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Ranitidine-lnduced Bradycardia in a Patient With Dextrocardia
Case Report: Ranitidine-lnduced Bradycardia in a Patient With Dextrocardia JUNPING YANG, MD, PHD,
DOUGLAS A. RUSSELL, MD,
ABSTRACT: Although rare, bradycardia and other cardiac arrhythmias have been associated with the use of H 2 -receptor antagonists. Ranitidine is among the most frequently prescribed drugs. In this article, the authors observed a ranitidine-mediated sinus bradycardia in a man with dextrocardia (situs inversus) who had acute bleeding from a duodenal ulcer. The bradycardia was resolved after ranitidine was discontinued. KEY INDEXING TERMS: Ranitidine; H 2 -antagonists; Bradycardia; Dextrocardia. [Am J Med Sci 1996;312(3):133-135.]
JAMES E. BOURDEAU, MD, PHD
Table 1. Hematology H ospital Variable
Day 1
Day2
Day 4
WBC (per mm 3 ) H GB (g/dL) H CT( %) MCV (~tm 3 ) PLAT (per mm 3 ) PT/aPTT (sec)
6600 13.8 41.3 91.3 364 10.4. /33.5t
3900 7.1 20.3 90.2 232
4900 9.8 28.3 91.1 251
• Control value, 9.1-11 .3.
t Control value, 21.2-37.3. WBC = white blood cells; HGB = hemoglobin; HCT = hematocrit;
H
istamine H 2 -receptor antagonists, first described by Black et al, 1 are widely used for the treatment of gastric and duodenal ulcers. Although they have a favo rable adverse-effect profile, they can produce headaches, delirium, constipation, diarrhea, nausea, vomiting, rash, pruritus, and gynecomastia. 2 •3 They rarely cause cardiovascular effects that may include hypotension, bradycardia,4 •5 atrioventricular block, 6 •7 and sinus arrest. 8 - 11 In humans, histamine affects the cardiovascular system via H 1 and H 2 receptors.12•13 Ranitidine appears to lack some of the above side effects and was the most frequently prescribed drug in 1993. 14 However, ranitidine-induced arrhythmias have been documented in a neonate, in a 4-year-old child, and in adults. 15 - 17 Here we describe a man with dextrocardia (situs inversus) who had ranitidine-mediated sinus bradycardia and was admitted for acute upper gastrointestinal bleeding.
MCV =mean corpuscular volume; PLAT= platelet; PT = prothrombin time; aPTT = activated partial thromboplastin time.
revealed a duodenal ulcer. He was treated with ranitidine and antacids. Two days before admission, the patient had epigastric pain and experienced emesis that was bright red and coffee-ground in color. Melena and hematochezia were also reported. He was otherwise healthy and on no medications. He admitted to using alcohol occasionally, but denied recent ethanol intake. He smoked one package of cigarettes per day for 5 years and had used cocaine in the past. There was no history of allergy or adverse drug reactions. The temperature was 35.9° C, and the respiratory rate was 16 breaths per minute. While in a supine position, pulse and blood pressure were 60 beats per minute (bpm) and 105/60 mm Hg, respectively. While standing, the values were 104 bpm and 90/60 mm Hg, respectively. On physical examination, the patient appeared pale but was in no acute distress. Results of the examination were negative, except for
Table 2. Serum Chemistry
Case Report The patient was a 30-year-old man admitted for evaluation and treatment of hematemesis and hematochezia with orthostatic hypotension. Two years before admission, ulcer disease with upper gastrointestinal bleeding was diagnosed. Esophagogastroduodenoscopy
From the Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Submitted January 10, 1996; accepted March 14, 1996. Correspondence: Junping Yang, MD, PhD, Division of Metabolism, Washington University School of M edicine, 660 South Euclid Avenue, Box 8127, St. Louis, MO 63110. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Hospital Variable
Day 1
Day 2
Day4
Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Glucose (mg/dL) BUN (mg/dL) Creatinine (mg/dL)
143 4.6 106 22 91 24 0.8
141 4.2 110 26 84 17 0.8
138 3.6 105 25 116 7 0.8
BUN= blood urea nitrogen.
133
Ranltidine-lnduced Bradycardia
Figure 1. Anteroposterior x-ray of the chest.
the location of the cardiac maximum impulse in the fifth intercostal space of the right mid-clavicular line, right-sided heart sounds, and mild epigastric tenderness. Rectal examination revealed melenic stools that tested positive for occult blood. The laboratory findings during his hospitalization are presented in Tables 1 and 2. The urine test was normal. Chest x-ray showed dextrocardia and situs inversus (Figure 1). Abdominal x-ray revealed no free air. Esophagogastroduodenoscopy showed a duodenal ulcer and probable situs inversus (Figure 2) . Abdominal ultrasonography confirmed complete situs inversus (Figure 3). Normal saline (0.9 % NaCI) was infused intravenously, and 50 mg of ranitidine were administered intravenously every 8 hours. On the second hospital day, hemoglobin and hematocrit dropped to 7.1 g/ dL and 20.3 % , respectively. His vital signs were stable. The patient was transfused with two units of packed erythrocytes. On the morning of third hospital day, the patient developed significant bradycardia
Figure 3. Ultrasonogram of abdomen that shows dextrocardia with situs inversus.
with a heart rate of 45 bpm soon after his seventh dose of ranitidine. An electrocardiogram revealed marked sinus bradycardia and right axis deviation (Figure 4) . His blood pressure remained stable at 90/ 60 mm Hg. One mg of atropine was given intravenously and repeated once in 10 minutes. His heart rate remained at 44-48 bpm, indicating that the bradycardia was not the consequence of vagal stimulation. Ranitidine was discontinued, and replaced by 20 mg of omeprazole twice daily. Bradycardia was resolved over the next 16 hours. The patient was discharged on the fifth hospital day.
Discussion
Histamine is present in high concentrations in the mast cells of cardiac tissues in most animal species and in humans. 18 •19 However, the physiologic role of his-
Figure 2. Esophagogastroduodenoscopy that shows a linear ulceration in the duodenal bulb.
134
September 1996 Volume 312 Number 3
Yang, Russell, and Bourdeau
Figure 4. Twelve-lead electrocardiogram during ranitidine-induced bradycardia.
tamine action on the heart, if any, is not well defined. zo Hz receptors are present in the sinus node and in the cardiac atrial tissues. In humans, the atrial and ventricular myocardium contains H z receptors that mediate a positive chronotropic and inotropic response. 1z Previous studies of the evidence indicate that the cardiac effects of H z-receptor stimulation are, like {31-adrenergic receptor responses, mediated via cAMP .13 ·z 1 This would explain, at least in part, why the blockade of Hz-receptors induces bradycardia. Ranitidine was shown to inhibit cholinesterase.zz However, ranitidineinduced sinus bradycardia in this patient was resistant to a repeated challenge of atropine, which implies a direct effect of histamine on the regulation of cardiac rate via Hz receptors. Molecular cloning of the Hz receptor has been achieved in dogs,z3 in humans,z 4 and in rats, zs and should help elucidate the cardiovascular effects of Hz blockers. At the same time, because three Hz antagonists: famotidine, cimetidine, and now ranitidine, have been approved for over-the-counter use,z6 their potential adverse cardiovascular actions should not be underestimated. Transposition of the viscera is relatively uncommon condition with an incidence that ranges from 1 to 2 cases in 5000.z7 The incidence of congenital cardiac defects and the tendency to develop noncardiac lesions, such as Kartagener's triad, has increased 9 times in patients with dextrocardia.zs Two previous casesz9 have been reported in which patients with dextrocardia also had a duodenal ulcer, which suggests that patients with dextrocardia may be at increased risk for developing a duodenal ulcer. This paper documents the first ranitidine-induced bradycardia in a patient with dextrocardia, and indicates that additional studies are warranted to characterize the physiologic and pathophysiologic actions of histamine on the heart. References 1. Black JW, Duncan W AM, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2 -receptors. Nature. 1972;236:385-90.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
2. Hansten PD. Overview of the safety profile of the H 2 -receptor antagonists. Ann Pharmacother. 1990;24(suppl):S38-41. 3. Nickell PV. Histamine-2 receptor blockers and delirium. Ann Intern Med. 1991;115:658. 4. Sjovall H, Jonsson C, Haggendal J, Olbe L. Effects of histamine H 2 -receptor blockade on the cardiovascular reflex response to low-body negative pressure in man. Acta Physiol Scand. 1990;139:161-72. 5. Halabi A, Kirch W. Negative chronotropic effects of nizatidine. Gut. 1991;32:630-34. 6. Allergri G, Pellegrini K, Dobrilla G. First-degree atrioventricular block in a young duodenal ulcer patient treated with a standard oral dose of ranitidine. Agents Actions. 1988;24:23742. 7. lschizaki M, Yamada Y, Kido T , Yamaya H, Nogawa K, Matsui S, et al. First-degree atrioventricular block induced by oral cimetidine. Lancet. 1987,225-26. 8. lberti TJ. Hemodynamic effects ofH 2-receptor antagonists. Ann Pharmacother. 1990;24(suppl):S35-7. 9. Jeffrey DB, Vale JA. Cimetidine and bradycardia. Lancet. 1978;1:828. 10. Johnson WS, Miller DR. Ranitidine and bradycardia. Ann Intern Med. 1988;108:493. 11. Ann Tanner L, Arrowsmith JB. Bradycardia and H 2 antagonists. Ann Intern Med. 1988;3:434- 35. 12. Ginsburg R, Bristow MR, Stinson EB, Harrison DC. Histamine receptors in the human heart. Life Sci. 1980;26:2245-49. 13. Levi RC, Alloatti G. Histamine modulates calcium current in guinea-pig ventricular myocytes. J Pharmacal Exp Ther. 1988;246:277- 83. 14. Top 200 survey. American Druggist. 1994;27- 31. 15. Nahum E, Reish 0, Naor N and Merlob P. Ranitidine-induced bradycardia in a neonate-a first report. Eur J Pediatr. 1993;152:933-34. 16. Balestrazzi P, Gregori G, Bernasconi, S Giovannelli. Bradycardia and neurologic disorders associated with ranitidine in a child. Am J Dis Child. 1985;139:442. 17. Hart AM. Cardiac arrest associated with ra nitidine. BMJ. 1989;299:519. 18. Marone G, Triggiani M, Cirillo R, Vigorito C, Genovese A, Spampinato N, et al. Chemical mediators and the human heart. Prog Biochem Pharmacal. 1985;20:38-54. 19. Triggiani M, Genovese C, Marone G. Histamine and human heart. Int Archs Allergy Appl Immun. 1985;77:174- 76. 20. Hill SJ. Distribution, properties, and functional characteristics of three classes of histamine receptor. Pharmacal Rev. 1990;42: 45- 83. 21. Delvalle J, Wang L , Gantz I, Yamada T. Characterization of H 2 histamine receptor: Linkage to both adenylate cyclase and [Ca2+); signaling systems. Am J Physiol. 1992;263:G967- 72. 22. Hansen WD, Berti S. Inhibition of cholinesterase by ranitidine. Lancet. 1983,235. 23. Gantz I, Schaffer M, DelValle J, Logsdon C, Campell V, Uhler M, et al. Molecular cloning of a gene encoding the histamine H 2 receptor. Proc Nat! Acad Sci U S A. 1991;88:429-33. 24. Gantz I, Munzert G, Tashiro T, Schaffer M, Wang L, DelValle J, et al. Molecular cloning of the human histamine H 2 receptor. Biochem Biophys Res Comm. 1991;178:1386-92. 25. Ruat M, Traiffort E, Arrang JM, Leurs R, Schwartz JC. Cloning and tissue expression of a rat histamine H 2-receptor gene. Biochem Biophys Res Comm. 1991;179:1470- 78. 26. From the Food and Drug Administration. JAMA. 1995;273:1897. 27. Uragoda CG. Dextrocardia and situs inversus in Sri Lanka. Trop Geogr Med. 1977;29:14- 18. 28. Hurst JW, Schlant RC. The Heart. Arteries and Veins, 7th ed. New York: McGraw-Hill; 1990:255. 29. Gandel DM, Warty PP, Pinto AC, and Shetty SV. Perforated duodenal ulcer with dextrocardia with situs inversus. J Postgrad Med. 1986;32:45-46.
135
DOUGLAS A. RUSSELL, MD,
ABSTRACT: Although rare, bradycardia and other cardiac arrhythmias have been associated with the use of H 2 -receptor antagonists. Ranitidine is among the most frequently prescribed drugs. In this article, the authors observed a ranitidine-mediated sinus bradycardia in a man with dextrocardia (situs inversus) who had acute bleeding from a duodenal ulcer. The bradycardia was resolved after ranitidine was discontinued. KEY INDEXING TERMS: Ranitidine; H 2 -antagonists; Bradycardia; Dextrocardia. [Am J Med Sci 1996;312(3):133-135.]
JAMES E. BOURDEAU, MD, PHD
Table 1. Hematology H ospital Variable
Day 1
Day2
Day 4
WBC (per mm 3 ) H GB (g/dL) H CT( %) MCV (~tm 3 ) PLAT (per mm 3 ) PT/aPTT (sec)
6600 13.8 41.3 91.3 364 10.4. /33.5t
3900 7.1 20.3 90.2 232
4900 9.8 28.3 91.1 251
• Control value, 9.1-11 .3.
t Control value, 21.2-37.3. WBC = white blood cells; HGB = hemoglobin; HCT = hematocrit;
H
istamine H 2 -receptor antagonists, first described by Black et al, 1 are widely used for the treatment of gastric and duodenal ulcers. Although they have a favo rable adverse-effect profile, they can produce headaches, delirium, constipation, diarrhea, nausea, vomiting, rash, pruritus, and gynecomastia. 2 •3 They rarely cause cardiovascular effects that may include hypotension, bradycardia,4 •5 atrioventricular block, 6 •7 and sinus arrest. 8 - 11 In humans, histamine affects the cardiovascular system via H 1 and H 2 receptors.12•13 Ranitidine appears to lack some of the above side effects and was the most frequently prescribed drug in 1993. 14 However, ranitidine-induced arrhythmias have been documented in a neonate, in a 4-year-old child, and in adults. 15 - 17 Here we describe a man with dextrocardia (situs inversus) who had ranitidine-mediated sinus bradycardia and was admitted for acute upper gastrointestinal bleeding.
MCV =mean corpuscular volume; PLAT= platelet; PT = prothrombin time; aPTT = activated partial thromboplastin time.
revealed a duodenal ulcer. He was treated with ranitidine and antacids. Two days before admission, the patient had epigastric pain and experienced emesis that was bright red and coffee-ground in color. Melena and hematochezia were also reported. He was otherwise healthy and on no medications. He admitted to using alcohol occasionally, but denied recent ethanol intake. He smoked one package of cigarettes per day for 5 years and had used cocaine in the past. There was no history of allergy or adverse drug reactions. The temperature was 35.9° C, and the respiratory rate was 16 breaths per minute. While in a supine position, pulse and blood pressure were 60 beats per minute (bpm) and 105/60 mm Hg, respectively. While standing, the values were 104 bpm and 90/60 mm Hg, respectively. On physical examination, the patient appeared pale but was in no acute distress. Results of the examination were negative, except for
Table 2. Serum Chemistry
Case Report The patient was a 30-year-old man admitted for evaluation and treatment of hematemesis and hematochezia with orthostatic hypotension. Two years before admission, ulcer disease with upper gastrointestinal bleeding was diagnosed. Esophagogastroduodenoscopy
From the Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Submitted January 10, 1996; accepted March 14, 1996. Correspondence: Junping Yang, MD, PhD, Division of Metabolism, Washington University School of M edicine, 660 South Euclid Avenue, Box 8127, St. Louis, MO 63110. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Hospital Variable
Day 1
Day 2
Day4
Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Glucose (mg/dL) BUN (mg/dL) Creatinine (mg/dL)
143 4.6 106 22 91 24 0.8
141 4.2 110 26 84 17 0.8
138 3.6 105 25 116 7 0.8
BUN= blood urea nitrogen.
133
Ranltidine-lnduced Bradycardia
Figure 1. Anteroposterior x-ray of the chest.
the location of the cardiac maximum impulse in the fifth intercostal space of the right mid-clavicular line, right-sided heart sounds, and mild epigastric tenderness. Rectal examination revealed melenic stools that tested positive for occult blood. The laboratory findings during his hospitalization are presented in Tables 1 and 2. The urine test was normal. Chest x-ray showed dextrocardia and situs inversus (Figure 1). Abdominal x-ray revealed no free air. Esophagogastroduodenoscopy showed a duodenal ulcer and probable situs inversus (Figure 2) . Abdominal ultrasonography confirmed complete situs inversus (Figure 3). Normal saline (0.9 % NaCI) was infused intravenously, and 50 mg of ranitidine were administered intravenously every 8 hours. On the second hospital day, hemoglobin and hematocrit dropped to 7.1 g/ dL and 20.3 % , respectively. His vital signs were stable. The patient was transfused with two units of packed erythrocytes. On the morning of third hospital day, the patient developed significant bradycardia
Figure 3. Ultrasonogram of abdomen that shows dextrocardia with situs inversus.
with a heart rate of 45 bpm soon after his seventh dose of ranitidine. An electrocardiogram revealed marked sinus bradycardia and right axis deviation (Figure 4) . His blood pressure remained stable at 90/ 60 mm Hg. One mg of atropine was given intravenously and repeated once in 10 minutes. His heart rate remained at 44-48 bpm, indicating that the bradycardia was not the consequence of vagal stimulation. Ranitidine was discontinued, and replaced by 20 mg of omeprazole twice daily. Bradycardia was resolved over the next 16 hours. The patient was discharged on the fifth hospital day.
Discussion
Histamine is present in high concentrations in the mast cells of cardiac tissues in most animal species and in humans. 18 •19 However, the physiologic role of his-
Figure 2. Esophagogastroduodenoscopy that shows a linear ulceration in the duodenal bulb.
134
September 1996 Volume 312 Number 3
Yang, Russell, and Bourdeau
Figure 4. Twelve-lead electrocardiogram during ranitidine-induced bradycardia.
tamine action on the heart, if any, is not well defined. zo Hz receptors are present in the sinus node and in the cardiac atrial tissues. In humans, the atrial and ventricular myocardium contains H z receptors that mediate a positive chronotropic and inotropic response. 1z Previous studies of the evidence indicate that the cardiac effects of H z-receptor stimulation are, like {31-adrenergic receptor responses, mediated via cAMP .13 ·z 1 This would explain, at least in part, why the blockade of Hz-receptors induces bradycardia. Ranitidine was shown to inhibit cholinesterase.zz However, ranitidineinduced sinus bradycardia in this patient was resistant to a repeated challenge of atropine, which implies a direct effect of histamine on the regulation of cardiac rate via Hz receptors. Molecular cloning of the Hz receptor has been achieved in dogs,z3 in humans,z 4 and in rats, zs and should help elucidate the cardiovascular effects of Hz blockers. At the same time, because three Hz antagonists: famotidine, cimetidine, and now ranitidine, have been approved for over-the-counter use,z6 their potential adverse cardiovascular actions should not be underestimated. Transposition of the viscera is relatively uncommon condition with an incidence that ranges from 1 to 2 cases in 5000.z7 The incidence of congenital cardiac defects and the tendency to develop noncardiac lesions, such as Kartagener's triad, has increased 9 times in patients with dextrocardia.zs Two previous casesz9 have been reported in which patients with dextrocardia also had a duodenal ulcer, which suggests that patients with dextrocardia may be at increased risk for developing a duodenal ulcer. This paper documents the first ranitidine-induced bradycardia in a patient with dextrocardia, and indicates that additional studies are warranted to characterize the physiologic and pathophysiologic actions of histamine on the heart. References 1. Black JW, Duncan W AM, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2 -receptors. Nature. 1972;236:385-90.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
2. Hansten PD. Overview of the safety profile of the H 2 -receptor antagonists. Ann Pharmacother. 1990;24(suppl):S38-41. 3. Nickell PV. Histamine-2 receptor blockers and delirium. Ann Intern Med. 1991;115:658. 4. Sjovall H, Jonsson C, Haggendal J, Olbe L. Effects of histamine H 2 -receptor blockade on the cardiovascular reflex response to low-body negative pressure in man. Acta Physiol Scand. 1990;139:161-72. 5. Halabi A, Kirch W. Negative chronotropic effects of nizatidine. Gut. 1991;32:630-34. 6. Allergri G, Pellegrini K, Dobrilla G. First-degree atrioventricular block in a young duodenal ulcer patient treated with a standard oral dose of ranitidine. Agents Actions. 1988;24:23742. 7. lschizaki M, Yamada Y, Kido T , Yamaya H, Nogawa K, Matsui S, et al. First-degree atrioventricular block induced by oral cimetidine. Lancet. 1987,225-26. 8. lberti TJ. Hemodynamic effects ofH 2-receptor antagonists. Ann Pharmacother. 1990;24(suppl):S35-7. 9. Jeffrey DB, Vale JA. Cimetidine and bradycardia. Lancet. 1978;1:828. 10. Johnson WS, Miller DR. Ranitidine and bradycardia. Ann Intern Med. 1988;108:493. 11. Ann Tanner L, Arrowsmith JB. Bradycardia and H 2 antagonists. Ann Intern Med. 1988;3:434- 35. 12. Ginsburg R, Bristow MR, Stinson EB, Harrison DC. Histamine receptors in the human heart. Life Sci. 1980;26:2245-49. 13. Levi RC, Alloatti G. Histamine modulates calcium current in guinea-pig ventricular myocytes. J Pharmacal Exp Ther. 1988;246:277- 83. 14. Top 200 survey. American Druggist. 1994;27- 31. 15. Nahum E, Reish 0, Naor N and Merlob P. Ranitidine-induced bradycardia in a neonate-a first report. Eur J Pediatr. 1993;152:933-34. 16. Balestrazzi P, Gregori G, Bernasconi, S Giovannelli. Bradycardia and neurologic disorders associated with ranitidine in a child. Am J Dis Child. 1985;139:442. 17. Hart AM. Cardiac arrest associated with ra nitidine. BMJ. 1989;299:519. 18. Marone G, Triggiani M, Cirillo R, Vigorito C, Genovese A, Spampinato N, et al. Chemical mediators and the human heart. Prog Biochem Pharmacal. 1985;20:38-54. 19. Triggiani M, Genovese C, Marone G. Histamine and human heart. Int Archs Allergy Appl Immun. 1985;77:174- 76. 20. Hill SJ. Distribution, properties, and functional characteristics of three classes of histamine receptor. Pharmacal Rev. 1990;42: 45- 83. 21. Delvalle J, Wang L , Gantz I, Yamada T. Characterization of H 2 histamine receptor: Linkage to both adenylate cyclase and [Ca2+); signaling systems. Am J Physiol. 1992;263:G967- 72. 22. Hansen WD, Berti S. Inhibition of cholinesterase by ranitidine. Lancet. 1983,235. 23. Gantz I, Schaffer M, DelValle J, Logsdon C, Campell V, Uhler M, et al. Molecular cloning of a gene encoding the histamine H 2 receptor. Proc Nat! Acad Sci U S A. 1991;88:429-33. 24. Gantz I, Munzert G, Tashiro T, Schaffer M, Wang L, DelValle J, et al. Molecular cloning of the human histamine H 2 receptor. Biochem Biophys Res Comm. 1991;178:1386-92. 25. Ruat M, Traiffort E, Arrang JM, Leurs R, Schwartz JC. Cloning and tissue expression of a rat histamine H 2-receptor gene. Biochem Biophys Res Comm. 1991;179:1470- 78. 26. From the Food and Drug Administration. JAMA. 1995;273:1897. 27. Uragoda CG. Dextrocardia and situs inversus in Sri Lanka. Trop Geogr Med. 1977;29:14- 18. 28. Hurst JW, Schlant RC. The Heart. Arteries and Veins, 7th ed. New York: McGraw-Hill; 1990:255. 29. Gandel DM, Warty PP, Pinto AC, and Shetty SV. Perforated duodenal ulcer with dextrocardia with situs inversus. J Postgrad Med. 1986;32:45-46.
135