Biliary atresia (BA) is a cholangiopathy of the newborn. Although some infants are cured with portoenterostomy, many develop end-stage liver disease and require liver transplantation.1 In addition to jaundice and portal hypertension, infants can develop end-stage liver disease–induced hepatopulmonary syndrome,2 portopulmonary hypertension, and cirrhosis-induced cardiomyopathy.3
For patients with cardiac or respiratory failure, extracorporeal life support (ECLS) may provide cardiopulmonary bypass, allowing time for resolution of illness. ECLS is most commonly employed in the neonatal period. Its role in older infants and children continues to evolve and has been indicated for sepsis, near-drowning, and postoperative support after cardiac repair.
ECLS use in pre- or post-liver transplantation is uncommon. Its use in BA has not been previously reported. We present the case of a 5-month-old with BA, who required both ECLS and hepatic dialysis to sustain life, before liver transplantation. This prompted a query of the Extracorporeal Life Support Organization (ELSO) registry, reviewing all cases of patients with a diagnosis of BA where ECLS was used. Interestingly, ours was the only pediatric case recorded of ECLS use before transplantation.
Materials and Methods
The ELSO registry was queried from 1995 to 2014 for patients with BA. All patients underwent liver transplantation and required ECLS at some point during their hospital stay. Data were collected in a standardized format.
A 5-month-old male with BA was admitted for hyponatremia. The patient’s medical history was pertinent for mild aortic valve and pulmonary stenosis with pulmonary dilation, left atrial enlargement, and polysplenia. Two months earlier, a diagnosis of BA had been established. Abdominal identified an atretic gallbladder and biliary system and a cirrhotic liver, precluding a portoenterostomy. The patient also had malrotation for which he underwent a Ladd procedure.
On physical examination, the patient was found to be tachycardic and tachypnic, with icteric sclera. His abdomen was soft with hepatosplenomegaly. He underwent laboratory testing demonstrating hyponatremia (sodium 123 mmol/l; range 135–145 mmol/l) and hyperbilirubinemia (total bilirubin 23.2 mg/dl; range 0–13 mg/dl) with a direct fraction of 15.5 mg/dl (range 0–0.3 mg/dl). His AST was 383 units/l (range 16–62 units/l), ALT 228 units/l (range 12–49 units/l), and alkaline phosphatase 530 units/l (range 82–383 units/l). There was a leukocytosis of 22.6 k/μl (range 5–19.5 k/μl) and hemoglobin of 9.4 g/dl (range 9.5–13.5 g/dl). An abdominal ultrasound showed a large amount of ascites.
The patient underwent transplant evaluation and was listed for liver transplantation. Because his respiratory status appeared compromised by the ascites, he underwent therapeutic paracentesis twice, which on biochemical examination showed no findings of spontaneous bacterial peritonitis. Six days post-admission, the patient developed respiratory distress, necessitating transfer to the pediatric intensive care unit. He was intubated and ultimately placed on oscillatory ventilation. Serial chest x-rays revealed worsening pulmonary edema. An echocardiogram was performed, revealing elevated right ventricular pressure (right ventricle to right atrial pressure gradient of 46 mm Hg), mild pulmonary stenosis, bicuspid aortic valve with mild aortic stenosis, mild mitral regurgitation, and left atrial enlargement. Subsequent echocardiograms included an agitated saline (“bubble”) study with no evidence for hepatopulmonary syndrome and abnormal mitral valve Doppler tracings, suggesting diastolic dysfunction and increased left atrial pressure (ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity E/e′ of 15). He developed oxygen desaturations to 60% and hypercarbia requiring hand-bagging. He required inotropic support for hypotension. The etiology of his cardiorespiratory failure was uncertain, with a differential diagnosis of sepsis, systemic inflammatory response syndrome, and decompensated cirrhosis-induced cardiomyopathy. After extensive discussion with family, it was decided that the only option that might result in salvage for the patient was ECLS for hypoxemic respiratory failure. The patient was placed on venoarterial ECLS via a 14-French venous cannula in the right internal jugular vein extending to the right atrium and a 10-French arterial cannula in the right carotid artery extending to the carotid–aortic junction. Initial flow rates were 100 ml/kg/min. The ventilator was maintained on synchronized intermittent mandatory ventilation settings. After initiation of ECLS, the patient’s oxygen saturation improved, and he was weaned off inotropes; however, he developed acute kidney injury and was started on continuous renal replacement therapy (CRRT). The patient’s blood gases before and after initiation of ECLS are reported in Table 1.
The patient underwent daily Molecular Adsorbent Recirculating System (MARS, Gambro Renal Products, Lakewood, CO) treatments over the subsequent 3 days. MARS, in acute liver failure, has been shown to clear protein-bound toxins normally metabolized by the liver, which may exacerbate cardiovascular and neurologic compromise in patients with a failing liver.4 The MARS machine was connected to the ECLS circuit with both the access and return lines connected in a post-pump, premembrane configuration, allowing the oxygenator to function as a potential trap for air bubbles introduced from the MARS system (Figure 1). Flow rates initially start at approximately 100 ml/kg/min on ECLS and are titrated based on the patient’s needs. With concomitant use of CRRT and MARS, the flow rates of these two modalities are typically matched and start at less than 10% of the ECLS flows and are also titrated based on the clinical necessities of the patient. The patient tolerated the three procedures without incident. Repeat echocardiography showed improvement in diastolic function and decreased mitral regurgitation. Throughout the course, ventricular systolic function was normal to hyperdynamic.
The ECLS circuit was continuously monitored, and flows were titrated to preserve the patient’s mean arterial pressure and perfusion, with the majority of the course maintaining flows at mid-120 to mid-130 ml/kg/min. Anticoagulation parameters and blood coagulopathy were evaluated with serial draws of prothrombin time/international normalized ratio, partial thromboplastin time, unfractionated heparin levels, fibrinogen degradation products, antithrombin III levels, fibrinogen levels, factor levels V, VII, VIII, and IX, in addition to serial thromboelastography. Anticoagulation was achieved using a continuous heparin infusion during the ECLS run along with a citrate dextrose solution. Blood products were transfused as needed based on laboratory values and clinical considerations. Transfused products included packed red blood cells, fresh frozen plasma, and platelets. Antithrombin III was also replaced during the ECLS run with an initial bolus dose followed by a standardized continuous infusion that was titrated off of laboratory values. Manipulations to the coagulation cascade during the ECLS run with transfusion and medication administration impacted laboratory values that otherwise would reflect liver function. The use of the thromboelastogram allowed for evaluation of the clotting cascade after removal of the heparin effect on anticoagulation, while serial liver function tests helped to assess the status of the liver. Table 2 displays the patient’s liver function tests and synthetic liver function before, during, and after completion of MARS treatment. Subsequently, the patient’s pulmonary function improved and his ECLS flows were weaned. On day 7 of his ECLS course, he was decannulated with ligation of the carotid artery and placement of a dialysis catheter into the internal jugular vein. CRRT was continued after decannulation.
One day after discontinuation of ECLS, a whole organ deceased donor liver became available, and the patient underwent liver transplantation. His intraoperative course was uneventful. Postoperatively, he was maintained on CRRT while ventilator support was weaned. On postoperative day three, his native kidney function improved and CRRT was discontinued. On postoperative day 12, the patient was extubated to high-flow nasal cannula, which was weaned to room air. The patient was transferred out of the pediatric intensive care unit on postoperative day 16, and the remainder of his recovery was uneventful. An echocardiogram before discharge revealed decreased left atrial volume and mitral valve gradient. The patient was discharged home 42 days after admission, on postoperative day 26. The patient is now 35 months post-transplant and remains well with a normal cognitive status for age.
Review of ELSO Database
The ELSO registry contains 17 patients treated with ECLS during a hospital admission with liver transplantation. Six had BA. Ours was the only case of ECLS before liver transplantation. The average age was 798 days (range 159–2655 ± 953.286) and weight 11.47 lbs (range 6.5–24 lbs ± 7.03). Our patient was younger at 159 days old, though was within the average range for weight (14.74 lbs).
Most (n = 5), including our patient, were placed on venoarterial ECLS. The remaining patient was placed on venovenous ECLS (VVDL + V). The average amount of time spent on the ECLS circuit was 215.6 hours (range 14–647 ± 219.32). Our patient spent 158 hours on ECLS.
Patients with BA required ECLS for a variety of reasons. Diagnoses included pneumonia (n = 2), respiratory arrest/failure (n = 3), acute renal failure (n = 1), cardiogenic shock (n = 1), and septicemia (n = 1). The survival to discharge was 50%.
ECLS was not without complications. Amongst the six BA patients treated with ECLS, bleeding was the most common complication (n = 5), followed by renal failure (n = 3). Less common complications included hyperbilirubinemia (n = 2), clotting (n = 1), and hypertension (n = 1). For our patient, complications included cannula site bleeding and acute renal injury requiring hemofiltration.
BA is a newborn cholangiopathy, often requiring liver transplantation. This disease may be exacerbated by cardiovascular and pulmonary complications including hepatopulmonary syndrome,2 portopulmonary hypertension, and cirrhosis-induced cardiomyopathy.3 Although all may be reversed with liver transplantation,5 perioperative respiratory failure in patients with significant liver disease requiring transplantation negatively impacts grafts as well as recipient outcomes.6
The combination of BA and cardiovascular compromise portends a poor prognosis. ECLS, though potentially life-saving, is rarely used in combination with liver transplantation. Our unique case features a patient with BA who experienced rapid cardiopulmonary decompensation. We believe this decompensation was a combination of a high cardiac output state induced by cirrhosis (as demonstrated by left atrial dilatation), diastolic dysfunction, and respiratory dysfunction because of pulmonary edema. ECLS was used as an extreme life-saving intervention to stabilize the patient’s pulmonary function and allow time for his cardiorespiratory compromise to stabilize.
Our patient received three MARS treatments on ECLS. Fulminant liver failure may result in inability to clear toxic substances and elevation of lactate, ammonia, bilirubin, and aromatic amino acids in the body. Through MARS, water-soluble and protein-bound toxins are removed from the body, thus, restoring the patient’s biochemical and hemodynamic status, as well as improving hepatic encephalopathy.4 MARS has been reported in 72 cases, including case reports and small series, as a method to stabilize the patient and act as a bridge to liver transplantation. Although most literature describes the use of MARS in adults with liver failure without cardiac or respiratory insult, few reports exist of combined MARS therapy with ECLS. Those that have used these two therapies together, however, confirm that the two modalities combined are safe and allow for recovery of hepatic function while on extracorporeal membrane oxygenation, without altering complication rates.7 Peek et al.8 describe the indication for initiation of MARS therapy in combination with ECLS as being a total bilirubin of >17 mg/dl. Using this indication, mortality of patients requiring MARS dropped to 40% as compared with 100% mortality when using a bilirubin level of >23 mg/dL. In reports utilizing MARS with ECLS, support is discontinued after serum liver function improves, as based on liver function tests for three consecutive days, or patient receives liver transplantation. In the case of our patient, who began receiving MARS treatments when total bilirubin level was 10.6 mg/dL, the use of MARS allowed our patient to stabilize until a donor liver became available.
BA is a rare indication for ECLS, accounting for only six patients, all of whom had undergone liver transplantation. In five, ECLS was used post-transplant. In 2010, Landsman and Karsanac9 reported a patient with BA who required ECLS after lateral section orthotopic liver transplantation. In this case, ECLS was used as a bridge postoperatively to retransplantation when the patient developed heparin-induced thrombocytopenia and thrombosis-induced ischemic liver.
Another 11 in the ELSO registry underwent both liver transplantation and ECLS support. Three reports utilized ECLS before transplantation including two that involved children—Son et al.10 reported ECLS use before transplantation for Wilson’s Disease and a propionic academia of propionyl-CoA carboxylase deficiency patient.11 Table 1, Supplemental Digital Content, http://links.lww.com/ASAIO/A231 describes all reports of ECLS utilization with liver transplant.
Our case demonstrated that ECLS with MARS therapy may be used as a life-saving measure to stabilize a patient with cardiopulmonary compromise while awaiting liver transplantation.
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