Correspondence
Seizures after Povidone-Iodine Mediastinal Irrigation
N Engl J Med 1993; 328:355-356February 4, 1993
- Article
To the Editor:
Zec et al. (June 25 issue)1 describe a suspected adverse drug reaction (with seizures and acute renal failure) to povidone-iodine used for mediastinal irrigation and suggest that an elevated serum iodine level was responsible. They cite the occurrence of seizures with iodinated contrast agents as supporting evidence.
Although elevated serum iodine levels may cause these events, the chronology leaves unanswered questions. The authors state that renal failure developed “coincident” with the seizure. We are not provided with measurements of blood urea nitrogen and creatinine to assess the pathophysiologic features of the impaired renal function. We are not informed of the patient's clinical condition before the seizure, the results of laboratory tests on blood routinely drawn after a seizure, or subsequent serum iodine levels for clinical correlation. The possibility remains that postoperative renal failure from myriad potential causes occurred before irrigation, leading to seizures and elevated serum iodine levels.
The analogy between povidone-iodine and iodinated contrast agents is flawed. Povidone-iodine is a loose complex of iodine and surfactant (polyvinylpyrrolidone), which serves to increase the solubility of the iodine while providing a sustained-release reservoir of the element2. Iodinated contrast agents contain covalently bound iodine and are excreted unchanged, primarily by glomerular filtration. No substantial metabolism, deiodination, or biotransformation occurs3. Solutions of contrast agents contain negligible amounts of free iodine. Toxicity from contrast agents has instead been attributed to ionic side groups, osmolality, protein binding, partition coefficients, and pi electron density4,5.
The neurotoxicity of contrast agents is probably related to disruption of the blood-brain barrier, disturbances in neuronal membranes, or both. Disruption of the blood-brain barrier has been correlated with osmolarity and hydrophilicity3,6. Effects on neuronal membranes have been related to the presence of ionic charges on the contrast molecule and osmolarity6,7. In animals the importance of ionic charge is demonstrated by the subarachnoid median lethal dose in mice and rats. For non-ionic contrast agents, this measurement ranges from 1000 to 2000 mg of iodine per kilogram of body weight, as compared with 200 mg of iodine per kilogram with ionic contrast agents8. A dramatic example of the importance of ionic charge to neurotoxicity in humans is the severity of adverse effects observed after the intrathecal administration of ionic contrast agents9. Indexes associated with toxicity from such agents do not support the notion that iodine had a role in this patient's seizures.
9 ReferencesManfred Hauben, M.D., M.P.H.
Sterling Winthrop, Inc., New York, NY 100161
Zec N ,Donovan JW ,Aufiero TX ,Kincaid RL ,Demers LM . Seizures in a patient treated with continuous povidone-iodine mediastinal irrigation. N Engl J Med 1992;326:1784-1784
Web of Science | Medline2
Harvey SC. Antiseptics and disinfectants: fungicides: ectoparasiticides. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 6th ed. New York: Macmillan, 1980:973.
3
Parvez Z. Contrast media: biological effects and clinical application. Vol. 1. Boca Raton, Fla.: CRC Press, 1987:96.
4
Dawson P. Factors dictating iodinated contrast agent toxicity. In: Excerpta Medica International Congress Series no. 976. Amsterdam: Excerpta Medica, 1991:66-70.
5
Bryan RN ,Hershkowitz N . Neuronal effects of water-soluble contrast agents. Invest Radiol 1984;19:329-332
CrossRef | Web of Science | Medline6
Wilson AJ ,Evill CA ,Sage MR . Effects of nonionic contrast media on the blood-brain barrier: osmolality versus chemotoxicity. Invest Radiol 1991;26:1091-1094
CrossRef | Web of Science | Medline7
Swanson DP, Shetty PC, Kastan DJ, Rollins N. Angiographic contrast media. In: Swanson DP, Chilton HM, Thrall JH, eds. Pharmaceuticals in medical imaging. New York: Macmillan, 1990:29-31.
8
Almen T. Relations between chemical structure, animal toxicity and clinical adverse effects of contrast media. In: Enge I, Edgren J, eds. Patient safety and adverse events in contrast medium examinations. International congress series no. 816. Amsterdam: Excerpta Medica, 1989:25-45.
9
Hilz MJ ,Huk WH ,Schellman B ,Sorgel F ,Druschky KF . Fatal complications after myelography with meglumine diatrizoate. Neuroradiology 1990;32:70-73
CrossRef | Web of Science | Medline
To the Editor:
Zec et al. describe a case in which povidone-iodine irrigation for postoperative infection of the mediastinum resulted in the systemic absorption of iodine, renal failure, and central nervous system toxicity -- a generalized seizure. The povidone-iodine irrigation was replaced with a solution containing neomycin and polymyxin B. Povidone-iodine irrigations may cause renal failure and seizures; unfortunately, neomycin irrigations may cause renal failure and permanent deafness.
In a parallel incident 22 years ago, Gruhl1 described a case in which irrigation with 0.3 percent neomycin for postoperative infection of the mediastinum resulted in systemic absorption of neomycin, renal failure, and central nervous system toxicity -- total deafness. More than three dozen published cases have shown that neomycin irrigations of various wound sites (such as bone or soft tissue) and body cavities can result in irreversible deafness due to systemic absorption2. Neomycin sulfate sterile powder was decertified by the Food and Drug Administration in 1972 because of the risk of nephrotoxicity and ototoxicity and the lack of documented efficacy3. Because of its continued use in irrigations, labeling changes were made to the nonsterile powder,2 and parenteral neomycin was decertified by the FDA in 19884. We repeat the call to abandon neomycin wound irrigations in any concentration. Will these calls continue to fall on deaf ears?
4 ReferencesEmory S. Martin, III, Pharm.D.
Seton Medical Center, Austin, TX 78705Paul J. Godley, Pharm.D.
University of Texas College of Pharmacy, Austin, TX 787121
Gruhl VR . Renal failure, deafness, and brain lesions following irrigation of the mediastinum with neomycin. Ann Thorac Surg 1971;11:376-379
CrossRef | Medline2
Food and Drug Administration, Department of Health and Human Services 3
Food and Drug Administration, Department of Health, Education, and Welfare 4
Nilges TC ,Northern JL . Iatrogenic ototoxic hearing loss. Ann Surg 1971;173:281-289
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Although there are likely to be multiple causes for new-onset seizures in critically ill patients, none of the recognized causes were found in our patient. The patient had mild hyponatremia (sodium, 128 mmol per liter) and mild renal insufficiency (creatinine, 2.0 mg per deciliter), but neither of these would be expected to cause central nervous system effects. The procainamide level just after the seizure was 21.6 μg per milliliter, and the N-acetylprocainamide level measured 10.6 μg per milliliter. Procainamide levels greater than 40 μg per milliliter have been reported to cause depression, hallucinations, and ataxia, but not seizures1. There were no other clinical or biochemical abnormalities at the time that would have caused seizures.
As Dr. Hauben correctly points out, the neurotoxicity of iodinated contrast agents is related to their lipid solubility, osmolarity, and ionic charges. These properties, however, do not entirely explain the mechanisms of interaction between iodinated contrast agents and neurons: increased osmolarity by itself does not induce neuronal spike activity, whereas both ionic and non-ionic contrast agents do2. The chemical structure of iodinated contrast agents, aside from the variables mentioned, is also thought to influence neurotoxicity3. The occurrence of seizures in association with both iodinated contrast agents and mediastinal irrigation with povidone-iodine raises the suspicion of the possible neurotoxicity of iodine.
Drs. Martin and Godley appropriately urge caution in the use of neomycin for wound irrigation. Our letter simply described the patient's course and did not endorse this therapy. The solution containing 40 mg of neomycin per liter, administered at 100 ml per hour, had a concentration less than 1 percent that of the solutions that produced ototoxicity in previously reported cases. Neomycin irrigation was not begun until after the renal insufficiency resolved, and it did not result in hearing impairment.
3 ReferencesNatasa Zec, M.D., Ph.D.
J. Ward Donovan, M.D.
Milton S. Hershey Medical Center, Hershey, PA 170331
Schwartz AB ,Klausner SC ,Yee S ,Turchyn M . Cerebellar ataxia due to procainamide toxicity. Arch Intern Med 1984;144:2260-2261
CrossRef | Web of Science | Medline2
Hershkowitz N ,Bryan RN . Neurotoxic effects of water-soluble contrast agents on rat hippocampus: extracellular recordings. Invest Radiol 1982;17:271-275
CrossRef | Web of Science | Medline3
Caille JM ,Allard M . Neurotoxicity of hydrosoluble iodine contrast media. Invest Radiol 1988;23:Suppl 1:S210-S212
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
R. H. L. Wong, C. S. H. Ng, M. J. Underwood. (2011) Iodine pleurodesis--a word of caution. European Journal of Cardio-Thoracic Surgery
CrossRef2
Nicholas A Edwards, Paul Quigley, L Peter Hackett, Ross James. (2005) Death by oral ingestion of iodine. Emergency Medicine Australasia 17:2, 173-177
CrossRef3
David L. Hepner, Mariana C. Castells. (2003) Anaphylaxis During the Perioperative Period. Anesthesia & Analgesia1381-1395
CrossRef
