Karolin Thiel

The enterohepatic circulation of amanitin: kinetics and therapeutical implications.

BACKGROUND Amatoxin poisoning induces a delayed onset of acute liver failure which might be explained by the prolonged persistence of the toxin in the enterohepatic circulation. Aim of the study was to demonstrate amanitin kinetics in the enterohepatic circulation. METHODS Four pigs underwent α-amanitin intoxication receiving 0.35 mg/kg (n=2) or 0.15 mg/kg (n=2) intraportally. All pigs remained under general anesthesia throughout the observation period of 72 h. Laboratory values and amanitin concentration in systemic and portal plasma, bile and urine samples were measured. RESULTS Amanitin concentrations measured 5h after intoxication of 219±5ng/mL (0.35 mg/kg) and 64±3 (0.15 mg/kg) in systemic plasma and 201±8ng/mL, 80±13ng/mL in portal plasma declined to baseline levels within 24h. Bile concentrations simultaneously recorded showed 153±28ng/mL and 99±58ng/mL and decreased slightly delayed to baseline within 32 h. No difference between portal and systemic amanitin concentration was detected after 24h. CONCLUSIONS Amanitin disappeared almost completely from systemic and enterohepatic circulation within 24 h. Systemic detoxification and/or interrupting the enterohepatic circulation at a later date might be poorly effective.

Personalized peptide vaccine-induced immune response associated with long-term survival of a metastatic cholangiocarcinoma patient

Graphical abstract

Standardized intensive care unit management in an anhepatic pig model: new standards for analyzing liver support systems

IntroductionSeveral anhepatic pig models were developed in the past. Most models suffer from short anhepatic survival times due to insufficient postoperative intensive care unit (ICU) management. The aim of this study was to analyze anhepatic survival time under standardized intensive care therapy in a pig model.MethodsEight pigs underwent total hepatectomy after Y-graft interposition between the infrahepatic vena cava and the portal vein to the suprahepatic vena cava. An intracranial probe was inserted for intracranial pressure (ICP) monitoring. Animals received pressure-controlled ventilation under deep narcosis. Vital parameters were continuously recorded. Urinary output, blood gas analysis, haemoglobin, hematocrit, serum electrolytes, lactate, and glucose were monitored hourly, and creatinine, prothrombin time, international normalised ratio, and serum albumin were monitored every 8 hours. Sodium chloride solution 0.9%, hydroxyethyl starch 6%, fresh frozen plasma, and erythrocyte units were used for volume substitution, and norepinephrine was used to prevent severe hypotension. Serum electrolytes and acid-base balance were corrected as required. Antibiotic prophylaxis with ceftriaxon was given daily, as well as furosemide, to maintain diuresis.ResultsPostoperative survival was 100% after 24 hours, with a maximum survival of 73 (mean, 58 ± 4) hours. Haemodynamic parameters such as heart rate, mean arterial pressure, and pulse oximetry remained stable during surgical procedures and following anhepatic status due to ICU therapy until escalating at time of death. Deteriorating pulmonary function could be stabilized by increasing oxygen concentration, positive end-expiratory pressure, and maximal airway pressure. Furosemide was used to maintain diuresis until renal failure occurred. ICP started at 15-17 mmHg and increased continuously up to levels of 41-43 mmHg at time of death. All animals died as a result of multiple-organ failure.ConclusionsUsing standardized intensive care management after total hepatectomy, we were able to prolong anhepatic survival over 58 hours without the use of liver support systems. The survival benefit of liver support systems in previous animal studies should be reevaluated against our model.

Contributors to individual quality of life after liver transplantation.

Eur J Clin Invest 2012

Correlation of the Intracranial Pressure to the Central Venous Pressure in the Late Phase of Acute Liver Failure in a Porcine Model

Volume loading is a common method used to ensure adequate circulation. However, in the late phase of acute liver failure complications that often lead to death are cerebral swelling and brainstem edema, which are considered to result from increasing intracranial pressure (ICP). In former studies cerebral venous pressure (CVP) and ICP were reported to be independent entities. Acute liver failure was induced in 25 German land race pigs by acetaminophen intoxication. CVP and ICP were measured continuously. Hydroxyethyl starch solution and noradrenalin were administered to stabilize the circulation at a mean arterial pressure above 60mmHg. There is an increasing correlation in quantity and quality between the CVP and ICP in the last 24 h before exitus. Beginning with a slope of 0.24 (ICP against CVP) and a low correlation coefficient of 0.08. 24h before exitus, this situation remained stable until 16 h to exitus (m = 0.22, r = 0.1). The correlation increased from 16 to 8 h prior to exitus to a slope of m = 0.5 and a correlation of r = 0.3 and remained until exitus. In late acute liver failure it seems therefore clinically reasonable to keep circulation within an adequate range by the use of noradrenalin and to avoid fluid overload.

Experimental Comparison of the Measurement Accuracy of the Licox® and Raumedic® Neurovent–PTO Brain Tissue Oxygen Monitors

BACKGROUND Only a few experimental reports are available on the direct comparison of Licox(®) and Raumedic(®)-Neurovent-PTO brain tissue oxygen pressure (P(br)O(2)) monitors. We compared the two systems regarding their measurement properties under experimental in vitro and in vivo conditions. MATERIALS AND METHODS Eight Licox(®) and Raumedic(®) Neurovent-PTO(®) sensors were tested for 10 min at 37°C, atmospheric pressure, at an oxygen content of 0% and 100% before and after the in vivo test. The same probes were implanted in German landrace pigs, which underwent hepatectomy. The mean P(br)O(2) values were recorded every minute. An O(2) challenge with inhalation of 100% O(2) for 10 min was performed 2 h post-abdominal surgery. RESULTS At 0% O(2) content values varied from 0.2 to 7 mmHg, at 100% O(2) content from 130 to 165 mmHg. No difference between probes was found. In vivo tests: Raumedic® showed higher P(br)O(2) values (mean +6.3 mmHg, p < 0.0001) compared with Licox®. During O(2) challenge, both probes responded similarly; however, Raumedic(®) had a 10% higher response amplitude (p < 0.005). After explantation there was again no difference between the two sensors. CONCLUSION Raumedic(®) sensors measured higher P(br)O(2) values. There was no significant difference regarding overall measurement of in vitro accuracy between the two probes, which proved to be robust when used consecutively for longer periods and in different environments.

Is PbrO2 Pressure Reactivity Index (ORx) Dependent on the Type of Oxygen Probe? An In Vivo Study

OBJECTIVE To evaluate if ORx is dependent on the type of brain tissue O(2) (P(br)O(2)) probe in an in vivo setting. METHODS In eight German landrace pigs two types of probes were implanted simultaneously in the same cerebral hemisphere. All pigs underwent hepatectomy and received neuromonitoring until death. A LICOX(®) probe CCI.S, representing a Clarke type electrode, was compared with a Raumedic Neurovent PTO, representing an optode. Data were sampled at 50 Hz. Average values were calculated every 30 s. Cerebral perfusion pressure (CPP) was averaged over 30 s. ORx was calculated for each probe. To increase the signal to noise ratio of the ORx, the ORx values, which had been assessed every minute, were averaged over 1 h. RESULTS The overall measurement time was 145.1 h (8,703 data pairs). Despite a mean difference of 6.2 mmHg (p < 0.0001) in the measured values of P(br)O(2), the mean ORx(licox) was 0.139, mean ORx(raumedic) 0.146 (p = 0.2098). Correlation coefficient of ORx values assessed every minute and every hour was 0.52 and 0.58 respectively. CONCLUSION Despite this significant difference in absolute values of P(br)O(2) the derived mean ORx values were not different. Similar to the established Licox system, the Raumedic system seems to enable a valid ORx recording.

A simple dummy liver assist device prolongs anhepatic survival in a porcine model of total hepatectomy by slight hypothermia

BackgroundAdvances in intensive care support such as therapeutic hypothermia or new liver assist devices have been the mainstay of treatment attempting to bridge the gap from acute liver failure to liver transplantation, but the efficacy of the available devices in reducing mortality has been questioned. To address this issue, the present animal study was aimed to analyze the pure clinical effects of a simple extracorporeal dummy device in an anhepatic porcine model of acute liver failure.MethodsTotal hepatectomy was performed in ten female pigs followed by standardized intensive care support until death. Five animals (dummy group, n = 5) underwent additional cyclic connection to an extracorporeal dummy device which consisted of a plasma separation unit. The separated undetoxified plasma was completely returned to the pigs circulation without any plasma substitution or exchange in contrast to animals receiving intensive care support alone (control group, n = 5). All physiological parameters such as vital and ventilation parameters were monitored electronically; laboratory values and endotoxin levels were measured every 8 hours.ResultsSurvival of the dummy device group was 74 ± 6 hours in contrast to 53 ± 5 hours of the control group which was statistically significant (p < 0.05). Body temperature 24 hours after hepatectomy was significantly lower (36.5 ± 0.5°C vs. 38.2 ± 0.7°C) in the dummy device group. Significant lower values were measured for blood lactate (1.9 ± 0.2 vs. 2.5 ± 0.5 mM/L) from 16 hours, creatinine (1.5 ± 0.2 vs. 2.0 ± 0.3 mg/dL) from 40 hours and ammonia (273 ± 122 vs. 1345 ± 700 μg/dL) from 48 hours after hepatectomy until death. A significant rise of endotoxin levels indicated the onset of sepsis at time of death in 60% (3/5) of the dummy device group animals surviving beyond 60 hours from hepatectomy.ConclusionsEpisodes of slight hypothermia induced by cyclic connection to the extracorporeal dummy device produced a significant survival benefit of more than 20 hours through organ protection and hemodynamic stabilisation. Animal studies which focus on a survival benefit generated by liver assist devices should especially address the aspect of slight transient hypothermia by extracorporeal cooling.

How much oxidative stress exists without the liver

BACKGROUND Oxidative stress (OS) represents an important pathogenetic factor of acute liver failure and chronic liver diseases. To elucidate whether the liver itself is a major source of OS, the present study was performed to assess OS and antioxidant status in an anhepatic porcine model. METHODS Six pigs underwent a total hepatectomy, five pigs were sham operated. OS and antioxidant status were evaluated by measuring plasma concentrations of malondialdehyde (MDA), xanthine oxidase (XO), superoxide dismutase (SOD) and the ferric reducing ability of plasma (FRAP). They were sampled at the start of the experiment, immediately after surgery, and then at 8 and 16 hours post hepatectomy. RESULTS Increased concentrations of MDA were observed in anhepatic pigs postoperatively (p < 0.02) and 8 hours after hepatectomy (p < 0.003) compared to controls. XO activity increased soon after hepatectomy (22.6 ± 5.4 mU/L versus 3.3 ± 2.1 mU/L in sham animals, p < 0.03) but returned to normal values in the further course. SOD levels did not change during the observational period in both groups. FRAP values rose significantly in the anhepatic animals compared to control (p < 0.015). A significant positive correlation was observed between MDA levels and FRAP levels (Spearmans ρ = 0.62; p < 0.0001). CONCLUSIONS These findings show that hepatectomy does not completely prevent the occurrence of OS because the production and regulation of OS are also located outside the liver.

Automated closed-loop management of body temperature using forced-air blankets: preliminary feasibility study in a porcine model

BackgroundManagement of a patient’s body temperature is an important aspect of care that should be addressed by targeted temperature management (TTM). Often, non-invasive methods like forced-air blankets are used. Especially in the operating room this management may be a subsidiary and repetitive task requiring constant observation of the patient’s body temperature and adaption using the limited set of available settings. Thus, automation of TTM is a feasible target to improve patient outcome and reduce caregiver workload.MethodsA Philips IntelliVue MP 50 patient monitor with an arterial PiCCO catheter system was used to measure patient blood temperature. Thermal management was performed with a 3M Bair Hugger 755 warming unit with forced air blankets. The warming unit was extended by a computer interface to allow for remote and automated control. A proposed closed-loop algorithm reads the measured temperature and performs automated control of the 3M Bair Hugger. Evaluation was performed in an experimental intensive care setting for animal studies. Two fully automated trials are compared with two manual and two uncontrolled trials in the same study setting using six female pigs for prolonged observation times of up to 90 hours in each trial.ResultsThe developed system and proposed algorithm allow more precise temperature management by keeping a set target temperature within a range of ± 0.5 °C in 88% of the observation time and within a range of ± 1.0 °C at all times. The proposed algorithm yielded better performance than did manual control or uncontrolled trials. It was able to adapt to individual patient needs as it is more dynamic than look-up table approaches with fixed settings for various temperatures.ConclusionsClosed-loop TTM using non-invasive forced-air warming blankets was successfully tested in a porcine study with the proposed hardware interface and control algorithm. This automation can be beneficial for patient outcome and can reduce caregiver workload and patient risk in clinical settings. As temperature readings are most often available, existing devices like the 3M Bair Hugger can easily be expanded. However, even if clinical application is feasible, open questions regarding approval and certification of such automated systems within the current legal situation still need to be answered.