Luc Van Obbergh

Size reduction of the donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation.

The development of pediatric liver transplantation is considerably hampered by the dire shortage of small donor organs. This is a very sad situation because in most experienced centers, liver replacement can offer a long-term hope of survival of more than 70% in a growing variety of pediatric liver disorders. The reported experience with 54 reduced-size grafts on a total of 141 transplants performed in 117 children between 1984 and 1988 demonstrates that the technique of reduced-size liver transplantation not only allows long-term survival but, in fact, offers the same survival hope with the same quality of liver function, regardless of the childs age and clinical condition. The prominent feature of our experience with the reduced liver concerns its deliberate use for elective cases. Seventy-seven per cent of the 30 children who electively received a reduced liver were alive 1 year after transplantation, as were 85% of the 62 children who received a full-size graft. There is no difference in the long-term survival rate of patients who received elective grafts, which is in the range of 75% with both techniques.

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 = 286), 87.3% for metabolic diseases (n = 59), and 72.7% for acute liver failure (n = 22). 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% (P < 0.05) for LRLT or cadaveric LT respectively. The 2-year post-transplant survival in children less than 1 year 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.

Extrahepatic glucuronidation of propofol in man: possible contribution of gut wall and kidney

Abstract.Objective: Results from clinical pharmacokinetic studies of propofol indicate that this i.v. anaesthetic agent may undergo significant extrahepatic glucuronidation. We have investigated whether glucuronidation of propofol takes place in the kidney and/or the gut wall. First, propofol concentrations were measured in arterial (radial artery) and portal venous blood of 12 cirrhotic patients with trans internal jugular porto-systemic shunting (TIPSS).Results: In 7 of the 12 patients arterial propofol concentrations were higher than portal venous concentrations. In the remaining patients, propofol concentrations were higher in the portal vein than the radial artery. Since an additional study in 5 patients anaesthetized with propofol while undergoing cholecystectomy showed propofol and an acid-labile conjugate of it in bile, it is difficult to interpret the results in patients with TIPSS due to the possibility of enterohepatic cycling. Next, in vitro studies with human liver (n = 5), kidney (n = 5) and small intestinal (n = 5) microsomes showed that all three tissues were capable of forming propofol glucuronide. Vmax for propofol glucuronidation was approximately 3 to 3.5 times higher in kidney (5.56 nmol ⋅ min−1⋅ mg−1 protein) than liver (1.80 nmol ⋅ min−1⋅ mg−1 protein) and small intestine (1.61 nmol ⋅ min−1⋅ mg−1 protein).Conclusion:Based on these in vitro results, it is concluded that extrahepatic glucuronidation in the small intestine and especially in the kidney may contribute to the overall glucuronidation of propofol in man.

Hemodynamic changes in patients with Alagille's syndrome during orthotopic liver transplantation.

UNLABELLED Children with Alagilles 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 Alagilles 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 Alagilles 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.

The effects of intraoperative intravenous clonidine on fluid requirements, hemodynamic variables, and support during liver transplantation: a prospective, randomized study.

In this prospective, nonblind study, we report the use of clonidine during orthotopic liver transplantation (OLT).Twenty adult patients in a stable medical condition were studied. General anesthesia consisted of isoflurane in air/oxygen and sufentanil. Patients in the clonidine group received a slow IV infusion (15 min) of 4 [micro sign]g/kg clonidine during induction. The other patients were used as controls. IV fluid requirements were determined as follows: albumin (4% solution) was administered to maintain filling pressures to a pulmonary capillary wedge pressure (PCWP) of more than 12 mm Hg. Packed red blood cells were transfused to maintain a hemoglobin level of 8-9 g/dL. Circulatory stability was evaluated using: systolic and diastolic arterial blood pressure and heart rate recorded at 2-min intervals; and the vasopressor/inotropic support required to maintain adequate hemodynamic variables after reperfusion. Intraoperative albumin and packed red blood cell requirements were significantly reduced in patients in the clonidine group (1644 +/- 140 and 50 +/- 50 mL vs 2867 +/- 226 mL and 1350 +/- 443 mL; P < 0.05). Heart rate was significantly slower in patients of the clonidine group. There were no differences in systolic arterial blood pressure. After reperfusion, patients in the control group showed significantly lower diastolic arterial blood pressure, required more vasopressor/inotropic support, and were more acidotic than patients in the clonidine group. We conclude that the administration of 4 [micro sign]g/kg clonidine during induction of OLT significantly reduced the intraoperative requirements of IV fluids and blood products without compromising circulatory stability. Improvement in immediate reperfusion-induced disturbances was observed. Implications: The administration of 4 [micro sign]g/kg clonidine during induction of liver transplantation significantly reduced the intraoperative requirements for IV fluids and blood products without compromising the circulatory stability. Improvement in immediate reperfusion-induced disturbances was also observed. (Anesth Analg 1998;86:468-76)

Cavocaval adult liver transplantation and retransplantation without venovenous bypass and without portocaval shunting: a prospective feasibility study in adult liver transplantation.

Background. The original method of liver transplantation (LT) included recipient inferior vena cava (IVC) resection and the use of extracorporeal venovenous bypass (VVB). Refinements in technique permit transplantation to be done with IVC preservation and without VVB use. Material and Methods. Between November 1993 and November 2000, 202 consecutive grafts were performed in 188 adults (≥16 years of age). Twelve patients (6.4%) received two and three retransplants (re-LT). Split grafting was performed 19 times (19 of 202 grafts, 9.4%). Risk factors included United Network of Organ Sharing status I (n=30, 16%), previous right upper abdominal surgery (n=32, 17.1%), caudate lobe encirclement of IVC (n=65, 32.2%), IVC (n=24, 11.9%), and splanchnic venous modification (n=58, 30.9%), transjugular intrahepatic portosystemic stent shunt (n=34, 16.8%), giant (>5 kg) liver tumor (n=6, 3%), septic necrosis of the caudate lobe (n=1, 0.5%), and previous cavocaval (n=13, 6.4%) or classical LT (n=5, 2.5%). Results. IVC preservation, avoidance of IVC cross clamping and of VVB use were possible in 98.9%, 93%, and 99.5% of 183 primary LT and in 89.5%, 84.2%, and 89.5% of 19 re-LT. Temporary portocaval shunting was never applied. Perioperative mortality was 1.2%. There was no allotransfusion in 73 (36%) grafts and 45 (22%) patients were immediately extubated. Permanent hepatic vein and caval problems were encountered in three (1.5%) grafts. One patient needed stent placement to treat IVC stenosis. Actual 3- and 12-month patient survival for whole, re-LT, and right-lobe split LT groups were 94.7%, 94.1%, 94.7%, 88.2%, 94.1%, and 89%. Three-month graft survival rates for these groups were 92.6%, 94.7%, and 84.2%. Conclusions. LT with IVC preservation and without VVB use and portocaval shunting is possible in nearly all primary transplants and in the majority of re-LT.

Loss of resistance to saline with a bubble of air to identify the epidural space in infants and children: a prospective study.

S ince 1986, epidural analgesia has been routinely used in our hospital to provide postoperative analgesia for children undergoing major surgery. Identification of the epidural space is accomplished by using the loss of resistance to saline with a bubble of air. This technique is used in our hospital to identify the epidural space in adults, and its use in children has already been suggested (1). As this technique has not yet been described in pediatric patients, we prospectively collected data to evaluate the incidence of technical problems at the time of identification of the epidural space and of subsequent insertion of an epidural catheter in infants and children.

Elevated right ventricular pressures are not a contraindication to liver transplantation in Alagille syndrome.

BACKGROUND Elevated right ventricle pressure resulting from pulmonary artery stenoses may affect outcome and survival after liver transplantation in patients with Alagille syndrome. METHODS AND RESULTS Between 1984 and 1997, among 444 pediatric liver transplant recipients, 17 had liver transplantation for Alagille syndrome (mean age 3.5 years, range 1.2-13 years), mainly because of poor quality of life with intractable pruritus, and failure to thrive. All patients had pulmonary artery stenosis. In 10 patients considered to have elevated RV pressure on ECG and/or Doppler-echocardiography, a cardiac catheterization was performed before liver transplantation. Mean RV systolic pressure was 55 mmHg (median 49.5 mmHg, range 35-98 mm Hg), mean RV to left ventricular systolic pressure ratio 0.53 (median 0.53, range 0.29-0.78) with a ratio above 0.5 in 6 patients (median 0.66, range 0.5-0.8). All patients underwent successful liver transplantation. Five patients died 1 to 9 months after transplantation from noncardiac causes. In two of them, cardiac catheterization before transplantation showed a RV to left ventricular pressure ratio of 0.51 in one and 0.37 in the second. In the three others, echocardiography before transplantation estimated RV pressures below 0.5 systemic pressures. At follow-up (median 6 years, range 1.5-15 years), liver tests were normal in all, none complained of pruritus and body weight was normalized in 70%. None of the patients presented cardiac symptoms, arrhythmias, or worsening of their cardiac status. CONCLUSIONS Liver transplantation can be performed safely in children with Alagille syndrome, even in the presence of elevated right ventricular pressure.

Biological monitoring of exposure to sevoflurane in operating room personnel by the measurement of hexafluoroisopropanol and fluoride in urine

The objectives of this study were to evaluate the value of urinary hexafluoroisopropanol (HFIP) and fluoride (F-) measurement for the biological monitoring of operating room personnel exposed to sevoflurane. Fifty members of operating room staffs from eight different hospitals took part in the study. To assess external exposure to sevoflurane, air samples were collected during the whole anaesthesia period by a passive sampling device (3M 3500 organic vapour monitor) attached close to the breathing zone of each subject. Urine was collected before (BA) and at the end of anaesthesia (EA) for the determination of HFIP, fluoride and creatinine. Average airborne concentration of sevoflurane was 19.0 ppm (range: ND-139.9 ppm) with a mean duration of anaesthesia of 221 min (range: 60-435 min). There was a better correlation between external and internal exposure as estimated by EA urinary HFIP (r = 0.78; p <0.0001) compared with EA urinary F- (r = 0.41; p = 0.0031). Furthermore determination of urinary HFIP seemed more suited than that of F- for the assessment of sevoflurane exposure because of lower background in BA samples (86 % of BA HFIP values were under the limit of detection). Based on these results, values of 9.6 and 4.3 mg HFIP g-1 creatinine correspond to airborne concentrations of 50 and 20 ppm of sevoflurane, respectively. Among the confounding parameters investigated (body mass index (BMI), sex, cytochrome P450 polymorphism) only BMI showed statistically significant influence on sevoflurane metabolism at these low levels of exposure. The measurement of HFIP in urine at the end of the surgical procedure constitutes a good index to assess occupational exposure to sevoflurane. Further studies will be necessary to propose an health-based limit value which remains to be determined from the relationship between effects and internal dose as can be assessed by HFIP measurement in urine.The objectives of this study were to evaluate the value of urinary hexafluoroisopropanol (HFIP) and fluoride (F(-)) measurement for the biological monitoring of operating room personnel exposed to sevoflurane. Fifty members of operating room staffs from eight different hospitals took part in the study. To assess external exposure to sevoflurane, air samples were collected during the whole anaesthesia period by a passive sampling device (3M 3500 organic vapour monitor) attached close to the breathing zone of each subject. Urine was collected before (BA) and at the end of anaesthesia (EA) for the determination of HFIP, fluoride and creatinine. Average airborne concentration of sevoflurane was 19.0 ppm (range: ND-139.9 ppm) with a mean duration of anaesthesia of 221 min (range: 60-435 min). There was a better correlation between external and internal exposure as estimated by EA urinary HFIP (r = 0.78; p <0.0001) compared with EA urinary F(-) (r = 0.41; p = 0.0031). Furthermore determination of urinary HFIP seemed more suited than that of F(-) for the assessment of sevoflurane exposure because of lower background in BA samples (86 % of BA HFIP values were under the limit of detection). Based on these results, values of 9.6 and 4.3 mg HFIP g(-1) creatinine correspond to airborne concentrations of 50 and 20 ppm of sevoflurane, respectively. Among the confounding parameters investigated (body mass index (BMI), sex, cytochrome P450 polymorphism) only BMI showed statistically significant influence on sevoflurane metabolism at these low levels of exposure. The measurement of HFIP in urine at the end of the surgical procedure constitutes a good index to assess occupational exposure to sevoflurane. Further studies will be necessary to propose an health-based limit value which remains to be determined from the relationship between effects and internal dose as can be assessed by HFIP measurement in urine.

In children, the addition of epinephrine modifies the pharmacokinetics of ropivacaine injected caudally.

PurposeTo describe the modification of the ropivacaine (R) pharmacokinetics produced by the addition of epinephrine (E).MethodsAfter Institutional Review Board approval, 18 ASA I boys received a caudal block (1 mL·kg−1) with either plain 0.2% R (Group E-) or with 0.2% R containing E (5 μg·mL−1; Group E+). Venous blood samples were taken at zero, 15, 30, 60, 90, 120, 180, 240, 420, 720, 1440 min after caudal injection. Total R concentration in plasma was determined by high pressure liquid chromatography. Maximal concentration (Cmax) and time to peak concentration (Tmax) were obtained from the data, terminal half-life (T1/2z), clearance (Cl) and volume of distribution (Vd) were estimated by a non-compartmental approach. Subsequently, in order to determine the absorption rate (Ka) and to reduce to number of blood samples, 25 other children, receiving plain R and another group of 25 receiving the E solution were studied using a population approach (NONMEM). A one compartment model with first order absorption was used. The effect of weight, age and E on Cl, Vd and Ka was estimated.ResultsCmax was significantly lower in Group E+ (0.93 mg·L−1 ±0.29vs 0.61 mg·L−1 ± 0.28,P = 0.05) and Tmax occurred later (124 min ± 53vs 47 min ± 16,P = 0.003). Weight was a significant covariate for Cl and Vd while E significantly slowed R Ka [Group I Ka 0.025 min−1 [coefficient of variation (CV) 21 %] vs 0.078 min−1 (CV 25%) in Group II].ConclusionThe addition of E significantly modifies the pharmacokinetics of R injected caudally.RésuméObjectifDécrire la modification de la pharmacocinétique de la ropivacaïne (R) induite par l’addition d’épinéphrine (E).MéthodeAyant reçu l’approbation du Comité d’examen, nous avons administré un bloc caudal à 18 garçons d’état physique ASA I (1 mL·kg−1) avec, soit de la R simple à 0,2 % (Groupe E-), soit dela R à 0,2 % contenant de l’E (5 μg·mL−1; Group E+). Des échantillons de sang veineux ont été prélevés à zéro, 15, 30, 60, 90, 120, 180, 240, 420, 720, 1 440 min après l’injection caudale. La concentration plasmatique totale de Ra été déterminée par chromatographie liquide haute pression. La concentration maximale (Cmax) et le temps d’atteindre la concentration maximale (Tmax) ont été obtenus des données; la demivie terminale (T1/2z), la clairance (Cl) et le volume de distribution (Vd) ont été évalués par une méthode non compartimentale. Par la suite, dans le but de déterminer la vitesse d’absorption (Ka) et de réduire le nombre d’échantillons sanguins, 25 enfants, recevant de la R simple et un autre groupe de 25, la solution d’E, ont été étudiés par une approche de population (NONMEM). Un modèle monocompartimental avec absorption du premier ordre a été utilisé. L’effet du poids, de l’âge et de l’E sur la Cl, le Vd et la Ka a été évalué.RésultatsLa Cmax a été significativement plus faible dans le Groupe E+ (0,93 mg·L−1 ± 0,29 vs 0,61 mg·L−1 ± 0,28, P = 0,05) et le Tmax a été plus tardif (124 min ± 53 vs 47min ± 16, P = 0,003). Lepoids a été une covariable significative pour la Cl et le Vd tandis que l’E a significativement ralenti la Kadela R [Groupe I, Ka 0,025 min−1 [coefficient de variation (CV) 21 %] vs 0,078 min−1 (CV 25 %) dans le Groupe II].ConclusionL’addition d’E modifie de façon significative la pharmacocinétique de la R en injection caudale.