Markus Golling

Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304).

Objective:Acute cholecystitis is a common disease, and laparoscopic surgery is the standard of care. Background:Optimal timing of surgery for acute cholecystitis remains controversial: either early surgery shortly after hospital admission or delayed elective surgery after a conservative treatment with antibiotics. Methods:The ACDC (“Acute Cholecystitis—early laparoscopic surgery versus antibiotic therapy and Delayed elective Cholecystectomy”) study is a randomized, prospective, open-label, parallel group trial. Patients were randomly assigned to receive immediate surgery within 24 hours of hospital admission (group ILC) or initial antibiotic treatment, followed by delayed laparoscopic cholecystectomy at days 7 to 45 (group DLC). For infection, all patients were treated with moxifloxacin for at least 48 hours. Primary endpoint was occurrence of predefined relevant morbidity within 75 days. Secondary endpoints were as follows: (1) 75-day morbidity using a scoring system; (2) conversion rate; (3) change of antibiotic therapy; (4) mortality; (5) costs; and (6) length of hospital stay. Results:Morbidity rate was significantly lower in group ILC (304 patients) than in group DLC (314 patients): 11.8% versus 34.4%. Conversion rate to open surgery and mortality did not differ significantly between groups. Mean length of hospital stay (5.4 days vs 10.0 days; P < 0.001) and total hospital costs (&OV0556;2919 vs &OV0556;4262; P < 0.001) were significantly lower in group ILC. Conclusions:In this large, randomized trial, laparoscopic cholecystectomy within 24 hours of hospital admission was shown to be superior to the conservative approach concerning morbidity and costs. Therefore, we believe that immediate laparoscopic cholecystectomy should become therapy of choice for acute cholecystitis in operable patients. (NCT00447304)

Immunogenicity of two accelerated hepatitis B vaccination protocols in liver transplant candidates

Objective It is common practice to immunize patients against hepatitis B virus infection prior to orthotopic liver transplantation (OLT). We compared the seroprotection rates of two accelerated schedules with a recombinant hepatitis B vaccine in patients awaiting OLT. Design and methods Patients were prospectively recruited and vaccinated with either 20 μg (group 1, n = 14) or 40 μg (group 2, n = 20) hepatitis B surface antigen per dosage. Thirty-nine healthy volunteers served as a historical control group. Patients in all groups were vaccinated with an accelerated schedule (0, 7 and 21 days). All patients underwent clinical and laboratory examinations (HBs antibodies, CD4/CD8 ratio, transaminases). Results The accelerated hepatitis B vaccination schedules were well tolerated. Eight weeks after the third injection, no significant differences in seroprotection rates were observed between group 1 (31%) and group 2 (26%). There was no correlation with respect to seroconversion rates and gender, smoking habits or CD4/CD8 ratio. Conclusion These data suggest that accelerated vaccination schedules with a recombinant hepatitis B vaccine are safe and well-tolerated, but only achieve poor seroconversion rates in OLT candidates. Increasing the vaccine dose to 40 μg hepatitis B surface antigen per injection did not result in a higher response rate. Because of the low risk of acquiring de novo hepatitis B infection after transplantation, it should be questioned whether routine hepatitis B vaccination with standard recombinant vaccines prior to liver transplantation should be recommended any longer.

Ischemic preconditioning improves liver microcirculation after ischemia/reperfusion.

THE ISCHEMIA/REPERFUSION injury plays an important role in liver transplantation and surgery. Oxidative stress after reperfusion results in activation and adherence of leucocytes and platelets. Consequently, alterations in microcirculation develop that lead to impairment of hepatic function. In 22% of the cases extensive reperfusion injury causes severe deterioration of microcirculation leading to primary dysfunction or primary graft failure. A more detailed understanding of pathophysiological mechanisms resulting into treatment possibilities is therefore essential. Ideal treatment makes use of intrinsic protective mechanisms and is offered before damage takes place. Ischemic preconditioning takes that into account. Ischemic preconditioning describes the phenomenon that a brief ischemia and reperfusion, the so-called preclamping, increases the ischemic tolerance of a following ischemic period. It was first described for the heart in 1986 by Murry and since then has been extensively examined. Studies concerning other organs such as muscle and kidney followed. The first study about preclamping in the liver was performed in 1993 by Lloris-Carsi et al. He and others studied different preclamping and reperfusion times, focusing on laboratory liver function tests, energy content of the tissue, histological analyses of cellular integrity, and survival after sublethal stress. The underlying effect of ischemic preconditioning has been of special interest ever since. Some substances such as heat shock protein, adenosine, and nitric oxide (NO) seem to be involved, the exact mechanism has not yet been identified. Thus far, analyses of liver microcirculation after ischemic preconditioning have not been performed. Microcirculatory disturbances can directly be related to organ function and, therefore, to the extent of ischemia/reperfusion injury, respectively, to the benefit of an applied treatment. Therefore, it was the goal of this study to evaluate the effect of ischemic preconditioning on the hepatic microcirculation after warm ischemia/reperfusion by intravital microscopy in rats.

Role of transarterial chemoembolization for hepatocellular carcinoma before liver transplantation with special consideration of tumor necrosis.

Abstract:  Several authors suggest that local ablative therapies, specifically transarterial chemoembolization (TACE), may control tumor progression of hepatocellular carcinoma (HCC) in patients who are on the waiting list for liver transplantation (orthotopic liver transplantation, OLT). There is still no evidence if TACE followed by OLT is able to prevent recurrence of tumor, to prolong survival rate of the patients on the waiting list, or to improve the survival after OLT. We report 27 patients with HCC who underwent OLT. From these patients, 15 were pre‐treated with TACE alone or in combination with percutaneous ethanol injection (PEI) or laser‐induced thermo therapy (LITT). Mean time on the waiting list was 214 d for treated patients and 133 d for untreated patients. Comparing pre‐operative imaging and histopathological staging post‐transplant, we found 13 patients with tumor progression out of which five were treated with TACE. In two of the TACE patients a decrease of lesions could be achieved. In a single patient, there was no evidence of any residual tumor. Only one patient displayed tumor progression prior to OLT despite undergoing TACE. Comparison of outcome in patients undergoing TACE or having no TACE was not statisitically significant (p = 0.5). In addition, our analysis showed that progression either in the total study population or in the TACE group alone is associated with a significant poorer outcome concerning overall survival (p = 0.02 and p = 0.02).

Sequential (domino) transplantation of the liver in a transthyretin-50 familial amyloid polyneuropathy

Abstract Background: General shortage of cadaveric organs has led to a search for alternative methods to expand the donor pool. Sequential (domino) transplantation is yet another attempt to compensate for the declining consent to organ donation. Patients and methods: To qualify for a domino liver transplantation, the following preconditions must be fulfilled: (1) extrahepatic disease must exist, (2) liver must be fully functional, and (3) the genetic defect in the host should recur within a sufficient latency period. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease which involves a genetic defect for transthyretin (TTR), which is predominantly produced in the liver. Results: In this report, we describe a rare case of a FAP TTR-50 variant undergoing domino liver transplantation. Since myocardial symptoms precede peripheral polyneuropathy, special emphasis should be placed on arrhythmias and the restrictive cardiomyopathy necessitating a veno-venous bypass or a cardiac pacemaker in order to improve cardiac contractility. The type of anastomosis of the suprahepatic inferior vena cava and possible alternatives are discussed. Conclusion: Despite ethical problems, the advantages of the domino procedure are obvious: (1) expansion of the donor pool, (2) ability to use living donors, and (3) presence of very short ischemic time and thus excellent liver function. Due to the kinetics of TTR production and deposition, donors and recipients of FAP livers should be followed up using an extensive neurological and cardiological protocol.

Negative impact of systemic catecholamine administration on hepatic blood perfusion after porcine liver transplantation

Catecholamines are often administered during and after liver transplantation (LTx) to support systemic perfusion and to increase organ oxygen supply. Some vasoactive agents can compromise visceral organ perfusion. We followed the hypothesis that the vasculature of transplanted livers presents with a higher sensitivity, which leads to an increased vulnerability for flow derangement after application of epinephrine (Epi) or norepinephrine (NorEpi). Hepatic macroperfusion and microperfusion during systemic Epi or NorEpi infusion were measured by Doppler flow and thermodiffusion probes in porcine native, denervated, and transplanted livers (n = 16 in each group). Epi or NorEpi were infused (n = 8 in each subgroup) in predefined dosages (low dose = 5 μg/kg/minute and high dose = 10 μg/kg/minute) over 240 minutes. Systemic cardiocirculatory parameters were monitored continuously. Hepatic perfusion data were compared between all groups at comparable time points and dosages. In all native, denervated, and transplanted liver groups, Epi and NorEpi induced an inconsistent rise of mean arterial pressure and heart rate shortly after onset of infusion in both dosages compared with baseline. No significant differences of cardiovascular parameters at comparable time points were observed. In native livers, Epi and NorEpi induced only temporary alterations of hepatic macrocirculation and microcirculation, which returned to baseline 2 hours after onset of infusion. No significant alterations of hepatic blood flow were detected after isolated surgical denervation of the liver. By contrast, transplanted livers showed a progressive decline of hepatic macrocirculation (33–75% reduction) and microcirculation (39–58% reduction) during catecholamine infusions in a dose‐dependent fashion. Characteristics of liver blood flow impairment were comparable for both vasoactive agents. In conclusion, pronounced disturbances of hepatic macrocirculation and microcirculation were observed during systemic Epi and NorEpi infusion after LTx compared with native and denervated livers. Microcirculation disturbances after LTx might be explained by impairment of hepatic blood flow regulation caused by an increased sensitivity of hepatic vasculature after ischemia‐reperfusion and by lengthening of vasopressor effects caused by reduced hepatocyte metabolism. Clinicians should be aware of this potentially hazardous effect. Therefore, application of catecholamines after clinical LTx should be indicated carefully. (Liver Transpl 2005;11:174–187.)

Distinct effects of surgical denervation on hepatic perfusion, bowel ischemia, and oxidative stress in brain dead and living donor porcine models

The liver function and perfusion following brain death is mainly influenced by the sympathetic nerves and hormones. We examined the specific influence of surgical liver denervation on systemic and hepatic perfusion parameters, bowel ischemia and oxidative stress in hemodynamically stable BD and control (living donor [LD]) pigs. Brain death was induced in 8 pigs via saline infusion into the balloon of an epidural Tieman‐catheter (1 mL/15 minutes) and compared to the control group (n = 6) over 4 hours. At 2 hours postoperatively, complete liver denervation was initiated. We analyzed systemic cardiocirculatory parameters (mean arterial pressure, aortic flow, bowel ischemia (endotoxin, and endotoxin‐neutralizing capacity) and oxidative stress (total glutathione in erythrocytes [tGSHE]) and compared them to local/hepatic perfusion parameters (hepatic artery and portal venous flow, liver blood flow index, and microperfusion), local bowel ischemia (intramucosal pH [pHi] of stomach [pHiS]/colon[pHiC]), and liver oxidative stress (glutathione [rGSHL, GSSGL]). Following brain death, the parameters including mean arterial pressure, aortic flow, pHi, endotoxin, and tGSHE showed no significant changes at 2 hours. Portal venous flow and microperfusion were decreased significantly and hepatic arterial buffer response was ineffective. Hepatic oxidative stress was increased in BD animals (↓rGSHL, ↑GSSGL). Surgical denervation/manipulation increased portal venous flow significantly, hepatic arterial buffer response became effective, and stomach pHi decreased (BD and LD groups). Hepatic oxidative stress was reduced in the BD group (↑rGSHL/GSSGL; P < 0.001) while it was increased in the LD group (↓rGSHL/GSSGL; P < 0.001). In conclusion, denervation reduces hepatic oxidative stress in BD only in contrast to the LD. The reciprocal effect of denervation depends on the state of neural activation and postulates a potential benefit of surgical denervation before organ harvesting in brain death. Liver Transpl 13:607–617, 2007.

Effects of hemodynamic instability on brain death-induced prepreservation liver damage.

Background. Brain death (BD) is an important multifactorial variable contributing to donor-specific liver damage. Our study aimed at assessing the specific effects of hemodynamic instability on systemic and hepatic parameters of perfusion, bowel ischemia, and oxidative stress in a porcine model of BD. Methods. BD was induced in 16 pigs (German Landrace, 18–28 kg) in two groups (hypotension-BD [HYPO-BD], n=8; normotension-BD [NORM-BD], n=8), which were compared with control animals/living donors (n=6) for a period of 2 hr. We analyzed systemic hemodynamic parameters, bowel ischemia (intramucosal pH in the stomach and colon, plasma endotoxin levels, and endotoxin-neutralizing capacity [ENC]), and oxidative stress (total glutathione levels in erythrocytes) and compared the findings with hepatic parameters of perfusion (hepatic arterial flow, portal venous flow, and microperfusion) and liver oxidative stress (reduced glutathione and oxidized glutathione levels in the liver). Results. Independent of the hemodynamic stability, liver macrocirculation and microcirculation decreased (HYPO-BD, 79±6 to 69±10 mL/100 g/min; NORM-BD, 81±10 to 73±7 mL/100 g/min;P <0.05). Hepatocellular damage (aspartate aminotransferase: NORM-BD, 49±20 units/L; HYPO-BD, 170±140 units/L;P <0.01) and hepatic oxidative stress (reduced glutathione in the liver/oxidized glutathione in the liver: NORM-BD, 29.4±2.3 to 13.0±1.3; HYPO-BD, 29.4±2.3 to 9.05±0.81;P <0.001) increased in both BD groups. With dependence on systemic hemodynamic parameters, bowel ischemia increased (intramucosal pH in the colon, 7.22±0.01, P <0.01; ENC, 75±14 endotoxin-neutralizing units/mL, P <0.01; endotoxin levels, 7±2 to 43±10 pg/mL, P <0.01) in the HYPO-BD group but not in the NORM-BD group or the living donor group. Furthermore, systemic oxidative stress was increased in the HYPO-BD group only (total glutathione levels in erythrocytes, 2.65±0.25 to 0.15±0.25 mM;P <0.01). Conclusions. During BD, liver-specific parameters (portal venous flow, microperfusion, aspartate aminotransferase activity, ENC, and hepatic oxidative stress) were compromised, independent of the hemodynamic status. Therefore, the systemic hemodynamic status does not reflect the functional status of the liver during BD.

Reduced glutathione in the liver as a potential viability marker in non-heart-beating donors.

Although the use of non–heart‐beating donors (NHBD) is the oldest type of organ transplantation, the results were and still are disappointing. To consider using a liver from NHBD, it is of importance to assess the graft viability. Our aim was to assess the role of reduced liver glutathione (rGSHL) as a potential predictive marker of liver function before transplantation. Autotransplanted livers were subjected to 0, 60, and 90 minutes of ischemia in 20 pigs. We analyzed systemic cardiocirculatory parameters, bowel ischemia by endotoxin, endotoxin‐neutralizing capacity, oxidative stress, hepatic perfusion parameters, liver enzymes, local bowel ischemia, and liver oxidative stress (rGSHL and oxidized glutathione in the liver). Autotransplantation was comparable to donor explantation/recipient transplantation with respect to systemic and hepatic parameters. Liver ischemia for 0, 60, and 90 minutes resulted in survival in 100% (NHBD‐0), 71% (NHBD‐60), and 57% (NHBD‐90) of animals. Of all parameters, only hepatic microperfusion, pHi of the sigmoid colon, and bowel ischemia by endotoxin in the NHBD‐90 group showed significant changes compared to NHBD‐60 and control animals. Although systemic endotoxin‐neutralizing capacity and total glutathione in erythrocytes levels were mainly influenced by cold perfusion, hepatic oxidative stress increased with ischemia time. The cut‐off value of 11.5 ng/mmol of rGSHL could distinguish survivors from nonsurvivors, independent of the ischemia time. In conclusion, rGSHL has the potential of becoming an important viability marker, as it could predict survival in autotransplantation NHBD model regardless of the ischemia time. Further investigation to declare reasons for differing rGSHL levels within the liver is required. Liver Transpl 14:1637–1647, 2008.

Characterization of hepatic parenchymous perfusion heterogeneity and regional flow kinetics after porcine liver transplantation

BACKGROUND In clinical practice, a heterogeneous hepatic tissue microperfusion (MC) is often observed after liver resection or transplantation (LTx). Nevertheless this hepatic perfusion phenomenon has never been really quantified with respect to its anatomic distribution and time course in detail. The aim of the study was to characterize liver perfusion heterogeneity and local flow kinetics both in the physiological situation and after standardized ischemia and reperfusion using an established model of porcine LTx. METHODS Regional distribution of hepatic MC in healthy native porcine livers (control group; n = 8) was analyzed in comparison with data derived 60 min, 24 h, and 72 h after porcine LTx (transplantation group; n = 8 each subgroup; cold ischemia time: 5.7 +/- 1.2 h). MC was measured with implanted thermal diffusion electrodes (TD). Flow in hepatic artery and portal vein was continuously detected by ultrasonic probes. For standardization of measurement localizations, porcine liver lobes were divided anatomically into three horizontal layers (cranial, medial, caudal), defining 12 distinct hepatic measurement regions. RESULTS In the control group, a homogenous liver MC with a mean flow of 81.6 +/- 13.9 ml/100 g/min was detected in all regions. After LTx, a marked MC heterogeneity was noted 60 min after reperfusion. MC rehomogenization was first documented within horizontal liver planes 24 h later. Comparison of MC between planes showed persisting heterogeneity with a significant intralober drop of mean MC in the cranio-caudal direction. Complete MC rehomogenization (both between horizontal and vertical liver planes) was detected 72 h after reperfusion. Still, an overall reduction of mean liver perfusion by about 15% was existent. CONCLUSIONS A homogenous tissue perfusion was observed in healthy porcine livers. In contrast, marked heterogeneity of hepatic MC was detected after LTx. Heterogeneity presents as a very dynamic and temporary phenomenon. Early horizontal flow rehomogenization and reconstitution of normal blood flow, particularly primarily in the cranial liver layers, appear to be characteristic features during early flow reconstitution after postischemic reperfusion. Due to heterogeneity and time-dependent flow dynamics, measurement of MC volumes at single hepatic regions may not always allow a valid characterization of liver perfusion quality during the first 24 h after postischemic reperfusion.