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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.

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.) Funding Agencies|Danish Medical Research CouncilDanish Medical Research Council; Danielsens Foundation; Scandinavian Society of Anesthesiology and Intensive Care Medicine

BACKGROUND The purpose of the study was to document the consumption of opioids in two surgical departments at the University Hospital of North Norway, Tromso, 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.

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.

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.

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.

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 (MEV50 ) and to estimate the MEV95, 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. MEV50 was determined by the staircase up-and-down method. Logistic regression and probit transformation were applied to estimate MEV95 . RESULTS MEV50 and MEV95 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 MEV95 of ropivacaine 7.5 mg/mL was estimated to 9.0 mL.

This is the peer reviewed version of the following article: Musso, D., Flohr-Madsen, S., Meknas, K., Wilsgaard, T., Ytrebø, L.M. & Klaastad, Ø. (2017). A novel combination of peripheral nerve blocks for arthroscopic shoulder surgery. Acta Anaesthesiologica Scandinavica, 61(9), 1192-1202, which has been published in final form at https://doi.org/10.1111/aas.12948. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Background - Interscalene brachial plexus block is currently the gold standard for intra‐ and post‐operative pain management for patients undergoing arthroscopic shoulder surgery. However, it is associated with block related complications, of which effect on the phrenic nerve have been of most interest. Side effects caused by general anesthesia, when this is required, are also a concern. We hypothesized that the combination of superficial cervical plexus block, suprascapular nerve block, and infraclavicular brachial plexus block would provide a good alternative to interscalene block and general anesthesia. Methods - Twenty adult patients scheduled for arthroscopic shoulder surgery received a combination of superficial cervical plexus block (5 ml ropivacaine 0.5%), suprascapular nerve block (4 ml ropivacaine 0.5%), and lateral sagittal infraclavicular block (31 ml ropivacaine 0.75%). The primary aim was to find the proportion of patients who could be operated under light propofol sedation, without the need for opioids or artificial airway. Secondary aims were patients' satisfaction and surgeons' judgment of the operating conditions. Results - Nineteen of twenty patients (95% CI: 85–100) underwent arthroscopic shoulder surgery with light propofol sedation, but without opioids or artificial airway. The excluded patient was not comfortable in the beach chair position and therefore received general anesthesia. All patients were satisfied with the treatment on follow‐up interviews. The surgeons rated the operating conditions as good for all patients. Conclusion - The novel combination of a superficial cervical plexus block, a suprascapular nerve block, and an infraclavicular nerve block provides an alternative anesthetic modality for arthroscopic shoulder surgery.

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.

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.

Background Ultrasound guidance has been shown to reduce the minimum effective volume (MEV) of local anaesthetics for several peripheral nerve blocks. Although the lateral sagittal infraclavicular block (LSIB) is a well-established anaesthesia method, MEV for this technique has not been established. Our aim with this study was to determine the MEV using ropivacaine 7.5 mg/ml for the LSIB method. Methods Twenty-five adult American Society of Anesthesiologists physical status I-II patients scheduled for hand surgery received an ultrasound-guided LSIB with ropivacaine 7.5 mg/ml. A successful block was defined as anaesthesia or analgesia for all five sensory nerves distal to the elbow, 30 min after local anaesthetic injection. The MEV for a successful block in 50% of the patients was determined by using the staircase up-and-down method introduced by Dixon and Massey. Logistic regression and probit transformation were applied to estimate the MEV for a successful block in 95% of the patients. Results The patients received ropivacaine 7.5 mg/ml volumes in the range of 12.5–30 ml. The MEVs in 50% and 95% of the patients were 19 ml [95% confidence interval (CI), 14–27] and 31 ml (95% CI, 18–45), respectively. Conclusions For surgery distal to the elbow, the MEV in 95% of patients for an ultrasound-guided LSIB with ropivacaine 7.5 mg/ml was estimated to be 31 ml (95% CI, 18–45 ml). Further studies should determine the factors that influence the volume of local anaesthetic required for a successful infraclavicular block.

To the Editor:We would like to comment on a recently published and interesting letter from Dr Bansal et al.1 They claim that “blockade at the level of the cords tends to result in inconsistent coverage of the axillary nerve.” We disagree with this statement, based on our clinical experience and stud

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 ornithinederived 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 μmol/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 μmol/L in ALF + OP-treated pigs versus 0.5 ± 0.04 μmol/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. (HEPATOLOGY 2009;50:165–174.)

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. (HEPATOLOGY 2009.)

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: thenitricoxide(NO)pathway,thecyclooxygenase (COX)pathway, andtheendothelium-derivedhyperpolarization(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 8C) hyperkalemic cardioplegia (n =8 ) or cardioplegia where hyperkalemia was substituted with 1.2 mM adenosine (n = 8). After 1 h of cold ischemic arrest, coronary blood flow was monitored for the following 2 h. The LAD artery was then explanted, and cylindrical rings were mounted for isometric tension recordings in organ chambers. Vessels were preconstricted with U46610 (Thromboxane A2 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: In vivo: The adenosine group had, as distinct from the hyperkalemic group, a significantly increased coronary blood flow index 1 h 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. In vitro: 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 EDHFdependent 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. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

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 γ-globulin.

Цели: Неприемливо висок процент пациенти, приети в отделения по интензивно лечение (ОИЛ), развиват свързани с приема на лекарства проблеми (СЛП). СЛП могат да причинят увреждания и да увеличат разноските и продължителността на престоя. Доказано е, че въвеждането на клинично фармацевтично обслужване разкрива голям брой СЛП и ефективно допринася за разрешаването на същите в различни системи на здравеопазване. Обаче това не е проучено в перспектива в смесени третични норвежки ОИЛ. Методи: През 12-месечен период от м. октомври 2012 г. насетне един клиничен фармацевт се посвети на прегледи на лекарства 3 часа на ден (от понеделник до петък). СЛП бяха докладвани на срещата на ОИЛ и включваха консултация от страна на фармацевта за всеки отделен случай. Всички СЛП бяха категоризирани и клиничното въздействие бе документирано за по-нататъшен анализ. Бяха категоризирани свързаните с лекарства въпроси от страна на персонала и бе даден отговор на същите. Резултати: 363 от 549 приети в ОИЛ пациенти получиха рецензии за лекарствата. Бяха установени 641 СЛП у 194 от тези пациенти (средно по 1,8 СЛП на пациент, диапазон 0–25). Сред най-често установените СЛП бяха твърде високи дози, значими взаимодействия на лекарства и ненужни или неподходящи лекарства. 87% от консултациите, дадени от страна на фармацевта, бяха приети или взети предвид. Типичните въпроси от страна на медицинските сестри бяха свързани с приготвянето на лекарства, генерични еквиваленти и прием на лекарства. Въпросите от страна на лекарите най-често бяха свързани с дозировката на лекарствата, ефикасността и нежеланите ефекти. Изводи: Добавянето на специален клиничен фармацевт към екипа на ОИЛ подобрява качеството и безопасността на лекарствата в смесеното норвежко ОИЛ.

Background: Increased intracranial pressure (ICP) worsens the outcome of acute liver failure (ALF). This study investigates the underlying pathophysiological mechanisms and evaluates the therapeutic effect of albumin dialysis in ALF with use of the Molecular Adsorbents Recirculating System without hemofiltration/dialysis (modified, M-MARS). Methods: Pigs were randomized into three groups: sham, ALF, and ALF + M-MARS. ALF was induced by hepatic devascularization (time = 0). M-MARS began at time = 2 and ended with the experiment at time = 6. ICP, arterial ammonia, brain water, cerebral blood flow (CBF), and plasma inflammatory markers were measured. Results: ICP and arterial ammonia increased significantly over 6 hrs in the ALF group, in comparison with the sham group. M-MARS attenuated (did not normalize) the increased ICP in the ALF group, whereas arterial ammonia was unaltered by M-MARS. Brain water in the frontal cortex (grey matter) and in the subcortical white matter at 6 hrs was significantly higher in the ALF group than in the sham group. M-MARS prevented a rise in water content, but only in white matter. CBF and inflammatory mediators remained unchanged in all groups. Conclusion: The initial development of cerebral edema and increased ICP occurs independently of CBF changes in this non-inflammatory model of ALF. Factor(s) other than or in addition to hyperammonemia are important, however, and may be more amenable to alteration by albumin dialysis.

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

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.

Objective: Intravenous administration of N-acetylcysteine beyond 15 hrs reduces mortality rates in patients suffering from paracetamol-induced fulminant hepatic failure, although the mechanism of the therapeutic benefit remains unclear. We hypothesized increased survival to be caused by improved hemodynamic performance. The main objective for the study was to explore the effect of N-acetylcysteine on hemodynamics, oxygen transport, and regional blood flow in pigs with fulminant hepatic failure. Design: Prospective, randomized, controlled trial. Setting: Surgical research laboratory in a university hospital. Subjects: Female Norwegian Landrace pigs. Interventions: Fulminant hepatic failure was induced by a total liver devascularization procedure. Five hours later, the pigs were allocated to N-acetylcysteine treatment (150 mg.kg -1 in 100 mL of 0.9% saline over 15 mins, followed by 50 mg.kg -1 in 500 mL of 0.9% saline over a period of 4 hrs) or placebo. Measurements and Main ResultsMean arterial pressure stabilized in the N-acetylcysteine group and increased slightly during the last 2 hrs (p GT =.009). Thus, mean arterial pressure was significantly higher compared with placebo after 3 hrs (p =.01). Cerebral perfusion pressure was significantly higher during the last 2 hrs in the N-acetylcysteine group (p GT =.033). Common carotid artery flow also increased and was maintained at a higher level compared with placebo (p G =.027). Systemic vascular resistance index initially decreased but then gradually increased (p GT

Warm continuous blood cardioplegia (WCBCP) has been recommended during prolonged cardiac arrest to minimize functional deterioration. Myocardial metabolism and efficiency after this cardioplegic modality are not well described.Substrate oxidation, blood flow, and myocardial function were measured before, during, and after 3 hours of WCBCP in 7 pigs.Free fatty acid and glucose oxidation decreased by 60% +/- 3.8% and 94% +/- 1.2%, respectively, during cardioplegia (both p0.05) and increased to 62% +/- 28% and 122% +/- 62% of baseline during the early recovery phase (p0.05 for glucose). One hour after WCBCP oxidation rates were similar to baseline. The transient postcardioplegic increase in substrate oxidation was associated with a 43% +/- 23% elevation of oxygen consumption (MVO2) compared with baseline and a 62% +/- 18% increase in myocardial blood flow. Cardiac output and mean arterial pressure did not change significantly after WCBCP, although myocardial function (stroke work, left ventricular end-systolic pressure, end-diastolic pressure, contractility, and efficiency) was depressed (p0.05). End-diastolic pressure and contractility improved from early to late phase of recovery, whereas the other indicators of ventricular function remained depressed.Myocardial substrate oxidation was preserved after 3 hours of WCBCP, although ventricular function was moderately impaired. Thus, WCBCP with a seemingly normal substrate and oxygen supply was associated with a reduced cardiac efficiency.

BACKGROUND: Acute hepatic failure (AHF) may cause encephalopathy. Intracranial pressure (ICP) is frequently monitored to guide therapy, but such monitoring may cause intracerebral haemorrhagic complications. We hypothesize that determination of serum levels of S-100beta, a protein synthesized in astroglial cells, will provide useful clinical information on the presence and extent of intracranial hypertension in AHF. METHODS: Continuous intraparenchymatous ICP monitoring and serial S-100beta measurements in serum were performed in 11 Norwegian Landrace pigs with surgically induced AHF and in 4 sham-operated controls. RESULTS: ICP increased hour by hour in the devascularized pigs in parallel with increased serum levels of protein S-100beta. In the sham-operated controls S-100beta was not detectable at any time point. CONCLUSIONS: Serum levels of S-100beta are increased early in experimental AHF. Determination of protein S-100beta may provide useful information on the presence and extent of intracranial hypertension in AHF.

The aim of this study was to assess the influence of growth hormone (GH) in sepsis on the immune system represented by the circulating TNF-levels and the neutrophil leukocytes phagocytic capacity and respiratory burst, 22 piglets were randomized to 3 groups; pretreatment with GH (16 i.u.) before sepsis (n = 8), non-treated septic controls (n = 8), and non-septic controls (n = 6). Sepsis was induced by a standardized infusion of live E. coli. TNF was measured by a cytotoxic bioassay, while neutrophil function tests were carried out by flowcytometric assays. In brief, phagocytosis was evaluated by the neutrophils' ability to ingest FITC-labelled (fluorescein isothiocyanate) E. coli and intracellular release of oxygen metabolites was detected by the oxidation of 2',7'-dichlorofluorescin (DCFH) to the fluorescent 2',7'-dichlorofluorescein (DCF). Our data show a suppression of phagocytosis in the GH-treated group before sepsis; however, when challenged with Gram-negative bacteria, the phagocytic capacity was similar to that of the non-treated animals. The serum levels of TNF in the non-treated septic control group were twice the levels of those in the GH-treated group, 65.7 pg/ml (septic controls) vs 32.8 pg/ml (GH). Pretreatment with a single dose of GH few hours prior to sepsis does not seem to entail any further imbalance of the neutrophil function in sepsis. Lowering of the circulating TNF-levels is a presumptive favourable effect of GH in sepsis.

Acute liver failure (ALF) remains a devastating, life-threatening clinical problem that is defined as sudden hepatocellular necrosis in the absence of pre-existing liver disease. The onset and clinical course of ALF is unpredictable, and despite improved critical care management, mortality remains unacceptably high. Currently, to date, liver transplantation is the only curative treatment. However, owing to the rapid progression of ALF-induced multi-organ failure, and the persistent shortage of available organs, liver transplantation is very limited. Therefore, treatment options to bridge to liver transplantation or to

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.

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.

We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using die 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.

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.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.Pigs with ALF developed a hyperdynamic circulation. Cardiac index increased (PGT0.001), while mean arterial pressure (PGT=0.012) and systemic vascular resistance decreased (PGT0.001) 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 (PGT0.001) 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.Endothelium dependent hyperpolarization of vascular smooth muscle contributes to the development of hyperdynamic circulation in ALF.

BACKGROUND: Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. METHODS: Norwegian Landrace pigs weighing 27.1 +/- 0.5 kg (mean +/- sx (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10(-13) - 10(-5) mol/L) or norepinephrine (10(-13) - 10(-3) mol/L). RESULTS: Pigs suffering from ALF developed a hyperdynamic circulation with an increased cardiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 +/- 7 versus 56 +/- 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 +/- 8 versus 93 +/- 16 mN, P = 0.55). CONCLUSIONS: This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.

Objective: Although water-soluble drugs can be removed by haemofiltration/haemodialysis, morbidity and mortality from intoxication with protein-bound drugs remains high. The present study investigates whether albumin dialysis in the form of the Molecular Adsorbents Recirculating System (MARS) is effective in removal of protein-bound drugs. Design: Prospective animal study. Setting: Surgical research laboratory in a university hospital. Subjects: Seven female Norwegian Landrace pigs. Intervention: We studied whether midazolam (97% albuminbound) and fentanyl (85% alpha-1- acid glycoprotein-bound), administered as anaesthetics to pigs with induced acute liver failure, could be removed by MARS dialysis lasting for 4 h. Measurements: After 4 h of dialysis, total and free anaesthetic concentrations were measured in the blood and dialysate from different segments of the MARS circuit. Main results: Midazolam: total plasma concentrations fell by 47.1€2.1% (in 4 h) across the MARS filter (p

Pre-clinical assessment of bioartificial liver support systems requires a highly reproducible large animal model. The main objective of the present study was to develop a valid large animal model for assessing novel bioartificial liver support systems in fulminant hepatic failure.A complete liver devascularization procedure was performed in 10 female pigs weighing 25-38 kg. Five matched pigs were sham-operated and served as controls.Pigs with fulminant hepatic failure developed a hyperdynamic circulation, with increased cardiac index (P(GT).0001), decreased systemic vascular resistance index (P(GT).0001) and mean arterial pressure (P(GT) = .001). Furthermore, intracranial hypertension developed (P(GT).0001). with increased common carotid artery flow (P(GT).0001) and decreased common carotid resistance (P(G) = .003). Femoral artery flow increased (P = .036). while hindleg resistance (P.001) and renal artery resistance decreased (P = .019). Oxygen consumption (P(GT) = .050) and oxygen extraction ratio (P(GT) = .001) increased compared to controls. Arterial ammonia, venous aspartate aminotransferase and bilirubin levels increased (P(GT).0001, respectively). Abnormal haemostasis developed with significant loss of platelets (P(GT) = .010), decreasing fibrinogen levels (P(G) = .001) and increasing international normalized ratio (P(GT) = .012) and activated clotting time (PGT.001). Urine became hypo-osmotic (P.001. P(G) = .011), with decreased sodium levels (P = .08) and increased potassium levels (P(G) = .025).This study characterizes a reproducible large animal model for fulminant hepatic failure that seems suitable for the assessment of bioartificial liver support systems.

Background Protein S-100beta is an established biochemical marker for cerebral injury in serum. For the further interpretation and possible use of S-100beta serum measurements in acute hepatic encephalopathy, renal elimination of S-100beta was measured in pigs with elevated S-100beta levels due to hepatic encephalopathy. Methods Eighteen female Norwegian Landrace pigs were randomly allocated to either hepatic devascularization (n=13) or sham operation (n=5). Repeated samples from the common carotid artery, right renal vein, and urine were simultaneously drawn for S-100beta analysis, using the Sangtec100 Liamat immunoassay. Results In hepatic devascularized pigs, arterial serum levels of S-100beta increased from 0.96+/-0.04 microg/L (mean +/- SEM) at t = 0h to 1.74+/-0.11 microg/L (mean +/- SEM) at t = 5 h. Urinary excretion increased simultaneously from 8.48+/-3.66 ng/h (mean +/- SEM) to 20.4+/-9.54 ng/h (mean +/- SEM), while renal arterial-venous fluxes for both kidneys increased from 1022+/-404 ng/h (mean +/- SEM) to 2444+/-590 ng/h (mean +/- SEM). Conclusions Increased arterial S-100beta levels in pigs with acute hepatic encephalopathy are not a result of decreased renal elimination. The large difference between the renal arterial venous S-100beta concentrations and the urinary excretion of S-100beta indicate that renal metabolism is the major route of elimination.

In the “virtual work model,” left ventricular total mechanical energy (TME) is linearly related to myocardial oxygen consumption (MV˙o2). This relationship (MV˙o2-TME) is supposedly independent of inotropic stimulation, vascular loading, and heart rate variations. We reexamined the effect of inotropic stimulation (dopamine) on the metabolic to mechanical energy transfer in nine open-chest anesthetized pigs. Left ventricular mechanical energy was calculated using TME (mean ejection pressure × end-diastolic volume + stroke work), TMEW(end-diastolic volume reduced by unstressed ventricular volume), and the pressure-volume area (PVA). A highly linear relationship between MV˙o2and mechanical energy was found for all three indexes during control and dopamine runs ( r = 0.87–0.99). The slopes were unaltered by dopamine. y-Axis intercepts were (control vs. dopamine) as follows (in J ⋅ beat−1⋅ 100 mg−1; means ± SD): TME, 0.36 ± 0.12 vs. 0.61 ± 0.30 ( P< 0.02); TMEW, 0.43 ± 0.16 vs. 0.72 ± 0.32 ( P < 0.02); and PVA, 0.34 ± 0.13 vs. 0.60 ± 0.30 ( P < 0.02). We conclude that the virtual work model is dependent on inotropic stimulation and that new insight into myocardial chemomechanical coupling is not added by this concept.