EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Alagille syndrome is an autosomal-dominant inherited disease characterized by intrahepatic bile duct involvement, congenital heart disease, eye anomalies, skeletal and central nervous system involvement, kidney anomalies, and facial appearance. Liver transplant is the only treatment option for patients with end-stage liver disease and Alagille syndrome. Bilateral peripheral pulmonary artery stenosis is a contraindication for liver transplant due to high mortality, and the decision for liver transplant in patients with bilateral peripheral pulmonary artery stenosis is extremely challenging for anesthesiologists and transplant surgeons. We present a 2-year-old female patient with successful anesthetic management of a pediatric living donor liver transplant with mild bilateral pulmonary artery stenosis, mild aortic stenosis, and mitral regurgitation due to Alagille syndrome. Anesthesiologists should know the underlying pathophysiological condition and perform a comp-rehensive preoperative evaluation to determine the correct anesthesia plan in patients with Alagille syndrome who will undergo liver transplants to treat multiple system disorders. Successful perioperative management of Alagille syndrome requires effective communication and collaboration between specialists through a multidisciplinary team approach.

Key words : Nedim Çekmen, Ahmed Uslu, Adnan Torgay, Coşkun Araz, Emre Karakaya, Sedat Yildirim, Kürşad Tokel, Mehmet Haberal

Alagille syndrome (AGS) is an autosomal-dominant genetic disorder that affects the liver, heart, eyes, skeleton, and facial appearance.¹ Most cases of AGS are associated with 20p12 chromosomal micro-deletion of the JAG1 gene, which is the homologue of the rat Jagged1 gene.² The incidence of AGS is approximately 1 in 70 000 to 100 000 live births.³ The prognosis and outcome of this syndrome are highly variable and are directly related to the severity of liver and cardiac anomalies. Cardiac abnormalities are found in 85% to 100% of AGS cases, the most common of which is pulmonary stenosis (PS).^4,5 End-stage liver disease (ESLD) coincident with congenital cardiac defects in patients with AGS may cause adverse effects on hemodynamics during liver transplant (LT) surgery, leading to perioperative problems and death.^5-7

The most common symptom of AGS is chronic cholestasis. Liver transplant is indicated for AGS in patients with ESLD who have growth retardation secondary to xanthomatosis with portal hypertension, severe cholestasis, jaundice, persistent pruritus, and impaired quality of life, and approximately 15% of patients with AGS require LT. Finally, 1-year and 5-year survival rates have been reported to be greater than 80%.^5,6

Elevated mean pulmonary arterial pressure (mPAP) and right ventricular (RV) pressure are com-mon in patients with peripheral PS. Lowering of RV pressure, mPAP, and pulmonary vascular resistance (PVR) before LT may contribute to treatment of peripheral PS, and thus less invasive interventions are required. However, accompanying comorbidities in patients with AGS with ESLD often lead to increased surgical risks. Due to these comorbidities, the evalua-tion of these patients for surgery requires meticulous attention to detail and a full understanding of the disease to optimize the process of general anesthesia.^7,8

Herein, we present the successful anesthetic management of pediatric living donor LT (LDLT) with mild bilateral PS due to AGS.

A 2-year-old female patient (11 kg body wt, 80 cm height) presented with cholestatic jaundice, mild bilateral PS, aortic stenosis (AS), and mitral regurgitation, cutaneous xanthomas, and facial appearance compatible with AGS (Figure 1). Because of untreatable deep cholestatic jaundice, itching, and growth retardation, LDLT was indicated for treatment. Due to the patient’s existing biliary atresia, Kasai surgery was performed for therapeutic purposes on day 40 after birth.

The electrocardiogram showed sinus tachycardia with RV hypertrophy. Preoperative transthoracic echocardiography revealed supravalvular mild AS (maximum gradient 38 mm Hg), mild bilateral PS, ejection fraction of 65% to 70% with increased left ventricular (LV) wall thickness, and enlarged RV and right atrium size and function with mild RV hypertrophy and tricuspid regurgitation. Turbulence was observed on the pulmonary artery and its branches, and a gradient of 37 mm Hg was obtained. A gradient of 67 mm Hg was obtained in the right pulmonary artery and 65 mm Hg in the left pulmonary artery. Preoperative angiography showed systolic pulmonary arterial pressure (sPAP) of 80/14 mm Hg, mPAP of 35 mm Hg, an estimated RV systolic pressure of 84 mm Hg, and mild bilateral PS. The radiograph showed no anomalies in heart size and configuration, and results from thorax computed tomography were unremarkable.

We evaluated the LT indication in the patient in a multidisciplinary approach with a team composed of a pediatric cardiologist, a cardiac anesthesiologist, a transplant surgeon, and an intensivist. The patient’s renal function tests were within reference ranges, and the preoperative laboratory values were as follows: hemoglobin 10.5 g/dL, hematocrit 29.5%, platelets 213 × 103 cells/mL, alanine aminotrans-ferase 384 IU/L, aspartate transaminase 647 IU/L, γ-glutamyl transferase 167 IU/L, alkaline phosphatase 534 IU/L, total bilirubin 40.4 mg/dL, direct bilirubin 33.8 mg/dL, albumin 3.6 g/dL, prothrombin time 14.9 seconds, activated partial thromboplastin time 37.6 seconds, international normalized ratio 1.3, sodium 135 mEq/L, and potassium 3.6 mEq/L. Arterial blood gas values measured before surgery were as follows: pH 7.38, PaCO2 34 mm Hg, PaO2 77.9 mm Hg, oxygen saturation 96.2%, base excess -6.1, and HCO3 20 mEq/L. After written and verbal informed consent was obtained from the patient’s parents, we performed LT on the patient. Although the pediatric cardiology department has reported a high risk for LT, our treatment approach was first to perform LT to correct cardiac pathologies. Our patient’s cholestatic jaundice advanced, and her clinical condition gradually deteriorated. Therefore, we predicted that, if we performed LT on our patient, then the other pathologies in our patient would improve clinically. The patient showed Pediatric End-Stage Liver Disease score of 20.4, a Child-Pugh-Turcotte score of B, an American Society of Anesthesiologists physical classification of III, and a Mallampati score of II. The patient, whose blood oxygen level in room air was 86% to 88% due to mild bilateral PS, was taken to the operating room without premedication. The living donor was the patient’s 31-year old mother, with American Society of Anesthesiologists score of I and a Mallampati score of II; donation was the left lateral lobe.

Standard monitoring was applied to the patient’s electrocardiogram, blood oxygen level, noninvasive blood pressure, nasopharyngeal temperature, and bispectral index. At anesthesia induction, the patient was given lidocaine 1 mg/kg, propofol 2 mg/kg, fentanyl 1 μg/kg, and rocuronium 0.6 mg/kg . After preoxygenation with 80% O2 for 3 minutes, she was intubated without complications with a number 4.5 cuffed endotracheal tube connected to a ventilator. Anesthesia maintenance was provided with 2% sevoflurane and 50% oxygen-50% air mixture, 0.01 to 0.05 μg/kg/min infusion of remifentanil, and 0.3 mg/kg/h infusion of rocuronium. After induction, we inserted a left radial artery catheter for hemo-dynamic monitoring, a left femoral artery catheter for monitoring the pulse index continuous cardiac output, and a right subclavian central venous catheter and a catheter for urine monitoring. Because the sPAP in the intraoperative period was 80 mm Hg and the mPAP was 35 mm Hg, milrinone infusion (0.375-0.75 μg/kg/min) was started to reduce RV afterload and increase cardiac contractility. Norepinephrine infusion (0.01-0.15 μg/kg/min) was also started as an inotrope to prevent hypotension. During the operation, sPAP was around 60 to 120 mm Hg, central venous pressure was around 8 to 10 mm Hg, and cardiac index was around 2.41 to 2.69 L/min/m².

The patient had 680 g of liver tissue removed without any problems (Figure 2). After the inferior vena cava was partially clamped, transection and hepatic vein reconstruction were performed, and a 280-g section of the mother’s lateral segment liver tissue was transplanted to the patient (Figure 3). In the anhepatic phase, which lasted 42 minutes, after the anastomoses were completed, the clamp on the portal vein was removed and reperfusion was achieved with good appearance of the liver after reperfusion (Figure 4). The patient’s blood pressure dropped to 60/34 mm Hg at 2 minutes after reperfusion, so we increased the norepinephrine infusion dose and gave two 5-mg doses of ephedrine and two 100-mg doses of calcium.

There was thinning in the bilateral PS and pulmonary artery branches, so the patient did not receive a pulmonary artery catheter. We apply transesophageal echocardiography in the intraope-rative period in patients with mild bilateral PS because it provides valuable information about RV functions. Nevertheless, due to the presence of esophageal varices, we did not apply direct tran-sesophageal echocardiography. Because our patient had mild bilateral PS, we attempted to ensure ventilation, oxygenation, and perfusion throughout the surgery and to prevent triggering factors that could increase RV afterload. We maintained normot-hermia in our patient by warming the fluids given throughout the operation and using a blanket. We avoided hypervolemia due to RV dysfunction and bilateral PS but also attempted to maintain adequate preload. We applied fluid and inotrope therapy according to pulse index continuous cardiac output parameters. The estimated blood loss during surgery was 250 mL, and ascites loss was 150 mL. During the surgery, the patient was given 1000 mL of crystalloid, 750 mL of 5% albumin, and 250 mL of intraoperative cell salvage, and 750 mL of urine output was achieved. The operation continued for 6 hours, and postoperatively all anesthetic agents were discon-tinued; sugammadex was administered to reverse the muscle relaxant.

The patient was extubated and transferred to the pediatric intensive care unit without any anesthesia complications. Immunosuppressive drugs, steroids, nutritional support, and necessary medical treatment were applied to the patient. Doppler ultrasonography performed at 12-hour intervals showed satisfactory vascular anastomoses, liver perfusion, liver functions, and arterial blood gas values. The patient, whose clinical condition and neurological examination were good, was transferred to her normal room after a 3-day stay in the pediatric intensive care unit, and her treatment and monitoring continued. She was discharged 10 days after the surgery without complications for regular follow-up at the LT clinic.

The quality of life of patients with AGS coincident with ESLD and serious cardiac comorbidities may be extremely poor due to persistent itching and due to cholestatic jaundice, growth retardation (in 50%-90% of cases), nutritional complications, and sleep disorders.4 The transplant team should first focus on monitoring and optimization of growth, development, and nutrition in these patients.5 Most patients with AGS become symptomatic in early in life. Medical treatment of these patients includes medium-chain triglycerides, essential fatty acids and fat-soluble vitamins, palliative medications (cholestyramine, rifampin, antihistamine agents), and ursodeo-xycholic acid.6 Patients with AGS with ESLD who do not improve despite medical treatment should be considered for LT.4-6

Although LT is performed in patients with AGS with ESLD, absolute contraindications exist, inclu-ding patients with severe cardiac anomalies, sepsis, or mPAP ≥50 mm Hg.⁹ Comprehensive and careful evaluation of mPAP and PVR is required for LT in patients with AGS and cardiac anomalies. If cardiac anomalies and mild bilateral PS are present, then it is critical to treat and correct these anomalies, reduce mPAP, and improve RV function before LT. Mortality and morbidity of LT are generally higher in patients with AGS because of existing cardiac anomalies.^7-10 Our patient had mild bilateral PS, stenosis, and mitral regurgitation due to AGS; she had advanced cholestatic jaundice advanced, and her clinical condition gradually deteriorated. Thus, we predicted that if we performed LT on our patient first, then other pathologies in our patient would improve clinically; the patient had successful LT after her family was informed of her high-risk status.

Common cardiovascular malformations of AGS include peripheral PS, atrial septal defect, patent foramen ovale, ventricle tubular septal defect, tetralogy of Fallot, and AS.^11,12 Pulmonary stenosis, which varies in severity but is generally nonprogressive, is the most common cardiac anomaly in patients with AGS. Concomitant cardiac diseases are the leading cause of death in patients diagnosed with AGS; the mortality rate due to cardiac complications in AGS is approximately 10%.¹² Because mild bilateral PS directly affects postoperative morbidity and mortality in these patients, the reduction of RV and mPAP pressures is critical for a successful LT, given the negative correlation with LT. A comprehensive preoperative evaluation and optimization of patients with AGS with ESLD with cardiac anomalies is extremely important. Severe cardiac abnormalities can be corrected with pre-LT balloon angioplasty or surgery, and these interventions should be considered before LT.¹⁰ However, in patients with AGS with mild bilateral PS, pulmonary artery stent placement may be considered to reduce RV afterload.^11-13 Akagi and colleagues¹⁴ performed a stent implant at 4 months in a patient diagnosed with AGS with severe pulmonary hypertension (PHT) and stenosis in the pulmonary arteries. There was a decrease in PAP after the stent, and the patient underwent successful LDLT. The PS was mild in our patient, so we did not consider stent placement in the pulmonary artery in the preoperative period.

In the pharmacological treatment of PHT due to PS, calcium channel blockers, prostacyclin, nitric oxide, and phosphodiesterase type 3-5 inhibitors are used.⁸ We started milrinone infusion for our patient in the intraoperative period to reduce mPAP and RV afterload and attempted to prevent triggering factors that would increase PVR.

Inherent patient factors can influence mPAP, PVR, and PaCO2. Anesthesiologists can directly control these factors using vasodilators, prostacyclin, nitric oxide, phosphodiesterase-type 3-5 inhibitors, inhalation anesthetics, and positive end-expiratory pressure.^7,8 Our anesthesia plan was designed to avoid these factors as much as possible. We started milrinone infusion to our patient in the intraope-rative period to reduce mPAP and RV afterload and attempted to prevent triggering factors that would increase PVR. However, we preferred propofol and remifentanil for the maintenance of anesthesia. We avoided hypercapnia and hypocapnia to the degree possible and applied the positive end-expiratory pressure between 4 and 6 mm Hg.

Yang and colleagues¹⁰ reported successful LT in 11 patients with AGS with PS and multiple comorbidities. Nevertheless, surgical complications and reoperation frequency were higher in patients with biliary atresia. Although our patient with AGS received Kasai surgery to treat biliary atresia on day of 40 of mild bilateral PS, AS, and mitral regurgitation, she had a successful LT. She was discharged without any complications in the postoperative period.

We measured pulse index continuous cardiac output to closely monitor changes in hemodynamics and oxygenation and for rapid and accurate management. A multidisciplinary approach and accurate risk assessment are crucial for the discovery of the etiology of multiple cardiac anomalies in patients with AGS. Liver transplant may not be an appropriate treatment modality for patients with AGS with severe bilateral PS. However, in our patient, we successfully performed LT after necessary prepa-rations and application of protective methods and discharged our patient without any complications.

For patients with AGS coincident with ESRD, early diagnosis of mild bilateral PS and cardiac comor-bidities is extremely important. In these patients, LT is the only treatment for AGS, and successful LT results in the regression of many pathologies and facilitates improved quality of life. Anesthesiologists must know the underlying pathophysiology, per-form a compre-hensive preoperative evaluation, and determine a correct anesthesia plan. Preservation of RV function and avoidance of sudden changes in PVR are critical in anesthesia management. Successful perioperative management of transplant patients requires effective communication and collaboration between specialists through a multidisciplinary team approach.

Volume: 22 Issue: 2 February 2024

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