Dipyridamole-Associated Shock and Pulmonary Edema

CASE REPORTS

Dipyridamole-Associated Shock and Pulmonary Edema Maria Dioverti, Robert Fishman, Robert Moskowitz, Sixto A Arias, Sumi Nair, Priyanka Lall, Adam E Schussheim, Stuart Zarich, and Constantine Manthous

ince the early 1980s, dipyridamole myocardial scintigraphy has been employed when exercise stress testing is not feasible.1,2 Intravenous infusion of dipyridamole causes a significant increase in myocardial blood flow in zones perfused by normal coronary arteries but only a slight increase in zones perfused by stenotic vessels.3 A number of complications have been attributed to dipyridamole use, but we present what we believe to be the first reported case of shock leading to pulmonary edema shortly after an infusion of dipyridamole.

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Case Report A 73-year-old female (weight 107 kg, height 160 cm) with a history of coronary artery disease (coronary angioplasty/stents), ischemic cardiomyopathy, low-output congestive heart failure and implantable cardioverter defibrillator placement, recent acute bronchitis (without documented chronic lung disease), and diabetes, presented for dipyridamole 82-Rb positron emission tomography perfusion imaging. An echocardiogram performed 1 month earlier showed infer-

OBJECTIVE: To report a case of fulminant shock and noncardiogenic pulmonary edema induced by intravenously administered dipyridamole. CASE SUMMARY: A 73-year-old woman presented to the office of her cardiologist for dipyridamole myocardial scintigraphy. Several minutes after administration of intravenous dipyridamole 0.57 mg/kg over 4 minutes she developed wheezing, followed by cardiovascular collapse and pulmonary edema requiring 100% oxygen and endotracheal intubation. She had never received dipyridamole before this, and no other medications or exposures were documented proximate to the collapse. On transfer to the hospital, she developed shock refractory to multiple vasopressors, which responded to continuous infusions of epinephrine. She also had severe pulmonary edema requiring invasive ventilation, 100% inspired oxygen, and 24 cm H2O positive end-expiratory pressure. An echocardiogram did not show new leftventricular dysfunction and there were signs of right-heart underfilling, supporting a diagnosis of noncardiogenic pulmonary edema. Both shock and pulmonary edema resolved within 12 hours. DISCUSSION: Dipyridamole-associated hypotension has been reported in a number of case series and registries. Detailed case descriptions, however, are not available in the literature to permit understanding of the mechanism of shock following hypotension resulting from dipyridamole myocardial scintigraphy. Our case is exceptional in that echocardiography results support a diagnosis of hypovolemic (rather than cardiogenic) shock. To our knowledge, this is the first case of severe (most likely noncardiogenic) pulmonary edema associated with intravenous infusion of dipyridamole. An objective causality assessment suggested that this patient’s cardiopulmonary collapse was probably related to dipyridamole. CONCLUSIONS:

While hypotension has been previously associated with intravenous use of dipyridamole, ours is the first report to suggest a noncardiogenic mechanism for shock. To our knowledge, this is the first reported case of noncardiogenic pulmonary edema following dipyridamole infusion.

KEY WORDS:

anaphylactoid, anaphylaxis, ARDS, dipyridamole, pulmonary edema, shock, stress scintigraphy.

Ann Pharmacother 2011;45:e42. Published Online, 13 Jun 2011, theannals.com, DOI 10.1345/aph.1P734

Author information provided at end of text.

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olateral hypokinesis and left-ventricular ejection fraction of 30%. Chest radiograph done at the same time showed no evidence of infiltrates or pulmonary congestion. She did not recall receiving dipyridamole in the past and had allergies to sulfa-containing medications and bee stings. Her medications included fosinopril 40 mg once daily, extended-release metoprolol 50 mg twice daily, glimepiride 4 mg twice daily, sotalol 120 mg twice daily, rosuvastatin 10 mg once daily, aspirin 81 mg each day, insulin detemir 40 units at bedtime, metformin 1000 mg twice daily, fish oil, and vitamins D and C. Approximately 6 minutes after completion of an intravenous infusion of dipyridamole 0.57 mg/kg given over 4 minutes, the patient began to experience dyspnea and audible wheezing. Her oxygen saturation decreased from 98% on room air to less than 90% on high-flow oxygen. The imaging protocol was aborted and the patient was removed from the scanner. She was promptly given aminophylline 75 mg intravenously, but her condition rapidly deteriorated. Attempts to measure blood pressure and pulse oximetry failed, and pulses were weakly palpable. An electrocardiogram obtained at that time showed no changes from baseline. She was given 1 mg each of intravenous atropine and epinephrine and was intubated for airway protection during transfer to the emergency department. She had no vomiting or witnessed aspiration. Upon arrival in the emergency department, the patient’s heart rate was 110 beats/min, blood pressure 190/100 mm Hg, and respiratory rate greater than 30 breaths/min on a ventilator. Large amounts of pink, frothy secretions continuously drained from her endotracheal tube. Physical examination demonstrated regular tachycardia without murmurs, and diffuse gurgling sounds were detected on auscultation of the lungs. No skin abnormalities or rashes were noted. An electrocardiogram showed nonspecific ST-T wave abnormalities and a chest radiograph showed diffuse, dense infiltrates in all lung regions. She was initially treated with intravenous furosemide 40 mg and intravenous nitroglycerin 10 µg/min titrated to a systolic blood pressure of 100-110 mm Hg for presumed acute congestive heart failure, without improvement. Continuous manipulation of the ventilator during 2 hours of resuscitation, applying acute respiratory distress syndrome (ARDS) net techniques,4 with positive end-expiratory pressure (PEEP) up to 20 cm H2O failed to improve oxygenation; highest saturations were only transiently in the mid-90s (immediately following endotracheal suctioning) and mean oxygen saturation averaged 70-80%. The patient’s systolic blood pressure dropped to less than 90 mm Hg, prompting initiation of an infusion of dobutamine 5 µg/kg/min and discontinuation of nitroglycerin. Immediately after initiation of dobutamine, emergent echocardiography revealed no new wall motion abnormalities and stable left-ventricular function and filling (ejection fraction 30- 40%); a bubble study e42

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showed no evidence of intracardiac shunt. The first troponin T level obtained prior to this hypotensive event was within normal limits (0.033 ng/mL, reference value less than 0.120 ng/mL). Despite these interventions, the patient’s blood pressure continued to fall and she developed pulseless electrical activity; cardiopulmonary resuscitation was then performed for 5 minutes. At this point, a lactic acid level was 2.3 mg/dL (reference range 0.6-1.9 mg/dL). Intravenous epinephrine 1 mg was administered and pulses returned, with a narrow-complex tachycardia of greater than 150 beats/min and systolic blood pressure greater than 200 mm Hg. Intravenous hydrocortisone 100 mg was administered but, again, blood pressure dropped in the 10-15 minutes following epinephrine infusion. Maximal doses of both phenylephrine (200 µg/min) and norepinephrine (20 µg/min) as sequential intravenous infusions failed to correct the hypotension, whereas small intravenous bolus doses of epinephrine (0.25-0.5 mg) rapidly reversed hypotension and improved oxygenation. An infusion of epinephrine 20 µg/min was started, with stabilization of her circulation. Famotidine 20 mg was also administered intravenously, with the working diagnosis of anaphylaxis. Over the next 12 hours, both shock and hypoxemia rapidly improved, allowing titration and discontinuation of the epinephrine infusion. Troponin T, measured 7 hours after admission (and cardiopulmonary resuscitation), was 1.070 ng/mL. In the same interval, initial ventilator settings (assist control 30/min, tidal volume 400 mL, PEEP 24 cm H2O, inspired oxygen 100% yielded saturations in low 90s) were gradually reduced to PEEP 5 cm H2O and inspired oxygen 50%. She awakened and was extubated successfully 12 hours after refractory shock/hypoxemia. Cultures revealed no infections and all antibiotics were discontinued. She was discharged home on hospital day 5, without cardiovascular or neurologic sequelae. Discussion To our knowledge, this is the first reported case of circulatory collapse associated with infusion of dipyridamole. While cause and effect cannot be proved, a number of features suggest that the mechanism of this patient’s shock might have been anaphylaxis. First, she was asymptomatic prior to, and symptoms began minutes after, administration of dipyridamole. Second, initial circulatory collapse was preceded by sudden onset of severe dyspnea and wheezing. Third, echocardiography during shock in the emergency department did not reveal new cardiac abnormalities (eg, new left or right ventricular or valvular dysfunction), and the inferior vena cava was collapsing, suggesting an underfilled right heart. Fourth, she had no response to dobutamine, phenylephrine, or norepinephrine, whereas small doses of epinephrine rapidly reversed her circulatory collapse. A counter argument for anaphylaxis is that there


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Dipyridamole-Associated Shock and Pulmonary Edema

was no record of her receiving dipyridamole in the past. However, some agents produce anaphylactoid reactions not mediated by immunoglobulin E in the absence of prior immunologic priming.5,6 Use of the Naranjo probability scale suggested a probable relationship between dipyridamole and the complications.7 Two cases of dipyridamole-associated anaphylaxis-like reactions have been reported. In one, symptoms began within a minute of infusion and were characterized as “sneezing, pruritus, urticaria on the upper torso, swelling on the inner surface of the cheeks, and increasing dyspnea, with sibilant rales.” In that case, epinephrine was administered before onset of hypotension.8 A second patient developed chest tightness, dyspnea, and generalized facial swelling immediately following infusion of dipyridamole. No hypotension was recorded. Promethazine and hydrocortisone were administered and the patient’s condition improved over several hours, with complete recovery and no further events.9 In a study of 3911 patients, dipyridamole scintigraphy was associated with 2 deaths from myocardial infarction, 2 nonfatal myocardial infarctions, and 6 cases of acute bronchospasm.2 Several minor adverse events were reported in 46.5% of the patients in this study, such as headaches, dizziness, chest pain, electrocardiographic changes, and hypotension. Intravenous aminophylline relieved symptoms associated with adverse events in 97% of patients in this study.2 A larger study included questionnaire responses pertaining to 24,599 patients who received dipyridamole during echocardiography; 4 patients were reported to have had hypotension or shock.10 Smaller studies have reported cases of transient hypotension provoked by cardiogenic shock related to ischemia, although not all reversed with epinephrine. Anaphylaxis associated with prolonged hypotension has not been reported or linked specifically to dipyridamole.10-14 Two cases of cardiogenic pulmonary edema have been reported. One was attributed to myocardial ischemia/stunning,15 and the mechanism of the second case was not listed.16 To our knowledge, no previous case of noncardiogenic pulmonary edema has been reported. While it is possible that our patient’s circulatory collapse was associated with transient left-ventricular dysfunction, the echocardiogram did not suggest severe (or new) wall motion abnormalities, and the imaging of inferior vena cava suggested an underfilled system. In addition, since positive pressure ventilation reduces venous return, it is an excellent treatment for congestive heart failure. A PEEP greater than 10 cm H2O is seldom required to stabilize patients with congestive heart failure and is one criterion chosen by experts to reflect ARDS.17 This case is also unique in that noncardiogenic pulmonary edema (ie, ARDS) is not typical of anaphylactic or anaphylactoid shock.5 It has been reported theannals.com

as a rare complication of anaphylaxis/anaphylactoid syndromes with protamine, hydrochlorothiazide, fentanyl, and intravenous injection of contrast agents.18-22 In conclusion, shortly after infusion of dipyridamole, this patient developed shock that was responsive only to continuous infusions of epinephrine and was complicated by severe pulmonary edema. Both resolved almost entirely by 12 hours. Since dipyridamole is administered to large numbers of patients for myocardial scintigraphy, clinicians should be aware of this very rare complication. Maria Dioverti MD, Resident Physician, Bridgeport Hospital and Yale University School of Medicine, Bridgeport, CT Robert Fishman MD, Attending Physician, Bridgeport Hospital and Yale University School of Medicine Robert Moskowitz MD, Attending Physician, Bridgeport Hospital and Yale University School of Medicine Sixto A Arias MD, Pulmonary Medicine Fellow, Bridgeport Hospital and Yale University School of Medicine Sumi Nair MD, Resident Physician, Bridgeport Hospital and Yale University School of Medicine Priyanka Lall MD, Resident Physician, Bridgeport Hospital and Yale University School of Medicine Adam E Schussheim MD, Attending Physician, Bridgeport Hospital and Yale University of Medicine Stuart Zarich MD, Assistant Clinical Professor of Medicine, Bridgeport Hospital and Yale University School of Medicine Constantine Manthous MD, Associate Clinical Professor of Medicine, Bridgeport Hospital and Yale University School of Medicine Correspondence: Dr. Manthous, [email protected] Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1P734 Conflict of interest: Authors reported none We acknowledge the teamwork of 4 cardiologists, 2 resident physicians, 1 intensivist, 1 respiratory therapist, and 3 intensive care unit-emergency department physicians who spent more than 2 hours at our patient’s bedside to resuscitate her. Her favorable outcome could not have been achieved without the excellence of all, working as a team.

References 1. Josephson MA, Brown G, Hecht SH, et al. Noninvasive detection and localization of coronary stenosis in patients: comparison of resting dipyridamole and exercise thallium-201 myocardial perfusion imaging. Am Heart J 1982;103:1008-19. 2. Ranhosky A, Kempthorne-Rawson J, Intravenous Dipyridamole Thallium Imaging Study Group, et al. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Circulation 1990;81:1205-9. 3. Gould KL. Pharmacologic intervention as an alternative to exercise stress. Semin Nucl Med 1987;17:121-30. 4. ARDSnet Study Group. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-8. 5. Carlson RW, Bowles AL, Haupt MT. Anaphylactic, anaphylactoid, and related forms of shock. Crit Care Clin 1986;2:347-72. 6. Boden WE. Anaphylactoid pulmonary edema (“shock lung”) and hypotension after radiologic contrast media injection. Chest 1982;81:759-61. 7. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. 8. Weinmann P, Moretti JL, Leynadier F. Anaphylaxis-like reaction induced by dipyridamole during myocardial scintigraphy. Am J Med 1994;97:488. 9. Angelides S, Van der Wall H, Freedman SB. Acute reaction to dipyridamole during myocardial scintigraphy. N Engl J Med 1999;340:394.


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M Dioverti et al. 10. Varga A, Garcia MAR, Picano E. Safety of stress echocardiography (from the International Stress Echo Complication Registry). Am J Cardiol 2006;98:541-3. 11. Beller GA. Dipyridamole thallium-201 imaging: how safe is it? Circulation 1990;81:1425-7. 12. Homma S, Gilliland Y, Guiney TE, Strauss HW, Boucher CA. Safety of intravenous dipyridamole for stress testing with thallium imaging. Am J Cardiol 1987;59:152- 4. 13. Meyers A, Topham L, Ballow J, Totah D, Wilke R. Adverse reactions to dipyridamole in patients undergoing stress/rest cardiac perfusion testing. J Nucl Med Technol 2002;30:21- 4. 14. Jafary FH, Basir N, Amin A, Ahmed N. Cardiogenic shock after dipyridamole administration for myocardial perfusion imaging. J Nucl Cardiol 2005;12:362-4. 15. Lette J, Gagnon A, Waters D. Acute pulmonary edema caused by prolonged myocardial stunning after dipyridamole-thallium imaging. Am J Med 1989;87:461-3. 16. Picano E, Marini C, Pirelli S, et al. Safety of intravenous high-dose dipyridamole echocardiography. Am J Cardiol 1992;70:252-8.

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17. Ferguson ND, Davis AM, Slutsky AS, Stuart TE. Development of a clinical definition for acute respiratory distress syndrome using the Delphi technique. J Crit Care 2005;20:147-54. 18. Urdaneta F, Lobato EB, Kirby RR, Horrow JC. Noncardiogenic pulmonary edema associated with protamine administration during coronary artery bypass graft surgery. J Clin Anesth 1999;11:675-81. 19. Saldaña A, Jalil J, Gaete P, et al. [Noncardiogenic pulmonary edema associated with hydrochlorothiazide use.] (Spanish) Rev Med Chil 1996; 124:720- 4. 20. Cummings KC 3rd, Arnaut K. Case report: fentanyl-associated intraoperative anaphylaxis with pulmonary edema. Can J Anaesth 2007;54:301-6. 21. Solomon DR. Anaphylactoid reaction and non-cardiac pulmonary edema following intravenous contrast injection. Am J Emerg Med 1986;4:146-9. 22. Borish L, Matloff SM, Findlay SR. Radiographic contrast media-induced noncardiogenic pulmonary edema: case report and review of the literature. J Allergy Clin Immunol 1984;74:104-7.


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