Anaphylaxis From Administration of Intravenous Thiamine JAMES M. STEPHEN,

The routine administration of intravenous thiamine in the emergency department has become widespread. Although anaphylaxis from intravenous thiamine is felt to be uncommon, it can be life threatening. The authors present such a case and review the literature regarding this clinical entity. This case of anaphylactic reaction appears to be the first instance reported since 1946 in the US literature. However a review revealed that cases of anaphyiaxis fmm thiamine have been reported with some mgutarfty in the non-US Uterature. Given the large number of patients treated without side effects, it seems that thiamine is relatively safe. However, this case illustrates that the assumptien that thiamine is a drug with a completely innocuous nature is not totally accurate. (Am J Emerg Med 1992;10:61-63. Copyright 0 1992 by W.B. Saunders Company)

Thiamine hydrochloride (vitamin B,) has been in clinical use for at least 55 years.’ The deficiency syndromes of thiamine that have been recognized include the cardiovascular, or “wet” beriberi, syndrome, and the central nervous system, or “dry” beriberi syndrome. The dry beriberi syndrome can be clinically separated into the peripheral neuropathies and the central Wernicke-Korsakoff syndrome. Certain individuals presenting to the emergency department, (including chronic alcoholics and other malnourished patients) are at high risk for thiamine deficiency. In these patients, many of whom have altered mental status, the administration of glucose containing intravenous solutions may precipitate the Wernicke-Korsakoff syndrome.* It is for this reason that thiamine has become the only regularly administered parenteral vitamin supplement in the emergency department. The use of thiamine in this regard has been cloaked in fact and legend. In some institutions, its use is restricted to administration by physicians only, because of the fear of anaphylaxis. Conversely, other hospitals allow its use freely, as it is felt to be completely safe.

A 32-year-old man presented to the emergency department complaining of left shoulder pain with weakness and numbness in his left

From the Division of Emergency Medicine, Tufts/New England Medical Center, Boston, MA; and *Tufts University School of Medicine, Boston, MA. Manuscript received July 8, 1991; revision accepted August 12. 1991. Address reprint requests to Dr Stephen, Division of Emeraencv Medicine. Tufts/New Enaland Medical Center, 750 Washh-g& St, NEM&i #311, Boston MA 02111. Key Words: Case reports, thiamine hydrochloride, anaphylaxis, toxicity. Copyright 0 1992 by W.B. Saunders Company 0735-8757/92/l OOl-0018$5.00/O

MD, ROBERT GRANT, BA,* CHARLOTTE S. YEH, MD

arm. He stated that he had consumed “seven or eight beers” that night, and while walking home had slipped on the ice, falling on his shoulder. He was in otherwise good health and took no medications. He reported no known allergies, and did not take vitamin supplements. He denied the recent use of recreational or over the counter drugs. The patient was an obese white male in no distress. Vital signs were: pulse 128 beats/min: respirations 18 breaths/min; blood pressure 170 over 98 mm Hg; and temperature 37.o”C. Orthostatic vital signs showed that when the patient stood up, his pulse increased to 150 beats/min, and his blood pressure fell to 150 over 79. Physical examination was unremarkable except for tenderness on the anterior aspect of the left shoulder joint and acromioclavicular joint as well as over the coccygeal area. No bony deformity was noted. His arm had strong pulses with intact pain sensation, two point discrimination, and a capillary refill time of 1.5 seconds. Pain on movement of the shoulder limited motor strength to %. The patient was slightly sleepy but awakened to verbal stimulation, and was oriented to time and place. Radiographs of the shoulder and coccyx were normal. Based on his orthostatic blood pressure changes, the patient was felt to be mildly dehydrated. An intravenous solution of lactated ringers was started. The patient’s ethanol level was 148 mg/dL. One hundred milligrams of thiamine hydrochloride (Thiamine Hydrochloride USP, Elkins-Sinn, Inc, Cherry Hill, NJ) was administered intravenously (IV). Next, one ampule of multivitamins (M.V.C. 9 + 3. LyphoMed, Melrose Park, IL) was added to the IV bag, and the infusion rate was estimated at 150 mL/h. Within 2 minutes, the patient complained of intense nausea. He denied pruritus, shortness of breath, or throat tightness. The infusion containing multivitamins had not reached the patient’s blood stream, since the yellow color of the additive had not run through the complete length of the IV tubing. The infusion was stopped, the tubing changed, and normal saline was substituted. The patient then complained of lightheadedness, and was quite anxious. Within 5 minutes, he became diffusely and intensely erythematous. He remained conscious, although anxious and confused. Blood pressure readings were consistently less than 50 mm Hg systolic; however, femoral pulses were maintained, suggesting a systolic pressure of about 70 mm Hg. The heart rate was in the 140 beats/min range. Chest examination revealed bilateral inspiratory and expiratory wheezes. No upper airway stridor was noted. There were no urticaria. The patient was placed in trendelenburg position, and high flow (15 L/min) oxygen was administered by face mask. Subcutaneous epinephrine, l:lOOO, 0.3 mL was administered, as were IV diphenhydramine, 50 mg, cimetidine, 300 mg, and methylprednisolone, 125 mg. The patient then complained of substemal chest pain and increasing shortness of breath. Albuterol, 0.5 mL via nebulizer mask, was given. A second IV line was inserted, and a fluid bolus of 20 mL/kg (1,800 mL) was given. Consideration was given to administration of IV epinephrine, but the chest pain persisted. Over the next 10 minutes, the patient’s blood pressure slowly improved, up to 118 over 50 mm Hg, and the pulse slowed into the 120 beats/min range. A 12.lead electrocardiogram revealed sinus tachycardia, with an abnormal rightward axis, and rsR’ pattern on V, (Figure 1). The patient’s blood pressure continued to improve, and the erythema and wheezes faded, but his chest pain continued. His blood pressure 61

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FIGURE 1. The patient’s electrocardiogram.

held steady, and his other physical signs and symptoms of anaphylaxis faded. Because his chest pain persisted, nitroglycerine, 0.2 mg sublingual was given. This was repeated twice over the next 20 minutes, and his pain slowly subsided. It was not completely clear if the nitroglycerine administration relieved the patient’s pain. The patient was admitted to the medical intensive care unit, where he was observed for 24 hours. Electrocardiogram showed no changes consistent with infarction, and creatine phosphokinase-MB isoenzymes did not rise. He remained asymptomatic except for musculoskeletal pain and was discharged on the second day after admission.

DISCUSSION Numerous patients present to the emergency department with conditions that place them at risk for thiamine deple-

tion. Ethanol intoxication/abuse, malnutrition, altered mental status, hypoglycemia, and the acquired immunodeficiency syndrome are among the conditions where thiamine may be administered. Thiamine-deficient patients that receive dextrose containing IV fluids are at risk for Wernicke’s encephalopathy, so thiamine is routinely given as well. The question of the safety of thiamine by intravenous injection has been around for some time. Many reports of adverse reactions to thiamine were from the 1930s to the 1940s. From these early reports, three different reactions were noted. Precipitation of episodes of herpes zoster secondary to thiamine were reported in three patients.3 All three patients were receiving chronic thiamine therapy. Since that report, there have been no recorded cases of herpes zoster associated with thiamine, so the association between the two must be considered dubious at best. The second type of adverse reaction to thiamine is an overdose syndrome with symptoms similar to hyperthyroidism.4,5 The patients so affected have nausea and vomiting, anorexia, headache, irritability, tremors, and palpitations. The third type of reaction, and that observed in this case, is an anaphylactic response. Anxiety, pruritus, respiratory distress, nausea, abdominal pain, and shock have been described, sometimes progressing to death.5-11 The anaphylactic response was most often seen after multiple administrations of the drug. These have occurred when the drug was given orally, IV, intramuscularly, or subcutaneously. Eczematous reactions to topical exposure to thiamine in pharmaceutical workers has also been observed.‘* Large doses of thiamine (126 mg/kg) in an animal model were considered lethali Death was felt to have occurred from inhibition of the medullary respiratory center. Wrenn et ali4 studied the clinical effects of IV thiamine in 989 patients, finding “minor” reactions (burning at the injection site) in 11 of 989 (l.l%), and “major” reaction (pru-

ritus) in 1 of 989 (. 10%). This study, along with the dearth of case reports from the US literature, lends credence to the opinion that thiamine administration is quite safe. The foreign literature however has several reports, both case studies and retrospective reviews, that report anaphylaxis and death from thiamine. We found nine cases of death attributed to thiamine administration from 1965 to 1985.15*‘”The manufacturer also cautions that “an occasional individual” may develop a life-threatening reaction to the drug (package insert, Thiamine Hydrochloride Injection, USP, ElkinsSinn. Inc, Cherry Hill, NJ). The Wrenn report may have found a lower than actual incidence of adverse reactions, since they excluded those individuals with past history of reaction to thiamine. We feel that it may be very difficult to elicit such a history from the typical emergency department patient requiring thiamine, since they often have an altered mental status. SUMMARY We have presented a case of thiamine-induced anaphylaxis from the parenteral administration of thiamine. Although felt to be quite rare, we found that the reaction can be life threatening, with several reported deaths. Although the drug probably does have a low incidence of adverse reactions, the clinician should be aware of the possibility it may occur, and be prepared to take appropriate action. Like any drug, it should be administered when required, with a clear realization of its risks versus its benefits. The authors thank Kazimiera Smierzchalska and Emily Manczuk for their help with translations, and Elkins-Sinn, Inc for supplying valuable references.

REFERENCES 1. Vorhaus MG, Williams RR, Waterman RE: Studies on crystalline vitamin 6,: Experimental and clinical observations. JAMA 1935;105:1580 2. Wilson JD, Braunwald E, lsselbacher KJ, et al (eds): Harrison’s Principles of Internal Medicine (ed 12). New York, NY, McGraw-Hill, 1991, p 2047 3. Steinberg CL: Untoward effects resulting from the use of large doses of vitamin B,. Am J Dig Dis 1938;5:680-681 4. Mills CA: Thiamine overdosage and toxicity. JAMA 1941; 116(18):2101 5. Leitner ZA: Untoward effects of vitamin B,. Lancet 1943;2: 474-47s 6. Stein W, Morgenstern M: Sensitization to thiamine hydrochloride: Report of a case. Ann Intern Med 1944;70:826-828 7. Laws CL: Sensitization to thiamine hydrochloride. JAMA 1941;117:146 8. Schiff L: Collapse following parenteral administration of solution of thiamine hydrochloride. JAMA 1941;117:609

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9. Stiles MH: Hypersensitivity to thiamine chloride, with a note on sensitivity to pyridoxine hydrochloride. J Allergy 1941;12: 507-509 10. Reingold IM, Webb FR: Sudden death following intravenous administration of thiamine hydrochloride. JAMA 1946;130: 491-492 11. Assem ESK: Anaphylactic reaction to thiamine. Practitioner 1973:565 12. Larsen Al, Jepsen JR, Thulin H: Allergic contact dermatitis from thiamine. Contact Dermatitis: 1989;20:387-388

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13. Haley TJ, Flesher AM: A toxicity study of thiamine hydrochloride. Science 1946;104:567-568 14. Wrenn KD, Murphy F, Slovis CM: A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 1989;18:867870 15. Thiamine/Vitamin B,: Deaths and/or LifeThreatening Side Effects, Information Analysis Search Request: 86-0268. Philadelphia PA, Elkins-Sinn Inc, 1986 16. Patlan BD, Lebedinsky RI, Petukh Ml: Anaphylactic shock due to vitamin B,. Terapeuticheskil Arkhiv 1968;40(9):116-117

Anaphylaxis from administration of intravenous thiamine.

The routine administration of intravenous thiamine in the emergency department has become widespread. Although anaphylaxis from intravenous thiamine i...
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