André G. Roy

Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8).

BACKGROUND Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation. METHODS A double-blind, randomized, comparison of Sandimmune (SIM) with Neoral (NEO) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation. Patients were induced with intravenous CsA then switched to NEO or SIM. Dose adjustments were made daily, or as needed, to reach a target trough CsA level of 350 ng/ml in both groups. Pharmacokinetic studies were performed on days 5, 10, 15, and 16 weeks after transplantation. RESULTS The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) for SIM (P = 0.007); otherwise the two groups were well balanced. The NEO group stopped intravenous CsA earlier (5.8+/-2.6 days vs. 8.7+/-4.7 days, P<0.0001). This group required a lower median daily oral dose (7.5 mg/kg vs. 9.0 mg/kg, P<0.01) to maintain comparable trough CsA levels. Five SIM patients, but no NEO patients, discontinued the study due to the inability to reach target trough levels of CsA within the prescribed time (P<0.05). At 4 months, there were no differences between the two groups with respect to patient survival (93% NEO vs. 91% SIM), graft survival (90% NEO vs. 86% SIM), and rejection-free survival (54.1% NEO, 51.8% SIM). The incidence of serious adverse events was also similar and did not correlate with CsA pharmacokinetic profiles. The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval (AUC0-6) and peak CsA levels (Cmax). There was a strong correlation between freedom from graft rejection during the first month after transplantation and (a) AUC0-6 and (b) Cmax at days 5 and 10 after transplantation, but only in the NEO group did this reach statistical significance. In contrast, there was a poor correlation between trough CsA and graft rejection. In patients on NEO, the concentration of CsA 2 hr after dosing (C2) closely reflected AUC0-6 (r2 = 0.93), whereas there was a poorer correlation in patients on SIM (r2 = 0.73) CONCLUSIONS Cmax and/or AUC0-6 may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation. Prospective studies are underway to determine whether dosing to C2, which provides a good estimation of Cmax, can be used to take full advantage of NEOs improved absorption profile.

Three‐dimensional measurement of river channel flow processes using acoustic doppler velocimetry

This paper describes and assesses: (i) the use of a new instrument for the determination of three-dimensional flow velocities in natural rivers, the acoustic Doppler velocimeter (ADV); and (ii) a method for positioning and orienting such measurements relative to a single local coordinate system to relate flow velocity vectors with the bed and water surface. The ADV uses the Doppler shift principle to measure the velocity of small particles, assuming to be moving at velocities similar to the fluid. Velocity is resolved into three orthogonal components, and measured in a volume 5 cm below the sensor head, minimizing interference of the flow field, and allowing measurements to be made close to the bed. A simple method for positioning and orienting the instrument using digital tacheometry is described, and is used to obtain velocity measurements concurrently with measurements of both bed and water surface topography. The paper includes a preliminary field assessment of the ADV by comparing velocity profiles with those generated from Marsh McBirney electromagnetic current meters, and a full field assessment of the position and orientation methodology. These results suggest that the recommended methods in combination with an ADV are able to provide reliable mean three-dimensional velocity field information and accurate bed and surface topography. Copyright

Effects of a pebble cluster on the turbulent structure of a depth-limited flow in a gravel-bed river

Pebble clusters are important morphological features of gravel-bed rivers and have a significant effect on the spatial and temporal response of the flow. This paper presents original results from measurements of velocity taken at a high spatial and temporal resolution in a turbulent flow upstream and downstream from a pebble cluster. Three electromagnetic current meters (0.013 m in diameter), mounted on a wading rod, were deployed upstream and downstream of an isolated pebble cluster along 31 vertical profiles that contained between 7 and 13 points in a 5-m long section. The high sampling resolutions in a natural environment permitted characterization of the complex dynamics of the turbulent flow in the vicinity of the cluster. The description of these dynamics is based on the interpretation of contour maps of several turbulence statistics, including moments of velocity distributions, Reynolds shear stress, quadrant analysis and autocorrelation function. Downstream from the cluster, flow is decelerated, the intensity of turbulence increases, and zones of strong vertical motions are present. The superimposition of the maps allowed us to decompose the field of turbulent flow around a pebble cluster into distinct regions. In a downstream direction from the cluster, we observed zones of flow acceleration, recirculation, vortex shedding, flow reattachment, fluid upwelling, and flow recovering. Results indicate the existence of highly dynamic boundaries between zones where strong intermittent events are generated. They also highlight the difference between shedding and upwelling motions of the flow.

Three-dimensional structure of flow at a confluence of river channels with discordant beds

This paper presents three-dimensional data of the mean and turbulent structure of flow collected at a natural confluence of rivers with discordant beds to (1) describe the three-dimensional flow field of a natural junction of channels; (2) assess the role of changes in bed morphology occurring during transport-effective events on the structure of flow at a confluence; and (3) examine how the three-dimensional structure of flow varies with changes in the ratio of momentum flux between the two confluent streams. Three-dimensional measurements of velocity were reconstructed from the measurements obtained with an array of four, two-component electromagnetic current meters. Six detailed velocity profiles were taken at five cross-sections in a wide range of flow conditions. The mean field of flow is characterised by (1) the acceleration of flow in the downstream portion of the post-confluence channel, but by lower velocities upstream in the mixing layer area; (2) a stagnation zone at the apex of the junction; (3) a zone of flow deviation, and strong fluid upwelling, close to the avalanche face and at the margin of the tributary mouth bar; and (4) reduced velocities over the depositional bar at the downstream junction corner. The position and extent of these zones vary with changes in the ratio of momentum flux. Very high intensity of turbulence (peaks up to 50%) and turbulent kinetic energy were observed in the mixing layer region. Distortion of the mixing layer, characteristic of flow where bed discordance is present between the two tributary channels, was evident from mean and turbulent flow data. This field study suggests that the effects of bed discordance on flow, sediment transport, and the resultant bed morphology must be incorporated into conceptual and numeric models of these sites of complex flow.

Investigation of controls on secondary circulation in a simple confluence geometry using a three-dimensional numerical model

Recent research into river channel confluences has identified confluence geometry, and particularly bed discordance, as a control on confluence flow structures and mixing processes, and this has been illustrated using both field measurements in natural confluences and laboratory measurements of simplified confluences. Generalization of the results obtained from these experiments is limited by the number of confluence geometries that can be examined in a reasonable amount of time. This limitation may be overcome by numerical models, in which confluence geometry is more readily varied, and data acquired more rapidly. This paper aims to: (i) validate the application of a three-dimensional numerical model to a simple confluence geometry; (ii) simulate the effects of different boundary condition values upon flow structures; and (iii) interpret the implications of these simulations for river channel confluence dynamics. The model used in this research solves the three-dimensional form of the Navier–Stokes equations and is used to simulate the flow in a parallel confluence of unequal depth channels and to investigate the effect of different combinations of velocity and depth ratio between the two tributaries. The results generally agree with empirical evidence that secondary circulation is generated in the absence of streamline curvature, but only for specific combinations of depth and velocity ratio. This research shows how understanding of the interaction of these controls is enhanced if pressure gradients are considered. The velocity ratio is the prime determinant of the cross-stream pressure gradient that initiates cross-stream velocities. However, for significant secondary circulation to form, cross-stream velocities must lead to significant transfer of fluid in the cross-stream direction. This depends on the vertical extent of the cross-stream pressure gradient which is controlled by the depth ratio. In this study, strong secondary circulation occurred for a depth differential of 25% or more, as long as the velocity in the shallower tributary was at least as great as that in the deeper channel. This provides an important context for interpretation of previous work and for the design of new experiments in both the field and the laboratory.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

BackgroundThe potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.Methods/DesignThe study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.DiscussionIf our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial RegisterTrial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36)

Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: A multicenter randomized clinical trial

Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low‐dose tacrolimus (target trough level 4‐8 ng/mL, starting day 4‐6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end‐points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m2; P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m2; P = 0.038). In conclusion, delayed low‐dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post–liver transplantation without the cost of increased acute rejection. (Liver Transpl 2005;11:1064–1072.)

Survival rate changes with transfusion of blood products during liver transplantation

PurposeTo determine whether red blood cell (RBC) or plasma transfusion is associated with the one-year survival rate variation previously detected in liver transplantation.MethodsA retrospective study of 206 consecutive liver transplantations was undertaken. Intraoperative transfusions of blood products were identified. Twenty-seven variables were studied using univariate and multivariate analyses to identify factors that were associated significantly with survival rate. For analysis of one-year survival, the cases were studied according to the transfused blood products. Patients were stratified according to the degree of RBC and plasma transfusion into four groups: more than four units of RBC, one to four units of RBC, plasma transfusion only, and no plasma or RBC transfusions.ResultsPatients received an average of 2.8 ± 3.5 units of RBC and 4.1 ± 4.1 units of plasma. Thirty-two percent of the patients did not receive any RBC transfusion and 19.4% did not receive any blood products. The one-year survival rate was 81.9% for all patients and 97.4% for patients without any transfusions. Of the 27 variables evaluated, only RBC and plasma transfusions were associated with significant decrease in the one-year survival rate, which was seen in the group who received only plasma (76.9%, P = 0.014) and the group who received more than four units of RBC (62.5%, P < 0.0001).ConclusionAlthough we cannot demonstrate causality, our analysis shows that our one-year survival rate following liver transplantation decreased significantly with the intraoperative transfusion of any amount of plasma or more than four units of RBC.RésuméObjectifDéterminer si la transfusion de globules rouges (GR) ou de plasma est associée à la variation du taux de survie d’un an déjà détectée pour une transplantation hépatique.MéthodeUne étude rétrospective de 206 transplantations hépatiques consécutives a été menée. Les transfusions peropératoires de produits sanguins ont été recensées. Nous avons étudié 27 variables par des d’analyses à une ou plusieurs variables pour repérer les facteurs associés de façon significative au taux de survie. Pour l’analyse du taux de survie d’un an a été faite selon les produits sanguins transfusés. Les patients ont été stratifiés en quatre groupes d’après le degré de transfusion de GR et de plasma: plus de quatre unités de GR, de une à quatre unités, transfusion de plasma seulement et aucune transfusion.RésultatsLes patients ont reçu en moyenne 2,8 ± 3,5 unités de GR et 4,1 ± 4,1 unités de plasma. Trente-deux pour cent n’ont reçu aucune transfusion de GRet 19,4% aucun produit sanguin. Le taux de survie d’un an a été de 81,9% pour tous les patients et de 97,4% pour ceux qui n’ont eu aucune transfusion. Des 27 variables évaluées, seules les transfusions de Gr et de plasma ont été associées à une baisse significative du taux de survie d’un an, notée chez les patients qui ont reçu du plasma seulement (76,9%, P = 0,014) ou plus de quatre unités de GR (62,5%, P < 0,0001).ConclusionSans pouvoir établir de causalité, notre analyse montre que le taux de survie d’un an après une transplantation hépatique diminue significativement avec la transfusion peropératoire de toute quantité de plasma ou de plus de quatre unités de GR.

Coagulation Defects Do Not Predict Blood Product Requirements During Liver Transplantation

Background. In our experience, correction of coagulation defects with plasma transfusion does not decrease the need for intraoperative red blood cell (RBC) transfusions during liver transplantation. On the contrary, it leads to a hypervolemic state that result in increased blood loss. A previous study has shown that plasma transfusion has been associated with a decreased 1-year survival rate. The aim of this prospective study was to evaluate whether anesthesiologists could reduce RBC transfusion requirements during liver transplantation by eliminating plasma transfusion. Methods. Two hundred consecutive liver transplantations were prospectively studied over a 3-year period. Patients were divided into two groups: low starting international normalized ratio (INR) value <1.5 and high INR ≥1.5. Low central venous pressure was maintained in all patients before the anhepatic phase. Coagulation parameters were not corrected preoperatively or intraoperatively in the absence of uncontrollable bleeding. Phlebotomy and auto transfusion of blood salvaged were used following our protocol. Independent variables were analyzed in both univariate and multivariate fashion to find a link with RBC transfusions or decreased survival rate. Results. The mean number of intraoperative RBC units transfused was 0.3±0.8. Plasma, platelet, albumin, and cryoprecipitate were not transfused. In 81.5% of the patients, no blood product was used during their transplantation. The average final hemoglobin (Hb) value was 91.2±15.0 g/L. There were no differences in transfusional rate, final Hb, or bleeding between two groups (low or high INR values). The overall 1-year survival rate was 85.6%. Logistic regression showed that avoidance of plasma transfusion, phlebotomy, and starting Hb value were significantly linked to liver transplantation without RBC transfusion. The need for intraoperative RBC transfusion and Pughs score were linked to the decreased 1-year survival rate. Conclusion. The avoidance of plasma transfusion was associated with a decrease in RBC transfusions during liver transplantation. There was no link between coagulation defects and bleeding or RBC or plasma transfusions. Previous reports indicating that it is neither useful nor necessary to correct coagulation defects with plasma transfusion before liver transplantation seem further corroborated by this study. We believe that this work also supports the practice of lowering central venous pressure with phlebotomy to reduce blood loss, during liver dissection, without any deleterious effect.

The effects of antecedent moisture conditions on the relationship of hydrology to hydrochemistry in a small forested watershed

The relationship between stream discharge and the concentration of different solutes reflects the hydrological processes occurring in a catchment, but is also strongly affected by antecedent moisture conditions. In this study, the effects of antecedent conditions were examined for a small forested watershed near Montreal (Quebec) by comparing data from sequences of fall events for two years of contrasting antecedent moisture conditions. The relationship between discharge and stream water chemistry was also quantified using cross-correlation analysis. Results show that concentrations of dissolved organic carbon, nitrate and calcium increased during storm events with dry antecedent conditions but that the relationships were weaker under wet conditions. For both years, concentrations of sulfate, silicon and sodium and the pH were negatively correlated with discharge (cross-correlations from −0·20 to −0·53). With dry antecedent conditions, there was a general decrease in the concentration of all solutes with time, whereas concentrations remained at about the same level under wet conditions. The concentration–discharge relationships for sulfate shifted frequently from higher concentrations during the rising limb to higher concentrations during the falling limb from one event to another as a result of changing antecedent conditions. Although the contrast in antecedent moisture conditions between the two years was moderate in comparison with that reported in other studies (25% dryer than average in 1995 and 12% wetter than average in 1996), the hydrochemistry of the stream was markedly different. Copyright