Arthur Revhaug

Detection of Circulating Tumor Necrosis Factor after Endotoxin Administration

Cytokines, products of stimulated macrophages, are thought to mediate many host responses to bacterial infection, but increased circulating cytokine concentrations have not been detected consistently in infected patients. We measured plasma concentrations of circulating tumor necrosis factor alpha (cachectin), interleukin-1 beta, and gamma interferon, together with physiologic and hormonal responses, in 13 healthy men after intravenous administration of Escherichia coli endotoxin (4 ng per kilogram of body weight) and during a control period of saline administration. Eight additional subjects received ibuprofen before receiving endotoxin or saline. Plasma levels of tumor necrosis factor were generally less than 35 pg per milliliter throughout the control period, but increased 90 to 180 minutes after endotoxin administration to mean peak concentrations of 240 +/- 70 pg per milliliter, as compared with 35 +/- 5 pg per milliliter after saline administration. Host responses were temporally associated with the increase in circulating tumor necrosis factor at 90 minutes, and the extent of symptoms, changes in white-cell count, and production of ACTH were temporally related to the peak concentration of tumor necrosis factor. Ibuprofen pretreatment did not prevent the rise in circulating tumor necrosis factor (mean peak plasma level, 170 +/- 70 pg per milliliter) but greatly attenuated the symptoms and other responses after endotoxin administration. Concentrations of circulating interleukin-1 beta and gamma interferon did not change after endotoxin administration. We conclude that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.

Consensus Review of Optimal Perioperative Care in Colorectal Surgery: Enhanced Recovery After Surgery (ERAS) Group Recommendations

OBJECTIVES To describe a consensus review of optimal perioperative care in colorectal surgery and to provide consensus recommendations for each item of an evidence-based protocol for optimal perioperative care. DATA SOURCES For every item of the perioperative treatment pathway, available English-language literature has been examined. STUDY SELECTION Particular attention was paid to meta-analyses, randomized controlled trials, and systematic reviews. DATA EXTRACTION A consensus recommendation for each protocol item was reached after critical appraisal of the literature by the group. DATA SYNTHESIS For most protocol items, recommendations are based on good-quality trials or meta-analyses of such trials. CONCLUSIONS The Enhanced Recovery After Surgery (ERAS) Group presents a comprehensive evidence-based consensus review of perioperative care for colorectal surgery. It is based on the evidence available for each element of the multimodal perioperative care pathway.

A protocol is not enough to implement an enhanced recovery programme for colorectal resection

Single‐centre studies have suggested that enhanced recovery can be achieved with multimodal perioperative care protocols. This international observational study evaluated the implementation of an enhanced recovery programme in five European centres and examined the determinants affecting recovery and length of hospital stay.

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.

Allowing normal food at will after major upper gastrointestinal surgery does not increase morbidity: a randomized multicenter trial.

Objective:The aim of this trial was to investigate whether a routine of allowing normal food at will increases morbidity after major upper gastrointestinal (GI) surgery. Summary Background Data:Nil-by-mouth with enteral tube feeding is widely practiced for several days after major upper GI surgery. After other abdominal operations, normal food at will has been shown to be safe and to improve gut function. Methods:Patients were randomly assigned to a routine of nil-by-mouth and enteral tube feeding by needle-catheter jejunostomy (ETF group) or normal food at will from the first day after major upper GI surgery. Primary end point was rate of major complications and death. Secondary outcomes were minor complications and adverse events, bowel function, and length of stay. All patients were invited to a follow-up at 8 weeks after discharge from the hospital. Results:Four hundred fifty-three patients who underwent major open upper GI surgery in 5 centers were enrolled between 2001 and 2006. Four hundred forty-seven patients were correctly randomized. Of 227 patients 76 (33.5%) had major complications in the ETF group compared with 62 (28.2%) of 220 patients allowed normal food at will (P = 0.26, 95% CI for the difference in rate from −3.3 to 13.9). In the ETF group, 36 (15.9%) patients were reoperated compared with 29 (13.2%) in the group allowed normal food at will (P = 0.50) and 30-day mortality was 10 (4.4%) of 227 and 11 (5.0%) of 220 patients, respectively (P = 0.83). Time to resumed bowel function was significantly in favor of allowing normal food at will (P = 0.01), as were the total number of major complications, length of stay, and rate of postdischarge complications. Conclusions:Allowing patients to eat normal food at will from the first day after major upper GI surgery does not increase morbidity compared with traditional care with nil-by-mouth and enteral feeding.

Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection

Accelerated recovery from surgery has been achieved when patients are managed within a multimodal Enhanced Recovery After Surgery (ERAS) protocol. This study evaluated the benefit of an ERAS programme for patients undergoing liver resection.

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.

Growth Hormone After Abdominal Surgery Attenuated Forearm Glutamine, Alanine, 3-Methylhistidine, and Total Amino Acid Efflux in Patients Receiving Total Parenteral Nutrition

OBJECTIVE The study clarified the effects of growth hormone treatment on forearm amino acid efflux in patients with full nutritional support after gastrointestinal surgery. SUMMARY BACKGROUND DATA Growth hormone attenuates net nitrogen loss after surgical trauma. An increase in net protein synthesis has been described, whereas the results regarding protein breakdown have been conflicting. METHODS Elective patients undergoing abdominal surgery were double blindly randomized to treatment with recombinant human growth hormone (GH, n = 9) 24 IU or placebo (PL, n = 10) the first 5 postoperative days. All received parenteral nutrition (nitrogen = 5.7 +/- .1 g/m2, energy = 1018 +/- 12 kcal/m2 (125 +/- .7% of BMR) and epidural analgesia. Amino acid plasma levels and forearm fluxes were measured. RESULTS The second postoperative day, growth hormone abolished forearm efflux of total amino acid nitrogen (GH: 170 +/- 117, PL: -785 +/- 192 nmol/100 mL/min, p = .0007) due to reduced losses of both essential and nonessential amino acids. Glutamine release was abolished (13 +/- 15 vs. -137 +/- 43 nmol/100 mL/min, p = .007) and alanine release attenuated (-61 +/- 17 vs. -211 +/- 51 nmol/100 mL/min, p = .01). 3-Methyl-histidine release was attenuated (-.20 +/- .11 vs. -.62 +/- .09 nmol/100 mL/min, p = .04). Growth hormone also induced decreased venous plasma amino acid levels. CONCLUSIONS When given after gastrointestinal surgery in patients treated with total parenteral nutrition, growth hormone treatment abolished glutamine, 3-methylhistidine, and total amino acid nitrogen loss from forearm tissue. Alanine loss from forearm tissue was attenuated.

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.