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INADVERTENT OVERDOSE OF PARENTERAL TERBUTALINE
485 is highly effective in distinguishing pregnancy-related disorders from other causes of low abdominal pain and bleeding. Ultrasonic examination may give further inforination on the site of pregnancy in some but not all hCG-positive cases.
ants
test
ent
produced. Comprehensive Sickle Cell Center, Department of Pathology, University of Chicago, Chicago, Illinois 60637, U.S.A.
RUTANEN
Department of Obstetrics and Gynæcology,
Jorvi District Hospital, 02740 Espoo 74, Finland
should be further investigated to determine how the prespattern of distribution of the G6PD polymorphism is
EEVA-MARJA HEIKKI TARJANNE JUHO HUOVINEN MARTTI IKONEN
SHELLY C. BERNSTEIN JAMES E. BOWMAN
INADVERTENT OVERDOSE OF PARENTERAL TERBUTALINE
G6PD/MALARIA HYPOTHESIS: A BALANCED OR
SiR,—To our knowledge, this is only the second case-report where the recommended subcutaneous dose of terbutaline (0-25 mg) was confused with the recommended starting oral dose (2-5mg).’I A 35-year-old woman with insulin-requiring diabetes was admitted to hospital with a 2 day history of lower abdominal and back pain following an amniocentesis. Her 21 week pregnancy was complicated by large uterine fibroids. Premature labour was suspected and an intravenous infusion of terbutaline was started at a rate of 0.25 mg/h. After about 12 h, during which time her heart-rate ranged from 90 to 114/min, it was decided to switch her to subcutaneous terbutaline 0-25 mg. However, she received an s.c. dose of 2-5mg in error 1 h after the continuous i.v. infusion of terbutaline was discontinued. 10 min after the s.c. dose non-radiating substernal chest pressure developed with a tachycardia of 150/min. An ECG showed inferolateral ischxmia and she was admitted to the coronary-care unit to rule.out a myocardial infarction. In the coronary-care unit, examination was remarkable for a pulse-rate of 150/min regular, blood-pressure 120/80 mm Hg, and a II/VI systolic ejection murmur. Her ECG revealed a sinus tachycardia of 150/min with ST segment depression in leads I, II, III, F and in V4 and V6 with inverted T waves in III and F. All medications except insulin were withheld. Her cardiac course remained essentially benign, the tachycardia resolving after 10 h and cardiac enzymes over 2 days being essentially normal. The ECG reverted to normal over these 2 days. Terbutaline was not successful in preventing the premature labour as she had a spontaneous abortion. a relatively specific (32 adrenergic receptor stimulant, is effective in reversible bronchospasm at s.c. doses of 0-25 mg or oral doses of 2.5 mg.2 It has also shown efficacy as an investigational agent in managing premature labour, both orally and parenterally.3.4 Adverse effects are generally mild and include muscle tremor, dizziness, nervousness, palpitations, tachycardia, and blood-pressure changes. With parenteral administration and larger oral doses, there is loss of &bgr;2-receptor selectivity with greater cardiovascular side-
TRANSIENT POLYMORPHISM
SIR,-Twenty years have elapsed since Allison’ and Motulsky2 suggested that the high gene frequency of glucose-6phosphate dehydrogenase (G6PD) deficiency in populations endemic for falciparum malaria might be maintained as an X-linked polymorphism by a balance of selective forces. Dr Martin (Jan. 5, p. 51) proposes a mechanism based on recent clinical and in vitro studies3 by which G6PD deficiency, oxidant stress, and malaria interact. Individuals with GdBor GdB/GdB are not protected against malaria and are not susceptible to oxidant stress. Individuals with Gd B-lGd B- and GdBare protected from lethal malaria but are also under negative selection from oxidant stress. The female heterozygote GdB/GdB-, who has both the normal and the deficient alleles, is protected from negative selection of favism and from falciparum malaria. Martin states that this will create a situation whereby balanced polymorphism could arise. However, the polymorphism will be balanced only if in the GdB/GdB and GdB individuals the susceptibility to malaria is greater than the protection against oxidant stress alone, and in the GdB-/GdB- and GdB- individuals the susceptibility to oxidant stress is greater than the protection against malaria. That is to say, the fitnesses of the homozygotes and of the hemizygotes must be less than that of the heterozygotes.. If either of these conditions is not met, then the polymorphism will be transient with the eventual loss’of one allele and the fixation of the other. This is based on a selection model assuming an X-linked locus with two alleles, no mutation, and genotypeindependent zygotic sex ratio, also assuming that total fitness is the product of fitness components.4 The magnitudes of opposing selective pressures, which vary from one population to another in different environments, will determine whether the polymorphism will be balanced or transient. Furthermore, Eaton5 and Friedman3 have shown that the malaria parasite itself exerts an oxidant stress on affected red cells. While this may in one sense contribute to the protection of GdB/GdB- heterozygotes from malaria, it also adds to other oxidant stress, such as fava beans and viral hepatitis. This additional stress’ may lead to increased relative fitness of GdB/GdB and GdBindividuals and at the same time decreased relative fitness of GdB-/GdB- and GdB- individuals, to such an extent that a transient polymorphism with the gradual fixation of the GdB allele and the eventual loss of the GdB- allele will
Terbutaline,
effects. 1,5,6 Doctors and
’
ensue.
Finally, the G6PD polymorphism in many parts of Africa is three-allele (GdA, Gd^-, GdB) polymorphism with GdA and GDA- alleles having similar geographic distributions. As yet, we have no reasonable explanation for the maintenance of the Gd^ allele. While Martin offers an attractive hypothesis for the mechanism of protection against malaria afforded by G6PD deficiency, the complex interaction of infectious disease, environmental factors as yet not know, and other genetic varia
1. Allison AC.
Glucose-6-phosphate dehydrogenase deficiency in red blood cells of East Africans. Nature 1960; 186: 531-32. 2. Motulsky AG. Metabolic polymorphisms and the role of infectious disease in human evolution. Hum Biol 1960, 32: 28-62. 3. Friedman MJ. Oxidant damage mediates variant red cell resistance to malaria. Nature 1979; 280: 245-47. 4. Nagylaki T. Selection in one- and two-locus systems. Lecture notes in biomathematics: vol. XV. Berlin: Springer-Verlag, 1977. 5 Eaton JW, Eckman JR, Berger E, Jacob HS. Suppression of malaria infection by oxidant-sensitive host erythrocytes. Nature 1976; 264: 758-60.
nurses must exercise caution when prescribing, administering this drug. The parenteral preparations of terbutaline (’Bricanyl’, Astra; ’Brethine’, Geigy) are both singleuse glass ampoules containing 1 mg/ml; thus’each -ampoule contains four normal doese of 0.25 mg each. Simply misplacing the decimal point can result in significant adverse effects, as in our patient. Furthermore, since the rest of each ampoule is thrown away, changing the packaging of this drug to singleor
dose ampoules could save lives and money. New York Hospital, New York, N.Y. 10021, U.S.A.
ROBERT D. BRANDSTETTER VINCENT GOTZ
Pond A. Problems with terbutaline. N Engl Med J 1977; 296: 821. 2. Dulfano MJ, Glass P. The bronchodilator effects of terbutaline: route of administration and patterns of response. Ann Allergy 1976; 37: 357-66. 3. Ryden G. The effect of salbutamol and terbutaline in the management of premature labor. Acta Obstet Gynecol Scand 1977; 56: 293-96. 4. Wallace RL, Caldwell DL, Ansbacher R, et al. Inhibition of premature labor by terbutaline. Obstet Gynecol 1978; 51: 387-92. 5. Sackner MA, Dougherty R, Watson H, et al. Hemodynamic effects of epinephrine and terbutaline in normal man. Chest 1975; 68: 616-24. 6. Smith PR, Heurich AE, Leffler CT, et al. A comparative study of subcutaneously administered terbutaline and epinephrine in the treatment of acute bronchial asthma. Chest 1977; 71: 129-34. 1.
Lawyer C,
ants
test
ent
produced. Comprehensive Sickle Cell Center, Department of Pathology, University of Chicago, Chicago, Illinois 60637, U.S.A.
RUTANEN
Department of Obstetrics and Gynæcology,
Jorvi District Hospital, 02740 Espoo 74, Finland
should be further investigated to determine how the prespattern of distribution of the G6PD polymorphism is
EEVA-MARJA HEIKKI TARJANNE JUHO HUOVINEN MARTTI IKONEN
SHELLY C. BERNSTEIN JAMES E. BOWMAN
INADVERTENT OVERDOSE OF PARENTERAL TERBUTALINE
G6PD/MALARIA HYPOTHESIS: A BALANCED OR
SiR,—To our knowledge, this is only the second case-report where the recommended subcutaneous dose of terbutaline (0-25 mg) was confused with the recommended starting oral dose (2-5mg).’I A 35-year-old woman with insulin-requiring diabetes was admitted to hospital with a 2 day history of lower abdominal and back pain following an amniocentesis. Her 21 week pregnancy was complicated by large uterine fibroids. Premature labour was suspected and an intravenous infusion of terbutaline was started at a rate of 0.25 mg/h. After about 12 h, during which time her heart-rate ranged from 90 to 114/min, it was decided to switch her to subcutaneous terbutaline 0-25 mg. However, she received an s.c. dose of 2-5mg in error 1 h after the continuous i.v. infusion of terbutaline was discontinued. 10 min after the s.c. dose non-radiating substernal chest pressure developed with a tachycardia of 150/min. An ECG showed inferolateral ischxmia and she was admitted to the coronary-care unit to rule.out a myocardial infarction. In the coronary-care unit, examination was remarkable for a pulse-rate of 150/min regular, blood-pressure 120/80 mm Hg, and a II/VI systolic ejection murmur. Her ECG revealed a sinus tachycardia of 150/min with ST segment depression in leads I, II, III, F and in V4 and V6 with inverted T waves in III and F. All medications except insulin were withheld. Her cardiac course remained essentially benign, the tachycardia resolving after 10 h and cardiac enzymes over 2 days being essentially normal. The ECG reverted to normal over these 2 days. Terbutaline was not successful in preventing the premature labour as she had a spontaneous abortion. a relatively specific (32 adrenergic receptor stimulant, is effective in reversible bronchospasm at s.c. doses of 0-25 mg or oral doses of 2.5 mg.2 It has also shown efficacy as an investigational agent in managing premature labour, both orally and parenterally.3.4 Adverse effects are generally mild and include muscle tremor, dizziness, nervousness, palpitations, tachycardia, and blood-pressure changes. With parenteral administration and larger oral doses, there is loss of &bgr;2-receptor selectivity with greater cardiovascular side-
TRANSIENT POLYMORPHISM
SIR,-Twenty years have elapsed since Allison’ and Motulsky2 suggested that the high gene frequency of glucose-6phosphate dehydrogenase (G6PD) deficiency in populations endemic for falciparum malaria might be maintained as an X-linked polymorphism by a balance of selective forces. Dr Martin (Jan. 5, p. 51) proposes a mechanism based on recent clinical and in vitro studies3 by which G6PD deficiency, oxidant stress, and malaria interact. Individuals with GdBor GdB/GdB are not protected against malaria and are not susceptible to oxidant stress. Individuals with Gd B-lGd B- and GdBare protected from lethal malaria but are also under negative selection from oxidant stress. The female heterozygote GdB/GdB-, who has both the normal and the deficient alleles, is protected from negative selection of favism and from falciparum malaria. Martin states that this will create a situation whereby balanced polymorphism could arise. However, the polymorphism will be balanced only if in the GdB/GdB and GdB individuals the susceptibility to malaria is greater than the protection against oxidant stress alone, and in the GdB-/GdB- and GdB- individuals the susceptibility to oxidant stress is greater than the protection against malaria. That is to say, the fitnesses of the homozygotes and of the hemizygotes must be less than that of the heterozygotes.. If either of these conditions is not met, then the polymorphism will be transient with the eventual loss’of one allele and the fixation of the other. This is based on a selection model assuming an X-linked locus with two alleles, no mutation, and genotypeindependent zygotic sex ratio, also assuming that total fitness is the product of fitness components.4 The magnitudes of opposing selective pressures, which vary from one population to another in different environments, will determine whether the polymorphism will be balanced or transient. Furthermore, Eaton5 and Friedman3 have shown that the malaria parasite itself exerts an oxidant stress on affected red cells. While this may in one sense contribute to the protection of GdB/GdB- heterozygotes from malaria, it also adds to other oxidant stress, such as fava beans and viral hepatitis. This additional stress’ may lead to increased relative fitness of GdB/GdB and GdBindividuals and at the same time decreased relative fitness of GdB-/GdB- and GdB- individuals, to such an extent that a transient polymorphism with the gradual fixation of the GdB allele and the eventual loss of the GdB- allele will
Terbutaline,
effects. 1,5,6 Doctors and
’
ensue.
Finally, the G6PD polymorphism in many parts of Africa is three-allele (GdA, Gd^-, GdB) polymorphism with GdA and GDA- alleles having similar geographic distributions. As yet, we have no reasonable explanation for the maintenance of the Gd^ allele. While Martin offers an attractive hypothesis for the mechanism of protection against malaria afforded by G6PD deficiency, the complex interaction of infectious disease, environmental factors as yet not know, and other genetic varia
1. Allison AC.
Glucose-6-phosphate dehydrogenase deficiency in red blood cells of East Africans. Nature 1960; 186: 531-32. 2. Motulsky AG. Metabolic polymorphisms and the role of infectious disease in human evolution. Hum Biol 1960, 32: 28-62. 3. Friedman MJ. Oxidant damage mediates variant red cell resistance to malaria. Nature 1979; 280: 245-47. 4. Nagylaki T. Selection in one- and two-locus systems. Lecture notes in biomathematics: vol. XV. Berlin: Springer-Verlag, 1977. 5 Eaton JW, Eckman JR, Berger E, Jacob HS. Suppression of malaria infection by oxidant-sensitive host erythrocytes. Nature 1976; 264: 758-60.
nurses must exercise caution when prescribing, administering this drug. The parenteral preparations of terbutaline (’Bricanyl’, Astra; ’Brethine’, Geigy) are both singleuse glass ampoules containing 1 mg/ml; thus’each -ampoule contains four normal doese of 0.25 mg each. Simply misplacing the decimal point can result in significant adverse effects, as in our patient. Furthermore, since the rest of each ampoule is thrown away, changing the packaging of this drug to singleor
dose ampoules could save lives and money. New York Hospital, New York, N.Y. 10021, U.S.A.
ROBERT D. BRANDSTETTER VINCENT GOTZ
Pond A. Problems with terbutaline. N Engl Med J 1977; 296: 821. 2. Dulfano MJ, Glass P. The bronchodilator effects of terbutaline: route of administration and patterns of response. Ann Allergy 1976; 37: 357-66. 3. Ryden G. The effect of salbutamol and terbutaline in the management of premature labor. Acta Obstet Gynecol Scand 1977; 56: 293-96. 4. Wallace RL, Caldwell DL, Ansbacher R, et al. Inhibition of premature labor by terbutaline. Obstet Gynecol 1978; 51: 387-92. 5. Sackner MA, Dougherty R, Watson H, et al. Hemodynamic effects of epinephrine and terbutaline in normal man. Chest 1975; 68: 616-24. 6. Smith PR, Heurich AE, Leffler CT, et al. A comparative study of subcutaneously administered terbutaline and epinephrine in the treatment of acute bronchial asthma. Chest 1977; 71: 129-34. 1.
Lawyer C,