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Too Close for Comfort: Fatal Zinc Overdose Narrowly Avoided

Problem: We recently learned about a frightening close call that almost led to the administration of a 1,000-fold overdose of intravenous (IV) zinc to a 2-year-old child via parenteral nutrition (PN). This incident is eerily similar to another event we described more than a decade ago in our September 6, 2007, newsletter about a preterm infant who received a fatal 1,000-fold overdose of zinc via PN. In both cases, the dose of zinc was accidentally entered in mg dosing units instead of the intended mcg dosing units. And in both cases, a critical dose warning did not fire for the prescriber entering the order and/or the pharmacists transcribing or verifying the PN orders. The details of these events are provided below to encourage hospitals across the nation to apply the lessons learned and take steps to prevent similar errors, and to encourage drug information database vendors to create much needed critical dose warnings for IV zinc and other trace elements.

Recent Close Call

A physician prescribed PN for a 2-year-old child using the hospital’s standard, electronic pediatric (1-12 years) PN template. To include the zinc (a trace element), the prescriber had to specifically choose this additive from a preference list in the order template. Once the additive was selected, the template provided no default dose or directions to guide the prescribing of a zinc dose within a safe range. Additionally, the dosing unit of measure defaulted to mg, as it did in the adult PN template, not mcg. Because the dosing units defaulted to mg, the physician inadvertently prescribed 700 mg instead of the intended 700 mcg of zinc per day. Incidentally, the prescriber would have been unable to change the dosing units from mg to mcg had he noticed the error since the mg dosing unit was hard coded in the pediatric PN template. He would have had to enter 0.7 mg as the dose.   

The order entry system (Epic) did not warn the physician that he had prescribed a massive 1,000-fold overdose of zinc. Nor did the system warn the two pharmacists who independently verified the PN order. They, too, overlooked the dosing unit error. When transmitting the PN order to an outsourcing admixture pharmacy for preparation, one of the pharmacists conducted an additional verification in the outsourcing pharmacy order entry system but overrode several critical warnings about the excessive dose of zinc sulfate, the salt that would be used. The critical warnings from the outsourcing pharmacy system noted that the prescribed dose of zinc was higher than the recommended dose per body weight and per day for acute dosing with zinc. However, the warnings were displayed on an ordinary-looking screen and embedded within many other alerts, many of which had, in the past, been clinically insignificant; thus, the warnings failed to capture the pharmacist’s attention, and alert fatigue likely played a role in overriding the alerts. 

Fortunately, before compounding the PN, the pharmacist at the outsourcing pharmacy noticed the large dose of zinc prescribed, and the corresponding large volume of the zinc sulfate additive (700 mL, 1 mg/mL) that would be needed to prepare the PN. The pharmacist at the outsourcing pharmacy contacted the hospital pharmacist to question the order. The error was identified, and the prescriber was contacted. The order was changed to 300 mcg of zinc per day when the prescriber realized he had also made a weight-based dose calculation error in the initial order.

During investigation of this event, the hospital was surprised to learn that a warning for a 1,000-fold dosing error with IV zinc did not fire in their order entry system. When the hospital’s drug information database vendor, First Databank, was contacted, the company confirmed that dose checking was not available for this medication. In fact, a dose warning report for “zinc sulfate, 700 mg, intravenous, continuous PN at 50 mL/hr” notes “there is no dose checking available for this medication.” This warning was filtered by the hospital’s system settings because it was categorized as a dose warning “excluded by policy due to low risk/low potential for harm.”

Prior Fatal Event

In 2006, a physician prescribed PN for a preterm infant using a pediatric PN order template. Zinc was not included as a possible additive in the order template, so the physician provided a free-text order for zinc 330 mcg/100 mL. The automated compounder used to prepare the PN required the zinc additive to be entered as a mcg/kg dose. A pharmacist correctly converted the dose but then mistakenly selected “mg” instead of “mcg” on a dropdown list when entering the dose in the automated compounder. This resulted in a final concentration of 330 mg/100 mL. As in the most recent case, the order entry system (and the automated compounder software, in this case) failed to warn the pharmacist of the 1,000-fold zinc overdose. Prior to PN preparation, another pharmacist compared the product labels and work labels to the original PN order but did not notice that the zinc dose was expressed in mg, not mcg.

During the evening, an inexperienced pharmacy technician prepared the PN using a 500 mL bag instead of the usual 250 mL pediatric bag since the needed volume of zinc sulfate was 481.8 mL. She had to replenish the zinc sulfate compounder syringe 11 times, which required dozens of vials. Although she found this unusual, she was uncertain whether it signaled an error and was not comfortable questioning the evening pharmacist. Several other PN additives had to be added to the bag manually, which the technician prepared and brought to a different pharmacist to check before adding them to the admixture. The pharmacist verified the patient information at the top of the label, then skipped to the bottom of the label to identify the additives that had to be added manually, thus failing to read the middle of the label which noted that 481.8 mL of zinc sulfate had been added to a bag that would contain 560 mL in total. The pharmacist verified the vials and syringes of the manual additives but never noticed the zinc sulfate error. The final PN bag was then dispensed to the neonatal intensive care unit (NICU).

In the NICU, two nurses conducted a double check of the PN but failed to notice the error. One nurse read the “numbers” associated with the dose for each ingredient from the PN label, but not the dosing units, to another nurse who was reading the original order. While the “numbers” matched, the accidental entry of mg instead of mcg was, again, not noticed. Sadly, many clues that pointed to the error were overlooked during the verification processes, including the fact that the PN bag was unusually large–bigger than the infant herself.

The next morning, the technician who prepared the PN told the oncoming lead technician about the unusual preparation of PN that required numerous replenishments of a zinc sulfate syringe. The oncoming technician checked the order, discovered the error, and alerted a pharmacist, who immediately called the NICU to stop the infusion. The infant received edetate calcium disodium, but the chelation therapy was unsuccessful, and the infant died. The coroner listed cardiac failure caused by zinc intoxication as the cause of death.

Safe Practice Recommendations: The hospital where the most recent close call occurred has made several system changes that should be implemented by all hospitals:

Build, test, and heed maximum dose alerts. The hospital built and tested a customized maximum dose warning for all forms of IV zinc (PN additive of zinc sulfate or zinc chloride; other forms of IV zinc that have been imported during US product shortages [e.g., zinc gluconate]). The warning for zinc doses above 250 mcg/kg fires upstream to prescribers during order entry, as well as downstream to pharmacists during order verification. With this warning, a provider making a catastrophic 1,000-fold dosing error with IV zinc caused by transposing mcg and mg dosing units would receive a critical dose warning with a hard stop (impossible to override).

Meanwhile, ISMP has contacted First Databank to further inquire about the lack of critical dose warnings for IV zinc (and other trace elements). The company noted that, historically, it has not included products exclusively used to compound PN solutions in its dose checking module because each component is dependent on patient-specific parameters (e.g., nutritional status, lab values). However, based on this close call, the vendor will be adding IV zinc to the dose range checking module and will revise its current policy to include additives with referenced dosing specific to PN use if they do not have additional dependencies. Additionally, the company will instruct users that PN component dose screening requires screening of each individual PN component and that it cannot address the total dose for an electrolyte derived from different salts.

Other drug information database vendors may include critical dose warnings for zinc. For example, for PN dosing, Medi-Span issues a warning if a daily pediatric (1-17 years) dose of zinc exceeds 125 mcg/kg for continuous infusions of PN. However, please check your system to determine if a critical dose warning would appear if a zinc overdose was entered, and if not, build and test a dose warning for this product.  

Default to mcg dosing units. The hospital changed all standard pediatric PN templates to default to mcg dosing units for zinc. Prescribers cannot change the dosing units from mcg to mg. As a general principle, the dosing units should always default to the appropriate units for prescribing.

Provide dosing guidance. The hospital is adding dosing buttons for additives, including zinc, in PN templates to help guide prescribers to doses within safe limits. The dosing buttons offer a few acceptable dose options (i.e., 50 mcg/kg, 125 mcg/kg, 250 mcg/kg) for the prescriber, although free-text orders are still allowed.  

Additional recommendations to help prevent PN dosing errors follow:

Standardize prescribing methods. Ensure that the dosing in PN templates in the electronic health record (EHR) corresponds to the way orders are entered in an automated compounder if used, so dose recalculation is not necessary.

Heighten suspicion of an error. Create a learning culture that encourages all staff, despite their level of experience or education, to speak up about unusual conditions.

Pharmacy technicians who compound PN and other products should feel comfortable stopping the process if they suspect any abnormality and should be required to do so if they need to add a drug, electrolyte, mineral, or trace element in a large dose or in a large volume in order to complete a single preparation. They should also stop the process if they need to prepare the admixture in a larger bag or bottle than usual. If the compounding process is stopped, pharmacists should suspect an error (e.g., transposed mcg and mg dosing; decimal point errors) and verify every step of the compounding process before proceeding.

Nurses who work in pediatric and neonatal units should be taught to (and never hesitate to) question products that are dispensed in larger (or smaller) volumes than typically supplied for children or neonates.

Conduct effective verification processes in the pharmacy. A pharmacist should be required to verify the initial PN order entry. If a compounder is used for preparation, and transcription of the order into the compounder is required, comparison between the original order and the transcribed order by a second pharmacist must occur. As appropriate, double check any dose calculations. Scan the barcodes of compounding products for verification, and conduct quality control checks and verification of replacement solutions on the compounder, if used. Visually verify the vials and syringes that contain all manually prepared additives before they are injected into the PN admixture. All source containers used should be presented to the pharmacist for verification, not just a representative vial when multiple vials are used. Additionally, using gravimetric analysis of the PN admixture ingredients for verification can help detect errors before reaching the patient. Review the final compounded PN prior to dispensing.

Provide education and validate competency. Establish a formal training process and validate competency for pharmacy technicians who are permitted to compound PN, and for pharmacists who check the compounded PN admixture. Focus training on dose and dose concentration, not just the volume of PN additives. If compounding services are provided for neonatal and pediatric patients, include age-specific training emphasizing weight-based dosing, and validate the competency of all who may prepare or check pediatric PN.

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