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Penicillin anaphylaxis: Fatality in elderly patients without a history of penicillin allergy
PenicillinAnaphylaxis: Fatality in Elderly Penicillin Allergy
Patients
Without
a History
MICHAEL A. SUE, MD, DEAN T. NORITAKE, WILLIAM B. KLAUSTERMEYER, MD
Two anaphylactic fatalities following penicillin administration are reported. Neither of the two patients had a history of previous penicillin allergy. Both were elderly and suffered from active cardiovascular dlsease. Penicillin skin testing may be indicated in some high-risk patients requiting parenteral penicillin, despite a negative history for penicillin allergy. (Am J Emerg Med 1988;6:456-458. 0 1988 by W.8. Saunders Company.)
It is known that most anaphylactic fatalities following penicillin administration occur in patients without a previous history of penicillin allergy. * This finding is certainly, in part, related to the selecting out of patients with a previous history of penicillin allergy for treatment with alternative antibiotics. The benefits of penicillin skin testing regardless of prior history was suggested by Adkinson et al.* However, Adkinson, Spence, and Wheeler later judged that prospective skin testing of all history-negative patients requiring penicillin was not a cost-effective means of reducing IgE-dependent penicillin allergy.3 We report two cases of anaphylactic fatalities following penicillin administration in patients without a history of penicillin allergy. Both patients were elderly and suffered from active cardiovascular disease. Penicillin skin testing may be routinely indicated in elderly history-negative patients requiring penicillin who have underlying illnesses likely to increase their mortality from an anaphylactic episode.
of
MD,
CASE REPORTS Case1 A 67-year-old man was admitted for an elective cardiac pacemaker change. He had a complicated medical history with previous myocardial infarction, angina, hypertension, gout, and obesity. A permanent demand pacemaker was implanted 5 years earlier and at that time he received intravenous (IV) methicillin, penicillin, and oral dicloxacillin. At 11:45 PM on the evening before the second implant, the patient received 2 g oxacillin followed by five million units of penicillin G intravenously, a standard protocol for routine pacemaker implant procedures at that time. Approximately one half of the dosage of penicillin was administered by 12:15 AM, when the patient complained
of generalized itching and a diffuse rash. The nurse immediately stopped the penicillin infusion, and continued IV hydration. Diphenhydramine, 25 mg, was administered orally at 12:25 AM. As the itching subsided, the patient complained of hoarseness, tightness of the throat, and dyspnea. Epinephrine 0.5 cc (1:lOOO) diluted in 10 cc saline was administered intravenously at 12:40 AM. Hoarseness and dyspnea persisted, and the patient complained of nausea, followed by vomiting. IV fluids were increased to a maximum as the heart rate was noted to be 180 beats per minute and irregular. The patient became cyanotic as his pulses diminished, and the cardiac arrest team was called at 12:45 AM. Cardiopulmonary resuscitation (CPR)
was unsuccessful and the patient was pronounced dead at 1:35 AM. Case2
From the Division of Allergy and Immunology, Department of Medicine, Wadsworth Veterans Administration Medical Center, and the Department of Medicine, University of California at Los Angeles. Manuscript 2, 1987.
received
June 24, 1987; revision
accepted
October
Address reprint requests to Dr. Klaustermeyer: Allergy/ Immunology Section 891/l 11 R, Wadsworth VA Medical Center, Los Angeles, CA 90073. Key Words:
Fatality,
penicillin,
Q 1988 by W.B. Saunders
0735-6757/88/0605-0007$5.00/O
456
anaphylaxis.
Company.
A 70-year-old white man with multiple medical problems, including diabetes mellitus, glaucoma, hypertension, and cerebrovascular and cardiovascular disease, was transferred to the Wadsworth VA Medical Center from a nearby hospital. He was admitted 3 days earlier for a myocardial infarction complicated by acute pulmonary edema. The patient had required mechanical ventilatory support, but responded very well to IV morphine and furosemide, and was extubated within 15 hours. Upon transfer, he appeared stable and denied symptoms of angina, dyspnea, or palpitations. Physical examination revealed stable vital signs with a BP of 130180 and a pulse of 70. He had bibasilar rales and a 216 midsystolic murmur at the apex with an S3 gallop rhythm. Bilateral lower extremity edema was present. The initial hospital course was uneventful while undergoing cardiac rehabilita-
SUE ET AL n FATAL PENICILLIN
tion. On the fourth hospital day, the patient was noted to have a cellulitis of the right forearm without evidence of thrombophlebitis. The patient denied any allergic history upon transfer, although he had reported an allergy to an unknown antibiotic on a prior admission. Review of his chart revealed that he had previously received courses of antimicrobial therapy with IV penicillin, oxacillin, and ampicillin without any complications. Dicloxacillin, 500 mg, orally four times daily was ordered. Twenty-four hours later, he developed fullness of the right olecranon bursa, which was aspirated, yielding cloudy fluid with an elevated leukocyte count and negative gram stain. The dicloxacillin was discontinued; IV penicillin G 1.5 million units every 4 hours and oxacillin 1.O g every 6 hours were ordered. Shortly after the oxacillin and penicillin were infused, the patient complained of a “funny sensation.” A generalized urticarial reaction involving the face, trunk, and upperarms was noted. Diphenhydramine, 50 mg, was administered intravenously. BP was 90/70 and a normal saline infusion was begun. After 10 minutes, 0.5 cc epinephine 1:lOOO diluted in 10 cc of saline was infused slowly. A decrease in erythema was noted but the patient complained of nausea and discomfort in the throat. He subsequently lost consciousness and developed generalized, tonic-clonic motor activity. The ECG revealed ventricular fibrillation which rapidly degenerated to asystole. CPR was unsuccessful, and the patient was pronounced dead.
DISCUSSION Penicillin therapy is the most common cause of anaphylaxis4 Moreover, it has been estimated that nearly 75% of fatal anaphylactic reactions are the result of penicillin administration.’ The best way to prevent fatality caused by penicillin-induced anaphylaxis is to prevent the occurrence of such reactions in pa-
tients who are at risk. Prospective skin testing with major and minor determinants of penicillin is one way to identify patients at risk of anaphylaxis to penicillin,2*6as patients with positive tests have a 50% to 75% risk of an accelerated or anaphylactic reaction following penicillin administration.7*8 Alternative antibiotics could then be prescribed to avoid such reactions. When skin testing to the relevant major and minor determinants in history-positive patients is negative, the risk of severe allergic reaction to penicillin is <1%.9 The major determinant (penicilloyl poly-lysine [Pre-Pen; Kremers Urban Company, Milwaukee]) and the minor determinant penicillin G are the only penicillin skin test reagents commercially available at this time. The other minor determinants (penicilloate and penilloate), also important in predicting anaphylactic reactivity, are not generally available but should be released in the near future. Patients should be skintested for penicillin allergy for the following indications: (1) need to administer penicillin to a patient possibly allergic to penicillin; (2) no suitable alternative
ANAPHYLAXIS
IN THE ELDERLY
antibiotic; or (3) lack of bactericidal activity, increased cost, toxicity, or difficulty of administration of alternative antibiotics. Only patients that require penicillin should be tested, and testing should be performed within 24 to 72 hours before therapy.’ Prick testing with major and minor determinants of penicillin is done initially. If the result is negative, intradermal testing is then performed. Diluent and histamine controls are used. The entire procedure takes less than 40 minutes. If properly performed, the risk of systemic reaction to penicillin skin testing itself is low, about 1%. lo The alternative to skin testing for penicillin allergy is the use of alternative antibiotics in all patients thought to be at risk for penicillin anaphylaxis (based on history). However, increased toxicity and cost may result. The management of anaphylaxis is well described, and universally includes epinephrine.4 As fatalities may occur in properly managed anaphylaxis, prevention is preferred. The effects of underlying illness in fatal anaphylaxis and anaphylaxis in the elderly have not been well studied. There is no convincing evidence that age, sex, or race predispose an individual to anaphylaxis.4 However, many elderly patients are likely to have multiple illnesses, including severe active cardiovascular disease, as did the two patients described above. The accepted treatment for anaphylaxis, particularly epinephrine administration, may have added further risk in these patients with cardiovascular disease. i ’ The geriatric p o p ulation may be at risk for unusual sensitivity to sympathetic agonists. I2 Furthermore, beta-adrenergic antagonists are widely used in the treatment of hypertension and ischemic heart disease, common conditions in the elderly. Potentiated anaphylaxis in patients with drug-induced betaadrenergic blockade has been reported.i3 While betaadrenergic blockade was not a factor in the two cases described here, it is a potential problem that one should be aware of when dealing with the elderly. Anaphylaxis in such patients is difficult to treat. I4 To summarize, penicillin administration is the most common cause of fatal anaphylaxis. The elderly may be at increased risk for fatal anaphylaxis in view of the possibility of multiple underlying illnesses, particularly cardiovascular diseases, unusual sensitivity to sympathetic agonists, and possible prior therapy for beta-adrenergic antagonists. Added caution, perhaps, is warranted in certain elderly, history-negative patients who require high and/or multiple doses of parenteral penicillin agents and who have underlying illnesses likely to increase their mortality from an anaphylactic episode. Skin testing such patients before high-dose parenteral penicillin therapy may prove to be life-saving. 457
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume 6, Number 5 n September
REFERENCES 1. ldsoe 0, Guthe T, Willcox RR, et al: Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968;38:159188 2. Adkinson NF, Thompson WL, Maddrey WC, et al: Routine use of penicillin in skin testing on an inpatient service. N Engl J Med 1971;285:22-24 3. Adkinson NF, Spence M, Wheeler B: Randomized clinical trial of routine penicillin skin testing (abstr). J Allergy Clin lmmunol 1984;73:163 (suppl) 4. Sheffer AL: Anaphylaxis. J Allergy Clin lmmunol 1985; 75:227-233 5. Parker CW: Allergic drug responses-mechanisms and unsolved problems. CRC Crit Rev Toxicol 1972;1:261 6. Sogn DD, Casale TB, Condemi JJ, et al: Interim results of the NIAID collaborative clinical trial of skin testing with major and minor penicillin derivatives in hospitalized adults (abst). J Allergy Clin lmmunol 1983;71:147(suppl) 7. Levine BB, Zolov DM: Prediction of penicillin allergy by immunological tests. J Allergy 1969;43:231-244
458
1988
8. Solley GO, Gleich GJ, Van Dellen RG: Penicillin allergyclinical experience with a battery of skin-test reagents. J Allergy Clin lmmunol 1982;69:238-244 9. Saxon A, Beall GN, Rohr AS, et al: Immediate ity reactions to beta-lactam antibiotics. 1987;107:204-215
hypersensitivAnn Int Med
10. Sullivan TJ: Penicillin allergy. In Lichtenstein L, Fauci A (eds): Current Therapy in Allergy and Immunology. St Louis, Mosby, 1985, pp 57-61 11. Sullivan TJ: Cardiac disorders in penicillin-induced laxis. Association with intravenous epinephrine JAMA 1982;248:2161-2162
anaphytherapy.
12. Heinsimer JA, Lefkowitz RJ: The impact of aging on adrenergic receptor function: Clinical and biochemical aspects. J Am Geriatr Sot 1985;33:184-188 13. Jacobs RL, Rake GW, Fournier DC, et al: Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin lmmunol 1981;68:125-127 14. Beall GN, Casburi R, Singer A. Anaphylaxis-everyone’s problem (Specialty Conference). West J Med 1986; 144 :329-337
Patients
Without
a History
MICHAEL A. SUE, MD, DEAN T. NORITAKE, WILLIAM B. KLAUSTERMEYER, MD
Two anaphylactic fatalities following penicillin administration are reported. Neither of the two patients had a history of previous penicillin allergy. Both were elderly and suffered from active cardiovascular dlsease. Penicillin skin testing may be indicated in some high-risk patients requiting parenteral penicillin, despite a negative history for penicillin allergy. (Am J Emerg Med 1988;6:456-458. 0 1988 by W.8. Saunders Company.)
It is known that most anaphylactic fatalities following penicillin administration occur in patients without a previous history of penicillin allergy. * This finding is certainly, in part, related to the selecting out of patients with a previous history of penicillin allergy for treatment with alternative antibiotics. The benefits of penicillin skin testing regardless of prior history was suggested by Adkinson et al.* However, Adkinson, Spence, and Wheeler later judged that prospective skin testing of all history-negative patients requiring penicillin was not a cost-effective means of reducing IgE-dependent penicillin allergy.3 We report two cases of anaphylactic fatalities following penicillin administration in patients without a history of penicillin allergy. Both patients were elderly and suffered from active cardiovascular disease. Penicillin skin testing may be routinely indicated in elderly history-negative patients requiring penicillin who have underlying illnesses likely to increase their mortality from an anaphylactic episode.
of
MD,
CASE REPORTS Case1 A 67-year-old man was admitted for an elective cardiac pacemaker change. He had a complicated medical history with previous myocardial infarction, angina, hypertension, gout, and obesity. A permanent demand pacemaker was implanted 5 years earlier and at that time he received intravenous (IV) methicillin, penicillin, and oral dicloxacillin. At 11:45 PM on the evening before the second implant, the patient received 2 g oxacillin followed by five million units of penicillin G intravenously, a standard protocol for routine pacemaker implant procedures at that time. Approximately one half of the dosage of penicillin was administered by 12:15 AM, when the patient complained
of generalized itching and a diffuse rash. The nurse immediately stopped the penicillin infusion, and continued IV hydration. Diphenhydramine, 25 mg, was administered orally at 12:25 AM. As the itching subsided, the patient complained of hoarseness, tightness of the throat, and dyspnea. Epinephrine 0.5 cc (1:lOOO) diluted in 10 cc saline was administered intravenously at 12:40 AM. Hoarseness and dyspnea persisted, and the patient complained of nausea, followed by vomiting. IV fluids were increased to a maximum as the heart rate was noted to be 180 beats per minute and irregular. The patient became cyanotic as his pulses diminished, and the cardiac arrest team was called at 12:45 AM. Cardiopulmonary resuscitation (CPR)
was unsuccessful and the patient was pronounced dead at 1:35 AM. Case2
From the Division of Allergy and Immunology, Department of Medicine, Wadsworth Veterans Administration Medical Center, and the Department of Medicine, University of California at Los Angeles. Manuscript 2, 1987.
received
June 24, 1987; revision
accepted
October
Address reprint requests to Dr. Klaustermeyer: Allergy/ Immunology Section 891/l 11 R, Wadsworth VA Medical Center, Los Angeles, CA 90073. Key Words:
Fatality,
penicillin,
Q 1988 by W.B. Saunders
0735-6757/88/0605-0007$5.00/O
456
anaphylaxis.
Company.
A 70-year-old white man with multiple medical problems, including diabetes mellitus, glaucoma, hypertension, and cerebrovascular and cardiovascular disease, was transferred to the Wadsworth VA Medical Center from a nearby hospital. He was admitted 3 days earlier for a myocardial infarction complicated by acute pulmonary edema. The patient had required mechanical ventilatory support, but responded very well to IV morphine and furosemide, and was extubated within 15 hours. Upon transfer, he appeared stable and denied symptoms of angina, dyspnea, or palpitations. Physical examination revealed stable vital signs with a BP of 130180 and a pulse of 70. He had bibasilar rales and a 216 midsystolic murmur at the apex with an S3 gallop rhythm. Bilateral lower extremity edema was present. The initial hospital course was uneventful while undergoing cardiac rehabilita-
SUE ET AL n FATAL PENICILLIN
tion. On the fourth hospital day, the patient was noted to have a cellulitis of the right forearm without evidence of thrombophlebitis. The patient denied any allergic history upon transfer, although he had reported an allergy to an unknown antibiotic on a prior admission. Review of his chart revealed that he had previously received courses of antimicrobial therapy with IV penicillin, oxacillin, and ampicillin without any complications. Dicloxacillin, 500 mg, orally four times daily was ordered. Twenty-four hours later, he developed fullness of the right olecranon bursa, which was aspirated, yielding cloudy fluid with an elevated leukocyte count and negative gram stain. The dicloxacillin was discontinued; IV penicillin G 1.5 million units every 4 hours and oxacillin 1.O g every 6 hours were ordered. Shortly after the oxacillin and penicillin were infused, the patient complained of a “funny sensation.” A generalized urticarial reaction involving the face, trunk, and upperarms was noted. Diphenhydramine, 50 mg, was administered intravenously. BP was 90/70 and a normal saline infusion was begun. After 10 minutes, 0.5 cc epinephine 1:lOOO diluted in 10 cc of saline was infused slowly. A decrease in erythema was noted but the patient complained of nausea and discomfort in the throat. He subsequently lost consciousness and developed generalized, tonic-clonic motor activity. The ECG revealed ventricular fibrillation which rapidly degenerated to asystole. CPR was unsuccessful, and the patient was pronounced dead.
DISCUSSION Penicillin therapy is the most common cause of anaphylaxis4 Moreover, it has been estimated that nearly 75% of fatal anaphylactic reactions are the result of penicillin administration.’ The best way to prevent fatality caused by penicillin-induced anaphylaxis is to prevent the occurrence of such reactions in pa-
tients who are at risk. Prospective skin testing with major and minor determinants of penicillin is one way to identify patients at risk of anaphylaxis to penicillin,2*6as patients with positive tests have a 50% to 75% risk of an accelerated or anaphylactic reaction following penicillin administration.7*8 Alternative antibiotics could then be prescribed to avoid such reactions. When skin testing to the relevant major and minor determinants in history-positive patients is negative, the risk of severe allergic reaction to penicillin is <1%.9 The major determinant (penicilloyl poly-lysine [Pre-Pen; Kremers Urban Company, Milwaukee]) and the minor determinant penicillin G are the only penicillin skin test reagents commercially available at this time. The other minor determinants (penicilloate and penilloate), also important in predicting anaphylactic reactivity, are not generally available but should be released in the near future. Patients should be skintested for penicillin allergy for the following indications: (1) need to administer penicillin to a patient possibly allergic to penicillin; (2) no suitable alternative
ANAPHYLAXIS
IN THE ELDERLY
antibiotic; or (3) lack of bactericidal activity, increased cost, toxicity, or difficulty of administration of alternative antibiotics. Only patients that require penicillin should be tested, and testing should be performed within 24 to 72 hours before therapy.’ Prick testing with major and minor determinants of penicillin is done initially. If the result is negative, intradermal testing is then performed. Diluent and histamine controls are used. The entire procedure takes less than 40 minutes. If properly performed, the risk of systemic reaction to penicillin skin testing itself is low, about 1%. lo The alternative to skin testing for penicillin allergy is the use of alternative antibiotics in all patients thought to be at risk for penicillin anaphylaxis (based on history). However, increased toxicity and cost may result. The management of anaphylaxis is well described, and universally includes epinephrine.4 As fatalities may occur in properly managed anaphylaxis, prevention is preferred. The effects of underlying illness in fatal anaphylaxis and anaphylaxis in the elderly have not been well studied. There is no convincing evidence that age, sex, or race predispose an individual to anaphylaxis.4 However, many elderly patients are likely to have multiple illnesses, including severe active cardiovascular disease, as did the two patients described above. The accepted treatment for anaphylaxis, particularly epinephrine administration, may have added further risk in these patients with cardiovascular disease. i ’ The geriatric p o p ulation may be at risk for unusual sensitivity to sympathetic agonists. I2 Furthermore, beta-adrenergic antagonists are widely used in the treatment of hypertension and ischemic heart disease, common conditions in the elderly. Potentiated anaphylaxis in patients with drug-induced betaadrenergic blockade has been reported.i3 While betaadrenergic blockade was not a factor in the two cases described here, it is a potential problem that one should be aware of when dealing with the elderly. Anaphylaxis in such patients is difficult to treat. I4 To summarize, penicillin administration is the most common cause of fatal anaphylaxis. The elderly may be at increased risk for fatal anaphylaxis in view of the possibility of multiple underlying illnesses, particularly cardiovascular diseases, unusual sensitivity to sympathetic agonists, and possible prior therapy for beta-adrenergic antagonists. Added caution, perhaps, is warranted in certain elderly, history-negative patients who require high and/or multiple doses of parenteral penicillin agents and who have underlying illnesses likely to increase their mortality from an anaphylactic episode. Skin testing such patients before high-dose parenteral penicillin therapy may prove to be life-saving. 457
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume 6, Number 5 n September
REFERENCES 1. ldsoe 0, Guthe T, Willcox RR, et al: Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968;38:159188 2. Adkinson NF, Thompson WL, Maddrey WC, et al: Routine use of penicillin in skin testing on an inpatient service. N Engl J Med 1971;285:22-24 3. Adkinson NF, Spence M, Wheeler B: Randomized clinical trial of routine penicillin skin testing (abstr). J Allergy Clin lmmunol 1984;73:163 (suppl) 4. Sheffer AL: Anaphylaxis. J Allergy Clin lmmunol 1985; 75:227-233 5. Parker CW: Allergic drug responses-mechanisms and unsolved problems. CRC Crit Rev Toxicol 1972;1:261 6. Sogn DD, Casale TB, Condemi JJ, et al: Interim results of the NIAID collaborative clinical trial of skin testing with major and minor penicillin derivatives in hospitalized adults (abst). J Allergy Clin lmmunol 1983;71:147(suppl) 7. Levine BB, Zolov DM: Prediction of penicillin allergy by immunological tests. J Allergy 1969;43:231-244
458
1988
8. Solley GO, Gleich GJ, Van Dellen RG: Penicillin allergyclinical experience with a battery of skin-test reagents. J Allergy Clin lmmunol 1982;69:238-244 9. Saxon A, Beall GN, Rohr AS, et al: Immediate ity reactions to beta-lactam antibiotics. 1987;107:204-215
hypersensitivAnn Int Med
10. Sullivan TJ: Penicillin allergy. In Lichtenstein L, Fauci A (eds): Current Therapy in Allergy and Immunology. St Louis, Mosby, 1985, pp 57-61 11. Sullivan TJ: Cardiac disorders in penicillin-induced laxis. Association with intravenous epinephrine JAMA 1982;248:2161-2162
anaphytherapy.
12. Heinsimer JA, Lefkowitz RJ: The impact of aging on adrenergic receptor function: Clinical and biochemical aspects. J Am Geriatr Sot 1985;33:184-188 13. Jacobs RL, Rake GW, Fournier DC, et al: Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin lmmunol 1981;68:125-127 14. Beall GN, Casburi R, Singer A. Anaphylaxis-everyone’s problem (Specialty Conference). West J Med 1986; 144 :329-337