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Clinical Biochemistry

Spuriously raised serum creatinine associated with an excipient present in an intravenous


dexamethasone formulation
Denise Darby, June So, Joanne Russell and Phillip J Monaghan
Ann Clin Biochem 2012 49: 292
DOI: 10.1258/acb.2011.011114

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Case Report

Spuriously raised serum creatinine associated with an excipient


present in an intravenous dexamethasone formulation

Denise Darby1, June So2, Joanne Russell1 and Phillip J Monaghan1


1
Department of Clinical Biochemistry; 2Department of Pharmacy, The Christie NHS Foundation Trust, Wilmslow Road, Manchester
M20 4BX, UK
Corresponding author: Dr Denise Darby. Email: Denise.darby@nhs.net

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 mmol/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 mmol/L, with a total of 170 mmol 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 mmol/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.

Ann Clin Biochem 2012; 49: 292– 294. DOI: 10.1258/acb.2011.011114

Introduction provided in its summary of product characteristics (SPC)


data sheet.
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 Case report
excipient found in one particular brand of intravenous A male patient with metastatic lung cancer had pre-
dexamethasone. chemotherapy blood taken which demonstrated a creatinine
Excipients are substances other than the active pharma- of 102 mmol/L (Table 1). As the sample was haemolysed, a
ceutical ingredient which are intentionally included in a repeat sample was sent to the laboratory to determine the
drug delivery system and have been appropriately evalu- potassium result. It was noted that the creatinine on this
ated for safety. They may be used for a number of different second sample appeared to have increased to 369 mmol/L.
reasons, including to aid in the processing of the drug deliv- The marked increase in creatinine over a relatively short
ery system during its manufacture; to protect, support or time period and the normal urea raised suspicions that
enhance stability, bioavailability or patient acceptability; to this was a spurious result, and the laboratory requested a
assist in product identification, or to enhance any other attri- repeat sample to confirm the results. This third sample
bute of the overall safety, effectiveness or delivery of the taken approximately an hour later was similar to the
drug during storage or use.2 There is a wide variety of initial value at 91 mmol/L.
natural and synthetic products used as excipients, with Investigations into the cause of the spurious result
sodium chloride, sucrose and polyethylene glycol being involved repeating the creatinine analysis by different
examples of those most commonly encountered.1 Details methods (O’Leary and enzymatic), both of which gave
of the excipients used in any particular medication are similar results. Discussions with the medical staff revealed

Annals of Clinical Biochemistry 2012; 49: 292 –294

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Darby et al. Dexamethasone interference in the measurement of serum creatinine 293
................................................................................................................................................

Table 1 Serum urea and electrolyte results pre- and post intravenous dexamethasone demonstrating a spurious rise in creatinine
3 h prior to intravenous 5 min post intravenous 75 min post intravenous
dexamethasone dexamethasone dexamethasone
Sodium (mmol/L) 136 136 136
Potassium (mmol/L) Haemolysed 4.1 4.5
Urea (mmol/L) 4.2 4.7 4.9
Creatinine (mmol/L) 102 369 91

that the only treatment the patient had received between the There is a lack of clear evidence as to the expected dur-
first and second blood samples was 8 mg intravenous ation of the distribution phase of intravenous creatinine, as
ondansetron (Wockhardt UK Ltd, Wrexham, UK) and this is not given as a therapeutic agent. However, the case
8 mg intravenous dexamethasone (Hospira UK Ltd, we observed suggests that at the time of venepuncture, the
Warwickshire, UK), administered approximately five creatinine, which had been administered peripherally into
minutes prior to the second blood sample. The medication the back of the hand, had not completely distributed
was administered as a bolus via a cannula in the dorsum throughout the body and was still at a relatively high con-
of the hand, and the blood sample was taken by venepunc- centration within the arm in which it had been administered.
ture of the antecubital fossa of the same arm approximately Similar spurious creatinine results may occur by direct con-
five minutes later. tamination 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
Further investigations and discussion stabilizing agent.1 A search for creatinine in the Electronic
Medicine Compendium did not reveal any other intravenous
Investigation into the likely cause of the interference formulations which currently use it as an excipient.
included examining the SPC data sheets for both medi- However, creatinine is included on the American Food
cations administered, along with the Electronic Medicine and Drug Administration (FDA) Approved Inactive
Compendium.3 This revealed that the particular brand of Ingredients Database.5 Items on this database may require
intravenous dexamethasone used contains creatinine as an a less extensive review when included in new drug products,
excipient; however, this is not the case for all brands com- and therefore it is possible that creatinine will be utilized as
mercially available. The manufacturer (Hospira UK Ltd) an excipient in other parenteral formulations in the future.
confirmed that a vial of 3.3 mg/mL dexamethasone contains
creatinine at a concentration of 70,720 mmol/L (compared
with a normal serum creatinine concentration of approxi-
Conclusion
mately 100 mmol/L). The patient only received 2.5 mL of
the dexamethasone solution; therefore, we calculated that In conclusion, based on this case, we would like to raise
a total of approximately 170 mmol of creatinine was given awareness that spuriously high creatinine results can occur
to the patient. Assuming a volume of distribution of 40 L due to contamination of the sample with some brands of
in a 70 kg man, this would equate to an increase in serum intravenous dexamethasone. This is not due to analytical
creatinine of only approximately 4– 5 mmol/L once equili- interference, but rather the analytically correct measurement
brated. This increase is unlikely to have been of clinical sig- of creatinine which has been added as an excipient. It will be
nificance. Even with much higher doses given to cachectic apparent not only if blood is taken from the same line used
patients as can be the case in oncology patients, the total to administer the infusion, but also if blood is taken from the
increase is unlikely to be above 15 –20 mmol/L. We, same limb soon after administration. It serves as a more
however, observed an increase in creatinine reaching general reminder that samples for analysis should not be
300 mmol/L. We feel this is due to the blood sample being taken from near the injection site so soon after intravenous
taken during the distribution phase, before it had fully equi- injection of any drug and is a good example of what can
librated throughout the body. Drug preparations which are happen if a sample is taken under inappropriate circum-
to be given as intravenous bolus injection are typically at stances. This case report clearly demonstrates the impact
very high concentrations within a relatively small volume. preanalytical factors can have on the accuracy of results.
After the drug is injected as a bolus, it is usually rapidly
distributed throughout the body, during which time the
DECLARATIONS
concentration of the drug falls as it is diluted within the
body compartments. The time taken to fully distribute Competing interests: The authors have no competing
will vary according to the nature of the drug and the site interests.
of the injection. Aminoglycosides are reported to take Funding: None.
15 –20 min, vancomycin 1 –3 h and digoxin 4 –6 h;4 and Ethical approval: None required.
a peripheral injection is likely to take longer to be fully Patient consent: None required.
distributed than one administered through a central line, Guarantor: DD.
particularly if the peripheral circulation is compromised in Contributorship: All authors contributed equally to this
response to disease states. report.

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294 Annals of Clinical Biochemistry Volume 49 May 2012
................................................................................................................................................

REFERENCES 4 DiPiro JT, Spruill WJ, Blouin RA, Pruemer JM, Wade WE. Concepts in
Clinical Pharmacokinetics. 4th edn. Bethesda, MD: American Society of
1 Akers MJ. Excipient –drug interactions in parenteral formulations. J Pharm Health-System Pharmacists, Inc, 2005
Sci 2002;91:2283 –300 5 United States Food and Drug Administration. Inactive Ingredient Search
2 The International Pharmaceutical Excipients Council. The IPEC Excipient for Approved Drug Products. See http://www.accessdata.fda.gov/
Composition Guide 2009. See http://www.ipec-europe.org/UPLOADS/ scripts/cder/iig/index.cfm (last checked 13 July 2011)
IPECCompositionGuidefinal.pdf (last checked 13 July 2011)
3 Dexamethasone 3.3 mg/ml Solution for Injection (vial). See http://emc.
medicines.org.uk/medicine/23141/SPC/Dexamethasone (last checked 4
November 2010) (Accepted 5 October 2011)

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