C.H.C. Dejong

The enhanced recovery after surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials.

BACKGROUND & AIMS The aim of the Enhanced Recovery After Surgery (ERAS) pathway is to attenuate the stress response to surgery and enable rapid recovery. The objective of this meta-analysis was to study the differences in outcomes in patients undergoing major elective open colorectal surgery within an ERAS pathway and those treated with conventional perioperative care. METHODS Medline, Embase and Cochrane database searches were performed for relevant studies published between January 1966 and November 2009. All randomized controlled trials comparing ERAS with conventional perioperative care were selected. The outcome measures studied were length of hospital stay, complication rates, readmission rates and mortality. RESULTS Six randomized controlled trials with 452 patients were included. The number of individual ERAS elements used ranged from 4 to 12, with a mean of 9. The length of hospital stay [weighted mean difference (95% confidence interval): -2.55 (-3.24, -1.85)] and complication rates [relative risk (95% confidence interval): 0.53 (0.44, 0.64)] were significantly reduced in the enhanced recovery group. There was no statistically significant difference in readmission and mortality rates. CONCLUSION ERAS pathways appear to reduce the length of stay and complication rates after major elective open colorectal surgery without compromising patient safety.

Systematic review of enhanced recovery programmes in colonic surgery.

Fast track (FT) programmes optimize perioperative care in an attempt to accelerate recovery, reduce morbidity and shorten hospital stay. The aim of this review was to assess FT programmes for elective segmental colonic resections.

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.

Determinants of outcome after colorectal resection within an enhanced recovery programme

Postoperative outcomes were studied in relation to adverse nutritional risk (body mass index (BMI) below 20 kg/m2), advanced age (80 years or more) and co‐morbidity (American Society of Anesthesiologists (ASA) grade III–IV) in patients undergoing colorectal resection within an enhanced recovery after surgery programme.

Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.

Renal glutamine uptake and subsequent urinary ammonia excretion could be an important alternative pathway of ammonia disposal from the body during liver failure (diminished urea synthesis), but this pathway has received little attention. Therefore, we investigated renal glutamine and ammonia metabolism in midly hyperammonemic, portacaval shunted rats and severely hyperammonemic rats with acute liver ischemia compared to their respective controls, to investigate whether renal ammonia disposal from the body is enhanced during hyperammonemia and to explore the limits of the pathway. Renal fluxes, urinary excretion, and renal tissue concentrations of amino acids and ammonia were measured 24 h after portacaval shunting, and 2, 4, and 6 h after liver ischemia induction and in the appropriate controls. Arterial ammonia increased to 247 +/- 22 microM after portacaval shunting compared to controls (51 +/- 8 microM) (P < 0.001) and increased to 934 +/- 54 microM during liver ischemia (P < 0.001). Arterial glutamine increased to 697 +/- 93 microM after portacaval shunting compared to controls (513 +/- 40 microM) (P < 0.01) and further increased to 3781 +/- 248 microM during liver ischemia (P < 0.001). In contrast to controls, in portacaval shunted rats the kidney net disposed ammonia from the body by diminishing renal venous ammonia release (from 267 +/- 33 to -49 +/- 59 nmol/100 g body wt per min) and enhancing urinary ammonia excretion from 113 +/- 24 to 305 +/- 52 nmol/100 g body wt per min (both P < 0.01). Renal glutamine uptake diminished in portacaval shunted rats compared to controls (-107 +/- 33 vs. -322 +/- 41 nmol/100 g body wt per min) (P < 0.01). However, during liver ischemia, net renal ammonia disposal from the body did not further increase (294 +/- 88 vs. 144 +/- 101 nmol/100 g body wt per min during portacaval shunting versus liver ischemia). Renal glutamine uptake was comparable in both hyperammonemic models. These results indicate that the rat kidney plays an important role in ammonia disposal during mild hyperammonemia. However, during severe liver insufficiency induced-hyperammonemia, ammonia disposal capacity appears to be exceeded.

Interorgan ammonia trafficking in liver disease

Patients with liver disease have reduced urea synthesis capacity resulting in reduced capacity to detoxify ammonia in the liver. The contribution of the gut to the hyperammonemic state observed during liver failure is mainly due to portacaval shunting and not the result of changes in the metabolism of ammonia in the gut. Small intestinal synthesis of ammonia is related to amino acid breakdown, predominantly glutamine, whereas large bowel ammonia production is caused by bacterial breakdown of amino acids and urea. The kidneys produce ammonia but adapt to liver failure in experimental portacaval shunting by reducing ammonia release into the systemic circulation. The kidneys have the ability to switch from net ammonia production to net ammonia excretion. Data from recent studies in patients with cirrhosis of the liver show that the kidneys have a major role in post upper gastrointestinal bleeding hyperammonemia. During hyperammonemia muscle takes up ammonia and plays a major role in (temporarily) detoxifying ammonia to glutamine. Net uptake of ammonia by the brain occurs in patients and experimental animals with acute and chronic liver failure. Insight will be given in recent developments on ammonia lowering therapies which are based on the information of interorgan ammonia trafficking.

Influence of storage conditions on normal plasma amino-acid concentrations

Conflicting information in the literature is given concerning the optimal preparation and storage conditions of plasma samples for amino-acid analysis. To assess the optimal pre-storage treatment, we compared several methods and studied their influence on plasma amino-acid levels of rats and humans, stored at different temperatures. In rat plasma, the frequently reported degradation of glutamine was not measurable at a storage temperature of -70 degrees C. However, storage of native, not deproteinised plasma at this temperature, resulted in a 32% decrease of arginine and a 30% increase in ornithine after 24 weeks. Deproteinisation prohibited this arginine decay. At -20 degrees C, arginine decay was even more pronounced, whereas glutamine decreased by 14% in untreated plasma, by 10% in sulfosalicylic acid deproteinised plasma and by 3% if the deproteinisation was followed by removal of the protein pellet and subsequent neutralisation. To confirm these unexpected results in humans, we repeated this experiment with plasma of 6 volunteers. In contrast to rat plasma, we did not observe any changes in arginine and ornithine concentrations in human plasma stored at -70 degrees C. At -20 degrees C the reduction in glutamine was only 4-5%. These results suggest that interspecies differences in enxymatic activity exist in plasma. Finally, having assessed the optimal treatment and storage conditions (deproteinisation followed by storage at -70 degrees C), samples were obtained from a total of 112 human volunteers, stratified for age and sex, and amino-acids were measured. In the female group, we found a tendency to a gradual increase in most amino-acid concentrations with advancing age, which however only reached significance for histidine, citrulline, alanine and leucine. These observations demonstrate that plasma samples for amino-acid analysis should be deproteinised and stored at -70 degrees C. Also important interspecies differences appear to exist in plasma enzymatic activity. Finally, control samples should be taken from an age and sex matched control group.

Modern multidisciplinary treatment of rectal cancer based on staging with magnetic resonance imaging leads to excellent local control, but distant control remains a challenge.

AIM The purpose of this multicenter cohort study was to evaluate whether a differentiated treatment of primary rectal cancer based on magnetic resonance imaging (MRI) can reduce the number of incomplete resections and local recurrences and improve recurrence-free and overall survival. METHODS From February 2003 until January 2008, 296 patients with rectal cancer underwent preoperative MRI using a lymph node specific contrast agent to predict circumferential resection margin (CRM), T- and N-stage. Based on expert reading of the MRI, patients were stratified in: (a) low risk for local recurrence (CRM>2mm and N0 status), (b) intermediate risk and (c) high risk (close/involved CRM, N2 status or distal tumours). Mainly based on this MRI risk assessment patients were treated with (a) surgery only (TME or local excision), (b) preoperative 5 × 5 Gy+TME and (c) a long course of chemoradiation therapy followed by surgery after a 6-8 week interval. RESULTS Overall 228 patients underwent treatment with curative intent: 49 with surgery only, 86 with 5 × 5 Gy and surgery and 93 with chemoradiation and surgery. The number of complete resections (margin>1mm) was 218 (95.6%). At a median follow-up of 41 months the three-year local recurrence rate, disease-free survival rate and overall survival rate is 2.2%, 80% and 84.5%, respectively. CONCLUSION With a differentiated multimodality treatment based on dedicated preoperative MR imaging, local recurrence is no longer the main problem in rectal cancer treatment. The new challenges are early diagnosis and treatment, reducing morbidity of treatment and preferably prevention of metastatic disease.

Cholecystokinin/Cholecystokinin-1 receptor-mediated peripheral activation of the afferent vagus by enteral nutrients attenuates inflammation in rats.

Objective:The current study investigates activation of the nutritional anti-inflammatory pathway by lipid-rich nutrition. Background:Enteral nutrition activates humoral and neural pathways to regulate food intake and sustain energy balance. Recently, we demonstrated that enteral nutrition and in particular lipid-rich nutrition modulates inflammation and prevents organ damage. Methods:Male rats were fasted or fed lipid-rich nutrition before hemorrhagic shock. Disruption of afferent vagal fibers with capsaicin (deafferentation) was used to investigate involvement of afferent fibers. Peripheral activation of afferent vagal fibers via cholecystokinin (CCK)-mediated activation of CCK-1 receptors was investigated using administration of the selectively peripheral acting CCK-1 receptor antagonist, A70104 and PEGylated-CCK9. Tissue and blood were collected 90 minutes after shock to assess systemic inflammation and intestinal integrity. Results:Deafferentation reversed the inhibitory effect of lipid-rich nutrition on systemic levels of tumor necrosis factor-&agr; and interleukin-6, and on intestinal leakage of horseradish peroxidase and bacterial translocation. Furthermore, the protective effects of lipid-rich nutrition were negated by A70104, indicating that lipid-rich nutrition triggers peripheral CCK-1 receptors on vagal afferents to modulate inflammation. These findings were substantiated by the fact that pretreatment of fasted rats with PEGylated-CCK9, which acts on peripheral CCK-1 receptors, attenuated systemic inflammation, and loss of intestinal integrity. Conclusion:These data demonstrate that enteral lipid-rich nutrition modulates inflammation and preserves intestinal integrity via CCK release which activates CCK-1 receptors located on afferent vagal fibers. Taken together, the current study reveals a novel gut-brain-immune axis and provides new insight into the applicability of enteral nutrition to treat inflammatory conditions.

The adaptive response of the reticuloendothelial system to major liver resection in humans

Objective:To evaluate the contribution of the liver to total circulatory reticuloendothelial system (RES) phagocytosis capacity in patients undergoing liver resection and to compare it with values in end-stage chronic liver disease. Summary Background Data:The mechanism whereby major liver resection is associated with a high incidence of infection is unknown. Significant impairment of RES phagocytosis has been described in liver failure, rendering such patients susceptible to infection; and we hypothesized that similar impairment might occur following major liver resection. Methods:A prospective study was conducted in which 99mTc-albumin microspheres blood clearance served as a parameter for RES phagocytosis and was studied together with indocyanine green blood clearance, actual liver volume measured by three-dimensional image analysis, and a clinical score of hepatic dysfunction in 17 patients undergoing liver resection and in 8 patients with end-stage chronic liver disease assessed for liver transplantation. Results:When expressed relative to volume unit of residual liver, microspheres clearance increased significantly in the immediate postoperative period (day 1) following major (0.009% versus 0.022% min−1mL−1, P < 0.001), but not minor liver resection. In contrast, the absolute rate of microsphere clearance decreased following major resection (15% min−1 versus 10% min−1, P < 0.001) and was comparable with the rate observed in end-stage chronic liver disease (9% min−1). This decrease in circulatory microspheres clearance after resection paralleled a decrease in indocyanine green clearance (R2 = 0.511, P = 0.006), and there was a trend for those with moderate liver dysfunction to have lower microspheres clearance rates (P = 0.068). Conclusion:Preservation of a minimum volume of functioning liver is a prerequisite for adequate RES phagocytosis capacity, and failure of this system may predispose patients undergoing major liver resection to infection as observed in clinical studies.