Malcolm K. Robinson

Glutamine preserves liver glutathione after lethal hepatic injury.

Glutathione (GSH) is a major antioxidant that protects tissues from free radical injury. Glutamine augments host defenses and may be important in GSH synthesis. Acetaminophen toxicity causes hepatic GSH depletion and hepatic necrosis. The authors hypothesized that glutamine-supplemented nutrition would enhance liver GSH stores and diminish hepatic injury and death after acetaminophen overdose. Wistar rats received either a standard total parenteral nutrition (TPN) solution (STD) or an isocaloric, isonitrogenous glutamine-supplemented solution (GLN). On the 5th day of feeding, animals were given acetaminophen (400 mg/kg intraperitoneally) and then killed at various time points/Standard TPN solution animals had a rapid depletion of hepatic glutathione, whereas GLN animals were resistant to this drop and rapidly repleted hepatic GSH stores. Glutamine-supplemented animals maintained higher plasma glutamine concentrations, had lesser elevations in hepatic enzymes, and sustained significantly fewer complications compared with STD animals. The authors conclude that glutamine-supplemented nutrition preserves hepatic glutathione, protects the liver, and improves survival during acetaminophen toxicity. Glutamine may augment host defenses by enhancing antioxidant protection.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease

BACKGROUND & AIMS Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohns disease and to explore the effects of dose and schedule on platelet count and Crohns disease activity. METHODS A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohns disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS Short-term treatment with rhIL-11 is well tolerated in patients with active Crohns disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohns disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Growth Hormone, Glutamine, and an Optimal Diet Reduces Parenteral Nutrition in Patients With Short Bowel Syndrome: A Prospective, Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Objective:To determine if growth hormone (GH) and glutamine (Gln) might allow for a reduction in parenteral nutrition (PN) in individuals with short bowel syndrome. Background Data:Following massive intestinal resection, patients frequently sustain severe nutrient malabsorption and are dependent on PN for life. GH treatment with or without Gln might allow for a reduction in PN. Methods:A prospective, double-blind, randomized, placebo-controlled clinical trial performed in 41 adults dependent on PN. Following screening, patients were admitted to an in-house facility for 6 weeks. After 2 weeks of stabilization and dietary optimization, patients were randomized to one of 3 treatment arms (1:2:2 ratio): oral Gln (30 g/day) + GH placebo (control group, n = 9), Gln placebo + GH (0.1 mg/kg per day, n = 16), or Gln + GH (n = 16). Standard criteria based on clinical and laboratory measurements were followed to determine PN volume and content. After 4 weeks of treatment, patients were discharged and monitored; GH and GH placebo were discontinued, but the diet with Gln or Gln placebo was continued for 3 months. Results:Patients receiving GH + Gln placebo + diet showed greater reductions in PN volume (5.9 ± 3.8 L/wk, mean ± SD), PN calories (4338 ± 1858 calories/wk), and PN infusions (3 ± 2 infusions/wk) than corresponding reductions in the Gln + diet group (3.8 ± 2.4 L/wk; 2633 ± 1341 calories/wk; 2 ± 1 infusions/wk, P < 0.05). Patients who received GH + Gln + diet showed the greatest reductions (7.7 ± 3.2 L/wk; 5751 ± 2082 calories/wk; 4 ± 1 infusions/wk, P < 0.001 versus Gln + diet). At the 3-month follow-up, only patients who had received GH + Gln + diet maintained significant reductions in PN (P < 0.005) compared with the Gln + diet. Conclusions:Treatment with GH + diet or GH + Gln + diet initially permitted significantly more weaning from PN than Gln + diet. Only subjects receiving GH + Gln + diet maintained this effect for at least 3 months.

Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways

BACKGROUND Ghrelin, an orexigenic 28-amino-acid peptide, has been studied primarily in relation to the control of appetite and fat metabolism. In addition to these well-known functions, ghrelin, and its target receptors, growth hormone secretagogue receptors (GHS-Rs), have been localized to neutrophils, lymphocytes, and macrophages, which suggests that ghrelin may be involved in immune modulation. METHODS To assess the therapeutic role of ghrelin in production of pro-inflammatory and anti-inflammatory cytokines, the effects of exogenous ghrelin administration on the regulation of cytokine release in lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages were analyzed. RESULTS Ghrelin and GHS-Rs are expressed in murine macrophages. In addition, exogenous ghrelin inhibited the production of pro-inflammatory cytokines IL-1beta and TNF-alpha in LPS-stimulated murine macrophages in a dose dependent and time-dependent fashion. Exogenous ghrelin pretreatment resulted in a decrease in LPS-induced NFkappaB activation and was presumably the reason for this ghrelin-mediated effect. In contrast to these findings, exogenous ghrelin significantly augmented the release of the anti-inflammatory cytokine IL-10 in a dose-dependent and time-dependent fashion from LPS-stimulated murine macrophages. Ghrelin administration enhanced activation of p38 MAPK, which is known to control the release of IL-10 in macrophages independent of the NFkappaB pathway. These effects of ghrelin on both pro-inflammatory and anti-inflammatory cytokines were offset when a specific GHS-R receptor antagonist was added to the culture media. CONCLUSIONS These data suggest that ghrelin has potent anti-inflammatory properties through modulation of secretion of both pro-inflammatory and anti-inflammatory cytokines from LPS-stimulated macrophages through distinct signaling cascades. Therapeutic utility of ghrelin to control, modulate, or treat pathologic inflammatory conditions like endotoxemic shock and ulcerative colitis requires additional investigation.

Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis

This 12-month, double-blind, placebo-controlled study randomized 205 ulcerative colitis patients in remission to placebo or controlled-release mesalamine at 4 g/day for 12 months. Patients were stratified to either pancolitis or left-sided disease, based on previous diagnosis. Maintenance of remission was defined as a sigmoidoscopic index of <5, less than five stools per day, and the absence of rectal bleeding. A significantly greater number of patients maintained remission on mesalamine 4 g/day than on placebo at each of five study visits, following the first one-month visit (P<0.05). The estimated 12-month remission rates for the mesalamine group were 64% (38% for placebo,P=0.0004). Baseline subgroups (disease location, time since last flare of active disease, and previous response to oral/rectal steroids or sulfasalazine) did not influence remission rates. Treatment-related adverse events were rare. Controlled-release mesalamine is a safe and efficacious single agent for maintaining remission of ulcerative colitis.

Improving Nutritional Screening of Hospitalized Patients: The Role of Prealbumin

BACKGROUND Limited resources prevent hospitals from having all patients formally evaluated by a nutrition expert. Thus, hospitals rely on nutrition-screening tools to identify malnourished patients. The purpose of this study was to determine the effectiveness of a nutrition-screening protocol, prealbumin (PAB), retinol binding protein (RBP), and albumin (ALB) in identifying malnourished hospitalized patients. METHODS A nutrition screening protocol was prospectively used in medical and surgical patients and consisted of a nurse administering a questionnaire to patients and requesting formal evaluation by a registered dietitian (RD) only if nutritional issues were identified. Patients also had ALB, PAB, and RBP drawn, which were used to both screen and identify the malnourished. PAB, RBP, and ALB were compared as predictors of RD classification of patient nutritional status. RESULTS The nutrition-screening protocol classified 104 of 320 patients (33%) as malnourished. However, 43% of the patients were not deemed at nutritional risk according to this protocol and therefore did not receive RD assessment. PAB was a significant predictor of RD-determined nutritional status (p < .05), whereas RBP and ALB were not. PAB screening/assessment identified 50% (162/320) of the patients as being malnourished. Notably, 50% of the patients (71 of 142) who were not evaluated by an RD were identified as malnourished using PAB criteria. The nutrition-screening protocol took 1.2 days longer to determine malnourishment compared with PAB (p = .0021). CONCLUSIONS Use of screening questionnaires may miss or delay identification of malnourished patients. PAB screening/assessment may improve identification of those patients requiring nutrition intervention and thus enhance the care of hospitalized individuals.

Short Bowel Syndrome

The short bowel syndrome is a symptom complex that occurs in adults who have less than 200 cm of jejunum-ileum remaining after intestinal resection. Similar symptoms are observed in infants and children following massive bowel resection or congenital anomalies and in individuals with longer segments of intestine with severe mucosal disease. Initial care should focus on a thorough excision of nonviable bowel, an exact measurement of the remaining viable bowel, placing all intestine in continuity at the initial or subsequent operation, and controlling initial food intake. With time, adaptation of the remnant intestine occurs, and absorptive function may be maximized by enhancing the enteral diet and minimizing parenteral nutrition. Growth factors and specialized nutrients may also enhance this process. Intestinal transplantation should be considered in selected individuals with the short bowel syndrome who fail intestinal rehabilitation protocols.

Improved care and reduced costs for patients requiring peripherally inserted central catheters: the role of bedside ultrasound and a dedicated team.

BACKGROUND We conducted a prospective quality assurance (QA) study to determine if a team dedicated to placing peripherally inserted central catheters (PICCs) would improve patient care and reduce costs. METHODS In April 2000, a dedicated team of physicians, physician assistants, nurses, and interventional radiologists (IR) was established to coordinate and approve all PICC placements at our hospital. Ultrasound (US) became available in November 2000 to assist with bedside PICC placement. A QA database was created allowing data from 3 time periods reflecting initiation of the PICC service (April-June 2000), initial implementation of bedside US-guided PICC placement (October-December 2000), and the current service (October-December 2002) to be analyzed and compared. RESULTS For all time periods analyzed, the PICC team found that one-third of PICC requests was inappropriate and, therefore, disapproved placement. With addition of US, the bedside PICC placement rate increased to 94% compared with 73% at service initiation. This was associated with an overall 80% decrease in average patient waiting time for a PICC, facilitating more timely discharges from the hospital. Finally, placement costs were reduced by 9% six months after initiation of our service and by 24% after US became available. CONCLUSIONS A dedicated PICC team improves patient care by preventing inappropriate PICC placements and decreasing patient waiting times. A PICC team with US capability also reduces costs by minimizing expensive use of IR facilities and reducing hospital lengths of stay. A dedicated PICC service should become the standard of care for all hospitals with high-volume PICC use.

The relationship among obesity, nutritional status, and mortality in the critically ill.

Introduction:The association between obesity and mortality in critically ill patients is unclear based on the current literature. To clarify this relationship, we analyzed the association between obesity and mortality in a large population of critically ill patients and hypothesized that mortality would be impacted by nutritional status. Methods:We performed a single-center observational study of 6,518 adult patients treated in medical and surgical ICUs between 2004 and 2011. All patients received a formal, in-person, and standardized evaluation by a registered dietitian. Body mass index was determined at the time of dietitian consultation from the estimated dry weight or hospital admission weight and categorized a priori as less than 18.5 kg/m2 (underweight), 18.5–24.9 kg/m2 (normal/referent), 25–29.9 kg/m2 (overweight), 30–39.9 kg/m2 (obesity class I and II), and more than or equal to 40.0 kg/m2 (obesity class III). Malnutrition diagnoses were categorized as nonspecific malnutrition, protein-energy malnutrition, or well nourished. The primary outcome was all-cause 30-day mortality determined by the Social Security Death Master File. Associations between body mass index groups and mortality were estimated by bivariable and multivariable logistic regression models. Adjusted odds ratios were estimated with inclusion of covariate terms thought to plausibly interact with both body mass index and mortality. We utilized propensity score matching on baseline characteristics and nutrition status to reduce residual confounding of the body mass index category assignment. Results:In the cohort, 5% were underweight, 36% were normal weight, 31% were overweight, 23% had class I/II obesity, and 5% had class III obesity. Nonspecific malnutrition was present in 56%, protein-energy malnutrition was present in 12%, and 32% were well nourished. The 30-day and 90-day mortality rate for the cohort was 19.1 and 26.6%, respectively. Obesity is a significant predictor of improved 30-day mortality following adjustment for age, gender, race, medical versus surgical patient type, Deyo-Charlson index, acute organ failure, vasopressor use, and sepsis: underweight odds ratio 30-day mortality is 1.09 (95% CI, 0.80–1.48), overweight 30-day mortality odds ratio is 0.93 (95% CI, 0.80–1.09), class I/II obesity 30-day mortality odds ratio is 0.80 (95% CI, 0.67–0.96), and class III obesity 30-day mortality odds ratio is 0.69 (95% CI, 0.49–0.97), all relative to patients with body mass index 18.5–24.9 kg/m2. Importantly, there is confounding of the obesity-mortality association on the basis of malnutrition. Adjustment for only nutrition status attenuates the obesity–30-day mortality association: underweight odds ratio is 0.74 (95% CI, 0.54–1.00), overweight odds ratio is 1.05 (95% CI, 0.90–1.23), class I/II obesity odds ratio is 0.96 (95% CI, 0.81–1.15), and class III obesity odds ratio is 0.81 (95% CI, 0.59–1.12), all relative to patients with body mass index 18.5–24.9 kg/m2. In a subset of patients with body mass index more than or equal to 30.0 kg/m2 (n = 1,799), those with either nonspecific or protein-energy malnutrition have increased mortality relative to well-nourished patients with body mass index more than or equal to 30.0 kg/m2: odds ratio of 90-day mortality is 1.67 (95% CI, 1.29–2.15; p < 0.0001), fully adjusted. In a cohort of propensity score matched patients (n = 3,554), the body mass index–mortality association was not statistically significant, likely from matching on nutrition status. Conclusions:In a large population of critically ill adults, the association between improved mortality and obesity is confounded by malnutrition status. Critically ill obese patients with malnutrition have worse outcomes than obese patients without malnutrition.

Effect of Leuprolide Acetate in Treatment of Abdominal Pain and Nausea in Premenopausal Women with Functional Bowel Disease: A Double-Blind, Placebo-Controlled, Randomized Study

We have previously reported impressive results in using a gonadotropin-releasing hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to severe symptoms (especially abdominal pain and nausea) in patients with functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and there is no consistent therapy for the treatment of these patients. The purpose of the present study was to expand the investigation to study similar patients (menstruating females) in a multicenter, double-blind, placebo-controlled, randomized study using Lupron Depot (which delivers a continuous dose of drug for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given intramuscularly every four weeks for 16 weeks. Symptoms were assessed using daily diary cards to record abdominal pain, nausea, vomiting, early satiety, anorexia, bloating, and altered bowel habits. Additional assessment tools were quality of life questionnaires, psychological profile, oralto-cecal transit using the hydrogen breath test, antroduodenal manometry, reproductive hormone levels, and global evaluations by both patient and investigator. Patients in both Lupron Depot-treated groups showed consistent improvement in symptoms; however, only the Lupron Depot 7.5 mg group showed a significant improvement for abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of life assessments and global evaluations completed by both patient and investigators were highly significant compared to placebo (P < 0.001). All reproductive hormone levels significantly decreased for both Lupron Depot-treated groups by week 4 and were significantly different compared to placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is effective in controlling the debilitating symptoms of abdominal pain and nausea in patients with FBD.