The Case

A 35-year-old patient on the neurology service was receiving carbamazepine for a seizure disorder. Daily serum drug levels consistently fell below the therapeutic range, which led the physicians to gradually increase the doses. On the seventh day of hospitalization, the patient appeared drowsy, which progressed to stupor, unresponsiveness, and hypotension. For completeness, the evaluating physician added a serum drug level to the other lab tests and was surprised to find the carbamazepine level markedly elevated, in the toxic range.

The cause of the toxic carbamazepine level was assumed to have been an iatrogenic overdose the day of the patent’s deterioration, so a medication error report was filed. When the pharmacist began investigating the report, she noted that the brand of carbamazepine suspension had recently been changed to a generic formulation that tended to settle out of suspension significantly faster than the original manufacturer’s suspension.

After satisfying herself that a dosing error had not occurred on the day of the patient’s deterioration, the pharmacist inferred that failure to shake the bottle prior to administration resulted in the initial doses being very dilute. As the others used the multi-dose suspension bottle, the remaining solution became increasingly concentrated, resulting in a toxic dose.

Because the healthcare organization had switched carbamazepine formulations at all its member hospitals, a Continuous Quality Improvement (CQI) process was initiated, which identified a similar medication error at another location. In the second case, a pharmacy technician failed to shake thoroughly a bottle of carbamazepine suspension prior to pouring it into a plastic bottle for dispensing. The nature of the second error was discovered after a sample of the remaining suspension was sent to an independent lab for analysis and found to be highly concentrated.

The Commentary

The medication distribution system involves prescribing (ordering), order review, transcription, order entry, dispensing, administering, and monitoring medication effects on the patient. This case demonstrates the importance of pharmacy (responsible for dispensing) and nursing (drug administration) working together to minimize errors in administration.

Drug administration techniques, such as shaking an oral suspension, are becoming difficult to keep up with as new, more complicated drugs are approved—entire textbooks are devoted to this topic.(1) Hospital pharmacy departments often provide important drug use information on each dose or on the medication administration record to remind nurses about special administration techniques that should be employed in the preparation of a dose. In this case, failure to vigorously shake the multi-dose suspension resulted in a wrong-dose medication administration error, due in part to the pharmaceutical qualities of the carbamazepine suspension.

The use of a multi-dose container of carbamazepine (for example, a 4-ounce bottle) contributed to this error. These containers have also contributed to other types of errors. For example, in a case reported to the Institute for Safe Medication Practices, 100 ml (an entire bottle) of Cipro oral suspension was administered to a patient by a nurse, who may have thought this was a single-dose container, consistent with how unit doses may have been provided for other forms of medication.(2) In another case (reported to me anecdotally), a trained medication observer intervened to prevent a nurse from administering the entire contents of an 8-ounce bottle of theophylline elixir. Any time a nurse is required to manipulate a medication (measure it or break a tablet in half), there is a greater risk that an error will occur. One of the goals of the unit-dose drug distribution system is to provide nurses with doses that are ready to administer to the patient, thus increasing nurse efficiency while decreasing errors.(3)

Any time a patient experiences an unexpected event that could be related to a medication, physicians should consider the potential that a medication administration error has occurred. Unfortunately, errors are common, occurring at a rate of 1 for every 5 doses in a recent study, with 7% having the potential for harming the patient.(4) Wrong dose errors, such as the case described, occur in 3% of all doses administered, based on the same study, which used direct observation to detect errors. In addition, 6% of doses are not administered; if a patient is not responding to therapy, an omission error may be a possible explanation.(4)

The investigation following the suspected error described in the case serves as a helpful model. The error was reported through the hospital’s medication reporting system. The pharmacist was aware of the change in manufacturer, and pursued possible causes for the dramatic change in patient status and serum drug concentration findings. A cause was found and disseminated not only at that institution but also at other member hospitals.

Medications that should be shaken prior to administration include oral suspensions, otic and ophthalmic suspensions, and inhalers. (As an aside, the assumption that a generic suspension is bioequivalent to a brand name standard is generally accurate and regulated by the US Food and Drug Administration, but this equivalence may depend on both agents being shaken properly prior to measuring doses.[5]) Some injectables require reconstitution, which the nurse would do for products such as antibiotics prepared using the ADD-Vantage® system. This system involves a specially designed medication vial connected to a flexible diluent container, which allows the nurse to reconstitute the medication by using the solution in the IV container. This avoids an additional step of transferring dissolved drug from the medication vial to the base solution for administration. Such preparations should be shaken until the drug is completely dissolved. There have been cases where patients did not receive a complete dose due to insufficient shaking of antibiotics prepared with the ADD-Vantage® system as well as the Baxter Mini-Bag Plus system.(6-9) Carbamazepine is not the only potentially toxic medication in which proper shaking may be critical. Phenytoin oral suspension has also been associated with toxic reactions, and requires close monitoring of serum drug concentrations.(10-12) In addition, isophane insulin human suspension and insulin human zinc suspension have special agitation requirements: the bottles should be rolled several times, since vigorous shaking can cause frothing and will affect the measurement of the correct dose.(13)

How can errors like this one be prevented?

• In general, physicians should prescribe tablets or capsules (when patients can tolerate them) instead of prescribing an oral suspension.
• Use unit-dose oral syringes that are labeled with brightly colored "Shake Well" stickers.
• Use manufacturer-prepared products when possible (there have been reports of pharmacy compounding errors, such as a case where a 5-year-old boy received a 5-fold overdose of imipramine suspension for enuresis[14]).
• Alert nurses to situations where oral liquids are not of a uniform consistency (or "pharmaceutically elegant"), and consult with the pharmacist when this is questionable.

The relatively infrequent occurrence of wrong-dose errors (3% of all doses) makes it difficult to maintain awareness that a patient’s inadequate response to medications, or an episode of drug toxicity, may be due to dispensing or administration errors. Review of cases such as this should help illustrate the importance of each player in the drug distribution system.

Elizabeth A. Flynn, PhD, RPh Associate Research Professor Center for Pharmacy Operations and Designs Auburn University Harrison School of Pharmacy Auburn, Alabama

References

1. Chernecky C, Butler SW, Graham P, Infortuna MH. Drug calculations and drug administration. Philadelphia, PA: W.B. Saunders; 2002.

2. ISMP Medication Safety Alert! The Institute For Safe Medication Practices (ISMP) Web site. November 3, 1999. [ go to related site ]

3. Barker KN. Ensuring safety in the use of automated medication dispensing systems. Am J Health Syst Pharm. 1995;52:2445-7.[ go to PubMed ]

4. Barker KN, Flynn EA, Pepper GA, Bates DW, Mikeal RL. Medication errors observed in 36 healthcare facilities. Arch Intern Med. 2002;162:1897-1903.[ go to PubMed ]

5. Electronic Orange Book Web site. [ go to related site ] (Search by Active Ingredient "carbamazepine"; Rx Prescription Drug Products.)

6. Cohen, MR. Improperly mixed IV antibiotics. Hosp Pharm. 1997;32:1462-1465.

7. El-Sabawy M, Threlkeld M. Improperly activated ADD-Vantage. Hosp Pharm. 1992;27:824-835.

8. Davis RL, Raymond GG, Geberbauer CW. Quality assurance audit of the ADD-Vantage system for intermittent intravenous drug administration. ASHP Annual Meeting. 1991;48:P-29E.

9. Schwarz HO, Dong DB. Evaluation of the intravenous ADD-Vantage intermittent delivery system (IV ADD-Vantage System). ASHP Midyear Clinical Meeting. 1992;27:P-172E.

10. Leventhal LJ, Gould J. Toxic reaction to improperly administered phenytoin suspension. Arch Intern Med. 1987;147:2221.[ go to PubMed ]

11. Anonymous. Diphenylhydantoin suspension hazard. JAMA. 1972;221:89.[ go to PubMed ]

12. Shelov SP. Dosing errors in the use of antiepileptic drug suspensions. Pediatr Rev. 1996;17:329.[ go to PubMed ]

13. Insulin human monograph. AHFSfirst [database on CD-ROM]. Version 2.74. San Bruno, CA: First Databank; 2003.

14. Oral liquid medications may be more vulnerable to errors than previously recognized. ISMP Medication Safety Alert! The Institute For Safe Medication Practices (ISMP) Web site. June 28, 2000. [ go to related site ]