Contrast medium induced pulmonary edema CASE REPORT Acute Non-cardiogenic Pulmonary Edema Associated with the Radiographic Contrast Medium Ioversol 1 1 1 2 Honda Hsu , Chih-Ming Lin , Chung-Yen Tsai , Shau-Bin Chou , Tzong-Bor Sun 1 1,3 2 Division of Plastic Surgery and Center for Hyperbaric Oxygen Therapy , Department of Radiology , Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Institute of Medical Sciences3, Tzu Chi University, Hualien, Taiwan ABSTRACT Ioversol is an iodinated, low-osmolality, nonionic contrast agent used in angiography. Life threatening non-cardiogenic pulmonary edema after intravenous administration of radiographic contrast medium is a rare event. We could find no report of ioversol-related pulmonary edema. We present a case of 65-year-old woman with diabetes mellitus and peripheral arterial occlusive disease who underwent angiography for evaluation of both lower limbs. Cold sweating, dyspnea, and lost of consciousness were noticed soon after 125 mL of ioversol injection. She was intubated immediately and chest radiograph showed severe pulmonary edema. After intensive mechanical ventilatory support, she recovered and was extubated 72 hours after the anaphylactic episode. Reports in the English literatures show that severe, life-threatening, adverse effects associated with radiographic contrast medium are rare. Our presenting case may be the first associated with the specific radiocontrast ioversol. Prompt differential diagnosis, aggressive ventilatory support, and avoid dehydration are essential to prevent a fatal outcome. (Tzu Chi Med J 2005; 17:273-277) Key words: contrast medium, pulmonary edema, ioversol, angiography, adverse effect INTRODUCTION Angiography is a common routine investigation in the diagnosis of peripheral arterial occlusive disease (PAOD). Most common adverse reactions include nausea, palpitations and heat sensation. Severe reactions such as dyspnea, hypotension and cardiac arrest are reported in 0.04% of all cases [1]. Life threatening noncardiogenic pulmonary edema after intravenous administration of radiographic contrast is a rare event. We present a 65-year-old diabetic woman who presented with a painful gangrene in the right foot for several months. She sustained acute pulmonary edema during the angiography for evaluation of both lower limbs. The initial symptoms/signs, resuscitation procedures, and physiological responses were collected and analyzed. Our experience in managing this rare case provides information for future management of this idiosyncratic life threatening situation. CASE REPORT A 65-year-old woman presented with right foot pain for several months. She had visited many clinics, but only intravenous analgesics were administered. Recently necrotic skin changes were noticed over the medial and lateral malleolar area. She was referred from a local clinic for further treatment. She reported persistent continuous leg pain, which was partially relieved by dangling her legs over the side of the bed. There was no history of claudication as she was wheelchair bound due to left Received: October 19, 2004, Revised: November 10, 2004, Accepted: November 26, 2004 Address reprint requests and correspondence to: Dr. Tzong-Bor Sun, Division of Plastic Surgery and Center for Hyperbaric Oxygen Therapy, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung Yang Road, Hualien, Taiwan Tzu Chi Med J 2005 17 No. 4 OTP H. Hsu, C. M. Lin, C. Y. Tsai, et al hemiparesis from a cerebral vascular accident 15 years previously. She also had a history of diabetes mellitus and hypertension with irregular medical treatment. She had no known allergies. Physical examination showed necrotic skin changes over the medial and lateral malleolar area measuring 7 cm × 8 cm and 5 cm × 5 cm respectively. Pulse was absent in both legs, and the femoral pulses were also very difficult to palpate. A diagnosis of diabetic foot and peripheral arterial occlusive disease was made. Routine chest radiograph on admission was normal (Fig. 1A). The electrocardiogram on admission demonstrated possible left ventricular hypertrophy by voltage criteria and ST-T depression which suggested possible chronic myocardial ischemia. The patient recalled several episodes of palpitation and chest tightness. Laboratory data revealed white blood cells 10100/µL, hemoglobin 6.8 g/dL, platelets 532000/µL, erythrocyte sedimentation rate (ESR) 70 mm/hr, blood urea nitrogen (BUN) 15 mg/dL, creatinine 1.4 mg/dL, glutamic oxaloacetic transaminase (GOT) 15 IU/L, and glutamic pyruvic transaminase (GPT) 6 IU/L. Angiography was done to evaluate the circulatory status of both lower limbs. In the Department of Radiology, 125 mL of ioversol (Optiray 320, Mallinckrodt Pharmaceuticals, St. Louis, MO, USA), an iodinated, low osmolality, non-ionic contrast medium, was injected intra-arterially. While the angiography was being performed, the patient complained of sudden dizziness, nausea and chillness. Cold sweating and lost of consciousness was noticed. Oxygen saturation was 80% on 10 L/min of oxygen by face mask. She was intubated immediately. After intubation, profuse pink, foamy sputum was secreted from the endotracheal tube. A chest radiograph was taken and she was then transferred to the surgical intensive care unit (SICU) immediately. Her blood pressure was 130-150/70-90 mmHg and did not decrease throughout the period of emergent management while she was in the radiological department. Chest radiograph showed interstitial changes with acinar shadows in both lung fields (Fig. 1B). An electrocardiogram showed sinus tachycardia with ischemic changes in the inferolateral area, although there was no chest pain. Arterial blood gases after intubation on 100% oxygen were pH 7.322, pCO2 42.5 mmHg, pO2 485 mmHg, HCO3 22.3 mmol/L, BE -3.1 mmol/L. Total creatine kinase (CK 451 IU/L) and MB isoform (CK-MB 17 IU/L), as well as troponin I (0.04 ng/dL) suggested a low possibility of acute myocardial infarction. Her central venous pressure was 1 mmHg. She was placed on mechanical ventilation with positive end expiratory pressure (PEEP). Fluid replacement was given, as well as OTQ coricosteroids (Solucortef 200 mg initially, and then 100 mg/day). Blood pressure was maintained at 130-150/7090 mmHg without infusion of inotropic agents. The cardiologists were consulted. Cardiac echography revealed a left ventricle ejection fraction of 50%, moderate mitral valve incompetence and normal wall motion. The skin turgor was dry with continuous clear urine output from the indwelling Foley catheter. In considering the underling myocardial ischemia from the routine ECG, a dopamine infusion 3 µg/kg/hr was given alone with fluid resuscitation. After mechanical ventilation with PEEP and fluid replacement, she gradually improved over the next 72 hours as confirmed by serial chest radiographs (Fig. 1C, D). Serial daily input/output amounts recorded from the first day were 2213/2345, 3165/1635, and 3886/ 3155 mL. Serum BUN and creatinine levels on the third day were 16 mg/dL and 1.5 mg/dL respectively. Angiograms of the legs showed diffuse segmental obstruction of the femoral artery with formation of collateral vessels. DISCUSSION We presented a patient with PAOD and underlining myocardial ischemia who developed pulmonary edema after injection of ioversol for lower limb angiography. The key to successful management of this challenging situation was to decide whether the pulmonary edema was cardiogenic or non-cardiogenic, because these two conditions had different principles of treatment, in regard to fluid restriction or supplement. Thinking retrospectively, the etiology of pulmonary edema for this case was not likely to be cardiogenic for the following reasons. First, a central venous pressure measurement of 1 mmHg suggested there was no right side heart failure. Second, the systemic blood pressure remained in the normal range without the aid of inotropic agents, so the possibility of left side heart failure was low. Third, the serum cardiac enzyme studies did not suggest acute myocardial infarction. Fourth, more than 1000 mL of crystalloid or colloid solution was infused every 8 hours over the first 3 days after the episode. Together with mechanical ventilatory support, this fluid resuscitation resolved the pulmonary edema despite cardiac size enlargement and the central venous pressure increased from 1 to 8 mmHg. Fortunately, the patient survived after proper treatment following initial recognition of ioversol induced non-cardiogenic pulmonary edema. Non-ionic radiographic contrasts are used worldwide. Ioversol, N,N'-Bis (2,3-Dihydroxypropyl)-5-[N(2-Hydroxyethyl)-Glycolamido]-2,4,6-Triiodoisoph- Tzu Chi Med J 2005 17 No. 4 Contrast medium induced pulmonary edema A B C D Fig. 1. Serial changes of the chest radiograph. (A) Chest radiograph of the patient on admission displays normal lung fields. (B) Chest radiograph immediately after angiography shows a butterflypattern, characterized by the central predominance of shadows with a clear zone at the peripheral lobes. (C) Chest radiograph shows improved lung fields after assisted mechanical ventilatory support for 24 hours. (D) Chest radiograph shows clear lung fields after assisted mechanical ventilatory support for 48 hours. Tzu Chi Med J 2005 17 No. 4 OTR H. Hsu, C. M. Lin, C. Y. Tsai, et al thalamide (molecular weight = 807.13), is an iodinated, low-osmolality, nonionic contrast agent, with an elimination half-life of 2 hours. It distributes rapidly throughout extracellular fluid following injection. There is no significant deposit in tissue. It does not cross the bloodbrain barrier, but accumulates within interstitial tissues of malignant tumors. Ioversol reaches a peak serum concentration immediately and the concentration falls rapidly within 5 to 10 minutes. It is excreted unchanged in the urine [2]. Adverse effects have been described as minimal. The most frequent adverse effect seen is nausea in less then 1% of patients [1]. It is particularly useful for painful examinations such as peripheral angiography, for patients with hemodynamic instability or for patients with limited cardiac reserve [3]. Adverse effects that have been described with ioversol include transient bradycardia in 1 patient [3], angina in 1 patient [4], and transient prolonged QT intervals and small increases in the left ventricular end diastolic pressure in patients undergoing left ventriculography [5]. Isolated dizziness, lightheadedness, vertigo and disorientation have also been observed. Headache associated with Ioversol has been reported in 0.5% of patients [6]. Nausea is the most common adverse effect, occurring in 0.8% of patients [3, 6]. Ioversol can also cause a slight elevation in the serum creatinine, but clinically significant changes in renal function have not been detected. There are also sporadic reports of blurred vision, hypoxia, pruritus and urticaria [6]. Pulmonary edema as a result of ioversol administration is a rare event. Two types of pulmonary edema are described: cardiogenic and non-cardiogenic. In the non-cardiogenic type there is a rise in microvascular permeability with fluid lost from the circulation. This leads to alveolar edema. The pathogenesis of contrast-induced, non-cardiogenic pulmonary edema is unclear. Edema could be caused by mediator release and complement activation resulting in endothelial damage or as the result of a direct irritant effect of the drug on the lungs [1]. Treatment of contrast medium related non-cardiogenic pulmonary edema is different from that of the cardiogenic type. Administration of furosemide and vasodilators may lead to fatal deterioration as described in previous case reports. Treatment as anaphylaxis is also not beneficial. Primary emergent treatment such as maintenance of the airway and ventilation with positive end expiratory pressure together with fluid resuscitation to increase the left ventricular preload is important [1]. The pathophysiology of radiographic contrast medium induced pulmonary edema is still unknown. Sendo et al demonstrated that contrast medium in high doses produces pulmonary edema by inhibiting endothelial OTS nitric oxide (NO) production, and nitrovasodilators protect against this adverse effect in rats [7]. Based on the experimental findings in rats, Hayshi et al suggested that the adverse phenomenon is induced by non-osmolality related toxicity of the contrast medium [8]. Carbazochrome sodium sulfonate (AC-17), a capillary stabilizer, was used to block radiographic contrast medium-induced pulmonary dysfunction by maintaining the endothelial barrier function in a rodent model [9]. The tryptase liberated from mast cells may also play a crucial role in the contrast medium-induced pulmonary dysfunction in rats [10]. Severe non-cardiogenic pulmonary edema as a result of ioversol injection is a rare event. Recent randomized, double-blind clinical trials have reported no cases of this disorder [11]. We found only 20 reports of noncardiogenic pulmonary edema associated with radiographic contrast [1,12-19] and none of these cases involved ioversol. Our presenting case maybe the first noncardiogenic pulmonary edema associated with ioversol. In conclusion, this case serves to remind us that although severe life-threatening adverse effects associated with radiographic contrast medium are rare, we still should remain vigilant. 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