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Technetium Tc-99m pyrophosphate for cerebrospinal fluid leaks: Radiopharmaceutical considerations James A. Ponto and Michael M. Graham

Abstract Objective: To confirm the anticipated image quality and absence of adverse reactions in patients undergoing clinical practice cerebrospinal fluid (CSF) leak imaging procedures using technetium Tc-99m pyrophosphate (PYP). Methods: Following the recent discontinuation of preservative-free calcium trisodium diethylene triamine pentaacetic acid kits, PYP was selected as a suitable alternative for CSF leak imaging procedures. Procedures were established for its preparation and dispensing, paying special attention to safety considerations, and its use in clinical practice was implemented. Medical records, including images, were reviewed for the first 15 patients undergoing clinical practice CSF imaging procedures using Tc-99m PYP to confirm anticipated image quality and absence of adverse effects. Results: Review of CSF leak imaging procedures using Tc-99m PYP in 15 patients showed images to be of uniformly high quality. The vast majority of injected radiopharmaceutical remained in the CSF throughout the duration of the imaging procedure, allowing visualization of CSF leaks. Only a small amount of Tc-99m PYP diffused into the blood with resultant uptake on the skeleton and excretion into the urine, which did not interfere with image interpretation. No adverse reactions were noted in any of the patients. Conclusion: With proper attention to safety considerations, Tc-99m PYP is a safe and effective alternative for performing CSF leak imaging procedures. Keywords: Cerebrospinal fluid leaks, technetium Tc99m pyrophosphate, radiopharmaceuticals, nuclear pharmacy. J Am Pharm Assoc. 2014;54:45–48. doi: 10.1331/JAPhA.2014.13059

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erebrospinal fluid (CSF) leaks are caused most commonly by trauma and occur most frequently between the region of the sphenoid sinus and temporal bone at the base of the skull.1 Such CSF leaks often can be detected and localized by the accumulation of an intrathecally injected radiopharmaceutical in pledgets placed in nasal cavities and ear canals. Active leaks also may be visualized with imaging. A less common but important type of CSF leak occurs with small defects or tears in the spinal meninges, leading to CSF hypovolemia and a condition referred to as spontaneous intracranial hypotension (SIH).2,3 Because lack of rhinorrhea and otorrhea effectively precludes the usefulness of pledgets in SIH, detection and localization of the leak requires imaging. Currently, the only radiopharmaceutical that is approved by the Food and Drug Administration for imaging of disruptions in CSF flow is indium In 111 pentetate injection (In-111 diethylene triamine pentaacetic acid [DTPA]). Although In-111 DTPA imaging can be useful in detecting and localizing CSF leaks,4 its image quality is limited by its relatively small administered radioactivity dose and its higher-energy gamma emissions, which necessitate a medium-energy collimator. Hence, technetium Tc-99m pentetate (Tc-99m DTPA) gained widespread acceptance for CSF imaging, albeit as an off-label use. Advantages of Tc-99m DTPA over In-111 DTPA included superior image quality, easier ability to perform single-photon emission computed tomography imaging, lower radiation absorbed dose per unit activity, lower cost, and greater availability.5–8 Based on safety considerations, it had been recommended that only a preservative-free, calcium trisodium formulation of DTPA should be used for CSF-related procedures.7 Following the recent discontinuation of preservative-free, calcium trisodium DTPA kits (Pharmalucence, Bedford, MA), the only DTPA kit remaining on the U.S. Received March 11, 2013, and in revised form May 23, 2013. Accepted for publication May 28, 2013. James A. Ponto, MS, BCNP, FAPhA, is Chief Nuclear Pharmacist, Department of Radiology, University of Iowa Hospitals and Clinics, and Professor (Clinical), College of Pharmacy, University of Iowa, Iowa City. Michael M. Graham, MD, PhD, is Director of Nuclear Medicine and Professor, Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City. Correspondence: James A. Ponto, MS, BCNP, Nuclear Medicine 3832 JPP, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA, 52242. Fax: 319-384-6389. E-mail: [email protected] Disclosure: The authors declare no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Previous presentation: American Pharmacists Association Annual Meeting & Exposition, Los Angeles, March 1–4, 2013. Published online ahead of print at www.japha.org on November 20, 2013.

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market was a pentetic acid formulation that also contains p-aminobenzoic acid (PABA) (Draximage, Kirkland, Canada). However, this particular product should not be used for CSF-related procedures7 because preservatives and other excipients, including PABA, administered into the CSF can result in allergic reactions or other toxicity.9–11 Hence, an alternative Tc-99m radiopharmaceutical for CSF leak imaging procedures is needed. Upon review of the formulation contents of all commercially available Tc-99m kits, pyrophosphate (PYP) was selected as the most suitable for this purpose. Unlike most other Tc-99m kits that contain preservatives or other excipients, PYP is a preservative-free kit that contains only sodium pyrophosphate and stannous chloride—substances that are normally present in low concentrations in the CSF. Procedures were established for its preparation and dispensing, paying special attention to safety considerations, and its use in clinical practice was implemented.

Objective The objective of this project was to confirm the anticipated image quality and absence of adverse reactions in patients undergoing clinical practice CSF leak imaging procedures using Tc-99m PYP.

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Methods Medical records, including images, were reviewed for the first 15 patients undergoing clinical practice CSF imaging procedures using Tc-99m PYP to confirm anticipated image quality and absence of adverse effects. Special attention was paid to the desired retention of Tc99m PYP in the CSF rather than its undesired diffusion into the blood. Indicators of adverse effects specifically addressed in these record reviews were increased temperature/fever, increased white blood cell counts, and increased neurological symptoms. Our institutional review board concluded that this project did not constitute human participant research because it was primarily a safety/quality assessment of a clinical imaging procedure.

Results The 15 patients included 6 women and 9 men with a mean age of 49 years (range 19–84). Seven were inpatients and eight were outpatients. Review of CSF leak imaging procedures using Tc-99m PYP in these patients showed images to be of uniformly high quality and comparable with previous images using Tc-99m DTPA (Figure 1). The vast majority of injected radiopharmaceutical remained in the CSF throughout the duration of the imaging procedure, allowing visualization of CSF

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Figure 1. CSF leak procedures Abbreviation used: CSF, cerebrospinal fluid. Panel A: CSF leak imaging procedure using formerly marketed Tc-99m calcium trisodium DTPA shows leak at L2 nerve root (bracket). Panel B: CSF leak imaging procedure using Tc-99m pyrophosphate (PYP) shows normal distribution without evidence of leak; faint uptake in kidneys (arrows) also is noted. Panel C: CSF leak imaging procedure using Tc-99m PYP shows leaks at multiple levels, most prominently at L2–L4 (brackets); faint uptake in kidneys (arrows), bladder (open arrow), and pelvic bones (arrow heads) also is noted.

Table 1. Administered masses and resulting concentrations of components in CSF Sodium 0.09 0.6 3,200

Nominal administered mass (mg) Resulting CSF concentration (mg/L) Concentration normally present in CSF (mg/L)

Pyrophosphate 0.15 1 13.9a

Stannous 0.050 0.33 0.0064b

Chloride 0.030 0.20 4,300

Abbreviation used: CSF, cerebrospinal fluid. a Reported as inorganic phosphate. b Reported as tin.

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leaks (Figure 1C). Only a small amount of Tc-99m PYP diffused into the blood with resultant uptake on the skeleton and excretion into the urine (Figure 1B and -C). Interpretations were positive for CSF leak in 3 patients, normal in 11 patients, and technically unsuccessful in one patient. Medical records reviewed for inpatients included progress notes and lab tests, whereas those for outpatients were limited to follow-up phone calls summarized by clinic staff. None of the 15 had or reported a fever, none of the 7 inpatients had an increase in white blood cell counts, and none of the 15 had or reported increased neurological symptoms.

Discussion Establishment of procedures for the preparation and dispensing of Tc-99m PYP for intrathecal administration included consideration of safety factors, namely mass of chemical components, bacterial endotoxins, and sterility.7 To minimize the injected mass of pyrophosphate and of tin, each PYP kit was reconstituted with 250 mCi (9.25 GBq) Tc-99m sodium pertechnetate and a patient dose of 3 to 5 mCi (111–185 MBq) withdrawn, resulting in only a small fraction (nominally 2%) of vial contents injected into the patient. PYP kits contains 11.9 or 12 mg sodium pyrophosphate and 3.2 to 4.4 or 2.8 to 4.9 mg stannous chloride dihydrate12,13; therefore, only submilligram amounts of components were administered. Assuming uniform distribution in a normal adult volume of CSF of 150 mL, the resulting concentrations of these components are favorable compared with concentrations normally present in CSF (Table 1).14–17 Hence, adverse reactions related to the mass of chemical components were anticipated to be absent. Because Tc-99m PYP is indicated for intravenous administration only, bacterial endotoxin content could potentially exceed that allowed for intrathecal administration. Specifically, U.S. Pharmacopeial Convention (USP) monographs for radiopharmaceuticals limit bacterial endotoxins to 14 endotoxin units (EU) per maximum dose for intrathecal injection and 175 EU per maximum dose for intravenous injection.18 USP Bacterial Endotoxins Test using Limulus Amebocyte Lysate (Charles River, Wilmington, MA) was performed on two reconstituted vials from each of three lots of PYP kits (Pharmalucence) to confirm that this preparation, as described above, contained less than 14 EU per dose. Because the maximum intravenous dose equals the entire contents of a vial, acceptable bacterial endotoxin content for intrathecal injection also can be ensured by administering no more than 8% of the vial contents (14 EU/175 EU = 8%).7,19 Hence, administering only about 2% of Tc99m PYP vial contents ensured that bacterial endotoxin content remained well below the maximum acceptable value for intrathecal injection.

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To ensure maintenance of sterility, all preparation and dispensing activities were performed in an ISO Class 5 hood in an ISO Class 7 clean room in accordance with USP standards20 and all doses were administered within 4 hours of preparation. Additional safety considerations that were followed included obtaining Tc-99m pertechnetate from an elution vial that had been punctured the fewest number of times, dilution with preservative-free 0.9% sodium chloride injection obtained from a previously unopened vial, and withdrawal and administration of only one patient dose per Tc-99m PYP vial.7 Radiochemical purity and stability were another concern because preparation of PYP with 250 mCi (9.25 GBq) Tc-99m exceeded the package insert recommendation of 100 mCi (3.7 GBq).12,13 A previous report using a different formulation of PYP radiolabeled with even greater activities of Tc-99m showed high radiochemical purity initially with stability extending over at least 4 hours.21 This was confirmed for the currently used Tc99m PYP formulation by in-house radiochemical purity testing using silica gel thin-layer chromatography strips developed in methyl ethyl ketone.22 Testing of each vial of Tc-99m PYP used in these 15 patients showed 98% or greater radiochemical purity for all preparations. Another initial concern was that Tc-99m PYP, being a relatively small molecule, might diffuse out of the CSF rather rapidly. In these patients, a small amount of Tc99m PYP was observed to have diffused into blood over several hours and demonstrated skeletal uptake and urinary tract excretion—areas normally visualized following intravenous injection of Tc-99m PYP (Figure 1B and -C). However, this faint activity in the skeleton and urinary tract was not a substantial problem and did not interfere with image interpretation.

Limitations Tc-99m radiopharmaceuticals considered for potential use in CSF leak imaging procedures were limited to products currently approved and marketed in the United States. Evaluation of image quality and adverse reactions were limited to information in patient medical records. Headache and neurologic symptoms such as numbness and altered coordination as indicators of potential adverse effects were difficult to evaluate because these are common symptoms of SIH and were preexisting in the majority of patients. Hence, an increase in neurologic symptoms was sought out during medical record review.

Conclusion With proper attention to safety considerations, Tc-99m PYP is a safe and effective alternative for performing CSF leak imaging procedures.

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References

12. Mallinckrodt. Kit for the preparation of technetium Tc 99m pyrophosphate injection. St. Louis, MO: Mallinckrodt; 2012.

1. Schlosser RJ, Bolger WE. Nasal cerebrospinal fluid leaks: critical review and surgical considerations. Laryngoscope. 2004;114(2):255– 65.

13. Pharmalucence. Kit for the preparation of technetium Tc 99m pyrophosphate injection. Bedford, MA: Pharmalucence; 2008.

2. Renowden SA, Gregory R, Hyman N, Hilton-Jones D. Spontaneous intracranial hypotension. J Neurol Neurosurg Psychiatry. 1995;59(5):511–5.

14. Heipertz R, Eickhoff K, Karstens KH. Magnesium and inorganic phosphate content in CSF related to blood-brain barrier function in neurological disease. J Neuro Sci. 1979;40(2-3):87–95.

3. Mokri B. Spontaneous intracranial hypotension. Curr Neurol Neurosci Rep. 2001;1(2):109–17.

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4. Benamor M, Tainturier C, Graveleau P, Pierot L. Radionuclide cisternography in spontaneous intracranial hypotension. Clin Nucl Med. 1998;23(3):150–1. 5. Lewis DH, Graham MM. Benefit of tomography in the scintigraphic localization of cerebrospinal fluid leak. J Nucl Med. 1991;32(11):2149– 51. 6. O’Connell M, Wong TZ, Forkheim KE, et al. Comparison of Tc99m-DTPA and indium-111 DTPA studies of baclofen pump function. Clin Nucl Med. 2004;29(9):578–80. 7. Ponto J. Special safety considerations in preparation of technetium Tc99m DTPA for cerebrospinal fluid-related imaging procedures. J Am Pharm Assoc. 2008;48(3):413–6. 8. Thomas DL, Menda Y, Graham MM. Radionuclide cisternography in detecting cerebrospinal fluid leak in spontaneous intracranial hypotension. Clin Nucl Med. 2009;34(7):410–6. 9. Rice SA, Fish KJ (Eds.). Anesthetic toxicity. New York: Raven; 1994. 10. Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg. 1999;88(4):797–809. 11. Cook AM, Mieure KD, Owen RD, et al. Intracerebroventricular administration of drugs. Pharmacotherapy. 2009;29(7):832–45.

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16. el-Yazigi A, Martin CR, Siqueira EB. Concentrations of chromium, cesium, and tin in cerebrospinal fluid of patients with brain neoplasms, leukemia or other noncerebral malignancies, and neurological diseases. Clin Chem. 1988;34(6):1084–6. 17. Rao D, Ghalaut VS, Ghalaut PS, Rao S. Cases series: CSF LDH, proteins and electrolyte levels in patients of acute lymphocytic leukemia. Clin Chim Acta. 2012;413(13-14):1045–8. 18. U.S. Pharmacopeial Convention. Official monographs. In: USP 35–NF 30. Rockville, MD: U.S. Pharmacopeial Convention; 2011. 19. Ponto JA. Letter to the editor. Clin Nucl Med. 1987;12:339. 20. U.S. Pharmacopeial Convention. Pharmaceutical compounding: sterile preparations. In: USP 35–NF 30. Rockville, MD: U.S. Pharmacopeial Convention; 2011. 21. Billinghurst MW, Rempel S, Westendorf BA. Radiation decomposition of technetium-99m radiopharmaceuticals. J Nucl Med. 1979;20(2):138–43. 22. Robbins PJ. Chromatography of technetium-99m radiopharmaceuticals: a practical guide. New York: Society of Nuclear Medicine; 1984.

Journal of the American Pharmacists Association

Technetium Tc-99m pyrophosphate for cerebrospinal fluid leaks: radiopharmaceutical considerations.

OBJECTIVE To confirm the anticipated image quality and absence of adverse reactions in patients undergoing clinical practice cerebrospinal fluid (CSF)...
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