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CARDIOVASCULAR ANESTHESIA

Hemodynamic Changes in Patients with Alagille’s Syndrome During Orthotopic Liver Transplantation

Kenneth Png, MMed(Anaes)^*, Francis Veyckemans, MD^*, Marc De Kock, MD, PhD^*, Marianne Carlier, MD^*, Thierry Sluysmans, MD, PhD, Jean B. Otte, MD, Raymond Reding, MD, PhD, Stephane Clement de Clety, MD^§, Etienne Sokal, MD, PhD^*, and Luc Van Obbergh, MD, PhD^*

Departments of *Anesthesiology, Pediatrics, Surgery, and §Intensive Care, Catholic University of Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium

Address correspondence and reprint requests to Luc Van Obbergh, MD, PhD, Department of Anesthesiology, Cliniques Universitaires Saint-Luc, 10 1821 Avenue Hippocrate, 1200 Brussels, Belgium.

	Abstract

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Children with Alagille’s syndrome are at increased perioperative risk during orthotopic liver transplantation due to the cardiopulmonary abnormalities and the hemodynamic changes associated with this procedure. We studied 16 children with Alagille’s syndrome who underwent 21 orthotopic liver transplantations. Peripheral pulmonary stenosis was present in all subjects. Right ventricular pressures were increased in 15 cases. Caval clamping resulted in a mean decrease of 15 ± 9 mm Hg in systolic blood pressure, 5 ± 3 mm Hg in mean pulmonary artery pressure, and 4 ± 3 mm Hg in central venous pressure. Systolic blood pressure decreased by 16 ± 13 mm Hg, whereas mean pulmonary artery pressure and central venous pressure increased by 3 ± 4 mm Hg and 1 ± 4 mm Hg, respectively, at portal vein unclamping. There was no correlation between severity of pulmonary artery stenosis and hemodynamic changes. Veno-venous bypass used in four cases resulted in smaller hemodynamic changes. Time to extubation and duration of intensive care unit stay were unrelated to severity of pulmonary artery stenosis.

Implications: Some children with Alagille’s syndrome require liver transplantation. In our study, associated pulmonary artery stenosis did not dramatically increase perioperative risk. Veno-venous bypass decreased intraoperative hemodynamic changes in these patients.

	Introduction

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Alagille’s syndrome, otherwise known as arteriohepatic dysplasia, was first described independently by Watson and Miller (1) and by Alagille et al. (2). This syndrome is an autosomal dominant disease with reduced penetrance and variable expressivity. There is equal gender distribution. The main feature in this syndrome is intrahepatic cholestasis, with a decreased ratio of the number of interlobular bile ducts to the number of portal tracts (<0.4). Two forms are described: syndromic and nonsyndromic. In the syndromic form, at least two of the four criteria must be present in addition to the paucity of interlobular bile ducts: peripheral pulmonary artery stenosis, typical facial features, butterfly vertebrae, and posterior embyotoxon. Other possible associated problems include growth retardation, renal impairment secondary to mesangiolipidosis, and other various skeletal, cardiopulmonary, and ocular abnormalities (2,3). Liver transplantation is indicated in these patients either when there is progression to liver cirrhosis (which only occurs in a small proportion of these patients) or when growth or quality of life are severely affected secondary to refractory pruritis, severe cholestasis, or crippling xanthomas (4,5). The perioperative hemodynamic changes encountered in this group of patients during liver transplantation have not been fully described. In this retrospective study, we reviewed the anesthetic experiences and perioperative courses of 21 orthotopic liver transplantations (OLTs) performed on 16 patients with Alagille’s syndrome at our institution.

	Methods

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From January 1984 to December 1997, 466 children underwent 532 OLT procedures at the Cliniques Universitaires Saint-Luc, Brussels. Of these patients, 16 (6 boys, 10 girls) had Alagille’s syndrome and between them underwent 21 OLT procedures. Preoperative cardiac evaluation consisted of a physical examination, Doppler echocardiography, and, in some cases, cardiac catheterization. The anesthetic records were reviewed, as were the events during the immediate postoperative stay in the intensive care unit (ICU). Peroperative monitoring included electrocardiography, invasive arterial blood pressure, end-tidal carbon dioxide and anesthetic vapors, pulse oximetry, central venous pressure, and, in some cases, pulmonary artery pressures via a 4F or 5F Swan Ganz catheter (Edwards Swan Ganz, Baxter Healthcare Corp., Irvine, CA).

	Results

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Pretransplant Evaluation
Mean age, weight, and height at first OLT were, respectively, 62 ± 40 mo (range 16–157 mo), 14 ± 6 kg (range 6.2–22.0 kg), and 94 ± 20 cm (range 68–136 cm). Jaundice, pruritis, hepatomegaly, and growth retardation were present in all the children, but splenomegaly was present in 13 children and mild psychomotor retardation was present in 3 children.

All prothrombin times and initial hemoglobin were normal (mean 10.4 ± 1.4 g/L). By ultrasonography, ascites was detected in one child and portal hypertension in three children.

Pulmonary artery stenosis was demonstrated either by echocardiography or cardiac catheterization in all patients. Associated cardiopulmonary abnormalities were pulmonary artery hypoplasia in two patients (Patients 1 and 10) and ventricular septal defect in one (Patient 5). The severity of pulmonary artery stenosis varied from mild to severe. Right ventricular pressure was increased in 11 children. Balloon angioplasty was performed on three of the children (Patients 10, 14, and 15) before OLT; two cases (Patients 14 and 15) were minimally successful in partially relieving stenosis in the pulmonary artery. Pulmonary artery stenosis did not result in hypoxemia, and peripheral arterial saturation was normal in all children (mean 99 ± 1%).

Intraoperative Variables
Twenty-one OLT procedures were performed on 16 patients. All the cases had central venous pressure monitoring, whereas 14 subjects also had pulmonary artery pressure monitoring.

Thirteen cases were induced with either halothane or sevoflurane and intubated with pancuronium. Five underwent IV induction with etomidate, four as part of rapid sequence induction with suxamethonium. Analgesia was provided with fentanyl or sufentanil. Three cases arrived previously intubated from the ICU for urgent retransplantation. All patients were hemodynamically stable at induction.

Mean duration of anesthesia was 519 ± 17 min, with the anhepatic phase lasting 83 ± 24 min on average. Mean perioperative blood transfusion was 156.7 ± 127 mL/kg (range 0–532.9 mL/kg). Hourly urine output was 2.7 ± 1.9 mL · kg^-1 · h^-1 (range 0.4–6.5 mL · kg^-1 · h^-1). At caval clamping, systolic blood pressure (SBP) decreased by a mean of 15 ± 9 mm Hg, with concomitant decreases in mean pulmonary artery pressures (5 ± 3 mm Hg) and central venous pressures (4 ± 3 mm Hg). Caval unclamping resulted in a further decrease in SBP (16 ± 13 mm Hg), but was accompanied by increases in mean pulmonary artery (3 ± 4 mm Hg) and central venous pressures (1 ± 4 mm Hg). When those cases done without bypass were divided into two groups based on right ventricular (RV) systolic pressures (severe RV > 50 mm Hg, less severe RV < 50 mm Hg), there were no great differences in hemodynamic changes between them (16 ± 4 vs 18 ± 19 mm Hg decrease in SBP at clamping; 21 ± 17 vs 16 ± 12 mm Hg decrease in SBP at unclamping). The intraoperative hemodynamic variables are described in Table 1. Veno-venous bypass was used during the anhepatic phase in 4 of the 21 transplants. The decision to use veno-venous bypass was made prior to the operations on the basis of the severity of pulmonary stenosis and consequent increased RV pressures. The left axillary vein was used in two cases. In the other two cases, the axillary vein was too small and a 16G IV cannula inserted in the internal jugular vein by the anesthetist was used for bypass instead. These four cases had smaller declines in pressure at clamping, compared with cases without bypass (5 ± 7 mm Hg vs 17 ± 14 mm Hg). Differences between the two groups at unclamping were less impressive (14 ± 13 mm Hg vs 17 ± 7 mm Hg). We were unable to disclose any relation between the gradient measured across pulmonary stenosis as shown in Table 1 and the systolic variation occurring at clamping (linear regression R = 0.46, P = 0.034) or at unclamping (linear regression R = 0.14, P = 0.54). Of the four cases using bypass, three were uneventful hemodynamically, but one had a transient episode of bradycardia and hypotension at unclamping of the portal vein. In the remaining 17 OLTs (no bypass), 15 were hemodynamically stable intraoperatively; also, there was one case with transient bradycardia associated with hypotension, and 1 case remained persistently hypotensive after unclamping requiring epinephrine and norepinephrine infusions. Surgically, total cross-clamping of the inferior vena cava was performed in eight cases. The piggyback technique (6) with caval lateral clamping was performed in the other 13 cases. All cases received small-dose dopamine (2–5 µg · kg^-1 · min^-1) during the anhepatic and reperfusion phases of the operation. Isoproterenol at low concentrations (0.01–0.02 µg · kg^-1 · min^-1) was infused for a short time in three of the cases in response to mild bradycardia (60–85/min) not associated with hypotension. At no time during the operation was there any significant decrease in pulse oximetry values.

Three cases (OLTs 2, 4, and 6) died, not due to cardiovascular complications, in the postoperative period. Discharge from the ICU was also not delayed by cardiovascular problems and was accomplished within 5 days in 10 of the 18 cases that did not require early retransplantation. Two others children died 6 and 9 mo after OLT.

	Discussion

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This article is the first report on the perioperative course of patients with Alagille’s syndrome undergoing OLT.

In our set of patients, liver cirrhosis as an indication accounted for only 19% (3 of 16) of all first OLTs; the remaining patients (81%) were transplanted because of severe limitation in the quality of life. Preoperative administration of clotting factors was not required, because protein synthesis is maintained with normal or near-normal serum protein levels and coagulation profiles (2). Patients with Alagille’s syndrome have greatly increased cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels, together with decreased high-density lipo-protein-cholesterol levels (7). All of our children had increased serum cholesterol, whereas nine (56%) of them had xanthomas. However, the cardiovascular implications of this abnormal lipoprotein profile in patients with Alagille’s syndrome have still not been fully studied.

The average time from diagnosis to OLT in our series was 4 yr and 10 mo. The slow deteriorating course of these patients allows time for full cardiovascular evaluation before transplantation (3,8). There are associated cardiac abnormalities in approximately 85% of patients with Alagille’s syndrome (3) (100% of the patients in our study). The most common anomaly is stenosis in the peripheral pulmonary arterial tree or in either or both of the main pulmonary arteries. Stenosis appears to be nonprogressive,¹and echocardiography repeated over several years on some of our patients showed stable degrees of pulmonary artery stenosis over time. Pulmonary vascular hypoplasia and/or intracardiac defects have also been reported either in isolation or in association with peripheral pulmonary stenosis (5). Reports on mortality rates in Alagille’s syndrome attributed to cardiopulmonary complications indicate rates ~10% (3,9,10). In cases with pulmonary vessel stenosis, RV hypertrophy is a common finding (11), but cardiac function is usually well preserved (2). Balloon angioplasty of the stenosis may be considered, especially for the more severe cases. However, this procedure is not without risk (12), and of the three patients on whom angioplasty was performed, two had only slight improvement whereas one had none. Nevertheless, OLT was performed successfully albeit with veno-venous bypass in two of these patients.

We encountered no hemodynamic problems during induction. Hemodynamic instability prior to the anhepatic phase is usually due to surgical blood loss from hepatic dissection. Although 75% of our children had previous abdominal surgery, we experienced no excessive bleeding during this phase. Apart from possibly massive and often rapid blood loss during OLT, other causes of intraoperative hemodynamic changes are clamping and unclamping of the inferior vena cava and portal vein, and various factors at reperfusion of the new liver, resulting in myocardial depression and vasodilatation. The periods of clamping and unclamping resulted in a significantly greater decrease in blood pressure, compared with that experienced in our average pediatric population undergoing OLT, despite relatively similar changes in central venous and pulmonary artery pressures (13). These decreases in blood pressure were transient and responded to fluid loading. The probable explanation is an increased dependency in these patients on preload to maintain RV ejection (14). However, no differences were found between "severe" (RV > 50 mm Hg) and "less severe" (RV < 50 mm Hg) cases, and there was no correlation between severity of pulmonary stenosis and intraoperative hemodynamic changes. The importance of optimization of preload in these patients is set in the scenario of preexisting vasodilatation and increased cardiac output secondary to liver disease. A decrease in RV preload may lead to a vicious cycle of decreased RV output, inadequate left ventricular preload and output, and decreased systemic blood pressure. Because RV hypertrophy, and therefore an increased susceptibility to RV myocardial ischemia, is common in these patients, an excessive decrease in systemic blood pressure should be avoided. In our institution, we accept a 30% decrease in blood pressure at clamping, beyond which (after judicious fluid loading) we tend toward the use of veno-venous bypass. We use central venous pressures as a guide to optimize preload, and thus RV contractility, and find pulmonary artery pressures measured via a pulmonary artery catheter to be less useful as an indication of RV function, because the catheter tip is often beyond stenosis in the pulmonary artery. However, central venous pressure is a less reliable indicator of RV preload in patients undergoing OLT (15). Thus, transesophageal echography would be useful in this setting to aid in optimizing right heart performance (16). In four (two children) of the more severe cases (RV 98 mm Hg, 60 mm Hg), veno-venous bypass was used resulting in smaller blood pressure changes especially at clamping. This observation is also probably related to the maintenance of adequate venous return during this critical period. Contrary to theoretical expectations, we found no differences in blood pressure changes at clamping between cases where the piggyback technique was used and those requiring total clamping of the inferior vena cava. However, our sample sizes are too small to draw any conclusions.

Postoperatively, most patients had no hemodynamic problems and no delay in extubation or discharge from intensive care attributable directly to Alagille’s syndrome. The incidence of retransplantation in our group of patients (31%) was higher than that expected from a contemporaneous non-Alagille’s population (17), but similar to other studies in this population (9). We could not account for this increased incidence.

In summary, patients with Alagille’s syndrome cope well with the major hemodynamic changes during OLT. Careful attention to ensuring adequate preload of the right ventricle is important, especially in these patients. The immediate postoperative cardiovascular and respiratory course is not affected by the disease. We are unable to determine a threshold (if one exists) in severity of pulmonary artery stenosis, whereby OLT would be contraindicated. However, in severe cases of pulmonary artery stenosis, veno-venous bypass, although not mandatory, is useful in minimizing potential changes in blood pressure during caval clamping and unclamping.

	Footnotes

 
¹ Elderedge WJ, Tingelstad JB, Robertson LW, et al. Observations on the natural history of pulmonary artery coarctation [abstract]. Circulation 1972;45:404.

	References

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4. Cardona J, Houssin D, Gauthier F, et al. Liver transplantation in children with Alagille syndrome—a study of twelve cases. Transplantation 1995;60:339–42.[Web of Science][Medline]
5. Silberbach M, Lashley D, Reller MD, et al. Arteriohepatic dysplasia and cardiovascular malformations. Am Heart J 1998;127:695–9.
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13. Carlier M, Van Obbergh LJ, Veyckemans F, et al. Intraoperative hemodynamic modifications during pediatric orthotopic liver transplantation. Intensive Care Med 1989;15:S73–5.
14. Bohn D. Anomalies of the pulmonary valve and pulmonary circulation. In: Lake CL, ed. Pediatric cardiac anesthesia. New York:Appleton & Lange, 1998:269–98.
15. De Wolf A, Begliomini B, Gasior T, et al. Right ventricular function during orthotopic liver transplantation. Anesth Analg 1993;76:562–8.[Abstract/Free Full Text]
16. Swenson JD, Harkin C, Pace NL, et al. Transesophageal echocardiography: an objective tool in defining maximum ventricular response to intravenous fluid therapy. Anesth Analg 1996;83:1149–53.[Abstract]
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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999