Abstract
Although the active pharmaceutical ingredient remains constant, the excipients used will vary according to the manufacturer. This case report is of spuriously raised serum creatinine due to an excipient in one particular intravenous dexamethasone formulation. A patient had three serum creatinine measurements of 102, 369 and 91 μmol/L over a four-hour period. The second result was believed to be spurious and appropriate investigations were instigated. The patient had received dexamethasone intravenously between the first and second blood samples. This was administered as a bolus via a cannula in the dorsum of the hand, and the blood sample was taken by venepuncture of the antecubital fossa of the same arm approximately five minutes later. The dexamethasone used (Hospira UK Ltd) contained creatinine at a concentration of 70,720 μmol/L, with a total of 170 μmol of creatinine given to the patient. Assuming a volume of distribution of 40 L in a 70-kg man, an increase in serum creatinine of 4–5 μmol/L would be expected once equilibrated. It is thought that the serum creatinine result observed was a consequence of the creatinine excipient in the dexamethasone not having completely distributed throughout the body and still being at relatively high concentrations within the limb into which it had been administered. Intravenous dexamethasone can lead to spurious creatinine results, not due to analytical interference but rather the analytically correct measurement of creatinine added as an excipient. This case clearly demonstrates the impact preanalytical factors can have on the accuracy of results.
Introduction
Although the active ingredient remains constant, the excipients used in a particular medication will vary according to the manufacturer. 1 We would like to report a case of spuriously raised serum creatinine due to an excipient found in one particular brand of intravenous dexamethasone.
Excipients are substances other than the active pharmaceutical ingredient which are intentionally included in a drug delivery system and have been appropriately evaluated for safety. They may be used for a number of different reasons, including to aid in the processing of the drug delivery system during its manufacture; to protect, support or enhance stability, bioavailability or patient acceptability; to assist in product identification, or to enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use. 2 There is a wide variety of natural and synthetic products used as excipients, with sodium chloride, sucrose and polyethylene glycol being examples of those most commonly encountered. 1 Details of the excipients used in any particular medication are provided in its summary of product characteristics (SPC) data sheet.
Case report
Serum urea and electrolyte results pre- and post intravenous dexamethasone demonstrating a spurious rise in creatinine
Investigations into the cause of the spurious result involved repeating the creatinine analysis by different methods (O'Leary and enzymatic), both of which gave similar results. Discussions with the medical staff revealed that the only treatment the patient had received between the first and second blood samples was 8 mg intravenous ondansetron (Wockhardt UK Ltd, Wrexham, UK) and 8 mg intravenous dexamethasone (Hospira UK Ltd, Warwickshire, UK), administered approximately five minutes prior to the second blood sample. The medication was administered as a bolus via a cannula in the dorsum of the hand, and the blood sample was taken by venepuncture of the antecubital fossa of the same arm approximately five minutes later.
Further investigations and discussion
Investigation into the likely cause of the interference included examining the SPC data sheets for both medications administered, along with the Electronic Medicine Compendium. 3 This revealed that the particular brand of intravenous dexamethasone used contains creatinine as an excipient; however, this is not the case for all brands commercially available. The manufacturer (Hospira UK Ltd) confirmed that a vial of 3.3 mg/mL dexamethasone contains creatinine at a concentration of 70,720 μmol/L (compared with a normal serum creatinine concentration of approximately 100 μmol/L). The patient only received 2.5 mL of the dexamethasone solution; therefore, we calculated that a total of approximately 170 μmol of creatinine was given to the patient. Assuming a volume of distribution of 40 L in a 70 kg man, this would equate to an increase in serum creatinine of only approximately 4–5 μmol/L once equilibrated. This increase is unlikely to have been of clinical significance. Even with much higher doses given to cachectic patients as can be the case in oncology patients, the total increase is unlikely to be above 15–20 μmol/L. We, however, observed an increase in creatinine reaching 300 μmol/L. We feel this is due to the blood sample being taken during the distribution phase, before it had fully equilibrated throughout the body. Drug preparations which are to be given as intravenous bolus injection are typically at very high concentrations within a relatively small volume. After the drug is injected as a bolus, it is usually rapidly distributed throughout the body, during which time the concentration of the drug falls as it is diluted within the body compartments. The time taken to fully distribute will vary according to the nature of the drug and the site of the injection. Aminoglycosides are reported to take 15–20 min, vancomycin 1–3 h and digoxin 4–6 h; 4 and a peripheral injection is likely to take longer to be fully distributed than one administered through a central line, particularly if the peripheral circulation is compromised in response to disease states.
There is a lack of clear evidence as to the expected duration of the distribution phase of intravenous creatinine, as this is not given as a therapeutic agent. However, the case we observed suggests that at the time of venepuncture, the creatinine, which had been administered peripherally into the back of the hand, had not completely distributed throughout the body and was still at a relatively high concentration within the arm in which it had been administered. Similar spurious creatinine results may occur by direct contamination if the blood for creatinine is taken from a line or cannula used to administer intravenous dexamethasone.
Creatinine is used in this dexamethasone formulation as a stabilizing agent. 1 A search for creatinine in the Electronic Medicine Compendium did not reveal any other intravenous formulations which currently use it as an excipient. However, creatinine is included on the American Food and Drug Administration (FDA) Approved Inactive Ingredients Database. 5 Items on this database may require a less extensive review when included in new drug products, and therefore it is possible that creatinine will be utilized as an excipient in other parenteral formulations in the future.
Conclusion
In conclusion, based on this case, we would like to raise awareness that spuriously high creatinine results can occur due to contamination of the sample with some brands of intravenous dexamethasone. This is not due to analytical interference, but rather the analytically correct measurement of creatinine which has been added as an excipient. It will be apparent not only if blood is taken from the same line used to administer the infusion, but also if blood is taken from the same limb soon after administration. It serves as a more general reminder that samples for analysis should not be taken from near the injection site so soon after intravenous injection of any drug and is a good example of what can happen if a sample is taken under inappropriate circumstances. This case report clearly demonstrates the impact preanalytical factors can have on the accuracy of results.
DECLARATIONS