Lars M. Ytrebø

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

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.

Liver sinusoidal endothelial cells represents an important blood clearance system in pigs

BackgroundNumerous studies in rats and a few other mammalian species, including man, have shown that the sinusoidal cells constitute an important part of liver function. In the pig, however, which is frequently used in studies on liver transplantation and liver failure models, our knowledge about the function of hepatic sinusoidal cells is scarce. We have explored the scavenger function of pig liver sinusoidal endothelial cells (LSEC), a cell type that in other mammals performs vital elimination of an array of waste macromolecules from the circulation.Results125I-macromolecules known to be cleared in the rat via the scavenger and mannose receptors were rapidly removed from the pig circulation, 50% of the injected dose being removed within the first 2–5 min following injection. Fluorescently labeled microbeads (2 μm in diameter) used to probe phagocytosis accumulated in Kupffer cells only, whereas fluorescently labeled soluble macromolecular ligands for the mannose and scavenger receptors were sequestered only by LSEC. Desmin-positive stellate cells accumulated no probes. Isolation of liver cells using collagenase perfusion through the portal vein, followed by various centrifugation protocols to separate the different liver cell populations yielded 280 × 107 (range 50–890 × 107) sinusoidal cells per liver (weight of liver 237.1 g (sd 43.6)). Use of specific anti-Kupffer cell- and anti-desmin antibodies, combined with endocytosis of fluorescently labeled macromolecular soluble ligands indicated that the LSEC fraction contained 62 × 107 (sd 12 × 107) purified LSEC. Cultured LSEC avidly endocytosed ligands for the mannose and scavenger receptors.ConclusionsWe show here for the first time that pig LSEC, similar to what has been found earlier in rat LSEC, represent an effective scavenger system for removal of macromolecular waste products from the circulation.

L-ORNITHINE PHENYLACETATE ATTENUATES INCREASED ARTERIAL AND EXTRACELLULAR BRAIN AMMONIA AND PREVENTS INTRACRANIAL HYPERTENSION IN PIGS WITH ACUTE LIVER FAILURE

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 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 (r2 = 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.)

EFFECT OF ALBUMIN DIALYSIS ON INTRACRANIAL PRESSURE INCREASE IN PIGS WITH ACUTE LIVER FAILURE: A RANDOMIZED STUDY

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 noninflammatory 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.

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

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.)

Enhanced Recovery After Surgery: Are We Ready, and Can We Afford Not to Implement These Pathways for Patients Undergoing Radical Cystectomy?

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.

N-acetylcysteine increases cerebral perfusion pressure in pigs with fulminant hepatic failure.

ObjectiveIntravenous 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. DesignProspective, randomized, controlled trial. SettingSurgical research laboratory in a university hospital. SubjectsFemale Norwegian Landrace pigs. InterventionsFulminant 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 (pGT = .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 (pGT = .033). Common carotid artery flow also increased and was maintained at a higher level compared with placebo (pG = .027). Systemic vascular resistance index initially decreased but then gradually increased (pGT < .001). Cardiac index increased after 15 mins of N-acetylcysteine infusion, causing a significant interaction (pGT = .038), but did not differ after 3 hrs. No significant differences in hindleg and mesentery hemodynamics were found. A short-lived increase in oxygen delivery caused by a temporary increase in cardiac index was observed but without any corresponding increase in oxygen consumption. ConclusionsIntravenous N-acetylcysteine infusion increases cerebral perfusion pressure in pigs with fulminant hepatic failure. Earlier reported effects on oxygen transport and uptake could not be confirmed.

An experimental large animal model for the assessment of bioartificial liver support systems in fulminant hepatic failure.

Background: 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. Methods: 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. Results: 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 ( P GT < .001). Urine became hypo-osmotic ( P < .001, P G = .011), with decreased sodium levels ( P = .08) and increased potassium levels ( P G = .025). Conclusions: This study characterizes a reproducible large animal model for fulminant hepatic failure that seems suitable for the assessment of bioartificial liver support systems.

ASSOCIATION OF REDUCED EXTRACELLULAR BRAIN AMMONIA, LACTATE, AND INTRACRANIAL PRESSURE IN PIGS WITH ACUTE LIVER FAILURE

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 (r2 = 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. (HEPATOLOGY 2007.)

Protein S-100ß: A Biochemical Marker for Increased Intracranial Pressure in Pigs with Acute Hepatic Failure

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.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-100 b, 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-100 b 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-100 b. In the sham-operated controls S-100 b was not detectable at any time point. Conclusions: Serum levels of S-100 b are increased early in experimental AHF. Determination of protein S-100 b may provide useful information on the presence and extent of intracranial hypertension in AHF.