Publications by authors named "Lars Ytrebo"

35 Publications

A combination of infraclavicular and suprascapular nerve blocks for total shoulder arthroplasty: A case series.

Acta Anaesthesiol Scand 2021 05 16;65(5):674-680. Epub 2021 Feb 16.

Department of Anaesthesiology, University Hospital of North Norway and Acute and Critical Care Research group, UiT - The Arctic University of Norway, Tromsø, Norway.

Background: Shoulder arthroplasty is associated with significant post-operative pain. Interscalene plexus block is the gold standard for pain management in patients undergoing this surgery, however, alternatives are currently being developed. We hypothesized that a combination of anterior suprascapular nerve block and lateral sagittal infraclavicular block would provide effective post-operative analgesia. Primary aims for this study were to document numeric rating scale (NRS) pain score and use of oral morphine equivalents (OMEq) during the first 24 hours after surgery. Secondary aim was to determine the incidence of hemidiaphragmatic paralysis.

Methods: Twenty patients (ASA physical status I-III) scheduled for shoulder arthroplasty were studied. Four mL ropivacaine 0.5% was administered for the suprascapular nerve block and 15 mL ropivacaine 0.75% for the infraclavicular block. Surgery was performed under general anaesthesia. Paracetamol and prolonged-release oxycodone were prescribed as post-operative analgesics. Morphine and oxycodone were prescribed as rescue pain medication. Diaphragm status was assessed by ultrasound.

Results: Median NRS (0-10) at 1, 3, 6, 8 and 24 hours post-operatively were 1, 0, 0, 0 and 3, respectively. NRS at rest during the first 24 post-operative hours was 4 (2.5-4.5 [0-5]), median (IQR [range]). Maximum NRS was 6.5 (5-8 [0-10]) median (IQR [range]). Total OMEq during the first 24 post-operative hours was 52.5 mg (30-60 [26.4-121.5]) median (IQR [range]). Hemidiaphragmatic paralysis was diagnosed in one patient (5%).

Conclusions: The combination of suprascapular and infraclavicular nerve block shows an encouraging post-operative analgesic profile and a low risk for hemidiaphragmatic paralysis after total shoulder arthroplasty.
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http://dx.doi.org/10.1111/aas.13787DOI Listing
May 2021

Opioid consumption in two surgical hospital wards.

Tidsskr Nor Laegeforen 2020 09 3;140(12). Epub 2020 Sep 3.

Background: The purpose of the study was to document the consumption of opioids in two surgical departments at the University Hospital of North Norway, Tromsø, in the period 2010-17.

Material And Method: The consumption of opioids in the department of gastrointestinal surgery and the department of cardiovascular and thoracic surgery was obtained from Nord hospital pharmacy. All opioids were converted to oral morphine equivalents.

Results: The consumption of morphine in the department of gastrointestinal surgery was reduced from 223 835 oral morphine equivalents per year in the period 2010-13, to 147 641 in the period 2014-17. In the department of cardiovascular and thoracic surgery, the yearly consumption of morphine was reduced from 28 652 oral morphine equivalents in the period 2010-13, to 22 945 in the period 2014-17. The consumption of oxycodone in the department of gastrointestinal surgery increased from 210 643 oral morphine equivalents per year in the period 2010-13, to 376 322 in the period 2014-17. In the department of cardiovascular and thoracic surgery, the consumption of oxycodone increased from 28 922 oral morphine equivalents per year in the period 2010-13, to 123 875 in the period 2014-17. In the department of gastrointestinal surgery, the increase was most evident for oxycodone administered intravenously or subcutaneously. In the department of cardiovascular and thoracic surgery, the largest increase was for oxycodone administered orally.

Interpretation: The consumption of opioids increased in both departments studied, and oxycodone constituted the largest part of the increase.
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http://dx.doi.org/10.4045/tidsskr.20.0161DOI Listing
September 2020

Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients.

N Engl J Med 2020 03 16;382(12):1103-1111. Epub 2020 Feb 16.

From the Departments of Anesthesiology and Intensive Care, Odense University Hospital-Svendborg Hospital, Svendborg (H.T.O.), the Departments of Clinical Research (H.T.O., H.K.N., T.S., J.O., P.T.) and Business and Economics (S.K., J.T.L.), University of Southern Denmark, and the Department of Anesthesiology and Intensive Care, Odense University Hospital (T.S., P.T.), Odense, the Department of Anesthesiology and Intensive Care, Hospital Lillebaelt, Kolding (H.K.N.), and the Department of Anesthesiology and Intensive Care, Esbjerg Hospital, Esbjerg (J.O.) - all in Denmark; the Department of Anesthesiology and Intensive Care, Vestfold Hospital, Tønsberg (K.-A.W.), and the Department of Anesthesiology and Intensive Care, University Hospital of North Norway, Tromsø (L.M.Y., B.A.K.) - both in Norway; and the Department of Anesthesiology and Intensive Care, Linköping University Hospital, Linköping, Sweden (M.C.).

Background: In critically ill, mechanically ventilated patients, daily interruption of sedation has been shown to reduce the time on ventilation and the length of stay in the intensive care unit (ICU). Data on whether a plan of no sedation, as compared with a plan of light sedation, has an effect on mortality are lacking.

Methods: In a multicenter, randomized, controlled trial, we assigned, in a 1:1 ratio, mechanically ventilated ICU patients to a plan of no sedation (nonsedation group) or to a plan of light sedation (i.e., to a level at which the patient was arousable, defined as a score of -2 to -3 on the Richmond Agitation and Sedation Scale [RASS], on which scores range from -5 [unresponsive] to +4 [combative]) (sedation group) with daily interruption. The primary outcome was mortality at 90 days. Secondary outcomes were the number of major thromboembolic events, the number of days free from coma or delirium, acute kidney injury according to severity, the number of ICU-free days, and the number of ventilator-free days. Between-group differences were calculated as the value in the nonsedation group minus the value in the sedation group.

Results: A total of 710 patients underwent randomization, and 700 were included in the modified intention-to-treat analysis. The characteristics of the patients at baseline were similar in the two trial groups, except for the score on the Acute Physiology and Chronic Health Evaluation (APACHE) II, which was 1 point higher in the nonsedation group than in the sedation group, indicating a greater chance of in-hospital death. The mean RASS score in the nonsedation group increased from -1.3 on day 1 to -0.8 on day 7 and, in the sedation group, from -2.3 on day 1 to -1.8 on day 7. Mortality at 90 days was 42.4% in the nonsedation group and 37.0% in the sedated group (difference, 5.4 percentage points; 95% confidence interval [CI], -2.2 to 12.2; P = 0.65). The number of ICU-free days and of ventilator-free days did not differ significantly between the trial groups. The patients in the nonsedation group had a median of 27 days free from coma or delirium, and those in the sedation group had a median of 26 days free from coma or delirium. A major thromboembolic event occurred in 1 patient (0.3%) in the nonsedation group and in 10 patients (2.8%) in the sedation group (difference, -2.5 percentage points; 95% CI, -4.8 to -0.7 [unadjusted for multiple comparisons]).

Conclusions: Among mechanically ventilated ICU patients, mortality at 90 days did not differ significantly between those assigned to a plan of no sedation and those assigned to a plan of light sedation with daily interruption. (Funded by the Danish Medical Research Council and others; NONSEDA ClinicalTrials.gov number, NCT01967680.).
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http://dx.doi.org/10.1056/NEJMoa1906759DOI Listing
March 2020

Nutritional support for critically ill patients in the intensive care unit.

Tidsskr Nor Laegeforen 2020 02 30;140(2). Epub 2020 Jan 30.

Patients in intensive care have increased nutritional needs but are often incapable of eating independently. When should intravenous parenteral nutrition be started, and what is the optimal dose? Here we review the recently updated European guidelines on nutritional support in intensive care patients.
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http://dx.doi.org/10.4045/tidsskr.19.0426DOI Listing
February 2020

Brachial plexus block of the posterior and the lateral cord using ropivacaine 7.5 mg/mL.

Acta Anaesthesiol Scand 2019 03 18;63(3):389-395. Epub 2018 Oct 18.

Department of Anaesthesiology, University Hospital of North Norway, Acute and Critical Care Research Group, Tromsø, Norway.

Background: We recently showed that the novel combination of a superficial cervical plexus block, a suprascapular nerve block, and the lateral sagittal infraclavicular brachial plexus block (LSIB) provides an alternative anaesthetic method for arthroscopic shoulder surgery. In this study, we hypothesised that the LSIB dose for this shoulder block could be significantly reduced by injecting only towards the shoulder relevant posterior and lateral cords. Our aim was to determine the minimum effective volume in 50% of the patients (MEV ) and to estimate the MEV when using ropivacaine 7.5 mg/mL to block these cords.

Methods: Twenty-three adult patients scheduled for hand surgery participated in the study. Considering the artery as a clock face with 12 o'clock ventral, the designated volume was injected immediately outside the arterial wall and between 8 and 9 o´clock. The in-plane technique was used. Block success was assessed 30 minutes after withdrawal of the needle. Successful posterior cord block was defined as anaesthesia or analgesia of the axillary nerve. Successful lateral cord block was defined as either anaesthesia or analgesia, or >50% motor block of the musculocutaneous nerve. MEV was determined by the staircase up-and-down method. Logistic regression and probit transformation were applied to estimate MEV .

Results: MEV and MEV were 7.8 mL [95% confidence interval (CI), 7.3-8.4] and 9.0 mL (95% CI, 7.8-10.3), respectively.

Conclusion: For single-deposit infraclavicular posterior and lateral cord block, the MEV of ropivacaine 7.5 mg/mL was estimated to 9.0 mL.
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http://dx.doi.org/10.1111/aas.13277DOI Listing
March 2019

Postoperative Analgesia after Shoulder Surgery.

Anesthesiology 2018 08;129(2):379-380

University Hospital of North Norway and the Arctic University of Norway, Tromsø, Norway (L.M.Y.).

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http://dx.doi.org/10.1097/ALN.0000000000002276DOI Listing
August 2018

The Effect of Infraclavicular Brachial Plexus Blocks on the Axillary Nerve.

Reg Anesth Pain Med 2018 02;43(2):222

Department of Anesthesiology University Hospital of North Norway and UiT The Arctic University of Norway Tromsø, Norway Department of Anesthesiology Sørlandet sykehus and UiT The Arctic University of Norway Tromsø, Norway Department of Anesthesiology University Hospital of North Norway and UiT The Arctic University of Norway Tromsø, Norway.

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http://dx.doi.org/10.1097/AAP.0000000000000722DOI Listing
February 2018

Effects of implementing a clinical pharmacist service in a mixed Norwegian ICU.

Eur J Hosp Pharm 2016 Jul 23;23(4):197-202. Epub 2015 Nov 23.

Critical Care Unit, University Hospital of North Norway and Institute of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.

Objectives: An unacceptably high proportion of patients admitted to intensive care units (ICUs) develop drug-related problems (DRPs). DRPs might cause harm and increase costs and length of stay. The implementation of a clinical pharmacist service has been shown to detect a high number of DRPs and contributes effectively to solving these across different healthcare systems. However, this has not been prospectively studied in a mixed tertiary Norwegian ICU.

Methods: During a 12-month period from October 2012, a clinical pharmacist was dedicated to review medications 3 h daily (Monday to Friday). DRPs were reported at the ICU conference and included advice by the pharmacist for each case. All DRPs were categorised and the clinical impact was documented for later analysis. Drug-related questions from the staff were categorised and answered.

Results: 363 of 549 patients admitted to the ICU received medication reviews. 641 DRPs were detected in 194 of these patients (mean 1.8 DRPs per patient, range 0-25). Too high a dose, significant drug interactions and unnecessary or inappropriate drugs were among the most frequently detected DRPs. 87% of advice given by the pharmacist was accepted or taken into consideration. Typical questions from the nursing staff were related to drug preparation, generic equivalents and drug administration. Questions from doctors were most frequently related to drug dosage, efficiency and adverse effects.

Conclusions: The addition of a dedicated clinical pharmacist to the ICU team improves the quality and safety of medication in a mixed Norwegian ICU.
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http://dx.doi.org/10.1136/ejhpharm-2015-000751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451479PMC
July 2016

Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy.

Metab Brain Dis 2016 12 23;31(6):1269-1273. Epub 2016 Jun 23.

Department of Anesthesiology, Anesthesia and Critical Care Research Group, University Hospital of North Norway and UiT-The Arctic University of Norway, Tromsø, Norway.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder caused by hepatic dysfunction. Numerous studies dictate that ammonia plays an important role in the pathogenesis of HE, and hyperammonemia can lead to alterations in amino acid homeostasis. Glutamine and glycine are both ammoniagenic amino acids that are increased in liver failure. Modulating the levels of glutamine and glycine has shown to reduce ammonia concentration in hyperammonemia. Ornithine Phenylacetate (OP) has consistently been shown to reduce arterial ammonia levels in liver failure by modulating glutamine levels. In addition to this, OP has also been found to modulate glycine concentration providing an additional ammonia removing effect. Data support that glycine also serves an important role in N-methyl D-aspartate (NMDA) receptor mediated neurotransmission in HE. This potential important role for glycine in the pathogenesis of HE merits further investigations.
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http://dx.doi.org/10.1007/s11011-016-9858-2DOI Listing
December 2016

Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure.

Ann Hepatol 2016 May-Jun;15(3):427-35

Department of Digestive Surgery, University Hospital Northern Norway.

Background: Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake.

Results: As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups.

Conclusion: Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.
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http://dx.doi.org/10.5604/16652681.1198821DOI Listing
January 2017

A new non-craniotomy model of subarachnoid hemorrhage in the pig: a pilot study.

Lab Anim 2016 Oct 6;50(5):379-89. Epub 2015 Dec 6.

Department of Anesthesiology, University Hospital of North Norway, Tromsø, Norway Institute of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.

Subarachnoid hemorrhage (SAH) from rupture of an intracranial arterial aneurysm is a devastating disease affecting young people, with serious lifelong disability or death as a frequent outcome. Large animal models that exhibit all the cardinal clinical features of human SAH are highly warranted. In this pilot study we aimed to develop a non-craniotomy model of SAH in pigs suitable for acute intervention studies. Six Norwegian Landrace pigs received advanced invasive hemodynamic and intracranial pressure (ICP) monitoring. The subarachnoid space, confirmed by a clear cerebrospinal fluid (CSF) tap, was reached by advancing a needle below the ocular bulb through the superior orbital fissure and into the interpeduncular cistern. SAH was induced by injecting 15 mL of autologous arterial blood into the subarachnoid space. Macro- and microanatomical investigations of the pig brain showed a typical blood distribution consistent with human aneurysmal SAH (aSAH) autopsy data. Immediately after SAH induction ICP sharply increased with a concomitant reduction in cerebral perfusion pressure (CPP). ICP returned to near normal values after 30 min, but increased subsequently during the experimental period. Signs of brain edema were confirmed by light microscopy post-mortem. None of the animals died during the experimental period. This new transorbital injection model of SAH in the pig mimics human aSAH and may be suitable for acute intervention studies. However, the model is technically challenging and needs further validation.
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http://dx.doi.org/10.1177/0023677215619806DOI Listing
October 2016

Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation (NONSEDA Trial): study protocol for a randomised controlled trial.

Trials 2014 Dec 20;15:499. Epub 2014 Dec 20.

Department Anaesthesiology and Intensive Care, Odense University Hospital, Sdr, Boulevard 29, DK - 5000 Odense C, Denmark.

Background: Through many years, the standard care has been to use continuous sedation of critically ill patients during mechanical ventilation. However, preliminary randomised clinical trials indicate that it is beneficial to reduce the sedation level. No randomised trial has been conducted comparing sedation with no sedation, a priori powered to have all-cause mortality as primary outcome.The objective is to assess the benefits and harms of non-sedation versus sedation with a daily wake-up trial in critically ill patients.

Methods/design: The non-sedation (NONSEDA) trial is an investigator-initiated, randomised, clinical, parallel-group, multinational trial designed to include 700 patients from at least six ICUs in Denmark, Norway and Sweden.Inclusion criteria are mechanically ventilated patients with expected duration of mechanical ventilation >24 hours.Exclusion criteria are non-intubated patients, patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO2/FiO2 < 9 where sedation might be necessary to ensure sufficient oxygenation or place the patient in prone position.Experimental intervention is non-sedation supplemented with pain management during mechanical ventilation.Control intervention is sedation with a daily wake-up trial.The primary outcome will be all cause mortality at 90 days after randomization. Secondary outcomes will be: days until death throughout the total observation period; coma- and delirium-free days; highest RIFLE score; days until discharge from the intensive care unit (within 28 days); days until the participant is without mechanical ventilation (within 28 days); and proportion of patients with a major cardiovascular outcome. Explorative outcomes will be: all cause mortality at 28 days after randomisation; days until discharge from the intensive care unit; days until the participant is without mechanical ventilation; days until discharge from the hospital; organ failure.Trial size: we will include 700 participants (2 × 350) in order to detect or reject 25% relative risk reduction in mortality with a type I error risk of 5% and a type II error risk of 20% (power at 80%).

Discussion: The trial investigates potential benefits of non-sedation. This might have large impact on the future treatment of mechanically ventilated critically ill patients.

Trial Register: ClinicalTrials.gov NCT0196768, 09.01.2014.
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http://dx.doi.org/10.1186/1745-6215-15-499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307177PMC
December 2014

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.

Am J Physiol Gastrointest Liver Physiol 2014 Nov 25;307(10):G1024-31. Epub 2014 Sep 25.

Department of Anesthesiology, University Hospital of North Norway and UiT The Arctic University of Norway, Tromsø, Norway;

Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: (1) sham operated + vehicle, (2) ALF + vehicle, and (3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 μmol/l; ALF + OP: 27,625 ± 2,670 μmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.
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http://dx.doi.org/10.1152/ajpgi.00244.2014DOI Listing
November 2014

Guidelines for perioperative care after radical cystectomy for bladder cancer: Enhanced Recovery After Surgery (ERAS(®)) society recommendations.

Clin Nutr 2013 Dec 17;32(6):879-87. Epub 2013 Oct 17.

Dept of Urology, University Hospital of Lausanne, Switzerland.

Purpose: Enhanced recovery after surgery (ERAS) pathways have significantly reduced complications and length of hospital stay after colorectal procedures. This multimodal concept could probably be partially applied to major urological surgery.

Objectives: The primary objective was to systematically assess the evidence of ERAS single items and protocols applied to cystectomy patients. The secondary objective was to address a grade of recommendation to each item, based on the evidence and, if lacking, on consensus opinion from our ERAS Society working group.

Evidence Acquisition: A systematic literature review was performed on ERAS for cystectomy by searching EMBASE and Medline. Relevant articles were selected and quality-assessed by two independent reviewers using the GRADE approach. If no study specific to cystectomy was available for any of the 22 given items, the authors evaluated whether colorectal guidelines could be extrapolated.

Evidence Synthesis: Overall, 804 articles were retrieved from electronic databases. Fifteen articles were included in the present systematic review and 7 of 22 ERAS items were studied. Bowel preparation did not improve outcomes. Early nasogastric tube removal reduced morbidity, bowel recovery time and length of hospital stay. Doppler-guided fluid administration allowed for reduced morbidity. A quicker bowel recovery was observed with a multimodal prevention of ileus, including gum chewing, prevention of PONV and minimally invasive surgery.

Conclusions: ERAS has not yet been widely implemented in urology and evidence for individual interventions is limited or unavailable. The experience in other surgical disciplines encourages the development of an ERAS protocol for cystectomy.
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http://dx.doi.org/10.1016/j.clnu.2013.09.014DOI Listing
December 2013

Enhanced recovery after surgery: are we ready, and can we afford not to implement these pathways for patients undergoing radical cystectomy?

Eur Urol 2014 Feb 22;65(2):263-6. Epub 2013 Oct 22.

Academic Urology Unit, University of Sheffield, Sheffield, UK.

Enhanced recovery after surgery (ERAS) for radical cystectomy seems logical, but our study has shown a paucity in the level of clinical evidence. As part of the ERAS Society, we welcome global collaboration to collect evidence that will improve patient outcomes.
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http://dx.doi.org/10.1016/j.eururo.2013.10.011DOI Listing
February 2014

Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure.

Am J Physiol Gastrointest Liver Physiol 2012 Aug 15;303(3):G435-41. Epub 2012 Mar 15.

UCL Institute of Hepatology, Royal Free Campus, University College London, London, UK.

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.
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http://dx.doi.org/10.1152/ajpgi.00268.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774247PMC
August 2012

[Intensive care of patients with acute liver failure].

Tidsskr Nor Laegeforen 2010 Aug;130(16):1609-13

Critical Care Unit, University College London Hospitals NHS Foundation Trust og Institutt for klinisk medisin, Universitetet i Tromsø, Norway.

Background: Acute liver failure and acute decompensated chronic liver failure are two diseases that demand extensive knowledge of etiology and triggering factors, pathophysiology, diagnosis, prognosis and recommended guidelines for treatment. The article defines the diseases, discusses etiological factors, treatment strategies, indications for referral to the transplantation unit at Rikshospitalet and prognostic factors of importance.

Material And Methods: The basis for this article is literature identified through a non-systematic search in PubMed and the authors' clinical experience and experimental research within the field.

Results: In the Western world paracetamol poisoning and toxic reactions to other drugs are the most common triggering factors for acute liver poisoning in adults. Patients can quickly develop multi organ failure requiring advanced intensive care. The most common complications are hepatic encephalopathy, acute renal failure and coagulation disturbances. Acute decompensated chronic liver failure strikes patients with known liver disease and is most often triggered by inflammation, infection, gastrointestinal bleeding, drugs, traumas or disturbances in acid/base/electrolyte balance. Early diagnosing of triggering factors and intensive medical supportive treatment is especially important. Acute renal failure indicates a very bad prognosis.

Interpretation: Patients diagnosed with acute liver failure or acute decompensated chronic liver failure remain a clinical challenge. Optimal treatment requires extensive knowledge of pathophysiological mechanisms and treatment strategies.
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http://dx.doi.org/10.4045/tidsskr.08.0345DOI Listing
August 2010

Neuropathological changes in the brain of pigs with acute liver failure.

Scand J Gastroenterol 2010 Aug;45(7-8):935-43

Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Sykehusveien, Tromsø, Norway.

Objective: Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF.

Materials And Methods: Sixteen female Norwegian Landrace pigs weighing 27-35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy.

Results: Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal.

Conclusions: Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.
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http://dx.doi.org/10.3109/00365521003675047DOI Listing
August 2010

Porcine liver sinusoidal endothelial cells contribute significantly to intrahepatic ammonia metabolism.

Hepatology 2009 Sep;50(3):900-8

Department of Digestive Surgery, University Hospital Northern Norway and Institute of Clinical Medicine, Norway.

Unlabelled: Ammonia metabolism in the liver has been largely credited to hepatocytes (HCs). We have shown that liver nonparenchymal cells that include liver sinusoidal endothelial cells (LSECs) produce ammonia. To address the limited knowledge regarding a role for LSECs in ammonia metabolism, we investigated the ammonia metabolism of isolated LSECs and HCs under three different conditions: (1) bioreactors containing LSECs (LSEC-bioreactors), (2) bioreactors containing HCs (HC-bioreactors), and (3) separate bioreactors containing LSECs and HCs connected in sequence (Seq-bioreactors). Our results showed that LSEC-bioreactors released six-fold more ammonia (22.2 nM/hour/10(6) cells) into the growth media than HC-bioreactors (3.3 nM/hour/10(6) cells) and Seq-bioreactors (3.8 nM/hour/10(6) cells). The glutamate released by LSEC-bioreactors (32.0 nM/hour/10(6) cells) was over four-fold larger than that released by HC-bioreactors and Seq-bioreactors (<7 nM/hour/10(6) cells). LSEC-bioreactors and HC-bioreactors consumed large amounts of glutamine (>25 nM/hour/10(6) cells). Glutaminase is known for catalyzing glutamine into glutamate and ammonia. To determine if this mechanism may be responsible for the large levels of glutamate and ammonia found in LSEC-bioreactors, immunolabeling of glutaminase and messenger RNA expression were tested. Our results demonstrated that glutaminase was present with colocalization of an LSEC-specific functional probe in lysosomes of LSECs. Furthermore, using a nucleotide sequence specific for kidney-type glutaminase, reverse-transcription polymerase chain reaction revealed that this isoform of glutaminase was expressed in porcine LSECs.

Conclusion: LSECs released large amounts of ammonia, perhaps due to the presence of glutaminase in lysosomes. The ammonia and glutamate released by LSECs in Seq-bioreactors were used by hepatocytes, suggesting an intrahepatic collaboration between these two cell types.
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http://dx.doi.org/10.1002/hep.23076DOI Listing
September 2009

L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure.

Hepatology 2009 Jul;50(1):165-74

Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Norway.

Unlabelled: Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001).

Conclusion: L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.
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http://dx.doi.org/10.1002/hep.22917DOI Listing
July 2009

L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats.

Hepatology 2009 Jul;50(1):155-64

Liver Failure Group, Institute of Hepatology, University College London, UK.

Unlabelled: Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups.

Conclusion: The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats.
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http://dx.doi.org/10.1002/hep.22897DOI Listing
July 2009

Adenosine instead of supranormal potassium in cardioplegic solution preserves endothelium-derived hyperpolarization factor-dependent vasodilation.

Eur J Cardiothorac Surg 2008 Jan 26;33(1):18-24. Epub 2007 Nov 26.

Department of Cardiothoracic and Vascular Surgery, University Hospital of North Norway and Institute of Clinical Medicine, University of Tromsø, Norway.

Objective: We have recently shown that adenosine instead of supranormal potassium in cold crystalloid cardioplegia improves cardioprotection. Studies indicate that hyperkalemia has unfavorable effects on vascular endothelial function. Three pathways have been identified as major vasodilatory pathways: the nitric oxide (NO) pathway, the cyclooxygenase (COX) pathway, and the endothelium-derived hyperpolarization (EDHF) pathway, where the EDHF pathway, in particular, seems susceptible to hyperkalemia. We hypothesized that adenosine cardioplegia improves postcardioplegic endothelial function.

Methods: Sixteen pigs were randomized to receive either cold (6 degrees C) hyperkalemic cardioplegia (n=8) or cardioplegia where hyperkalemia was substituted with 1.2 mM adenosine (n=8). After 1h of cold ischemic arrest, coronary blood flow was monitored for the following 2h. The LAD artery was then explanted, and cylindrical rings were mounted for isometric tension recordings in organ chambers. Vessels were preconstricted with U46610 (Thromboxane A(2) analog) and then bradykinin-mediated relaxation was investigated. To differentiate between the vasodilatory pathways the relaxation was assessed in the absence and presence of inhibitors of the COX (indomethacin), NO (L-NAME+carboxy-PTIO), and EDHF (apamin+charybdotoxin) pathways.

Results: Invivo: The adenosine group had, as distinct from the hyperkalemic group, a significantly increased coronary blood flow index 1h after cross-clamp release (from (ml/min/100 g, mean+/-SD) 50.9+/-13.9 to 72.8+/-21.9, p=0.010). The difference was, however, not statistically significant between groups. Invitro: Maximal relaxation without blockers was 27.4+/-10.1% of maximal tension in the adenosine group and 22.2+/-7.5% in the hyperkalemic group. To investigate EDHF-dependent vasodilation the vessel rings were simultaneously treated with indomethacin, L-NAME, and carboxy-PTIO. Maximal relaxation in the hyperkalemic group was then reduced to 47.4+/-17.4% of maximal tension, which was a significant reduction compared to the adenosine group with a maximal relaxation of 20.6+/-8.7% (p=0.028).

Conclusion: Adenosine instead of supranormal potassium in cold crystalloid cardioplegia increases postcardioplegic myocardial blood flow and preserves EDHF-dependent vasodilation.
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http://dx.doi.org/10.1016/j.ejcts.2007.10.013DOI Listing
January 2008

Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure.

Hepatology 2007 Dec;46(6):1883-92

Department of Cellular Neuroscience, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.

Unlabelled: We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups.

Conclusion: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia requires further investigation.
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http://dx.doi.org/10.1002/hep.21877DOI Listing
December 2007

[Disturbances in ammonia metabolism in hepatic failure].

Tidsskr Nor Laegeforen 2007 May;127(11):1514-7

Anestesiavdelingen, Universitetssykehuset Nord-Norge, 9038 Tromsø.

Background: Serious hepatocellular dysfunction leads to disturbances in the ammonia metabolism and increases the risk for development of hepatic encephalopathy. The present paper describes pathophysiological patterns for development of hyperammonemia in patients with liver diseases and discusses the rationale for novel ammonia lowering strategies.

Material And Methods: The present paper is based on experimental research performed in a porcine model of acute liver failure and a literature search in Pubmed.

Results: Under normal conditions the intestines and the kidneys are the main ammonia producing organs, whereas the liver and skeletal muscles are the major ammonia consuming organs. Small and large intestines contribute equally to the release of ammonia. Development of intra- and extra hepatic portasystemic shunts, impaired urea synthesis, and reduced hepatic perivenous glutamine synthesis capacity, contribute to the development of hyperammonaemia with hepatic failure. The kidneys are quantitatively as important as the portal drained viscera in ammonia production, but can adapt to hyperammonaemia by reducing the production of ammonia to the blood and at the same time increase its excretion in urine. Furthermore, the lungs are metabolically active, but their role in hyperammonaemia remains unsettled. Skeletal muscle contributes to reducing the ammonia level in the body through synthesis of glutamine from equimolar quantities of glutamate and ammonia.

Interpretation: Current therapeutic recommendations on protein restriction, use of antibiotics and lactulosis to patients with hepatic failure are not sufficiently documented. There is a need for development of novel ammonia lowering strategies.
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May 2007

Significant contribution of liver nonparenchymal cells to metabolism of ammonia and lactate and cocultivation augments the functions of a bioartificial liver.

Am J Physiol Gastrointest Liver Physiol 2007 Jul 15;293(1):G75-83. Epub 2007 Mar 15.

Department of Digestive Surgery, University Hospital of Northern Norway, 9038 Tromsø, Norway.

A bioartificial liver (BAL) will bridge patients with acute liver failure (ALF) to either spontaneous regeneration or liver transplantation. The nitrogen metabolism is important in ALF, and the metabolism of nonparenchymal liver cells (NPCs) is poorly understood. The scope of this study was to investigate whether cocultivation of hepatocytes with NPCs would augment the functions of a BAL (HN-BAL) compared with a BAL equipped with only hepatocytes (H-BAL). In addition, NPCs were similarly cultivated alone. The cells were cultivated for 8 days in simulated microgravity with serum-free growth medium. With NPCs, initial ammonia and lactate production were fivefold and over twofold higher compared with later time periods despite sufficient oxygen supply. Initial lactate production and glutamine consumption were threefold higher in HN-BAL than in H-BAL. With NPCs, initial glutamine consumption was two- to threefold higher compared with later time periods, whereas initial ornithine production and arginine consumption were over four- and eightfold higher compared with later time periods. In NPCs, the conversion of glutamine to glutamate and ammonia can be explained by the presence of glutaminase, as revealed by PCR analysis. Drug metabolism and clearance of aggregated gamma globulin, probes administered to test functions of hepatocytes and NPCs, respectively, were higher in HN-BAL than in H-BAL. In conclusion, NPCs produce ammonia by hydrolysis of amino acids and may contribute to the pathogenesis of ALF. High amounts of lactate are produced by NPCs under nonhypoxic conditions. Cocultivation augments differentiated functions such as drug metabolism and clearance of aggregated gamma-globulin.
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http://dx.doi.org/10.1152/ajpgi.00245.2006DOI Listing
July 2007

Endothelium-derived hyperpolarization factor (EDHF) is up-regulated in a pig model of acute liver failure.

Scand J Gastroenterol 2007 Mar;42(3):356-65

Department of Anesthesiology and Intensive Care, University of Tromsø, University Hospital Northern Norway, Tromsø, Norway.

Background: Acute liver failure (ALF) is hemodynamically characterized by hyperdynamic circulation, but the pathophysiologic mechanisms underlying these disturbances are not known. The purposes of the present experiments were: to study systemic and peripheral hemodynamics in vivo, to measure changes in vascular reactivity in vitro, and to determine the role of endothelium-dependent vasodilator pathways in a well-validated porcine model of ALF.

Methods: Landrace pigs (24-29 kg) were allocated to sham operation (n=8) or ALF induced by hepatic devascularization (n=9). Systemic and regional hemodynamics were monitored. Femoral artery rings were prepared for isometric tension recordings 8 h after ALF induction. Contractile responses to phenylephrine were assessed in ring segments of endothelium-intact femoral arteries in the absence or presence of inhibitors of endothelium-derived hyperpolarizing factor, nitric oxide synthase, cyclooxygenase and heme oxygenase pathways.

Results: Pigs with ALF developed a hyperdynamic circulation. Cardiac index increased (PGT<0.001), while mean arterial pressure (PGT=0.012) and systemic vascular resistance decreased (PGT<0.001) in this group. Femoral artery blood flow decreased in controls, while it remained unchanged in ALF (PGT=0.010). Accordingly, vascular resistance across the hind leg was significantly decreased (PGT<0.001) in ALF. The combination of Ca2+-activated potassium channel inhibitors charybdotoxin and apamin, which block the release of endothelium-derived hyperpolarizing factor, increased the contraction force (ANOVA, PGT=0.05) and Emax (P=0.01) to phenylephrine in ALF. In contrast, inhibitors of nitric oxide synthase, cyclooxygenase and heme oxygenase pathways did not increase isometric contraction force.

Conclusions: Endothelium dependent hyperpolarization of vascular smooth muscle contributes to the development of hyperdynamic circulation in ALF.
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http://dx.doi.org/10.1080/00365520600930636DOI Listing
March 2007

Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis.

Scand J Gastroenterol 2006 Nov;41(11):1350-60

Department of Digestive Surgery, University Hospital Northern Norway, Tromsø, Norway.

Objective: Acute liver failure (ALF) is haemodynamically characterized by a hyperdynamic circulation. The aims of this study were to investigate the systemic and regional haemodynamics in ALF, to measure changes in nitric oxide metabolites (NOx) and to evaluate whether these haemodynamic disturbances could be attenuated with albumin dialysis.

Material And Methods: Norwegian Landrace pigs (23-30 kg) were randomly allocated to groups as controls (sham-operation, n = 8), ALF (hepatic devascularization, n = 8) and ALF + albumin dialysis (n = 8). Albumin dialysis was started 2 h after ALF induction and continued for 4 h. Systemic and regional haemodynamics were monitored. Creatinine clearance, nitrite/nitrate and catecholamines were measured. A repeated measures ANOVA was used to analyse the data.

Results: In the ALF group, the cardiac index increased (PGT < 0.0001), while mean arterial pressure (PG = 0.02) and systemic vascular resistance decreased (PGT < 0.0001). Renal resistance (PG = 0.04) and hind-leg resistance (PGT = 0.003) decreased in ALF. There was no difference in jejunal blood flow between the groups. ALF pigs developed renal dysfunction with increased serum creatinine (PGT = 0.002) and decreased creatinine clearance (P = 0.02). Catecholamines were significantly higher in ALF, but NOx levels were not different. Albumin dialysis did not attenuate these haemodynamic or renal disturbances.

Conclusions: The haemodynamic disturbances during the early phase of ALF are characterized by progressive systemic vasodilatation with no associated changes in metabolites of NO. Renal vascular resistance decreased and renal dysfunction developed independently of changes in renal blood flow. After 4 h of albumin dialysis there was no attenuation of the haemodynamic or renal disturbances.
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http://dx.doi.org/10.1080/00365520600714527DOI Listing
November 2006
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