0148-6071/90/1402-021~$02.00/0
Vol. 14, No. 2 Printed in U.S. A .
J O URNAL O F PARENTERAI. A N D ENTERAL NUTRITION Copyright (c 1990 by the American Society for Parenteral and Enteral Nutrition
Parenteral Nutrition Hypersensitivity MAURICELEVY,M.D., L. LEE DUPUIS,M.SC.PHM. From the Department of Paediatrics, Division of Clinical Pharmacology, and Department of Pharmacy, T h e Hospital for Sick Children, Toronto, Canada
ABSTRACT. Total parenteral nutrition (TPN) is widely used. Although mechanical, septic, and metabolic complications are well known, hypersensitivity skin reactions are rare. We describe a 16-year-old boy with Burkitt’s lymphoma who devel-
oped a urticaria1 skin rash when treated with T P N and vitamins. The adverse skin reaction was probably caused by the inactive component of excipient, polysorbate. (Journal of Parenteral and Enteral Nutrition 14:213-215, 1990)
Total parenteral nutrition ( T P N ) is indicated whenever the gastrointestinal tract cannot be used or a n adequate nutrient intake cannot be provided via the gastrointestinal tract. I t has become more widely used in cancer patients a s oncologists have become increasingly aware of the need t o meet the nutritional requirements of cancer patients.’ Chemotherapy and radiotherapy frequently interfere with the patient’s nutritional intake.’ Patients on T P N usually receive two types of infusates, a n amino acid/glucose/mineral solution and a n intravenous fat emulsion. Th e addition of vitamins is also necessary to restore deficits and meet the individual’s daily needs. Mechanical, septic, and metabolic complications of T P N are well known, but allergies to T P N an d vitamins are rarely observed. We report a case in which the multivitamin product given with a T P N solution was associated with a skin rash. T o the best of our knowledge, this is the first published report of a n immediate urticarial reaction to a n excipient in a T P N solution.
oriented, and in no distress. Other findings were as follows: blood pressure 122/78 mm Hg, pulse rate 96 beats/min, respirations 18/min, oral temperature 38°C. His height was 169 cm (below the 50th percentile) and weight was 55.4 kg (at the 25th percentile). He had swollen lips with cracks a n d ulcers. In addition, he had severe buccal ulcers and a n erythematous pharynx. The rest of the physical examination was unremarkable. Laboratory data on admission were a s follows: white blood cell count, 0.50 X 10g/liter; red blood cell count, 0.30 x 1O1’/liter; hemoglobin 86 g/liter; hematocrit, 0.248; mean corpuscular volume, 82.4 fl; mean corpuscular hemoglobin 28.6 pg; mean corpuscular hemoglobin concentration 347.5 g/liter; platelet count, 127 X log/ liter; total polymorphs, 0.01 x 10g/liter; bands, 0.01 x 10g/liter;eosinophils 0.01 X lo9 g/liter; lymphocytes, 0.46 X 10g/liter; monocyte, 0.28 x 10g/liter; urea, 2.4 mmol/ liter; creatinine, 34 pmol/liter; Na, 135 mmol/liter; K, 4 mmol/liter; C1, 101 mmol/liter; glucose, 5.65 mmol/liter; Ca, 2.20 mmol/liter; phosphate, 1.19 mmol/liter. Initially the patient was given a n intravenous infusion of 6.6% dextrose-3.3% saline. Piperacillin, 2770 mg, every six h r a n d 140 mg of gentamicin every 8 hr were started and continued until the 10th day of hospitalization. Because of the patient’s poor clinical status and oral intake, T P N was given on the 3rd day of admission as amino acid/glucose solution with vitamins (MVI Pediatric; Rorer Canada, Inc.)3 (Tables I and 11) at a rate of 100 ml/hr. T h e total daily amount of T P N solution was divided into two intravenous bags, only one of which contained vitamins. Shortly after starting the T P N with vitamins, the patient developed a raised whitish rash on his arms, chest, back, a n d head. T h e rash was intensely pruritic and resolved quickly after the infusion was stopped. T P N solution without vitamins was given after 24 h r and was not associated with any adverse effect. However, when the patient was restarted on a T P N solution with vitamins the next day, he developed a rash similar to that previously observed. Again the rash disappeared after the infusion was discontinued. T P N without vitamins was then continued for 4 days. T h e patient was discharged after 10 days with no fever
CASE REPORT
A 16-year-old boy with Burkitt’s lymphoma, which had been diagnosed a few months before, was admitted to The Hospital for Sick Children, Toronto, with high fever of 2 days duration, sore throat, mouth lesions which had worsened over the preceding few days, difficulty in opening his mouth, and decreased oral intake. No other associated symptoms were noted. Th e week before admission, he had completed a course of chemotherapy with cyclophosphamide, methotrexate, and doxorubicin. He had a past history of hypersensitivity to sulfonamide drugs which was manifested as a diffuse erythematous pruritic rash distributed over his entire body. I t appeared 10 days after the drug was started and disappeared 4 days later under antihistamine treatment. At physical examination on admission, the patient looked unwell. He was pale, mildly dehydrated but alert, Received for publication, June 26, 1989. Accepted for publication, November 2, 1989. Reprint requests: Lee Dupuis, Dept. of Pharmacy, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1x8.
213
214
Vol. 14, No. 2
LEVY AND DUPUIS
TABLE I Constituents of TPN solution (without uitarnins) Constituent
Quantity
Amino acids Dextrose Na
30.0 g/liter 100.0 g/liter 30.0 mmol/liter 30.0 mmol/liter 32.1 mmol/liter 9.0 mmol/liter 9.0 mmol/liter 4.0 mmol/liter 46.0 pmol/liter 6.3 pmol/liter 5.0 pmol/liter 0.47 pmol/liter 0.076 pmol/liter 0.25 pmol/liter 18.0 pmol/liter
K c1 Ca
P Mg Zn cu Mn I Cr
Se Fe
TABLE I1 Constituents of MVZ uediatric (Rorer Canada Inc.) Constituent
Quantity
Ascorbic acid Vitamin A Vitamin D Thiamine Riboflavin Pyridoxine Niacinamide d-Pantothenic acid Vitamin E Biotin Folic acid Vitamin B,, Vitamin K, Mannitol Polysorbate 80 Polysorhate 20 Butylated hydroxytoluene Butylated hydroxyanisole Sodium hvdroxide to adiust DH
80.0 mg 2300.0 1U 400.0 1U 1.2 mg 1.4 mg 1.0 mg 17.0 mg 5.0 mg 7.0 1U 20.0 pg 0.14 mg 1.0 Pg 0.2 mg 375.0 mg 50.0 mg 0.8 mg 58.0 pg 14.0 pg
and looking well. Results of initial cultures (blood, urine, oral swabs, stool) and chest x-ray were negative. Throughout the period of antibiotic treatment, gentamicin levels were in the normal therapeutic range. DISCUSSION
Since our patient was able to tolerate T P N solution without vitamins as well as oral multivitamin tablets, it is unlikely that his skin rash was caused by one of the therapeutically active components of the T P N and vitamin solution (Tables I and 11). Rather, a n inactive component or excipient may have been the cause. MVI pediatric contains polysorbate 80, polysorbate 20, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA) and excipients (Table 11). The polysorbates or tweens act as emulsifiers, solubilizers, and wetting agents in pharmaceutical formulations. They are fatty acid esters of sorbitol and its anhydrides, copolymerized with a varying number of ethylene oxide molecules. Polysorbate 80 is known to inhibit lymphocyte trans, ~ has been associated with hepatic formation in ~ i t r oand impairment in rabbits5 and renal hepatic impairment in rats.' It is suspected of causing pulmonary deterioration,
hepatomegaly, cholestatic jaundice, ascites, splenomegaly, renal failure, azotemia, and thrombocytopenia in premature neonate^.^ However, one 4-month-old infant was given 19.2 g of polysorbate 80 orally on 2 consecutive days with no adverse effects apart from passing six loose stools during this p e r i ~ d . ~ There are no reported cases of toxicity due to polysorbate 20 exposure. Men have received 15 g/day by mouth for several months with no apparent adverse effect^.^ Since residues of unpolymerized ethylene dioxide may be present in polysorbate 80 or 20, ethylene dioxide hypersensitivity must be considered in the differential diagnosis in our patient. B H T and BHA are phenolic antioxidants which are included in pharmaceutical formulations to delay or prevent the oxidation of fats and oils. A single, oral BHT dose of 4 g has been reported to cause nausea, vomiting, dizziness, confusion, and loss of consciousness in an adult.8 Much larger oral doses (80 g) have caused headache, visual and auditory hallucination, slurred speech, and unsteady gait.' Consumption of food products containing BHT and/or BHA has been shown to cause urticaria and rash."," Hypersensitivity to these chemicals has also been implicated as the cause of chronic nasal congestion, headaches, sinusitis, and asthma." BHT and BHA are commonly used to preserve food products such as potato chips. Our patient consumes a diet typical of North American teen-agers; therefore he has probably ingested BHT and BHA in the past and continues to do so without difficulty. Therefore, we believe that B H T and BHA are unlikely to have caused his reaction. Since gaseous ethylene oxide is commonly used to sterilize plastic medical equipment, our patient probably continues to be exposed to this chemical without adverse effect. Consequently, the polysorbates are the most likely cause of our patient's urticaria1 eruption. Of course, this could be confirmed only by rechallenging him with single ingredients. Increased awareness is required in patients receiving T P N not only for mechanical, septic, or metabolic complications, but also for hypersensitivity reactions. Although such reactions are rare, allergic skin tests should be considered when they appear since T P N is crucial in severely ill patients. REFERENCES 1. Schein PS, Macdonald JS, Waters C, et al: Nutritional complications of cancer and its treatment. Semin Oncol 2:337-347, 1975 2. Donaldson SS, Lenon RA: Alteration of nutritional status. Impact of chemotherapy and radiation therapy. Cancer 43:2036-2052,1979 3. Product monograph. MVI Paediatric. Rorer Canada Inc. Bramalea, Ontario 4. Mezei M: Effect of polysorbate 85 on human skin. J Invest Dermatol 64:165-168, 1975 5. Bhat R, Jiang J-X, Walsh JM, Mortensen ML, et al: Effect of vitamin E and polysorbate on bile acid transport in newborn rabbit hepatocytes (abstr). Pediatr Res 19:213A, 1985 6. Nityanand S, Kapoor N K Effect of chronic oral administration of Tween-80 in Charles Foster rats. Indian J Med Res 69:664-670, 1979 7. Gosselin RE, Smith RP, Hodge HC: Clinical Toxicology of Com-
MarchlAprill990
PARENTERAL NUTRITION HYPERSENSITIVITY
mercial Products. Williams & Wilkins, Baltimore, 1984, pg. 11, p. 278 8. Shlian DM, Goldstone J: Toxicity of butylated hydroxytoluene (lett). N Eng J Med 314:648-649, 1986 9. Grogan MW: Toxicity from B H T ingestion (lett). West J Med. 145:245-246, 1986 10. Moneret-Vautrin DA, Bene MC, Faure G: She should not have
215
chewed. Lancet 1:617, 1986 11. Juhlin L: Recurrent urticaria: Clinical investigation of 330 patients. Br J Dermatol 104:369-381, 1981 12. Fisherman EW, Cohen G: Chemical intolerance to butylated-hydroxyanisole (BHA) and butylated-hydroxytoluene and vascular response as an indicator and monitor of drug intolerance. Ann Allergy 31:126-133, 1973
Vol. 14, No. 2 Printed in U.S. A .
J O URNAL O F PARENTERAI. A N D ENTERAL NUTRITION Copyright (c 1990 by the American Society for Parenteral and Enteral Nutrition
Parenteral Nutrition Hypersensitivity MAURICELEVY,M.D., L. LEE DUPUIS,M.SC.PHM. From the Department of Paediatrics, Division of Clinical Pharmacology, and Department of Pharmacy, T h e Hospital for Sick Children, Toronto, Canada
ABSTRACT. Total parenteral nutrition (TPN) is widely used. Although mechanical, septic, and metabolic complications are well known, hypersensitivity skin reactions are rare. We describe a 16-year-old boy with Burkitt’s lymphoma who devel-
oped a urticaria1 skin rash when treated with T P N and vitamins. The adverse skin reaction was probably caused by the inactive component of excipient, polysorbate. (Journal of Parenteral and Enteral Nutrition 14:213-215, 1990)
Total parenteral nutrition ( T P N ) is indicated whenever the gastrointestinal tract cannot be used or a n adequate nutrient intake cannot be provided via the gastrointestinal tract. I t has become more widely used in cancer patients a s oncologists have become increasingly aware of the need t o meet the nutritional requirements of cancer patients.’ Chemotherapy and radiotherapy frequently interfere with the patient’s nutritional intake.’ Patients on T P N usually receive two types of infusates, a n amino acid/glucose/mineral solution and a n intravenous fat emulsion. Th e addition of vitamins is also necessary to restore deficits and meet the individual’s daily needs. Mechanical, septic, and metabolic complications of T P N are well known, but allergies to T P N an d vitamins are rarely observed. We report a case in which the multivitamin product given with a T P N solution was associated with a skin rash. T o the best of our knowledge, this is the first published report of a n immediate urticarial reaction to a n excipient in a T P N solution.
oriented, and in no distress. Other findings were as follows: blood pressure 122/78 mm Hg, pulse rate 96 beats/min, respirations 18/min, oral temperature 38°C. His height was 169 cm (below the 50th percentile) and weight was 55.4 kg (at the 25th percentile). He had swollen lips with cracks a n d ulcers. In addition, he had severe buccal ulcers and a n erythematous pharynx. The rest of the physical examination was unremarkable. Laboratory data on admission were a s follows: white blood cell count, 0.50 X 10g/liter; red blood cell count, 0.30 x 1O1’/liter; hemoglobin 86 g/liter; hematocrit, 0.248; mean corpuscular volume, 82.4 fl; mean corpuscular hemoglobin 28.6 pg; mean corpuscular hemoglobin concentration 347.5 g/liter; platelet count, 127 X log/ liter; total polymorphs, 0.01 x 10g/liter; bands, 0.01 x 10g/liter;eosinophils 0.01 X lo9 g/liter; lymphocytes, 0.46 X 10g/liter; monocyte, 0.28 x 10g/liter; urea, 2.4 mmol/ liter; creatinine, 34 pmol/liter; Na, 135 mmol/liter; K, 4 mmol/liter; C1, 101 mmol/liter; glucose, 5.65 mmol/liter; Ca, 2.20 mmol/liter; phosphate, 1.19 mmol/liter. Initially the patient was given a n intravenous infusion of 6.6% dextrose-3.3% saline. Piperacillin, 2770 mg, every six h r a n d 140 mg of gentamicin every 8 hr were started and continued until the 10th day of hospitalization. Because of the patient’s poor clinical status and oral intake, T P N was given on the 3rd day of admission as amino acid/glucose solution with vitamins (MVI Pediatric; Rorer Canada, Inc.)3 (Tables I and 11) at a rate of 100 ml/hr. T h e total daily amount of T P N solution was divided into two intravenous bags, only one of which contained vitamins. Shortly after starting the T P N with vitamins, the patient developed a raised whitish rash on his arms, chest, back, a n d head. T h e rash was intensely pruritic and resolved quickly after the infusion was stopped. T P N solution without vitamins was given after 24 h r and was not associated with any adverse effect. However, when the patient was restarted on a T P N solution with vitamins the next day, he developed a rash similar to that previously observed. Again the rash disappeared after the infusion was discontinued. T P N without vitamins was then continued for 4 days. T h e patient was discharged after 10 days with no fever
CASE REPORT
A 16-year-old boy with Burkitt’s lymphoma, which had been diagnosed a few months before, was admitted to The Hospital for Sick Children, Toronto, with high fever of 2 days duration, sore throat, mouth lesions which had worsened over the preceding few days, difficulty in opening his mouth, and decreased oral intake. No other associated symptoms were noted. Th e week before admission, he had completed a course of chemotherapy with cyclophosphamide, methotrexate, and doxorubicin. He had a past history of hypersensitivity to sulfonamide drugs which was manifested as a diffuse erythematous pruritic rash distributed over his entire body. I t appeared 10 days after the drug was started and disappeared 4 days later under antihistamine treatment. At physical examination on admission, the patient looked unwell. He was pale, mildly dehydrated but alert, Received for publication, June 26, 1989. Accepted for publication, November 2, 1989. Reprint requests: Lee Dupuis, Dept. of Pharmacy, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1x8.
213
214
Vol. 14, No. 2
LEVY AND DUPUIS
TABLE I Constituents of TPN solution (without uitarnins) Constituent
Quantity
Amino acids Dextrose Na
30.0 g/liter 100.0 g/liter 30.0 mmol/liter 30.0 mmol/liter 32.1 mmol/liter 9.0 mmol/liter 9.0 mmol/liter 4.0 mmol/liter 46.0 pmol/liter 6.3 pmol/liter 5.0 pmol/liter 0.47 pmol/liter 0.076 pmol/liter 0.25 pmol/liter 18.0 pmol/liter
K c1 Ca
P Mg Zn cu Mn I Cr
Se Fe
TABLE I1 Constituents of MVZ uediatric (Rorer Canada Inc.) Constituent
Quantity
Ascorbic acid Vitamin A Vitamin D Thiamine Riboflavin Pyridoxine Niacinamide d-Pantothenic acid Vitamin E Biotin Folic acid Vitamin B,, Vitamin K, Mannitol Polysorbate 80 Polysorhate 20 Butylated hydroxytoluene Butylated hydroxyanisole Sodium hvdroxide to adiust DH
80.0 mg 2300.0 1U 400.0 1U 1.2 mg 1.4 mg 1.0 mg 17.0 mg 5.0 mg 7.0 1U 20.0 pg 0.14 mg 1.0 Pg 0.2 mg 375.0 mg 50.0 mg 0.8 mg 58.0 pg 14.0 pg
and looking well. Results of initial cultures (blood, urine, oral swabs, stool) and chest x-ray were negative. Throughout the period of antibiotic treatment, gentamicin levels were in the normal therapeutic range. DISCUSSION
Since our patient was able to tolerate T P N solution without vitamins as well as oral multivitamin tablets, it is unlikely that his skin rash was caused by one of the therapeutically active components of the T P N and vitamin solution (Tables I and 11). Rather, a n inactive component or excipient may have been the cause. MVI pediatric contains polysorbate 80, polysorbate 20, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA) and excipients (Table 11). The polysorbates or tweens act as emulsifiers, solubilizers, and wetting agents in pharmaceutical formulations. They are fatty acid esters of sorbitol and its anhydrides, copolymerized with a varying number of ethylene oxide molecules. Polysorbate 80 is known to inhibit lymphocyte trans, ~ has been associated with hepatic formation in ~ i t r oand impairment in rabbits5 and renal hepatic impairment in rats.' It is suspected of causing pulmonary deterioration,
hepatomegaly, cholestatic jaundice, ascites, splenomegaly, renal failure, azotemia, and thrombocytopenia in premature neonate^.^ However, one 4-month-old infant was given 19.2 g of polysorbate 80 orally on 2 consecutive days with no adverse effects apart from passing six loose stools during this p e r i ~ d . ~ There are no reported cases of toxicity due to polysorbate 20 exposure. Men have received 15 g/day by mouth for several months with no apparent adverse effect^.^ Since residues of unpolymerized ethylene dioxide may be present in polysorbate 80 or 20, ethylene dioxide hypersensitivity must be considered in the differential diagnosis in our patient. B H T and BHA are phenolic antioxidants which are included in pharmaceutical formulations to delay or prevent the oxidation of fats and oils. A single, oral BHT dose of 4 g has been reported to cause nausea, vomiting, dizziness, confusion, and loss of consciousness in an adult.8 Much larger oral doses (80 g) have caused headache, visual and auditory hallucination, slurred speech, and unsteady gait.' Consumption of food products containing BHT and/or BHA has been shown to cause urticaria and rash."," Hypersensitivity to these chemicals has also been implicated as the cause of chronic nasal congestion, headaches, sinusitis, and asthma." BHT and BHA are commonly used to preserve food products such as potato chips. Our patient consumes a diet typical of North American teen-agers; therefore he has probably ingested BHT and BHA in the past and continues to do so without difficulty. Therefore, we believe that B H T and BHA are unlikely to have caused his reaction. Since gaseous ethylene oxide is commonly used to sterilize plastic medical equipment, our patient probably continues to be exposed to this chemical without adverse effect. Consequently, the polysorbates are the most likely cause of our patient's urticaria1 eruption. Of course, this could be confirmed only by rechallenging him with single ingredients. Increased awareness is required in patients receiving T P N not only for mechanical, septic, or metabolic complications, but also for hypersensitivity reactions. Although such reactions are rare, allergic skin tests should be considered when they appear since T P N is crucial in severely ill patients. REFERENCES 1. Schein PS, Macdonald JS, Waters C, et al: Nutritional complications of cancer and its treatment. Semin Oncol 2:337-347, 1975 2. Donaldson SS, Lenon RA: Alteration of nutritional status. Impact of chemotherapy and radiation therapy. Cancer 43:2036-2052,1979 3. Product monograph. MVI Paediatric. Rorer Canada Inc. Bramalea, Ontario 4. Mezei M: Effect of polysorbate 85 on human skin. J Invest Dermatol 64:165-168, 1975 5. Bhat R, Jiang J-X, Walsh JM, Mortensen ML, et al: Effect of vitamin E and polysorbate on bile acid transport in newborn rabbit hepatocytes (abstr). Pediatr Res 19:213A, 1985 6. Nityanand S, Kapoor N K Effect of chronic oral administration of Tween-80 in Charles Foster rats. Indian J Med Res 69:664-670, 1979 7. Gosselin RE, Smith RP, Hodge HC: Clinical Toxicology of Com-
MarchlAprill990
PARENTERAL NUTRITION HYPERSENSITIVITY
mercial Products. Williams & Wilkins, Baltimore, 1984, pg. 11, p. 278 8. Shlian DM, Goldstone J: Toxicity of butylated hydroxytoluene (lett). N Eng J Med 314:648-649, 1986 9. Grogan MW: Toxicity from B H T ingestion (lett). West J Med. 145:245-246, 1986 10. Moneret-Vautrin DA, Bene MC, Faure G: She should not have
215
chewed. Lancet 1:617, 1986 11. Juhlin L: Recurrent urticaria: Clinical investigation of 330 patients. Br J Dermatol 104:369-381, 1981 12. Fisherman EW, Cohen G: Chemical intolerance to butylated-hydroxyanisole (BHA) and butylated-hydroxytoluene and vascular response as an indicator and monitor of drug intolerance. Ann Allergy 31:126-133, 1973
