This case highlights two important clinical issue: first, lymphography with even in the amount of less than 10 ml can cause ARDS, and second, Lipiodol-induced ARDS can cause severe pulmonary fibrosis.
Lipiodol (iodine organically combined with ethyl esters of poppy seed fatty acids) is a long-standing medical contrast agent. Japanese package inserts suggest that the appropriate dosage for unilateral lymphography from the lower extremities is 10 ml. Dolan et al. reported complications in 166 of 522 cases (31.8%) of lymphography [7], including fever (18.6%), nausea/vomiting (4.4%), pain (3.3%), and respiratory signs/symptoms (1.3%). Although most complications were slight and transient, two patients experienced severe cardiovascular difficulties. Seven patients developed respiratory signs and symptoms, including chest tightness, dyspnea, cough, and wheezing, but ARDS was not noted. We searched PubMed from 1946 to 2018 using the keywords “lymphangiography” and “respiratory” and found only three reports of ARDS after lymphangiography in the English published literature [5, 6]. Goff and Gaensler reported a case of respiratory distress syndrome following lymphangiography and retroperitoneal lymph node dissection [5] in a patient who received 20 ml of ethiodized oil injected into each leg. The respiratory distress syndrome was so severe that the patient required artificial ventilation and hydrocortisone. Their hypoxemia improved after 26 days, but mild restrictive ventilatory impairment and reduced diffusing capacity were still evident at discharge. Silvestri et al. reported two cases of respiratory distress syndrome due to lymphangiography [6], both of whom underwent bipedal lymphography with approximately 10 ml of ethiodized oil. These previous and current cases all demonstrated high fever, suggesting that the ethiodized oil acted as an inflammatory substance.
Gold et al. reported that the mechanism of pulmonary injury due to lymphography was a reduction of diffusing capacity and pulmonary capillary blood volume [8]. These signs initiated between 3 and 13 h and lasted until a maximum of 256 h. Silvestri et al. described the pathophysiology of oil inflammation in rats [6]. They showed that small numbers of polymorphonuclear leukocytes and mononuclear phagocytes were present around the lipid and within the interstitium at 4 h after injection of ethiodized oil, and a mild multifocal interstitial inflammatory response developed 1 day after injection. This inflammatory response became more extensive, with flooding of the air spaces with hemorrhage and edema. These responses had completely disappeared by 6 weeks. In our case, acute exacerbation of symptoms was observed 5 days after onset. This clinical course indicated pulmonary embolism of Lipiodol as a cause. We considered that Lipiodol deposited in the lung was chronically inflamed, immune system reacted, and the respiratory condition worsened rapidly 5 days later which led to ARDS.
The current patient developed severe pulmonary fibrosis after ARDS, despite steroid administration. The indication of steroids for ARDS is controversial, and patients with ARDS for > 14 days should not receive steroids because methylprednisolone was shown to increase 60-day mortality [9]. In patients with early ARDS (< 72 h), however, glucocorticoids reduced the duration of mechanical ventilation, and the length of intensive care unit stay and mortality [10]. The current patient received prednisolone on the seventh day after the onset of ARDS. Although fibroblast migration and collagen deposition have been recognized as late events, fibroproliferation and collagen deposition start at the onset of ARDS [11], suggesting that earlier administration of steroids might prevent lung fibrosis.
Chylothorax is a life-threatening complication after esophagectomy, and conservative treatments such as thoracostomy drainage, low-fat diet, nil per os (NPO), and TPN should be administered before resorting to lymphography. Marts et al. reported that chylothorax was resolved by conservative treatment in 79% of patients [12]. Octreotide [13] and etilefrine [14] were also reported to be effective for chylothorax, and a pleurodesis is a conservative option if NPO is ineffective [15]. Thoracic duct ligation is also an effective therapy, and the success rate is now 85–100% [3, 16]. Even if the location of the lymphatic leakage is not detected during surgery, ligation of the lymphatic duct just above the diaphragm improves chylothorax [1]. Reisenauer et al. reported an algorithm for the management of postoperative chylothorax [16], including surgical thoracic duct ligation if the chest tube output is > 1100 ml after NPO and TPN. If surgical ligation is ineffective, they advocated lymphangiography and thoracic duct embolization. We chose lymphography before surgical ligation because we considered that lymphography was less invasive than surgery and the location of lymphatic leakage could be identified. Given that our case presented with a rare but critical complication of Lipiodol lymphography, surgical ligation was an appropriate prevenient treatment strategy when the chest tube output exceeded 1100 ml after NPO.
