Information Exchange System, Alert No. 115. July 18, 2007.
6) ISMP. IV vinCRIStine survey shows safety improvements needed. ISMP Medication Safety Alert! 2006;11(4):1-2.
7) Johnson PE, Chambers CR, Vaida AJ. Oncology medication safety: a 3D status report 2008. J Oncol Pharm Pract. 2008;14:169-80.
8) Schochet SS, Lampert PW, Earle KM. Neuronal changes induced by intrathecal vincristine sulfate. J Neuropathol Exp Neurol. 1968;27(4):645–58.
9) Lagman JL, Tigue CC, Trifilio SM, et al. Inadvertent intrathecal administration of vincristine. Commun Oncol. 2007;4(1):45–6.
10) ISMP. Fatal vindesine event. ISMP Medication Safety Alert! 2008;13(16):1.
11) ISMP. Worth Repeating… Prevent vinCRIStine wrong route injections. ISMP Medication Safety Alert! 2010;15(10):3.
12) D’Addario A, Galuppo J, Navari C, et al. Accidental intrathecal administration of vincristine. Am J Forensic Med Pathol. 2010; 31(1):83–4.
13) Reddy GK, Brown B, Nanda A. Fatal consequences of a simple mistake: how can a patient be saved from inadvertent intrathecal vincristine? Clin Neurol Neurosurg. 2011;113:68–71.
14) Seger AC. Personal communication from Andrew C. Seger, PharmD. Division of General Medicine and Primary Care. Brigham and Women’s Hospital, Boston, MA. September 3, 2013.
15) Pongudom S, Chinthammitr Y. Inadvertent intrathecal vincristine administration: report of a fatal case despite cerebrospinal fluid lavage and a review of the literature. J Med Assoc Thai. 2011;94(Suppl 1):S258–63.
16) Schulmeister L. Preventing vincristine administration errors: does evidence support minibag infusions? Clin J Oncol Nurs. 2006;10(2):271-3.
17) Gilbar PJ, Dooley MJ. Review of case reports of inadvertent intrathecal administration of vincristine: recommendations to reduce occurrence. Asia Pac J Clin Oncol. 2007;3(2):59-65.
18) Gilbar P. Inadvertent intrathecal administration of vincristine: has anything changed? J Oncol Pharm Pract. 2012;18(1):155-7.
19) Trissel AL, Zhang Y, Cohen MR. The stability of diluted vincristine sulfate used as a deterrent to inadvertent intrathecal injection. Hosp Pharm. 2001;36:740–5.
20) Gilbar PJ, Carrington CV. The incidence of extravasation of vinca alkaloids supplied in syringes or mini-bags. J Oncol Pharm Pract. 2006;12(2):113-8.
21) Nurgat Z, Smythe MP, Aljedai A. Assessment of the risk of extravasation with the introduction of vincristine mini-bags to eliminate inadvertent intrathecal administration. J Oncol Pharm Pract. 2012;18(suppl):16-7.
22) Gilbar PJ. Accidental administration of vincristine in pediatric patients. J Pediatr Oncol. 2013;1(1): 9-16.
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