[Show abstract][Hide abstract] ABSTRACT: Background: The cost-effectiveness of non-invasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC).Methods: We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage ≥F2, testing with liver biopsy and treating patients with ≥F2, treat none and treat all irrespective of fibrosis. We compared all NITs and tested the cost-effectiveness using current triple therapy with boceprevir or telaprevir but also modeled new, more potent antivirals.Findings: Treating all patients without any prior NIT was the most effective strategy and had an incremental cost-effectiveness ratio (ICER) of £9,204/additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective compared to using an NIT to decide on treatment, with an ICER of £16,028/QALY gained. The exploratory analysis to assess the possible impact on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the “treat all” strategy to remain the most cost-effective strategy would be £37,500. Above this threshold, the most cost-effective option would be non-invasive testing with MR elastography (ICER=£9,189).Conclusions: Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries. (Hepatology 2014)
[Show abstract][Hide abstract] ABSTRACT: BackgroundA recent Cochrane review suggested that laparoscopic cholecystectomy carried out early following mild gallstone pancreatitis was safe. This study compared the cost-effectiveness of laparoscopic cholecystectomy performed within 3 days of admission, during the same admission but after more than 3 days, or electively in a subsequent admission.MethodsA model-based cost–utility analysis was performed estimating mean costs and quality-adjusted life-years (QALYs) per patient in the UK National Health Service with a 1-year time horizon. A decision tree model was constructed and populated with probabilities, outcomes and cost data from published sources for mild gallstone pancreatitis, including one-way and probabilistic sensitivity analyses.ResultsThe costs of laparoscopic cholecystectomy performed within 3 days of admission, beyond 3 days but in the same admission, and electively in a subsequent admission were €2748, €3543 and €3752 respectively; the QALYs were 0·888, 0·888 and 0·884 respectively. Early laparoscopic cholecystectomy had a 91 per cent probability of being cost-effective at the maximum willingness to pay for a QALY commonly used in the UK. It is acknowledged that many hospitals do not have access to magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography, especially at weekends, and that implementing a 3-day target is unrealistic without allocating new resources that could erode the cost-effectiveness.Conclusion
Performing laparoscopic cholecystectomy for mild gallstone pancreatitis within 3 days of admission is cost-effective, but may not be feasible without significant resource allocation. After 3 days there is little financial advantage to same-admission operation.
British Journal of Surgery 04/2014; · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This meta-analysis aimed to investigate whether preoperative biliary drainage (PBD) is beneficial to patients with obstructive jaundice.
Data from randomized clinical trials related to safety and effectiveness of PBD versus no PBD were extracted by two independent reviewers. Risk ratios, rate ratios or mean differences were calculated with 95 per cent confidence intervals (c.i.), based on intention-to-treat analysis, whenever possible.
Six trials (four using percutaneous transhepatic biliary drainage and two using endoscopic sphincterotomy) including 520 patients with malignant or benign obstructive jaundice comparing PBD (265 patients) with no PBD (255) were included in this review. All trials had a high risk of bias. There was no significant difference in mortality (risk ratio 1.12, 95 per cent c.i. 0·73 to 1·71; P = 0·60) between the two groups. Overall serious morbidity (grade III or IV, Clavien-Dindo classification) was higher in the PBD group (599 complications per 1000 patients) than in the direct surgery group (361 complications per 1000 patients) (rate ratio 1·66, 95 per cent c.i. 1·28 to 2·16; P < 0·001). Quality of life was not reported in any of the trials. There was no significant difference in length of hospital stay between the two groups: mean difference 4·87 (95 per cent c.i. -1·28 to 11·02) days (P = 0·12).
PBD in patients undergoing surgery for obstructive jaundice is associated with similar mortality but increased serious morbidity compared with no PBD. Therefore, PBD should not be used routinely.
British Journal of Surgery 11/2013; 100(12):1589-1596. · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA).
103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy.
No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted.
Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276: Randomised study for immunosuppression regimen in liver transplantation.
[Show abstract][Hide abstract] ABSTRACT: Hypothermic machine perfusion (HMP) is better than conventional cold storage in kidney transplantation. Large animal models suggest that HMP may be beneficial for the liver as well, but questions remain about perfusion mode (dual portal/arterial flow versus single flow) and hepatic vascular injury including endothelial dysfunction or potential microbial infectivity during HMP.
Sixteen human livers rejected for transplantation by all UK centers with appropriate consent for research were randomized into 4 groups (n = 4 each): group 1: ≥7 hours cold storage (CS) and 1 hour HMP through hepatic artery (HA) alone; group 2: ≥7 hours CS and 1 hour HMP through HA and portal vein (PV); group 3: ≥7 hours CS and 1 hour HMP through PV alone; and group 4: ≥8 hours CS. A pressure-controlled prototype based on Lifeport Kidney Transporter (Organ Recovery Systems) was used. Livers were perfused at 4-8°C under sterile conditions with Belzer MPS KPS-1. Perfusion parameters (pressure, flow, resistance, and temperature) were recorded every 15 minutes. Perfusate for microbial culture and sensitivity were taken before and after HMP. Electron microscopy of 3 liver biopsy samples taken before perfusion, were compared with 3 samples from adjacent areas after perfusion.
Preset HA pressure of 30 mm Hg and PV pressure of 7 mm Hg were maintained throughout the perfusion. HA and PV flow ranged, respectively, from 11 to 107 mL/min (mean 59.5) and 39 to 199 mL/min (mean 96.2), with no differences between groups. The same was true for resistance: HA and PV resistance ranged, respectively from 0.17 to 1.99 mm Hg/mL/min (mean 0.71) and 0.07 to 0.17 mm Hg/mL/min (mean 0.08). Temperature was maintained at 4-8°C with the use of an external heat exchanger. No difference in sinusoidal endothelial ultrastructure was seen before and after machine perfusion or between any of the groups. Sterility was maintained throughout the HMP.
HMP of human livers did not produce evidence of sinusoidal endothelial injury or breach of sterility. Single or dual perfusion modes did not affect vascular resistance or flow. The results suggest that further studies of HMP with human livers are warranted.
[Show abstract][Hide abstract] ABSTRACT: Background
Hypothermic machine perfusion (HMP) has shown superior results to conventional cold storage method in kidney preservation. Similar promising results have been reported for HMP of livers in large animal models; however data from human livers remain scarce. The aims of this study is to establish a reproducible method of HMP of human livers using a pressure controlled system, to assess if sterility can be maintained throughout the procedure, and evaluate modes of perfusion (artery alone, portal vein alone, or both simultaneously).
16 human livers rejected for transplant by all UK centres with appropriate consent for research were randomised into four groups. Group 1: 7 h cold storage and 1 h HMP through hepatic artery (HA) alone (n = 4). Group 2: 7 h cold storage and 1 h HMP through hepatic artery (HA) and portal vein (PV) (n = 4). Group 3: 7 h cold storage and 1 h HMP through PV (n = 4). Group 4: 8 h simple cold storage (CS). A pressure controlled system where flow is automatically adjusted according to resistance to maintain a constant pressure (7 mmHg for PV and 30 mmHg for HA) was used, based on the Lifeport kidney machine using Belzers KPS perfusate. Livers were perfused at 4–8 °C using KPS solution under sterile conditions. Perfusion parameters (pressure, flow, resistance and temperature) were recorded every 15 min. Perfusate samples for microbial culture and sensitivity were taken before and after the perfusion.
HA pressure of 30 mmHg and PV pressure of 7 mmHg were maintained throughout the perfusion. HA and PV flow ranged from 11 to 107 ml/min (average 59.5 ml/min) and 39–199 ml/min (average 96.2 ml/min). HA and PV resistance ranged from 0.17 to 1.99 (average 0.71) and 0.07 to 0.17 mmHg/ml/min (average 0.08). Temperature was maintained between 4 and 8 °C using the supplied heat exchanger. Culture and sensitivity results from the perfusate showed that sterility was maintained throughout the procedure.
Our technique proved to be a reliable and reproducible method of donor liver HMP. Resistance in HA was higher than in PV, while flow in the HA was less than the PV. Sterility could be maintained throughout the perfusion process. These data provide a basis for further evaluation of liver HMP as a method for preserving livers during clinical hepatic transplantation.
[Show abstract][Hide abstract] ABSTRACT: Background: Although hepatocytes have a remarkable regenerative power, the rapidity of acute liver failure makes liver transplantation the only definitive treatment. Attempts to incorporate engineered three-dimensional liver tissue in bioartificial liver devices or in implantable tissue constructs, to treat or bridge patients to self-recovery, were met with many challenges, amongst which is to find suitable polymeric matrices. We studied the feasibility of utilising nanocomposite polymers in three-dimensional scaffolds for hepatocytes.Materials and methods: Hepatocytes (HepG2) were seeded on a flat sheet and in three-dimensional scaffolds made of a nanocomposite polymer (Polyhedral Oligomeric Silsesquioxane [POSS]-modified polycaprolactone urea urethane) alone as well as with porogen particles, i.e. glucose, sodium bicarbonate and sodium chloride. The scaffold architecture, cell attachment and morphology were studied with scanning electron microscopy, and we assessed cell viability and functionality.Results: Cell attachment to the scaffolds was demonstrated. The scaffold made with glucose particles as porogen showed a narrower range of pore size with higher porosity and better inter-pore communications and seemed to encourage near normal cell morphology. There was a steady increase of albumin secretion throughout the experiment while the control (monolayer cell culture) showed a steep decrease after day 7. At the end of the experiment, there was no significant difference in viability and functionality between the scaffolds and the control.Conclusion: In this initial study, porogen particles were used to modify the scaffolds produced from the novel polymer. Although there was no significance against the control in functionality and viability, the demonstrable attachment on scanning electron microscopy suggest potential roles for this polymer and in particular for scaffolds made with glucose particles in liver tissue engineering.
Journal of Biomaterials Applications 04/2012; · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Remote ischemic preconditioning (RIPC) protects against liver ischemia reperfusion (IR) injury. An essential circulating mediator of this protection is nitric oxide (NO) induced by lower limb RIPC. One of the mechanisms through which NO generally acts is the soluble guanylyl cyclase-cyclic GMP (sGC-cGMP) pathway. The present study aimed to assess the role of hepatic sGC-cGMP in lower limb RIPC-induced protection against liver IR injury.
Mice were allocated to 4 groups: 1.Sham; 2.IR: 40 min of lobar hepatic ischemia and 2 hr reperfusion; 3.RIPC+IR: 6 cycles of 4x4 min IR of the lower limb followed by IR group procedure; (4) 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ)+RIPC+IR: ODQ (sGC inhibitor) was administered followed by RIPC+IR group procedure. Hepatic microcirculatory blood flow (MBF) was measured throughout the experiment. Plasma transaminases, hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic cGMP levels were measured in groups 1-3 in addition to an RIPC alone group.
Compared to liver IR alone, RIPC+IR increased hepatic MBF during liver reperfusion (P<0.05), and reduced plasma transaminases (P<0.05) and ultrastructural markers of injury. In contrast compared to RIPC+IR, ODQ+RIPC+IR decreased hepatic MBF (P<0.05) and ultrastructural markers of injury. However, plasma transaminases were not significantly different in the ODQ+RIPC+IR compared to the RIPC+IR group. Hepatic cGMP levels were significantly elevated in the RIPC compared to sham group.
The hepatic sGC-cGMP pathway is required for mediating the protective effects of lower limb RIPC on hepatic MBF in liver IR injury.
[Show abstract][Hide abstract] ABSTRACT: Ischaemia reperfusion (IR) injury is a clinical entity with a major contribution to the morbidity and mortality of liver surgery and transplantation. A central pathway of protection against IR injury utilizes nitric oxide (NO). Nitric oxide synthase (NOS) enzymes manufacture NO from L-arginine. NO generated by the endothelial NOS (eNOS) isoform protects against liver IR injury, whereas inducible NOS (iNOS)-derived NO may have either a protective or a deleterious effect during the early phase of IR injury, depending on the length of ischaemia, length of reperfusion and experimental model. In late phase hepatic IR injury, iNOS-derived NO plays a protective role. In addition to NOS consumption of L-arginine during NO synthesis, this amino acid may also be metabolized by arginase, an enzyme whose release is increased during prolonged ischaemia, and therefore diverts L-arginine away from NOS metabolism leading to a drop in the rate of NO synthesis. NO most commonly acts through the soluble guanylyl cyclase-cyclic GMP- protein kinase G pathway to ameliorate hepatic IR injury. Both endogenously generated and exogenously administered NO donors protect against liver IR injury. The beneficial effects of NO on liver IR are not, however, universal, and certain conditions, such as steatosis, may influence the protective effects of NO. In this review, the evidence for, and mechanisms of these protective actions of NO are discussed, and areas in need of further research are highlighted.
Liver international: official journal of the International Association for the Study of the Liver 02/2012; 32(4):531-43. · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Realistic modelling of mechanical interactions between tissues is an
important part of surgical simulation, and may become a valuable asset
in surgical computer guidance. Unfortunately, it is also computationally
very demanding. Explicit matrix-free FEM solvers have been shown to be a
good choice for fast tissue simulation, however little work has been
done on contact algorithms for such FEM solvers. This work introduces
such an algorithm that is capable of handling both deformable-deformable
(soft-tissue interacting with soft-tissue) and deformable-rigid (e.g.
soft-tissue interacting with surgical instruments) contacts. The
proposed algorithm employs responses computed with a fully matrix-free,
virtual node-based version of the model first used by Taylor and
Flanagan in PRONTO3D. For contact detection, a bounding-volume hierarchy
(BVH) capable of identifying self collisions is introduced. The proposed
BVH generation and update strategies comprise novel heuristics to
minimise the number of bounding volumes visited in hierarchy update and
collision detection. Aside from speed, stability was a major objective
in the development of the algorithm, hence a novel method for
computation of response forces from C0-continuous normals, and a gradual
application of response forces from rate constraints has been devised
and incorporated in the scheme. The continuity of the surface normals
has advantages particularly in applications such as sliding over
irregular surfaces, which occurs, e.g., in simulated breathing. The
effectiveness of the scheme is demonstrated on a number of meshes
derived from medical image data and artificial test cases.
[Show abstract][Hide abstract] ABSTRACT: Roux-en-Y loop is considered the reconstruction method of choice in Orthotopic Liver Transplantation (OLT) for Primary Sclerosing Cholangitis (PSC). We have adopted an approach of duct-to-duct (D-D) reconstruction when recipient common bile duct is free of gross disease. Patients were divided into two groups: patients who underwent a Roux-en-Y choledochojejunostomy and patients who had a D-D anastomosis. Morbidity, mortality, disease recurrence and graft and patient survival were compared between the two groups and analyzed. Ninety-one patients had OLT for PSC. Sixty-three patients underwent a D-D biliary reconstruction, whereas 28 patients had a Roux-en-Y loop. Biliary leak complicated 8% from the D-D group, and 14% from the Roux-en-Y group (P = 0.08), whereas biliary strictures were identified in 10% vs. 7% patients from the D-D and Roux-en-Y group, respectively (P = 0.9). Actuarial 1, 3 and 10 year survival for D-D and Roux-en-Y group was (87%, 80% and 62%) and (82%, 73% and 73%), respectively (P = 0.7). The corresponding 1, 3 and 10 year graft survival was (72%, 58% and 42%) and (67%, 58% and 53%), respectively (P = 0.6). No difference was seen in disease recurrence rates. D-D biliary reconstruction in OLT for selected PSC patients remains our first option of reconstruction.
Transplant International 01/2012; 25(1):64-8. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cold preservation injury influences islet graft function. Reliable tools for real-time assessment of pancreas viability before islet isolation are lacking. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) was used immediately after organ harvest to study rat pancreases at 4 °C to 6 °C in five randomized preservation groups: Marshall's solution, static two-layer method (TLM), continuous TLM with oxygen perfused at 0.5 L/min, and static TLM or continuous TLM both the latter following 30 minutes of warm ischemia (WI). (31)P spectra were analyzed for phosphomonoesters, inorganic phosphate (Pi) and α-, β-and γ-nucleotide triphosphate. Intergroup rates of change of [γ-adenosine triphosphate (ATP)]/[Pi] and [β-ATP]/[Pi] throughout preservation period were significantly different. For continuous TLM there was an increase relative to baseline (0.043 (SD0.033) h(-1) and 0.029 (0.029) h(-1), respectively) but a decrease for both static TLM (-0.023 (0.016) h(-1) and 0.015 (0.026), P < .001 and < .05, respectively) and Marshall's (-0.049 (0.025) h(-1) and -0.036 (0.019) h(-1), respectively, both P < .001) with respect to continuous TLM. Rate of decrease was similar for the Marshall's and static TLM groups. [γ-ATP]/[Pi] and [β-ATP]/[Pi] increased with WI continuous TLM (0.008 [0.009] h(-1) and 0.007 [0.008] hr(-1), respectively) but decreased for WI static TLM (-0.018 (0.008) h(-1) and -0.014 (0.004) hr(-1), respectively, P < .001). (31)P-MRS is an effective tool for noninvasive assessment of pancreas bioenergetics. Continuous TLM preserves cellular bioenergetics and is superior to current non-perfluorocar bone based solutions for pancreas preservation.
[Show abstract][Hide abstract] ABSTRACT: Hindlimb remote ischemic preconditioning (RIPC) reduces liver ischemia/reperfusion (IR) injury in wild-type mice. The underlying mechanisms of RIPC are currently unknown. In this study, we investigated the role of endothelial nitric oxide synthase (eNOS) in mediating the protective effects of RIPC. Endothelial nitric oxide synthase knockout (eNOS(-/-) ) mice were divided into 4 groups: (1) a sham surgery group, (2) an RIPC group (6 cycles of 4 minutes of hindlimb ischemia and 4 minutes of hindlimb reperfusion), (3) an IR group [40 minutes of lobar (70%) hepatic ischemia and 2 hours of reperfusion], and (4) an RIPC+IR group (RIPC followed by the IR group procedures). Plasma liver aminotransferases, hepatic histopathological injury scores, transmission electron microscopy studies, and hepatic microcirculatory blood flow (MBF) were assessed. eNOS protein expression was analyzed in the livers and hindlimb muscles of wild-type mice. Hindlimb RIPC did not protect against subsequent liver IR injury in eNOS(-/-) mice; this was demonstrated by the lack of reduction in the plasma aminotransferase levels, histopathological scores, or ultrastructural features of IR injury in the RIPC+IR group versus the IR group. Hepatic MBF did not recover during liver reperfusion in the RIPC+IR group versus the IR group. eNOS protein expression was similar among all wild-type groups. In conclusion, eNOS is essential for the protective effects of hindlimb RIPC on liver IR injury. eNOS exerts its protective effects through the preservation of hepatic MBF. At 2 hours of reperfusion, eNOS protection is likely due to the increased activation of eNOS rather than increased expression.