Effects of Intra-abdominally Instilled Isotonic Saline on Pain, Recovery, and Health-Related Quality-of-Life Following Laparoscopic Cholecystectomy: A Randomized Prospective Double-Blind Controlled Study.

INTRODUCTION: The postoperative installation of isotonic saline in the abdomen has been suggested as a method to reduce the effect of local toxins, thereby reducing postoperative pain in patients undergoing laparoscopic surgery. The aim of this randomized prospective double-blind trial was to assess whether installation of isotonic saline can reduce postoperative pain and nausea following laparoscopic cholecystectomy (LC). METHODS: Altogether 71 LC patients were randomized to either intra-abdominal instillation of isotonic saline group (S) (n = 36) or no saline (NS) group (n = 35) at the end of surgery. Data were collected by means of questionnaires. The postoperative recovery profile questionnaire was answered prior to surgery and 1 week postoperatively, SF-36 prior to surgery and at 1 month postoperatively, and a pain diary recording a Visual Analogue Scale score each day during the first week. RESULTS: The overall response rate was 94%. No significant differences were seen between the groups regarding abdominal and shoulder pain. However, the NS group reported more pain (NS = 53 %, S = 29 %) and fatigue (NS = 50%, S = 35%) than the S group postoperative day 7. Moreover, the most frequently reported problem in both groups 7 days after surgery was getting back to normal life (60%). Females reported a slower recovery profile than males and also more postoperative symptoms day 7. HRQoL results were similar between the groups. CONCLUSION: Instillation of isotonic saline does not improve recovery after laparoscopic cholecystectomy. Postoperative pain was more often reported in the NS group than in the S group, though the difference was not significant.

Incidence and risk factors for symptomatic venous thromboembolism following cholecystectomy.

BACKGROUND: The benefit of thromboembolism prophylaxis in cholecystectomy is controversial. This population-based study report on the incidence of and risk factors for symptomatic venous thromboembolism (VTE) after cholecystectomy. METHOD: All cholecystectomies registered in the Swedish Register of Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) between 2006 and 2011 were reviewed. By linking patient data to the Swedish National Patient Register (NPR), the 30-day postoperative incidence of VTE (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]) was identified. Age- and gender-standardized incidence ratio (SIR) for deep venous thrombosis (DVT) and pulmonary embolism (PE) were calculated. Multivariable analysis determined risk factors for VTE by calculating odds ratio (OR). RESULTS: Altogether 62,488 procedures were registered and postoperative VTE was seen in 154 (0.25%) patients. DVT was seen in 36 (0.06%) patients and PE in 25 (0.04%) patients within 30 days after surgery. The SIR for DVT was 22.2 (95% confidence interval (CI) 13.1-31.3) and for PE 5.6 (95% CI 2.3-8.9). Risk factors for VTE within 30 days after cholecystectomy were age >70 years (odds ratio [OR] = 2.69; 95% confidence interval [CI] 1.68-4.30), open cholecystectomy (OR = 1.95; CI 1.31-2.92), operation time >120 min (OR = 1.66; CI 1.18-2.35), acute cholecystitis (OR = 1.69; CI 1.18-2.42), and previous history of VTE (OR = 50.5; CI 27.3-92.8). Thromboembolism prophylaxis (TP) increased the risk for postoperative bleeding (OR = 1.72; 1.44-2.05). CONCLUSION: The incidence of VTE after cholecystectomy is low and thromboembolism prophylaxis (TP) increases the risk for postoperative bleeding. Patients with previous VTE events should be given TP when undergoing cholecystectomy.

Increased expression of pro-inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients.

OBJECTIVES: Low-grade systemic inflammation, oxidative stress and peripheral insulin resistance are intimately associated and contribute to the increased risk of cardiovascular complications in advanced chronic kidney disease (CKD). Because altered adipose tissue activities have previously been linked to pathophysiological processes in various inflammatory and metabolic diseases we hypothesized that the uraemic milieu in patients with CKD may interact with the adipose tissue, provoking an unfavourable shift in its transcriptional output. DESIGN: Twenty-one adipokine mRNAs were quantified in abdominal subcutaneous adipose tissue (SAT) biopsies and serum/plasma concentrations of inflammatory markers and related protein products were measured. SETTING: The study was conducted at the Karolinska University Hospital, Huddinge, and Karolinska Institutet, Stockholm, Sweden. SUBJECTS: Thirty-seven patients with CKD [15 women, median 58 (interquartile range 49-65) years] and nine nonuraemic individuals [four women, age 62 (45-64) years] were recruited prior to initiation of peritoneal dialysis catheter insertion or elective hernia repair/laparoscopic cholecystectomy, respectively. RESULTS: Even after correction for body mass index, SAT from patients showed a significant upregulation of inflammatory pathway genes interleukin 6 (3.0-fold, P=0.0002) and suppressor of cytokine signalling 3 (2.5-fold, P=0.01), as well as downregulation of leptin (2.0-fold, P=0.03) and the oxidative stress genes uncoupling protein 2 (1.5-fold, P=0.03) and cytochrome b-245, alpha polypeptide (1.5-fold, P=0.005), in relation to controls. CONCLUSIONS: These gene expression differences suggest that inflammatory and oxidative stress activities may be important features of the intrinsic properties of uraemic adipose tissue, which may have significant effects on the uraemic phenotype.

Validation of the harmless acute pancreatitis score in predicting nonsevere course of acute pancreatitis.

BACKGROUND: The Harmless Acute Pancreatitis Score (HAPS) is a scoring algorithm to identify patients with nonsevere acute pancreatitis. The aim of this study was to evaluate the reproducibility of HAPS outside its original study setting. METHOD: Baseline information of all hospitalized patients with acute pancreatitis at Karolinska University Hospital, Stockholm, Sweden, between 2004 and 2009 was collected. The parameters constituting HAPS were signs of peritonitis, hematocrit and serum creatinine levels. Since hematocrit was not available in all patients, complete sample analysis was performed by replacing hematocrit with hemoglobin (strongly correlated with hematocrit; r = 0.86). RESULTS: In total, 531 patients with a first-time or a recurrent attack of acute pancreatitis were included. Among 353 patients with complete information on parameters constituting HAPS, 79 patients were predicted to have a nonsevere course, of whom 1 patient developed severe acute pancreatitis. The specificity of HAPS in predicting a nonsevere course of acute pancreatitis was 96.3% (95% CI: 81.0-99.9) with a corresponding positive predictive value of 98.7% (95% CI: 93.1-100). Complete sample analysis replacing hematocrit with hemoglobin level predicted a nonsevere course in 182 patients, of whom 2 patients had severe acute pancreatitis (94.3% specificity and 98.9% positive predictive value). CONCLUSION: HAPS is a highly specific scoring algorithm that predicts a nonsevere course of acute pancreatitis. Therefore, HAPS might be an additional tool in the clinical assessment of acute pancreatitis where early screening is important to treat the patients at an optimal level of care.

ESPEN Guidelines on Enteral Nutrition: Gastroenterology.

Undernutrition as well as specific nutrient deficiencies have been described in patients with Crohn's disease (CD), ulcerative colitis (UC) and short bowel syndrome (SBS). The present guideline gives evidence-based recommendations for the indication, application and type of formula of enteral nutrition (EN) (oral nutritional supplements (ONS) or tube feeding (TF)) in these patients. It was developed in an interdisciplinary consensus-based process in accordance with officially accepted standards and is based on all relevant publications since 1985. ONS and/or TF in addition to normal food is indicated in undernourished patients with CD or CU to improve nutritional status. In active CD EN is the first line therapy in children and should be used as sole therapy in adults mainly when treatment with corticosteroids is not feasible. No significant differences have been shown in the effects of free amino acid, peptide-based and whole protein formulae for TF. In remission ONS is recommended only in steroid dependent patients in CD. In patients with SBS TF should be introduced in the adaptation phase and should be changed with progressing adaptation to ONS in addition to normal food.

Temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure.

OBJECTIVE: This study investigated the temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure. DESIGN AND SETTING: Prospective and descriptive pilot study performed in an ICU with eight beds at a university hospital. PATIENTS: Critically ill patients (n=11) with multiple organ failure and ICU stay of at least 6 days were consecutively included. Patients with chronic obstructive pulmonary disease (n=21) and healthy volunteers (n=10) were used as reference groups. MEASUREMENTS AND RESULTS: Whole-blood and plasma glutathione were measured every 72 h. Total glutathione and the reduced fraction were determined in whole blood. The oxidized fraction and the redox status were calculated from these values. In plasma only the total concentration was determined. Patients were studied for 6-15 days. Nutrition was supplied according to routines supplying basal needs including glutamine. Both total and reduced glutathione was found to be depleted in whole blood compared to the reference groups. Redox status indicated continuing oxidative stress. Plasma glutathione showed higher values in total concentrations than the reference groups. CONCLUSIONS: This study demonstrates that glutathione remains depleted in whole blood. This contrasts to what has previously been shown in skeletal muscle where a restitution of glutathione concentration is seen.

Growth hormone treatment prevents the decrease in insulin-like growth factor I gene expression in patients undergoing abdominal surgery.

Acquired GH resistance together with reduced skeletal muscle mass are found in patients with increased protein catabolism due, for example, to sepsis, trauma, or major surgery. Both administration of glutamine-containing parenteral nutrition and GH treatment have been found to diminish this catabolism. The effects of GH are mediated in part by insulin-like growth factor I (IGF-I) that is produced in the liver and locally in GH target tissues. The aim of this study was to investigate the effect of GH treatment on expression of the IGF-I gene and GH receptor (GHR) gene in skeletal muscle after major surgery. A new quantitative RT-PCR-based assay was established to measure IGF-I gene expression. Metabolically healthy patients, without significant preoperative weight loss, who were undergoing elective abdominal surgery were included in the study. Five patients (one woman and four men) were treated with daily injections of GH (0.3 IU/kg.day) in addition to being given total parenteral nutrition including glutamine (0.28 g/kg.day). The control group consisted of eight patients (three women and five men), who were given glutamine-enriched total parenteral nutrition but no GH. A muscle biopsy was taken from the lateral portion of the quadriceps femoris muscle preoperatively (day 0) after induction of anesthesia. A second biopsy was taken under local anesthesia on postoperative day 3. Total ribonucleic acid (RNA) was extracted from the muscle biopsies, and IGF-I messenger RNA (mRNA) and GHR mRNA were measured by competitive quantitative RT-PCR assays. IGF-I mRNA and GHR mRNA levels were related to the expression of a housekeeping gene (cyclophilin). In the control group, IGF-I mRNA levels decreased from 1505 +/- 265 (mean +/- SEM) transcripts/cpm cyclophilin on day 0 to 828 +/- 172 on day 3 (P < 0.05). In contrast, IGF-I mRNA levels did not change in the GH-treated group (1188 +/- 400 transcripts/cpm cyclophilin on day 0 vs. 1089 +/- 342 transcripts/cpm cyclophilin on day 3). No statistically significant changes were seen in GHR expression. We conclude that administration of GH prevents the reduction in IGF-I gene expression in skeletal muscle after abdominal surgery.

Measurement of human growth hormone receptor messenger ribonucleic acid by a quantitative polymerase chain reaction-based assay: demonstration of reduced expression after elective surgery.

Studies of GH receptor (GHR) gene expression in human tissues have been hampered by the limited amount of tissue available for analysis and the low sensitivity of conventional methods. We have developed a quantitative reverse transcriptase-PCR assay for measurement of GHR messenger ribonucleic acid levels in small human tissue biopsies. To compensate for sample to sample variation, an internal RNA standard, which differs from the wild-type GHR transcript by only a few nucleotides, was reverse transcribed and amplified together with the GHR transcripts. PCR was carried out using one biotinylated primer to permit the purification of single stranded PCR products on streptavidin-coated microtiter plates. The ratio between the wild-type and mutated transcripts was determined by two separate minisequence reactions in which a primer, annealed immediately 3' of a variable nucleotide, was extended by a single 3H-labeled nucleotide, complementary to either the wild-type or mutated sequence. The assay range was 0.125-8 x 10(5) transcripts/sample, the mean intraassay coefficient of variation was 8.7%, and the lower limit of detection was 0.125 x 10(5) transcripts/sample. GHR messenger ribonucleic acid levels were detectable in small amounts (10-100 ng) of total RNA extracted from adipose tissue, skeletal muscle, and liver. The GHR gene expression in liver was approximately 10-fold higher than that in skeletal muscle, whereas intermediate levels were found in adipose tissue. In nine patients undergoing elective abdominal surgery, GHR gene expression in skeletal muscle was reduced on day 3 after surgery compared to the baseline level. The decrease in GHR gene expression was accompanied by a decrease in skeletal muscle glutamine. This suggests that the postoperative protein catabolism may be caused at least partly by acquired GH insensitivity due to reduced expression of the GHR gene.

Alpha-ketoglutarate preserves protein synthesis and free glutamine in skeletal muscle after surgery.

Serving as a reproducible human trauma model, patients (n = 21) undergoing elective cholecystectomy received postoperative total parenteral nutrition with (n = 9) or without (n = 12) alpha-ketoglutarate (AKG) supplementation. Skeletal muscle biopsy specimens were taken before surgery and on the third postoperative day. The postoperative decreases in the concentrations of free glutamine and basic amino acids seen in the control group were counteracted in the AKG group (p less than 0.05). Muscle protein synthesis was estimated by ribosome analysis. On the third postoperative day the control group showed a decline in the polyribosome concentration (25.8% +/- 4.5%; p less than 0.001). No significant change was observed in the AKG group. On each postoperative day the nitrogen balance was negative in the control group but not in the AKG group. In the control group the cumulative nitrogen balance amounted to -9.9 +/- 1.8 gm of nitrogen and in the AKG group -2.6 +/- 2.6 gm of nitrogen, which was significantly different (p less than 0.05). Administration of AKG, the carbon skeleton corresponding to glutamine, produced results similar to those seen when glutamine is added to postoperative total parental nutrition. The results suggest that the availability of precursors for glutamine synthesis in skeletal muscle is crucial for the degree of muscle protein catabolism after surgical trauma.

Temporal changes in muscle glutathione in ICU patients.

OBJECTIVE: This study investigated the changes over time in glutathione and its constituent amino acids in skeletal muscle of ICU patients with multiple organ failure. DESIGN AND SETTING: Prospective and descriptive pilot study in two medium-sized ICUs with ten beds. PATIENTS: Critically ill patients ( n=10) with multiple organ failure and with an expected ICU stay longer than 6 days were included during their initial 3 days after admission to the ICU. MEASUREMENTS AND RESULTS: Muscle biopsy and blood samples were taken on days 0, 3, and 6 after inclusion and total, reduced, and oxidized glutathione and the related amino acids were determined. During the study period both total and reduced glutathione increased and was in the normal range on day 6. The constituent amino acids normalized during the study period as well. CONCLUSIONS: This pilot study demonstrates a recovery of muscle glutathione concentrations in critically ill patients with ongoing multiple organ failure within 1 week. Restoration of muscle glutathione seems to be a biological process of high priority in this group of patients.

Decrease in muscle glutamine, ribosomes, and the nitrogen losses are similar after laparoscopic compared with open cholecystectomy during the immediate postoperative period.

BACKGROUND: The purpose of the study was to compare the postoperative muscle amino acid pattern, the ribosome concentration and size distribution, and postoperative nitrogen balance in patients who underwent either laparoscopic or open cholecystectomy. METHODS: Patients who underwent cholecystectomy by means of either laparoscopy (n=8;LAP) or laparotomy (n=8;OPEN) were studied. The concentrations of amino acids, ribosomes, and polyribosomes, reflecting protein synthesis, were determined in skeletal muscle tissue before operation and on postoperative day 2. The cumulated nitrogen balance was determined. RESULTS. Decreases in muscle glutamine (26.7% +/- 8.4% in the LAP group and 30.3% and +/- 4.5% in the OPEN group) and in polyribosomes (28.7% +/- 6.5% in the LAP group and 23.6% +/- 8.5% in the OPEN group) were observed without differences between the groups (mean +/- SEM). The nitrogen losses were similar in both groups (15.2 +/-1.6 gm in the LAP group and 15.5 +/- 1.2 gm in the OPEN group). CONCLUSION: A stress++ response with effects on amino acid and protein metabolism in muscle in present also after laparoscopic cholecystectomy. On postoperative day 2 this response is of similar magnitude after both the laparoscopic and the open procedures.

Growth hormone together with glutamine-containing total parenteral nutrition maintains muscle glutamine levels and results in a less negative nitrogen balance after surgical trauma.

BACKGROUND: Muscle protein catabolism, reflected by a decrease in glutamine (GLN), a decrease in muscle protein synthesis, and a negative nitrogen balance can be reduced by either administration of GLN or growth hormone (GH). In this study, the effects of a combination of GH and GLH were studied. METHODS: Patients (n = 16) undergoing abdominal operation were given total parenteral nutrition (TPN) containing either GLN alone or GLN together with GH (GH/GLN) during 3 postoperative days. The amino acid concentration and protein synthesis in muscle tissue and the nitrogen balance were measured. RESULTS: GH/GLN reduced nitrogen losses compared with GLN alone (-5.8 +/- 1.4 g nitrogen versus -10.6 +/- 1.1 g nitrogen, P <.05). GH/GLN maintained muscle GLN at preoperative levels compared with a 47.5% +/- 6.3% decline in the GLN group. A similar decrease was seen in the fractional synthesis rate of muscle protein postoperatively in both groups. CONCLUSIONS: GH has an additive effect given together with GLN on muscle amino acid metabolism, preventing the decrease in the GLN concentration in skeletal muscle and diminishing the loss of whole body nitrogen. However, the improvements in muscle amino acid concentrations and nitrogen loss were not associated with differences between the groups in muscle protein synthesis postoperatively.

Stress hormone and amino acid infusion in healthy volunteers: short-term effects on protein synthesis and amino acid metabolism in skeletal muscle.

To study the immediate effects of stress hormones and intravenous amino acid support, healthy male volunteers were administered a stress-hormone infusion including epinephrine, cortisol, and glucagon either alone (Triple, n = 8) or combined with a balanced glutamine-free amino acid solution (Triple AA, n = 8) over a period of 6 hours. The amino acid infusion was started 2 hours after the hormone infusion. A third group (AA, n = 8) received the balanced amino acid solution alone. After 6 hours of the stress-hormone infusion, a decrease was observed in skeletal muscle protein synthesis as measured by the size distribution and concentration of ribosomes. The decrease was prevented by an infusion of the balanced amino acid solution. Following the triple-hormone infusion, a decrease was noted in the content of the total free amino acids in both muscle and plasma. After including amino acids in the infusion solution, the significant decrease in muscle glutamine caused by the triple hormones was not seen. Plasma cortisol, insulin, and glucose increased in response to the triple-hormone infusion alone or in combination with amino acids. In summary, the results show that the signs of muscle protein catabolism elicited by administration of stress hormones can be attenuated by simultaneous administration of a conventional amino acid solution, although it does not contain glutamine.

Glutamine and alpha-ketoglutarate prevent the decrease in muscle free glutamine concentration and influence protein synthesis after total hip replacement.

After surgical trauma, protein synthesis, as well as the concentration of free glutamine in muscle, decreases. Total parenteral nutrition (TPN) alone does not prevent the decrease of glutamine in muscle, but TPN supplemented with glutamine or its precursor, alpha-ketoglutarate, maintains amino acid concentration in muscle and preserves protein synthesis. The aim of this study was to characterize a human trauma model using patients undergoing total hip replacement, and furthermore to investigate whether glutamine or alpha-ketoglutarate alone without TPN can prevent the postoperative decrease in muscle free glutamine. Metabolically healthy patients undergoing total hip replacement were randomized into three groups. The control group (n = 13) received glucose 2 g/kg body weight (BW) during surgery and the first 24 postoperative hours. The glutamine group (n = 10) received glucose 2 g/kg BW and glutamine 0.28 g/kg BW, and the alpha-ketoglutarate group (n = 10) received glucose 2 g/kg BW and alpha-ketoglutarate 0.28 g/kg BW. Muscle biopsies were performed before surgery and 24 hours postoperatively. Free glutamine concentration in muscle decreased from 11.62 +/- 0.67 to 9.80 +/- 0.36 mmol/kg wet weight in the control group (P < .01), whereas it remained unchanged in both the glutamine group and alpha-ketoglutarate group. Protein synthesis, as reflected by the concentration of total ribosomes, decreased significantly in the control group, but not in glutamine and alpha-ketoglutarate groups. Polyribosome concentration decreased significantly in both the control and alpha-ketoglutarate groups. Total hip replacement can be used as a reproducible trauma model, with characteristic changes in the muscle amino acid pattern and protein synthesis 24 hours postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects on skeletal muscle amino acids and whole body nitrogen metabolism of total parenteral nutrition following laparoscopic cholecystectomy and given to healthy volunteers.

In this descriptive study total parenteral nutrition (TPN) without glutamine was administered over 2 days to patients undergoing laparoscopic cholecystectomy (n = 8) and to volunteers (n = 8). Effects on muscle amino acids and nitrogen economy were studied. Muscle protein synthesis, determined by ribosome and polyribosome concentrations were measured in the patients. In both patients and volunteers the muscle amino acid patterns indicated muscle protein catabolism. Decreases in glutamine were seen in both groups (21.8 +/- 4.6% in patients and 17.5 +/- 5.4% in the volunteers). In both groups a negative nitrogen balance was seen (-4.1 +/- 1.2 gram and -10.3 +/- 2.4 gram respectively). The patients also showed decreased ribosome (by 13.7 +/- 4.5%) and polyribosome concentration (by 17.4 +/- 4.6%), indicating a decrease in muscle protein synthesis. No comparisons are made between the two groups since they are not comparable. However, it is concluded in these two descriptive studies, that during these conditions, TPN does not prevent muscle protein catabolism either during basal conditions or after a minor surgical trauma such as laparoscopic cholecystectomy.

The effects of a new amino-acid dipeptide solution on nitrogen balance and humoral growth factors in the postoperative state in man.

27 patients admitted for elective abdominal surgery were allocated to receive postoperative total parenteral nutrition supplemented with glutamine (glycyl-glutamine) and tyrosine (glycyl-tyrosine) containing dipeptides (DP-Gln 20; 0.16 g glutamine/kg BW/24 h) or isonitrogenous Vamin 18 for 5 days. The aim was to evaluate safety and effects on short-life plasma proteins, nitrogen balance, 3-methylhistidine excretion and alimentary growth factors in plasma. No differences in transthyretin or retinol binding protein levels, nitrogen balance or 3-methylhistidine excretion were found in patients receiving DP-Gln 20 compared to Vamin 18. There were higher plasma levels of peptide YY in the dipeptide group 5 days after surgery (p < 0.05). A correlation between insulin levels and nitrogen balance was found only in DP-Gln 20 treated patients day 6 (r = 0.91, p < 0.01). DP-Gln 20 is a glutamine dipeptide (Gly-Gln) containing amino acid solution which is considered safe in the postoperative state in man. No beneficial effects on whole body protein metabolism were found by adding DP-Gln 20 to total parenteral nutrition.

Role of glutamine and its analogs in posttraumatic muscle protein and amino acid metabolism.

Skeletal muscle protein catabolism following trauma has until recently not been possible to counteract by intravenous nutritional means. The obligatory loss of nitrogen with concomitant reduction of skeletal muscle protein synthesis is also accompanied by a decrease of muscle free glutamine, the extent of which is proportional to the muscle protein catabolism. Serving as a human model of surgical trauma, patients undergoing elective cholecystectomy were given total parenteral nutrition including additions of either glutamine or its analogs (ornithine-alpha-ketoglutarate, alpha-ketoglutarate, or alanylglutamine) during 3 postoperative days. The polyribosome concentration and the intracellular glutamine concentration in skeletal muscle, as well as nitrogen balance, showed a less pronounced skeletal muscle catabolism in these groups than when conventional total parenteral nutrition was given. It is concluded that a support of either glutamine or its carbon skeleton, alpha-ketoglutarate, counteracts the postoperative fall of muscle free glutamine and of muscle protein synthesis. Furthermore, statistical correlations could be shown between the changes of muscle glutamine and muscle protein synthesis and the postoperative nitrogen losses.