Evaluation of procalcitonin as a marker to predict antibiotic response in adult patients with acute appendicitis: a prospective observational study.

BACKGROUND: The aim of the study was to investigate the value of serum procalcitonin (PCT) as a predictor of early antibiotic treatment response in patients with acute appendicitis. Procalcitonin is a biochemical marker that increases rapidly in cases of bacterial infection and sepsis; however, the benefit of PCT as a diagnostic tool in acute appendicitis has not been confirmed. METHODS: Observations of PCT dynamics were conducted as part of a prospective clinical trial at Sahlgrenska University Hospital between May 2009 and February 2010 on adult patients with acute appendicitis treated with antibiotics as first-line therapy. Procalcitonin, C-reactive protein (CRP), and white blood cell count (WBC) were measured before administration of antibiotics and subsequently between 4-24 h following treatment. RESULTS: Three hundred sixteen patients were included in the study. Almost 80% recovered on antibiotics without the need of surgery. Serum PCT concentrations before initiation of antibiotic therapy and during treatment did not differ significantly between antibiotic responders and non-responders (p<0.94). However, differences were observed for CRP (p<0.04) and WBC (p<0.001), with a trend for body temperature (p<0.06). CONCLUSION: Procalcitonin has limited additional value, compared with standard laboratory tests as CRP, WBC, and body temperature to predict antibiotic treatment response in adult patients with acute appendicitis.

Antibiotics as first-line therapy for acute appendicitis: evidence for a change in clinical practice.

BACKGROUND: Randomized studies have indicated that acute appendicitis may be treated by antibiotics without the need of surgery. However, concerns have been raised about selection bias of patients in such studies. Therefore, the present study was aimed to validate previous findings in randomized studies by a full-scale population-based application. METHODS: All patients with acute appendicitis at Sahlgrenska University Hospital (May 2009 and February 2010) were offered intravenous piperacillin plus tazobactam according to our previous experience, followed by 9 days out-hospital oral ciprofloxacin plus metronidazole. Endpoints were treatment efficacy and complications. Efficient antibiotic treatment was defined as recovery without the need of surgery beyond 1 year of follow-up. RESULTS: A total of 558 consecutive patients were hospitalized and treated due to acute appendicitis. Seventy-nine percent (n = 442) received antibiotics as first-line therapy and 20 % (n = 111) had primary surgery as the second-line therapy. Seventy-seven percent of patients on primary antibiotics recovered while 23 % (n = 100) had subsequent appendectomy due to failed initial treatment on antibiotics. Thirty-eight patients (11 %) of the 342 had experienced recurrent appendicitis at 1-year follow-up. Primary antibiotic treatment had fewer complications compared to primary surgery. CONCLUSIONS: This population-based study confirms previous results of randomized studies. Antibiotic treatment can be offered as the first-line therapy to a majority of unselected patients with acute appendicitis without medical drawbacks other than the unknown risk for long-term relapse, which must be weighed against the unpredicted but well-known risk for serious major complications following surgical intervention.

Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients: a randomized double-blind study.

BACKGROUND: The short-term provision of ghrelin to patients with cancer indicates that there may be benefits from long-term provision of ghrelin for the palliative treatment of weight-losing cancer patients. This hypothesis was evaluated in a randomized, double-blind, phase 2 study. METHODS: Weight-losing cancer patients with solid gastrointestinal tumors were randomized to receive either high-dose ghrelin treatment (13 microg/kg daily; n = 17 patients) or low-dose ghrelin treatment (0.7 microg/kg daily; n = 14 patients) for 8 weeks as a once-daily, subcutaneous injections. Appetite was scored on a visual analog scale; and food intake, resting energy expenditure, and body composition (dual x-ray absorpitometry) were measured before the start of treatment and during follow-up. Serum levels of ghrelin, insulin, insulin-like growth factor 1, growth hormone (GH), triglycerides, free fatty acids, and glucose were measured. Health-related quality of life, anxiety, and depression were assessed by using standardized methods (the 36-item Short Form Health Survey and the Hospital Anxiety and Depression Scale). Physical activity, rest, and sleep were measured by using a multisensor body monitor. RESULTS: Treatment groups were comparable at inclusion. Appetite scores were increased significantly by high-dose ghrelin analyzed both on an intent-to-treat basis and according to the protocol. High-dose ghrelin reduced the loss of whole body fat (P < .04) and serum GH (P < .05). There was a trend for high-dose ghrelin to improve energy balance (P < .07; per protocol). Otherwise, no statistically significant differences in outcome variables were observed between the high-dose and low-dose groups. Adverse effects were not observed by high-dose ghrelin, such as serum levels of tumor markers (cancer antigen 125 [CA 125], carcinoembryonic antigen, and CA 19-9). CONCLUSIONS: The current results suggested that daily, long-term provision of ghrelin to weight-losing cancer patients with solid tumors supports host metabolism, improves appetite, and attenuates catabolism.

Survival and erythropoietin receptor protein in tumours from patients randomly treated with rhEPO for palliative care.

BACKGROUND: Recombinant erythropoietin (rhEPOalpha) corrects anaemia, improves physical functioning and quality of life in cancer patients. However, published reports have suggested risks for tumour stimulation by provision EPO to patients with remaining tumour cells perhaps related to the presence of EPO receptor protein in tumour tissue. Therefore, the aim of the present study was to exclude a possibility that cancer patients who respond favourably to EPO treatment have mainly tumours with low EPO receptor protein expression. METHODS: Tumour tissue was evaluated in 87 patients out of 108 randomly allocated for treatment with rhEPOalpha (n = 50) versus controls (n = 58). Tumour cell proliferation (Ki-67 index) and EPO receptor protein expression were evaluated by immunohistochemistry. RESULTS: EPO treatment varied between 2 and 35 months, in doses between 10,000 and 40,000 Units/week. Ki-67 index did not differ between study and control patients before EPO treatment. Tumour tissue erythropoietin receptor protein was also similar between treated and untreated patients. Around 40% of tumour cells contained EPO receptors. Survival did not differ among EPO treated and control patients analysed as intention to treat, while survival was significantly improved in EPO treated patients per protocol treatment (P < 0.05). Ki-67 index and tumour tissue erythropoietin receptor protein did not predict survival, which systemic inflammation (ESR) did (P < 0.02). CONCLUSIONS: Our results support that reported risk to accelerate disease progression by EPO treatment in palliative care is not justified in patients with solid, gastrointestinal cancer despite tumour presence of EPO receptor protein.

Initiation factors for translation of proteins in the rectus abdominis muscle from patients on overnight standard parenteral nutrition before surgery.

Previous studies have provided conflicting conclusions concerning the efficacy of improving protein balance in patients by standard intravenous nutrition [TPN (total parenteral nutrition)], which is either explained by suboptimal nutritional regimens or insensitive clinical methods. The aim of the present study was therefore to evaluate the effects on the initiation of translation of skeletal muscle proteins by standard overnight TPN. A total of 12 patients who underwent standard surgery were included. TPN was provided as an all-in-one treatment by constant infusion [0.16 gN.kg(-1) of body weight.day(-1) (30 kcal.kg(-1) of body weight.day(-1))]. Saline-infused patients served as controls. Rectus abdominis muscle biopsies were taken at the time of the operation. The phosphorylation state of the proteins for initiation of translation was quantified. Plasma glucose, and serum insulin, glycerol, triacylglycerols (triglycerides) and NEFAs (non-esterified fatty acids; 'free fatty acids') were not significantly altered during TPN infusion, whereas total plasma amino acids increased, as shown by increases in methionine, phenylalanine, threonine, alanine, arginine, aspartic acid, glycine and histidine (P<0.05). Overnight TPN increased the formation of active eIF4G-eIF4E (where eIF is eukaryotic-initiation factor) complexes (P<0.05), whereas the inhibitory complex 4E-BP1 (eIF4E-binding protein)-eIF4E was moderately decreased (P<0.06). TPN increased the amount of the most phosphorylated form of 4E-BP1 (P<0.05), and increased the amount (P<0.04) and phosphorylation (P<0.01) of p70(S6K) (70 kDa ribosomal protein S6 kinase). In conclusion, an overnight pre-operative constant infusion of standard TPN altered initiation factor complexes, indicating activation of the initiation of protein translation in rectus abdominis muscle in the presence of increased plasma amino acid levels, but without a concomitant increase in energy substrates and insulin. In contrast with our results from previous studies, the methodology used in the present study appears to be more sensitive in reflecting directional changes in human muscle protein synthesis compared with traditional methods, particularly based on measurements of amino acid flux.

Daily physical-rest activities in relation to nutritional state, metabolism, and quality of life in cancer patients with progressive cachexia.

PURPOSE: To evaluate daily physical-rest activities in cancer patients losing weight in relation to disease progression. EXPERIMENTAL DESIGN: Physical activity-rest rhythms were measured (ActiGraph, armband sensor from BodyMedia) in relation to body composition (dual-energy X-ray absorptiometry), energy metabolism, exercise capacity (walking test), and self-scored quality of life (SF-36, Hospital Anxiety and Depression Scale) in weight-losing outpatients with systemic cancer (71 +/- 2 years, n = 53). Well-nourished, age-matched, and previously hospitalized non-cancer patients served as controls (74 +/- 4 years, n = 8). Middle-aged healthy individuals were used as reference subjects (49 +/- 5 years, n = 23). RESULTS: Quality of life was globally reduced in patients with cancer (P < 0.01), accompanied by significantly reduced spontaneous physical activity during both weekdays and weekends compared with reference subjects (P < 0.01). Spontaneous physical activity declined over time during follow-up in patients with cancer (P < 0.05). However, overall physical activity and the extent of sleep and bed-rest activities did not differ between patients with cancer and age-matched non-cancer patients. Spontaneous physical activity correlated weakly with maximum exercise capacity in univariate analysis (r = 0.41, P < 0.01). Multivariate analysis showed that spontaneous physical activity was related to weight loss, blood hemoglobin concentration, C-reactive protein, and to subjectively scored items of physical functioning and bodily pain (SF-36; P < 0.05-0.004). Anxiety and depression were not related to spontaneous physical activity. Patient survival was predicted only by weight loss and serum albumin levels (P < 0.01), although there was no such prediction for spontaneous physical activity. CONCLUSIONS: Daily physical-rest activities represent variables which probably reflect complex mental physiologic and metabolic interactions. Thus, activity-rest monitoring provides a new dimension in the evaluation of medical and drug interventions during palliative treatment of patients with cancer.

Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning.

PURPOSE: The present study was designed to evaluate whether daily insulin treatment for weight-losing cancer patients attenuates the progression of cancer cachexia and improves metabolism and physical functioning in palliative care. EXPERIMENTAL DESIGN: One hundred and thirty-eight unselected patients with mainly advanced gastrointestinal malignancy were randomized to receive insulin (0.11 +/- 0.05 units/kg/d) plus best available palliative support [anti-inflammatory treatment (indomethacin), prevention of anemia (recombinant erythropoietin), and specialized nutritional care (oral supplements + home parenteral nutrition)] according to individual needs. Control patients received the best available palliative support according to the same principles. Health-related quality of life, food intake, resting energy expenditure, body composition, exercise capacity, metabolic efficiency during exercise, and spontaneous daily physical activity as well as blood tests were evaluated during follow-up (30-824 days) according to intention to treat. RESULTS: Patient characteristics at randomizations were almost identical in study and control groups. Insulin treatment for 193 +/- 139 days (mean +/- SD) significantly stimulated carbohydrate intake, decreased serum-free fatty acids, increased whole body fat, particularly in trunk and leg compartments, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity. Tumor markers in blood (CEA, CA-125, CA 19-9) did not indicate the stimulation of tumor growth by insulin; a conclusion also supported by improved survival of insulin-treated patients (P<0.03). CONCLUSION: Insulin is a significant metabolic treatment in multimodal palliation of weight-losing cancer patients.

Appearance of individual amino acid concentrations in arterial blood during steady-state infusions of different amino acid formulations to ICU patients in support of whole-body protein metabolism.

BACKGROUND: Previous work has demonstrated a relationship between arterial amino acid concentrations and uptake of amino acids across peripheral tissues in healthy volunteers, as well as in chronically and acutely ill patients. The aim of the present study was to evaluate whether different amino acid profiles in commercially available amino acid formulations are translated into significantly different arterial amino acid concentrations presumably high enough to promote protein metabolism in intensive care unit (ICU) patients. METHODS: Nonprotein calories (60% glucose: 40% lipid) were simultaneously and constantly infused over 72 hours. Different free amino acid solutions were infused at random to each patient for 24 hours in order to determine the appearance of steady-state arterial concentrations of individual amino acids. Basal metabolic and nutrition states were defined after a 12-hour infusion period with glucose in each patient. Healthy volunteers receiving a standardized oral meal served as reference subjects in measurements of venous amino acid concentrations after normal oral food intake. RESULTS: The sum of all amino acids in arterial plasma increased significantly during steady-state infusions of all the free amino acid solutions vs basal state in ICU patients. Only glutamine, taurine, and tyrosine did not increase at all vs basal state during steady-state infusions of the 3 formulations. Alanine, arginine, citrulline, glycine, histidine, serine, methionine, phenylalanine, valine, and ornithine showed different concentration among the amino acid solutions during infusions. Healthy volunteers had significantly higher overall concentrations of amino acids in both fasted and fed state compared with ICU patients, which indicates that free amino acid solutions remain a limiting component in artificial nutrition to patients to promote arterial amino acid concentrations in the artificially fed state. CONCLUSIONS: It appears important to continue further improvement of composition profile in solutions of free amino acids to promote adequate uptake across organ beds in promotion of protein balance in artificially nourished patients.

Supportive nutrition on recovery of metabolism, nutritional state, health-related quality of life, and exercise capacity after major surgery: a randomized study.

BACKGROUND & AIMS: The aim of this study was to investigate whether specialized supportive enteral and parenteral feeding have superior effects compared to oral nutrition on recovery during long-term postoperative treatment of cancer patients with preoperative weight loss and reduced maximum exercise capacity. METHODS: One hundred twenty-six patients referred for resection of the esophagus (n = 48), stomach (n = 28), or pancreas (n = 50) were considered to be included before operation. Included patients (n = 80) received supportive enteral or parenteral nutrition postoperatively at home corresponding to 1000 kcal/d until the patients did not wish to continue with artificial nutrition for any reason. Patients randomized to oral nutrition only served as control subjects. Caloric intake, body composition (dual-energy x-ray absorptiometry), and respiratory gas exchanges at rest and during exercise were measured including health-related quality of life. RESULTS: Survival and hospital stay did not differ among the groups, whereas overall complications were higher on artificial nutrition (P < .05). Changes in resting energy expenditure and biochemical tests did not differ during follow-up among the groups. Body weight and whole body fat declined similarly over time in all groups (P < .005), whereas lean body mass was unchanged during follow-up compared to preoperative values. Maximum exercise capacity and maximum oxygen consumption were normalized within 6 months postoperatively in all groups. There was no difference in recovery of food intake among the groups. Parenteral feeding was associated with the highest rate of nutrition-related complications, whereas enteral feeding reduced quality of life most extensively. CONCLUSION: After major surgery, specialized supportive enteral and parenteral nutrition are not superior to oral nutrition only when guided by a dietitian.

Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care--correlations with food intake, metabolism, exercise capacity, and hormones.

BACKGROUND: Several investigations that yielded different results in terms of net changes in body composition of weight-losing cancer patients have been reported that employed a variety of methods based on fundamentally different technology. Most of those reports were cross-sectional, whereas to the authors' knowledge there is sparse information available on longitudinal follow-up measurements in relation to other independent methods for the assessment of metabolism and performance. METHODS: For the current report, the authors evaluated time course changes in body composition (dual-energy X-ray absorptiometry) with measurements of whole body and regional distribution of fat and lean tissue in relation to food and dietary intake, host metabolism (indirect calorimetry), maximum exercise capacity (walking test), and circulating hormones in cancer patients who were receiving palliative care during 4-62 months of follow-up. The entire cohort comprised 311 patients, ages 68 years +/- 3 years who were diagnosed with solid gastrointestinal tumors (84 colorectal tumors, 74 pancreatic tumors, 73 upper gastrointestinal tumors, 51 liver-biliary tumors, 3 breast tumors, 5 melanomas, and 21 other tumor types). RESULTS: Decreased body weight was explained by loss of body fat, preferentially from the trunk, followed by leg tissue and arm tissue, respectively. Lean tissue (fat-free mass) was lost from arm tissue, whereas trunk and leg tissue compartments increased, all concomitant with declines in serum albumin, increased systemic inflammation (C-reactive protein, erythrocyte sedimentation rate), increased serum insulin, and elevated daily caloric intake; whereas serum insulin-like growth factor 1 (IGF-1), resting energy expenditure, and maximum exercise capacity remained unchanged in the same patients. Serum albumin levels (P < 0.001), whole body fat (P < 0.02), and caloric intake (P < 0.001) predicted survival, whereas lean tissue mass did not. Daily intake of fat and carbohydrate was more important for predicting survival than protein intake. Survival also was predicted by serum IGF-1, insulin, leptin, and ghrelin levels (P < 0.02 - P < 0.001). Serum insulin, leptin, and ghrelin (total) levels predicted body fat (P < 0.001), whereas IGF-1 and thyroid hormone levels (T3, free T3) predicted lean tissue mass (P < 0.01). Systemic inflammation primarily explained variation in lean tissue and secondarily explained loss in body fat. Depletion of lean arm tissue was related most to short survival compared with the depletion of lean leg and trunk tissue. CONCLUSIONS: The current results demonstrated that body fat was lost more rapidly than lean tissue in progressive cancer cachexia, a phenomenon that was related highly to alterations in the levels of circulating classic hormones and food intake, including both caloric amount and diet composition. The results showed importance in the planning of efficient palliative treatment for cancer patients.

Effects of recombinant erythropoietin in palliative treatment of unselected cancer patients.

PURPOSE: The purpose is to evaluate relationships between objectively assessed exercise capacity and subjectively assessed scoring of physical functioning and well-being after erythropoietin treatment in cancer patients on palliative care. EXPERIMENTAL DESIGN: Unselected cancer patients (n = 108) who experienced progressive cachexia were randomized to receive either anti-inflammatory treatment alone (indomethacin) or recombinant erythropoietin plus indomethacin to prevent the appearance of disease-induced anemia and thereby protect patients' exercise capacity. Follow-up investigations of nutritional status, exercise capacity, and health-related quality of life assessed by SF-36 and the European Organization for Research and Treatment of Cancer QLQ-C30 were compared. RESULTS: Effective treatment by erythropoietin on top of basal whole body anti-inflammatory treatment was confirmed and indicated by time course changes of biochemical, physiologic, and nutritional objectives, whereas individual self-reported scoring of physical functioning and general health did not indicate a clear-cut effectiveness, particularly at moderately subnormal hemoglobin levels. CONCLUSIONS: Discrepancies between objective and subjective self-reported measures may be either fundamental or indicate scoring limitations for evaluation of therapeutic results. Present results demonstrate a clinical benefit of erythropoietin treatment in cancer patients with subnormal to normal hemoglobin levels, whereas the patients' own subjective scoring was insufficient to sense such improvements. The discrepancy may be either fundamental or methodological but emphasizes the importance to document therapeutic outcome in both subjective and objective perspectives in palliative care of cancer patients.

Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: Effects on survival, metabolism, and function.

BACKGROUND: The role of nutrition in the palliative treatment of patients with malignancy-related cachexia is unclear. The goal of the current study was to determine whether specialized, nutrition-focused patient care could improve integrated whole-body metabolism and functional outcome in unselected weight-losing patients with malignant disease who were receiving systemic antiinflammatory (cyclooxygenase [COX]-inhibitory) treatment along with erythropoietin (EPO) support. METHODS: Three hundred nine patients with malignant disease who experienced progressive cachexia due to solid tumors (primarily gastrointestinal lesions) were randomized to receive a COX inhibitor (indomethacin, 50 mg twice daily) and EPO (15-40,000 units per week) along with specialized, nutrition-focused patient care (oral nutritional support and home total parenteral nutrition [TPN]) provided on a patient-by-patient basis to attenuate inflammation, prevent anemia, and improve nutritional status. Control patients received the same indomethacin and EPO doses that study patients received without the added nutritional support. All patients were treated and followed until death. Biochemical assays (blood, liver, kidney, and thyroid), nutritional state assessment (food intake and body composition), and exercise testing with simultaneous measurement of whole-body respiratory gas exchange before and during exercise were performed before the start of treatment and then at regular intervals during the treatment period (every 2-30 months after treatment initiation). Statistical analyses were performed on 'intention-to-treat' and 'as-treated' bases. RESULTS: Home TPN was provided to approximately 50% of the study patients without severe complications. Over the entire observation period, rhEPO prevented the development of anemia in both study patients and control patients. Intention-to-treat analysis revealed an improvement in energy balance for nutritionally supported patients (P < 0.03); no other significant differences in outcome between study patients and control patients were observed. As-treated analysis demonstrated that patients receiving nutrition experienced prolonged survival (P < 0.01), which was accompanied by improved energy balance (P < 0.001), increasing body fat (P < 0.05), and a greater maximum exercise capacity (P < 0.04). A trend toward increased metabolic efficiency at maximum exercise (P < 0.06) for study patients relative to control patients also was observed. CONCLUSIONS: The results of the current study strongly support that nutrition is a limiting factor influencing survival and that nutritional support protects integrated metabolism and metabolic function in patients with progressive cachexia secondary to malignant disease.

Evidence that long-term COX-treatment improves energy homeostasis and body composition in cancer patients with progressive cachexia.

Cancer patients lose weight due to negative energy balance because of insufficient appetite and inappropriately high energy expenditure. Host and tumor derived cytokines and more recently eicosanoids have been held responsible as mediators. Accordingly, observations in animal experiments and short-term clinical trials in selected groups of cancer patients, have implied that cyclo-oxygenase (COX) blockade can improve host metabolism and well-being, and long-term COX-treatment of unselected groups have implied improved survival. The aim of this study was to search for evidence that long-term COX-treatment improves energy and cardiovascular homeostasis in unselected weight-losing cancer patients. A retrospective case control analysis was performed on a data-base material collected consecutively. Weight-losing untreated cancer patients had elevated resting energy expenditure compared to undernourished non-cancer patients (23.3+/-0.1, n=702 vs 20.9+/-0.3 kcal/kg/day, n=132, p<0.001). This difference became significantly reduced by long-term indomethacin treatment (p<0.003). Heart rate was correspondingly decreased, while systolic blood pressure increased following indomethacin treatment of cancer patients (p<0.006-0.008). Total body fat was more preserved (p<0.005), while lean body mass was uninfluenced by long-term indomethacin to cancer patients. All these beneficial effects were parallel to a decrease in systemic inflammation (C-reactive protein, erythrocyte sedimentation rate) in cancer patients on indomethacin (p<0.0004). Systemic inflammation and resting energy metabolism predicted weight loss in progressive cancer (p<0.0001). Our data support the concept that COX-treatment may offer beneficial metabolic effects to weight-losing cancer patients by attenuation of resting metabolism and improved appetite due to decreased systemic inflammation.