Stéphan Clément de Cléty

Pediatric liver transplantation: from the full-size liver graft to reduced, split, and living related liver transplantation

Abstract Between 1984 and 1996, the authors performed 499 liver transplants in 416 children less than 15 years old. The overall patient survival at 10 years was 76.5%. It was 71.3% for the 209 children grafted in 1984–1990; 78.5% for biliary atresia (n =u2009286), 87.3% for metabolic diseases (nu2009=u200959), and 72.7% for acute liver failure (nu2009=u200922). The 5-year survival was 73.6% for the 209 children grafted in 1984–1990 and 85% for the 206 grafted in 1991–1996. Scarcity of size-matched donors led to the development of innovative techniques: 174 children who electively received a reduced liver as a first graft in our center had a 5-year survival of 76% while 168 who received a full-size graft had a survival of 85% (NS). Results of the European Split Liver Registry showed 6-month graft survival similar to results obtained with full-size grafts collected by the European Liver Transplant Registry. Extensive use of these techniques allowed the mortality while waiting to be reduced from 16.5% in 1984–1990 to 10% in 1991–1992. It rose again to 17% in 1993, leading the authors to develop a program of living related liver transplantation (LRLT). The legal and ethical aspects are analyzed. Between July 1993 and October 1997, the authors performed 53 LRLTs with 90% survival. In elective cases, a detailed analysis was made of the 45 children listed for LRLT between July 1993 and March 1997 and the 79 registered on the cadaveric waiting list during the same period. Mortality while waiting was 2% and 14.5% for the LRLT and cadaveric lists, respectively. The retransplantation rate was 4.6% and 16.1% for LRLT and cadaveric transplants, respectively. Overall post-transplant survival was 88% and 82% for children who received a LRLT or a cadaveric graft, respectively. Overall survival from the date of registration was 86% and 70% (Pu2009<u20090.05) for LRLT or cadaveric LT respectively. The 2-year post-transplant survival in children less than 1u2009year of age at transplantation was 88.8% and 80.3% with a LRLT or cadaveric graft, respectively; patient survival after 3 months post-transplant was 95.8% and 91.9% for stable children waiting at home, 93.7% and 93.7% in children hospitalized for complications of their disease, and 89.5% and 77.7% for children hospitalized in an intensive care unit at the time of transplantation for children who received a LRLT or cadaveric graft, respectively. It is concluded that LRLT seems to be justified for multidisciplinary teams having a large experience with reduced and split liver grafting.

Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients

SummaryThe pharmacokinetics of intravenous and oral tacrolimus was assessed in paediatric liver transplant patients at two centers in Europe. Sixteen patients, age 0.7 to 13 years, participated in the study; 12 patients were evaluable for intravenous pharmacokinetics, and 16 for oral. Intravenous tacrolimus was given as a continuous 24 h infusion (mean 0.037±0.013 mg/kg/day), and oral tacrolimus was given in 2 doses per day (mean 0.152±0.015 mg/kg). Whole blood samples for the intravenous pharmacokinetic profile were taken before initiation of the first infusion, 4, 8, 12 and 24 h post-infusion, and every 24 h thereafter until intravenous administration was discontinued. During the 12 h wash-out period between intravenous and oral administration, samples were taken every 3 h. Samples for the oral pharmacokinetic profile were taken immediately before the first oral dose and 0.5, 0.75, 1, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-administration. Non-compartmental procedures were used to characterise the pharmacokinetic parameters. Mean estimates for clearance and terminal half-life were 2.3±1.2 ml/min/kg and 11.5±3.8 h, respectively, following intravenous tacrolimus. The mean bioavailability of oral tacrolimus was 25±20%. A strong correlation was observed between AUC and trough whole blood levels of tacrolimus (r=0.90). The clearance was approximately 2-fold higher than that previously observed in adults; this could explain the higher dosage requirements in children.

Levosimendan in Congenital Cardiac Surgery: A Randomized, Double-Blind Clinical Trial

OBJECTIVEnIn this study, the authors used a continuous infusion of either levosimendan or milrinone as inotropic support after corrective congenital cardiac surgery. The hemodynamic and biochemical parameters were compared.nnnDESIGNnA prospective, randomized, double-blind clinical study.nnnSETTINGnA university hospital.nnnPARTICIPANTSnForty-one patients between 0 and 5 years old requiring inotropic support for corrective congenital heart surgery under cardiopulmonary bypass (CPB) were enrolled in this trial. Thirty-six patients completed the study.nnnINTERVENTIONSnPatients were randomized in a double-blind fashion to a continuous infusion of either levosimendan at 0.05 μg/kg/min or milrinone at 0.4 μg/kg/min started at the onset of CPB. Epinephrine was started at 0.02 μg/kg/min after aortic cross-clamp release in both groups.nnnMEASUREMENTS AND MAIN RESULTSnThere was no significant difference between serum lactate levels of groups. The rate-pressure index (the product of heart rate and systolic blood pressure), which is an indicator of myocardial oxygen demand, was significantly lower at 24 hours and 48 hours postoperatively in the levosimendan group (p < 0.001) in comparison to the milrinone group. Although not significantly different, the troponin values in the levosimendan group were less at 1 hour (median [P(25)-P(75)]: 20.7 [15.3- 48.3] v 34.6 [23.8- 64.5] ng/mL and 4 hours postoperatively: 30.4 [17.3-59.9] v 33.3 [25.5-76.7] ng/mL).nnnCONCLUSIONnLevosimendan is at least as efficacious as milrinone after corrective congenital cardiac surgery in neonates and infants.

'Piece' of mind: end of life in the intensive care unit: statement of the Belgian Society of Intensive Care Medicine

End-of-life decisions are common in the intensive care unit (ICU) with most deaths occurring in the ICU now preceded by a decision to limit treatment [1-4]. However, it is important to define the degree of “limitation of therapy.” Restricting discussion to nonintervention in case of cardiac arrest—the “not to be resuscitated” or “do not resuscitate” order—is not sufficient. Other treatments must also be included in the global term limitation of therapy, including, for example, not applying mechanical ventilation in case of respiratory failure, not giving renal replacement therapy in case of acute renal failure, or not administering adrenergic support in case of acute circulatory shock. In this context, the principle of proportionality of care, as clearly defined in a French law [5], is an important concept, stating that therapies should only be administered in proportion to expected benefits. Hence, therapies that will act solely to artificially prolong life should not be started or should be discontinued. Belgium [6,7] has specific laws dealing with euthanasia in terminally ill patients, but less than 1% of all deaths (approximately 1000 deaths/105000 total deaths per year in Belgium) occur as a result of requested euthanasia. Discontinuing therapies at the end of life in the ICU is performed in more than 10 times (N10000 deaths a year) the number of individuals who die under the conditions of the euthanasia law. Indeed, critically ill patients dying in the ICU are usually not in a position to request euthanasia. As a result, in Belgium, there is uncertainty about the legal consequences of starting a process that will result in death in the ICU. Although forgoing futile treatment is not against current Belgian legislation, difficulty can arise when the purpose of the drugs used for comfort and pain relief in end-of-life management is misconstrued as deliberate use to speed the dying process [8]. This statement paper, developed by members of the Belgian Society of Intensive Care Medicine Council, is not about giving analgesics or sedative agents to combat pain or agitation, nor about the so-called double effect, wherein analgesics given to alleviate pain may have the adverse effect of shortening the dying process. The discussion here is about the administration of sedative agents with the direct intention of shortening the process of terminal palliative care in patients with no prospect of a meaningful recovery. Importantly, many of the issues discussed may seem obvious and may even reflect current practice; nevertheless, in view of the emotive, ethical and potential legal nature of these issues, we believe that there is a need for them to be clearly stated. Moreover, we explain our belief in the concept that shortening the dying process by administering sedatives beyond what is needed for patient comfort can be not only acceptable but in many cases desirable. Three generally well-accepted principles:

Living Donor Liver Transplantation in Children: Surgical and Immunological Results in 250 Recipients at Université Catholique de Louvain.

Objectives: To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance. Background: LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field. Methods: Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate. Results: Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (nu200a=u200a58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; Pu200a=u200a0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; Pu200a=u200a0.041), but only in BA patients. Conclusions: LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.

Self-requested euthanasia for children in Belgium

In the complex patient—doctor relationship, the principle of personal autonomy has gradually acquired more weight against medical paternalism, both in clinical practice and in bioethical thinking.1 In many countries, this change has been incorporated into national legislation in the past 20 years. The Belgian Act on Patients Rights was promulgated in 2002. In the same year, the Belgian Act on Palliative Care was adopted, which grants access to palliative care that focuses on improving quality of life. Later in 2002, just a few weeks after the Netherlands,2 Belgium adopted a law decriminalising euthanasia under well-defined conditions.3 These conditions include a voluntary, carefully considered, and repeated request from a patient with unbearable suffering that cannot be alleviated and that results from a serious and incurable disorder. The physician must comprehensively discuss the palliative care options with the patient, who needs to consult another physician before the decision on euthanasia can be taken. Under the terms of this law, euthanasia is a medical procedure. This situation contrasts with patient-driven assisted suicide, which has been decriminalised in Switzerland and in four American states, Oregon, Washington, Montana, and Vermont, in which a physician prescribes the lethal drug under strict circumstances but does not administer it.4

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Abstract. Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half‐lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post‐transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r= 0.93 and r= 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half‐life and a remarkably improved bioavailability.

Feasibility Study on Neurally Adjusted Ventilatory Assist in Noninvasive Ventilation After Cardiac Surgery in Infants

BACKGROUND: Our objective was to evaluate the feasibility, the quality of synchronization, and the influence on respiratory parameters of the noninvasive neurally adjusted ventilatory assist (NIV-NAVA) mode in infants after cardiac bypass surgery. We conducted a prospective, randomized cross-over study in infants undergoing noninvasive ventilation (NIV) after cardiac surgery. METHODS: Subjects were 10 infants < 5 kg. After extubation, subjects underwent 2 consecutive ventilatory modes after randomization into groups. In the CPAP first group, the subjects were ventilated first in nasal CPAP-1 and then in NIV-NAVA-2 for 30 min in each mode. In the NIV-NAVA first group, periods were reversed. All children were ventilated using the same interface. RESULTS: The analysis of curves showed a synchronization rate of 99.3% for all respiratory cycles. The rate of pneumatic inspiratory trigger was 3.4%. Asynchronies were infrequent. Some typical respiratory patterns (continuous effort and discontinuous inspiration) were found at rates of 10.9% and 31.1%, respectively. The respiratory trends showed a lower maximum diaphragmatic electrical activity (EAdi(max)) in NIV-NAVA periods compared with CPAP periods (P < .001 in the beginning of periods). The breathing frequency decreased significantly during the nasal CPAP-2 and NIV-NAVA-1 periods (P < .05). The inspiratory pressure increased significantly during the NIV-NAVA-1 and NIV-NAVA-2 periods (P < .05), but there was no significant difference for each parameter when comparing Δ values between the beginning and the end of each period. The EAdi signal was easy to obtain in all subjects, and no major side effects were associated with the use of NIV-NAVA. CONCLUSIONS: NIV-NAVA allows good synchronization in bi-level NIV in infant cardiac subjects weighing < 5 kg. The analysis of respiratory parameters shows that NIV NAVA decreases the work of breathing more effectively than nasal CPAP. The study shows some typical respiratory patterns in infants. (ClinicalTrials.gov registration NCT01570933.)

Acute amiodarone toxicity due to an administration error: could excipient be responsible?

Amiodarone is widely used for ventricular and supraventricular tachyarrythmia and is a relatively safe choice of drug, particularly in its enteral form in paediatric patients, because of its low negative inotropic action. Severe side-effects have been described, mostly dose and treatment duration dependent. The use of the intravenous form has aroused concern because of the presence of excipients, polysorbate 80 and benzyl alcohol, considered as possible alternative causes for severe hypotensive events. We report the case of a newborn presenting with supraventricular tachycardia. After receiving a high loading dose of amiodarone intravenously instead of orally, the infant rapidly developed cardiogenic shock and multiple organ dysfunction. n nThis case report illustrates an underestimated side-effect of a supposiedly safe drug, probably related to the negative haemodynamic effects of the excipients. n nA previously healthy newborn presented on day 4 with re-entrant supraventricular tachycardia, confirmed by electrocardiograph in a regional hospital. n nThe arrhythmia spontaneously ceased before any manoeuvre was attempted. In order to prevent recurrence of arrhythmia, the physician prescribed a loading dose (1200 mg/m2 = 47 mg kg−1) of amiodarone, without determining the route of administration. The ‘oral’ loading dose was administrated intravenously, over a 30-min period (preparation infused in glucose). The baby remained stable during the infusion. n nThirty minutes after the end of the infusion, the child suddenly deteriorated, with profound hypotension, requiring cardiopulmonary resuscitation for 20 min. Inotropic support with epinephrine and dobutamine at high doses was started. n nOn arrival of the PICU medical transport team, the baby was unreactive and presenting signs of systemic and peripheral hypoperfusion with severe lactic acidosis. Inotropic support treatment was adapted with introduction of milrinone and weaning of catecholamines, considering the haemodynamic stabilization. n nDuring the first 24 h, he developed multiple organ failure with acute hepatic and renal failure, myocardial ischaemia and severe encephalopathy. n nOrgan function slowly recovered. No recurrence of supraventricular tachycardia occurred, but mild sinus bradycardia down to 90 min−1 spontaneously resolved. We eliminated every other major aetiologies (allergies, infection) causing profound shock, and therefore concluded that the 10 times recommended i.v. dose of Cordarone® was the most probable cause of this adverse event. n nSerum amiodarone and desethylamiodarone (DEA) levels were monitored (Figure 1). The highest serum concentrations never exceeded the usual steady-state concentrations (between 1 and 3 µg ml−1). Excipient dosage was unfortunately not available. n n n nFigure 1 n nTime-dependent evolution (hours after administration) of desethylamiodarone and amiodarone levels. amiodarone (); desethylamiodarone () n n n nThe child was discharged 1 week after admission with normal cardiac and neurological functions. n nAmiodarone is a Vaughan-Williams class III antiarrythmic drug, with negative chronotropic and dromotropic effects. The vasodilatory action is responsible for decreased cardiac workload and myocardial oxygen consumption. Amiodarone accumulates in various sites, especially in adipose tissue. Amiodarone is metabolized to DEA by two cytochromes P450, CYP3A4 and CYP2C8. The CYP3A4 isoenzyme is present in the liver and the intestines, with large interindividual variability in its activity and consequently variable systemic availability of oral amiodarone (between 33 and 65%) [1]. Amiodarone and its metabolite are eliminated by hepatic metabolism and biliary excretion; neither amiodarone nor DEA is dialysable. n nDEA has similar haemodynamic properties, but accumulates to a greater extent than its precursor. n nRecommended loading dose ranges from 800 to 1200 mg m−2 orally and 5 mg kg−1 intravenously. Maintenance dose ranges from 200 to 500 mg m−2 orally and 5 to 20 µg kg−1 min−1 intravenously. After a single i.v. loading dose, the expected serum peak concentration in healthyvolunteers ranges from 5 to 41 mg l−1. Serum concentration decreases to 10% of its peak value 30–45 min after the end of the loading dose [1]. n nThe commercial presentation of amiodarone contains two solvents, benzyl alcohol and polysorbate 80. Those molecules exert haemodynamic effects [2–4]. n nBenzyl alcohol is an aromatic alcohol used as a bacteriostatic and solvent. Based on animal studies, it is estimated that in normal adults a rapid infusion with up to 4.5 mg kg−1 remains safe [5]. In the 1980s, numerous cases of neonatal death after the use of benzyl alcohol-containing intravenous solutions were published [6]. Benzyl alcohol has been responsible for metabolic acidosis, respiratory insufficiency, seizures, intracranial haemorrhage and hypotension leading to cardiovascular collapse [7]. Benzyl alcohol is metabolized to benzoic acid, glycinoconjugated into the liver and excreted as hippuric acid by the kidneys. This pathway could be underdeveloped in the newborn, resulting in metabolite accumulation and toxic side-effects [7]. n nToxic effects have also been described with polysorbate 80 (Tween 80®). In 1982, Gough et al. studied the cardiovascular effects of the commercial form of amiodarone (amiodarone plus polysorbate) and amiodarone alone in anaesthetized dogs. Only the commercial form caused a 60% drop in mean blood pressure and left ventricular work. They concluded that those adverse events were related to the potent vasodilator and negative inotropic effects of polysorbate 80 [3]. n nTwo studies (Gallik, and Somberg) have compared the classic Cordarone® formulation with the Amio-Aqueous® formula, free of the two previously incriminated solvents. Amio-Aqueous® formula infusion resulted in an increase of peripheral vascular resistance, compensating for an initial decrease in myocardial contractility. Conversely, the classic Cordarone® formulation containing polysorbate 80 resulted in vasodilation and hypotension [8, 9]. n nAmiodarone itself produces bradycardia and progressive negative inotropic effects [10], minimized by a slower rate of infusion, especially in hypovolaemic patients [2, 11]. n nOne single study on amiodarone use for the treatment of supraventricular and ventricular tachycardias has been conducted in paediatric patients. It showed that amiodarone given intravenously was as safe and effective as the oral form. Half of the infants were haemodynamically unstable, under inotropic support. This instability may have altered the final results and underestimated the side-effects of amiodarone and its solvents [12]. n nThe hypothesis that the two excipients, benzyl alcohol and polysorbate 80, precipitated the occurrence of the cardiogenic shock seems plausible, and appears particularly realistic because the plasma concentration of amiodarone and DEA never reached toxic level. Unfortunately, we were unable to measure the serum level of the two excipients to confirm the hypothesis. n nThis report underlines the potential for severe, even lethal, haemodynamic side-effects of a drug recognized as safe and widely used for paediatric arrhythmia. The actual i.v. formulation used in Belgium should be reconsidered and be replaced by an excipient-free formulation like Amio-Aqueous®, preventing serious side-effects. n nWe emphasize also the need to double check at both physician and nursing levels when unusual medications are prescribed.

Fomepizole alone for severe infant ethylene glycol poisoning.

Objective: To report a case of a massive ingestion of ethylene glycol in an infant successfully treated by fomepizole without hemodialysis. Design: Descriptive case report. Setting: Pediatric intensive care unit. Patient: A 5-mo-old boy who ingested 200 mL of an antifreeze solution. Interventions: Antidotal therapy with a total of seven doses of fomepizole administered intravenously with an interval of 12 hrs (15 mg/kg as loading dose, then 10 mg/kg). Hemodialysis was not performed. Measurements and Main Results: Iterative determination of ethylene glycol concentration was obtained in blood and urine. Kinetics were calculated for ethylene glycol and fomepizole elimination. The infant made a complete recovery with no change in renal function. Conclusions: Although not yet approved for this indication in the child, fomepizole seemed safe and effective in a case of severe ethylene glycol poisoning, without the need for hemodialysis.