Improvement in oxygenation with a calcium channel blocker in a patient with hepatopulmonary syndrome during tacrolimus therapy following living donor liver transplantation - A case report

Dear Editor, Hepatopulmonary syndrome (HPS) is an oxygenation disorder caused by dilated intrapulmonary blood vessels resulting from the triad of advanced liver disease, portal hypertension, and portal vein shunts.[1] Treatment of hypoxemia after liver transplantation includes the patient being placed in the Trendelenburg position, as well as inhalation of nitric oxide (NO), intravenous administration of methylene blue, pulmonary vascular embolisation, and extracorporeal membrane oxygenation.[2] We report a case of oxygenation failure in a living liver transplant recipient with HPS, which may have been caused by vasoconstriction due to postoperative tacrolimus therapy and improved with the use of calcium channel blockers. A 4-year-old male, 101 cm in height and 16 kg in weight, was scheduled to undergo living donor liver transplantation. His past medical history included a hepaticojejunostomy for biliary atresia at 1 month of age, followed by progressive cirrhosis and portal hypertension; he was diagnosed with HPS at age 3 years and was undergoing home oxygen therapy. Pre-transplant pulmonary blood flow scintigraphy using technetium-99m-labelled macroaggregated human serum albumin revealed a 33% intrapulmonary shunt rate, with peripheral oxygen saturation (SpO2) of 85% in room air, and arterial blood gas analysis showed a partial arterial oxygen pressure (PaO2) of 47.9 mmHg. The patient’s preoperative medications included oral ursodeoxycholic acid 240 mg/day, monoammonium glycyrrhizinate 25 mg/day, mofetil mycophenolate 150 mg/day, and sulphamethoxazole-trimethoprim 0.8 g/day. Living donor liver transplantation was performed with the patient’s father as the donor, and completed without any complications. The operative time was 14 hours and 47 minutes, the anaesthesia time was 17 hours and 57 minutes, and the intraoperative fluid balance was + 3500 mL. During the procedure, inhaled NO was administered at 10 ppm, and arterial blood gas analysis 1 hour before the end of surgery showed a PaO2 of 64.1 mmHg and arterial oxygen saturation (SaO2) of 88.3 mmHg, with a fraction of inspired oxygen (FiO2) of 100%. Lung ultrasound after intensive care unit (ICU) admission showed no findings suggestive of atelectasis or pleural effusion, and increased shunt blood flow due to HPS was suspected as the cause of hypoxemia. Tacrolimus was administered for immunosuppression at a dose of 1.2 mg via a gastric tube at 6, 18, and 33 hours after ICU admission. The patient did not pass the criteria for extubation concerning oxygenation because of hypoxemia due to HPS but was extubated 31 hours after ICU admission because he passed all the other items of spontaneous breathing trial (positive end-expiratory pressure 5 cm H2O, pressure support 5 cm H2O conditions, 30 spontaneous breaths per minute or less after 30 minutes, heart rate of 140 bpm or less, and no elevated blood pressure or respiratory distress symptoms), and placed on high-flow nasal cannula (HFNC) with inhalation of NO, but his SpO2 remained low at around 80%. Seven hours after extubation, HFNC therapy was changed to non-invasive positive pressure ventilation, but methylene blue, embolisation of abnormal vessels, or extracorporeal membrane oxygenation was not an option after discussion with the paediatric surgeon. Three hours later, the blood level of tacrolimus was 23.0 ng/mL, above the target trough value of 10 ng/mL, and the patient’s systolic blood pressure increased to 130–139 mmHg. Therefore, we hypothesised vasoconstriction due to high blood levels of tacrolimus. Immediately following the initiation of nicardipine administration at 0.3 mg/h, SaO2, SpO2, and PaO2 increased significantly, and urine output increased, along with a decrease in blood pressure [Table 1].Table 1: Postoperative changes in oxygenation, blood pressure, and blood levels of tacrolimusTacrolimus, a calcineurin inhibitor used as an immunosuppressive agent after transplant surgery, can cause vasoconstriction due to sympathetic activation and oxidation of vasodilatory NO.[3] Given that blood levels of tacrolimus fluctuate widely, particular caution is required regarding complications in children, who typically require higher doses than adults.[4] Calcium channel blockers, beta-blockers, and angiotensin-converting enzyme inhibitors have been investigated as anti-hypertensive agents for tacrolimus-related hypertension, but none have been found to show superiority.[3] Because hypoxemia associated with HPS is primarily caused by increased shunt blood flow due to intrapulmonary vasodilation, using calcium channel blockers, which generally have vasodilatory effects, may further exacerbate this shunt blood flow. However, in the present case, oxygenation rapidly improved after administering nicardipine. This result suggests that tacrolimus-induced vasoconstriction tends to occur in normal vessels, not shunted vessels associated with HPS, and that calcium channel blockers may primarily act on constricted normal vessels. If oxygenation does not improve in patients with HPS despite appropriate oxygen therapy, fluid management, and the use of NO, the effect of calcineurin inhibitor-induced vasoconstriction should be considered. Calcium antagonists may reverse the increase in intrapulmonary shunt induced by calcineurin inhibitors to the state before using said inhibitors. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient consented to his images and other clinical information being reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.